(19)
(11)EP 3 042 906 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
23.10.2019 Bulletin 2019/43

(21)Application number: 14842419.5

(22)Date of filing:  03.09.2014
(51)Int. Cl.: 
C07D 487/10  (2006.01)
B01J 27/122  (2006.01)
B01J 31/04  (2006.01)
C07B 53/00  (2006.01)
C07B 61/00  (2006.01)
B01J 23/72  (2006.01)
B01J 31/02  (2006.01)
B01J 31/22  (2006.01)
C07D 491/20  (2006.01)
(86)International application number:
PCT/JP2014/073233
(87)International publication number:
WO 2015/033974 (12.03.2015 Gazette  2015/10)

(54)

METHOD FOR PRODUCING A SPIROOXINDOLE DERIVATIVE

VERFAHREN ZUR HERSTELLUNG EINES SPIROOXINDOLDERIVATS

PROCÉDÉ DE PRODUCTION D'UN DÉRIVÉ DE SPIRO-OXINDOLE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 04.09.2013 JP 2013182928

(43)Date of publication of application:
13.07.2016 Bulletin 2016/28

(73)Proprietor: Daiichi Sankyo Company, Limited
Tokyo 103-8426 (JP)

(72)Inventors:
  • YAMAUCHI, Motoshi
    Hiratsuka-shi Kanagawa 254-0014 (JP)
  • NAKAYAMA, Keiji
    Hiratsuka-shi Kanagawa 254-0014 (JP)

(74)Representative: Wallace, Sheila Jane 
Marks & Clerk LLP 15 Fetter Lane
London EC4A 1BW
London EC4A 1BW (GB)


(56)References cited: : 
WO-A1-2012/121361
JP-A- 2013 142 071
US-A1- 2012 264 738
WO-A2-2012/155066
US-A1- 2012 071 499
  
  • AWATA A. ET AL: "Catalytic asymmetric exo-selective [3+2] cycloaddition for constructing stereochemically diversified spiro[pyrrolidin-3-3'-oxindole]s", CHEMISTRY A EUROPEAN JOURNAL, vol. 18, 11 June 2012 (2012-06-11), pages 8278-8282, XP002765318,
  • SHU,L. ET AL.: 'SYNTHESIS OF A SPIROINDOLINONE PYRROLIDINECARBOXAMIDE MDM2' ORGANIC PROCESS RESEARCH & DEVELOPMENT vol. 17, no. 2, AN, 15 January 2013, pages 247 - 256, XP055277896 DOI: TAGONIST
  • ANTONCHICK,A.P. ET AL.: 'HIGHLY ENANTIOSELECTIVE SYNTHESIS AND CELLULAR EVALUATION OF' NATURE CHEMISTRY vol. 2, no. 9, SP, 11 July 2010, pages 735 - 740, XP009145349 DOI: IROOXINDOLES INSPIRED BY NATURAL PRODUCTS
  • LIU,T-L. ET AL. ORGANIC & BIOMOLECULAR CHEMISTRY vol. 9, 2011, pages 1980 - 1986, XP008182907
  • LIU,J. ET AL.: 'DIRECT CONSTRUCTION OF NOVEL EXO'-SELECTIVE SPIROPYRROLIDINE' TETRAHEDRON LETTERS vol. 53, no. 18, BI, 2012, pages 2336 - 2340, XP055140710 DOI: SOXINDOLES VIA A THREE-COMPONENT 1,3-DIPOLAR
  • LOPEZ-PEREZ A. ET AL: "Bis-suflonyl ethylene as masked acetylene equivalent in catalytic asymmetric [3+2] cycloaddition of azomethine ylides", JOURNAL OF AMERICAN CHEMICAL SOCIETY, vol. 130, 10 July 2008 (2008-07-10), pages 10084-10085,
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

Technical Field



[0001] The present invention relates to a method for producing a pyrrolidine compound having a spirooxindole structure.

Background Art



[0002] A method which involves using, as a reaction substrate, aldimine synthesized from an aldehyde and an amine as starting materials to synthesize a racemic compound through a 1,3-dipolar cycloaddition reaction in the presence or absence of a catalyst that promotes the reaction is known as a method for synthesizing a pyrrolidine compound having a bicyclic spirooxindole structure (Non Patent References 1 to 4). The obtained racemic compound can be resolved using a chiral column based on a technique such as HPLC or supercritical fluid chromatography (SFC) to separate a desired optically active form.

[0003] An asymmetric synthesis method through a 1,3-dipolar cycloaddition reaction using a chiral element has been reported as a method for stereoselectively synthesizing the compound mentioned above (Non Patent References 5 and 6). In addition, a method for producing a pyrrolidine compound having a tricyclic dispirooxindole structure through a 1,3-dipolar addition reaction using, as a reaction substrate, ketimine synthesized with an amine and a ketone as starting materials has also been reported (Patent Reference 1).

[0004] Meanwhile, as for catalytic asymmetric synthesis methods of the compound mentioned above, a large number of studies have been made on catalytic asymmetric 1,3-dipolar cycloaddition reactions using aldimine as a reaction substrate (Non Patent References 7 to 18). Nonetheless, no report has been made on the synthesis of a tricyclic dispiroindole using ketimine with a ketone and an amine as reaction substrates.

Citation List


Patent References



[0005] Patent Reference 1: WO2012/121361

Non Patent References



[0006] 

Non Patent Reference 1: Jorgensen, K. A. et al., Org. Lett. 2005, 21, 4569

Non Patent Reference 2: Jorgensen, K. A. et al., Chem. Rev. 1998, 98, 863

Non Patent Reference 3: Grigg, R. et al., Tetrahedron, 1992, 48, 10431

Non Patent Reference 4: Schreiber, S. L. et al., J. Am. Chem. Soc. 2003, 125, 10174

Non Patent Reference 5: Carretero, J. C. et al., Tetrahedron, 2007, 63, 6587

Non Patent Reference 6: Wang, S. et al., J. Am. Chem. Soc., 2005, 127, 10130

Non Patent Reference 7: Wang, S. et al., J. Med. Chem. 2006, 49, 3432

Non Patent Reference 8: Williams, R. M. et al., J. Am. Chem. Soc. 2000, 122, 5666

Non Patent Reference 9: Gong, L.-Z. et al., J. Am. Chem. Soc., 2009, 131, 13819

Non Patent Reference 10: Gong, L.-Z. et al., Org. Lett., 2011, 13, 2418

Non Patent Reference 11: Gong, L.-Z. et al., Chem. Eur. J., 2012, 18, 6885

Non Patent Reference 12: Waldmann, H. et al., Nat. Chem., 2010, 2, 735

Non Patent Reference 13: Waldmann, H. et al., Tetrahedron, 2011, 67, 10195

Non Patent Reference 14: Wang, C.-J. et al., Org. Biomol. Chem., 2011, 9, 1980

Non Patent Reference 15: Arai, T. et al., Chem. Eur. J., 2012, 18, 8287

Non Patent Reference 16: Amedohkouh, M. et al., Tetrahedron Asymmetry, 2005, 8, 1411

Non Patent Reference 17: Cordova, A. et al., Chem. Comm. 2006, 460

Non Patent Reference 18: Ma, J. A. et al., Org. Lett. 2007, 9, 923


Summary of Invention


Technical Problem



[0007] The present invention is intended to provide a method for efficiently producing and providing a compound having a spirooxindole skeleton, for example, a compound having a spirooxindole skeleton and having antitumor activity that inhibits the interaction between Mdm2 protein and p53 protein, or an intermediate thereof using an asymmetric catalyst.

Solution to Problem



[0008] The present inventors have conducted diligent studies and consequently established a method for efficiently synthesizing a compound having an optically active tricyclic dispiroindole skeleton by screening for a chiral ligand that promotes a catalytic asymmetric 1,3-dipolar cycloaddition reaction using ketimine as a reaction substrate, and a Lewis acid serving as a central metal thereof, and the optimum reaction conditions.

[0009] Specifically the present invention relates to the following (1) to (20):
  1. (1) A method for reacting a compound represented by formula (I) :

    a compound represented by formula (II):

    and a compound represented by formula (III):

    in a solvent using an asymmetric catalyst to stereoselectively produce a compound represented by formula (IV) or a salt thereof:

    wherein

    R1 represents a hydrogen atom, a C1-C6 alkylcarbonyl group optionally having 1 to 3 substituents independently selected from group A below, or a C1-C6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group A below,

    R2 represents a 5- or 6-membered heteroaryl group having, in the ring, 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, a phenyl group, a C3-C6 cycloalkyl group, or a C3-C6 cycloalkenyl group, wherein
    the 5- or 6-membered heteroaryl group, the phenyl group, the C3-C6 cycloalkyl group, and the C3-C6 cycloalkenyl group each optionally have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a vinyl group, an ethynyl group, a cyano group, a hydroxy group, an amino group, a carboxy group, an aminocarbonyl group, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group A below, a C3-C4 cycloalkyl group optionally having 1 to 3 substituents independently selected from group A below, a C1-C6 alkoxy group optionally having 1 to 3 substituents independently selected from group A below, a C3-C4 cycloalkoxy group optionally having 1 to 3 substituents independently selected from group A below, a C1-C6 alkylamino group optionally having 1 to 3 substituents independently selected from group A below, a di-C1-C6 alkylamino group optionally having 1 to 3 substituents independently selected from group A below, a 4- to 7-membered saturated heterocyclic group containing one nitrogen atom in the ring and optionally having 1 to 3 substituents independently selected from group B below, a C1-C6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group A below, a C3-C4 cycloalkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group A below, a C1-C6 alkylaminocarbonyl group optionally having 1 to 3 substituents independently selected from group A below, and a C3-C4 cycloalkylaminocarbonyl group optionally having 1 to 3 substituents independently selected from group A below,

    R3 and R4 each independently represent a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group C below, or

    R3 and R4 optionally together form a C4-C6 cycloalkyl ring, a tetrahydrofuran ring, a tetrahydropyran ring, or a piperidine ring, wherein
    the C4-C6 cycloalkyl ring, the tetrahydrofuran ring, the tetrahydropyran ring, and the piperidine ring each optionally have 1 to 8 substituents independently selected from group D below,

    R5 represents a C1-C6 alkoxy group optionally having 1 to 3 substituents independently selected from group E below, a C3-C8 cycloalkoxy group optionally having 1 to 3 substituents independently selected from group E below, a C2-C6 alkenyloxy group, or -NR51R52,

    R51 and R52 each independently represent a hydrogen atom, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group E below, a C3-C8 cycloalkyl group optionally having 1 to 3 substituents independently selected from group E below, or a 3- to 6-membered saturated heterocyclic group having, in the ring, one heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally having 1 to 3 substituents independently selected from group E below, and

    ring Z represents a benzene ring optionally having 1 to 4 substituents independently selected from group E below, a pyridine ring optionally having 1 to 3 substituents independently selected from group E below, or a pyrimidine ring optionally having 1 or 2 substituents independently selected from group E below:

    group A: a halogen atom, a hydroxy group, a C1-C6 alkyl group, an amino group, and a phenyl group,

    group B: a C1-C6 alkyl group and a hydroxy group

    group C: a halogen atom, a hydroxy group, a phenyl group, a pyridyl group, and an amino group

    group D: a halogen atom and a C1-C6 alkyl group optionally having 1 to 3 halogen atoms, and

    group E: a halogen atom, a hydroxy group, a vinyl group, an ethynyl group, a cyano group, a C1-C6 alkoxy group, an aminocarbonyl group, and a C1-C6 alkyl group optionally having 1 to 3 halogen atoms.

  2. (2) A method for reacting a compound represented by formula (I):

    and a compound represented by formula (V):

    in a solvent using an asymmetric catalyst to stereoselectively produce a compound represented by formula (IV) or a salt thereof:

    wherein R1, R2, R3, R4, R5, and Z are as defined in (1) .
  3. (3) A method according to (1) or (2), wherein the asymmetric catalyst is a catalyst prepared from a Lewis acid and a chiral ligand, wherein
    the Lewis acid is a Lewis acid selected from the group consisting of a Zn(II) Lewis acid, a Ag(I) Lewis acid, a Ni(II) Lewis acid, a Co(II) Lewis acid, a Ru(I) Lewis acid, a Cu(I) Lewis acid, and a Cu(II) Lewis acid, and the chiral ligand is a chiral ligand selected from the group consisting of a compound represented by the following formula (VI):

    a compound represented by the following formula (VII):

    a compound represented by the following formula (VIII):

    a compound represented by the following formula (IX):

    a compound represented by the following formula (X):

    a compound represented by the following formula (XI):

    and a compound represented by the following formula (XII) :

    wherein

    R6 represents a phenyl group optionally having 1 to 3 substituents independently selected from group F below, ring Y represents a benzene ring, a cyclohexane ring, or a dioxolane ring optionally having 1 to 4 halogen atoms,

    R7 represents a phenyl group optionally having 1 to 3 substituents independently selected from group G below, or a furanyl group optionally having 1 to 3 substituents independently selected from group G below,

    R8 represents a hydrogen atom or a C1-C6 alkoxy group,

    R9 represents a C1-C6 alkoxy group, or

    two R9 moieties optionally together form a 7- to 12-membered heterocyclic ring containing two oxygen atoms in the ring,

    X represents CH, CR10, or a nitrogen atom, wherein
    R10 represents a C1-C6 alkoxy group,

    V represents a phenyl group having one P(R11)2, PH(O)R12, or P(R11)2, wherein

    R11 represents a C1-C6 alkyl group, a cyclohexyl group, or a phenyl group optionally having two trifluoromethyl groups, and

    R12 represents a C1-C6 alkyl group or a phenyl group, W represents a C1-C6 alkylthio group, a dihydrooxazolyl group optionally having one C1-C6 alkyl group, CH(CH3)P(R13)2, or CHR14R15, wherein

    R13 represents a cyclohexyl group, a C1-C6 alkyl group, or a phenyl group optionally having 1 or 2 substituents independently selected from group H below,

    R14 represents a phenyl group optionally substituted by one P(R16)2,

    R15 represents a C1-C6 alkyl group or a di-C1-C6 alkylamino group, and

    R16 represents a phenyl group or a cyclohexyl group, U represents any one of the following Ua to Ud:





    R17 represents a phenyl group optionally having 1 to 3 substituents independently selected from group F below,

    R18 represents a C1-C6 alkyl group or a phenyl group,

    R19 represents a hydrogen atom or a C1-C6 alkyl group, and

    R20 and R21 each independently represent a C1-C6 alkyl group:

    group F: a C1-C6 alkyl group and a C1-C6 alkoxy group,

    group G: a C1-C6 alkyl group, a C1-C6 alkoxy group, and a di-C1-C6 alkylamino group, and

    group H: a C1-C6 alkyl group and a C1-C6 alkyl group optionally having three halogen atoms.

  4. (4) A method according to (3), wherein the Lewis acid used in the preparation of the asymmetric catalyst is a Cu(I) Lewis acid or a Cu(II) Lewis acid.
  5. (5) A method according to (3) or (4), wherein the Lewis acid used in the preparation of the asymmetric catalyst is a Lewis acid selected from the group consisting of CuOAc, CuCl, CuBr, CuI, CuOTf, CuPF6, CuBF4, Cu(OAc)2, Cu(OTf)2, and CuSO4.
  6. (6) A method according to any one of (3) to (5), wherein the chiral ligand used in the preparation of the asymmetric catalyst is a chiral ligand selected from the group consisting of a compound represented by formula (VI), a compound represented by formula (VII), a compound represented by formula (VIII), a compound represented by formula (IX), a compound represented by formula (X), a compound represented by formula (XI), and a compound represented by formula (XII), in which the compounds of formulae (VI) to (XII) are as defined in (3),
    wherein
    R6 represents a phenyl group optionally having 1 to 3 substituents independently selected from the group consisting of a methyl group, a t-butyl group, and a methoxy group,
    ring Y represents a benzene ring, a cyclohexane ring, or a dioxolane ring,
    R7 represents a phenyl group or a furanyl group, wherein
    the phenyl group and the furanyl group each optionally have 1 to 3 substituents independently selected from the group consisting of a methyl group, a t-butyl group, and a methoxy group,
    R8 represents a hydrogen atom or a methoxy group,
    R9 represents a methoxy group, or,
    two R9 moieties optionally together form a 9-membered heterocyclic ring containing two oxygen atoms in the ring, X represents CH, CR10, or a nitrogen atom,
    R10 represents a methoxy group,
    V represents P(R11)2, wherein
    R11 represents a phenyl group optionally having two trifluoromethyl groups,
    W represents a t-butylthio group, a dihydrooxazolyl group optionally substituted by one isopropyl group, or CH(CH3)P(R13)2, wherein
    R13 represents a phenyl group optionally having 1 or 2 methyl groups,
    U represents Ua or Ud mentioned above,
    R17 represents a phenyl group,
    R18 represents an isopropyl group, a t-butyl group, or a phenyl group,
    R19 represents a hydrogen atom, and
    R20 and R21 each independently represent a methyl group or a t-butyl group.
  7. (7) A method according to any one of (3) to (6), wherein the chiral ligand used in the preparation of the asymmetric catalyst is a chiral ligand selected from the following group:









    where Cy represents a cyclohexyl group.
  8. (8) A method according to any one of (1) to (7), wherein the solvent used in the reaction is one or more solvents selected from the group consisting of N,N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, 2-propanol, toluene, and ethyl acetate.
  9. (9) A method according to any one of (1) to (8), wherein the compound produced or salt thereof has the following configuration:

    wherein R1, R2, R3, R4, R5, and Z are as defined in (1) .
  10. (10) A method according to any one of (1) to (9), wherein R1 is a hydrogen atom.
  11. (11) A method according to any one of (1) to (10), wherein in formula (I),
    ring Z is a benzene ring optionally having 1 to 4 halogen atoms.
  12. (12) A method according to any one of (1) to (11), wherein in formula (I) or formula (IV),
    R2 is a pyridyl group optionally having 1 to 3 halogen atoms, or a phenyl group optionally having 1 to 3 halogen atoms.
  13. (13) A method according to any one of (1) to (12), wherein in formula (II) or formula (V),
    R3 and R4 each represent a methyl group, or R3 and R4 together form a cyclopentane ring, a cyclohexane ring, or a tetrahydropyran ring, wherein
    the cyclopentane ring, the cyclohexane ring, and the tetrahydropyran ring each optionally have 1 to 4 C1-C6 alkyl groups on the ring.
  14. (14) A method according to any one of (1) to (13), wherein in formula (III) or formula (V),
    R5 is a substituent represented by the following:

  15. (15) A method according to any one of (1) to (13), wherein in formula (III) or formula (V),
    R5 is a C1-C6 alkoxy group.
  16. (16) A method according to (15) which includes the further steps of hydrolyzing the compound of formula (IV) thus produced or a salt thereof to produce a compound represented by the following formula (XIV) or a salt thereof:

    and condensing the compound or the salt with a compound represented by NHR22R23 to produce a compound represented by the following formula (XV) or a salt thereof:

    wherein

    R1, R2, R3, R4, and Z are as defined in any one of (1) to (13), and

    R22 and R23 each independently represent a hydrogen atom, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group I below, a C1-C6 alkylsulfonyl group optionally having 1 to 3 substituents independently selected from group I below, a C3-C6 cycloalkyl group optionally having 1 to 3 substituents independently selected from group I below, a 3- to 6-membered saturated heterocyclic group having, in the ring, one heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally having 1 to 3 substituents independently selected from group I below, a phenyl group optionally having 1 to 3 substituents independently selected from group I below, or a 5- or 6-membered heteroaryl group having, in the ring, 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally having 1 to 3 substituents independently selected from group I below, or

    R22 and R23 optionally together form a piperazine ring optionally having 1 to 3 substituents independently selected from group I below:

    group I: a halogen atom, a hydroxy group, an oxo group, a carboxy group, a formyl group, an amino group, an aminocarbonyl group, a cyano group, a C1-C6 alkylamino group, a C1-C6 alkylsulfonyl group, a C1-C6 alkylsulfonylamide group, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group J below, a C1-C6 alkoxy group optionally having 1 to 3 substituents independently selected from group J below, a C1-C6 alkylcarbonyl group optionally having 1 to 3 substituents independently selected from group J below, a C3-C6 cycloalkylcarbonyl group optionally having 1 to 3 substituents independently selected from group J below, a C4-C6 cycloalkyl group optionally having 1 to 3 substituents independently selected from group J below, a C1-C6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group J below, a piperidinyl group optionally having 1 to 3 substituents independently selected from group J below, a pyrrolidinyl group optionally having 1 to 3 substituents independently selected from group J below, a piperazinyl group optionally having 1 to 3 substituents independently selected from group J below, a phenyl group optionally having 1 to 3 substituents independently selected from group J below, a tetrazolyl group, an azetidinyl group optionally having 1 to 3 substituents independently selected from group J below, a morpholino group optionally having 1 to 3 substituents independently selected from group J below, a dihydropyrazolyl group optionally having 1 to 3 substituents independently selected from group J below, and an oxadiazolyl group, and

    group J: a halogen atom, a hydroxy group, an amino group, a carboxy group, an aminocarbonyl group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkylamino group, a di-C1-C6 alkylamino group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkyl group, a C1-C6 alkylsulfonyl group, and a C1-C6 alkylsulfonylamide group.

  17. (17) A method according to (16), wherein
    R22 represents a hydrogen atom, and
    R23 is a substituent represented by the following:

  18. (18) A method for reacting
    a compound represented by formula (XVI):

    a compound represented by formula (XVII):

    and a compound represented by formula (XVIII):

    in a solvent using an asymmetric catalyst prepared from a Lewis acid selected from the group consisting of a Cu(I) Lewis acid and a Cu(II) Lewis acid and a chiral ligand selected from the following group:









    where Cy represents a cyclohexyl group,
    to stereoselectively produce a compound represented by formula (XIX) or a salt thereof:

    wherein

    M represents a nitrogen atom or CH,

    L represents a single bond, an oxygen atom, CH2, or C(CH3)2, and

    R53 represents a C1-C6 alkyl group.

  19. (19) A method for reacting a compound represented by formula (XVI):

    and a compound represented by formula (XX):

    in a solvent using an asymmetric catalyst prepared from a Lewis acid selected from the group consisting of a Cu(I) Lewis acid and a Cu(II) Lewis acid and a chiral ligand selected from the following group:









    where Cy represents a cyclohexyl group,
    to stereoselectively produce a compound represented by formula (XIX) or a salt thereof:

    wherein M, L, and R53 are as defined in (18) .
  20. (20) A method according to (18) or (19) which includes the further steps of hydrolyzing the compound of formula (XIX) thus produced or a salt thereof to produce a compound represented by the following formula (XXI) or a salt thereof:

    and condensing the compound or the salt with a compound represented by the following formula:

    to produce a compound represented by the following formula (XXII) or a salt thereof:

    wherein
    M and L are as defined in (18) or (19).

Advantageous Effects of Invention



[0010] According to the present invention, a compound having a spirooxindole skeleton, for example, a compound having a spirooxindole skeleton and having antitumor activity that inhibits the interaction between Mdm2 protein and p53 protein can be stereoselectively synthesized in an efficient and inexpensive manner.

Description of Embodiments



[0011] In the present invention, a "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0012] In the present invention, a "C1-C6 alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms and is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a s-butyl group, a t-butyl group, a pentyl group, an isopentyl group, a 2-methylbutyl group, a neopentyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, or a 4-methylpentyl group.

[0013] In the present invention, a "C3-C6 cycloalkyl group" is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0014] In the present invention, a "C3-C4 cycloalkyl group" is a cyclopropyl group or a cyclobutyl group.

[0015] In the present invention, a "C1-C6 alkoxy group" refers to a group in which a C1-C6 alkyl group mentioned above is substituted by an oxy group, and is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a s-butoxy group, a t-butoxy group, a pentoxy group, an isopentoxy group, a 2-methylbutoxy group, a hexyloxy group, or an isohexyloxy group.

[0016] In the present invention, a "C3-C6 cycloalkoxy group" refers to a group in which a C3-C6 cycloalkyl group mentioned above is substituted by an oxy group, and is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, or a cyclohexyloxy group.

[0017] In the present invention, a "C3-C4 cycloalkoxy group" is a cyclopropoxy group or a cyclobutoxy group.

[0018] In the present invention, a "C3-C8 cycloalkoxy group" is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, or a cyclooctyloxy group.

[0019] In the present invention, a "C1-C6 alkylthio group" refers to a group in which a C1-C6 alkyl group mentioned above is substituted by a thio group. Examples thereof include a methylthio group, an ethylthio group, a propylthio group, and an isopropylthio group.

[0020] In the present invention, a "C1-C6 alkylsulfonyl group" refers to a group in which a C1-C6 alkyl group mentioned above is substituted by a sulfonyl group. Examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and an isopropylsulfonyl group.

[0021] In the present invention, a "C1-C6 alkylsulfonylamide group" refers to a group in which a C1-C6 alkylsulfonyl group mentioned above is substituted by an amino group. Examples thereof include a methylsulfonylamide group, an ethylsulfonylamide group, a propylsulfonylamide group, and an isopropylsulfonylamide group.

[0022] In the present invention, a "C1-C6 alkylcarbonyl group" refers to a group in which a C1-C6 alkyl group mentioned above is substituted by a carbonyl group. Examples thereof include an acetyl group, an ethylcarbonyl group, a propylcarbonyl group, and an isopropylcarbonyl group.

[0023] In the present invention, a "C1-C6 alkoxycarbonyl group" refers to a group in which a C1-C6 alkoxy group mentioned above is substituted by a carbonyl group. Examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and an isopropoxycarbonyl group.

[0024] In the present invention, a "C3-C6 cycloalkylcarbonyl group" refers to a group in which a C3-C6 cycloalkyl group mentioned above is substituted by a carbonyl group, and is a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, or a cyclohexylcarbonyl group.

[0025] In the present invention, a "C3-C6 cycloalkoxycarbonyl group" refers to a group in which a C3-C6 cycloalkoxy group mentioned above is substituted by a carbonyl group, and is a cyclopropoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopentyloxycarbonyl group, or a cyclohexyloxycarbonyl group.

[0026] In the present invention, a "C1-C6 alkylamino group" refers to a group in which a C1-C6 alkyl group mentioned above is substituted by an amino group. Examples thereof include a methylamino group, an ethylamino group, a propylamino group, and an isopropylamino group.

[0027] In the present invention, a "di-C1-C6 alkylamino group" refers to a group in which two identical or different C1-C6 alkyl groups mentioned above are substituted by an amino group. Examples thereof include a dimethylamino group, a diethylamino group, a dipropylamino group, and a diisopropylamino group.

[0028] In the present invention, a "C1-C6 alkylaminocarbonyl group" refers to a group in which a C1-C6 alkylamino group mentioned above is substituted by a carbonyl group. Examples thereof include a methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, and an isopropylaminocarbonyl group.

[0029] In the present invention, a "C3-C6 cycloalkylaminocarbonyl group" refers to a group in which a C3-C6 cycloalkyl group mentioned above is bonded to the amino group side of a (-NH-C(=O)-) group, and is a cyclopropylaminocarbonyl group, a cyclobutylaminocarbonyl group, a cyclopentylaminocarbonyl group, or a cyclohexylaminocarbonyl group.

[0030] In the present invention, a "C3-C8 cycloalkylamino group" refers to a group in which a C3-C8 cycloalkyl group mentioned above is bonded to an amino group, and is a cyclopropylamino group, a cyclobutylamino group, or a cyclopentylamino group.

[0031] In the present invention, a "C2-C6 alkenyloxy group" refers to a group in which a linear or branched C2-C6 alkenyl group having 2 to 6 carbon atoms is bonded to an oxy group. Examples thereof include a vinyloxy group, an allyloxy group, and an isopropenyloxy group.

[0032] In the present invention, a "C3-C6 cycloalkenyl group" is a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, or a cyclohexenyl group.

[0033] In the present invention, a "5- or 6-membered heteroaryl group" refers to a group derived from a 5- or 6-membered monocyclic aromatic compound containing 1 to 3 atoms each independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon as atoms constituting the ring. Examples thereof include a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, and a pyridazinyl group.

[0034]  In the present invention, a "3- to 6-membered saturated heterocyclic group" refers to a group derived from a 3- to 6-membered monocyclic saturated heterocyclic compound containing one atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon as atoms constituting the ring. Examples thereof include an aziridinyl group, an oxiranyl group, a thiiranyl group, an azetidinyl group, an oxetanyl group, a thietanyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a piperidinyl group, a tetrahydropyranyl group, and a tetrahydrothiopyranyl group.

[0035] In the present invention, an "asymmetric catalyst" refers to a catalyst for use in asymmetric synthesis. Examples thereof include catalysts having a metal atom therein.

[0036] In the present invention, a "Lewis acid" refers to a substance capable of accepting an electron pair. Examples thereof include Zn(OTf)2, AgOAc, Cu(OTf)2, CuOAc, Ni(OAc)2, Co(OAc)2, CuCl, CuBr, CuI, CuPF6, CuBF4, Cu(OAc)2, Cu(OTf)2, and CuSO4.

[0037] In the present invention, a "chiral ligand" refers to a substance having asymmetry and capable of forming a coordinate bond with a metal and includes not only unidentate ligands but multidentate ligands. Examples thereof include BINAP derivatives, MeBIPHEP derivatives, TunePHOS derivatives, P-Phos derivatives, JOSIPHOS derivatives, Walphos derivatives, FESULPHOS derivatives, Taniaphos derivatives, Jospophos derivatives, FOXAP derivatives, Mandyphos derivatives, Ferrocelane derivatives, PHOX derivatives, and QuinoxP derivatives.

[0038] In the present invention, the phrase "having asymmetry" means having an asymmetric center, axial chirality, or planar chirality.

[0039] In the present invention, the symbol "*" means an asymmetric center or axial chirality.

[0040] In the present invention, the symbol "Cy" is an abbreviation of a cyclopentyl group.

[0041] In the present invention, a "ketimine" refers to an imine formed from a ketone and an amine and is a compound having a structure in which the carbonyl group of the ketone is substituted by the nitrogen atom of the amine.

[0042] A compound represented by formula (I), a compound represented by formula (II), a compound represented by formula (III), a compound represented by formula (IV) or a salt thereof, a compound represented by formula (V), a compound represented by formula (VI), a compound represented by formula (VII), a compound represented by formula (VIII), a compound represented by formula (IX), a compound represented by formula (X), a compound represented by formula (XI), a compound represented by formula (XII), a compound represented by formula (XIII) or a salt thereof, a compound represented by formula (XIV) or a salt thereof, a compound represented by formula (XV) or a salt thereof, a compound represented by formula (XVI), a compound represented by formula (XVII), a compound represented by formula (XVIII), a compound represented by formula (XIX) or a salt thereof, a compound represented by formula (XX), a compound represented by formula (XXI) or a salt thereof, and a compound represented by formula (XXII) or a salt thereof according to the present invention encompass all isomers (diastereomers, optical isomers, geometric isomers, rotational isomers, etc.)

[0043] In the compound represented by formula (I), the compound represented by formula (II), the compound represented by formula (III), the compound represented by formula (IV) or a salt thereof, the compound represented by formula (V), the compound represented by formula (VI), the compound represented by formula (VII), the compound represented by formula (VIII), the compound represented by formula (IX), the compound represented by formula (X), the compound represented by formula (XI), the compound represented by formula (XII), the compound represented by formula (XIII) or a salt thereof, the compound represented by formula (XIV) or a salt thereof, the compound represented by formula (XV) or a salt thereof, the compound represented by formula (XVI), the compound represented by formula (XVII), the compound represented by formula (XVIII), the compound represented by formula (XIX) or a salt thereof, the compound represented by formula (XX), the compound represented by general formula (XXI) or a salt thereof, and the compound represented by formula (XXII) or a salt thereof, their isomers and mixtures of these isomers are all represented by single formulae. Thus, the present invention includes all of these isomers and mixtures of these isomers in arbitrary ratios.

[0044] A compound represented by formula (IV), a compound represented by formula (XIII), a compound represented by formula (XIV), a compound represented by formula (XV), a compound represented by formula (XIX), a compound represented by formula (XXI), and a compound represented by formula (XXII) according to the present invention may each be converted into a salt through its reaction with an acid when having a basic group or through its reaction with a base when having an acidic group.

[0045] Examples of a salt based on a basic group can include: hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; C1-C6 alkylsulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; and carboxylates such as acetate, oxalate, tartrate, and maleate.

[0046] On the other hand, examples of a salt based on an acidic group can include: alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; metal salts such as aluminum salt and iron salt; inorganic salts such as ammonium salt; amine salts of organic salts, etc., such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, and tris(hydroxymethyl)aminomethane salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.

[0047]  A compound represented by formula (IV) or a salt thereof, a compound represented by formula (XIII) or a salt thereof, a compound represented by formula (XIV) or a salt thereof, a compound represented by formula (XV) or a salt thereof, a compound represented by formula (XIX) or a salt thereof, a compound represented by formula (XXI) or a salt thereof, and a compound represented by formula (XXII) or a salt thereof according to the present invention, when left in air or recrystallized, may each incorporate a water molecule to form a hydrate. Such a hydrate is also included in a salt of the present invention.

[0048] A compound represented by formula (IV) or a salt thereof, a compound represented by formula (XIII) or a salt thereof, a compound represented by formula (XIV) or a salt thereof, a compound represented by formula (XV) or a salt thereof, a compound represented by formula (XIX) or a salt thereof, a compound represented by formula (XXI) or a salt thereof, and a compound represented by formula (XXII) or a salt thereof according to the present invention, when left in a solvent or recrystallized, may each absorb a certain kind of solvent to form a solvate. Such a solvate is also included in a salt of the present invention.

[0049]  Examples of a solvent include: ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, and 2-propanol; hydrocarbon solvents such as toluene; nitrile solvents such as acetonitrile; aliphatic ester solvents such as ethyl acetate; and amide solvents such as N,N-dimethylacetamide and N,N-dimethylformamide.

[0050] Next, preferred embodiments of the present invention will be described.

[0051] Preferred forms of each substituent in a compound represented by formula (I), a compound represented by formula (II), a compound represented by formula (III), a compound represented by formula (IV), a compound represented by formula (V), a compound represented by formula (XIII), a compound represented by formula (XIV), and a compound represented by formula (XV) are given below.

[0052] R1 represents a hydrogen atom, a C1-C6 alkylcarbonyl group, or a C1-C6 alkoxycarbonyl group optionally having one phenyl group. R1 is more preferably a hydrogen atom, an acetyl group, a t-butoxycarbonyl group, or a benzyloxycarbonyl group, further preferably a hydrogen atom.

[0053]  R2 represents a 5- or 6-membered heteroaryl group having, in the ring, 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or a phenyl group, wherein the 5- or 6-membered heteroaryl group and the phenyl group each optionally have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an aminocarbonyl group, and a C1-C6 alkyl group.

[0054] R2 is more preferably a phenyl group optionally having 1 to 3 halogen atoms, or a pyridyl group optionally having 1 to 3 halogen atoms, even more preferably a phenyl group having one fluorine atom and one chlorine atom, or a pyridyl group having one fluorine atom and one chlorine atom.

[0055] Ring Z is a benzene ring optionally having 1 to 4 halogen atoms and is more preferably a benzene ring having one chlorine atom.

[0056] R3 and R4 each independently represent a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, and an amino group. Both R3 and R4 are more preferably the same C1-C6 alkyl groups, even more preferably methyl groups.

[0057]  In another form of R3 and R4, preferably, R3 and R4 together form a C4-C6 cycloalkyl ring optionally having 1 to 3 C1-C6 alkyl groups on the ring, a piperidine ring optionally having 1 to 3 C1-C6 alkyl groups on the ring, or a tetrahydropyran ring optionally having 1 to 3 C1-C6 alkyl groups on the ring. The ring formed is more preferably a cyclopentane ring optionally having 1 to 3 C1-C6 alkyl groups on the ring, a cyclohexane ring optionally having 1 to 3 C1-C6 alkyl groups on the ring, or a tetrahydropyran ring optionally having 1 to 3 C1-C6 alkyl groups on the ring, even more preferably a 4,4-dimethylcyclohexane ring.

[0058] R5 represents a C1-C6 alkoxy group, a C3-C8 cycloalkoxy group, a C2-C6 alkenyloxy group, a C1-C6 alkylamino group, a C3-C8 cycloalkylamino group, or a tetrahydropyranylamino group. R5 is more preferably a C1-C6 alkoxy group or a tetrahydropyranylamino group, even more preferably a C1-C6 alkoxy group.

[0059] R22 and R23 each independently represent a hydrogen atom, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group I below, a C1-C6 alkylsulfonyl group optionally having 1 to 3 substituents independently selected from group I below, a C3-C6 cycloalkyl group optionally having 1 to 3 substituents independently selected from group I below, an azetidinyl group optionally having 1 to 3 substituents independently selected from group I below, a pyrrolidinyl group optionally having 1 to 3 substituents independently selected from group I below, a piperidinyl group optionally having 1 to 3 substituents independently selected from group I below, a piperazinyl group optionally having 1 to 3 substituents independently selected from group I below, a morpholino group optionally having 1 to 3 substituents independently selected from group I below, a phenyl group optionally having 1 to 3 substituents independently selected from group I below, a pyridyl group optionally having 1 to 3 substituents independently selected from group I below, a pyrimidinyl group optionally having 1 to 3 substituents independently selected from group I below, a pyridazinyl group optionally having 1 to 3 substituents independently selected from group I below, a pyrrolyl group optionally having 1 to 3 substituents independently selected from group I below, a pyrazolyl group optionally having 1 to 3 substituents independently selected from group I below, an imidazolyl group optionally having 1 to 3 substituents independently selected from group I below, an oxazolyl group optionally having 1 to 3 substituents independently selected from group I below, an oxadiazolyl group optionally having 1 to 3 substituents independently selected from group I below, or a triazolyl group optionally having 1 to 3 substituents independently selected from group I below:
group I: a halogen atom, a hydroxy group, an oxo group, a carboxy group, a formyl group, an amino group, an aminocarbonyl group, a cyano group, a C1-C6 alkylamino group, a C1-C6 alkylsulfonyl group, a C1-C6 alkylsulfonylamide group, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group J below, a C1-C6 alkoxy group optionally having 1 to 3 substituents independently selected from group J below, a C1-C6 alkylcarbonyl group optionally having 1 to 3 substituents independently selected from group J below, a C3-C6 cycloalkylcarbonyl group optionally having 1 to 3 substituents independently selected from group J below, a C4-C6 cycloalkyl group optionally having 1 to 3 substituents independently selected from group J below, a C1-C6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group J below, a piperidinyl group optionally having 1 to 3 substituents independently selected from group J below, a pyrrolidinyl group optionally having 1 to 3 substituents independently selected from group J below, a piperazinyl group optionally having 1 to 3 substituents independently selected from group J below, a phenyl group optionally having 1 to 3 substituents independently selected from group J below, a tetrazolyl group, an azetidinyl group optionally having 1 to 3 substituents independently selected from group J below, a morpholinyl group optionally having 1 to 3 substituents independently selected from group J below, a dihydropyrazolyl group optionally having 1 to 3 substituents independently selected from group J below, and an oxadiazolyl group: group J: a halogen atom, a hydroxy group, an amino group, a carboxy group, an aminocarbonyl group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkylamino group, a di-C1-C6 alkylamino group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkyl group, a C1-C6 alkylsulfonyl group, and a C1-C6 alkylsulfonylamide group.

[0060] R22 and R23 are, more preferably, each independently a hydrogen atom, a methyl group, a methylsulfonyl group, or any of the following T1 to T35:















[0061] M is a nitrogen atom or CH and is more preferably a nitrogen atom.

[0062] L is CH2 or C(CH3)2 and is more preferably C(CH3)2.

[0063] R53 is a C1-C6 alkyl group.

[0064] In a preferred combination of the substituents in the compound represented by the formula (I), R1 is a hydrogen atom, R2 is a phenyl group having one fluorine atom and one chlorine atom, and ring Z is a benzene ring having one chlorine atom.

[0065] In a preferred combination of the substituents in the compound represented by formula (V), R3 and R4 together form a 4,4-dimethylcyclohexane ring, and R5 is a C1-C6 alkoxy group.

[0066] In a preferred combination of the substituents in the compound represented by formula (IV) or the compound represented by formula (XIII) in the present invention, R1 is a hydrogen atom, R2 is a phenyl group having one fluorine atom and one chlorine atom, ring Z is a benzene ring having one chlorine atom, R3 and R4 together form a 4,4-dimethylcyclohexane ring, and R5 is a C1-C6 alkoxy group.

[0067] In a preferred combination of the substituents in the compound represented by formula (XIV), R1 is a hydrogen atom, R2 is a phenyl group having one fluorine atom and one chlorine atom, ring Z is a benzene ring having one chlorine atom, and R3 and R4 together form a 4,4-dimethylcyclohexane ring.

[0068] In a preferred combination of the substituents in the compound represented by formula (XV), R1 is a hydrogen atom, R2 is a phenyl group having one fluorine atom and one chlorine atom, ring Z is a benzene ring having one chlorine atom, R3 and R4 together form a 4,4-dimethylcyclohexane ring, and each of R22 and R23 is T24 mentioned above.

[0069] In a preferred combination of the substituents in the compound represented by formula (XIX), M is a nitrogen atom, L is C(CH3)2, and R53 is a C1-C6 alkyl group.

[0070] In a preferred combination of the substituents in the compound represented by formula (XX), L is C(CH3)2, and R53 is a C1-C6 alkyl group.

[0071] In a preferred combination of the substituents in the compound represented by formula (XXI) or the compound represented by formula (XXII), M is a nitrogen atom, and L is C(CH3)2.

[0072] Next, preferred compounds of the compound represented by formula (VI), the compound represented by formula (VII), the compound represented by formula (VIII), the compound represented by formula (IX), the compound represented by formula (X), the compound represented by formula (XI), and the compound represented by formula (XII) will be described.

[0073] The compound represented by formula (VI) is a BINAP derivative and is preferably a compound represented by any of the following formulae:







[0074]  more preferably a compound represented by any of the following formulae:





[0075] The compound represented by formula (VII) is a MeBIOPHEP derivative, a P-Phos derivative, or a TunePHOS derivative and is preferably a compound represented by any of the following formulae:









more preferably a compound represented by any of the following formulae:





[0076] The compound represented by formula (VIII) is a JOSIPHOS derivative, a Walphos derivative, a FESULPHOS derivative, a Taniaphos derivative, a Jospophos derivative, or a FOXAP derivative and is preferably a compound represented by any of the following formulas:































more preferably a compound represented by any of the following formulae:







[0077] The compound represented by formula (IX) is a Mandyphos derivative and is preferably a compound represented by any of the following formulae:





[0078] The compound represented by formula (X) is a Ferrocelane derivative and is preferably a compound represented by any of the following formula:







[0079] The compound represented by formula (XI) is a PHOX derivative and is preferably a compound represented by any of the following formulae:





[0080]  The compound represented by formula (XII) is a QuinoxP derivative and is preferably a compound represented by the following formula:



[0081] In the present invention, the Lewis acid is CuOAc, CuCl, CuBr, CuI, CuOTf, CuPF6, CuBF4, Cu(OAc)2, Cu(OTf)2, or CuSO4 and is more preferably CuOAc or Cu(OAc)2.

[0082] In the present invention, a preferred combination of the Lewis acid and the chiral ligand is CuOAc or Cu(OAc)2 as the Lewis acid and a compound represented by any of the following formulae as the chiral ligand:











[0083] In the present invention, the solvent is preferably one or two selected from the group consisting of N,N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, 2-propanol, toluene, and ethyl acetate, more preferably one or two selected from the group consisting of N,N-dimethylacetamide and ethyl acetate. Alternatively, a mixture of the solvents in an arbitrary ratio may be used.

[0084] Next, the present invention will be described. It should be understood that the reaction conditions of the present invention are not limited to those described herein. In the present invention, a functional group in a compound may be protected with an appropriate protective group. Examples of such a functional group can include a hydroxy group, a carboxy group, and an amino group. For the type of protective group and conditions for the introduction and removal of the protective group, see those described in, for example, Protective Groups in Organic Synthesis (T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 2006).

[Production method]


1) Method for producing a compound represented by formula (IV)



[0085] 



[0086] A compound represented by formula (IV) is obtained by reacting a compound represented by formula (I), a compound represented by formula (II), and a compound represented by formula (III) in the presence of an asymmetric catalyst prepared from a Lewis acid and a chiral ligand, and a solvent. Also, the compound represented by formula (IV) can be obtained by forming in advance a compound represented by formula (V) (ketimine) from a compound represented by formula (II) and a compound represented by formula (III) and then reacting the ketimine with a compound represented by formula (I).

[0087] The reaction is preferably carried out in the presence of a base.

[0088] A compound represented by the formula (I) can be produced according to various references (e.g., WO2006/091646 and WO2012/121361).

[0089] The amount of the compound represented by formula (II) used is in the range of 0.5 equivalents to 10 equivalents with respect to the compound represented by formula (I) and is preferably in the range of 1.0 equivalent to 3.0 equivalents with respect to the compound represented by formula (I).

[0090] The amount of the compound represented by formula (III) used is in the range of 0.5 equivalents to 10 equivalents with respect to the compound represented by formula (I) and is preferably in the range of 1.0 equivalent to 3.0 equivalents with respect to the compound represented by formula (I).

[0091] Examples of the Lewis acid that can be used include a Zn(II) Lewis acid, a Ag(I) Lewis acid, a Ni(II) Lewis acid, a Co (II) Lewis acid, a Ru(I) Lewis acid, a Cu(I) Lewis acid, and a Cu(II) Lewis acid. The Lewis acid is preferably CuOAc, CuCl, CuBr, CuI, CuOTf, CuPF6, CuBF4, Cu(OAc)2, Cu(OTf)2, or CuSO4.

[0092] As for the amounts of the Lewis acid and the chiral ligand used, the ligand is preferably added in the range of 0.8 to 3.0 equivalents with respect to the Lewis acid and in the range of 0.01 to 100 mol% of the Lewis acid with respect to the compound represented by formula (I). More preferably, the ligand is added in the range of 1.01 to 2.4 equivalents with respect to the Lewis acid and in the range of 0.5 to 20 mol% of the Lewis acid with respect to the compound (I).

[0093] Examples of the chiral ligand that can be used include BINAP derivatives, MeBIPHEP derivatives, TunePHOS derivatives, P-Phos derivatives, JOSIPHOS derivatives, Walphos derivatives, FESULPHOS derivatives, Taniaphos derivatives, Jospophos derivatives, FOXAP derivatives, Mandyphos derivatives, Ferrocelane derivatives, PHOX derivatives, and QuinoxP derivatives. The chiral ligand is preferably a BINAP derivative, a Tunephos derivative, a MeBIPHEP derivative, a P-Phos derivative, a JOSIPHOS derivative, a FOXAP derivative, a FESULPHOS derivative, or the like.

[0094]  The chiral ligand can be purchased from, for example, Sigma-Aldrich Inc., Tokyo Chemical Industry Co., Ltd., Wako Pure Chemical Industries, Ltd., or Strem Chemicals Inc.

[0095] Examples of the base that can be used include: tertiary amines such as triethylamine and N,N-diisopropylethylamine; organic bases such as sodium ethoxide and t-butoxy potassium; and inorganic bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, potassium hydroxide, potassium carbonate, potassium bicarbonate, and potassium acetate. The base is preferably a tertiary amine such as triethylamine or N,N-diisopropylethylamine, more preferably triethylamine.

[0096] The amount of the base used is in the range of 0.01 equivalents to 10 equivalents with respect to the compound represented by formula (I) and is preferably in the range of 0.01 equivalents to 0.2 equivalents with respect to the compound represented by formula (I).

[0097] Examples of the solvent include: ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, and 2-propanol; hydrocarbon solvents such as toluene; nitrile solvents such as acetonitrile; aliphatic ester solvents such as ethyl acetate; and amide solvents such as N,N-dimethylacetamide and N,N-dimethylformamide. These solvents can be used alone or as a mixture in an arbitrary ratio. Preferably, ether solvents such as tetrahydrofuran, amide solvents such as N,N-dimethylacetamide, and aliphatic ester solvents such as ethyl acetate are preferably used alone or as a mixture in an arbitrary ratio.

[0098] The amount of the solvent used is in the range of 1 to 100 times the amount of the compound (I) and is preferably in the range of 5 to 50 times the amount of the compound represented by formula (I), more preferably in the range of 8 to 25 times the amount of the compound represented by formula (I).

[0099] The reaction temperature is in the range of -88°C to the boiling point of the solvent used and is preferably in the range of -20°C to 60°C.

[0100] The reaction time is in the range of 30 minutes to 96 hours and is preferably in the range of 30 minutes to 64 hours, more preferably in the range of 30 minutes to 48 hours.

2) Method for producing a compound represented by formula (XIV)



[0101] 



[0102] A compound represented by formula (XIV) is obtained by hydrolyzing a compound represented by formula (IV) (provided that R5 is not -NR51R52).

[0103] The hydrolysis can be carried out by the addition of a base or an acid in a solvent.

[0104] Examples of the base that can be used include: organic bases such as sodium ethoxide and t-butoxy potassium; and inorganic bases such as sodium hydroxide, lithium hydroxide, sodium carbonate, potassium hydroxide, and potassium carbonate. The base is preferably an inorganic base such as sodium hydroxide, lithium hydroxide, or potassium hydroxide, more preferably sodium hydroxide.

[0105] The amount of the base used is in the range of 1 equivalent to 10 equivalents with respect to the compound represented by formula (IV) and is preferably in the range of 1 equivalent to 5 equivalents with respect to the compound represented by formula (IV), more preferably in the range of 1 equivalent to 3 equivalents with respect to the compound represented by formula (IV).

[0106] Examples of the acid include: hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; inorganic acids such as nitric acid, perchloric acid, sulfuric acid, and phosphoric acid; C1-C6 alkylsulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and ethanesulfonic acid; arylsulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; and carboxylic acids such as acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, and maleic acid. The acid is preferably trifluoroacetic acid or hydrochloric acid.

[0107] The amount of the acid used is in the range of 1 equivalent to 100 equivalents with respect to the compound represented by formula (IV) and is preferably in the range of 1 equivalent to 10 equivalents with respect to the compound represented by formula (IV).

[0108] Examples of the solvent include: ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, and 2-propanol; hydrocarbon solvents such as toluene; nitrile solvents such as acetonitrile; aliphatic ester solvents such as ethyl acetate; amide solvents such as N,N-dimethylacetamide and N,N-dimethylformamide; and halogen solvents such as dichloromethane and chloroform. These solvents can be used alone or as a mixture at an arbitrary ratio. The solvent is preferably a halogen solvent such as dichloromethane, an alcohol solvent such as methanol, or a mixed solvent of an ether solvent such as tetrahydrofuran and an alcohol solvent such as methanol.

[0109] The amount of the solvent used is in the range of 1 to 100 times the amount of the compound represented by formula (IV) and is preferably in the range of 5 to 50 times the amount of the compound represented by formula (IV), more preferably in the range of 8 to 25 times the amount of the compound represented by formula (IV).

[0110] The reaction temperature is in the range of -88°C to the boiling point of the solvent used and is preferably in the range of -20°C to 60°C.

[0111] The reaction time is in the range of 30 minutes to 96 hours and is preferably in the range of 30 minutes to 64 hours, more preferably in the range of 30 minutes to 48 hours.

3) Method for producing a compound represented by formula (XV)



[0112] 



[0113] A compound represented by formula (XV) is obtained by condensing a compound represented by formula (XIV) with an amine NHR22R23 using a condensing agent in a solvent. The amine can be produced according to various references (e.g., WO2006/091646 and WO2012/121361).

[0114] The amount of the amine used is in the range of 0.5 equivalents to 10 equivalents with respect to the compound represented by formula (XIV) and is preferably in the range of 1.0 equivalent to 2.0 equivalents with respect to the compound represented by formula (XIV).

[0115] Examples of the condensing agent include: azodicarboxylic acid di-lower alkyl ester-triphenylphosphines such as azodicarboxylic acid diethyl ester-triphenylphosphine; carbodiimide derivatives such as N,N'-dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; diarylphosphorylazides such as diphenylphosphorylazide (DPPA); phosphoryl chlorides such as diethylphosphoryl chloride; imidazole derivatives such as N,N'-carbodiimidazole (CDI); benzotriazole derivatives such as benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(benzotriazol-1-yl)-N,N,N' ,N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), and (1H-benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP); and triazine derivatives such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DM-TMM). The condensing agent is preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), (1H-benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphorylazide (DPPA), or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DM-TMM).

[0116] The amount of the condensing agent used is in the range of 1 equivalent to 10 equivalents with respect to the compound represented by formula (XIV) and is preferably in the range of 1 equivalent to 5 equivalents with respect to the compound represented by formula (XIV), more preferably in the range of 1 equivalent to 2 equivalents with respect to the compound represented by formula (XIV).

[0117] Examples of the solvent that can be used include: ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, and 2-propanol; hydrocarbon solvents such as toluene; nitrile solvents such as acetonitrile; aliphatic ester solvents such as ethyl acetate; and amide solvents such as N,N-dimethylacetamide and N,N-dimethylformamide. The solvent is preferably an amide solvent such as N,N-dimethylacetamide.

[0118] The amount of the solvent used is in the range of 1 to 100 times the amount of the compound represented by formula (XIV) and is preferably in the range of 3 to 50 times the amount of the compound represented by formula (XIV), more preferably in the range of 5 to 25 times the amount of the compound represented by formula (XIV).

[0119] The reaction temperature is in the range of -88°C to the boiling point of the solvent used and is preferably in the range of -20°C to 60°C.

[0120] The reaction time is in the range of 30 minutes to 96 hours and is preferably in the range of 30 minutes to 64 hours, more preferably in the range of 30 minutes to 48 hours.

Examples



[0121] Hereinafter, the present invention will be described in more detail with reference to Examples. However, the scope of the present invention is not intended to be limited by them.

[0122] Abbreviations used in the Examples are as defined below.
mg: milligram, g: gram, ml: milliliter, L: liter, MHz: megahertz.

[0123] In the Examples below, nuclear magnetic resonance (hereinafter, referred to as 1H NMR; 500 MHz) spectra were indicated by the δ value (ppm) of chemical shift with tetramethylsilane as a standard. As for split patterns, s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, and br: broad. In the present Examples, "UHPLC" or "ultrahigh-performance liquid chromatography" was performed using Prominence UFLC (Shimadzu Corp.).

[Example 1]


Ethyl (3'R, 4'S, 5'R) -6''-chloro-4'- (3-chloro-2-fluorophenyl)-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate



[0124] 



[0125] To a mixture of (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) (99.9 mg, 0.32 mmol), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of cyclohexanone (50.4 µL, 0.49 mmol), glycine ethyl ester (39.6 µL, 0.39 mmol) and triethylamine (6.8 µL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 40 hours. To the reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20% aqueous ammonium chloride solution (1 mL) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (2 mL each), and the organic layers were all combined and then washed with water three times (5 mL each). The organic layer obtained was concentrated under reduced pressure. To the residue, ethyl acetate (6 mL) and silica gel (500 mg) were added, and the silica gel was filtered off. The filtrate was concentrated under reduced pressure. To the residue, ethanol (1.25 mL) was added, then water (1 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The deposited solid was filtered and dried under reduced pressure at 40°C to obtain the title compound (102.9 mg, yield: 65%, 91% ee) as a solid. 1H NMR (500 MHz, CDCl3): δ = 0.91-1.60 (m, 2H), 1.17 (t, J=7.3 Hz, 3H), 1.38-1.74 (m, 6H), 1.87-2.0 (m, 1H), 2.12-2.20 (m, 1H), 3.19 (s, 1H), 4.07-4.20 (m, 2H), 4.54 (d, J = 9.0 Hz, 1H), 4.84 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.83-6.89 (m, 1H), 7.05 (dd, J = 8.3, 1.8 Hz, 1H), 7.10-7.16 (m, 1H), 7.36 (dd, J = 8.0, 2.0 Hz, 1H), 7.49-7.55 (m, 1H), 7.65 (s, 1H).

(Conditions for high-performance liquid chromatography (HPLC) for optical purity measurement)



[0126] 

Column: CHIRALPAK IC 4.6 × 250 mm, 5 µm

Mobile phase: 10 mM AcOH buffer:MeCN = 40:60

Flow rate: 1.0 min/min

Column temperature: 40°C

Detection wavelength: 254 nm

Injection quantity: 5 µL

Retention time: title compound = 14.1 min, enantiomer = 11.4 min


[Example 2]


Ethyl (3'R, 4'S, 5'R) -6"-chloro-4'- (3-chloro-2-fluorophenyl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate



[0127] 



[0128] To a mixture of (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) (98.7 mg), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of 4,4-dimethlcyclohexanone (61.4 mg, 0.48 mmol), glycine ethyl ester (39.5 µL, 0.39 mmol) and triethylamine (6.8 µL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 22 hours. To the reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20% aqueous ammonium chloride solution (1 mL) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (2 mL each), and the organic layers were all combined and then washed with water three times (5 mL each). The organic layer obtained was concentrated under reduced pressure. To the residue, ethyl acetate (6 mL) and silica gel (500 mg) were added, and the silica gel was filtered off. The filtrate was concentrated under reduced pressure. To the residue, ethanol (1.0 mL) was added, then water (1 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The deposited solid was filtered and dried under reduced pressure at 40°C to obtain the title compound (137 mg, yield: 82%, 94% ee) as a solid.
1H NMR (500 MHz, CDCl3) : δ = 0.67 (s, 3H), 0.91 (s, 3H), 1.10-1.19 (m, 2H), 1.17 (t, J=7.3 Hz, 3H), 1.25-1.33 (m, 1H), 1.44-1.72 (m, 3H), 1.87-2.01 (m, 1H), 3.16 (s, 1H), 4.07-4.21 (m, 2H), 4.52 (d, J = 8.5 Hz, 1H), 4.83 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 1.5Hz, 1H), 6.81-6.86 (m, 1H), 7.06 (dd, J = 8.3, 2.8 Hz, 1H), 7.10-7.16 (m, 1H), 7.37 (dd, J = 8.3, 1.8 Hz, 1H), 7.48-7.54 (m, 1H), 7.81 (s, 1H) .

(Conditions for HPLC for optical purity measurement)



[0129] 

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 µm

Mobile phase: 10 mM phosphate buffer:MeCN = 40:60

Flow rate: 1.0 min/min

Column temperature: 40°C

Detection wavelength: 254 nm

Injection quantity: 5 µL

Retention time: title compound = 13.8 min, enantiomer = 12.9 min


[Example 3]


Ethyl (3'R,4'S,5'R)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate



[0130] 



[0131] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/121361) (99.2 mg), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of cyclohexanone (50.4 µL, 0.49 mmol), glycine ethyl ester (39.6 µL, 0.39 mmol), and triethylamine (6.8 µL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 18 hours. To the reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20% aqueous ammonium chloride solution (1 mL) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (2 mL each), and the organic layers were all combined and then washed with water three times (5 mL each). The organic layer obtained was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate = 1:1 (v/v)]. To the residue obtained, ethanol (1.0 mL) was added, then water (1 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The deposited solid was filtered and dried under reduced pressure at 40°C to obtain the title compound (101.2 mg, yield: 64%, 99% ee) as a solid.
1H NMR (500 MHz, CDCl3) : δ = 0.9-1.1 (m, 2H), 1.19 (t, J=7.3 Hz, 3H), 1.44 (td, J = 12.9, 3.2 Hz, 1H)m, 1.48-1.70 (m, 1H), 3.2 (s, 1H), 4.12-4.20 (m, 2H), 4.53 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 10.0 Hz, 1H), 6.77 (d, J = 2.0Hz, 1H), 7.07 (dd, J = 8.0, 1.5 Hz, 1H), 7.34 (dd, J = 8.3, 1.8 Hz, 1H), 7.5-7.56 (m, 1H), 7.59 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H).

(Conditions for HPLC for optical purity measurement)



[0132] 

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 µm

Mobile phase: 10 mM phosphate buffer:MeCN = 40:60

Flow rate: 1.0 min/min

Column temperature: 40°C

Detection wavelength: 254 nm

Injection quantity: 5 µL

Retention time: title compound = 7.7 min, enantiomer = 8.7 min


[Example 4]


Ethyl (3'R,4'S,5'R)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate



[0133] 



[0134] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/121361) (100.7 mg), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of 4,4-dimethylcyclohexanone (61.4 mg, 0.48 mmol), glycine ethyl ester (39.5 µL, 0.39 mmol), and triethylamine (6.8 µL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 14 hours. To the reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20% aqueous ammonium chloride solution (1 mL) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (2 mL each), and the organic layers were all combined and then washed with water three times (5 mL each). The organic layer obtained was concentrated under reduced pressure. To the residue, ethyl acetate (6 mL) and silica gel (500 mg) were added, and the silica gel was filtered off. The filtrate was concentrated under reduced pressure. To the residue, ethanol (1.0 mL) was added, then water (1 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The deposited solid was filtered and dried under reduced pressure at 40°C to obtain the title compound (134.9 mg, yield: 80%, 99% ee) as a solid.
1H NMR (500 MHz, CDCl3) : δ = 0.67 (s, 3H), 0.91 (s, 3H), 1.11-1.21 (m, 2H), 1.19 (t, J=7.0 Hz, 3H), 1.24-1.34 (m, 1H), 1.43-1.58 (m, 2H), 1.60-1.72 (m, 1H), 1.85-1.95 (m, 1H), 3.19 (s, 1H), 4.10-4.21 (m, 2H), 4.51 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 9.5 Hz, 1H), 6.77 (d, J = 2.0Hz, 1H), 7.07 (dd, J = 8.5, 1.5 Hz, 1H), 7.36 (dd, J = 8.3, 1.8 Hz, 1H), 7.5-7.55 (m, 1H), 7.68 (bs, 1H), 8.05 (d, J = 5.5 Hz, 1H) .

(Conditions for HPLC for optical purity measurement)



[0135] 

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 µm

Mobile phase: 10 mM phosphate buffer:MeCN = 40:60

Flow rate: 1.0 min/min

Column temperature: 40°C

Detection wavelength: 254 nm

Injection quantity: 5 µL

Retention time: title compound = 9.4 min, enantiomer = 10.5 min


[Example 5]


Ethyl (3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-3',3'-dimethyl-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate



[0136] 



[0137] To a mixture of (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) (50.8 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of acetone (23.8 µL, 0.32 mmol), glycine ethyl ester (26.4 µL, 0.26 mmol), and triethylamine (3.4 µL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (1 mL each), and the organic layers were all combined and then washed with water three times (2.5 mL each). The organic layer obtained was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 50:50:1 (v/v)] and dried under reduced pressure at 40°C to obtain a mixture of the title compound and diastereomers (66.8 mg, yield: 90%, diastereomer ratio: 84 (title compound):13:3, optical purity of the title compound: 92% ee) as an oil compound.
1H NMR (500 MHz, CDCl3) : δ = 1.07 (s, 3H), 1.17 (t, J =7.0 Hz, 3H), 1.48 (s, 3H), 3.40-3.62 (m, 1H), 4.07-4.23 (m, 2H), 4.55 (d, J = 9.0 Hz, 1H), 4.91 (d, J = 9.5 Hz, 1H), 6.75-6.80 (m, 1H), 6.80 (d, J = 1.5Hz, 1H), 7.06 (dd, J = 8.0, 2.0 Hz, 1H), 7.09-7.15 (m, 1H), 7.38 (dd, J = 8.3, 2.3 Hz, 1H), 7.45-7.50 (m, 1H), 8.62 (s, 1H).

(Conditions for HPLC for optical purity measurement)



[0138] 

Column: CHIRALPAK IC 4.6 × 250 mm, 5 µm

Mobile phase: 0.1% HCOOH aq.: MeCN = 70:30

Flow rate: 1.0 min/min

Column temperature: 27°C

Detection wavelength: 254 nm

Injection quantity: 5 µL

Retention time: title compound = 10.3 min, enantiomer = 11.1 min


[Example 6]


Ethyl (3'R,4'S,5'R)-6-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-2-oxo-1,2-dihydrodispiro[indole-3,3'-pyrrolidine-2',4"-pyran]-5'-carboxylate



[0139] 



[0140] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/121361) (48.7 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of tetrahydro-4H-pyran-4-one (22.4 µL, 0.24 mmol), glycine ethyl ester (20 µL, 0.20 mmol), and triethylamine (3.4 µL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (1 mL each), and the organic layers were all combined and then washed with water three times (2.5 mL each). The organic layer obtained was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 50:50:1 (v/v)] and dried under reduced pressure at 40°C to obtain a mixture of the title compound and diastereomers (74.9 mg, yield: 96%, diastereomer ratio: 75 (title compound):20:5, optical purity of the title compound: 98% ee) as an oil compound.
1H NMR (500 MHz, CDCl3) : δ = 1.19 (t, J=7.3 Hz, 3H), 1.31-1.41 (m, 1H), 1.42-1.50 (m, 1H), 1.85-1.98 (m, 2H), 3.18-3.38 (m, 1H), 3.67-3.77 (m, 2H), 3.84-3.92 (m, 1H), 3.88-4.06 (m, 1H), 4.08-4.20 (m, 2H), 4.56 (d, J = 9.5 Hz, 1H), 4.78 (d, J = 9.5 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (dd, J = 8.3, 2.3 Hz, 1H), 7.49-7.54 (m, 1H), 8.06 (d, J = 5.0 Hz, 1H), 8.43 (s, 1H) .

(Conditions for HPLC for optical purity measurement)



[0141] 

Column: CHIRALPAK IC 4.6 × 250 mm, 5 µm

Mobile phase: 10 mM AcOH buffer: MeCN = 40:60

Flow rate: 1.0 min/min

Column temperature: 27°C

Detection wavelength: 220 nm

Injection quantity: 5 µL

Retention time: title compound = 26.2 min, enantiomer = 22.8 min


[Example 7]


Ethyl (3'R,4'S,5'R)-6-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-3',3'-dimethyl-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate



[0142] 



[0143] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/121361) (51 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of acetone (17.8 µL, 0.24 mmol), glycine ethyl ester (20 µL, 0.20 mmol), and triethylamine (3.4 µL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (1 mL each), and the organic layers were all combined and then washed with water three times (2.5 mL each). The organic layer obtained was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 50:50:1 (v/v)] and dried under reduced pressure at 40°C to obtain a mixture of the title compound and diastereomers (68.9 mg, yield: 92%, diastereomer ratio: 87 (title compound):13, optical purity of the title compound: 98% ee) as an oil compound.
1H NMR (500 MHz, CDCl3) : δ = 1.08 (s, 3H), 1.20 (t, J =7.0 Hz, 3H), 1.46 (s, 3H), 3.40-3.65 (m, 1H), 4.09-4.26 (m, 2H), 4.54 (d, J = 9.5 Hz, 1H), 4.89 (d, J = 9.0 Hz, 1H), 6.79 (d, J = 1.5 Hz, 1H), 7.07 (dd, J = 8.5, 2.0 Hz, 1H), 7.36 (dd, J = 8.0, 1.5 Hz, 1H), 7.49-7.55 (m, 1H), 7.86 (s, 1H), 8.07 (d, J = 5.0 Hz, 1H).

(Conditions for HPLC for optical purity measurement)



[0144] 

Column: CHIRALPAK AS-RH 4.6 × 150 mm, 5 µm

Mobile phase: 10 mM AcOH buffer: MeCN = 60:40

Flow rate: 1.0 min/min

Column temperature: 40°C

Detection wavelength: 254 nm

Injection quantity: 5 µL

Retention time: title compound = 8.4 min, enantiomer = 7.1 min


[Example 8]


Ethyl (3'R,4'S,5'R)-6"-chloro-4'-(3-chloro-2-fluorophenyl)-2"-oxo-1",2"-dihydrodispiro[cyclopentane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate



[0145] 



[0146] To a mixture of (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) (52.1 mg, 0.17 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of cyclopentanone (28.7 µL, 0.32 mmol), glycine ethyl ester (26.4 µL, 0.26 mmol), and triethylamine (3.4 µL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (1 mL each), and the organic layers were all combined and then washed with water three times (2.5 mL each). The organic layer obtained was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 100:50:1.5 (v/v)] and dried under reduced pressure at 40°C to obtain a mixture of the title compound and diastereomers (69 mg, yield: 86%, diastereomer ratio: 84 (title compound):14:2, optical purity of the title compound: 99% ee) as an oil compound.
1H NMR (500 MHz, CDCl3) : δ = 1.17 (t, J=7.3 Hz, 3H), 1.22-1.30 (m, 1H), 1.32-1.42 (m, 1H), 1.50-1.60 (m, 2H), 1.66-1.83 (m, 2H), 1.86-1.97 (m, 1H), 2.07-2.15 (m, 1H), 3.25-3.64 (m, 1H), 4.07-4.23 (m, 2H), 4.53 (d, J = 9.5 Hz, 1H), 4.76 (d, J = 9.0 Hz, 1H), 6.72-6.77 (m, 1H), 6.80 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.0, 1.5 Hz, 1H), 7.08-7.13 (m, 1H), 7.38 (dd, J = 8.0, 2.0 Hz, 1H), 7.43-7.50 (m, 1H), 8.68 (s, 1H).

(Conditions for HPLC for optical purity measurement)



[0147] 

Column: CHIRALPAK IC 4.6 × 250 mm, 5 µm

Mobile phase: 0.1% HCOOH aq.: MeCN = 50:50

Flow rate: 1.0 min/min

Column temperature: 27°C

Detection wavelength: 220 nm

Injection quantity: 5 µL

Retention time: title compound = 6.0 min, enantiomer = 5.6 min


[Example 9]


Ethyl (3'R,4'S,5'R)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-2"-oxo-1",2"-dihydrodispiro[cyclopentane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate



[0148] 



[0149] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/121361) (50.9 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of cyclopentanone (21.6 µL, 0.24 mmol), glycine ethyl ester (20 µL, 0.20 mmol), and triethylamine (3.4 µL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (1 mL each), and the organic layers were all combined and then washed with water three times (2.5 mL each). The organic layer obtained was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 50:50:1 (v/v)] and dried under reduced pressure at 40°C to obtain a mixture of the title compound and diastereomers (69.1 mg, yield: 88%, diastereomer ratio: 87 (title compound):13, optical purity of the title compound: 98% ee) as an oil compound.
1H NMR (500 MHz, CDCl3) : δ = 1.19 (t, J=7.3 Hz, 3H), 1.22-1.30 (m, 1H), 1.32-1.43 (m, 1H), 1.48-1.60 (m, 2H), 1.66-1.82 (m, 2H), 1.86-1.96 (m, 1H), 2.02-2.09 (m, 1H), 3.40-3.62 (m, 1H), 4.08-4.24 (m, 2H), 4.53 (d, J = 9.0 Hz, 1H), 4.73 (d, J = 9.0 Hz, 1H), 6.82 (d, J = 1.5 Hz, 1H), 7.07 (dd, J = 8.3, 1.8 Hz, 1H), 7.36 (dd, J = 8.3, 2.3 Hz, 1H), 7.50-7.54 (m, 1H), 8.04 (d, J = 5.5 Hz, 1H), 8.60 (s, 1H) .

(Conditions for HPLC for optical purity measurement)



[0150] 

Column: CHIRALPAK IC 4.6 × 250 mm, 5 µm

Mobile phase: 0.1% HCOOH aq.: MeCN = 50:50

Flow rate: 1.0 min/min

Column temperature: 27°C

Detection wavelength: 220 nm

Injection quantity: 5 µL

Retention time: title compound = 6.7 min, enantiomer = 13.3 min


[Example 10]


(3'R,4'S,5'R)-N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide



[0151] 


[Step 1]


(4'S,5'R)-6''-Chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylic acid



[0152] To a solution of the compound (5.00 g, 9.61 mmol) obtained in Example 4 in methanol (25 mL) and tetrahydrofuran (25 mL), a 1 N aqueous sodium hydroxide solution (18.3 mL, 18.3 mmol) was added under ice cooling, and the mixture was stirred at 0°C for 41.5 hours. The reaction mixture was neutralized to pH 3 by the addition of concentrated hydrochloric acid under ice cooling. Water (75 mL) was added dropwise thereto, and the mixture was then stirred at room temperature for 4 hours. The deposited solid was filtered at 0°C and dried under reduced pressure at 40°C to obtain the title compound (4.52 g, yield: 96%) as a solid.

[Step 2]


(3'R,4'S,5'R)-N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide



[0153] To a solution of the compound (2.00 g, 4.06 mmol) obtained in the preceding step 1 in N,N-dimethylacetamide (20 mL), 1-hydroxybenzotriazole monohydrate (310 mg, 2.02 mmol), (2S,5R)-5-aminotetrahydro-2H-pyran-2-carboxamide (WO2012/121361) (707 mg, 4.90 mmol), diisopropylethylamine (850 µL, 4.88 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (934 mg, 4.87 mmol) were added, and the mixture was stirred at 0°C for 47.5 hours. To the reaction mixture, ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (20 mL each), and the organic layers were all combined and then washed with water three times (20 mL each). The solvent was distilled off under reduced pressure. To the residue, acetonitrile (30 mL) was then added, and the mixture was stirred at 60°C for 2 hours. The reaction mixture was allowed to cool, and the deposited solid was then filtered and dried under reduced pressure at 40°C to obtain the title compound (2.13 g, yield: 80%) as a solid.

[Example 11]


11-1) Influence of various asymmetric catalysts



[0154] 



[0155] To a solution of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), and triethylamine (15 mol%) in THF (10-fold amount), a catalyst solution separately prepared by stirring a Lewis acid (5 mol%), a chiral ligand (6 mol%), and THF (10-fold amount) for 1 hour under a nitrogen atmosphere was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 12 to 16 hours. Then, the optical purity and HPLC yield of the obtained trans-1 compound ((ethyl (3'S,4'R,5'S)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate) were measured by HPLC.

(Conditions for HPLC for optical purity measurement)



[0156] 

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 µm

Mobile phase: 10 mM phosphate buffer:MeCN = 40:60

Flow rate: 1.0 min/min

Column temperature: 40°C

Detection wavelength: 254 nm

Injection quantity: 5 µL

Retention time: title compound = 13.8 min, enantiomer = 12.9 min



[0157] Main results are shown in Table 1



[Table 1-2]
6

26.0 27.9 72.5
7

48.9 -- 86.9 (76.3)
8

32.9 -- 43.9

11-2) Influence of various solvents



[0158] 



[0159] To (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), triethylamine (15 mol%), and a solvent (10-fold amount), a catalyst solution separately prepared by stirring CuOAc (5 mol%), (S)-BINAP (6 mol%), and a solvent (10-fold amount) for 1 hour under a nitrogen atmosphere was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 21.5 hours. Then, the HPLC yield and optical purity of the obtained trans-2 compound (ethyl (3'S,4'R,5'S)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate) were measured by HPLC.

[0160] Main results are shown in Table 2.
[Table 2]
No.SolventHPLC yield (%)ee (%)trans/cis
1 THF 78.7 91.3 92/8
2 MeOH - 66.2 84/16
3 EtOH - 72.8 86/14
4 IPA - 83.8 85/15
5 toluene - 87.5 9/1
6 MeCN - 56.4 86/14
7 DMAc 85.2 97.1 94/6
8 DME 85.5 93.4 93/7
9 AcOEt - 88.7 92/8

11-3) Study on Cu(I) Lewis acid



[0161] 



[0162] To (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), triethylamine (15 mol%), and N,N-dimethylacetamide (10-fold amount), a catalyst solution separately prepared by stirring Cu(I) Lewis acid (5 mol%), (S)-BINAP (6 mol%), and N,N-dimethylacetamide (10-fold amount) for 1 hour under a nitrogen atmosphere was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 17 to 21.5 hours. Then, the HPLC yield and optical purity of the obtained trans-2 compound (ethyl (3'S,4'R,5'S)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate) were measured by HPLC.

[0163] Main results are shown in Table 3.
[Table 3]
No.Lewis AcidHPLC yield (%)ee (%)trans/cis
1 CuOAc 85.2 97.1 94/6
2 CuCl 38.2 52.8 87/13
3 CuBr 55.9 76.4 92/8
4 CuI 72.9 89 94/6
5 Cu2O 25.4 23.5 83/17
6 (CuOTf)2 toluene 84.1 95 93/7
7 Cu(CH3CN)4PF6 88.6 95.9 95/5
8 Cu(CH3CN) 4BF4 89.1 95.8 94/6

11-4) Study on Cu(II) Lewis acid



[0164] 



[0165] (3E/Z)-6-Chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), Cu(II) Lewis acid (5 mol%), (R)-BINAP (6 mol%), and N,N-dimethylacetamide (20-fold amount) were stirred at room temperature for 15 hours under a nitrogen atmosphere. Then, the UPLC yield and optical purity of the obtained trans-2 compound (ethyl (3'R,4'S,5'R)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate) were measured by UPLC and HPLC, respectively.

[0166] Main results are shown in Table 4.
[Table 4]
No.Lewis AcidHPLC yield(%)ee (%)trans/cis
1 Cu(OAc)2.H2O 79.4 97.1 95/5
2 Cu(OTf)2 58.5 88.5 92/8
3 CuSO4.5H2O 53.4 83.1 92/8
4 CuO 14.3 -13.3 49/51
5 CuCl2 17.8 -6.7 72/28
6 CuBr2 19.0 -3.3 74/26
7 CuCO3.Cu(OH)2.H2O 13.8 -15.8 74/26
*: Sign "-" in the column "ee" indicates that the trans-2 compound (ethyl (3'S,4'R,5'S)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate) was a main product.

11-5) Study using CuOAc and various chiral ligands



[0167] 



[0168] To a solution of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), and triethylamine (15 mol%) in THF (10-fold amount), a catalyst solution separately prepared by stirring CuOAc (5 mol%), a chiral ligand (6 mol%), and THF (10-fold amount) for 1 hour under a nitrogen atmosphere was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 12 to 16 hours. Then, the yield and optical purity of the obtained trans-1 compound (ethyl (3'S,4'R,5'S)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate) were measured by HPLC.

[0169] Main results are shown in Table 5.
[Table 5-1]
No.Ligandee%Yield%
1

88.0 76.8
2

88.8 76.3
3

76.2 -
4

72.6 -
5

89.0 74.2
[Table 5-2]
6

72.5 -
7

91.4 79.2
8

90.2 76.9
9

76.1 -
10

59.9 -
[Table 5-3]
11

51.4 -
12

91.9 78.0
13

-54.1 -
14

53.0 -
15

86.9 76.3
16

-85.9 71.0
17

-94.6 73.7
[Table 5-4]
18

-86.2 75.5
*: Sign "-" in the column "ee" indicates that the trans-2 compound (ethyl (3'S,4'R,5'S)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate) was a main product.

[Example 12]


tert-Butyl (3'R,4'S,5'R)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate



[0170] 



[0171] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/121361) (50.0 mg, 0.16 mmol), (R)-BINAP (6.0 mg, 0.009 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of 4,4-dimethylcyclohexanone (31.0 mg, 0.25 mmol), glycine tert-butyl ester (27.8 mg, 0.21 mmol), and triethylamine (3.4 µl, 0.024 mmol) in N,N-dimethylacetamide (1.0 ml) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 19.5 hours. To the reaction mixture, ethyl acetate (2.0 ml), water (0.5 ml), and a 20% aqueous ammonium chloride solution (0.5 ml) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (2.0 ml each), and the organic layers were all combined and then washed with water three times (2.0 ml each). The organic layer obtained was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 50:50:1 (v/v)] and dried under reduced pressure at 40°C to obtain a mixture of the title compound and a diastereomer (61.0 mg, yield: 69%, diastereomer ratio: 90 (title compound):10, optical purity of the title compound: 97% ee) as an oil compound.
1H NMR (500 MHz, CDCl3) : δ = 0.67 (s, 3H), 0.92 (s, 3H), 1.10-1.25 (m, 3H), 1.33 (s, 9H), 1.45-1.75 (m, 3H), 1.80-2.00 (m, 2H), 3.15-3.20 (m, 1H), 4.42 (d, J = 9.0 Hz, 1H), 4.68 (d, J = 9.5 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (dd, J = 8.5, 2.0 Hz, 1H), 7.53-7.63 (m, 2H), 8.06 (d, J = 5.0 Hz, 1H)

(Conditions for HPLC for optical purity measurement)



[0172] 

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 µm

Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN = 50:50

Flow rate: 1.0 ml/min

Column temperature: 40°C

Detection wavelength: 254 nm

Injection quantity: 5 µl

Retention time: title compound = 9.4 min, enantiomer = 11.4 min


[Reference Example 1]


(2S,5R)-5-[(2-Aminoacetyl)amino]tetrahydro-2H-pyran-2-carboxamide



[0173] 


[Step 1]


tert-Butyl N-(2-{[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]amino}-2-oxoethyl)carbamate



[0174] To a slurry of N-(tert-butoxycarbonyl)glycine (1.01 g, 5.77 mmol), (2S,5R)-5-aminotetrahydro-2H-pyran-2-carboxamide (WO2012/121361) (0.85 g, 5.90 mmol), and diisopropylethylamine (994 µl, 5.71 mmol) in tetrahydrofuran (40 ml), O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate (2.21 g, 5.83 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [ethyl acetate:methanol = 98:2 → 80:20 (v/v)]. To the solid obtained, ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 4 hours. The slurry obtained was filtered and dried under reduced pressure at 40°C to obtain the title compound (1.47 g, yield: 83%) as a white solid.
1H NMR (500 MHz, CDCl3): δ = 1.40-1.50 (m, 1H), 1.46 (s, 9H), 1.57-1.66 (m, 1H), 2.08-2.16 (m, 1H), 2.22-2.28 (m, 1H), 3.09 (t, J = 10.5 Hz, 1H), 3.70-3.82 (m, 3H), 3.90-4.02 (m, 1H), 4.16 (ddd, J = 10.9, 4.9, 1.9 Hz, 1H), 5.08-5.15 (m, 1H), 5.38-5.46 (m, 1H), 5.95-6.05 (m, 1H), 6.43-6.53 (m, 1H)

[Step 2]


(2S,5R)-5-[(2-Aminoacetyl)amino]tetrahydro-2H-pyran-2-carboxamide



[0175] To the compound (500 mg, 1.66 mmol) obtained in the preceding step 1, a solution of 4 N hydrogen chloride in cyclopentyl methyl ether (5 ml, 20 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered and washed with cyclopentyl methyl ether (5 ml). To a solution of the solid obtained in methanol (5 ml), a solution of 28% sodium methoxide in methanol (810 µl, 3.32 mmol) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture obtained, neutral silica gel (500 mg) was added, and the mixture was concentrated under reduced pressure. To the residue, ethyl acetate (50 ml) and methanol (5 ml) were added, and the silica gel was filtered off. The filtrate was concentrated under reduced pressure. To the residue, tetrahydrofuran (2.0 ml) was added, and the mixture was stirred at room temperature for 17 hours. The slurry obtained was filtered and dried under reduced pressure at 40°C to obtain the title compound (111 mg, yield: 33%) as a white solid.
1H NMR (500 MHz, CD3OD) : δ = 1.50-1.61 (m, 2H), 2.00-2.18 (m, 2H), 3.16 (t, J = 10.8 Hz, 1H), 3.21 (d, J = 16.5 Hz, 1H), 3.25 (d, J = 17.0 Hz, 1H), 3.72-3.78 (m, 1H), 3.80-3.90 (m, 1H), 4.07 (ddd, J = 10.9, 4.9, 1.9 Hz, 1H)

[Example 13]


(3'R,4'S,5'R)-N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide



[0176] 



[0177] To a mixture of the compound (39.1 mg, 0.19 mmol) obtained in Reference Example 1, (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) (48.6 mg, 0.16 mmol), (R)-BINAP (6.6 mg, 0.011 mmol), and CuOAc (1.2 mg, 0.010 mmol), a solution of 4,4-dimethylcyclohexanone (30.6 mg, 0.24 mmol) in N,N-dimethylacetamide (1.0 ml) was added under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 17 hours. The whole amount of the reaction mixture was diluted with methanol (100 ml) to obtain the title compound (ultrahigh-performance liquid chromatography (UHPLC) yield: 65%, 96% de) as a solution in methanol.

(Conditions for UHPLC measurement for UHPLC yield calculation)



[0178] 

Column: CAPCELL CORE ADME 2.1 × 100 mm, 2.7 µm

Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN

Gradient: MeCN 20% → 92%

Gradient conditions: 0-2.5 min MeCN 20%, 2.5-7.3 min MeCN 20 → 92%, 7.3-14 min MeCN 92%, 14.01-17 min MeCN 20% Flow rate: 0.6 ml/min

Column temperature: 40°C

Detection wavelength: 254 nm

Injection quantity: 5 µl

Retention time: title compound = 6.6 min


(Conditions for HPLC for de measurement)



[0179] 

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 µm

Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN = 60:40

Flow rate: 1.0 ml/min

Column temperature: 40°C

Detection wavelength: 254 nm

Injection quantity: 10 µl

Retention time: title compound =17.7 min, diastereomer = 8.5 min


[Example 14]


(3'R,4'S,5'R)-6"-Chloro-4'-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycyclohexyl)-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide



[0180] 


[Step 1]


(4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycyclohexyl)-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5"-carboxylic acid



[0181] To a slurry of the compound (1.00 g, 2.04 mmol) obtained in Example 1 and methanol (10 ml), a 25% (w/v) aqueous sodium hydroxide solution (1.0 ml, 6.25 mmol) was added under ice cooling, and the mixture was stirred at 0°C for 27.5 hours. The reaction mixture was neutralized by the addition of 35% (w/w) concentrated hydrochloric acid (651 mg, 6.25 mmol) under ice cooling. Water (15 ml) was added dropwise thereto, and the mixture was then stirred at 0°C for 18 hours. The deposited crystals were filtered at 0°C and dried under reduced pressure at 40°C to obtain the title compound (0.90 g, yield: 95%, >99.5% ee) as a pale yellow solid.
1H NMR (500 MHz, CD3OD) : δ = 1.10-1.30 (m, 2H), 1.50-1.68 (m, 1H), 1.70-2.13 (m, 5H), 2.18-2.28 (m, 1H), 2.50-2.62 (m, 1H), 4.81 (d, J = 10.0 Hz, 1H), 5.01 (d, J = 10.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 7.07-7.15 (m, 2H), 7.28-7.35 (m, 1H), 7.54 (dd, J = 8.0, 2.5 Hz, 1H), 7.60-7.68

(m, 1H)


(Conditions for HPLC for optical purity measurement)



[0182] 

Column: CHIRALPAK QN-AX 4.6 × 150 mm, 3 µm

Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN = 60:40

Flow rate: 1.0 ml/min

Column temperature: 40°C

Detection wavelength: 254 nm

Injection quantity: 5 µl

Retention time: title compound = 7.5 min, enantiomer = 4.0 min


[Step 2]


(3'R,4'S,5'R)-6"-Chloro-4'-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycyclohexyl)-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide



[0183] To a solution of the compound (501 mg, 1.08 mmol, 99% ee) obtained in the preceding step 1 and trans-4-aminocyclohexanol (157 mg, 1.36 mmol) in N,N-dimethylacetamide (5 ml), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (392 mg, 1.42 mmol) was added under ice cooling, and the mixture was stirred at 0°C for 1 hour. To the reaction mixture, ethyl acetate (10 ml) and water (5 ml) were added, and the mixture was stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate (10 ml), and the organic layers were all combined and then washed with water three times (10 ml each). The solvent was distilled off under reduced pressure. To the residue, acetonitrile (15 ml) was then added, and the mixture was stirred at room temperature for 18 hours. The deposited crystals were filtered and dried under reduced pressure at 40°C to obtain the title compound (426 g, yield: 70%, >99.5% ee) as a white solid.
1H NMR (500 MHz, CD3OD) : δ = 0.93 (td, J = 13.5, 4.2 Hz, 1H), 1.0-1.15 (m, 1H), 1.25-1.45 (m, 4H), 1.5-2.05 (m, 12H), 3.5-3.65 (m, 2H), 4.49 (d, J = 9.5 Hz, 1H), 4.65 (d, J = 9.0 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 7.02 (td, J = 8.5, 2.0 Hz, 1H), 7.20 (td, J = 15.0, 1.5 Hz, 1H), 7.39 (dd, J = 8.5, 2.5 Hz, 1H), 7.61 (td, J = 14.8, 1.3 Hz, 1H)

(Conditions for HPLC for optical purity measurement)



[0184] 

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 µm

Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN = 60:40

Flow rate: 1.0 ml/min

Column temperature: 40°C

Detection wavelength: 254 nm

Injection quantity: 5 µl

Retention time: title compound = 4.9 min, enantiomer = 4.2 min




Claims

1. A method for reacting a compound represented by formula (I):

a compound represented by formula (II):

and a compound represented by formula (III):

in a solvent using an asymmetric catalyst to stereoselectively produce a compound represented by formula (IV) or a salt thereof:

wherein

R1 represents a hydrogen atom, a C1-C6 alkylcarbonyl group optionally having 1 to 3 substituents independently selected from group A below, or a C1-C6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group A below,

R2 represents a 5- or 6-membered heteroaryl group having, in the ring, 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, a phenyl group, a C3-C6 cycloalkyl group, or a C3-C6 cycloalkenyl group, wherein
the 5- or 6-membered heteroaryl group, the phenyl group, the C3-C6 cycloalkyl group, and the C3-C6 cycloalkenyl group each optionally have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a vinyl group, an ethynyl group, a cyano group, a hydroxy group, an amino group, a carboxy group, an aminocarbonyl group, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group A below, a C3-C4 cycloalkyl group optionally having 1 to 3 substituents independently selected from group A below, a C1-C6 alkoxy group optionally having 1 to 3 substituents independently selected from group A below, a C3-C4 cycloalkoxy group optionally having 1 to 3 substituents independently selected from group A below, a C1-C6 alkylamino group optionally having 1 to 3 substituents independently selected from group A below, a di-C1-C6 alkylamino group optionally having 1 to 3 substituents independently selected from group A below, a 4- to 7-membered saturated heterocyclic group containing one nitrogen atom in the ring and optionally having 1 to 3 substituents independently selected from group B below, a C1-C6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group A below, a C3-C4 cycloalkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group A below, a C1-C6 alkylaminocarbonyl group optionally having 1 to 3 substituents independently selected from group A below, and a C3-C4 cycloalkylaminocarbonyl group optionally having 1 to 3 substituents independently selected from group A below,

R3 and R4 each independently represent a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group C below, or

R3 and R4 optionally together form a C4-C6 cycloalkyl ring, a tetrahydrofuran ring, a tetrahydropyran ring, or a piperidine ring, wherein
the C4-C6 cycloalkyl ring, the tetrahydrofuran ring, the tetrahydropyran ring, and the piperidine ring each optionally have 1 to 8 substituents independently selected from group D below,

R5 represents a C1-C6 alkoxy group optionally having 1 to 3 substituents independently selected from group E below, a C3-C8 cycloalkoxy group optionally having 1 to 3 substituents independently selected from group E below, a C2-C6 alkenyloxy group, or -NR51R52,

R51 and R52 each independently represent a hydrogen atom, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group E below, a C3-C8 cycloalkyl group optionally having 1 to 3 substituents independently selected from group E below, or a 3- to 6-membered saturated heterocyclic group having, in the ring, one heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally having 1 to 3 substituents independently selected from group E below, and

ring Z represents a benzene ring optionally having 1 to 4 substituents independently selected from group E below, a pyridine ring optionally having 1 to 3 substituents independently selected from group E below, or a pyrimidine ring optionally having 1 or 2 substituents independently selected from group E below:

group A: a halogen atom, a hydroxy group, a C1-C6 alkyl group, an amino group, and a phenyl group,

group B: a C1-C6 alkyl group and a hydroxy group

group C: a halogen atom, a hydroxy group, a phenyl group, a pyridyl group, and an amino group

group D: a halogen atom and a C1-C6 alkyl group optionally having 1 to 3 halogen atoms, and

group E: a halogen atom, a hydroxy group, a vinyl group, an ethynyl group, a cyano group, a C1-C6 alkoxy group, an aminocarbonyl group, and a C1-C6 alkyl group optionally having 1 to 3 halogen atoms.


 
2. A method for reacting a compound represented by formula (I):

and a compound represented by formula (V):

in a solvent using an asymmetric catalyst to stereoselectively produce a compound represented by formula (IV) or a salt thereof:

wherein R1, R2, R3, R4, R5, and Z are as defined in claim 1.
 
3. A method according to claim 1 or 2, wherein the asymmetric catalyst is a catalyst prepared from a Lewis acid and a chiral ligand, wherein
the Lewis acid is a Lewis acid selected from the group consisting of a Zn(II) Lewis acid, a Ag(I) Lewis acid, a Ni(II) Lewis acid, a Co(II) Lewis acid, a Ru(I) Lewis acid, a Cu(I) Lewis acid, and a Cu(II) Lewis acid, and the chiral ligand is a chiral ligand selected from the group consisting of a compound represented by the following formula (VI):

a compound represented by the following formula (VII):

a compound represented by the following formula (VIII):

a compound represented by the following formula (IX):

a compound represented by the following formula (X):

a compound represented by the following formula (XI):

and a compound represented by the following formula (XII) :

wherein

R6 represents a phenyl group optionally having 1 to 3 substituents independently selected from group F below, ring Y represents a benzene ring, a cyclohexane ring, or a dioxolane ring optionally having 1 to 4 halogen atoms,

R7 represents a phenyl group optionally having 1 to 3 substituents independently selected from group G below, or a furanyl group optionally having 1 to 3 substituents independently selected from group G below,

R8 represents a hydrogen atom or a C1-C6 alkoxy group,

R9 represents a C1-C6 alkoxy group, or

two R9 moieties optionally together form a 7- to 12-membered heterocyclic ring containing two oxygen atoms in the ring,

X represents CH, CR10, or a nitrogen atom, wherein
R10 represents a C1-C6 alkoxy group,

V represents a phenyl group having one P(R11)2, PH(O)R12, or P(R11)2, wherein

R11 represents a C1-C6 alkyl group, a cyclohexyl group, or a phenyl group optionally having two trifluoromethyl groups, and

R12 represents a C1-C6 alkyl group or a phenyl group, W represents a C1-C6 alkylthio group, a dihydrooxazolyl group optionally having one C1-C6 alkyl group, CH(CH3)P(R13)2, or CHR14R15, wherein

R13 represents a cyclohexyl group, a C1-C6 alkyl group, or a phenyl group optionally having 1 or 2 substituents independently selected from group H below,

R14 represents a phenyl group optionally substituted by one P(R16)2,

R15 represents a C1-C6 alkyl group or a di-C1-C6 alkylamino group, and

R16 represents a phenyl group or a cyclohexyl group, U represents any one of the following Ua to Ud:



R17 represents a phenyl group optionally having 1 to 3 substituents independently selected from group F below,

R18 represents a C1-C6 alkyl group or a phenyl group,

R19 represents a hydrogen atom or a C1-C6 alkyl group, and

R20 and R21 each independently represent a C1-C6 alkyl group:

group F: a C1-C6 alkyl group and a C1-C6 alkoxy group,

group G: a C1-C6 alkyl group, a C1-C6 alkoxy group, and a di-C1-C6 alkylamino group, and

group H: a C1-C6 alkyl group and a C1-C6 alkyl group optionally having three halogen atoms.


 
4. A method according to claim 3, wherein the Lewis acid used in the preparation of the asymmetric catalyst is a Cu(I) Lewis acid or a Cu(II) Lewis acid.
 
5. A method according to claim 3 or claim 4, wherein the Lewis acid used in the preparation of the asymmetric catalyst is a Lewis acid selected from the group consisting of CuOAc, CuCl, CuBr, CuI, CuOTf, CuPF6, CuBF4, Cu(OAc)2, Cu(OTf)2, and CuSO4.
 
6. A method according to any one of claims 3 to 5, wherein the chiral ligand used in the preparation of the asymmetric catalyst is a chiral ligand selected from the group consisting of a compound represented by formula (VI), a compound represented by formula (VII), a compound represented by formula (VIII), a compound represented by formula (IX), a compound represented by formula (X), a compound represented by formula (XI), and a compound represented by formula (XII), in which the compounds of formulae (VI) to (XII) are as defined in claim 3,
wherein
R6 represents a phenyl group optionally having 1 to 3 substituents independently selected from the group consisting of a methyl group, a t-butyl group, and a methoxy group,
ring Y represents a benzene ring, a cyclohexane ring, or a dioxolane ring,
R7 represents a phenyl group or a furanyl group, wherein
the phenyl group and the furanyl group each optionally have 1 to 3 substituents independently selected from the group consisting of a methyl group, a t-butyl group, and a methoxy group,
R8 represents a hydrogen atom or a methoxy group,
R9 represents a methoxy group, or,
two R9 moieties optionally together form a 9-membered heterocyclic ring containing two oxygen atoms in the ring, X represents CH, CR10, or a nitrogen atom,
R10 represents a methoxy group,
V represents P(R11)2, wherein
R11 represents a phenyl group optionally having two trifluoromethyl groups,
W represents a t-butylthio group, a dihydrooxazolyl group optionally substituted by one isopropyl group, or CH(CH3)P(R13)2, wherein
R13 represents a phenyl group optionally having 1 or 2 methyl groups,
U represents Ua or Ud as defined in claim 3,
R17 represents a phenyl group,
R18 represents an isopropyl group, a t-butyl group, or a phenyl group,
R19 represents a hydrogen atom, and
R20 and R21 each independently represent a methyl group or a t-butyl group.
 
7. A method according to any one of claims 3 to 6, wherein the chiral ligand used in the preparation of the asymmetric catalyst is a chiral ligand selected from the following group:









where Cy represents a cyclohexyl group.
 
8. A method according to any one of claims 1 to 7, wherein the solvent used in the reaction is one or more solvents selected from the group consisting of N,N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, 2-propanol, toluene, and ethyl acetate.
 
9. A method according to any one of claims 1 to 8, wherein the compound produced or salt thereof has the following configuration:

wherein R1, R2, R3, R4, R5, and Z are as defined in claim 1.
 
10. A method according to any one of claims 1 to 9, wherein R1 is a hydrogen atom.
 
11. A method according to any one of claims 1 to 10, wherein in formula (I),
ring Z is a benzene ring optionally having 1 to 4 halogen atoms.
 
12. A method according to any one of claims 1 to 11, wherein in formula (I) or formula (IV),
R2 is a pyridyl group optionally having 1 to 3 halogen atoms, or a phenyl group optionally having 1 to 3 halogen atoms.
 
13. A method according to any one of claims 1 to 12, wherein in formula (II) or formula (V),
R3 and R4 each represent a methyl group, or R3 and R4 together form a cyclopentane ring, a cyclohexane ring, or a tetrahydropyran ring, wherein
the cyclopentane ring, the cyclohexane ring, and the tetrahydropyran ring each optionally have 1 to 4 C1-C6 alkyl groups on the ring.
 
14. A method according to any one of claims 1 to 13, wherein in formula (III) or formula (V),
R5 is a substituent represented by the following:


 
15. A method according to any one of claims 1 to 13, wherein in formula (III) or formula (V),
R5 is a C1-C6 alkoxy group.
 
16. A method according to claim 15 which includes the further steps of hydrolyzing the compound of formula (IV) thus produced or a salt thereof to produce a compound represented by the following formula (XIV) or a salt thereof:

and condensing the compound or the salt with a compound represented by NHR22R23 to produce a compound represented by the following formula (XV) or a salt thereof:

wherein
R1, R2, R3, R4, and Z are as defined in any one of claims 1 to 13, and
R22 and R23 each independently represent a hydrogen atom, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group I below, a C1-C6 alkylsulfonyl group optionally having 1 to 3 substituents independently selected from group I below, a C3-C6 cycloalkyl group optionally having 1 to 3 substituents independently selected from group I below, a 3- to 6-membered saturated heterocyclic group having, in the ring, one heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally having 1 to 3 substituents independently selected from group I below, a phenyl group optionally having 1 to 3 substituents independently selected from group I below, or a 5- or 6-membered heteroaryl group having, in the ring, 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally having 1 to 3 substituents independently selected from group I below, or
R22 and R23 optionally together form a piperazine ring optionally having 1 to 3 substituents independently selected from group I below:

group I: a halogen atom, a hydroxy group, an oxo group, a carboxy group, a formyl group, an amino group, an aminocarbonyl group, a cyano group, a C1-C6 alkylamino group, a C1-C6 alkylsulfonyl group, a C1-C6 alkylsulfonylamide group, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group J below, a C1-C6 alkoxy group optionally having 1 to 3 substituents independently selected from group J below, a C1-C6 alkylcarbonyl group optionally having 1 to 3 substituents independently selected from group J below, a C3-C6 cycloalkylcarbonyl group optionally having 1 to 3 substituents independently selected from group J below, a C4-C6 cycloalkyl group optionally having 1 to 3 substituents independently selected from group J below, a C1-C6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group J below, a piperidinyl group optionally having 1 to 3 substituents independently selected from group J below, a pyrrolidinyl group optionally having 1 to 3 substituents independently selected from group J below, a piperazinyl group optionally having 1 to 3 substituents independently selected from group J below, a phenyl group optionally having 1 to 3 substituents independently selected from group J below, a tetrazolyl group, an azetidinyl group optionally having 1 to 3 substituents independently selected from group J below, a morpholino group optionally having 1 to 3 substituents independently selected from group J below, a dihydropyrazolyl group optionally having 1 to 3 substituents independently selected from group J below, and an oxadiazolyl group, and

group J: a halogen atom, a hydroxy group, an amino group, a carboxy group, an aminocarbonyl group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkylamino group, a di-C1-C6 alkylamino group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkyl group, a C1-C6 alkylsulfonyl group, and a C1-C6 alkylsulfonylamide group.


 
17. A method according to claim 16, wherein
R22 represents a hydrogen atom, and
R23 is a substituent represented by the following:


 
18. A method for reacting a compound represented by formula (XVI):

a compound represented by formula (XVII):

and a compound represented by formula (XVIII):

in a solvent using an asymmetric catalyst prepared from a Lewis acid selected from the group consisting of a Cu(I) Lewis acid and a Cu(II) Lewis acid and a chiral ligand selected from the following group:









where Cy represents a cyclohexyl group,
to stereoselectively produce a compound represented by formula (XIX) or a salt thereof:

wherein

M represents a nitrogen atom or CH,

L represents a single bond, an oxygen atom, CH2, or C(CH3)2, and

R53 represents a C1-C6 alkyl group.


 
19. A method for reacting a compound represented by formula (XVI):

and a compound represented by formula (XX):

in a solvent using an asymmetric catalyst prepared from a Lewis acid selected from the group consisting of a Cu(I) Lewis acid and a Cu(II) Lewis acid and a chiral ligand selected from the following group:









where Cy represents a cyclohexyl group,
to stereoselectively produce a compound represented by formula (XIX) or a salt thereof:

wherein
M, L, and R53 are as defined in claim 18.
 
20. A method according to claim 18 or 19 which includes the further steps of hydrolyzing the compound of formula (XIX) thus produced or a salt thereof to produce a compound represented by the following formula (XXI) or a salt thereof:

and condensing the compound or the salt with a compound represented by the following formula:

to produce a compound represented by the following formula (XXII) or a salt thereof:

wherein
M and L are as defined in claim 18 or 19.
 


Ansprüche

1. Verfahren zur Umsetzung einer Verbindung, dargestellt durch Formel (I):

einer Verbindung, dargestellt durch Formel (II):

und einer Verbindung, dargestellt durch Formel (III):

in einem Lösungsmittel unter Verwendung eines asymmetrischen Katalysators zwecks stereoselektiver Produktion einer Verbindung, dargestellt durch Formel (IV), oder eines Salzes davon:

wobei

R1 steht für ein Wasserstoffatom, eine C1-C6-Alkylcarbonylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A, oder eine C1-C6-Alkoxycarbonylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A,

R2 steht für eine 5- oder 6-gliedrige Heteroarylgruppe mit, im Ring, 1 bis 3 Heteroatomen, unabhängig ausgewählt aus der Gruppe, bestehend aus einem Stickstoffatom, einem Sauerstoffatom und einem Schwefelatom, eine Phenylgruppe, eine C3-C6-Cycloalkylgruppe oder eine C3-C6-Cycloalkenylgruppe, wobei

die 5- oder 6-gliedrige Heteroarylgruppe, die Phenylgruppe, die C3-C6-Cycloalkylgruppe und die C3-C6-Cycloalkenylgruppe jeweils gegebenenfalls 1 bis 3 Substituenten aufweisen, unabhängig ausgewählt aus der Gruppe, bestehend aus einem Halogenatom, einer Vinylgruppe, einer Ethinylgruppe, einer Cyanogruppe, einer Hydroxygruppe, einer Aminogruppe, einer Carboxygruppe, einer Aminocarbonylgruppe, einer C1-C6-Alkylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A, einer C3-C4-Cycloalkylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A, einer C1-C6-Alkoxygruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A, einer C3-C4-Cycloalkoxygruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A, einer C1-C6-Alkylaminogruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A, einer Di-C1-C6-alkylaminogruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A, einer 4- bis 7-gliedrigen gesättigten heterocyclischen Gruppe, enthaltend ein Stickstoffatom im Ring und gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe B, einer C1-C6-Alkoxycarbonylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A, einer C3-C4-Cycloalkoxycarbonylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A, einer C1-C6-Alkylaminocarbonylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A, und einer C3-C4-Cycloalkylaminocarbonylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe A,

R3 und R4 jeweils unabhängig stehen für eine C1-C6-Alkylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe C, oder

R3 und R4 gegebenenfalls zusammen einen C4-C6-Cycloalkylring, einen Tetrahydrofuranring, einen Tetrahydropyranring oder einen Piperidinring bilden, wobei

der C4-C6-Cycloalkylring, der Tetrahydrofuranring, der Tetrahydropyranring und der Piperidinring jeweils gegebenenfalls 1 bis 8 Substituenten aufweisen, unabhängig ausgewählt aus nachstehender Gruppe D,

R5 steht für eine C1-C6-Alkoxygruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe E, eine C3-C8-Cycloalkoxygruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe E, eine C2-C6-Alkenyloxygruppe oder -NR51R52,

R51 und R52 jeweils unabhängig stehen für ein Wasserstoffatom, eine C1-C6-Alkylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe E, eine C3-C8-Cycloalkylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe E, oder eine 3- bis 6-gliedrige gesättigte heterocyclische Gruppe mit, im Ring, einem Heteroatom, unabhängig ausgewählt aus der Gruppe, bestehend aus einem Stickstoffatom, einem Sauerstoffatom und einem Schwefelatom, und gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe E, und

Ring Z steht für einen Benzolring, gegebenenfalls mit 1 bis 4 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe E, einen Pyridinring, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe E, oder einen Pyrimidinring, gegebenenfalls mit 1 oder 2 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe E:

Gruppe A: ein Halogenatom, eine Hydroxygruppe, eine C1-C6-Alkylgruppe, eine Aminogruppe und eine Phenylgruppe,

Gruppe B: eine C1-C6-Alkylgruppe und eine Hydroxygruppe,

Gruppe C: ein Halogenatom, eine Hydroxygruppe, eine Phenylgruppe, eine Pyridylgruppe und eine Aminogruppe,

Gruppe D: ein Halogenatom und eine C1-C6-Alkylgruppe, gegebenenfalls mit 1 bis 3 Halogenatomen, und

Gruppe E: ein Halogenatom, eine Hydroxygruppe, eine Vinylgruppe, eine Ethinylgruppe, eine Cyanogruppe, eine C1-C6-Alkoxygruppe, eine Aminocarbonylgruppe und eine C1-C6-Alkylgruppe, gegebenenfalls mit 1 bis 3 Halogenatomen.


 
2. Verfahren zur Umsetzung einer Verbindung, dargestellt durch Formel (I):

und einer Verbindung, dargestellt durch Formel (V):

in einem Lösungsmittel unter Verwendung eines asymmetrischen Katalysators zwecks stereoselektiver Produktion einer Verbindung, dargestellt durch Formel (IV), oder eines Salzes davon:

wobei R1, R2, R3, R4, R5 und Z wie in Anspruch 1 definiert sind.
 
3. Verfahren nach Anspruch 1 oder 2, wobei der asymmetrische Katalysator ein aus einer Lewis-Säure und einem chiralen Liganden hergestellter Katalysator ist, wobei
die Lewis-Säure eine Lewis-Säure ist, ausgewählt aus der Gruppe, bestehend aus einer Zn(II)-Lewis-Säure, einer Ag(I)-Lewis-Säure, einer Ni(II)-Lewis-Säure, einer Co(II)-Lewis-Säure, einer Ru(I)-Lewis-Säure, einer Cu(I)-Lewis-Säure und einer Cu(II)-Lewis-Säure, und der chirale Ligand ein chiraler Ligand ist, ausgewählt aus der Gruppe, bestehend aus einer Verbindung, dargestellt durch die folgende Formel (VI):

einer Verbindung, dargestellt durch die folgende Formel (VII):

einer Verbindung, dargestellt durch die folgende Formel (VIII):

einer Verbindung, dargestellt durch die folgende Formel (IX):

einer Verbindung, dargestellt durch die folgende Formel (X):

einer Verbindung, dargestellt durch die folgende Formel (XI):

und einer Verbindung, dargestellt durch die folgende Formel (XII):

wobei

R6 steht für eine Phenylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe F,

Ring Y steht für einen Benzolring, einen Cyclohexanring oder einen Dioxolanring, gegebenenfalls mit 1 bis 4 Halogenatomen,

R7 steht für eine Phenylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe G, oder eine Furanylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe G,

R8 steht für ein Wasserstoffatom oder eine C1-C6-Alkoxygruppe,

R9 steht für eine C1-C6-Alkoxygruppe, oder

zwei R9-Teile gegebenenfalls zusammen einen 7- bis 12-gliedrigen heterocyclischen Ring bilden, der zwei Sauerstoffatome im Ring enthält,

X steht für CH, CR10 oder ein Stickstoffatom, wobei

R10 steht für eine C1-C6-Alkoxygruppe,

V steht für eine Phenylgruppe mit einem P(R11)2, PH(O)R12 oder P(R11)2, wobei

R11 steht für eine C1-C6-Alkylgruppe, eine Cyclohexylgruppe oder eine Phenylgruppe, gegebenenfalls mit zwei Trifluormethylgruppen, und

R12 steht für eine C1-C6-Alkylgruppe oder eine Phenylgruppe,

W steht für eine C1-C6-Alkylthiogruppe, eine Dihydrooxazolylgruppe, gegebenenfalls mit einer C1-C6-Alkylgruppe, CH(CH3)P(R13)2 oder CHR14R15, wobei

R13 steht für eine Cyclohexylgruppe, eine C1-C6-Alkylgruppe oder eine Phenylgruppe, gegebenenfalls mit 1 oder 2 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe H,

R14 steht für eine Phenylgruppe, gegebenenfalls substituiert durch ein P(R16)2,

R15 steht für eine C1-C6-Alkylgruppe oder eine Di-C1-C6-alkylaminogruppe, und

R16 steht für eine Phenylgruppe oder eine Cyclohexylgruppe,

U steht für eines der folgenden Ua bis Ud:



R17 steht für eine Phenylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe F,

R18 steht für eine C1-C6-Alkylgruppe oder eine Phenylgruppe,

R19 steht für ein Wasserstoffatom oder eine C1-C6-Alkylgruppe, und

R20 und R21 jeweils unabhängig stehen für eine C1-C6-Alkylgruppe:

Gruppe F: eine C1-C6-Alkylgruppe und eine C1-C6-Alkoxygruppe,

Gruppe G: eine C1-C6-Alkylgruppe, eine C1-C6-Alkoxygruppe und eine Di-C1-C6-alkylaminogruppe, und

Gruppe H: eine C1-C6-Alkylgruppe und eine C1-C6-Alkylgruppe, gegebenenfalls mit drei Halogenatomen.


 
4. Verfahren nach Anspruch 3, wobei die in der Herstellung des asymmetrischen Katalysators verwendete Lewis-Säure eine Cu(I)-Lewis-Säure oder eine Cu(II)-Lewis-Säure ist.
 
5. Verfahren nach Anspruch 3 oder Anspruch 4, wobei die in der Herstellung des asymmetrischen Katalysators verwendete Lewis-Säure eine Lewis-Säure ist, ausgewählt aus der Gruppe, bestehend aus CuOAc, CuCl, CuBr, CuI, CuOTf, CuPF6, CuBF4, Cu(OAc)2, Cu(OTf)2 und CuSO4.
 
6. Verfahren nach einem der Ansprüche 3 bis 5, wobei der in der Herstellung des asymmetrischen Katalysators verwendete chirale Ligand ein chiraler Ligand ist, ausgewählt aus der Gruppe, bestehend aus einer durch Formel (VI) dargestellten Verbindung, einer durch Formel (VII) dargestellten Verbindung, einer durch Formel (VIII) dargestellten Verbindung, einer durch Formel (IX) dargestellten Verbindung, einer durch Formel (X) dargestellten Verbindung, einer durch Formel (XI) dargestellten Verbindung und einer durch Formel (XII) dargestellten Verbindung, wobei die Verbindungen der Formeln (VI) bis (XII) wie in Anspruch 3 definiert sind,
wobei
R6 steht für eine Phenylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus der Gruppe, bestehend aus einer Methylgruppe, einer t-Butylgruppe und einer Methoxygruppe,
Ring Y steht für einen Benzolring, einen Cyclohexanring oder einen Dioxolanring,
R7 steht für eine Phenylgruppe oder eine Furanylgruppe, wobei
die Phenylgruppe und die Furanylgruppe jeweils gegebenenfalls 1 bis 3 Substituenten aufweisen, unabhängig ausgewählt aus der Gruppe, bestehend aus einer Methylgruppe, einer t-Butylgruppe und einer Methoxygruppe,
R8 steht für ein Wasserstoffatom oder eine Methoxygruppe,
R9 steht für eine Methoxygruppe, oder
zwei R9-Teile gegebenenfalls zusammen einen 9-gliedrigen heterocyclischen Ring bilden, der zwei Sauerstoffatome im Ring enthält,
X steht für CH, CR10 oder ein Stickstoffatom,
R10 steht für eine Methoxygruppe,
V steht für P(R11)2, wobei
R11 steht für eine Phenylgruppe, gegebenenfalls mit zwei Trifluormethylgruppen,
W steht für eine t-Butylthiogruppe, eine Dihydrooxazolylgruppe, gegebenenfalls substituiert durch eine Isopropylgruppe, oder CH(CH3)P(R13)2, wobei
R13 steht für eine Phenylgruppe, gegebenenfalls mit 1 oder 2 Methylgruppen,
U steht für Ua oder Ud gemäß Definition in Anspruch 3,
R17 steht für eine Phenylgruppe,
R18 steht für eine Isopropylgruppe, eine t-Butylgruppe oder eine Phenylgruppe, R19 steht für ein Wasserstoffatom, und
R20 und R21 jeweils unabhängig stehen für eine Methylgruppe oder eine t-Butylgruppe.
 
7. Verfahren nach einem der Ansprüche 3 bis 6, wobei der in der Herstellung des asymmetrischen Katalysators verwendete chirale Ligand ein chiraler Ligand ist, der aus der folgenden Gruppe ausgewählt ist:









worin Cy steht für eine Cyclohexylgruppe.
 
8. Verfahren nach einem der Ansprüche 1 bis 7, wobei das in der Umsetzung verwendete Lösungsmittel ein oder mehrere Lösungsmittel sind, ausgewählt aus der Gruppe, bestehend aus N,N-Dimethylacetamid, Tetrahydrofuran, Dimethoxyethan, 2-Propanol, Toluol und Ethylacetat.
 
9. Verfahren nach einem der Ansprüche 1 bis 8, wobei die produzierte Verbindung oder ein Salz davon die folgende Konfiguration aufweist:

wobei R1, R2, R3, R4, R5 und Z wie in Anspruch 1 definiert sind.
 
10. Verfahren nach einem der Ansprüche 1 bis 9, wobei R1 ein Wasserstoffatom ist.
 
11. Verfahren nach einem der Ansprüche 1 bis 10, wobei, in Formel (I),
Ring Z ein Benzolring ist, gegebenenfalls mit 1 bis 4 Halogenatomen.
 
12. Verfahren nach einem der Ansprüche 1 bis 11, wobei, in Formel (I) oder Formel (IV),
R2 eine Pyridylgruppe, gegebenenfalls mit 1 bis 3 Halogenatomen, oder eine Phenylgruppe, gegebenenfalls mit 1 bis 3 Halogenatomen, ist.
 
13. Verfahren nach einem der Ansprüche 1 bis 12, wobei, in Formel (II) oder Formel (V),
R3 und R4 jeweils stehen für eine Methylgruppe, oder R3 und R4 zusammen einen Cyclopentanring, einen Cyclohexanring oder einen Tetrahydropyranring bilden, wobei
der Cyclopentanring, der Cyclohexanring und der Tetrahydropyranring jeweils gegebenenfalls 1 bis 4 C1-C6-Alkylgruppen am Ring aufweisen.
 
14. Verfahren nach einem der Ansprüche 1 bis 13, wobei, in Formel (III) oder Formel (V),
R5 ein Substituent ist, dargestellt durch das Folgende:


 
15. Verfahren nach einem der Ansprüche 1 bis 13, wobei, in Formel (III) oder Formel (V),
R5 eine C1-C6-Alkoxygruppe ist.
 
16. Verfahren nach Anspruch 15, einschließend die weiteren Schritte des Hydrolysierens der so produzierten Verbindung der Formel (IV) oder eines Salzes davon zwecks Produktion einer durch die folgende Formel (XIV) dargestellten Verbindung oder eines Salzes davon:

und des Kondensierens der Verbindung oder des Salzes mit einer durch NHR22R23 dargestellten Verbindung zwecks Produktion einer durch die folgende Formel (XV) dargestellten Verbindung oder eines Salzes davon:

wobei

R1, R2, R3, R4 und Z wie in einem der Ansprüche 1 bis 13 definiert sind, und

R22 und R23 jeweils unabhängig stehen für ein Wasserstoffatom, eine C1-C6-Alkylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe I, eine C1-C6-Alkylsulfonylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe I, eine C3-C6-Cycloalkylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe I, eine 3- bis 6-gliedrige gesättigte heterocyclische Gruppe mit, im Ring, einem Heteroatom, unabhängig ausgewählt aus der Gruppe, bestehend aus einem Stickstoffatom, einem Sauerstoffatom und einem Schwefelatom, und gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe I, eine Phenylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe I, oder eine 5- oder 6-gliedrige Heteroarylgruppe mit, im Ring, 1 bis 3 Heteroatomen, unabhängig ausgewählt aus der Gruppe, bestehend aus einem Stickstoffatom, einem Sauerstoffatom und einem Schwefelatom, und gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe I, oder

R22 und R23 gegebenenfalls zusammen einen Piperazinring bilden, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe I:

Gruppe I: ein Halogenatom, eine Hydroxygruppe, eine Oxogruppe, eine Carboxygruppe, eine Formylgruppe, eine Aminogruppe, eine Aminocarbonylgruppe, eine Cyanogruppe, eine C1-C6-Alkylaminogruppe, eine C1-C6-Alkylsulfonylgruppe, eine C1-C6-Alkylsulfonylamidgruppe, eine C1-C6-Alkylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine C1-C6-Alkoxygruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine C1-C6-Alkylcarbonylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine C3-C6-Cycloalkylcarbonylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine C4-C6-Cycloalkylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine C1-C6-Alkoxycarbonylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine Piperidinylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine Pyrrolidinylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine Piperazinylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine Phenylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine Tetrazolylgruppe, eine Azetidinylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine Morpholinogruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, eine Dihydropyrazolylgruppe, gegebenenfalls mit 1 bis 3 Substituenten, unabhängig ausgewählt aus nachstehender Gruppe J, und eine Oxadiazolylgruppe, und

Gruppe J: ein Halogenatom, eine Hydroxygruppe, eine Aminogruppe, eine Carboxygruppe, eine Aminocarbonylgruppe, eine Phenylgruppe, eine C1-C6-Alkylgruppe, eine C1-C6-Alkylaminogruppe, eine Di-C1-C6-alkylaminogruppe, eine C1-C6-Alkylcarbonylgruppe, eine C3-C6-Cycloalkylgruppe, eine C1-C6-Alkylsulfonylgruppe und eine C1-C6-Alkylsulfonylamidgruppe.


 
17. Verfahren nach Anspruch 16, wobei
R22 steht für ein Wasserstoffatom, und
R23 ein Substituent ist, dargestellt durch das Folgende:


 
18. Verfahren zur Umsetzung
einer Verbindung, dargestellt durch Formel (XVI):

einer Verbindung, dargestellt durch Formel (XVII):

und einer Verbindung, dargestellt durch Formel (XVIII):

in einem Lösungsmittel unter Verwendung eines asymmetrischen Katalysators, hergestellt aus einer Lewis-Säure, ausgewählt aus der Gruppe, bestehend aus einer Cu(I)-Lewis-Säure und einer Cu(II)-Lewis-Säure, und einem chiralen Liganden, ausgewählt aus der folgenden Gruppe:









worin Cy steht für eine Cyclohexylgruppe,
zwecks stereoselektiver Produktion einer Verbindung, dargestellt durch Formel (XIX), oder eines Salzes davon:

wobei

M steht für ein Stickstoffatom oder CH,

L steht für eine Einfachbindung, ein Sauerstoffatom, CH2 oder C(CH3)2, und

R53 steht für eine C1-C6-Alkylgruppe.


 
19. Verfahren zur Umsetzung einer Verbindung, dargestellt durch Formel (XVI):

und einer Verbindung, dargestellt durch Formel (XX):

in einem Lösungsmittel unter Verwendung eines asymmetrischen Katalysators, hergestellt aus einer Lewis-Säure, ausgewählt aus der Gruppe, bestehend aus einer Cu(I)-Lewis-Säure und einer Cu(II)-Lewis-Säure, und einem chiralen Liganden, ausgewählt aus der folgenden Gruppe:









worin Cy steht für eine Cyclohexylgruppe,
zwecks stereoselektiver Produktion einer Verbindung, dargestellt durch Formel (XIX), oder eines Salzes davon:

wobei
M, L und R53 wie in Anspruch 18 definiert sind.
 
20. Verfahren nach Anspruch 18 oder 19, einschließend die weiteren Schritte des Hydrolysierens der so produzierten Verbindung der Formel (XIX) oder eines Salzes davon zwecks Produktion einer Verbindung, dargestellt durch die folgende Formel (XXI), oder eines Salzes davon:

und des Kondensierens der Verbindung oder des Salzes mit einer Verbindung, dargestellt durch die folgende Formel:

zwecks Produktion einer Verbindung, dargestellt durch die folgende Formel (XXII), oder eines Salzes davon:

wobei
M und L wie in Anspruch 18 oder 19 definiert sind.
 


Revendications

1. Méthode pour la réaction d'un composé représenté par la formule (I):

d'un composé représenté par la formule (II):

et d'un composé représenté par la formule (III):

dans un solvant en utilisant un catalyseur asymétrique pour produire par stéréosélectivité un composé représenté par la formule (IV) ou un sel de celui-ci:

dans laquelle:

R1 représente un atome d'hydrogène, un groupe C1-C6 alkylcarbonyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous ou un groupe C1-C6 alcoxycarbonyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous,

R2 représente un groupe hétéroaryle de 5 ou 6 membres possédant, dans le cycle, 1 à 3 hétéroatomes indépendamment choisis dans le groupe constitué de: un atome d'azote, un atome d'oxygène et un atome de soufre, un groupe phényle, un groupe C3-C6 cycloalkyle ou un groupe C3-C6 cycloalcényle, dans laquelle:
le groupe hétéroaryle de 5 ou 6 membres, le groupe phényle, le groupe C3-C6 cycloalkyle et le groupe C3-C6 cycloalcényle possèdent chacun optionnellement 1 à 3 substituants indépendamment choisis dans le groupe constitué de: un atome d'halogène, un groupe vinyle, un groupe éthynyle, un groupe cyano, un groupe hydroxy, un groupe amino, un groupe carboxy, un groupe aminocarbonyle, un groupe C1-C6 alkyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous, un groupe C3-C4 cycloalkyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous, un groupe C1-C6 alcoxy possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous, un groupe C3-C4 cycloalcoxy possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous, un groupe C1-C6 alkylamino possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous, un groupe di-C1-C6 alkylamino possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous, un groupe hétérocyclique de 4 à 7 membres saturé contenant un atome d'azote dans le cycle et possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe B ci-dessous, un groupe C1-C6 alcoxycarbonyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous, un groupe C3-C4 cycloalcoxycarbonyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous, un groupe C1-C6 alkylaminocarbonyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous et un groupe C3-C4 cycloalkylaminocarbonyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe A ci-dessous,

R3 et R4 représentent chacun indépendamment un groupe C1-C6 alkyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe C ci-dessous, ou

R3 et R4 optionnellement forment ensemble un cycle C4-C6 cycloalkyle, un cycle de tétrahydrofurane, un cycle de tétrahydropyrane ou un cycle de pipéridine, dans laquelle:
le cycle C4-C6 cycloalkyle, le cycle de tétrahydrofurane, le cycle de tétrahydropyrane et le cycle de pipéridine possèdent chacun optionnellement 1 à 8 substituants indépendamment choisis dans le groupe D ci-dessous,

R5 représente un groupe C1-C6 alcoxy possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe E ci-dessous, un groupe C3-C8 cycloalcoxy possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe E ci-dessous, un groupe C2-C6 alcényloxy ou -NR51R52,

R51 et R52 représentent chacun indépendamment un atome d'hydrogène, un groupe C1-C6 alkyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe E ci-dessous, un groupe C3-C8 cycloalkyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe E ci-dessous ou un groupe hétérocyclique de 3 à 6 membres saturé possédant, dans le cycle, un hétéroatome indépendamment choisi dans le groupe constitué de: un atome d'azote, un atome d'oxygène et un atome de soufre et possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe E ci-dessous, et

le cycle Z représente un cycle de benzène possédant optionnellement 1 à 4 substituants indépendamment choisis dans le groupe E ci-dessous, un cycle de pyridine possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe E ci-dessous ou un cycle de pyrimidine possédant optionnellement 1 ou 2 substituants indépendamment choisis dans le groupe E ci-dessous:

groupe A: un atome d'halogène, un groupe hydroxy, un groupe C1-C6 alkyle, un groupe amino et un groupe phényle,

groupe B: un groupe C1-C6 alkyle et un groupe hydroxy,

groupe C: un atome d'halogène, un groupe hydroxy, un groupe phényle, un groupe pyridyle et un groupe amino,

groupe D: un atome d'halogène et un groupe C1-C6 alkyle possédant optionnellement 1 à 3 atomes d'halogène, et

groupe E: un atome d'halogène, un groupe hydroxy, un groupe vinyle, un groupe éthynyle, un groupe cyano, un groupe C1-C6 alcoxy, un groupe aminocarbonyle et un groupe C1-C6 alkyle possédant optionnellement 1 à 3 atomes d'halogène.


 
2. Méthode pour la réaction d'un composé représenté par la formule (I):

et d'un composé représenté par la formule (V):

dans un solvant en utilisant un catalyseur asymétrique pour produire par stéréosélectivité un composé représenté par la formule (IV) ou un sel de celui-ci:

dans laquelle R1, R2, R3, R4, R5 et Z sont tels que définis dans la revendication 1.
 
3. Méthode selon la revendication 1 ou 2, dans laquelle le catalyseur asymétrique est un catalyseur préparé à partir d'un acide de Lewis et d'un ligand chiral, dans laquelle:

l'acide de Lewis est un acide de Lewis choisi dans le groupe constitué de: un acide de Lewis de Zn(II), un acide de Lewis de Ag(I), un acide de Lewis de Ni(II), un acide de Lewis de Co(II), un acide de Lewis de Ru(I), un acide de Lewis de Cu(I) et un acide de Lewis de Cu(II), et

le ligand chiral est un ligand chiral choisi dans le groupe constitué de: un composé représenté par la formule (VI) suivante:

un composé représenté par la formule (VII) suivante:

un composé représenté par la formule (VIII) suivante:

un composé représenté par la formule (IX) suivante:

un composé représenté par la formule (X) suivante:

un composé représenté par la formule (XI) suivante:

et un composé représenté par la formule (XII) suivante:

dans laquelle:

R6 représente un groupe phényle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe F ci-dessous,

le cycle Y représente un cycle de benzène, un cycle de cyclohexane ou un cycle de dioxolane possédant optionnellement 1 à 4 atomes d'halogène,

R7 représente un groupe phényle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe G ci-dessous ou un groupe furanyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe G ci-dessous,

R8 représente un atome d'hydrogène ou un groupe C1-C6 alcoxy,

R9 représente un groupe C1-C6 alcoxy, ou

deux fractions R9 optionnellement forment ensemble un cycle hétérocyclique de 7 à 12 membres contenant deux atomes d'oxygène dans le cycle,

X représente CH, CR10 ou un atome d'azote, où:

R10 représente un groupe C1-C6 alcoxy,

V représente un groupe phényle possédant un P(R11)2, PH(O)R12 ou P(R11)2, où:

R11 représente un groupe C1-C6 alkyle, un groupe cyclohexyle ou un groupe phényle possédant optionnellement deux groupes trifluorométhyles, et

R12 représente un groupe C1-C6 alkyle ou un groupe phényle,

W représente un groupe C1-C6 alkylthio, un groupe dihydrooxazolyle possédant optionnellement un groupe C1-C6 alkyle, CH(CH3)P(R13)2 ou CHR14R15, où:

R13 représente un groupe cyclohexyle, un groupe C1-C6 alkyle ou un groupe phényle possédant optionnellement 1 ou 2 substituants indépendamment choisis dans le groupe H ci-dessous,

R14 représente un groupe phényle optionnellement substitué par un P(R16)2,

R15 représente un groupe C1-C6 alkyle ou un groupe di-C1-C6 alkylamino, et

R16 représente un groupe phényle ou un groupe cyclohexyle,

U représente n'importe lequel des Ua to Ud suivants:



R17 représente un groupe phényle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe F ci-dessous,

R18 représente un groupe C1-C6 alkyle ou un groupe phényle,

R19 représente un atome d'hydrogène ou un groupe C1-C6 alkyle, et

R20 et R21 représentent chacun indépendamment un groupe C1-C6 alkyle;

groupe F: un groupe C1-C6 alkyle et un groupe C1-C6 alcoxy,

groupe G: un groupe C1-C6 alkyle, un groupe C1-C6 alcoxy et un groupe di-C1-C6 alkylamino, et

groupe H: un groupe C1-C6 alkyle et un groupe C1-C6 alkyle possédant optionnellement trois atomes d'halogène.


 
4. Méthode selon la revendication 3, dans laquelle l'acide de Lewis utilisé dans la préparation du catalyseur asymétrique est un acide de Lewis de Cu(I) ou un acide de Lewis de Cu(II).
 
5. Méthode selon la revendication 3 ou la revendication 4, dans laquelle l'acide de Lewis utilisé dans la préparation du catalyseur asymétrique est un acide de Lewis choisi dans le groupe constitué de CuOAc, CuCl, CuBr, CuI, CuOTf, CuPF6, CuBF4, Cu(OAc)2, Cu(OTf)2 et CuSO4.
 
6. Méthode selon l'une quelconque des revendications 3 à 5, dans laquelle le ligand chiral utilisé dans la préparation du catalyseur asymétrique est un ligand chiral choisi dans le groupe constitué de: un composé représenté par la formule (VI), un composé représenté par la formule (VII), un composé représenté par la formule (VIII), un composé représenté par la formule (IX), un composé représenté par la formule (X), un composé représenté par la formule (XI) et un composé représenté par la formule (XII), où les composés des formules (VI) à (XII) sont tels que définis dans la revendication 3,
dans laquelle:

R6 représente un groupe phényle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe constitué de: un groupe méthyle, un groupe t-butyle et un groupe méthoxy,

le cycle Y représente un cycle de benzène, un cycle de cyclohexane ou un cycle de dioxolane,

R7 représente un groupe phényle ou un groupe furanyle, dans laquelle:

le groupe phényle et le groupe furanyle possèdent chacun optionnellement 1 à 3 substituants indépendamment choisis dans le groupe constitué de: un groupe méthyle, un groupe t-butyle et un groupe méthoxy,

R8 représente un atome d'hydrogène ou un groupe méthoxy,

R9 représente un groupe méthoxy, ou

deux fractions R9 optionnellement forment ensemble un cycle hétérocyclique de 9 membres contenant deux atomes d'oxygène dans le cycle,

X représente CH, CR10 ou un atome d'azote,

R10 représente un groupe méthoxy,

V représente P(R11)2, où:

R11 représente un groupe phényle possédant optionnellement deux groupes trifluorométhyles,

W représente un groupe t-butylthio, un groupe dihydrooxazolyle optionnellement substitué par un groupe isopropyle ou CH(CH3)P(R13)2, où:

R13 représente un groupe phényle possédant optionnellement 1 ou 2 groupes méthyles,

U représente Ua ou Ud tels que définis dans la revendication 3,

R17 représente un groupe phényle,

R18 représente un groupe isopropyle, un groupe t-butyle ou un groupe phényle,

R19 représente un atome d'hydrogène, et

R20 et R21 représentent chacun indépendamment un groupe méthyle ou un groupe t-butyle.


 
7. Méthode selon l'une quelconque des revendications 3 à 6, dans laquelle le ligand chiral utilisé dans la préparation du catalyseur asymétrique est un ligand chiral choisi dans le groupe suivant:









où Cy représente un groupe cyclohexyle.
 
8. Méthode selon l'une quelconque des revendications 1 à 7, dans laquelle le solvant utilisé dans la réaction est un ou plusieurs solvants choisis dans le groupe constitué de N,N-diméthylacétamide, tétrahydrofurane, diméthoxyéthane, 2-propanol, toluène et acétate d'éthyle.
 
9. Méthode selon l'une quelconque des revendications 1 à 8, dans laquelle le composé produit ou un sel de celui-ci présente la configuration suivante:

dans laquelle R1, R2, R3, R4, R5 et Z sont tels que définis dans la revendication 1.
 
10. Méthode selon l'une quelconque des revendications 1 à 9, dans laquelle R1 est un atome d'hydrogène.
 
11. Méthode selon l'une quelconque des revendications 1 à 10, dans laquelle dans la formule (I),
le cycle Z est un cycle de benzène possédant optionnellement 1 à 4 atomes d'halogène.
 
12. Méthode selon l'une quelconque des revendications 1 à 11, dans laquelle dans la formule (I) ou la formule (IV),
R2 est un groupe pyridyle possédant optionnellement 1 à 3 atomes d'halogène ou un groupe phényle possédant optionnellement 1 à 3 atomes d'halogène.
 
13. Méthode selon l'une quelconque des revendications 1 à 12, dans laquelle dans la formule (II) ou la formule (V),
R3 et R4 représentent chacun un groupe méthyle ou R3 et R4 forment ensemble un cycle de cyclopentane, un cycle de cyclohexane ou un cycle de tétrahydropyrane, dans laquelle:
le cycle de cyclopentane, le cycle de cyclohexane et le cycle de tétrahydropyrane possèdent chacun optionnellement 1 à 4 groupes C1-C6 alkyles sur le cycle.
 
14. Méthode selon l'une quelconque des revendications 1 à 13, dans laquelle dans la formule (III) ou la formule (V),
R5 est un substituant représenté par ce qui suit:


 
15. Méthode selon l'une quelconque des revendications 1 à 13, dans laquelle dans la formule (III) ou la formule (V),
R5 est un groupe C1-C6 alcoxy.
 
16. Méthode selon la revendication 15 qui inclut les étapes supplémentaires d'hydrolyse du composé de la formule (IV) ainsi produit ou d'un sel de celui-ci pour produire un composé représenté par la formule (XIV) suivante ou un sel de celui-ci:

et de condensation du composé ou du sel avec un composé représenté par NHR22R23 pour produire un composé représenté par la formule (XV) suivante ou un sel de celui-ci:

dans laquelle:

R1, R2, R3, R4 et Z sont tels que définis dans l'une quelconque des revendications 1 à 13, et

R22 et R23 représentent chacun indépendamment un atome d'hydrogène, un C1-C6 groupe alkyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe I ci-dessous, un groupe C1-C6 alkylsulfonyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe I ci-dessous, un groupe C3-C6 cycloalkyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe I ci-dessous, un groupe hétérocyclique de 3 à 6 membres saturé possédant, dans le cycle, un hétéroatome indépendamment choisi dans le groupe constitué de: un atome d'azote, un atome d'oxygène et un atome de soufre et possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe I ci-dessous, un groupe phényle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe I ci-dessous ou un groupe hétéroaryle de 5 ou 6 membres possédant, dans le cycle, 1 à 3 hétéroatomes indépendamment choisis dans le groupe constitué de: un atome d'azote, un atome d'oxygène et un atome de soufre et possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe I ci-dessous, ou

R22 et R23 optionnellement forment ensemble un cycle de pipérazine possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe I ci-dessous:

groupe I: un atome d'halogène, un groupe hydroxy, un groupe oxo, un groupe carboxy, un groupe formyle, un groupe amino, un groupe aminocarbonyle, un groupe cyano, un groupe C1-C6 alkylamino, un groupe C1-C6 alkylsulfonyle, un groupe C1-C6 alkylsulfonylamide, un groupe C1-C6 alkyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe C1-C6 alcoxy possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe C1-C6 alkylcarbonyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe C3-C6 cycloalkylcarbonyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe C4-C6 cycloalkyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe C1-C6 alcoxycarbonyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe pipéridinyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe pyrrolidinyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe pipérazinyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe phényle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe tétrazolyle, un groupe azétidinyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe morpholino possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous, un groupe dihydropyrazolyle possédant optionnellement 1 à 3 substituants indépendamment choisis dans le groupe J ci-dessous et un groupe oxadiazolyle, et

groupe J: un atome d'halogène, un groupe hydroxy, un groupe amino, un groupe carboxy, un groupe aminocarbonyle, un groupe phényle, un groupe C1-C6 alkyle, un groupe C1-C6 alkylamino, un groupe di-C1-C6 alkylamino, un groupe C1-C6 alkylcarbonyle, un groupe C3-C6 cycloalkyle, un groupe C1-C6 alkylsulfonyle et un groupe C1-C6 alkylsulfonylamide.


 
17. Méthode selon la revendication 16, dans laquelle:

R22 représente un atome d'hydrogène, et

R23 est un substituant représenté par ce qui suit:


 
18. Méthode pour la réaction d'un composé représenté par la formule (XVI):

d'un composé représenté par la formule (XVII):

et d'un composé représenté par la formule (XVIII):

dans un solvant en utilisant un catalyseur asymétrique préparé à partir d'un acide de Lewis choisi dans le groupe constitué de: un acide de Lewis de Cu(I) et un acide de Lewis de Cu(II) et d'un ligand chiral choisi dans le groupe suivant:









où Cy représente un groupe cyclohexyle,
pour produire par stéréosélectivité un composé représenté par la formule (XIX) ou un sel de celui-ci:

dans laquelle:

M représente un atome d'azote ou CH,

L représente une liaison simple, un atome d'oxygène, CH2 ou C(CH3)2, et

R53 représente un groupe C1-C6 alkyle.


 
19. Méthode pour la réaction d'un composé représenté par la formule (XVI):

et d'un composé représenté par la formule (XX):

dans un solvant en utilisant un catalyseur asymétrique préparé à partir d'un acide de Lewis choisi dans le groupe constitué d'un acide de Lewis de Cu(I) et d'un acide de Lewis de Cu(II) et d'un ligand chiral choisi dans le groupe suivant:









où Cy représente un groupe cyclohexyle,
pour produire par stéréosélectivité un composé représenté par la formule (XIX) ou un sel de celui-ci:

dans laquelle:
M, L et R53 sont tels que définis dans la revendication 18.
 
20. Méthode selon la revendication 18 ou 19 qui inclut les étapes supplémentaires d'hydrolyse du composé de la formule (XIX) ainsi produit ou d'un sel de celui-ci pour produire un composé représenté par la formule (XXI) suivante ou un sel de celui-ci:

et de condensation du composé ou du sel avec un composé représenté par la formule suivante:

pour produire un composé représenté par la formule (XXII) suivante ou un sel de celui-ci:

dans laquelle:
M et L sont tels que définis dans la revendication 18 ou 19.
 




REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




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