(19)
(11)EP 3 421 468 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
04.11.2020 Bulletin 2020/45

(21)Application number: 18164040.0

(22)Date of filing:  12.11.2014
(51)International Patent Classification (IPC): 
C07D 471/04(2006.01)
C07C 51/083(2006.01)

(54)

METHODS OF PREPARING INHIBITORS OF INFLUENZA VIRUSES REPLICATION

VERFAHREN ZUR HERSTELLUNG VON INHIBITOREN DER INFLUENZAVIRENREPLIKATION

PROCÉDÉS DE PRÉPARATION D'INHIBITEURS DE RÉPLICATION DE VIRUS DE LA GRIPPE


(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: 13.11.2013 US 201361903893 P

(43)Date of publication of application:
02.01.2019 Bulletin 2019/01

(60)Divisional application:
20199383.9

(62)Application number of the earlier application in accordance with Art. 76 EPC:
14802788.1 / 3068782

(73)Proprietor: Vertex Pharmaceuticals Incorporated
Boston, MA 02210 (US)

(72)Inventors:
  • TANOURY, Gerald J.
    Marlborough, MA 01752 (US)
  • NUGENT, William, Aloysius
    Manomet, MA 02345 (US)
  • DVORNIKOVS, Vadims
    Lancester, MA 01523 (US)
  • ROSE, Peter, Jamison
    Littleton, MA 01460 (US)

(74)Representative: Cohausz & Florack 
Patent- & Rechtsanwälte Partnerschaftsgesellschaft mbB Bleichstraße 14
40211 Düsseldorf
40211 Düsseldorf (DE)


(56)References cited: : 
US-A- 4 349 552
  
  • CONCEPTION NEMECEK ET AL: "Design of Potent IGF1-R Inhibitors Related to Bis-azaindoles", CHEMICAL BIOLOGY & DRUG DESIGN, vol. 76, no. 2, 9 August 2010 (2010-08-09) , pages 100-106, XP055127265, ISSN: 1747-0277, DOI: 10.1111/j.1747-0285.2010.00991.x
  • N. KHASELEV ET AL: "The role of the C-C double bond in alcohol elimination from MH+ ions of unsaturated bicyclic esters upon chemical ionization", JOURNAL OF MASS SPECTROMETRY, vol. 30, no. 11, 1 November 1995 (1995-11-01), pages 1533-1538, XP055160717, ISSN: 1076-5174, DOI: 10.1002/jms.1190301103
  • JAESCHKE G ET AL: "HIGHLY ENANTIOSELECTIVE RING OPENING OF CYCLIC MESO-ANHYDRIDES TO ISOPROPYL HEMIESTERS WITH TI-TADDOLATES: AN ALTERNATIVE TO HYDROLYTIC ENZYMES?", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 63, 1 January 1998 (1998-01-01), pages 1190-1197, XP002444554, ISSN: 0022-3263, DOI: 10.1021/JO971731T
  • KIM H S ET AL: "Heterogeneous organocatalysis for the asymmetric desymmetrization of meso-cyclic anhydrides using silica gel-supported bis-cinchona alkaloids", TETRAHE, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 60, no. 52, 20 December 2004 (2004-12-20), pages 12051-12057, XP004768164, ISSN: 0040-4020, DOI: 10.1016/J.TET.2004.10.046
  
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

CROSS REFERENCE TO RELATED APPLICATION



[0001] This PCT application claims the benefit of U.S. provisional application no. 61/903,893, filed on November 13, 2013.

FIELD OF THE INVENTION



[0002] The present invention relates to processes and intermediates for the preparation of compounds useful as inhibitors of Influenza virus replication.

BACKGROUND OF THE INVENTION



[0003] Influenza spreads around the world in seasonal epidemics, resulting in the deaths of hundreds of thousands annually - millions in pandemic years. For example, three influenza pandemics occurred in the 20th century and killed tens of millions of people, with each of these pandemics being caused by the appearance of a new strain of the virus in humans. Often, these new strains result from the spread of an existing influenza virus to humans from other animal species.

[0004] Influenza is primarily transmitted from person to person via large virus-laden droplets that are generated when infected persons cough or sneeze; these large droplets can then settle on the mucosal surfaces of the upper respiratory tracts of susceptible individuals who are near (e.g. within 6 feet) infected persons. Transmission might also occur through direct contact or indirect contact with respiratory secretions, such as touching surfaces contaminated with influenza virus and then touching the eyes, nose or mouth. Adults might be able to spread influenza to others from 1 day before getting symptoms to approximately 5 days after symptoms start. Young children and persons with weakened immune systems might be infectious for 10 or more days after onset of symptoms.

[0005] Influenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises five genera: Influenza virus A, Influenza virus B, Influenza virus C, ISA virus and Thogoto virus.

[0006] The Influenza virus A genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics. The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are: H1N1 (which caused Spanish influenza in 1918), H2N2 (which caused Asian Influenza in 1957), H3N2 (which caused Hong Kong Flu in 1968), H5N1 (a pandemic threat in the 2007 - 2008 influenza season), H7N7 (which has unusual zoonotic potential), H1N2 (endemic in humans and pigs), H9N2, H7N2, H7N3 and H10N7.

[0007] The Influenza virus B genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal. This type of influenza mutates at a rate 2-3 times slower than type A and consequently is less genetically diverse, with only one influenza B serotype. As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible. This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.

[0008] The Influenza virus C genus has one species, influenza C virus, which infects humans and pigs and can cause severe illness and local epidemics. However, influenza C is less common than the other types and usually seems to cause mild disease in children.

[0009] Influenza A, B and C viruses are very similar in structure. The virus particle is 80-120 nanometers in diameter and usually roughly spherical, although filamentous forms can occur. Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of segmented negative-sense RNA. The Influenza A genome encodes 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), M1, M2, NS1, NS2(NEP), PA, PB1, PB1-F2 and PB2.

[0010] HA and NA are large glycoproteins on the outside of the viral particles. HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. Thus, these proteins have been targets for antiviral drugs. Furthermore, they are antigens to which antibodies can be raised. Influenza A viruses are classified into subtypes based on antibody responses to HA and NA, forming the basis of the H and N distinctions (vide supra) in, for example, H5N1.

[0011] Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs. Preventative costs are also high. Governments worldwide have spent billions of U.S. dollars preparing and planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.

[0012] Current treatment options for influenza include vaccination, and chemotherapy or chemoprophylaxis with anti-viral medications. Vaccination against influenza with an influenza vaccine is often recommended for high-risk groups, such as children and the elderly, or in people that have asthma, diabetes, or heart disease. However, it is possible to get vaccinated and still get influenza. The vaccine is reformulated each season for a few specific influenza strains but cannot possibly include all the strains actively infecting people in the world for that season. It may take six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time and infects people although they have been vaccinated (as by the H3N2 Fujian flu in the 2003-2004 influenza season). It is also possible to get infected just before vaccination and get sick with the very strain that the vaccine is supposed to prevent, as the vaccine may take several weeks to become effective.

[0013] Further, the effectiveness of these influenza vaccines is variable. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time, and different strains become dominant.

[0014] Also, because of the absence of RNA proofreading enzymes, the RNA-dependent RNA polymerase of influenza vRNA makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, nearly every newly-manufactured influenza virus is a mutant-antigenic drift. The separation of the genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one viral line has infected a single cell. The resulting rapid change in viral genetics produces antigenic shifts and allows the virus to infect new host species and quickly overcome protective immunity.

[0015] Antiviral drugs can also be used to treat influenza, with neuraminidase inhibitors being particularly effective, but viruses can develop resistance to the standard antiviral drugs.

[0016] Thus, there is still a need for drugs for treating influenza infections, such as for drugs with expanded treatment window, and/or reduced sensitivity to viral titer. Further, there is a need for methods for preparing such drugs efficiently. US 4349552 discloses the synthesis of the intermediate D,L-6-ethoxycarbonylbicyclo[2.2.2]oct-2-en-5-carboxylic acid which is useful in the preparation of such drugs.

SUMMARY OF THE INVENTION



[0017] The present invention generally relates to a method of preparing Compound (C) or a pharmaceutically acceptable salt thereof, wherein R1 is ethyl,

(g) reacting Compound (A)

with quinine

and ethyl alcohol to form an adduct of the quinine and Compound (C-1)

wherein R1 is ethyl;

(h) breaking the adduct of the quinine and Compound (C-1) by treating the adduct with HCl to form Compound (C-1) or a pharmaceutically acceptable salt thereof;

(i) epimerizing Compound (C-1) or a pharmaceutically acceptable salt thereof to form Compound (C) (c) or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt thereof, wherein R1 is ethyl, comprising:

(g) reacting Compound (A)

with quinine

and ethyl alcohol to form an adduct of the quinine and Compound (C-1)

(h) breaking the adduct of the quinine and Compound (C-1) by treating the adduct with HCl to form Compound (C-1) or a pharmaceutically acceptable salt thereof;

(i-1) reacting Compound (C-1) with a C1-6 alkoxide selected from tert-butoxide or tert-amylate to form Compound (C)

or a pharmaceutically acceptable salt thereof;


DETAILED DESCRIPTION OF THE INVENTION


I. COMMONLY USED ABBREVIATIONS



[0018] 
ACN
acetonitrile
tBuOAc
tert-butyl acetate
DABCO
1,4-diazabicyclo[2.2.2]octane
DCM
dichloromethane
EtOAc
ethyl acetate
IPAc
iso-propyl acetate
MIBK
methyl iso-butyl ketone
TEA
triethylamine
THF
tetrahydrofuran
PG
protecting group
LG
leaving group
Ac
acetyl
TMS
trimethylsilyl
TBS
tert-butyldimethylsilyl
TIPS
tri-iso-propylsilyl
TBDPS
tert-butyldiphenylsilyl
TOM
tri-iso-propylsilyloxymethyl
DMP
Dess-Martin periodinane
IBX
2-iodoxybenzoic acid
DMF
dimethylformamide
MTBE
methyl-tert-butylether
TBAF
tetra-n-butylammonium fluoride
d.e.
diastereomeric excess
e.e.
enantiomeric excess
d.r.
diastereomeric ratio
DMSO
dimethyl sulfoxide
TCA
trichloroacetic acid
ATP
adenosine triphosphate
EtOH
ethanol
Ph
phenyl
Me
methyl
Et
ethyl
Bu
butyl
DEAD
diethylazodicarboxylate
HEPES
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
DTT
dithiothreitol
MOPS
4-morpholinepropanesulfonic acid
NMR
nuclear magnetic resonance
HPLC
high performance liquid chromatography
LCMS
liquid chromatography-mass spectrometry
TLC
thin layer chromatography
Rt
retention time
HOBt
hydroxybenzotriazole
Ms
mesyl
Ts
tosyl
Tf
triflyl
Bs
besyl
Ns
nosyl
Cbz
carboxybenzyl
Moz
p-methoxybenzyl carbonyl
Boc
tert-butyloxycarbonyl
Fmoc
9-fluorenylmethyloxycarbonyl
Bz
benzoyl
Bn
benzyl
PMB
p-methoxybenzyl
AUC
area under the curve
DMPM
3,4-dimethoxybenzyl
PMP
p-methoxyphenyl
XRPD
X-ray powder diffraction

II. PREPARATION OF COMPOUNDS



[0019] The method of the invention is directed to the preparation of Compound (C) or a pharmaceutically acceptable salt thereof, as shown in Scheme 4 below.



[0020] The preparation of Compound (C) or a pharmaceutically acceptable salt thereof comprises: (g) reacting Compound (A):

with quinine:

and R1OH to form an adduct of the quinine and Compound (C-1):

or a pharmaceutically acceptable salt thereof; (h) breaking the adduct by treating the adduct with HCl to form Compound (C-1) or a pharmaceutically acceptable salt thereof, wherein R1 is ethyl, and epimerizing Compound (C-1) or a pharmaceutically acceptable salt thereof to Compound (C) or a pharmaceutically acceptable salt thereof. The epimerization of Compound (C-1) or a pharmaceutically acceptable salt thereof can be done employing any suitable conditions known in the art. Typically, it is performed by treating it with a base, such as an alkoxide. In one specific embodiment, a C1-6 alkoxide (e.g., alkaline metal (e.g., sodium or potassium) or alkaline earth metal (e.g., calcium or magnesium) C1-6 alkoxide) is employed. In another specific embodiment, a tert-butoxide (e.g., potassium tert-amylate) or a tert-amylate (e.g., potassium tert-amylate) is employed. Without intending to be bound to a particular theory, the adduct of quinine and Compound (C) having ethyl for R1 precipitates out of the reaction mixture of quinine and Compound (A), which can provide Compound (C) in over 99% enantiomeric pure form.

[0021] The compounds described herein are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0022] It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds described above may involve, at various stages, the addition and removal of one or more protecting groups. The protection and deprotection of functional groups is described in "Protective Groups in Organic Chemistry." edited by J. W. F. McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis," 3rd edition, T. W. Greene and P. G. M. Wuts, Wiley Interscience, and "Protecting Groups," 3rd edition, P. J. Kocienski, Thieme (2005).

[0023] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0024] The term "protecting group" and "protective group" as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired functional groups in a compound with multiple reactive sites. In certain embodiments, a protecting group has one or more, or specifically all, of the following characteristics: a) is added selectively to a functional group in good yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other reactive sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group. As would be understood by one skilled in the art, in some cases, the reagents do not attack other reactive groups in the compound. In other cases, the reagents may also react with other reactive groups in the compound. Examples of protecting groups are detailed in Greene, T. W., Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book). The term "nitrogen protecting group", as used herein, refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics exemplified for a protecting group above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999.

[0025] The compounds described herein are defined by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0026] In one embodiment, the compounds in accordance with the present invention are provided in the form of a single enantiomer at least 95%, at least 97% and at least 99% free of the corresponding enantiomer.

[0027] In a further embodiment, the compounds in accordance with the present invention are in the form of the (+) enantiomer at least 95% free of the corresponding (-) enantiomer.

[0028] In a further embodiment, the compounds in accordance with the present invention are in the form of the (+) enantiomer at least 97% free of the corresponding (-) enantiomer.

[0029] In a further embodiment, the compounds in accordance with the present invention are in the form of the (+) enantiomer at least 99% free of the corresponding (-) enantiomer.

[0030] In a further embodiment, the compounds in accordance with the present invention are in the form of the (-) enantiomer at least 95% free of the corresponding (+) enantiomer.

[0031] In a further embodiment, the compounds in accordance with the present invention are in the form of the (-) enantiomer at least 97% free of the corresponding (+) enantiomer.

[0032] In a further embodiment the compounds in accordance with the present invention are in the form of the (-) enantiomer at least 99% free of the corresponding (+) enantiomer.

VII. EXAMPLES


Preparation of Compounds 8a and 9a



[0033] 



[0034] Compound 8a: Anhydride 7a (24.6 kgs, Apex) and quinine (49.2 kgs, Buchler) were added to a reactor followed by the addition of anhydrous PhMe (795.1 kgs). The reactor was then cooled to -16 °C and EtOH (anhydrous, 41.4 kgs) was added at such a rate to maintain the internal reactor temperature < -12 °C. The maximum reaction temp recorded for this experiment was -16 °C. The reaction mixture was then stirred for 16 h at -16 °C. A sample was removed and filtered. The solid was dried and evaluated by 1H-NMR which showed that no anhydride remained. The contents of the reactor were filtered. The reactor and subsequent wet cake were washed with PhMe (anhydrous, 20 kgs). The resulting solid was placed in a tray dryer at < 45 °C with a N2 sweep for at least 48 h. In this experiment, the actual temperature was 44 °C and the vacuum was -30 inHG. Material was sampled after 2.5 d drying and showed 3% PhMe by NMR. After an additional 8 hrs, the amt of PhMe analyzed showed the same 3% PhMe present and the drying was stopped. The weight of the white solid was 57.7 kgs, 76% yield. 1H-NMR showed consistent with structure and Chiral SFC analysis showed material >99% de.

[0035] Compound 9a: The reactor was charged with quinine salt 8a (57.7 kgs) and PhMe (250.5 kgs, Aldrich ACS grade, >99.5%) and the agitator was started. The contents were cooled to <15 °C and was treated with 6N HCl (18 kgs H2O were treated with 21.4 kgs of conc. HCl) while keeping the temperature <25 °C. The mixture was stirred for 40 min and visually inspected to verify that no solids were present. Stirring was stopped and the phases were allowed to settle and phases were separated. The aqueous phases were extracted again with PhMe (160 kgs; the amount typically used was much less, calc. 43 kgs. However, for efficient stirring due to minimal volume, additional PhMe was added. The organic phases were combined. Sample the organic phase and run HPLC analysis to insure product is present; for information only test.

[0036] To the organic phases were cooled to <5 °C (0-5 °C) and was added sodium sulfate (anhydrous, 53.1 kgs) with agitation for 8 hrs (in this instance 12 hrs). The contents of the reactor containing the organic phase were passed through a filter containing sodium sulfate (31 kgs, anhydrous) and into a cleaned and dried reactor. The reactor was rinsed with PhMe (57.4 kgs), passed through the filter into reactor 201. The agitator was started and an additional amount of PhMe (44 kgs) was added and the reaction mixture cooled to -20 °C. At that temperature PhMe solution of potassium tert-pentoxide was added over 2 h while keeping the temperature between -15 and -22 °C. The reaction mixture was held at approximately -20 °C for an additional 30 min before being sampled. Sampling occurred by removing an aliquat with immediate quenching into 6N HCl.

[0037] Having achieved the target ratio (96:4 (trans:cis), the reactor was charged with acetic acid (2.8 kgs) over 6 min. The temperature stayed at -20 °C. The temperature was then adjusted to -5 °C and aqueous 2N HCl (65.7 kgs water treated with 15.4 kgs of conc HCl) was added. The contents were warmed to 5 °C +/- 5 °C, agitated for 45 min before warming to 20 °C +/- 5 °C with stirring for 15 min. The agitator was stopped and the phases allowed to settle. The aqueous layer was removed. The organic phase was washed with water (48 kgs, potable), agitated for 15 min and phases allowed to settle (at least 15 min) and the aqueous layer was removed and added to the aqueous layer. 1/3 of a buffer solution (50 L) that was prepared (7.9 kgs NaH2PO4, 1.3 kgs of Na2HPO4 and 143.6 kgs water) was added to the organic phase and stirred for at least 15 min. Agitation was stopped and phases were allowed to separate for at least 15 min. The lower layer was discarded. Another portion of the buffered solution (50 L) was used to wash the organic layer as previously described. The wash was done a third time as described above.

[0038] Vacuum distillation of the PhMe phase (150 L) was started at 42 °C/-13.9 psig and distilled to an oil of approximately 20 L volume. After substantial reduction in volume the mixture was transferred to a smaller vessel to complete the distillation. Heptanes (13.7 kgs) was added and the mixture warmed to 40 +/- 5 °C for 30 min then the contents were cooled to 0-5 °C over 1.5 h. The solids were filtered and the reactor washed with approximately 14 kgs of cooled (0-5 °C) heptanes. The solids were allowed to dry under vacuum before placing in the oven at <40 °C under house vac (-28 psig) until LOD is <1%. 15.3 kgs, 64%, 96% HPLC purity. 1H NMR (400 MHz, CDCl3) δ 11.45 (br. s, 1H), 6.41 (t, J = 7.2 Hz, 1H), 6.25 (t, J = 7.2 Hz, 1H), 4.18 (m, 2H), 3.27 (m, 1H), 3.03 (m, 1H), 2.95 (m, 1H), 2.77 (m, 1H), 1.68 (m, 1H), 1.49 (m, 1H), 1.25 (t, J = 7.2Hz), 1.12 (m, 1H).

OTHER EMBODIMENTS



[0039] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.


Claims

1. A method of preparing Compound (C)

or pharmaceutically acceptable salt thereof, wherein R1 is ethyl, comprising:

(g) reacting Compound (A)

with quinine

and ethyl alcohol to form an adduct of the quinine and Compound (C-1)

(h) breaking the adduct of quinine and Compound (C-1) by treating the adduct with HCl to form Compound (C-1) or a pharmaceutically acceptable salt thereof; and

(i) epimerizing Compound (C-1) or a pharmaceutically acceptable salt thereof to form Compound (C):

or a pharmaceutically acceptable salt thereof.


 
2. The method of claim 1, wherein epimerization step (i) includes treating Compound (C-1) with a C1-6 alkoxide.
 
3. The method of claim 2, wherein the C1-6 alkoxide comprises tert-butoxide, tert-amylate, or any combination thereof.
 


Ansprüche

1. Verfahren zum Herstellen einer Verbindung (C)

oder eines pharmazeutisch verträglichen Salzes davon, wobei R1 Ethyl ist, umfassend:

(g) Umsetzen einer Verbindung (A)

mit Chinin

und Ethylalkohol, um ein Addukt aus dem

Chinin und einer Verbindung (C-1) zu bilden

(h) Spalten des Addukts aus Chinin und Verbindung (C-1) durch Behandeln des Addukts mit HCl, um Verbindung (C-1) oder ein pharmazeutisch verträgliches Salz davon zu bilden; und

(i) Epimerisieren der Verbindung (C-1) oder eines pharmazeutisch verträglichen Salzes davon, um Verbindung (C):

oder ein pharmazeutisch verträgliches Salz davon zu bilden.


 
2. Verfahren nach Anspruch 1, wobei der Epimerisierungsschritt (i) das Behandeln der Verbindung (C-1) mit einem C1-6 Alkoholat umfasst.
 
3. Verfahren nach Anspruch 2, wobei das C1-6 Alkoholat tert-Butoxid, tert-Amylat oder eine beliebige Kombination davon umfasst.
 


Revendications

1. Méthode de préparation du composé (C)

ou d'un sel pharmaceutiquement acceptable de celui-ci, où R1 est éthyle, comprenant:

(g) la réaction du composé (A)

avec quinine

et alcool éthylique pour former un adduit de la quinine et du composé

(h) la rupture de l'adduit de la quinine et du composé (C-1) en traitant de l'adduit avec HCl pour former le composé (C-1) ou un sel pharmaceutiquement acceptable de celui-ci; et

(i) épimériser le composé (C-1) ou un sel pharmaceutiquement acceptable de celui-ci pour former le composé (C):

ou un sel pharmaceutiquement acceptable de celui-ci.


 
2. Méthode de la revendication 1, dans laquelle l'étape d'épimérisation (i) comprend le traitement du composé (C-1) avec un alcoxyde C1-6
 
3. Méthode de la revendication 2, dans laquelle l'alcoxyde C1-6 comprend du tert-butoxyde, du tert-amylate, ou aucune combinaison de ceux-ci.
 






Cited references

REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description




Non-patent literature cited in the description