(19)
(11)EP 2 963 026 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
29.04.2020 Bulletin 2020/18

(21)Application number: 14756865.3

(22)Date of filing:  26.02.2014
(51)International Patent Classification (IPC): 
C07D 307/24(2006.01)
C07F 7/10(2006.01)
C07D 491/107(2006.01)
(86)International application number:
PCT/RU2014/000122
(87)International publication number:
WO 2014/133416 (04.09.2014 Gazette  2014/36)

(54)

SUBSTITUTED (R)-3-(4-METHYLCARBAMOYL-3-FLUOROPHENYLAMINO)TETRAHYDROFURAN-3-ENECARBOXYLIC ACID (VARIANTS) AND ESTER THEREOF, METHOD FOR PRODUCING AND USING SAME

SUBSTITUIERTE (R)-3-(4-METHYLCARBAMOYL-3-FLUORPHENYLAMINO-)TETRAHYDROFURAN-3-ENECARBONSÄURE (VARIANTEN) UND ESTER DAVON, VERFAHREN ZUR HERSTELLUNG UND VERWENDUNG DAVON

ACIDE SUBSTITUÉ (R)-3-(4-MÉTHYLCARBAMOYL-3-FLUOROPHÉNYLAMINO)TÉTRAHYDROFURAN-3-ÈNE-CARBONÉ (ET VARIANTES) ET SON ÉTHER, PROCÉDÉ DE PRODUCTION ET D'UTILISATION


(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: 27.02.2013 RU 2013108672

(43)Date of publication of application:
06.01.2016 Bulletin 2016/01

(73)Proprietor: R-Pharm International, LLC
123154 Moscow (RU)

(72)Inventors:
  • IVACHTCHENKO, Alexandre Vasilievich
    Encinitas, CA 92024 (US)
  • MITKIN, Oleg Dmitrievich
    Khimki Moskovskaya obl. 141400 (RU)
  • KRAVCHENKO, Dmitry Vladimirovich
    Khimki Moskovskaya obl. 141100 (RU)
  • VOROBEV, Anton Aleksandrovich
    Aleksandrov Vladimirskaya obl. 601655 (RU)
  • TRIFILENKOV, Andrey Sergeevich
    Moscow 125473 (RU)

(74)Representative: Zellentin & Partner mbB Patentanwälte 
Rubensstrasse 30
67061 Ludwigshafen
67061 Ludwigshafen (DE)


(56)References cited: : 
EP-A1- 2 597 086
WO-A1-2010/118354
WO-A2-2007/127010
WO-A1-2006/124118
WO-A1-2011/106570
RU-C1- 2 434 851
  
      
    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

    Field of invention



    [0001] The present invention relates to novel chemical compounds - intermediate products in synthesis of androgen receptor inhibitors which are of interest as anticancer medicaments. The subject of the invention is also methods for preparation of novel compounds - androgen receptor inhibitors.

    Background of the invention



    [0002] There are known inhibitors of androgen receptors, among them Enzalutamide, previously known as MDV3100, which at the end of 2012 entered the market as Xtandi and which is intended for prostate cancer treatment [WO 2011/106570 A1] and ARN-509, successfully passing phase II of clinical trial as a drug for prostate cancer treatment [WO 2008/119015 A2].


    Disclosure of the invention



    [0003] In context of the invention, terms are generally defined as follows:

    "Alkyl" means an aliphatic hydrocarbon straight or branched group with 1-5 carbon atoms in chain, preferably 1-4 carbon atoms (C1-C4 alkyl). Branched alkyl means that the alkyl chain has one or more substituents, preferably C1-C4 alkyl, C1-C4 alkyloxymethyl, trimethylsilylethoxymethyl.

    "Amino group" means RkaRk+1aN- group substituted or not with "amino group substituent" Rka and Rk+1a, the meanings of which is defined in this section, for example, amino (H2N-), methylamino, dimethylamino, N-(trimethylsilylethoxymethyl)methylamino, diethylamino, pyrrolidine, morpholine, benzylamino, or phenethylamino.

    "Aminocarbonyl" means C(=O)NRkaRk+1a -group, substituted or not with optionally the same "carbamoyl substituents" Rka and Rk+1a, including hydrogen, alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meanings of which are defined in this section.

    "Aryl" means an aromatic monocyclic or polycyclic system, including 6-14 carbon atoms, preferably 6-10 carbon atoms. Aryl may contain one or more "cyclic system substituents" of the same or different structure. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl may be annelated with non-aromatic cyclic system or heterocycle.

    "Acylamino" means acyl-NH-group, for which the meaning of acyl is defined in this section.

    "Halogen" means fluorine, chlorine, bromine and iodine. Fluorine, chlorine, and bromine are preferable.

    "Heterocyclyl" means aromatic or non-aromatic saturated monocyclic or polycyclic system, including 3-10 carbon atoms, preferably 5-6 carbon atoms, wherein one or more carbon atoms are substituted with heteroatom such as nitrogen, oxygen, or sulfur. Prefix "aza", "oxa", or "thia" before heterocyclyl means the presence of atoms N, O, or S in the cyclic system, respectively. Heterocyclyl may have one or more "cyclic system substituents" of the same or different structure. N- and S- atoms, which are in heterocyclyl may be oxidized to N-oxide, S-oxide, and S-dioxide. Representatives of heterocyclyls are tetrahydrofuran, piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, thiazolidine, 1,4-dioxane, tetrahydrothiophene and others.

    "Substituent" means a chemical radical, which is attached to scaffold (fragment), for example, "alkyl substituent", "amino group substituent", "hydroxy group substituent", "carbamoyl substituent", "cyclic system substituent", the meanings of which are defined in this section.

    "Amino group substituent" means a substituent attached to amino group. Amino group substituent represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, heterocyclylaminocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl. Preferably, substituents are selected from hydrogen, trimethylsilylethoxymethyl, methyl, substituted fluorophenyl, substituted alkyl.

    "Carboxyl substituent" means a substituent attached to O-atom of carboxyl group, the meaning of which is defined in this section. Carboxyl substituent is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl, or RkaRk+1aN- alkyl, RkaRk+1aNC(=O)-alkyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl. Preferably, "carboxyl substituents" are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl, or RkaRk+1aN- alkyl, RkaRk+1aNC(=O)-alkyl, arylheterocyclenyl, annelated arylheterocyclyl. Preferable substituents are C1-C4alkyl (methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and others).

    "Carboxyl" means HOC(=O) - (carboxyl) group.
    Recently have been prepared effective androgen receptor inhibitors representing 4-[3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methylbenzamide A1 and (R)- A2 and (S)- A3 stereoisomers thereof [RU patent 2434851, publ. 27.11.2011; WO 2012/011840, publ. 26.01.2012].





    [0004] Synthesis of 4-[3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1 ,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methylbenzamide A1 was carried out by interaction of 4-thioisocyanate-2-(trifluoromethyl)benzonitrile B1 with 4-(3-cyano-tetrahydrofuran-3-ylamino)-2-fluoro-N-methylbenzamide B2 in dimethylformamide in microwave oven at 100°C for 12 hours according to Scheme 1. Product A1 of the reaction was isolated from the reaction mixture by means of high pressure liquid chromatography and divided into stereoisomers A2 and A3 using high pressure liquid chromatography on Chiralpak HD-H 25x1cm (Chiral Technologies Inc., USA).



    [0005] Separation of the final product A1 and optical isomers A2 and A3 thereof by means of high pressure liquid chromatography, including usage of chiral chromatographic columns, makes the process of their preparation more difficult and expensive. Therefore, the search of novel intermediates for synthesis of androgen receptor inhibitors A1, A2, and A3 is an actual task.

    [0006] The subject of the present invention is unknown before compounds 3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylic acid esters of the general formula 1 and stereoisomers thereof,

    wherein:

    R1 = C1-C4alkyl;

    R2 = H, CH2OCH2CH2Si(CH3)3.



    [0007] The more preferable compounds of the general formula 1 are methyl (R)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylate 1(2) or butyl (R)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylate 1(3)

    1(2): R = CH3, 1(3): R = C4H9

    [0008] The subject of the present invention is a method for preparation of compounds of the general formula 1 and stereoisomers 1(2)-1(3) thereof by interaction of 4-bromo-2-fluoro-N-methylbenzamide of the general formula 2 with 3-aminotetrahydrofuran-3-carboxylic acid ester of the general formula 3.2 or stereoisomers thereof

    2: R2 = H, CH2OCH2CH2Si(CH3)3. 3.2: R1 = C1-C4alkyl.

    [0009] The best results were achieved when compounds 2 reacted with compound 3.2 in the medium of water dimethylformamide in the presence of copper iodide (I), potassium carbonate, triethylamine and 2-acetylcyclohexanone.

    [0010] The subject of the present invention are also intermediates in the synthesis of 4-[3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methylbenzamides A1, A2, and A3, representing compounds of the general formula 1 or stereisomers thereof

    R2 = H, CH2OCH2CH2Si(CH3)3; R1 = C1-C4alkyl.

    [0011] The more preferable intermediates are methyl (R)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylate 1(2) and butyl (R)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylate 1(3).

    1(2): R = CH3, 1(3): R = C4H9

    [0012] The subject of the present invention is also a method for preparation of 4-[3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methylbenzamides A1, A2, and A3, consisting in interaction of a compound of the general formula 1 or stereoisomer thereof with 4-isocyanato-2-trifluoromethylbenzonirile B1 in a mixture of dimethyl sulphoxide and ethyl acetate at elevated temperature according to Scheme 2.

    R2 = H, CH2OCH2CH2Si(CH3)3;

    R1 = C1-C4 alkyl.



    [0013] The best results were achieved when the reaction was carried out in argon atmosphere in the mixture of dimethyl sulphoxide and ethyl acetate taken in ratio 1:2, respectively.

    [0014] Utilization of this invention allows to simplify the process of preparation of androgen receptor inhibitors A1, A2, and A3, increase the yield of the products to 70% and eliminate the use of chiral chromatography.

    The best embodiment of the invention



    [0015] Below the invention is described by means of specific examples which illustrate, but not limit the scope of the invention.

    Example 1. The general method for preparation of 3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylic acid, its ester of the general formula 1 and stereoisomer thereof.



    [0016] In a round bottom flask provided with magnetic stirrer, reflux condenser and oil bath with a temperature controller, was placed 1.2 eq. of acid 3.1 or its ester of the general formula 3.2, 1 eq. of 4-bromo-2-fluoro-N-methylbenzamide of the general formula 2, 0.35 g (0.15 eq.) of copper iodide (I), 6.76 g (4 eq.) of potassium carbonate, 6 ml of water, 27.5 ml of dimethylformamide, and 0.2 ml of triethylamine. After 10 min of stirring 0.35 g (0.2 eq.) of 2-acetylcyclohexanone was added. The reaction mixture was stirred at 100°C for two days. After the reaction was completed solvents were distilled in vacuo. It gave ester of the general formula 1, wherein R1 = C1-C4alkyl, which was mixed with water and acidified with hydrochloric acid (conc.) till pH about 2-3. In 20-30 min. at stirring a solid was formed, which was filtered off, washed with water, and dried. Then it was washed with ether. It gave an acid of the general formula 1, where R1 = H. Yield is above 80%.

    (R)-3-{4-[Methyl-(2-trimethylsilylethoxymethyl)carbamoyl]-3-fluorophenylamino}tetra hydrofuran-3-carboxylic acid 1 [R1 = H, R2 = CH2OCH2 CH2Si(CH3)3] (reference example).



    [0017] LC MS m/e 413 (M+1); 1H NMR (DMSO, 400 MHz) δ 12.85 (br. s, 1H), 7.05 (t, 1H), 6.97 (br. s, 1H), 6.30 (m, 1H), 6.15 (d, 1H), 4.84 (s, 1H), 4.60 (s, 1H), 4.09 (d, 1H), 3.88 (t, 3H), 3.50 (br. s, 1H), 3.32 (br. s, 1H), 2.90 (m, 3H), 2.56 (m, 1H), 2.16 (m, 1H), 0.87 (br. s, 1H), 0.76 (br. s, 1H), 0.00 (m, 9H).

    [0018] (R)-3-(4-Methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylic acid 1(1) (reference example), LC MS m/e 283 (M+1); 1H NMR (DMSO, 400 MHz) δ 13.01 (br. s, 1H), 7.68 (s, 1H), 7.46 (t, 1H), 7.13 (s, 1H), 6.31 (d, 1H), 6.11 (d,1H), 4.09 (d, 1H), 3.86 (m, 3H), 2.71 (m, 4H), 2.14 (m, 1H).

    Example 2. Method for preparation of methyl (R)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylate 1(2).



    [0019] 

    Process A. 500 mg of (R)-3-(4-Methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylic acid 1(1) and 294 mg of potassium carbonate (1.2 eq.) were mixed together in 4 ml of DMF. The mixture was heated to 30°C and 1.2 eq. of methyl iodide was introduced. The temperature was raised to 40°C and mixture was kept for one hour. Then 40 ml of water was added, and mixture was heated to 60°C. The mixture was filtered, water layer was extracted with chloroform (2 x 50ml). Combined organic layers were washed with saturated water solution of sodium chloride, the solvent was evaporated in vacuo. The product was mashed with ether. It gave 372 mg (70%) of product 1(2).

    Process B. To a solution of 10 g of (R)-3-(4-Methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylic acid 1(1) in acetonitrile was added 6.89 g (1.2 eq.) of carbodiimide. The mixture was stirred at 60°C for 1 h, and 20 ml of methanol was introduced. The mixture was left stirring for 2-3 hours. Then solvents were evaporated in vacuo, water was added to the residue. Precipitated solid was filtered off and dried. Yield of ester 1(2) was 7.5 g (71%).

    Process C. 15.5 g of (R)-3-(4-Methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylic acid 1(1) was dissolved in 150 ml of methanol. The flask was cooled with ice and water and the excess of thionyl chloride (1.2 eq.) was added dropwise to the solution for 10 min. Then the reaction mixture was brought to boiling and refluxed for 4 hours. After that the solvent and the excess of thionyl chloride were evaporated in vacuo. The residue was dissolved in 200 ml of chloroform, washed with saturated solution of sodium hydrocarbonate (50 ml), and saturated solution of sodium chloride (50 ml). Chloroform was evaporated in vacuo, ether was added to the residue, and the product was filtered off. Yield of ester 1(2) was 12.5 g (77%).



    [0020] Methyl (R)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylate 1(2), LC MS m/e 297 (M+1); 1H NMR (CDCl3, 400 MHz) δ 7.94 (t, 1H), 6.59 (br. s, 1H), 6.38 (d, 1H0, 6.20 (d, 1H), 4.80 (br. s, 1H), 4.19 (d, 1H), 4.05 (m,3H), 3.76 (s, 3H), 3.01 (d, 3H), 2.51 (m,1H), 2.19 (m,1H).

    Example 3. Method for preparation of butyl (R)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylate 1(3).



    [0021] 0.55g of Butyl (R)-3-aminotetrahydrofuran-3-carboxylate 3.2(1), 0.68 g (1 eq.) of 4-bromo-2-fluoro-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzamide 2.1, 0.27 g (0.1eq.) of Pd*DBA, 0.37 g (0.2 eq.) of BINAP were mixed together in 10 ml of dioxane. The mixture was refluxed in argon atmosphere for 2 days. After that it was poured into water, extracted with chloroform, extract was washed with saturated solution of sodium chloride. Chloroform was evaporated in vacuo, the residue was subjected to chromatography on silica. It gave butyl (R)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylate 1(3), yield ∼ 10%, LC MS m/e 339 (M+1).

    [0022] Example 4. Methods for preparation of 4-[3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methylbenzamide A1, 4-[(R)-3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methylbenzamide A2, 4-[(S)-3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methylbenzamide A3, 4-[(R)-3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methyl-N-(2-trimethylsilylethoxymethyl)benzamide A4. Process A (reference example). In a round bottom flask of 250 ml, provided with magnetic stirrer, reflux condenser, calcium chloride tube, and an oil bath with temperature controller IKAR- ETS-D4, 10.7 g of (R)-3-{4-methyl-(2-trimethylsilylethoxymethyl)carbamoyl]-3-fluorophenylamino}tetrahydrofuran-3-carboxylic acid 1 [R1=H, R2= CH2OCH2CH2Si(CH3)3] and 1.5 eq. of 4-thioisocyanate-2-(trifluoromethyl)benzonitrile B1 in 100 ml of pyridine were placed. The reaction mixture was stirred for 48 hours at 80°C. When the reaction was completed (LCMS control) the most part of pyridine was evaporated in vacuo. The residue was dissolved in ethyl acetate and filtered through a layer of silica, the solvent was distilled in vacuo, ethanol was added to the residue. Precipitated solid was filtered off and dried. It gave 4.84 g of 4-[(R)-3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methyl-N-(2-trimethylsilylethoxymethyl)benzamide A4, LC MS m/e 623 (M+1); 1H NMR (CDCl3, 400 MHz) δ 8.01 (d, 1H), 7.98 (s, 1H), 7.85 (d, 1H), 7.57 (m, 1H), 7.22 (m, 2H), 4.97 (s, 1H0, 4.55 (s, 1H), 4.32 (d, 1H), 4.06 (d, 1H), 3.86 (qv, 1H), 3.66 (m, 1H), 3.57 (t, 1H), 3.26 (t, 1H), 3.10 (s, 2H), 2.89 (s, 1H), 2.64 (m, 1H), 2.41 (m, 2H), 0.91 (t, 1H), 0.77 (t, 1H), 0.06 (s, 3H), 0.00 (s, 6H).



    [0023] 4.8 g of 4-[(R)-3-(3-Trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methyl-N-(2-trimethylsilylethoxymethyl)benzamide A4 were stirred with 15 ml of trifluoroacetic acid in 30 ml of methylene chloride at room temperature for 2-3 hours. After the reaction was completed (no starting compound A4 according to LCMS control), the reaction mixture was evaporated in vacuo, the residue was purified by chromatography on silica. A system of chloroform-methanol (60:1) was used as eluent. The fraction with Rf = 0.4 was collected. It gave 4-[(R)-3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methylbenzamide A2, 78%, LC MS m/e 493 (M+1); 1H NMR (CDCl3, 400 MHz) δ 8.30 (t, 1H), 8.06 (d, 1H), 7.96 (s, 1H), 7.83 (d, 1H), 7.32 (d, 1H), 7.23 (d, 1H), 6.71 (m, 1H), 4.93 (d, 1H), 4.16 (d, 1H), 3.95 (qv, 1H), 3.42 (qv, 1H), 3.08 (d, 3H), 2.73 (m, 1H), 2.47 (m, 1H).

    [0024] Process B (reference example). 5.09 g of (R)-3-(4-Methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylic acid 1(1) and 1.5 eq. of 4-thioisocyanate-2-(trifluoromethyl)benzonitrile B1 in 50 ml of pyridine were stirred at 80°C for 48 hours. After the reaction was completed (LCMS control), the most part of pyridine was evaporated in vacuo. The residue was subjected to chromatography on silica. A system of chloroform-methanol (60:1) was used as eluent. The fraction with Rf = 0.6 was collected. It gave 630 mg (yield 7.6%) of product A2 with purity 99.2%, LC MS m/e 493 (M+1); 1H NMR (CDCl3, 400 MHz) δ 8.30 (t, 1H), 8.06 (d, 1H), 7.96 (s, 1H), 7.83 (d, 1H), 7.32 (d, 1H), 7.23 (d, 1H), 6.71 (m, 1H), 4.93 (d, 1H), 4.16 (d, 1H), 3.95 (qv, 1H), 3.42 (qv, 1H), 3.08 (d, 3H), 2.73 (m, 1H), 2.47 (m, 1H).

    [0025] Note. Carrying out the reaction: in a microwave reactor in pyridine (70°C, 3 h) gave final product A2 with yield 10%; in acetonitrile in the presence of K2CO3 (60°C, 12 h) gave final product A2 with yield 8%; in acetonitrile in the presence of (C2H5)3N in argon atmosphere (75°C, 3 h) gave final product A2 with yield 28%.

    [0026] Process C. 1.05 g of methyl (R)-3-(4-methylcarbamoyl-3-fluorophenylamino) tetrahydrofuran-3-encarboxylate 1(2) and 1.62 g (2eq.) of 4-thioisocyanate-2-(trifluoromethyl)benzonitrile B1 in a mixture of 252 µl (1 eq.) of DMSO and 692 µl (2 eq.) of ethyl acetate were stirred together at 85°C for 48 hours. After the reaction was completed (LCMS and TLC control) the solvents were evaporated in vacuo. The residue was subjected to flash-chromatography on silica. Chloroform was used as eluent. Fraction with Rf = 0.6 was collected (TLC was in system chloroform-methanol 60:1), the solvent was evaporated in vacuo, the residue was crystallized from ethanol. It gave product A2 with yield 60-70% and 99.5% of basic material, LC MS m/e 493 (M+1); 1H NMR (CDCl3, 400 MHz) δ 8.30 (t, 1H), 8.06 (d, 1H), 7.96 (s, 1H), 7.83 (d, 1H), 7.32 (d, 1H), 7.23 (d, 1H), 6.71 (m, 1H), 4.93 (d, 1H), 4.16 (d, 1H), 3.95 (qv, 1H), 3.42 (qv, 1H), 3.08 (d, 3H), 2.73 (m, 1H), 2.47 (m, 1H).

    [0027] In analogous manner 4-[(S)-3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methylbenzamide A3 was prepared, starting from the corresponding (S)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylic acid of formula 1, yield 60-65%, LC MS m/e 493 (M+1).

    [0028] In analogous manner 4-[3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methylbenzamide A1 was prepared, starting from the corresponding 3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylic acid of formula 1, yield 60-65%, LC MS m/e 493 (M+1).

    Industrial applicability



    [0029] The invention could be used in medicine, veterinary, biochemistry.


    Claims

    1. Compounds of the general formula 1 or stereoisomers thereof,

    wherein:

    R1 = C1-C4alkyl;

    R2 = H, CH2OCH2CH2Si(CH3)3.


     
    2. Compounds according to claim 1, representing methyl (R)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylate 1(2) or butyl (R)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-encarboxylate 1(3)

    1(2): R = CH3, 1(3): R = C4H9
     
    3. A method for preparation of compounds of the general formula 1 or stereoisomers thereof

    wherein:

    R1 = C1-C4alkyl;

    R2 = H, CH2OCH2CH2Si(CH3)3;

    by simultaneous interaction of 4-bromo-2-fluoro-N-methylbenzamide of the general formula 2, K2CO3, 3-aminotetrahydrofuran-3-carboxylic acid ester of the general formula 3.2 or stereoisomers thereof

    2: R2 = H, CH2OCH2CH2Si(CH3)3; 3.2: R1 = C1-C4alkyl;

    in DMF, characterized in that copper iodide (I), water and triethylamine were added to the reaction mixture concurrently.


     
    4. Method for preparation of 4-[3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-methylbenzamides A1, A2, and A3



    consisting in reacting a compound of the general formula 1 or stereoisomer thereof,

    wherein:

    R1 = C1-C4 alkyl;

    R2 = H, CH2OCH2CH2Si(CH3)3;

    prepared according to claim 3,

    with 4-isothiocyanate-2-trifluoromethylbenzonitrile B1

    wherein the reagents are stirred in dimethyl sulphoxide and ethyl acetate mixture in ratio 1:2 at elevated temperature.


     


    Ansprüche

    1. Verbindungen der allgemeinen Formel 1 oder Stereoisomere davon

    worin:

    R1 = C1-C4-Alkyl;

    R2 = H, CH2OCH2CH2Si(CH3)3.


     
    2. Verbindungen gemäß Anspruch 1, die Methyl-(R)-3-(4-methylcarbamoyl-3-fluorphenylamino)tetrahydrofuran-3-encarboxylat 1(2) oder Butyl-(R)-3-(4-methylcarbamoyl-3-fluorphenylamino)tetrahydrofuran-3-encarboxylat 1(3) darstellen

    1(2): R = CH3, 1(3): R = C4H9.
     
    3. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel 1 oder Stereoisomeren davon

    worin:

    R1 = C1-C4-Alkyl;

    R2 = H, CH2OCH2CH2Si(CH3)3;

    durch gleichzeitige Wechselwirkung von 4-Brom-2-Fluor-N-Methylbenzamid der allgemeinen Formel 2, K2CO3, 3-Aminotetrahydrofuran-3-carbonsäure 3.1 oder deren Ester der allgemeinen Formel 3.2 oder Stereoisomere davon

    2: R2 = H, CH2OCH2CH2Si(CH3)3; 3.2: R1 = C1-C4-Alkyl;

    in DMF, dadurch gekennzeichnet, dass dem Reaktionsgemisch gleichzeitig Kupfer(I)-iodid, Wasser und Triethylamin zugesetzt wurden.


     
    4. Verfahren zur Herstellung von 4-[3-(3-Trifluormethyl-4-cyanophenyl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluor-N-methylbenzamiden A1, A2 und A3



    bestehend aus der Umsetzung einer Verbindung der allgemeinen Formel 1 oder eines Stereoisomers davon

    worin:

    R1 = C1-C4 alkyl;

    R2 = H, CH2OCH2CH2Si(CH3)3;

    hergestellt gemäß Anspruch 3,

    mit 4-lsothiocyanat-2-trifluormethylbenzonitril B1

    wobei die Reagenzien in einer Mischung aus Dimethylsulfoxid und Ethylacetat im Verhältnis 1:2 bei erhöhter Temperatur gerührt werden.


     


    Revendications

    1. Composés répondant à la formule générale 1 ou leurs stéréo-isomères :

    formule dans laquelle:

    R1 représente un groupe alkyle en C1-C4;

    R2 représente un atome d'hydrogène, un groupe CH2OCH2CH2Si(CH3)3.


     
    2. Composés selon la revendication 1, représentant le (R)-3-(4-méthylcarbamoyl-3-fluorophénylamino)tétrahydrofuran-3-ènecarboxylate de méthyle 1(2) ou le (R)-3-(4-méthylcarbamoyl-3-fluorophénylamino)-tétrahydrofuran-3-ènecarboxylate de butyle 1(3)

    1(2): R représente un groupe CH3, 1(3) : R représente un groupe C4H9.
     
    3. Procédé pour la préparation de composés répondant à la formule générale 1 ou de leurs stéréo-isomères

    formule dans laquelle:

    R1 représente un groupe alkyle en C1-C4;

    R2 représente un atome d'hydrogène, un groupe CH2OCH2CH2Si(CH3)3;

    par l'intermédiaire d'une interaction simultanée du 4-bromo-2-fluoro-N-méthylbenzamide répondant à la formule générale 2, du K2CO3, de l'ester de l'acide 3-aminotétrahydrofuran-3-carboxylique répondant à la formule générale 3.2 ou de ses stéréo-isomères

    2: R2 représente un atome d'hydrogène, un groupe CH2OCH2CH2Si(CH3)3;

    3.2: R1 représente un groupe alkyle en C1-C4;

    dans du DMF, caractérisé en ce que l'on ajoute de manière concourante au mélange réactionnel de l'iodure de cuivre(I), de l'eau et de la triéthylamine.


     
    4. Procédé pour la préparation des 4-[3-(3-trifluorométhyl-4-cyanophényl)-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl]-2-fluoro-N-méthylbenzamides A1, A2 et A3:



    consistant à faire réagir un composé répondant à la formule générale 1 ou un de ses stéréo-isomères:

    formule dans laquelle:

    R1 représente un groupe alkyle en C1-C4;

    R2 représente un atome d'hydrogène, un groupe CH2OCH2CH2Si(CH3)3;

    préparé conformément à la revendication 3;

    avec du 4-isothiocyanate-2-trifluorométhylbenzonitrile B1 :

    dans lequel on agite les réactifs dans un mélange de diméthylsulfoxyde et d'acétate d'éthyle dans un rapport 1:2 à une température élevée.


     






    Cited references

    REFERENCES CITED IN THE DESCRIPTION



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    Patent documents cited in the description