MXPA00000063A - Novel stereoselective processes for the preparation of gabapentin analogues - Google Patents

Abstract

This invention is novel processes for the stereoselective preparation of gabapentin analogues.

Description

NEW STEREOSELECTIVE PROCESSES FOR THE PREPARATION OF GABAPENTIN ANALOGS BACKGROUND OF THE INVENTION The Patent of E.U.A. No. 5,091, 567, incorporated herein by reference, describes a process for the preparation of gabapentin (acetic acid 1-amino-methyl-1-cyclohexane) which is a useful medicine, for example, in the treatment of epilepsy. The process is illustrated by the following scheme: Stage (a) Stage (b) Stage (c) Stage (d) Stage (e) The present invention provides a stereoselective synthesis for substituted cyclic analogs of gabapentin and for gabapentin per se. The advantages of the synthesis mentioned here are: the control of the stereochemistry and not requiring any resolution at the end of the synthesis.

SUMMARY OF THE INVENTION The present invention involves a novel synthetic route for the preparation of substituted analogues of gabapentin. The route allows the synthesis in particular of certain stereoisomers of individual derivatives of the alkylated gabapentin with a high degree of stereochemical purity.

The present invention is summarized in the general route shown below. The first step involves the conversion of a substituted cyclohexanone to an α, β unsaturated ester via the use of a trialkylphosphonoacetate or a (alkoxycarbonylmethyl) tpphenyl-phosphonium halide and a base, such as sodium hydride, potassium hydride, hexamethyldisilazide of lithium, sodium or potassium, butyllithium or potassium t-butoxide in a solvent such as tetrahydrofuran, dimethyl formamide, diethyl ether or dimethyl suiphoxide at the appropriate temperature in the range from -78 ° C to 100 ° C.

The second step involves the reaction of α, β-unsaturated ester with nitromethane and an appropriate base such as tetrabutylammonium fluoride, tetramethylguanidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] -7-undecene, a sodium or potassium alkoxide, sodium hydride or potassium fluoride in a solvent such as hydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, dichloromethane, chloroform or tetrachloromethane at a suitable temperature in the range from -20 ° C to 100 ° C.

The third stage involves a catalytic hydrogenation of the nitro part using a catalyst such as Raney nickel, a palladium or rhodium on carbon catalyst or another catalyst containing nickel or palladium in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, acetic acid, 1,4-dioxane, chloroform or diethyl ether at the appropriate temperature in the range from 20 ° C to 80 ° C.

The final stage involves a hydrolysis using hydrochloric acid and can also use a cosolvent such as tetrahydrofuran or 1,4-dioxane or another inert solvent miscible in water at a suitable temperature in the range from 20 ° C to reflux.

General scheme: DETAILED DESCRIPTION OF THE INVENTION The following experimental procedures provide a new route used to stereoselectively synthesize gabapentin and its analogues. This route provides access to pure stereoisomers.

Example 1 shows the route used to synthesize gabapentin per se.

Said route is also useful in the synthesis of the compounds of formula a pharmaceutically acceptable salt thereof or a prodrug thereof, wherein A is a bridging ring selected from: (i) (2) (3) wherein: Ri and R2 are each independently selected from hydrogen and methyl; R3 and R4 are each independently selected from hydrogen and methyl; n is an integer from 1 to 4 and m is an integer from 0 to 2.

The route is also useful in the synthesis of compounds that have the formula: or a pharmaceutically acceptable salt thereof wherein: X is O, S, S (O), S (O) 2 or NRi is hydrogen, alkyl of straight or branched structure of from 1 to 6 carbon atoms, benzyl, or -C (0) R2 wherein R2 is a straight or branched alkyl of from 1 to 16 carbon atoms, benzyl or phenyl, or -CO2R3 where R3 is straight or branched alkyl of from 1 to 6 carbon atoms, or benzyl wherein the benzyl and phenyl groups may they are unsubstituted or substituted by and from 1 to 3 substituents, each independently selected from halogen, CF and nitro and R is hydrogen or lower alkyl.

Example 2 below shows the use of 4-substituted cyclohexanone to provide a pure trans gabapentin analogue.

Example 3 below shows the use of a disubstituted cyclohexanone. Example 4 below shows the use of a 3-substituted gabapentin analog to provide a pure cis product which is a mixture of enantiomers. The use of an enantiomerically pure 3-substituted cyclohexanone provides a pure product.

General Route (iii) Reagents and conditions: (i) (R10) 2P (0) CH2C02R, base (e.g., NaH, LiN (SiMe3) 2, K, H BuLi) (ii) MeN02, base (for example, Bu N + F, Tetramethylguanidine, KF) (iii) Catalytic hydrogenation using for example, Raney nickel or Palladium on carbon) (iv) Hydrolysis using HCl EXAMPLE 1 (i) (EtO) 2P (0) CH2CO2Et, NaH, THF (ii) MeN02, Bu4N + F, THF, 70 ° C (ii) Ni Raney, H2, MeOH unsaturated a.ß ester Sodium hydride (60% dispersion in oil, 1.16 g, 28.99 mmol) was suspended in dry tetrahydrofuran (40 mL) and cooled to 0 ° C. Triethylphosphonoacetate (6.35 mL, 31.89 mmol) was added. Once the effervescence settled, the mixture was stirred for 15 minutes at a temperature of 0 ° C. Subsequently, cyclohexanone (3 mL, 28.99 mmol) was added and the mixture was allowed to warm to room temperature. After one hour, the mixture was partitioned between 2N HCl (50 mL) and diethyl ether (100 mL). The ether layer was collected, a clear oil which was purified by flash chromatography (silica, ethyl acetate: heptane 1: 9) to give 3.8 g (78%) of a colorless oil which was used without further purification.

Nitro ester The α, β-unsaturated ester (1605 g, 9.55 mmol) was dissolved in tetrahydrofuran (30 mL) with nitromethane (1.03 mL, 19.1 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 14 mL, 14.0 mmol) and the mixture The resulting mixture was heated to 70 ° C. After 18 hours, the mixture was diluted with ethyl acetate (60 mL) and washed with 2N HCl (40 mL) followed by the brine (40 mL). The organic phase was separated, dried (MgSO 4) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate: heptane, 1: 9) to give 996 mg (46%) as a colorless oil. 1HNMR 400 MHz (CDCl 3) d: 1.27 (3H, t, J = 6 Hz), 1.38-1.62 (1 OH, m), 2.54 (2H, s), 4.15 (2H, q, J = 6 Hz), 4.70 (2H, s). MS (ES +) m / e: 230 ([MH] +; 78%), 170 (100%) IR thin film v (crrf1): 1031, 1180, 1377, 1548, 1732, 2935. C11H19NO4 calculated: C, 57.63 %; H, 8.35%; N, 6.11% Found: C, 57.88%; H, 8.61%; N, 6.01% Lactam The nitro ester (935 mg, 4.08 mmol) was dissolved in methanol (40 mL) and stirred on Raney nickel (catalytic) under an atmosphere of hydrogen gas (50 psi) at 35 ° C. After 18 hours, the catalyst was removed by filtration through celite. The methanol was removed in vacuo to give 622 mg (100%) of an oil which crystallized on standing. 1 H NMR 400 MHz (CDCl 3) d: 1.38-1.61 (10H, m), 2.18 (2H, s), 3.14 (2H, s), 5.61 (1 H, br s). MS (ES +) m / e: 154 ([MH] +; 100%) IR thin film v (cm "1): 1252, 1451, 1695, 2925. C9H15NO calculated: C, 70.55%; H, 9.87%; N , 9.14% Found: C, 70.46%; H, 9.72%; N, 8.97% Amino hydrochloric acid The lactam (608 mg, 4.0 mmol) was heated to reflux in a mixture of 6N HCl (15 mL) and 1,4-dioxane (5 mL). After 4 hours the solvent was removed in vacuo and the solid residue was recrystallized from a methanol / ethyl acetate / heptane mixture to give 682 mg (71%) of a white solid. 1 H NMR 400 MHz (d-6 DMSO) d: 1.12-1.51 (10H, m), 2.41 (2H, s), 2.91 (2H, s), 8.06 (3H, br s), 12.36 (1 H, br s ).

MS (APCI) m / e: 172 ([MH-HCI] +; 100%) C9H18N02CI calculated: C, 52.05%; H, 8.74%; N, 6.74%; Cl, 17.07% Calculated: C, 51.97%; H, 8.77%; N, 6.63%; Cl, 16.94% EXAMPLE 2 (i) (EtO) 2 P (O) CH2CO2Et, NaH, THF (ii) MeN02, Bu4N + F ', THF, 70 ° C (iii) Ni Raney, H2, MeOH (iv) HCI / H2O Ester a.β unsaturated Sodium hydride (69% dispersion in oil, 0.98 g, 24.45 mmol) was suspended in dry tetrahydrofuran (50 ml) and cooled to 0 ° C. Triethylphosphonoacetate (5.12 mL) was added25.67 mmol). Once the effervescence settled, the mixture was stirred for 15 minutes at a temperature of 0 ° C. 4-Methyl cyclohexanone (3 mL, 24.45 mmol) was added and the mixture was allowed to warm to room temperature. After 1.5 hours, the solvent was decanted from the thick oil that formed and the oil was washed with diethyl ether (3 x 50 mL). The decanted solvent and the ether washings were combined and washed with 2N HCl (50 mL) followed by brine (50 mL), dried (MgSO4) and the solvent removed in vacuo to give a clear oil which was used without purification .

Trans-nitro ester The α, β-unsaturated ester (2.94 g, 16.15 mmol) was dissolved in tetrahydrofuran (20 mL) with nitromethane (1.75 mL, 32.3 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 24 mL, 24.0 mmol) and the resulting mixture it was heated to 70 ° C. After 18 hours, the mixture was diluted with ethyl acetate (60 mL) and washed with 2N HCl (40 mL) followed by brine (40 mL). The organic phase was separated, dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate: heptane, 1: 9) to give 2.74 g (70%) as a colorless oil. 1 H NMR 400 MHz (CDCl 3) d: 0.93 (3 H, d, J = 6 Hz), 1.08-1.23 (8 H, m), 1.58 (2 H, m), 1.73 (2 H, m), 2.59 (2 H, s), 4.15 (2H, q, J = 6Hz), 4.60 (2H, s). MS (APCI) m / e: 244 ([MHf; 8%), 198 (100%), 183 (68%), 168 (66%) IR thin film v (crtT1): 1029, 1179, 1195, 1377, 1457 1549, 1732, 2929. C12H2? NO4 calculated: C, 59.24%; H, 8.70%; N, 5.76% Found: C, 50.99%; H, 8.73%; N, 5.70% Lactam The nitro ester (2.70 g, 4.08 mmol) was dissolved in methanol (60 mL) and stirred on Raney nickel (catalytic) under an atmosphere of hydrogen gas (40 psi) at 35 ° C. After 18 hours, the catalyst was removed by filtration through celite. The methanol was removed in vacuo and the residue was purified by flash chromatography (silica, ethyl acetate / heptane 1: 1) to give 721 mg (39%) of a white solid. 1 H NMR 400 MHz (CDCl 3) d: 0.91 (3 H, d, J = 6 Hz), 0.94-1.12 (2 H, m), 1.25-1.43 (3 H, m), 1.60 (2 H, m), 1.71 (2 H, br d, J = 16 Hz), 2.21 (2H, s), 3.10 (2H, s), 5.64 (1H, br s). MS (APCI) m / e: 168 ([MHf; 100%) IR thin film c (cm "1): 1254, 1305, 1446, 1494, 1668, 1693, 2910, 3219. C10H17 NOT calculated: C, 71.18%; H, 10.25%: N, 8.37% Found: C, 71.76%; H, 10.33%; N, 8.10% Amino hydrochloric acid The lactam (715 mg, 4.0 mmol) was heated to reflux in a mixture of 6N HCl (15%). mL) and 1,4-dioxane (5 mL) After 4 hours, the solvent was removed in vacuo and the solid residue was recrystallized from a methanol / ethyl acetate / heptane mixture to give 664 mg (70%) of a white solid.1H NMR 400 MHz (d-6 DMSO) d: 0.88 (3H, d, J = 6Hz), 1.10 (2H, m), 1.22 (3H, m), 1.22 (3H, m), 1.51 ( 2H, m), 2.43 (2H, s), 2.85 (2H, s), 7.92 (3H, br s), 12.39 (1 H, br s) MS (APCI) m / e: 186 ([MH-HCI ] +; 100%) C? 0H20NO2CI calculated: C, 54.17%; H, 9.09%; N, 6.32%; Cl, 15.99% Found: C, 54.33%; H, 9.38%; N, 6.32%; Cl, 15.78 % EXAMPLE 3 (i) EtO) 2 P (O) CH2CO2Et, NaH, THF (i) MeN02, Bu4N + F-, THF, 70 ° C (iii) Ni Raney, H2, MeOH (iv) HCI / H2O Hydride Sodium (60% dispersion in oil, 1029 g, 25.7 mmol) in dry tetrahydrofuran (50 mL) and cooled to 0 ° C. Triethylphosphonoacetate (5.36 mL, 27.0 mmol) was added. Once the effervescence settled, the mixture was stirred at 0 ° C for 15 minutes. 3,5 cis-dimethyl cyclohexanone (3.24 g, 25.7 mmol) was added and the mixture was allowed to warm to room temperature. After 1.5 hours, the solvent was decanted from the thick oil that had formed and the oil was washed with diethyl ether (3 x 50 mL). The decanted solvent and the ether washings were combined and washed with 2N HCl (50 mL) followed by brine (50 mL), dried (MgSO4) and the solvent removed in vacuo to give a clear oil that was used without purification .

Ester trans-Nitro The α, β-unsaturated ester (2.08 g, 10.36 mmol) was dissolved in tetrahydrofuran (20 mL) with nitromethane (1.12 mL, 20.7 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 15.5 mL, 15.5 mmol ) and the resulting mixture was heated to 70 ° C. After 18 hours, the mixture was diluted with ethyl acetate (50 mL) and washed with 2N HCl (40 mL) followed by brine (40 mL). The organic phase was separated, dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate: heptane, 1: 9) to give 1.53 g (56%) as a colorless oil. 1 H NMR 400 MHz (CDCl 3) d: 0.80-0.98 (1 OH, m), 1.27 (3 H, t, J = 6 Hz), 1.58-1.80 (4 H, m), 2.59 (2 H, s), 4.15 (2 H, q, J = 6Hz), 4.57 (2H, s).

MS (APCI) m / e: 258 ([MH] +, 12%) IR thin film v (crrf1): 1028, 1182, 1377, 1461, 1549, 1732, 2954.

Lactam The nitro ester (1495 g, 5.8 mmol) was dissolved in methanol (60 mL) and stirred on Raney nickel (catalytic) under an atmosphere of hydrogen gas (40 psi) at 35 ° C. After 18 hours, the catalyst was removed by filtration through celite. The methanol was removed under vacuum to give 997 mg (95%) of a white solid. 1 H NMR 400 MHz (CDCl 3) d: 0.52 (1H, m), 0.80-0.98 (7H, m), 1.51 (2H, m), 1.69 (4H, m), 2.20 (2H, s), 3.09 (2H, s), 6.03 (1H, br s). MS (APCI) m / e: 182 ([MH] +; 100%) IR thin film v (crn "1): 1258, 1278, 1324, 1373, 1432, 1456, 1679, 1693, 2908, 3208. C11H19NO calculated: C, 72.88%; H, 10.56%; N, 7.73% Calculated: C, 72.76%; H, 10.74%; N, 7.61% Amino hydrochloric acid Lactam (981 mg, 5.4 mmol) was heated to reflux in a mixture of HCl 6N (15 mL) and 1,4-dioxane (5 mL). After 4 hours, the solvent was removed in vacuo and the solid residue was recrystallized from a methanol / ethyl acetate / heptane mixture to give 516 mg (40%) of a white solid. 1 H NMR 400 MHz (d-6 DMSO) d: 0.47 (1 H, m), 0.77-0.91 (8H, m), 1.46-1.63 (5H, m), 2.45 (2H, s), 2.84 (2H, s) ), 8.00 (3H, br s), 12.37 (1 H, br s). MS (APCI) m / e: 200 ([MH-HCl] +; 100%) C 11 H 22 NO 2 Cl calculated: C, 56.04%; H, 9.41%; N, 5.94%; Cl, 15.04% Found: C, 56.00%; H, 9.40%; N, 6.09%; Cl, 15.09% EXAMPLE 4 (i) (EtO) 2 P (0) CH2CO2Et, NaH, THF (ii) MeNO2, Bu4N + F ", THF, 70 ° C (iii) Ni Raney, H2, MeOH (iv) HCI / H2O Ester a, ß unsaturated Sodium hydride (60% dispersion in oil, 1048 g, 26.2 mmol) was suspended in dry tetrahydrofuran (50 mL) and cooled to 0 ° C. Triethylphosphonyl acetate (4.76 mL, 23.9 mmol) was added. The effervescence was settled, the mixture was stirred for 15 minutes at a temperature of 0 ° C. Subsequently, 3R 3-methyl ciciohexanone (2.45 g, 21.8 mmol) was added and the mixture was allowed to warm to room temperature After 1.5 hours, The solvent was decanted from the thick oil that had formed and was diluted with diethyl ether (50 mL), the decanted solvent was washed with water (50 mL) followed by brine (50 mL), dried (MgSO4) and the solvent was added. removed under vacuum to give a clear oil that was used without purification.

Ester Trans-Nitro The ester, β-unsaturated (2.48 g, 13.6 mmol) was dissolved in tetrahydrofuran (20 mL) with nitromethane (1.96 mL, 27.2 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 20.4 mL, 20.4 mmol) and the resulting mixture was heated to 70 ° C. After 18 hours, the mixture was diluted with ethyl acetate (50 mL) and washed with 1 N HCl (2x25 mL) followed by brine (25 mL). The organic phase was rated, dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate: heptane, 1:10) to give 2.43 g (73%) as a colorless oil. 1 H NMR 400 MHz (CDCl 3) d: 0.78-0.98 (4H, m), 1.27 (3H, t, J = 6Hz), 1.40-1.81 (8H, m), 2.61 (2H, s), 4.17 (2H, q , J = 6Hz), 4.58 (2H, s). MS (APCI) m / e: 244 ([MHj +; 10%) IR thin film v (crtf1): 1027, 1097, 1155, 1190, 1378, 1457, 1549, 1732, 2929.

Lactam The nitro ester (2.01 g, 8.28 mmol) was dissolved in methanol (30 mL) and stirred on Raney nickel (catalytic) under an atmosphere of hydrogen gas (40 psi) at 35 ° C. After 3 hours, the catalyst was removed by filtration through celite. The methanol was removed in vacuo and the residue was purified by flash chromatography (silica, ethyl acetate) to give 902 mg (65%) of a white solid. 1 H NMR 400 MHz (CDCl 3) d: 0.77-0.96 (4H, m), 1.18-1.52 (3H, m), 1.62-1.78 (5H, m), 2.22 (2H, s), 3.08 (2H, s ), 5.82 (1 H, br s). MS (APCI) m / e: 168 ([MH] +; 100%) IR thin film v (crn-): 1252, 1455, 1698, 2920, 3220 Amino hydrochloric acid The lactam (0.858 mg, 5.1 mmol) was heated to reflux in a mixture of HCl 6N (10 mL). After 3 hours, the mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the solid residue was recrystallized from a methanol / ethyl acetal / heptane mixture to give 341 mg (30%) of a white solid. 1 H NMR 400 Mhz (d-6 DMSO) d: 0.74-0.91 (5H, m), 1.02-1.18 (1 H, m), 1.38-1.65 (6H, m), 2.46 (2H, s), 2.84 (2H , s), 7.97 (3H, br s), 12.37 (1 H, br s). IR KBr disk v (cnT1): 1187, 1214, 1400, 1515, 1710, 2922, 3370 C11H22NO2CI calculated: C, 54.30%; H, 9.04%; N 6.33%; Cl, 16.06% Found: C, 54.19%; H, 8.99%; N, 6.27%; Cl, 16.01%

Claims (4)

1. CLAIMS process for the preparation of a compound of formula comprising: a) adding cyclohexanone to a mixture of sodium hydride suspended in dry tetrahydrofuran to which triethyl phosphonoacetate has been added; b) divide the mixture in HCl and diethyl ether and collect the ether layer; c) disambiguate the product of step b) mentioned above, the α, β-unsaturated ester in THF with nitromethane and tetrabutylammonium fluoride and heat the resulting mixture to produce a nitro ester; d) dissolving the product of step c) mentioned above, a nitro ester in methanol and stirring on a catalyst to produce the corresponding lactam and e) heating the product of step d) above, a lactam, to reflux in a mixture of HCl and dioxane to produce a compound of formula I and convert it, if desired, to a pharmaceutically acceptable salt. 1.
2. A process for the preparation of a compound of formula comprising: a) adding 4-methylcyclohexanone to a mixture of sodium hydride suspended in dry tetrahydrofuran to which triethyl phosphonoacetate has been added to produce a mixture; b) decanting the solvent from the mixture of step a) mentioned above to produce an α, β-unsaturated ester; c) disover the ester of step b) mentioned above in nitromethane and heat the resulting mixture; d) dissolving the nitro ester of step c) mentioned above in methanol and stirring on a catalyst to produce the corresponding lactam and e) heating the product from step d) above, to reflux in a mixture of HCl and dioxane to produce a compound of formula II and converting it, if desired, to a pharmaceutically acceptable salt.
3. 3. A process for the preparation of a compound of formula comprising: a) adding 5.3 cis-dimethylcyclohexanone to a mixture of sodium hydride suspended in dry tetrahydrofuran to which triethyl phosphonoacetate has been added to produce a mixture; b) decanting the solvent from the mixture of step a) mentioned above to produce an α, β-unsaturated ester; c) disover the product of step b) mentioned above in nitromethane and heat the resulting mixture; d) dissolving the nitro ester of step c) mentioned above in methanol and stirring on a catalyst to produce the corresponding lactam and e) heating the product of step d) above, to reflux in HCl and dioxane to produce a compound of formula III identified above and converting it, if desired, to a pharmaceutically acceptable salt thereof.
4. 4. A process for the preparation of a compound of formula comprising: adding 3R 3-methylcyclohexanone to a mixture of sodium hydride suspended in dry tetrahydrofuran to which triethyl phosphonoacetate has been added to produce a mixture; b) decanting the solvent from the mixture of step a) mentioned above to produce the corresponding α, β-unsaturated ester; C) disrupt the ester in step b) mentioned above in nitromethane and heat the resulting mixture; d) dissolving the nitro ester of step c) mentioned above in methanol and stirring on a catalyst to produce the corresponding lactam and e) heating the product of step d) above, to reflux in a mixture of HCl and 1,4-dioxane to produce a compound of formula IV identified above and converting it, if desired, to a pharmaceutically acceptable salt thereof.