(1R,2R)-(-)-1,2-CYCLOHEXANEDICARBOXYLIC ACID

A round bottom flask was charged with methanol (500 mL), IPA (500 mL) and trans (racemic)-l, 2-cyclohexane dicarboxylic acid (100 g). In this reaction mass (R)-l- phenylethyl amine (74 mL) was added over a period of 30 minutes and stirred for 2-3 hrs at 30-40 °C. The solid obtained was filtered, washed with methanol and IPA solution (50+50 mL) and dried under reduced pressure to obtain crude salt of iran5(R, R)-l, 2-cyclohexane dicarboxylic acid. The obtained salt was stirred in a solution of methanol (500 mL) and IPA (500 mL) at 65-70 °C for 2-3 hours, cooled to room temperature and filtered. The solid was washed with methanol and IPA solution (50+50 mL) and dried under reduced pressure. The solid thus obtained was dissolved in about 2N hydrochloric acid and extracted two times with ethyl acetate (1000 mL+200 mL). Organic layers were combined and washed with brine solution (100 mL). Ethyl acetate was distilled off under vacuum at 50-55 °C and cyclohexane was added to the residue. The solid separated out was filtered and washed with cyclohexane and dried under vacuum at 45-50 °C for 8-10 hours. Yield = 29.4 gR-(+)-1-phenylethane-1-amine (11) (35.25 g, 290.69 mmol) was added to a solution of mixture of trans-diacid (9 and 10) (50.0 g, 290.69 mmol) in methanol (150.0 mL) at 0 °C. Mixture was stirred about 30 min and the nstirred for 3 h at 25–35 °C.The reaction mixture was cooled to -5 to 0 °C and stirred for 1h, then filtered. The solid was dried under suction and we obtained 30 g of wet compound.The wet compound and MeOH (90.0 mL) were charged in a round-bottomed flash and heated to 65 °C. Stirring was maintained at the same temperature for 2h, and the mixture was cooled to -5 °C, stirred for 2h, and filtered. The obtained compound was suspended in 1N HCl (345 mL) and extracted with ethyl acetate (2×230mL). The organic layer was separated and concentrated to dryness under reduced pressure to obtain a white solid. Yield: 25percent. 100 g (0.34 M) of the compound obtained from example-3 was taken in 300 ml of chloroform, and 400 ml of DM water was added at room temperature. pH of the reaction mass was adjusted to 10-11 by using sodium hydroxide (NaOH). The reaction mass was stirred for about 30 minutes. Aqueous and organic layers were separated. Aqueous layer was again extracted with chloroform and the combined chloroform layers were taken for recovery of R-1phenylethylamine . The pH of the aqueous layer was adjusted to 1 to 2 using hydrochloric acid and the aqueous layer was then extracted twice with 80 ml of ethyl acetate. The combined ethyl acetate layer was dried over sodium sulphate. The dried organic layer( Ethyl acetate layer) was concentrated under vacuum at below 40°C and was co-distilled with 0.5 V of cyclohexane to obtain the crude. The resulting crude material was added 1.0 V of cyclohexane and stirred for lhr at room temperature. The resulting mass was filtered, washed with 0.2V of cyclohexane and dried at about 50° C to obtain the product of HPLC purity more than 99 percent(1R, 2R)-Cyclohexane-1, 2-dicarboxylic acid (150 mg, 0.87 mmol) was suspended in acetic anhydride (2 mL) and stirred at 80° C. for 1 hour. The mixture was cooled, concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give (3aR, 7aR)-hexahydro-2-benzofuran-1, 3-dione as a white solid. It was taken up in DMF (5 mL), 8-fluoro-2, 3, 4, 5-tetrahydropyrido[4, 3-B]indole (166 mg, 0.87 mmol) was added and the solution stirred at room temperature for 3 hours. 1-Aminocyclopropanecarbonitrile hydrochloride (114 mg, 0.96 mmol) was added followed by triethylamine (0.36 mL, 2.61 mmol) and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 499 mg, 0.96 mmol) and the mixture stirred overnight. DMF was removed in vacuo and the residue partitioned between DCM (2.x.30 mL) and 50percent brine (10 mL). The combined organics were treated with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried (magnesium sulphate), concentrated in vacuo and adsorbed onto silica for purification by flash chromatography (0-80percent ethyl acetate/isohexane). To purify further, the sample was triturated twice with anhydrous diethyl ether (2.x.5 mL), filtered and dried under vacuum. This gave (1R, 2R)-N-(1-cyanocyclopropyl)-2-[(8-fluoro-1, 3, 4, 5-tetrahydro-2H-pyrido[4, 3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide as a white solid (24.0 mg, 7percent).MS (+ve ESI): 408.9 (M+H)+ 1H NMR (400 MHz, DMSO) delta 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 (m, 1H), 2.7-3.0 (m, 3H), 3.8 (m, 2H), 4.5-4.7 (m, 2H), 9.9 (m, 1H), 7.2 (m, 1H), 7.3 (s, 1H), 8.65 (s, 1H), 11.0 (s, 1H)(1 R, 2R)-cyclohexane-1 , 2-dicarboxylic acid (300 mg, 1.74 mmol) was suspended in acetic anhydride and stirred at 80 °C overnight. The mixture was concentrated in vacuo and the residue was used directly in the next step.(li?, 2R)-Cyclohexane-l, 2-dicarboxylic acid (150 mg, 0.87 mmol) was suspended in acetic anhydride (2 mL) and stirred at 80 0C for 1 hour. The mixture was cooled, concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give (3ai?, 7ai?)-hexahydro-2-benzofuran-l, 3-dione as a white solid. It was taken up in DMF (5 mL), 6, 7-dimethoxy-l, 2, 3, 4-tetrahydroisoquinoline hydrochloride (230 mg, 0.87 mmol) added followed by triethylamine (0.13 mL, 0.87 mmol) to free up the base and the mixture stirred at room temperature for 3 hours. 1-Aminocyclopropanecarbonitrile hydrochloride (114 mg, 0.95 mmol) was added followed by triethylamine (0.36 mL) and benzotriazol-1- yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 473mg, 0.91 mmol) and the solution stirred over the weekend. DMF was removed in vacuo and the residue partitioned between ethyl acetate (2 x 30 mL) and brine (10 mL). The separated organic portion was adsorbed onto silica for purification by flash chromatography (0-80percent ethyl acetate / isohexane) to give the product as a brittle white solid (119 mg, 33percent). MS (+ve ESI) : 411.9 (M+H)+1R NMR (400 MHz, DMSO) d 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4-3.0 (m, 4H), 3.75 (m, 8H), 4.5 (m, 2H), 6.75 (m, 2H), 8.7 (s, IH)(ii) The reaction solution was cooled, then 15 ml of water and 30 ml of methanol were added thereto, then the mixture was left to stand followed by separation of the phases. To the lower phase (methanol/water), 55.6 g of concentrated hydrochloric acid (0.53 mol) was added dropwise at an internal temperature in the range of from 0° C. to 5° C. under cooling. After the addition, the resulting mixture was stirred at the same temperature for about 1 hr. The precipitated crystals were filtered off, dispersed to wash in 30 ml of water at a room temperature, filtered and dried to give 18.4 g of trans-2-cyclohexane dicarboxylic acid (Purity 97.5percent, Yield 81percent). The above obtained trans-1, 2-cyclohexane dicarboxylic acid was dispersed and washed in acetone to give the same in a purity of 99.6percent. m.p. 228°-230° C.(a) (l-trans)-1, 2-Cyclohexanedicarboxylic acid To a filtered solution of (trans)-1, 2-cyclohexanedicarboxylic acid (52 g., 0.302 mole) [prepared as set forth in Example 26(a)] in n-propanol (1.85 l.) is added a solution of d(+)alpha-methyl benzyl amine (36.6 g., 0.302 mole) in n-propanol (0.11 l). After standing for 2 days under refrigeration, the crude salt is collected as white solids (22 g.). This crude salt is dissolved in 1N hydrochloric acid (300 ml.) and extracted into ether (5*300 ml.). The combined ether extracts are dried (MgSO4) and concentrated on a rotary evaporator into 12.3 g. of white solids. In order to purify the compound, the free acid is reconverted into its salt and then liberated again to afford 10.1 g. of (l-trans)-1, 2-cyclohexanedicarboxylic acid as white solids; [alpha]D25 =-18.06° (c=1.5, acetone).