(cis)-2-fluorocyclopropanecarboxylic acid

To a solution of 1-1 (2.5 g, 8.1 mmol, 1 eq) and trans-2-fluorocyclopropanecarboxylic acid(1.0 g, 9.8 mmol, 1.2 eq) in DMF (20 mL) was added HATU (3.7 g, 9.8 mmol, 1.2 eq) and DIEA(1.6 g, 12.2 mmol, 2.1 mL, 1.5 eq). The mixture was stirred at 25 C for 16 hr. The reaction was diluted with ethyl acetate (150 mL) and was washed with saturated NaHCO3 (50 mL) and brine100 mL (50 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated in tert-butyl methyl ether (20 mL) and collected byfiltration to give 1-31 as a yellow solid. 1H NMR (400 MHz, DMSO-d6) O ppm 10.74 (s, 1 H), 8.91(d, J=2.51 Hz, 1 H), 8.75 (d, J=2.26 Hz, 1 H), 8.62 (d, J=2.26 Hz, 1 H), 8.36 (dd, J=7.03, 2.51Hz, 1 H), 7.60-7.74 (m, 1 H), 7.55 (dd, J=11.17, 9.16 Hz, 1 H), 4.70-5.12 (m, 1 H), 2.89 (s, 1H), 2.23 -2.41 (m, 1 H), 1.46 - 1.66 (m, 1 H).To a solution of (+-)-trans-2-fluorocyclopropanecarboxylic acid (250 mg, 2.4 mmol) in dichloromethane (5 mL) and DMF (0.1 mL) was added dropwise oxalyl dichloride (375 mg, 2.95 mmol). The mixture was stirred at 20 C. for 2 hours. The reaction mixture was then concentrated under vacuum to give a yellow residue, which was then used in the next step directly.A mixture of trans-2-fluorocyclopropanecarboxylic acid (25.0 g, 240 mmol) and N, N-dimethylformamide (1.8 g, 24 mmol) in dichloromethane (227 mL) was added oxalyl chloride (30.5 mL, 360 mmol) at 0 C. The mixture was stirred at 20 C. for 16 h and concentrated under reduced pressure to give crude trans-2-fluorocyclopropanecarbonyl chloride (29.4 g, 99%).General procedure: Example 254 Preparation of (S, R)-N-{4-[6, 6-dimethyl-4-oxo-3-(phenylamino)-4, 5, 6, 7-tetrahydro-1H-indol-2-yl]p ridin-2-yl}-2-fluorocyclopropanecarboxamideUsing Method G2 at 50C: Example 122 (250 mg, 722 muiotatauiotaomicronIota) gave the desired racemic trans-product (181 mg, 58 %) after silica chromatography.1 H-NMR (400 MHz , DMSO-d6), Shift [ppm]= 1.06 (6H), 1.20 (1 H), 1 .44-1 .60 (1 H), 2.22 (2H), 2.52-2.60 (1 H), 2.73 (2H), 4.75 (1 H), 4.84-5.01 (1 H), 6.49-6.56 (2H), 6.59 (1 H), 7.01 (2H), 7.17 (1 H), 7.36 (1 H), 8.09 (1 H), 8.16 (1 H), 10.81 (1 H), 1 1.86 (1 H).Method G2 Acylation of 2-(2-aminopyrid-4-yl)-3-amino-1, 5, 6, 7-tetrahydro-4H-indol-4-ones (Formula la)To a mixture of the carboxylic acid (2eq) in DMF was added HATU (2 eq) followed by DIPEA (2eq). Stirred at RT for 10-15 mins, then 2-(2-aminopyrid-4-yl)-3-amino-1, 5, 6, 7- tetrahydro-4H-indol-4-one (1 eq) was added and stirred at room temperature unless otherwise stated. The reaction was concentrated and purified either by column chromatography or preparative HPLC.To a stirring solution of trans-2-Fluoro-cyclopropanecarboxylic acid (0.38 g, 3.68 mmol) in anhydrous NMP (12 mL) was added 1, 1?-carbonyldiimidazole (CDI) (0.59 g, 3.68 mmol). The reaction was stirred for 3 minutes. N?-hydroxy-4-methyl-3-nitrobenzimidamide (27) (0.72 g, 3.68 mmol) was added and the reaction was stirred for minutes then heated in the microwave at 120 C. for 15 minutes. The crude product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified on silica gel using ethyl acetate and hexane to yield 5-(2-fluorocyclopropyl)-3-(4-methyl-3-nitrophenyl)-1, 2, 4-oxadiazole (129). MS m/z 264.1 (M+1)+.; To a suspension of 5-(2-fluorocyclopropyl)-3-(4-methyl-3-nitrophenyl)-1, 2, 4-oxadiazole (129) (162 mg, 0.62 mmol) in EtOH:H2O (4:1) (3.3 mL) was added zinc dust (161 mg, 2.46 mmol) and ammonium chloride (132 mg, 2.46 mmol). The reaction mixture was heated at 85 C. for 24 hours, then filtered hot over celite and rinsed with ethyl acetate. The solvent was concentrated to give 5-(5-(2-fluorocyclopropyl)-1, 2, 4-oxadiazol-3-yl)-2-methylaniline (130).; The separation of enantiomers was performed using a 21.2×250 mm Lux-Cellulose-2 column at a flow rate of 80 g/min, using CO2/Methanol (85:15) at 30 C. Analytical methods using the same column and solvent mixture showed peak 1 eluting at 2.80 min, and peak 2 at 3.28 min. Peak 1 was arbitrarily assigned to be the isomer 5-(5-((1R, 2S)-2-fluorocyclopropyl)-1, 2, 4-oxadiazol-3-yl)-2-methylaniline (131) and Peak 2 was assigned to be the isomer 5-(5-((1S, 2R)-2-fluorocyclopropyl)-1, 2, 4-oxadiazol-3-yl)-2-methylaniline (132). MS m/z 234.1 (M+1)+.To the toluene solution (150 mL) of tert-butyl 2-fluoro-cyclopropane-1-carboxylate (3a) (12.4 g, cis/trans = 93/7) obtained in Example 2, p-toluenesulfonic acid monohydrate (732.0 mg, 3.85 mmol) was added, and the resultant mixture was heated under reflux for 1 hour and 30 minutes. After the resultant reaction mixture was cooled, 3.5 N aqueous sodium hydroxide solution (30 mL) was added to the reaction mixture, and the resultant organic layer was separated. Concentrated hydrochloric acid (6.2 mL) was added to the aqueous layer for adjusting the pH to about 1. Subsequently, the aqueous layer was subjected to extraction with methyl tert-butyl ether, and the resultant organic layer was dried over magnesium sulfate. The solvent was removed through evaporation under reduced pressure, to thereby yield 2-fluoro-cyclopropane-1-carboxylic acid (6.75 g, cis/trans = 93/7) as an oily substance. To the oily substance, n-heptane (100 mL) was added, followed by slurrying at room temperature for 30 minutes and at -15C for 1 hour and 30 minutes. The thus-precipitated crystals were collected through filtration, and then dried, to thereby yield 6.43 g of the title compound as white crystals. The crystals were subjected to gas chromatography analysis, and the cis/trans ratio was found to be 99.2/0.8.