A. Preparation of methyl (2R)-2-benzylamino-propionate (1A)
Benzaldehyde (20 mL, 0.2 mol) and triethylamine (TEA, 25 mL, 0.18 mol) were added to a THF (300 mL) solution of D-alanine methyl ester hydrochloride (25 g, 0.18 mol) and the reaction was carried out at room temperature for 48 hours. The reaction mixture was filtered through diatomaceous earth (washed with 150 mL of THF) and concentrated. The crude product was dissolved in methanol (MeOH, 400 mL) and cooled to 0°C. Sodium borohydride (7.5 g, 0.2 mol) was added slowly in batches and the reaction mixture was stirred at 0°C for 3 h. The reaction was purified with 1N NaOH (125 mL). The reaction was quenched with 1N NaOH (125 mL), concentrated and extracted with dichloromethane (DCM, 4 x 200 mL), dried over anhydrous sodium sulfate (Na2SO4), and concentrated to give 1A as a clear off-white oil (31.7 g, 91%). [M + H]+ = 194.
B. Preparation of (3S,6R)-1-benzyl-3,6-dimethyl-piperazine-2,5-dione (1B)
Methyl (2R)-2-benzylamino-propionate (1A, 1.0 g, 5.2 mmol) and N-tert-butoxycarbonyl-L-alanine (0.98 g, 5.2 mmol) were added to a solution of DCC (1.07 g, 5.2 mmol) in DCM (55 mL) at 0°C. The reaction was completed by addition of N-(2R)-2-benzylamino-propionate (1A, 1.0 g, 5.2 mmol) and N-tert-butoxycarbonyl-L-alanine (0.98 g, 5.2 mmol). After addition, the reaction mixture was warmed to room temperature, stirred for 24 h, filtered through diatomaceous earth (washed with 2 x 50 mL of ether) and concentrated. The reaction mixture was dissolved in DCM (30 mL), cooled to 0°C, and trifluoroacetic acid (TFA, 5 mL) was added. after 10 minutes, the reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched with saturated NaHCO3 (100 mL), extracted with DCM (3 x 75 mL), dried over Na2SO4, and purified by rapid chromatography on silica gel (EtOAc) to afford 1B as a clear oil (0.68 g, 57%). [M + H]+ = 233.14.
C. Preparation of (2S,5R)-1-benzyl-2,5-dimethyl-piperazine (1C)
LiAlH4 (60 mmol, 60 mL of a 1.0 M THF solution) was added to a THF (100 mL) solution of (3S,6R)-1-benzyl-3,6-dimethyl-piperazine-2,5-dione (1B, 3.48 g, 15 mmol) at 0°C. The reaction was completed by addition of LiAlH4 (60 mmol, 60 mL of a 1.0 M THF solution). After addition, the reaction mixture was heated at 70°C for 24 hours. After cooling to 0°C, it was quenched by slow addition of H2O (3.5 mL), 1N NaOH (3.5 mL) and H2O (3.5 mL). The reaction mixture was filtered through diatomaceous earth, washed with THF (100 mL) and EtOAc (100 mL), dried over Na2SO4, concentrated and purified by fast chromatography (15% MeOH/CHCl3 with 1% TEA) to give 1C as a clear oil (2.43 g, 79%). [M + H]+ = 205.16.
D. Preparation of 5-bromo-quinoline-8-carbonitrile (1D)
A solution of NaNO2 (345 mg, 5.0 mmol) in H2O (2.0 mL) was added to a 48% aqueous HBr solution (2.0 mL) of 5-amino-quinoline-8-carbonitrile (770 mg, 4.6 mmol) at 0°C. After 30 min, a 48% aqueous HBr solution (1.5 mL) of CuBr (522 mg, 3.6 mmol) was added. (1.5 mL). After addition, the reaction mixture was heated at 100°C for 1 h and cooled to room temperature. It was neutralized to pH 8 with 1N NaOH and extracted with EtOAc (2 × 100 mL). The organic phases were combined, washed with H2O (100 mL), saturated NH4OH (100 mL), dried over Na2SO4, concentrated and purified by rapid chromatography on silica gel (stepwise gradient: DCM to 2% EtOAc/DCM) to afford 1D as a white solid (550 mg, 51%). [M + H]+ = 235.
E. Preparation of (2S,5R)-5-(4-benzyl-2,5-dimethyl-piperazin-1-yl)-quinoline-8-carbonitrile (1E)
In a microwave reaction flask, (+)-(S)-N,N-dimethyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine (15.4 mg, 0.035 mmol), Compound 1D (82 mg, 0.35 mmol), and Compound 1C (86 mg, 0.42 mmol) were dissolved in toluene (3.5 mL), and degassed with N2 for 5 min. Tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol), sodium tert-butoxide (50 mg, 0.52 mmol) were added and the reaction mixture was degassed with N2 for 5 min. The reaction mixture was microwaved at 120°C for 40 min, diluted with EtOAc (2 mL), filtered, concentrated, and purified by preparative HPLC to afford the TFA salt of 1E. 1E was diluted in saturated aqueous NaHCO3 (10 mL), extracted with DCM (2 × 10 mL), and concentrated to give 1E as a yellow film (17.8 mg, 14%). [M + H]+ = 357.
F. Preparation of (2S,5R)-5-(2,5-dimethyl-piperazin-1-yl)-quinoline-8-carbonitrile (1F)
1-Chloroethyl chloroformate (0.054 mL, 0.5 mmol) was added to a dichloroethane (1 mL) solution of compound 1E (18 mg, 0.05 mmol). The reaction mixture was heated at 85°C for 18 hours, concentrated, dissolved in MeOH and heated at 65°C for 24 hours. The reaction mixture was diluted in saturated aqueous NaHCO3 (10 mL), extracted with DCM (2 x 10 mL), dried over Na2SO4, concentrated and purified by rapid chromatography on silica gel (10% MeOH/CHCl3 with 1% TEA) to give 1F as a yellow film (4.5 mg, 34%). [M + H]+ = 267.36.
G. Preparation of (2R,5S)-4-(8-cyano-quinolin-5-yl)-2,5-dimethyl-piperazine-1-carboxylic acid (4-trifluoromethyl-pyridin-3-yl)-amide (1)
A solution of 4-trifluoromethyl-pyridin-3-ylamine (4 mg, 0.025 mmol) and triethylamine (TEA, 0.0035 mL, 0.025 mmol) in DCM (0.5 mL) was added to...
