| 60% |
With potassium carbonate; In methanol; at 20℃; |
Cyclohexanone Compound 2a (20.54 g, 0.25 mol) in Et2O (100 mL) was added to a solution of LHMDS (250 mL, 0.25 mol) in Et2O (400 mL) at -78 C. under a N2 atmosphere. The mixture was maintained at -78 C. and stirred for 60 min. A diethyloxylate Compound 2b (36.53 g, 0.25 mMol) in Et2O (100 mL) was added to the mixture, which was stirred at -78 C. for 1 hr. The reaction mixture was allowed to warm to r.t. over 3 hrs and the reaction was quenched with 1N HCl (150 mL), The organic layer was extracted with Et2O (200 mL), washed with brine and separated, then dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 48.50 g, 95% of oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester Compound 2c as a yellow oil. Compound 2c was used in the next step without further purification. Benzylhydrazine dihydrochloride Compound 2d (1.75 g, 9.0 mMol) and K2CO3 (2.77 g, 19.5 mMol) were added to a solution of Compound 2c (1.88 g, 8.85 mMol) in MeOH (50 mL) at ambient temperature under a N2 atmosphere. The resultant heterogeneous mixture was stirred overnight. The reaction mixture was concentrated to dryness and diluted with H2O (100 mL) and EtOAc (500 mL). The organic layer was washed with brine, separated, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a product as a crude oil. Purification by flash chromatography (eluted with 20% EtOAc in hexane) afforded a major isomer 1-benzyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester Compound 2e (1.51 g, 60%) and a minor isomer 2-benzyl-4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid ethyl ester Compound 2f as a colorless oil. 1N NaOH (10 mL) was added to Compound 2e (0.30 g, 1.05 mMol) in THF (10 mL). The mixture was stirred for 30 hours, acidified to pH 2 with 1N HCl and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over sodium sulfate, then filtered and concentrated in vacuo to yield 1-benzyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid Compound 2g (0.190 g, 70%) as a white solid. Thionyl chloride (0.17 g, 0.39 mMol) was added to a solution of the carboxylic acid Compound 2g (0.15 g, 0.55 mMol) in CH2Cl2 (10 mL) at ambient temperature under a N2 atmosphere. The reaction was stirred for 3 hrs and concentrated in vacuo to afford the corresponding acid chloride Compound 2h in quantitative yield. NEt3 (triethylamine) (0.10 g, 0.98 mMol) and acid chloride Compound 2h (0.17 g, 0.39 mMol) were added to a solution of 1,3,3-trimethyl-bicyclo[2.2.1]hept-2-ylamine hydrochloride Compound 2i (0.071 g, 0.39 mMol) (prepared from commercially available L(-)-fenchone as described in Suchocki J A; May E L; Martin T J; Clifford G; Martin, B R, J. Med. Chem., 1991, 34, 1003) in CH2Cl2 (10 mL) at ambient temperature under a N2 atmosphere. The reaction was stirred at r.t. for 3 hrs, then diluted with water (10 mL) and CH2Cl2 (50 mL). The organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a crude oil. Purification by flash chromatography (eluted with 20% EtOAc in hexane) afforded Compound 194 (0.09 g, 41%), as a white solid. 1H NMR (CDCl3, 400 MHz) delta 7.37-7.27 (m, 3H), 7.14-7.09 (m, 2H), 7.03-6.99 (d,J=12 Hz, 2H), 5.23 (s, 2H), 3.76-3.72(m, 1H), 2.85-2.80 (m, 1H), 2.44-2.40 (m, 1H), 1.80-1.70 (m, 7H), 1.55-1.42 (m, 2H), 1.24-1.28 (m, 1H), 1.17 (s, 3H), 1.12 (s, 3H), 0.86 (s, 3H). MS m/z 392 (M+). |
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