Benzylamine → Ethyl 4-{[(aminosulfonyl)(benzyl)amino]methyl}cyclohexanecarboxylate

The hydrochloride salt of trans 4-[benzylamino]methyl]cyclohexane carboxylic acid ethyl ester (CAS 140406-44-6) (275 mg, 0.88 mmole, 1.0 eq) was suspended in 1,2-dimethoxyethane. Triethylamine (139 μL, 1.0 mmole, 1.13 eq) and sulfamide (481 mg, 5.0 mmole, 5.67 eq) were added and the mixture was heated to reflux overnight. DME was evaporated and the crude reconstituted in ethyl acetate, then washed with water. The organic was dried over sodium sulfate, filtered and evaporated. NMR confirms formation of title compound. 1H NMR (500 MHz, DMSO-d6): δ 7.40-7.20 (m, 5H), 6.79 (s, 2H), 4.18 (s, 2H), 3.99 (m, 2H), 2.81 (d, 2H), 2.08 (m, 1H), 1.74 (m, 2H), 1.61 (m, 2H), 1.25 (m, 1H), 1.12 (t, 3H), 1.02 (dq, 2H), 0.68 (dq, 2H). Ethyl 4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino } sulfonyl)amino]methyl}cyclohexanecarboxylate (17): A solution of (16) (250 mg, 0.71 mmole, 1.0 eq), dimethyaminopyridine (129 mg, 1.06 mmole, 1.5 eq) and 3,5-bis(trifluoromethyl)benzoyl chloride (141 μL, 0.78 mmole, 1.1 eq) in dichloromethane (5 mL) was stirred overnight. The mixture was diluted further with dichloromethane, washed twice with dilute hydrochloric acid and twice with 5% aqueous sodium bicarbonate. The organic was dried over sodium sulfate, filtered and evaporated and the crude purified by silica gel chromatography to give >85% pure title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.29 (s, 1H), 7.40-7.20 (m, 5H), 4.46 (s, 2H), 3.98 (m, 2H), 3.09 (d, 2H), 2.09 (m, 1H), 1.74 (m, 2H), 1.61 (m, 2H), 1.25 (m, 1H), 1.11 (t, 3H), 1.02 (dq, 2H), 0.68 (dq, 2H). 4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino }sulfonyl)amino]methyl}cyclohexanecarboxylic acid (18): Intermediate (17) (30 mg, 50 mmole, 1.0 eq) was dissolved in methanol (0.5 mL) and 0.5 N sodium hydroxide was added (0.23 mL, 115 mmole, 2.3 eq). The hydrolysis reaction was heated to 40° C. for 2 hours, at which point hydrolysis was complete. The reaction mixture was diluted with water, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic was dried over sodium sulfate, filtered and evaporated to give the title compound in nearly quantitative yield. 1H NMR (500 MHz, DMSO-d6): δ 12.47 (s, 1H), 11.93 (s, 1H), 8.45 (s, 2H), 8.39 (s, 1H), 7.40-7.20 (m, 5H), 4.52 (s, 2H), 3.21 (d, 2H), 2.09 (m, 1H), 1.76 (m, 2H), 1.61 (m, 2H), 1.33 (m, 1H), 1.02 (m, 2H), 0.80 (m, 2H). N-benzyl-4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexane carboxamide (19): Carboxylic acid (18) (27 mg, 48 μmole, 1.0 eq) was dissolved in dichloromethane (250 μL), treated with 1-hydroxybenzotriazole (7.7 mg, 57 μmole, 1.2 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11 mg, 57 μmole, 1.2 eq) and benzylamine (5.7 μL, 52 μmole, 1.1 eq) and stirred for 96 hours. Diluted with dichloromethane, then washed with dilute sodium bicarbonate and dilute hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and evaporated and the crude purified by silica gel chromatography to give the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.16 (s, 1H), 8.13 (t, 1H), 7.40-7.20 (m, 9H), 4.37 (s, 2H), 4.17 (d, 2H), 2.96 (d, 2H), 1.98 (m, 1H), 1.63 (m, 4H), 1.22 (m, 1H), 1.06 (m, 2H), 0.66 (m, 2H).

1. washwashed with dilute sodium bicarbonate and dilute hydrochloric acid
2. dry with materialThe organic layer was dried over sodium sulfate
3. filtrationfiltered
4. customevaporated
5. customthe crude purified by silica gel chromatography

ORD record

ord-629d4b2ee7964bc0a0d1dbb222092e53

Source dataset

uspto-grants-2005_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06852738B2