Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → 4-(2,6-Dichlorobenzoylamino)-L-phenylalanine methyl ester

Participants

Reaction Steps

To a solution of (1S-cis)-1,2,2-trimethylcyclopentane-1,3-dicarboxylic acid3-methyl ester, 36-B(501.3 mg) in DMF(5 mL) and DIEA(3 mL) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(1.0445 g) and the reaction stirred at ambient temperature for 1 hour. To the reaction was added 4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine methyl ester, hydrochloride salt(1.0093 g), 37-B-1, and the reaction stirred for 3 days. The reaction was then diluted with water and extracted with AcOEt. The concentrated extract was purified by flash chromatography on silica gel eluting with methanol in methylene chloride to obtain (1S-cis)-N-[(3-Methoxycarbonyl)-1,2,2-trimethylcyclopentyl)carbonyl]-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine methyl ester(2.272 g). A solution of LiOH(552 mg) in H2O (20 mL) and 4 mL of 30% hydrogen peroxide was added to a solution of the above (1S-cis)-N-[((3-Methoxycarbonyl)-1,2,2-trimethylcyclopentyl)carbonyl]-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine methyl ester(C28H32Cl2N2O6) (2.272 g) in 15 mL of methanol. The solution was stirred for 6 days. The methanol is then removed in vacuo. The aqueous layer is further diluted with water and extracted with diethyl ether and the extract discarded. The aqueous layer is acidified to pH 3-4 with 0.6N HCl resulting in a precipitate. The precipitate is filtered washing with water to obtain (1S-cis)-N-[(3-Carboxy-1,2,2-trimethylcyclopentyl)carbonyl]-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine(1.1265 g). Physical properties as follows: m.p. 152-157° C. 1H NMR(300 MHz, DMSO-d6). δ12.3(1H), 10.63(1H), 7.50(5H), 7.27(1H), 7.18(2H), 4.45(1H), 2.99(2H), 2.63(1H), 2.25(1H), 1.93(1H), 1.69(1H), 1.28(1H), 1.16(3H), 1.05(3H), 0.50(3H); MS−ESI (m/z): 533([M−H−]); MS−ESI (m/z): 535([M+H+]).

Provenance & Evidence