(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester → (S)-8-[(S)-2-(4'-chloro-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester

Participants

Reaction Steps

(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (50 mg) was coupled with (S)-2-amino-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (31 mg) according to General Procedure L to give (S)-8-[(S)-2-(4′-chloro-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (39 mg). This intermediate was deprotected as described in General Procedure C to give (S)-3-(4′-chloro-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester hydrochloride salt. This compound was further reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride to furnish (S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure E. This compound, upon reaction with ethyl iodide and K2CO3 in DMF, gave (S)-2-({(S)-7-[2-(acetyl-ethyl-amino)-5-methyl-thiazole-4-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure O. This product (15 mg) was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 950.

Provenance & Evidence