Hydrochloric Acid → HCID 66719460, compound

Participants

Reaction Steps

(S)-3-[2-(4-Acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-tert-butoxycarbonyl-amino-propionic acid methyl ester was converted to the HCl salt of (S)-3-[2-(4-acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-amino-propionic acid methyl ester according to General Procedure C. This intermediate (450 mg) dissolved in dioxane (32 mL) and TFA (8 mL). To this solution was added paraformaldehyde (60 mg) and stirred at room temperature for 6 hours. After completion of the reaction, the mixture was poured into water (100 mL) and extracted with EtOAc. The organic layer was neutralized to a pH of 7 using NaHCO3 and washed with water and brine, and then dried to get an oil. The oil was taken up in fresh EtOAc (200 mL) and benzoyl chloride and saturated Na2CO3 (20 mL) were added. The mixture was stirred for 2-3 hours and the organic layer was separated, washed dried and concentrated and purified (silica; hexanes/EtOA, 8:2 to 7:3) to get (3S,8S)-3-(4-acetoxy-phenyl)-7-benzoyl-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (468 mg). This ester (215 mg) was hydrolyzed according to General Procedure B to afford (3S,8S)-7-benzoyl-3-(4-hydroxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (200 mg). LCMS (m/z) 431. This acid was coupled with (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedure L gave (S)-2-{[(3S,8S)-7-Benzoyl-3-(4-hydroxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (224 mg). LCMS (m/z): 699.

Provenance & Evidence