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Crystalline forms of methyl 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoate dihydrochloride

IP.com Disclosure Number: IPCOM000245114D
Publication Date: 2016-Feb-09
Document File: 5 page(s) / 372K

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Crystalline forms of methyl 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)- 1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoate dihydrochloride

Methyl 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H- imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoate dihydrochloride (referred to as Compound A) has the following structure

Compound A

Compound A is involved in the synthesis of 5-[[[(2S)-2-amino-3-(4-carbamoyl-2,6- dimethylphenyl) propanoyl]-[(1S)-1-(5-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2- methoxybenzoic acid (referred to as Compound B)

Compound A Compound B



Page 02 of 5

Preparation of crystalline 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-

phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoate dihydrochloride,

Compound A,Form I

Methyl-5-(((S)-2-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)- 1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoate hydrochloride (750 g, 1.04mol) was charged in the reactor, followed by acetonitrile (4.0 L) addition. The suspension was cooled to 15-20 °C and hydrochloric acid (10.3 M, 1750 mL, 20.8mol, 20eq) was added maintaining temperature. The mixture is stirred for a minimum 4 hours at 15-20 °C, cooled to 0-5°C and stirred for additional period of minimum 5hours. The crystals were filtered off, washed extensively with acetonitrile and dried under vacuum at maximal temperature of 30°C till constant weight. White crystals were identified as a methyl 5-(((S)-2- amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2- yl)ethyl)propanamido)methyl)-2-methoxybenzoate dihydrochloride Form I. The product was isolated in 90 % yield with HPLC purity of 97.86 %area.

The obtained crystalline product was characterized by XRPD presenting in the following figure

Main XRD peak positions of crystalline methyl 5-(((S)-2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate dihydrochloride, Compound A, Form I are: 6.4, 6.8, 8.7, 9.3, 9.5, 10.9,
13.1, 13.6, 14.4, 15.1, 18.7, 19.6, 20.1, 20.8, 22.7, 25.0, 25.8,...