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Impurities of Methyl N-[(2S)-1-[(6S)-6-[5-[9,9-Difluoro-7-[2-[(1S,2S,4R)-3-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]-3-azabicyclo[2.2.1]heptan-2-yl]-3H-benzimidazol-5-yl]fluoren-2-yl]-1H-imidazol-2-yl]-5-azaspiro[2.4]heptan-5-yl]-3-methyl-1-oxobutan-2-yl]carbamate

IP.com Disclosure Number: IPCOM000247500D
Publication Date: 2016-Sep-12

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Impurities of Methyl N-[(2S)-1-[(6S)-6-[5-[9,9-Difluoro-7-[2-[(1S,2S,4R)-3-[(2S)-2- (methoxycarbonylamino)-3-methylbutanoyl]-3-azabicyclo[2.2.1]heptan-2-yl]-3H- benzimidazol-5-yl]fluoren-2-yl]-1H-imidazol-2-yl]-5-azaspiro[2.4]heptan-5-yl]-3- methyl-1-oxobutan-2-yl]carbamate

Disclosed herein are impurities of intermediates of Methyl N-[(2S)-1-[(6S)-6-[5-[9,9-Difluoro-7-[2- [(1S,2S,4R)-3-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]-3-azabicyclo[2.2.1]heptan-2-yl]- 3H-benzimidazol-5-yl]fluoren-2-yl]-1H-imidazol-2-yl]-5-azaspiro[2.4]heptan-5-yl]-3-methyl-1- oxobutan-2-yl]carbamate (referred to as Compound 1). The impurities may be formed in the synthesis of the intermediates of compound 1, and react in subsequent stages, thus forming the corresponding impurities of compound 1.

Methyl ((S)-1-((S)-6-(5-(9,9-difluoro-7-(2-((1R,3S,4S)-2-formyl-2-azabicyclo[2.2.1]heptan-3-yl)-

1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-

methyl-1-oxobutan-2-yl)carbamate, referred to as Compound A:

Preparation of compound A:

N-Methyl Morpholine (1.8gm, 0.0178moles) and formic acid (750ml) were added to solution of methyl ((S)-1-((S)-6-(5-(7-(2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6- yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1- oxobutan-2-yl)carbamate trihydrochloride (5.0gm, 0.0059moles) in toluene (50ml) and stirred at 90- 100°C for 8 hrs . On completion of reaction, the solvent was distilled off and the residue was purified by column chromatography using flash column in 100-200 mesh silica and eluting with 5% MeOH in MDC to give the title compound (purity >94%).

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1H NMR (400 MHz, CDCl3): 8.49-8.42(m,1H), 7.92(s,1H), 7.85-7.76(d,2H), 7.55-7.41(m,7H), 7.1-
7.03(s,1H), 5.61-5.59(d,1H), 5.43-5.38(m,1H), 4.86(s,1H), 4.39(s,1H), 4.34-4.3(t,1H), 4.0-
3.89(m,1H), 3.83-3.81(d,1H),3.76(s,3H), 3.73-3.65(m,1H), 3.54-3.51(m,1H), 2.86(s,1H), 2.63-
2.55(m,1H), 2.32-2.29(d,1H), 2.26-2.19(m,2H), 2.13-1.9(m,5H), 1.86-1.79(m,1H), 1.73-1.63(m,2H),
1.26-1.25(d,1H), 1.13-1.10(t,1H), 1.0-0.88(m,6H), 0.73-.66(m,3H)

Methyl ((S)-1-((S)-6-(5-(7-(2-((1R,3S,4S)-2-acetyl-2-azabicyclo[2.2.1]heptan-3-yl)-1H-

benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-

5-yl)-3-methyl-1-oxobutan-2-yl)carbamate, referred to as Compound B:

Preparation of Compound B:

N-Methyl Morpholine (0.72gm, 0.071moles) and acetyl chloride (100ml) were added to solution of methyl ((S)-1-((S)-6-(5-(7-(2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6- yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1- oxobutan-2-yl)carbamate trihydrochloride (2.0gm, 0.0023moles) in toluene (20ml) and stirred at 90- 100°C for 8 hrs. On completion of reaction, the solvent was distilled off and purified by column chromatography using flash column in 100-200 mesh silica and eluting with...