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Intermediates of methyl ((S)-1-((S)-6-(5-(9,9-difluoro-7-(2-((1R,3S,4S)-2-((methoxycarbonyl)-L-valyl)-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. Disclosure Number: IPCOM000248187D
Publication Date: 2016-Nov-06

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Intermediates of methyl ((S)-1-((S)-6-(5-(9,9-difluoro-7-(2-((1R,3S,4S)-2- ((methoxycarbonyl)-L-valyl)-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.

Methyl ((S)-1-((S)-6-(5-(9,9-difluoro-7-(2-((1R,3S,4S)-2-((methoxycarbonyl)-L-valyl)-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 has the following chemical structure (referred to herein as Compound I):

Compound - I

Provided are processes for preparing and crystallizing its intermediates, which are presented in the following scheme:

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1-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-chloroethan-1-one (referred to herein as compound
A); (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (referred to herein as compound B); tert-butyl (S)-6-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5- azaspiro[2.4]heptane-5-carboxylate (referred to herein as compound C); (S)-6-(5-(7-bromo-9,9- difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptane dihydrochloride (referred to herein as compound D); methyl ((S)-1-((S)-6-(5-(7-bromo-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 herein as compound E); tert-butyl (1R,3S,4S)-3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (referred to herein as compound F); tert-butyl (1R,3S,4S)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (referred to herein as compound G); 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 (referred to herein as compound H).

Powder X-ray Diffraction (XRPD) method

X-ray diffraction was performed on X-Ray powder diffractometer:

Bruker D8 Advance; CuK_ radiation (λ = 1.54 Å); Lynx eye detector; laboratory temperature 22- 25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.

Measurement parameters:

Scan range: 2 - 40 degrees 2-theta;

Scan mode: continuous;

Step size: 0.05 degrees;

Time per step: 0.5 s;

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Sample spin: 30 rpm;

Sample holder: PMMA specimen holder ring.

Example-1: Preparation of Compound A

A solution of compound A (75g) in acetonitrile (375ml) and water (150ml) was heated at 90C for 60 min. Reaction mixture was slowly cooled to 25-30°C and stirred for 30min and further cooled at 5-10°C and stirred for 30min. The product was filtered (60gm). A solution of...