Browse Prior Art Database

PROCESS FOR THE PREPARATION OF INTERMEDIATES OF BOCEPREVIR

IP.com Disclosure Number: IPCOM000234096D
Publication Date: 2014-Jan-10
Document File: 4 page(s) / 101K

Publishing Venue

The IP.com Prior Art Database

Abstract

Disclosed herein is a process for the preparation of intermediates of boceprevir, for example, tert-butyl (1-cyclobutyl-3-hydroxypropan-2-yl) carbamate and 3-amino-4-cyclobutyl-2-oxobutanamide hydrochloride.

This text was extracted from a Microsoft Word document.
At least one non-text object (such as an image or picture) has been suppressed.
This is the abbreviated version, containing approximately 39% of the total text.

PROCESS FOR THE PREPARATION OF INTERMEDIATES OF BOCEPREVIR

Abstract

            Disclosed herein is a process for the preparation of intermediates of boceprevir, for example, tert-butyl (1-cyclobutyl-3-hydroxypropan-2-yl) carbamate and 3-amino-4-cyclobutyl-2-oxobutanamide hydrochloride.


Boceprevir is chemically known as (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3- dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexan-2(S)-carboxamide and is represented by Formula I.

Formula I

Reported herein is a process for the preparation of tert-butyl (1-cyclobutyl-3-hydroxypropan-2-yl) carbamate, wherein the process comprises treating ethyl N-(tert-butoxycarbonyl)-3-cyclobutyl alaninate with sodium borohydride in a 3,5-dinitrosalicylic acid solvent.  Further reported herein is a process for the preparation of ethyl N-(tert-butoxycarbonyl)-3-cyclobutyl alaninate from ethyl 3-cyclobutyl alaninate, and consecutive intermediates ethyl 3-cyclobutyl-N-(diphenylmethylidene) alaninate and ethyl N-(diphenylmethylidene)glycinate, which is carried out in-situ, in toluene.  

Also reported herein is a process for the preparation of 3-amino-4-cyclobutyl-2-oxobutanamide hydrochloride, wherein the process comprises treating tert-butyl (4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl) carbamate with dichloroacetic acid in the presence of N, N’-dicyclohexylcarbodiimide.

The starting materials, ethyl N-(diphenylmethylidene) glycinate and tert-butyl (4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl) carbamate, can be prepared using known methods, for example, as described in U.S. Patent Nos. 6,992,220 and 7,326,795.

EXAMPLE

Preparation of 3-amino-4-cyclobutyl-2-oxobutanamide hydrochloride

Step 1: Preparation of ethyl 3-cyclobutyl-N-(diphenylmethylidene) alaninate

Ethyl N-(diphenylmethylidene) glycinate (300 g) was added into toluene (1.5 L) at 20°C to 25°C followed by potassium-tert-butoxide (138.24 g) while stirring.  To the resultant reaction mixture, bromomethylcyclobutane (200.64 g) was added and the mixture was heated to 95°C.  The reaction mixture was stirred for 5 hours at 90°C to 95°C.  The reaction mixture was cooled to 20°C to 25°C and washed with deionized water (1.5 L).  The organic layer was separated and was used as such in the next step.

Step 2:  Preparation of Ethyl 3-cyclobutyl alaninate

Hydrochloric acid (2N, 1000 mL) was added into the organic layer (obtained in Step 1) at 10°C to 15°C and stirred for 2 hours.  The organic layer was separated and the aqueous layer was washed with toluene (600 mL).  To the aqueous layer, sodium hydroxide solution (15% w/v, 1000 mL) was added, stirred for 30 minutes, and extracted with toluene (1500 mL).  Toluene was recovered at 50°C to 55°C under vacuum to obtain an oily residue (145 g), which was used as such in the next step.

Step 3: Preparation of ethyl N-(tert-butoxycarbonyl)-3-cyclobutyl alaninate

Toluene (290 mL...