WO2016095879A1

WO2016095879A1 - Preparation of a highly pure intermediate for the synthesis of odanacatib

Info

Publication number: WO2016095879A1
Application number: PCT/CZ2015/000151
Authority: WO
Inventors: Peter BABIAK; Josef Zezula
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2014-12-19
Filing date: 2015-12-14
Publication date: 2016-06-23
Anticipated expiration: 2017-06-19
Also published as: CZ2014941A3

Abstract

A process for producing (S)-2-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)-N- (1-cyanocyclopropyl)-4-fluoro-4-methylpentanamide of formula 1 by reaction of the acid or its salts of formula 3 with the compound of formula 4, the reaction being performed in a solvent in the presence of the n-propanephosphonic acid anhydride of formula 5 and a base.

Description

Preparation of a highly pure intermediate for the synthesis of Odanacatib

Technical Field

The invention relates to an improved process for the preparation and purification of

(S)-2-({(S)-1-{4-bromophenyl)-2,2,2-trifluoroethyl)amino)-N-(1-cyanocyclopropyl)-4- fiuoro-4-methylpentanamide

This compound, is an advanced intermediate for the synthesis of Odanacatib - an inhibitor of cathepsin of the K structure, which has been developed by Merck for the treatment of osteoporosis (

Background Art

The amide coupling reaction, used to prepare the derivatives of type 1 in the basic patent (WO2003/075836), was carried out with the following activation agents: PyBOP (benzotriazol-1 -yloxytris(pyrrolidino)phosphonium hexafluorophosphate), HATU (o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) or EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride). A patent to Merck Frosst (WO2008/119176) mentions the use of the following activation agents: N-hydroxysuccinimide, 2-hydroxypyridine, N-hydroxyphtalimide, carbonyldiimidazole (CDI), HOBt (hydroxybenzotriazole) and the agent is the carbodiimide or phosphonium or uronium salt. Specifically, EDCI (1-(3- dimethylaminopropyl)-3-ethy!carbodiirnide hydrochloride) is preferred. Scheme 1 :

Another process patent (WO2012/148555) claims for the coupling reaction in scheme 1 a wide range of agents based on benzotriazole as well as carbodiimide derivatives such as EDCI with the use of pyridine bases.

However, these agents used so far have exhibited quite high toxicity and, moreover, the accompanying water-insoluble side products complicate the process of isolation and purification of the amidation product.

Disclosure of Invention

By testing various agents, bases, and solvents we have found out that the most suitable agent for the amide coupling reaction of Scheme 2 is the commercially available T3P cyclic anhydride (n-propane phosphonic acid anhydride). Compared to the benzotriazole, uronium and carbodiimide derivatives this agent exhibits the advantage of lower toxicity and also its side products are soluble in water, which means that they do not complicate the isolation and purification of the amide coupling reaction product. Easier separation of the side products is mainly manifested in a higher purity of the intermediate 1 and in a higher yield. Also, the risk of using the potentially explosive agent HOBt (K.D. Wehrstedt et ai., J Hazardous Materials (2005), A126, 1-7) is eliminated.

The present invention relates to a process for producing (S)-2-(((S)-1-(4- bromophenyl)-2,2,2-trifluoroethyl)amino)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl- pentanamide of formula 1 by reaction of the acid, or its sal

(3)

with the compound of formula 4:

(4)

the reaction being performed in the presence of the n-propanephosphonic acid anhydride of formula 5:

(5) and of a solvent and a base.

Further, Ν,Ν-dimethylaminopyridine (DMAP) is present in the reaction mixture. A preferred solvent for this reaction is dimethylformamide (DMF) and the base is preferably diisopropylethylamine (DIEA). Detailed description of the invention

Scheme 2:

The optimized procedure makes use of the above mentioned advantages of T3P, the addition of Ν,Ν-dimethylaminopyridine (DMPA) is used to accelerate the reaction. The reaction is preferably conducted in WjW-dimethylformarnide (DMF), wherein after completion of the reaction a highly pure product is obtained in a high yield by slow addition of water to the reaction mixture.

Examples Example 1: EDC

The carboxylate (1 g, 1.82 mmol), 1-amino-1-cyclopropariecarbonitrile hydrochloride (0.216 g, 1.82 mmol) and pyridine (0.25 g, 5.5 mmol) was suspended in DMF (8.5 ml) and the suspension was stirred at the room temperature for 1 hour. After that, the reaction mixture was cooled down to -10°C and then EDC (0.4 ml, 2.26 mmol) was slowly added. The reaction mixture was stirred at -10°C for 1 hour and then at -5°C for 3 hours. Then, it was slowly heated up to 35°C and after 1 hour a 5% by weight aqueous solution of H₃P0₄ was added to adjust the pH value to 7. The first fraction of the precipitate was isolated by filtration. The filtrate was additionally diluted with water and the second product fraction crystallized overnight. Total yield 0.1 g (12.6 %), HPLC purity 89%.

Example 2: HATU in DMF.

The carboxylate (1 g, 1.82 mmol) and 1-amino-1-cyclopropanecarbonitrile hydrochloride (0.216 g, 1.82 mmol) was suspended in DMAC (5 ml) and the stirred suspension was cooled down to 3°C and then HATU (0.83 g, 2.2 mmol) was slowly added. The reaction mixture was then stirred for 15 min and then diisopropylethylamine (DIEA, 1 ml, 5.5 mmol) was added. The mixture was stirred at 5°C for another 4 hours (check by TLC 50/1 chloroform/methanol), then at -5°C for 3 hours. The reaction was terminated by slow dropwise addition of water (6 ml) at 5°C and the suspension was stirred for 1 hour more. The precipitate was isolated by filtration and washed with a mixture of DMAC-H₂O (10 ml - 10 ml) and dried in vacuo (180 mbar) at 45°C. A white crystalline product of 0.66 g was obtained (84%, HPLC 91.00%).

Example 3: T3P in EA.

The carboxylate (1 g, 1.82 mmol), 1-amino-1-cyclopropanecarbonitrile hydrochloride (0.216 g, 1.82 mmol) and diisopropylethylamine (DIEA, 1 m!, 5.5 mmol) was suspended in DMF (7 ml) and the suspension was stirred at the room temperature for 1 hour. Then, a 50% solution of T3P in EtOAc (1.16 g, 1.82 mmol) was slowly added dropwise during ca. 5 min. The reaction mixture was then stirred at the room temperature for 16 hours. Then, the mixture was diluted with EtOAc (5 ml) and the insoluble fraction was removed by filtration. The organic layer was washed with 1x 10 ml of water, 1x 10 ml of a 5% solution of NaHC0₃, 1x 10 ml of brine and dried over Na₂S04. After filtration of the desiccant and evaporation of the solvent at a reduced pressure a solid product (0.81 g, HPLC 72%) was obtained. Recrystallization from toluene provided a white crystalline product (0.47 g, HPLC 99.40%).

Example 4: T3P DMF.

A 50% solution of T3P in DMF (V=53.8 ml, n=84,57 mmol) was added to a suspension of the carboxylate (40 g, 70.48 mmol), 1-aminocyclopropane-1- carbonitrile hydrochloride (10.02 g, 84.57 mmol) and DMAP (0.86 g, 7.04 mmol) in DIEA (49 ml, 281.92 mmol) and DMF (200 ml) at the room temperature during 0.5 hours. The reaction mixture was further stirred at 22°C for 4 hours. Then, the mixture being stirred (400 rpm), water (280) ml was added during 3 hours. After the addition of water the suspension was further stirred at the room temperature (100 rpm) for 16 hours. After 16 hours the offwhite crystalline product was aspirated, washed with 100 ml of DMF/water 1 :1 voi./vol and 100 ml of water. The product was dried at 40°C in a vacuum drier (ca. 180 mbar) for 24 hours. After drying, a white crystalline product was obtained (30.5 g, 96 %, T_t= 167.8 to 169,5 °C, HPLC purity 96.5%, residual solvents: DIPEA 120 ppm, DMF 1100 ppm, water 0.10 %, titration 108.8 %, sulphate ash <0.05 %, DMAP content <0.01 %).

Claims

1. A process for producing (S)-2-{((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)- amino)-N-(1-cyanocyclop namide of formula 1

(1) by reaction of the acid, or its salt, of formula 3

(31 with the compound of formula 4:

(4)

characterized in that the reaction is performed in a solvent in the presence of the /?-propanophosphonic acid ula 5

(5) and of a base.

2. The process according to claim 1 , characterized in that N,N- dimethylaminopyridine is further present in the reaction mixture.

3. The process according to any one of claims 1 or 2, characterized in that the solvent is dimethylformamide.

4. The process according to any one of the preceding claims, characterized in that the base is diisopropylethylamine.