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Process for production of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl-propanenitrile

A technology of alkyl and phenyl, applied in the field of preparing 2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl-propionitrile

Active Publication Date: 2017-12-01
SANOFI AVENTIS DEUTSCHLAND GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Experimental validation of the reaction showed that the reaction of dimethyl-phenyl-acetonitrile of formula XVIII with 4-chlorobutyl chloride proceeded poorly using several Friedel Crafts acylated variants

Method used

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  • Process for production of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl-propanenitrile
  • Process for production of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl-propanenitrile
  • Process for production of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl-propanenitrile

Examples

Experimental program
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Effect test

Embodiment

[0260] The invention is described in more detail by the following examples. These examples are intended to illustrate the invention, but not to limit its scope. Each step of the methods described in this invention can be expanded on a much larger basis than described here.

[0261] Based on the one-dimensional 1 Analysis of H NMR spectra, NMR assignments are for illustrative purposes only. A more detailed analysis of the spectrum may have resulted in a slight reassignment of some NMR peaks, which obviously does not change the overall assignment. All recorded on a 500MHz instrument at room temperature 1 H NMR spectrum. Shifts are relative to TMS [ppm]; solvent is always DMSO-d 6 .

[0262] Reference Example 1

[0263] Between-and p-2-[(cyclopropanecarbonyl-)-phenyl]-2-methyl-propionitrile according to formula XIX of scheme 6

[0264] At 3 Added to 6.4 g (45 mmol, 1.3 equiv) of 4-chlorobutyryl chloride. 5 g (34 mmol) of 2-methyl-2-phenyl-propionitrile of the formula XVI...

Embodiment 3

[0276] 2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propionitrile of formula I (using KHMDS as base)

[0277] 33.7 g (487 mmol, 4 equivalents) of isobutyronitrile were added to 435 ml (305 mmol) of a 0.7M solution of KHMDS in toluene at 60°C. After 10 min, 20.0 g (122 mmol) cyclopropyl-(4-fluorophenyl)-methanone was slowly added at 60-62°C. The mixture was stirred at 60 °C for 80 min.

[0278] Aqueous workup: the mixture was cooled to room temperature and poured on 500 ml of aqueous sodium bicarbonate. After phase separation, the organic layer was washed with Na 2 CO 3 Aqueous solution, water, KHSO 4 Washed, dried over MgSO4 and concentrated. According to scheme 9, 25.8 g (121 mmol, 99%) of the title compound I and 15% by-product of formula XXV and 5% starting material are obtained.

[0279] HPLC: (Merck Chromolith Performance RP18e, A.H. 2 O / 0.05%TFA, B:MeCN / 0.05%TFA, 10->70%B 10min, 4ml / min, 40°C): title compound I R t =3.00min; by-product XXV R t = 3.32min, starti...

Embodiment 4

[0283] 2-[4-(Cyclopropanecarbonyl-)-phenyl]-2-methyl-propionitrile of formula I (using commercially available NaHMDS as base)

[0284] 5.5 ml NaHMDS (0.6M in toluene from Sigma Aldrich), 3.3 mmol, 1.1 equiv), 1.1 ml (12 mmol, 4 equiv) of isobutyronitrile and 0.5 g (3.0 mmol) of cyclopropyl-(4-fluorobenzene base)-methanone was mixed for 1 h at <35 °C. An additional 5.5 ml of NaHMDS solution was added and the mixture was heated to 85 °C for 3 h. Workup (Example 3) and evaporation of the solvent provided the crude product of formula I. Analysis of the crude product showed about 66% product and 13% starting material cyclopropyl-(4-fluorophenyl)-methanone.

[0285] Compound I: LC-MS: (YMC J'sphere ODS H 80 20x2.1mm, 4μm, A:H 2 O+0.05%TFA, B: MeCN, 4% → 95% B after 2min, 1ml / min, 30℃): R t =1.40min-LC-MS:MH + 214;

[0286] Cyclopropyl-(4-fluorophenyl)methanone XXa:LC-MS:(YMC J’sphere ODS H 8020x2.1mm, 4μm, A:H 2 O+0.05%TFA, B: MeCN, 4% → 95% B after 2min, 1ml / min, 30℃): R t ...

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Abstract

A new process for the production of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl- propanenitrile is described. This compound can be used for the production of drugs, such as Fexofenadine.

Description

Background of the invention [0001] The present invention relates to a chemical process for the preparation of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl-propionitrile (compound of formula I) and its use as an intermediate for the preparation of medicines. For example, 2-[4-(cyclopropanecarbonyl)phenyl]-2-methyl-propionitrile is a key intermediate for the preparation of fexofenadine (compound of formula II). [0002] [0003] Fexofenadine II is an antihistamine drug used to treat allergic symptoms, and it is a bronchodilator (USP 4,254,129, Richardson-Merrell Inc.). [0004] 2-[4-(Cyclopropanecarbonyl)phenyl]-2-methyl-propionitrile of formula I is an intermediate in the synthesis of fexofenadine and several prior art methods describe its preparation. These methods involve procedures using a large number of intermediates, as shown in Scheme 1 below, which summarizes this strategy. In USP 6,340,761 (Merrell Pharm. Inc.), the corresponding intermediates were prepared in Exam...

Claims

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Application Information

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IPC IPC(8): C07C253/30C07C255/40C07D211/22
CPCC07C253/30C07D211/22C07C255/40C07C2601/02
Inventor H·韦兰K·罗森A·谢弗
Owner SANOFI AVENTIS DEUTSCHLAND GMBH
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