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Preparation methods of 1-(mercaptomethyl)cyclopropyl acetic acid and intermediate thereof

A technology of mercaptomethylcyclopropylacetic acid and cyclopropyldimethanol cyclosulfite, applied in the field of preparation of 1-mercaptomethylcyclopropylacetic acid and its intermediates, can solve the problem of poor selectivity and difficult operation and other problems, to achieve the effect of simple and easy process flow, conducive to industrial production, and ingenious design

Inactive Publication Date: 2014-01-29
SHANGHAI PUYI CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The above various methods all need to synthesize 1-hydroxymethylcyclopropyl acetonitrile (VIII) earlier, and the synthesis of this compound or reaction is difficult to operate, or selectivity is not good

Method used

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  • Preparation methods of 1-(mercaptomethyl)cyclopropyl acetic acid and intermediate thereof
  • Preparation methods of 1-(mercaptomethyl)cyclopropyl acetic acid and intermediate thereof
  • Preparation methods of 1-(mercaptomethyl)cyclopropyl acetic acid and intermediate thereof

Examples

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preparation example Construction

[0029] The general synthetic route of the method for preparing 1-mercaptomethylcyclopropylacetic acid (I) of the present invention is as follows:

[0030]

[0031] Using dibromoneopentyl glycol (VII) as the starting material, cyclization in the presence of zinc powder to obtain cyclopropyldimethanol (VI), and then react with thionyl chloride to obtain cyclopropyldimethanol cyclosulfite (V). Cyclopropyl dimethanol cyclic sulfite (V) is ring-opened with potassium thioacetate to obtain compound (IV), then reacted with methanesulfonyl chloride or p-toluenesulfonyl chloride to obtain compound (III), and then substituted with cyano to form compound ( II), and finally hydrolyze under alkaline conditions to obtain 1-mercaptomethylcyclopropylacetic acid (I).

Embodiment 1

[0033] Embodiment 1: the preparation of cyclopropyl dimethanol (1-2)

[0034]

[0035] Dissolve 25 g of the raw material dibromoneopentyl glycol (1-1) (Suzhou Jinghua Chemical) in 150 mL of ethanol, and add 10 g of zinc powder. Heated to 100°C under nitrogen protection, and refluxed for 4 hours until TLC (PE:EA=1:1 potassium permanganate color development) showed that the raw material point disappeared. Suction filtration, after removing the zinc powder, feed ammonia gas at about 10°C, a large amount of white solids are precipitated, continue feeding ammonia gas until ammonia overflows from the gas outlet. Keep stirring for 30 minutes, filter with suction, wash with a small amount of ethanol, concentrate the filtrate to dryness to obtain a milky white oil, and distill under reduced pressure with an oil pump to obtain 8.3 g of cyclopropyldimethanol (1-2) as a colorless liquid. GC98%, molar yield 85%. 1 H NMR (CDCl 3 ,500Hz)δ4.02(s,2H),3.56(s,4H),0.48(s,4H); MS(ESI)m / z=103...

Embodiment 2

[0036] Embodiment 2: the preparation of cyclopropyl dimethanol (1-2)

[0037]

[0038] Dissolve 25 g of the raw material dibromoneopentyl glycol (1-1) (Suzhou Jinghua Chemical) in 150 mL of methanol, and add 10 g of zinc powder. Heated to 80° C. under nitrogen protection, and refluxed for 6 hours until TLC (PE:EA=1:1 potassium permanganate color development) showed that the raw material point disappeared. Suction filtration, after removing the zinc powder, feed ammonia gas at about 10°C, a large amount of white solids are precipitated, continue feeding ammonia gas until ammonia overflows from the gas outlet. Keep stirring for 30 minutes, filter with suction, wash with a small amount of ethanol, concentrate the filtrate to dryness to obtain a milky white oil, and distill under reduced pressure with an oil pump to obtain 7.3 g of cyclopropyldimethanol (1-2) as a colorless liquid. GC99%, molar yield 75%. See Example 1 for spectrogram data.

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Abstract

The invention relates to a preparation method of 1-(mercaptomethyl)cyclopropyl acetic acid (I). The preparation method comprises the steps of carrying out ring opening on cyclopropanedimethanol cyclic sulfite (V) with potassium thioacetate, so that a compound (IV) is obtained; carrying out sulfonic acid esterification reaction on the compound (IV) and methanesulfonyl chloride or paratoluensulfonyl chloride to obtain a compound (III); carrying out cyano group substitution on the compound (III) to obtain a compound (II); and hydrolyzing the compound (II) under an alkaline condition so as to obtain the 1-(mercaptomethyl)cyclopropyl acetic acid (I), wherein R is a methyl or a p-methylphenyl. The invention further provides a preparation method of an 1-(mercaptomethyl)cyclopropyl acetic acid intermediate. The preparation methods of the 1-(mercaptomethyl)cyclopropyl acetic acid and the 1-(mercaptomethyl)cyclopropyl acetic acid intermediate are ingenious in design, initial raw materials are low in cost and easily available, and the technological process is simple and practicable, so that the production cost can be greatly reduced; the preparation methods are beneficial to industrial production and suitable for large-scale popularization and application.

Description

technical field [0001] The present invention relates to the technical field of montelukast intermediates for the prevention and treatment of asthma, in particular to the technical field of 1-mercaptomethylcyclopropylacetic acid, specifically to a kind of 1-mercaptomethylcyclopropylacetic acid and its intermediates method of preparation. Background technique [0002] Montelukast is a drug for the prevention and treatment of asthma, inflammation, angina pectoris, cerebral syndrome, glomerulonephritis, hepatitis, endotoxemia, uveitis and allograft rejection, And 1-mercaptomethylcyclopropylacetic acid is an important intermediate for the synthesis of montelukast. [0003] [0004] Regarding the synthetic method of 1-mercaptomethylcyclopropylacetic acid (I), US Patent No. 5,614,632A first reported its synthetic route, as shown in Route 1. It uses cyclopropyldimethanol (VI) as raw material, first reacts with thionyl chloride to generate cyclopropyldimethanol cyclosulfite (V),...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/53C07C319/02C07D327/10
Inventor 屠常刚李涛王博
Owner SHANGHAI PUYI CHEM CO LTD
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