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A kind of synthetic method of (s)-moprorol

A synthesis method and a technology of formula, applied in the synthesis field of moprol, can solve problems such as unfavorable industrial application, low optical purity, complicated operation, etc., and achieve good industrial application prospect, high optical purity and yield, and easy operation. simple effect

Inactive Publication Date: 2014-10-29
ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method is cumbersome to operate, the steps are long, and the optical purity of (S)-moprolol is low, which is not conducive to the realization of industrial application

Method used

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  • A kind of synthetic method of (s)-moprorol
  • A kind of synthetic method of (s)-moprorol
  • A kind of synthetic method of (s)-moprorol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040]Embodiment 1: the preparation of (S)-moprorol [compound 4 or formula (I)]

[0041] (1) Preparation of compound 1 or formula (II) [(S)-3-chloro-1,2-propanediol]

[0042] The temperature of 2wt.% dilute sulfuric acid (120g, 0.024mol) was slowly raised to 80°C, compound 1 (160mL, 2.043mol) was added dropwise, and the temperature was controlled at 100-105°C for 3 hours. Cool to room temperature, adjust the pH value to 7 with a 30wt.% sodium hydroxide solution in a water bath, concentrate under reduced pressure to remove water, and then distill under reduced pressure to collect fractions at 130-136°C / 2.67KPa to obtain a colorless and viscous Liquid (S)-3-chloro-1,2-propanediol 168g, yield 76.5%, experimental data are as follows:

[0043] Gas chromatography content: 99.4% (analysis conditions: AT SE-30 capillary column with column length 30m and diameter 0.25mm; hydrogen flame detection; column temperature: 180°C, monitor temperature: 230°C; carrier gas is N 2 , flow rate: 3...

Embodiment 2

[0054] (1) Preparation of compound 1 or formula (II) [(S)-3-chloro-1,2-propanediol]

[0055] The temperature of 1.5wt.% dilute sulfuric acid (80g, 0.012mol) was slowly raised to 80°C, compound 1 (160mL, 2.043mol) was added dropwise, and the temperature was controlled at 100-105°C for 3 hours. Cool to room temperature, adjust the pH value to 7 with a 30wt.% potassium hydroxide solution in a water bath, concentrate under reduced pressure to remove water, and then distill under reduced pressure to collect fractions at 130-136°C / 2.67KPa to obtain a colorless and viscous product Liquid (S)-3-chloro-1,2-propanediol 162g, yield 73.8%, GC content: 99.4%, [α] D 20 =+7.3(c 1.0, H 2 O).

[0056] (2) Preparation of compound 2 or formula (III) (S)-guaifenesin [(S)-3-o-methoxyphenoxy-1,2-propanediol]

[0057] Guaiacol (12.4g, 0.1mol) was dissolved in 100mL of anhydrous methanol, sodium hydroxide (8.0g, 0.2mol) was added in batches at room temperature, and then a phase transfer catalyst ...

Embodiment 3

[0063] (1) Preparation of compound 1 or formula (II) [(S)-3-chloro-1,2-propanediol]

[0064] The concentration of 1wt.% dilute sulfuric acid (150g, 0.015mol) was slowly heated to 80°C, compound 1 (160mL, 2.043mol) was added dropwise, and the temperature was controlled at 100-105°C for 2 hours. Cool to room temperature, adjust the pH value to 7 with a 30wt.% sodium carbonate solution in a water bath, concentrate under reduced pressure to remove water, and then distill under reduced pressure to collect fractions at 130-136°C / 2.67KPa to obtain a colorless viscous liquid (S)-3-Chloro-1,2-propanediol 172g, yield 78.3%, gas chromatography content: 99.6%, [α] D 20 =+7.4(c 1.0, H 2 O).

[0065] (2) Preparation of compound 2 or formula (III) (S)-guaifenesin [(S)-3-o-methoxyphenoxy-1,2-propanediol]

[0066] Guaiacol (12.4g, 0.1mol) was dissolved in 100mL of isopropanol, sodium hydroxide (7.0g, 0.18mol) was added in batches at room temperature, and then a phase transfer catalyst benz...

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Abstract

The invention discloses a synthesis method of (R)-moprolol, which comprises the following steps: taking (R)-3-chlorine-1, 2-propanediol with high optical purity as raw material, and undergoing hydrolysis, condensation with guaiacol, cyclization of thionyl chloride, and open-cycle of isopropamide to obtain (R)-moprolol with high enantiomeric purity. The synthesis method has the advantage of low cost and easy taking of raw material, simple operation, temperate condition, short period, high yield and optical purity of the product, and better industrialized application prospect.

Description

technical field [0001] The invention relates to a method for synthesizing organic matter, in particular to a method for synthesizing (S)-moprorol. Background technique [0002] Moprolol (Moprolol), also known as methotrexate, chemical name 1-isopropylamine-3-o-methoxyphenoxy-2-propanol, is a representative of β-receptor blockers drug. β-receptor blockers are a class of drugs developed in the 1960s to treat cardiovascular diseases. They have shown good effects in fighting angina pectoris, arrhythmia and hypertension, and their importance has been recognized by the global medical community. It has become one of the basic medicines for the treatment of cardiovascular diseases. It is particularly effective against heart failure and myocardial infarction, and is an important means for the current treatment of chronic heart failure and myocardial infarction. [0003] At present, the drug is mainly supplied in the form of racemate in clinical practice, and pharmacological studie...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/34C07C213/02A61P9/10A61P9/12A61P9/06
Inventor 王朝阳陈小丽朱锦桃王燕愈开新孙斌李忠雷
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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