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Method for synthesizing (S)-toliprolol

A synthesis method and technology of molar ratio, applied in the field of synthesis of tolirolol, can solve the problems of unfavorable industrial application, low optical purity, low yield, etc., and achieve good industrial application prospects, high optical purity and high yield , the effect of simple operation

Inactive Publication Date: 2010-02-17
ZHEJIANG SCI-TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method has many steps, low yield, and the optical purity of (S)-tolirolol is low, which is unfavorable for realizing industrial application

Method used

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  • Method for synthesizing (S)-toliprolol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1: the preparation of (S)-tolilool (compound 4)

[0025] (1) Preparation of compound 1 [(S)-3-chloro-1,2-propanediol]

[0026] The temperature of 2% dilute sulfuric acid (120g, 0.024mol) was slowly raised to 80°C, (S)-epichlorohydrin (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 to 7 with 30% sodium hydroxide solution in a water bath, concentrate under reduced pressure to remove water, then distill under reduced pressure, collect fractions at 130-136°C / 2.67KPa to obtain a colorless viscous liquid (S)-3-chloro-1,2-propanediol 168g, productive rate 76.5%, experimental data is as follows:

[0027] 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: 30ml / min, hydrogen flow rate: 1.5ml / m...

Embodiment 2

[0038] (1) Preparation of compound 1 [(S)-3-chloro-1,2-propanediol]

[0039] Slowly heat up 2% dilute sulfuric acid (60g, 0.012mol) to 70°C, add (S)-epichlorohydrin (160mL, 2.043mol) dropwise, and react at a temperature of 80-90°C for 3 hours. Cool to room temperature, adjust the pH to 7 with 25% potassium hydroxide solution in a water bath, concentrate under reduced pressure to remove water, and then distill under reduced pressure to collect fractions at 130-134°C / 2.67KPa to obtain a colorless viscous liquid (S)-3-chloro-1,2-propanediol 162g, productive rate 73.8%, experimental data is as follows:

[0040] Gas chromatography content: 99.6% (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: 30ml / min, hydrogen flow rate: 1.5ml / min); [α] D 20 =+7.4(c 1.0, H 2 O).

[0041] (2) Preparation of compound 2 [(S)-3-m-tolyloxy-1,2...

Embodiment 3

[0048] (1) Preparation of compound 1 [(S)-3-chloro-1,2-propanediol]

[0049] Slowly heat up dilute sulfuric acid (130g, 0.02mol) with a concentration of 1.5% to 60°C, add (S)-epichlorohydrin (160mL, 2.043mol) dropwise, and react at a temperature of 105-110°C for 1 hour. Cool to room temperature, adjust the pH value to 7 with sodium carbonate 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 colorless viscous liquid (S)-3-chloro -1,2-propanediol 170g, productive rate 77.4%, gas chromatographic content: 99.6% (analysis conditions are: column length 30m, the AT SE-30 capillary column of diameter 0.25mm; Hydrogen flame detection; Column temperature: 180 ℃, Monitor temperature: 230°C; carrier gas is N 2 , flow rate: 30ml / min, hydrogen flow rate: 1.5ml / min); [α] D 20 =+7.3(c 1.0, H 2 O).

[0050] (2) Preparation of compound 2 [(S)-3-m-tolyloxy-1,2-propanediol]

[0051...

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Abstract

The invention discloses a method for synthesizing (S)-toliprolol, which takes an (S)-epichlorohydrin with a high optical purity as raw material to get the (S) - toliprolol with high enantiomeric purity through hydrolysis, concentration with m-cresol, cyclization of thionyl chloride and cyclization and open-loop of isopropylamine. The synthesizing method has the advantages of cheap and easy-findingraw materials, easy operation, mild condition, short cycle and the products of the invention have a high yield and a high optically purity as well as a better prospect of industrial application.

Description

technical field [0001] The invention relates to a method for synthesizing organic matter, in particular to a method for synthesizing (S)-tolirolol. Background technique [0002] Toliprolol (Betasantin, Toliprolol), also known as propranolol, has a chemical name of (R, S)-1-isopropylamino-3-m-tolyloxy-2-propanol. It is a non-selective beta-receptor blocker with no intrinsic activity and membrane stabilizing effect. 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 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/30C07C213/02
Inventor 朱锦桃王燕王朝阳宋光伟
Owner ZHEJIANG SCI-TECH UNIV
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