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Method for synthesizing (R)-toliprolol

A kind of synthesis method, the technology of molar ratio, is applied in the synthesis field of -tolirolol, can solve the problems such as not being suitable for industrialized application, reagent price is expensive, needs, achieves good industrialized application prospect, optical purity and yield are high, reduces by-product effects

Inactive Publication Date: 2010-03-24
ZHEJIANG SCI-TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method requires stoichiometric chiral reagents, which are expensive and unsuitable for industrial applications

Method used

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  • Method for synthesizing (R)-toliprolol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Embodiment 1: Preparation of (R)-Toliolol (Compound 3)

[0020] (1) Preparation of compound 1 [(R)-3-m-tolyloxy-1,2-propanediol]

[0021] Dissolve m-cresol (10.8g, 0.1mol) in 120mL absolute ethanol, add sodium hydroxide (5.1g, 0.13mol) in batches at room temperature, then add phase transfer catalyst tetrabutylammonium bromide (0.16g, 0.5mmol), drop (R)-3-chloro-1,2-propanediol (14.4g, 0.13mol), dropwise, 70 ~ 73 ° C reaction for 5 hours, the reaction is complete, filtered while hot, and the filtrate was concentrated under reduced pressure, Petroleum ether was recrystallized to obtain 14.8 g of white solid (R)-3-m-tolyloxy-1,2-propanediol with a yield of 81.2%. The experimental data are as follows:

[0022] mp 60-62°C, [α] D 20 = -9.5 (c 1.0, EtOH); 1 HNMR (400MHz, CDCl 3 )δ (ppm): 2.33 (s, 3H, CH 3 ), 3.71-3.84 (m, 2H, CH 2 OH), 4.04-4.06 (m, 2H, ArO CH 2 ), 4.11-4.13 (m, 1H, CH), 6.72-7.20 (m, 4H, ArH); IR (KBr) cm -1 : 3390, 2930, 1610, 1590, 1490, 1453...

Embodiment 2

[0030](1) Preparation of compound 1 [(R)-3-m-tolyloxy-1,2-propanediol]

[0031] Dissolve m-cresol (10.8g, 0.1mol) in 120mL of anhydrous methanol, add sodium hydroxide (8.0g, 0.2mol) in batches at room temperature, then add phase transfer catalyst tetrabutylammonium bromide (0.16g, 0.5mmol), drop (R)-3-chloro-1,2-propanediol (25.4g, 0.23mol), dropwise, 55 ~ 60 ° C reaction for 10 hours, the reaction is complete, filtered while hot, and the filtrate was concentrated under reduced pressure, Recrystallization from absolute ethanol and carbon tetrachloride (V:V=5:95) gave 14.9 g of (R)-3-m-tolyloxy-1,2-propanediol as a white solid, yield 81.6%, mp 60-62 °C, [α] D 20 = -9.3 (c 1.0, EtOH).

[0032] (2) Preparation of compound 2 [(S)-4-m-cresyloxymethyl-1,3,2-dioxathiolane-2-oxide]

[0033] Compound 1 (9.1g, 0.05mol) was dissolved in 70mL of dichloromethane, and the mixed solution of thionyl chloride (8.8g, 0.074mol) and 10mL of dichloromethane was added dropwise under temperature...

Embodiment 3

[0037] (1) Preparation of compound 1 [(R)-3-m-tolyloxy-1,2-propanediol]

[0038] Dissolve m-cresol (10.8g, 0.1mol) in 120mL of isopropanol, add sodium hydroxide (6.0g, 0.15mol) in batches at room temperature, and then add phase transfer catalyst tetrabutylammonium bromide (0.16g, 0.5mmol), drop (R)-3-chloro-1,2-propanediol (44.3g, 0.4mol), dropwise, 80 ~ 85 ° C reaction for 3 hours, the reaction is complete, filtered while hot, and the filtrate was concentrated under reduced pressure, Cyclohexane was recrystallized to obtain 15.1 g of white solid (R)-3-m-tolyloxy-1,2-propanediol, yield 82.8%, mp 60-62°C, [α] D 20 = -9.5 (c 1.0, EtOH).

[0039] (2) Preparation of compound 2 [(S)-4-m-cresyloxymethyl-1,3,2-dioxathiolane-2-oxide]

[0040] Compound 1 (9.1g, 0.05mol) was dissolved in 70mL of dichloromethane, and a mixed solution of thionyl chloride (7.7g, 0.065mol) and 10mL of dichloromethane was added dropwise at a temperature of 0-5°C. React at 20-25°C for about 0.5 hours. Aft...

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Abstract

The invention discloses a method for synthesizing (R)-toliprolol. The method takes an m-cresol and a (R)-3-chlorine-1, 2-propanediol with a high optically pure as raw materials to get the (R)-toliprolol with high enantiomeric purity through concentration, cyclization of thionyl chloride and cyclization and open-loop of isopropylamine. The synthesizing method has the advantages of cheap and easy-finding raw 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 (R)-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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