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Purification method for propranolol hydrochloride key intermediate

A technology of propranolol hydrochloride and a purification method is applied in the field of purification of key intermediates of propranolol hydrochloride, and can solve the problems of low purity and yield, strict requirements for purification equipment, large post-treatment pollution, etc. Simple, overcoming stringent requirements and high boiling pollution problems, the effect of reducing production costs

Inactive Publication Date: 2021-03-05
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The purpose of the present invention is to overcome defects such as low purity and yield of key intermediates in the prior art, harsh requirements for purification equipment, and large post-treatment pollution, and provide a purification method that significantly improves the purity and yield of key intermediates of propranolol hydrochloride. method, and has a simple purification method, low equipment requirements, safety and environmental protection, and is suitable for industrial production

Method used

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  • Purification method for propranolol hydrochloride key intermediate
  • Purification method for propranolol hydrochloride key intermediate
  • Purification method for propranolol hydrochloride key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Weigh 1-naphthol (144.1g, 1.0mol, 1.0eq), N,N-diisopropylethylamine (6.5g, 0.05mol, 0.05eq), epichlorohydrin (277.5g, 3.0mol, 3.0 eq) was added to a 1L four-necked flask, stirred and heated to 95°C for reflux reaction, and TLC monitored the reaction end point (V PE / EA=5:1). After the reaction reached the end point, the temperature was lowered to 50°C, and 30wt% NaOH aqueous solution (200g , 1.5mol, 1.5eq), quenched the reaction, the reaction solution was down to room temperature, 500ml ethyl acetate was added thereto, stirred for 5min, the solution was layered and separated, the organic phase was washed 2 times with 200ml of water respectively, and the organic phase was washed for 35 Concentrate to dryness at ~45°C under reduced pressure to obtain 215.3 g of the crude key intermediate, and load the crude key intermediate into a silica gel chromatography column (the weight of the silica gel packed in the chromatography column is 2.5 kg), using a volume ratio of PE / EA=17: ...

Embodiment 2

[0036] Weigh 1-naphthol (144.1g, 1.0mol, 1.0eq), N,N-diisopropylethylamine (6.5g, 0.05mol, 0.05eq), epichlorohydrin (277.5g, 3.0mol, 3.0 eq) was added into a 1L four-neck flask, stirred and raised to 95°C to reflux for reaction, and the reaction endpoint was monitored by TLC (V PE / EA=5:1).

[0037] After the reaction reached the end point, the temperature was lowered to 50°C, and 30wt% NaOH aqueous solution (200g, 1.5mol, 1.5eq) was added dropwise to quench the reaction. The layers were separated, the organic phase was washed twice with 200ml water respectively, and the organic phase was concentrated to dryness under reduced pressure at 35~45°C to obtain 208.1g of the crude product of the key intermediate, and the crude product of the key intermediate was loaded into a silica gel chromatography column (chromatographic column The weight of loaded silica gel is 2.0kg), the small polar impurities are eluted with a mixed solvent with a volume ratio of PE / EA=15:1, TLC monitors the ...

Embodiment 3

[0039]Weigh 1-naphthol (144.1g, 1.0mol, 1.0eq), N,N-diisopropylethylamine (6.5g, 0.05mol, 0.05eq), epichlorohydrin (277.5g, 3.0mol, 3.0 eq) was added into a 1L four-neck flask, stirred and raised to 95°C to reflux for reaction, and the reaction endpoint was monitored by TLC (V PE / EA=5:1).

[0040] After the reaction reached the end point, the temperature was lowered to 50°C, and 30wt% NaOH aqueous solution (200g, 1.5mol, 1.5eq) was added dropwise to quench the reaction. The layers were separated, the organic phase was washed twice with 200ml of water, and the organic phase was concentrated to dryness under reduced pressure at 35 to 45°C to obtain 210.0g of the crude product of the key intermediate, and the crude product of the key intermediate was loaded into a silica gel chromatography column (chromatographic column packing The weight of the silica gel is 1.5kg), and the small polar impurities are eluted with a mixed solvent with a volume ratio of PE / EA=18:1. TLC monitors the...

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Abstract

The invention discloses a purification method of a propranolol hydrochloride key intermediate, namely 3-(1-naphthoxy)-1,2-epoxypropane. According to the method, lower fatty acid ester and a low-polarity solvent are adopted, and 1-naphthol and epoxy chloropropane are used as raw materials and are subjected to an etherification reaction under the catalytic action of N,N-diisopropylethylamine to obtain the key intermediate 3-(1-naphthoxy)-1,2-epoxypropane. According to the invention, a reaction system is subjected to extraction washing and column chromatographic purification so as to remove organic impurities and inorganic impurities contained in the reaction system; the method is simple to operate and beneficial to recovery and environmental protection, overcomes the problems of strict requirements on instruments and equipment and high-boiling pollution caused by adopting a high-vacuum and high-temperature repeated reduced-pressure distillation method in the prior art, and remarkably improve the yield and the quality of the key intermediate. The purification method is more beneficial to subsequent preparation of propranolol hydrochloride, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a method for purifying a key intermediate of propranolol hydrochloride. Background technique [0002] Propranolol hydrochloride chemical name: 1-isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride. The activity of the left-handed body is stronger than that of the right-handed body, and its racemic body is used clinically. Its structural formula is as follows: [0003] [0004] Propranolol hydrochloride is the first beta-receptor blocker used clinically in the world, and has made great contributions to the treatment of hypertension and angina pectoris. Scientist James Blake won the 1988 Nobel Prize in Medicine and the Queen's Award for this. Propranolol hydrochloride is a commonly used clinical β-adrenoceptor blocker, which can competitively inhibit the effect of catecholamine (catecholamine), and is often used to prevent and treat ar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D303/23C07D301/00C07D301/32
CPCC07D303/23C07D301/00C07D301/32
Inventor 代先朋付林曾建华王运波邹谨霜邓伟
Owner HUAZHONG PHARMA
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