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Synthesis method of propranolol hydrochloride

A technology of propranolol hydrochloride and a synthesis method, which is applied in the field of -1,2-propylene oxide, can solve the problems of unfavorable separation and purification, unfavorable industrialized production, and high raw material cost, and achieves easy industrialized production, low cost and simple operation. Effect

Active Publication Date: 2020-06-09
玉门千华制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] (2) Using 1-naphthol and 1,3-dibromo(iodo)acetone as raw materials to obtain an intermediate through alkylation reaction, and then through sodium borohydride Reduction reaction, nucleophilic substitution reaction with isopropylamine, and hydrochloric acid salt formation are a total of four-step reactions to obtain propranolol hydrochloride. Its synthetic route is simple and the reaction conditions are mild, but it needs to use more expensive 1,3-dibromo (iodine) acetone , the raw material cost is on the high side, and at the same time, because the raw material 1,3-dibromo(iodo)acetone has high activity in the first step reaction process, it is easy to produce disubstituted ether compounds, which is not conducive to separation and purification, and is not conducive to industrial production

Method used

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  • Synthesis method of propranolol hydrochloride
  • Synthesis method of propranolol hydrochloride
  • Synthesis method of propranolol hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1-1

[0026] Example 1-1 Synthesis of 3-(1-naphthyloxy)-1,2-propylene oxide

[0027] Weigh methylnaphthol (144.1g, 1.0mol, 1.0eq), benzyltriethylammonium chloride (13.9g, 0.05mol, 0.05eq), epichlorohydrin (277.5g, 3.0mol, 3.0eq) and add Put it into a 1L four-neck flask, stir and raise the temperature to 50°C to dissolve and clarify, then add dropwise 30% NaOH aqueous solution (200g, 1.5mol, 1.5eq) for 1h, then control the temperature at 50°C for 6h, and monitor the disappearance of the raw material (V PE / EA＝ 5:1), stop the reaction, cool to room temperature, stand to separate the organic layer, wash once with water, and then concentrate the organic layer to dryness under reduced pressure at 50°C to obtain reddish-brown oil 3-(1-naphthyloxy)- 188.4 g of 1,2-propylene oxide, and the molar yield was 94.1%.

Embodiment 1-2

[0028] Example 1-2 Synthesis of 3-(1-naphthyloxy)-1,2-propylene oxide

[0029] Weigh methyl naphthol (216.2g, 1.5mol, 1.0eq), polyethylene glycol 6000 (18.0g, 0.03mol, 0.02eq), epichlorohydrin (347g, 3.75mol, 2.5eq) and join in 2L In an open flask, stir and heat up to 65°C to dissolve and clarify, then add dropwise 30% NaOH aqueous solution (320g, 2.4mol, 1.6eq) for 1h, then keep the temperature at 65°C for 4h, and TLC monitors that the raw material disappears (V PE / EA＝ 5:1), stop the reaction, cool to room temperature, stand to separate the organic layer, wash once with water, and then concentrate the organic layer to dryness under reduced pressure at 50°C to obtain reddish-brown oil 3-(1-naphthyloxy)- 286.5 g of 1,2-propylene oxide, and the molar yield was 95.4%.

Embodiment 2-1

[0030] Embodiment 2-1 propranolol is synthesized

[0031] Dissolve 3-(1-naphthyloxy)-1,2-epoxypropane (160g, 0.8mol, 1.0eq), isopropylamine (108g, 1.6mol, 2.0eq) in 300mL of toluene, and then add N , N-diisopropylethylamine (25.9g, 0.2mol, 0.25eq), added dropwise for 30min, after the dropwise completion, the temperature was raised to 45°C, and the reaction was kept for 4h, and the raw material disappeared under TLC monitoring (V CHCl3 / MeOH =20:1), stop the reaction, cool to 5°C, precipitate solid, filter and dry to obtain 189.4g of propranolol crude product, the yield is 91.3%, and the HPLC purity is 99.1%.

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Abstract

The invention discloses a synthesis method of propranolol hydrochloride. The synthesis method of propranolol hydrochloride comprises the following steps: by taking menaphthol and epoxy chloropropane as raw materials, carrying out etherification reaction under an alkaline condition and under the action of a phase transfer catalyst to obtain a key intermediate 3-(1-naphthoxy)-1, 2-epoxypropane; carrying out ring-opening reaction and salifying reaction on the 3-(1-naphthoxy)-1, 2-epoxypropane and isopropylamine under the catalytic action of alkali to obtain a crude propranolol hydrochloride product; and finally refining the crude propranolol hydrochloride product to obtain propranolol hydrochloride with the purity of 99.8% or above. The synthesis method is a preparation method which is shortin synthesis route, simple to operate and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a synthetic method of propranolol hydrochloride. Specifically, the method uses methyl naphthol and epichlorohydrin as raw materials to obtain the key intermediate 3-(1-naphthyloxy) through etherification reaction Base)-1,2-epoxypropane, then with isopropylamine through alkali-catalyzed ring-opening reaction, salt-forming reaction to obtain the crude product of propranolol hydrochloride, and finally obtain pure propranolol hydrochloride through refining, which is a short synthetic route, The preparation method is simple in operation and suitable for industrial production. Background technique [0002] Propranolol hydrochloride (Propranolol hydrochloride), chemical name is 1-isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride, its chemical structure is as follows: [0003] [0004] Propranolol hydrochloride is the first beta-receptor blocker invented by scienti...

Claims

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Application Information

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IPC IPC(8): C07C213/04C07C213/08C07C213/10C07C217/30C07D303/23
CPCC07C213/04C07C213/08C07C213/10C07D303/23C07C217/30
Inventor 李剑平李光文
Owner 玉门千华制药有限公司
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