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Industrial preparation method of cloperastine

A technology for cloperastine and piperidine, which is applied in the field of preparing cloperastine, can solve the problems of unsuitable industrialized production, high equipment corrosion, long reaction time, etc., and achieves low equipment corrosion, less pollution of three wastes, and catalytic effect. active effect

Inactive Publication Date: 2015-04-22
CHONGQING KANGLE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] In the above-disclosed preparation methods of cloperastine, there are some insufficient factors, there are limitations in various degrees, and it is not suitable for industrialized production; and most of the processes have long reaction times, high production costs, and low overall yields. , highly corrosive to equipment, and there is serious pollution of three wastes

Method used

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  • Industrial preparation method of cloperastine
  • Industrial preparation method of cloperastine
  • Industrial preparation method of cloperastine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 1.1 Preparation of ether compound (III)

[0037] In the reactor, add 4-chlorobenzhydryl alcohol (V) (60.0Kg, 274.35mol), 2-chloroethanol (IV) (33.1Kg, 411.18mol), sodium bisulfate (10.8Kg, 90mol), toluene respectively 90.0Kg, start stirring, heat up to 95°C-100°C and keep it warm for 2 hours, cool to 45°C-50°C after the reaction, filter, wash the organic phase twice with 100Kg of drinking water, and concentrate the organic phase to dryness under reduced pressure to obtain Ether compound (III) (HPLC purity>99.0%, yield 94.5%).

[0038] 1.2 Preparation of cloperastine (I)

[0039] In the reaction kettle, add ether compound (III) (70.0Kg, 248.93mol), piperidine (II) (31.8Kg, 373.40mol), potassium carbonate (51.6Kg, 373.40mol), start stirring, and heat up to 100°C~ 105 ° C heat preservation reaction for 4 hours, cooled to 45 ° C ~ 50 ° C after the end of the reaction, filtered, added 300Kg purified water to the organic phase, precipitated crystals, recrystallized from abs...

Embodiment 2

[0041] 2.1 Preparation of ether compound (III)

[0042] In the reactor, add 4-chlorobenzhydryl alcohol (V) (60.0Kg, 274.35mol), 2-chloroethanol (IV) (33.1Kg, 411.18mol), sodium bisulfate monohydrate (12.4Kg, 90mol) respectively , Toluene 90.0Kg, start stirring, heat up to 95°C-100°C and keep it warm for 2 hours, cool to 45°C-50°C after the reaction, filter, wash the organic phase twice with 100Kg of drinking water, and concentrate the organic phase to dryness under reduced pressure , to obtain ether compound (III) (HPLC purity>99.0%, yield 94%).

[0043] 2.2 Preparation of Cloperastine (I)

[0044]In the reaction kettle, add ether compound (III) (70.0Kg, 248.93mol), piperidine (II) (31.8Kg, 373.40mol), sodium carbonate (39.6Kg, 373.40mol), start stirring, and heat up to 100°C~ 105 ° C heat preservation reaction for 4 hours, cooled to 45 ° C ~ 50 ° C after the end of the reaction, filtered, added 300Kg purified water to the organic phase, precipitated crystals, recrystallized...

Embodiment 3

[0046] 3.1 Preparation of ether compound (III)

[0047] In the reactor, add 4-chlorobenzhydryl alcohol (V) (60.0Kg, 274.35mol), 2-chloroethanol (IV) (33.1Kg, 411.18mol), sodium bisulfate (10.8Kg, 90mol), toluene respectively 90.0Kg, start stirring, raise the temperature to 80°C-85°C and keep it warm for 2 hours, cool to 45°C-50°C after the reaction, filter, wash the organic phase twice with 100Kg drinking water, and concentrate the organic phase to dryness under reduced pressure to obtain Ether compound (III) (HPLC purity>99.0%, yield 89%).

[0048] 3.2 Preparation of Cloperastine (I)

[0049] In the reaction kettle, add ether compound (III) (68.0Kg, 241.82mol), piperidine (II) (30.9Kg, 362.73mol), potassium carbonate (33.4Kg, 241.82mol), start stirring, and heat up to 100°C~ 105 ° C heat preservation reaction for 4 hours, cooled to 45 ° C ~ 50 ° C after the end of the reaction, filtered, added 300Kg purified water to the organic phase, precipitated crystals, recrystallized ...

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Abstract

The invention discloses an industrial preparation method of cloperastine, and in particular relates to a method for preparing cloperastine (formula I) by taking sodium acid sulfate as a catalyst, implementing reaction on cheap and easily obtained 4-chlorobenzhydrol (formula V) and 2-chloroethanol (formula IV) to prepare etherate (formula III), and by implementing reaction on a compound of the formula III and piperidine (formula II) in the presence of an acid-binding agent. The method is simple and short in produce, the whole process is convenient and rapid to operate, the used catalyst is cheap and easy available, high in catalysis activity, free of corrosion on equipment and small in waste pollution, and a prepared product is excellent in quality, high in yield and applicable to industrialization production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to an industrialized method for preparing cloperastine. Background technique [0002] Cloperastine, a non-addictive central antitussive drug, has a CAS number of 3703-76-2 and its chemical structure is as follows: [0003] [0004] Cough is one of the most common clinical symptoms, and its cause is that the sensitive receptors located in the larynx and upper respiratory tract are stimulated by certain factors. Cough usually occurs with other diseases, such as bronchitis, asthma, pneumonia and lung cancer, so the treatment target should be the disease itself that causes the cough. However, if the cough is not relieved or persists despite this treatment, antitussives must be used to control or eliminate it. At present, there are mainly two types of antitussive drugs, peripheral and central. Among them, the former is represented by levodropropizi...

Claims

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Application Information

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IPC IPC(8): C07D295/088
CPCC07D295/088
Inventor 张运辉杨忠鑫蔡中文丁瑞李锡伦张巍章俊杨继斌
Owner CHONGQING KANGLE PHARMA
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