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Preparation method of cyproheptadine hydrochloride

A technology of cyproheptadine hydrochloride and concentrated hydrochloric acid, applied in organic chemistry and other directions, can solve the problems of unfavorable employee health, unsuitability for industrialized large-scale production, and high energy consumption, reduce the use of organic solvents and hazardous chemicals, and is conducive to large-scale production. The effect of large-scale industrial production, production costs and production consumption reduction

Active Publication Date: 2019-11-05
广州普星药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Although the above-mentioned method can prepare higher purity hydrochloride, this method uses a large amount of toluene as extraction solvent in the synthesis process, and the actual extraction effect is difficult to control, and uses a large amount of glacial acetic acid and Controlled acetic anhydride not only increases production costs, but also increases environmental pollution, and is not conducive to the health of employees. In addition, a large amount of hydrogen chloride gas is used in the reaction and post-processing, which poses great challenges to transportation, equipment, use and management. High requirements, which also invisibly increase the cost, and its refined post-processing method is also very complicated, making it difficult for enterprises to obtain profitability, and it is also very unfavorable for large-scale industrial production
[0004] Therefore, aiming at the defects that the current synthetic method of cyproheptadine hydrochloride is complex, consumes high energy, is difficult to repeat in practical application, and is not suitable for large-scale industrial production, it is necessary to provide a synthetic method that is simpler and easier to operate and is suitable for large-scale industrial production

Method used

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  • Preparation method of cyproheptadine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] A preparation method of cyproheptadine hydrochloride, comprising the steps of:

[0051] 1) Add 0.89g of freshly polished magnesium bars to a 500mL reaction bottle, fill with nitrogen protection, add 50mL of tetrahydrofuran, heat to 60-65°C, then dropwise add 3.80g of 1-methyl-4-chloropiperidine to dissolve in 10mL For the solution of tetrahydrofuran, keep the reaction slightly boiling during the dropwise addition, and reflux for 1 hour after the dropwise addition, to obtain a 1-methyl-4-chloropiperidine magnesium solution;

[0052] 2) After cooling the 1-methyl-4-chloropiperidine magnesium solution to 0°C, slowly add 5.38g of dibenzo[a,e]cycloheptatrien-5-one, and react at room temperature for 1h to obtain 1- Methyl 4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)piperidine solution;

[0053] 3) Distill the solution of 1-methyl 4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)piperidine to tetrahydrofuran under reduced pressure at 40~50℃, then stir and cool to 0°C, slowly add ...

Embodiment 2

[0057] A preparation method of cyproheptadine hydrochloride, comprising the steps of:

[0058] 1) Add 9.0g of newly polished magnesium chips into a 2L reaction flask, fill with nitrogen protection, add 350mL of tetrahydrofuran, heat to 60-65°C, then add 300mL of 38g of 1-methyl-4-chloropiperidine in tetrahydrofuran , keep the reaction slightly boiling during the dropwise addition, and reflux for 1 hour after the dropwise addition, to obtain a 1-methyl-4-chloropiperidine magnesium solution;

[0059] 2) After cooling the 1-methyl-4-chloropiperidine magnesium solution to 5°C, slowly add 52g of dibenzo[a,e]cycloheptatrien-5-one, and react at room temperature for 1h to obtain 1- Methyl 4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)piperidine solution;

[0060] 3) Distill 1-methyl 4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)piperidine solution to tetrahydrofuran under reduced pressure at 40~50℃, then stir and cool to 4℃ , slowly add 1000mL distilled water, the speed of adding dist...

Embodiment 3

[0064] A preparation method of cyproheptadine hydrochloride, comprising the steps of:

[0065] 1) Add 1.96kg of newly polished magnesium chips into a 300L reaction bottle, fill it with nitrogen protection, add 30kg of tetrahydrofuran, heat to 60-65°C, and then add tetrahydrofuran containing 7.5kg of 1-methyl-4-chloropiperidine The solution was 70kg, and the reaction was kept slightly boiling during the dropwise addition. After the dropwise addition, the reaction was refluxed for 1h to obtain a 1-methyl-4-chloropiperidine magnesium solution;

[0066] 2) After cooling the 1-methyl-4-chloropiperidine magnesium solution to 5°C, slowly add 10.2 kg of dibenzo[a,e]cycloheptatrien-5-one, and react at room temperature for 1 hour to obtain 1- Methyl 4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)piperidine solution;

[0067] 3) Distill 1-methyl 4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)piperidine solution at 40~50℃ to remove tetrahydrofuran under reduced pressure, then stir and cool t...

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Abstract

The invention discloses a preparation method of cyproheptadine hydrochloride. According to the invention, the existing preparation method of the cyproheptadine hydrochloride is integrally improved, sothat the whole synthesis step is greatly simplified; and the prepared cyproheptadine hydrochloride has higher purity and yield, and the preparation method reduces the use of organic solvents and hazardous chemicals, simplifies the operation steps, reduces the operation difficulty, not only reduces the cost but also lightens the environmental burden, and is more beneficial to large-scale industrial production.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a preparation method of cyceproheptadine hydrochloride. Background technique [0002] At present, the preparation method of cyproheptadine hydrochloride involves less, and the patent US3014911 discloses the reaction of 1-methyl-4-chloropiperidine and magnesium in tetrahydrofuran to generate 1-methyl-4-chloropiperidine magnesium chloride, and then with Dibenzo[a,e]cycloheptatrien-5-one reacts to form 1-methyl-4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)piperidine during Use toluene extraction, ethanol aqueous crystallization to separate and purify 1-methyl-4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)piperidine, and then use glacial acetic acid, hydrogen chloride gas and acetic acid Anhydride treatment of 1-methyl-4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)piperidine dehydrates 1-methyl-4-(5H-dibenzo[a ,e] cycloheptatriene-5-ylidene) piperidine, then treat 1-methyl-4-(5H dib...

Claims

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Application Information

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IPC IPC(8): C07D211/70
CPCC07D211/70
Inventor 蒲含林郑忠旺朱义波相东方
Owner 广州普星药业有限公司
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