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Synthetic method of clomipramine hydrochloride intermediate

A technology of clomipramine hydrochloride and a synthetic method, which is applied in the field of preparation of clomipramine hydrochloride intermediates, can solve the problems of being difficult to promote to industrial production, long preparation routes, and high equipment requirements, and is suitable for large-scale industrialization The production and synthesis steps are simple and the product yield is high

Active Publication Date: 2015-09-02
JIANGSU TOHOPE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] This method has a long preparation route, resulting in a yield of only about 10%, and the diazotization reaction needs to be carried out at a low temperature of -50°C, which requires high equipment and is difficult to promote to industrial production.

Method used

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  • Synthetic method of clomipramine hydrochloride intermediate
  • Synthetic method of clomipramine hydrochloride intermediate
  • Synthetic method of clomipramine hydrochloride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Add N-acetyliminodibenzyl (II) (23.73g, 100mmol), potassium carbonate (13.82, 100mmol), tetrabutylammonium bromide (2.78g, 10mmol), dichloroethane 100mL in a 500ml reaction flask , after stirring and mixing evenly, the temperature was lowered to 0°C, and then bis(trichloromethyl)carbonate (38.58g, 130mmol) was added dropwise to the system. Concentrate to dryness under normal pressure to obtain 24.45 g of the target product N-acetyl-3-chloroiminodibenzyl (I) as light yellow oil, with a yield of 90.0%.

Embodiment 2

[0022] Add N-acetyliminodibenzyl (II) (23.73g, 100mmol), potassium carbonate (13.82, 100mmol), tetrabutylammonium bromide (2.78g, 10mmol), dichloroethane 100mL in a 500ml reaction flask , after stirring and mixing evenly, the temperature was lowered to 0°C, and then bis(trichloromethyl)carbonate (14.84g, 50mmol) was added dropwise to the system. Concentrate to dryness under normal pressure to obtain 14.40 g of the target product N-acetyl-3-chloroiminodibenzyl (I) as light yellow oil, with a yield of 53.0%.

Embodiment 3

[0024] Add N-acetyliminodibenzyl (II) (23.73g, 100mmol), potassium carbonate (13.82, 100mmol), tetrabutylammonium bromide (2.78g, 10mmol), dichloroethane 100mL in a 500ml reaction flask , after stirring and mixing evenly, the temperature was lowered to 0°C, and then bis(trichloromethyl)carbonate (29.68g, 100mmol) was added dropwise to the system, after the dropping, the temperature was raised to 10°C, and the reaction was carried out with stirring for 5 hours. Concentrate to dryness under normal pressure to obtain 23.38 g of the target product N-acetyl-3-chloroiminodibenzyl (I) in a light yellow oily substance, with a yield of 86.1%.

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Abstract

The invention discloses a synthetic method of a clomipramine hydrochloride intermediate, i.e. N-acetyl-3-chloroiminodibenzyl as shown in a structural formula (I), and the N-acetyl-3-chloroiminodibenzyl (I) is prepared by the step that N-acetyl iminodibenzyl as shown in a structural formula (II) as raw materials and chloride agents generate substitution reaction in a solvent in the presence of a catalyst and an acid-binding agent. Compared with the prior art, the synthetic method has the advantages of high yield, simple process, safety and reliability in operation, greenness and environmental friendliness and is suitable for industrial production, and economic and technical development of the bulk drug is promoted.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of a clomipramine hydrochloride intermediate. Background technique [0002] Clomipramine hydrochloride (also known as clomipramine hydrochloride, the chemical name is 3-chloro-5-(3-dimethylaminopropyl)-10,11-dihydro-5H-dibenzo(6,5) Azapine hydrochloride) is a tricyclic antidepressant developed by Novartis, Switzerland. Its main function is to block the reuptake of norepinephrine and 5-hydroxytryptamine in the central nervous system, and can effectively improve depression and anxiety. Symptoms, can also play a sedative and anticholinergic effect, the drug was approved by the FDA in December 1989, the trade name is Clomipramine HCl, in September 1993, the Ministry of Health of my country approved the domestic listing of Clomipramine of Beijing Novartis Pharmaceuticals , The Chin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/22
CPCC07D223/22
Inventor 袁跃华陆惠刚龚利锋顾晔殷屹峰钱振青周小军
Owner JIANGSU TOHOPE PHARMA