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Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material

A technology for methyl ortho-halomethylbenzoate and doxepin hydrochloride, which is applied in the field of preparing doxepin hydrochloride and can solve problems such as low yield and low product purity

Inactive Publication Date: 2016-03-02
SUZHOU HUANGHE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the reaction catalyst Ni(OAc) of this step 2 Relatively cheap and easy to obtain, but the yield of this step reaction is low, and the purity of the product is low

Method used

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  • Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material
  • Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material
  • Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] In the reaction vessel of 20L, put methyl o-bromomethylbenzoate, the ethanol solvent of sodium methylate that consumption is 3 (the total mass of methyl o-bromomethylbenzoate and phenol is 1 meter), adjust the temperature of reaction solution After reaching 50°C, start to drop phenol with a substance quantity of 1.05 (based on the substance quantity of methyl o-bromomethylbenzoate as 1), and the dropwise addition time is 1 h. After the dropwise addition was completed, after constant temperature reaction for 5 h, a known separation method was used to obtain methyl o-formate benzyl phenyl ether, which was named compound H.

[0043] The above compound H and sodium hydroxide aqueous solution were placed in a reaction vessel, the temperature was adjusted at 30°C, the reaction was stirred for 8 hours, and (o-formyl)benzyl phenyl ether was separated by known separation means, which will be named as compound I.

[0044] Put the above compound I, trifluoroacetic anhydride (based...

Embodiment 2

[0051] In the reaction vessel of 20L, put methyl o-bromomethylbenzoate, the ethanol solvent of sodium methylate that consumption is 10 (the total mass of methyl o-bromomethylbenzoate and phenol is 1 meter), adjust the temperature of reaction solution After reaching 60°C, start to drop phenol with a substance quantity of 1.15 (calculated that the substance quantity of methyl o-bromomethylbenzoate is 1), and the dropwise addition time is 1 h. After the dropwise addition was completed, after constant temperature reaction for 5 h, a known separation method was used to obtain methyl o-formate benzyl phenyl ether, which was named compound H.

[0052] Put the above-mentioned compound H and aqueous solution of sodium hydroxide into a reaction vessel, adjust the temperature at 40°C, stir the reaction for 4 hours, and obtain (o-formyl)benzylphenyl ether by using known separation methods, which will be named compound I.

[0053] Put the above compound I, trifluoroacetic anhydride (based ...

Embodiment 3

[0060] In the reaction vessel of 20L, put methyl o-chloromethylbenzoate, the ethanol solvent of sodium methylate that consumption is 6 (the total mass of methyl o-bromomethylbenzoate and phenol is 1 meter), adjust the temperature of reaction solution After reaching 55°C, phenol with a substance quantity of 1.10 (calculated as 1 substance quantity of methyl o-bromomethylbenzoate) was started to be added dropwise, and the dropwise addition time was 1 h. After the dropwise addition was completed, after constant temperature reaction for 3.5 h, a known separation method was used to obtain methyl o-formate benzyl phenyl ether, which was named compound H.

[0061] The above-mentioned compound H and sodium hydroxide aqueous solution were placed in a reaction vessel, the temperature was adjusted at 35°C, the reaction was stirred for 6 hours, and (o-formyl)benzyl phenyl ether was separated by known separation means, which will be named compound I.

[0062] Put the above compound I, trif...

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Abstract

The present invention discloses a method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as a raw material. In the method, o-halogen methyl methyl benzoate which is wide in source is used as a starting raw material, and sulfasalazine is obtained through substitution, hydrolysis, cyclization, nucleophilic addition, elimination reaction, nucleophilic substitution and neutralization reaction. The method comprises: during a nucleophilic substitution reaction obtained in the seventh step, using an organic lithium compound in an ether solution, so that the organic lithium compound and dimethylamine form an ammonium lithium salt (the formula is as shown in the description); then conducting an alkylation reaction on the ammonium lithium salt and a halide to improve the yield of tertiary amine, thereby ensuring the yield and purity of doxepin hydrochloride.

Description

technical field [0001] The invention relates to the technical field of doxepin hydrochloride, in particular to a method for preparing doxepin hydrochloride by using methyl o-halogenomethylbenzoate as a raw material. Background technique [0002] Doxepin hydrochloride, chemical name N,N-Dimethyl-3-dibenzo(b,e)-oxepin-11(6H)ylidene-1-alanine salt of cis-trans isomers mixture. Its CAS number is 1229-29-4, and its structural formula is [0003] [0004] Doxepin hydrochloride is a drug used to treat depression and anxiety neurosis. Its function is to inhibit the reuptake of serotonin and norepinephrine in the central nervous system, so that the two neurotransmitters in the synaptic cleft Increased concentration exerts antidepressant effects, and also has anti-anxiety and sedative effects. Doxepin hydrochloride oral absorption is good, and bioavailability is 13-45%, half-life (t 1 / 2 ) for 8-12 hours, the apparent volume of distribution (Vd) 9-33L / kg. It is mainly metaboliz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D313/12
CPCC07D313/12
Inventor 苏子轩屈孝銘肖祖华
Owner SUZHOU HUANGHE PHARMA CO LTD
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