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Synthesis of terbinafine hydrochloride

A technology for the synthetic route of terbinafine hydrochloride, which is applied in the field of synthetic route of terbinafine hydrochloride, can solve the problems of not being suitable for industrialized production, difficult preparation of intermediates, expensive catalyst, etc., and achieve high cost Problems, ease of reaction control, and improved yield

Inactive Publication Date: 2002-08-07
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above routes are not high in yield, rare raw materials, difficult to prepare intermediates, or expensive catalysts that are not suitable for industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] 1. 1-bromo-6,6-dimethyl-2-hepten-4-yne

[0024] 1000ml reaction bottle, in N 2 Under protection, 150ml THF and 24.8g tert-butylacetylene were added. After cooling, 180 ml (2.0 M) of butyllithium cyclohexane solution was added dropwise. After the dropwise addition, the mixture was kept warm for 2 hours, and then heated to a weak reflux state for reaction for 4 hours. Cool to -10~0℃.

[0025] Add a mixed solution of 17.9 g of acrolein and 100 ml of THF, and react at room temperature for 3 to 5 hours. Cool the reaction solution and adjust the pH value to 5-6. The reaction solution is separated into layers, the organic phase is separated, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined. It was washed with saturated NaCl aqueous solution, dried and concentrated to obtain 66.6 g (GC content: 51.5%).

[0026] Add 10g anhydrous zinc chloride in the reaction bottle of 3000ml, N 2 Add 165gPBr under protection 3 , heated to 80-90°C for ...

Embodiment 2

[0034] 1. 1-Chloro-6,6-dimethyl-2-heptene-4-yne

[0035] 1000ml reaction bottle, in N 2 Under protection, 150ml THF and 24.8g tert-butylacetylene were added. Add 245ml (1.43M) of THF solution of ethylmagnesium bromide, heat up to weak reflux and react for 4 hours. Cool to -10~0℃.

[0036] Add a mixed solution of 17.9 g of acrolein and 100 ml of THF, and react at room temperature for 3 to 5 hours. Cool the reaction solution and adjust the pH value to 5-6. The reaction solution is separated into layers, the organic phase is separated, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined. It was washed with saturated NaCl aqueous solution, dried and concentrated to obtain 60.2 g (GC content: 57.6%).

[0037] Add 10g anhydrous zinc chloride in the reaction bottle of 3000ml, N 2 Add 70gSOCl under protection 2, reflux for 0.5 hours. After cooling, add 1000ml cyclohexane and 500ml THF, add the mixture of 60.2g concentrate and 200ml cyclohexane...

Embodiment 3

[0052] 1. 1-Chloro-6,6-dimethyl-2-heptene-4-yne

[0053] 1000ml reaction bottle, in N 2 Under protection, 150ml THF and 25.6g tert-butylacetylene were added. Add 250ml (1.52M) of vinylmagnesium bromide THF solution, heat up to a weak reflux state and react for 4-6 hours. Cool to -10~5°C.

[0054] Add a mixture of 17.9 g of acrolein and 100 ml of THF, and react at room temperature for 2 to 4 hours. Cool the reaction solution and adjust the pH value to 5-6. The reaction solution is separated into layers, the organic phase is separated, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined. It was washed with saturated NaCl aqueous solution, dried and concentrated to obtain 63.2 g (GC content: 57.6%).

[0055] Add 10g anhydrous zinc chloride in the reaction bottle of 3000ml, N 2 Add 70gSOCl under protection 2 , reflux for 0.5 hours. After cooling, add 1000ml cyclohexane and 500ml THF, add the mixture of 63.2g concentrate and 200ml cyclohexa...

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PUM

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Abstract

The method for synthesizing terbinafine hydrochloride includes the following steps: using tert-butyl acetylene as raw material, converting it into 3,3-dimethyl-1-butyne litihium or 3,3-dimethyl-1-butyne Grignard reagent, then synthesizing intermediate 1-halo-6,6-diemthyl-2-hepten-4-acetylene, heating said intermediate and N-methyl-1-naphthoamine and making them produce condensation reaction in alkaline system, using HCl to form salt to obtain the invented product.

Description

technical field [0001] The invention relates to a synthetic route of Terbinafine Hydrochloride. Background technique [0002] As an allylamine antifungal drug, terbinafine hydrochloride can effectively inhibit squalene cyclooxygenase, and in the process of fungal reproduction, the biosynthesis of ergosterol requires squalene The role of cyclooxygenase, so inhibition of squalene cyclooxygenase can effectively kill fungi, thereby curing diseases caused by fungal infections. Therefore terbinafine hydrochloride has larger market demand, and its molecular formula is: The synthetic route of terbinafine has multiple: 1.W.Granitzer etc. (Tetra.Lett.1979,34,3145.) in toluene solution, diyne compound can be selectively reduced to trans- Formula enyne, the reaction formula is as follows: ② In the presence of formaldehyde and sodium borohydride, A.Stutz (Canadian Patent 1157023) reductively aminated naphthylamine and trans-6,6-dimethylhept-2-en-4-yne-1-aldehyde to obtain Terbin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/60C07C209/68C07C211/27
Inventor 姜标周健李欢李斌刘冲解德良张华欣陈琦
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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