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Synthesis method of dapoxetine and dapoxetine hydrochloride

A synthetic method, dapoxetine technology, applied in the field of organic drug synthesis, can solve the problems of high price, cumbersome reaction route, high production cost, etc., and achieve the effect of low cost, easy availability of raw materials, and good product quality

Inactive Publication Date: 2021-10-01
上海科利生物医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Using 3-phenylacrolein and N-benzyloxycarbonyl hydroxylamine as starting materials, according to route five reactions, synthesize dapoxetine hydrochloride (see Chinese patent CN103304434); however, the reaction route of this method is cumbersome and expensive Expensive chiral catalysts and precious metals such as palladium, high production costs

Method used

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  • Synthesis method of dapoxetine and dapoxetine hydrochloride
  • Synthesis method of dapoxetine and dapoxetine hydrochloride
  • Synthesis method of dapoxetine and dapoxetine hydrochloride

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preparation example Construction

[0037] The invention provides a kind of synthetic method of dapoxetine, comprising the following steps:

[0038] (1) 1-naphthol, paraformaldehyde, hydrogen bromide and the first organic solvent are mixed, carry out bromomethylation reaction, obtain 1-naphthol bromomethyl ether;

[0039] (2) Under a protective atmosphere, the 1-naphthol bromomethyl ether, magnesium, an initiator and a second organic solvent are mixed to carry out a substitution reaction to obtain a 1-naphthol bromomethyl ether Grignard reagent solution;

[0040] (3) The 1-naphthol bromomethyl ether Grignard reagent solution, R-styrene oxide and the third organic solvent are mixed to carry out a Grignard reaction to obtain R-3-(1-naphthyloxy)- 1-phenylpropanol; R in the R-epoxy styrene includes tosyl, methanesulfonyl or m-nitrobenzenesulfonyl;

[0041] (4) Mix the R-3-(1-naphthyloxy)-1-phenylpropanol, the brominating reagent and the fourth organic solvent, and carry out the bromination reaction to obtain S-1-br...

Embodiment 1

[0089] (1) 1-naphthol bromomethyl ether

[0090] Add 400g of dichloromethane, 144.2g of 1-naphthol (1mol) and 36g of paraformaldehyde (1.2mol) into a 1000mL reaction flask, stir to form a suspension, feed dry hydrogen bromide gas, and control the temperature of the system not to exceed 30 °C until the solids are completely dissolved, transfer the reaction solution into a separatory funnel, add anhydrous sodium sulfate to the obtained lower organic phase to dry, filter, and distill the resulting filtrate to constant weight under reduced pressure to obtain 1-naphthol bromomethyl ether (Pale yellow oily liquid).

[0091] (2) R-3-(1-naphthyloxy)-1-phenylpropanol

[0092] Mix 0.5mol 1-naphthol bromide with 300mL tetrahydrofuran to obtain a 1-naphthol bromide solution; under nitrogen protection, add 150mL tetrahydrofuran, 14.6g magnesium strips (0.6mol) and 0.1g iodine and mix well , add 20mL of 1-naphthol bromide methyl ether solution dropwise, and slowly heat to reflux. When the...

Embodiment 2

[0101] (1) 1-naphthol bromomethyl ether

[0102] Add 400g of dichloromethane, 144.2g of 1-naphthol (1mol) and 36g of paraformaldehyde (1.2mol) into a 1000mL reaction flask, stir to form a suspension, feed dry hydrogen bromide gas, and control the temperature of the system not to exceed 30 °C until the solids are completely dissolved, transfer the reaction solution into a separatory funnel, add anhydrous sodium sulfate to the obtained lower organic phase to dry, filter, and distill the resulting filtrate to constant weight under reduced pressure to obtain 1-naphthol bromomethyl ether (Pale yellow oily liquid).

[0103] (2) R-3-(1-naphthyloxy)-1-phenylpropanol

[0104] Mix 0.5mol 1-naphthol bromide methyl ether with 300mL methyl tert-butyl ether to obtain 1-naphthol bromide methyl ether solution; under nitrogen protection, add 150mL methyl tert-butyl ether, 18.2g magnesium bar (0.75mol) and 1mL ethyl bromide were mixed evenly, and 15mL of 1-naphthol bromomethyl ether solution ...

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Abstract

The invention provides a synthesis method of dapoxetine and dapoxetine hydrochloride, and belongs to the technical field of organic synthesis of medicines. The synthesis method of dapoxetine provided by the invention comprises the following steps: 1-naphthol and paraformaldehyde generate 1-naphthol bromomethyl ether under the action of hydrogen bromide, the 1-naphthol bromomethyl ether reacts with magnesium to obtain a 1-naphthol bromomethyl ether Grignard reagent, the 1-naphthol bromomethyl ether Grignard reagent reacts with R-styrene oxide to obtain R-3-(1-naphthyloxy)-1-phenyl propanol, and the R-3-(1-naphthyloxy)-1-phenyl propanol reacts with a bromination reagent to obtain S-1-bromo-1-phenyl-3-(1-naphthyloxy)propane; or the S-1-bromo-1-phenyl-3-(1-naphthyloxy)propane reacts with sulfonyl chloride to obtain S-1-sulfonyloxy-1-phenyl-3-(1-naphthyloxy) propane, or and the S-1-sulfonyloxy-1-phenyl-3-(1-naphthyloxy)propane reacts with sulfonyl chloride to obtain dapoxetine hydrochloride. The synthesis method provided by the invention has the advantages of short synthesis route, high product yield, good product quality, easily available raw materials, low cost and small environmental pollution, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of organic synthesis of medicines, in particular to a synthesis method of dapoxetine and dapoxetine hydrochloride. Background technique [0002] The chemical name of dapoxetine hydrochloride is: (S)-(+)-N,N-dimethyl-3-(1-naphthyloxy)-1-phenylpropylamine hydrochloride, which is a selective 5 -Hydroxylamine reuptake inhibitor, which has the advantages of short half-life and less adverse reactions, was developed by Eli Lilly and Company of the United States and launched in Europe in 2009 for the treatment of premature ejaculation in men. [0003] According to the difference of preparation raw material, the synthetic method of dapoxetine hydrochloride is divided into following several classes: be starting with benzaldehyde and malonic acid, obtain dapoxetine according to route one reaction (referring to J.Label.Compd.Radionpharm, 1993, (31): 305-315, European Patent EP0288188 and "Chinese Journal of New Drugs",...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/02C07C213/00C07C217/16
CPCC07C41/01C07C41/30C07C41/22C07C303/28C07C213/00C07C213/02C07C43/225C07C43/23C07C309/66C07C217/16
Inventor 李舸刘婷李海林苏宏文张建现彭自祥张明明
Owner 上海科利生物医药有限公司
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