Method for preparing dapoxetine hydrochloride

A technology of dapoxetine hydrochloride and hydrochloride, which is applied in the field of medicine, can solve the problems of increased synthesis cost, product loss, and tediousness, and achieve the effects of reducing production cost and loss, short synthesis route, and cost saving

Active Publication Date: 2015-11-18
KAMP PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] It can be seen that the existing synthetic route has the following disadvantages: (1) use achiral reagent as a synthetic raw material, and finally resolve the chiral problem of the product with a resolution reagent for the intermediate or product, which will cause the product The loss is serious, and the final yield is very low; (2) the overall route is too long and cumbersome, which reduces the total yield of the product and increases the synthesis cost; (3) uses dangerous and highly toxic reagents, which require high equipment. Not conducive to mass production
(4) Salt formation requires the introduction of dry hydrogen chloride gas, and the reaction operation and control are difficult

Method used

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  • Method for preparing dapoxetine hydrochloride
  • Method for preparing dapoxetine hydrochloride
  • Method for preparing dapoxetine hydrochloride

Examples

Experimental program
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specific Embodiment approach

[0059] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. The NaBH used in the following implementation 4 -ZnC1 2 The system is prepared by the following preparation method:

[0060] (1) Commercially available zinc chloride solids are heated and melted on an electric furnace to remove crystal water inside to prevent its reducing effect, and then cooled to obtain anhydrous zinc chloride;

[0061] (2) Add 30mL of anhydrous tetrahydrofuran to a 100mL single-necked bottle. At room temperature, take anhydrous zinc chloride (40.12, 0.295mol) and dissolve it in anhydrous tetrahydrofuran, add sodium borohydride (22.4g, 0.59mol) ), stirred for 2h to obtain a white suspension for use.

Embodiment 1

[0063] The present embodiment is a kind of preparation method of dapoxetine hydrochloride, specifically comprises the following steps:

[0064] (1) Preparation of Intermediate II

[0065]

[0066] Add 57.6g (0.267mol) of chiral L-phenylalanine methyl ester hydrochloride (I) into a 1000ml three-necked reaction flask, add 300ml of anhydrous THF and stir, then suspend the newly prepared sodium borate-zinc chloride The solution was slowly added dropwise to the reaction system. After the dropwise addition, the temperature was raised to reflux for 4 hours, and the reaction progress was tracked by TLC until the reaction of the raw materials was completed. Cool down to 30-35°C and add 255ml of methanol dropwise. After the dropwise addition, reflux for 30min, cool down, filter, and concentrate the filtrate under reduced pressure to obtain 47.1g of white solid (Intermediate II), with a yield of 99.6%.

[0067] (2) Preparation of Intermediate III

[0068]

[0069] Add 44.25g (0.2...

Embodiment 2

[0074] The difference between this embodiment and Example 1 is that the preparation method of intermediate II in step (1) is different: in this embodiment, L-phenylalanine butyl ester hydrochloride is used as the reaction raw material, and its addition is also 0.267mol, and finally obtained 46.3g of intermediate II with a yield of 97.9%.

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Abstract

The invention relates to the field of medicines, and in particular relates to a method for preparing dapoxetine hydrochloride. The method comprises the following concrete steps: (1) by taking chiral L-phenylalanine hydrochloride as a starting material, and reducing by adopting a reducing system to obtain an intermediate II; (2) performing Eschweiler-Clark reaction on the intermediate II and paraformaldehyde or formaldehyde to obtain an intermediate III; and (3) performing Williamson aethrization reaction on the intermediate III and 1-naphthaline to obtain the dapoxetine hydrochloride. According to the invention, chiral L-phenylalanine hydrochloride is used as the raw material, so resolution of a product is avoided, the raw material is easily obtained and relatively low in price, conventional equipment can meet production requirements, expensive and virulent reagents are not used, reaction conditions are mild, pollution is little, control is easy and industrialized production is facilitated.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of dapoxetine hydrochloride. Background technique [0002] The chemical name of dapoxetine hydrochloride is (S)-(+)-N,N-dimethyl-1-phenyl-3-(1-naphthyloxy)-1-propylammonium hydrochloride, It is a selective serotonin reuptake inhibitor (SSRI), developed by Eli Lilly (Eli Lilly), and launched in Europe in 2009 under the trade name Priligy, for the treatment of premature ejaculation (PE) in men. The drug has a short half-life, few adverse reactions, and significant effects. It is the first oral prescription drug approved for the treatment of PE in the world. In early 2009, Johnson & Johnson announced that dapoxetine hydrochloride (dapoxetinehydrochloride), a new drug for the treatment of PE, had been approved by the European countries Finland and Sweden, and men aged 18 to 64 were the applicable population. The listing of dapoxetine in the European market has greatly e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/48C07C213/06
Inventor 曾培安何雄吴健民贺莲刘娟
Owner KAMP PHARMA
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