A kind of preparation method of dapoxetine hydrochloride

Abstract

The invention discloses a method for preparing dapoxetine hydrochloride. The method comprises the following steps: subjecting (s)-3-amino-3-phenylpropionic acid or an ester thereof to a reduction reaction in a reduction system prepared from a hydroborate and a boron trifluoride complex, so as to obtain an intermediate 1, i.e. (s)-3-amino-3-phenylpropanol; subjecting the (s) intermediate 1 to an Eschweiler-Clark reaction with formic acid and formaldehyde, so as to obtain an intermediate 2; subjecting the intermediate 2 to a Williamson ether forming reaction with 1-fluoronaphthalene, so as to obtain a free alkali, i.e. (s)-N,N-dimethyl-3-(1-naphthyloxy)phenyl propyl amine; subjecting the free alkali to a salt forming reaction with alcohol-acyl chloride or a chloride thereof, a hydrochloric acid organic solution or hydrochloric acid gas, thereby obtaining dapoxetine hydrochloride. According to the method, the synthesis route is low in production cost, the reaction conditions are mild, all the materials are readily available, the raw materials are low in toxicity, the reaction is simple in operation and high in safety, and the product is high in purity and yield and is environmentally friendly, so that the method is applicable to industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a preparation method of dapoxetine hydrochloride. Background technique [0002] Dapoxetine Hydrochloride is a selective serotonin reuptake inhibitor (SSRI). Developed by Eli Lilly of the United States, it was launched in Europe in 2009 under the trade name Priligy, and it is an ideal drug for treating premature ejaculation (PE) in men. Chemical name: (s)-N,N-dimethyl-3-(naphthyl-1-oxyl)-1-phenylpropylamine hydrochloride. The chemical structural formula is: [0003] [0004] Relevant dapoxetine hydrochloride preparation method in the prior art mainly contains following several kinds: [0005] method one: [0006] In 1992, it was published in J Label Compd Radiopharm by Eli Lilly and Company using ethyl cinnamate as a starting material to prepare the synthetic route of dapoxetine hydrochloride. The specific route is as follows: [0007] [00...

AI Technical Summary

Problems solved by technology

[0036] 1) Part of the reducing agent uses flammable, explosive and expensive lithium aluminum hydride; red aluminum or highly toxic borane, which is more difficult to post-process, is less safe and has higher requirements for personnel protection and equipment, increasing production costs and Difficulty of operation

[0037] 2) Some routes use chiral resolution reagents. The chiral purity needs multiple purifications to meet the requirements. The operation is complicated and difficult, and the yield is low, resulting in a great waste of products and increased production costs.

Not conducive to industrial production

[0038] 3) Part of the synthetic route is long, the total yield is low, the production cost is high and the cycle is long

[0039] 4) Some route operations are purified by means of column chromatography, which is not conducive to industrial production

[0040] 5) The free base after purification is not obtained, but the direct salt formation is adopted, the operation is complicated, the impurities are not easy to remove, the quality control of the final product is difficult, and the amount of hydrochloric acid is difficult to control, resulting in a decrease in product yield and an increase in energy consumption

Excess hydrochloric acid gas is easy to leave the system, which requires high safety and protection for personnel and equipment. The solubility of the product increases sharply under acidic conditions, and the yield decreases, causing unnecessary economic losses.

Images