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Method for preparing dapoxetine hydrochloride

A technology of dapoxetine hydrochloride and amino, which is applied in the field of preparation of dapoxetine hydrochloride, and can solve problems such as difficult control of hydrochloric acid dosage, high safety and protection requirements, and unfavorable industrial production

Active Publication Date: 2017-06-23
SPRINGPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0037] 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
[0038] 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
[0039] 3) Part of the synthetic route is long, the total yield is low, the production cost is high and the cycle is long
[0040] 4) Some route operations are purified by means of column chromatography, which is not conducive to industrial production
[0041] 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.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Disperse 1.8kg (10.90mol) (s) 3-amino-3-phenylpropionic acid in 18L tetrahydrofuran, add 1.2kg (32.68mol) sodium borohydride, slowly add 9.1kg (48-50%, 32.68mol ) boron trifluoride-tetrahydrofuran solution, after the dropwise addition, react at 30°C for 5h, stop the reaction, quench the reaction with 9L methanol, concentrate, extract with ethyl acetate 4.8L / time*4 times, combine the ethyl acetate layers, Wash twice with 4.8L saturated saline. Dry and concentrate to give (s) 3-amino-3-phenylpropanol. Dry weight 1.57kg, purity (HPLC): 99.91%, yield 95.35%. Ethyl acetate recovery recycling.

[0098] Weigh 1.5kg (9.9mol) of (S)-3-amino-3-phenylpropanol obtained above and dissolve it in 1.6kg (88%, 30mol) of formic acid, add 2.8kg (37%, 35mol) of formaldehyde The solution was heated to reflux and reacted for 8h. Stop the reaction, concentrate under reduced pressure, add 2L of water, adjust the pH to 12 with 10% aqueous sodium hydroxide solution, and then extract with 3L / ...

Embodiment 2

[0103] Disperse 20.0g (0.11mol) (s) methyl 3-amino-3-phenylpropionate in 200ml tetrahydrofuran, add 12.48g (0.33mol) sodium borohydride, add dropwise 92.34g (50%, 0.33mol) boron trifluoride-tetrahydrofuran solution, control the internal temperature to less than 10°C, after the dropwise addition, react at 30°C for 4h, stop the reaction, add dropwise 100ml of methanol to quench the reaction, concentrate, use 100ml / time*4 times of dichloro After extraction with methane, the organic layer was washed twice with saturated brine and water, dried and concentrated to obtain 15.44 g (s) of 3-amino-3-phenylpropanol. Yield 92.0%, purity (HPLC): 99.82%.

Embodiment 3

[0105] Disperse 10.0g (0.060mol) (s) 3-amino-3-phenylpropionic acid in 300ml methyl tert-butyl ether, add 6.87g (0.18mol) sodium borohydride in batches, cool to 0°C, drop Add 53.70g (48%, 0.18mol) boron trifluoride-diethyl ether solution, control the internal temperature to be less than 10°C, after the dropwise addition, react at 30°C for 6h, stop the reaction, add dropwise 10ml of ethanol to quench the reaction, concentrate, and use 30ml / time*4 dichloromethane extractions, the organic layer was washed twice with saturated brine and water respectively, dried and concentrated to obtain 8.30 g(s) of 3-amino-3-phenylpropanol. Yield 90.6%, purity 99.32%.

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PUM

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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...

Claims

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Application Information

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IPC IPC(8): C07C213/08C07C213/06C07C213/10C07C217/48C07C213/00C07C215/28
CPCC07C213/00C07C213/06C07C213/08C07C213/10C07C217/48C07C215/28
Inventor 刘小红吴云登许建张思晗
Owner SPRINGPHARMA CO LTD
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