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Preparation method of dapoxetine hydrochloride

A dapoxetine hydrochloride and compound technology, which is applied in the field of preparation of dapoxetine hydrochloride, can solve the problems of low yield and low optical purity, and achieve simple post-processing, chemical purity and optical purity High, optically pure effect

Active Publication Date: 2017-02-15
SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] The present invention provides a new method for the preparation of dapoxetine in order to overcome defects such as the need for split operation, low yield or low optical purity in the preparation process of the intermediate of dapoxetine in the prior art

Method used

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  • Preparation method of dapoxetine hydrochloride
  • Preparation method of dapoxetine hydrochloride
  • Preparation method of dapoxetine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Dissolve 16.85g of compound of formula VI and 14.51g of compound of formula V in 150mL of dry tetrahydrofuran, add 5.60g of solid KOH, heat to 60°C for reaction, monitor by TLC, after the compound of formula VI is completely reacted, cool to room temperature, add 20g of water CuSO 4 And 14.52g (S)-tert-butylsulfinamide, under stirring, add 27.36g condensing agent Ti(OEt) 4 , reflux reaction, after the reaction, pour the reaction solution into ethyl acetate and brine, separate the organic layer, extract the water layer with ethyl acetate several times, combine the organic layers, concentrate to oil, add isopropyl ether, stir 34.5 g of the intermediate of formula IV was precipitated as a pale yellow solid, with a yield of 91.0% and a purity of 95% (HPLC area normalization method).

[0040] MS(ES+) m / z: 402[M+Na] + . 1 H-NMR (CDCl 3 )δ: 1.37(s,9H); 3.71-4.06(m,2H); 4.46-4.59(m,2H); 6.83(d,1H); 7.26-7.52(m,8H); 7.77(m,1H) ; 8.12(m,1H).

Embodiment 2

[0042] Dissolve 18.8g of the compound of formula IV in 150mL of anhydrous THF, lower the temperature to below 0°C, and add the reducing agent BH in batches 3Tetrahydrofuran complex (50mL, 1eq), after the addition is complete, continue to stir the reaction below 0°C, and the reaction is completed for 3h; add HCl ethanol solution (3eq) to the reaction solution at room temperature, stir for 0.5-2h, concentrate under reduced pressure, add Stir with isopropyl ether, filter, dissolve the filter cake in water, slowly add 10% NaOH aqueous solution dropwise, adjust the pH to be greater than or equal to 7, then extract with ethyl acetate (90mL×2), dry, and concentrate to obtain intermediate 12.6 of formula III g, yield 91.9%, purity 98% (HPLC area normalization method), 99% ee.

[0043] MS(ES+) m / z: 278[M+H] + . 1 H-NMR (CDCl 3 )δ: 2.33(m,2H); 4.10(m,1H); 4.21(m,1H); 4.33(m,1H); 6.73(d,1H); 7.26-7.49(m,8H); ,1H); 8.23(m,1H).

Embodiment 3

[0045] Dissolve 10 g of the compound of formula III in 80 mL of CH 2 Cl 2 , add 12mL triethylamine, lower the temperature to below 0°C, put 6mL CH 3 I was dissolved in 20 mL CH 2 Cl 2 , and then drop it slowly, drop it, react at room temperature for 5h, after the reaction, add Na 2 SO 3 The aqueous solution was stirred and allowed to stand, and the organic layer was separated, dried, and evaporated to dryness to obtain 9.8 g of the compound of formula II, namely dapoxetine, with a yield of 89.1% and a purity of 94% (HPLC area normalization method).

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Abstract

The invention discloses a preparation method of dapoxetine hydrochloride. The preparation method comprises that 3-chloropropiophenone and naphthol as initial raw materials and (S)-tert-butanesulfinyl amide undergo a condensation reaction in a solvent, the intermediate is reduced through a reducer BH3 and then is further subjected to deprotection, the reaction product undergoes a methylation reaction and the reaction product undergoes a salification reaction to produce dapoxetine hydrochloride. The preparation method has mild conditions, can be operated simply, realizes a low cost, is free of resolution or use of an expensive heavy metal catalyst, has a simple aftertreatment process, has a high product yield, produces the product with high chemical purity and optical purity and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of dapoxetine hydrochloride. Background technique [0002] Dapoxetine hydrochloride (dapoxetine hydrochloride), the chemical name is S-(+)-N,N-dimethyl-1-phenyl-3-(1-naphthyloxy)propylamine hydrochloride, the structural formula is as follows : [0003] [0004] It is a selective serotonin reuptake inhibitor (SSRI), developed by Eli Lilly (Eli Lilly), and launched in Europe in 2009. Its trade name is Priligy, and it is used to treat premature ejaculation (PE) in men. It is the first oral prescription drug approved to treat PE. In early 2009, Johnson & Johnson announced that dapoxetine hydrochloride (dapoxetine hydrochloride), as a new drug for the treatment of PE, has been approved by European countries Finland and Sweden. Men aged 18 to 64 are the applicable population. The drug has a short half-life and few adverse reactions. , The effect is remarkable. The listing of dapoxetine in the European mark...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C215/28C07C303/40C07C311/04
CPCC07B53/00C07B2200/07C07C213/02C07C213/08C07C303/40C07C215/28C07C311/04
Inventor 张宁付丙月刘宪华段崇刚孔祥雨孙晋瑞赵思太邓玉晓任业明崔新强于治见冯光玲马新成李丹
Owner SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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