Dapoxetine hydrochloride synthetic method

A technique for the synthesis of dapoxetine hydrochloride, which is applied in the field of preparation of small-molecule chemical drugs, can solve the problems of low asymmetric reduction yield, reduced optical purity, and low total yield, so as to improve the optical purity of the product and the process The effect of shortening the route and increasing the yield

Inactive Publication Date: 2015-04-08
ARROMAX PHARMATECH
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  • Abstract
  • Description
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Problems solved by technology

[0015] So far, the problems in the routes reported in the literature are as follows: in the synthetic routes (1), (2) and (3), the last step needs to use L-(+)-tartaric acid as a resolving agent for chiral resolution, half of which (R )-configuration product becomes waste and cannot be reused, so the overall yield of the route is lower
Synthetic route (4) needs to use SnCl 2 , high toxicity, chiral reducing agent ligand ((S)-(-)-α, α-diphenyl-2-pyrrolinemethanol) is more expensive, and the yield of asymmetric reduction is low
Synthetic route (5) requires the use of expensive chiral reducing agent (S)-α, α-diphenyl-2-pyrrolinol is more expensive and costly
In addition, during the reaction of routes (4) and (5), methanesulfonyl chloride needs to be used to sulfonylate (R)-alcoholate 13, and the reaction will produce a by-product (S)-configured chloride, which Amination of (S)-configured chloride with dimethylamine to give (R)-dapoxetine, resulting in reduced optical purity of the final product
In the final step, HCl gas is used for salt formation, and the reaction operation and control are difficult

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0035] Synthetic compound(12)

[0036]

[0037] Compound (9) (16.8g, 0.1mol) was dissolved in 1,4-dioxane (40mL), and (-) diisopinepinyl chloride borane [(-)-DIPCl] was added at 25°C (64g, 0.12mol, 1.2eq, 60% tetrahydrofuran solution), at this temperature, reacted for 12h. Ice water (200 mL) was added slowly, keeping the temperature not exceeding 25°C, stirred for 30 minutes, and the layers were separated, and the aqueous phase was extracted with ethyl acetate (3×100 mL). The organic phases were combined, washed with saturated aqueous sodium bicarbonate to near neutrality, dried over anhydrous MgSO4, filtered, concentrated and evaporated to remove the organic solvent to obtain compound (12) (white solid, mp=56-58 ° C, yield 92%, HPLC purity 99.2 %, ee value = 99.2%).

[0038] 1 H-NMR (CDCl 3, 400MHz, δppm): 2.00(s,1H,OH),2.05-2.10(m,1H),2.12-2.26(m,1H),3.52-3.60(m,1H),3.72-3.80(m,1H) , 5.00 (dd, J=4.8Hz, J=8.2Hz, 1H), 7.33-7.40 (m, 5H).

Embodiment 2

[0040] Compound (9) (16.8g, 0.1mol) was dissolved in 2-methyltetrahydrofuran (60mL), and (-)-DIPCl (80g, 0.15mol, 1.5eq, 60% n-hexane solution) was added at 10°C, At this temperature, the reaction was 14h. Add ice water (250 mL) slowly, keep the temperature not exceeding 10°C, stir for 50 minutes, let stand to separate the layers, and extract the aqueous phase with ethyl acetate (3×100 mL). Combine the organic phases, wash with saturated aqueous sodium bicarbonate to nearly neutral, anhydrous MgSO 4 Dry, filter, concentrate and evaporate the organic solvent to obtain compound (12) (white solid, yield 95%, HPLC purity 99.5%, ee value=99.1%).

Embodiment 3

[0042] Compound (9) (16.8g, 0.1mol) was dissolved in THF (100mL), and (-)-DIPCl (106g, 0.20mol, 2.0eq, 60% n-heptane solution) was added at 40°C. Next, react for 16h. Add ice water (300 mL) slowly, keep the temperature not exceeding 0° C., stir for 50 minutes, stand to separate the layers, and extract the aqueous phase with ethyl acetate (3×100 mL). Combine the organic phases, wash with saturated aqueous sodium bicarbonate to nearly neutral, anhydrous MgSO 4 Dry, filter, concentrate and evaporate the organic solvent to obtain compound 12 (white solid, yield 96%, HPLC purity 99.3%, ee value=99.2%).

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Abstract

The invention provides a dapoxetine hydrochloride synthetic method. The method includes the steps of (1) subjecting a compound (9) and (-)-beta-chlorodiisopinocampheylborane to reduction reaction in an organic solvent at the temperature of 10 DEG C-80 DEG C to obtain a compound (12); (2) subjecting a compound (8) and alkali to reaction in an organic solvent for 2 hours-14 hours at the temperature of 0 DEG C-10 DEG C, adding the compound (12) obtained in step (1), and performing alkylation reaction for 15 hours-40 hours at the temperature of 0 DEG C-10 DEG C to obtain a compound (13); (3) subjecting the compound (13) obtained in step (2) and thionyl chloride to reaction in an organic solvent at the temperature of -10 DEG C-0 DEG C to obtain a compound (14); (4) subjecting the compound (14) obtained in step (3) and dimethylamine to reaction in an organic solvent at the temperature of 20 DEG C-30 DEG C to obtain dapoxetine free amine and to reaction with an ethanol solution of hydrogen chloride to obtain hydrochloric acid dapoxetine. The dapoxetine hydrochloride synthetic method is high in yield and product optical purity. The reaction scheme is shown in the description.

Description

technical field [0001] The invention relates to the field of preparation of small molecule chemical drugs, and more particularly relates to a method for synthesizing dapoxetine hydrochloride. Background technique [0002] Dapoxetine (Dapoxetine, LY-210448), the chemical name is (S)-N,N-dimethyl-3-(1-naphthyloxy)-1-phenyl-1-propanamine, originally a It is a selective serotonin reuptake inhibitor used to treat depression, but relevant medical clinical trial data show that it has a significant effect in treating premature ejaculation in men, and has a very broad market prospect. Its hydrochloride is used clinically. It was first launched in Finland and Sweden in Europe in February 2009. It is used for the on-demand treatment of premature ejaculation in adult men and has become a new drug for improving premature ejaculation in men. The clinical research results show that dapoxetine can rapidly inhibit the reuptake of serotonin in the blood, has no direct effect on neuronal rece...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/48C07C213/02
Inventor 洪健刘国斌王景炳
Owner ARROMAX PHARMATECH
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