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Preparation method of duloxetine hydrochloride

A technology for duloxetine hydrochloride and hydrochloric acid, which is applied in the field of preparation of duloxetine hydrochloride, can solve the problems of difficult control of salt-forming process operation, poor optical purity of crude product, low product yield and the like, and achieves reduction of operational difficulty and danger. The effect of stability, avoidance of racemization, and high optical purity

Active Publication Date: 2013-06-26
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0024] In summary, the salt-forming process of the duloxetine hydrochloride preparation method disclosed in the prior art is difficult to control, the product yield is low, and the obtained crude product has poor optical purity and needs to be purified through multiple recrystallizations, which is not conducive to industrialization

Method used

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  • Preparation method of duloxetine hydrochloride
  • Preparation method of duloxetine hydrochloride

Examples

Experimental program
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Embodiment 1

[0034] Embodiment 1: Preparation of duloxetine hydrochloride (I)

[0035] In the reaction kettle, add 1Kg (3.36 mol) of duloxetine, 1 L of dichloromethane, 5 L of ethyl acetate, add 8 Kg of saturated ammonium chloride solution under stirring, and dropwise add 1 N hydrochloric acid solution at 20°C to pH For 1~2, stirring and reacting for 2h. The phases were separated, and the aqueous phase was extracted with 2 L of ethyl acetate. Combine the organic phases, remove dichloromethane under reduced pressure, add 3 L of ethyl acetate, and stir at room temperature for 30 min. After filtering, washing and drying, 1.07 Kg of white solid was obtained, the yield was 95%, the HPLC purity was 99.2%, and the optical purity (ee%) was 98.5%.

Embodiment 2

[0036] Embodiment 2: Preparation of duloxetine hydrochloride (I)

[0037] In the reaction kettle, add duloxetine 1Kg (3.36 mol), 1 L dichloromethane, 10 L ethyl acetate, add 6 Kg saturated ammonium chloride solution under stirring, add 2N hydrochloric acid solution dropwise at 30°C until the pH is 3~4, stirring and reacting for 1h. The phases were separated, and the aqueous phase was extracted with 2 L of ethyl acetate. Combine the organic phases, remove dichloromethane under reduced pressure, and stir at room temperature for 30 min. Filter, wash, and dry to obtain 1.04Kg of white solid, with a yield of 93%, HPLC purity of 99.1%, and optical purity (ee%) of 98.3%.

Embodiment 3

[0038] Embodiment 3: Preparation of duloxetine hydrochloride (I)

[0039] In the reaction kettle, add duloxetine 1Kg (3.36 mol), 1 L dichloromethane, 20 L ethyl acetate, add 4 Kg saturated sodium chloride solution under stirring, add 4N hydrochloric acid solution dropwise at 25°C until the pH is 4~5, stirring and reacting for 2h. Separate the phases, remove the dichloromethane from the organic phase under reduced pressure, and stir at room temperature for 30 min. Filter, wash, and dry to obtain 1.0 Kg of a white solid, with a yield of 90%, an HPLC purity of 99.0%, and an optical purity (ee%) of 98.1%.

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Abstract

The invention relates to a preparation method of duloxetine hydrochloride. The preparation method comprises the step of performing hydrochloride salifying reaction on duloxetine, wherein an organic solvent immiscible with water is taken as a reaction solvent; and simultaneously, adding a saturated saline solution to the reaction liquid, and adding hydrochloric acid with concentration of 1-8 N until the pH of the reaction liquid is 1-5. The salifying method disclosed by the invention has moderate reaction conditions, is simple to operate, is capable of greatly improving the yield and optical purity of the product and reducing the operation difficulty and danger, and is more suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of duloxetine hydrochloride. Background technique [0002] Duloxetine Hydrochloride (Duloxetine Hydrochloride, structural formula shown in formula I), chemical name is (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thiophene) -Propylamine is a 5-hydroxytryptamine and norepinephrine reuptake inhibitor (SNRI) developed by Eli Lilly Company of the United States. It was approved by the U.S. FDA in August 2004. Its trade name is Cymbalta. Used to treat depression. [0003] . [0004] Duloxetine hydrochloride is an optically active substance, and its enantiomers have no antidepressant activity. Therefore, the optical purity of duloxetine hydrochloride raw materials must be limited. [0005] The salt-forming methods in the preparation methods of duloxetine hydrochloride disclosed in prior art documents mainly include the following types. [0006] ① Concentrated hydroch...

Claims

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Application Information

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IPC IPC(8): C07D333/20
Inventor 龚登凰吕健武仙英马玉秀杨杰高利康宏艳刘然
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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