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New preparation method of duloxetine intermediate

A technology for duloxetine and intermediates, which is applied in the field of preparation of duloxetine intermediates, and can solve the problems of high yield and high cost

Inactive Publication Date: 2015-11-25
CHONGQING CHANGJIE MEDICINE CHEM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the carbonyl reduction reaction, the reduction method mainly used is metal borohydride or lithium aluminum hydride reduction method, and then splits. The advantage of this method is that the yield is high, and the disadvantage is that the cost is high. With the increase of market competition It is very necessary to develop a low-cost reduction method to prepare duloxetine

Method used

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  • New preparation method of duloxetine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Preparation of 3-chloro-1-(2-thiophene)-1-propanol

[0024]

[0025] Add 50 g (0.286 mol) of 3-chloro-1-(2-thiophene)-1-propanone and 300 mL of isopropanol to the reaction flask, stir well, add 175 g (0.858 mol) of aluminum isopropoxide and 3.8 g of aluminum trichloride g (0.0286mol), the temperature was raised to 75°C, and the reaction was stirred for 6 hours. After the completion of the reaction, cool down to room temperature, add 600 mL of water and adjust the pH to 5.0 with hydrochloric acid, extract with ethyl acetate (300 mL×3), dry over sodium sulfate, and evaporate to dryness under reduced pressure to give 3-chloro-1-(2-thiophene)-1 -Propanol oil 43.8g, yield 86.7%, purity 97.2%. 1 HNMR (CDCl 3 ): 7.26(m,1H,Ar-H), 6.99(m,2H,Ar-H), 5.21(m,1H,CH), 3.73-3.60(m,2H,CH-CH 2 ), 2.24(m,2H,Cl-CH 2 ).

Embodiment 2

[0026] Example 2: Preparation of 3-bromo-1-(2-thiophene)-1-propanol

[0027]

[0028] Add 10g (0.046mol) of 3-bromo-1-(2-thiophene)-1-propanone and 50mL of tert-butanol into the reaction flask, stir well, add 56.4g (0.276mol) of aluminum isopropoxide, and heat up to 70°C , stirred for 5 hours. After the reaction was completed, cool down to room temperature, add 100 mL of water, adjust the pH to 7.0 with 6M sulfuric acid, extract with ethyl acetate (50 mL×3), dry over sodium sulfate, and evaporate to dryness under reduced pressure to give 3-bromo-1-(2-thiophene) -1-propanol oil 9.3g, yield 91.3%, purity 95.4%.

Embodiment 3

[0029] Example 3: 3-Bromo-1-(2-thiophene)-1-propanol refined

[0030] Take 5.0g of crude 3-bromo-1-(2-thiophene)-1-propanol (purity 95.4%), add methanol 10mL, isopropyl ether 40mL, heat to reflux to dissolve, cool to room temperature, stir for 1 hour, 0~ Stir at 5°C for 3 hours, filter with suction, and dry under normal pressure to obtain 4.5 g of solid, with a yield of 90.0% and a purity of 98.7%.

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Abstract

A new preparation method of a duloxetine intermediate is disclosed. According to the method, 1-(2-thiophene)substituted acetone, which is used as a raw material, undergoes a heating reaction in a certain organic solvent under the action of a specific reducing agent, and a reaction product undergoes pH value regulation and treatment so as to obtain 1-(2-thiophene)substituted propanol. The 1-(2-thiophene) substituted n-propanol intermediate prepared by the method has advantages of low cost, simple operation and high yield, and is suitable for industrial application. The intermediate is a duloxetine key intermediate. After further resolution and introduction of naphthalene ring, duloxetine can be obtained.

Description

Technical field [0001] The present invention involves a method of preparation in the middle of Losin. Background technique [0002] Duloxetinehydrochloride (Duloxetinehydrochloride) is a high-affinity 5-hydroxyline-nailopase reinforcement dual inhibitors (SNRIS) developed by Elililly. It is a clinical effective antidepressant.(S)-(+) -n-methyl-3- (1-萘 oxygen) -3- (2-pneumophyte) salt hydrochloride, the chemical structure is shown below. [0003] [0004] The main three dosage forms of this product are capsules, capsules cache agents and tablets, respectively. They were listed in Norway, the United States and India in 2004 in 2004. The product names are YENTREVE, Cymbalta and Symbal, and then in Europe and Australia in Europe and Australia.The listing of many countries such as Japan and China is a medical insurance catalog of China in 2010. [0005] This product is mainly used to treat adult depression (J.Clin.PSY.2002,63 (4), 308–315), medium to severe pressure urinary incontin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/16C07D333/20
CPCC07D333/16C07D333/20
Inventor 王庆
Owner CHONGQING CHANGJIE MEDICINE CHEM
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