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Synthesis method of key intermediate for preparing duloxetine hydrochloride from 2-acetylthiophene

A technology of duloxetine hydrochloride and acetylthiophene, which is applied in the field of synthesis of key intermediates of duloxetine hydrochloride prepared from 2-acetylthiophene, can solve problems such as volatile, expensive and unstable DMF-DMA raw materials, and achieve The effect of short reaction cycle, avoiding the use of expensive catalysts, and easy operation

Inactive Publication Date: 2018-10-16
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] In 2012, SHAO-RUI CHEN reported the reaction of 2-acetylthiophene with DMF-DMA, DMF, LiAlH 4 The method of obtaining compound (I) by reduction, the DMF-DMA raw material in this route is relatively expensive, volatile and unstable (Asian J. Chem. 2012, 24(4), 1680-1684.)

Method used

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  • Synthesis method of key intermediate for preparing duloxetine hydrochloride from 2-acetylthiophene
  • Synthesis method of key intermediate for preparing duloxetine hydrochloride from 2-acetylthiophene

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Embodiment 1

[0030] Embodiment 1: Preparation of (dimethylamino)-1-(2-thienyl)-2-propene-1-one

[0031] Preparation of sodium methoxide / methanol solution: Dissolve 2.7g (50mmol) of sodium methoxide in 10mL of methanol and dissolve evenly to obtain sodium methoxide / methanol solution;

[0032] Add 18.45g (100mmol) of cyanuric chloride, 9.5mL of 1,4-dioxane, and 7.31g (100mmol) of N,N-dimethylformamide into a 250mL three-necked flask and mix well to obtain a mixed solution; solution and 12.60g (100mmol) of 2-acetylthiophene, added to the sodium methoxide / methanol solution, stirred and mixed, the temperature of the reaction solution was controlled to 20°C for the reaction, followed by TLC (petroleum ether: ethyl acetate = 2:1), the reaction ended Afterwards, the solvent was distilled off under reduced pressure, and crystals were precipitated. The crystals were recrystallized in a mixed solvent of dichloromethane:petroleum ether (V:V=1:3), and 14.12g of a light yellow solid was obtained after s...

Embodiment 2

[0034] Preparation of 3-(dimethylamino)-1-(2-thienyl)-2-propen-1-one:

[0035] Preparation of sodium methoxide / methanol solution: Dissolve 10.8g (200mmol) of sodium methoxide in 33mL of methanol and dissolve evenly to obtain sodium methoxide / methanol solution;

[0036] Add 55.35g (300mmol) of cyanuric chloride, 148mL of 1,4-dioxane, and 36.54g (500mmol) of N,N-dimethylformamide into a 250mL three-necked bottle and mix well to obtain a mixed solution; and 12.60 g (100 mmol) of 2-acetylthiophene, added to the sodium methoxide / methanol solution, stirred and mixed, controlled the temperature of the reaction solution to 40°C for the reaction, followed by TLC (petroleum ether: ethyl acetate = 2:1), after the reaction , the solvent was distilled off under reduced pressure, and crystals were precipitated. The crystals were recrystallized in a mixed solvent of dichloromethane:petroleum ether (V:V=1:3), and after suction filtration and drying, 15.31g of a light yellow solid was obtained...

Embodiment 3

[0038] Preparation of 3-(dimethylamino)-1-(2-thienyl)-2-propen-1-one:

[0039] Preparation of sodium methoxide / methanol solution: Dissolve 5.4g (100mmol) of sodium methoxide in 22mL of methanol and dissolve evenly to obtain sodium methoxide / methanol solution;

[0040] Add 7.38g (40mmol) of cyanuric chloride, 73mL of 1,4-dioxane, and 58.5g (800mmol) of N,N-dimethylformamide into a 250mL three-necked bottle and mix well to obtain a mixed solution; Add 12.60 g (100 mmol) of 2-acetylthiophene to sodium methoxide / methanol solution, stir and mix, control the temperature of the reaction solution to 50°C for reaction, TLC tracking (petroleum ether: ethyl acetate = 2:1), after the reaction , the solvent was distilled off under reduced pressure, and crystals were precipitated. The crystals were recrystallized in a mixed solvent of dichloromethane:petroleum ether (V:V=1:3), and 16.51g of a light yellow solid was obtained after suction filtration and drying, which was 3-(di Methylamino)-...

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Abstract

The invention provides a synthesis method of a key intermediate for preparing duloxetine hydrochloride from 2-acetylthiophene and belongs to the technical field of chemical synthesis. The synthesis method comprises the following steps: reacting cyanuric chloride and N,N-dimethylformamide with 2-acetylthiophene to obtain 3-(dimethylamino)-1-(2-thienyl)-2-propenyl-1-one; reducing 3-(dimethylamino)-1-(2-thienyl)-2-propenyl-1-one through lithium aluminum hydride to obtain a duloxetine hydrochloride intermediate which is (R,S)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. The synthesis method iscapable of synthesizing a target product which is a key intermediate of duloxetine hydrochloride through two-step reaction, is cheap in raw materials, simple in process, simple and convenient to operate, mild in reaction condition, short in reaction period and free of expensive catalysts, is environmentally friendly, and is suitable for industrial production; the prepared products are high in yield and purity.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical and chemical intermediates, in particular to a synthesis method of a key intermediate for preparing duloxetine hydrochloride from 2-acetylthiophene. Background technique [0002] Duloxetine hydrochloride (Duloxetine) is a third-generation antidepressant drug, serotonin and norepinephrine reuptake inhibitor (SSNRI), developed by Eli Lilly and Company of the United States, and is suitable for the treatment of severe depression. This product has the characteristics of good chemical stability, safety and effectiveness, few side effects, and low affinity to other nervous systems. Its chemical name is: (S)-(+)-N,N-dimethyl-3-(1-naphthalene Oxy)-3-(2-thiophene)-propylamine hydrochloride, CAS number: 136434-34-9, its molecular structure is as follows: [0003] . [0004] The compound whose molecular structure is shown in formula (I), its name is N,N-dimethyl-3-hydroxyl-3-(2-thienyl...

Claims

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Application Information

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IPC IPC(8): C07D333/20
CPCC07D333/20
Inventor 李坚军方叶蒋珺孙坚裴金凤苏为科
Owner ZHEJIANG UNIV OF TECH
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