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Purification method for preparing high-purity duloxetine hydrochloride intermediate

A technology of duloxetine hydrochloride and purification method, which is applied in the field of medicinal chemistry, can solve the problems of impurity purity less than 0.1%, high quality duloxetine hydrochloride, etc., and achieve the effect of simple operation

Active Publication Date: 2017-05-10
苏州正济药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, the duloxetine hydrochloride produced by the original pharmaceutical factory is of high quality, with a single impurity purity of less than 0.03%, and a total impurity purity of less than 0.1%.

Method used

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  • Purification method for preparing high-purity duloxetine hydrochloride intermediate
  • Purification method for preparing high-purity duloxetine hydrochloride intermediate
  • Purification method for preparing high-purity duloxetine hydrochloride intermediate

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Embodiment 1

[0021] Embodiment 1: Purification of S-(-)-N, N-dimethyl-3-hydroxyl-3-(2-thiophene) propylamine

[0022] Weigh 30.1g of S-(-)-N,N-dimethyl-3-hydroxy-3-(2-thiophene) propylamine and add it into a 500mL four-neck flask, measure methanol and water with a volume ratio of 1 / 10 Add 293.7g of mixed solvent, heat up the water bath to 72°C, reflux, stir at 5 rpm, stir for 5 minutes, slowly cool down and crystallize by adjusting the temperature control device, control the speed at 6 rpm, and the internal temperature drops to 8 after 140 minutes Suction filtration at ℃, and the filter cake was vacuum-dried at 45 ℃ to obtain 26.8 g of off-white solid. The yield is 89.1%, the HPLC analysis purity is 99.9%, and the purity of the isomer impurity formula (9) is less than 0.03%. The prepared S-(-)-N,N-dimethyl-3-hydroxy-3-(2-thiophene)propylamine is condensed with 1-fluoronaphthalene in the presence of sodium hydride, and finally N-demethylated , refined after salt formation to obtain high-p...

Embodiment 2

[0023] Embodiment 2: Purification of S-(-)-N,N-dimethyl-3-hydroxyl-3-(2-thiophene) propylamine

[0024] Weigh 90.0g of S-(-)-N,N-dimethyl-3-hydroxy-3-(2-thiophene)propylamine and add it into a 1000mL four-neck flask, measure methanol and water with a volume ratio of 1 / 10 Add 881.1g of mixed solvent, raise the temperature of the water bath to 74°C, reflux, stir at 4 rpm, stir for 5 minutes, slowly cool down and crystallize by adjusting the temperature control device, control the speed at 6 rpm, and the internal temperature will drop to 9 after 150 minutes. Suction filtration at ℃, and the filter cake was vacuum-dried at 45 ℃ to obtain 81.9 g of off-white solid. The yield is 91.0%, the HPLC analysis purity is 99.9%, and the purity of isomer impurity formula (9) is less than 0.03%. The prepared S-(-)-N,N-dimethyl-3-hydroxy-3-(2-thiophene)propylamine is condensed with 1-fluoronaphthalene in the presence of sodium hydride, and finally N-demethylated , refined after salt formation...

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Abstract

The invention relates to a purification method for preparing high-purity duloxetine hydrochloride intermediate (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine; (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine is subjected to program-controlled recrystallization in a solvent to obtain a purified product, wherein the solvent is a mixed solvent of methanol and water, and program-controlled recrystallization includes the specific steps of heating and refluxing at 72-74 DEG C for 5-60 min, stirring at a speed of 0.5-15 r / min, cooling for crystallization at a temperature range of 72-80 DEG C for 120-150 min, and stirring at a speed of 6-15 r / min. The purification method is simple to perform, purity of isomer impurity is less than 0.03%, and the purification method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation of high-purity loxetine hydrochloride intermediate S-(-)-N,N-dimethyl-3-hydroxyl-3-(2-thiophene)propylamine purification method. Background technique [0002] Duloxetine hydrochloride (Duloxetine hydrochloride), the chemical name is (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-3-propanamine hydrochloride, the structural formula is as follows As shown in formula (1), [0003] [0004] It is a new type of antidepressant jointly developed by Eli Lilly and Company of the United States and Boehringer Ingelheim of Germany. It is a dual serotonin and norepinephrine reuptake inhibitors (serotonin&norepinephrine reuptake inhibitors, SNRIs), which can cause depression in high doses. Produces inhibitory effect on dopamine (DA) uptake. It was approved by FDA in September 2002 and listed in the United States for the treatment of severe depression and anxiety. For...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/20
CPCC07D333/20
Inventor 张为成段世英刘中华
Owner 苏州正济药业有限公司
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