Refining method of tadalafil crystal form I

A technology of tadalafil and purification method, applied in the field of medicinal chemistry, can solve the problems of large amount of solvent, low yield and high cost, and achieve the effects of improving quality and yield, simple preparation method and high reproducibility

Inactive Publication Date: 2018-05-29
西安吉泰医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The amount of solvent is too large, the cost is too high, it is not suitable for commercial production, and the purification of impurities is not considered
[0008] Published unauthorized Chinese patent document CN106674223A discloses a method for refining tadalafil. After distilling off the solvent, the remaining solvent is basically acetic acid, which has the risk of forming tadalamorph V; It is not easy to control the amount of evaporation, which affects the yield and the stability of impurity purification, and is not suitable for commercial production
[0009] Published and unauthorized Chinese patent document CN106588927A discloses a preparation method of Tadara amorphous form I, the amount of water added is small, and the yield is low; methanol is not used to remove impurities, and the purification of impurities is not considered

Method used

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  • Refining method of tadalafil crystal form I
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  • Refining method of tadalafil crystal form I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Add 10.00 g of crude tadalafil to a 500 mL three-neck round bottom flask, and then add 150 g of acetic acid / methanol / water mixed solvent (acetic acid:methanol:water mass ratio 95:5:1). Start stirring, raise the temperature to 90-110°C, dissolve the material, cool down to 80-90°C, add activated carbon and stir to raise the temperature to 90-110°C, then keep warm and stir for 30 minutes. After filtering, the temperature of the filtrate was lowered to 30-40°C, crystals were precipitated, and 200 g of water was slowly added. Cool down to 0-5°C and continue crystallization for 60 minutes, filter, wash with water, and dry in vacuum at 75-85°C for 8 hours to obtain 9.68g of Tadala amorphous form A, yield 96.8%, purity (HPLC): 99.83% , Impurity A (HPLC): 0.07%, Impurity 2 (HPLC): 0.06%.

Embodiment 2

[0040] Add 10.00 g of crude tadalafil to a 500 mL three-necked round bottom flask, and then add 150 g of acetic acid / methanol / water mixed solvent (acetic acid:methanol:water mass ratio 99:10:6). Start stirring, raise the temperature to 90-110°C, dissolve the material, cool down to 80-90°C, add activated carbon and stir to raise the temperature to 90-110°C, then keep warm and stir for 30 minutes. After filtering, the temperature of the filtrate was lowered to 30-40°C, crystals were precipitated, and 200 g of water was slowly added. Cool down to 0-5°C and continue crystallization for 60 minutes, filter, wash with water, and dry in vacuum at 75-85°C for 8 hours to obtain Tadalamorph A9.63g, yield 96.3%, purity (HPLC): 99.99% , Impurity A (HPLC): N.D, Impurity 2 (HPLC): N.D.

Embodiment 3

[0042] Add 10.00 g of crude tadalafil to a 500 mL three-neck round bottom flask, and then add 150 g of acetic acid / methanol / water mixed solvent (acetic acid:methanol:water mass ratio 96:7:3). Start stirring, raise the temperature to 90-110°C, dissolve the material, cool down to 80-90°C, add activated carbon and stir to raise the temperature to 90-110°C, then keep warm and stir for 30 minutes. After filtering, the temperature of the filtrate was lowered to 30-40°C, crystals were precipitated, and 200 g of water was slowly added. Cool down to 0-5°C and continue crystallization for 60 minutes, filter, wash with water, and dry in vacuum at 75-85°C for 8 hours to obtain Tadalamorph A9.72g, yield 97.2%, purity (HPLC): 99.96% , Impurity A (HPLC): 0.02%, Impurity 2 (HPLC): N.D.

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Abstract

The invention relates to a refining method of a tadalafil crystal form I. The refining method comprises the following steps: adding a tadalafil crude product into a mixed solvent of acetic acid, methanol and water; heating, stirring and dissolving; filtering and cooling to 30 to 40 DEG C; dropwise adding water; after dropwise adding the water, cooling to 0 to 5 DEG C; stirring and crystallizing for 60min, wherein the yield of the tadalafil reaches 97 percent or more, the purity reaches 99.9 percent and the content of cefotaxime is less than 0.05 percent; centrifuging and drying to obtain the tadalafil crystal form I. The refining method provided by the invention has the advantages that the refining method is suitable for commercial production and the quality and the yield of a product areimproved (the content of biggest cefotaxime is less than 0.05 percent and the yield is 97 percent or more); the preparation method is simple and the repeatability is good.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for refining tadala amorphous form I. Background technique [0002] Tadalafi, the English name of Tadalafi, is a PDE5 inhibitor jointly developed by ICOS and Eli Lilly and Company. Tadalafil was approved for marketing in the United States in August 2003, and its indication is mainly erectile dysfunction; in May 2009, the second indication of this drug was approved: pulmonary hypertension; in October 2011, the drug was approved again For the treatment of secondary benign prostatic hyperplasia. my country approved its domestic listing in May 2005. [0003] The chemical name of tadalafil is (6R-12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-six Hydrogenated pyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione, the structural formula is: [0004] [0005] Tadalafil is a second-generation phosphodiesterase inhibitor type 5 (PDE5 inhibitor), developed by Eli Lill...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14
CPCC07B2200/13C07D471/14
Inventor 王亦群白静波张永利宋彦妮
Owner 西安吉泰医药有限公司
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