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Production process of high-purity dutasteride

A dutasteride, high-purity technology, applied in the field of pharmaceutical synthesis, can solve the problems of low product yield and purity, complicated purification steps, and high purification costs, and achieves improved purity, improved yield and purity, and improved product quality. The effect of purity

Active Publication Date: 2018-02-16
JIANGXI GUOYAO PHARMA LLC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] This process has been used in production until now, the yield and purity of the product are both low, and the purification steps are relatively cumbersome, time-consuming and labor-intensive, and the cost of purification is relatively high

Method used

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  • Production process of high-purity dutasteride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] 1) Add ethanol, 2A6, water, and NaOH (molar ratio: 4:1:9:2) to the reaction kettle in sequence, heat to 75-85°C for 6-8 hours, and TLC detects that the raw material 2A6 is completely reacted ( Developing agent: EA:PE=1:1, UV254nm, product Rf=0). When the temperature is lowered to 60-70°C, add hydrochloric acid to adjust the pH to about 0.8-1.5, and solids are precipitated. Continue to cool down to 20-25°C and stir for 30-45 minutes. °C and dried under reduced pressure for 6-8 hours to obtain off-white powder 2A7.

[0053] 2) Add DMF, 2,5-bis(trifluoromethyl)aniline, DBU, CDI (molar ratio: 5:1:1.3) to the reaction kettle in turn under stirring, and heat to 105-110°C for 2.5-3 After 1 hour, add 2A7 and DMF (molar ratio: 1.1:5) in sequence, continue the heat preservation reaction for 20-24 hours, and monitor the reaction by TLC (developing agent: EA / PE=1 / 1, UV254nm, product Rf=0.5-0.8 or so) , cool down to 85-95°C, add water, stir to precipitate solids, slowly cool down ...

Embodiment 2

[0057] 1) Add ethanol, 2A6, water, and NaOH (molar ratio: 6:1.5:15:2.8) to the reaction kettle in sequence, heat to 75-85°C for 6-8 hours, and TLC detects that the raw material 2A6 has reacted completely ( Developing agent: EA:PE=1:1, UV254nm, product Rf=0). When the temperature is lowered to 60-70°C, add hydrochloric acid to adjust the pH to about 0.8-1.5, and solids are precipitated. Continue to cool down to 20-25°C and stir for 30-45 minutes. °C and dried under reduced pressure for 6-8 hours to obtain off-white powder 2A7.

[0058] 2) Add DMF, 2,5-bis(trifluoromethyl)aniline, DBU, CDI (molar ratio: 4:1.5:1.8) in turn to the reaction kettle under stirring, and heat to 105-110°C for 2.5-3 After 1 hour, add 2A7 and DMF (molar ratio: 1.2:4) in sequence, and continue the heat preservation reaction for 20-24 hours. TLC monitors the reaction (developing agent: EA / PE=1 / 1, UV254nm, product Rf=0.5-0.8 or so) , cool down to 85-95°C, add water, stir to precipitate solids, slowly cool...

Embodiment 3

[0061] Embodiment 3, comparative test

[0062] In order to investigate the optimal preparation method of dutasteride, the preparation method of the present invention was compared with the prior art,

[0063] Among them: Scheme 1: using toluene or directly pyridine as a solvent, using thionyl chloride or oxalyl chloride as an acid chloride reagent, through DT4-acyl chloride (III) and 2,5-bistrifluoromethylaniline (2,5- bis (trifluoromethyl)aniline, BTFMA) reaction method for preparing DTS (document WO, 95 / 07927);

[0064] Scheme 2: The DT4 acid chloride method is reacted with ammonia to produce DT4-amide (II), and BTFMA is diazotized to replace 2,5-bistrifluoromethyl iodobenzene (VI), both of which use xylene as a solvent. Catalyzed with potassium carbonate and copper powder, reflux reaction for 50-60 hours to prepare DTS (document US, 2005 / 0059692A1); scheme 3: using acetonitrile as solvent, DT4 is prepared with pivaloyl chloride or methanesulfonyl chloride under the catalysi...

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Abstract

The invention discloses a purification production process of high-purity dutasteride. The problems to be solved are that the purity of the dutasteride is improved while the production cost is reduced.According to the method, after a dutasteride crude product is obtained, twice crystallization is carried out, so that the dutasteride with high yield and high purity can be obtained. The production process provided by the invention has the advantages of high efficiency and clean production, and the operability is high. An intermediate is refined, so that the quality of the dutasteride finished product is more easily controlled, the purity of the obtained dutasteride product is not lower than 99.5%, and any single impurity in the product is not higher than 0. 1%.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and relates to a preparation method of medicine, in particular to a preparation method of dutasteride. Background technique [0002] Dutasteride (Avodart) belongs to azasteroid compounds, is the only selective inhibitor of type I and type II 5α reductase, and is a new type of drug for the treatment of benign prostatic hyperplasia. Researched and developed by Glaxo Company and launched in the United States on October 10, 2002, it is used for the treatment of benign prostatic hyperplasia (BHP), enlarged prostate, male pattern hair loss, seborrheic alopecia, and hereditary alopecia. [0003] At present, the domestic dutasteride synthesis process is to use toluene or directly pyridine as a solvent, and thionyl chloride or oxalyl chloride as an acid chloride reagent, through DT4-acyl chloride (III) and 2,5-bistrifluoromethyl A method for preparing DTS by reacting aniline (2, 5-bis(trifluoromethyl)an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00
CPCC07J73/005
Inventor 万义斌葛友群左飞鸿杨明余承祥李进进于莲欣刘威谢亮亮熊昌秦建民刘林华邓愍民
Owner JIANGXI GUOYAO PHARMA LLC
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