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Simple preparation method of vemurafenib and analogues thereof

A technology of compounds and meanings, applied in the field of medicinal chemistry, can solve the problems of complicated operation, long production cycle, low purity, etc., and achieve the effects of simple process operation, less waste water production, and high yield and purity.

Active Publication Date: 2019-07-05
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] All the above synthetic routes have long reaction steps, low overall yields (all lower than 45%), cumbersome operations, high requirements for low-temperature reactions or high-temperature reaction operations involved, long reaction times, and low production efficiency; raw material 5-bromo-7- Azaindole, p-chlorophenylboronic acid, and palladium catalysts are expensive and difficult to obtain
The use of palladium catalysts leads to more by-products of dehalogenation or rearrangement of halogen substitution positions, especially the post-palladium catalyzed coupling route, which produces many impurities, poor product purity, and high cost
[0018] In summary, the existing synthetic route of vemurafenib has problems such as long production cycle, cumbersome operation, high process requirements, high cost, high heavy metal residues, low yield, and low purity.

Method used

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  • Simple preparation method of vemurafenib and analogues thereof
  • Simple preparation method of vemurafenib and analogues thereof
  • Simple preparation method of vemurafenib and analogues thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: the preparation of vemurafenib (I)

[0059] In a 500 ml four-necked flask connected with stirring, a thermometer, and a reflux condenser with a water separator, add 250 grams of toluene, 31.5 grams (0.10 moles) of N-[2,4-difluoro-3-(cyano N-propionyl) phenyl] n-propanesulfonamide, 17.0 grams (0.11 moles) p-chlorophenylacetaldehyde, 0.5 grams of piperidine, heating, stirring, 83-85 ° C azeotropic reflux with water condensation reaction for 5 hours; cooling to 30 ℃, add 38.0 g (0.32 moles) of N,N-dimethylformamide dimethyl acetal, and stir at 85-90°C for 6 hours; cool to 30°C, add 70.0 g of 10wt% ammonia-methanol solution, and stir at 50-55°C React for 4 hours. Recover methanol and toluene by distillation under reduced pressure, add 200 grams of isopropanol to the residue, heat to 80 ° C, cool, recrystallize, filter, and dry to obtain 43.9 grams of vemurafenib, with a yield of 89.6% and a liquid phase purity of 99.91 %.

[0060] The NMR data of the produc...

Embodiment 2

[0063] Embodiment 2: the preparation of vemurafenib (I)

[0064] Add 300 g of 1,2-dichloroethane, 31.5 g (0.10 moles) of N-[2,4-bis Fluoro-3-(cyano-n-propionyl)phenyl]n-propanesulfonamide, 17.0 g (0.11 mole) p-chlorophenylacetaldehyde, 0.5 g DBU, heating, stirring, 71-73 ° C azeotropic reflux with water condensation reaction 5 hours; cooled to 30°C, added 38.0 g (0.32 moles) of N,N-dimethylformamide dimethyl acetal, stirred and reacted at 90-95°C for 5 hours, while recovering 1,2-dichloroethane; cooled to 30° C., 70.0 g of 10 wt % ammonia methanol solution was added to the residue, and the mixture was stirred and reacted at 50-55° C. for 4 hours. Recover methanol and 1,2-dichloroethane by distillation under reduced pressure, add 200 grams of isopropanol to the residue, heat to 80 ° C, cool, recrystallize, filter, and dry to obtain 44.7 grams of vemurafenib, yield 91.2%, liquid phase purity 99.89%.

Embodiment 3

[0065] Embodiment 3: the preparation of vemurafenib (I)

[0066] In a 500 ml four-necked flask connected with a stirring, thermometer, and a reflux condenser with a water separator, add 250 g of cyclohexane, 31.5 g (0.10 moles) of N-[2,4-difluoro-3-( Cyanopropionyl) phenyl] n-propanesulfonamide, 17.0 grams (0.11 moles) p-chlorophenylacetaldehyde, 0.5 grams of DBU, heating, stirring, 68-70 ° C azeotropic reflux with water condensation reaction for 8 hours; cooling to 30°C, add 5.0g (0.33 moles) of trimethyl orthoformate, 2.5g of anhydrous zinc chloride, stir and react at 60-65°C for 8 hours; cool to 30°C, add 70.0g of 10wt% ammonia methanol solution, 50-55 The reaction was stirred at °C for 5 hours. Recover cyclohexane and methanol by distillation under reduced pressure, add 300 grams of 80 wt% aqueous isopropanol to the residue, heat to 80 ° C, cool, recrystallize, filter, and dry to obtain 43.5 grams of vemurafenib, yield 88.8% , Liquid phase purity 99.79%.

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Abstract

The invention provides a simple preparation method of vemurafenib and analogues thereof. The method includes: subjecting para-substituted phenylacetaldehyde II and N-[2, 4-disubstituted-3-(cyanopropionyl)phenyl]n-propanesulfonamide III to azeotropic dewatering and condensation reaction under alkaili catalysis, condensing the obtained condensation product and the methylenation reagent V(N, N-dimethylformamide or tri-orthoformate), and then performing cyclization with ammonia to obtain vemurafenib or analogues thereof. The method for preparation of vemurafenib provided by the invention has the characteristics of low cost, mild process conditions, low operation requirements, short reaction time, high production efficiency, simple process operation, little waste water production, green and environmental protection, high yield and purity, and is beneficial to green industrial production of vemurafenib. At the same time, the method provided by the invention can prepare vemurafenib analogues,and is of important significance for the drug efficacy study of similar compounds.

Description

technical field [0001] The invention relates to a simple and convenient preparation method of vemurafenib and its analogues, belonging to the technical field of medicinal chemistry. Background technique [0002] Vemurafenib (Vemurafenib), trade name Zelboraf, is a kinase inhibitor developed by Roche (Hoffmann La Roche), for the treatment of unresectable or metastatic melanoma, FDA-approved BRAFV600E mutation patients, in 2011 Approved by the FDA in August 2012 for the treatment of advanced metastatic or unresectable melanoma; on February 20, 2012, the European Commission approved vemurafenib for the treatment of adults with BRAFV600 mutation-positive, surgically unresectable or metastatic melanoma . On November 7, 2017, the U.S. Food and Drug Administration expanded the scope of indications for vemurafenib, which can be used to treat lipogranulomatous disease (Erdheim-Chester, referred to as ECD, a a rare blood cancer), Vemurafenib is currently the first FDA-approved ECD d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 戚聿新张明峰鞠立柱刘月盛
Owner XINFA PHARMA
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