Tecarfarin preparation method

A compound and catalyst technology, applied in the field of preparation of Tecarfarin, can solve the problems of unsuitability for large-scale industrial production, expensive condensing agent, severe reaction conditions, etc., and achieve good industrial application prospects, high yield and high controllability Effect

Inactive Publication Date: 2018-10-09
SHANGHAI DUDE MEDICAL SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The first step of this synthetic route adopts EDCI condensing agent to carry out condensation reaction, and this reaction condensing agent is expensive, and by-product is many, and yield is low, only has 29%
The second step uses triethylamine / formic acid as a solvent, the reaction conditions are severe (130°C), there are many by-products, and the yield is lower, only 11%
Because the yields of the two-step reactions are all low, the final overall yield of the reaction route is too low, which is not suitable for large-scale industrial production

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0030]

[0031] Under N2 protection, 1 (2.0 g, 1.0 eq) was suspended in anhydrous DCM (20 ml), and DMF (0.05 ml) was added. Oxalyl chloride (3.3g, 2.0eq) was added dropwise at 0-10°C, dissolved, stirred for 10min, kept at 0-10°C for 8h. Sample TLC. After the reaction was completed, it was concentrated to dryness under reduced pressure, and the concentrate was dissolved in anhydrous DCM for later use.

[0032] 3 (2.4g, 1.0eq) was dissolved in anhydrous DCM, triethylamine (1.75g, 1.3eq) was added, stirred at 0-10°C for 10min. Slowly add the above acid chloride solution dropwise. After dropping, stir at 25-30°C for 4h. After the reaction was completed, it was concentrated to dryness under reduced pressure, and water was added to dissolve EA. The layers were separated, the aqueous layer was extracted with EA, and the organic layers were combined. Wash with 10% citric acid, twice with dilute sodium hydroxide solution, and saturated brine, and concentrate under reduced press...

Embodiment 2

[0034]

[0035] Dissolve III, 5 in THF and stir for 10 min. Add 6,7,20-30 ℃ and keep stirring for 12h. After the reaction was completed, it was concentrated under reduced pressure, EA was dissolved, and washed with 1N NaOH solution. Separate the liquid, remove the organic layer, adjust the pH to 5-6 with 1N HCl, and extract with EA. Separate the liquid and remove the aqueous layer. Washed with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a white solid, which was recrystallized from acetone to obtain the target product V. Yield: 60%

Embodiment 3

[0037]

[0038] Under N2 protection, 1 (1.0eq) was suspended in anhydrous THF, and DMF was added. Add oxalyl chloride (2.0eq) dropwise at 0-10°C, dissolve, stir for 10min, keep stirring at 0-10°C for 8h. Sample TLC. After the reaction was completed, it was concentrated to dryness under reduced pressure, and the concentrate was dissolved in anhydrous tetrahydrofuran for later use.

[0039] Dissolve 3 (1.0eq) in anhydrous tetrahydrofuran, add pyridine (1.3eq), and stir at 0-10°C for 10min. Slowly add the above acid chloride solution dropwise. After dropping, stir at 25-30°C for 4h. After the reaction was completed, it was concentrated to dryness under reduced pressure, and water was added to dissolve EA. The layers were separated, the aqueous layer was extracted with EA, and the organic layers were combined. Wash with 10% citric acid, twice with sodium hydroxide solution, and with saturated brine, and concentrate under reduced pressure to dryness to obtain pale yellow so...

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Abstract

The invention provides a new Tecarfarin preparation method, which comprises: carrying out acyl chlorination on 4-carboxybenzaldehyde, carrying out condensation with 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-ol to form an ester, and carrying out a reaction on the obtained ester intermediate and 4-hydroxycoumarin under the catalysis of proline and under a alkyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate reducing condition to prepare the target product Tecarfarin. According to the present invention, the method has advantages of high controllability of each reaction, mild reaction condition,simple post-treatment, significantly improved yield of the target product, and good industrial application prospects; and with the method, the starting raw material has characteristics of easy obtaining and low price so as to substantially reduce the whole production cost.

Description

technical field [0001] The invention relates to the technical field of preparation methods of Tecarfarin. Background technique [0002] Vitamin K is a substance necessary for the formation of active coagulation factors II, VII, XI, and X, and the lack of vitamin K will prolong the coagulation time. As a new generation vitamin K antagonist, Tecarfarin was developed by ARYx Therapeutics of the United States, and its indications are atrial fibrillation, heart valve disease and deep vein thrombosis. Its chemical name is 4-(4-hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid 2,2,2-trifluoro-1-methyl-1-trifluoromethyl -Ethyl ester, CAS No. 867257-26-9: The structural formula is as follows: [0003] [0004] Through literature search, only ARYx Therapeutics company mentions in its compound patent (WO 2005100336 / CN200580012074) to the report of preparation method of Tecarfarin at home and abroad at present, with 4-carboxybenzaldehyde as starting material, and 1,1,1, 3,3,3-Hexa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/56
CPCC07D311/56
Inventor 刘新孔锐袁哲东
Owner SHANGHAI DUDE MEDICAL SCI & TECH CO LTD
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