Preparation method of tecarfarin

A technology of ticarfarin and compounds, which is applied in the field of drug synthesis, can solve the problems of many hydrolyzed impurities, difficult to remove, and long reaction time, so as to improve product quality and yield, reduce the production of hydrolyzed impurities, and reduce reaction time Effect

Active Publication Date: 2017-09-19
JIANGSU CHIA TAI FENGHAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] It has been verified by experiments that there are defects in this process route: in the experiment, it was found that the reaction time of step 1 was longer, and the yield was less than 30%; the reaction temperature of step 2 was higher, and there were more impurities, and the ester bond in the structure was easily destroyed during the reaction process. There are many hydrolyzed impurities, reaching more than 35%, and it is difficult to remove them in the post-processing process, and it is impossible to obtain qualified finished products

Method used

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  • Preparation method of tecarfarin
  • Preparation method of tecarfarin
  • Preparation method of tecarfarin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: the preparation of compound 1

[0030]

[0031] React 100g (0.66mol) p-aldehyde benzoic acid, 140g (0.86mol) 4-hydroxycoumarin, 500ml formic acid, 200ml triethylamine, 200ml N,N-dimethylacetamide mixed solvent at 120℃ for 1h . After the reaction, cool down to 50°C, add 200ml of 50% ethanol, cool down to 10-20°C for crystallization, filter the feed solution, wash the filter cake with 50% ethanol, and dry to obtain 151g of white compound 1 with a yield of 77%, HPLC Detect product purity 98.8%.

Embodiment 2

[0032] Embodiment 2: the preparation of compound 1

[0033]

[0034] React 100g (0.66mol) of p-aldehyde benzoic acid, 107g (0.86mol) of 4-hydroxycoumarin, 500ml of formic acid, 200ml of triethylamine, and 200ml of N,N-dimethylformamide at 100°C for 1 hour . After the reaction, cool down to 50°C, add 400ml of methanol, cool down to 10-20°C to crystallize, filter the feed liquid, wash the filter cake with methanol, and dry to obtain 140g of white compound 1 with a yield of 72%. The purity of the product detected by HPLC is 98.6%. .

Embodiment 3

[0035] Embodiment 3: the preparation of compound 1

[0036]

[0037] React 100g (0.66mol) p-aldehyde benzoic acid, 160g (0.99mol) 4-hydroxycoumarin, 500ml formic acid, 200ml triethylamine, 200ml N,N-dimethylacetamide mixed solvent at 120°C for 1h . After the reaction, the temperature was lowered to 50°C, 500ml of n-butanol was added, the temperature was lowered to 10-20°C for crystallization, the feed liquid was filtered, the filter cake was washed with n-butanol, and dried to obtain 142g of white compound 1 with a yield of 73%, detected by HPLC The product purity is 98.5%.

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Abstract

The invention relates to a preparation method of tecarfarin. The method comprises the steps of adopting formylbenzoic acid and 4-hydroxycoumarin as substrates, carrying out addition reaction, and condensing with 1,1,1,3,3,3-hexafluoro-tert-butanol to obtain the end product tecarfarin. According to the method, esterolysis impurities caused by condensation reaction carried out at high temperature in the prior art is avoided, the purity and the yield are greatly improved, and the method is simple to operate, convenient to post-process, and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis and relates to a preparation method of vitamin K antagonist ticarfarin. Background technique [0002] Ticarfarin is a new oral vitamin K antagonist (vitamin K epoxide reductase inhibitor), which is an analog of warfarin and has the same mechanism of action as warfarin. Therapeutics has been authorized to develop it for anticoagulation therapy, and its structural formula is: [0003] [0004] For patients with atrial fibrillation and patients with prosthetic valves or long-term renal insufficiency, existing oral anticoagulants are contraindicated. Thrombosis in patients with valvular or chronic renal insufficiency. The published phase II and III clinical trial data show that the efficacy of ticarfarin is comparable to that of warfarin, and may reduce more drug-food or drug-drug interactions, which is among all oral anticoagulants One of the potential drugs. In April 2014, Armetheon reached a sp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/56
CPCC07D311/56
Inventor 杨杨刘佳朱永强
Owner JIANGSU CHIA TAI FENGHAI PHARMA
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