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Preparation method, intermediate and preparation method of anticoagulant

An intermediate and volumetric technology, applied in organic chemistry and other fields, can solve the problems of high toxicity of reagents, environmental pollution, unsuitable for industrial production, etc.

Active Publication Date: 2020-08-14
CHEMVON BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The technical problem to be solved by the present invention is to overcome the key steps in the preparation method of the anticoagulant in the prior art, the preparation method from fatty carboxylic acid to fatty aldehyde is cumbersome, the reagents used are highly toxic, dangerous to operate, serious environmental pollution, Low yield, unsuitable for industrial production and other defects, but provide the preparation method of anticoagulant, intermediate and preparation method thereof

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  • Preparation method, intermediate and preparation method of anticoagulant
  • Preparation method, intermediate and preparation method of anticoagulant
  • Preparation method, intermediate and preparation method of anticoagulant

Examples

Experimental program
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Effect test

Embodiment 1

[0079] The preparation of embodiment 1 compound II

[0080] Take a 250ml three-necked flask, add 3.5g of solid material compound I, then add 70mL of dichloromethane to completely dissolve it, then add 0.017mL of N,N-dimethylformamide (DMF), nitrogen ( N 2 under protection), stirring.

[0081] Then, 4 g of oxalyl chloride was added dropwise to the reaction system. After the addition was complete, the temperature was raised to 30° C., and stirring was continued at this temperature for 30 minutes. TLC detection showed that the raw material completely disappeared. Then the reaction was stopped, and the reaction system was directly evaporated to dryness under reduced pressure to obtain 3.2 g of light yellow solid compound II. Without purification, the next reaction was carried out directly, and the yield was 100%.

Embodiment 2

[0082] The preparation of embodiment 2 compound II

[0083] Take a 2500mL three-necked flask, add 200g of solid raw material compound I, then add 1500mL of dichloromethane to completely dissolve it, then add 1mL of N,N-dimethylformamide (DMF), nitrogen (N 2 ) under protection, stirring.

[0084]Then, 200 g of oxalyl chloride was added dropwise to the reaction system. After the addition was complete, the temperature was raised to 30° C., and stirring was continued at this temperature for 30 minutes. TLC detection showed that the raw material completely disappeared. Then the reaction was stopped, and the reaction system was directly evaporated to dryness under reduced pressure to obtain 210 g of light yellow solid compound II. Without purification, the next reaction was carried out directly, and the yield was 100%.

Embodiment 3

[0085] The preparation of embodiment 3 compound III

[0086] Get a 250mL three-necked flask, add 3.2g of light yellow solid compound II, then add 80mL of tetrahydrofuran (THF), make it completely dissolved, nitrogen (N 2 ) under protection and cooled to 0°C. Then add 10mL of 2M Zn(BH 4 ) 2 THF solution, and keep the temperature of the reaction system not exceeding 10 degrees, after the addition, continue to stir and react at about 10 degrees C for 30 minutes, TLC detection, the reaction is complete.

[0087] Add 10 mL of ice water, add dropwise 2N hydrochloric acid, adjust the pH of the reaction system to 2-3, separate layers, and extract the water phase with ethyl acetate (EA) twice until the water phase has no product. The organic phases were combined, washed successively with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, concentrated, and recrystallized with ethyl acetate (EA) / n-heptane to obtain 0.9 g of white solid compoun...

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Abstract

Disclosed are a method for preparing an anticoagulant, and an intermediate and a preparation method therefor. Provided is a method for preparing an intermediate IV of vorapaxar sulfate, which comprises the following steps: in an organic solvent, performing an oxidation reaction on compound III and an oxidant, so as to obtain the intermediate IV of vorapaxar sulfate. The preparation method of the present invention has a simple operation, mild reaction conditions, a high reaction conversion rate and a high yield; and the prepared product has a high purity, a low production cost, a simple post-treatment, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method, an intermediate and a preparation method of an anticoagulant. Background technique [0002] On May 8, 2014, Merck's anticoagulant Zontivity (vorapaxar) was approved by the FDA, and the new cardiovascular drug vorapaxar sulfate (vorapaxar sulfate) was officially launched. Vorapaxar, a first-in-class protease-activated receptor 1 (PAR-1) antagonist, is an antiplatelet agent designed to reduce the propensity of platelets to aggregate and inhibit the formation of blood clots. The researchers found that giving Vorapaxar to patients who had suffered a heart attack or had blocked arteries in the legs significantly reduced the risk of further heart attacks, strokes, cardiovascular death and the need for surgery. Previously, Merck's another new drug for cardiovascular disease, Tredaptive, was rejected by the FDA. So far, Merck has invested 8 billion US dollars in the research and development of vorapaxar, and now...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/92C07D405/06
CPCC07D307/92C07D405/06
Inventor 蔡茂军王方道王猛王东周杰
Owner CHEMVON BIOTECH CO LTD