Preparation method of edoxaban and intermediate thereof

A technology for edoxaban and its intermediates, which is applied in the field of preparation of edoxaban and its intermediates, and can solve the problems of large-scale production costs, harsh reaction conditions, and low reaction yields

Active Publication Date: 2021-06-11
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In summary, the main problems in the current production process of edoxaban are as follows: 1) The preparation method of formula I and its salts involves noble metal catalysts, and the cost of large-scale production is high; the reaction conditions are harsh and the reaction yield is low, etc.
2) The reaction system in the ammonolysis process is solidified, resulting in the production of impurities 1, which affects the yield and quality of intermediates

Method used

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  • Preparation method of edoxaban and intermediate thereof
  • Preparation method of edoxaban and intermediate thereof
  • Preparation method of edoxaban and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0054]

[0055] At room temperature, compound 5 (10 g, 0.043 mol) and 200 mL of tetrahydrofuran were added to a 500 mL three-necked flask, and the system was cooled to 0 °C and the atmosphere was replaced with nitrogen. At low temperature of 0°C, 21 mL (20.58 g, 0.2 mol) of isopropylmagnesium chloride was added dropwise, and after stirring for one hour, 1.2 g of lithium hydroxide was added to the reaction system and carbon dioxide gas was continuously introduced and stirred for 2 to 3 hours. After the reaction was completed, concentrated hydrochloric acid was added dropwise to the reaction system to quench the reaction, and the stirring was continued for 2-3 hours. After the reaction, the reaction solution was filtered, the filter cake was washed and refined with methanol / toluene, and dried at 50°C to obtain compound 6 (9.2 g), with a molar yield of 91% and an HPLC purity of 98.35%.

Embodiment 1-2

[0057] At room temperature, compound 5 (10 g, 0.043 mol) and 200 mL of 2-methyltetrahydrofuran were added to a 500 mL three-necked flask, and the system was cooled to 0 °C and the atmosphere was replaced with nitrogen. At low temperature of 0°C, 21 mL (20.58 g, 0.2 mol) of isopropylmagnesium chloride was added dropwise, and after stirring for one hour, 1.2 g of lithium hydroxide was added to the reaction system and carbon dioxide gas was continuously introduced and stirred for 2 to 3 hours. After the reaction was completed, concentrated hydrochloric acid was added dropwise to the reaction system to quench the reaction, and the stirring was continued for 2-3 hours. After the reaction, the reaction solution was filtered, the filter cake was washed and refined with methanol / toluene, and dried at 50°C to obtain compound 6 (8.9 g), with a molar yield of 88% and an HPLC purity of 97.85%.

Embodiment 1-3

[0059] At room temperature, compound 5 (10 g, 0.043 mol) and 200 mL of tetrahydrofuran were added to a 500 mL three-necked flask, and the system was cooled to 0 °C and the atmosphere was replaced with nitrogen. At a low temperature of 0°C, 33mL of cyclohexylmagnesium chloride (28.74g, 0.2mol) was added dropwise, and after stirring for one hour, 1.2g of lithium hydroxide was added to the reaction system and carbon dioxide gas was continuously introduced and stirred for 2 to 3 hours. After the reaction was completed, concentrated hydrochloric acid was added dropwise to the reaction system to quench the reaction, and the stirring was continued for 2-3 hours. After the reaction, the reaction solution was filtered, the filter cake was washed and refined with methanol / toluene, and dried at 50°C to obtain compound 6 (8.5 g), with a molar yield of 84% and an HPLC purity of 98.14%.

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Abstract

The invention relates to a preparation method of edoxaban and an intermediate thereof. A compound 1, a compound 2 and a compound 5 which are taken as initial raw materials are subjected to an ammonolysis reaction, a deprotection reaction, a carboxylation reaction and a condensation reaction to generate edoxaban. Compared with the prior art, the preparation method is higher in operability and safety during amplified production, and the obtained product is high in yield and purity.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, more specifically to a preparation method of edoxaban and an intermediate thereof. Background technique [0002] Thrombosis refers to abnormal blood clots in the circulating blood due to certain incentives in the human body or animals, or blood deposits on the inner wall of the heart or on the blood vessel wall to block the vascular lumen, causing significant blood flow in the blood vessel. Reduction, or even complete cessation, of a group of diseases. Thrombosis occurs in arteries leading to severe ischemia or interruption of blood flow in organs or tissues that supply blood, such as cerebral insufficiency, unstable angina, or even necrosis, such as acute myocardial infarction and stroke. Thrombosis occurs in veins, such as deep vein thrombosis of the lower extremities, which can cause blood reflux disorders in the lower extremities, causing edema and venous insufficiency, etc. The embolism c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04C07D213/75
CPCC07D213/75C07D513/04
Inventor 陈刚胜郭彦亮刘栓栓游军辉王磊
Owner SHANGHAI HANSOH BIOMEDICAL
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