Synthesis method of edoxaban intermediate and intermediate product

A technology of edoxaban and a synthesis method, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problem of high production risk of sodium azide, low diastereoselectivity, azide The problem of low chemical yield and other problems can be achieved to reduce the risk of industrial production, reduce production costs, and achieve the effect of high reaction conversion rate.

Active Publication Date: 2017-06-20
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In summary, the existing synthetic techniques often have low yields of azidation of ester groups or amide para-positions, low diastereoselectivity, high risk of industrial production of the explosive hazardous reagent sodium azide, Transformation steps are relatively cumbersome and other deficiencies, it is necessary to improve the synthesis process of edoxaban intermediates, improve yield, reduce production costs

Method used

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  • Synthesis method of edoxaban intermediate and intermediate product
  • Synthesis method of edoxaban intermediate and intermediate product
  • Synthesis method of edoxaban intermediate and intermediate product

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The preparation of embodiment 1 compound 3a:

[0037]

[0038] Add 200mL water, 200mL dichloromethane, 2.0g NaBr, 4.2g NaHCO to the reaction flask 3 27.3 g of compound 2a (ie compound 2 when R is C1 alkoxy) was stirred until dissolved. The mixture was cooled to -5~0°C, then, a solution of 30 mg TEMPO reagent and 68 g NaClO (12% w / w active chlorine content) was added dropwise while maintaining the temperature at -5~0°C. The mixture was stirred at this temperature until all starting material was consumed (controlled by HPLC). Then, 100 mL of 10% aqueous sodium thiosulfate solution was added, and the mixture was stirred for about half an hour. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 24.9 g of white solid compound 3a (that is, R was C1 alkane). Compound 3) in the case of an oxy group has a melting point of 80-82° C. and a yield of 92%.

[0039] [α] 20...

Embodiment 2

[0043] The preparation of embodiment 2 compound 3b:

[0044]

[0045] Add 200mL water, 200mL dichloromethane, 2.0g NaBr, 4.2g NaHCO to the reaction flask 3 , 28.7 g of compound 2b (ie, compound 2 when R is C2 alkoxy) stirred the mixture until dissolved. The mixture was cooled to -5~0°C, then, a solution of 30 mg TEMPO reagent and 68 g NaClO (12% w / w active chlorine content) was added dropwise while maintaining the temperature at -5~0°C. The mixture was stirred at this temperature until all starting material was consumed (controlled by HPLC). Then, 100 mL of 10% aqueous sodium thiosulfate solution was added, and the mixture was stirred for about half an hour. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 27.4 g of white solid compound 3b (that is, R was C2 alkane). Compound 3) in the case of an oxy group has a melting point of 42-44° C. and a yield of 96%.

[00...

Embodiment 3

[0050] The preparation of embodiment 3 compound 3c:

[0051]

[0052] Add 200mL water, 200mL dichloromethane, 2.0g NaBr, 4.2g NaHCO to the reaction flask 3 30.1 g of compound 2c (ie compound 2 when R is C3 alkoxy) was stirred until dissolved. The mixture was cooled to -5~0°C, then, 30mg TEMPO reagent and 68g NaClO (12% w / w active chlorine content) solution were added dropwise while maintaining the temperature at -5~0°C. The mixture was stirred at this temperature until all starting material was consumed (controlled by HPLC). Then, 100 mL of 10% aqueous sodium thiosulfate solution was added, and the mixture was stirred for about half an hour. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 27.1 g of white solid compound 3c (that is, R was C3 alkane). Compound 3) in the case of an oxy group has a melting point of 61-63° C. and a yield of 91%.

[0053] [α] 20 D (C...

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Abstract

Relating to the field of pharmaceutical chemistry, the invention a synthesis method of an edoxaban intermediate (compound 1) and an intermediate product (compound 4) to solve the disadvantages of tedious conversion steps, high risk of production explosiveness, low yield and the like in the prior art. The reaction steps are shown as the specification. The synthesis process of the edoxaban intermediate provided by the invention has the characteirsitcs of easy acquisition of ammonia source and high reaction conversion rate, effectively reduces the cost of industrial production, avoids the use of dangerous reagent sodium azide, and improves the safety of the synthesis process.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing an edoxaban intermediate and an intermediate product during the synthesis of the edoxaban intermediate. Background technique [0002] Edoxaban, trade name Lixiana, is a coagulation factor Xa inhibitor developed by Daiichi Sankyo Co., Ltd., which was approved by the U.S. FDA on January 8, 2015 to reduce the risk of non-cardiac valve problems. Risk of stroke and dangerous blood clots (systemic embolism) in patients with atrial fibrillation. The chemical name of Edoxaban is N-(5-chloropyridin-2-yl)-N′-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)]-2 -[(5-Methyl-4,5,6,7-tetrahydro-1,3-thiazolo[5,4-c]-pyridine-2-carboxamido)cyclohexyl]oxamide, commercially available drug The active ingredient is edoxaban tosylate monohydrate. At present, edoxaban is mostly synthesized through the docking of the intermediate described in compound 1 with the clopyridine fragment a...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C237/24
CPCC07C231/10C07C231/12C07C237/24C07C235/14
Inventor 朱国荣何祖伟王臻陈军荣邓中华屠勇军
Owner ZHEJIANG TIANYU PHARMA
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