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Intermediate of eldoxaban tosylate and preparation method thereof

A technology of edoxaban and toluenesulfonic acid, applied in the direction of organic chemistry and the like, can solve the problems of unsuitable for industrial scale production, easy ignition of n-butyl lithium, and many hidden dangers in production safety, and achieves simple, convenient and cost-effective post-processing. Low, easy-to-operate effect

Pending Publication Date: 2022-05-10
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route uses the flammable and explosive S element, as well as the expensive and easy-to-ignite n-butyllithium, which has many production safety hazards, is not conducive to cost control, and is not suitable for industrial-scale production.

Method used

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  • Intermediate of eldoxaban tosylate and preparation method thereof
  • Intermediate of eldoxaban tosylate and preparation method thereof
  • Intermediate of eldoxaban tosylate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] The intermediate 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid of this edoxaban tosylate is obtained by the following process steps.

[0097] (1) Synthesis of compound (II)

[0098]

[0099] Add 40g of glacial acetic acid to the reaction bottle, and the temperature is below 25°C, add 22.6g (199.7mmol) of N-methyl-4-piperidone dropwise, add 34g (201.7mmol) of 48% hydrobromic acid aqueous solution and 40g of glacial acetic acid to prepare The resulting solution; the temperature is below 20°C, add dropwise the solution prepared by bromine 32g (200.2mmol) and glacial acetic acid 30g, keep stirring overnight at 20-25°C after dripping, filter, filter cake with ethyl acetate rinse, collect the solid , and dried to obtain 52g of compound II with a yield of 95.4%.

[0100] (2) Synthesis of compound (III)

[0101]

[0102] Add 10g of water and 3.7g (22.0mmol) of Na in the reaction flask 2 S.5H 2 O, stirred and dissolved, the temperature dropped t...

Embodiment 2

[0116] The intermediate 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid of this edoxaban tosylate is obtained by the following process steps.

[0117] (1) Synthesis of compound (II)

[0118] Add 30g of glacial acetic acid to the reaction bottle, and the temperature is below 25°C, add 17.0g (149.8mmol) of N-methyl-4-piperidone dropwise, add 25.5g (151.3mmol) of 48% hydrobromic acid aqueous solution and 30g of glacial acetic acid The prepared solution; the temperature is below 20°C, add dropwise the solution prepared by bromine 24g (150.2mmol) and glacial acetic acid 22.5g, keep stirring overnight at 20-25°C after dripping, filter, filter cake with ethyl acetate rinse, The solid was collected and dried to obtain 40 g of compound II with a yield of 97.9%.

[0119] (2) Synthesis of compound (III)

[0120] Add 10g of water and 3.36g (20.0mmol) of Na in the reaction flask 2 S.5H 2 O, stir to dissolve, lower the temperature to -5-0°C, add 4.55g (16.7mmol) of...

Embodiment 3

[0133] The intermediate 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid of this edoxaban tosylate is obtained by the following process steps.

[0134] Compound (II), compound (III) and compound (IV-1) are shown in Example 1.

[0135] (4) Synthesis of compound (V-3)

[0136]

[0137] Add 10ml of isopropanol and 0.6g of crude compound IV-1 to the reaction bottle, stir to dissolve, control the temperature at 0-5°C, add 0.5ml (5mmol) of concentrated sulfuric acid dropwise, and slowly raise the temperature to 20-25°C while stirring for reaction 12 After hours, use saturated sodium bicarbonate solution to neutralize the pH=7-8, and concentrate the reaction under reduced pressure at 50°C. The concentrate is added with 10ml of methanol, stirred, filtered, and the filtrate is concentrated under reduced pressure at 40°C to obtain 0.55g of crude compound V-3.

[0138] (5) Synthesis of compound (VI-3)

[0139]

[0140] Add methanol 20ml, compound IV-3 crude p...

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Abstract

The invention relates to the field of organic chemical synthesis, in particular to an esdoxaban tosylate intermediate and a preparation method thereof, and the esdoxaban tosylate intermediate has the advantages of simple and convenient preparation process, mild reaction conditions, low cost and easily available raw materials. The synthesis method comprises the following synthesis steps: by taking a compound N-methyl-4-piperidone as a raw material, carrying out substitution reaction on the compound N-methyl-4-piperidone and bromine to generate a compound as shown in a formula (II); the compound shown in the formula (II) and sodium sulfide are subjected to a sulfo-reaction, and a compound shown in a formula (III) is obtained; carrying out cyclization reaction on the compound as shown in the formula (III) and glyoxylic acid to obtain a compound as shown in a formula (IV); carrying out esterification reaction on the compound shown in the formula (IV) and alcohol to obtain a compound shown in a formula (V), and reacting to obtain a compound shown in a formula (VI); or directly reacting the compound shown in the formula (IV) under the action of alcohol and acid to obtain the compound shown in the formula (VI); and carrying out alkaline hydrolysis and acid neutralization on the compound shown in the formula (VI) to obtain a compound shown in a formula (VII). The reaction formula is shown in the specification.

Description

technical field [0001] The invention relates to the field of organic chemical synthesis, in particular to an intermediate of edoxaban tosylate and a preparation method thereof. Background technique [0002] Edoxaban tosylate is a direct anticoagulant factor Xa inhibitor used for the treatment of venous thromboembolism in patients after total knee arthroplasty, total hip arthroplasty, or hip fracture surgery; its pharmacological Methods for the preparation of salts or their hydrates are accepted. [0003] Edoxaban tosylate was developed by Daiichi Sankyo Co., Ltd., and was approved for marketing by the Japan Pharmaceuticals and Medical Devices Agency (PMDA) on April 22, 2011, and then on January 8, 2015. It was approved for marketing by the US Food and Drug Administration (FDA), approved by the European Medicines Agency (EMA) on June 19, 2015, and approved by the National Medical Products Administration (NMPA) on December 25, 2018. It is marketed and sold in Japan by Daiich...

Claims

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Application Information

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IPC IPC(8): C07D513/04C07D211/74
CPCC07D513/04C07D211/74Y02P20/55A61K31/444
Inventor 梅义将刘声民李永刚范锦敏胡剀高世朝
Owner ZHEJIANG JIUZHOU PHARM CO LTD