Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of idosaban and intermediate thereof

A technology of reaction time and methylation, applied in the direction of organic chemistry, can solve the problems of difficult large-scale production, troublesome post-processing, low yield, etc., and achieve the effect of short reaction steps, simple post-processing, and high yield

Active Publication Date: 2022-02-15
江苏美迪克化学品有限公司
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, there are long steps in the above three methods, troublesome post-processing, and low yield (the total yield is substantially less than 40%), and all three methods need to carry out the Sandmeyer reaction, which is dangerous and difficult to obtain. mass production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of idosaban and intermediate thereof
  • Preparation method of idosaban and intermediate thereof
  • Preparation method of idosaban and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Dissolve 3-bromo-1-methyl-piperidin-4-one (10mmol, 1.92g) and ethyl thiooxamide (11mmol, 1.46g) in 10mL of ethanol, add sodium carbonate (2mmol, 212mg), Reaction under reflux conditions for 10h. After the reaction, cool to room temperature, filter the insoluble matter, evaporate the filtrate to dryness, add aqueous sodium bicarbonate solution to wash until slightly alkaline, then extract with ethyl acetate, dry, concentrate, and separate through column to obtain 5-methyl-4 , Ethyl 5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate.

[0047] It was further dissolved in 10 mL of ethanol, 4 mL (0.02 mol) of 5 mol / L NaOH aqueous solution was added, and the reaction was refluxed for 4 h. After cooling to room temperature, distill off the solvent, dissolve the residue with water, extract with ethyl acetate / water to remove organic impurities, adjust the pH of the aqueous phase to 2 with concentrated hydrochloric acid (37%) in an ice bath, and stir to precipitate a white so...

Embodiment 2

[0049] 3-Bromo-1-methyl-piperidin-4-one (10mmol, 1.92g) and ethyl thiooxamide (11mmol, 1.46g) were dissolved in 10mL ethanol, NaOH (2mmol, 80mg) was added, and Reaction under reflux conditions for 10h. After the reaction, cool to room temperature, filter the insoluble matter, evaporate the filtrate to dryness, add aqueous sodium bicarbonate solution to wash until slightly alkaline, then extract with ethyl acetate, dry, concentrate, and separate through column to obtain 5-methyl-4 , Ethyl 5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate.

[0050] It was further dissolved in 10 mL of ethanol, 4 mL (0.02 mol) of 5 mol / L NaOH aqueous solution was added, and the reaction was refluxed for 4 h. After cooling to room temperature, distill off the solvent, dissolve the residue with water, extract with ethyl acetate / water to remove organic impurities, adjust the pH of the aqueous phase to 2 with concentrated hydrochloric acid (37%) in an ice bath, and stir to precipitate a white so...

Embodiment 3

[0052] Dissolve 3-bromo-1-methyl-piperidin-4-one (10mmol, 1.92g) and ethyl thiooxamide (11mmol, 1.46g) in 10mL of methanol, add sodium carbonate (2mmol, 212mg), Reaction under reflux conditions for 16h. After the reaction, cool to room temperature, filter the insoluble matter, evaporate the filtrate to dryness, add aqueous sodium bicarbonate solution to wash until slightly alkaline, then extract with ethyl acetate, dry, concentrate, and separate through column to obtain 5-methyl-4 , Ethyl 5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate.

[0053] It was further dissolved in 10 mL of ethanol, 4 mL (0.02 mol) of 5 mol / L NaOH aqueous solution was added, and the reaction was refluxed for 4 h. After cooling to room temperature, distill off the solvent, dissolve the residue with water, extract with ethyl acetate / water to remove organic impurities, adjust the pH of the aqueous phase to 2 with concentrated hydrochloric acid (37%) in an ice bath, and stir to precipitate a white s...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a preparation method of idosaban and an intermediate thereof. The preparation method of the idosenban intermediate 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride comprises the following steps: carrying out condensation reaction on 3-bromo-1-methyl-piperidine-4-ketone and thiooxamide ethyl ester in a solvent at the reaction temperature of 50-85 DEG C in the presence of alkali to generate the 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride, and carrying out hydrolysis and hydrochlorination to obtain the intermediate. The invention also relates to a preparation method of the idosaban, including preparing the 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride. Compared with existing methods in references, the method has the advantages of being short in reaction step, high in yield, simple in aftertreatment and the like, the reaction process is controllable, safety is high, and the method is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of edosapan and its intermediate. Background technique [0002] Edoxaban (DU-176) is an oral FXa inhibitor in clinical development for stroke prevention. Among them, 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylate hydrochloride is an important intermediate in the synthesis of edoxaban. There are three main methods of synthesizing the compound: [0003] (1) Using 3-bromo-1-methyl-piperidin-4-one and thiourea as raw materials to synthesize 4,5,6,7-tetrahydro-5-methyl-2-aminothiazolo[5 ,4-c]pyridine, which generates 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine through Sandmeyer reaction and dehalogenation reaction. This intermediate generates the final target product through a series of conversions with trichloroacetyl chloride again, [0004] [0005] (2) One-step condensation synthesis of 4,5,6,7-tetrahydro-5-methyl-2...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04
CPCC07D513/04
Inventor 杨盟孙璐马圣峰
Owner 江苏美迪克化学品有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com