Preparation method for alogliptin intermediate R-3-aminopiperidine dihydrochloride

A technology of aminopiperidine and bishydrochloride, which is applied in the field of medicine, can solve the problems of high requirements for reaction equipment, high catalyst price, unfavorable scale-up production, etc., and achieve the effect of low price, simple reaction conditions, and easy monitoring

Active Publication Date: 2013-09-25
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires a pressurized reaction, the requirements for the reaction equipment are relatively high and the price of the required catalyst is high, the steps are cumbersome, the total yield is 58.5%, the cost is high, and it is not conducive to scale-up production:

Method used

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  • Preparation method for alogliptin intermediate R-3-aminopiperidine dihydrochloride
  • Preparation method for alogliptin intermediate R-3-aminopiperidine dihydrochloride
  • Preparation method for alogliptin intermediate R-3-aminopiperidine dihydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] In a 2L reaction flask, add 146g of 1-fluoronaphthalene (1mol) to a mixed solution of 925mL of ethanol and 75mL of water, add 105.4g (1.2mol) of fluoboric acid and 136g (1.2mol) of 30% hydrogen peroxide under stirring, and stir at room temperature for 0.5 After 1 hour, 128.2 g (1 mol) of 3-formamidopiperidine was added and reacted at room temperature for 8 hours. The solvent was evaporated to dryness, the residue was dispersed with 500 mL of ethyl acetate, 150 mL of concentrated hydrochloric acid was added, stirred for 0.5 hour, filtered, and dried to obtain 167.0 g of racemic 3-aminopiperidine dihydrochloride with a yield of 96.5%.

[0019] Mix 165g (0.95mol) of racemic 3-aminopiperidine dihydrochloride and 500mL of absolute ethanol in a 1L reaction flask, add sodium hydroxide under stirring to adjust the pH to neutral, then add 143g of D-tartaric acid (0.95 mol), reflux reaction for 2 hours, naturally cooled to room temperature under stirring, and filtered to obtain a...

Embodiment 2

[0022] In a 2L reaction flask, add 146g of 1-fluoronaphthalene (1mol) into a mixed solution of 900mL of ethanol and 100mL of water, add 105.4g (1.2mol) of fluoboric acid and 136g (1.2mol) of 30% hydrogen peroxide under stirring, and stir at room temperature for 0.5 After 1 hour, 128.2 g (1 mol) of 3-formamidopiperidine was added and reacted at room temperature for 8 hours. The solvent was evaporated to dryness, the residue was dispersed with 500 mL of ethyl acetate, 150 mL of concentrated hydrochloric acid was added, stirred for 0.5 hour, filtered, and dried to obtain 163.2 g of racemic 3-aminopiperidine dihydrochloride with a yield of 94.3%.

[0023] Mix 147g (0.85mol) of racemic 3-aminopiperidine dihydrochloride and 450mL of absolute ethanol in a 1L reaction flask, add sodium hydroxide under stirring to adjust the pH to neutral, then add 127.5g of D-tartaric acid ( 0.85mol), reflux reaction for 2 hours, naturally cooled to room temperature under stirring, and filtered to obt...

Embodiment 3

[0025] In a 2L reaction flask, add 146g of 1-fluoronaphthalene (1mol) to a mixed solution of 950mL of ethanol and 50mL of water, add 105.4g (1.2mol) of fluoboric acid and 136g (1.2mol) of 30% hydrogen peroxide under stirring, and stir at room temperature for 0.5 After 1 hour, 128.2 g (1 mol) of 3-formamidopiperidine was added and reacted at room temperature for 8 hours. The solvent was evaporated to dryness, the residue was dispersed with 500 mL of ethyl acetate, 150 mL of concentrated hydrochloric acid was added, stirred for 0.5 hour, filtered, and dried to obtain 164.1 g of racemic 3-aminopiperidine dihydrochloride with a yield of 94.8%.

[0026] Mix 164g (0.95mol) of racemic 3-aminopiperidine dihydrochloride and 500mL of absolute ethanol in a 1L reaction flask, add sodium hydroxide under stirring to adjust the pH to neutral, then add 142g of D-tartaric acid (0.95 mol), reflux reaction for 2 hours, naturally cooled to room temperature under stirring, and filtered to obtain a...

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Abstract

The invention aims to provide a preparation method for an alogliptin intermediate R-3-aminopiperidine dihydrochloride. The method has a brief route and is environmentally friendly and low-cost. A racemic compound 3- piperidine carboxamide which is cheap and easy to get is taken as a raw material, and is subjected to Hoffmann rearrangement reaction under the action of 1- fluoronaphthalene, hydrogen peroxide and fluoboric acid, which is similar to acid amides, to obtain 3-aminopiperdine which has one less carbon than the substrate. The method has simple reaction conditions, can be implemented at the room temperature, has simple operations in process, and is easy to monitor. The solvents are an ethanol-water mixture, and are low-cost and environmentally friendly. The carbon-lessened product 3-aminopiperidine is acidized and salified by concentrated hydrochloric acid. The hydrochloride is separated and salified by D-tartaric acid to obtain the target product R-3-aminopiperidine dihydrochloride. The chirality purity is high. The ee value is more than 99.5%. The reaction overall yield can reach 89%-93%. The cost is low. The method is suitable for industrial mass production.

Description

Technical field: [0001] The invention relates to a preparation method of an alogliptin intermediate R-3-aminopiperidine dihydrochloride, which belongs to the field of medicine. Background of the invention: [0002] Alogliptin benzoate (Alogliptin benzoate) is a serine protease dipeptidyl peptidase IV (DPP-IV) inhibitor developed by Japan's Takeda Company, which can maintain glucagon-like peptide 1 (GLP-1) and glucose dependence in the body. Insulin-promoting polypeptide (GIP) level can promote the secretion of insulin, thereby exerting the hypoglycemic effect. In April 2010, it was approved by the Ministry of Health, Labor and Welfare of Japan. [0003] Alogliptin is another orally effective specific DPP-IV inhibitor after sitagliptin and vildagliptin. DPP-IV inhibitors have high oral bioavailability, which greatly improves patient compliance compared with injections. In addition, DPP-IV inhibitors can maintain endogenous GLP-1 and other insulin-stimulating hormones at phy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56C07D211/02C07B57/00
Inventor 刘春丛日刚王路泰
Owner 迪嘉药业集团股份有限公司
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