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Preparation and after-treatment method for high-purity alogliptin benzoate

A technology for the preparation of benzoic acid, which is applied in the fields of metabolic diseases, organic chemistry, drug combination, etc., can solve problems such as cumbersome operation, and achieve the effects of improving yield and quality, convenient operation, and low cost

Inactive Publication Date: 2017-05-10
HANGZHOU BIO SINCERITY PHARMA TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In the routes reported by patents such as CN105367546A and CN102942556A (see the following formula), in the nucleophilic substitution reaction, (R)-3-Boc-aminopiperidine is used to replace (R)-3-aminopiperidine to complete the substitution reaction to obtain The alogliptin of Boc protection, obtains free base again through deprotection, and benzoic acid salify, makes alogliptin benzoate, and this method has effectively avoided the generation of dimer impurity by the protection of amino group, improves However, in the process of removing Boc protection, in addition to using relatively severe reaction conditions, it also involves multiple material transfers, and the operation is too cumbersome

Method used

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  • Preparation and after-treatment method for high-purity alogliptin benzoate
  • Preparation and after-treatment method for high-purity alogliptin benzoate
  • Preparation and after-treatment method for high-purity alogliptin benzoate

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Effect test

Embodiment 1

[0029] Step 1, the synthesis of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile:

[0030] Add 600ml of acetonitrile, 100.0g of o-bromomethylbenzonitrile, 81.9g of 3-methyl-6 chlorouracil, and 113.5g of tri-n-butylamine into a 1000ml three-necked flask, stir, and heat up to reflux for 6 hours (TLC monitors the reaction end point , the spots of o-bromomethylbenzonitrile disappear), cool down, remove the solvent by rotary evaporation at 40°C, add 500ml of absolute ethanol, reflux and stir to dissolve, cool down to below 10°C for crystallization, filter, and filter the cake with 100ml of cyclohexane After washing and air drying at 60°C, 121.9 g of the product was obtained with a yield of 86.7% and a purity of 98.97% by HPLC.

[0031] Synthesis of the alogliptin of step 2, Boc protection:

[0032] Add 600ml of acetonitrile, 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile (intermediate Body 1) 100.0g, (R)-3-Boc-amin...

Embodiment 2

[0036] Basically the same as embodiment 1, on this basis:

[0037] Step 3: Synthesis of Alogliptin Benzoate

[0038] Add 2.8L of dichloromethane and 1410g of Boc-protected alogliptin (intermediate 2) into a 10L reactor, stir, add 2750g of trifluoroacetic acid dropwise at room temperature, and stir at room temperature for 8 hours after the addition is complete (TLC monitors the reaction end point, Intermediate 2 spots disappear). After adding 20L ethyl acetate to the reaction system and stirring evenly, wash 3 times with 2mol / L hydrochloric acid, 3L each time, combine the water phase, add 20% sodium hydroxide solution to adjust the pH of the system to 10-11, and wash with dichloromethane Extract the aqueous phase 3 times, 3 L each time, combine the organic phases, wash with 1.2 L saturated brine, add 500 g of anhydrous sodium sulfate to dry, spin the filtrate, add 8.5 L of methanol and stir to dissolve, cool down to below 5 °C, add 392 g After the benzoic acid was stirred and...

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Abstract

The invention relates to optimization and improvement of a preparation and after-treatment method for alogliptin benzoate. In the Boc deprotection process, alkali extraction and acid precipitation methods are adopted, and impurities which do not contain basic groups are effectively removed on the basis of simplifying the process. Moreover, the solvent and temperature control is optimized in the salifying process, and the product quality and yield are improved.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a post-preparation and post-treatment method of high-purity alogliptin benzoate. Background technique [0002] Alogliptin Benezoate, chemical name 2-((6-((3R)-3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3, 4-dihydropyrimidin-1 (2H) base) methyl) benzonitrile benzoic acid, its chemical structural formula is: [0003] . [0004] Alogliptin benzoate is a highly selective serine protease dipeptidyl peptidase IV (DPP-IV) inhibitor developed by Takeda Pharmaceutical, Japan. It is a highly selective DPP-4 activity inhibitor, which can improve the body's Increase the plasma concentration of GLP-1 to promote the secretion of insulin related to glucose concentration. It can maintain the level of glucagon-like-1 peptide and glucose-dependent insulinotropic peptide in the body, increase the secretion of insulin, and thus play a hypoglycemic effect. [0005] Clinical studi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61K31/513A61P3/10
CPCC07D401/04
Inventor 叶鑫杰罗瑾刘晓峰楼金芳张冯敏衣丽娜
Owner HANGZHOU BIO SINCERITY PHARMA TECH CO LTD
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