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Synthesis method of Alogliptin intermediate

A synthetic method and an intermediate technology, which are applied in the field of synthesis of alogliptin intermediate 2-[-pyrimidinyl)methyl]benzonitrile, can solve problems such as toxicity, difficulty in obtaining, and difficulty in purification, and achieve synthesis Simple steps, easy-to-obtain raw materials, and low-cost effects

Inactive Publication Date: 2014-11-19
SICHUAN TONGSHENG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In said method, following shortcoming is arranged: (1) use dangerous substance NaH, require solvent to do anhydrous treatment
(2) The solvent used is a mixed solvent of DMF and DMSO, and both DMF and DMSO are high-boiling solvents, which are difficult to purify, separate and recover
(3) Anhydrous LiBr is used as a catalyst in the reaction process, and this catalyst is easy to absorb moisture and lose its catalytic effect
(4) The use of methyl iodide in the reaction process is more expensive, and the reagent is toxic
In the above method, highly toxic methyl isocyanate is used, and methyl isocyanate will produce highly toxic hydrocyanic acid gas and other irritating and toxic gases when heated or met with water; the raw material o-cyano group used in scheme 2 Benzylamine is expensive and not easy to obtain, resulting in high cost, and when the product is finally purified, the method of column chromatography is used, which does not conform to industrial production

Method used

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  • Synthesis method of Alogliptin intermediate
  • Synthesis method of Alogliptin intermediate
  • Synthesis method of Alogliptin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Take 100g of methyl urea and 165mL of malonic acid, dissolve them in 300mL of acetic acid, stir and heat to 90°C. Take 540 mL of acetic anhydride and slowly drop it into the reaction solution. After the dropwise addition, keep warm and continue to stir the reaction. After the completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature and concentrated under reduced pressure to an oily state. Add 500 mL of ethanol and stir overnight at 0° C., a solid precipitates, and is filtered to obtain a yellow solid. The yellow solid was recrystallized with ethanol and decolorized by activated carbon to obtain 165 g of a light yellow solid with a yield of 86%, m.p. 3.03 (s, 3H, NCH3), 3.56 (s, 2H, CH2), 11.31 (s, 1H, NH).

Embodiment 2

[0029] Take 100 g of methyl urea and 237 g of diethyl malonate, dissolve them in a methanol solution of sodium methoxide (364 g), stir and heat to 90° C. for 12 hours. Cool down to room temperature, filter, and dissolve the filter cake in 500 mL of water. The aqueous solution was adjusted to pH 2-3 with concentrated hydrochloric acid, cooled to 0°C and stirred for 1 hour, a solid was precipitated, and a yellow solid was obtained by filtration. The yellow solid was recrystallized with ethanol and decolorized with activated carbon to obtain 126 g of a light yellow solid with a yield of 66%.

Embodiment 3

[0031] Take 100 g of methyl urea and 279 g of diisopropyl malonate, dissolve them in a methanol solution of sodium methoxide (364 g), stir and heat to 90° C. for 12 hours. Cool down to room temperature, filter, and dissolve the filter cake in 500 mL of water. The aqueous solution was adjusted to pH 2-3 with concentrated hydrochloric acid, cooled to 0°C and stirred for 1 hour, a solid was precipitated, and a yellow solid was obtained by filtration. The yellow solid was recrystallized with ethanol and decolorized by activated carbon to obtain 100 g of light yellow solid with a yield of 52%.

[0032] Synthesis of 3-methyl-6-chlorouracil

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Abstract

The invention provides a method for synthesizing Alogliptin intermediate 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl) methyl] cyanobenzene, and belongs to the field of preparation methods of chemical drug intermediates. The preparation method comprises the following steps: (1) obtaining 1-methyl barbituric acid through reaction of methylurea with malonic acid; (2) obtaining 3-methyl-6-chlorouracil through chlorination reaction of 1-methyl barbituric acid and phosphorus oxychloride; (3) obtaining Alogliptin intermediate 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl) methyl] cyanobenzene through reaction of 3-methyl-6-chlorouracil with 2-cyanobenzyl bromide. The synthesis method of Alogiptin intermediate adopts safe reagents and achieves good convenience in postprocessing and high yield rate of product preparation, thereby being suitable for industrial production.

Description

technical field [0001] The present invention relates to alogliptin intermediate 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]benzidine Nitrile synthesis method. Background technique [0002] Alogliptin, chemical name: 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-di Oxo-1(2H)-pyrimidinyl]methyl]benzonitrile benzoate. 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 Japanese Ministry of Health, Labor and Welfare, and it was approved by the FDA on January 25, 2013 for the treatment of type II diabetes. [0003] The synthetic method of its key intermediate 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/553
CPCC07D239/553
Inventor 燕青李德勇汪有斌王玲
Owner SICHUAN TONGSHENG BIOTECH
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