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Synthesis method of anagliptin intermediate 2-amino-2-methylpropylamine tert-butyl ester

A technique for the synthesis of tert-butyl methylpropylamine, which is applied in the field of medicine, can solve the problems of expensive raw materials, time-consuming, difficult to obtain, etc., and achieve the effects of short synthesis route, mild reaction conditions, and little pollution

Inactive Publication Date: 2014-07-30
成都诺维尔生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] (1) The starting materials 2,2-dimethylcyclopropylamine and 2,2-dimethyl-5-ethoxyimidazole themselves need multi-step reaction synthesis, the raw materials are expensive and difficult to obtain in the market;
[0008] (2) The route of synthesizing 2-amino-2-methylpropylamine is complicated, and the conditions of the synthesis process are harsh and time-consuming;
[0009] (3) The yield of the resulting product is low, which is unfavorable for industrialized large-scale production

Method used

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  • Synthesis method of anagliptin intermediate 2-amino-2-methylpropylamine tert-butyl ester
  • Synthesis method of anagliptin intermediate 2-amino-2-methylpropylamine tert-butyl ester

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Embodiment 1

[0030] Embodiment 1: the synthetic method of alalogliptin intermediate 2-amino-2-methylpropylamine tert-butyl ester, specifically comprises the following steps:

[0031] S1. In a three-necked flask, suspend 2-amino-2-methylpropionitrile hydrochloride in toluene, slowly add aluminum hydride dropwise within 30 minutes, raise the temperature to 100°C and stir for 1 hour after the addition, and wait for After the reaction is completed, cool to room temperature, slowly add distilled water dropwise to decompose excess aluminum hydride, adjust the pH to 8 with sodium hydroxide solution, add ethyl acetate, separate the liquids, and concentrate the combined organic phase after drying over anhydrous sodium sulfate , intermediate A is obtained; wherein, the weight ratio of 2-amino-2-methylpropionitrile, toluene, aluminum hydride is 1:1:0.05;

[0032] S2. In a three-necked flask, dissolve intermediate A and triethylamine in toluene, add tert-butoxycarbonyl anhydride, stir at room temperat...

Embodiment 2

[0033] Embodiment 2: the synthetic method of alalogliptin intermediate 2-amino-2-methylpropylamine tert-butyl ester, specifically comprises the following steps:

[0034] S1. In a three-necked flask, suspend 2-amino-2-methylpropionitrile hydrochloride in tetrahydrofuran, slowly add borane dropwise within 30 minutes, raise the temperature to 25°C and stir for 100 hours after the addition, and wait for After the reaction is completed, cool to room temperature, slowly add distilled water dropwise to decompose excess borane, adjust the pH to 9 with sodium hydroxide solution, add ethyl acetate, separate the layers, and concentrate the combined organic phase after drying over anhydrous sodium sulfate. Prepare intermediate A; Wherein, the weight ratio of 2-amino-2-methylpropionitrile, tetrahydrofuran, borane is 1:20:4;

[0035] S2. In a three-necked flask, dissolve intermediate A and triethylamine in tetrahydrofuran, then add tert-butoxycarbonyl chloride, stir at room temperature afte...

Embodiment 3

[0036] Embodiment 3: the synthetic method of alalogliptin intermediate 2-amino-2-methylpropylamine tert-butyl ester, specifically comprises the following steps:

[0037] S1. In the reaction kettle, suspend Raney nickel and 2-amino-2-methylpropionitrile hydrochloride in methanol, and replace the air in the reaction kettle with hydrogen for 3 times. After completion, pressurize and heat up to 40°C and stir 24h, then cooled to room temperature, filtered, and the organic phase was concentrated to obtain intermediate A; wherein, the weight ratio of 2-amino-2-methylpropionitrile, dichloromethane, and Raney nickel was 1:8:1.2;

[0038] S2. In a three-necked flask, dissolve intermediate A and diisopropylamine in dichloromethane, add tert-butoxycarbonylphenyl ester, stir at room temperature after the addition, then raise the temperature to 45°C and stir for 8 hours, and cool down after the reaction is complete to room temperature, adjust the pH to 9 with sodium hydroxide solution, extr...

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Abstract

The invention discloses a synthesis method of an anagliptin intermediate 2-amino-2-methylpropylamine tert-butyl ester, belonging to the technical field of medicines. The synthetic route is characterized by using 2-amino-2-methylpropionitrile as a starting material, generating an intermediate A through reduction reaction and amidating the intermediate A in an alkaline solution to generate 2-amino-2-methylpropylamine tert-butyl ester. The preparation method can achieve synthesis of the anagliptin key intermediate 2-amino-2-methylpropylamine tert-butyl ester only through two-step conventional reactions, has the advantages of short synthetic route, low cost, mild reaction conditions and environment friendliness, has little harm to operating personnel, is little in pollution and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing an alalogliptin intermediate 2-amino-2-methylpropylamine tert-butyl ester. Background technique [0002] Alagliptin (anagliptin) is a DPP-Ⅳ inhibitor developed by Takeda Corporation and first launched in Japan in June 2010 in 25mg, 12.5mg and 6.25mg tablets. The IC50 value of the inhibitory effect of this product on DPP-Ⅳ was 10nmol / L in the in vitro study of human plasma. Healthy adults take 25 mg of this product once, and the inhibition rate of DPP-IV in the blood is as high as 81% after 24 hours, so that the circulating concentration of active GLP-I and GIP is increased by 2 to 3 times. Alalogliptin is a new type of drug for the treatment of diabetes. The drug has three main fragments: 2-methyl-pyrazolo[1,5-A]pyrimidine-6-carboxylic acid, (2S)-N-chloroacetyl- 2-cyanotetrahydropyrrole, 2-amino-2-methylpropylamine tert-butyl ester. [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/20C07C269/04
Inventor 支永刚赵玉燕李桃桃吴德志张振
Owner 成都诺维尔生物医药有限公司
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