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A kind of convenient preparation method of alogliptin benzoate

A technology of benzoic acid and acid solution, applied in the field of medicinal chemistry, can solve the problems of weak acidity of benzoic acid, unsuitability for industrialization, high price, etc., and achieve the effects of high product yield and purity, favorable industrial production, and mild process conditions

Active Publication Date: 2020-04-28
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The total yield of this scheme is less than 25%, and the DMF / DMSO mixed solvent is used in the process, which is difficult to post-process and difficult to recycle; the dangerous reagent NaH is used, which requires anhydrous reaction conditions, which is not suitable for industrial production; Methyl iodide reagent is highly toxic and expensive; (R)-3-aminopiperidine dihydrochloride is used as raw material, and the 3-amino group is not protected, which is prone to disubstitution side reactions, and the reaction selectivity is general
[0017] This process route uses phosphorus oxychloride reagent, which is toxic and produces a large amount of waste acid wastewater, which is not suitable for industrialization; the total route is too long, the total yield is less than 20%, and there is no cost advantage
[0020] This method uses cyanoacetic acid to belong to highly toxic reagent, and uses sodium hydroxide solution to carry out hydrolysis, easily destroys product, and the purity of hydrolyzate is lower simultaneously; Weaker, deprotection is more difficult, so it is difficult to obtain completely deprotected alogliptin benzoate

Method used

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  • A kind of convenient preparation method of alogliptin benzoate
  • A kind of convenient preparation method of alogliptin benzoate
  • A kind of convenient preparation method of alogliptin benzoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Preparation of (R)-3-(3-Boc amino)piperidin-1-yl-3-(2-cyano)benzylamino-N-methacrylamide (Ⅴ)

[0064]

[0065] Into a 500 ml four-neck flask connected with a stirring, thermometer, and constant pressure low liquid funnel, add 100 g of methyl tert-butyl ether, 15.4 g (0.1 mole) of 3,3-dichloro-N-methacrylamide in sequence (II), stir, cool down to -5°C, keep the temperature at -5°C to 0°C, add 20.1 grams (0.1 moles) of (R)-3-Boc-aminopiperidine and 30 grams of methyl in drops within 2 hours The solution of tert-butyl ether was added dropwise and stirred at 0-5°C for 6 hours. Then add 27.5 grams (0.2 moles) of N,N-diisopropylethylamine (DIPEA), 13.9 grams (0.1 moles) of 2-cyanobenzylamine (IV), stir for 8 hours at 35 to 40°C, and add 50 grams of water, filtered, washed the filter cake with 20 grams of water, and dried to obtain 34.1 grams of (R)-3-(3-Boc amino)piperidin-1-yl-3-(2-cyano)benzylamino -N-methacrylamide (Ⅴ), yield 82.5%, purity 98.9%.

Embodiment 2

[0066] Example 2: Preparation of (R)-3-(3-Boc amino)piperidin-1-yl-3-(2-cyano)benzylamino-N-methacrylamide (Ⅴ)

[0067] To a 500 ml four-necked flask connected with a stirring, thermometer, and constant-pressure low-liquid funnel, add 120 g of ether and 15.4 g (0.1 mole) of 3,3-dichloro-N-methacrylamide (II) successively, and stir , lower the temperature to -15°C, keep the temperature at -15°C to -10°C, add dropwise a solution of 20.1 g (0.1 mole) (R)-3-Boc-aminopiperidine and 40 g of ether within 2 hours, dropwise After completion, stir at -15°C for 8 hours. Then add 15.8 grams (0.2 moles) of pyridine, 14.5 grams (0.11 moles) of 2-cyanobenzylamine (Ⅳ), and stir at 35°C for 8 hours. After the reaction finishes, add 50 grams of water to the system, filter, and wash with 20 grams of water The filter cake was dried to obtain 36.2 grams of (R)-3-(3-Boc amino)piperidin-1-yl-3-(2-cyano)benzylamino-N-methacrylamide (Ⅴ), Yield 87.6%, purity 99.1%.

Embodiment 3

[0068] Embodiment 3: the preparation of alogliptin (Ⅵ)

[0069]

[0070] In a 250 ml reaction bottle, 20.7 grams of (R)-3-(3-Boc amino)piperidin-1-yl-3-(2-cyano)benzylamino-N-methacrylamide (V) ( 50 mmol) was dissolved in 50 milliliters of tetrahydrofuran, at room temperature, 14.8 grams (50 millimoles) of triphosgene was dissolved in 30 milliliters of tetrahydrofuran, and the tetrahydrofuran solution of triphosgene was added dropwise to the tetrahydrofuran solution of compound V within 30 minutes while stirring During the reaction, the temperature was raised to 45°C, and the reaction was carried out for 5 hours. Solids were precipitated during the reaction. Cool down, filter, dissolve the filter cake in water, add 100 ml of dichloromethane, adjust the pH of the aqueous layer to 9-10 with NaOH aqueous solution, and stir for 30 minutes. , the organic phase was separated, the aqueous phase was extracted with 50 ml of dichloromethane, the organic phases were combined, dried, f...

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Abstract

The invention relates to an alogliptin benzoate preparation method, which comprises that 3,3-dihalogenated-N-methyl acrylamide sequentially reacts with (R)-3-Boc-aminopiperidine and 2-cyano benzylamine to prepare (R)-3-(3-Bocamino)piperidine-1-yl-3-(2-cyano)benzylamino-N-methacrylamide, the obtained material reacts with a carbonylation reagent to prepare alogliptin, and the alogliptin and benzoicacid are subjected to salt forming to prepare alogliptin benzoate. According to the present invention, the method has advantages of inexpensive and easily available raw materials, simple operation andless wastewater, and is suitable for the industrial production of alogliptin benzoate.

Description

technical field [0001] The invention relates to a convenient preparation method of alogliptin benzoate, which belongs to the technical field of medicinal chemistry. Background technique [0002] Alogliptin benzoate (Alogliptin benzoate), the chemical name is 2-({6-[(3R)-3-amino-1-piperidinyl]-3-methyl-2,4-dioxo-3 ,4-Dihydropyrimidinyl-1-(2H)-yl}methyl)benzonitrile benzoate is a dipeptidyl peptidase IV (DPP-IV) inhibitor developed by Takeda Corporation of Japan. Launched in September 2011. It is used for the treatment of type Ⅱ diabetes, and is a highly selective inhibitor of DPP-Ⅳ activity, which can maintain the levels of glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and promote insulin Secretion, play a hypoglycemic effect. The structural formula of alogliptin benzoate is as follows: [0003] [0004] At present, the synthetic routes of alogliptin mainly include the following types: [0005] Patent documents CN102134231 (WO20...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
CPCC07D401/04Y02P20/55
Inventor 范岩森马尊志张明峰鞠立柱陈军戚聿新
Owner XINFA PHARMA