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A kind of preparation method of trexagliptin and salt thereof

一种曲格列汀琥珀酸盐、体积比的技术，应用在曲格列汀及其盐的制备领域，能够解决粗品分离纯化步骤繁琐、不适合工业化生产、曲格列汀收率低等问题，达到减少副反应以及杂质化合物的生成、成本低、分离纯化方法简便的效果

Active Publication Date: 2021-01-26
SICHUAN KELUN PHARMA RES INST CO LTD
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AI Technical Summary

Problems solved by technology

[0007] Due to the molecular structure of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile, There is a fluorine atom on the benzene ring, and there is a strong electric-absorbing cyano group at the para-position, so that fluorine becomes a good leaving group, which is easy to participate in the substitution reaction to generate impurity compound 5. In the actual reaction, the impurity compound 5 The content in the crude product is as high as 12%, resulting in a low yield of trexagliptin; and the impurity compound 5 is similar in nature to trexagliptin, the separation of the two is difficult, the separation and purification steps of the crude product are cumbersome, and are not suitable for industrial production

Method used

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  • A kind of preparation method of trexagliptin and salt thereof
  • A kind of preparation method of trexagliptin and salt thereof
  • A kind of preparation method of trexagliptin and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] 6-Chloro-3-methyluracil (1.5g), potassium carbonate (3.88g), 2-cyano-5-fluorobenzyl bromide (2.6g) were dissolved in 20mL of DMSO, and the above mixture was heated to 50-60°C for 5h , cooled to 10°C, added 20 mL of water to the reaction solution, a light yellow solid precipitated, filtered, washed the solid with isopropanol, and dried in vacuo to obtain 1.6 g of the product (compound 3);

[0064] Under nitrogen protection, compound 3 (1g, 3.41mmol) was dissolved in 10mL DMSO, stirred until clear, and (Pd(OAc) 2 (7.7mg, 0.034mmol), BINAP (32mg, 0.051mmol), K 3 PO 4 (2.17g, 10.23mmol), the above mixture was heated to 80°C, 3-Boc-aminopiperidine (compound 7, 0.82g, 4.1mmol) was dissolved in 1mL DMSO and added to the above reaction mixture, stirred at 80°C for 5h, TLC Detect the disappearance of compound 3; cool down to room temperature, filter the reaction solution, pour the filtrate into water, extract with dichloromethane, dry the organic phase, and evaporate to drynes...

Embodiment 2

[0074] 6-Chloro-3-methyluracil (30g), potassium carbonate (77.6g), 2-cyano-5-fluorobenzyl bromide (52g) were dissolved in 200mL of DMSO, and the above mixture was heated to 50-60°C for 5h, then cooled After reaching 10°C, 200 mL of water was added to the reaction solution, and a pale yellow solid precipitated out. After filtration, the solid was washed with isopropanol and dried in vacuo to obtain 33 g of the product (compound 3);

[0075] Under nitrogen protection, compound 3 (10g, 34.1mmol) was dissolved in 50mL DMSO, stirred until clear, and Pd(OAc) (77mg, 0.34mmol), BINAP (320mg, 0.51mmol), K 3 PO 4 (21.7g, 102.3mmo), the above mixture was heated to 80°C, 3-Boc-aminopiperidine (compound 7, 8.2g, 40.9mmol) was dissolved in DMSO (10ml) and added to the above reaction mixture, stirred at 80°C for 5h , TLC detects that compound 3 disappears; cool down to room temperature, filter the reaction solution, pour the filtrate into water, extract with dichloromethane, dry the organi...

Embodiment 3

[0079] 6-Chloro-3-methyluracil (3g, 18.8mmol), potassium carbonate (12.9g, 94mmol), 2-cyano-5-fluorobenzyl bromide (6g, 28.1mmol) were dissolved in 60mL of DMSO, and the above mixture was heated React at 50-60°C for 5h, cool down to 10°C, add 60mL of water to the reaction solution, and a pale yellow solid precipitates out. After filtration, the solid was washed with isopropanol and dried in vacuo to obtain 2.8 g of the product (compound 3);

[0080] Under nitrogen protection, compound 3 (2g, 6.8mmol) was dissolved in 20mL DMSO, stirred until clear, and Pd(OAc) (153mg, 0.68mmol), BINAP (622mg, 1mmol), K 3 PO 4 (4.3g, 20.4mmol), the above mixture was warmed to 80°C, (R)-3-Boc-aminopiperidine (compound 7, 2g, 10.2mmol) was dissolved in DMSO (50ml) and added to the above reaction mixture, 80 Stir at ℃ for 5 h, TLC detects that compound 3 disappears; cool down to room temperature, filter the reaction solution, pour the filtrate into water, extract with dichloromethane, dry the or...

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Abstract

The invention discloses a preparation method of trexagliptin and its salt, which comprises the following steps: a. under nitrogen protection, compound 3, Pd(OAc) 2 , ligand, K 3 PO 4 , 3-tert-butoxycarbonyl-aminopiperidine in an organic solvent, stirred and reacted to obtain a reaction solution; b, separated and purified to obtain compound 6; c, take compound 6, and the ethyl acetate solution of ethyl acetate and HCl , after stirring and reacting, separate and purify to obtain a solid; d. Take the solid in step c, add water to dissolve, adjust the pH to 8-9, separate and purify to obtain compound 4, which is trexagliptin. The method of the present invention reduces the generation of side reactions and impurity compounds; the separation and purification method of trexagliptin is simple and convenient, and has the advantages of short production cycle, high yield, high purity, and low cost; the yield of trexagliptin of the present invention is It can be as high as more than 95%, which is very suitable for industrial production.

Description

[0001] This application is a divisional application of a patent application with the application number 201510073686.1, the application date is February 11, 2015, and the title is "a preparation method of trexagliptin and its salt". technical field [0002] The invention relates to a preparation method of trexagliptin and a salt thereof. Background technique [0003] Trelagliptin, chemical name: 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4- Dioxy-1 (2H)-pyrimidinyl] methyl]-4-fluoro-benzonitrile, its structure is shown in formula I; Trexagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor , is a long-acting DPP-IV inhibitor developed by Japan's Takeda Corporation (Takeda Corporation), mainly used for the treatment of type 2 diabetes (see Chinese patent CN 104003975 A). [0004] [0005] At present, the preparation method of Trexagliptin comprises the following steps: 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl )-4-fluoro-benzoni...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
Inventor 陈丽李洋李正林段继龙葛建华王利春王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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