Preparation method of trelagliptin and salt of trelagliptin

A technology of methylation and dioxo generation, which is applied in the field of preparation of trexagliptin and its salts, can solve the problems of cumbersome separation and purification steps of crude products, unsuitability for industrial production, low yield of trexagliptin, etc., and achieve reduction of side effects The effect of reaction and formation of impurity compounds, low cost, and simple separation and purification method

Active Publication Date: 2018-11-13
SICHUAN KELUN PHARMA RES INST CO LTD
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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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  • Preparation method of trelagliptin and salt of trelagliptin
  • Preparation method of trelagliptin and salt of trelagliptin
  • Preparation method of trelagliptin and salt of trelagliptin

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Experimental program
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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 trelagliptin and salt of the trelagliptin. The preparation method comprises the following steps: a, stirring a compound 3, Pd(OAc)2, a ligand, K3PO4 and3-tert-butoxycarbonyl-aminopiperidine for a reaction in an organic solvent under the protection of nitrogen to obtain a reaction liquid; b, separating and purifying to obtain a compound 6; c, takingthe compound 6, stirring the the compound 6 with ethyl acetate and an ethyl acetate solution of HCl for the reaction, and separating and purifying to obtain a solid; d, taking the solid of the step c,adding water to dissolve, adjusting the pH to 8-9, and separating and purifying to obtain a compound 4 which is the trelagliptin. By adopting the method provided by the invention, side reactions andthe formation of impurity compounds are reduced; the separation and purification method of trelagliptin is simple, and has the advantages of short production cycle, high yield, high purity, low cost and the like; the yield of trelagliptin of the invention reaches up to 95% or more than 95%; and the preparation method 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 Applications(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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