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Trelagliptin preparation method

A compound and methyl technology, applied in the field of preparation of trelagliptin, can solve the problem of low purity of trelagliptin, and achieve the effects of high conversion rate, high total yield and mild reaction conditions

Active Publication Date: 2016-10-12
山东四环药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this reaction, since the structure of R-3-aminopiperidine bishydrochloride contains both primary amine and secondary amine, two nucleophilic substitution products at different positions are generated in the reaction, resulting in poor purity of the target product trexagliptin. High, multiple refining and purification treatments are required to obtain high-purity trexagliptin

Method used

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Examples

Experimental program
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Effect test

example 1

[0048] Example 1: Preparation of compound shown in formula 4

[0049] The compound shown in formula 6 (100g, 340.5mmol), the compound shown in formula 5 (49.0g, 375mmol) and potassium carbonate (94.0g, 682.0mmol) were added in N,N-dimethylformamide (600ml), Raise the temperature to 70°C and react for 2 hours. After the reaction, cool down to 20°C. Add 1800ml of water and 2M / L dilute hydrochloric acid to adjust the pH of the feed solution to ≤ 6. A large amount of solids are precipitated. After stirring for 30 minutes, filter, rinse with 100ml of ethanol, and dry to obtain Off-white compound 130.2g, purity 99.7%, maximum single impurity 0.1%. The yield was 98.9%.

[0050] ESI-MS: m / z([M+H] + ) is 387.4.

example 2

[0051] Example 2: step2-1, the preparation of compound (X is Cl) shown in formula 3-1

[0052] The compound shown in formula 4 (5g, 12.94mmol) was added in 50ml of dichloromethane, and the temperature was lowered to 0°C, and thionyl chloride (1.8g, 15mmol) was added dropwise. Concentrate under reduced pressure to dryness to obtain 4.9 g of a light yellow solid, with a yield of 93.5%, a purity of 98.7%, and a maximum single impurity of 0.1%.

[0053] ESI-MS: m / z([M+H] + ) is 405.8.

example 3

[0054] Example 3: step2-1, the preparation of compound (X is Br) shown in formula 3-1

[0055] Add the compound shown in Formula 4 (5g, 12.94mmol) into 50ml of dichloromethane, drop the temperature to 0°C, and add a solution of phosphorus oxybromide (4.3g, 15.0mmol) dropwise in dichloromethane, and continue the reaction for 1 hour after dropping , heated to 30° C. and concentrated under reduced pressure to dryness to obtain 5.5 g of a light yellow solid with a yield of 94.6%, a purity of 98.4%, and a maximum single impurity of 0.13%.

[0056] ESI-MS: m / z([M+H] + ) is 450.3.

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Abstract

The invention discloses a Trelagliptin preparation method. The method comprises that a compound shown in the formula 6 and a compound shown in the formula 5 undergo a condensation reaction in the presence of an organic solvent and an alkali to produce a compound shown in the formula 4, a compound shown in the formula 2 is prepared through halogenations and azidation, or acid anhydride formation and azidation, or direct azidation, or esterification, hydrazide formation and azidation, or esterification and azidation, and Trelagliptin is prepared through a rearrangement hydrolysis reaction. The method has the advantages of mild reaction conditions, high conversion rate, less impurities, low cost and high finished product purity and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of trexagliptin. Background technique [0002] Trexagliptin is a once-weekly dipeptidyl peptidase IV (DPP-4) inhibitor that controls blood glucose levels through selective and sustained inhibition of DPP-4. DPP-4 is an enzyme that triggers the inactivation of incretin (glucagon-like peptide-1) and diabetes-dependent insulinotropic polypeptide (GIP), two incretins that play a role in blood glucose regulation important role. Inhibition of DPP-4 can increase blood glucose level-dependent insulin secretion, thereby controlling blood glucose levels. [0003] Trexagliptin, chemical name: 2-{[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo -1(2H)-pyrimidinyl]methyl}-4-fluoro-benzonitrile. Its structural formula is as follows: [0004] [0005] Chinese patent CN102675221 discloses a method for preparing trexagliptin, and its synthetic route is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 李刚孙崇国郭建军刘慧敏
Owner 山东四环药业股份有限公司
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