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Preparation method of Linagliptin

A technology for compounds and inorganic salts, applied in the field of API preparation, can solve problems such as increased cost, process complexity, purification difficulties, etc., and achieve the effects of improving product purity, reducing purification pressure, and improving yield

Active Publication Date: 2015-08-19
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the D compound is a paste substance, purification is difficult, and it is generally purified in the final product linagliptin step, but this process undoubtedly increases the cost and process complexity

Method used

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  • Preparation method of Linagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Add 54g (0.182mol) of compound B, 40g (0.2mol) of compound F, 50g (0.364mol) of potassium carbonate, and 0.6g (0.04mol) of potassium iodide into a 2L reaction flask, and then add 270ml of NMP. Stir and heat up to 40-50°C, and stir for 2-3h. After the reaction was detected by TLC, 36.5 g (0.192 mol) of compound E was added, and the reaction was continued for 3-4 h. After the reaction was detected by TLC (DCM:MeOH=20:1), the heating was stopped and the temperature was lowered to room temperature.

[0032] Post-treatment: Add 540ml of dichloromethane and 1080ml of water, stir until the solid dissolves. Separate the liquid, extract the aqueous layer with 270ml*2DCM, combine the organic phases; add 500ml of 1% acetic acid aqueous solution to wash once, and wash once with saturated sodium chloride to obtain the organic phase. Evaporate the organic phase to dry the light yellow solid, then add 300ml of ethanol, heat to reflux to dissolve, slowly add 300ml of w...

Embodiment 2

[0033] Example 2: Add 54g (0.182mol) of compound B, 36.5g (0.192mol) of compound E, 50g (0.364mol) of potassium carbonate, and 0.6g (0.04mol) of potassium iodide into a 2L reaction flask, and then add 270ml of NMP. Stir and heat up to 40-50°C, and stir for 2-3h. After the reaction was detected by TLC, 40 g (0.2 mol) of compound F was added, and the reaction was continued for 3-4 h. After the reaction was detected by TLC (DCM:MeOH=20:1), the heating was stopped and the temperature was lowered to room temperature.

[0034] Post-treatment: Add 540ml of dichloromethane and 1080ml of water, stir until the solid dissolves. Separate the liquid, extract the aqueous layer with 270ml*2DCM, combine the organic phases; add 500ml of 1% acetic acid aqueous solution to wash once, and wash once with saturated sodium chloride to obtain the organic phase. Evaporate the organic phase to dry the light yellow solid, then add 300ml of ethanol, heat to reflux to dissolve, slowly add 300ml of w...

Embodiment 3

[0035] Example 3: Add 54g (0.182mol) of compound B, 40g (0.2mol) of compound F, 38.5g (0.364mol) of sodium carbonate, and 0.6g (0.04mol) of potassium iodide into a 2L reaction flask, and then add 270ml of NMP. Stir and heat up to 40-50°C, and stir for 2-3h. After the reaction was detected by TLC, 6.5 g (0.192 mol) of compound E was added, and the reaction was continued for 3-4 h. After the reaction was detected by TLC (DCM:MeOH=20:1), the heating was stopped and the temperature was lowered to room temperature.

[0036] Post-treatment: Add 540ml of dichloromethane and 1080ml of water, stir until the solid dissolves. Separate the liquid, extract the aqueous layer with 270ml*2DCM, combine the organic phases; add 500ml of 1% acetic acid aqueous solution to wash once, and wash once with saturated sodium chloride to obtain the organic phase. Evaporate the organic phase to dry the light yellow solid, then add 300ml of ethanol, heat to reflux to dissolve, slowly add 300ml of wat...

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Abstract

The invention relates to a preparation method of Linagliptin. According to the preparation method, potassium carbonate or sodium carbonate is taken as an alkali; an iodine-containing inorganic salt is taken as a catalyst; N-methyl-2-pyrrolidone (NMP) or N,N-Dimethylformamide (DMF) is taken as a solvent; 8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1H-purine-2,6-dione is reacted with a (R)-3-aminopiperidine compound firstly at 40 to 50 DEG C; after reaction, 2-(chloromethyl)-4-methylquinazoline is directly added for reaction so as obtain a compound D; and the compound D is subjected to step 1-2 to prepare Linagliptin. The preparation method is capable of shortening reaction time, and increasing yield.

Description

technical field [0001] The present invention relates to the preparation of Linagliptin (Linagliptin) (8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl The preparation method of base-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione) belongs to the technical field of preparation of raw materials. Background technique [0002] Linagliptin (compound A shown in the formula) is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which can improve the blood pressure of adult patients with type 2 diabetes mellitus (T2DM) on the basis of diet control and physical exercise. Blood sugar control level. Compared with other gliptins, linagliptin has excellent renal safety. It does not require dose adjustment for patients with impaired renal function or the elderly over 75 years old, thus greatly expanding the scope of the drug population and improving the compliance of patients with medication. The U.S. Food and Drug Administration approved Linagliptin tablets on May 2,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04
CPCC07D473/04
Inventor 秦立太丛日刚郭路蒲永潇毕可兴
Owner 迪嘉药业集团股份有限公司
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