Industrial production method of sitagliptin

A technique for sitagliptin and a production method, which is applied in the field of industrial production of sitagliptin, can solve the problems of low chiral purity of the product, certain difficulty, complex process, etc., and achieve high yield, cost reduction, and high chirality The effect of purity

Inactive Publication Date: 2013-08-07
LIAOCHENG JIUZHOU HEGU BIOTECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0007] The process is simple, easy to operate, and does not need to use expensive chiral metal catalysts. However, due to the low chiral purity of the product, a chiral resolving agent is required for resolution. The process is complicated and the yield is low. This process uses There are still some difficulties in industrial production

Method used

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  • Industrial production method of sitagliptin
  • Industrial production method of sitagliptin
  • Industrial production method of sitagliptin

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Experimental program
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Embodiment Construction

[0020] (1) Preparation of chiral catalyst: under nitrogen protection, add (1,5 cyclooctadiene) ruthenium dichloride 165.3mg (0.59mmol) and S-(-)-1,1 to a 500ml reaction flask, 367.4 mg (0.59 mmol) of -binaphthyl-2,2,-diphenylphosphine, 200 ml of deoxygenated methanol, and the mixture was stirred at room temperature for one hour for later use.

[0021] (2) Preparation of sitagliptin free base: add 7-[3-amino-1-oxygen-4-(2,4,5-trifluorophenyl)-2-butenyl to 4l autoclave ]-5,6,7,8-tetrahydro-3-(1-trifluoromethyl)-1,2,4-triazol[4,3,α]pyrazine 118g (0.29mol) and deoxymethanol l Replace with nitrogen 3 times under stirring, add the chiral catalyst solution prepared in (1), replace with nitrogen 3 times under stirring, close all valves, slowly raise the temperature to 50°C, open the hydrogen valve, and slowly introduce hydrogen When the hydrogen pressure rises to 150 psi, keep the pressure and keep the reaction for 12-36 hours. Take a sample in the middle and analyze it by HPLC until...

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Abstract

The invention relates to an industrial production method of sitagliptin. The preparation method using 7-[3-amino-1-oxy-4(2,4,5-trifluorophenyl)-2-butenyl]-5,6,7,8-tetrahydro-3-(1-trifluoromethyl)-1,2,4-triazole[4,3,alpha] pyrazine as a starting material comprises the following steps of: (1), carrying out asymmetric catalytic hydrogenation reaction on the 7-[3-amino-1-oxy-4(2,4,5-trifluorophenyl)-2-butenyl]-5,6,7,8-tetrahydro-3-(1-trifluoromethyl)-1,2,4-triazole[4,3,alpha] pyrazine to generate sitagliptin free alkali with ee of more than 95% in the presence of catalytic amount of (1,5-cyclooctadiene) ruthenium dichloride and S-(-)-1,1-binaphthyl-2,2-diphenyl phosphine; (2) salifying the sitagliptin free alkali and phosphoric acid in methyl tert-butyl methyl ether to obtain the sitagliptin with ee of more than 99%, wherein the sitagliptin can completely achieve clinical medication requirements. The used catalyst is low in price and the used amount of the catalyst is only 0.2mol%, and therefore, the industrial production method of the sitagliptin is lower in cost and suitable for industrial production.

Description

technical field [0001] The invention relates to an industrial production method of sitagliptin. Background technique [0002] Sitagliptin (sitagliptin) is a new anti-type II diabetes drug approved by the FDA, and it is the first dipeptidyl peptidase-IV inhibitor drug for the treatment of type II diabetes. The mechanism of action of sitagliptin is different. Compared with the previous oral hypoglycemic drugs, it increases the secretion of insulin when the blood sugar rises by improving the insulin production ability of the diabetic patients' own pancreatic β cells, thereby controlling the blood sugar level of the diabetic patients. Clinical studies have shown that sitagliptin is an oral drug. Effective drug with good market prospect, used alone or in combination with metformin and pioglitazone, has a significant hypoglycemic effect, and is safe to take, well tolerated, and has few adverse reactions; the structural formula of sitagliptin is as follows: figure 1 shown. [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04B01J31/24
Inventor 刘钦松陈世杰王绍文张丛丛刘孟刚郭宝柱
Owner LIAOCHENG JIUZHOU HEGU BIOTECH
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