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Low cost method for preparing sitagliptin phosphate salt key intermediate

A technology of sitagliptin and phosphate, applied in the direction of organic chemistry, etc., to achieve the effect of reducing the amount of waste water, low production cost and less impurities

Active Publication Date: 2015-10-21
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But at present, the estimated number of diabetic patients in China has reached 60 million, of which about 95% are type 2 diabetic patients, and the vast majority of diabetic patients cannot use sitagliptin phosphate due to its high price

Method used

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  • Low cost method for preparing sitagliptin phosphate salt key intermediate
  • Low cost method for preparing sitagliptin phosphate salt key intermediate
  • Low cost method for preparing sitagliptin phosphate salt key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H )yl]-1-(2,4,5-trifluorophenyl)-2-butanone (Ⅱ)

[0047] Step 1: 3-oxo-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H) Preparation of propionitrile (Ⅳ) toluene solution

[0048] Add 200 grams of toluene, 12 grams of sodium carbonate, 9.9 grams (0.1 moles) of methyl cyanoacetate, 22.8 grams (0.1 moles) of 5,6,7,8-tetrahydro-1,2 , 4-triazolo[4,3-a]pyrazine hydrochloride (Ⅲ), stirred and reacted at 92-95°C for 3 hours. Cool to 20-25°C, filter, and wash the filter cake (a mixture of sodium bicarbonate and sodium chloride) with 30 grams of toluene (washing a small amount of product adsorbed by the filter cake); combine the filtrates, and wash the combined filtrates with 5 grams of anhydrous Sodium sulfate was dried for 4 hours, filtered, and the filtrate (3-oxo-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a ] pyrazin-7 (8H) base] the toluene solution of pr...

Embodiment 2

[0053] Example 2: 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H )yl]-1-(2,4,5-trifluorophenyl)-2-butanone (Ⅱ)

[0054] Replace 9.9 grams (0.1 mole) of methyl cyanoacetate of embodiment 1 step 1 with 11.3 grams (0.1 moles) ethyl cyanoacetate, all the other are the same as embodiment 1, obtain 34.7 grams of white crystals 4-oxo-4-[ 3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)yl]-1-(2,4,5 -Trifluorophenyl)-2-butanone (II), the yield is 85.3% (calculated as III), and the liquid phase purity is 99.97%.

Embodiment 3

[0055] Example 3: 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H )yl]-1-(2,4,5-trifluorophenyl)-2-butanone (Ⅱ)

[0056] Replace 12 grams of sodium carbonate in Example 1 step 1 with 16.5 grams of potassium carbonate, and all the other are the same as in Example 1 to obtain 36.4 grams of white crystal 4-oxo-4-[3-(trifluoromethyl)-5,6-di Hydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)yl]-1-(2,4,5-trifluorophenyl)-2-butanone (Ⅱ) , the yield is 89.5% (calculated based on the compound of formula III), and the liquid phase purity is 99.95%.

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Abstract

The invention relates to a low cost method for preparing a sitagliptin phosphate salt key intermediate. The method comprises the steps of: with existence of suitable solvents and inorganic bases, preparing 3-oxalysine-[3-(trifluoromethyl)-5,6-dihydrogen[1,2,4]triazolo[4,3-a]pyrazinyl-7(8H)]propionitrile(IV) by reacting cyanoethanoate ester with 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride(III)amidation and removing alcohol; and compound IV then reacting with a Grignard reagent that is prepared by 2,4,5-trifluoro-1-halogenated methyl benzene and magnesium, so as to obtain 4-oxalysine-4-[3-(trifluoromethyl)-5,6-dihydrogen[1,2,4]triazolo[4,3-a]pyrazinyl-7(8H)]-1-(2,4,5-trifluorophenyl)-2-butanone(II). According to the method provided by the invention, the expensive Michaelis acid, trimethylacetyl chloride and diisopropylethylamine are not used; the raw material used is cheap and easy to obtain and has less waste water in the production process; the product is high in yield, has few impurities, and is low in cost.

Description

technical field [0001] The present invention relates to a low-cost method for preparing sitagliptin phosphate key intermediate 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazinamide derivatives The method belongs to the field of medicine and chemical industry. Background technique [0002] Since the US FDA approved sitagliptin phosphate for marketing in October 2006, sitagliptin phosphate has been approved for the treatment of type 2 diabetes in 95 countries including China. Sitagliptin phosphate, the chemical name is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one phosphate, CAS number is 654671-78-0, English name is Sitagliptin Phosphate is a dipeptidyl peptidase-1V (DPP-1V) inhibitor developed by Merck & Co. of the United States. The structural formula of sitagliptin phosphate is shown in Formula I. [0003] Sitagliptin phosphate is the first dipeptidyl enzyme-4 (DPP-4) inhibitor type 2 diabe...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 戚聿新鞠立柱张明峰陈军李新发
Owner XINFA PHARMA
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