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Preparation method of sitagliptin phosphate intermediate

A technology for sitagliptin phosphate and intermediates, applied in the field of preparation of sitagliptin phosphate intermediates, can solve the problems of low solvent recovery rate, unfavorable environmental protection, influence and the like, achieve high purity, improve yield and purity, simple craftsmanship

Inactive Publication Date: 2021-11-19
ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] 5-[1-Hydroxy-2-(2,4,5-trifluorophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione ( Formula Ⅱ) and 4-oxo-4-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7- (8H)-base}-1-(2,4,5-trifluorophenyl)butan-2-one (formula Ⅲ) is the key intermediate of sitagliptin phosphate, and the quality of these two intermediates has a great influence on the synthesis of phosphoric acid in the later stage. Sitagliptin will have a greater impact, and its yield will affect the process cost
[0005] WO2004087650, J.AM.CHEM.SOC, 2004,126:13002-13009 and other documents have synthesized formula II and formula III, but no corresponding post-treatment method or reported post-treatment method has been reported in these documents The operation is cumbersome, the solvent recovery rate is low, and a large amount of three wastes are generated, which is not conducive to environmental protection

Method used

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  • Preparation method of sitagliptin phosphate intermediate
  • Preparation method of sitagliptin phosphate intermediate
  • Preparation method of sitagliptin phosphate intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0028] The preparation of compound shown in embodiment 1 formula II

[0029] Add 2.50kg of acetonitrile, 1.00kg of trifluorophenylacetic acid, 0.85kg of Michaelis acid, 50.00g of 4-dimethylaminopyridine in a 10L reaction kettle, and then dropwise add 1.50kg of N,N-diisopropylethylamine and 0.70kg of pivaloyl chloride After the addition, the reaction was carried out at 45°C for 6.0h. After the reaction was completed, the solvent was recovered under reduced pressure. After recovering to dryness, add 10.00kg of 75% ethanol, add 1.00kg of hydrochloric acid under stirring, stir and crystallize at 10°C, stir for 5.0h and then filter, wash the filter cake with 1.00kg of 75% ethanol, and vacuum dry at 45°C for 20.0h to obtain Sigiryl Phosphate Gliptin intermediate II, yield 93%, purity 99.7%.

Embodiment 2

[0030] Preparation of compound shown in embodiment 2 formula III

[0031] Drop into 5.00kg acetonitrile, 1.50kg sitagliptin phosphate intermediate II, 0.80kg N,N-diisopropylethylamine, 1.20kg pyrazine hydrochloride in 10L reactor, add 0.20kg trifluoroacetic acid, heat up to React at 75°C for 6.0h. After the reaction is completed, the solvent is recovered under reduced pressure. After the recovery under reduced pressure, 6.00kg of 75% ethanol is added to stir and crystallize at 10°C. After stirring for 5.0h, the filter cake is washed with 2.00kg of 75% ethanol. Dry in a vacuum oven at 45°C to obtain sitagliptin phosphate intermediate III with a yield of 93% and a purity of 99.1%.

Embodiment 3

[0032] Preparation of compound shown in embodiment 3 formula II

[0033] Add 25g of acetonitrile, 10g of trifluorophenylacetic acid, 8.5g of Michaelis acid, 0.5g of 4-dimethylaminopyridine into a 100mL flask, and add 15g of N,N-diisopropylethylamine and 7g of pivaloyl chloride dropwise successively. The reaction was carried out at 45°C for 6 hours. After the reaction was completed, the solvent was recovered under reduced pressure. After recovering to dryness, add 100g of 30% ethanol, add 10g of hydrochloric acid under stirring, stir and crystallize at 10°C, stir for 5.0h and then filter, wash the filter cake with 10g of 30% ethanol, and vacuum dry at 45°C for 20h to obtain sitagliptin phosphate intermediate Body II, yield 95%, purity 99.2%.

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Abstract

The invention discloses a preparation method of a sitagliptin phosphate intermediate. In the existing synthesis method of the sitagliptin phosphate intermediate, a corresponding post-treatment method is not reported or the reported post-treatment method is tedious in operation, low in solvent recovery rate, capable of generating a large amount of three wastes, and not beneficial to environmental protection. The method comprises the following steps: directly evaporating to remove a solvent after the synthesis reaction of the sitagliptin phosphate intermediate is completed, adding a crystallization solvent, cooling, stirring for crystallization, washing and drying to obtain the corresponding sitagliptin phosphate intermediate. According to the invention, the yield and the purity of the sitagliptin phosphate intermediate are improved; the method is simple in process, high in solvent recovery rate and suitable for large-scale industrial production, and wastewater is not generated in the production process.

Description

technical field [0001] The invention relates to the field of synthesis technology of organic compounds, in particular to a preparation method of a sitagliptin phosphate intermediate. Background technique [0002] Sitagliptin Phosphate (English name: Sitagliptin Phosphate, chemical name: (3R)-3-amino-1-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazole [4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)-1-butanone phosphoric acid monohydrate), its structure is as shown in formula I As the first DPP-4 inhibitor for the treatment of diabetes, it was first launched in the United States in 2006. [0003] [0004] 5-[1-Hydroxy-2-(2,4,5-trifluorophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione ( Formula Ⅱ) and 4-oxo-4-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7- (8H)-base}-1-(2,4,5-trifluorophenyl)butan-2-one (formula Ⅲ) is the key intermediate of sitagliptin phosphate, and the quality of these two intermediates has a great influence on the synthesis of...

Claims

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Application Information

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IPC IPC(8): C07D319/06C07D487/04
CPCC07D319/06C07D487/04
Inventor 钱武张嘉懿徐诗谣马娟盛力沈大冬
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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