A kind of synthetic method of sitagliptin phosphate intermediate

A technique for the synthesis of sitagliptin phosphate, which is applied in the field of organic synthesis, can solve the problems of difficult recovery of solvent N,N-dimethylacetamide, high cost of pivaloyl chloride, and low product purity, and meet the requirements of reaction equipment Low cost, low cost and high product purity

Active Publication Date: 2019-02-22
SULI PHARMA TECH JIANGYIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] There are many impurities in the product reacted by this method, which leads to the difficulty of crystallization in the later stage of the second step reaction, and the phenomenon that crystallization cannot be easily occurred. The product purity is not high and needs to be refined, resulting in a low overall yield, and the cost of pivaloyl chloride is relatively high. The solvent N,N-dimethylacetamide is not easy to recycle, and the amount of waste and solid waste water in the later stage is relatively large, and the treatment cost is also high, which is not conducive to environmental protection

Method used

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  • A kind of synthetic method of sitagliptin phosphate intermediate
  • A kind of synthetic method of sitagliptin phosphate intermediate
  • A kind of synthetic method of sitagliptin phosphate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Step 1. Condensation

[0030] Add 3kg of 2,4,5-trifluorophenylacetic acid, 2.5kg of McBurney's acid, 4.18kg of N,N-diisopropylethylamine, and 0.154kg of DMAP into organic solvent A, protect with nitrogen, and lower the temperature from -10 to 0 After dropping 1.5kg of acetyl chloride, drop it for about 2 hours, then raise the temperature to 0°C for 5 hours, and then raise the temperature to 30-40°C to obtain 5-hydroxy-[(2,4,5-trifluoro The reaction solution of phenyl)-ethylene]-dimethyl-[1,3]dioxo-4,6-dione is directly used in the next step without discharging.

[0031] Step 2, open loop

[0032] Add 3.6 kg of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride into Step 1 at one time In the reaction solution, after stirring for 0.5 hours at a temperature of 30-40°C, start to add 0.54kg of trifluoroacetic acid dropwise, about 1 hour after the drop, and then raise the temperature to 55-60°C, keep the temperature for 6-8 hours, after the ...

Embodiment 2

[0035] Step 1. Condensation

[0036] With embodiment 1.

[0037] Step 2, open loop

[0038] Add 3.6 kg of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride into Step 1 at one time In the reaction solution, after stirring for 0.5 hours at a temperature of 30-40°C, start to add 0.54kg of trifluoroacetic acid dropwise, about 1 hour after the drop, and then raise the temperature to 55-60°C, keep the temperature for 6-8 hours, after the end of the heat preservation, Add the reaction solution dropwise to 18L of aqueous solution containing 5% sodium bicarbonate, control the temperature at 10-15°C, and finish dropping in about 3 hours. After suction filtration, and rinse the filter cake with 1.5L of mixed solvent (acetonitrile: water=6:1), the filter cake is sent to a decompression oven for drying, (control temperature 50 ~ 55 ° C, vacuum degree ≥ 0.085MPa) after drying to obtain ( 2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]...

Embodiment 3

[0041] Step 1. Condensation

[0042] With embodiment 1.

[0043] Step 2, open loop

[0044]Add 3.6 kg of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride into Step 1 at one time In the reaction solution, after stirring for 0.5 hours at a temperature of 30-40°C, start to add 0.54kg of trifluoroacetic acid dropwise, about 1 hour after the drop, and then raise the temperature to 55-60°C, keep the temperature for 6-8 hours, after the end of the heat preservation, Add the reaction solution dropwise to 18L of aqueous solution containing 5% sodium bicarbonate, control the temperature at 10-15°C, and finish dropping in about 3 hours. After suction filtration, and rinse the filter cake with 1.5L of mixed solvent (acetonitrile: water=6:1), the filter cake is sent to a decompression oven for drying, (control temperature 50 ~ 55 ° C, vacuum degree ≥ 0.085MPa) after drying to obtain ( 2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]p...

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Abstract

The invention relates to a synthesis method of a sitagliptin phosphate intermediate, and belongs to the technical field of organic synthesis. The method comprises the following technological steps of synthesizing a reaction liquid of 5-hydroxyl-[(2,4,5-trifluoro-phenyl)-ethylidene]-dimethyl-[1,3] dioxo-4,6-diketone from 2,4,5-trifluoro-phenylacetic acid, meldrum's acid, N,N-diisopropylethylamine, DMAP and acetylchloride; adding 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4] triazol [4,3-alpha] pyrazine hydrochloride and trifluoroacetic acid to obtain the product. According to the method, the reaction raw materials are easily available; the reaction process is simple in operation; the requirements on reaction equipment are low; the reaction conditions are relatively mild; the yield and content are high, the quantity of waste water and solid wastes is relatively low, the cost is saved, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a sitagliptin phosphate intermediate ((2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazole A synthetic method of [4,3-a]pyrazin-7-(8H)-yl]-1-(2,4,5-,trifluorophenyl)butan-2-one) belongs to the technical field of organic synthesis . Background technique [0002] (2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7- (8H)-yl]-1-(2,4,5-,trifluorophenyl)butan-2-one, CAS No.:764667-65-4, molecular structure: [0003] [0004] It is an important intermediate in the synthesis of sitagliptin phosphate. Sitagliptin phosphate is the first DPP-4 inhibitor approved for the treatment of type 2 diabetes. It can inhibit β cell apoptosis, promote β cell regeneration, and increase 2 The number of β cells in patients with type 2 diabetes can be significantly reduced, and it still has a significant hypoglycemic effect on patients who have failed sulfonylureas. Sitagliptin phosphate mainly realizes blood su...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 梁朝阳汪静莉
Owner SULI PHARMA TECH JIANGYIN
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