Synthesis 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, large amount of waste solid waste water, etc. The effect of low equipment requirements, low cost, and less waste

Active Publication Date: 2017-06-13
SULI PHARMA TECH JIANGYIN
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  • 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

Method used

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  • Synthesis method of sitagliptin phosphate intermediate
  • Synthesis method of sitagliptin phosphate intermediate
  • Synthesis 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 cool down to -10~0 After dropping 1.5kg of acetyl chloride, drop it for about 2 hours, then raise the temperature to 0°C for 5 hours, 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]dioxy-4,6-dione is directly used for the next step reaction 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 0.5h at a temperature of 30~40°C, start to add 0.54kg of trifluoroacetic acid dropwise, after about 1h, the temperature is raised to 55~60°C, and the reaction is kept for 6~8h. Add the reaction solution dropwise to 18L of...

Embodiment 2

[0034] Step 1. Condensation

[0035] With embodiment 1.

[0036] Step 2, open loop

[0037] 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 0.5h at a temperature of 30~40°C, start to add 0.54kg of trifluoroacetic acid dropwise, after about 1h, the temperature is raised to 55~60°C, and the reaction is kept for 6~8h. Add the reaction solution dropwise to 18L of aqueous solution containing 5% sodium bicarbonate, control the temperature at 10-15°C, and finish the dripping in about 3 hours. After suction filtration, rinse the filter cake with 1.5L of mixed solvent (acetonitrile: water = 6:1), and send the filter cake to a decompression oven for drying (control temperature 50~55°C, vacuum degree ≥ 0.085MPa) to obtain ( 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 solid dry product 5...

Embodiment 3

[0039] Step 1. Condensation

[0040] With embodiment 1.

[0041] Step 2, open loop

[0042]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 0.5h at a temperature of 30~40°C, start to add 0.54kg of trifluoroacetic acid dropwise, after about 1h, the temperature is raised to 55~60°C, and the reaction is kept for 6~8h. Add the reaction solution dropwise to 18L of aqueous solution containing 5% sodium bicarbonate, control the temperature at 10-15°C, and finish the dripping in about 3 hours. After suction filtration, rinse the filter cake with 1.5L of mixed solvent (acetonitrile: water = 6:1), and send the filter cake to a decompression oven for drying (control temperature 50~55°C, vacuum degree ≥ 0.085MPa) to obtain ( 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 solid dry product 5....

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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 ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 梁朝阳汪静莉
Owner SULI PHARMA TECH JIANGYIN
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