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Recovery method of sitagliptin phosphate key intermediate

A technology of sitagliptin phosphate and recovery method, which is applied in the field of preparation of sitagliptin phosphate, and can solve problems such as difficult effective separation and recovery of key intermediates of sitagliptin phosphate

Active Publication Date: 2022-01-18
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

[0005] The main purpose of the present invention is to provide a method for recovering the key intermediate of sitagliptin phosphate, so as to solve the problem of unreacted sitagliptin phosphate in the prior art when using sitagliptin phosphate transaminase to convert the key intermediate of sitagliptin phosphate. Difficult to effectively separate and recover key intermediates of Gliptin

Method used

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  • Recovery method of sitagliptin phosphate key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The HPLC content of the key intermediate of sitagliptin phosphate in the mother liquor is 62% (calculated by the external standard method, the concentration of the key intermediate of sitagliptin phosphate is 77mg / L), and the HPLC content of sitagliptin phosphate is 15%.

[0039] Add 10L of mother liquor (about 9 kg) into the reaction kettle, evaporate the solvent under the conditions of 50°C and vacuum degree ≥ 0.08MPa, and obtain a sticky substance after the solvent is recovered under reduced pressure. Add 10L of water and 10L of ethyl acetate to the sticky substance, stir and separate the liquids to obtain an aqueous phase and an organic phase, and then extract the aqueous phase with 10L of ethyl acetate to obtain an organic phase, and combine the obtained organic phases to be the extract. The solvent in the extract was distilled off at 50°C and vacuum degree ≥0.08MPa to obtain 1.20 kg of solid residue. In the solid residue, the HPLC content of the key intermediate of...

Embodiment 2

[0041] The mother liquor of embodiment 2 is identical with the mother liquor of embodiment 1.

[0042] Add 10L of mother liquor into the reaction kettle, evaporate the solvent under the conditions of 50°C and vacuum degree ≥ 0.08MPa, and obtain a sticky substance after the solvent is recovered under reduced pressure. Add 10L of water and 10L of dichloromethane to the sticky substance, stir and separate the liquids to obtain an aqueous phase and an organic phase, then extract the aqueous phase with 10L of dichloromethane to obtain an organic phase, and combine the obtained organic phases to be the extract. The solvent in the extract was distilled off at 50°C and vacuum ≥0.08MPa to obtain 1.34kg of solid residue. In the solid residue, the HPLC content of the key intermediate of sitagliptin phosphate was 80%. Phosphoric acid The HPLC content of sitagliptin was 2%. Add 8.00kg of 75% ethanol aqueous solution to the solid residue, and stir and crystallize at 10°C, and filter after ...

Embodiment 3

[0044] The mother liquor of embodiment 3 is identical with the mother liquor of embodiment 1.

[0045] Add 10L of mother liquor into the reaction kettle, evaporate the solvent under the conditions of 50°C and vacuum degree ≥ 0.08MPa, and obtain a sticky substance after the solvent is recovered under reduced pressure. Add 10L of water and 10L of dichloromethane to the sticky substance, stir and separate the liquids to obtain an aqueous phase and an organic phase, then extract the aqueous phase with 10L of dichloromethane to obtain an organic phase, and combine the obtained organic phases to be the extract. The solvent in the extract was distilled off at 50°C and vacuum degree ≥0.08MPa to obtain 1.20 kg of solid residue. In the solid residue, the HPLC content of the key intermediate of sitagliptin phosphate was 83%. Phosphoric acid HPLC content of sitagliptin 3%. Add 20.00kg of 70% methanol aqueous solution to the solid residue, and stir and crystallize at 20°C. After stirring ...

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Abstract

The invention provides a recovery method of a sitagliptin phosphate key intermediate. The recovery method comprises the steps: S1, concentrating a mother liquor to obtain a sticky matter, wherein the mother liquor is a liquid system, and the liquid system is prepared from the following steps that sitagliptin phosphate transaminase catalyzes conversion of a sitagliptin phosphate key intermediate to a sitagliptin free alkali to obtain a product system, phosphoric acid is added into the product system, and thensitagliptin phosphate is separated; S2, washing and extracting the sticky matter to obtain an extracting solution; S3, removing the solvent in the extracting solution to obtain solid-state residues; and S4, mixing the solid-state residues and a crystallization solvent, and carrying out crystallization treatment to obtain a crystallization system containing the sitagliptin phosphate key intermediate, wherein the crystallization solvent is alcohol or an alcohol-water mixture. According to the method disclosed by the invention, the sitagliptin phosphate key intermediate with relatively high purity can be obtained, and the conversion rate of the sitagliptin phosphate key intermediate cannot be influenced when the sitagliptin phosphate key intermediate is recycled, so that the synthesis process cost of sitagliptin phosphate is effectively reduced.

Description

technical field [0001] The invention relates to the technical field of preparation of sitagliptin phosphate, in particular to a method for recovering a key intermediate of sitagliptin phosphate. Background technique [0002] 4-oxo-4-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7 having the structure of formula I -(8H)-yl}-1-(2,4,5-trifluorophenyl)butan-2-one is the key intermediate of sitagliptin phosphate, and its process cost directly affects the price of API. [0003] [0004] At present, there are many ways to prepare sitagliptin phosphate by using the above-mentioned sitagliptin phosphate key intermediate, wherein the use of phosphate sitagliptin transaminase to convert the above-mentioned sitagliptin phosphate key intermediate into sitagliptin is a Efficient conversion method. However, this reaction is a reversible reaction. After the reaction is completed, some of the key intermediates of sitagliptin phosphate still do not participate in the re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 钱武董登峰王玲玲张秋萍徐诗谣盛力沈大冬
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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