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Preparation method of sitagliptin intermediate

A technology for sitagliptin and an intermediate is applied in the field of preparation of a sitagliptin intermediate for diabetes medicine, can solve problems such as restricting large-scale production, and achieve the effects of improving production efficiency, easy implementation and low price

Active Publication Date: 2017-08-04
JIANGSU HANKUO BIOLOGICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as shown in the previous route 2, the existing (S)-(2,4,5-trifluorophenyl)-3-hydroxy-butyric acid preparation method has many defects, which greatly restricts its large-scale production

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Step 1. Preparation of (S)-(2,4,5-trifluorophenyl)-3-hydroxy-pentanone (compound III):

[0056] Add 298g of acetone, 800g of ethanol, and 115g of L-proline into the reaction flask, stir to dissolve, then slowly cool down to -40~-50°C, add 174.1g of 2,4,5-trifluorophenylacetaldehyde dropwise, about two The reaction was continued for about 8 hours, and the gas chromatography GC monitored that the content of the 2,4,5-trifluorophenylacetaldehyde system was less than 1%. The system was heated to -5°C, and 600ml of water and 700ml of ethyl acetate were added to separate The organic layer was dried by adding magnesium sulfate, and filtered. The obtained filtrate had a GC purity of 94% after subtracting the solvent ethyl acetate, and was directly used in the next reaction.

[0057] Step 2. Preparation of (S)-(2,4,5-trifluorophenyl)-3-tert-butyldimethylsilyloxy-butanone (compound IV):

[0058] Cool the ethyl acetate solution obtained in step 1 to 0°C, add 79.0 g of pyridine, a...

Embodiment 2

[0064] Step 1. Preparation of (S)-(2,4,5-trifluorophenyl)-3-hydroxy-pentanone (compound III):

[0065] Add 298g of acetone, 1000g of ethanol, and 170g of L-proline into the reaction flask, stir to dissolve, then slowly cool down to -40--50°C, add 174.1g of 2,4,5-trifluorophenylacetaldehyde dropwise, about two After hours of dripping, continue to react for about 10 hours. GC monitors that the content of 2,4,5-trifluorophenylacetaldehyde system is less than 1%. The system is heated to -5°C, 600ml of water and 700ml of ethyl acetate are added, and the organic layer is separated , added magnesium sulfate to dry, filtered, and the resulting filtrate had a GC purity of 95% of compound III after deducting the solvent ethyl acetate, and was directly used for the next step reaction.

[0066] Step 2~4.

[0067] Except that the starting reactant was replaced by the product of step 1 of this example, the remaining steps were carried out according to steps 2-4 of example 1.

[0068] Fina...

Embodiment 3

[0070] Add 240g of acetone, 700g of methanol, and 140g of L-proline into the reaction flask, stir to dissolve, then slowly cool down to -45--50°C, add 174.1g of 2,4,5-trifluorophenylacetaldehyde dropwise, about two After hours of dripping, continue to react for about 10 hours. GC monitors that the content of 2,4,5-trifluorophenylacetaldehyde system is less than 1%, and the system is heated to -5°C. Add 500ml of water and 700ml of ethyl acetate, and separate the organic layer , added magnesium sulfate to dry, filtered, and the resulting filtrate had a GC purity of 94% of compound III after deducting the solvent ethyl acetate, and was directly used for the next step reaction.

[0071] Step 2~4.

[0072] Except that the starting reactant was replaced by the product of step 1 of this example, the remaining steps were carried out according to steps 2-4 of example 1.

[0073] Finally, 110 g of off-white crystals were obtained, with a yield of 47% based on 2,4,5-trifluorophenylaceta...

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Abstract

The invention discloses a preparation method of a sitagliptin intermediate, which comprises the following steps: carrying out asymmetric Aldol reaction of raw materials 2,4,5-trifluoro-phenylacetaldehyde and acetone under the induced catalysis of L-proline, and then carrying out hydroxyl group protection, Baeyer-Villiger reaction, deprotection and esterolysis to obtain the intermediate VI. The preparation method has the following advantages: the raw materials are cheap and readily available, the cost is low, few synthesis steps are involved, the reaction condition is mild, the method is environment-friendly, the stereoselectivity is high, and the method can be used for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of a sitagliptin intermediate for diabetes medicine. Background technique [0002] Sitagliptin is an important drug for diabetes. It has clear and significant clinical effect and drug safety. It is one of the blockbuster drugs for the treatment of diabetes at present and in the future. For the synthesis of this important drug, there are mainly The following four routes. [0003] Route 1: [0004] [0005] This route is the earliest preparation route developed by Merck. Because many expensive reagents are used in this route, the reaction conditions are relatively harsh, and the separation of intermediates is difficult. Therefore, this route is not suitable for large-scale production. [0006] Route two: [0007] [0008] Compared with route 1, the raw material cost of this route has been greatly reduced, and the operability ha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/72C07C49/245C07F7/08C07C51/09C07C59/56
CPCC07B2200/07C07C45/72C07C51/09C07F7/081C07F7/0827C07C49/245C07C59/56Y02P20/55
Inventor 潘庆华周熹
Owner JIANGSU HANKUO BIOLOGICAL
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