Sitagliptin intermediates as well as preparation method and application of intermediate

A synthesis method and reaction technology, applied in the intermediates of sitagliptin and its preparation and application fields, can solve problems such as expensive, difficult to control product quality, obvious amplification effect, etc.

Inactive Publication Date: 2012-12-26
ZHEJIANG HISOAR PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] 2) The international patent WO 2004087650 publicly reported the synthesis route of sitagliptin from Merck, using a chiral phosphorus ruthenium catalyst to carry out asymmetric catalytic hydrogenation of ketones to construct a chiral secondary alcohol, and then convert the chiral secondary alcohol to It is a chiral secondary amine to achieve the purpose of constructing a chiral amine; in this synthetic route, asymmetric catalytic hydrogenation catalyzed by rhodium is required in the key step. In the process of process amplification, the amplification effect is more obvious, and the quality of the product is difficult to control
[0009] 4) The international patent WO 2007050485 publicly reported the synthesis method of sitagliptin from Merck, using a chiral rhodium catalyst to construct a chiral center by asymmetric catalytic hydrogenation of enamines. The synthesis route is simple and the steps are relatively short , but this method requires the use of expensive catalysts and chiral auxiliary agents, and this method also has an amplification effect in industrialization, resulting in unstable product quality

Method used

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  • Sitagliptin intermediates as well as preparation method and application of intermediate
  • Sitagliptin intermediates as well as preparation method and application of intermediate
  • Sitagliptin intermediates as well as preparation method and application of intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082]

[0083] Under nitrogen protection conditions, magnesium powder (2.4g, 99mmol) was added to a 250mL three-neck flask equipped with a thermometer, a constant pressure dropping funnel and a reflux condenser, 10mL THF was added, a grain of iodine was added, and 0.5g bromoethane was added to initiate the reaction. Add n-butyl chloride (8.4g, 90mmol) dissolved in 60mL THF to maintain reflux. After dripping, the oil bath is refluxed and kept for 4 hours, and the system is cooled to -10°C in an ice-salt bath. Fluorobromobenzene (21.8g, 103.5mmol), the system exothermic, the temperature was controlled below -5°C, after the dropwise addition was completed, the reaction was continued for 10min, and 1.6g of cuprous iodide was added. Then chlorinated propylene oxide III (9.3 g, 0.1 mol) dissolved in 10 mL of tetrahydrofuran was added dropwise to the system, and the reaction was exothermic. After reacting at 0° C. for 5 hours, 70 mL of saturated ammonium chloride aqueous solution ...

Embodiment 2

[0085]

[0086] The product obtained in the previous step was dissolved in 90mL THF, and 4.8g of 50% NaH was slowly added to this system, and the system was heated to 60°C for 5 hours of reaction. Thin-plate chromatography showed that the raw material had reacted completely (thin-plate chromatography conditions: petroleum ether: acetic acid Ethyl ester=10:1), standing to separate layers, extracting the aqueous phase with dichloromethane (30mL×1), combining the organic phases, drying over anhydrous magnesium sulfate, filtering, and removing the solvent from the filtrate to obtain 17g of light yellow oily liquid, two The yield of the first step reaction is 90%.

[0087] 1 H NMR (400MHz, CDCl 3 )δ: 7.12 (dd, J 1 =6Hz,J 2 =9Hz, 1H), 6.93(dd, J 1 =6Hz,J 2 =9Hz, 1H), 3.15(s, 1H), 2.81-2.83(m, 1H), 2.75-2.77(m, 2H).

[0088] ESI-MS: 189 (M + +1).

Embodiment 3

[0090]

[0091] The product obtained in Example 1 was dissolved in 90 mL of THF, and 5.4 g of NaOH in 20 mL of aqueous solution was added to this system. The system was heated to 60°C for 5 hours. Thin-plate chromatography showed that the raw materials were completely reacted (thin-plate chromatography conditions: petroleum ether: ethyl acetate = 10:1), and the layers were allowed to stand, and dichloromethane (30mL×1) was used for the aqueous phase. Extract, combine the organic phases, dry over anhydrous magnesium sulfate, filter, and remove the solvent from the filtrate to obtain 16 g of light yellow oily liquid, and the yield of the two-step reaction is about 85%.

[0092] 1 H NMR (400MHz, CDCl 3 )δ: 7.12 (dd, J 1 =6Hz,J 2 =9Hz, 1H), 6.93(dd, J 1 =6Hz,J 2 =9Hz, 1H), 3.15(s, 1H), 2.81-2.83(m, 1H), 2.75-2.77(m, 2H).

[0093] ESI-MS: 189 (M + +1).

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Abstract

The invention relates to a Sitagliptin intermediates and a preparation method thereof as well as application of the intermediates in a method for preparing the Sitagliptin. According to the invention, epoxy chloropropane which is low in price and easy to obtain is used as a raw material to synthesize intermediates (S)-(2, 4, 5-trifluorophenyl) epoxy propane and (S)-3-hydroxy-4-(2, 4, 5-trifluorophenyl) butyronitrile, thus a chiral center is introduced, the use of various complex chiral reagents are avoided, and the chiral asymmetric catalytic hydrogenation reaction can be avoided; and the preparation method has the advantages of simple synthetic route, environment conservation, low raw material cost, etc.

Description

technical field [0001] The present invention relates to sitagliptin intermediates, their preparation methods, and the application of these intermediates in the preparation of sitagliptin. Background technique [0002] Sitagliptin phosphate (Sitagliptin phosphate) is the first dipeptidyl peptidase-IV (DPP-4) inhibitor approved by the FDA in 2006 for the treatment of type 2 diabetes. It is used alone or in combination with metformin and pioglitazone. Combined use has obvious hypoglycemic effect, and it is safe to take, well tolerated, and has few adverse reactions. Sitagliptin phosphate was developed by Merck, and was approved by the Mexican Ministry of Health on August 8, 2006 for the treatment of type 2 diabetes once a day. The marketed product is Januvia. In the United States, sitagliptin phosphate was approved by the FDA on October 16, 2006. Sitagliptin phosphate has been approved for use in 60 countries around the world, and the revenue in the third quarter of 2007 alon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/36C07C253/16C07C59/56C07C51/08C07D487/04C07D303/08C07D301/26
CPCY02P20/55
Inventor 潘仙华张群辉阮礼波于万盛刘峰邓飞马天华彭锡江王玲燕
Owner ZHEJIANG HISOAR PHARMA
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