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Method for recycling 3-(S)-amino-4-(2,4,5-trifluoro-phenyl)-butyrate

A technology of trifluorophenyl and butyrate, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve problems such as difficult large-scale production, complex reaction, environmental pollution, etc. Easy to get, high yield effect

Active Publication Date: 2012-03-28
大道隆达(北京)医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this technology, RS-I is prepared by S-I reaction, and S-I is recycled. Although the production cost of intermediate R-I can be reduced to a certain extent, it is difficult to scale up because of the shortcomings of low yield, environmental pollution, and complex reactions. chemical production

Method used

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  • Method for recycling 3-(S)-amino-4-(2,4,5-trifluoro-phenyl)-butyrate
  • Method for recycling 3-(S)-amino-4-(2,4,5-trifluoro-phenyl)-butyrate

Examples

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Effect test

Embodiment 13

[0019] Example 13-Benzyl imine-4-(2,4,5-trifluorophenyl)-butyric acid methyl ester (S-II, R 1 = Preparation of Me)

[0020] 3-(S)-amino-4-(2,4,5-trifluorophenyl)-butyric acid methyl ester (S-I, R 1 =Me) (24.7g, 0.10mol), benzaldehyde (10.6g, 0.10mol) and methanol (150mL) were placed in a 500mL three-neck reaction flask, heated to reflux at 70-80°C for 4 hours, and detected by TLC. After the reaction was completed, the temperature was lowered to room temperature. The reaction solution can be directly carried out to the next step without treatment.

Embodiment 23

[0021] Example 23-Benzylamino-4-(2,4,5-trifluorophenyl)-butanoic acid methyl ester (S-III, R 1 =Me) preparation method

[0022] The temperature of the reaction solution in Example 1 was lowered to 0 °C, and sodium borohydride (4.6 g, 0.12 mol) was added in batches to control the reaction temperature not to be higher than 5 °C. After the addition was completed, the reaction was continued at room temperature for 5 hours. TLC detection. After the reaction was completed, the temperature was lowered to 0° C., and 10 wt % hydrochloric acid (30 mL) was added dropwise, and the temperature was controlled not to be higher than 5° C. After dropping, keep at 0°C, continue to stir for 30 minutes, and filter under reduced pressure to obtain white solid 3-benzylamino-4-(2,4,5-trifluorophenyl)-butyric acid methyl ester hydrochloride (33.5 g, two-step yield 90%).

Embodiment 33

[0023] Example 33-Amino-4-(2,4,5-trifluorophenyl)-butyric acid methyl ester (RS-I, R 1 =Me) preparation method

[0024] 3-benzylamino-4-(2,4,5-trifluorophenyl)-butyric acid methyl ester hydrochloride (S-III, R 1 =Me) (37.3 g, 0.10 mol), 10 wt% palladium-carbon (0.4 g), triethylamine (10.1 g, 0.10 mol) and methanol (300 mL) were placed in a 1000 mL hydrogenation kettle. Hydrogen was passed under normal pressure, reacted at room temperature for 5 hours, and detected by TLC. After the reaction was completed, the catalyst was filtered off under reduced pressure, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain the sitagliptin intermediate RS-I (23.5 g, yield 95%).

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Abstract

The invention discloses a method for recycling 3-(S)-amino-4-(2,4,5-trifluoro-phenyl)-butyrate. The method comprises the following steps of: condensing the 3-(S)-amino-4-(2,4,5-trifluoro-phenyl)-butyrate and substituted benzaldehyde to obtain 3-substituted benzyl imine-4-(2,4,5-trifluoro-phenyl))-butyrate, and performing reduction reaction to prepare 3-substituted benzyl amino-4-(2,4,5-trifluoro-phenyl))-butyrate; and performing debenzylation protection on the 3-substituted benzyl amino-4-(2,4,5-trifluoro-phenyl))-butyrate serving as an intermediate to obtain the 3-amino-4-(2,4,5-trifluoro-phenyl)-butyrate serving as a racemic sitagliptin intermediate. The method is mild in reaction condition, easy and convenient to operate and high in yield and has a good industrial prospect, and raw materials are readily available.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthetic chemistry and relates to a method for preparing 3-amino-4-(2,4, 5-trifluorophenyl)-butyrate, a method for its recycling. Background technique [0002] Sitagliptin is the first dipeptidyl peptidase-IV (DPP-IV) inhibitor drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of type II diabetes, developed by Merck, Listed in 2006. Sitagliptin improves the ability of diabetic patients to produce insulin by their own pancreatic β cells, and increases the secretion of insulin in the body when blood sugar rises, thereby controlling the blood sugar level of the patient. Clinical studies have shown that sitagliptin is an orally effective drug with good market prospects. It has a significant hypoglycemic effect when used alone or in combination with metformin and pioglitazone. It is safe, well tolerated, and has few adverse reactions. [0003] In the existing synthetic tec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/34C07C227/18
Inventor 张立鹏张高峰赵孝杰陈贵军
Owner 大道隆达(北京)医药科技发展有限公司
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