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Novel method for synthesizing sitagliptin

A technology of sitagliptin and its compound, which is applied in the field of synthesizing sitagliptin, can solve the problems of high cost, high price, unfavorable industrial production, etc., and achieve the effects of low environmental pollution, low cost and simple operation

Active Publication Date: 2012-10-31
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In several methods for preparing sitagliptin described above, without exception, chiral precursors, chiral auxiliary agents or expensive chiral catalysts are used, and the cost is too high, which is not conducive to industrial production

Method used

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  • Novel method for synthesizing sitagliptin
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  • Novel method for synthesizing sitagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1: Synthesis of 3-oxo-4-(2,4,5-trifluorophenyl) benzyl butyrate

[0061] At room temperature, add 5-[1-hydroxy-2-(2,4,5-trifluorophenyl)ethylene]-2,2-dimethyl-1,3-di Oxane-4,6-dione (31.6 g), toluene (200 mL) and benzyl alcohol (10.8 g). When the system is uniformly mixed, heat it up and stir and react for 5-6 hours under reflux. After the reaction was completed, the system was cooled to room temperature, 100 mL of water was added, and liquid separation was performed. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 29 g of off-white solid with a yield of 90%. 1 H NMR(400MHz, CDCl 3 ) δ 3.61 (s, 2H), 3.84 (s, 2H), 5.21 (s, 2H), 6.94-6.98 (m, 2H), 7.37-7.41 (m, 5H).

Embodiment 2

[0062] Example 2: Synthesis of 3-amino-4-(2,4,5-trifluorophenyl)-2-butenoic acid benzyl ester

[0063] At room temperature, 3-oxo-4-(2,4,5-trifluorophenyl) benzyl butyrate (29 g), acetonitrile (200 mL), and ammonium acetate (35 g) were sequentially added to the eggplant-shaped flask. When the system is uniformly mixed, heat it up and stir and react for 5-6 hours under reflux. After the reaction was completed, the system was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, then 200 mL of ethyl acetate and 100 mL of water were added for separation, the organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Off-white solid 26g, yield 90%. 1 H NMR (400MHz, DMSO-d6) δ 3.45 (s, 2H), 4.24 (s, 1H), 4.99 (s, 2H), 7.22 (b, 1H), 7.29-7.36 (m, 5H), 7.50- 7.56 (m, 2H), 7.80 (b, 1H).

Embodiment 3

[0064] Example 3: Synthesis of 3-amino-4-(2,4,5-trifluorophenyl) benzyl butyrate

[0065] At room temperature, add 3-amino-4-(2,4,5-trifluorophenyl)-2-butenoic acid benzyl ester (32g), THF (300mL) and tert-butylamine borane (8.7 g). When the system is uniformly mixed, cool down to 0-5°C. At 0-5°C, slowly drop a pre-prepared solution of concentrated sulfuric acid (20g) in isopropanol (60mL) into the system. After the addition is completed, it is naturally warmed to room temperature, and the reaction is stirred for about 8 hours. After the reaction is complete, add 200 mL of water, adjust the pH to 8-9 with 2N NaOH aqueous solution, concentrate under reduced pressure to remove the organic solvent, then add 300 mL of ethyl acetate and 200 mL of water, separate the layers, wash the organic phase with 200 mL of saturated brine, and anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure to obtain 28 g of pale yellow oil with a yield of 87%. 1 H NMR(400MHz, CDCl...

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Abstract

The invention discloses a novel method for synthesizing sitagliptin. The method has the advantages of low cost, simplicity in operation, low environmental pollution, high yield and purity of product and the like, and is particularly applicable to industrial production.

Description

Technical field [0001] The present invention relates to a new method for synthesizing sitagliptin (X). [0002] Background technique [0003] Sitagliptin phosphate monohydrate is the first dipeptidyl peptidase-IV (DDP-4) approved by the U.S. Food and Drug Administration (FDA) for the treatment of type II diabetes in October 2006 Inhibitor drugs. The drug was developed by Merck & Co., Inc. under the trade name Januvia. Chinese name: 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3 -(Trifluoromethyl)-1,2,4-triazole [4,3-a]pyrazole phosphoric acid monohydrate; English chemical name: 7-[(3R)-3-Amino-1-oxo- 4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine monophosphate monohydrate. Clinical studies have shown that sitagliptin phosphate as a single-agent treatment of type II diabetes patients can significantly reduce the level of glycosylated hemoglobin (HbA1c). When used in combination with metformin or...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C229/34C07C227/34C07C227/08C07C227/16
Inventor 竺伟樊钱永阮洪亮
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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