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Preparation of Sitagliptin

A technology selected from and compound, applied in the direction of organic chemistry, can solve the problems of high price, long hydrogenation reaction time, unsuitable for scale-up production, etc., and achieve the effect of short reaction time and high ee value

Active Publication Date: 2016-02-10
LIANYUNGANG RUNZHONG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the metal rhodium used or iridium, the price of ferrocenyl bisphosphine ligand are all very expensive, and the hydrogenation reaction time is longer, is not suitable for large-scale production

Method used

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  • Preparation of Sitagliptin
  • Preparation of Sitagliptin
  • Preparation of Sitagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The synthesis of embodiment 1 formula IV compound

[0046]

[0047] Add 2,4,5-trifluorophenylacetic acid (5.5kg, 28.93mol), McFarlandic acid (4.62kg, 31.8mol), DMAP (0.283kg, 2.3mol) and acetonitrile (16.5L ). DIEA (11L, 62.2mol) was added dropwise to the above suspension, and then t-BuCOCl (3.92L, 31.8mol) was slowly added dropwise. After the addition, the temperature was kept at 45-50°C for 2-3 hours. After the reaction is finished, there is no need to deal with and continue to the next step of synthesis.

Embodiment 2

[0048] The synthesis of embodiment 2 formula III compound

[0049]

[0050] Add 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine to the previous reaction system (Example 1) Hydrochloride (6.62kg, 29.04mol), then slowly add CF 3COOH (0.66L, 8.69mol), after the dropwise addition, set the reaction temperature to 50-55°C for about 6 hours. After the reaction, no treatment is required to continue the next step of synthesis.

Embodiment 3

[0052] (2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7( Synthesis of 8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (Formula II)

[0053]

[0054] Add ammonium acetate (2kg, 26mol), ammonia water (4L) and methanol (59.4L) respectively in the 200L reaction kettle, this solution is warmed up to 45 ℃, takes 10% volume of previous step reaction solution (Example 2) dropwise added to the above solution. After the dropwise addition, the reaction was maintained at 45° C. for 2.5 hours. Continue to add the remaining 90% of the reaction solution dropwise. After the dropwise addition was completed, the reaction was continued for 3 hours, and then methanol (26.4 L) was added dropwise. After the dropwise addition, the temperature of the system was slowly lowered to 0-5°C. And continue to stir at this temperature for 1 hour, then shake off and filter. Add the filter cake into a 100L reaction kettle, add purified water, stir and make a slurry for 1 ...

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PUM

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Abstract

The invention belongs to the field of medicine synthesis and particularly provides a preparation method for Sitagliptin. According to the method, a cheap metal ruthenium complex and cheap R-BINAP serve as ligands, and the asymmetric hydrogenation reduction of an enamine intermediate is catalyzed, so that R-configuration Sitagliptin can be obtained in a high-selectivity manner; and the reaction time is short, and both the yield of reduction and the ee value of the product are relatively high, so that the method is applicable to industrialized amplified production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of sitagliptin. Background technique [0002] The chemical name of sitagliptin is 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetra Hydrogen-3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyrazine (Formula I) has the following structural formula. Is an oral DPP-IV inhibitor for the treatment of type II diabetes. [0003] [0004] There are various synthesis methods for sitagliptin. The method for synthesizing sitagliptin disclosed in Chinese patent CN200480007313.4 requires multiple steps and multiple post-reaction treatments. [0005] In addition, there is a chiral carbon atom in the R configuration in the molecular formula of sitagliptin, and the chiral purity of the drug directly affects the absorption and curative effect of the drug. Therefore, for chiral drugs, providing a method for preparing a pure single configuration has the advantages of...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 桑光明赵瑞张爱明张喜全夏春光
Owner LIANYUNGANG RUNZHONG PHARMA CO LTD
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