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A kind of chiral resolution method of sitagliptin intermediate

A technology for splitting reagents and compounds, which is applied in the field of chiral splitting of sitagliptin intermediates, and can solve problems such as difficult salt formation, unsatisfactory splitting effect, and poor salt-forming effect of R-camphorsulfonic acid. , to achieve the effect of stable process, recyclable solvent and easy operation

Active Publication Date: 2016-04-27
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in alcohol solvents, the separation effect of it and the resolution reagent is not very satisfactory, such as R-mandelic acid and its difficult to form a salt, L-tartaric acid and R-camphorsulfonic acid are not effective in forming a salt, and D-diphenyl Methyl tartaric acid and D-di-p-toluic acid tartaric acid can form salts, but the separation effect is not ideal

Method used

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  • A kind of chiral resolution method of sitagliptin intermediate
  • A kind of chiral resolution method of sitagliptin intermediate
  • A kind of chiral resolution method of sitagliptin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Example 1: Preparation of compound (2)

[0026] 50 g (263 mmol) of 2,4,5-trifluorophenylacetic acid, 42 g of Meldrum's acid were added to 125 ml of acetonitrile, 2.6 g of DMAP and 94 ml of N,N-diisopropylethylamine were added with stirring, and the mixture was stirred to clear. 36ml of pivaloyl chloride was added dropwise at room temperature. After the addition, the temperature was raised to 50°C for reaction for 2 hours, cooled to 0°C, poured into 300ml of 1N hydrochloric acid solution, stirred for 30 minutes, and filtered. The filter cake was vacuum dried at 40°C to obtain 65 g of yellow solid. Add 65g of the yellow solid to 450ml of acetonitrile, add 23g of benzyl alcohol at room temperature, heat to reflux and react for 2 hours, then add 80g of ammonium acetate to continue the reaction for 2 hours, cool to 45°C, distill off the acetonitrile under reduced pressure, and then add ethyl acetate 500ml, water 300ml, saturated sodium carbonate 300ml, stirred for 15 minutes, ...

Embodiment 2

[0028] Example 2: Preparation of compound (1) resolving salt

[0029] 32.3g (100mmol) of benzyl 3-amino-4-(2,4,5-trifluorophenyl)butyrate was dissolved in 600ml of acetone, and 38.6g of D-di-p-toluoyltartaric acid was added in batches at room temperature ( 100mmol), stirred for 30 minutes, a large amount of solid precipitated, and then heated to reflux and stirred for 1 hour. Cool to room temperature and stir for 2 hours, filter, and directly beat the filter cake.

[0030] The filter cake obtained above was added to 400ml of acetone, heated to reflux and stirred for 1 hour. Cool to room temperature and stir for 2 hours, filter, add the obtained filter cake to 300ml of acetone, heat to reflux and stir for 1 hour. The temperature was lowered to room temperature and stirred for 2 hours, filtered, and dried under vacuum at 40°C to obtain 22 g (31 mmol) of D-di-p-toluoyl tartrate of compound (1) with a yield of 31%. Sampling and testing showed that the ee value reached more than 99%,...

Embodiment 3

[0031] Example 3: Preparation of compound (1) resolving salt

[0032] 32.3g (100mmol) of benzyl 3-amino-4-(2,4,5-trifluorophenyl)butyrate was dissolved in 600ml of acetone, and 35.8g (100mmol) of D-xyltoyltartaric acid was added in batches at room temperature. ), stirred for 30 minutes, a large amount of solids precipitated, and then heated to reflux and stirred for 1 hour. Cool to room temperature and stir for 2 hours, filter, and directly beat the filter cake.

[0033] The filter cake obtained above was added to 400ml of acetone, heated to reflux and stirred for 1 hour. Cool to room temperature and stir for 2 hours, filter, add the obtained filter cake to 300ml of acetone, heat to reflux and stir for 1 hour. The temperature was lowered to room temperature and stirred for 2 hours, filtered, and dried under vacuum at 40°C to obtain 17.7 g (26 mmol) of D-dyltoyl tartrate of compound (1) with a yield of 26%. Sampling and testing showed that the ee value reached more than 99% and t...

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Abstract

The invention relates to a preparation method of a sitagliptin intermediate compound (R)-3-amino-4-(2,4,5-trifluorobenzene)benzyl butyrate (compound (1)). According to the method, a racemate of the compound (1) form a salt with a resolving agent in a solvent; the salt is precipitated, and the mixture is filtered; the resolved salt is dissociated, such that the compound (1) is obtained. With the method provided by the invention, the compound (1) with high purity and high chirality can be obtained. The method has advantages of stable process and simple operation. The solvent can be recycled and applied. Therefore, the method is suitable for industrialized productions.

Description

Technical field [0001] The present invention mainly relates to a chiral resolution method of sitagliptin intermediate for treating type II diabetes. technical background [0002] Sitagliptin has an inhibitory effect on dipeptidyl peptidase-IV (DPP-4), and can improve the body's own ability to reduce excessive blood sugar levels. It is used to treat type II diabetes. Its structural formula is as follows: [0003] [0004] (R)-β-aminophenylbutyric acid derivatives (compound (3)) are widely used as an important chiral drug intermediate of sitagliptin. In the synthesis of compound (3), most of the compounds are directly obtained by chiral reduction, but the price of chiral catalysts is expensive, which leads to greater pressure on the cost of synthetic drugs. At present, there are many patents using chiral resolution reagents to resolve the method, which greatly reduces the cost. [0005] [0006] The above R represents: an alkyl group having 1 to 6 carbon atoms or a benzyl group. [00...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/34C07C227/34
Inventor 葛建峰颜峰峰
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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