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A kind of preparation method of sitagliptin intermediate

A reaction time, amino acid technology, applied in the preparation of organic compounds, chemical instruments and methods, preparation of carbamate derivatives, etc., can solve the problems of reducing atom economy, serious environmental pollution, unavailability, etc., and achieve good industrial application. and economic value, high yield and low cost

Active Publication Date: 2015-08-05
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] The raw materials of this synthetic route are cheap, and the cost is relatively low, but the other half of the S configuration after splitting the racemate cannot be used, thereby reducing the atom economy of the reaction. In addition, the reaction uses toxic and harmful reagent dichlorohydrin Sulfone, serious environmental pollution, and highly toxic and explosive reagent diazomethane, dangerous to operate, so that the application of this synthetic route is limited

Method used

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  • A kind of preparation method of sitagliptin intermediate
  • A kind of preparation method of sitagliptin intermediate
  • A kind of preparation method of sitagliptin intermediate

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0058] The preparation of embodiment 1 compound enamine 3

[0059] 3.0 g of Compound 2 was dissolved in methanol, 4.12 g of R-(+)-α-phenethylamine was added, and the reaction was stirred at room temperature for 24 h. Concentrate under reduced pressure to remove methanol, add a small amount of water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 3.92 g of colorless oil 3 with a yield of 92%.

Embodiment 2

[0060] The preparation of embodiment 2 compound enamine 3

[0061] 3.0 g of compound 2 was dissolved in methanol, 4 g of D-(-)-phenylglycinol was added, and the reaction was stirred at room temperature for 24 h. Concentrate under reduced pressure to remove methanol, add a small amount of water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 4.0 g of a colorless oil with a yield of 90%.

Embodiment 3

[0062] The preparation of embodiment 3 compound 4

[0063] Add 2.4 g of sodium cyanoborohydride into 30 mL of tetrahydrofuran, then add 24 mL of acetic acid, add 3.0 g of compound 3 prepared in Example 1 under ice-cooling, slowly warm to room temperature, and stir overnight. Adjust the pH value to 7.0 with saturated sodium carbonate solution, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (petroleum ether-ethyl acetate, volume ratio 2:1) to obtain Colorless oil (5) 2.51g, yield 83%.

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Abstract

The invention discloses a preparation method of a sitagliptin intermediate represented by formula 1. The preparation method comprises the following steps: step A, carrying out a reaction of beta-ketonic ester 2 with a chiral amine to obtain a chiral enamine 3, wherein the chiral amine is R(+)-alpha-phenylethylamine or D-(-)-phenylglycinol; step B, reducing the chiral enamine 3 to obtain a compound 4; step C, carrying out catalytic hydrogenation of the compound 4 to remove a chiral auxiliary group, and thus obtaining a compound 5; step D, protecting amino of the compound 5 by Boc to obtain a compound 6; and step E, hydrolyzing the compound 6 to obtain beta-amino acid 1. The method has the advantages of cheap and easily obtained chiral raw materials, short reaction route, simple operation, mild reaction conditions, no special requirements on equipment, high yield, low cost and small environment protection pressure, and has relatively good industrial application and economic value.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a method for preparing an intermediate β-amino acid (shown in formula 1) of the antidiabetic drug sitagliptin; [0002] Background technique [0003] Sitagliptin (sitagliptin) is a new anti-type 2 diabetes drug developed by Merck, chemical name: (3R)-3-amino-1-[3-(trifluoromethyl)-5, 6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1 - Ketone, the structural formula is as follows: [0004] [0005] Sitagliptin is mainly synthesized from two fragments of chiral β-amino acid and piperazine derivative, as shown below, in which chiral β-amino acid is an important intermediate of sitagliptin. About the synthesis of sitagliptin The focus is on the synthesis of chiral β-amino acids. [0006] [0007] The current literature reports that the synthesis method of this chiral β-amino acid mainly contains the following types: [0008] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/22C07C269/06
Inventor 张兴贤吕承林孙鑫哲沈方亮
Owner ZHEJIANG UNIV OF TECH
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