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Preparation method of Sitagliptin midbody of beta-amino acid

A sitagliptin and amino acid technology, applied in the field of preparation of intermediate β-amino acids, can solve the problems of reduced atom economy, unusable, serious environmental pollution, etc., achieve good industrial application and economic value, low cost, The effect of high yield

Inactive Publication Date: 2016-09-28
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0027] 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. 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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  • Preparation method of Sitagliptin midbody of beta-amino acid
  • Preparation method of Sitagliptin midbody of beta-amino acid
  • Preparation method of Sitagliptin midbody of beta-amino acid

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Experimental program
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Effect test

Embodiment 1

[0052] The preparation of embodiment 1 compound 3

[0053] Dissolve 1.74g (10mmol) of compound 2 (2,4,5-trifluorophenylacetaldehyde, the same below) and 1.66g (11mmol) of L-amphetamine alcohol in 50mL of dichloromethane, and add di Magnesium iodide 278mg (1.0mmol), after stirring for 10 minutes, add dropwise 4.0g (12mmol) tributylallyl stannane, react at 20°C, TLC detects that the reaction is over, add Na 2 S 2 o 3 The aqueous solution was used to quench the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain 2.86 g of compound (3), with a yield of 82%.

Embodiment 2

[0054] The preparation of embodiment 2 compound 3

[0055] Dissolve 1.4g (8mmol) of compound 2 and 1.33g (8.8mmol) of L-amphetamine in 40mL of dichloromethane, add 145mg (0.8mmol) of magnesium dibromide at 20°C under nitrogen protection, stir for 10 minutes and then add dropwise 3.2 g (9.6 mmol) tributylallylstannane. React at 20°C, TLC detects the end of the reaction, add Na 2 S 2 o 3 The aqueous solution was used to quench the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain 2.1 g of compound (3) with a yield of 75%.

Embodiment 3

[0056] The preparation of embodiment 3 compound 3

[0057] 3.48 g (20 mmol) of compound 2 and 3.32 g (22 mmol) of L-amphetamine were dissolved in 100 mL of dichloromethane. Magnesium perchlorate 246mg (2.0mmol) was added at 20°C under nitrogen protection. After stirring for 10 minutes, 8.0 g (24 mmol) of tributylallylstannane was added dropwise, reacted at 20° C., and TLC detected that the reaction was completed, and Na 2 S 2 o 3 The aqueous solution was used to quench the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain 4.8 g of compound (3) with a yield of 70%.

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Abstract

The invention discloses a preparation method of a Sitagliptin midbody of beta-amino acid. The method comprises the following steps of 2,4,5-fluorobenzene acetaldehyde 2, L-benzedrine alcohol and tributyl allyl tin alkanes perform asymmetrical allylation reaction under the effect of a catalyst A to obtain a compound 3; the compound 3 is oxidized to remove chiral auxiliary radials to obtain a compound 4; the compound 4 is subjected to amino radial protection to obtain a compound 5; the compound 5 is subjected to double-bond oxidation to obtain beta-aminobutyric acid 1. The method provided by the invention has the advantages that the raw materials are cheap and can be easily obtained; the reaction route is short; the operation is simple and convenient; the reaction conditions are mild; no special requirements exist on the equipment; the yield is high; the selectivity is high; good industrial application and economic values are realized.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for preparing an intermediate β-amino acid of an antidiabetic drug sitagliptin. Background technique [0002] 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: [0003] [0004] Sitagliptin is mainly synthesized from two fragments of chiral β-amino acid and piperazine derivatives, as shown in the following equation, wherein chiral β-amino acid is an important intermediate of sitagliptin, about the synthesis of sitagliptin The work focuses on the synthesis of chiral β-amino acids. [0005] [0006] The current literature reports that the synthesis method of this chiral β-amino acid mainly contains the following types: [0007...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/22
CPCC07C269/06C07B2200/07C07C209/62C07C213/08C07C269/04C07C271/22C07C271/12C07C211/29C07C215/28
Inventor 张兴贤谢晓强
Owner ZHEJIANG UNIV OF TECH
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