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Method for preparing chiral alpha-fluoro-beta-amino acid derivatives

An amino acid and derivative technology, applied in the field of preparing chiral α-fluoro-β-amino acid derivatives, can solve the problems of poor stereoselectivity, long route and expensive preparation method, and achieve high universality and mild process conditions. Effect

Active Publication Date: 2016-05-11
SHANGHAI UNIV OF ENG SCI
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AI Technical Summary

Problems solved by technology

Currently known synthetic methods include the preparation method of deoxyfluorination of α-hydroxy-β-amino acid esters, but this method has a long route (starting from α-amino acid, more than ten steps of reaction), and the fluorination process is accompanied by rearrangement reactions (T. Yoshinari, F. Gessier, C. Noti, A.K. Beck, D. Seebach, Helv. Chim. Acta 2011, 94, 1908–1942)
In addition, the fluorination of chiral enolate anions has also been used to synthesize such compounds, but the selectivity and yield of this method are often not high, and the preparation method is expensive ((a) P.J.Duggan, M.Johnston, T.L.March, J. Org. Chem. 2010, 75, 7365–7372; (b) V. Peddie, A.D. Abell, Helv. Chim. Acta 2012, 95, 2460–2472)
[0004] Recently, the addition reaction of α-fluoro-β-dicarbonyl compounds and imines under the catalysis of organic bases can achieve good yield and diastereoselectivity, but the subsequent decarboxylation to prepare α-fluoro-β- However, a considerable degree of racemization occurred in the amino acid process, resulting in low stereoselectivity of C-F bond formation (Y.Pan, Y.Zhao, T.Ma, Y.Yang, H.Liu, Z.Jiang, C.-HTan , Chem. Eur. J. 2010, 16, 779–782)
The Reformatsky reaction of chiral imines with ethyl fluorobromoacetate has also been used to construct α-fluoro-β-amino acids, but with poor stereoselectivity (Z.-T.Jing, Y.-G.Huanga, F.-L . Qing, Chin. Chem. Lett. 2011, 22, 919–922)

Method used

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  • Method for preparing chiral alpha-fluoro-beta-amino acid derivatives
  • Method for preparing chiral alpha-fluoro-beta-amino acid derivatives
  • Method for preparing chiral alpha-fluoro-beta-amino acid derivatives

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] At -80°C, LiHMDS (1.0 mL, 1.0 M dissolved in THF) was added dropwise containing methyl fluoroacetate (92 mg, 1.0 mmol), the imine represented by formula (2a) (209 mg, 1 mmol), And in a 3ml anhydrous THF reaction flask, the reaction system is protected by nitrogen. After the addition is complete, continue the low-temperature reaction for 0.5 hours. After the reaction was completed, 4ml of ammonium chloride aqueous solution was added to quench the reaction at low temperature. The reaction solution was transferred to a separatory funnel and extracted with ethyl acetate (10 ml×3). After the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. Using ethyl acetate / petroleum ether (1:2) flash column chromatography, product 3a (265 mg) was obtained with a yield of 88% (265 mg) and a dr of 47:1.

[0030]

[0031] Compound 3 a Characterization data:

[0032]

[0033] Off-white to white crystalline solid, m.p.91.5-92.3℃; 1 HNMR(400M...

Embodiment 2

[0035] At -70℃, LiHMDS (1.4mL, 1.0M dissolved in THF) was added dropwise containing tert-butyl fluoroacetate (187 mg, 1.4 mmol) and the imine represented by formula (2a) (209 mg, 1 mmol) And in a 3ml ether reaction flask, the reaction system is protected by nitrogen. After the addition is complete, continue the low-temperature reaction for 0.5 hours. After the reaction was completed, 4ml of ammonium chloride aqueous solution was added to quench the reaction at low temperature. The reaction solution was transferred to a separatory funnel and extracted with ethyl acetate (10 ml×3). After the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. Using ethyl acetate / petroleum ether (1:2) flash column chromatography, the product 3a' (281 mg) was obtained, the yield was 82% (281 mg), and the dr was 37:1.

[0036]

[0037] Characterization data of compound 3a:

[0038]

[0039] Off-white to white crystalline solid, m.p. 83.5-85.3℃; 1 HN...

Embodiment 3

[0041] At -20°C, NaHMDS (2.5 mL, 1.0M dissolved in THF) was added dropwise containing methyl fluoroacetate (184 mg, 2.0 mmol), the imine represented by formula (2b) (223 mg, 1 mmol) and In a 3ml dichloromethane reaction flask, the reaction system was protected with nitrogen. After the addition was completed, the reaction at low temperature was continued for 0.5 hours, and the reaction was quenched by adding 4 ml of ammonium chloride aqueous solution. The reaction solution was then transferred to a separatory funnel, and extracted with ethyl acetate (10 ml×3). After the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. Using ethyl acetate / petroleum ether (1:2) flash column chromatography, product 3b was obtained with a yield of 80% (252 mg) and a dr of 15:1.

[0042]

[0043] Characterization data of compound 3b

[0044]

[0045] Off-white to white crystalline solid, m.p. 94.9-95.5℃; 1 HNMR(400MHz, CDCl 3 )δ7.80–6.24(m,4H), 5.1...

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Abstract

The invention relates to a method for preparing chiral alpha-fluoro-beta-amino acid derivatives. In an organic solvent, chiral (Rs)-N-(tert-butylsulfinyl)imine, alkyl fluoroacetate and an alkali undergo a reaction at a temperature of -90 to 30 DEG C for 0.5-5h to produce chiral alpha-fluoro-beta-amino acid. Compared with the prior art, the method utilizes alkyl fluoroacetate as an initial raw material and produces the chiral alpha-fluoro-beta-amino acid through an addition reaction of the chiral alpha-fluoro-beta-amino acid and the chiral imine. The method has high efficiency and high universality and is simple. The method utilizes easily available and cheap raw materials, has mild technical conditions and high efficiency and can produce high-optical purity alpha-fluoro-beta-amino acid. The chiral alpha-fluoro-beta-amino acid is a latent bioactive molecule synthesis building block and can be used in the fields of asymmetric syntheses and medicine research and development.

Description

Technical field [0001] The invention relates to a method for preparing organic synthesis intermediates, in particular to a method for preparing chiral α-fluoro-β-amino acid derivatives. Background technique [0002] β-amino acid is the closest to α-amino acid in structure, and β-peptide formed by β-amino acid can not only form a stable secondary structure, but also has better stability to peptide hydrolase (D. Seebach, JL Matthews, Chem. Commun. 1997, 2015-2022). Therefore, the synthesis of fluorinated β-amino acids and corresponding fluorinated β-peptides has been widely used in the development of medicine and bioactive molecules (Enantioselective Synthesis of β-Amino Acids, 2nded. (Eds.: E. Juaristi, VASoloshonok) ), Wiley, New York, 2005). [0003] Because it involves the construction of a chiral sp3 carbon-fluorine bond, α-fluoro-β-amino acids are very difficult to synthesize. The currently known synthetic methods include deoxyfluorination of α-hydroxy-β-amino acid esters, b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C313/06
Inventor 李亚黄海吉尚华奇李洪森任新锋
Owner SHANGHAI UNIV OF ENG SCI
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