Method for preparing Alpha-methyl-Alpha, Alpha-disubstituted-Alpha-aminophenol and derivatives thereof

Abstract

The invention discloses a method for preparing an Alpha-methyl-Alpha, Alpha-disubstituted-Alpha-aminophenol and derivatives thereof, comprising the following steps of: a) synthesizing S1/R1: leading proline to react with o-chlorobenzyl chloride; b) synthesizing S2/R2: leading methylene dichloride solution of S1/R1 to react with phosphorus trichloride and 2-aminobenzophenone; c) synthesizing S3/R3: leading S2/R2 and alanine to react with nickelous nitrate hexahydrate; d) synthesizing S4/R4: leading the redistilled tetrahydrofuran to react with sodium iodide, sodium hydride and RX/RX; e) synthesizing S5/R5: leading the methanol solution of S4/R4 to react with hydrochloric acid and concentrated ammonia liquor; and f) synthesizing S6/R6: leading S5/R5 to react with anhydrous sodium carbonate and Fmoc-Osu. The invention uses easily obtained raw materials with low price to obtain the Alpha-methyl-Alpha, Alpha-disubstituted-Alpha-aminophenol and derivatives thereof with extremely high optical activity by a normal six-step organic chemistry method. The method has moderate reaction condition and is easy for operation and amplification.

Description

technical field [0001] The present invention relates to a preparation method of α-methyl-α,α-disubstituted-α-amino acid and derivatives thereof, in particular to an α-methyl-α,α-disubstituted-α-amino acid and its derivatives Methods of Organic Synthesis of Derivatives. Background technique [0002] Unnatural amino acids are amino acids encoded by non-protein genes, and have important applications in frontier biotechnology research such as genomics and proteomics. For example, α-unnatural amino acids have been widely used in the study of proteins, nucleosides and nucleic acids: they can limit the flexibility of polypeptide conformation, provide deoxyribonucleic acid or ribonucleic acid molecules with stable secondary structure, enhance the ability of polypeptides to enzymatic β-unnatural amino acids are precursors of β-lactams and key components of many potential enzyme inhibitors, and have quite interesting pharmacological activities. β-unnatural amino acids have become in...

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Problems solved by technology

[0006] In the above method of synthesizing optically pure α-methyl-α, α-disubstituted-α-amino acids, there are generally the following problems: 1) the synthesis steps of cyclic chiral template molecules are relatively long, and some different materials need to be used. 2) Bislactam ethers, oxazolidinones and imidazolinones, diphenylazinones, etc. Enolization reactions of cyclic chiral template molecules are usually carried out at very low temperatures using strong bases (such as n-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazide); For the enolization of cyclic chiral template molecules such as diketopiperazine, azinone, and pyrazine, although the above-mentioned strong base is not required, it is necessary to use a chiral phase transfer catalyst or a noble metal catalyst such as Pd. α-Alkylation

3) When using the above-mentioned cyclic chiral template molecule to synthesize α-methyl-α, α-disubstituted-α-amino acid, sometimes the optical purity of the obtained product is low

[0007] These above-mentioned problems prevent the use of cyclic chiral template molecules for the large-scale preparation of optically pure α-methyl-α,α-disubstituted-α-amino acids

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