Preparation method of N-trimethyl silicon ethoxycarbonyl-N-methyl-L/D-leucine

Abstract

The invention relates to a preparation method of N-(trimethylsilyl) ethoxycarbonyl group-N-methyl-L / D-leucine. The preparation method comprises the following steps: adding N-methyl-L / D-leucine hydrochloride, a trimethylsilylethoxycarbonyl protecting group reagent and alkali into a mixed solution of a polar solvent and water, and carrying out a reaction, so as to obtain the N-trimethylsilylethoxycarbonyl-N-methyl-L / D-leucine. According to the preparation method, the N-trimethyl silicon ethoxycarbonyl-N-methyl-L / D-leucine with high chiral purity, high chemical purity and high yield can be obtained, the chiral purity and the chemical purity can reach 99% or above, the yield can reach 60% or above, and the preparation method is simple in process, mild in condition and suitable for being applied to large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis and relates to a preparation method of N-trimethylsilylethoxycarbonyl-N-methyl-L / D-leucine. Background technique [0002] Optically pure N-methylleucine and its derivatives are important components of many biologically active peptide-containing natural products. The N-methyl structure can significantly enhance their biological activity. At the same time, N-methylleucine N-methylleucine and its polypeptide analogs have stronger degradation resistance to proteases, therefore, N-methylleucine and its polypeptide analogs are widely used in the preparation of polypeptide drugs. [0003] In chemical synthesis, it is often necessary to add protection to N-methylleucine to protect its N-methyl structure and carry out subsequent synthesis processes. Therefore, N-methylleucine with protective groups is an ideal building block for many drug development and synthesis units have a huge market deman...

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Problems solved by technology

[0004] CN102329376A discloses ring (phenylalanyl-N-methylleucyl-leucyl-N-methylleucyl-leucyl) and its synthesis method and application, using di-tert-butyl dicarbonate in the scheme Esters as protecting groups through leucine protection, nitrogen methylation, phenylpropionic acid protection, dipeptide tert-butyloxycarbonyl-N-methylleucyl-leucine benzyl ester condensation and tripeptide butyloxycarbonyl Phenylalanyl-N-methyl-leucyl-leucine benzyl ester condensation and other steps, the dipeptide and tripeptide condensation reaction to obtain a protected linear pentapeptide, and the linear pentapeptide is removed from both ends Protecting group, the product is obtained through cyclization reagent ring closure, but in this method, di-tert-butyl dicarbonate (Boc) is used as protecting group, Boc and commonly used protecting group Cbz, Fmoc and Alloc etc. have the ability to acid or basic The disadvantage of being unstable under conditions limits the scope of application

[0005] As a special amino acid protecting group, trimethylsilylethoxycarbonyl is stable under conditions such as acid, most alkalis and noble metal catalysis. Therefore, amino acids protected by trimethylsilylethoxycarbonyl have unique advantages in the synthesis of peptide drugs. However, it is still difficult to economically and efficiently synthesize trimethylsilylethoxycarbonyl-protected amino acids with high chiral purity

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