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Alpha-n-methylation of amino acids

A technology for amino acids and amino acid side chains, applied in organic chemistry, peptide preparation methods, organic chemistry methods, etc., can solve problems such as complex chromatographic purification steps, inability to penetrate catalyst particles, low yield, etc.

Inactive Publication Date: 2009-10-21
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

First, most methods employ catalytic hydrogenation, which has long been considered unsuitable for solid-phase synthesis because the solid support is practically impermeable to the catalyst particles used in these reactions
In the second aspect, for the use of temporary α N-protecting group, final deprotection step is done by strong acid, it is not suitable for most protecting groups and peptide-resin bonding in modern SPPS (solid phase peptide synthesis)
This is due to the fact that the overall deprotection step in the presence of Arg(Mtr) is accompanied by several severe side reactions which can lead to unacceptably low yields and complicated chromatographic purification steps

Method used

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  • Alpha-n-methylation of amino acids
  • Alpha-n-methylation of amino acids
  • Alpha-n-methylation of amino acids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Step 1 - Dbs Protection:

[0134] 0.01mol H was obtained after Fmoc deprotection 2 N-Arg(Pbf)-Tyr(tBu)-Rink-Ahx-resin, the resin was washed appropriately (2×DMF, 2×CH 2 Cl 2 , 2×DMF) and drained. 0.05 mol Dbs-Cl was dissolved in 150 mL DMF, and 50 mL 1:1 DIEA:toluene was added thereto. This solution was then added to the above resin, which was then stirred for 4 hours. At this point ninhydrin was negative. The resin was then washed (5 x DMF) and suspended in DMF for the next step.

[0135] 2-methylation:

[0136] The following methylating reagent solutions were prepared immediately before use: 300 mL NMP, 80 mL THF, 20 mL formaldehyde solution (0.246 mol), 4 mL acetic acid.

[0137] The resin from step 1 was sucked dry, and then the above methylation reagent solution was added. The resin was then stirred for 15 minutes to form the methylimine. Then weigh 0.1mol (6.2g) NaCNBH 3 , added to the stirred peptide resin in one portion via a powder funnel, with a mini...

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Abstract

The present invention is directed to a method for alpha-N-methylation of amino acids suitable for on-resin methylation, compatible with Fmoc / tBu SPPS, and compatible with amino acids bearing protected or unprotected nucleophilic side-chains, notably Arg(Pbf), Met, Cys, and Trp. The present invention is further directed to a compound of Formula I wherein m, n, X and Y are defined as described herein.

Description

technical field [0001] The present invention relates to α Synthesis of N-methylated amino acids. Background technique [0002] In peptide synthesis, the amide bond α N-methylation is commonly used to eliminate susceptibility to proteolysis, increasing the stability of peptides with minimal structural perturbation. The methylation of amino acids can be traced back to the research of Emil Fischer, who was the first to complete the mono-methylation of α-amino acids (Fischer, E.; Lipschitz, W. Chem. Ber. 1915, 48, 360.) . Fischer's three-step synthetic route includes the following three key steps: temporarily protect the primary α-amino group to retain a single N-H group, carry out α N-methylated to N-CH 3 group replaces the N-H group, deprotecting the temporary protecting group to release the now secondary α N-methylamino acids. Despite differences in chemical details, most of the currently applied α The N-methylation chemistry still employs the same three key steps. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/16C07B51/00C07D307/79C07K1/06C07K1/04
CPCC07C229/14C07C279/14C07K1/1077C07C2103/32C07K1/063C07C323/58C07K5/06095C07C229/26C07K1/04C07D307/79C07C2603/32
Inventor J·A·摩丝J·斯韦斯托克
Owner F HOFFMANN LA ROCHE & CO AG
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