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Fast peptide-synthesizing process in solution

A technology for synthesizing peptides and solutions, which is applied in the field of rapid solution synthesis of peptides, can solve the problems of ineffective extraction and incomplete purification in the aqueous phase, and achieve the effect of efficient removal

Inactive Publication Date: 2003-02-26
MERCK SHARP & DOHME BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this procedure has been found to result in in many cases intermittent incomplete purification due to the hydrophobicity of the compound being scavenged (the inherent hydrophobicity of the aminoacyl moiety of the carboxyl component is enhanced by the amino protecting group still present).
Therefore, aqueous phase extraction is not very effective

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1B

[0033] Embodiment 1Boc-Gly-Phe-Asp (O t Bu)-Ser( t Bu)-O t Bu

[0034] The first cycle: 4.34g H-Ser ( t Bu)-O t In a stirred solution of Bu in a mixture of ethyl acetate and dichloromethane, 3.24 g of 1-hydroxybenzotriazole, 7.76 g of Z-Asp(O t Bu)-OH, 4.20 g 1-(3'-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.42 ml 4-methylmorpholine. The resulting solution was stirred until the reaction was complete, after which 1.21 ml of 4-methylmorpholine and 3.51 g of β-alanine benzyl ester p-toluenesulfonate were added. The mixture was stirred for another 30 min and washed with 5% Na 2 CO 3 / 10% NaCl, 5% KHSO 4 / 10% NaCl and 5% Na 2 CO 3 / 10% NaCl extraction.

[0035] In the presence of palladium on activated carbon, the protected dipeptide Z-Asp(O t Bu)-Ser( t Bu)-O t The organic layer of Bu was subjected to catalytic hydrogenolysis. After the reaction is complete, add 5% Na 2 CO 3 / 10% NaCl and filter the resulting suspension. The residue was washed wi...

Embodiment 2

[0041] Embodiment 2H-His-Trp-Ser(tBu)-Tyr( t Bu)-D-Leu-Leu-Orn(Boc)-Pro-O t Bu

[0042] The first cycle: 1300gH-Pro-O at 20°C t To a stirred solution of Bu.HCl in ethyl acetate, 1014 g of 1-hydroxybenzotriazole, 2756 g of Z-Orn(Boc)-OH, 1378 g of 1-(3'-dimethylaminopropyl)-3-ethane Carbodiimide hydrochloride and 1495ml 4-methylmorpholine. The resulting solution was stirred until the reaction was complete, after which 377 ml of 4-methylmorpholine and 1105 g of β-alanine benzyl ester p-toluenesulfonate were added. The mixture was stirred for another 30 min and washed with 5% Na 2 CO 3 / 10% NaCl, 5% KHSO 4 / 10% NaCl and 5% Na 2 CO 3 / 10% NaCl extraction.

[0043] In the presence of palladium on activated carbon, for the protected dipeptide Z-Orn(Boc)-Pro-O t The organic layer of Bu was subjected to catalytic hydrogenolysis. After the reaction is complete, add 5% Na 2 CO 3 / 10% NaCl and filter the resulting suspension. The residue was washed with ethyl acetate and wa...

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PUM

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Abstract

The present invention relates to a process for rapid solution synthesis of a peptide, the process comprising repetitive cycles of steps (a)-(d): (a) a coupling step, using an excess of an activated carboxylic component to acylate an amino component, (b) a quenching step in which a scavenger is used to remove residual activated carboxylic functions, wherein the scavenger may also be used for deprotection of the growing peptide, (c) one or more aqueous extractions and optionally, (d) a separate deprotection step, followed by one or more aqueous extractions, characterised in that the process comprises at least one step (b), referred to as step (b'), in which an amine or a thiol comprising a free anion or a latent anion is used as a scavenger of residual activated carboxylic functions. During the process of this invention the growing peptide need not be isolated until the final peptide sequence has been obtained. This highly efficient process is useful for the production of oligo- and polypeptides of high purity.

Description

technical field [0001] The present invention relates to a novel and versatile method for rapid solution synthesis of peptides in which the growing peptide does not need to be isolated until assembly of the desired sequence is complete. Background technique [0002] Peptides are synthesized on solid supports or in solution. In both methods, the coupling and deprotection steps alternate repeatedly and can be separated by batch purifications. In solid phase methods, sequences are fully assembled and attached to a solid support before final cleavage from the support. Excess reagents and by-products were removed by filtration. Solid-phase synthesis clearly has the advantage of being more or less versatile and easy to automate. However, this method also has serious drawbacks. For example, reactions are diffusion controlled and often very slow under the heterogeneous conditions applied; relatively large excesses of reagents are required to avoid missing sequences. Furthermore,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/08C07K1/02C07K2/00C07K7/06
CPCC07K1/02
Inventor I·F·艾根P·B·W·坦科特纳尔C·A·G·哈斯努特
Owner MERCK SHARP & DOHME BV
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