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Production method of N-tert-butoxycarbonyl-L-leucyl-L-methyl phenylalanine

A technology of phenylalanine methyl ester and tert-butoxycarbonyl, applied in the field of continuous production of N-tert-butoxycarbonyl-L-leucyl-L-phenylalanine methyl ester, can solve the problem of long reaction time, Low yield, inconvenient storage of activated esters and need to be used as soon as possible to achieve the effects of shortened reaction time, high material utilization, easy to carry and mobile production

Inactive Publication Date: 2019-05-31
湖南华腾制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In summary, at present, the production of N-Boc-L-Leu-L-Phe-OMe is usually carried out in a tank reactor, using a batch process, which requires strict control of the feeding sequence, longer reaction time, and a reaction temperature usually Below 25°C, and nitrogen protection is required, the yield is low, and intermediate products such as activated esters are inconvenient to store and should be used as soon as possible

Method used

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  • Production method of N-tert-butoxycarbonyl-L-leucyl-L-methyl phenylalanine
  • Production method of N-tert-butoxycarbonyl-L-leucyl-L-methyl phenylalanine
  • Production method of N-tert-butoxycarbonyl-L-leucyl-L-methyl phenylalanine

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Embodiment 1

[0045] Two Series II advection pumps (Scientific Systems, Inc.) were used to control the output of HATU solution and N-Boc-L-Leu solution, so that both HATU and N-Boc-L-Leu were simultaneously pumped into microreactor 1 at 1ml / min , the residence time of the fluid in the microreactor 1 is 0.5min, the molar ratio of HATU to N-Boc-L-Leu is 1.05:1, the temperature of the microreactor 1 is controlled by a constant temperature water bath to be 50°C, and the three-way valve G from The concentration of activated ester produced by bypass test was 1.575 mol / L. The activated ester flowing out of the outlet of microreactor 1 and the L-Phe-OMe HCl controlled by the Series II advection pump (Scientific Systems, Inc.) at an output flow rate of 1ml / min were simultaneously pumped into microreactor 2, and the microreactor The residence time of the fluid in 2 is 2.5min, the molar ratio of N-Boc-L-Leu to L-Phe-OMe HCl is 1.05:1, and the temperature of microreactor 2 is controlled by a constant t...

Embodiment 2

[0048]The first microreactor and the second microreactor reaction temperature are 60 ℃, all the other conditions are identical with embodiment 1. Through the three-way valve G from the bypass test to produce the concentration of activated ester is 1.575 mol / L. Implementation results: The concentration of activated esters produced by the bypass test through the three-way valve G is 1.575 mol / L. In collection bottle H: L-Phe-OMe·HCl was completely converted, and the yield of the product N-tert-butoxycarbonyl-L-leucyl-L-phenylalanine methyl ester was 99.2%.

Embodiment 3

[0050] The first microreactor and the second microreactor reaction temperature are 40 ℃, all the other conditions are identical with embodiment 1. Implementation results: The concentration of activated esters produced through the three-way valve G from the bypass inspection is 1.55 mol / L. In collection bottle H: L-Phe-OMe·HCl was completely converted, and the yield of the product N-tert-butoxycarbonyl-L-leucyl-L-phenylalanine methyl ester was 98.4%.

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Abstract

The invention relates to a production method of N-tert-butoxycarbonyl-L-leucyl-L-methyl phenylalanine ((N-Boc-L-Leu-L-Phe-OMe). The method includes the following steps that a solution of 2-(7-enzotriazole oxide)-N, N', N'-tetramethylurea hexafluorophosphate (HATU) and a solution of N-tert-butoxycarbonyl-L-leucine (N-Boc-L-Leu) are continuously pumped into a first micro-reactor to produce activatedesters on-line, and then the on-line activated esters and a solution of L-phenylalanine methyl ester hydrochloride (L-Phe-OMe-HCl) are continuously pumped into a second micro-reactor for a peptide formation reaction. The method is used for producing N-tert-butoxycarbonyl-L-leucyl-L-methyl phenylalanine, the L-phenylalanine methyl ester hydrochloride as the raw material is completely converted under optimized conditions, and the yield of the product N-tert-butoxycarbonyl-L-leucyl-L-methyl phenylalanine is more than 99.5%. The method has the advantages that the reaction time is short, consumption of the raw materials is small, the yield is high and the process is continuous.

Description

technical field [0001] The invention relates to a production method of N-tert-butoxycarbonyl-L-leucyl-L-phenylalanine methyl ester, in particular to N-tert-butoxycarbonyl-L-leucyl-L-phenylalanine Process for the continuous production of methyl esters. Background technique [0002] N-tert-butoxycarbonyl-L-leucyl-L-phenylalanine methyl ester (abbreviated as N-Boc-L-Leu-L-Phe-OMe, CAS No.: 5874-73-7), in peptide synthesis It has a wide range of applications in biological and organic aspects, and is also an important intermediate for the synthesis of the proteasome inhibitor carfilzomib. At present, the main synthesis method is to use N-tert-butoxycarbonyl-L-leucine (referred to as N-Boc-L-Leu, CAS number: 13139-15-6) and L-phenylalanine methyl ester hydrochloride ( Abbreviated as L-Phe-OMe·HCl, CAS No.: 7524-50-7) produced by amino acid condensation reaction to produce peptide bonds. [0003] Peptide bond formation is a nucleophilic substitution reaction of an amino group on...

Claims

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Application Information

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IPC IPC(8): C07K5/062C07K1/06C07K1/02
Inventor 陈毅征金艳娟蒋江平许慧张安林
Owner 湖南华腾制药有限公司
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