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Method for synthesizing dipeptide with glutamic acid as first amino acid residue

A glutamic acid and amino acid technology, applied in the direction of peptides, etc., can solve the problems of restricted application, inability to crystallize the product, and low total yield, and achieve the effects of facilitating industrial scale production, shortening the process flow, and simplifying the synthesis steps

Inactive Publication Date: 2014-11-19
SICHUAN TONGSHENG AMINO ACID CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main report of the synthetic route is that Z-Glu (Obzl) is used as the starting material to activate the terminal carboxyl group for peptide grafting. However, the active ester obtained from this starting material cannot be obtained as a solid, and the product after peptide grafting cannot be crystallized.
Then further synthesize the target product (Shiba, T.; Kaneko, T.Bulletin of the Chemical Society of Japan, 1960, vol.33, p.1721–1730), the target product obtained is difficult to extract, and its application in medicine is restricted. certain restrictions
Another kind of synthetic technique is also activated with Z-Glu (Obzl) as a raw material, and the reaction substrate is bisbenzyl glutamate hydrochloride or its p-toluenesulfonate to react, but its synthetic steps are too long, and the total Low yield, not suitable for industrial production
Another process is the synthesis of solid-phase peptides. Solid-phase peptide synthesis is mainly for long peptides, and the production volume is also small, and the cost of industrialization is too high.
[0003] The above-mentioned synthetic processes all restrict the application of this product in practice, so it is necessary to seek a more convenient, feasible, well-operated, environmentally friendly, and lower-cost industrial production process

Method used

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  • Method for synthesizing dipeptide with glutamic acid as first amino acid residue
  • Method for synthesizing dipeptide with glutamic acid as first amino acid residue
  • Method for synthesizing dipeptide with glutamic acid as first amino acid residue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Add 1000L water and 200KG 5-methyl glutamate to a 2000L reaction tank, and add sodium carbonate in portions to adjust the pH value until the raw materials are dissolved, and the pH value should be between 8-9. Add the protective reagent Z-OSU at 0-10°C and react for about 10 hours. During the reaction, TLC monitors the reaction. After the reaction of 5 methyl glutamate is over 95%, adjust the pH to 2-3 with 6N hydrochloric acid solution, and add 600L ethyl acetate Ester extraction, separate the organic layer, TLC monitors the extraction of the product in the water, 25 kg of anhydrous sodium sulfate is dried for 6 hours, filtered and concentrated to obtain 330 kg of solid benzyloxycarbonylglutamic acid 5-methyl ester Z-Glu (OMe), HPLC: 98.32%.

Embodiment 2

[0020] Add 2000L of methylene chloride in a 3000L reaction tank, add 330 kg of benzyloxycarbonylglutamic acid 5 methyl ester Z-Glu (OMe), then add 154.4 kg of N-hydroxysuccinimide HOSU, add 276.5 kg Kilograms of dicyclohexylcarbodiimide DCC, react at 10-25 degrees for 8 hours, wait for Z-Glu (OMe) to react to more than 95%, filter and concentrate to obtain benzyloxycarbonyl glutamic acid 5 methyl ester 1 succinimide ester Z -Glu(OMe)-OSU white solid 381.5KG, HPLC: 97.1%.

Embodiment 3

[0022] Add 1140L water in the reaction tank of 2000L, add 138.8 kilograms of glutamic acid, add 200 kilograms of sodium carbonate, 114 kilograms of tetrahydrofuran, add 5 methyl benzyloxycarbonyl glutamic acid 1 succinimide ester Z-Glu (OMe )-OSU solid 381.5 kg, the temperature is controlled at 25-30 degrees for 3-5 hours, TLC confirms that the Z-Glu(OMe)-OSU reaction is above 98%, add 38L of 10N sodium hydroxide solution, and react at 40-45 degrees After 5-6 hours, TLC monitored the reaction, added 6N hydrochloric acid to adjust the pH value to 2-3, and precipitated a solid to obtain (full Chinese chemical name) benzyloxycarbonyl glutamyl glutamic acid, centrifuge, and dry to obtain 335KG.

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Abstract

The invention discloses a method for synthesizing dipeptide with glutamic acid as the first amino acid residue. The method comprises the following steps: protecting the amino group of glutamic acid-5 methyl ester serving as an initial raw material by using carbobenzoxy; reacting with dicyclohexyl carbodiimide and N-hydroxy succinimide to prepare a high-purity midbody; further reacting with another group of amino acid under the alkali condition to obtain protected dipeptide; finally hydrogenating to obtain high-purity dipeptide which takes glutamic acid as the first amino acid residue. The method is environment-friendly, simple to operate, nearly free of waste discharge and beneficial to industrial production.

Description

technical field [0001] The invention relates to a process for synthesizing 5 methyl benzyloxycarbonyl glutamate 1 succinimide ester and further synthesizing a dipeptide with glutamic acid as the first amino acid residue, belonging to the technical field of chemical synthesis. Background technique [0002] Glutamic acid dipeptide is not only an important chemical raw material, but also widely used in the synthesis of drug carriers, peptides, and medical biomaterials. For example: glutamyl tryptophan can be directly used in medicines, and it is a broad-spectrum immune regulation compound (for example: SCV-07); its sodium salt in another configuration is used in the field of polypeptide drug positioning release preparations (patent ZL 2011 10347965.4); glutamyl glutamic acid dipeptide can also be used for the synthesis of anticoagulant drug bivalirudin (Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe -Glu-Glu-I le-Pro-Glu-Glu-Tyr-Leu); glutamyl threonine can also be used for t...

Claims

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Application Information

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IPC IPC(8): C07K5/072C07K1/06
Inventor 李德勇彭秀明陈书娟陈勇苏先兰
Owner SICHUAN TONGSHENG AMINO ACID CO LTD
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