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Synthesis of diapin (gly-gly-leu, gly-gly-leu) by chemical method

A chemical acyl chloride method, a technology for synthesizing tripeptides, applied in the direction of peptides, etc., can solve the problems of non-recycling, large environmental pollution, and high cost of waste liquid treatment

Active Publication Date: 2022-02-01
BEIJING SL PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

High raw material and production costs
[0004] In above-mentioned two big classes of methods, raw material all needs to be protected with protecting group, deprotection at last, then prepare and purify with liquid chromatography HPLC, so yield is low, and raw material and production cost are high; A large amount of dichloromethane, DMF, piperidine , TFA cannot be recycled, causing serious environmental pollution and high cost of waste liquid treatment

Method used

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  • Synthesis of diapin (gly-gly-leu, gly-gly-leu) by chemical method
  • Synthesis of diapin (gly-gly-leu, gly-gly-leu) by chemical method
  • Synthesis of diapin (gly-gly-leu, gly-gly-leu) by chemical method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Embodiment one: the preparation of chloroglycyl-leucine (intermediate I)

[0020] Table 1 Preparation of intermediate I material table

[0021]

[0022]

[0023] 1.1. Reaction formula:

[0024]

[0025] 1.2. Operation process:

[0026] In a 200L enamel reaction kettle, add 6.6kg (50.38mol) of L-leucine and 16kg of water, stir and cool down to 10±5°C, add 12.2kg of 5M NaOH dropwise, keep the temperature below 30°C, after dropping, PH≥ 10. The system is basically dissolved, add 21.5kg of toluene, cool to below 0°C, add dropwise the solution of 6.8 (60.18mol) of chloroacetyl chloride, 17.5kg of toluene and 17.8kg of 5M NaOH solution, the temperature is controlled at -10-0°C, Make the pH always ≥ 10, drop the process for 2-3 hours, after the drop is completed, keep warm at 0-5°C for 1 hour; about 20-30 minutes. Measure the pH value once to make the pH ≥ 10. Separate the liquid, wash the toluene layer with 10kg water once, combine the water phase, adjust the pH t...

Embodiment 2

[0027] Example 2: Preparation of dipeptide glycyl-leucine (II)

[0028] Table 2 Preparation of intermediate II material table

[0029]

[0030] Note: Chlorinated dipeptide: concentrated ammonia water (W / W) = 9-10

[0031] 2.1. Reaction formula:

[0032]

[0033] 2.2. Operation process:

[0034] In a 200L enamel reaction kettle, add 90kg of concentrated ammonia water, cool to below 10°C, add 9.8kg (47.23mol) of chlorinated dipeptide under stirring, and control the temperature at 15±5°C for 6 days (the system dissolves on the third day) clear). Concentrate under reduced pressure into a viscous shape, with solid precipitation, suction filtration, wash the solid with 4 kg of water, and beat the solid with 16 kg of absolute ethanol for 2 h; continue to concentrate the mother liquor to about 12 L, add 16 kg of absolute ethanol, stir for 4 h, and filter; combine the solid, Add 10kg of water and stir for 1 hour, then add 32kg of absolute ethanol and stir for 4 hours, filter,...

Embodiment 3

[0035] Example Three: Preparation of Chloroglycyl-Glycyl-Leucine (III)

[0036] Table 3 Preparation of intermediate III material list

[0037]

[0038] 3.1. Reaction formula:

[0039]

[0040]3.2. Operation process:

[0041] In a 200L enamel reaction kettle, add dipeptide G-L 6.16g (32.76mol), water 30kg, stir and cool down to 10±5°C, add 5M NaOH 8.0kg dropwise, keep the temperature below 30°C, after dropping, PH≥10, The system was basically dissolved, and 14.5kg of toluene was added, cooled to below 0°C, and at the same time, 4.45kg (39.32mol) of chloroacetyl chloride, 4.5kg of toluene solution and 11.30kg of 5M NaOH solution were added dropwise, and the temperature was controlled at -10-0°C, so that The pH is always ≥ 10, the dropping process is 2-3 hours, after the drop is completed, the temperature is kept at 0-5°C for 1 hour; about 20-30 minutes. Measure the PH value once to make the PH ≥ 10. Separate the liquid, wash the toluene layer with 8kg water once, combin...

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Abstract

The invention relates to a process for synthesizing Diapin (Gly-Gly-Leu) by a chemical method, which belongs to the field of chemical synthesis, and is characterized in that leucine and chloroacetyl chloride are used as starting materials, and an acylation reaction is first carried out to generate glycyl-leu amino acid chlorinated dipeptide, and then ammonolysis to obtain glycyl-leucine dipeptide; the dipeptide is acylated with chloroacetyl chloride to generate glycyl-glycyl-leucine chlorinated tripeptide, and then Ammonolysis to obtain glycyl-glycyl-leucine tripeptide, the content is greater than 99%, and the yield is greater than 56%. The present invention synthesizes the tripeptide Diapin by chemical acid chloride method, and is applicable to the polypeptide of the general formula (Gly)n-Leu, including its L- and D-configurations. The method has simple experimental steps, easy-to-obtain raw materials, high yield and easy industrial production. Unlike the solid-phase method and liquid-phase method, the protection and deprotection of the group are carried out, followed by cleavage, and then liquid-phase HPLC preparation, which is costly and cumbersome to operate.

Description

Technical field: [0001] The invention relates to a process for chemically synthesizing tripeptide Diapin, which belongs to the field of chemical synthesis. Background technique [0002] Curtius artificially synthesized the first polypeptide more than 100 years ago. In the following 50 years, the method of generating peptide bonds through azido acid and acid chloride was clearly established, but a general way to synthesize polypeptides has not yet been provided. Although the benzyloxycarbonyl group provided by Bergmann and Zervas in 1932 paved the way for peptide synthesis, it was not until 1953 that Vigneaud and colleagues synthesized oxytocin due to the backward sequencing methodology. Undoubtedly, this is the first brilliant achievement in the field of synthetic peptides. Interestingly, in the early 1950s, some progress was made every few years, and the mixed anhydride method, active ester method and coupling reagents succeeded one after another. Now solid-phase and liqu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/083
Inventor 艾海马郭景军张冬平吴彦卓李亚军白福英陈起迅徐明波
Owner BEIJING SL PHARMA