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Production process of tripeptide-29

A production process and intermediate technology, applied in the production process field of tripeptide-29, can solve the problems of large amount of organic solvent, waste of resources, high price, etc., and achieve the effect of reducing production cost, production cycle and low price

Active Publication Date: 2022-07-05
山东济肽生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the conventional synthesis of collagen tripeptide H-Gly-Pro-Hyp-OH adopts the liquid- Solid-phase synthesis method, the raw material Fmoc-Hyp(tBu)-OH used is relatively expensive, and the self-synthesis process is complicated
In specific analysis, this process route uses solid-phase synthesis, which has the following disadvantages: one is that the raw materials are all amino acids protected by Fmoc, the raw materials are expensive, the production cycle is long, and the discharge of three wastes is large, and in the solid-phase reaction process, raw materials Use at least 2 equivalents or more, which causes a substantial increase in raw material costs and a waste of resources; the second is that solid-phase synthesis must use a matching, custom-made reactor, which has a high cost and is expensive to customize. The key is that the solid-phase reactor cannot be very large in volume, which causes low batch yield and low production capacity of the H-Gly-Pro-Hyp-OH produced by this process; the third is that the resin used in solid-phase synthesis is expensive, And it cannot be reused; the fourth is that the liquid-solid phase synthesis method is used in the patent, and the amount of organic solvent used is huge, which is inconsistent with the current concept of green chemistry and sustainable development; the fifth is that the solid phase synthesis used in the patent is tripeptide- 29 TFA (trifluoroacetic acid) salts, as everyone knows, TFA (trifluoroacetic acid) salts cannot be sold, so this process is not conducive to industrialization
The above five points show that the production cost of tripeptide-29 in the prior art is high, the three wastes are many, and the added value is low

Method used

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  • Production process of tripeptide-29

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Step 1: Synthesis of Mca-Pro-OH (Intermediate-1)

[0022] In a 5L three-necked bottle, add 270g Pro, 540ml water, and 540ml toluene, keep the temperature at -5-0°C, drop a mixed solution of 292g chloroacetyl chloride and 146ml toluene into the feed liquid, and keep the pH of the system during the feeding and dropping process. At 8.5-9.0, after the reaction is detected by TLC, keep the temperature at 0-5 degrees, adjust the pH of the feed liquid to 2.0 ± 0.2, stir, filter with suction, wash the filter cake, and dry to obtain 414g Mca-Pro-OH, the yield 92.3%.

[0023] Step 2: Synthesis of H-Gly-Pro-OH (Intermediate-2)

[0024] In a 5L three-necked flask, add Mca-Pro-OH and 3L concentrated ammonia water, stir, and after TLC detects that the reaction is complete, the reaction solution is heated and concentrated to obtain H-Gly-Pro-OH.

[0025]Step 3: Synthesis of Fmoc-Gly-Pro-OH (Intermediate-3)

[0026] In a 5L three-necked bottle, add H-Gly-Pro-OH, 1242ml water, 1242ml...

Embodiment 2

[0034] Step 1: Synthesis of Mca-Pro-OH (Intermediate-1)

[0035] In the 5L three-necked bottle, add 200g Pro, 400ml water, 400ml ethyl acetate, keep the temperature at -5-0°C, add the mixed solution of 216g of chloroacetyl chloride and 108ml of ethyl acetate dropwise to the feed liquid, add materials and dropwise process The pH of the system was maintained at 8.5-9.0 in the middle, and after the reaction was detected by TLC, the temperature was maintained at 0-5 degrees, the pH of the feed liquid was adjusted to 2.0±0.2, stirred, suction filtered, and the filter cake was washed and dried to obtain 303 g of Mca-Pro- OH, yield 91.1%.

[0036] Step 2: Synthesis of H-Gly-Pro-OH (Intermediate-2)

[0037] In a 5L three-necked flask, add Mca-Pro-OH and 3L concentrated ammonia water, stir, and after TLC detects that the reaction is complete, the reaction solution is heated and concentrated to obtain H-Gly-Pro-OH.

[0038] Step 3: Synthesis of Fmoc-Gly-Pro-OH (Intermediate-3)

[003...

Embodiment 3

[0047] Step 1: Synthesis of Mca-Pro-OH (Intermediate-1)

[0048] In a 5L three-necked bottle, add 230g Pro, 460ml of water, and 460ml of acetonitrile, keep the temperature at -5-0°C, dropwise add a mixed solution of 249g of chloroacetyl chloride and 150ml of acetonitrile to the feed liquid, and keep the pH of the system during the addition and dropwise addition. At 8.5-9.0, after the reaction is detected by TLC, keep the temperature at 0-5 degrees, adjust the pH of the feed liquid to 2.0±0.2, stir, filter with suction, wash the filter cake, and dry to obtain 357g Mca-Pro-OH, the yield 93.3%.

[0049] Step 2: Synthesis of H-Gly-Pro-OH (Intermediate-2)

[0050] In a 5L three-necked flask, add Mca-Pro-OH and 3L concentrated ammonia water, stir, and after TLC detects that the reaction is complete, the reaction solution is heated and concentrated to obtain H-Gly-Pro-OH.

[0051] Step 3: Synthesis of Fmoc-Gly-Pro-OH (Intermediate-3)

[0052] In a 5L three-necked flask, add H-Gly-...

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Abstract

The invention relates to a production process of tripeptide-29, and belongs to the field of biological medicine, a process route of sequentially synthesizing Mca-Pro-OH, H-Gly-Pro-OH, Fmoc-Gly-Pro-OH, Fmoc-Gly-Pro-ONp and Fmoc-Gly-Pro-Hyp-OH, and finally hydrolyzing the obtained Fmoc-Gly-Pro-Hyp-OH to obtain the tripeptide-29 is adopted, and a qualified product can be obtained by adopting minimum protection and six-step reaction, so that the production cycle is greatly shortened, the production cost is reduced, and the production efficiency is improved. And the production cost is reduced.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a production process of tripeptide-29. Background technique [0002] Tripeptide-29 or collagen tripeptide H-Gly-Pro-Hyp-OH is a tripeptide containing glycine, proline and hydroxyproline. Due to the small molecular weight of collagen tripeptide, it can be fully absorbed by the human body At the same time, collagen tripeptide can also penetrate into the stratum corneum, dermis and hair root cells very effectively. It is the smallest molecular weight at present and has the same basic structure as skin collagen. It does not need to be decomposed and can be directly absorbed by the skin. High absorption rate. Collagen tripeptide can promote the production of dermal collagen, the regeneration of the dermal junction layer, and the regeneration and differentiation of the epidermis. [0003] At present, the conventional synthesis of collagen tripeptide H-Gly-Pro-Hyp-OH adopts the liquid-solid...

Claims

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Application Information

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IPC IPC(8): C07K5/083C07K14/78C07K1/02C07K1/12C07K1/06
CPCC07K5/0806C07K14/78Y02P20/55
Inventor 于更立李江涛刘聪林志乐李开庆赵帅
Owner 山东济肽生物科技有限公司
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