Liquid-phase synthesis method of dipeptide diaminobutyroyl benzylamide diacetate

A technology for liquid phase synthesis and snake venom, applied in the field of cosmetics, can solve the problems of high cost and complicated synthesis process, and achieve the effects of low cost, easy separation and simple process

Inactive Publication Date: 2018-04-20
SHAANXI HUIKANG BIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the conventional method for synthesizing snake venom-like tripeptide (H-β-Ala-Pro-DAB-NH-Bzl) mostly adopts the method of combining solid phase and liquid phase. The synthesis process is complicated and costly, so the development process is simple and low cost. Low-cost snake venom tripeptide synthesis method has important implications for snake venom tripeptides widely used in cosmetics

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 1. Synthesis of Boc-β-Ala-Pro-OMe

[0025] Add 3.78g (0.02mol) of Boc-β-Ala-OH to 55mL of nitromethane, and add 6.2mL (0.044mol) of triethylamine, stir and dissolve until clear, then add 5.07g (0.02mol) of N -Ethyl-5-phenylisoxazole-3'-sulfonic acid inner salt, stir and dissolve, then add 3.31g (0.02mol) proline methyl ester hydrochloride (H-Pro-OMe HCl), room temperature Stir the reaction for 10 hours. After the reaction, the reaction solution is concentrated by rotary evaporation. The concentrated product is dissolved in ethyl acetate and washed 3 times with water. The organic phase is concentrated to dryness at 30-40°C to obtain 5.50g of Boc-β-Ala-Pro-OMe , yield 91.51%.

[0026] 2. Synthesis of Boc-β-Ala-Pro-OH

[0027] Add the Boc-β-Ala-Pro-OMe obtained in step 1 into a mixed solution of 60mL tetrahydrofuran, methanol, and 5% LiOH aqueous solution at a volume ratio of 2:1:1, stir and react at room temperature for 2 hours, adjust to 1mol / L hydrochloric acid pH to...

Embodiment 2

[0037] In step 1 of this example, the moles of Boc-β-Ala-OH, triethylamine, N-ethyl-5-phenylisoxazole-3'-sulfonic acid inner salt and H-Pro-OMe·HCl The ratio was 1:2.2:1.2:1, and the reaction time was 11 hours. The other steps of this step were the same as in Example 1, and 5.61g of Boc-β-Ala-Pro-OMe was obtained with a yield of 93.34%.

[0038] In step 2 of this embodiment, the mass fraction of LiOH in the LiOH aqueous solution is 7.5%, and the reaction time is 3 hours. Other steps of this step are the same as in embodiment 1.

[0039] In step 3 of this example, Boc-β-Ala-Pro-OH, triethylamine, N-ethyl-5-phenylisoxazole-3'-sulfonic acid inner salt and H-DAB(Boc)- The mol ratio of OMeHCl is 1:2.2:1.2:1, and the reaction time is 11 hours, other steps of this step are identical with embodiment 1, obtain 7.59g Boc-β-Ala-Pro-DAB(Boc)-OMe, Yield 86.15%.

[0040] In step 4 of this embodiment, the mass fraction of LiOH in the LiOH aqueous solution is 7.5%, and the reaction time is ...

Embodiment 3

[0043] In step 1 of this example, the moles of Boc-β-Ala-OH, triethylamine, N-ethyl-5-phenylisoxazole-3'-sulfonic acid inner salt and H-Pro-OMe·HCl The ratio was 1:2.4:1.5:1, and the reaction time was 12 hours. The other steps of this step were the same as in Example 1, and 5.35g of Boc-β-Ala-Pro-OMe was obtained with a yield of 89.59%.

[0044] In step 2 of this embodiment, the mass fraction of LiOH in the LiOH aqueous solution is 10%, and the reaction time is 4 hours. Other steps of this step are the same as in embodiment 1.

[0045] In step 3 of this example, Boc-β-Ala-Pro-OH, triethylamine, N-ethyl-5-phenylisoxazole-3'-sulfonic acid inner salt and H-DAB(Boc)- The mol ratio of OMeHCl is 1:2.4:1.5:1, and the reaction time is 12 hours, other steps of this step are identical with embodiment 1, obtain 7.39g Boc-β-Ala-Pro-DAB(Boc)-OMe, Yield 83.88%.

[0046] In step 4 of this embodiment, the mass fraction of LiOH in the LiOH aqueous solution is 10%, and the reaction time is 4 ...

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Abstract

The invention discloses a liquid-phase synthesis method of dipeptide diaminobutyroyl benzylamide diacetate. The method comprises the following steps of enabling Boc-Beta-Ala-OH, N-ethyl-5-phenylisoxazole-3'-sulfonic acid inner salt and H-Pro-OMe.HCl to react to obtain Boc-Beta-Ala-Pro-OMe, and enabling the Boc-Beta-Ala-Pro-OMe to react with LiOH to obtain Boc-Beta-Ala-Pro-OH; afterwards, synthesizing Boc-Beta-Ala-Pro-DAB(Boc)-OH with the Boc-Beta-Ala-Pro-OH and H-DAB(Boc)-OMe.HCl by adopting the same method; next, enabling the Boc-Beta-Ala-Pro-DAB(Boc)-OH, 1-hydroxybenzotriazole, N,N-diisopropylcarbodiimide and benzylamine to react to obtain Boc-Beta-Ala-Pro-DAB(Boc)-NH-Bzl, finally, removing a Boc protecting group by using trifluoroacetic acid, separating and purifying, so as to obtain the dipeptide diaminobutyroyl benzylamide diacetate with purity being more than 95 percent. According to the liquid-phase synthesis method, amino acid methyl ester which is low-cost and is easily obtained is used as a raw material; a by-product generated and synthesized by a peptide bond in each step has water solubility and is easily separated, and the liquid-phase synthesis method which has a simple and convenient process and lower cost is provided for the synthesis of the dipeptide diaminobutyroyl benzylamide diacetate.

Description

technical field [0001] The invention belongs to the technical field of cosmetics, and in particular relates to a liquid phase synthesis method of short peptides in polypeptides. Background technique [0002] Snake venom-like tripeptide (H-β-Ala-Pro-DAB-NH-Bzl) is a small peptide that mimics the activity of snake venom WaglerinI. WaglerinI was found in the venom of Temple Viper (Tripidolaemus wagleri) and is a receptor for muscle nicotinic acetylcholine. body (nmAChR) antagonists. H-β-Ala-Pro-DAB-NH-Bzl is a small molecule tripeptide synthesized by PENTAPHARM, a wholly-owned subsidiary of DSM Royal DSM Group, through high-tech biochemical technology, imitating fragments of effective molecular proteins (Waglerin1). The structure is similar to snake serum, but it is safer and more effective than botulinum toxin, so it can be safely applied to cosmetics, and has excellent smooth skin and rapid wrinkle removal properties. [0003] At present, the conventional method for synthes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/46C07K5/083C07K1/02
CPCC07K5/0806C07K14/46Y02P20/55
Inventor 张忠旗王万科陈科高长波张博王昕杨小琳赵金礼
Owner SHAANXI HUIKANG BIO TECH CO LTD
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