Solid-liquid phase synthesis method of Bremelanotide

A synthesis method and technology of bumenotide, which are applied in the field of solid-liquid phase synthesis of bumenotide, can solve the problems of large steric hindrance, difficult end-to-end connection, reduced synthesis yield, etc., and achieve low cost and high purity. Effect

Active Publication Date: 2020-04-03
SUZHOU UNIV OF SCI & TECH
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

Solid-phase cyclization is mainly to remove the protection after coupling the main chain, and the peptide chain is connected end to end, but the peptide chain is difficult to fold to end to end due to too much steric hindrance, which leads to low efficiency and large steric hindrance. The reasons include the following two aspects: (1) the various protecting group structures on the peptide chain make the peptide chain have a rigid structure, which is difficult to fold back into a ring; (2) after the ring is formed, the cyclic peptide has a larger Spatial structure, making it difficult for uncycled peptides to fold back into a ring
Patent CN200610086841.4 adopts a step-by-step synthesis method. After the peptide resin is synthesized, the protective groups of Asp and Lys are selectively removed, and then a ring is formed on the resin, and finally cracked with HF. Because of the severe corrosiveness of HF, this method cannot It is used on a large scale, and the yield of refined peptides published in the examples is 30-35%; patent CN200710048824.6 also adopts the method of selective deprotection, but the deprotection method selected by it is effective in removing the protec

Method used

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  • Solid-liquid phase synthesis method of Bremelanotide
  • Solid-liquid phase synthesis method of Bremelanotide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: the synthesis of AC-Nle-OSu activated ester

[0054] Weigh 173.21g AC-Nle-OH (1.0mol), add 138.10g HOSu (1.2mol) into 2000ml DMF, add 247.59g DCC (1.2mol) under ice-water bath, react for 1 hour, heat up to room temperature for 3 hours, and react The liquid was filtered, the mother liquor was spin-dried, dissolved in DCM, filtered, recrystallized from ice ethanol three times, filtered, and dried by a solid oil pump to obtain 240.57g of AC-Nle-OSu activated ester with a yield of 89%.

Embodiment 2

[0055] Example 2: Synthesis of H-Asp-O-2-Phipr

[0056] Weigh 395.41g Fmoc-Asp(OAll)-OH (1.0mol), add it into 3000ml dichloromethane, add dropwise 561.16g 2,2,2-trichloroiminoacetic acid 2- Phenylpropan-2-yl ester (2.0 mol), react at room temperature for 16 hours. Under ice-cooling, 198.65 g of 2-phenylpropan-2-yl chloroformate (1.0 mol) dissolved in 2000 ml of dichloromethane was added dropwise, and reacted at room temperature for 16 hours. Concentrate the solution. Add 2000ml THF to dissolve, add 60g Pd(PPh 3 )4 (0.05mol) and 244mL PhSiH3 (2.0mol), react at room temperature for 2 hours. Concentrate the solution. 4000ml of dichloromethane and 1000ml of diisopropylethylamine. Reaction at room temperature for 0.5 hours. Concentrate the solution. Recrystallized from ice ethanol three times, filtered, and dried by pumping solid oil to obtain 201.02 g of H-Asp-O-2-Phipr, with a yield of 80%.

Embodiment 3

[0057] Example 3: Synthesis of AC-Nle-Asp-O-2-Phipr

[0058] Weigh 125.76g H-Asp-O-2-Phipr (0.5mol), 135.15g AC-Nle-OSu (0.5mol) and 79.50g Na 2 CO 3 (0.75mol) was added to a mixed solution of 500ml water and 500ml THF to dissolve, react overnight at room temperature, adjust the pH to 7 with 10% dilute hydrochloric acid, remove THF by rotary evaporation, and then adjust the pH to 3. A large white precipitate was obtained which was filtered. The obtained white precipitate was recrystallized with ice ethanol, the obtained solid was stirred and recrystallized in dioxane hydrochloride solution for 2 hours, and the obtained solid oil was pumped dry to 172.55g AC-Nle-Asp-O-2-Phipr, Yield 85%.

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Abstract

The invention discloses a solid-liquid phase synthesis method of Bremelanotide. The method comprises the following steps: synthesizing an AC-Nle-Asp-O-2-Phipr dipeptide fragment by virtue of a liquidphase method; coupling a main chain and a side chain of the Lys respectively to prolong a peptide sequence, obtaining Fmoc-His(Boc)-D-Phe-Arg(pbf)-Trp(Boc)-Lys(AC-Nle-Asp-O-2-Phipr)-Wang resin, and after the protecting group is removed, cyclizing the main chain and the side chain. The head and the tail are prevented from being folded into a ring, the problem of large steric hindrance of the foldedring is solved, and the influence of the formed peptide on the non-formed peptide is also reduced to the minimum due to the fact that the ring forming sites are closer. In addition, alkali is not adopted for hydrolysis, and corresponding impurities cannot be generated. The Bremelanotide synthesized by the synthesis method is high in purity, low in cost and suitable for large-scale production.

Description

technical field [0001] The invention relates to a solid-liquid phase synthesis method of bumenotide, which belongs to the technical field of polypeptide synthesis. Background technique [0002] Bremelanotide, English name Bremelanotide, was originally researched and developed by the University of Arizona. Its target is MC3R / MC4R. Its structure belongs to peptide analogs and is used for the treatment of premenopausal female libido disorder; Paladin Company obtained the research and development rights of this compound in 2007. , then entered the development, and the clinical research was concentrated in North America; in March 2018, the NDA application was submitted to the US FDA, and it was approved by the FDA on June 21, 2019. Bumenotide is composed of 7 amino acids and has the same core sequence as α-melanocyte-stimulating hormone, the receptor of which plays an important role in appetite and sexual arousal. Its peptide sequence is AC-Nle-[Asp-His-D-Phe-Arg-Trp-Lys]cycle-O...

Claims

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Application Information

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IPC IPC(8): C07K7/56C07K1/10C07K1/06C07K1/04
CPCC07K7/56Y02P20/55
Inventor 陈丰诸旻陈辉顾海东金晶
Owner SUZHOU UNIV OF SCI & TECH
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