Synthetic method for goserelin

A synthesis method and the technology of desirelin, applied in the field of chemical pharmacy, can solve the problems of high pollution of three wastes and low yield of peptides, and achieve the effect of simplifying cumbersomeness, avoiding unsafe cutting, and shortening synthesis time.

Inactive Publication Date: 2014-08-27
ANHUI RUBIOX VISION BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] In order to solve the technical problems of low yield of deserelin synthesis and high pollution of three wastes in the prior art, the present invention provides a synthesis method of deserelin, and the technical scheme adopted is as follows:

Method used

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  • Synthetic method for goserelin

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Effect test

Embodiment 1

[0033] 1. Preparation of Fmoc-Pro-CTC resin

[0034] The preparation of Fmoc-Pro-CTC resin is carried out according to the following steps:

[0035] 1). Take 1g of CTC resin (Loading: 1.2mmol / g, 1.2mmol), soak it in 15ml of DCM to fully swell the resin;

[0036] 2). Take 0.607g Fmoc-Pro-OH (FW:337.4, 1.8mmol), dissolve it with 15ml of peptide reagent, add it to the reactor, and react at room temperature for 1.5 hours;

[0037] 3) Blow dry, wash with DMF and methanol three times respectively, and blow dry.

[0038] 2. Linkage of Deserelin Amino Acids

[0039] 2.1 Preparation of Fmoc-Arg(pbf)-Pro-CTC resin

[0040] 1). Add 15ml of deprotection reagent, react at room temperature for 15 minutes, dry, wash with DMF and methanol 3 times, dry,

[0041] 2) Take 2.4g Fmoc-Arg(pbf)-OH (FW: 648.8, 3.6mmol), 1.2gTBTU (FW: 321, 3.6mmol), 0.5gHOBT (FW: 135, 3.6mmol), dissolve it with 15ml peptide reagent, Add to the reactor, react at room temperature for 1.5h,

[0042] 3) Blow dry, wa...

Embodiment 2

[0078] 1. Preparation of Fmoc-Pro-CTC resin

[0079] The preparation of Fmoc-Pro-CTC resin is carried out according to the following steps:

[0080] 1). Take 10g of CTC resin (Loading: 1.2mmol / g, 12mmol), soak it in 100ml of DCM to fully swell the resin;

[0081] 2). Take 6.1g of Fmoc-Pro-OH (FW: 337.4, 18mmol), dissolve it with 100ml of peptide reagent, add it to the reactor, and react at room temperature for 1.5 hours;

[0082] 3) Blow dry, wash with DMF and methanol three times respectively, and blow dry.

[0083] 2. Linkage of Deserelin Amino Acids

[0084] 2.1 Preparation of Fmoc-Arg(pbf)-Pro-CTC resin

[0085] 1) Add 100ml of deprotection reagent, react at room temperature for 15 minutes, dry, wash with DMF and methanol 3 times, and dry;

[0086] 2) Take 23.3g Fmoc-Arg(pbf)-OH (FW: 648.8, 36mmol), 11.6gTBTU (FW: 321, 36mmol), 4.8 HOBT (FW: 135, 36mmol), dissolve it with 100ml peptide reagent, and add it to the reactor. Reaction at room temperature for 1.5h;

[0087...

Embodiment 3

[0123] 1. Preparation of Fmoc-Pro-CTC resin

[0124] The preparation of Fmoc-Pro-CTC resin is carried out according to the following steps:

[0125] 1). Take 150g of CTC resin (Loading: 1.2mmol / g, 180mmol), soak it in 1000ml of DCM to fully swell the resin;

[0126] 2). Take 91.1g Fmoc-Pro-OH (FW: 337.4, 270mmol), dissolve it with 1000ml peptide reagent, add it to the reactor, and react at room temperature for 1.5 hours;

[0127] 3) Blow dry, wash with DMF and methanol three times respectively, and blow dry.

[0128] 2. Linkage of Deserelin Amino Acids

[0129] 2.1 Preparation of Fmoc-Arg(pbf)-Pro-CTC resin

[0130] 1). Add 1000ml deprotection reagent, react at room temperature for 15 minutes, dry, wash with DMF and methanol 3 times, and dry;

[0131] 2) Take 350.1g Fmoc-Arg(pbf)-OH (FW: 648.8, 540mmol), 173.4g TBTU (FW: 321, 540mmol), 72.9 HOBT (FW: 135, 540mmol), dissolve it with 1000ml of peptide reagent, and add it to the reactor , react at room temperature for 1.5h; ...

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Abstract

The invention discloses a synthetic method for goserelin and belongs to the technical field of chemical pharmacy. The synthetic method comprises: taking 2-chlorotritylchloride polymer resin as a raw material, linking 2-chlorotritylchloride polymer resin with carboxyl of fluorenylmethyloxycarbonyl-protected proline under an alkaline condition, so as to obtain fluorenylmethyloxycarbonyl-protected proline-2-chlorotritylchloride polymer resin, then successively linking with residual amino acids of goserelin through peptide linking connections, using a full-protection cutting reagent for cracking and obtain a full-protection nine-peptide fragment, then performing ethylamination to obtain a full-protection goserelin fragment, and finally cracking the full-protection goserelin fragment to obtain a goserelin crude product. Goserelin is synthesized by employing a solid-liquid combination method and the yield reaches 84.1%. Also, the synthetic method helps to avoid the problems that a pure solid phase is not safe and convenient to cut from resin, the synthetic time is shortened, the tedious process for synthesizing a pure liquid phase is simplified, the production cost is substantially reduced, and the synthetic method is suitable for industrialized popularization.

Description

technical field [0001] The invention relates to a method for synthesizing deserelin, which belongs to the technical field of chemical pharmacy. Background technique [0002] Deserelin is also known as LHRH-Hydrogel implant, RL0903, and its molecular formula is: C 64 h 83 N 17 o 12 , the molecular weight is: 1282.47, the structural formula is as figure 1 shown. Deserelin is a synthetic nonapeptide used in the treatment of central precocious puberty. [0003] Deserelin is a luteinizing hormone-releasing hormone (LHRH) agonist. American scholars Shore et al. reported that for patients with advanced prostate cancer, subcutaneous implantation of deserelin long-acting implants once a year can stably inhibit testosterone for a long time. , to keep it castrated. [0004] The existing synthetic methods all have certain shortcomings. Trifluoroacetic acid is required for each deprotection, so there is a lot of pollution from the three wastes, low peptide yield, and high producti...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04
Inventor 张旭光汪国兴
Owner ANHUI RUBIOX VISION BIOTECH
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