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Histrelin synthesizing method

A technology of histrelin and a synthesis method, applied in the field of solid-liquid phase synthesis of histrelin, can solve the problems of high pollution of three wastes, low yield of peptides and the like

Inactive Publication Date: 2013-01-02
上海吉尔多肽有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to provide a synthetic method for histrelin, which mainly solves the technical problems of low peptide yield and high three-waste pollution in the existing synthetic method of histrelin

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Preparation of Fmoc-Pro-CTC resin

[0077] 1). Take 1g of CTC resin (Loading: 1.2mmol / g, 1.2mmol), soak it in 15ml of DCM to fully swell the resin,

[0078] 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.

[0079] 3) Blow dry, wash with DMF and methanol three times respectively, and blow dry.

[0080] Preparation of Fmoc-Arg(pbf)-Pro-CTC resin

[0081] 1). Add 15ml of deprotection reagent, react at room temperature for 15 minutes, dry, wash with DMF and methanol 3 times, dry,

[0082] 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) and dissolve it with 15ml peptide reagent, add Reactor, room temperature reaction 1.5h,

[0083] 3) Blow dry, wash 3 times with DMF and methanol respectively, and blow dry.

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

[0085] 1). Add 15ml of deprotection reag...

Embodiment 2

[0119] Preparation of Fmoc-Pro-CTC resin

[0120]1). Take 10g of CTC resin (Loading: 1.2mmol / g, 12mmol), soak it in 100ml of DCM to fully swell the resin,

[0121] 2). Take 6.1g Fmoc-Pro-OH (FW:337.4, 18mmol), dissolve it with 100ml peptide reagent, add it to the reactor, and react at room temperature for 1.5 hours.

[0122] 3) Blow dry, wash with DMF and methanol three times respectively, and blow dry.

[0123] Preparation of Fmoc-Arg(pbf)-Pro-CTC resin

[0124] 1) Add 100ml deprotection reagent, react at room temperature for 15 minutes, blow dry, wash with DMF and methanol 3 times, blow dry,

[0125] 2) Take 23.3g Fmoc-Arg(pbf)-OH (FW:648.8, 36mmol), 11.6gTBTU (FW:321, 36mmol), 4.8HOBT (FW:135, 36mmol) and dissolve them with 100ml peptide reagent, add to the reactor, Reaction at room temperature for 1.5h,

[0126] 3) Blow dry, wash 3 times with DMF and methanol respectively, and blow dry.

[0127] Preparation of Fmoc-Leu-Arg(pbf)-Pro-CTC resin

[0128] 1) Add 100ml dep...

Embodiment 3

[0162] Preparation of Fmoc-Pro-CTC resin

[0163] 1). Take 150g CTC resin (Loading: 1.2mmol / g, 180mmol), soak it in 1000ml DCM to fully swell the resin,

[0164] 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.

[0165] 3) Blow dry, wash with DMF and methanol three times respectively, and blow dry.

[0166] Preparation of Fmoc-Arg(pbf)-Pro-CTC resin

[0167] 1). Add 1000ml deprotection reagent, react at room temperature for 15 minutes, blow dry, wash with DMF and methanol 3 times, dry,

[0168] 2) Take 350.1g Fmoc-Arg(pbf)-OH (FW: 648.8, 540mmol), 173.4gTBTU (FW: 321, 540mmol), 72.9HOBT (FW: 135, 540mmol) and dissolve them with 1000ml peptide reagent, add to the reactor, Reaction at room temperature for 1.5h,

[0169] 3) Blow dry, wash 3 times with DMF and methanol respectively, and blow dry.

[0170] Preparation of Fmoc-Leu-Arg(pbf)-Pro-CTC resin

[0171] 1). Add ...

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Abstract

The invention relates to a synthesizing method of histrelin. The invention mainly aims at solving technical problems of low peptide-coupling yield and high three-waste pollution of existing histrelin synthesizing methods. A technical scheme of the histrelin synthesizing method comprises the steps that: a, CTC resin is adopted as an initial raw material and is connected to carboxyl group of Fmoc-Pro-OH under an alkaline condition, such that Fmoc-Pro-CTC resin is obtained; b, the rest 8 amino acids are sequentially synthesized according to histrelin; c, full-protection peptide cutting is carried out, wherein a yr-His(Trt)-Trp(Boc)-Ser(tbu)-Tyr(tbu)-D-His(Bzl)-Leu-Arg(pbf)-Pro 9 peptide fragment is obtained by cleavage by using a full-protection cutting reagent; d, under the effect of HOBT, a full-protection histrelin fragment is obtained by using ethanamine and the full-protection 9 peptide fragment; and e, the full-protection histrelin fragment is subjected to cleavage, such that a histrelin crude product is obtained.

Description

technical field [0001] The present invention relates to a method for synthesizing histrelin, in particular to a method for synthesizing histrelin in solid-liquid phase Background technique [0002] Histrelin also known as LHRH-Hydrogel implant, RL 0903, the structural formula is [0003] The molecular formula is: C66H86N18O12 and the molecular weight is: 1323.5 [0004] Histrelin is a synthetic nonapeptide used in the treatment of central precocious puberty. [0005] Histrelin is a luteinizing hormone-releasing hormone (LHRH) agonist. American scholar Shore (Shore) reported that for patients with advanced prostate cancer, subcutaneous implantation of histrelin long-acting implants once a year can improve long-term Steadily suppresses testosterone, keeping it at castrated levels. [0006] The existing synthetic methods all have certain disadvantages. Trifluoroacetic acid is required for each deprotection, so there is a lot of pollution from three wastes, low peptide yi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04
Inventor 徐红岩张旭光
Owner 上海吉尔多肽有限公司
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