Solid-liquid phase synthesis method for alarelin acetate

A synthesis method, solid-liquid phase technology, applied in the field of solid-liquid phase synthesis method of alarelin, can solve the problems of high cost, large pollution, low yield and the like

Active Publication Date: 2012-10-03
GL BIOCHEM SHANGHAI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems of low yield, high cost, harsh reaction conditions and heavy pollution existing in the existing synthetic methods

Method used

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  • Solid-liquid phase synthesis method for alarelin acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] 1) Preparation of Fmoc-Arg(pbf)-Pro-2Cl-Trt-Cl resin

[0063] Weigh 50 grams of H-Pro-2Cl-Trt-Cl resin (Loading 0.6mmol / g, 30mmol), soak it with 800ml DCM for 30 minutes, fully swell the resin, drain it, add Fmoc-Arg(pbf)-OH (MW : 648.8, 60mmol) 38.9g, TBTU (MW: 321.1, 60mmol) 19.3g, HOBT (MW: 135.1, 60mmol) 8.1g, DIEA (MW: 129.24, 120mmol) 20ml, DMF500ml, reacted for 1.5 hours, ninhydrin detection The resin was colorless and transparent, drained, washed 3 times with DMF, and dried to obtain Fmoc-Arg(pbf)-Pro-2Cl-Trt-Cl resin.

[0064] 2) Preparation of pGlu-His(Trt)-Trp(Boc)-Ser(tbu)-Tyr(tbu)-D-Ala-Leu-Arg(pbf)-Pro-2Cl-Trt-Cl resin

[0065] In the Fmoc-Arg(pbf)-Pro-2Cl-Trt-Cl resin in step (1), add 800ml decapping reagent (20% PIP / DMF(v / v) solution), react for 30 minutes, drain, and use Wash with DMF 6 times, drain, use DMF as solvent, add amino acid with Fmoc protection, DIEA, TBTU / HOBT, react for 1.5 hours, detect the reaction end point, drain, wash with DMF 3-5 ti...

Embodiment 2

[0074] 1) Preparation of Fmoc-Arg(pbf)-Pro-2Cl-Trt-Cl resin

[0075] Weigh 67 grams of H-Pro-2Cl-Trt-Cl resin (Loading 0.45mmol / g, 30mmol), soak it with 800ml DCM for 30 minutes, fully swell the resin, drain it, add Fmoc-Arg(pbf)-OH (MW : 648.8, 90mmol) 58.4g, HBTU (MW: 379.2, 90mmol) 34.1g, HOBT (MW: 135.1, 90mmol) 12.2g, NMM (MW: 102.1, 180mmol) 20ml, DMF500ml, reaction for 1 hour, ninhydrin detection The resin was colorless and transparent, drained, washed 3 times with DMF, and dried to obtain Fmoc-Arg(pbf)-Pro-2Cl-Trt-Cl resin.

[0076] 2) Preparation of pGlu-His(Trt)-Trp(Boc)-Ser(tbu)-Tyr(tbu)-D-Ala-Leu-Arg(pbf)-Pro-2Cl-Trt-Cl resin

[0077] In the Fmoc-Arg(pbf)-Pro-2Cl-Trt-Cl resin in step (1), add 800ml decapping reagent (20% PIP / DMF(v / v) solution), react for 30 minutes, drain, and use Wash with DMF 6 times, drain, use DMF as solvent, add amino acid with Fmoc protection, NMM, HBTU / HOBT, react for 1 hour, detect the reaction end point, drain, wash with DMF 3-5 times, d...

Embodiment 3

[0086]1) Preparation of Fmoc-Arg(pbf)-Pro-2Cl-Trt-Cl resin

[0087] Weigh 42 grams of H-Pro-2Cl-Trt-Cl resin (Loading 0.72mmol / g, 30mmol), soak it with 800ml DCM for 30 minutes, fully swell the resin, drain it, add Fmoc-Arg(pbf)-OH (MW :648.8, 60mmol) 38.9g, HATU (MW: 380.23, 60mmol) 22.8g, HOAT (MW: 136.1, 60mmol) 8.2g, NMM (MW: 102.1, 120mmol) 14ml, DMF500ml, reacted for 0.5 hours, ninhydrin detection The resin was colorless and transparent, drained, washed 3 times with DMF, and dried to obtain Fmoc-Arg(pbf)-Pro-2Cl-Trt-Cl resin.

[0088] 2) Preparation of pGlu-His(Trt)-Trp(Boc)-Ser(tbu)-Tyr(tbu)-D-Ala-Leu-Arg(pbf)-Pro-2Cl-Trt-Cl resin

[0089] In the Fmoc-Arg(pbf)-Pro-2Cl-Trt-Cl resin in step (1), add 800ml decapping reagent (20% PIP / DMF(v / v) solution), react for 30 minutes, drain, and use Wash with DMF 6 times, drain, use DMF as solvent, add amino acid with Fmoc protection, NMM, HATU / HOAT, react for 0.5 hours, detect the reaction end point, drain, wash with DMF 3-5 times...

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Abstract

The invention relates to a solid-liquid phase synthesis method for alarelin acetate, and mainly solves the technical problems of low yield, high cost, severe reaction conditions and serious pollution existing in the conventional synthesis method. The solid-liquid phase synthesis method mainly comprises the synthesis steps of: (1) coupling each protective amino acid one by one by using a fluorenylmethoxycarbonyl solid phase synthesis method by taking proline-dichloro-trityl-chlorine resin as initial resin and synthesizing to obtain side chain fully protected peptide chain resin; (2) cutting the side chain fully protected peptide chain resin to obtain a fully protected peptide chain segment pGluP-9; (3) performing C-terminal ethylamination on the fully protected peptide chain segment pGluP-9 to obtain a fully protected segment of the alarelin acetate; and (4) cutting the fully protected segment of the alarelin acetate to remove a side chain protective group to obtain alarelin acetate rough product peptide. The solid-liquid phase synthesis method has the advantages of high large-scale production capacity, easy operation, stable process, low production cost and total yield of exceeding 40 percent.

Description

technical field [0001] The present invention relates to a synthetic method of alarelin, in particular to a solid-liquid phase synthesis method of alarelin. Background technique [0002] Alarelin, the Chinese name is Alarelin acetate, also known as alanine, the English name is Alarelin Acetate, the polypeptide sequence is pGlu-His-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-NHC2H5, and the molecular formula C56H78N16O12, the molecular weight is 1167.30, and the structural formula is as follows: [0003] [0004] This product is a synthetic nonapeptide analogue of gonadotropin-releasing hormone (GnRH), which can stimulate the pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH) at the initial stage of medication, causing a transient increase in ovarian-derived steroid hormones; repeat Medication can inhibit the release of LH and FSH from the pituitary gland to reduce the level of estradiol in the blood to achieve the effect of drug ovariectomy. Thi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/04
CPCY02P20/55
Inventor 徐红岩竺剑峰饭岛悠介
Owner GL BIOCHEM SHANGHAI
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