Solid-phase synthesis method for edotreotide

A solid-phase synthesis method and technology of enatreptide, which is applied in the field of solid-phase synthesis of etreptide, can solve problems such as the lack of industrial synthesis methods, and achieve the effect of facilitating later industrial scale-up, less pollution, and greater application value

Inactive Publication Date: 2018-10-19
滨海吉尔多肽有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Mainly solve the technical problem that the compo

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  • Solid-phase synthesis method for edotreotide
  • Solid-phase synthesis method for edotreotide
  • Solid-phase synthesis method for edotreotide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] (1) Preparation of Fmoc-Thr(tbu)-Ol-2Cl-Trt Cl resin

[0058] Weigh 10g of dichlorotriphenyl chloride resin, Fmoc-Thr(tbu)-Ol 3.84g (MW: 383.5, 10mmol), add 180ml of dichloromethane, 20ml of DIEA, react for 2 hours, add 100ml of methanol, react for 30 minutes, filter The filtrate was removed, and the resin was washed 3 times with dichloromethane to obtain Fmoc-Thr(tbu)-Ol-2Cl-Trt Cl resin;

[0059] (2) Preparation of Enatreptide Resin Peptide I

[0060] Place the Fmoc-Thr(tbu)-Ol-2Cl-Trt Cl resin in a polypeptide reactor, add 200ml of deprotection reagent, stir and react with nitrogen gas for 30 minutes, drain, wash with DMF 5 times, weigh the protected amino acid, condensing agent, Add it into the reactor, then add 100ml DMF, stir the reaction with nitrogen for 60-120 minutes, detect the end point of the reaction with ninhydrin, drain the reaction solution after the reaction, wash with DMF 3 times, repeat the cycle until the last amino acid is connected, and obtain the ...

Embodiment 2

[0077] (1) Preparation of Fmoc-Thr(tbu)-Ol-2Cl-Trt Cl resin

[0078] Weigh 10g of dichlorotriphenyl chloride resin, Fmoc-Thr(tbu)-Ol 3.84g (MW: 383.5, 10mmol), add 180ml of dichloromethane, 20ml of DIEA, react for 2 hours, add 100ml of methanol, react for 30 minutes, filter The filtrate was removed, and the resin was washed 3 times with dichloromethane to obtain Fmoc-Thr(tbu)-Ol-2Cl-Trt Cl resin;

[0079] (2) Preparation of Enatreptide Resin Peptide I

[0080] Place Fmoc-Thr(tbu)-Ol-2Cl-Trt Cl resin in a polypeptide reactor, add 200ml of deprotection reagent, stir and react with nitrogen gas for 30 minutes, drain, wash with DMF for 5 times, weigh the protected amino acid, condensing agent, Add it into the reactor, then add 100ml DMF, stir the reaction with nitrogen for 60-120 minutes, detect the end point of the reaction with ninhydrin, drain the reaction solution after the reaction, wash with DMF 3 times, repeat the cycle until the last amino acid is connected, and obtain th...

Embodiment 3

[0097] (1) Preparation of Fmoc-Thr(tbu)-Ol-2Cl-Trt Cl resin

[0098] Weigh 10g of dichlorotriphenyl chloride resin, Fmoc-Thr(tbu)-Ol 3.84g (MW: 383.5, 10mmol), add 180ml of dichloromethane, 20ml of DIEA, react for 2 hours, add 100ml of methanol, react for 30 minutes, filter The filtrate was removed, and the resin was washed 3 times with dichloromethane to obtain Fmoc-Thr(tbu)-Ol-2Cl-Trt Cl resin;

[0099] (2) Preparation of Enatreptide Resin Peptide I

[0100] Place the Fmoc-Thr(tbu)-Ol-2Cl-Trt Cl resin in a polypeptide reactor, add 200ml of deprotection reagent, stir and react with nitrogen gas for 30 minutes, drain, wash with DMF 5 times, weigh the protected amino acid, condensing agent, Add it into the reactor, then add 100ml DMF, stir the reaction with nitrogen for 60-120 minutes, detect the end point of the reaction with ninhydrin, drain the reaction solution after the reaction, wash with DMF 3 times, repeat the cycle until the last amino acid is connected, and obtain th...

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Abstract

The invention relates to a solid-phase synthesis method for edotreotide. The technical problem that an industrial synthesis method for the compound does not exist at present is mainly solved. The method disclosed by the invention mainly comprises the following steps: 1, coupling Fmoc-Thr(tbu)-Ol and dichlorotriphenyl chloride resin to obtain Fmoc-Thr(tbu)-Ol-2Cl-Trt Cl resin; 2, connecting remaining amino acids in sequence by virtue of a solid-phase synthesis method so as to obtain an edotreotide resin peptide I; 3, performing oxidative cyclization on the resin by using iodine so as to obtainan edotreotide resin peptide II; 4, performing Fmoc-removing protection, and coupling DOTA(Otbu)-3-COOH so as to obtain an edotreotide resin peptide III; 5, cracking to obtain crude edotreotide, purifying and refining through reversion phase chromatography, and freezing, so as to obtain the refined edotreotide. The invention provides a chemical synthesis method of edotreotide.

Description

technical field [0001] The invention relates to the technical field of polypeptide compound synthesis, in particular to a solid-phase synthesis method of enatreptide. Background technique [0002] The English name of Enalreptide is Edotreotide, the CAS number is: 204318-14-9, and the molecular formula is C 65 h 92 N 14 o 18 S 2 , molecular weight: 1421.65. The sequence is DOTA-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-Ol (Cys2-Cys7), consisting of eight amino acids, one end is labeled with DOTA, and contains a pair of disulfide bond loops octapeptide. It is a substance that binds a variety of nuclides and can locate malignant cancer cells without damaging normal cells. It is mainly used for the treatment and diagnosis of certain types of cancer. Applicable specific cancers include neuroblastoma, children's brain tumors and gastric cancer bowel cancer. [0003] [0004] But this compound lacks the method of industrialization synthesis at present. Contents of the invent...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04C07K1/20
CPCC07K7/06Y02P20/55
Inventor 徐红岩竺剑峰
Owner 滨海吉尔多肽有限公司
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