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Preparation method for octreotide

A technology of octreotide and peptide resin, which is applied in the field of compound synthesis, can solve the problems of low purity, low octreotide yield, and high loss rate of fragment 6, etc., and achieve the goals of reducing operation steps, increasing product yield and purity, and increasing reaction yield Effect

Active Publication Date: 2013-05-15
HANGZHOU HUADI GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Patent CN1355173A adopts the 3+5 fragment condensation method, but the loss rate of fragment 5 is relatively high; patent US 4395403 adopts the Boc method to synthesize, and condenses 2+6 fragments to prepare linear octreotide, but the loss rate of fragment 6 is relatively high; patent CN1810829A The linear octreotide is synthesized by the solid-phase synthesis method using the Fmoc method, and finally the terminal Fmoc group is removed and then cracked to obtain a linear crude peptide; the patent CN1923849B adopts the 1+7 fragment condensation method, and (D)Phe-OH is protected by a Boc protecting group , but the yield of octreotide is low and the purity is not high

Method used

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  • Preparation method for octreotide
  • Preparation method for octreotide
  • Preparation method for octreotide

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[0034] The invention discloses a preparation method of octreotide, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and the relevant personnel can obviously make changes or appropriate changes and combinations to the method and application described herein without departing from the content, spirit and scope of the present invention to realize and Apply the technology of the present invention.

[0035] A preparation method of octreotide, comprising the steps of:

[0036] Step 1: obtaining a dipeptide whose amino acid sequence is D-Phe-Cys;

[0037] Using the resin as a carrier, a hexapeptide re...

Embodiment 1

[0075]Dissolve 107g of Boc-(D)Phe-OH in 800ml of tetrahydrofuran, add 34.8g of HOSU and 62.3g of DCC, dissolve and react at 15°C for 2 hours, TLC detects that the reaction of Boc-(D)Phe-OH is complete, filter Obtain the filtrate; add the filtrate dropwise to the H-Cys(Trt)-OH solution (prepared by adding 5g sodium carbonate and 110g H-Cys(Trt)-OH to 2000ml water), react at 10°C for 15h, and detect Boc-(D) After the Phe-OSU reaction is complete, adjust the pH value of the solution to 3.0 with acetic acid, filter, add 1000ml of ethyl acetate for extraction, wash the ethyl acetate layer with saturated brine for 3 times, then dry with anhydrous sodium sulfate for 4 hours, filter the filtrate Ethyl acetate was distilled off under pressure, crystallized by adding petroleum ether, and dried under pressure to obtain 165.7 g of Boc-(D)Phe-Cys(Trt)-OH with a yield of 99.1%.

[0076] Amino acid activation: according to the molar ratio of Fmoc-AA-OH, HOBT, and DIC ratio of 1:1.2:1.2, the ...

Embodiment 2

[0091] Dissolve 107g of Boc-(D)Phe-OH in 800ml of tetrahydrofuran, add 34.8g of HOSU and 62.3g of DCC, dissolve and react at 10°C for 3 hours, TLC detects that the reaction of Boc-(D)Phe-OH is complete, filter Obtain the filtrate; add the filtrate dropwise to the H-Cys(Trt)-OH solution (prepared by adding 5g sodium carbonate and 110g H-Cys(Trt)-OH to 2000ml water), react at 14°C for 12h, and detect Boc-(D) After the Phe-OSU reaction is complete, adjust the pH value of the solution to 4.0 with acetic acid, filter, add 1000ml ethyl acetate for extraction, wash the ethyl acetate layer with saturated brine three times, then dry it with anhydrous sodium sulfate for 4 hours, filter the filtrate Ethyl acetate was distilled off under pressure, crystallized by adding petroleum ether, and dried under pressure to obtain 166.0 g of Boc-(D)Phe-Cys(Trt)-OH with a yield of 99.3%.

[0092] Amino acid activation: according to the molar ratio of Fmoc-AA-OH, HOBT, and DIC ratio of 1:1.2:1.2, the...

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Abstract

The invention relates to the field of preparation of compounds, especially to a preparation method for octreotide. The preparation method comprises the following steps: subjecting dipeptide and a solid-phase synthetic hexapeptide resin to condensation so as to prepare linear octapeptide; dissolving linear octapeptide obtained after cracking in an aqueous solution of N,N-dimethyl formamide; and adding an oxidizing agent for cyclization and purification so as to prepare octreotide. The preparation method enables yield and purity of octreotide to be improved.

Description

technical field [0001] The invention relates to the field of compound synthesis, in particular to a preparation method of octreotide. Background technique [0002] Octreotide, chemical name D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophanyl-L-lysyl-L-threonyl-L-cysteinyl -L-threoninol ring-(2→7)-disulfide acetate, a cyclic octapeptide containing a disulfide bond in the molecule is an analogue of natural somatostatin, and its chemical formula is C 49 h 66 N 10 o 10 S 2 , the molecular weight is 1019.24, and its simplified structure is shown in formula Ⅰ: [0003] [0004] The chemical formula of octreotide is shown in formula II: [0005] [0006] Octreotide has a variety of physiological activities, such as inhibiting the pathological hypersecretion of growth hormone, thyrotropin, gastrointestinal and pancreatic endocrine hormones, and inhibiting the secretion of gastric acid, pancreatic enzymes, glucagon and insulin. Gastric motility and gallbladder empty...

Claims

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Application Information

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IPC IPC(8): C07K7/06
Inventor 谷海涛赵呈青顾含华
Owner HANGZHOU HUADI GRP CO LTD
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