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Preparation method of octreotide acetate

A technology of octreotide and crude product, applied in the field of peptide chemistry, can solve the problems of many side reactions, high preparation cost of octreotide, complicated process and the like

Inactive Publication Date: 2020-07-07
JIANGSU GENSCRIPT BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to provide a simple and efficient method for preparing octreotide, which solves the problems of high cost of octreotide preparation or many side reactions or complex processes

Method used

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  • Preparation method of octreotide acetate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: preparation of octreotide

[0069] (1) Preparation of Fmoc-Thr-resin complex

[0070] Add 1 g of 4-benzyloxybenzaldehyde resin (1.0 mmol / g) into a reactor with a filter device, inject 10 ml of anhydrous chloroform, let stand for 1 h, and filter.

[0071] Take 1mmol Fmoc-Thr-Ol and 0.1mmol TsOH, dissolve in 10ml anhydrous chloroform, add to the resin, and reflux for 8h. After the reaction, filter. Then add 10ml of DMF, wash the resin six times, and filter.

[0072] (2) Preparation of protected octreotide-resin complexes

[0073] Add 10ml of PIP / DMF solution with a volume ratio of 1:1 into the reactor, and react at 20°C for 10min. After the reaction is complete, filter. Then add 10ml DMF to wash the resin six times and filter.

[0074] Take 3mmol Fmoc-Cys(Trt)-OH, 3mmol HBTU, 3mmol HOBt and 6mmol DIEA, dissolve in 10ml DMF, add the resulting solution into the reactor, and react at 20°C for 1h. After the reaction, filter. Then add 10ml of DMF, wash th...

Embodiment 2

[0081] Embodiment 2: preparation of octreotide

[0082] (1) Preparation of Fmoc-Thr-resin complex

[0083] Add 1 g of 4-benzyloxybenzaldehyde resin (1.0 mmol / g) into a reactor with a filter device, inject 10 ml of anhydrous chloroform, let stand for 1 h, and filter.

[0084] Take 3mmol Fmoc-Thr-Ol and 0.5mmol TsOH, dissolve in 10ml of anhydrous chloroform, add to the resin, and reflux for 16h. After the reaction, filter. Then add 10ml of DMF, wash the resin six times, and filter.

[0085] (2) Preparation of protected octreotide-resin complexes

[0086] Add 10ml of PIP / DMF solution with a volume ratio of 1:4 into the reactor, and react at 30°C for 10min. After the reaction is complete, filter. Then add 10ml DMF to wash the resin six times and filter.

[0087] Take 6mmol Fmoc-Cys(Trt)-OH, 6mmol DIC, 6mmol HOBt, dissolve in 10ml DMF, add the resulting solution into the reactor, and react at 30°C for 2h. After the reaction, filter. Then add 10ml of DMF, wash the resin six ...

Embodiment 3

[0094] Embodiment 3: preparation of octreotide

[0095] (1) Preparation of Fmoc-Thr-resin complex

[0096] Add 1 g of 4-benzyloxybenzaldehyde resin (1.0 mmol / g) into a reactor with a filter device, inject 10 ml of anhydrous chloroform, let stand for 1 h, and filter.

[0097] Take 2mmol Fmoc-Thr-Ol and 0.2mmol TsOH, dissolve it in 10ml anhydrous chloroform, add it to the resin, and reflux for 24h. After the reaction, filter. Then add 10ml of DMF, wash the resin six times, and filter.

[0098] (2) Preparation of protected octreotide-resin complexes

[0099] Add 10ml of PIP / DMF solution with a volume ratio of 1:2 into the reactor, and react at 60°C for 60min. After the reaction is complete, filter. Then add 10ml DMF to wash the resin six times and filter.

[0100] Take 4mmol Fmoc-Cys(Trt)-OH, 4mmol PyBOP, 4mmol HOBt and 8mmol DIEA, dissolve in 10ml DMF, add the resulting solution into the reactor, and react at 60°C for 4h. After the reaction, filter. Then add 10ml of DMF,...

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Abstract

The invention relates to a preparation method of octreotide acetate. 4-Benzyloxybenzaldehyde resins are used as a solid phase carrier, N-(9-fluorenylmethyloxycarbonyl )-L-threoninol and aldehyde groups on resins directly form stable acetals on a solid phase, and through washing, by-products can be separated, so that the technology is greatly simplified. The invention provides a preparation technology of full-solid-phase octreotide acetate, and the problems that in the production course of the octreotide acetate at current, the cost is high, many side effects are generated and the technology iscomplex are solved.

Description

Technical field: [0001] The invention belongs to the field of polypeptide chemistry, in particular to a preparation method of octreotide. Background technique: [0002] Octreotide (Formula 1) is a cyclic octapeptide containing a disulfide bond in the molecule. It is a synthetic octapeptide derivative of human somatostatin, and its effect is similar to that of natural somatostatin. Chemical name D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophanyl-L-lysyl-L-threonyl-L-cysteinyl-L -Threoninol ring-(2→7)-disulfide; the English name is Octreotide Acetate. It was synthesized in 1982 by Sandoz company in Switzerland. In 1988, U.S. FDA approved octreotide acetate for the treatment of gastrointestinal secretion tumors, pituitary tumors and acromegaly; in 1998, U.S. FDA approved octreotide acetate for extremity Treatment of terminal obesity. [0003] [0004] The disclosed preparation methods of octreotide mainly contain two kinds: solid-phase method and liquid-phase method...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/04C07K1/06
CPCC07K7/06
Inventor 王卫国王克全朱家培
Owner JIANGSU GENSCRIPT BIOTECH CO LTD