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A kind of synthetic method of industrialized production of octreotide

A synthetic method and technology of octreotide, applied in the field of synthesis of octreotide industrial production, can solve the problems of low purity and low yield of octreotide finished products, and the synthesis process is not suitable for large-scale industrial production, so as to reduce the number of subsequent purifications and reduce the yield. rate, avoiding the effects of long reaction times

Active Publication Date: 2020-06-02
苏州天马医药集团天吉生物制药有限公司
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The purpose of the present invention is to provide a synthetic method for the industrial production of octreotide, which solves the problems that the synthetic process existing in the above-mentioned prior art is not suitable for large-scale industrial production, and the purity of the finished product of octreotide is not high, and the yield is not high.

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  • A kind of synthetic method of industrialized production of octreotide
  • A kind of synthetic method of industrialized production of octreotide
  • A kind of synthetic method of industrialized production of octreotide

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Embodiment 1

[0054] Embodiment 1: A kind of synthetic method of industrialized production of octreotide

[0055] Budget produces 5mmol octreotide, and the synthetic method of octreotide comprises the following steps successively:

[0056] (1) Weigh 8.33g of AM Resin with a substitution degree of 0.60mmol / g and place it in a solid-phase reactor;

[0057] (2) Add 30ml of DCM / DMF mixed solvent to swell the resin for 30 minutes, wherein the volume ratio of DCM to DMF in the DCM / DMF mixed solvent is 1:1~3:1;

[0058] (3) Add 30ml of DMF to wash 6 times, remove the washing solution, weigh 6.6g of Fmoc-Thr-x, 2.025g of HOBT, put into the reaction column, add an appropriate amount of DMF to blow nitrogen, make it stir evenly, and then drop 2.32ml of DIC, reacted for 2~3h, the ninhydrin test showed colorless, if the color developed, repeated re-dosing until the reaction was colorless, and Fmoc-Thr-x-AM Resin was obtained;

[0059] (4) Take out the reaction solution, wash the resin twice with DMF,...

Embodiment 2

[0070] Embodiment 2: A kind of synthetic method of industrialized production of octreotide

[0071] Budget produces 200mmol octreotide, and the synthetic method of octreotide comprises the following steps successively:

[0072] (1) Weigh 350.8g of AM Resin with a substitution degree of 0.57mmol / g and place it in a solid-phase reactor;

[0073] (2) Add 1200ml of DCM / DMF mixed solvent to swell the resin for 30 minutes, wherein the volume ratio of DCM to DMF in the DCM / DMF mixed solvent is 1:1~3:1;

[0074] (3) Take out the swelling solution and add 1200ml of DMF to wash 6 times, take out the washing solution, weigh 265g of Fmoc-Thr-x and 81g of HOBT, put them into the reaction column, add an appropriate amount of DMF and blow nitrogen, make it stir evenly, and then Add 93ml of DIC dropwise, react for 2~3h, the ninhydrin test shows colorless, if the color develops, repeat re-dosing until the reaction is colorless, and get Fmoc-Thr-x-AM Resin;

[0075] (4) Take out the reaction ...

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Abstract

The invention relates to synthesis method for industrial production of octreotide. The method is characterized by comprising the following steps of: 1. taking aminomethyl resin as the starting resin, utilizing condensation reagents HOBT and DIC to couple the raw material Fmoc-Thr-x to the resin to generate Fmoc-Thr-x AM Resin; then coupling amino acids Cys, Thr, Lys, Trp, Phe, Cys and Phe to Fmoc-Thr-x AM Resin one by one in order, thus obtaining octreotide peptide resin; 2. adding a lysate solution, stirring the substances evenly and performing cracking for 2-3h; 3. dissolving octreotide crude peptide into a TFA / water mixed solution, then putting the mixture into 35DEG C-38DEG C water bath to perform heating for 2-3h to make the linear peptide of octreotide have single peak pattern in HP LC chromatogram; and 4. adding DMSO, then performing oxidation for 1-1.5h, conducting HPLC detection of a cyclization end point, and performing separation and purification to obtain a refined product of octreotide. In short, the synthesis method provided by the invention has simple technique, and is suitable for industrial production. After post-treatment, the HPLC peak pattern of octreotide crude peptide is simple, the cyclization method is easy to operate, cyclization is complete, the yield is high and the purity is 98% or more.

Description

technical field [0001] The invention belongs to the field of octreotide synthesis, and in particular relates to a synthesis method for industrial production of octreotide. Background technique [0002] The peptide sequence of octreotide acetate is as follows: D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-OL (Disulfidebridge cys2-cys7) mainly contains 7 conventional amino acids and a threoninol. Octreotide is a synthetic octapeptide cyclic compound, which has a similar effect to natural endogenous somatostatin, but has a stronger and lasting effect, and its half-life is 30 times longer than natural somatostatin. 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. It is mainly used clinically in the following aspects: esophageal variceal bleeding caused by portal h...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/14C07K1/10C07K1/06C07K1/04
CPCC07K7/06
Inventor 夏丹王良友陈逸民黄保胜徐瑞
Owner 苏州天马医药集团天吉生物制药有限公司
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