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All-solid-phase method for synthesizing octreotide

A solid-phase synthesis, octreotide technology, applied in the field of pharmaceutical synthesis, can solve the problems of shortening the preparation time, reducing the production cost, etc., and achieve the effects of shortening the preparation time, reducing the production cost, high purity and total yield

Active Publication Date: 2018-03-09
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these two methods still have not achieved an all-solid-phase synthesis scheme. Due to technical reasons, it is still impossible to achieve high total yield and high purity under the conditions of all-solid-phase synthesis in the current domestic technology, while the real all-solid-phase Synthesis can greatly simplify the preparation process, shorten the preparation time, and reduce production costs

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the synthesis of linear heptapeptide resin

[0042] Take 0.15 mol Fmoc-Cys (Trt) and 0.15 mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15 mol DIC, slowly add it to the protected amino acid DMF solution under stirring, and stir and react at room temperature for 30 minutes to obtain the activated Protected amino acid solution, spare.

[0043] Take 0.05mol of Boc-Thr(Bzl)-OL-Merrifield resin (substitution value about 0.5mmol / g), deprotect with 30% TFA / DCM solution for 30 minutes, neutralize with DIEA / DCM solution, wash with DMF and DCM Filter, add the activated Fmoc-Cys (Trt) solution, stir at room temperature for 3 hours, remove the reaction solution, wash 3 times with DMF, wash 3 times with DCM, each washing time is 3min, and then use 20% PIP / DMF The solution was deprotected for 25 minutes, washed and filtered to complete the access of Fmoc-Cys(Trt).

[0044] Fmoc-Thr(tBu), Fmoc-Lys(Boc), Fmoc-D-Trp, Fmoc-Phe and Fmoc-Cys(...

Embodiment 2

[0045] Embodiment 2: the synthesis of linear heptapeptide resin

[0046] Take 0.15 mol Fmoc-Cys (Trt) and 0.15 mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15 mol DIC, slowly add it to the protected amino acid DMF solution under stirring, and stir and react at room temperature for 30 minutes to obtain the activated Protected amino acid solution, spare.

[0047] Take 0.05mol of Boc-Thr(Bzl)-OL-Merrifield resin (substitution value about 0.5mmol / g), deprotect with 30% TFA / DCM solution for 30 minutes, neutralize with DIEA / DCM solution, wash with DMF and DCM Filter, add the activated Fmoc-Cys (Trt) solution, stir at room temperature for 3 hours, remove the reaction solution, wash 3 times with DMF, wash 3 times with DCM, each washing time is 3min, and then use 20% PIP / DMF The solution was deprotected for 25 minutes, washed and filtered to complete the access of Fmoc-Cys(Trt).

[0048] Insert Fmoc-Thr(tBu), Fmoc-Lys(Boc), Fmoc-D-Trp(Boc), Fmoc-Phe a...

Embodiment 3

[0049] Embodiment 3: the synthesis of linear heptapeptide resin

[0050] Take 0.15mol Fmoc-Cys (Acm) and 0.15mol HOBt, and dissolve it with an appropriate amount of DMF; take another 0.15mol DIC, slowly add it to the protected amino acid DMF solution under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid solution, set aside.

[0051] Take 0.05mol of Boc-Thr(Bzl)-OL-Merrifield resin (substitution value about 0.5mmol / g), deprotect with 30% TFA / DCM solution for 30 minutes, neutralize with DIEA / DCM solution, wash with DMF and DCM Filter, add the activated Fmoc-Cys (Trt) solution, stir at room temperature for 3 hours, remove the reaction solution, wash 3 times with DMF, wash 3 times with DCM, each washing time is 3min, and then use 20% PIP / DMF The solution was deprotected for 25 minutes, washed and filtered to complete the access of Fmoc-Cys (Acm).

[0052] Fmoc-Thr(tBu), Fmoc-Lys(Boc), Fmoc-D-Trp, Fmoc-Phe and Fmoc-Cys(...

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PUM

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Abstract

The invention relates to the field of medicinal synthesis and discloses a method for synthesizing octreotide. According to the method disclosed by the invention, special Boc-Thr(Bzl)-OL-Merrifield serves as an initial resin, an iodine oxidation method, a trifluoroacetic acid solution acidolysis resin of hydrogen bromide, protecting groups and other manners are matched to realize all-solid-phase preparation of the octreotide. Finally, the prepared octreotide has high purity and total yield. Meanwhile, the preparation process is greatly simplified, the preparation time is shortened, and the production cost is reduced.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for all-solid-phase synthesis of octreotide. Background technique [0002] 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. This product has a variety of physiological activities, such as inhibiting the pathological hypersecretion of growth hormone, thyrotropin, gastrointestinal and pancreatic endocrine hormones, and also inhibiting the secretion of gastric acid, pancreatic enzymes, glucagon and insulin. Octreotide can reduce gastric motility and gallbladder emptying, inhibit gallbladder emptying, inhibit the secretion of cholecystokinin-pancreatin, reduce pancreatic secretion, and have a direct protective effect on pancreatic parenchymal cell membranes. This product can inhibit gastrointestina...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04
CPCC07K7/06Y02P20/55
Inventor 王晓莉郭德文曾德志文永均
Owner CHENGDU SHENGNUO BIOPHARM
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