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Solid-phase synthesis process of octreotide acetate

A technology for solid-phase synthesis of octreotide acetate, which is applied in the field of solid-phase synthesis of octreotide acetate, can solve the problems of long liquid-phase synthesis preparation time, strong corrosive environmental pollution, waste of organic solvents, etc., and achieve high yield and few side reactions , the effect of less by-products

Active Publication Date: 2006-05-03
SINOPHARM A THINK PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] With comprehensive reference to the characteristics of the synthetic methods of octreotide at home and abroad, we have systematically explored the solid-phase octreotide synthetic methods of relevant reports and the liquid-phase synthetic methods of octreotide in domestic literature, and have drawn some deficiencies in the methods in the technology, mainly as follows: 1 .The preparation time in the liquid phase synthesis is long, and the product in each step needs to be further purified, and the final salt conversion process is time-consuming and wastes organic solvents
2. The reaction conditions of Boc-HF deprotection system are severe, and HF is highly corrosive and pollutes the environment

Method used

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  • Solid-phase synthesis process of octreotide acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063]Example 1: Synthesis of Fmoc-Thr-ol-Acetal

[0064] Add Fmoc-Thr-ol (3.28g) into a four-necked flask, dissolve it with anhydrous chloroform (200ml), add 1.90g p-carboxybenzaldehyde, and add 100mg p-toluenesulfonic acid, and then heat and reflux in a water bath at 60°C for reaction. TLC monitoring, after the completion of the reaction, concentrated under reduced pressure on a rotary evaporator to remove the solvent to obtain a light yellow viscous substance. After diluting the viscous substance, it was chromatographed on silica gel, using the developing solution dichloromethane: ethyl acetate (3:1), collecting the solution, and distilling to obtain 3.0 g of the product.

[0065] Among them, Fmoc-Thr-ol can be used directly, or can be prepared by the following example method:

[0066] Fmoc-Thr-OH (7.5g) was added to 100ml THF to dissolve, then 3.1mL ethyl chloroformate and 3.5mL NMM were added, and reacted at 0℃ for 10min, then NaBH was added 1 1.50g, reacted for 10min, stirre...

Embodiment 2

[0067] Example 2 Synthesis of the first peptide

[0068] 1) Add NMP (30ml) to the acetalized product (3.4g), DCC (1.2g) and HOBt (1.6g) in an ice bath, stir electromagnetically, and react at room temperature for 1 hour.

[0069] 2) Put the resin (5.00g) in a solid phase reactor, add dichloromethane / dimethylformamide=1 / 1 30ml solvent, and pass high-purity nitrogen through it and stir for 60 minutes.

[0070] 3) Add the reaction solution of the acetalization product to the solid phase reactor, ventilate and stir, and react at room temperature for 16 hours.

Embodiment 3

[0071] Example 3: Synthesis of the second peptide

[0072] 1) The reaction solution was forced out through the waste liquid outlet with gas, washed with dichloromethane, and then 30 mL of dichloromethane and 1.5 mL of acetic anhydride and 1.5 mL of pyridine were added to the resin in the solid phase reactor, and the reaction was stirred at room temperature for 2 hours.

[0073] 2) The reaction solution was forced out through the waste liquid outlet with gas, washed with dichloromethane, and then 15 mL each of hexahydropyridine and dimethylformamide were added, and reacted at room temperature for 1 hour.

[0074] 3) The reaction solution was forced out through the waste liquid outlet with gas, washed with dichloromethane, and then Fmoc-Cys(Trt)-OH (4.34g), HOBt (1.10g), HBTU (3.10g) were added to the container In the solid phase reactor where the resin was reacted in the previous step, NMP (30 ml) was added to it, while nitrogen gas was introduced, and the reaction was carried out ...

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Abstract

The solid-phase synthesis method of octreotide acetate of the present invention belongs to the field of polypeptide synthesis. First, the acetalization product is bonded to a polymer resin; the bonded product is sequentially bonded to the protected amino acid residues and deprotected to obtain an octapeptide resin; the octapeptide is cut from the resin to make an aqueous solution, and Octreotide is made after natural oxidation in the air; glacial acetic acid is added to the octreotide aqueous solution and then freeze-dried to make octreotide acetate. The invention has simple synthesis process, easy operation, shortened process time, small reaction ratio, saved raw materials, reduced cost, improved yield and purity, fewer side reactions and by-products, convenient purification, and beneficial to mass production.

Description

Technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a solid-phase synthesis method of octreotide acetate. Background technique [0002] The structure of octreotide acetate is a polypeptide containing 7 amino acid residues and 1 threoninol. Octreotide Acetate is mainly clinically used in the treatment of the following diseases: emergency treatment of esophageal-gastric varices bleeding caused by liver cirrhosis, combined with special treatments (such as endoscopic sclerotherapy), peptic ulcer and emergency ulcer , Acute pancreatitis, acute pancreatitis, prevention of post-pancreatic complications, patients with acromegaly who have failed surgery, radiotherapy or dopamine receptor agonist therapy, can control symptoms and reduce the concentration of growth hormone and growth hormone medium C . It is also suitable for patients with acromegaly who are unable or unwilling to operate, as well as patients with intermittent periods for whi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06A61K9/19A61K38/08A61P1/04A61P1/18
Inventor 贾志丹王恩思
Owner SINOPHARM A THINK PHARMA
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