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, severe reaction conditions, etc., and achieve high yield and few side reactions , the effect of fast reaction rate

Active Publication Date: 2005-01-26
SINOPHARM A THINK PHARMA
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  • Abstract
  • Description
  • Claims
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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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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 of p-carboxybenzaldehyde, and add 100mg of p-toluenesulfonic acid, and then heat and reflux in a water bath at 60°C. TLC monitoring, after the reaction was complete, the solvent was concentrated under reduced pressure on a rotary evaporator to obtain a light yellow viscous substance. After diluting the viscous matter, it was subjected to silica gel chromatography, and the developing solution was dichloromethane: ethyl acetate (3:1). The solution was collected, and 3.0 g of the product was obtained after distillation.

[0065] Wherein Fmoc-Thr-ol can be used directly, and can also be prepared by the following embodiment method:

[0066] Add Fmoc-Thr-OH (7.5g) into 100ml THF to dissolve, then add ethyl chloroformate 3.1mL, NMM 3.5mL, and react at 0°C for 10min, then add NaBH 4 1.50g, reacted for 10min and then stir...

Embodiment 2

[0067] Example 2 Synthesis of the first peptide

[0068] 1) Add NMP (30ml) to the acetalization product (3.4g), DCC (1.2g), HOBt (1.6g) under ice-cooling, electromagnetically stir, 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 ammonia gas into it and stir for 60 minutes.

[0070] 3) Add the reaction solution of the acetalization product into 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) Press out the reaction solution with gas through the waste liquid outlet, wash with dichloromethane, then add 30 mL of dichloromethane, 1.5 mL of acetic anhydride and 1.5 mL of pyridine to the resin in the solid-phase reactor, and stir at room temperature for 2 hours.

[0073] 2) Press out the reaction solution with gas through the waste liquid outlet, wash with dichloromethane, then add 15 mL each of hexahydropyridine and dimethylformamide, and react at room temperature for 1 hour.

[0074] 3) The reaction solution is pressed out through the waste liquid outlet with gas, cleaned with dichloromethane, then Fmoc-Cys(Trt)-OH (4.34g), HOBt (1.10g), HBTU (3.10g) are added to the In the solid-phase reactor of the reaction resin in the previous step, NMP (30 ml) was added thereto, and nitrogen gas was introduced at the same time, and the reaction was carried out overnight at room temperature for 16 hours.

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Abstract

The invention discloses the solid-phase synthesis process of octreotide acetate which consists of, bonding acetal product with macromolecular resin, merging the bonded products with protection amino acid residue in sequence to obtain octapeptide resin, cutting the octapeptide from the resin to obtain aqueous solution, carrying out naturally oxidation in air to obtain Octreotide, charging glacial acetic acid into Octreotide aqueous solution, and freeze-drying.

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 variceal bleeding caused by liver cirrhosis, combined with special treatment (such as endoscopic sclerosing agent treatment), peptic ulcer and emergency ulcer , acute pancreatitis, acute pancreatitis, prevention of complications after pancreatic surgery, acromegaly patients who have failed surgery, radiation therapy or dopamine receptor agonist therapy, can control symptoms, 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 undergo surgery, and for patients in...

Claims

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Application Information

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