Preparation method of buserelin or goserelin

A technology for goserelin and protection of goserelin, which is applied in the field of preparation of buserelin or goserelin, can solve the problems of uncertainty, increase the impurity content, and is difficult to remove, and achieves mild reaction conditions and easy operation. Simple, selective effect

Active Publication Date: 2018-01-05
HYBIO PHARMA
View PDF9 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

We found that the Trt protecting group in His(Trt) is difficult to remove by conventional hydrogen transfer reaction or catalytic hydrogenolysis or the reaction is very slow. The content of large impurities
Therefore, in actual production, the dichloromethane solution of TFA is currently used for removal, but this method will inevitably have two problems: (1) the tert-butyl ether of D-Ser that needs to be retained in the molecule is also sensitive to acid group, so there will be a side reaction to remove the tert-butyl ether; (2) after the reaction is completed, when the reaction solvent is evaporated under reduced pressure, the composition ratio of TFA in the reaction system will continue to change, and the distillation time will also be affected

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of buserelin or goserelin
  • Preparation method of buserelin or goserelin
  • Preparation method of buserelin or goserelin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Synthesis of embodiment 1 fully protected peptide resin

[0031] Weigh 55.0 g (50 mmol) of 2-CTC resin with a substitution degree of 0.91 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes. Weigh 33.7g (100mmol) Fmoc-Pro-OH, add appropriate amount of DMF to dissolve, add 12.9g (100mmol) DIPEA under ice-water bath, stir for 4-6 minutes, then add to the resin, after coupling reaction for 5 minutes, add more 12.9g (100mmol) DIPEA, after coupling reaction 1 hour, add methanol 55ml in the reaction solution, after blocking reaction 20 minutes, extract reaction solution, DMF washes resin three times, obtains Fmoc-Pro-CTC resin.

[0032] Add DBLK for deprotection for 5+7 minutes, and wash the resin 6 times with DMF. Weigh 66.2g (150mmol) Fmoc-Arg (NO 2 )-OH and 22.5g (165mmol) HOAt were dissolved with an appropriate amount of DMF. Add 22.6g (180mmol) DICPDI in an ice-water bath, stir for 4 to 6 minutes, add to...

Embodiment 2

[0035] The synthesis of embodiment 2 fully protected peptide resins

[0036]Weigh 48.4 g (30 mmol) of 2-CTC resin with a substitution degree of 0.62 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes. Weigh 20.2g (60mmol) Fmoc-Pro-OH, add appropriate amount of DMF to dissolve, add 7.7g (60mmol) DIPEA under ice-water bath, stir for 4-6 minutes, then add to the resin, after coupling reaction for 5 minutes, add more 7.7g (60mmol) DIPEA, after coupling reaction 1 hour, add methanol 45ml in the reaction solution, after blocking reaction 20 minutes, extract reaction solution, DMF washes resin three times, obtains Fmoc-Pro-CTC resin.

[0037] Add DBLK for deprotection for 5+7 minutes, and wash the resin 6 times with DMF. Weigh 39.7g (90mmol) Fmoc-Arg (NO 2 )-OH and 13.5g (99mmol) HOAt were dissolved with an appropriate amount of DMF. Add 13.6g (108mmol) DICPDI in an ice-water bath, stir for 4-6 minutes, add to the r...

Embodiment 3

[0040] Example 3 Cleavage Preparation of Fully Protected Crude Peptide

[0041] 101.5 g of the fully protected peptide resin obtained in Example 2 was added into a 2000 ml round bottom flask. Add pre-prepared TFA:DCM=2:98 (V:V) 1015ml, react at room temperature for 2.5 hours, filter the resin, and collect the filtrate. The resin was washed with a small amount of DCM, and the filtrates were combined. The filtrate was slowly added to 10.15 L of glacial ether for precipitation, centrifuged, washed twice with ether, and dried under reduced pressure to obtain 50.2 g of a fully protected crude peptide with an HPLC purity of 93.9%. The theoretical yield is 55.0 g, and the weight yield is 91.4%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention relates to a preparation method of buserelin or goserelin. The method comprises the following steps: 1) preparing Fmoc-Pro-resin by using 2-CTC resin as a carrier; 2) preparing fully-protected 9 peptide resin by a solid-phase synthesis technology; 3) pyrolyzing the fully-protected 9 peptide resin to obtain a fully-protected 9 peptide; 4) reacting the fully-protected 9 peptide with ethylamine hydrochloride under the action of a coupling agent to obtain fully-protected buserelin, or reacting the fully-protected 9 peptide with semicarbazide hydrochloride under the action of the coupling agent to obtain fully-protected goserelin; 5) carrying out a palladium-carbon catalyzed hydrogenolysis reaction on the fully-protected buserelin or the fully-protected goserelin in a solvent Z, and filtering out the palladium-carbon after the reaction is finished in order to obtain a buserelin solution or a goserelin solution; and 6) purifying and freeze-drying the buserelin solution or the goserelin solution to obtain the buserelin or goserelin, wherein the solvent Z in step 5) is a methanol solution containing 5% of pyridine hydrochloride or an aqueous solution containing 85-95% of acetic acid.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of buserelin or goserelin. Background technique [0002] Both Buserelin and Goserelin belong to gonadotropin-releasing hormone (GnRH) analogues, and their structures are represented by amino acid abbreviations: Pyr-His-Trp-Ser-Tyr-D-Ser( tBu)-Leu-Arg-Pro-R, when R=NHEt in buserelin, R=Azgly-NH in goserelin 2 , the structural formula is as follows: [0003] [0004] Currently, the synthesis methods of buserelin and goserelin include solid-phase synthesis and liquid-phase synthesis. Liquid phase synthesis methods are mostly found in early literature, such as WO97 / 48726 and EP1008656. However, the liquid-phase synthesis operation is complicated, and each synthesis step must be purified, which is not conducive to industrial production and has low application value. Since the D-Ser side chain tBu in buserelin and goserelin is not compatible with the Fmo...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07K7/23C07K1/16C07K1/10C07K1/06C07K1/04
Inventor 姚志军聂涛宓鹏程陶安进袁建成
Owner HYBIO PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap