Solid-liquid synthesizing method for leuprorelin

A technology for leuprolide and solid-liquid synthesis, which is applied in the field of solid-liquid synthesis of leuprolide, can solve the problems of inconvenient cutting of liquid ethylamine, synthesis time of unsafe liquid phase fragments, etc., and shorten the synthesis time, Avoid inconvenient cutting and simplify cumbersome effects

Active Publication Date: 2008-06-11
GL BIOCHEM SHANGHAI
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  • Abstract
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Problems solved by technology

[0003] The purpose of the present invention is to provide a method for synthesizing leuprolide, which solves the problems of inconvenient and unsafe cutting of liquid ethylamine in the current solid-phase synthesis method and long synthesis time of liquid-phase fragments

Method used

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  • Solid-liquid synthesizing method for leuprorelin

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Embodiment 1

[0043] Example 1, with reference to the synthetic route, 5g of Arg(pbf).Trt(2-Cl)-ClResin (load: 0.4mmol / g) was placed in the peptide bottle and soaked in DMF solution, and Fomc-Leu-OH was added (molar ratio 1:3), DIC (molar ratio 1:1), HOBT (molar ratio 1:1), collidine (molar ratio 1:1), after shaking in a shaker at 25°C for 40min, wash 3 times with DMF, CH 2 Cl 2 Wash 3 times, then use 20% piperide-DMF solution to remove Fmoc, then use the same method to react sequentially until PGLu is connected, use 1% TFA-CH 2 Cl 2 The solution was cleaved to obtain 3gPGlu-His(Trt)-Trp-Ser(tBu)-Tyr(tBu)-(D)-Leu-Leu-Arg(Pbf)-OH. Dissolve 13g (60mmol) of BOC-Pro-OH in 100ml tetrahydrofuran, add 6.6ml (60mmol) of NMM, add 6ml (60mmol) of ethyl chloroformate at -10℃~-15℃, stir for 15~30min, then add ethylamine salt Acetate 4.8g (60mmol), stirred overnight at room temperature, after treatment to obtain the compound BOC-Pro-NHEt. The synthesized BOC-Pro-NHEt 6g was deprotected by 2mol / L dio...

Embodiment 2

[0044] Example 2, the fully protected polypeptide PGluR-8 (2mmol) and Pro-NHEt.HCl (2.2mmol) were dissolved in 100ml DMF, HOBt (2mmol), DIEA (4mmol) were added, stirred in an ice bath for 5-15min, and BOP ( 2mmol), after 25min, the ice bath was removed, and after stirring for 28 hours at 15°C, the fully protected peptide PGluP-9-NHEt was processed to obtain the fully protected peptide PGluP-9-NHEt, which was dissolved in the cutting solution (V / V%, trifluoroacetic acid: Cresol: water: thioanisole: thiol (82.5:5:5:5:2.5) was deprotected to obtain 1400 mg of crude leuprolide. All the other are identical with embodiment 1.

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Abstract

The invention relates to a synthesis method of leuprorelin, which can resolve the problems that prior art uses solid-phase synthesis which cuts leuprorelin from resin unsafely, and has long liquid phase synthesis time. The invention comprises a, solid-phase synthesizing whole-protected peptide chain PGIuR-8, b, synthesizing material Pro-NHEt. HCI, c, condensing liquid-phase fractions to synthesize whole-protected PGIuP-9-NHEt via using DIC or BOP to react for 24-36h at 10-30DEG C, d, removing protection to obtain crude leuprorelin. The invention can synthesize polypeptide whose C end is amide.

Description

Technical field: [0001] The invention relates to a synthesis method of leuprolide, in particular to a solid-liquid synthesis method of leuprolide. Background technique: [0002] Leuprolide acetate is a highly active derivative of luteinizing-releasing hormone (LH-RH), which is widely used in the treatment of women with precocious puberty, endometriosis, uterine fibroids or premenopausal breast cancer and prostate cancer and other male patients. In previous reports, leuprolide (ref: Tetrahedron.53, 9, 1997, 3179-3194) was synthesized by solid-phase synthesis, that is, Merrifield-like resin was used, and the first four amino acids from the carbon end were synthesized by the BOC method, and the latter The four amino acids are connected sequentially by the Fmoc method, and finally cleaved from the resin using ethylamine liquid. However, cutting with liquid ethylamine needs to be carried out under low temperature and pressure sealing, which is inconvenient in industrial product...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23
Inventor 徐红岩朱琦
Owner GL BIOCHEM SHANGHAI
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