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Method for synthesizing leuprorelin in full liquid phase

A liquid-phase synthesis, leuprolide technology, applied in the field of medicine, can solve the problems of low product crude product purity, high cost, high environmental protection pressure and the like

Inactive Publication Date: 2021-12-31
HUNAN SANTAI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, at present, leuprolide is mainly prepared by solid-phase reaction, which has high cost, many solvents are used, environmental protection pressure is high, and the purity of the crude product is low.

Method used

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  • Method for synthesizing leuprorelin in full liquid phase
  • Method for synthesizing leuprorelin in full liquid phase
  • Method for synthesizing leuprorelin in full liquid phase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] 1. Synthesis of compound 1: Fmoc-Trp(Boc)-Ser(tBu)-Tyr(tBu)-OH

[0067] 1.1 Feeding:

[0068] Feed according to the materials in Table 2.

[0069] Table 2 Types and dosage of materials

[0070] abbreviation Dosage Fmoc-Trp(Boc)-Ser(tBu)-OSU 100mmol H-Tyr(tBu)-OH 110mmol TEA 110mmol DMF 400ml 0.5M hydrochloric acid solution 1L

[0071] 1.2 Operation process

[0072] After the synthesized Fmoc-Trp(Boc)-Ser(tBu)-OSu was completely dissolved in DMF, the H-Tyr(tBu)-OH was accurately weighed and added to the above reaction flask, and TEA 110mmol was added to start the reaction. After stirring and reacting for 60 min, HPLC detected that the reaction was complete.

[0073] The reaction solution was poured into the Erlenmeyer flask twice, and then 0.5M hydrochloric acid was added to rapidly stir and precipitate, and the filtered solid was then washed with purified water until neutral, and dried at 30°C. Collect the solids int...

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Abstract

The invention provides a method for synthesizing leuprorelin in a full liquid phase, which comprises the following steps: carrying out condensation reaction on R4-Pyr-His(R3)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-D-Leu-Leu-OH and H-Arg(pbf)-Pro-NHEt to obtain R4-Pyr-His(R3)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-D-Leu-Leu-Arg(pbf)-Pro-NHEt, and then carrying out reaction on the R4-Pyr-His(R3)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-D-Leu-Leu-Arg(pbf)-Pro-NHEt in the cutting fluid to obtain leuprorelin. Compared with the prior art, the method adopts a full liquid phase synthesis method, the production process is green and mild, any highly toxic and precursor reagent is not used, the purity of the product is high, the crude product can reach 90% or above, the cost is greatly reduced, and the preparation method is very suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing leuprolide in full liquid phase. Background technique [0002] Leuprolide is a gonadotropin-releasing hormone (GnRH) with a structure of Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt. Clinically, leuprolide is often used in endometriosis, uterine fibroids with menorrhagia, lower abdominal pain, low back pain and anemia, premenopausal breast cancer, and estrogen receptor positive patients, prostate cancer, central nervous system Sexual precocious puberty. [0003] Leuprolide was first discovered in 1974 by Fujino Masahiko et al. of Takeda Chemical Industry in Japan that the nonapeptide amide analogue of luteinizing hormone releasing hormone has good activity, and invented the synthesis process. It has applied for patents in Japan, Germany, the United States and other countries, and the patent numbers are JP19740027442, DE2446005, US4008209 and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/02
CPCC07K7/23Y02P20/55
Inventor 孙鹏程唐勇擘王志锋杜一雄郭林余辅松
Owner HUNAN SANTAI PHARM CO LTD
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