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Method for solid-liquid synthesis of leuprorelin

A technology for leuprolide and solid-liquid synthesis, which is applied to the preparation methods of peptides, chemical instruments and methods, organic chemistry, etc., can solve the problems of low product yield and low purity, and achieve high purity, improve purity, and purity. Good results

Pending Publication Date: 2022-04-05
HUNAN SANTAI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Therefore, the technical problem to be solved in the present invention is to overcome the defects of low product yield and low purity in the prior art, thereby providing a method for solid-liquid synthesis of leuprolide

Method used

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  • Method for solid-liquid synthesis of leuprorelin
  • Method for solid-liquid synthesis of leuprorelin
  • Method for solid-liquid synthesis of leuprorelin

Examples

Experimental program
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Embodiment 1

[0069] A method for solid-liquid synthesis of leuprolide, comprising the following steps:

[0070] S1. Compound 1 was synthesized by polypeptide solid-phase method:

[0071] Boc-Pyr-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-OH;

[0072] S2. Synthesis of compound 2: D-Leu-Leu-OMe by polypeptide liquid phase method;

[0073] S3. Compound 3 was synthesized by polypeptide liquid phase method: H-Arg(pbf)-Pro-NHEt;

[0074] S4, compound 4 is synthesized in liquid phase:

[0075] Boc-Pyr-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-D-Leu-Leu-OMe;

[0076] S5. Compound 5 is synthesized in liquid phase:

[0077] Boc-Pyr-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-D-Leu-Leu-OH;

[0078] S6, compound 6 synthesized by liquid phase method:

[0079] Boc-Pyr-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-D-Leu-Leu-Arg(pbf)-Pro-NHEt

[0080] S7. Synthesis of crude leuprolide: Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt.

[0081] In step S1, compound 1 is synthesized sequentially from C to N-terminus by a solid-phase me...

Embodiment 2

[0151] The difference from Example 1 is that the molar ratio of compound 1 and compound 2 in step S4 is 1:1.5; the molar ratio of compound 5 and compound 3 in step S6 is 1:1.5. All the other are with embodiment 1.

[0152] The yield of the obtained leuprolide crude product was 83.3%, and the purity was 90.1%.

Embodiment 3

[0154] The difference from Example 1 is that compound 1 is synthesized after recovering the resin used in step S1. The recycling steps are as follows:

[0155] 1) the resin is washed with DMF;

[0156] 2) washing with methanol, taking out the filtrate, and drying in vacuum;

[0157] 3) Prepare a DCM solution of thionyl chloride and add it to a solid-phase synthesis reactor equipped with resin. After reacting for 2 hours, remove the reaction liquid, wash with DCM, wash and dry with methanol for later use. All the other are with embodiment 1.

[0158] The yield of the obtained leuprolide trifluoroacetate crude product was 82.9%, and the purity was 90%.

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Abstract

The invention provides a method for solid-liquid synthesis of leuprorelin, and belongs to the technical field of medicine synthesis. The method comprises the following steps: S1, synthesizing a compound 1: Boc-Pyr-His (Boc)-Trp (Boc)-Ser (tBu)-Tyr (tBu)-OH by using a solid phase method; s2, synthesizing a compound 2, namely D-Leu-Leu-OMe, by using a liquid phase method; s3, synthesizing a compound 3: H-Arg (pbf)-Pro-NHEt by using a liquid phase method; s4, synthesizing a compound 4 in the liquid phase by taking the compound 1 and the compound 2 as reaction units; S5, saponifying the compound 4 in the liquid phase to synthesize a compound 5; s6, synthesizing a compound 6 by taking the compound 3 and the compound 5 as reaction units through a liquid phase method; and S7, removing a side chain protecting group from the compound 6 to synthesize a leuprorelin crude product. The purity of the leuprorelin crude product synthesized by the method provided by the invention is more than 90%.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a method for solid-liquid synthesis of leuprolide. Background technique [0002] Leuprorelin, English name Leuprorelin, chemical name: 5-oxo-prolyl-histidyl-tryptophanyl-seryl-tyrosyl-D-leucyl-leucyl-arginyl -N-ethyl-prolinamide, CAS number: 53714-56-0, peptide sequence: Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt, molecular formula: C 61 h 88 N 16 o 14 , Molecular weight: 1209.41, is a gonadotropin drug, villous solid, commonly used clinically for endometriosis; uterine fibroids accompanied by menorrhagia, lower abdominal pain, low back pain and anemia; premenopausal breast cancer, And estrogen receptor positive patients; prostate cancer; central precocious puberty. Leuprolide is a nonapeptide amide analogue of luteinizing hormone releasing hormone first discovered by Fujino Masahiko et al. of Takeda Chemical Industry in Japan in 1974. It has good activity a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/04C07K1/08C07K1/02
Inventor 孙鹏程潘静唐勇擘杜一雄陈秋阳黄华黎明宋艳辉
Owner HUNAN SANTAI PHARM CO LTD