Method for synthesizing leuprorelin from polypeptide solid-liquid fragment

A leuprolide and peptide solid-liquid technology, applied in the field of medicine, can solve the problems of difficult management, inconvenient transportation and storage, and high production costs, and achieve the effects of convenient transportation and storage, convenient automatic production, and reduced production costs

Inactive Publication Date: 2021-01-29
湖南津安生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The solid-phase synthesis method of leuprolide provided by this scheme uses aminolysis to obtain the terminal amido group, and uses piperidine as the capping reagent. The price is high, and it is a liquid precursor reagent, which is difficult to manage and easy to deteriorate.
[0016] The existing synthetic method of leuprolide still has the problems of relatively high production cost in the synthetic steps, the uncapping reagent is a precursor reagent, the price is relatively high, and it is inconvenient to transport and store.

Method used

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  • Method for synthesizing leuprorelin from polypeptide solid-liquid fragment
  • Method for synthesizing leuprorelin from polypeptide solid-liquid fragment
  • Method for synthesizing leuprorelin from polypeptide solid-liquid fragment

Examples

Experimental program
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Effect test

Embodiment 1

[0077] A method for synthesizing leuprolide from polypeptide solid-liquid fragments, comprising the following steps:

[0078] 1) Compound 1 was synthesized by polypeptide solid-phase synthesis:

[0079] Boc-Pglu-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-D-Leu-Leu-OH;

[0080] 2) Compound 2: H-Arg(pbf)-Pro-NHEt was synthesized by polypeptide liquid phase synthesis;

[0081] 3) Synthesis of compound 3 in liquid phase:

[0082] Boc-Pglu-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-D-Leu-Leu-Arg(pbf)-Pro-NHEt;

[0083] 4) Synthesis of crude leuprolide: Pglu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt.

[0084] Further, in step 1), the compound 1 can be synthesized sequentially from C to N-terminus by a solid-phase method, and the steps include:

[0085] 1) The solid phase carrier is CTC resin;

[0086] Amino acid monomers are Boc-Pglu-OH, Fmoc-His(Boc)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-D- Leu-OH, Fmoc-Leu-OH;

[0087] The condensing agent is one of HBTU, HATU, TATU...

Embodiment 2

[0170] The difference from the above examples is that Compound 1 is synthesized by recycling the resin:

[0171] 1. Resin recycling;

[0172] 1). The resin of Example 1 was washed with DMF, washed with methanol, and the filtrate was sucked out, and dried in vacuum.

[0173] 2). Separately prepare a DCM solution of thionyl chloride (thionyl chloride 10ml, DCM=200ml), add it to a 250ml solid-phase synthesis reactor filled with resin, react for 2 hours, remove the reaction solution, and wash with DCM.

[0174] The feeding table is as follows:

[0175]

[0176]

[0177] Two, the synthesis of Leu-resin;

[0178] 1). Weigh 25g of CTC resin in a 250ml solid-phase synthesis reactor, take Fmoc-Leu-OH in a 250ml Erlenmeyer flask, measure 120ml of DCM in a 100ml graduated cylinder, shake well, add 41ml of DIEA, shake well to dissolve, pour into the reactor to start the reaction. When reacting for 1 hour, remove the reaction solution with a suction filter and wash 4 times with DM...

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Abstract

The invention provides a method for synthesizing leuprorelin by using a polypeptide solid-liquid fragment. The method comprises the following steps: 1) synthesizing a compound 1: Boc-Pglu-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-D-Leu-Leu-OH by a polypeptide solid phase synthesis method; 2) synthesizing a compound 2: H-Arg(pbf)-Pro-NHEt by using a polypeptide liquid phase synthesis method; (3) synthesizing a compound 3: Boc-Plu-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-D-Leu-Leu-Arg(pbf)-Pro-NHEt in a liquid phase; 4) synthesizing a leuprorelin crude product, namely Pglu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt. Piperazine is used as an uncapping reagent, CTC resin is used for synthesizing a fragment, a liquid phase method is combined for synthesizing leuprorelin, and the CTC resin synthesized fragmentcan be conveniently and automatically produced; CTC resin can be recycled, piperazine is not a precursor reagent, the cost of piperazine is lower than that of a precursor reagent piperidine used in aclassical synthesis method, and piperazine is more convenient to transport and store; the method is suitable for large-scale industrial production, does not have violent chemical reaction, and lowersthe production cost.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing leuprolide from polypeptide solid-liquid fragments. 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-NH-Et, 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 goo...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/04C07K1/06
CPCC07K7/23
Inventor 孙鹏程
Owner 湖南津安生物科技有限公司
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