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Synthesis method of high-purity leuprorelin

A technology of leuprolide and solid-phase method, which is applied in the field of high-purity leuprolide synthesis, can solve the problems of large ether consumption, increased production cost, unfavorable industrial production, etc., and achieves reduced racemization side reactions and mild reaction , to avoid the effect of excessive reaction

Active Publication Date: 2018-01-12
上海丽珠制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the cracking and precipitation process, a large amount of ether needs to be consumed, which increases the production cost and the cost of waste liquid treatment in the later stage, which is not conducive to industrial production
At the same time, this method cannot completely avoid the side reaction of diketopiperazine. When the production is scaled up, the side reaction of diketopiperazine will cause the peptide chain to fall off, which will significantly reduce the yield.
[0006] The currently published leuprolide preparation processes have certain defects, and cannot achieve a good combination in terms of operational complexity, risk, production cycle, total product yield, product cost, and environmental pollution. not tall

Method used

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  • Synthesis method of high-purity leuprorelin
  • Synthesis method of high-purity leuprorelin
  • Synthesis method of high-purity leuprorelin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Preparation of Fmoc-Pro-CTC resin

[0041] 1.1 Weigh 200g of CTC resin, add it to the reaction kettle, add 1500ml of DCM, make the resin fully swell in the DCM solvent, swell for 1h, and drain. If the reagent cannot completely soak the resin during the swelling process, additional reagent should be added as appropriate. Weigh 54.0g of Fmoc-Pro-OH, dissolve it with 700ml DCM, add 28ml DIEA and mix well, then add it into the reaction kettle, blow nitrogen gas from the bottom of the reaction kettle, and react for 120min.

[0042] 1.2 Head, prepare 800ml of methanol: DIEA:DCM (volume ratio 1:1:2) mixed solution; add it to the reaction kettle, and shake it with nitrogen for 20min. The reaction solution was drained and washed 4 times with DMF.

[0043] 1.3 The degree of substitution was measured by a spectrophotometer, and the degree of substitution was detected to be 0.51 mmol / g.

Embodiment 2

[0045] Preparation of Leuprolide Precursor Peptide-CTC Resin with Fully Protected Side Chains

[0046] Pyr-His(trt)-Trp(boc)-Ser(tbu)-Tyr(tbu)-D-Leu-Leu-Arg(pbf)-Pro-CTCResin

[0047] 2.1. Dipeptide connection

[0048] Deprotection: after the DMF washing is completed, add 700ml of 20% piperidine / DMF solution to the reactor (this value can be adjusted, it is advisable to fully mix the resin well, and react for 20min. The deprotection solution is drained, and the DMF is washed 8 times, 700ml each time. After washing, it can be detected by Kaiser reagent. If the value is reddish brown, it indicates that the deprotection is successful.

[0049] Peptide: Fmoc-Arg(pbf)-OH 97g(150mmol)

[0050] Hobt 20g (150mmol)

[0051] DIC 54ml (300mmol)

[0052] Put the weighed Fmoc-Arg(pbf)-OH and HOBT in a beaker, add DMF to dissolve them, then add DIC to the beaker for activation for 20 seconds, and mix well. Added to the reaction kettle and reacted for 60min. During the condensation pro...

Embodiment 3

[0097] Preparation of leuprolide precursor peptide with fully protected side chains:

[0098]Pyr-His(trt)-Trp(boc)-Ser(tbu)-Tyr(tbu)-D-Leu-Leu-Arg(pbf)-Pro-OH

[0099] Weigh the leuprolide precursor peptide-resin and add it to two 3L Erlenmeyer flasks. Prepare 20% trifluoroethanol / DCM solution according to 10ml of cutting reagent per gram of dry resin, after cooling in the refrigerator for 1 hour, add it into two reaction flasks respectively, shake at a speed of 100r / min, and react for 120min; Place in a rotary evaporator and evaporate to dryness under reduced pressure at 35°C to obtain 175.2 g of leuprolide precursor peptide, MS: 1889.

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Abstract

The invention provides a method for preparing leuprorelin. The method comprises the following steps: (1) taking Fmoc-Pro-CTC-OH and CTC (Carbon Tetrachloride) resin as starting raw materials and treating to obtain Fmoc-Pro-CTC-OH resin; (2) sequentially connecting the Fmoc-Pro-CTC-OH resin with an amino acid with a protecting group by adopting a gradual coupling manner of a Fmoc / tBu solid-phase method to synthesize side chain wholly-protected leuprorelin precursor peptide-resin; (3) taking a 20 percent trifluoroethanol / DCM (Dichloromethane) solution as a cutting reagent and cutting the side chain wholly-protected leuprorelin precursor peptide-resin, so as to obtain a side chain wholly-protected leuprorelin precursor peptide; (4) carrying out ethyl amination on the side chain wholly-protected leuprorelin precursor peptide to obtain side chain wholly-protected leuprorelin; (5) carrying out side chain cutting on the side chain wholly-protected leuprorelin to obtain a leuprorelin crude peptide; (6) carrying out CM purification and HPLC (High Performance Liquid Chromatography) purification, concentration, dissolving and freeze-drying on the leuprorelin crude peptide to obtain a high-purity leuprorelin crude drug. The method provided by the invention has the advantages of simplicity in operation, short period, low cost, high product yield and small environment pollution and is very suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a high-purity leuprolide synthesis method combining a solid-phase method and a liquid-phase method. Background technique [0002] Leuprolide, the Chinese name of the preparation is Leuprorelin acetate, Yi Natong or Leuprolide for short, and the English name is Leuprorelinacetate, Enanton, Lucrin, etc. The indications for leuprolide are endometriosis; uterine fibroids accompanied by menorrhagia, lower abdominal pain, low back pain and anemia; premenopausal breast cancer patients with positive estrogen receptors; prostate cancer; Sexual precocious puberty. It is mainly used clinically for prostate cancer and endometriosis. [0003] Leuprolide was first discovered in 1974 by Fujino Masahiko et al. of Takeda Chemical Industry, Japan, and invented a synthetic process. As a nonapeptide amide analogue of luteinizing hormone releasing hormone, it has good activity. It has applied for...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/04C07K1/06C07K1/107C07K1/16C07K1/14
CPCY02P20/55
Inventor 单连民刘兵王林鹏安宁万龙岩张道桂江晓漫
Owner 上海丽珠制药有限公司
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