Method for preparing leuprorelin acetate, product and application

A technology of leuprolide acetate and resin, which is applied in the field of medicine, can solve the problems of short service life of fillers, low yield, and high product safety.

Active Publication Date: 2012-05-23
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

[0003] At present, the synthesis of domestic leuprolide crude products mostly adopts the Fmoc (fluorenylmethoxycarbonyl) protection method. Although the synthesis efficiency of this method is high and the reaction cycle is short, due to the need to adopt a large amount of hexahydropyridine, trifluoroacetic acid, Very toxic deprotection reagents such as ethanethiol and phenol have great environmental pollution and pose a greater risk to product safety
[0004] And in the purifying process of leuprolide, although domestic basically all use C18 liquid chromatography column chromatography stuffing to purify, but the buffer system that adopts trifluoroacetic acid-acetonitrile-water to purify more in the present technique, this method The yield is low, and at the same time, more toxic reagents such as trifluoroacetic acid are brought into the product; at the same time, because the crude leuprolide is directly subjected to C18 chromatography, the service life of the packing is very short

Method used

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  • Method for preparing leuprorelin acetate, product and application
  • Method for preparing leuprorelin acetate, product and application
  • Method for preparing leuprorelin acetate, product and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] 1. Preparation of Boc-Pro-

[0067] Weigh 103.2g of Boc-Pro in a 3L three-necked flask and dissolve it in 600ml of methanol. Weigh 101.4g of Cs in a 1L three-neck flask 2 CO 3 Dissolved in 600mlH 2 Slowly add to the above Boc-Pro solution in O to obtain a colorless and transparent Boc-Pro-Cs solution with a pH value of 7.0-7.5; concentrate under reduced pressure in a water bath at 40°C, evaporate the solvent to obtain a solid Add methanol 250ml, evaporate to dryness under reduced pressure, add methanol 250ml and evaporate to dryness under reduced pressure again, in P 2 o 5 Dry under reduced pressure in a desiccator to constant weight to obtain 160-185 g of dried Boc-Pro-Cs.

[0068] Weigh the resin Cl-CH 2 - Put 300g in a 3L Erlenmeyer flask; add the above-mentioned Boc-Pro-Cs into anhydrous DMF solvent, heat to 40°C, pour the Boc-Pro-Cs into the resin after dissolving, then rinse the three-necked flask with anhydrous DMF, Merge into the resin, share 1000ml o...

Embodiment 2

[0162] Example 2 is a comparison of the yield and purity of the leuprolide acetate product prepared by the existing production process with the leuprolide acetate product prepared in Example 1 of the present invention, see Table 3.

[0163] Table 3 existing technology and the leuprolide acetate product that technology of the present invention prepares compares

[0164] Finished product HPLC purity

[0165] As can be seen from Table 3, the HPLC purity of the leuprolide acetate product prepared by the method provided by the invention is high, and the yield of the finished product is also high.

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Abstract

The invention provides a method for preparing leuprorelin acetate. The method comprises the following steps of: Boc-Pro-(p)preparation-solid phase peptide connection-aminolysis-HPLC (High Performance Liquid Chromatography) purification-concentration-filtering and drying, wherein in the solid-phase peptide connection step, obtaining a leuprorelin nonapeptide resin by preparing raw materials and connecting dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide and nonapeptide. According to the preparation method provided by the invention, the leuprorelin acetate with higher purity and yield can be obtained, the preparation process has little pollution to environments and the safety of the product is high.

Description

technical field [0001] The invention relates to a method for preparing leuprolide acetate, which belongs to the field of medicine. Background technique [0002] Leuprorelin acetate (Leuprorelin Acetate), which belongs to the raw material drug, is a highly active derivative of artificially synthesized luteinizing-releasing hormone (LH-RH), widely used in the treatment of premature puberty, endometriosis, uterine fibroids Or premenopausal female patients such as breast cancer and male patients such as prostate cancer. [0003] At present, the synthesis of domestic leuprolide crude products mostly adopts the Fmoc (fluorenylmethoxycarbonyl) protection method. Although the synthesis efficiency of this method is high and the reaction cycle is short, due to the need to adopt a large amount of hexahydropyridine, trifluoroacetic acid, Very toxic deprotection reagents such as ethanethiol and phenol are very polluting to the environment and pose a greater risk to product safety. [0...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/20C07K1/06C07K1/04A61K38/09A61P5/24A61P15/00A61P35/00
Inventor 万龙岩籍晓涛肖建国王林鹏谢振东程元亨
Owner 上海丽珠制药有限公司
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