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Method for preparing Leuprorelin by combination of solid phase method and liquid phase method

A technology of leuprolide and solid-phase method is applied in the field of preparing leuprolide by combining solid-phase method and liquid-phase method, which can solve problems such as low application value, complicated operation and production cycle, and achieves low cost and considerable Economical and practical value, less environmental pollution

Active Publication Date: 2012-11-28
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] 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; application value not tall

Method used

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  • Method for preparing Leuprorelin by combination of solid phase method and liquid phase method
  • Method for preparing Leuprorelin by combination of solid phase method and liquid phase method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The preparation of embodiment 1 Fmoc-Pro-HMPB-AM resin

[0045] Using HMPB-AM resin with a substitution degree of 0.2mmol / g for the reaction, the obtained Fmoc-Pro-HMPB-AM resin has a detection substitution degree of 0.15mmol / g, and the production process of the same molar amount consumes a large amount of resin and a large amount of solvent , uneconomical and not conducive to environmental protection, should not be used; the HMPB-AM resin with a substitution degree of 1.2mmol / g is used for the reaction, and the detection substitution degree of the obtained Fmoc-Pro-HMPB-AM resin can reach 0.87mmol / g, although the same The molar production process consumes a small amount of resin, but the purity of the obtained crude peptide is reduced by 30%, so that the downstream purification yield is reduced by 60-70%.

[0046] The more preferred scheme of this embodiment is to add 111.0 g of HMPB-AM resin, with a substitution degree of 0.9 mmol / g, into the solid-phase reaction colu...

Embodiment 2

[0047] Example 2 Preparation of Leuprolide Precursor Peptide-HMPB-AM Resin with Fully Protected Side Chains

[0048] Weigh 100 g of Fmoc-Pro-HMPB-AM resin (0.6 mmol / g, 60 mmol) into the reactor, wash once with DMF, and swell with DCM for 0.5 hours. After swelling, 20% DBLK was used to remove Fmoc protection, and then washed 4 times with DMF and 2 times with DCM. 77.76g Fmoc-Arg(pbf)-OH (120mmol), 24.315g HOBt (180mmol), 37.8g DCC were dissolved in DCM (a small amount of DMF can be added to aid dissolution), added to a solid phase reactor, and reacted at room temperature for 2h (reaction The end point was determined by the ninhydrin method). Repeat the above steps to complete Fmoc-Leu-OH, Fmoc-D-Leu-OH, Fmoc-Tyr-OH, Fmoc-Ser(Trt)-OH, Fmoc-Trp(Boc)-OH, Fmoc-His(Trt) )-OH and the linkage of remaining amino acids such as pGlu. After the pGlu coupling was completed, the resin was washed 3 times with DMF and 3 times with DCM, then shrunk with methanol, and dried overnight in a va...

Embodiment 3

[0049] Example 3 Preparation of Leuprolide Precursor Peptide-HMPB-AM Resin with Fully Protected Side Chains

[0050] Weigh 1111.1 g of Fmoc-Pro-HMPB-AM resin (0.45 mmol / g, 500 mmol) into the reactor, wash once with DMF, and swell with DCM for 0.5 hours. After swelling, 20% DBLK was used to remove Fmoc protection, and then washed 4 times with DMF and 2 times with DCM. With 648.8g Fmoc-Arg (pbf)-OH (1000mmol), 202.7g HOBt (1500mmol), 568.8g HBTU (1500mmol) are dissolved in DCM (can add a small amount of DMF to aid dissolution), add in the solid phase reactor, then 523.0ml (3000mmol) DIPEA was introduced into the reaction column, and reacted at room temperature for 2h (the end point of the reaction was determined by the ninhydrin method). Repeat the above steps to complete Fmoc-Leu-OH, Fmoc-D-Leu-OH, Fmoc-Tyr-OH, Fmoc-Ser(Trt)-OH, Fmoc-Trp(Boc)-OH, Fmoc-His(Trt) )-OH and the linkage of remaining amino acids such as pGlu. After the pGlu coupling was completed, the resin was was...

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Abstract

The invention discloses a new technique for synthesizing Leuprorelin by the combination of a solid phase method and a liquid phase method, which comprises the following steps of: 1) using Fmoc-Pro-OH and HMPB-AM resin as starting material, and obtaining Fmoc-Pro-HMPB-AM resin; 2) coupling in sequence and synthesizing Leuprorelin precursor peptide-HMPB-AM resin with full protective lateral chains;3) cutting the resin and obtaining Leuprorelin precursor peptide with full protective lateral chains; 4) processing the Leuprorelin precursor peptide with full protective lateral chains with methylamine, and obtaining Leuprorelin with full protective lateral chains; 5) removing the protective groups of the lateral chains of Leuprorelin with full protective lateral chains, and obtaining the crude product of Leuprorelin; and 6) conducting separation and purification and freeze drying to the crude product of Leuprorelin, and obtaining refined Leuprorelin peptide. The technology has the capability of large-scale production, easy operation, stable technique, low production cost and total yield of more than 50 percent, and has considerable economical and practical value and wide application prospect.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to a new process for preparing leuprolide by combining a solid-phase method and a liquid-phase method. Background technique [0002] Leuprorelin, the Chinese name of the preparation is Leuprorelin acetate, Innaton or Leuprolide for short, and the English name is Leuprorelin acetate, Enanton, Lucrin, etc. Its structure is: [0003] [0004] Molecular formula: C 59 h 84 N 16 o 12 [0005] Molecular weight: 1209.41 [0006] CAS accession number: 53714-56-0 [0007] Leuprolide is a GnRH analogue with the same effect as buserelin. Repeated administration of large doses of luteinizing-releasing hormone (LH-RH) or its highly active derivative leuprolide acetate can produce a transient excitatory effect on the pituitary-gonadal system immediately after the first administration (acute effect), It then inhibits the production and release of gonadotropins by the pituita...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/04C07K1/02A61P15/00A61P35/00
CPCY02P20/55
Inventor 刘建李红玲马亚平袁建成
Owner HYBIO PHARMA
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