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Preparation method of [2-D-histidine]-leuprolide acetate

A technology of leuprolide acetate and histidine, which is applied in the preparation methods of peptides, chemical instruments and methods, organic chemistry, etc., can solve the problems of long production cycle and high cost

Inactive Publication Date: 2019-04-09
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

This method is a Boc method solid-phase synthesis method, through the application of different activators and de-BOC protecting group reagents to the reaction temperature, different amino acids, and the continuous improvement of the degree of substitution of BOC-Pro in the BOC-Pro-resin, not only overcomes the The shortcoming of long production cycle and high cost of the Fmoc method, the biggest advantage of the present invention is to minimize side reactions, significantly improve the crude product synthesis yield of the BOC method to more than 60%, greatly improve the quality of the crude product, and reduce production costs

Method used

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  • Preparation method of [2-D-histidine]-leuprolide acetate
  • Preparation method of [2-D-histidine]-leuprolide acetate
  • Preparation method of [2-D-histidine]-leuprolide acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1 Boc-Pro- preparation

[0081] 1.1 Preparation of Boc-Pro-Cs: Weigh Boc-Pro, dissolve in methanol, feed 95% excess Cs2CO3, weigh Cs2CO3, dissolve in purified water. Slowly add the Cs2CO3 solution to the Boc-Pro solution, and react fully. At this time, the Boc-Pro-Cs solution should be colorless and transparent, with a pH of 7.0-7.5. In a water bath at 40-50°C, concentrate under reduced pressure with water and evaporate the solvent to obtain solid matter. Add methanol, evaporate to dryness under reduced pressure, and repeat twice, and then vacuum-dry in a P2O5 desiccator to constant weight to obtain a dry product of Boc-Pro-Cs.

[0082] 1.2 Boc-Pro- Preparation: Follow ClCH2- Calculation of chlorine substitution amount, weigh 2 times the monomer molar amount of ClCH2- Add DMF to Boc-Pro-Cs, pour it into a three-neck flask after completely dissolving, then wash the eggplant-shaped flask with DMF, and incorporate it into the resin. Stir and react in a wa...

Embodiment 2

[0083] Embodiment 2 Incorporation of peptides (taking 300mmol input as an example)

[0084] 2.1. Dipeptide connection

[0085] Weigh 300mmol of Boc-Pro- Place in a 10L reactor, wash with CH2Cl2 for 2 to 3 times, and drain.

[0086] Deprotection group: add 9-10N HCl / iPrOH780ml+CH2Cl2624ml+mercaptoethanol156ml, stir for 40 minutes, and drain. Washing: wash once with CH2Cl2 and drain; wash once with DMF and drain.

[0087] Neutralization: add triethylamine / CH2Cl2 (10 / 90) to wash once, and drain.

[0088] Washing: Wash once with DMF and drain; wash with CH2Cl2 three times until neutral, then drain.

[0089] Peptide: Boc-Arg·HCl(·H2O) 279.0 grams (295.92 grams) (900mmol)

[0090] HOBt 140.0 g (1035 mmol)

[0091] DCCI 213g (1035mmol)

[0092] Amino acid monomer; HOBt and DCCI were dissolved in 600ml of DMF respectively. Firstly, the solution of amino acid monomer was mixed with the solution of HOBt, stirred and reacted in ice bath for 30 minutes, then DCCI solution was adde...

Embodiment 3

[0131] Example 3 Aminolysis

[0132] 3.1. Aminolysis: put the above-mentioned dried nonapeptide resin into four 3L suction filtration bottles, add about 750ml of anhydrous methanol to each bottle, add about 1125ml of ethylamine, and seal it. Shake at room temperature for 24 hours, open the stopper under cooling, filter, wash the resin 4 times with methanol, and combine the filtrate and washings.

[0133] 3.2 Concentration: Concentrate the filtrate at 40~45℃ under reduced pressure (vacuum degree is -0.08~-0.1Mpa) to dryness, add methanol to dissolve and then concentrate under reduced pressure (vacuum degree is -0.08~-0.1Mpa) to dryness, repeat this process Three times, it becomes foamy, and concentrate I is obtained.

[0134] 3.3, transfer acetate: weigh the concentrate I, dissolve with 5 times the volume of methanol, precipitate with 50 times the volume of acetone at -22°C, filter, dissolve the filter cake with 5 times the volume of 50% acetic acid, concentrate under reduced pr...

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Abstract

The invention provides a preparation method of [2-D-histidine]-leuprolide acetate. The preparation method comprises steps as follows: (1) solid phase peptide linking: leuprolide nonapeptide resin is obtained by steps of raw material preparation, dipeptide linking, tripeptide linking, tetrapeptide linking, pentapeptide linking, hexapeptide linking, heptapeptide linking, octapeptide linking and nonapeptide linking, wherein the steps from the dipeptide linking to the nonapeptide linking all comprise the process of protecting group removal; then washing, neutralization, secondary washing, peptidelinking and free ammonia detection are performed; (2), aminolysis: a crude product is dissociated from the leuprolide nonapeptide resin through ethylamine; (3), HPLC purification: an intermediate purified product of leuprolide acetate is obtained through purification by an HPLC preparation column; (4), concentration; (5), filtering and lyophilization.

Description

technical field [0001] The invention relates to a chemical synthesis method, in particular to a preparation method for [2-D-histidine]-leuprolide acetate. Background technique [0002] At present, the production of leuprolide acetate raw materials adopts the preparation of Boc-Pro--solid-phase peptide-aminolysis-HPLC purification-concentration-filtration and freeze-drying process or the preparation of FMoc-Pro--solid-phase peptide-acid cleavage-B Amination modification-side chain full protection cleavage-HPLC purification-concentration-filtration and freeze-drying process. Among them, the solid phase peptide is obtained by preparing raw materials, connecting dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide and nonapeptide to obtain leuprolide Nonapeptide resin. [0003] During the solid-phase peptide grafting process, due to side reactions such as racemization, various by-products will be produced. Although the by-products are remov...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/04C07K1/16C07K1/14
CPCC07K7/23Y02P20/55
Inventor 单连民万龙岩江晓漫张道桂王林鹏
Owner 上海丽珠制药有限公司
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