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Preparation method of Degarelix

A degarelix and resin technology, which is applied in the field of degarelix preparation, can solve the problems that cannot be effectively avoided, the process is cumbersome, and the process is unstable, and achieves the effects of easy quality control, simple operation and little environmental pollution.

Pending Publication Date: 2020-12-25
SHENZHEN JYMED TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The hydrogenated orotic acid at the para-position of the 5-phenylalanine phenyl ring is introduced after the completion of the entire peptide chain. However, the process of selectively removing Trt is not stable and is not suitable for industrial production.
This route process is extremely cumbersome and is not suitable for industrial production
[0007] Patent CN102428097 describes the use of Fmoc solid-phase synthesis strategy, with 20% piperidine / DMF as the deprotection solution, and the corresponding amino acids are gradually coupled, although the hydantoin generated by the rearrangement of the 5-position amino acid under 20% piperidine / DMF The urea impurity can be controlled below 0.3% by weight, but the racemic impurity of Pro cannot be effectively avoided [D-Pro 9 ] Degarelix production

Method used

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  • Preparation method of Degarelix
  • Preparation method of Degarelix

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The synthesis of embodiment 1Fmoc-Pro-D-Ala-Rink MBHA resin

[0038]Weigh Rink Amide MBHA resin (75g, 30mmol, degree of substitution: 0.40mmol / g) into a solid-phase reaction synthesis column. Add 500ml DMF to swell for 30min, and remove the DMF. The resin was washed with 3×400ml DMF, and the DMF was sucked off. Add 400 ml of DBLK solution (20% morpholine / DMF solution, v / v), deprotect twice, the first time is 5 min, the second time is 15 min. After deprotection, wash the resin with 400ml DMF each time for 6 times. After the 4th washing, pick a little resin with a glass rod, and the ninhydrin test is positive, indicating that Fmoc has been removed.

[0039] Weigh 40.24g Fmoc-Pro-D-Ala-OH and 9.73g HOBt, add 120ml DMF to dissolve, after complete dissolution, cool the solution below 5°C, then add 11.36g DIC (pre-cooled to <0°C), Activate in the solution for about 4 minutes, control the activated solution into the reaction column, react at 20-30°C for 2 hours, the ninhydr...

Embodiment 2

[0040] Synthesis of embodiment 2 degarelix resin

[0041] Weigh the Fmoc-Pro-D-Ala-Rink MBHA resin (30 mmol) obtained in Example 1 into a solid-phase reaction synthesis column. The resin was washed with 3×400ml DMF, and the DMF was sucked off. Add 400 ml of DBLK solution (20% morpholine / DMF solution, v / v), deprotect twice, the first time is 5 min, the second time is 15 min. After deprotection, wash the resin with 400ml DMF each time for 6 times. After the 4th washing, pick a little resin with a glass rod, and the Chloranil test is positive, indicating that Fmoc has been removed.

[0042] Weigh 30.64g Fmoc-ILys(Boc)-OH and 9.73g HOBt, add 120ml DMF to dissolve, after complete dissolution, cool the solution below 5°C, then add 11.36g DIC (pre-cooled to <0°C), Activate in the solution for about 4 minutes, add the activated solution to the reaction column, react at 20-30°C for 2 hours, Chloranil test is negative, remove the reaction solution, add 400ml of DMF to wash the resin, ...

Embodiment 3

[0048] Example 3 Cleavage of Degarelix Resin

[0049] Take 1100ml of frozen lysate (not higher than 10°C), the ratio is TFA:TIS::H 2 O=92.5:2.5:2.5 (v / v / v), add 110g (28mmol) of the degarelix peptide resin obtained in Example 2, react at 20-30°C for 2.0h, filter with suction, wash the resin with TFA, and concentrate the filtrate to 1 / 2-2 / 3 volume, then add 10 times the volume of isopropyl ether to settle, centrifuge to collect the precipitate, wash with isopropyl ether 6 times, and dry in vacuum to obtain 41.38 g of crude peptide, with a yield of 98.3%.

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Abstract

The invention provides a preparation method of Degarelix. According to the preparation method, a dipeptide fragment Fmoc-Pro-D-Ala-OH is introduced, and a morpholine / DMF deprotection reagent is adopted, so that a hydantoin impurity [4Aph(D / L-Hydantoinacetyl)<5>]Degarelix and an impurity [D-Pro<9>]Degarelix can be effectively controlled. The Degarelix preparation method, which is simple and convenient to operate, easy in quality control, small in environmental pollution and suitable for large-scale production, is creatively provided.

Description

technical field [0001] The invention relates to a preparation method of degarelix, which belongs to the technical field of biomedicine. Background technique [0002] Degarelix, whose trade name is Firmagon, is a gonadotropin-releasing hormone (GnRH) receptor inhibitor developed by the Danish company Ferring and approved by the US FDA on December 24, 2008. Dosage drugs. Degarelix is ​​mainly used to treat patients with advanced prostate cancer. Its mechanism is to delay the growth and progression of prostate cancer by inhibiting testosterone, which is crucial for the continued growth of prostate cancer. [0003] Degarelix is ​​a linear decapeptide containing 7 unnatural amino acids, 5 of which are in the D configuration. The decapeptide skeleton contains 10 chiral centers, and the side chain substituent of the amino acid residue at position 5 of the sequence has another chiral center. Therefore, the whole degarelix contains 11 chiral centers. The six-membered ring L-Hor of...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/04C07K1/06C07K1/10
CPCC07K7/23C07K1/10C07K1/04C07K1/06
Inventor 刘自成姚志勇李新宇吴峰谢雨翔
Owner SHENZHEN JYMED TECH
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