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Preparation method of degarelix acetylation impurity

A technology of degarelix and rick acetylation, which is applied in the field of polypeptide drug preparation and can solve problems such as side chain acetylation

Pending Publication Date: 2022-05-10
深圳市健翔生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If the acetylation of the 4-position Ser side chain is directly carried out in the degarelix raw material drug, it will bring about the problem of acetylation of the 8-position Lys (iPr) side chain

Method used

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  • Preparation method of degarelix acetylation impurity
  • Preparation method of degarelix acetylation impurity
  • Preparation method of degarelix acetylation impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The synthesis of embodiment 1 Fmoc-D-Ala-Rink MBHA resin

[0045] 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 aspirated. Add 400 mL of DBLK solution (20% piperidine / DMF solution, V / V), deprotect twice, the first time is 5 min, the second time is 15 min. After deprotection, the resin was washed with 400mL DMF each time for 6 times. After the fourth wash, a little resin was picked with a glass rod, and the ninhydrin test was positive, indicating that Fmoc was completely removed.

[0046] Weigh 18.68g Fmoc-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), in the solution Activated in medium for about 3-5 minutes, control the activated solution into the reaction column, react at 20-30°C f...

Embodiment 2

[0047] Synthesis of Example 2 Degarelix 1-10 Peptide Resin

[0048] Weigh Fmoc-D-Ala-Rink MBHA resin (30mmol) in the solid phase reaction synthesis column. The resin was washed with 3*400mL DMF, and the DMF was aspirated. Add 400 mL of DBLK solution (20% piperidine / DMF solution, V / V), deprotect twice, the first time is 5 min, the second time is 15 min. After deprotection, the resin was washed with 400mL DMF each time for 6 times. After the fourth wash, a little resin was picked with a glass rod, and the ninhydrin test was positive, indicating that Fmoc was completely removed.

[0049] Weigh 20.24g Fmoc-Pro-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) to activate in the solution For about 3-5 minutes, add the activated solution to the reaction column under control, and react at 20-30°C for 2-3 hours. When the ninhydrin test is negative, remove the reaction solution, add 400mL of...

Embodiment 3

[0057] Example 3 Synthesis of degarelix acetylated impurity peptide resin

[0058] Continue the reaction of the product of Example 2, weigh 18.02g of acetic acid, 11.00g of DMAP and 48.64g of HOBt, add 120mL of DMF to dissolve, after complete dissolution, cool the solution to below 5°C, add to the reaction column, and then add 56.79 gDIC (pre-cooled to <0°C), react at 20-30°C for 3-5 hours, and end the reaction, add 400mL of DMF each time to wash the resin, and wash 6 times. After washing, the washing liquid was extracted, and then the resin was washed with DCM, 400 mL each time, and washed 4 times to obtain the degarelix acetylated impurity peptide resin: Ac-D-2Nal-D-4Cpa-D-3Pal-Ser( Ac)-4Aph(Hor)-D-4Aph(Cbm)-Leu-ILys(Boc)-Pro-D-Ala-Rink MBHA resin, the resin is vacuum-dried at 20-30°C until it becomes quicksand. The peptide resin was 110.22 g after drying, and the weight gain rate of the resin was 119%.

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Abstract

The invention provides a preparation method of degarelix acetylation impurities, and belongs to the field of polypeptide drug preparation. The method comprises the following steps that 1, amino resin serves as initial resin, degarelix peptide fragment resin or degarelix peptide resin from the nth site to the tenth site is synthesized according to the degarelix peptide sequence, Fmoc-Ser-OH is adopted for the fourth amino acid, and corresponding protected amino acid or fragments are adopted for the rest; 2) carrying out acetylation by using an acetylation reagent; 3) continuing to couple residual amino acids to obtain degarelix acetylation impurity peptide resin; if the degarelix peptide resin is synthesized in the step 1), the step can be omitted; 4) cracking and purifying to obtain a degarelix acetylation impurity, namely [Ser (Ac) 4] degarelix; wherein n is equal to 1, 2 or 3. The method has the advantages of high purity and high yield, provides a qualified impurity reference substance for impurity analysis and research of degarelix bulk drugs and preparations thereof, and further improves the production and medication safety of degarelix.

Description

technical field [0001] The invention belongs to the field of preparation of polypeptide medicines, in particular to a method for preparing degarelix acetylated impurities. Background technique [0002] Degarelix is ​​a linear decapeptide containing 7 unnatural amino acids, the composition is as follows: [0003] Ac-D-2Nal 1 -D-4Cpa 2 -D-3Pal 3 -Ser 4 -4Aph(Hor) 5 -D-4Aph(Cbm) 6 -Leu 7 -Lys(iPr) 8 -Pro 9 -D-Ala 10 -NH 2 . 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. [0004] WO9846634 is the earliest patent for synthesizing degarelix, using the solid-phase synthesis met...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/04C07K1/06
CPCC07K7/23
Inventor 刘自成张利香李新宇付玉清
Owner 深圳市健翔生物制药有限公司
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