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A method for preparing degarelix by solid-liquid combination

A degarelix and solution technology, which is applied in the field of solid-liquid combination preparation of degarelix, can solve the problems of high operator requirements, complicated operation, troublesome post-processing, etc. The effect of the synthesis process is simple

Inactive Publication Date: 2020-04-14
JINAN KANGHE MEDICAL TECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0010] To sum up, the solid-phase strategy of Boc chemistry requires the use of highly toxic HF, which is limited in mass production, and the liquid-phase synthesis is complex and requires high requirements for operators, which also restricts industrial scale-up; in Fmoc chemistry, it is necessary to repeat The use of alkaline conditions to deaminate the protecting group Fmoc results in the generation of rearrangement impurities. In addition, the strategies adopted in the Fmoc chemical solid-phase synthesis all have the problems of troublesome post-processing, the use of protected amino acid raw materials is not easy to obtain, and the problem of high cost; therefore, the present invention People have studied the synthetic method of degarelix, thus obtaining the technical scheme of the present invention

Method used

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  • A method for preparing degarelix by solid-liquid combination
  • A method for preparing degarelix by solid-liquid combination

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: Synthesis of Ac-D-2Nal-D-4Cpa-D-3Pal-Ser(tBu)-4Aph(Fmoc)-OH

[0066] Accurately weigh 199.6g (1.0mol) of H-D-4Cpa-OH and 127.2g (1.2mol) of sodium carbonate and dissolve them in 2400mL of water, slowly add Ac-D-2Nal-OSu THF solution (298.3 g, 1.0mol) / 2000ml, stir the reaction, TLC monitors the reaction end point, after the reaction is complete, spin off THF, add dilute hydrochloric acid in an ice-water bath to adjust the pH value of the solution to 2~3, extract 3 times with 2000ml ethyl acetate, combine organic phase, washed 3 times with 400ml of saturated brine, dried over anhydrous sodium sulfate, concentrated to 2000ml by rotary evaporation, and stood for crystallization to obtain 390.3g of Ac-D-2Nal-D-4Cpa-OH, with a yield of 82.1%.

[0067] Accurately weigh 136.3g (0.82mol) of H-D-3Pal-OH and 106.0g (1.0mol) of sodium carbonate and dissolve in 2400mL of water, slowly add Ac-D-2Nal-D-4Cpa-OSu at low temperature (2-8°C) Tetrahydrofuran solution (390.3g, 0...

Embodiment 2

[0070] Example 2: Synthesis of Ac-D-2Nal-D-4Cpa-D-3Pal-Ser(tBu)-4Aph(Fmoc)-OH

[0071] Weigh 500.0g (sub=1.0mmol / g) of CTC resin and place it in a synthesis column, wash twice with 4000mL DMF, add 4000mL DCM to swell for 30min; (tBu)-OH DCM / DMF (3 / 1, volume ratio) solution 1500ml, after stirring, add DIPEA 330ml (2000mmol), drum N 2 React for 60min, remove the reaction liquid, add DCM / CH 33000ml of OH / DIPEA (volume ratio 17:2:1) mixed solution was capped 3 times, 10min each time; then washed 6 times with DMF, a small sample was taken to measure the substitution degree of 0.75mmol / g, and the synthesis scale was 0.5mol.

[0072] The resin in the synthesis column was deprotected twice by 3000ml 20% piperidine / DMF solution, washed 6 times with DMF; then added the activated Fmoc-D-3Pal-OH / HOBT / DIC solution, reacted at room temperature for 3h, filtered off After the reaction solution, wash 6 times with DMF; then recycle the above operation, respectively react with Fmoc-D-4Cpa-OH a...

Embodiment 3

[0075] Example 3: Preparation of H-D-4Aph(Cbm)-Leu-Lys(Boc, iPr)-Pro-D-Ala-NH-Resins

[0076] Accurately weigh 220 g of RinkAmideAM resin (initial substitution degree 0.91 mmol / g) and place it in a peptide resin synthesis reactor, add 1.0 LDCM to swell for 2 h. After the swelling is completed, wash with DMF three times, 1.0 L each time, and then add 2.0 L of 20% piperidine / DMF solution for deprotection twice, for 10 min and 10 min respectively. After the deprotection was completed, the resin was washed 6 times with DMF, 2.0 L each time. Weigh 124.4g (0.40mol) of Fmoc-D-Ala-OH, 59.4g (0.44mol) of HOBt and dissolve it in 0.8L DMF, add 68mL (0.44mol) of DIC to activate, add the solution into the reactor, and react for 2h. The Kaiser test monitors the progress of the reaction. After the reaction, the resin was washed 6 times with DMF. Then repeat the above operation, and sequentially react with Fmoc-Pro-OH, Fmoc-Lys(Boc, iPr)-OH, Fmoc-Leu-OH to prepare H-Leu-Lys(Boc, iPr)-Pro-D...

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Abstract

The present invention relates to the field of polypeptide synthesis, in particular to a method for preparing degarelix using a solid-liquid combination chemical method. The present invention synthesizes a fragment peptide Ac-D-2Nal-D-4Cpa-D-3Pal-Ser(tBu) for the first time ‑4Aph(Fmoc)‑OH is used for the solid-phase synthesis of degarelix, the synthesis process is simple, the raw materials used are cheap and easy to obtain, and it is easy to scale up production; the present invention avoids the use of highly toxic reagent HF, and adopts TFA combination cracking, after purification, The refined peptide with a purity of 99.5% was obtained by lyophilization, and the total yield reached 65%.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a method for preparing degarelix by solid-liquid combination. [0002] technical background [0003] Degarelix (Degarelix) was developed by Ferring Pharmaceuticals and was launched in the United States on December 24, 2008 under the trade name Firmagon for the treatment of advanced prostate cancer; Degarelix is ​​a gonadotropin-releasing hormone (GnRH) receptor Body inhibitor drugs, reversibly inhibit the pituitary GnRH receptor to reduce the release of gonadotropin and then inhibit the release of testosterone, which delays the growth and progression of prostate cancer by inhibiting testosterone, which is critical for the continued growth of prostate cancer; it can avoid Using hormones to treat prostate cancer to reduce the concentration of testosterone at the initial stage causes the disadvantage of a surge in testosterone concentration, which can avoid the initial stimulatio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/04C07K1/02
CPCC07K7/23Y02P20/55
Inventor 张颖李同金王仁友石鑫磊
Owner JINAN KANGHE MEDICAL TECH
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