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A technology of cetrorelix and solid-phase synthesis, which is applied in the field of polypeptide drug preparation, and can solve problems such as product heavy metal pollution, process impurities, and environmental pollution
Inactive Publication Date: 2015-09-09
CHINESE PEPTIDE CO
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[0027] The object of the present invention is to provide a kind of preparation method of cetrorelix, mainly solve the [D-Cit(Ac)]- Problems with impurities in the cetroreli
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Embodiment 1
[0046] Step 1. Fmoc Rink Amide resin (3.0 mmol, 5.1 g, degree of substitution 0.59 mmol / g) was placed in a reactor and swelled with N,N-dimethylformamide (100 ml) for 30 minutes. The suspension was filtered, and 20% piperidine / N,N-dimethylformamide (100 ml) was added to the resin and stirred for 30 min to remove the Fmoc protecting group. After Fmoc deprotection, the resin was washed thoroughly with N,N-dimethylformamide, ready for step 2 coupling.
[0047] Step 2. Dissolve 3.11 g of Fmoc-DAla-OH, 1.35 g of 1-hydroxybenzotriazole, and 1.58 mL of N,N-diisopropylcarbodiimide in N,N-dimethylformamide , to activate amino acids at 0 - 10 degrees Celsius for 20 minutes. After activation, the solution was added to the reactor containing the peptide resin, and then 2.2 mL of N-methylmorpholine was also added to the reactor of the resin. The coupling reaction is performed for 1 - 4 hours, or until the ninhydrin test is negative. The resin suspension was filtered and the peptide resi...
Embodiment 2
[0061] The nonapeptide resin was synthesized according to the method from step 1 to step 10 in Example 1, and then Ac-D-2Nal-OH was connected.
[0062] Add Ac-D-2Nal-OH (78 mg, 0.3 mmol) and o-(7-azabenzotriazol-1-yl)-1 to the nonapeptide resin (340 mg, 0.1 mmol) obtained in step 10, 1,3,3-Tetramethyluronium hexafluorophosphate (HATU) (114 mg, 0.3 mmol) in N,N-dimethylformamide. Then N,N-diisopropylethylamine (52 μl, 0.3 mmol) was added, and the coupling reaction was carried out at 0–5°C for 1–4 hours, or until the ninhydrin test was negative. The resin suspension was filtered and washed five times with N,N-dimethylformamide and twice with methanol. After drying under vacuum, the resin was then subjected to trifluoroacetic acid cleavage.
[0063] Trifluoroacetic acid cleavage: suspend the dried peptide resin in trifluoroacetic acid cutting solution, trifluoroacetic acid:water (95:5, 10 ml / g resin), and cut at room temperature for 2.5 hours. After filtration, the filtrate wa...
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Abstract
The invention discloses a solid-phase synthesis method of cetrorelix. The method completely avoids toxic [D-Cit(Ac)]-cetrorelix impurities of D-citrulline side chain acetylation. According to the method, amino resin is used as an initial resin carrier, corresponding Fmoc-amino acids in a cetrorelix sequence are sequentially connected with the solid-phase synthesis method, and all-protected cetrorelix peptide resin is obtained through a condensation reaction and a deprotection reaction; then acidolysis cutting and sedimentation by the aid of diethyl ether are performed, and crude cetrorelix peptides are obtained; cetrorelix acetate is obtained through chromatographic purification, acetate conversion and freeze-drying. According to the method, Ac-D-2Nal-OH is selected as connection of the last amino acid, so that acetylation termination is avoided. Both a solid-phase synthesis technology and a liquid-phase synthesis technology can be adopted, few technological byproducts are produced, and separation and purification are easy. The purity of the finally obtained cetrorelix acetate product is up to 99%, the yield is up to 40%, and the method has the considerable economical application value and the broad application prospect.
Description
technical field [0001] The invention belongs to the technical field of polypeptide drug preparation methods, in particular to a solid-phase synthesis method of cetrorelix. Background technique [0002] Cetrorelix (trade name Cetrotide) is a potent progesterone-releasing hormone-releasing hormone (LH-RH) receptor antagonist, which can control the stimulation of the ovaries, prevent premature expulsion of immature follicles, and help conception. And can be used for the treatment of breast cancer and gynecological cancer, endometriosis, precocious puberty, uterine fibroids, ovarian androgen excess and premenstrual syndrome. [0003] Cetrorelix is used in assisted reproduction to suppress premature luteinizing hormone surges. The mechanism of action of the drug is due to blocking the action of gonadotropin-releasing hormone, thereby rapidly inhibiting the production and action of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Cetrorelix is used to treat h...
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