A kind of fragment condensation prepares the method for atosiban acetate
A technology of atosiban acetate and atosiban, which is applied to the preparation methods of peptides, chemical instruments and methods, organic chemistry, etc., can solve the problems of difficulty in obtaining high-purity atosiban, high cost of preparation methods, and high product cost. Difficulty in purification and other problems, to achieve the effect of reducing the number of preparations, low price, and simple method
Active Publication Date: 2018-03-30
海南建邦制药科技有限公司
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Problems solved by technology
[0007] The technical problem to be solved by the present invention is that the cost of the existing preparation method is high, and the product purification is difficult, and it is difficult to obtain high-purity atosiban. The method of combining solid-liquid phase condensation with fragments is used to prepare atosiban acetate, which improves the production efficiency of atosiban. The yield and purity are improved, and the cost is reduced due to the use of 2-chloro-trityl chloride resin and solid-phase cyclization, which is conducive to large-scale production
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Embodiment 1
[0046] 1. Resin preparation
[0047] Prepare Fmoc-Orn(Boc)-2-chloro-trityl resin: add 2-chloro-trityl chloride resin (5g, substitution value 0.84mmol / g resin, 1eq) into the peptide synthesizer, and use 60mL DCM Wash the resin. The solvent was drained, and 30 mL DCM solution of Fmoc-Orn(Boc)-OH (1.3eq) and DIEA (2.5eq) was added. The mixture was stirred for 1 hour under an argon atmosphere. Add 10mL of chromatographic methanol (2ml / g resin) to block the active part on the resin for 30 minutes. The solvent was drained, washed with 3×50 mL DMF, 3×50 mL DCM, 3×50 mL MeOH, and dried in vacuum to constant weight to obtain 6.29 g of Fmoc-Orn(Boc)-2-chloro-trityl resin. The amount of Fmoc in the piperidine deprotection solution was measured by ultraviolet spectrophotometry, and the resin loading was 0.62 mmol / g.
[0048] 2. Fragment preparation
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The invention discloses a method for preparing atosiban acetate by fragment condensation, which is characterized in that the fully protected first peptide fragment sequence resin of atosiban is prepared in a solid phase, oxidized in the solid phase to form a disulfide bond, and then The cyclized fully protected first peptide fragment sequence is cleaved from the resin; the fully protected first peptide fragment sequence cyclized in the liquid phase is condensed with H-Gly-NH2 to obtain fully protected atosiban; and then removed The side chain protecting group is used to obtain the crude atosiban peptide, and the atosiban acetate is obtained through purification and salt conversion; wherein, the sequence of the first peptide fragment is the 1st to 8th amino acids in the atosiban sequence. The invention utilizes a solid-liquid phase combination method to prepare atosiban acetate, which increases the yield and purity, reduces the cost due to the use of 2-chloro-trityl chloride resin and solid-phase cyclization, and facilitates large-scale production.
Description
Technical field [0001] The invention belongs to the technical field of pharmacy, and specifically relates to a method for preparing atosiban acetate through fragment condensation. Background technique [0002] Atosiban acetate is a cyclic nonapeptide, an oxytocin analogue, and a competitive antagonist of oxytocin receptors in the uterus, decidua, and fetal membrane. It can inhibit uterine contractions in a dose-dependent manner and delay childbirth. , To achieve the purpose of fetal protection, clinically used to treat premature birth. The structure is as follows: [0003] [0004] In the existing synthesis method of atosiban acetate, the liquid phase synthesis produces more waste liquid, the reaction time is long, each amino acid needs to be purified, the post-treatment is complicated, the yield is low, and it is not conducive to industrial production. [0005] In the solid-phase synthesis method, Chinese patents CN101314613, CN101696236, and CN103980350 use RinkAmide AM Resin to ...
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IPC IPC(8): C07K7/16C07K1/06C07K1/04C07K1/02
CPCY02P20/55
Inventor 彭雅丽常民王锐方泉薛宏祥
Owner 海南建邦制药科技有限公司