Carbetocin preparation method

A technology of carbetocin and solid-phase synthesis, which is applied in the field of preparation of carbetocin, can solve the problems of many protective side reactions, high price, and unfavorable large-scale production, so as to avoid process problems and cost low effect

Active Publication Date: 2013-12-25
HYBIO PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Chinese patent CN200910106889.0 discloses a solid-phase method for preparing carbetocin, which uses solid-phase synthesis to sequentially connect amino acids with Fmoc protecting groups to obtain carbetocin precursor peptide-amino resin; Use triphenylphosphine palladium to remove the allyl protecting group of the cysteine ​​side chain, add an organic base, lithium chloride, cyclize, crack, purify, and freeze-dry to obtain refined carbetocin. Reagents for allyl protecting groups are expensive and not conducive to large-scale production
[0009] Chinese patent CN201110151928.6 discloses a preparation method of carbetocin, which uses a novel thiol-protected amino acid Fmoc-Cys ((CH 2 ) 3 COOAll), the reagent price of de-side chain allyl protecting group is also very expensive in this method, is unfavorable for large-scale production
[0010] Chinese patent CN201110001400.0 discloses a method for preparing carbetocin from polypeptide synthesis. This method uses solid-phase synthesis to synthesize linear carbetocin precursor peptide, and then cyclizes it in liquid phase. In this method, Cyclization requires very dilute solvent (10 -4 -10 -5 mol / L), a large amount of waste liquid is produced, and polymers are easily produced at the same time, which has the disadvantages of low cyclization efficiency and complicated follow-up treatment.
[0011] Chinese patent CN102796178A has announced a kind of preparation method of carbetocin, and this method adopts novel thiol-protected amino acid Fmoc-Cys ((CH 2 ) 3 COOCH 2 CH 2 CN) as a raw material, the raw material is expensive, and Fmoc-Cys ((CH 2 ) 3 COOCH 2 CH 2 CN) There are many protective side reactions, which is not conducive to large-scale production

Method used

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Examples

Experimental program
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Embodiment 1

[0054] Embodiment 1 prepares linear peptide resin A

[0055] Weigh 1 mmol (2 g) of Rinkamide Resin with a substitution degree of 0.50 mmol / g, add it to a solid-phase reaction column, and wash it twice with DMF. After swelling Rinkamide Resin with DMF for 30 minutes, remove the Fmoc protection with DBLK, and then wash it six times with DMF. Dissolve Fmoc-Gly–OH (0.8g, 3mmol), HOBt (0.45g, 3.3mmol) in DMF and add DIC (0.52ml, 3.3mmol) under ice bath conditions, then add the resulting solution to the solid phase reaction column , react at room temperature for 2 hours (the end point of the reaction is determined by the ninhydrin method, if the resin is colorless and transparent, the reaction is complete, and the resin develops color, indicating that the reaction is incomplete, and another 1 hour of coupling reaction is required). Repeat the steps of removing Fmoc protection and adding corresponding amino acids for coupling, and complete Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-A(Cl)-OH, Fmo...

Embodiment 2

[0058] Embodiment 2 prepares peptide resin B

[0059] Weigh Na 2 S (0.32g, 4mmol) was dissolved in 50ml of DMF, and after the dissolution was completed, it was added to the reaction column in Example 1 to start the cyclization reaction. Reacted at room temperature for 24 hours, washed with DMF for 6 times, and finally added methanol for 3 times, and dried to obtain 3.3 g of peptide resin B.

Embodiment 3

[0060] Embodiment 3 prepares crude product carbetocin

[0061] The 3.3g peptide resin B among the embodiment 2 is added in the 50ml flask, configures cracking reagent 35ml (TFA:H 2 O=95:5 (v / v)), pour the lysis reagent into the flask, and react at room temperature for 2 hours. After the reaction, filter the resin and collect the filtrate. The resulting filtrate was added dropwise to 350 ml of ether reagent, centrifuged, washed with anhydrous ether, and dried in vacuo to obtain 0.95 g of crude carbetocin with an HPLC purity of 72.36%.

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Abstract

The invention belongs to the technical field of medicinal chemistry and particularly relates to a carbetocin preparation method. The carbetocin preparation method comprises the following steps of: (1) sequentially coupling to an amino resin by adopting an Fmoc sold-phase synthesis process so as to obtain a linear peptide resin A the structural formula of which is shown in the specification, wherein X is C1, Br or I, and Y is C1, Br or I; (2) adding a Na2S solution to the linear peptide resin and carrying out cyclization reaction so as to obtain peptide resin B; and (3) splitting the peptide resin B so as to obtain a carbetocin crude product. The carbetocin preparation method has the advantages that the process problems of expensive raw materials, need of heavy metal reagents and the like caused by using sulfydryl protected amino acids are avoided, the cost is low, no lots of waste liquid is generated, reaction conditions are mild, and the large-scale production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of carbetocin. Background technique [0002] Carbetocin is a synthetic long-acting nonapeptide analog of oxytocin with agonist properties. A single dose intravenously may be administered immediately after cesarean section under epidural or spinal anesthesia to prevent uterine hypotonia and postpartum hemorrhage. [0003] The clinical and pharmacological properties of carbetocin are similar to those of naturally occurring oxytocin. Like oxytocin, carbetocin binds to the oxytocin receptor of uterine smooth muscle, causing rhythmic contraction of the uterus, increasing its frequency and increasing uterine tension on the basis of the original contraction. Oxytocin receptor levels in the uterus are low in the non-pregnant state, increase during pregnancy, and peak at parturition. Carbetocin therefore has no effect on the non-pregnant ute...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/16C07K1/06C07K1/04
Inventor 肖庆潘俊锋马亚平袁建成
Owner HYBIO PHARMA
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