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Carbetocin synthesis method

A carbetocin, solid-phase synthesis technology, which is applied in the preparation methods of peptides, chemical instruments and methods, oxytocin/vasopressin, etc. Not applicable to industrial production and other issues

Inactive Publication Date: 2014-08-20
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The technical problems to be solved in the present invention are: (1) choose a suitable raw material such as resin to solve the problem that amino resin is expensive and not suitable for industrial production; (2) choose a suitable process route to solve the problem of carbetine During the synthesis of carbetocin, impurities such as polyglycan or lack of sugar are prone to occur, so as to obtain products with higher purity and yield (3) Choose a solid-phase synthesis of carbetocin that is cheap and easy to produce on an industrial scale method

Method used

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Examples

Experimental program
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Embodiment 1

[0071] (1) Amino acid resin synthesis: Weigh 1.25g (1.0mmol) Wang Resin (substitution degree of 0.80mmol / g) into the reaction column, add 15ml DCM, stir and swell at 15-35°C for 30min, and remove the liquid by suction filtration . 1.06 g (3.0 mmol) of Fmoc-Leu-OH and 0.41 g (3.0 mmol) of HOBt were weighed into the dissolution tank. Measure 6ml of DMF solvent into the tank, stir to dissolve, after complete dissolution, cool down to about 0-15°C in an ice bath, add 464μl (3.0mmol) of DIC, stir evenly, control the temperature at 10-25°C for 5min, add 0.04g (0.3 mmol) DMAP, then added to the reaction column, reacted at 25-35 ° C for 5 h, sampling to detect the substitution degree of 0.63 mmol / g, and the reaction solution was removed. Add 10 ml of DMF to the reaction column, stir and wash for 3 minutes, and repeat the washing 3 times. Measure 525 μl (5.5 mmol) of acetic anhydride, 445 μl (5.5 mmol) of pyridine, and 10 ml of DMF solution, mix them evenly, add them into the reactio...

Embodiment 2

[0127] Example 2: 100 mmol

[0128] (1) Amino acid resin synthesis: Weigh 125g (100.0mmol) of Wang Resin (with a substitution degree of 0.80mmol / g) and add it to the reaction column, add 1.4L DCM, stir and swell at 15-35°C for 30min, and remove the liquid by suction filtration . Weigh 106 g (300 mmol) of Fmoc-Leu-OH and 41 g (300 mmol) of HOBt into a dissolution tank. Measure 500ml of DMF solvent into the tank, stir to dissolve, after complete dissolution, cool down to about 0-15°C in an ice bath, add 46.4mL (300mmol) of DIC, stir evenly, control the temperature at 10-25°C for 5min, add 4.0g (30 mmol) DMAP, then added to the reaction column, reacted at 25-35 ° C for 5 h, sampling to detect the substitution degree of 0.63 mmol / g, and removing the reaction solution. Measure 900ml of DMF and add it to the reaction column, stir and wash for 3 minutes, and repeat the washing 3 times. Measure 52.5 mL (550 mmol) of acetic anhydride, 44.5 mL (550 mmol) of pyridine, and 900 mL of DM...

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Abstract

The invention relates to a carbetocin synthesis method. The carbetocin synthesis method solves the problem that the prior art has a high cost, low purity and more impurities. The carbetocin synthesis method comprises the following steps of orderly coupling seven amino acids to wang resin, wherein the coupled amino acids orderly comprise Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(Me)-OH, removing a protective group Fmoc, connecting 4-chlorobutyric acid, carrying out cracking to obtain an acylated carbetocin seven-peptide linear peptide, carrying out liquid cyclizing under alkaline conditions to obtain a carbetocin seven-peptide crude cyclopeptide, carrying out purification and freeze-drying on the crude cyclopeptide to obtain a carbetocin seven-peptide fine cyclopeptide, and coupling the fragment of the carbetocin seven-peptide fine cyclopeptide subjected to purification and freeze-drying and H-Gly-NH2.HCl to obtain carbetocin. The invention provides the carbetocin synthesis method having a low cost and a high yield and suitable for large-scale production.

Description

technical field [0001] The invention relates to a method for synthesizing polypeptide drugs, which is a method for synthesizing the long-acting oxytocin carbetocin with agonist properties. Background technique [0002] Carbetocin, the British name: Carbetocin, is a cyclic polypeptide, is a synthetic long-acting oxytocin nonapeptide analog with agonist properties. A single intravenous dose can be administered immediately after epidural or cesarean section under spinal anesthesia to prevent uterine hypotonia and postpartum hemorrhage. The clinical and pharmacological properties of carbetocin are similar to those of naturally occurring oxytocin. Like oxytocin, carbetocin binds to oxytocin receptors in uterine smooth muscle, causing rhythmic contractions of the uterus, increasing their frequency and increasing uterine tone on top of the original contractions. Oxytocin receptor levels in the uterus are low in the non-pregnant state, increase during pregnancy, and peak during la...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/16C07K1/06C07K1/04
CPCY02P20/55
Inventor 程丽杨东晖路杨周亮
Owner ADLAI NORTYE BIOPHARMA CO LTD
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