A kind of synthetic method of carbetocin

A carbetocin and synthesis method technology, applied in the field of polypeptide drug preparation, can solve the problems of unfavorable purification process development, poor continuity, and low overall yield of the process, so as to improve the efficiency of cyclization reaction, reduce the overall production cost, Process green effect

Active Publication Date: 2022-05-03
NINGBO SANSHENG BIOLOGICAL TECH CO LTD
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AI Technical Summary

Problems solved by technology

[0006] Chinese patent applications CN 201110001400.0, CN 201410331088.5, CN 201610189424.6, and CN201610728294.9 disclose the synthesis route of carbetocin. The cyclization method of linear chain peptide is realized by the condensation of carboxyl and amino groups to form amide bonds. Such a technical route requires the use of Sulfhydryl-modified special amino acids have high synthesis costs and are not conducive to large-scale commercial production
[0007] Chinese patent applications CN 201310392663.8, CN 201310412014.X, CN 201410076731.4, CN201410461695.3, CN 201510001735.0, CN 201510848044.4, and CN 201610328262.X disclose the synthesis route of carbetocin through linear cysteine ​​ring The sulfhydryl group on the side chain and the halogen at the end of the linear peptide are eliminated by the elimination reaction. This reaction has more by-products and impurities, and the reaction time is longer. The cyclization reaction usually exceeds 20 hours, and the continuity of the process is poor. It is conducive to the development of subsequent purification processes, and the overall yield of the process is low

Method used

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  • A kind of synthetic method of carbetocin
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preparation example Construction

[0050] The synthetic method of carbetocin in some examples of the present invention comprises the following steps:

[0051] (1) With Rink Amide-MBHA Resin as the carrier, after swelling treatment, the protected Gly, protected Leu, protected Pro, protected Cys, protected Asn, protected Gln, protected Ile and protected Tyr were condensed in sequence The reaction is coupled to the swelling Rink Amide-MBHA Resin, and dried to obtain the peptide resin 1;

[0052] (2) Peptide resin 1 reacts with vinyl acetic acid to obtain peptide resin 2, which has the following structure: CH 2 =CH-CH 2 -CO-Tyr(me)-Ile-Gln(Trt)-Asn(Trt)-Cys(Trt)-Pro-Leu-Gly-Rink Amide-MBHA Resin;

[0053] (3) Peptide resin 2 is cracked to obtain carbetocin intermediate I, whose structure is as follows:

[0054] CH 2 =CH-CH 2 -CO-Tyr(me)-Ile-Gln(Trt)-Asn(Trt)-Cys(Trt)-Pro-Leu-Gly-NH 2 ;

[0055] (4) Carbetocin intermediate I was cyclized to obtain carbetocin.

[0056] During the synthesis process, the coupli...

Embodiment 1

[0080] The carbetocin synthesis process of the present embodiment 1 is as follows: figure 1 As shown, specifically:

[0081] (1) Rink Amide-MBHA Resin swelling

[0082] Calculate and weigh 100mmol Rink Amide-MBHA Resin (the degree of substitution is 0.8mmol / g), pour it into the reaction kettle, add DCM in an amount of 20ml / g, and let it stand for swelling for 3 hours.

[0083] Washing: Wash twice with DMF, each time 1.0L, and each washing time is not less than 2min.

[0084] Deprotection: Add 1.0L of 20v / v% piperidine / DMF, stir for 30 minutes, then drain the reaction solution, and the reaction is terminated.

[0085] Washing: Wash twice with DMF, twice with methanol, twice more with DMF, each time with 1.0L, and each time of washing should not be less than 2min.

[0086] (2) Coupling of Fmoc-Gly-OH

[0087] Weigh Fmoc-Gly–OH: 89.25g, HOBt: 40.54g, DIC: 47.33ml.

[0088]Dissolve Fmoc-Gly-OH and HOBt with 300ml DMF, slowly add DIC to the swollen Rink Amide-MBHA Resin for pr...

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Abstract

The invention belongs to the field of preparation methods of polypeptide drugs, and relates to a synthesis method of carbetocin, comprising the following steps: (1) taking Rink Amide-MBHA Resin as a carrier, after swelling treatment, sequentially adding protected Gly, protected Leu, protected Pro, protected Cys, protected Asn, protected Gln, protected Ile and protected Tyr condensation reaction coupled to swelling Rink Amide‑MBHA Resin, dried to obtain peptide resin 1; (2) peptide resin 1 and vinyl acetic acid reaction to obtain peptide resin 2; (3) cleavage of peptide resin 2 to obtain carbetocin intermediate I; (4) carbetocin intermediate I to obtain carbetocin intermediate I after cyclization reaction. The synthesis method has high reaction selectivity, quick reaction, few by-products and impurities, high yield, safety and environmental protection, and simple and easy operation.

Description

technical field [0001] The invention belongs to the field of polypeptide drug preparation methods and relates to a synthesis method of carbetocin. Background technique [0002] Carbetocin, a cyclic polypeptide, is a synthetic long-acting nonapeptide analogue of oxytocin with agonist properties. [0003] The molecular formula of carbetocin is C 45 h 69 N 11 o 12 S, the molecular weight is 998.17, the chemical name is: deamin-2-oxo-methyltyrosine-1-к-oxytocin, and the structure is: [0004] [0005] Carbetocin can be administered as a single intravenous dose immediately following epidural or spinal cesarean delivery 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 the oxytocin receptors of uterine smooth muscle, causing rhythmic contractions of the uterus, increasing its frequency and increasing uterine tension on th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/16C07K1/08C07K1/06C07K1/04
CPCC07K7/16
Inventor 沙乐陈璐孙慕懿李开刚胡晨良
Owner NINGBO SANSHENG BIOLOGICAL TECH CO LTD
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