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Solid-phase synthesis method of ularitide

A solid-phase synthesis method and a technology for uralibide, which are applied in the field of solid-phase synthesis of uralibide, can solve the problems of no industrialized method for preparing uralibide, etc., and achieve the effects of low production cost, simple operation and stable process.

Inactive Publication Date: 2013-06-12
GL BIOCHEM SHANGHAI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problem that there is no suitable method for industrialized preparation of ulalipide at present

Method used

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  • Solid-phase synthesis method of ularitide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] 1) Preparation of Fmoc-Arg(pbf)-Tyr(tbu)-King resin

[0065] Weigh 47.6 grams of Fmoc-Tyr(tbu)-King resin (0.42mmol / g, 20mmol), soak it with 800ml DMF for 30 minutes, fully swell the resin, drain it, add Fmoc-Arg(pbf)-OH (MW:648.8 , 60mmol) 38.9g, TBTU (MW: 321.1, 60mmol) 19.3g, HOBT (MW: 135.1, 60mmol) 8.1g, DIEA (MW: 129.24, 120mmol) 20ml, DMF500ml, reacted for 1.5 hours, ninhydrin detection resin without The color was transparent, drained, washed 3 times with DMF, and drained to obtain Fmoc-Arg(pbf)-Tyr(tbu)-King resin.

[0066] 2) Preparation of Thr(tbu)-Ala-Pro-Arg(pbf)-Ser(tbu)-Leu-Arg(pbf)-Arg(pbf)-Ser(tbu)-Ser(tbu)-Cys(Trt)-Phe -Gly-Gly-Arg(pbf)-Met-Asp(Otbu)-Arg(pbf)-Ile-Gly-Ala-Gln(Trt)-Ser(tbu)-Gly-Leu-Gly-Cys(Trt)-Asn (Trt)-Ser(tbu)-Phe-Arg(pbf)-Tyr(tbu)- Wang resin.

[0067] In the Fmoc-Arg(pbf)-Tyr(tbu)-King resin obtained in step (1), add 800ml decapping reagent (20% PIP / DMF(v / v) solution), react for 30 minutes, drain, and use Wash with DMF 6 times, d...

Embodiment 2

[0106] 1) Preparation of Fmoc-Arg(pbf)-Tyr(tbu)-King resin

[0107]Weigh 57.1 grams (0.35mmol / g, 20mmol) of Fmoc-Tyr(tbu)-King resin, soak it with 800ml DMF for 30 minutes, fully swell the resin, drain it, add Fmoc-Arg(pbf)-OH (MW:648.8 , 40mmol) 26.0g, HBTU (MW: 379.2, 40mmol) 15.2g, HOBT (MW: 135.1, 40mmol) 5.4g, NMM (MW: 102.1, 80mmol) 9.0ml, DMF500ml, react for 1 hour, ninhydrin detection resin Colorless and transparent, drained, washed 3 times with DMF, and drained to obtain Fmoc-Arg(pbf)-Tyr(tbu)-King resin.

[0108] 2) Preparation of Thr(tbu)-Ala-Pro-Arg(pbf)-Ser(tbu)-Leu-Arg(pbf)-Arg(pbf)-Ser(tbu)-Ser(tbu)-Cys(Trt)-Phe -Gly-Gly-Arg(pbf)-Met-Asp(Otbu)-Arg(pbf)-Ile-Gly-Ala-Gln(Trt)-Ser(tbu)-Gly-Leu-Gly-Cys(Trt)-Asn (Trt)-Ser(tbu)-Phe-Arg(pbf)-Tyr(tbu)- Wang resin.

[0109] In the Fmoc-Arg(pbf)-Tyr(tbu)-King resin obtained in step (1), add 800ml decapping reagent (20% PIP / DMF(v / v) solution), react for 30 minutes, drain, and use Wash with DMF 6 times, drain, use DMF a...

Embodiment 3

[0148] 1) Preparation of Fmoc-Arg(pbf)-Tyr(tbu)-King resin

[0149] Weigh 43.5 grams of Fmoc-Tyr(tbu)-King resin (0.46mmol / g, 20mmol), soak it with 800ml DMF for 30 minutes, fully swell the resin, drain it, add Fmoc-Arg(pbf)-OH (MW:648.8 , 40mmol) 26.0g, HATU (MW: 380.2, 40mmol) 15.2g, HOAT (MW: 136.1, 40mmol) 5.4g, NMM (MW: 102.1, 80mmol) 9.0ml, DMF500ml, reacted for 0.5 hours, ninhydrin detection resin Colorless and transparent, drained, washed 3 times with DMF, and drained to obtain Fmoc-Arg(pbf)-Tyr(tbu)-King resin.

[0150] 2) Preparation of Thr(tbu)-Ala-Pro-Arg(pbf)-Ser(tbu)-Leu-Arg(pbf)-Arg(pbf)-Ser(tbu)-Ser(tbu)-Cys(Trt)-Phe -Gly-Gly-Arg(pbf)-Met-Asp(Otbu)-Arg(pbf)-Ile-Gly-Ala-Gln(Trt)-Ser(tbu)-Gly-Leu-Gly-Cys(Trt)-Asn (Trt)-Ser(tbu)-Phe-Arg(pbf)-Tyr(tbu)- Wang resin.

[0151] In the Fmoc-Arg(pbf)-Tyr(tbu)-King resin obtained in step (1), add 800ml decapping reagent (20% PIP / DMF(v / v) solution), react for 30 minutes, drain, and use Wash 6 times with DMF, drain, use DM...

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Abstract

The invention relates to a method for synthesizing ularitide by a solid phase and mainly solves the technical problem that a suitable industrial method for preparing the ularitide does not exist. The solid-phase synthesis method disclosed by the invention mainly comprises the following steps of: 1) taking Fmoc-Tyr(tbu)-Wang resin as starting resin; gradually coupling each protected amino acid by adopting a Fmoc solid-phase synthesis method to synthesize a peptide chain tree which is wholly protected by a side chain; 2) cutting the peptide chain tree which is wholly protected by the side chain by utilizing a cutting reagent; and cracking 32 peptide from the resin and removing a side chain protective group to obtain a straight-chain peptide coarse product of the ularitide; and 3) dissolving the straight-chain peptide coarse product of the ularitide in water and carrying out air oxidization to form a ring to obtain the coarse peptide of the ularitide. The method disclosed by the invention has the advantages of large-scale production capability, simplicity in operation, stability of process and low production cost; and the total yield exceeds 20%.

Description

technical field [0001] The invention relates to a synthesis method of uralitide, in particular to a solid-phase synthesis method of uralitide. Background technique [0002] Ularitide, Chinese name Ularitide, English name Ularitide; Urodilatin, is a disulfide-bridged cyclic peptide containing 32 amino acid residues, its molecular formula is C 145 h 234 N 52 o 44 S 3 , molecular weight: 3506.00, CAS number: 118812-69-4, polypeptide sequence: Thr-Ala-Pro-Arg-Ser-Leu-Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Met- Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly-Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr[Disulfidebridge:11-27], the structural formula is as follows: [0003] [0004] Ularitide is classified as a natriuretic peptide drug. It is a bioengineering product that secretes natriuretic peptides in the kidneys. It not only has natriuretic and diuretic effects, but also has obvious vasodilator effects, and is suitable for decompensated heart failure. Failure, acute heart failure, acute renal failure...

Claims

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Application Information

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IPC IPC(8): C07K14/58C07K1/06C07K1/04
CPCY02P20/55
Inventor 徐红岩竺剑峰张所德
Owner GL BIOCHEM SHANGHAI
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