Method for solid cyclizing synthesis of desmopressin

A technology of desmopressin and preparation method, which is applied in the field of preparation of polypeptide drugs, and can solve the problems of low yield, low yield, and many by-products of solid-phase synthesis

Active Publication Date: 2014-08-20
上海飞腾医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The technical problems to be solved in the present invention are: (1) select a solid ring synthesis method to solve the problem of a large amount of waste liquid brought by liquid phase oxidation and low solid phase synthesis yield, (2) select an oxidizing agent to replace iodine, Solve the problem that there are many by-products in the oxidation of iodine as an oxidant and the yield is not high

Method used

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  • Method for solid cyclizing synthesis of desmopressin
  • Method for solid cyclizing synthesis of desmopressin
  • Method for solid cyclizing synthesis of desmopressin

Examples

Experimental program
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Effect test

Embodiment 1

[0072] Preparation of oxidizing agent: 56.56g of urea peroxide was dissolved in 1500 mL of DMSO.

Embodiment 2

[0074] Step 1 Synthesis of Fmoc-Gly-RinkAmide-AM-Resin

[0075] Weigh Rink Amide AM resin (substitution degree 0.73mmol / g) (164.85 g, 1.0 equiv) into a solid phase reactor, add DCM (1000mL), stir and swell at a temperature of 10-30°C for 30min, and remove the liquid by suction filtration. Then add DMF (1000mL×2) to wash. Measure 20% (v / v, the same below) Piperidine / DMF solution (850 mL), add it into the solid-phase reactor, control the temperature at 20-30°C and stir for 5 minutes, then remove the liquid by suction filtration. Measure 20% Piperidine / DMF solution (850 mL) again, add it to the solid-phase reactor, control the temperature at 20-30°C and stir for 10 minutes, then remove the liquid by suction filtration. Measure DMF (1000 mL×6) into the solid-phase reactor for washing, and remove the liquid by suction filtration. Separately weigh Fmoc-Gly-OH (107.13 g, 3.0 equiv) and Cl-HOBt (67.15 g, 3.3 equiv) into the beaker. Measure DMF (450 mL) into a beaker, stir to dissol...

Embodiment 3

[0089] Step 1 Synthesis of Fmoc-Gly-RinkAmide-AM-Resin

[0090] Weigh Rink Amide AM resin (substitution degree 0.73mmol / g) (1648.5 g, 1.0 equiv) into a solid phase reactor, add DCM (10 L), stir and swell at a temperature of 10-30°C for 30 minutes, and remove the liquid by suction filtration. Then add DMF (10 L×2) to wash. Measure 20% (v / v, the same below) Piperidine / DMF solution (8.50 L), add it into the solid phase reactor, control the temperature at 20-30°C and stir for 5 minutes, then remove the liquid by suction filtration. Measure 20% Piperidine / DMF solution (8.50 L) again, add it into the solid phase reactor, control the temperature at 20-30°C and stir for 10 min, then remove the liquid by suction filtration. Measure DMF (10L×6) into the solid-phase reactor for washing, and then remove the liquid by suction filtration. Separately weigh Fmoc-Gly-OH (1071.3 g, 3.0 equiv) and Cl-HOBt (671.5 g, 3.3 equiv) into the dissolution kettle. Measure DMF (4.50 L) into the dissolut...

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Abstract

The invention relates to a method for solid cyclizing synthesis of desmopressin. The method solves the technical problem that the existing air liquid-phase oxidation method produces a large amount of waste liquid, utilizes behindhand processes, has low efficiency and produces more by-products because of oxidation adopting iodine as an oxidizing agent. The method comprises the following steps of orderly coupling nine amino acids to a RinkAmideAm resin, wherein the coupled amino acids orderly comprise Fmoc-Gly-OH, Fmoc-D-Arg(pbf)-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Phe-OH, Fmoc-Tyr(tBu)-OH and Mpa(Trt)-OH, removing protective groups Trt on Cys(Trt) and Mpa(Trt) by TFA/DCM having content of 1%, carrying out solid cyclizing synthesis by an oxidation reagent to obtain a cyclopeptide resin and carrying out cracking to obtain desmopressin. The invention provides the method for solid cyclizing synthesis of desmopressin and the method has simple processes, a low cost and a high yield and is suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of polypeptide medicine, in particular to a solid-phase synthesis method of desmopressin. Background technique [0002] Desmopressin, whose English name is: Desmopressin, is a structural analogue of natural arginine salt vasopressin, which is obtained by making two changes to the chemical structure of the natural hormone, namely, deamination of L-cysteine ​​and Replace 8-L-arginine with 8-D-arginine. Desmopressin acetate has good hemostatic effect and does not cause deep vein thrombosis. It is mainly used for the treatment of hemophilia, diabetes insipidus, therapeutic control of bleeding and prevention of bleeding before surgery. The effect is good and the side effect is small, and it is a polypeptide drug with a good market prospect. Its peptide sequence structure is as follows: [0003] Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-NH 2 (Sulfide bond between Mpa and Cys) [0004] WO2011011342 discloses a m...

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 杨东晖路杨陈晓航
Owner 上海飞腾医药科技有限公司
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