Preparation method of desmopressin acetate

A technology of desmopressin and acetic acid, which is applied in the field of preparation of desmopressin acetate, can solve the problems of reduced yield, insoluble crude peptide, and low oxidation efficiency, so as to increase the concentration of oxidized samples and reduce side effects. Reduction of reaction and waste liquid

Active Publication Date: 2013-05-15
HYBIO PHARMA
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  • Abstract
  • Description
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Problems solved by technology

However, this method is difficult to dissolve the crude peptide obtained by solid-phase synthesis. When the sam

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  • Preparation method of desmopressin acetate

Examples

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Example Embodiment

[0057] Example 1: Preparation of Fmoc-Gly-SieberAmide resin

[0058] Add 20g of Sieber Amide resin (substitution degree of 1.2mmol / g) to a 200mL reaction column, add DMF to swell for 30 minutes, after swelling, use 20% hexahydropyridine / DMF(V:V) solution to remove Fmoc protection Group. Wash three times with DMF, then three times with DCM. Dissolve Fmoc-Gly-OH (50mmol) and HOBt (60mmol) with an appropriate amount of DMF. Add DIC (60mmol) under ice water bath, activate for 3 minutes, and add to the above reaction column , The reaction was stirred at room temperature for 120 min. After the reaction, the reaction solution was vacuumed off and washed with DMF three times. Use Kaiser reagent to detect the reaction and block with 20% acetic anhydride or pyridine for 2 hours. The reaction solution was drawn off, washed with DMF three times, and washed three times with DCM. A small amount of resin was shrunk with methanol three times and dried by vacuum. The resin substitution degree ...

Example Embodiment

[0059] Example 2: Preparation of Fmoc-Gly-SieberAmide resin

[0060] Add 100 g of Sieber Amide resin (substitution degree 0.5mmol / g) to a 500mL reaction column, add DMF to swell for 30 minutes, then add N-methylpyrrolidone for 30 minutes, after swelling, use 20% hexahydropyridine DMF The solution removes the Fmoc protecting group. Wash three times with DMF, then three times with DCM. After dissolving Fmoc-Gly-OH (150mmol) and HOBt (200mmol) with an appropriate amount of DMF, add it under ice water bath and activate with DIC (300mmol) for 3 minutes, then add to the above reaction column In, the reaction was stirred at room temperature for 120 min. After the reaction, the reaction solution was vacuumed off and washed with DMF three times. Use Kaiser reagent to detect the reaction and block with 20% acetic anhydride or pyridine for 2 hours. DMF was washed three times, DCM washed three times, a small amount of resin was shrunk with methanol three times, and then vacuumed to drynes...

Example Embodiment

[0061] Example 3: Preparation of linear desmopressin peptide resin

[0062] Add 25g of Fmoc-Gly-Sieber Amide resin prepared in Example 1 (substitution degree is 0.90mmol / g) into a 500mL reaction column, add DMF to swell for 30 minutes, and then use 20% hexahydropyridine DMF solution to remove Fmoc The protecting group is 10 minutes, and then washed three times with DMF and DCM respectively. Dissolve Fmoc-D-Arg(Pbf)-OH (50mmol), HOBt (75mmol), and DIC (100mmol) with an appropriate amount of DMF and add them to the above reaction column. Stir under nitrogen for 120 minutes at room temperature. After the reaction was detected with Kaiser reagent, the reaction solution was vacuumed out, washed with DMF three times, and DCM washed three times. According to the above method of coupling Fmoc-D-Arg(Pbf)-OH, sequentially couple Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt) -OH, Fmoc-Phe-OH, Fmoc-Tyr(tBu)-OH and Mpr(Trt)-OH. Finally, Mpr(Trt)-Tyr(tBu)-Phe-Gln(Trt)-Asn(T...

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Abstract

The invention belongs to the technical field of medicinal chemistry and discloses a preparation method of desmopressin acetate. The preparation method comprises the following steps of: synthesizing peptide resin of linear desmopressin by solid-phase synthesis, conducting cracking to obtain crude peptide of the linear desmopressin, then purifying the crude peptide of the linear desmopressin through reversed-phase high-performance liquid chromatography, afterwards carrying out liquid-phase oxidation, and finally conducting salt conversion to obtain the desmopressin acetate. Compared with the prior art, the preparation method integrates the advantages of solid-phase synthesis and liquid-phase oxidation, combines solid-phase synthesis, purification and liquid-phase oxidation, and is simple in operation, low in production cost and environmental pollution, high in yield of desmopressin acetate, and suitable for large-scale industrial production of desmopressin acetate. Besides, the desmopressin acetate product prepared by the method is fine in quality, high in purity and low in impurity content, therefore the method has a substantial economically practical value and wide application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a preparation method of desmopressin acetate. Background technique [0002] Desmopressin acetate, the English name is Desmopressin Acetate, the molecular formula is C 50 h 72 N 14 o 16 S 2 , with a molecular weight of 1129.27, is a structural analogue of natural arginine salt vasopressin, which is obtained by making two changes to the chemical structure of the natural hormone, that is, deamination of 1-cysteine ​​and deamination of 8-D-arginine Acid substitution 8-L-arginine. Acetate deammonia is mainly used in the treatment of central diabetes insipidus, nocturnal enuresis and hemophilia, etc. It is also used in the test of renal urine concentration function and postoperative hemostasis. Its peptide sequence structure is as follows: [0003] [0004] There are mainly two types of synthesis of desmopressin acetate reported in the literature at present. The f...

Claims

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Application Information

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IPC IPC(8): C07K7/16C07K1/20C07K1/06C07K1/04
Inventor 唐青林刘剑马亚平袁建成
Owner HYBIO PHARMA
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