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Synthesis method of desmopressin

A technology of desmopressin and a synthesis method, which is applied to the synthesis field of desmopressin, can solve the problems of unfavorable industrial sustainable development, consumption of large organic solvents, and high production cost, and achieves considerable economical and practical value. Easy to handle, low-cost effects

Inactive Publication Date: 2015-09-23
HYBIO PHARMA
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AI Technical Summary

Problems solved by technology

[0005] In the solid-phase synthesis method of the prior art, the coupling of each amino acid monomer needs to be carried out in an organic solvent (DMF). Moreover, the product needs to be washed many times with an organic solvent during the synthesis process, and a large amount of organic solvent is also consumed. Solvent (DMF, etc.)
This not only has high production costs, but also seriously pollutes the environment, which is not conducive to the sustainable development of the industry.
[0006] In addition, the prior art Fmoc solid-phase peptide synthesis strategy needs to use piperidine (hexahydropyridine) in DMF solution to remove the temporary protecting group Fmoc, and some residues are easy to be generated during the removal process, resulting in many side reactions. , which requires protection of the side chain functional groups in the peptide sequence to avoid side reactions when amino acid monomers are coupled into peptide chains, which also increases the cost

Method used

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  • Synthesis method of desmopressin
  • Synthesis method of desmopressin
  • Synthesis method of desmopressin

Examples

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preparation example Construction

[0034] The present invention provides a kind of synthetic method of desmopressin, and described synthetic method comprises:

[0035] 1) Preparation of desmopressin linear peptide peptide resin: firstly mix the amino acid monomer PG-Gly-OH and coupling agent with water evenly, let it stand, and then react the obtained mixture on the solid phase carrier from which the protecting group is removed, Obtain PG-Gly-solid phase carrier, then remove PG to obtain H-Gly-solid phase carrier; repeat the above steps, amino acid monomers and Mpa are sequentially coupled on H-Gly-solid phase carrier, and the coupling sequence is sequentially Coupling PG-D-Arg-OH, PG-Pro-OH, PG-Cys(Trt)-OH, PG-Asn-OH, PG-Gln-OH, PG-Phe-OH, PG-Tyr-OH, Mpa , the PG is a water-soluble amino protecting group; thus obtain the desmopressin linear peptide peptide resin Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-solid phase of the formula (I) Carrier (I);

[0036] 2) Preparation of desmopressin cyclic peptide resin: Oxid...

Embodiment 1

[0080] Preparation of H-Rink-PEG Amide Resin

[0081] Place 100g (50mmol, 1eq) of Fmoc-Rink-PEG Amide resin with a substitution degree of 0.5mmol / g in a solid-phase reaction column (1000ml), add a mixture of 800ml Triton X-100 and water (molar ratio Triton X-100 : water = 12:2000), nitrogen bubbling and swelling for 60 minutes; then, add DBLK to the solid phase reaction column to remove Fmoc, then add 800ml Triton X-100 and water mixture to the above solid phase reaction column ( molar ratio as above), repeated 4 times to obtain H-Rink-PEG Amide resin.

[0082] Preparation of linear peptide resins of desmopressin

[0083] Add 35.9g (150mmol, 3eq) Esc-Gly-OH, 32.3g (180mmol, 3.6eq) HONB, 32.4 g (180mmol, 3.6eq) EDC·HCl, mix well, then add 23.3g (180mmol, 3.6eq) DIPEA under ice-water bath at 0°C, mix well and let stand for 5 minutes, put the resulting mixture into the above solid phase reaction column , react for 2 hours to obtain Esc-Gly-Rink-PEG Amide resin; then, add 5...

Embodiment 2

[0093] Preparation of H-Rink-PEG Amide Resin

[0094] The same method as in Example 1, except that 83.3 g (50 mmol, 1 eq) of Fmoc-Rink-PEG Amide resin with a substitution degree of 0.6 mmol / g was used.

[0095] Preparation of linear peptide resins of desmopressin

[0096] The same method as in Example 1, except that the amount of amino acid monomer protected by Esc and Mpa(Trt)-OH is 23.9g (100mmol, 2eq) respectively; the amount of HONB, EDC·HCl, and DIPEA are respectively 21.5g (120mmol, 2.4eq), 21.6g (120mmol), 15.5g (120mmol, 2.4eq).

[0097] Preparation of Desmopressin Cyclic Peptide Resin

[0098] Add a mixture of iodine 76.2g (300mmol, 6eq) and 400mlDMF (5188mmol, 103.8eq) to the solid-phase reaction column obtained from the previous step, react for 2h, then add 800mlDMF to wash, repeat 3 times, then add 800ml methanol to shrink, Repeat 3 times, and obtain desmopressin cyclic peptide resin 175g after draining.

[0099] Preparation of desmopressin

[0100] Th...

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Abstract

The invention provides a synthesis method of desmopressin. The method comprises the following steps: coupling amino acid monomers and Mpa onto a solid carrier, from which the protective groups have been moved, in a water solution according to a sequence of PG-Gly-OH, PG-D-Arg-OH, PG-Pro-OH, PG-Cys(Trt)-OH, PG-Asn-OH, PG-Gln-OH, PG-Phe-OH, PG-Tyr-OH, and Mpa, wherein the PG represents a water-soluble amino protective group, oxidizing, cracking, and purifying. The provided synthesis method does not use any organic solvent, the cost is saved, the environment is protected, moreover, part of the side-chain functional groups in the peptide sequence does not need to be protected, the operation is simple, the cost is low, the yield is high, and thus the provided synthesis method can generate considerable economic benefits, is very practical, and has a wide application prospect.

Description

technical field [0001] The invention relates to a synthesis method of desmopressin. Background technique [0002] Desmopressin is a structural analogue of natural arginine vasopressin, which is obtained by making two changes to the chemical structure of the natural hormone, namely deamination of 1-cysteine ​​and substitution of 8-D-arginine Substitution of 8-L-arginine. The peptide sequence structure of desmopressin is: Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-NH 2 (where Mpa and Cys form a ring through a disulfide bond). [0003] Desmopressin is mainly used for the treatment of central diabetes insipidus, nocturnal enuresis and hemophilia, etc. It is also used for the test of renal urine concentration function, and it can also be used for postoperative hemostasis. [0004] With the increasing development of the Fmoc solid-phase peptide synthesis method and the maturity of the preparation process, at present, in the peptide synthesis, the solid-phase synthesis gradually repl...

Claims

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Application Information

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IPC IPC(8): C07K7/16C07K1/06C07K1/04
CPCY02P20/55
Inventor 戴政清刘建马亚平袁建成
Owner HYBIO PHARMA
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