Method for preparing vapreotide

A technology of vapreotide and solid-phase synthesis method, which is applied to the preparation method of peptides, chemical instruments and methods, peptides, etc., can solve the problems of low application value, complicated operation, unfavorable industrial production, etc., and achieve low cost and high reaction rate. The effect of simple operation and less input of raw materials

Inactive Publication Date: 2010-05-26
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, there is no report on the synthesis process of vapreotide in China; although there are reports on the synthesis process of vapreotide abroad, most of them are liquid-phase synthesis processes, which are complicated to operate, are not conducive to industrial production, and have low application value.

Method used

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  • Method for preparing vapreotide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1, Fmoc-Trp (Boc)-RinkAmide resin preparation

[0037] 1. Put 50g Rink Amide Resin (Sub=0.8mmol / g) in a reaction bottle, add DMF to wash twice, and then swell with DMF for 30 minutes.

[0038] 2. Use 20% DBLK to remove the Fmoc protecting group of Rink Amide Resin, wash with DMF for 4 times and DCM for 2 times after removal, and detect with ninhydrin detection method, the resin is reddish brown.

[0039] 3. Weigh 63.2g of Fmoc-Trp(Boc)-OH and 19.5g of HOBT, add 500ml of DMF and 24.4ml of DIC, dissolve, add to the reaction bottle, and start the reaction.

[0040] 4. React for 2 hours, finish the reaction, wash with DMF three times, measure 56.4ml of acetic anhydride, 48.4ml of pyridine and mix them in 400ml of DMF, add to the reaction bottle to seal for two hours, then wash with DMF for 3 times, DCM for 2 times, methanol Washed twice, directly used for the next step of amino acid coupling.

Embodiment 2

[0041] Embodiment 2, the preparation of Fmoc-Cys(Trt)-Trp(Boc)-Rink Amide Resin

[0042] 1. After washing Fmoc-Trp(Boc)-Rink Amide Resin with DMF, remove Fmoc with 20% DBLK, then wash 4 times with DMF, wash 2 times with DCM, and detect with ninhydrin detection method. The resin is yellow.

[0043] 2. Weigh 70.2g Fmoc-Cys(Trt)-OH, 19.5g HOBT, add 500ml DMF and 24.4ml DIC, dissolve, add to the reaction bottle, and start the reaction.

[0044] 3. After 1.5 hours of reaction, the ninhydrin detection method was used to detect that the resin was transparent, and the reaction was terminated.

[0045] 4. After the reaction is completed, wash with DMF for 3 times, and couple amino acids one by one according to the peptide sequence of vapreotide until the last amino acid.

Embodiment 3

[0046] Embodiment 3, the oxidation of vapreotide

[0047] 1. Weigh 203.2g of iodine and dissolve it in 500ml of N,N-dimethylformamide. After the dissolution is complete, add it to the reaction bottle to start the oxidation reaction. The temperature of the reaction system is 35°C.

[0048] 2. Oxidation for 20 hours, the oxidation is over.

[0049]3. DMF was washed 5 times, DCM was washed 4 times, and finally methanol was added to wash 3 times, and dried to obtain 166 g of vapreotide-Rink Amide Resin.

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Abstract

The invention discloses a method for preparing vapreotide, comprising the following steps: 1) starting from Fmoc-Trp(Boc)-OH and Rink Amide resin to obtain Fmoc-Trp(Boc)-Rink Amide resin; 2) coupling the Fmoc-Trp(Boc)-Rink Amide resin by a solid phase synthesis method to obtain linear vapreotide-Rink Amide resin according to the peptide sequence; 3) utilizing a solid phase to oxide the vapreotide-Rink Amide resin; and 4) cracking the vapreotide-Rink Amide resin, purifying and freeze-drying to obtain the vapreotide. The invention utilizes iodine to oxide the linear vapreotide resin in the solid phase, thereby avoiding the trouble brought by traditional liquid phase oxidation and improving oxidation yield by 10%-20%. The process of the invention has the characteristics of simple reaction operation, low raw material investment, low cost, high yield and the like, the total reaction yield can reach 68%, and the purification of crude peptide can reach 85%. Therefore, the method has considerable economic value and practical value.

Description

technical field [0001] The invention relates to a synthesis process for preparing Vapreotide. Background technique [0002] The molecular structure of vapreotide contained in this product is: D-phenylpropionyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-valyl-L -Cysteinyl-L-tryptophanamide (2-7 disulfide bond), is a highly potent 8-peptide homologue of the somatostatin 14-peptide. In vitro experiments show that this product can significantly inhibit the secretion of pancreas, and its action strength is stronger than that of natural growth hormone release inhibitory factor, and the duration is longer. Studies with experimental dogs have shown that the effect of this product on the pancreas is similar to that of artificially prepared somatostatin 14 peptide (SS14) and atropine, but it inhibits bicarbonate (HCO 3 -) The secretion effect is 2 to 4 times that of SS14, and the secretion of protease can be inhibited at a lower dose, and the duration of the effect is longer tha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04
Inventor 肖庆李红玲马亚平袁建成
Owner HYBIO PHARMA
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