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Preparation of carperitide by solid-phase convergence process

A caperitide and fragment technology, which is applied in the preparation field of caperitide, can solve the problems of low drug purity, complicated operation, unfavorable large-scale industrial production and the like

Active Publication Date: 2013-07-17
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Using gene recombination technology, the operation is cumbersome, the investment is large, the drug purity is not high, and there are high technical barriers
Liquid or solid phase synthesis using the Boc route requires the use of HF and a large amount of TFA, which brings serious pollution to the environment
At the same time, the liquid phase method has the disadvantages of long operation period and cumbersome operation, which is not conducive to large-scale industrial production.
However, the preparation of capecritide by coupling one by one with the solid-phase Fmoc route has the disadvantages of long synthesis period and low yield.

Method used

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  • Preparation of carperitide by solid-phase convergence process
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  • Preparation of carperitide by solid-phase convergence process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1: Synthesis of Peptide Resin A'

[0077] Weigh 15.38 g of 2-CTC resin with a substitution degree of 0.65 mmol / g, add it to the solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, and take 5.94 g of Fmoc-Gly-OH (here and The amino acid used later was purchased from Chengdu Kaitai New Technology Co., Ltd.) was dissolved in DMF, activated by adding 6.97ml of DIEA under an ice-water bath, and then added to the above-mentioned reaction column containing the resin. After 2 hours of reaction, 20ml of anhydrous methanol was added to seal 1 h, washed 6 times with DMF. The Fmoc protection was removed with DBLK for 3 minutes, and the Fmoc protection was continued with new DBLK for 7 minutes, and then washed with DMF for 6 times.

[0078] Dissolve 8.92g Fmoc-Gly-OH, 4.46g HOBT, and 5.13ml DIC in 60ml of DCM and DMF mixed solution with a volume ratio of 1:1, add it to the solid-phase reaction column, and react at room temperature f...

Embodiment 2

[0079] Example 2: Synthesis of Peptide Resin A'

[0080] Weigh 9.17 g of 2-CTC resin with a substitution degree of 1.09 mmol / g, add it to the solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, take 5.94 g of Fmoc-Gly-OH and dissolve it in DMF, After adding 6.97 ml of DIEA under ice-water bath for activation, it was added to the above reaction column containing resin. After 2 hours of reaction, 20 ml of anhydrous methanol was added to block for 1 hour, and washed 6 times with DMF. The Fmoc protection was removed with DBLK for 3 minutes, and the Fmoc protection was continued with new DBLK for 7 minutes, and then washed with DMF for 6 times.

[0081] Dissolve 8.92g Fmoc-Gly-OH, 4.46g HOBT, 9.63g TBTU, 10.45ml DIEA in 60ml DMF, activate it in an ice-water bath for 3 minutes, add it to the solid-phase reaction column, and react at room temperature for 2h (the reaction end point is detected by the ninhydrin method If the resin is colorless...

Embodiment 3

[0082] Example 3: Synthesis of Peptide Fragment A

[0083] The peptide resin obtained in Example 2 was put into a round bottom flask. The lysis solution was prepared according to the ratio of 1 gram of resin to 10 ml of lysis solution (the ratio of lysis solution: TFE:DCM=1:4, V:V), poured the lysis solution into the flask, and reacted at room temperature for 2.5h. After the reaction was completed, the resin was filtered and the filtrate was collected. After the filtrate was evaporated to dryness on a rotary evaporator, 20 ml of DCM was added, the mixture was added dropwise to 200 ml of ether, a white solid was precipitated, centrifuged, washed with anhydrous ether, and dried in vacuo to obtain a side chain fully protected peptide fragment A (sequence ( 1-10)) 21.27g, purity 94.8%, yield 93.7%.

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Abstract

The invention discloses a synthetic method of carperitide by Fmoc (fluorenylmethyloxycarbonyl) route solid-liquid convergent synthesis. Multiple segments are synthesized simultaneously. The synthetic cycle is decreased by two thirds. Intermediate is easy to purify. The cost is low. The finished product is highly pure. Side products are few. The product yield is high. Large-scale production of carperitide is facilitated. The carperitide prepared by the method is above 75% in crude peptide purity and above 25% in total yield.

Description

technical field [0001] The present invention relates to a preparation method of a polypeptide, in particular to a preparation method of caperitide. Background technique [0002] Carperitide (Carperitide), alias gene recombinant atrial peptide, caperidine, Hamp, human brain natriuretic peptide, its indication is acute heart failure (including chronic heart failure aggravation). The pharmacological effect of caperitide is to stimulate the stretching of the myocardium, which is synthesized by particles in the ventricle, and then distributed throughout the body through the coronary arteries, acting on tissues such as vascular smooth muscle and kidneys, regulating blood pressure and electrolyte balance in the body. Caperitide is a 28 amino acid circulatory regulator hormone that acts as a vasodilator and diuretic. The vasodilation caused by caperitide is achieved by binding to ANP (atrial natriuretic polypeptide) receptors in vascular smooth muscle and by increasing the activity...

Claims

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Application Information

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IPC IPC(8): C07K14/58C07K1/06C07K1/04
Inventor 张文治刘建马亚平袁建成
Owner HYBIO PHARMA
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