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A kind of synthetic method of romidepsin

A synthesis method and technology for romidepsin, which are applied in the field of solid-phase synthesis of medicinal chemistry, can solve the problems of cumbersome steps, not simple enough, and affect the production efficiency of romidepsin, and achieve the effects of simple steps and high synthesis efficiency.

Active Publication Date: 2022-03-08
GANSU CHANGEE BIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method has cumbersome steps and is not easy enough. More importantly, its total liquid phase yield is only about 18%. These problems have always been the main factors affecting the production efficiency of romidepsin.

Method used

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  • A kind of synthetic method of romidepsin
  • A kind of synthetic method of romidepsin
  • A kind of synthetic method of romidepsin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] The preparation of embodiment 1 intermediate I

[0061] Weigh 2g of CTC Resin with a degree of substitution of 0.5mmol / g (synthesis scale 1mmol), add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then weigh 1.01g of Fmoc-Val-OH , 0.38g HOBt and 0.03g DMAP were dissolved in DMF, activated by adding 0.6mL DIPEA in an ice-water bath, then added to the above-mentioned reaction column equipped with resin, reacted for 2 hours and the reaction was completed, washed 6 times with DMF to obtain intermediate I.

Embodiment 2

[0062] The preparation of embodiment 2 intermediate V

[0063] Use 20% DBLK to remove the Fmoc protecting group of intermediate I in the solid-phase reaction column, then wash it with DMF for 6 times, take a small amount of resin for ninhydrin test, and the resin will develop color. Weigh 1.02g Fmoc-Thr-OH, 0.38g HOBt, 0.03g DMAP and dissolve in a mixed solution of DMF and NMP with a volume ratio of 1:1, add 0.3mL DIC to activate it in an ice-water bath, add it to a solid-phase reaction column, and react at room temperature 2h (the end point of the reaction is determined by the ninhydrin method. If the resin is colorless and transparent, the reaction is complete, and the resin develops color, indicating that the reaction is incomplete, and another coupling reaction is required for 1h). Repeat the steps of removing Fmoc protection and adding the corresponding amino acid coupling steps to complete Fmoc-D-Cys(Trt)-OH, Fmoc-D-Val-OH and (R)-3-tert-butoxy-7-mercapto -4-Heptenoic a...

Embodiment 3

[0064] The preparation of embodiment 3 intermediate VI

[0065] Weigh 0.03g DMAP, 0.20g p-toluenesulfonyl chloride dissolved in 10mL dichloromethane, then add 0.60ml piperidine. Then the mixed solution was added to the solid-phase reaction column containing intermediate V, and reacted for 2 hours. After the reaction, it was washed with DMF for 6 times, then shrunk with methanol for 3 times, and vacuum-dried to obtain 3.0 g of intermediate VI.

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Abstract

The invention provides a synthetic method of romidepsin, which comprises the following steps: 1) under the action of an activator, solid-phase synthetic resin is coupled with Fmoc-L-Val-OH to obtain intermediate I; 2) According to the Fmoc solid-phase synthesis strategy, Fmoc‑L‑Thr‑OH, Fmoc‑D‑Cys(R)‑OH, Fmoc‑D‑Val‑OH, (R)‑3‑tert-butoxy‑7‑ ‑Mercapto‑4‑heptenoic acid is subjected to polypeptide chain extension coupling to obtain intermediate V; 3) intermediate V removes the hydroxyl group on the side chain of the L‑Thr residue to form a double bond to obtain intermediate VI; 4) intermediate Cleavage of VI to remove resin and side chain protecting groups to obtain intermediate VII; 5) intermediate VII is oxidized to form an intramolecular disulfide bond to obtain intermediate VIII; 6) intermediate VIII is obtained through intramolecular esterification pungent.

Description

technical field [0001] The invention relates to the field of solid-phase synthesis of medicinal chemistry, in particular to a method for synthesizing romidepsin. Background technique [0002] Romidepsin, the English name is Romidepsin, its chemical name is (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-diisopropyl-2-oxa-12, 13-dithio-5,8,20,23-tetraazabicyclo[8,7,6]tricos-16-ene-3,6,9,19,22-pentone, the molecular formula is C 24 h 36 N 4 o 6 S 2 , is a bicyclic tetrapeptide with a stable hydrophobic structure, and the unique disulfide bond in its structure is the key group for its activity. In 2009, romidepsin was approved by the US Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL). Its chemical structure is as follows: [0003] [0004] Romidepsin is an inhibitor of histone deacetylases (HDACs), which enters the cytoplasm through the tumor cell membrane, and the disulfide bond in the cell is reduced to a sulfhydryl group by glutath...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/103C07K1/06C07K1/04
CPCC07K5/101C07K1/04C07K1/06Y02P20/55
Inventor 陈学明林欣媛宓鹏程陶安进袁建成
Owner GANSU CHANGEE BIO PHARMA
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