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A method for synthesizing romidepsin

A technology for synthesizing romidepsin and romidepsin, which is applied in the field of synthesizing romidepsin, can solve the problems of low product yield, cumbersome operation, complex overall process, etc., and achieve the effect of high purity and total yield

Active Publication Date: 2021-04-13
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, there are mainly two methods to prepare romidepsin, one is biological fermentation method, such as patent CN201310430220, but the overall process is relatively complicated; the other is to prepare by chemical synthesis, such as patent CN201010133961, which synthesizes linear peptides through liquid phase, Carry out the liquid phase amide ring cyclization first, and then carry out the liquid phase disulfide bond cyclization, the operation is cumbersome, and the product yield is low; base) Thio]-4-heptenoic acid, starting with 2-Cl-Trt resin, using the solid phase method to synthesize linear peptides, after iodine oxidation cyclization to form disulfide bonds, remove the resin in the liquid phase Carry out amide ring cyclization, but the highest purity of the crude product is only 67.53%, and the highest total yield after simultaneous purification and transacetate is only 33.7%

Method used

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  • A method for synthesizing romidepsin
  • A method for synthesizing romidepsin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Synthesis of Peptide Resin 1 (Coupling of Fmoc-Thr-OAll)

[0051] Take 0.3mol of Trt resin (substitution value is about 0.6mmol / g), wash it with DMF for 3 times; take another 0.6mol of Fmoc-Thr-OAll, dissolve it with an appropriate amount of DMF, add it to the above resin, add 1.2mol of DIPEA under stirring, 65 Stir and react at ℃ for 6 hours, remove the reaction liquid, wash with DMF for 3 times, wash with 10% DIPEA / methanol for 3 times, and wash with DMF for 3 times, each washing time is 3min to obtain Fmoc-Thr-OAll-Trt resin, namely peptide Resin1.

Embodiment 2

[0052] Example 2: Synthesis of Peptide Resin 2

[0053] Take 0.3mol Fmoc-D-Cys(Trt) and 0.3mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.3mol DIC, slowly add it to the DMF solution of the protected amino acid under stirring, and stir and react at room temperature for 30 minutes to obtain the activated The final protected amino acid solution is set aside.

[0054] Take 0.1 mol of the peptide resin 1 prepared in Example 1, deprotect it with 20% PIP / DMF solution for 25 minutes, wash with DMF, filter, add the activated Fmoc-D-Cys (Trt) solution, and stir at room temperature for 3 hours , take out the reaction solution, after DMF washing 3 times, DCM washing 3 times, each washing time is 3min, then use 20% PIP / DMF solution to deprotect for 25 minutes, wash and filter, complete the Fmoc-D-Cys (Trt) access.

[0055] Insert Fmoc-D-Val and (3S,4E)-3-hydroxy-7-[(Trt)thio]-4-heptenoic acid in the same way, wash and filter to obtain (3S,4E)-3-hydroxy-7 -...

Embodiment 3

[0056] Example 3: Synthesis of Peptide Resin 2

[0057] Take 0.3 mol Fmoc-D-Cys (Acm) and 0.3 mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.3 mol DIC, slowly add it to the DMF solution of the protected amino acid under stirring, and stir and react at room temperature for 30 minutes to obtain the activated The final protected amino acid solution is set aside.

[0058] Take 0.1 mol of the peptide resin 1 prepared in Example 1, deprotect it with 20% PIP / DMF solution for 25 minutes, wash with DMF, filter, add the activated Fmoc-D-Cys (Acm) solution, and stir at room temperature for 3 hours , take out the reaction solution, after DMF washes 3 times, DCM washes 3 times, each washing time is 3min, then deprotects with 20% PIP / DMF solution for 25 minutes, washes and filters, and completes the Fmoc-D-Cys (Acm) access.

[0059] Insert Fmoc-D-Val and (3S,4E)-3-hydroxyl-7-[(Acm)thio]-4-heptenoic acid in the same way, wash and filter to obtain (3S,4E)-3-hy...

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Abstract

The invention relates to the field of medicine synthesis and discloses a method for synthesizing romidepsin. The present invention synthesizes romidepsin linear peptide chains one by one with suitable protected amino acids, completes amide bond cyclization and disulfide bond cyclization successively by solid-phase means, and optimizes the details of the solid-phase synthesis scheme, and finally obtains romidepsin Midesin has high purity and total yield.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing romidepsin. Background technique [0002] Romidepsin, known in English as Romidepsin, is a synthetic pentapeptide cyclic compound 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 amino acid structure is as follows: [0003] [Val 1 -(R 2 -D-Val 3 -D-Cys 4 )-DH-Thr 5 ] [0004] Among them, R is (3S,4E)-3-hydroxy-7-thio-4-heptenoic acid, which forms a disulfide bond with the D-cysteine ​​at the 4th position, and the valine at the 1st position and the 5th position Threonine forms an amide bond. [0005] Romidepsin is an inhibitor of histone deacetylases (HDACs), which enters the cytoplasm through the tumor cell membrane, and the disulfide b...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/103C07K1/08C07K1/06
CPCC07K5/101
Inventor 马中刚郭德文曾德志文永均
Owner CHENGDU SHENGNUO BIOPHARM
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