Preparation method of histone deacetylase inhibitor FK228

A technology of FK228 and condensing agent, which is applied in the direction of chemical instruments and methods, cyclic peptides, etc., can solve the problems of limiting the preparation of FK228, and achieve the effects of avoiding product deterioration, high yield, and simple reaction conditions

Inactive Publication Date: 2011-01-05
无锡好芳德药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main disadvantage of this method is that the product is easy to deteriorate in a methanol solution higher than 25 ° C. Using a single solvent methanol as a solvent will inevitably heat and concentrate the organic phase in the post-treatment of the preparation of FK228, which greatly limits the gram level. The preparation process of FK228

Method used

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  • Preparation method of histone deacetylase inhibitor FK228
  • Preparation method of histone deacetylase inhibitor FK228
  • Preparation method of histone deacetylase inhibitor FK228

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Synthesis of compound (II)

[0029] At room temperature, 30.5g of compound (I) was dissolved in 500mL of dichloromethane and 50mL of piperidine was added, stirred for 30 minutes, and the above solution was slowly added dropwise to 4L of vigorously stirred 14.4gHATU and 10mL of diisopropylethylamine. Dichloromethane solution, added dropwise for more than 3 hours, stirred for 12 hours, quenched with saturated ammonium chloride, extracted three times with dichloromethane, washed the organic layer with saturated brine, dried, concentrated, and separated by column chromatography (ethyl acetate:petroleum ether) =1:4-2:1) to obtain 12.2 g of white solid.

[0030] Synthesis of compound (III) namely FK228

[0031] At room temperature, 24.8g iodine simple substance is dissolved in 20L methanol / dichloromethane ratio is 1 / 10 in the mixed solvent, under vigorous stirring slowly drips 10L methanol / dichloromethane ratio of 11.5g compound (I) is 1 / 10 solution, dropwise for not less t...

Embodiment 2

[0034] Synthesis of compound (II)

[0035] At room temperature, 30.5g of compound (I) was dissolved in 500mL of dichloromethane and 50mL of triethylamine was added, stirred for 12 hours, and the above solution was slowly added dropwise to 4L of vigorously stirred 28.8gHATU and 10mL of diisopropylethylamine. in dichloromethane solution, added dropwise for more than 3 hours, stirred for 12 hours, quenched with saturated ammonium chloride, extracted three times with dichloromethane, washed the organic layer with saturated brine, dried, concentrated, and separated by column chromatography (ethyl acetate: petroleum ether=1:4-2:1) to obtain 13.0 g of white solid.

[0036] Synthesis of compound (III) namely FK228

[0037] At room temperature, 24.8g iodine simple substance is dissolved in 20L methanol / dichloromethane ratio is 6 / 4 in the mixed solvent, slowly drips 11.5g compound (I) under vigorous stirring 10L methanol / dichloromethane ratio is 6 / 4 solution, dropwise for not less tha...

Embodiment 3

[0040] Synthesis of compound (II)

[0041] At room temperature, 30.5g of compound (I) was dissolved in 500mL of dichloromethane and 50mL of morpholine was added, stirred for 3 hours, and the above solution was slowly added dropwise to 4L of vigorously stirred 14.4gHATU and 5mL of diisopropylethylamine. Dichloromethane solution, added dropwise for more than 4 hours, stirred for 12 hours, quenched with saturated ammonium chloride, extracted three times with dichloromethane, washed the organic layer with saturated brine, dried, concentrated, and separated by column chromatography (ethyl acetate:petroleum ether) =1:4-2:1) to obtain 14.9 g of white solid.

[0042] Synthesis of compound (III) namely FK228

[0043] At room temperature, 12.4g elemental iodine was dissolved in 10L methanol / dichloromethane ratio of 9 / 1 mixed solvent, and slowly added dropwise 11.5g of compound (I) in 5L methanol / dichloromethane ratio of 9 / 1 under vigorous stirring Solution, dropwise for not less than ...

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Abstract

The invention discloses a new method for preparing depsipeptide FK228, comprising the following steps of: firstly forming annular polypeptide in a ring-closing way through the condensation reaction of an amido bond; and then forming the coupling of sulfide-sulfide bonds through radical reaction catalyzed by iodine by using a mixed solution of methylene dichloride and methanol as a solvent so as to synthesize the FK228. The preparation method of the FK228 has the advantages of easy operation and low cost, primarily discloses a process for preparing gram-grade FK228, greatly enhances the yield compared with past literatures and patents and provides new selection for the preparation and the production of the FK228.

Description

technical field [0001] The invention relates to a method for preparing medicine, in particular to a method for preparing FK228. Background technique [0002] Desipeptide FK228 (Dep sipep tide FK228) is a bicyclic tetrapeptide isolated from the broth medium of Chlorobacter violaceum. In addition to forming a bicyclic structure through disulfide bonds and ester bonds, its amino acid sequence also has the characteristics of alternately connecting through amide bonds and ester bonds. In addition, FK228 contains both common L-valine, D-valine, D-cysteine ​​and a special amino acid (Z)-2-amino-2-butenoic acid with a double bond And mercapto-containing chain structure unit (3S, 4E)-3-hydroxyl-7-mercapto-4-heptenoic acid. In vitro experiments on human cancer cell lines and in vivo experiments on human tumor grafts and mouse tumors, FK228 showed good anti-tumor activity, and was listed by the US Food and Drug Administration (FDA) in October 2004. "Express Approval" channel. The c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/12
Inventor 沈立新卞禹卜刘福双吴鹏程姜坤
Owner 无锡好芳德药业有限公司
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