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Method for refining histone deacetylase (HDAC) inhibitor vorinostat

A technology of vorinostat and refining method, which is applied in the field of refining vorinostat, a protein deacetylase inhibitor, can solve the problems of high production cost, unfavorable environmental protection requirements, unsuitability, etc., and achieve the effect of low cost

Active Publication Date: 2012-02-08
杭州容立医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The effects of these several crystallization methods to remove impurity caprylanilic acid (the main impurity in the vorinostat bulk drug) are all not ideal; It is also difficult to dry out under the same conditions, so it is not suitable for use as a medicine; except that the vorinostat obtained by the first crystallization method is a single crystal form, other crystallization methods obtain mixed crystal vorinostat, which is not suitable for use as a medicine
In addition, compared with water, organic solvents have higher production costs and are not conducive to environmental protection requirements.

Method used

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  • Method for refining histone deacetylase (HDAC) inhibitor vorinostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Synthesis of Vorinostat

[0027] 1. Synthesis of suberic anhydride:

[0028] ①Reaction formula:

[0029]

[0030] ②Operation method:

[0031] Add 1280 grams of suberic acid and 3.2 liters of acetic anhydride into a 10L reaction flask, heat and reflux for 1.5 hours under the protection of nitrogen, evaporate the solvent under vacuum, add 3.2 liters of acetonitrile to dissolve, and stand at -15°C overnight, and a large amount of white solids are precipitated , filtered, the solid was washed with 1.9 liters of acetonitrile at -15°C, and dried by suction, and the filter cake was vacuum-dried at room temperature to a constant weight to obtain 1100 grams of white powder.

[0032] 2. Synthesis of Octanoanilic Acid:

[0033] ①Reaction formula:

[0034]

[0035] ②Operation method:

[0036] At room temperature, add 720 grams of suberic anhydride and 6350 ml of tetrahydrofuran into a 10L reaction bottle, stir to dissolve, add 432 grams of aniline dropwise, and then stir...

Embodiment 2

[0043] Water (sodium bicarbonate) crystallization method of vorinostat

[0044] In Example 1, 436 grams of crude product (without drying, containing about 43% moisture) was refluxed with 43.6 liters of water to dissolve, and then 250ml of aqueous sodium bicarbonate solution (10 g / liter) was added to cool down to below 30°C to precipitate orange-yellow powder, which was filtered , dried to obtain 225 grams of orange powder (HPLC normalization method detected caprylanilic acid containing about 0.7%).

Embodiment 3

[0046] Water crystallization method of vorinostat

[0047] 6.75 liters of water was heated to reflux, 25 grams of the product of Example 2 was added, and stirred to dissolve. Cool down to below 30°C to precipitate an orange powder, filter, and dry to obtain 22 grams of an orange powder (octanoanilide acid content is about 0.3% detected by HPLC normalization method).

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Abstract

The invention provides a method for refining a medicine vorinostat for treating cutaneous T-cell lymphomas. The method, which allows an impurity suberanilic acid to be rapidly removed and high purity vorinostat to be prepared and has the advantages of simple operation and high yield, is suitable for the industrialization production.

Description

technical field [0001] What the present invention relates to is a kind of medicine vorinostat (vorinostat) for the treatment of skin T-cell lymphoma, namely the new refining method of N-hydroxyl-N'-phenylsuberamide. technical background [0002] Vorinostat (formula I) is a protein deacetylase (HDAC) inhibitor. The drug was approved by the U.S. FDA in 2006 as a rare disease drug for the treatment of cutaneous T-cell lymphoma (CTCL), which is used when the disease continues to deteriorate or recurs during or after treatment with other drugs . [0003] [0004] The synthesis method of vorinostat has been reported in WO9307148, J Med Chem 1995, 38(8): 1411, Org Prep Proced Int 2001, 33(4): 391, CN200680000867.0 and other documents. Through these several synthetic methods, the synthesized vorinostat inevitably contains caprylanilic acid (formula II) as an impurity. [0005] [0006] The current crystallization method published in the literature is summarized in the paten...

Claims

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Application Information

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IPC IPC(8): C07C259/06
Inventor 任建强王万青钟万德
Owner 杭州容立医药科技有限公司
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