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A PROCESS FOR THE PREPARATION OF N-HYDROXY-N-PHENYL-OCTANEDIAMIDE AND ITS INTERMEDIATES THEREOF

IP.com Disclosure Number: IPCOM000181377D
Publication Date: 2009-Mar-31

Publishing Venue

The IP.com Prior Art Database

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A PROCESS FOR THE PREPARATION OF N-HYDROXY-N-PHENYL- OCTANEDIAMIDE AND ITS INTERMEDIATES THEREOF

8-oxo-8-(phenylamino)octanoic acid methyl ester (referred as OPO) of the following structure:

is an intermediate of N-hydroxy-N-phenyl-octanediamide (referred as VRT) of the following structure:

VRT is histone deacetylase inhibitor ("HDI") used for the treatment of cutaneous T cell lymphoma and Sezary's lymphoma. VRT is marketed under the trade name Zolinza® by Merck.

Improved processes for the preparation of OPO and VRT, a process for the purification of VRT and new polymorphs of OPO and VRT potassium salt were found, and are described below.

Preparation of OPO via an acylchloride intermediate (Rout A):

OPO can be prepared by a process comprising a) reacting 8-methoxy-8-oxooctanoic acid (referred as SAME) of the following structure:

and thionyl chloride to obtain methyl 8-chloro-8-oxooctanoate (referred as MCO) intermediate, of the following structure:

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and b) reacting MCO with aniline to obtain OPO.

SAME can be purified prior to the reaction with thionyl chloride.

The purification comprises dissolving SAME in toluene to obtain a solution; combining the said solution with an aqueous solution of a base, such as sodium bicarbonate, to obtain a second solution. The solution is then maintained, preferably for a period of about 30 minutes to about 40 minutes, during which the phases are separated. The phases are separated and the organic phase is extracted. Preferably, extraction of the organic phase is repeated 3 times. After the extractions, the organic phase is combined with toluene to obtain a third solution, and the third solution is concentrated, providing a concentrate comprising SAME. Preferably, the concentration is done under vacuum, preferably at a temperature of about 40ºC. Preferably, the water content is determined by KF, and controlled by additional distillation is necessary.

The said concentrate is combined with triethyl amine (referred as TEA)and thionyl chloride, to obtain a mixture. Preferably, thionyl chloride is added dropwise, preferably, the addition is done at a temperature of about -5ºC to about 0ºC. Then, the mixture is maintained, preferably upon stirring. Preferably, maintaining is done at a temperature of about -5ºC to about 0ºC, preferably for a period of about 0.5 hour to about 1 hour. The said mixture is further maintained until it reaches to a temperature of about 18ºC to about 22º, at which it is kept for a period of about 1.5 hours to about 20 hours, during which the MCO intermediate is formed.

The said mixture is then combined with an aqueous solution of sodium chloride and the phases are separated. The organic phase is combined with aniline and TEA providing a reaction mixture. Preferably, TEA is added in a...