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4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzimino ester

IP.com Disclosure Number: IPCOM000181299D
Publication Date: 2009-Mar-29
Document File: 7 page(s) / 42K

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The IP.com Prior Art Database

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4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzimino ester

    4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzimino ester ("IminoPMX"), and salt thereof, of the formula VII:

is an intermediate of 4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl]benzoyl]-L-glutamic acid ("PMX"), and salt thereof of the following formula:

wherein n is either 0 or 1, HX is either HCl or HBr; where R1 is linear or branched hydrocarbyl group or an aromatic hydrocarbyl group and M is either an alkali metal or H, preferably, M is disodium.

     Herein will be described an improved process for the preparation of PMX and salt thereof via a new intermediate, iminoPMX and salt thereof.

The process can be described in the following scheme:

1

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wherein n is either 0 or 1, HX is either HCl or HBr, HY is selected from a group consisting of HCl, HBr and P-toluenesulfonic acid (PTSA); and R1, R2 and R3 are independently selected from a group consisting of linear or branched hydrocarbyl group and an aromatic hydrocarbyl group.

    First, iminoPMX is prepared from the nitrile derivative of formula VI. The process comprises reacting 4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzonitrile("nitrile") of formula VI:

with a mixture comprising an alcohol of the following formula R1OH and a hydrogenhalide acid of the formula HX, wherein HX is either HCl or HBr; and R1 is linear or branched hydrocarbyl group or an aromatic hydrocarbyl group.

2

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    The linear or branched hydrocarbyl group can be a C 1-7 linear or branched hydrocarbyl group, for example: methyl, ethyl, propyl or butyl.

    The aromatic hydrocarbyl group is a C 6-8 aromatic hydrocarbyl group. First, 4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzonitrile ("nitrile") of formula VI is dissolved in a solvent to obtain a solution. Preferably, the solvent is dimethylsulfoxide (DMSO).

    The solution is then admixed with a mixture of the said hydrogenhalide acid and the said alcohol to obtain a reaction mixture, providing an acid salt of iminoPMX.

    The hydrogenhalide acid is added after the alcohol. The hydrogenhalide can be for example, HCl.

    The acid salt of iminoPMX is then precipitated. The precipitation is done by cooling the reaction mixture. The cooling is done for example, to a temperature of about -10°C to about +5°C, for a period of about 1 to about 3 days.

    The acid salt of iminoPMX can then be recovered by raising the temperature of the reaction mixture and adding a water immiscible organic solvent to obtain an oily phase comprising of the acid salt of iminoPMX, separating the oily phase and maintaining the oily phase...