Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-25
2001-07-03
Higel, Floyd D. (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06255492
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an improved process for the production of diesters of phosphoric acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester, which are key intermediates in the preparation of 5,5-diphenyl-[(3-phosphonooxy)methyl]-2,4-imidazolidinedione disodium salt (Cerebyx®, also known as fosphenytoin sodium) described in U.S. Pat. Nos. 4,260,769 and 4,925,860, which are herein incorporated by reference. Cerebyx® is useful as an anticonvulsant, antiepileptic, and antiarrhythmic agent.
A synthetic procedure for preparing 3-(hydroxymethyl)-5,5-diphenylhydantoin dibenzyl phosphate ester is disclosed in Varia S. A., et al.,
Journal of Pharmaceutical Sciences,
1984;73:1068-1073. The aforementioned procedure requires the use of silver dibenzyl phosphate. This reagent is expensive, light sensitive, and silver byproducts are difficult to remove. Thus, special procedures are required to purify the desired product.
Metal salts of dialkyl phosphates have been used for phosphorylation of alkyl halides, and in general, the cation of choice is silver (Sasse K., “Methoden der Organisation Chemis” (Houben-Weyl), Band XLI/2, Thieme Verlag, Stuttgart, 1964:302-306). Precipitation of silver halide from the reaction mixture drives the reaction to completion. Salts of dialkyl phosphates with sodium or potassium as the gegenion have been used with some substrates, but are generally considered to be very poor nucleophiles for reaction with alkyl halides (Khorana H. G., “Some Recent Developments in the Chemistry of Phosphates of Biological Interest,” John Wiley & Sons, New York, N.Y., 1961:13-14; Zwierak A, and Kluba M.,
Tetrahedron,
1971;27:3163-3170; U.S. Pat. Nos. 2,494,126, 2,494,283, and 2,494,284). In point of fact, Zwierzak A. and Kluba M.,
Tetrahedron,
1971;27:3163-3170 disclose that sodium or potassium salts of dialkyl phosphates are too unreactive to give satisfactory phosphorylation.
We have surprisingly and unexpectedly found that alkali metal phosphate esters react with either 3-(chloromethyl)- or 3-(bromomethyl)-5,5-diphenyl-2,4-imidazolidinedione to afford diesters of phosphoric acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester. The object of the present invention is an improved, short, efficient, and economical process that can be carried out on a manufacturing scale for the preparation of diesters of phosphoric acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester. Thus, the present process avoids the use of costly and unstable reagents such as silver phosphate esters and associated silver by-products, which are difficult to remove and is amenable to large-scale synthesis.
SUMMARY OF THE INVENTION
Accordingly, a first aspect of the present invention is an improved process for the preparation of a compound of Formula I
wherein R is aryl,
arylalkyl, or
alkyl;
which comprises treating a compound of Formula II
wherein X is chloro or bromo with a compound of Formula III
wherein M is an alkali metal, and R is as defined above in a solvent to afford a compound of Formula I.
A second aspect of the present invention is a novel intermediate of Formula I
wherein R is aryl,
arylalkyl, or
alkyl with the exclusion of:
phosphoric acid dibenzyl ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester.
DETAILED DESCRIPTION OF THE INVENTION
In the compounds of Formula I, the term “alkyl” means a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.
The term “aryl” means an aromatic radical which is a phenyl group, a naphthyl group, unsubstituted or substituted by 1 to 4 substituents selected from alkyl as defined above, nitro or halogen.
The term “arylalkyl” means an aromatic radical attached to an alkyl radical wherein aryl and alkyl are as defined above, for example, benzyl and the like.
“Halogen” is fluorine, chlorine, bromine, or iodine.
“Alkali metal” is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium, cesium, and the like.
The process of the present invention is a new, improved, economical, and commercially feasible method for preparing compounds of Formula I, which are useful as intermediates in the preparation of fosphenytoin sodium, which is useful as an anticonvulsant, antiepileptic, and antiarrhythmic agent.
The process of the present invention is outlined in the following scheme:
A compound of Formula I wherein R is aryl, arylalkyl, or alkyl is prepared by reacting a compound of Formula II wherein X is chlorine or bromine with a compound of Formula III wherein M is an alkali metal such as, for example, lithium, sodium, potassium, cesium, and the like, and R is as defined above in a solvent such as, for example, acetonitrile and the like at about 25° C. to about the reflux temperature of the solvent for about 1 hour to about 24 hours to afford a compound of Formula I. When M is potassium, optionally a catalytic amount of potassium iodide may be used. When M is sodium, optionally a catalytic amount of tetrabutylammonium iodide or 18-crown-6 may be used. Preferably, the reaction is carried out in acetonitrile at reflux for about 2 hours to about 11 hours.
5,5-Diphenyl-2,4-imidazolidinedione (phenytoin) is readily available or may be prepared according to procedures disclosed in U.S. Pat. No. 2,409,154.
Compounds of Formula III are either known or capable of being prepared by methods known in the art.
REFERENCES:
patent: 3741978 (1973-06-01), Jamison
patent: 3892765 (1975-07-01), Porret et al.
patent: 3925406 (1975-12-01), Porret et al.
patent: 3980647 (1976-09-01), Porret et al.
patent: 4260769 (1981-04-01), Stella et al.
patent: 4925860 (1990-05-01), Herbranson et al.
patent: 6022975 (2000-02-01), Davis et al.
Davis Edward M.
Ellis James E.
Katonak David A.
Higel Floyd D.
Merchant & Gould P.C.
Warner-Lambert & Company
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