MXPA98007826A - Improved process for the synthesis of phosphoric acid 2,5-dioxo-4,4-difenil-imidazolidin-1-ilmetil es - Google Patents

Abstract

An improved process for the preparation of a diester of phosphoric acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester is described wherein a metacalcali phosphate is treated with a 3- (chloromethyl) -or a 3- (bromomethyl) -5,5-diphenyl-2,4-imidazolidinedione to produce the desired product, as well as valuable intermediates used in the process

Description

IMPROVED PROCESS FOR THE SYNTHESIS OF PHOSPHORIC ACID 2, 5 - DIOXO - 4, 4 - DIFENIL - HWIDAZOLIDIN - 1 - ILMETIL ESTER BACKGROUND OF THE INVENTION The present invention relates to an improved process for the preparation of a diester of phosphoric acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester, which are key intermediates in the preparation of salt 5, 5-diphenyl - [(3-phosphonooxy) methyl] -2,4-imidazolidinedione disodium (Cerebyx®, also known as sodium fosphenytoin) described in U.S. Patents 4,260,769 and 4,925,860, which are incorporated herein by reference. way of reference. Cerebix® is useful as an anticonvulsant, antiepileptic and antiarrhythmic agent.

A synthetic procedure for preparing 3- (hydroxymethyl) -5,5-diphenylhydantoin dibenzyl phosphate ester is presented by 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, sensitive to light and the products derived from silver are difficult to remove. Thus, special procedures are required to purify the desired product.

Metal salts of dialkyl phosphates have been used for the phosphorylation of alkyl halides, and in general, the cation of choice is silver (Sasse K., "Methoden der Organization Chemis" (Houbern-Weyl, Band XLI / 2, Thieme Verlag , Stutgart, 1964: 302-306) The precipitation of the silver halide from the reaction mixture drives the reaction to completion.The salts of dialkyl phosphates with sodium or potassium such as gegenion have been used with some sub-strata, but they are generally considered as very poor nucleophiles for reaction alkyl halides (Khorana HG, "Some Recent Developments in Phosphate Chemistry of Biological Interest", John Wiley &Sons, New York, New York, 1961: 13-14; Zwierak A, and Kluba M, Tetrahedron, 1971; 27: 3163-3170; Patents in the United States number 2,494, 126, 2,494,283 and 2,494,284). In fact, Zwierzak A. and Kluba M, Tetrahedron, 1971; 27: 3163-3170 discloses that the sodium or potassium salts of dialkyl phosphates are too unreactive to give satisfactory phosphorylation.

We have surprisingly and unexpectedly found that phosphate esters of alkali metals react with either 3 - (chloromethyl) - or 3 - (bromomethyl) - 5,5 - diphenyl - 2,4 - imidazolidinedione to produce 2,3,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester phosphate acid diesters. 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. - ilmethyl ester. Thus, the present process avoids the use of expensive and unstable reagents such as silver phosphate esters and related silver products, which are difficult to remove and are recommended for 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 JJ where X is chlorine of the Formula ffl: wherein M 0 is an alkali metal and R is as defined above in solvents to produce a compound of Formula I.

A second aspect of the invention is a novel intermediate of Formula I wherein R is aryl, arylalkyl or alkyl with the exclusion of: phosphoric acid ester dibenzyl 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 from 1 to 4 substituted substitutes of 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 sodium fosphenytoin, which is useful as an anticonvulsant, antiepileptic and anti-arrhythmic agent.

The process of the present invention is defined in the following scheme: SCHEME I A compound of Formula I wherein R is aryl, arylalkyl or alkyl is prepared by the reaction of 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 is , for example, lithium, sodium, potassium, cesium or the like and R is as defined above in a solvent such as, for example, acetonitrile and the like at about 25 ° C to the reflux temperature of the solvent for about 1 hour up to about 24 hours to produce a compound of Formula I. When M is potassium, optionally a catalytic amount of potassium iodide can be used. When M is sodium, a catalytic amount of iodide tetrabutylammonia or 18-crown-6 may optionally be used. Preferably, the reaction is carried out in acetonitrile at reflux for about 2 hours to about 11 hours. , 5-diphenyl-2,4-imidazolidinedione (phenytoin) is readily available or can be prepared according to the procedures presented in U.S. Patent No. 2,409,154.

The compounds of Formula III are either known or capable of being prepared by methods known in the art.

The following examples are illustrative to illustrate the present process, the preparation of the starting materials, and the use of a compound of Formula I obtained by the present process to prepare 5,5-diphenyl - [(3-phosphonooxy) methyl salt ] - 2,4-imidazolidinedione disodium useful as an anticonvulsant, antiepileptic and antiarrhythmic agent.

EXAMPLE 1 Phosphoric acid dibenzyl ester 2,5-dioxo-4. 4-diphenyl-1-imidazolidin-1-ylmethyl ester Step (A): Preparation of 3- (chloromethyl) -5,5-diphenyl-2,4-imidazolidinedione A mixture of 250 kg of 5, 5-diphenyl-2,4-imidazolidinedione (phenytoin), 2.6 kg of potassium carbonate and 454 1 of ethyl alcohol is heated at 70 ° C to 80 ° C. One hundred thirty-five kilograms of formaldehyde solution at 37% are added, and heating is continued for at least 2 hours. The reaction mixture is slowly cooled and 600 1 of water are added during the cooling cycle. The resulting slurry is cooled to less than 25 ° C. The product, 3-hydroxymethyl-5, 5-diphenyl-2,4-imidazolidinedione. The wet cake is dried at 20 ° C to 50 ° C. The dried product and 1350 kg of ethyl acetate are charged to a reactor. Five kilograms of dimethyl formamide and 135 kg of thionyl chloride are added at 25 ° C to 35 ° C. The reaction mixture is heated at 35 ° C to 60 ° C for about 2 hours or until the reaction is essentially complete. The reaction mixture is cooled to 20 ° C to 30 ° C and combined with 2200 1 of aqueous sodium bicarbonate. The organic layer is separated and concentrated by distillation. Heptane is added, and the resulting slurry is cooled. The title compound is collected by filtration and washed with heptane. The wet cake is dried at 20 ° C to 50 ° C under vacuum to give 3- (chloromethyl) -5,5-diphenyl -2,4-imidazolidinedione, 268 kg (90% yield); melting point 161.2 - 161.8 ° C.

Step (B): Preparation of phosphoric acid dibenzyl ester 2. 5-dioxo-4, 4-diphenyl-imidazolidin-1-ylmethyl-ester Method A A mixture of 250 kg of 3- (chloromethyl) -5,5-diphenyl- 2, 4-imidazolidinedione from Step (A), 270 kg of potassium dibenzyl phosphate, 6 kg of potassium carbonate, 0.75 kg of potassium iodide and 500 kg of acetonitrile is heated at 70 ° C to reflux for 2 hours until during 5 hours or until the reaction is essentially finished. The reaction mixture is cooled to 40 ° C to 60 ° C and filtered. The solution is stirred with at least 11 kg of activated carbon and filtered using a filter aid. The solvent of the reaction is replaced by adding toluene in portions and distilling in vacuo. The resulting slurry is cooled to less than 5 ° C. The title compound is collected by filtration and washed with cold toluene. The wet cake is dried at 50 ° C under vacuum to give phosphoric acid dibenzyl ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl-ester, 315 kg (70% yield); melting point 118.6 - 119.7 ° C.

Method B Ten grams of 3- (chloromethyl) -5,5-diphenyl-2,4-imidazolidinedione from Step (A), 10.3 g of sodium dibenzyl phosphate and 0.5 g of sodium carbonate were slurried in 50 ml of acetonitrile. The reaction mixture was heated to reflux for 11 hours. The solution was filtered to remove the precipitate of sodium chloride, then 40 ml of toluene were added. The solution was seeded and cooled to 0 ° C. The product was filtered and dried under vacuum at 40 ° C. 7.38 grams of the title compound were obtained (43% yield) (identical product with method A by retention time in high pressure liquid chromatography (HPLC)).

Method C Ten grams of 3- (chloromethyl) -5,5-diphenyl-2,4-imidazolidinedione from Step (A), 14 g of cesium dibenzyl phosphate and 0.48 g of cesium carbonate were slurried in 50 ml of acetonitrile. The reaction mixture was heated to reflux for 4 hours. The solution was filtered to remove the precipitate of cesium chloride. The filtered volume was reduced in vacuo. The solution was seeded and cooled to 10 ° C. The product was filtered and dried under vacuum at 40 ° C. 11.5 grams of the title compound were obtained (yield of 63.9%) (identical product with method A by retention time in high pressure liquid chromatography (HPLC)).

EXAMPLE 2 Phosphoric acid 2. 5-dioxo-4. 4-diphenyl-imidazolidin-1-ylmethyl ester dimethyl ester Thirty grams of 3- (chloromethyl) -5,5-diphenyl-2,4-imidazolidinedione from Step (A), 17.1 g of potassium dimethyl phosphate, 0.6 g of potassium carbonate and 0.15 g of potassium iodide were washed in 75 ml of acetonitrile. The reaction mixture was heated to reflux for 3 hours. The solution was filtered to remove the precipitate of potassium chloride and concentrated in a coarse oil. Isopropyl alcohol was added to the oil and cooled | 0 ° C. The product was filtered and dried under vacuum. Sixteen grams of the title compound were obtained (yield of 40.9%); melting point 123.1 - 124.3 ° C. Nuclear magnetic resonance spectroscopy (rNMR) deuterized dimethyl sulfoxide (DMSO-de): 3.6 ppm (d, 6H), 5.3 (d, 2H), 7.3-7.5 (m, 10H), 10.0 (s, 1H); doublets of long range phosphorous couplings.

EXAMPLE 3 Phosphoric acid dibutyl ester 2. 5-dioxo-4. 4-diphenyl-imidazolidin-1-ylmethyl ester 23.1 grams of di (n-butyl) -phosphate and 6.2 g of potassium hydroxide were slurried in 100 ml of t - Butyl methyl ester. The reaction was stirred until homogeneous and concentrated in vacuo to a coarse potassium di (n-butyl) phosphate oil. The oil, together with 30 g of 3 - (chloromethyl) -5,5-diphenyl-2,4-imidazolidinedione from Step (A), 0.6 g of potassium carbonate and 0.15 g of potassium iodide were slurried in 75 ml of acetonitrile. The reaction mixture was heated to reflux for 2.5 hours. The solution was filtered to remove the precipitate of potassium chloride and then concentrated in vacuo. The residue was crystallized from ethyl acetate / heptane to give 32.8 g of the title compound (yield of 69.2%); melting point 94.8 - 96.9 ° C. 1H NMR (DMO-d6): 0.8 ppm (t, 3H), 1.2 (dq, 2H9, 1.45 (dt, 2H), 3.85 (dq, 2H), 5.3 (d, 2H), 7.3-7.5 (m, 10H ), 9.8 (s, 1H) (maximum a 3. 85 and 5.3 long-range phosphorous coupling doublets).

EXAMPLE 4 Phosphoric acid di-tert-butyl ester 2,5-, 4-diphenyl-imidazolidin-1-ylmethyl ester 35.5 grams of 3- (chloromethyl) -5,5-diphenyl-2,4-imidazolidinedione from Step (A) ), 30.7 g of potassium di (t-butyl) phosphate, 0.6 g of potassium carbonate and 0.15 g of potassium iodide were added in 200 ml of acetonitrile. The reaction mixture was heated to reflux for 2.5 hours. The solution was filtered to remove the precipitate of potassium chloride. The filtrate was cooled to 0 ° C and filtered to give 22.3 g of the title compound (38.6% yield); melting point 108.5 ° C (d). 1H (DMSO-d6): 1.3 ppm (s, 18H), 5.2 (d, 2H), 7.3-7.5 (m, 10H), 9.9 (s, 1H); doublet of phosphorous coupling of long range. EXAMPLE 5 5,5-Diphenyl - [(3-phosphonooxy) methyl] -2,4-imidazolidinedione disodium salt A mixture of 250 kg of phosphoric acid dibenzyl ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1 - ilmethyl ester (Example 1, Step (B)), 9 kg of activated carbon (optional aid filter may be added), and 1025 1 of acetone was heated to a temperature range of 45 ° C to reflux. The activated carbon is removed by filtration. The filtrate was charged to a hydrogenerator containing about 6.6 kg of palladium on carbon (wet in 50% water) and the total water was adjusted to around 28 1. The hydrogenation is run at 20 ° C to 40 ° C and it is continued until the accumulation of hydrogen decreases. The mixture was filtered to remove the catalyst. A minimum of 700 ml of water are added and the solution is concentrated by vacuum distillation at a container temperature of less than 60 ° C. The pH of the solution is adjusted to 8.2 to 8.9 with diluted aqueous sodium hydroxide and dilute hydrochloric acid while maintaining a solution temperature of 20 ° C to 35 ° C. At least 27.5 kg of activated carbon is added to the solution. The solution was filtered using a help filter. The acetone is added, and the resulting slurry is cooled. The product is collected by filtration, washed with acetone and dried at 20 ° C to 25 ° C under vacuum to give the title compound 168 kg (90% yield) in an anhydrous base. 1H NMR deuterated water (D2O): 5.2 ppm (d, 2H), 7.35-7.5 (m, 10H); NH proton exchanged in D2O, double long-range phosphorous coupling.

Claims (9)

1. CLAIMS: 1. A 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 where X is chlorine of the Formula m: wherein M is an alkali metal and R is as defined above in solvents to produce a compound of Formula I.
2. 2. A process according to Claim 1 wherein the solvent is acetonitrile.
3. 3. A process according to Claim 1 for the preparation of a compound selected from the group consisting of: phosphoric acid dibenzyl ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl-ester; Phosphoric acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester dimethyl ester; Phosphoric acid dibutyl ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester; and phosphoric acid di-tert-butyl ester 2,5-, 4-diphenyl-imidazolidin-1-ylmethyl ester.
4. 4. A process according to Claim 3 for the preparation of phosphoric acid dibenzyl ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl-ester.
5. 5. A process according to Claim 1 wherein the compound of Formula III is 3- (chloromethyl) -5,5-diphenyl-2,4-imidazolidinedione.
6. 6. A process according to Claim 1 wherein a compound of Formula HI is selected from the group consisting of potassium dibenzyl phosphate; sodium dibenzyl phosphate; Cesium dibenzyl phosphate; potassium dibenzyl phosphate; sodium dibenzyl phosphate; cesium dimethyl phosphate; potassium di (n-butyl) phosphate; sodium di (n-butyl) phosphate; (potassium di (t-butyl) phosphate; sodium di (t-butyl) phosphate; and cesium di (t-butyl) phosphate.
7. 7. A process according to Claim 6 wherein the compound of the
8. Formula ITÍ is dibenzil potassium phosphate.
9. 9. A compound according to claim 8 which is selected from the group consisting of: phosphoric acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester dimethyl ester; Phosphoric acid dibutyl ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester; and Phosphoric acid di-tert-butyl ester 2,5-4,4-diphenyl-imidazolidin-1-ylmethyl ester. EXTRACT OF THE INVENTION An improved process for the preparation of a phosphoric acid diester is described 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester wherein an alkali metal phosphate is treated with a 3- (chloromethyl) - or a 3- (bromomethyl) -5,5-diphenyl-2 , 4-imidazolidinedione to produce the desired product, as well as valuable intermediates used in the process.