MXPA00010539A - Process for making 1,3-disubstituted-4-oxocyclic ureas - Google Patents

Abstract

A process for making 1,3-disubstituted-4-oxocyclic ureas of general formula (I) wherein R1, R2, and R3 are independently selected from the group consisting of nil, C1, F, Br, NH2, NO2, COOH, CH3SO2, NH, SO3H, OH, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyalkyl, and acyloxy;R4 is selected from the group consisting of a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylacyl, and heteroalkyl;and A is a substituted or unsubstituted, saturated or unsaturated, straight-chain or branched alkyl or alkenyl amino group comprised of 1-7 carbon atoms;or A is a substituted or unsubstituted, saturated or unsaturated heterocycle having 5, 6, or 7 members containing at least one nitrogen, and R4 is attached to this nitrogen;wherein said 1,3- disubstituted-4- oxocyclic urea is made without isolation of intermediates and comprising the steps:Ia) reacting a 1-substituted- 4-oxocyclic urea with a carbon chain containing at least two leaving groups in the presence of a mild base and a solvent to form an adduct containing at least one leaving group, and;Ib) condensing the adduct with an amine to form a 1,3-disubstituted-4-oxocyclic urea, and;II) recovering said 1,3-disubstituted-4-oxocyclic urea, are disclosed. This method is particularly preferred for making 1 [[[5-(4-Chlorophenyl)- 2-furanyl]methylene]amino]- 3-[4-(4-methyl- 1-piperazinyl) butyl)- 2, 4-imidazolidinedione.

Description

PROCEDURE FOR ELABORATING UREAS 4-OXOCICLICAS 1.3- DISUSTITUTE FIELD OF THE INVENTION This invention relates to chemical methods for making compounds useful in the treatment of various medical disorders; these uses are like antifibrillating and antiarrhythmic agents, but are not limited to them. The methods of this invention are useful for making 1,3-disubstituted 4-oxocyclic ureas, particularly 1 - [[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3- [4- (4- methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione. and you come out of them.

BACKGROUND OF THE INVENTION This invention relates to a process for making 1,3-disubstituted 4-oxocyclic ureas, particularly 1 - [[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3- [4- (4- methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione, or salts thereof, in which the final product is obtained in pure form and high yield. 1 - [[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [4- (4-methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione dihydrochloride (Azimilide) is described in the US patent no. 5,462,940 (1995) of Norwich E? Aton Pharmaceuticals, Inc .; said description is incorporated herein by reference. Two general methods are described in the patent of E.U.A. no. 5,4 € l2,940, issued to Yu et al on October 31, 1995 for this type of compound. Each one describes a series of reactions, which include isolation of 3 to 5 intermediary compounds. The disadvantages of both methods are the use of highly flammable and moisture-sensitive sodium hydride, potentially explosive sodium / DMF hydride mixtures, excessive volumes of solvent, sodium iodide and several isolation steps. Further disadvantages of one of the methods are the use of an amino protecting group and the need for a hydrogenation reaction for its extraction. It is evident, from the technique, that safer, higher yielding and more economical methods of preparing Azimilide would be advantageous. A reduction in the number of synthetic steps, increased reaction production (higher reaction concentrations), elimination of a hydrogenation reaction, removal of an amino protecting group, higher total yields, large-scale processing capacity would be particularly advantageous. and better isolations of final product. Surprisingly, it has been discovered that the disadvantages of the syntheses of these compounds exposed in the literature can be overcome by carrying out the sequence of reactions with a soft base, such as potassium carbonate for alkylation, eliminating the use of sodium iodide to facilitate alkylation of the amino portion, and using solvents such as dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP) to obtain considerably higher reaction concentrations, increased product yield and purity.

The subject of this patent is a procedure for making 1, 3-disubstituted 4-oxocyclic ureas, by which 1,3-disubstituted 4-oxocyclic ureas are properly synthesized in high yields, without isolation of intermediates, by first alkylating urea 4-substituted 1-substituted oxocyclic with a carbon chain containing up to two leaving groups to form an adduct which is used without isolation to rent an amine, so as to form a 1,3-disubstituted 4-oxocyclic urea which is finally made react with an acid to form the desired salt. The present process takes into account the preparation of 1,3-disubstituted 4-oxocyclic ureas under reaction conditions which eliminate the need for a hydrogenation step and the use of an amino protecting group. This procedure takes into account improved yields, product purity, higher production and provides additional synthetic simplicity for the preparation of these classes of molecules. In particular, the preferred methods of this invention provide a new methodology that is especially suitable for scale up and manufacture of Azimilide.

BRIEF DESCRIPTION OF THE INVENTION This invention provides a process for making 1, 3-disubstituted 4-oxocyclic ureas of the general formula: wherein Ri, R2 and R3 are independently selected from the group consisting of H, Cl, F, Br, NH2, N02, COOH, CH3SO2NH, SO3H, OH, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyalkyl and acyloxy; R 4 is selected from the group consisting of a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylazole and heteroalkyl; and A is a substituted or unsubstituted, saturated or unsaturated, straight or branched chain alkenylamino or alkylamino group, consisting of 1 to 7 carbon atoms; or A is a substituted or unsubstituted, saturated or unsaturated heterocycle, having 5, 6 or 7 members containing at least one nitrogen, and R4 is attached to this nitrogen; wherein said 1,3-disubstituted 4-oxocyclic urea is made without isolation of intermediates and comprises the steps of: (the) reacting a 1-substituted 4-oxocyclic urea with a carbon chain reagent comprising at least of two leaving groups, in the presence of a soft base and a solvent, to form an adduct containing at least one leaving group, and (Ib) condensing the adduct with an amine to form a 1,3-disubstituted 4-oxocyclic urea , and (II) recovering said 1,3-disubstituted 4-oxocyclic urea. This method is particularly preferred for making Azimilide. The 1-substituted 4-oxocyclic urea used to make Azimilide is 1 - [[[5- (4-chlorophenyl) -2-furan] l] methylene] amino] -2,4-imidazolidinedione.

DEFINITIONS AND USE OF THE TERMS The following is a list of definitions for terms used herein: As used herein, 'acid' means an inorganic or organic acid. An inorganic acid is a mineral acid, such as sulfuric, nitric, hydrochloric and phosphoric. An organic acid is an organic carboxylic acid, such as formic acid, acetic acid, chloroacetic acid, dichloroacetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid and tartaric acid. As used herein, 'adduct' refers to a product or chemical reaction intermediate compound that contains a newly installed functional group. As used herein, 'alkenyl' means a hydrocarbon substituent with one or more double bonds, straight or branched chain, unsubstituted or substituted.

As used herein, "alkoxy" refers to a substituent having the structure Q-O-, wherein Q is an alkyl or alkenyl. As used herein, "alkyl" means a saturated, straight or branched chain, hydrocarbon substituent, unsubstituted or substituted. As used herein, "base" refers to a basic reagent, which is added to a reaction mixture to facilitate the alkylation of nitrogen using an alkylating agent. Bases include nitrogen bases and inorganic bases, such as N, N-diisopropylethylamine, triethylamine, trimethylamine, 4-dimethylaminopyridine, pyridine, sodium hydride potassium hydride, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate. As used herein, "halogen" is a chloro, bromo, fluoro or iodo atom radical. Bromine and chlorine are the preferred halogens. As used herein, "heterocyclic ring" is a saturated, unsaturated or aromatic ring radical consisting of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monocyclic ring systems or fused, bridged or spiropolycyclic ring systems. The monocyclic rings contain from 3 to 9 atoms, preferably from 4 to 7 atoms and, more preferably, from 5 or 6 atoms. The polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 14 atoms and, most preferably, from 9 or 10 atoms. As used herein, "leaving group" means any substituted or unsubstituted alkylsulfonate or arylsulfonate, or substituted or unsubstituted alkyl halide. Preferred substituents are halogens.

As used herein, 'methylene' is a radical -CH2-. As used herein, "polar aprotic solvent" is a solvent that possesses the property of high polarity, but does not have the ability to yield a proton. Preferred polar aprotic solvents include N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO). As defined above and as used herein, the substituent groups can be substituted by themselves. Said substitution can be by one or more substituents. These substituents include those mentioned in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated herein by reference. Preferred substituents comprise (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (eg, aminomethyl, etc.), cyano, halogen, alkoxy, alkoxyacyl, (eg, carboethoxy, etc.), thiol , aryl, cycloalkyl, heteroaryl, heterocycloalkyl (eg, piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof. As used herein, 'volumes' refers to the liters of the indicated solvent per kilogram of raw material.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a process for making 1,3-disubstituted 4-oxocyclic ureas, including, but not limited to, Azimilide, and other pharmaceutically acceptable salts, which can be obtained in high yields, high product purity, high production and with synthetic simplicity. The invention comprises a sequential process consisting in reacting a 1-substituted 4-oxocyclic urea with a carbon chain reagent containing two leaving groups in a polar aprotic solvent, in the presence of a soft base; in reacting it also with an amine, in precipitating salts with a cosolvent, filtering and finally adding an acid, as well as in recovering a 1,3-disubstituted 4-oxocyclic urea or other salts thereof. The first alkylation occurs at temperatures of 40 ° to 120 ° C, preferably of about 60 ° to 75 ° C. The base that can be used is selected from those with easily filterable or extractable salts in any other way. Specifically, preferred bases include N, N-diisopropylethylamine, triethylamine, trimethylamine, 4-dimethylaminopyridine, pyridine, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate. The bases that follow in preference are potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate. The most preferred base is potassium carbonate, generally from 0.8 to 4.0 equivalents, preferably from 1.2 to 2 equivalents, per mole of imidazolidinedione. The preferred carbon chain reagents are selected from the group containing halogen groups, including, but not limited to, 1-bromo-4-chlorobutane, 1,4-dichloro- or 1,4-dibromobutane; more preferred is 1-bromo-4-chlorobutane. Those skilled in the art will recognize that butyl alcohols, butylsulfonylates and tetrahydrofuran are also used as carbon chain reagents. Generally, from 0.8 to 2.5 equivalents, preferably from 1 to 1.2, are used per mole of imidazolidinedione. The solvents used are DMF, DMAC, DMSO and NMP, preferably NMP. Generally, 2 to 20 volumes, preferably 2.5 to 5 volumes, of NMP are used. Preferred 1-substituted-4-oxocyclic ureas are selected from the group consisting of: 1 - [[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -2,4-imidazolidinedione; 1 - [[[5- (4-methanesulfonamidophenyl) -2-furanyl] methylene] amino] -2,4-imidazolidinedione; 1 - [[5- (4-fluorophenyl) -2-furanyl] methylene] amino] -2,4-imidazolidinedione; 1 - [[5- (4-nitrophenol) -2-oxazoiidinyl] methylene] amino] -2,4-imidazolidinedione; 1 - [[5- (4-Methylphenyl) -2-furanyl] methylene] amino] 2,4-imidazolidinedione; 1 - [[[5- (3,4-dimethoxy] phenyl] -2-furanyl] methylene] amino] -2,4-imidazolidinedione. In making Azimilide, the 1-substituted 4-oxocyclic urea that is used is 1 - [[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -2,4-imidazolidinedione. The second alkylation occurs at temperatures from 50 ° C to 120 ° C, preferably from about 75 ° C to 95 ° C. Preferred amines for this step are selected from the group consisting of dimethylamine; diethylamine; N, N-bis- (2-hydroxyethyl) amine; isopropylamine; N-benzyl-N-methylamine; N- (2-hydroxyethyl) -N-methylamine; N-methylpiperazine; morpholine; 4-hydroxypiperidine; N-methyl-N-phenylamine. The amine used to make Azimilide is N-methylpiperazine. In general, from 0.8 to 5 equivalents of amine, preferably from 1.2 to 3 equivalents, are added per mole of imidazolidinedione.

Following the second alkylation, the reaction mixture is generally cooled from 10 ° to 50 ° C, preferably from 5 ° to 35 ° C. The cosolvent used to precipitate the salts is either acetone, methanol, ethanol or mixtures of the above, preferably acetone. Generally, from 0 to 20 volumes are used, preferably from 6 to 10 volumes. The insoluble salts are collected by filtration and washed with the cosolvent. Water is added to the reaction mixture to prepare for salt formation. In general, 0 to 5 volumes, preferably 0.5 to 2.8 volumes of water, are used. The acid that is used to form the desired salt is hydrochloric. Usually, the pH is controlled on the pH scale of 3 to 7, preferably a pH of 4.5 to 5, for nucleation, followed by an additional acid addition at a pH of 0 to 3 to precipitate said Azimilide, which is collects by filtration, with a yield of 80 to 90%. The azimilide made according to the process of this invention is useful for the treatment of various medical disorders; these uses are like antifibrillating and antiarrhythmic agents, but are not limited to them. Those skilled in the art will also recognize that several acids may be added in the final steps of the process to form various salt forms that may facilitate their isolation and handling. Other pharmaceutically acceptable salts, such as sulfate and hydrobromide, can be prepared according to the process of this invention and are included within the scope thereof.

This procedure is illustrated by the following general scheme: 1. A, Base, Solvent 2. HQ wherein Ri, R2 and R3 are independently selected from the group consisting of H, Cl, F, Br, NH2, NO2, COOH, CH3S02NH, S03H, OH, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyalkyl and acyloxy; R 4 is selected from the group consisting of a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylazole and heteroalkyl; A is a substituted or unsubstituted, saturated or unsaturated, straight or branched chain alkenylamino or alkylamino group, consisting of 1 to 7 atoms carbon; or A is a substituted or unsubstituted, saturated or Unsaturated, having 5, 6 or 7 members containing at least one nitrogen, and R4 is attached to this nitrogen; "i" - "- 'X and Y are, independently, an outgoing group, preferably different outgoing groups; wherein said 1,3-disubstituted 4-oxocyclic urea is made without isolation of intermediate compounds and comprises the steps of: reacting a 1-substituted 4-oxocyclic urea with a carbon chain reagent comprising less than two leaving groups, in the presence of a soft base and a solvent, to form an adduct containing at least one leaving group, and (Ib) condensing the adduct with an amine to form a 4-10-oxocyclic urea. -disubstituted, and (II) recovering said 1,3-disubstituted 4-oxocyclic urea. The following non-limiting examples illustrate the procedures of this invention: ____________ EXAMPLE 1 Use of dimethylformamide (DMF) as a reaction solvent for the preparation of Azimilide A 12-liter, three-necked flask equipped with a thermometer, mechanical stirrer, heating jacket, reflux condenser and addition funnel is charged with DMF (4.77 I) and heated to 50 ° C. Add 1 - [[[5- (4-chloro-phenyl) -furanyl-methyl-methyleneamino-1-imidazolidinedione (597 g) and continue heating.When the solution is complete, the potassium carbonate (276 g) is charged into the flask and heating to 85 ° C. After 10 minutes, add 1-bromo-4-chlorobutane (370 g) and continue heating to approximately 100 ° C. After 35 minutes, add N-methylpiperazine (465 g) and The mixture is allowed to stir for 1 hour at 100 ° C. The reaction mixture is cooled to about 10 ° C. and filtered to remove insolubles.The DMF is extracted under reduced pressure at a temperature of 65 ° to 68 ° C. it is replaced with absolute ethanol (3.6 I) The mixture is heated to dissolve the free base and filtered to extract insolubles The product is precipitated from ethanol (a total of 6.0 I) and 418 g of concentrated hydrochloric acid are added and it is then filtered to give 680 g of the compound.

EXAMPLE 2 Use of dimethyl sulfoxide (DMSO) as a reaction solvent for the preparation of Azimilide A 500 ml three neck flask equipped with a thermometer, mechanical stirrer, heating jacket, flow coolant and addition funnel is charged with DMSO (200 ml) and 1 - [[5- (4-chlorophenyl)] 2-furanyl] methylene] amino] -2,4-imidazolidinedione (20 g). In solution, potassium carbonate (15.5 g) and 1-bromo-4-chlorobutane (13.6 g) are added, and the mixture is heated at 70 ° C for more than 30 minutes. N-methylpiperazine (19.8 g) is added to the mixture for 15 minutes, while heating to 90 ° C. After a total of 2 hours and 15 minutes, the reaction mixture is cooled to about 30 ° C and methanol (200 ml) is added. The mixture is cooled to room temperature and filtered to extract insoluble substances. The filtrate is acidified with concentrated hydrochloric acid at a pH of 1 to 2. The mixture is cooled to 15 ° C and filtered to obtain 30.4 g of the compound.

EXAMPLE 3 Use of N. N-dimethylacetamide (DMAC) as a reaction solvent for the preparation of Azimilide A 3-neck, 2-liter flask equipped with a thermometer, mechanical stirrer, heating jacket, reflux condenser and addition funnel is charged with DMAC (200 ml), 1 - [[5- (4-chlorophenyl)] 2-furanyl] methylene] amino] -2,4-imidazolidinedione (100 g), 1-bromo-4-chlorobutane (59 g) and potassium carbonate (73 g). The mixture is stirred for approximately 100 minutes, while heating to 70 ° C. N-Methylpiperazine (59.5 g) is added and the mixture is stirred for a further 3 hours and heated to 86 ° C. The reaction mixture is cooled to 20 ° C and acetone (900 ml) is added. The mixture is filtered to extract insoluble substances. The filtrate is acidified with concentrated hydrochloric acid to a pH of 1 to 2, cooled to 15 ° C and filtered to obtain 122.7 g of the compound.

EXAMPLE 4 Use of N-methylpyrrolidone (NPM) as a reaction solvent for the preparation of Azimilide A three-neck, 5-liter flask, equipped with a thermometer, mechanical stirrer, heating jacket, reflux condenser and addition funnel, is charged with NMP (1.2 I), 1 - [[5- (4-chlorophenyl) - 2-furanyl] methylene] amino] -2,4-imidazolidinedione (300 g), 1-bromo-4-chlorobutane (187 g) and potassium carbonate (219 g). The mixture is stirred for about 1 hour, while heating to 70 ° C. N-Methylpiperazine (149 g) is added and the mixture is stirred for approximately 150 minutes, while heating to 90 ° C. The reaction mixture is cooled to 20 ° C and acetone (2.4 I) is added. The mixture is filtered to extract insoluble substances. Water (0.42 I) is added to the filtrate and the mixture is heated to 30 ° to 35 ° C. The mixture is acidified with concentrated hydrochloric acid At a pH of 4.5 to 5, it is seeded with product, stirred for 1 hour and then acidified further with concentrated hydrochloric acid at a pH of 0 to 3. The mixture is cooled to 10 ° C and filtered to obtain 382.8 g of the compound. 1. N-mßtUpIperazine 2. Acetone, HCl X2HCI

Claims (1)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for making 1 - [[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3- [4- (4-methyl-1-piperazinyl) butyl] -2,4- dihydrochloride imidazolidinedione, which consists of the steps of: (the) reacting 1 - [[5- (4-chlorophenyl) -2-furanyl] methylen] amino] -3- [4- (4-methyl-1) -piperazinyl) butyl] -2,4-imidazolidinedione with carbon chain reagent containing two leaving groups, in the presence of a soft base and N-methylpyrrolidone, to form an adduct consisting of a leaving group, and (Ib) condensing the adduct with N-methylpiperazine to form a 1,3-disubstituted 4-oxocyclic urea; likewise, (II) recovering said 1,3-disubstituted 4-oxocyclic urea by means of the following steps: (lia) a cosolvent is added, such as methanol, ethanol, acetone or mixtures thereof; (llb) filter the precipitated salts and water is added; (lie) adjust the pH with hydrochloric acid, first to a pH of 4.5 to 5, followed by an adjustment to a pH of 0 to 3; and (lid) filter the product. SUMMARY OF THE INVENTION A process for making 1, 3-disubstituted 4-oxocyclic ureas of the general formula (I): wherein R., R2 and R3 are independently selected from the group consisting of Cl, F, Br, NH2, N02 > COOH, CH3SO2NH, SO3H, OH, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyalkyl and acyloxy, or none; R 4 is selected from the group consisting of a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylazole and heteroalkyl; and A is a substituted or unsubstituted, saturated or unsaturated, straight or branched chain alkenylamino or alkylamino group, consisting of 1 to 7 carbon atoms; or A is a substituted or unsubstituted, saturated or unsaturated heterocycle, having 5, 6 or 7 members containing at least one nitrogen, and R. is attached to this nitrogen; wherein said 4-oxocyclic, 1,3-disubstituted urea is made without isolation of intermediate compounds and consists of the steps already described of: (the) reacting a 1-substituted 4-oxocyclic urea with a carbon chain reagent containing at least two leaving groups, in the presence of a soft base and a solvent, to form an adduct containing at least one leaving group, and (Ib) condensing the adduct with an amine to form a 4-oxocyclic urea 1 , 3-disubstituted, and (II) recovering said 1,3-disubstituted 4-oxocyclic urea; this method is particularly preferred for the preparation of 1 [[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3- [4- (4-methyl-1-piperazinyl) butyl) -2.4 -imidazolidinedione. MR / igp * rcp * osu * P00 / 1261 F