Process for making 1,3-disubstituted-4-oxocyclic ureas

Details Process for making 1,3-disubstituted-4-oxocyclic ureas Process for making 1,3-disubstituted-4-oxocyclic ureas

2000-10-27

2002-07-02

Bernhardt, Emily (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C548S316100

Reexamination Certificate

active

06414151

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to chemical processes for making compounds useful in the treatment of various medical disorders; such uses include but are not limited to uses as antifibrillatory and antiarrhythmic agents. The processes 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 salts thereof.
BACKGROUND OF THE INVENTION
The present 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, where the end 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 disclosed in U.S. Pat. No. 5,462,940 (1995) to Norwich Eaton Pharmaceuticals, Inc.; said disclosure is incorporated herein by reference. Two general methods are disclosed in U.S. Pat. No. 5,462,940 issued to Yu et al Oct. 31, 1995 for this type of compound. Each describes a series of reactions which involve isolation of three to five intermediate compounds. The disadvantages of both methods are the use of highly flammable and moisture sensitive sodium hydride, potentially explosive DMF/sodium hydride mixtures, excessive solvent volumes, sodium iodide, and several isolation steps. Added disadvantages of one method are: the use of an amine protecting group and the need for a hydrogenation reaction for its removal.
It is apparent from the art that safer, higher yielding, more economical methods of preparing Azimilide would be advantageous. Particularly advantageous would be a reduction in the number of synthetic steps, increased reaction throughput (higher reaction concentrations), removal of a hydrogenation reaction, elimination of an amine protecting group, higher overall yields, ability to process at large scale, and better final product isolations. It has been surprisingly discovered that the disadvantages of the literature syntheses of these compounds may be overcome by carrying out the sequence of reactions with a mild base such as potassium carbonate for alkylation, eliminating the use of sodium iodide to facilitate alkylation of the amine moiety, and using solvents such as methyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP) to allow considerably higher reaction concentrations. increased product yield and purity.
The subject of this patent is a process for making 1,3-disubstituted-4-oxocyclic ureas whereby the 1,3-disubstituted-4-oxocyclic ureas are conveniently synthesized in high yields, without isolation of intermediates, by first alkylating the corresponding 1-substituted-4-oxocyclic urea with a carbon chain containing up to two leaving groups to form an adduct that is used without isolation to alkylate an amine to form a 1,3-disubstituted-4-oxocyclic urea that is finally reacted with an acid to form the desired salt. The present process allows for the preparation of 1,3-disubstituted-4-oxocyclic ureas under reaction conditions that eliminate the need for a hydrogenation step and the use of an amine protecting group. This process allows for improved yields and product purity, higher throughput, and provides additional synthetic simplicity for the preparation of these classes of molecules.
In particular, the preferred processes of the present invention provide a new methodology that is especially suited for the scale-up and manufacture of Azimilide.
SUMMARY OF THE INVENTION
The present invention provides a process for making 1,3-disubstituted-4-oxocyclic ureas of the general formula:
wherein
R
1
, R
2
, and R
3
are independently selected from the group consisting of H, Cl, F, Br, NH
2
, NO
2
, COOH, CH
3
SO
2
NH, SO
3
H, OH, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyalkyl, and acyloxy;
R
4
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 R
4
is attached to this nitrogen;
wherein said 1,3-disubstituted-4-oxocylic 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. This method is particularly preferred for making Azimilide. The 1-subsituted-4-oxocyclic urea used in making Azimilide is 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione.
DEFINITIONS AND USAGE OF 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” means a chemical reaction intermediate or product containing 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” means a substituent having the structure Q—O—, where Q is alkyl or alkenyl.
As used herein, “alkyl” means a saturated hydrocarbon substituent, straight or branched chain, unsubstituted or substituted.
As used herein, “base” means a basic reagent which is added to a reaction mixture to facilitate 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. Bromo, and chloro are preferred halogens.
As used herein, “heterocyclic ring” is a saturated, unsaturated, or aromatic ring radical comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monocyclic or are fused, bridged, or Spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 4 to 7 atoms, and most preferably 5 or 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 14 atoms, and most preferably 9 or 10 atoms.
As used herein, “leaving group” means any substituted or unsubstituted alkyl or aryl sulfonate or substituted or unsubstituted alkyl halide. Preferred substituents are halogens.
As used herein, “methylene” is a —CH
2
— radical.
As used herein, “polar aprotic solvent” is a solvent that possesses the property of high polarity, yet does not have the ability to donate a proton. Preferred polar aprotic solvents include, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), and methyl sulfoxide (DMSO).
As defined above and as used herein, substituent groups may themselves be substituted. Such substitution may be with one or more substituents. Such substituents include those listed in C. Hansch and A. Leo,
Substituent Constants for Correlation Analysis in Chemistry and Biology
(1979), incorporated by reference herein. Preferred substituents include (for exa

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