Process for preparing torsemide intermediate

Details Process for preparing torsemide intermediate Process for preparing torsemide intermediate

2003-05-02

2003-12-30

Morris, Patricia L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06670478

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new processes for making the torsemide intermediate, (3-sulfonamide-4-chloro)pyridine. The present invention relates to new processes for making torsemide.
BACKGROUND OF THE INVENTION
1-Isopropyl-3-[(4-m-toluidino-3-pyridyl) sulfonyl] urea, which has the chemical structure
is approved, under the trademark DEMADEX®, by the U.S. Food and Drug Administration for the treatment of hypertension and edema associated with congestive heart failure, renal disease, or hepatic disease. The USAN approved generic name for this compound is torsemide, although this compound is also referred to as “torasemide” in the art. Torsemide is a loop diuretic that has been found to be particularly effective for the treatment of edema associated with chronic renal failure.
The synthesis of torsemide, torsemide intermediates and torsemide derivatives are described in the following references: Delarge,
Ann. Pharm. Fr
. 31, 467-474 (1973);
Delarge, Mem. Acad. R. Med. Belg
. 47(3), 131-210 (1974); E. Koenigs et al,
Chem. Ber
. 57, 2080-2082 (1924); L. Thunus,
Ann. Pharm. Fr
. 33, 487 -494 (1975); Kondo, et al.
Iyakuhin Kenkyu
, 25(9), 734-50 (1994); EP 618,209; and U.S. Pat. Nos. 2,516,025; 6,674,794; 4,244,950 and Re. 30,633; all of which are incorporated herein by reference. U.S. Pat. No. 4,244,950 and Re. 30,633, all of which are incorporated herein by reference.
A process for the preparation of the torsemide intermediates (3-sulfonamide-4-chloro)pyridine, 3-sulfomamide-4-(3′-methylphenyl) aminopyridine and torsemide is described in Scheme I.
In known processes where (3-sulfonamide-4-chloro)pyridine is made from (3-sulfonylchloride-4-chloro)pyridine (SCCPY→SAMPCY), the reaction is performed in a polar solvent, such as, acetone or dioxane, or in melted reagent as a solvent in the presence of large excess of ammonium hydroxide. By these known processes, (3-sulfonamide-4-chloro)pyridine (SCCPY), is added dropwise into an aqueous solution of ammonium hydroxide. The dropwise addition of (3-sulfonamide-4-chloro)pyridine into an excess of ammonium hydroxide is a method to try to minimize the condensation of (3-sulfonamide-4-chloro)pyridine with the newly formed desired product, (3-sulfonamide-4-chloro)pyridine (SAMPCY). These harsh reaction conditions necessitate a great effort in purifying the resulting product as well as creating environmental waste disposal issues associated with neutralizing and disposing of large volumes of concentrated basic solutions. The highly basic conditions make the procedures employing a large excess of base very costly. Thus in such conditions the desired (3-sulfonamide-4-chloro)pyridine is made in low yields, of about 50%, and is isolated with a high percentage of impurities thus requiring additional purification steps. It is desirable to have a process for making (3-sulfonamide-4-chloro)pyridine without the condensation of (3-sulfonamide-4-chloro)pyridine and (3-sulfonamide-4-chloro)pyridine. It is also desirable to have a process for making (3-sulfonamide-4-chloro)pyridine which gives high yields and high purity which is suitable for large scale manufacturing procedures.
In known processes where torsemide is made from 3-sulfonamide-4-3′-methylphenyl) aminopyridine, the reaction may be performed in dioxane or dichloromethane in the presence of triethyl amine and isopropyl-isocyanate. Under such conditions the desired torsemide is made in low yields and is isolated with a high percentage of impurities thus requiring additional purification steps. The yields of these processes are low, highly variable and not are not suitable for large scale manufacturing processes. It is therefore desirable to have processes for making torsemide which gives high yields and high purity which uses solvents that are suitable for large scale manufacturing procedures.
SUMMARY OF THE INVENTION
The present invention relates to s process for making a compound of the formula:
comprising the steps of: (a) adding a compound of the formula
to an organic solvent; (b) adding ammonium hydroxide in an amount of about 1.75 to about 2.25 mole equivalents; and (c) isolating the compound of the formula:
wherein X
1
and X
2
are each independently chloro, fluoro or bromo.
In a preferred embodiment of the present invention, X
1
and X
2
are both chloro.
In another preferred embodiment of the present invention, the organic solvent is selected from the group consisting of t-butyl-methyl ether, toluene, acetonitrile, methyl-isobutyl ketone, ethyl-methyl ketone, acetone, benzene, xylene, ethanol and isopropanol.
In another embodiment of the present intention, the organic solvent is t-butyl-methyl ether.
In another embodiment of the present intention, the ammonia is an aqueous solution.
In another embodiment of the present intention, the ammonia is added to the solution of step (a).
In another embodiment of the present invention, the ammonia is added in an amount of about 1.75 to about 2.25 mole equivalents
The present invention also relates to a process for making (3-sulfonamide-4-chloro)-pyridine comprising the steps of: (a) adding (3-sulfonylchloride-4-chloro)pyridine to an organic solvent; (b) adding ammonia; and isolating (3-sulfonamide-4-chloro)pyridine.
In a preferred embodiment of the present invention, the organic solvent is selected from the group consisting of t-butyl-methyl ether, toluene, acetonitrile, methyl isobutyl ketone, ethyl methyl ketone, acetone, benzene, xylene, ethanol and isopropanol. In another embodiment of the present intention, the organic solvent is t-butyl methyl ether. In another embodiment of the present intention, the ammonia is added as an aqueous solution. In another embodiment of the present intention, the ammonia is added to the solution of step (a). In another embodiment of the present invention, the ammonia is added in an amount of about 1.75 to about 2.25 mole equivalents
The present invention also relates to a process for preparing torsemide comprising the step of reacting 3-sulfonylamide-4(3′-methylphenyl)aminopyridine with isopropyl isocyanate in the presence of triethyl amine in a solvent selected from the group consisting of acetonitrile, toluene, acetone, ethyl acetate and butyl acetate, and mixtures thereof. In a preferred embodiment of the present invention, the solvent is acetone. In another preferred embodiment of the present invention, the solvent is acetonitrile.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to new processes for making the torsemide intermediate (3-sulfonamide-4-chloro)pyridine. The methods of the present invention provide for the synthesis of (3-sulfonamide-4-chloro)pyridine in substantially higher yields and higher purity than previously reported. The intermediate (3-sulfonylchloride-4-chloro)pyridine may be prepared from 4-hydroxy-3-pyridine sulfonic acid by methods known in the art, including methods disclosed in Canadian Patent No.: 1,051,888, and
J. Med. Chem
., 36, 3211-3213, 1993, the content of both are incorporated herein by reference.
By the methods of the present invention, a compound of formula II′, wherein X
1
and X
2
are each independently chloro, fluoro or bromo; is added to a suitable organic solvent (Scheme II). Preferably, X
1
and X
2
are chloro. Suitable organic solvents include acetonitrile, ethers, such as, t-butyl methyl ether (MTBE), alcohols, such as, ethanol and isopropanol, ketones, such as, methyl-isobutyl ketone (MIBK), ethyl methyl ketone and acetone; and substituted or unsubstituted aromatics, such as, benzene and xylene. A preferred solvent is t-butyl methyl ether. Ammonia is then added to the mixture which may cause the mixture to rise in temperature. Preferably, about 2 mole equivalents of ammonia are added. Ammonia may be added in the form of gaseous ammonia or ammonium hydroxide, and more preferably as an aqueous solution of ammonium hydroxide. Preferably ammonium hydroxide is added as a 25% aqueous solution. The solution is cooled to room temperature and stirred until the reaction is s

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