FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"PROCESSES FOR PREPARING (3-SULFONAMIDE-4-CHLORO)PYRIDINE, (3-SULFONAMIDE-4-FLUORO)PYRIDINE OR (3-SULFONAMIDE-4-
BROMO)PYRIDINE"
TEVA PHARMACEUTICAL INDUSTRIES, LTD., of 5 Basel Street, P.O. Box 3190,
Petah Tiqva 49131, Israel,
The following specification particularly describes the invention and the manner in which it is to be performed:

The present invention relates to processes for preparing ,3-sulfonamide-4-chloro)pyridine. ,3-sulfonamide-4-fluoro)pyridine or ,3-Sulfonamide-4.
bromo)pyridine.
BACKGROUND OF THE INVENTION
I-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.2\yA61-AlA(l973); 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. Patent Nos. 2,516?025; 6,674,794; . 4,244,950 and Re. 30,633; all of which are incorporated herein by reference.
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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 1.

In known processes where (3-sulfonamide-4-chloro)pyridine is made from (3-sufonamide-4-chloro)pyridine (SCCPY -> SAMCPY), 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-sulfonylchloride-4-chloro)pyridine (SCCPY), is added dropwise into an aqueous solution of ammonium hydroxide. The dropwise addition of (3-sulfonylchloride-4- chloro)pyridine into an excess of ammonium hydroxide is a method to try to minimize the condensation of (3-sulfonylchloride-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
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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-sulfonylchloride-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 S-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:

WO 01/70226 PCT/US01/08866

In an embodiment of the present invention, a compound of the formula II, (3-
sulfonylchloride-4-chloro)pyridine, is added to an organic solvent. 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. Approximately 1.75 to about 2.25 mole equivalents
of ammonia is then added to the solution. Preferably, about 2.15 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. Addition of the
ammonia may cause the temperature of the solution to rise. The solution is cooled to room
temperature and stirred until the reaction is substantially complete, e.g., 1 to 1.5 hours,
preferably one hour. Completion of the reaction may be monitored by pH; which is
indicated when the pH stops decreasing and stabilizes. The pH of the solution is adjusted to
about 8 ± 1 by the addition of ammonium hydroxide to induce the precipitation of crystals of
(3-sulfonamide-4-chloro)pyridine, the compound of the formula III. (3-Sulfonamide-4-
chloro)pyridine, the compound of the formula HI, is isolated upon filtering the solution
followed by drying. The (3-sulfonamide-4-chloro)pyridine is isolated in a high yield of
about 74 %. By the present methods, the (3-sulfonamide-4-chloro)pyridine is isolated in an
unexpectedly high purity of about 93% to about 97%.
Thus, surprisingly the present methods provide processes for making high purity (3-sulfonamide-4-chloro)pyridine while using a high concentration of the starting material, (3-sulfonylchloride-4-chloro)pyridine. In contrast to the known methods, the present methods surprisingly yield (3-sulfonamide-4-chloro)pyridine substantially free of by-products resulting from the condensation of the starting material and product, (3-sulfonylchloride-4-chloro)pyridine and (3-sulfonamide-4-chloro)pyridine, which is observed in the known processes.
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WO 01/70226 PCT/US01/08866

The present method thus provides a new process with high yields and high purity which is suitable for use in large scale reactions. The high purity also reduces the need for
additional purification steps. .
The present invention also relates to a new process for making torsemide from 3-sulfonamide-4-(3'-methylphenyl) aminopyridine. 3-Sulfomamide-4-(3'-methylphenyl) aminopyridine may be prepared from (3-sulfonamide-4-chloro)pyridine by methods known in the art, including methods disclosed in U.S. Patent No.: 3,904,636, the content of which is
incorporated herein by reference.
By the processes of the present invention, a compound of the formula IV, 3-sulfomamide-4-(3,-methylphenyl) aminopyridine, is added to triethylamine (TEA) and an organic solvent (Scheme IV). Suitable solvents are acetonitrile, toluene, acetone, ethyl acetate and butyl acetate, and mixtures thereof. Preferred solvents are acetonitrile and acetone. A more preferred solvent is acetonitrile. Isopropyl isocyanate (IPIC) is then added dropwise to the solution and the solution is heated to about 40°C. The resulting mixture is then stirred at about 38°C to about 42°C until there is complete dissolution of all the reactants, about 45 to 90 minutes. The mixture is then cooled to room temperature and stirred for a suitable time, about 1.5 to about 2.5 hours and preferably about 2 hours. The pH of the mixture is then adjusted to about 4.3±0.3, preferably to 4.3 with increasing the temperature to about 35°C. The pH may be lowered with hydrochloric acid. The mixture is cooled room temperature, followed by filtration and washing. The wet crude product is triturated, followed by drying to yield crude torsemide. The yield of isolated crude torsemide is about 81.5%. The purity of the isolated crude torsemide is about 98% to about 99.9% which is a substantial improvement over the methods known in the art.
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WO 01/70226

PCT/US01/08866

Scheme IV

EXAMPLES
1.
The present invention will now be further explained in the following example. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results
Example 1
Synthesis of (3-sulfonamide-4-chIoro)pyridine
In a 100 mL three necked flask equipped with magnetic stirrer, condenser, thermometer and dropping funnel (3-sulfonylchloride-4-chloro)pyridine (10 g, 1 eq., 46.7 mmoles) was suspended in MTBE (30 mL) at room temperature. Ammonium hydroxide, 25% solution (13.5 mL, 2.13 eq.) was dropped into the suspension in a rate such that die temperature is allowed to increase to about 22 to abut 26 °C, this temperature was maintained until all die ammonium hydroxide was added. The suspension was then to cooled to room temperature and was stirred for one hour. The pH of the suspension was adjusted to 8±0.1 by the addition of a few drops of ammonium hydroxide, 25% solution. The suspension was filtered and washed with water (2x10 mL) and the wet product (-8 g) dried at 40°C, under the 1mm Hg vacuum. (3-Sulfonamide-4-chloro)pyridine was isolated in 74.4% yield, 6.7 g.
Example 2
Synthesis of Torsemide
A 100 mL three necked flask, equipped with mechanical stirrer, thermometer and a
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WO 01/70226 PCT/US01/08866

condenser was charged with acetonitrile (15 mL), 3-sulfomamide-4-(3'-methylphenyl) aminopyridine (5 g), and triethyl amine (TEA.) (5.3 mL). Isopropyl isocyanate (1.87 mL) was added dropwise over 10 minutes and the whole mixture was stirred at 40 ± 2°C to complete dissolution. The mixture was cooled to room temperature and stirred for another 2 hours. The pH of the mixture was adjusted to 4.3 while increasing the temperature around 35 °C. The mixture was cooled again to room temperature, filtered and washed with acetonitrile:water (1:1) mixture (10 mL). The wet crude product was triturated in acetonitrile water mixture (5:1, 13 mL) at 60 °C for half an hour, filtered and washed with acetonitrile: water (5:1) mixture (2x7 mL). The triturated product was then dried under high vacuum (3 mm Hg) at 50°C for 6 hours to get 5.4 g of crude torsemide (81.5% crude yield).
Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiment may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.

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WE CLAIM:
1. A process for making (3-sulfonamide-4-chloro) pyridine, (3-sulfonamide-4-fiuoro) pyridine or (3-sulfonamide-4-bromo) pyridine represented by the formula

comprising the steps of:
(a) adding a (3-sulfonylchloride-4-chloro) pyridine, (3-sulfonylchloride-4-fluoro) pyridine, (3-sulfonylchloride-4-bromo)pyridine, (3-sulfonylfluoride-4-chloro )pyridine 3-sulfonylfluoride-4-fiuoro)pyridine, (3 -sulfonylfluoride-4-bromo)pyridine, ( 3-sulfonylbromide-4-chloro)pyridine, (3 -sulfonylbromide-4-fiuoro )pyridine or (3-sulfonylbromide-4-bromo pyridine represented by the formula

to an organic solvent;
(b) adding ammonia; and

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(c) isolating the (3-sulfonamide4-chloro)pyridine, (3-sulfonamide-4-fluoro)pyridine or (3-sulfonamide-4-bromo) pyridine of the formula

wherein X1 and X2 are each independently chloro, fluoro or bromo.
2. The process as claimed in claim 1 wherein X1 and X2 are both chloro.
3. The process as claimed in claim 1 wherein 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.
4. The process as claimed in claim 3 wherein the organic solvent is t-butyl-methyl ether.
5. The process as claimed in claim 1 wherein the ammonia is an aqueous solution.
6. The process as claimed in claim 1 wherein the ammonia is a gas.
7. The process as claimed in claim 1 for making (3-sulfonamide-4-chloro) pyridine, wherein X1 is chloro.
8. The process as claimed in claim 7 wherein 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.

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9. The process as claimed in claim 8 wherein the organic solvent is t-butyl
methyl ether.
10. The process as claimed in claim 7 wherein the ammonia is added as an aqueous solution.
11. The process as claimed in claim 7 wherein the ammonia is a gas.
12. The process as claimed in claim 1 wherein the ammonia is added in an amount of about 1.75 to about 2.25 mole equivalents.
13. The process as claimed in claim 7 wherein the ammonia is added
in an amount of about 1.75 to about 2.25 mole equivalents.
14. The process as claimed in claim 5, wherein the aqueous solution of
ammonia is added drop-wise.
15. The process as claimed in claim 5, wherein the aqueous solution of ammonia is 25% ammonia hydroxide
16. The process as claimed in claim 10, wherein the aqueous solution of ammonia is added drop-wise.

17. The process as claimed in claim 10, wherein the aqueous solution of ammonia is 25% ammonia hydroxide.
18. The process as claimed in claim 1, wherein the isolated (3-sulfonamide-4-chloro) pyridine, (3-sulfonamide-4-fluoro) pyridine or (3-sulfonamide- 4-bromo) pyridine of the formula
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has a yield of at least about 74%.
19. The process as claimed in claim 1, wherein the isolated (3-sulfonamide-4-chloro) pyridine, (3-sulfonamide-4-fiuoro) pyridine or (3-sulfonamide-4-bromo)pyridine of the formula

has a purity of at least about 93%.
20. The process as claimed in claim 7, wherein the isolated (3-sulfonamide-4-chloro) pyridine has a yield of at least about 74%.
21. The process as claimed in claim 7, wherein the isolated (3-sulfonamide-4-chloro)pyridine has a purity of at least about 93%.

Dated this 11th day of January, 2006.