WO2004089904A2

WO2004089904A2 - Preparation of torasemide

Info

Publication number: WO2004089904A2
Application number: PCT/CA2004/000366
Authority: WO
Inventors: Wen-Lung Yeh; Kanjai Khumtaveeporn; David John Mckenzie
Original assignee: Torcan Chemical Ltd
Current assignee: Torcan Chemical Ltd
Priority date: 2003-04-07
Filing date: 2004-03-12
Publication date: 2004-10-21
Anticipated expiration: 2005-10-07
Also published as: CA2424644A1; WO2004089904A3

Abstract

The stable polymorphic form of torasemide, Modification I, is prepared from other, less stable torasemide forms, by forming a solution of the starting polymorphic form of torasemide in water and methanol, stirring for at least 20 hours and then phase separating the solid torasemide modification I from the liquid medium.

Description

PREPARATION OF TORASEMIDE

BENEFIT OF PRIOR APPLICATION

This application claims the benefit of Canadian Patent Application 2,424,644 filed on April 7, 2003.

FIELD OF THE INVENTION

This invention relates to pharmaceutical compounds and processes for their preparation. More specifically, it relates to the preparation of specific polymorphic forms of the pharmaceutical compound torasemide, a known compound useful as a diuretic.

BACKGROUND OF THE INVENTION

Torasemide, also known as torsemide, is, chemically, N-[[(1- methylethyl)amino]-carbonyl]-4-[(3-methylphenyl)amino]-3-pyridinesulfonamide, of chemical formula:

It is classified as a sulfonyl-urea loop diuretic, and is marketed under various trade names as a diuretic for treating human patients. Torsemide is the subject of entry no. 9690 of the Merck Index, 12^th Edition. Torasemide is known to exist in at least three different polymorphic forms, known as Modification I, Modification II and Modification III. As initially obtained from a chemical synthesis procedure, torasemide crude material normally appears as Modification II, with a melting point of 162°C. This Modification II is, however, relatively unstable. On storage, it will gradually rearrange its crystalline form to become Modification I. Since the two modifications have different solubility characteristics, it is undesirable to make and store oral pharmaceutical dosage units of torasemide Modification II, because its solubility and hence its bioavailability will change over time.

Modification III is also deficient in stability, in comparison with

Modification I torasemide. Accordingly, it is desirable that torasemide be produced as, or converted into, Modification I, as completely as possible, before it is made into oral dose formulations.

PRIOR ART

German patent 2516025, June 1975, describes the preparation and properties of torasemide.

Acta Cryst, 1978, B34, pp 1304 - 1310 and pp 2659 - 2662 describe the different modifications and different crystallographic patterns of torasemide.

United States Re-issue patent 34,580 Topfmeier et.al., re-issue of U.S. 4,743,693 issued May 10, 1988, describes a process for preparation of crystalline torasemide in the pure Modification I (monoclinic, space group P2₁/c) from torasemide crystalline Modification II (monoclinic, space group P2/n), by seeding an aqueous suspension of torasemide Modification II with a catalytic amount of torasemide Modification I, and stirring.

A problem associated with the prior process of converting Modification

II torasemide to Modification I torasemide is the requirement for the use of seed crystals, which is inconvenient, expensive and introduces purity and careful handling requirements. Moreover, the prior art, as far as the applicants are aware, does not disclose a process whereby torasemide Modification III, often obtained as a direct product of chemical synthesis, may be converted to.the more stable Modification I. .

Preparation of torasemide in Modification II or III form is taught in the prior art, and involves two steps. Firstly; 4-chloro-3-pyridinesulfonamide is reacted with m-toluidine at elevated temperature in the presence of a catalytic amount of copper powder and in the absence of solvent (J.E. Delarge et al., Canadian patent 1070313) to prepare 4-[(3-methylphenyl)amino]pyridine- sulfonamide. Secondly, the 4-[3-methylphenyl)amino]pyridinesulfonamide so prepared is reacted with isocynates in the presence of triethylamine, with or without the presence of solvent (see for example, J.Pharm. Pharmacol. 1992, 44, 589; Canadian patent 1 ,070,313). The use of copper powder as catalyst in the process tends to give a green discoloration to the final product, and purification of it to remove the discoloration is difficult and adds to the cost of the final product.

It is an object of the present invention to provide a novel process for the preparation of Modification I torasemide, which overcomes or at least reduces one or more of the disadvantages of the prior art processes.

A further object is to provide a novel process for preparing crude torasemide.

SUMMARY OF THE INVENTION.

The present invention from one aspect provides a process of converting a polymorphic form of torasemide selected from torasemide Modification II, torasemide Modification III and mixtures containing both Modification II and Modification III, into the more stable polymorphic torasemide Modification I, which comprises forming a solution or suspension of the selected polymorphic form of torasemide in a mixture of water and methanol, the mixture comprising at least 2.5% v/v methanol and not more than 75% methanol by volume, stirring the solution or suspension so formed for at least 24 hours at temperatures in the range from about 10°C to about 90°C, and phase separating the solid torasemide Modification I from the liquid medium. According to this process, torasemide Modification I can be obtained which shows no evidence of the presence of the other modifications on its diffraction patterns, and no other impurities. From a second aspect, the present invention provides a process of preparing 4-[(3-methylphenyl)amino]pyridinesulfonamide, which comprises reacting 4-chloro-3-pyridinesulfonamide with m-toluidine at elevated temperature, the reaction being conducted in the presence of an aqueous solvent, and using not more than a stoichiometric amount of 4-chloro- pyridinesulfonamide, in the form of its hydrochloride salt. This process does not require the use of copper powder as catalyst, and hence reduces the purification problems associated with prior art processes. In particular, it avoids the green discoloration of the resulting product otherwise obtained, and enables the reaction to go to completion. Thirdly, avoidance of excess 4-chloro-3- pyridinesulfonamide leads to greater yield and purity of the resulting 4-[(3- methylphenyl)amino]-pyridinesulfonamide product. In addition, in this process, the exothermic nature of the reaction is better controlled in the presence of aqueous solvent, thereby simplifying the scale-up problems of the process.

BRIEF REFERENCE TO THE DRAWINGS

FIGURE 1 is a diagrammatic illustration of the reaction process for preparing crude torasemide according to preferred embodiments of the invention;

FIGURE 2 shows the X-ray diffraction pattern of the product of Example 3 below;

FIGURE 3 shows the differential scanning calorimetry (DSC) of the product of Example 3 below.

BRIEF REFERENCE TO THE DRAWINGS

In one preferred process according to the invention, a preliminary solution of a small amount of the selected torasemide, typically from 0.5 - 5% by weight of the total amount of torasemide to be converted, is prepared in methanol. Heating may be employed in order to completely dissolve the material. This preliminary solution is suitably very dilute, e.g. 1 part by weight in 20 - 60 parts of methanol. This preliminary solution is then mixed with water, and the rest of the torasemide is added to this methanol/water mixed solution, which is then stirred at raised temperature for a sufficient period of time to effect substantially complete conversion of the torasemide in the solution to Modification I.

Suitable such temperatures for this preferred method will be found in the approximate range 70 - 90°C. The conversion can be monitored by extracting samples from the solution, cooling and filtering to obtain solid, and determining the melting point of the solid. The melting point of Modification I torasemide is 165°C, and when this melting point of the solid sample is obtained (typically after 60 - 96 hours), the stirring of the solution can be discontinued, the solution cooled and the Modification I torasemide recovered therefrom, e.g. by vacuum filtration and drying.

A second preferred method according to the invention comprises suspending substantially the entire batch of selected torasemide to be converted in methanol, under stirring, for a period of time such as 1 - 6 hours, adding water to this mixture, and continuing to stir the mixed solution, e.g. for 60 - 96 hours until the conversion is complete, as indicated by the monitoring of the progress of the conversion carried out as described above. In this second preferred process, lower temperatures, e.g. in the 15 - 35°C range and conveniently room temperatures, can be used for either or both of the stirring stages. Recovery of the Modification I torasemide by vacuum filtration and drying is again suitable.

Another feature of the present invention, however, as disclosed above, is an improved method of conducting the first process step, i.e. the process of preparing 4-[(3-methylphenyl)amino]pyridinesulfonamide.

According to this aspect of the invention, 4-chloro-3- pyridinesulfonamide hydrochloride salt is used as the starting material in this reaction, as opposed to the free base taught in the aforementioned prior art. The hydrochloride salt is commercially available (from Chordip). It provides a greater degree of consistency to the purity profile of the end product. This process is diagrammatically illustrated in the top portion of accompanying Fig. 1.

Another feature of the preferred process is an improved method of preparing crude torasemide from 4-[(3-methylphenyl)amino]pyridinesulfonamide, i.e. an improvement in the second process step. The second step of the process, in which the 4-[(3-methylphenyl)amino]pyridinesulfonamide so prepared is reacted with isocyanates in the presence of triethylamine according to the prior art, is also improved in that an alkali metal salt of 4-[(3- methylphenyl)amino]pyridinesulfonamide is prepared and reacted with isopropyl isocyanate. This apparently serves to increase the nucleophilicity of the sulfonamide functionality, to attack the isocyanate, and greatly accelerates the reaction to give an increased yield. The conversion of the 4-[(3- methylphenyI)amino]pyridinesulfonamide to its alkali metal salt (formation of its anion) may be conducted prior to reaction with the isocyanate, or the anion may be formed in situ.

In pre-formation, an equivalent amount of an alkali metal base such as sodium hydroxide aqueous solution may be added, water removed and the anion suspended in a suitable polar solvent preferably dioxane or tetrahydrofuran, for conducting the reaction with isocyanate. A more convenient, preferred procedure is to suspend the 4-[3-methylphenyl)amino]pyridine- sulfonamide base in the chosen polar solvent for the reaction with isocyanate, preferably THF, and add a solution of sodium hydride in THF thereto, prior to or along with the, addition of isopropyl isocyanate. This process is diagrammatically illustrated in the lower portion of Fig. 1 of the accompanying drawings. Other non-aqueous solvents may also be present. The reaction proceeds typically at room temperatures, for several hours. The crude torasemide so formed may be isolated by removal of solvent, followed by addition of water.

The product may be precipitated from water by adjusting the pH to 7 - 8 with acid, and isolated by vacuum filtration and drying. The invention is further described, for illustrative purposes, in the following specific examples.

EXAMPLE 1 - Preparation of 4-1(3-methylphenyl)aminolpyridine- sulfonamide

2L three-neck flask, equipped with a mechanical stirrer, thermometer and condenser, was charged with water (500 ml) and 4-chloro-3- pyridinesulfonamide hydrochloride (100g, 0.44 mol). To this suspension was added m-toluidine (49.2 ml, 0.46 mol) at room temperature. The reaction mixture was heated to 90°C for a minimum period of 3 h. The progress of the reaction was followed by HPLC. After completion, the mixture was cooled to room temperature. The pH of the reaction was then adjusted carefully to pH 7-8 with sat. NaHCO₃(ca. 1.1 L). The product was precipitated out and isolated by vacuum filtration as beige solid (126.2 g wet weight). The product was then dissolved in MeOH (1.0 L) at room temperature and charged with Darco KB (25g). The solution was refluxed for 0.5 h and then filtered through a patch of celite to remove Darco KB, while still hot, and rinsed with hot MeOH (200 ml). The filtrate was then charged with water (1.2 L) and stirred for a minimum of 1 h at room temperature. The product, which had precipitated out, was isolated by vacuum filtration to obtain a solid 106.3 g (92% wet weight/ ^9.8% purity a/a). ¹{H NMR (de-DMSO); 2.30 (s, 3H), 7.00-7.15 (m. 5H), 7.32 (m, 1 H), 7.75 (brs, 1.5H), 8.05 (brs, 0.5H), 8.25 (d,1 H), 8.68 (s,1 H).

EXAMPLE 2 - Preparation of torasemide crude

A suspension of 4-[(3-methylphenyl)amino]pyridine-3-sulfonamide (100 g) in toluene (800 ml) was distilled azeotropically to remove water. After all water was removed (5 ml), the reaction mixture was concentrated by distillation to a final volume of 200 ml. The calculation for other reagents was based on this dry weight, 95 g (0.36 mol). The mixture was cooled to room temperature. This mixture was charged with anh. THF (1.8 L), which dissolved all material to yield a clear pale yellow solution. This solution was cooled to 5-10°C with an ice bath. THF solution was charged with NaH (60% in oil, 10.91 g, 0.27 mol) portion wise in order to control the amount of hydrogen generated. The reaction mixture was then allowed to come to room temperature and stirred overnight (ca. 16 h). To this reaction mixture was added isopropyl isocyanate (26.8 ml, 0.27 mol) in THF (100 ml). The reaction was left stirring at room temperature overnight. The 5 reaction mixture, at room temperature, was charged with NaH (60% in oil, 4.89 g, 0.13 mol) and stirred for a period of 3 h. The reaction mixture was charged with a second portion of isopropyl isocyanate (15.5 ml, 0.16 mol) at room temperature and stirred overnight. The reaction mixture was worked up by removing THF under vacuum at the temperature ^33°C. The crude material was 10. charged with water (200 ml) and washed with hexane (500 ml). The aqueous phase was collected and adjusted to pH 7.4 with 1 M AcOH. At this point the product, torasemide, precipitated out and was isolated by vacuum filtration to obtain 174 g (138%) (wet weight) as a white solid. The crude product had the purity of 99.8% a/a with no impurity more than 0.1 %.

15 Purification of crude torasemide

In some cases, the purity of the crude products did not meet the specification so further purification was required and carried out as follows:

One batch of the crude torasemide (47.1 g, purity: 99.0%, RRT 0.3 = 0.08%, RRT 0.6 = 0.33%, RRT 0.8 = 0.5%) was dissolved in 2N NaOH (70 ml) 0 and water (70 ml). To this solution was added with Darco G-60 (11.5 g). The mixture was then heated to reflux for 1 h. The solution was filtered through celite to remove activated charcoal while it was still hot and then rinsed with water (room temperature, 100 ml). The solution was cooled to room temperature and adjusted to pH 7.5-8 with 1 M AcOH to obtain a white precipitate (40.8 g, 87%; 5 purity: 99.5%, RRT 0.3 = 0.35%, RRT 0.6 = 0.06%).

Another batch of the crude torasemide (as big chunks), after charcoal treatment, (97 g wet weight, purity: 99.5%, RRT 0.3 = 0.4%) was stirred, at room temperature in MeOH (2.5 L) until a smooth uniform suspension was obtained. The suspension was then heated to reflux and stirred for 15-30 min. The suspension was then filtered, while still hot, to remove insoluble material through filter paper. The filtrate was charged with water (2 L) and left stirring for a minimum of 1 h at room temperature. The product was isolated by vacuum filtration to yield a white solid in 59.1 g (61 %; purity: 99.9% with no impurity more than 0.1 %).

EXAMPLE 3 - Conversion to torasemide modification I - First method.

1 g of the crude wet torasemide was dissolved in MeOH (50 ml) at 50°C. This solution was then poured into water (1 L) at room temperature. To this solution, the remaining crude torasemide (99 g) was added and stirred at 75-80°C (batch temperature, bath temperature 95°C) for 72 h. The product was then isolated by vacuum filtration and dried under vacuum at 40°C to yield a white solid (100 g, 100% yield, 99.8% a/a purity). ¹H NMR (d6-DMSO): 1.05 (d, J=7 Hz, 6H), 2.30 (s, 3H), 3.65 (sept, J= 7 Hz, 1 H), 6.60 (brs, 1 H), 7.00 - 7.15 (m. 5H), 7.40 (m, 1 H), 8.20 (d, I H), 8.68 (s, I H), 9.10 (brs, 1 H), 11.25 (brs, 1 H). ¹³C NMR (de - DMSO): 21.8, 23.3, 42.4, 108.8, 121.5, 121.9, 124.9, 127.3, 130.4, 138.6, 140.2, 149.8, 151.9, 153.8. Figure 2 of the accompanying drawings is the x-ray diffraction pattern (PXRD) of this product confirming it to be pure torasemide modification 1.

Fig. 3 of the accompanying drawings is the differential scanning calorimetry (DSC) curve of the product, further confirming that it is pure torasemide modification 1.

EXAMPLE 4 - Conversion to torasemide modification ,l- Second method.

Crude torasemide 80 g (wet weight) was stirred in MeOH (1 L) at room temperature for 4 h. Water (1 L) was then charged into the mixture and then left stirring at room temperature for 4 days. The product was isolated by ^' vacuum filtration to obtain a white solid (50 g, 62%), which was identical in crystal structure to that obtained in Example 3.

Claims

CLAIMS:

1. A process of converting a polymorphic form of torasemide selected from torasemide Modification II, torasemide Modification III and mixtures containing both Modification II and Modification III, into the more stable polymorphic torasemide Modification I, which comprises forming a solution or suspension of the selected polymorphic form of torasemide in a mixture of water and methanol, the mixture comprising at least 2.5% v/v methanol and not more than 75% methanol by volume, stirring the solution or suspension so formed for at least 24 hours at temperatures in the range from about 10°C to about 90°C, and phase separating the solid torasemide Modification I from the liquid medium.

2. The process of claim 1 , further comprising preparing a preliminary dilute solution of the selected polymorphic form of torasemide in methanol, mixing the preliminary dilute solution with water, and adding further quantities of the selected polymorphic form of torasemide to the resulting mixture to form said solution or suspension.

3. The process of claim 2, wherein said preliminary dilute solution comprises 1 part by weight of the selected polymorphic form of torasemide in 20 - 60 parts of methanol.

4. The process of claim 3, wherein the amount of the selected polymorphic form of torasemide in said preliminary dilute solution is from 0.5 - 5% by weight of the total quantity of the selected polymorphic form of torasemide undergoing the converting process.

5. The process of claim 4 wherein the temperatures at which the stirring of said solution or suspension takes place are from 70°C to 90°C.

6. The process of claim 5 wherein the time for which the stirring takes place is from 60 - 96 hours.

7. The process of claim 1 , additionally comprising the steps of initially suspending the selected polymorphic form of torasemide in methanol under stirring, then adding water to the stirred mixture so formed to prepare said solution or suspension, and continuing to stir the solution or suspension for a period of from about 60 - 96 hours.

8. The process of claim 7, wherein the torasemide in methanol is stirred for a period of about 1 - 6 hours prior to the addition of the water.

9. The process of claim 8, wherein the stirring of the solution or suspension takes place at temperatures from about 15°C to about 35°C.

10. The process of any preceding claim, wherein the selected polymorphic form of torasemide is prepared by reacting 4-chloro-3- pyridinesulfonamide with m-toluidine at elevated temperature to form 4-[(3- methylphenyl)amino]pyridinesulfonamide, followed by reaction of the 4-[(3- methylphenyl)amino]pyridinesulfonamide with isopropyl isocyanate in the presence of triethylamine.

11. The process of claim 10, wherein the reaction of 4-chloro-3- pyridinesulfonamide with m-toluidine is conducted in the absence of copper powder.

12. The process of claim 11 , wherein said reaction is conducted in the presence of an aqueous solvent, and using not more than a stoichiometric amount of 4-chloro-3-pyridinesulfonamide.

13. The process of claim 10,- claim 11 or claim 12 wherein the 4- chloro-3-pyridinesulfonamide is used in the form of its hydrochloride salt.

14. The process of claim 10 wherein the 4-[(3- methylphenyl)amino]pyridinesulfonamide is converted to an anion thereof prior to or during its reaction with isopropyl isocyanate.

15. The process of claim 14 wherein the 4-[(3- methylphenyl)amino]pyridinesulfonamide is converted to anion by suspension in a polar solvent and addition of sodium hydride thereto.

16. A process of preparing 4-[(3-methylphenyl)amino]pyridine- sulfonamide, which comprises reacting 4-chloro-3-pyridinesulfonamide with m- toluidine at elevated temperature in the presence of an aqueous solvent, and using not more than a stoichiometric amount of 4-chloro3-pyridinesulfonamide, in the form of its hydrochloride salt.

17. A process of preparing torasemide, which comprises reacting an anion of 4-[(3-methylphenyl)amino]pyridinesulfonamide with isopropyl isocyanate in the presence a polar solvent.

18. The process of claim 17 wherein the anion of 4-[(3- methylphenyl)amino]pyridinesulfonamide ϊs prepared by reaction with sodium hydride.

19. Torasemide Modification I produced by the process of any of claims 1 - 18.