WO2009050595A2

WO2009050595A2 - An improved process for preparing a 2,4-thiazolidinedione derivative

Info

Publication number: WO2009050595A2
Application number: PCT/IB2008/003821
Authority: WO
Inventors: Ernesto Duran Lopez
Original assignee: Medichem, S.A.
Priority date: 2007-10-17
Filing date: 2008-10-17
Publication date: 2009-04-23
Also published as: AR068925A1; WO2009050595A3

Abstract

The present invention relates to a process for preparing rosiglitazone maleate with a low content of undesired by-products.

Description

AN IMPROVED PROCESS FOR PREPARING A 2.4-THIAZOLIDINEDIONE DERIVATIVE

Incorporation by Reference Any foregoing applications and all documents cited therein or during their prosecution

("application cited documents") and all documents cited or referenced in the application cited documents, and all documents cited or referenced herein ("herein cited documents"), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. Field of the Invention

The present invention relates to a process for preparing rosiglitazone maleate with a low content of undesired by-products. Background of the Invention

Rosiglitazone maleate is a commercially marketed pharmaceutically active substance known to be useful for the treatment of non-insulin dependent diabetes mellitus. Rosiglitazone maleate has an empirical formula of Ci₈H^N₃O₃S C₄H₄O₄. Rosiglitazone maleate, is the international common accepted name for 5-{4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl-2,4-thiazolidinedione maleate, which is represented in Formula I.

I

Rosiglitazone free base, or a tautomeric form and/or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate, are claimed in U.S. Patent No. 5,002,953 (EP 306 228 Bl).

Rosiglitazone maleate is specifically referred to in U.S. Patent No. 5,741 ,803 (EP 658 161 Bl) as well as to a process for its preparation, which comprises treating rosiglitazone with maleic acid in ethanol under reflux temperature. However, this process gives rise to rosiglitazone maleate together with a considerable amount of certain impurity. European patent application No. 1854794 Al refers to an impurity associated with rosiglitazone maleate, which is represented in formula II below. However, EP 1854794 Al does not provide a method for preparing rosiglitazone maleate having low content of compound of Formula II.

II

U.S. Patent Application Publication No. 2007/0293546 Al refers to a process for the preparation of rosiglitazone maleate having less than 0.15% of compound of Formula II. More precisely, Example 6 of US2007/0293546 Al affords rosiglitazone maleate having a purity of 99.6% and less than 0.03% of compound of formula II. However, the process provided in this reference has a number of drawbacks which are especially relevant for industrial production, i.e. uses large volumes of acetone solvent, requires the distillation of solvent under reduced pressure, and makes use of extended drying times.

It is well-known that the presence of impurities may adversely affect the safety and shelf life of formulations. Since rosiglitazone maleate is an active pharmaceutical substance that is included in pharmaceutical compositions, there is still a need to provide an improved process for preparing rosiglitazone maleate having a minimum amount of undesired by- products, especially having a minimum amount of the compound of formula II, and avoid the drawbacks of other processes known in the art for making rosiglitazone maleate.

Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention. SUMMARY OF THE INVENTION The invention relates to a process for preparing rosiglitazone maleate with a low content of undesired by-products.

The invention relates to a process for preparing rosiglitazone maleate with a low content of undesired by-products, which overcomes the drawbacks of the prior art, i.e. uses small volumes of solvent, does not require the distillation of solvent under reduced pressure, and does not make use of extended drying times, which is efficient and cost-effective, and which is suitable for industrial implementation.

In particular, the invention relates to minimizing the presence and effects of a certain by-product present in rosiglitazone maleate occurring during the steps of synthesis and/or purification and/or drying of rosiglitazone maleate.

It has been observed that during the steps of synthesis and/or purification and/or drying of rosiglitazone maleate the compound of Formula II (2-[5-(4-{2-[methyl(pyridin-2- yOaminoJethoxyJbenzyl^^-dioxo-l^-thiazolidin-S-y^succinic acid) can be obtained as a by-product.

II

Rosiglitazone maleate obtained according to the teaching of Example 1 of U.S. Patent No. 5,741,803 shows an amount of 0.38% of compound of Formula II.

In a first aspect, the invention includes a process for preparing rosiglitazone maleate and/or its solvates thereof that provides the desired product with a minimum amount of the compound of Formula II. These aims can be achieved by adjusting the temperature of the reaction, the temperature of the crystallization, and the drying temperature conditions to avoid the undesired side reaction. Further, it has been observed that milling rosiglitazone maleate can increase the content of the compound of Formula II. In another aspect, the process for preparing rosiglitazone maleate and/or its solvates thereof, which provides rosiglitazone maleate and/or its solvates thereof with a minimum amount of compound of Formula II, comprises the steps of: (i) reacting rosiglitazone with maleic acid in a C₂-C₅ alcohol solvent or mixtures thereof at a temperature not higher than 78 ⁰C, (ii) optionally, purifying the obtained rosiglitazone maleate and/or its solvates thereof, and (iii) drying the obtained rosiglitazone maleate and/or its solvates thereof.

In an embodiment of the invention, the reaction of step (i) is carried out at a temperature not higher than 70 ⁰C.

In an embodiment of the invention, step (ii) comprises recrystallizing the rosiglitazone maleate and/or its solvates thereof in a C₂-C₅ alcohol solvent or mixtures thereof in the presence of traces of maleic acid and at a temperature not higher than 78 ⁰C. In an embodiment of the invention, the recrystallization is carried out at a temperature not higher than 70 ⁰C.

In an embodiment of the invention, step (iii) comprises drying rosiglitazone maleate and/or its solvates thereof at a temperature not higher than approximately 60 ⁰C. The C₂-C₅ alcohol solvent is a primary C₂-C₅ alcohol solvent, a secondary C₃-C₅ alcohol solvent, a tertiary C₄-C₅ alcohol solvent, or a mixture thereof. In an embodiment of the invention, the C₂-C₅ alcohol solvent is ethanol.

Additionally, another aspect of the invention further includes monitoring the production of undesirable compound of Formula II in the reaction of rosiglitazone with maleic acid and/or in the purified product obtained after the purification of rosiglitazone maleate and/or in the dried product obtained after the drying of rosiglitazone maleate.

In another embodiment of the invention, the compound 2-[5-(4-{2-[methyl(pyridin-2- yOaminoJethoxyJbenzyl^^-dioxo-l.S-thiazolidin-S-ylJsuccinic acid (as depicted in Formula II) is used as a reference marker to analyze the purity of a sample of rosiglitazone maleate and/or of a pharmaceutically acceptable dosage form containing rosiglitazone maleate. According to this aspect of the invention, the level of compound of Formula II is controlled in order to achieve the required purity level for commercial production of the active pharmaceutical ingredient rosiglitazone maleate.

In a further aspect, the invention includes identification of and a method for preparing the compound of Formula II.

In another aspect, the invention includes a process for preparing 2-[5-(4-{2-

[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-2,4-dioxo-l ,3-thiazolidin-3-yl]succinic acid

(Formula II) comprising the steps of (i) reacting rosiglitazone with maleic acid at a temperature higher than about 80 ⁰C, optionally in the presence of a solvent, and (ii) optionally, purifying compound of Formula II.

In another aspect, the invention includes rosiglitazone maleate substantially free of 2- [5-(4- {2-[methyl(pvridin-2-yl)amino]ethoxy}benzyl)-2,4-dioxo- 1 ,3-thiazolidin-3-yl]succinic acid (i.e., the compound of Formula II).

In another aspect, the invention includes rosiglitazone maleate having less than a range selected from the group consisting of approximately 0.3 wt.% of the compound of Formula II, less than approximately 0.1 wt.% of the compound of Formula II, less than approximately 0.05 wt.% of the compound of Formula II, less than approximately 0.03 wt.% of the compound of Formula II and less than approximately 0.015 wt.% of the compound of Formula II. It is further noted that the invention does not intend to encompass within the scope of the invention any previously disclosed product, process of making the product or method of using the product, which meets the written description and enablement requirements of the USPTO (35 U.S.C. 112, first paragraph) or the EPO (Article 83 of the EPC), such that applicant(s) reserve the right and hereby disclose a disclaimer of any previously described product, method of making the product or process of using the product.

It is noted that in this disclosure and particularly in the claims and/or paragraphs, terms such as "comprises", "comprised", "comprising" and the like can have the meaning attributed to it in U.S. Patent law; e.g., they can mean "includes", "included", "including", and the like; and that terms such as "consisting essentially of and "consists essentially of have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention.

The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended, nor should they be interpreted to, limit the scope of the invention. EXAMPLES

General Experimental Conditions: HPLC Method: The chromatographic separation was carried out at 45 ⁰C in a Zorbax Eclipse XDB-

C18, 5 μm, 250 x 4.6 mm LD. column with a Zorbax Eclipse XDB-C18, 5 μm, 12.5 x 4.6 mm LD. guard column.

The mobile phase A was prepared by dissolving 3.40 g of potassium dihydrogenphosphate in 1000 mL of water and by adjusting the pH to 6.5 with dilute sodium hydroxide. The mobile phase A was filtered through 0.22 μm nylon filter under vacuum. The mobile phase B was acetonitrile. The chromatogram was programmed as follows:

Initial 0-10 minutes isocratic 75% mobile phase A, 10-15 minutes linear gradient to 65% mobile phase A, 15-30 minutes isocratic 65% mobile phase A, 30-35 minutes linear gradient to 75% mobile phase A and 35-45 minutes equilibration to 75% mobile phase A.

The chromatograph was equipped with a 245 nm detector, and the flow rate was 1.0 mL per minute. Test samples (10 μL) were prepared by dissolving the appropriate amount of sample in order to obtain 1 mg per mL of diluent. The diluent was prepared by mixture (50:50) of acetonitrile and mobile phase A. The mixture was filtered through 0.22 μm nylon filter under vacuum. Approximate HPLC retention times:

Specific Surface Area Method

The BET (Brunauer, Emmett and Teller) specific surface area for rosiglitazone maleate was measured using a Micromeritics® GEMINI V equipment (GEMINI CONFIRM V2.00 Software®). The sample for analysis was degassed at 30° C for 10 minutes and at 80° C for one hour. The determination of the adsorption of N₂ at 77° K was measured for relative pressures in the range of 0.07-0.2 for a weighed amount of rosiglitazone maleate (i.e., approximately 0.5 g).

Example 1: Preparation of 2-[5-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-2,4- dioxo-l,3-thiazolidin-3-yl]succinic acid (Compound II)

20.01 g (42.2 mmols) of rosiglitazone maleate was heated at 100 ⁰C for 7 days. The material was grinded and homogenized every 24 hours. The final residue was suspended in 100 mL of methanol and stirred at 40-50 ⁰C for 1 hour. After cooling to room temperature, the resulting suspension was filtered off. 12.59 g of 2-[5-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}benzyl)-2,4-dioxo-l ,3-thiazolidin-3-yl]succinic acid was obtained. Yield: 63 %. Purity (HPLC): 84.92 %. Example 2: Purification of Compound II

19.55 g (41.2 mmol) of 2-[5-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-2,4- dioxo-l,3-thiazolidin-3-yl]succinic acid (of about 85% purity by HPLC) was suspended in 98 mL of methanol and stirred at 40-50 ⁰C for 1 hour. After cooling to room temperature, the resulting suspension was filtered off. The filtered material was dried in a vacuum oven at 40 ⁰C for 5.5 hours. 16.29 g of 2-[5-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-2,4- dioxo-l,3-thiazolidin-3-yl]succinic acid was obtained. Yield: 83 %. Purity (HPLC):

95.99 %. m.p. 175.0 - 180.3 ⁰C IR (v, cm^"1) 3806, 3743, 3673, 3426, 3042, 2942, 1969, 1755, 1715, 1688, 1647,

161 1 , 1574, 1544, 1513, 1469, 1451 , 1418, 1377, 1294, 1245, 1 180, 1 151, 1 1 10, 1077, 1061 ,

1030, 998, 971 , 918, 865, 830, 81 1, 765, 729, 688, 667, 654, 636, 615.

¹H NMR (DMSO-d₆, 400 MHz) (δ, ppm) 8.07 (dd, J = 4.4 Hz, J = 1.2 Hz, 1 H), 7.48

(m, 1 H), 7.14 (d, J = 8.8 Hz, 2 H), 6.86 (d, J = 8.4 Hz, 2 H), 6.63 (d, J = 8.8 Hz, 1 H), 6.55 (dd, J = 6.8 Hz, J = 5.2 Hz, 1 H), 5.05 (m, 1 H), 4.96 (m, 1 H), 4.1 1 (t, J = 6.0 Hz, 2 H), 3.89

(t, J = 5.8 Hz, 2 H), 3.37 (m, 1 H), 3.07 (s, 3 H), 3.02 (m, 2 H), 2.61 (m, 1 H).

¹³C NMR (DMSOd₆, 100.6 MHz) (δ, ppm) 173.1 (C), 171.10 (C), 171.08 (C), 170.2

(C), 168.8 (C), 157.8 (C), 157.4 (C), 147.3 (CH), 137.2 (CH), 130.2 (CH), 130.1 (CH), 128.1

(C), 1 14.2 (CH), 1 1 1.3 (CH), 105.6 (CH), 65.2 (CH₂), 50.6 (CH), 50.5 (CH), 48.4 (CH₂), 36.9 (CH₃), 36.5 (CH₂), 33.1 (CH₂), 33.0 (CH₂).

Example 3: Comparative example of preparation of rosiglitazone maleate

14.74 g (41.2 mmol) of rosiglitazone base and 5.75 g (49.5 mmol, 1.2 equivalents) of maleic acid were suspended in 81 mL of ethanol and stirred at reflux temperature for 6 hours.

After cooling to 0 ⁰C, the resulting suspension was filtered off. 18.0 g of rosiglitazone maleate was obtained. Yield: 92 %. Amount of 2-[5-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}benzyl)-2,4-dioxo-l ,3-thiazolidin-3-yl]succinic acid in wet product

(HPLC): 0.38%.

Example 4: Preparation of rosiglitazone maleate

70.89 g (198.3 mmol) of rosiglitazone base and 27.62 g (238.0 mmol, 1.2 equivalents) of maleic acid were suspended in 500 mL of ethanol and stirred at 69 ⁰C for 2.5 hours. The resulting solution was filtered to remove mechanical impurities, and heated again to 70 ⁰C.

The solution was cooled to 63 ⁰C and seeded at this temperature using the desired polymorph of rosiglitazone maleate (form III). The resulting suspension was cooled down to 0 ⁰C, stirred at this temperature for 1 hour and filtered off. The filtered solid was washed with 70 mL of ethanol. 63.9 g of rosiglitazone maleate was obtained. Yield: 68%. Amount of 2-[5-(4-{2-

[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-2,4-dioxo- 1 ,3-thiazolidin-3-yl]succinic acid in wet product (HPLC): 0.02%.

Example 5: Crystallization of rosiglitazone maleate 62.85 g (132.7 mmol) of rosiglitazone maleate (as obtained in Example 4) and 2.62 g (22.6 mmol, 0.17 equivalents) of maleic acid were suspended in 315 mL of ethanol and heated up to 70 ⁰C in 35 minutes to get a solution. The resulting solution was cooled down to 59 ⁰C in 15 minutes and was seeded at this temperature using the desired polymorph of rosiglitazone maleate (form III). The resulting suspension was cooled down to 0 ⁰C in about 3 hours, stirred at this temperature for 2 hours and filtered off. The filtered solid was washed with 63 mL of ethanol, and dried at 50 ⁰C under vacuum until constant weight. 59.7 g of rosiglitazone maleate was obtained. Yield: 95%. Amount of 2-[5-(4- {2-[methyl(pyridin-2- yOaminoJethoxyJbenzyl^^-dioxo-l ^-thiazolidin-S-ylJsuccinic acid (HPLC): 0.01 %. Example 6: Preparation of rosiglitazone maleate

49.95 g (139.75 mmol) of rosiglitazone base and 19.48 g (167.83 mmol, 1.2 equivalents) of maleic acid were suspended in 350 mL of isopropanol and stirred at 70 ⁰C for 4 hours. The solution was cooled down to 5-10 ⁰C in about 2.5 hours, stirred at this temperature for 30 minutes and filtered off. The filtered solid was washed with 50 mL of isopropanol. 58.17 g of rosiglitazone maleate was obtained. Yield: 88%. Amount of 2-[5-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-2,4-dioxo-l ,3-thiazolidin-3-yl]succinic acid in wet product (HPLC): 0.01 %.

Example 7: Crystallization of rosiglitazone maleate 58.17 g (122.85 mmol) of rosiglitazone maleate (as obtained in Example 6) were suspended in 472 mL of ethanol and heated up to 70 ⁰C in about 30 minutes to get a solution. The resulting solution was kept at 70 ⁰C for 1 hour, and then heated up to reflux temperature (78 ⁰C). After distilling 135 mL of ethanol under atmospheric pressure, the resulting solution was cooled down to 63 ⁰C in 45 minutes and was seeded at this temperature using the desired polymorph of rosiglitazone maleate (form III). The resulting suspension was cooled down to 5-10 ⁰C in about 60 minutes, stirred at this temperature for 30 minutes and filtered off. The filtered solid was washed with 58 mL of ethanol. 57.10 g of rosiglitazone maleate was obtained. Yield: 94%. Amount of 2-[5-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)- 2,4-dioxo-l ,3-thiazolidin-3-yl]succinic acid (HPLC): 0.05%. Example 8: Crystallization of rosiglitazone maleate

57.10 g (1 15.95 mmol) of rosiglitazone maleate (as obtained in Example 7) and 2.23 g (19.21 mmol, 0.17 molar equivalents) of maleic acid were suspended in 387 mL of ethanol and heated up to 70 ⁰C in about 1 hour to get a solution. The resulting solution was cooled down to 62 ⁰C in 20 minutes and was seeded at this temperature using the desired polymorph of rosiglitazone maleate (form III). The resulting suspension was cooled down to 5-10 ⁰C in about 90 minutes, stirred at this temperature for 30 minutes and filtered off. The filtered solid was washed with 55 mL of ethanol, and dried at 50 ⁰C under vacuum until constant weight.

52.34 g of rosiglitazone maleate was obtained. Yield: 95%. Purity (HPLC): 99.95%. Amount of 2-[5-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-2,4-dioxo-l,3-thiazolidin-3- yl]succinic acid (HPLC): 0.03%.

The rosiglitazone maleate obtained according to this example typically has the following surface area: 1.0481 ± 0.0097 to 1.1459 ± 0.0079 m²/g.

Example 9: Milling of rosiglitazone maleate Rosiglitazone maleate (as obtained in Example 8) was milled at 14.000 rpm. Amount of 2-[5-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-2,4-dioxo-l,3-thiazolidin-3- yljsuccinic acid in the milled rosiglitazone maleate product (HPLC): 0.17%.

Having thus described in detail various embodiments of the present invention, it is to be understood that the invention defined by the above paragraphs is not to be limited to particular details set forth in the above description as many apparent variations thereof are possible without departing from the spirit or scope of the present invention.

Claims

What is claimed is:

1. A process for preparing rosiglitazone maleate and/or its solvates thereof, which provides rosiglitazone maleate and/or its solvates thereof with a minimum amount of compound of Formula II, said process comprising the steps of: (i) reacting rosiglitazone with maleic acid in a C₂-C₅ alcohol solvent or mixtures thereof at a temperature not higher than 78 ⁰C, (ii) optionally, purifying the obtained rosiglitazone maleate and/or its solvates thereof, and

(iii) drying the obtained rosiglitazone maleate and/or its solvates thereof.

2. The process of claim 1, wherein the reaction of step (i) is carried out at a temperature not higher than 70 ⁰C.

3. The process of any one of claims 1 and 2, wherein the step (ii) comprises recrystallizing the rosiglitazone maleate and/or its solvates thereof in a C₂-C₅ alcohol solvent or mixtures thereof in the presence of traces of maleic acid and at a temperature not higher than 78 ⁰C.

4. The process of claim 3, wherein the recrystallizing is carried out at a temperature not higher than 70 ⁰C.

5. The process of any one of claims 1-4, wherein the step (iii) comprises drying rosiglitazone maleate and/or its solvates thereof at a temperature not higher than 60 ⁰C.

6. The process of any one of claims 1-5, wherein the C₂-C₅ alcohol solvent is a primary

C₂-C₅ alcohol solvent, a secondary C₃-C₅ alcohol solvent, a tertiary C₄-C₅ alcohol solvent, or a mixture thereof, preferably is ethanol.

7. A process for monitoring the content of compound of Formula II in rosiglitazone maleate.

8. A process for analyzing the chemical purity of rosiglitazone maleate and/or its solvates thereof and/or pharmaceutical compositions comprising rosiglitazone maleate, said process comprising using compound of Formula II as a marker to monitor the chemical purity of rosiglitazone maleate.

9. Rosiglitazone maleate obtained according to any one of the processes of claims 1-6.

10. The Rosiglitazone maleate of claim 9 and/or its solvates thereof wherein said rosiglitazone maleate has less than approximately 0.3% of 2-[5-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}benzyl)-2,4-dioxo-l,3-thiazolidin-3-yl]succinic acid (Formula II) as measured by HPLC.

1 1. The Rosiglitazone maleate of claim 9 and/or its solvates thereof wherein said rosiglitazone maleate has less than approximately 0.1% of 2-[5-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}benzyl)-2,4-dioxo-l,3-thiazolidin-3-yl]succinic acid (Formula II) as measured by HPLC.

12. The Rosiglitazone maleate of claim 9 and/or its solvates thereof wherein said rosiglitazone maleate has less than approximately 0.05% of 2-[5-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}benzyl)-2,4-dioxo-l,3-thiazolidin-3-yl]succinic acid (Formula II) as measured by HPLC.

13. The Rosiglitazone maleate of claim 9 and/or its solvates thereof wherein said rosiglitazone maleate has less than approximately 0.03% of 2-[5-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}benzyl)-2,4-dioxo-l,3-thiazolidin-3-yl]succinic acid (Formula II) as measured by HPLC.

14. The Rosiglitazone maleate of claim 9 and/or its solvates thereof wherein said rosiglitazone maleate has less than approximately 0.015% of 2-[5-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}benzyl)-2,4-dioxo-l,3-thiazolidin-3-yl]succinic acid (Formula II) as measured by HPLC.

15. Use of the rosiglitazone maleate and/or its solvates thereof according to any of claims 9-14 in the manufacture of a medicament for the treatment and/or prophylaxis of diabetes.