WO2004089904A2 - Preparation de torasemide - Google Patents

Preparation de torasemide Download PDF

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Publication number
WO2004089904A2
WO2004089904A2 PCT/CA2004/000366 CA2004000366W WO2004089904A2 WO 2004089904 A2 WO2004089904 A2 WO 2004089904A2 CA 2004000366 W CA2004000366 W CA 2004000366W WO 2004089904 A2 WO2004089904 A2 WO 2004089904A2
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WO
WIPO (PCT)
Prior art keywords
torasemide
pyridinesulfonamide
solution
modification
suspension
Prior art date
Application number
PCT/CA2004/000366
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English (en)
Other versions
WO2004089904A3 (fr
Inventor
Wen-Lung Yeh
Kanjai Khumtaveeporn
David John Mckenzie
Original Assignee
Torcan Chemical Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Torcan Chemical Ltd. filed Critical Torcan Chemical Ltd.
Publication of WO2004089904A2 publication Critical patent/WO2004089904A2/fr
Publication of WO2004089904A3 publication Critical patent/WO2004089904A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • 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.
  • Torasemide also known as torsemide, is, chemically, N-[[(1- methylethyl)amino]-carbonyl]-4-[(3-methylphenyl)amino]-3-pyridinesulfonamide, of chemical formula:
  • 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.
  • Modification II 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 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.
  • German patent 2516025 June 1975, describes the preparation and properties of torasemide.
  • 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.
  • the prior art 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. .
  • a further object is to provide a novel process for preparing crude torasemide.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 is an improved method of conducting the first process step, i.e. the process of preparing 4-[(3-methylphenyl)amino]pyridinesulfonamide.
  • 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.
  • 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 suitable polar solvent preferably dioxane or tetrahydrofuran
  • 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
  • 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.
  • 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).
  • 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.
  • the crude product had the purity of 99.8% a/a with no impurity more than 0.1 %.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La forme polymorphe stable de torasémide, Modification I, est préparée à partir d'autres formes moins stables de torasémide, par la formation d'une solution de la forme polymorphe de départ de torasémide dans l'eau et du méthanol, une agitation d'au moins 20 heures et la séparation de phases du torasémide solide, Modification I, du milieu liquide.
PCT/CA2004/000366 2003-04-07 2004-03-12 Preparation de torasemide WO2004089904A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA 2424644 CA2424644A1 (fr) 2003-04-07 2003-04-07 Preparation de torasemide
CA2,424,644 2003-04-07

Publications (2)

Publication Number Publication Date
WO2004089904A2 true WO2004089904A2 (fr) 2004-10-21
WO2004089904A3 WO2004089904A3 (fr) 2004-12-23

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CA (1) CA2424644A1 (fr)
WO (1) WO2004089904A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104370805A (zh) * 2013-08-13 2015-02-25 天津汉瑞药业有限公司 托拉塞米化合物
EP3173075A1 (fr) 2015-11-27 2017-05-31 ACCUPHARMA Spolka z ograniczona odpowiedzialnoscia Préparation pharmaceutique combinée constituée d'un inhibiteur ace et diurétique de l'anse
CN115417810A (zh) * 2022-09-22 2022-12-02 南京正科医药股份有限公司 一种托拉塞米晶型ⅰ的精制方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102079721B (zh) * 2011-01-28 2012-05-09 海南美大制药有限公司 一种托拉塞米化合物及其制法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000020395A1 (fr) * 1998-10-02 2000-04-13 Pliva, Farmaceutska Industrija, Dionicko Drustvo Nouvelle modification cristalline iii de torasemide
WO2001010441A1 (fr) * 1999-08-11 2001-02-15 Teva Pharmaceutical Industries Ltd. Polymorphes de torsemide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000020395A1 (fr) * 1998-10-02 2000-04-13 Pliva, Farmaceutska Industrija, Dionicko Drustvo Nouvelle modification cristalline iii de torasemide
WO2001010441A1 (fr) * 1999-08-11 2001-02-15 Teva Pharmaceutical Industries Ltd. Polymorphes de torsemide

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DUPONT L ET AL: "Structure cristalline et moléculaire d'un diurétique dérivé de l'alkyl-1[(phénylamino-4-pyridyl-3)sulfony lÜ-3 urée: la torasémide (C15H20N4SO3)" ACTA CRYSTALLOGRAPHICA. SECTION B, STRUCTURAL CRYSTALLOGRAPHY AND CRYSTAL CHEMISTRY, MUNKSGAARD, COPENHAGEN, DK, vol. B34, no. 4, April 1978 (1978-04), pages 1304-1310, XP002128455 ISSN: 0567-7408 cited in the application *
ROLLINGER J M ET AL: "Crystal forms of torasemide: new insights" EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 53, no. 1, January 2002 (2002-01), pages 75-86, XP004331334 ISSN: 0939-6411 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104370805A (zh) * 2013-08-13 2015-02-25 天津汉瑞药业有限公司 托拉塞米化合物
EP3173075A1 (fr) 2015-11-27 2017-05-31 ACCUPHARMA Spolka z ograniczona odpowiedzialnoscia Préparation pharmaceutique combinée constituée d'un inhibiteur ace et diurétique de l'anse
CN115417810A (zh) * 2022-09-22 2022-12-02 南京正科医药股份有限公司 一种托拉塞米晶型ⅰ的精制方法
CN115417810B (zh) * 2022-09-22 2023-10-10 南京正科医药股份有限公司 一种托拉塞米晶型ⅰ的精制方法

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Publication number Publication date
CA2424644A1 (fr) 2004-10-07
WO2004089904A3 (fr) 2004-12-23

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