WO2007119109A2 - Compositions et procédés utiles pour la préparation de maléate de tégaserod - Google Patents

Compositions et procédés utiles pour la préparation de maléate de tégaserod Download PDF

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Publication number
WO2007119109A2
WO2007119109A2 PCT/IB2006/004222 IB2006004222W WO2007119109A2 WO 2007119109 A2 WO2007119109 A2 WO 2007119109A2 IB 2006004222 W IB2006004222 W IB 2006004222W WO 2007119109 A2 WO2007119109 A2 WO 2007119109A2
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Prior art keywords
tegaserod
approximately
hydroiodide
maleate
base
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PCT/IB2006/004222
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English (en)
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WO2007119109A3 (fr
Inventor
Maria Carmen Burgarolas Montero
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Medichem, S.A.
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Publication of WO2007119109A2 publication Critical patent/WO2007119109A2/fr
Publication of WO2007119109A3 publication Critical patent/WO2007119109A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • the invention relates to a new process for the production of tegaserod maleate that includes the isolation of tegaserod hydroiodide as an intermediate.
  • the invention provides an improved process for preparing 3-(5-methoxy-lH-indol-3- ylmethylene)-N-pentylcarbazimidamide hydrogen maleate (i.e., tegaserod maleate).
  • This process includes reacting 5-methoxyindole-3-carbaldehyde withN-pentyl-N'- aminoguanidine hydroiodide and isolating solid 3-(5-methoxy-lH-indol-3-ylmethylene)-N- pentylcarbazimidamide hydroiodide (i.e., tegaserod hydroiodide).
  • Tegaserod maleate (“tegaserod”) is the common name for 3-(5-methoxy-lH-indol-
  • Tegaserod is alternatively referred to herein as (2 J E)-2-[(5-methoxy-liir-indol-3- yl)methylene]-N-pentylhydrazinecarboximidamide.
  • Tegaserod and related compounds are serotonin 5HT 4 receptor partial agonists and are useful in the treatment of irritable bowel syndrome. According to WO 2005/058819 A2 (discussed below), tegaserod base exhibits polymorphism.
  • U.S. Patent No. 5,510,353 describes a process for obtaining tegaserod that can be prepared according to the process described in Example 2a for 5-benzyloxy-indole-3- carboxaldehyde amino(N-methyl-N-heptylamino) methylene hydrazone.
  • Example 13 of Table I describes a melting point of 124° C for the base and 190° C for the hydrogen maleate salt.
  • Tegaserod base prepared according to this method is characterized only by a melting point of 155° C (See Table 3, Compound 5b).
  • Chinese Patent No. CN 1425651 also describes (Reference 1) a method for the preparation, of tegaserod maleate.
  • the aminoguanidine moiety is used as its hydroiodide salt.
  • Zhongguo Yaowu Huaxue Zazhi 2003, 13(1), 40-41 discloses the production of tegaserod base (Example 1.3) involving the condensation of 5 -methoxyindole-3- carbaldehyde (Compound II) with N-pentyl-N' -aminoguanidine hydrobromide (Compound IHb) in methanol and in the presence of concentrated HCl (pH 3-4).
  • WO 2005/014544 Al discloses a process (Example 1) for producing tegaserod involving preparing N-pentyl-N' -aminoguanidine (Compound III) by reacting s-odecylisothio semi carbazide hydrobromide with 1-pentylamine. Without isolating the N-pentyl-N' -amino guanidine, ethanol, hydrogen chloride and 5-methoxyindol-3-carbaldehyde (Compound II) are added.
  • tegaserod base in solid state shows a purity of at least about 99% as area percentage HPLC, and having about 0.2% as area percentage
  • the presence of such impurities in tegaserod maleate may pose a problem for formulation because impurities often affect the safety and shelf life of a formulation.
  • IPCOM000021161D characterizes the marketed polymorphic form of tegaserod maleate (Zelnorm®) and designates the crystalline form of Zelnorm® as tegaserod maleate Form A, which is characterized by a specific X-ray diffraction pattern.
  • Tegaserod maleate is poorly soluble in water, which necessitates special formulation procedures for achieving a desired pharmacokinetic profile. Low solubility compounds can be problematic in the pharmaceutical arts from a formulations perspective.
  • particle size can affect the solubility properties of a compound, like tegaserod maleate. Particle size reduction may be tried in order to increase a compound's solubility. Particle size reduction increases the surface area of the solid phase that is in contact with the liquid medium.
  • Increases in specific surface area of low aqueous solubility materials may improve therapeutic activity.
  • the surface area of a solid material provides information about the void spaces on the surfaces of individual particles or aggregates of particles.
  • factors such as chemical activity, adsorption, dissolution, and bioavailabilty of the drug may depend on the surface of the solid.
  • WO 2005/058819 A2 discloses seven forms of tegaserod maleate characterized by X- ray diffraction patterns that are designated as Form B, Form Bl, Form B2, Form B3, Form C, Form D and Form E. These polymorphic forms have a maximum particle size of less than about 250 ⁇ m, more preferably less than about 200 ⁇ m, most preferably less than about 100 ⁇ m.
  • the invention relates to a new process for the production of tegaserod maleate that includes the isolation of tegaserod hydroiodide as an intermediate.
  • the invention provides an improved process for preparing 3-(5-methoxy-lH-indol-3- ylmethylene)-N-pentylcarbazimidamide hydrogen maleate (i.e., tegaserod maleate).
  • This process includes reacting 5-methoxyindole-3-carbaldehyde withN-pentyl-N'- aminoguanidine hydroiodide (i.e., N-pentyUiydrazinecarboximidamide hydroiodide) and isolating solid 3-(5-methoxy-lH-indol-3-ylmethylene)-N-pentylcarbazimidamide hydroiodide (i.e., tegaserod hydroiodide).
  • N-pentyUiydrazinecarboximidamide hydroiodide i.e., N-pentyUiydrazinecarboximidamide hydroiodide
  • the invention further includes the preparation of tegaserod maleate without requiring complicated separation procedures and a process for producing tegaserod maleate of high quality and purity (e.g., 99.7% or higher by HPLC).
  • the invention further includes the crystalline compound 3-(5-methoxy-lH-indol-3- ylmethylene)-N-pentylcarbazimidamide hydroiodide (i.e., tegaserod hydroiodide), designated as tegaserod hydroiodide Form A.
  • tegaserod hydroiodide Form A the crystalline compound 3-(5-methoxy-lH-indol-3- ylmethylene)-N-pentylcarbazimidamide hydroiodide
  • the invention further includes the use of the crystalline compound 3-(5-methoxy- lH-indol-3-ylmethylene)-N-pentylcarbazimidamide hydroiodide (i.e., tegaserod hydroiodide) for the preparation of 3-(5-methoxy-lH-indol-3-ylmethylene)-N-pentyl carbazimidamide (i.e., tegaserod base).
  • the crystalline compound 3-(5-methoxy- lH-indol-3-ylmethylene)-N-pentylcarbazimidamide hydroiodide i.e., tegaserod hydroiodide
  • the invention further includes the crystalline compound 3-(5-methoxy-lH-indol-3 ⁇ yl methylene)-N-pentylcarbazimidamide (i.e., tegaserod base), designated as tegaserod base Form B.
  • the invention further includes the use of crystalline compound 3-(5-methoxy-lH- indol-3-ylmethylene)-N-pentylcarbazimidamide (i. e. , tegaserod base) for the production of pharmaceutically acceptable salts of 3-(5-methoxy-lH-indol-3-ylmethylene)-N-pentyl carbazimidamide (i.e., tegaserod salts).
  • the invention further includes tegaserod hydroiodide having less than approximately 0.1% as area percentage HPLC of impurity A.
  • the invention further includes tegaserod hydroiodide having less than approximately 0.1% as area percentage HPLC of impurity B.
  • the invention further includes tegaserod base having less than approximately 0.1% as area percentage HPLC of impurity A.
  • the invention further includes tegaserod base having less than approximately 0.1% as area percentage HPLC of impurity B.
  • the invention further includes tegaserod maleate having less than approximately
  • the invention further includes tegaserod maleate having less than approximately 0.1% as area percentage HPLC of impurity B.
  • the invention further includes a powder composition of tegaserod maleate having a particle size distribution wherein approximately 10% of the total volume is made of particles having a diameter less than approximately 3 ⁇ m, approximately 50% of the total volume is made of particles having a diameter less than approximately 10 ⁇ m and approximately 90% of the total volume is made of particles having a diameter less than approximately 20 ⁇ m.
  • the invention further includes tegaserod maleate particles having a surface area of approximately 5 to approximately 20 m 2 /g. More preferably, the tegaserod maleate particles having a surface area of approximately 8 to approximately 13 m Ig.
  • FIG. 1 illustrates the X-ray powder diffractogram of tegaserod hydroiodide Form A obtained according to one aspect of the invention
  • FIG. 2 illustrates the IR spectrum of tegaserod hydroiodide Form A obtained according to another aspect of the invention
  • FIG. 3 illustrates the x-ray diffractogram pattern of tegaserod base Form B obtained according to a further aspect of the invention
  • FIG. 4 illustrates the IR spectrum of tegaserod base Form B obtained according to another aspect of the invention.
  • FIG. 5 illustrates the x-ray diffractogram pattern of 5-methoxyindole-3- carbaldehyde Form III.
  • Processes according to the invention include the reaction of 5-methoxyindole-3- carbaldehyde withN-pentyl-N'-aminoguanidine hydroiodide (i.e., N-pentylhydrazine carboximidarnide hydroiodide) in a solvent system, which includes at least one polar solvent.
  • Preferred polar solvents include ethyl acetate, acetonitrile or water.
  • the process of the invention can optionally include performing the reaction in the presence of an organic acid, including, more preferably, glacial or aqueous acetic acid.
  • an organic acid including, more preferably, glacial or aqueous acetic acid.
  • the quantity of the acid is the amount necessary to achieve a reaction mixture pH in the range of approximately 2 to approximately 4, and preferably in the range of approximately 2.5 to approximately 3.5.
  • the presence of the organic acid reduces reaction time and increases yield of the reaction. 1
  • the reaction can be conducted at a temperature in the range of approximately 0° C to reflux temperature, and for a time of approximately 10 minutes to approximately 48 hours.
  • the reaction is conducted at reflux temperature for at least approximately 20 minutes, and more preferably the reaction is conducted at reflux temperature for approximately 1 hour.
  • the reaction mixture is cooled to room temperature and the precipitate is removed by filtration.
  • Tegaserod hydroiodide produced by this process can be used without further purification to obtain tegaserod base, or alternatively can be purified by traditional purification techniques.
  • a preferred purification of tegaserod hydroiodide includes contacting tegaserod hydroioide with a solvent system, optionally treating the obtained solution with a decolorizing agent (e.g., activated charcoal, silica gel, ambosol and mixtures thereof) or a reducing agent (e.g., sodium metabisulfite, sodium hydrosulfite and sodium thiosulfate (pentahydrate) and mixtures thereof), and finally contacting the solution with water to precipitate tegaserod hydroiodide.
  • a preferred solvent system includes a mixture of an alcoholic solvent (e.g., methanol, ethanol, isopropanol n-butanol and mixtures thereof) and acetonitrile.
  • a preferred alcoholic solvent is methanol.
  • a preferred decolorizing agent is activated charcoal.
  • a preferred reducing agent is sodium metabisulfite.
  • the obtained crystalline tegaserod hydroiodide has a powder X-ray diffraction pattern as illustrated in Figure 1 and an infrared spectrum as illustrated in Figure 2.
  • Tegaserod hydroiodide can be converted to tegaserod base by contacting tegaserod hydroiodide with an inert solvent and a base.
  • the preferred inert solvent is deionized water.
  • the quantity of the base is an amount necessary to obtain a reaction pH value of approximately 9 to approximately 13.
  • An organic or inorganic base can be used.
  • Preferred organic bases include alkyl amines (e.g., diethylamine or triethylamine), or aryl amines.
  • Preferred inorganic bases include metal alkaline or earth metals (e.g. , KOH or NaOH).
  • the reaction media can be seeded with the desired polymorphic form of tegaserod base.
  • the reaction can be conducted at temperatures in the range of approximately 0° C to 60° C, and for a time of approximately 10 minutes to approximately 6 hours. Preferably, the reaction is conducted at approximately 20-25° C for at least approximately 1 hour, and more preferably the reaction is conducted at approximately 20-25° C for approximately 2 hours.
  • the obtained crystalline tegaserod base has a powder X-ray diffraction pattern as illustrated in Figure 3 and an infrared spectrum as illustrated in Figure 4.
  • the obtained tegaserod base can be used without further purification to prepare tegaserod maleate, or alternatively can be purified by traditional purification techniques.
  • Preferred purification techniques include treatment with a reducing agent, preferably sodium metabisulfite.
  • a preferred additional purification includes treatment with a decolorizing agent.
  • Another preferred further purification includes treatment with acetonitrile, a ketone solvent, an alcoholic solvent or mixtures thereof, preferably methyl isobutyl ketone (MIBK), acetonitrile or methanol.
  • MIBK methyl isobutyl ketone
  • Another aspect of the invention includes the identification of several by-products arising during the synthesis of tegaserod maleate.
  • One such by-product referred to herein as impurity A, is characterized by an HPLC RRT (relative retention time) of approximately 0.58 using HPLC Method 1 described below.
  • Impurity A is very difficult to remove when detected in the final product, tegaserod maleate.
  • another aspect of the invention includes preparation of crystalline tegaserod hydroioide and tegaserod base having less than approximately 0.1 % as area percentage HPLC of impurity A as characterized by an HPLC RRT of approximately 0.58, using HPLC Method 1 described below and the use of the same to prepare tegaserod maleate.
  • Impurity A is characterized by an HPLC RRT of approximately 0.93 using HPLC method 2 described below.
  • impurity B Another by-product identified during the synthesis of tegaserod maleate, referred to herein as impurity B, has the following structure:
  • Impurity B is characterized as having an HPLC RRT of approximately 1.10 and a molecular weight of 403, using the HPLC method 2 described below.
  • Another aspect of the invention includes preparation of tegaserod hydroiodide and tegaserod base having less than 0.1% as area percentage HPLC of impurity B 5 as characterized by an HPLC RRT of approximately 1.10 and a molecular weight of 403 using HPLC method 2 described below, and the use of the same to prepare tegaserod maleate.
  • Another aspect of the invention includes a process for preparing tegaserod maleate by contacting tegaserod base with an inert solvent (e.g., isopropanol, acetone, n-butanol, MDC (methylisobutylketone), iso-butanol, isopropyl acetate, isobutyl acetate, mixtures of isopropyl acetate and isopropanol, mixtures of MIK and methanol, mixtures of isopropanol and water, mixtures of methanol and water and mixtures thereof) and maleic acid.
  • an inert solvent e.g., isopropanol, acetone, n-butanol, MDC (methylisobutylketone), iso-butanol, isopropyl acetate, isobutyl acetate, mixtures of isopropyl acetate and isopropanol, mixtures of MIK and
  • the solution of tegaserod base and the organic solvent can be purified and filtered off, and/or the solution of tegaserod base in the organic solvent can be seeded with the desired polymorphic form of tegaserod maleate.
  • a preferred procedure for purifying tegaserod maleate includes treating tegaserod maleate with a decolorizing agent, preferably activated charcoal, or a reducing agent, preferably sodium metabisulfite.
  • a decolorizing agent preferably activated charcoal, or a reducing agent, preferably sodium metabisulfite.
  • the molar quantity of maleic acid used ranges between approximately 0.9 to approximately 1.5 moles per mole of tegaserod base.
  • the molar quantity of maleic acid is between approximately 1.0 and approximately 1.2 moles per mole of tegaserod base.
  • the addition of maleic acid can be conducted at temperatures in the range of approximately 0° C to approximately 85° C, and for a time of approximately 10 minutes to approximately 3 hours. Preferably, the addition of maleic acid is conducted at approximately 70° C to approximately 80° C for approximately 1 hour.
  • Precipitation of tegaserod maleate can be conducted using a range of temperatures of approximately 0° C to approximately 80° C and for a time of approximately 15 minutes to approximately 24 hours.
  • the precipitation is conducted at approximately 20° C to approximately 25° C for approximately 1 hour and at approximately 0° C to approximately 10° C for approximately 1 hour and 30 minutes.
  • the precipitate is filtered off or isolated from the solution by methods well known to those skilled in the art.
  • the crystalline tegaserod maleate obtained by the above-described processes has less than approximately 0.1% as area percentage HPLC of impurity A as characterized by an HPLC RRT (relative retention time) of approximately 0.58, using HPLC Method 1 described below.
  • the crystalline tegaserod maleate obtained by the above-described processes has less than 0.1% as area percentage HPLC of impurity B characterized by an HPLC RRT of approximately 1.10 and a molecular weight of 403, using the HPLC method 2 described below.
  • Another aspect of the invention includes a powder composition of tegaserod maleate having a defined particle size distribution.
  • the invention further includes crystalline tegaserod maleate obtained by the above-described processes having a particle size distribution wherein approximately 10% of the total volume (D 10 ) is made of particles having a diameter less than approximately 3 ⁇ m, approximately 50% of the total volume (D 50 ) is made of particles having a diameter less than approximately 10 ⁇ m, and approximately 90% of the total volume (Dg 0 ) is made of particles having a diameter less than approximately 20 ⁇ m, and the use of tegaserod maleate having this particle size distribution in powdered compositions and various dosage units (e.g., pill, capsule and tablet formulations).
  • various dosage units e.g., pill, capsule and tablet formulations
  • the crystalline tegaserod maleate obtained by the above-described processes has a surface area of approximately 5 to approximately 20 m 2 /g. More preferably, the tegaserod maleate has a surface area of approximately 8 to approximately 13 m 2 /g.
  • the invention further includes formulations containing crystalline tegaserod maleate having these sizes.
  • the invention further includes a process for preparing a 3-(5-methoxy ⁇ lH-indol-3- ylmethylene)-N-pentylcarbazimidamide hydroiodide salt.
  • Another aspect of the invention includes a process for preparing 3-(5-methoxy-lH- indol-3-ylmethylene)-N-pentylcarbazimidamide hydroiodide salt, which optionally includes using an organic acid to adjust the pH of the reaction mixture.
  • Another aspect of the invention includes a process for preparing tegaserod free base from tegaserod hydroiodide.
  • Another aspect of the invention includes a process for preparing tegaserod maleate, which includes isolating tegaserod hydroiodide, neutralizing tegaserod hydroiodide to yield tegaserod free base and converting the tegaserod free base to its maleate salt.
  • Another aspect of the invention includes a process for preparing tegaserod maleate, which includes isolating tegaserod hydroiodide, neutralizing tegaserod hydroiodide to yield tegaserod free base and converting the tegaserod free base to its maleate salt in isopropanol.
  • Another aspect of the invention includes the crystalline product tegaserod hydroiodide.
  • Another aspect of the invention includes the crystalline product tegaserod hydroiodide of high purity.
  • Another aspect of the invention includes the crystalline product tegaserod hydroiodide having a purity higher than 98% when analyzed by reverse phase high performance liquid chromatography (HPLC).
  • Another aspect of the invention includes the crystalline product tegaserod hydroiodide having a purity higher than 99% when analyzed by reverse phase HPLC.
  • Another aspect of the invention includes the crystalline product tegaserod hydroiodide having a purity higher than 99.5% when analyzed by reverse phase HPLC.
  • Another aspect of the invention includes the crystalline tegaserod hydroiodide having an X-ray diffraction pattern substantially similar to that of Figure 1.
  • Another aspect of the invention includes the solid form of tegaserod hydroiodide having an X-ray diffraction pattern showing characteristics peaks at 5.10, 5.24, 13.96, 18.21, 18.54, 20.90, 21.68, 22.98, 24.40, 26.12, 28.68 and 32.23 degrees two theta.
  • Another aspect of the invention includes the solid form of tegaserod hydroiodide having an infrared spectrum substantially similar to that of Figure 2.
  • Another aspect of the invention includes purifying isolated tegaserod hydroiodide by using organic solvents.
  • Another aspect of the invention includes using the crystalline form of tegaserod hydroiodide for the manufacture of tegaserod maleate.
  • Another aspect of the invention includes using tegaserod hydroiodide of high purity for the manufacture of tegaserod maleate.
  • Another aspect of the invention includes a process for neutralizing tegaserod hydroiodide to tegaserod base, which includes treating tegaserod hydroiodide with an organic or inorganic base and filtering the resulting solid.
  • Another aspect of the invention includes a process for neutralizing tegaserod hydroiodide to tegaserod base, which includes treating a suspension of tegaserod hydroiodide in a mixture of water and organic solvent with an organic or inorganic base and filtering the resulting solid.
  • Another aspect of the invention includes the solid form of tegaserod base that has an X-ray diffraction pattern substantially similar to that of Figure 3.
  • Another aspect of the invention includes the solid form of tegaserod base having an
  • Another aspect of the invention includes the solid form of tegaserod base that has an infrared spectrum substantially similar to that of Figure 4.
  • Another aspect of the invention includes purifying tegaserod free base by decolorizing a dissolution of tegaserod free base in an organic solvent.
  • Another aspect of the invention includes purifying tegaserod free base by treating tegaserod free base with sodium metabisulfite.
  • Another aspect of the invention includes tegaserod base of high purity.
  • Another aspect of the invention includes tegaserod base having a purity higher than 98% when analyzed by reverse phase HPLC.
  • Another aspect of the invention includes tegaserod base having a purity higher than 99% when analyzed by reverse phase HPLC.
  • Another aspect of the invention includes tegaserod base having a purity higher than
  • Another aspect of the invention includes using tegaserod base for manufacturing tegaserod maleate.
  • Another aspect of the invention includes using tegaserod base of high purity for manufacturing tegaserod maleate.
  • Another aspect of the invention includes using N-pentyl-N'-aminoguanidine hydroiodide having a purity of higher than 95% when analyzed by reverse phase high performance liquid chromatography for manufacturing tegaserod base.
  • Another aspect of the invention includes using N-pentyl-N'-aminoguanidine hydroiodide having a purity of higher than 95% when analyzed by reverse phase high performance liquid chromatography for manufacturing tegaserod maleate.
  • 5-methoxyindole-3-carbaldehyde can be additionally treated with an organic solvent (e.g., acetonitrile) or ketone solvents (e.g., MEK, MIBK or acetone).
  • organic solvent e.g., acetonitrile
  • ketone solvents e.g., MEK, MIBK or acetone
  • N-pentyl-N'-aminoguanidine hydroiodide can be removed by treatment with ethyl acetate.
  • the filtrate obtained can be used for the reaction. Solids were dried at 40° C under vacuum.
  • the stationary phase was silica gel 60 F 254 .
  • the eluant was AcOEt (16) / Toluene (4) / MeOH (5) / H 2 O (2) / HCOOH 85% (1) (v:v). Run to length / total length: 8 cm / 10 cm. Development / Detection: UV 254 and ninhydrin. Sample Preparation and Application: Samples 1% (5 ⁇ L).
  • Chromatographic separation was carried out using a Symmetry C8, 5 ⁇ m, 4.6 x 250 mm LD. column at room temperature ( ⁇ 20-25° C).
  • the chromatograph was equipped with a 238 nm detector, and the flow rate was 1.0 mL per minute.
  • Test samples (20 ⁇ l) were prepared by dissolving the appropriate amount of sample in order to obtain 1 mg per mL of a mixture of mobile phase.
  • Chromatographic separation was carried out using a Atlantis dC18, 5 ⁇ m, 4.6 x 150 mm LD column at 25° C.
  • the mobile phase A was prepared by mixing 200 niL of acetonitrile with 800 mL of 0.02 M OfKH 2 PO 4 buffer prepared from 2.18 g OfKH 2 PO 4 dissolved in 800 mL of water. The pH was adjusted to 5.0 with orthophosphoric acid. The mobile phase was mixed and filtered through 0.22 ⁇ m nylon filter under vacuum.
  • the mobile phase B was acetonitrile.
  • the chromatograph was programmed as follows: Initial: 100% mobile phase A; 0- 25 minutes: linear gradient to 50% mobile phase A; 25-30 minutes: isocratic 50% mobile phase A; 30-40 minutes: linear gradient to 100% mobile phase A; and 40-45 minutes: equilibration with 100% mobile phase A.
  • the chromatograph was equipped with a 238 nm detector, and the flow rate was 1.0 mL per minute.
  • Test samples (20 ⁇ l) were prepared by dissolving the appropriate amount of sample in order to obtain 1 mg per mL in a mixture of acetonitrile and water (6:4).
  • the chromatographic separation was carried out in a Symmetry C8, 5 ⁇ m, 4.6 x 150 mm LD column at 25° C.
  • the mobile phase A was 0.02 M ammonium formate buffer. The pH was adjusted to 2.5 with formic acid. The mobile phase was mixed and filtered through 0.22 ⁇ m nylon filter under vacuum.
  • the mobile phase B was acetonitrile.
  • the chromatograph was programmed in isocratic mode with 30% mobile phase B and 70% mobile phase A.
  • the chromatograph was equipped with a triple quadrupole mass spectrophotometer detector with a ionization source at atmospheric pressure (API) with electrospray interface. The flow rate was 1.0 mL per minute. Test samples (10 ⁇ l) were prepared by dissolving the appropriate amount of sample in order to obtain 10 mg per mL of a mixture of acetonitrile and mobile phase A (3:7). v. Particle Size Method 1
  • the particle size for tegaserod maleate was measured using a Malvern Mastersizer S particle size analyzer with an MSl Small Volume Recirculating unit attached. A 300RF mm lens and a beam length of 2.4 mm were used. Samples for analysis were prepared by dispersing a weighed amount of tegaserod maleate (approximately 0.4 g) in 20 mL of paraffin oil/n-butylacetate (50:50). The suspension was sonicated for 2 minutes and delivered drop- wise to a background corrected measuring cell previously filled with paraffin oil/n-butyl acetate (50:50) until the obscuration reached the desired level. Volume distributions were obtained for three times.
  • the sample cell was emptied and cleaned, refilled with suspending medium, and the sampling procedure repeated again.
  • the values of D 10 , D 5 o and Dg 0 were specifically listed, each one being the mean of the six values available for each characterization parameter.
  • the BET (Brunauer, Emmett and Teller) specific surface area for tegaserod maleate was measured using a Micromeritics ASAP2010 equipment. Samples for analysis were degassed at 150° C under vacuum for an hour. The determination of the adsorption of N 2 at 77° K was measured for relative pressures in the range of 0.06-0.2 for a weighed amount of tegaserod maleate (i.e., approximately 0.3 g).
  • the pH of the resulting suspension was adjusted to 2.5 - 3.5 (actual value 2.95) with glacial acetic acid (7 mL, 1.43 molar equivalents of acid) added at 20-25° C.
  • the suspension was then heated to reflux and maintained at this temperature for 24 minutes.
  • the resulting yellow suspension was then cooled.
  • the reaction mixture was monitored by TLC analysis and stirred for an additional 30 minutes at 20-25° C.
  • the solution was then filtered to yield 29.03 g of wet tegaserod hydroiodide (28.16 g of dry product; Yield: 76.62 %).
  • the resulting suspension was heated to reflux and maintained at this temperature for 40 minutes.
  • the reaction mixture was monitored by TLC.
  • the resulting yellow suspension was cooled, stirred for 1 hour at 20-25° C and filtered to yield 18.46 g of wet tegaserod hydroiodide (18.45 g of dry product; Yield: 50.19 %).
  • the pH of the resulting suspension was adjusted to 2.5 - 3.5 (actual value 2.98) with glacial acetic acid (13.6 mL, 4.16 molar equivalents of acid) at 20-25° C.
  • the suspension was heated to reflux and maintained at this temperature for 1 hour.
  • the resulting thick yellow suspension obtained was cooled.
  • the reaction mixture was monitored by TLC, stirred for approximately 1 hour at 20-25° C and filtered to yield 21.35 g of wet tegaserod hydroiodide (20.43 g of dry product; Yield: 83.40 %).
  • the pH of the resulting suspension was adjusted to 2.5 - 3.5 (actual value 3.10) with glacial acetic acid (14 mL, 4.28 molar equivalents of acid) at 20-25° C.
  • the suspension was heated to reflux and maintained at this temperature for 1 hour to yield a solution.
  • the solution was cooled to 20-25° C and a precipitation begins at approximately 61° C.
  • the reaction mixture was monitored by TLC. After stirring for approximately 1 hour at 20-25° C, the solid was filtered to yield 20.05 g of wet tegaserod hydroiodide (17.46 g of dry product; Yield: 71.25 %).
  • Example 5 Preparation of "(21 ⁇ -2- [(5-methoxy-l//-indol-3-yl)methylene] -iV- pentylhydrazinecarboximidamide hydroiodide" (tegaserod hydroiodide) To a 250 mL flask were charged 10.00 g of 5-methoxy-lH " -indole-3-carbaldehyde
  • the pH of the resulting suspension was adjusted to 2.5 — 3.5 (actual value 3.04) with glacial acetic acid (6.4 mL, 1.96 molar equivalents of acid) at 20-25° C.
  • the suspension was heated to reflux and maintained at this temperature for 1 hour to yield an orange suspension with foam.
  • the orange suspension obtained was cooled.
  • the reaction mixture was monitored by TLC, stirred for approximately 1 hour at 20-25° C and filtered to yield 28.55 g of wet tegaserod hydroiodide.
  • the pH of the resulting suspension was adjusted to 2.5 — 3.5 with glacial acetic acid (12 mL, 3.67 molar equivalents of acid) at 20-25° C.
  • the resulting thick suspension was heated to reflux and maintained at this temperature for 1 hour.
  • the orange suspension obtained was cooled.
  • the reaction mixture is monitored by TLC, stirred for approximately 1 hour at 20-25° C and filtered to yield 23.50 g of wet tegaserod hydroiodide (23.10 g of dry product; Yield: 94.29%).
  • the pH of the resulting suspension was adjusted to 3.0-3.5 (actual value 3.38) with glacial acetic acid (50 mL, 3.83 molar equivalents of acid) at 20-25° C.
  • the suspension was heated to reflux and maintained at this temperature for 1 hour.
  • the orange suspension obtained was cooled, stirred for approximately 1 hour at 20-25° C and filtered to yield 118.63 g of wet tegaserod hydroiodide (93.36 g of dry product, according to loss on drying data; Yield: 95.25%).
  • the pH of the resulting suspension was adjusted to 3.0-3.5 (actual value 3.45) with 80% aqueous acetic acid (15 mL, 1.22 molar equivalents of acid) at 20-25° C.
  • the suspension was heated to reflux and maintained at this temperature for 1 hour.
  • the orange suspension obtained was cooled, stirred for approximately 1 hour at 20-25° C and filtered to yield 94.01 g of wet tegaserod hydroiodide (70.57 g of dry product, according to loss on drying data; Yield: 96.01%).
  • the pH of the resulting suspension was adjusted to 9-10 (actual value 9.54) with potassium hydroxide (KOH) (0.882 g, 1.35 molar equivalents).
  • KOH potassium hydroxide
  • the suspension was stirred at 20-25° C for 30 minutes.
  • the resulting solid was filtered and washed twice with 5 mL of water to yield 9.8 g of wet solid.
  • the pH of the resulting suspension was adjusted to 12-13 (actual value 12.99) with 30% aqueous sodium hydroxide (4 mL). The suspension was stirred at 20-25° C for 30 minutes. The resulting solid was filtered and washed twice with 10 mL of water to yield 6.30 g of wet solid (3.55 g of dry product, according to loss on drying data, partial yield: 101.14%, HPLC Method 1 (area %): 97.20 %).
  • the pH of the resulting suspension was adjusted to 12-13 (actual value 12.80) with 50% aqueous sodium hydroxide (15 mL). The suspension is stirred at 20-25° C for 1 hour. The resulting solid was filtered and washed twice with 25 mL of water to yield 36.18 g of wet solid (17.74 g of dry product, according to loss on drying data, partial yield: 93.57, HPLC Method 1 (area %): 98.34%).
  • the pH of the resulting suspension was adjusted to 11-11.5 (actual value 11.30) with 30 mL sodium hydroxide (50% aqueous solution). The suspension was then stirred at 20-25° C for 2 hours, and the pH was adjusted as necessary with sodium hydroxide (15 mL). The solution was filtered, and the solid was washed twice with 100 mL of water to yield 187.55 g of wet solid (91.37 g of dry product, according to loss on drying data, partial yield: 81.02%, HPLC Method 1 (area %): 95.74%).
  • the pH of the resulting suspension was adjusted to 11-11.5 (actual value 11.48) with diethylamine (2.1 mL). The suspension was stirred at 20-25° C for 2 hours, and the pH was adjusted if necessary (7.8 mL more of diethylamine were added). The resulting solid was filtered and washed twice with 20 mL of water to yield 24.82 g of wet solid (11.10 g of dry product, according to loss on drying data, partial yield: 105.53 %, HPLC Method 1 (area %): 95.74 %).
  • the pH of the resulting suspension was adjusted to 3-3.5 (actual value 2.98) with glacial acetic acid (17 mL, 0.65 molar equivalents) at 20-25° C.
  • the suspension was heated to reflux and maintained at this temperature for 1 hour.
  • the thick yellow suspension obtained was cooled.
  • the reaction mixture was monitored by TLC, stirred for approximately 1 hour at 20- 25° C and filtered to yield 233.14 g of wet tegaserod hydroiodide (174.08 g of dry product, according to loss on drying data, partial yield: 88.28%, HPLC Method 1 (area %): 98.46%).
  • the pH of the resulting suspension was adjusted to 11-11.5 (actual value 11.12) with diethylamine (74.6 mL).
  • the suspension was stirred at 20-25° C for 2 hours, and the pH was adjusted as needed with diethylamine (54.7 mL).
  • the suspension was filtered and washed twice with 174 mL of water to yield 172.39 g of wet solid (119.67 g of dry product, according to loss on drying data, partial yield: 97.91%, HPLC Method 1 (area %): 96.28 %).
  • the pH of the resulting suspension was adjusted to 3—3.5 (actual value 3.35) with glacial acetic acid (25 mL, 2.55 molar equivalents of acid), which was added at 20-25° C.
  • the suspension was then heated to reflux and maintained at this temperature for 1 hour.
  • the resulting thick yellow suspension was then cooled, and the reaction mixture was monitored by TLC analysis and stirred for an additional 1 hour at 20-25° C.
  • the pH of the resulting suspension was adjusted to 3-3.5 (actual value 3.31) with glacial acetic acid (40 mL) added at 20-25° C. The suspension was then heated to reflux and maintained at this temperature for 1 hour. The resulting yellow suspension was then cooled, and the reaction mixture was monitored by TLC and stirred for an additional hour at 20-25° C. The suspension was then filtered and washed with 50 mL of ethyl acetate to yield 144.57 g of wet crude tegaserod hydroiodide (109.95 g of dry product, according to loss on drying data, partial yield: 89.74%, HPLC Method 1 (area %): main product: 98.98 %, impurity A: 0.11%).
  • the quality of the N-pentyl-N'-aminoguanidine hydroiodide used to produce tegaserod hydroiodide has an important effect on the yield of the reaction.
  • the N-pentyl-N'-aminoguanidine hydroiodide i.e., N- pentylhydrazinecarboximidamide hydroiodide
  • the N-pentyl-N'- aminoguanidine hydroiodide i.e., N-pentylhydrazine carboximidamide hydroiodide
  • HPLC purity area % of about 91% when analyzed by HPLC Method 1 ("Quality 2").
  • Quantality 2 the only difference between this example and Example 1 is the quality of the N-pentyl-N'- aminoguanidine hydroiodide used.
  • N-pentylhydrazinecarboximidamide hydroiodide Quality 2 i.e., N-pentyl-N'-aminoguanidine hydroiodide Quality 2 (24.49 g, 0.090 moles, 1.050 molar equivalents) dissolved in 50 mL of ethyl acetate over 5-10 minutes to yield an orange suspension having a pH of 7.10.
  • the pH of the resulting suspension was adjusted to 2.5 - 3.5 (actual value 3.04) with glacial acetic acid (11 mL, 2.24 molar equivalents of acid) added at 20-25° C.
  • the suspension was then heated to reflux and maintained at this temperature for 2 hours.
  • the resulting yellow suspension was then cooled.
  • the reaction mixture is monitored by TLC and stirred for 20 minutes at 20-25° C.
  • the solution was then filtered to yield 13.58 g of wet tegaserod hydroiodide (13.55 g of dry product; Yield: 36.86%).
  • the reaction mixture was cooled at 5° C, and the pH of the resulting suspension is adjusted to 3 (actual value 3.06) with a mixture of MeOH/HCl (2 mL of a solution 0.85 N, 0.134 molar equivalents of acid were needed). The suspension was maintained at 3-5° C for 2 hours during which it became more fluid with stirring and became an orange solution. The reaction mixture was then evaporated to dryness to yield 6.16 g of a brown-orange powder (HPLC Method 1 (area %): 95.37%).
  • the pH of the resulting suspension was adjusted to 3 — 3.5 (actual value 3.33) with glacial acetic acid at 20-25° C (9 mL, 1.16 molar equivalents of acid were needed). The suspension was then heated to reflux and maintained at this temperature for 1 hour. Next, 474 mL of methanol was added to the reaction mixture and the fluid suspension obtained was stirred at 20-25 ° C for about 24 hours. During mixing, the reaction mixture was monitored by TLC. The resulting green-yellow suspension was filtered to yield 55.93 g of wet impurity B hydrochloride (41.43 g, according to loss on drying data, partial yield: 69.57%, HPLC Method 1 (area %): 99.473%).
  • the obtained wet solid and 469.02 mL of deionised water were combined to yield a thick, crude suspension having a pH of 3.89.
  • the pH of the resulting suspension was then adjusted to 11.5-12 (actual value 11.62) with diethylamine (44.04 mL are needed), and the suspension was stirred at 20-25° C for 2 hours (the pH was adjusted as needed with 11.01 mL more of diethylamine).
  • the suspension was then filtered and the obtained solid was washed twice with 55.05 mL of water to yield 19.96 g of wet solid (36.30 g of dry product, according to loss on drying data, partial yield: 95.53%, HPLC Method 1 (area %): 99.76%).
  • the resulting solid was combined with 413.97 mL of water. The suspension was then heated at 40-50° C, stirred at this temperature for 30 minutes. Next, the suspension was filtered and the resulting solid was washed twice with 55.05 mL of water to yield 109.68 g of wet Impurity B base (34.61 g of dry product, according to loss on drying data, partial yield 95.34%, HPLC Method 1: 99.73 area %).
  • the obtained wet solid and 277 niL of isopropanol were combined in a 500 niL flask. The suspension was then heated at reflux temperature, stirred at this temperature for 10 minutes, and cooled at 75° C. To the resulting suspension, a solution of 10.48 g of maleic acid and 73.31 mL of isopropanol was added over about 15-30 minutes while maintaining the temperature at 70-80° C. Once the addition was completed, the reaction mixture was allowed to cool to 20-25° C over about 1 hour. The obtained suspension was then stirred at 20-25° C for 1 hour, at 0-10° C for an additional one and a half hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé de production de maléate de tégaserod qui inclut l'isolement d'iodhydrate de tégaserod à titre d'intermédiaire. En particulier, l'invention concerne un procédé amélioré permettant de préparer le maléate de 3-(5-méthoxy-lH-indol-3-ylméthylène)-N-pentylcarbazimidamide hydrogéné (c'est-à-dire le maléate de tégaserod). Ce procédé consiste à faire réagir de l'iodhydrate de 5-méthoxyindole-3-carbaldéhyde avec de l'iodhydrate de N-pentyl-N'-aminoguanidine et à isoler l'iodhydrate de 3-(5-méthoxy-lH-indol-3-ylméthylène)-N-pentylcarbazimidamide solide (c'est-à-dire l'iodhydrate de tégaserod).
PCT/IB2006/004222 2005-10-06 2006-10-05 Compositions et procédés utiles pour la préparation de maléate de tégaserod WO2007119109A2 (fr)

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US60/723,962 2005-10-06
US72528205P 2005-10-12 2005-10-12
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010015794A1 (fr) * 2008-08-07 2010-02-11 Generics [Uk] Limited Nouvelles formes polymorphes

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005014544A1 (fr) * 2003-07-24 2005-02-17 Novartis Ag Modifications stables du maleate d'hydrogene tegaserod
WO2006116953A1 (fr) * 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005014544A1 (fr) * 2003-07-24 2005-02-17 Novartis Ag Modifications stables du maleate d'hydrogene tegaserod
WO2006116953A1 (fr) * 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010015794A1 (fr) * 2008-08-07 2010-02-11 Generics [Uk] Limited Nouvelles formes polymorphes

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