WO2009072139A1 - Process for producing 2-[1-methyl-5-(4-methylbenzoyl)- pyrrol-2- yl]acetic acid or salt thereof - Google Patents

Process for producing 2-[1-methyl-5-(4-methylbenzoyl)- pyrrol-2- yl]acetic acid or salt thereof Download PDF

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WO2009072139A1
WO2009072139A1 PCT/IN2008/000231 IN2008000231W WO2009072139A1 WO 2009072139 A1 WO2009072139 A1 WO 2009072139A1 IN 2008000231 W IN2008000231 W IN 2008000231W WO 2009072139 A1 WO2009072139 A1 WO 2009072139A1
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methyl
methylbenzoyl
acetic acid
process according
pyrrol
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PCT/IN2008/000231
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French (fr)
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WO2009072139A8 (en
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Nageswara Rao Karusala
Bhausaheb Chavhan
Jebaraj Rathinapandian
Muneendra Kumar Veeranki
Purna Chandra Ray
Om Dutt Tyagi
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Matrix Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • This invention in general relates to the field of 2-[l-methyl-5-(4- methylbenzoyl)pyrrol-2-yl]acetic acid. More particularly the present invention provides a novel process for producing 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2- yljacetic acid or salt thereof.
  • Tolmetin 2-[l-Methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid (Tolmetin) or salt thereof (Tolmetin Sodium) is effectively used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, treatment of acute flares and the long-term management of the chronic disease as well as in the treatment of juvenile rheumatoid arthritis.
  • Tolmetin as a product and its process is first disclosed in US Patent No.
  • the disclosed process comprises the reaction of N- methylpyrroleacetonitrile with p-methyl benzoylchloride in the presence of anhydrous aluminium chloride in carbon disulfide solvent yielded l-methyl-5-(p-toluoyl)pyrrole- 2-acetonitrile, which on hydrolysis with sodium hydroxide in a mixture of ethanol and water leads to the formation of sodium salt of Tolmetin.
  • US Patent No. 3,846,447 ('447) reveals the process wherein, the treatment of l-methylpyrrole-2-acetonitrile with phosgene in ether to afford 5-chlorcarbonyl-l- methylpyrrole-2-acetonitrile, which is further, hydrolyzed and esterified to yield ethyl-5-chlorocarbonyl-l-methylpyrrolacetate.
  • the ethyl-5-chlorocarbonyl-l- methylpyrrolacetate further undergoes Grignard reaction with p- toluylmagnesiumbromide at -60 0 C in dry toluene, followed by acid base treatment lead to a product.
  • This final product is purified through column chromatography, crystallized in methanol to afford pure ethyl- l-methyl-5-(p-toluoyl) pyrroleacetate, which is further, subjected to hydrolysis in aqueous ethanolic sodium hydroxide solution to afford Tolmetin sodium.
  • a novel process for producing tolmetin or its pharmaceutically acceptable salts thereof employing toluoyl morpholide as an intermediate in a way to improve the yield and purity and obviate the formation of byproducts.
  • a novel process for producing tolmetin or its pharmaceutically acceptable salts thereof wherein the intermediate toluoyl morpholide is condensed with methyl ester of l-methylpyrrole-2-acetic acid in the presence of halogenating agent followed by basic hydrolysis.
  • tolmetin or its pharmaceutically acceptable salts thereof comprises the condensation of an intermediate toluoyl morpholide with methyl ester of l-methylpyrrole-2-acetic acid in the presence of halogenating agent and then treated with acid to get tolmetin free base which is further treated with base to get tolmetin sodium.
  • tolmetin which is further converted to its salt by conventional method.
  • the process comprises the condensation of toluoyl morpholide with methyl ester of l-methylpyrrole-2-acetic acid in presence of halogenating agent followed by acid hydrolysis.
  • a novel process for producing methyl 5-(4-methylbenzoyl)-l- methylpyrrole-2-acetate used in the production of tolmetin or its pharmaceutically acceptable salts thereof comprises the condensation of toluoyl morpholide with methyl ester of l-methylpyrrole-2-acetic acid in presence of halogenating agent.
  • the process for producing tolmetin or its pharmaceutically acceptable salts thereof is provided and crystalline tolmetin sodium Form I and Form II characterized by powder X-ray diffraction, differential scanning calorimetry (DSC) and thermo gravemetric analysis (TGA).
  • DSC differential scanning calorimetry
  • TGA thermo gravemetric analysis
  • a crystalline tolmetin characterized by powder X-ray diffraction, differential scanning calorimetry (DSC) and thermo gravemetric analysis (TGA).
  • a crystalline methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate characterized by powder X-ray diffraction, differential scanning calorimetry (DSC) and thermo gravemetric analysis (TGA).
  • the process for producing methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2- acetate used in the production of tolmetin or its pharmaceutically acceptable salts thereof is provided and the crystalline methyl 5-(4-methylbenzoyl)-l-methylpyrrole- 2-acetate is characterized by powder X-ray diffraction, differential scanning calorimetry (DSC) and thermo gravemetric analysis (TGA).
  • the present invention provides a process for producing 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid or salt thereof, wherein the process comprises:
  • the present invention provides a process for producing 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid or salt thereof, wherein the process comprises:
  • the presenst invention provides a process for producing methyl 5-(4-methylbenzoyl)-l -methylpyrrole-2-acetate used for production of 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid or salt thereof wherein the process comprises:
  • [l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid obtained by the process of the present invention, wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 4.13, 8.29, 11.39, 11 ⁇ 91, 12.46, 12.77, 15.36, 16.67, 18.33, 18.50, 19.81, 20.15, 21.33, 22.06, 22.52, 22.96, 23.51, 24.93, 25.14, 25.71, 26.25, 27.83, 28.08, 28.92, 29.33, 31.11, 31.81, 32.33, 33.54, 34.13, 34.64, 35.3, 37.2, 37.62, 38.86 and 39.81 + 0.2 2 ⁇ values.
  • the invention provides a crystalline Form I of sodium salt of 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid obtained by the process of the present invention, wherein said form is characterized by having IR absorption bands at 3512, 3106, 2295, 1676, 1597, 1488, 1453, 1414, 1370, 1342, 1306, 1279, 1229, 1191, 1179, 1152, 1133, 1043, 979, 889, 835, 789, 749, 728, 705, 647 and 485 cm '1 .
  • the invention provides a further process of heating the crystalline Form I of sodium salt of 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2- yl] acetic acid or salt thereof to produce crystalline Form II of said compound.
  • the invention also provides a crystalline Form II of sodium salt of 2-[l- methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid obtained by the process of the present invention, wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 4.09, 5.40, 9.21, 10.86, 12.20, 15.35, 16.08, 16.45, 18.77, 21.51, 22.83, 23.53, 24.19, 26.44, 26.99, 27.53, 28.11, 29.66, 29.93, 31.99, 33.55, 34.40, 37.30, 38.26, 39.47, 42.16 and 45.81 ⁇ 0.2 2 ⁇ values.
  • a crystalline Form II of sodium salt of 2-[l-methyl-5-(4-methylbenzoyl)-pyrrol-2-yl] acetic acid wherein said form is characterized by having IR absorption bands at 3478, 3029, 2921, 1623, 1607, 1586, 1508, 1490, 1454, 1406, 1374, 1343, 1307, 1271, 1222, 1179, 1151, 1133, 1043, 980,
  • a crystalline form of 2-[l-methyl-5-(4-methylbenzoyl)pyrrol- 2-yl] acetic acid wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 3.58, 4.57, 5.84, 7.19, 8.56, 9.16, 9.85, 10.80, 11.77, 13.81, 14.30, 15.19, 15.67, 17.08, 17.51, 18.48, 19.81, 21.13, 21.34, 21.67, 22.53, 23.97, 25.34, 26.18, 27.14, 28.05, 28.84, 30.61, 34.46, 35.75, 38.09 and 40.47 ⁇ 0.2 2 ⁇ values.
  • 2-[l-methyl-5-(4-methylbenzoyl)pyrrol- 2-yl] acetic acid wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 3.58, 4.57, 5.84, 7.19, 8.56, 9.16, 9.85, 10.80, 11.77, 13.
  • (4-methylbenzoyl)pyrrol-2-yl]acetic acid wherein said form is characterized by having IR absorption bands at 3217, 3029, 2958, 2920, 2737, 2633, 1732, 1701, 1617, 1568, 1486, 1459, 1427, 1406, 1374, 1267, 1237, 1195, 1177, 1154, 1045, 977, 931, 886, 831, 780, 746, 719, 676, 661, 566, 536 and 482 cm "1 .
  • the invention also provides for a crystalline Methyl 5-(p-methylbenzoyl)-l- methylpyrrole-2-acetate, wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 5.42, 10.13, 10.90, 13.88, 16.41, 17.17, 18.02, 18.54, 20.39, 20.98, 21.95, 22.71, 23.20, 23.59, 24.02, 25.11, 26.47, 27.25, 28.01, 28.19, 29.77, 30.47, 30.82, 31.66, 32.655, 33.45, 34.35, 35.19, 36.27, 37.60, 38.17, 38.95, 39.94, 40.45, 41.52, 42.86, 44.59 and 45.70 ⁇ 0.2 2 ⁇ values.
  • the invention provides a crystalline methyl 5-(p- methylbenzoyl)-l-methylpyrrole-2-acetate, wherein said form is characterized by having IR absorption bands at 3444, 3030, 3001, 2954, 2923, 2851, 1925, 1723, 1624,
  • Fig. 1 shows a characteristic X-ray powder diffraction pattern for crystalline tolmetin methyl ester.
  • Fig. 2 shows a characteristic infrared absorption spectrum of crystalline tolmetin methyl ester in potassium bromide. [Vertical axis: Transmission (5); horizontal axis: wave number (cm "1 )].
  • Fig. 3 gives thermo gravimetric analysis of crystalline tolmetin methyl ester.
  • Fig. 4 shows a characteristic X-ray powder diffraction pattern for crystalline tolmetin.
  • Fig. 5 shows a characteristic infrared absorption spectrum of crystalline tolmetin in potassium bromide. [Vertical axis: Transmission (5); horizontal axis: wave number (cm "1 )].
  • Fig. 6 gives thermo gravimetric analysis of crystalline tolmetin.
  • Fig. 7 shows a characteristic X-ray powder diffraction pattern for crystalline tolmetin sodium Form I.
  • Fig. 8 shows a characteristic infrared absorption spectrum of crystalline tolmetin sodium Form I in potassium bromide. [Vertical axis: Transmission (5); horizontal axis: wave number (cm "1 )]. Fig. 9 gives thermo gravimetric analysis of crystalline tolmetin sodium Form
  • Fig. 10 shows differential scanning calorimetry thermogram of crystalline tolmetine sodium Form I.
  • Fig. 11 shows a characteristic X-ray powder diffraction pattern for crystalline tolmetin sodium Form II.
  • Fig. 12 shows a characteristic infrared absorption spectrum of crystalline tolmetin sodium Form II in potassium bromide. [Vertical axis: Transmission (5); horizontal axis: wave number (cm "1 )].
  • Fig. 13 gives thermo gravimetric analysis of crystalline tolmetin sodium Form II.
  • Fig. 14 shows differential scanning calorimetry thermogram of crystalline tolmetin sodium Form II.
  • the disclosed embodiment of the present invention deals with a process for producing tolmetin or its pharmaceutically acceptable salts thereof by using easily available starting material and suitable reaction conditions.
  • the present invention in its aspect is a new, improved, economical and industrially feasible method for producing tolmetin or its pharmaceutically acceptable salts thereof.
  • the process for the preparation of tolmetin or its pharmaceutically acceptable salts thereof is outlined in scheme 1 and comprises the condensation of toluoyl morpholide (I) with methyl ester of l-methylpyrrole-2-acetic acid (II) in presence of halogenating agent to get methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2- acetate (III).
  • the process for the preparation of tolmetin or its pharmaceutically acceptable salt the 4-methylbenzoyl chloride is first treated with morpholine in presence of base and solvent to get the toluoyl morpholide (I) intermediate as a product.
  • the base used herein is selected from the group consisting of but not limited to sodium carbonate, potassium carbonate, potassium tert-butoxide, triethylamine, trimethylamine, diethyl amine, dimethyl amine preferably triethyl amine.
  • the reaction is carried out in a solvent selected from the group consisting of but not limited to aromatic hydrocarbon such as toluene, benzene, xylene; ester such as ethyl acetate, methyl acetate, preferably toluene.
  • a solvent selected from the group consisting of but not limited to aromatic hydrocarbon such as toluene, benzene, xylene; ester such as ethyl acetate, methyl acetate, preferably toluene.
  • the reaction is carried out at a temperature from O 0 C to 4O 0 C, preferably 25-35 0 C.
  • the intermediate toluoyl morpholide (I) is then condensed with methyl ester of l-methylpyrrole-2-acetic acid (II) to get crude methyl 5-(4-methylbenzoyl)-l- methylpyrrole-2-acetate (III).
  • the condensation reaction is carried out in presence of halogenating agent and inert atmosphere.
  • the halogenating agent used herein is selected from the group consisting of but not limited to POCl 3 , POBr 3 , preferably POCl 3 .
  • the condensation is carried out with or without solvent, wherein solvent is selected from the group consisting of halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, preferably dichloromethane.
  • the reaction is carried out at a temperature from 10-35 0 C, preferably at 25-3O 0 C for a time period of 10-40 hrs preferably 15-40 hrs.
  • the crude product is then treated with organic solvent selected from the group consisting of methanol, ethanol and isopropyl alcohol, preferably methanol to get the pure compound of formula III.
  • Methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate (III) obtained from the above process is crystalline in nature and well characterized by powder X-ray diffraction pattern as shown in Fig. 1 with peaks at 5.42, 10.13, 10.90, 13.88, 16.41, 17.17, 18.02, 18.54, 20.39, 20.98, 21.95, 22.71, 23.20, 23.59, 24.02, 25.11, 26.47, 27.25, 28.01, 28.19, 29.77, 30.47, 30.82, 31.66, 32.655, 33.45, 34.35, 35.19, 36.27, 37.60, 38.17, 38.95, 39.94, 40.45, 41.52, 42.86, 44.59 and 45.70 ⁇ 0.2 2 ⁇ values.
  • Crystalline methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate (III) is further characterized by IR with absorption bands at 3444, 3030, 3001, 2954, 2923, 2851, 1925, 1723, 1624, 1606, 1486, 1459, 1439, 1405, 1375, 1355, 1331, 1262, 1214, 1182, 1152, 1039, 1002, 973, 885, 834, 763, 745, 722, 686, 622, 577 and 481 cm “1 as depicted in Fig. 2 and by TGA data as shown in Fig. 3.
  • Methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2 -acetate (III) is further converted to tolmetin or its pharmaceutically acceptable salt directly by treating it with base in a solvent to get the tolmetin or its pharmaceutically acceptable salt.
  • the base used herein is selected from the group consisting of hydroxide, carbonate, alkoxide of alkali metal such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium t-butoxide; alkaline earth metal hydroxide such magnesium hydroxide, calcium hydroxide, preferably sodium hydroxide.
  • the solvent used herein is selected from the group consisting of but not limited to alcohol such as methanol, ethanol, isopropyl alcohol, n-propanol; ketone such as acetone, methyl ethyl ketone; water or mixture thereof, preferably ethanol and water mixture.
  • the reaction is carried out at ambient temperature to 4O 0 C.
  • Tolmetin or its pharmaceutically acceptable salt can also be prepared from methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate (III) by first converting it to tolmetin (IV) and then transform it into its salt by conventional methods.
  • methyl 5-(4-methylbenzoyl)-l-rnethylpyrrole-2-acetate (III) is first treated with base in water at ambient temperature and then by acid to get the tolmetin (IV).
  • the base used herein is selected from the group consisting of but not limited to hydroxide, carbonate and alkoxide of alkali metal such as, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium t-butoxide, preferably sodium hydroxide.
  • the acid used herein is selected from the group consisting of but not limited to hydrochloric acid, sulfuric acid, acetic acid, preferably hydrochloric acid.
  • the reaction is carried out at a temperature of 15-4O 0 C, preferably 20-30 0 C.
  • Tolmetin (FV) obtained from the above process is crystalline in nature and well characterized by powder X-ray diffraction pattern as shown in Fig.
  • Crystalline tolmetin is further characterized by IR with absorption bands at
  • the base used herein is selected from the group consisting of hydroxide, carbonate, alkoxide of alkali metal such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium t-butoxide; alkaline earth metal hydroxide such magnesium hydroxide, calcium hydroxide, preferably sodium hydroxide.
  • tolmetin sodium as a product, which is crystalline in nature and designated as Form I.
  • the crystalline Form I is well characterized by its powder X-ray diffraction pattern as shown in Fig.
  • Crystalline tolmetin sodium Form I is further characterized by IR with absorption bands at 3512, 3106, 2295, 1676, 1597, 1488, 1453, 1414, 1370, 1342, 1306, 1279, 1229, 1191, 1179, 1152, 1133, 1043, 979, 889, 835, 789, 749, 728, 705, 647 and 485 cm '1 as depicted in Fig. 8 as well as characterized by differential scanning calorimetry as shown in Fig. 10.
  • the crystalline Form I is having the water content of 10-12.5% which clearly indicated from its TGA data as shown in Fig. 9
  • Tolmetin sodium obtained from above process is when heated further then it is converted into novel crystalline tolmetin sodium Form II.
  • the crystalline tolmetin sodium Form II is well characterized by powder X- ray diffraction pattern as shown in Fig. 11 with peaks at 4.09, 5.40, 9.21, 10.86, 12.20, 15.35, 16.08, 16.45, 18.77, 21.51, 22.83, 23.53, 24.19, 26.44, 26.99, 27.53, 28.11, 29.66, 29.93, 31.99, 33.55, 34.40, 37.30, 38.26, 39.47, 42.16 and 45.81 ⁇ 0.2 2 ⁇ values.
  • Crystalline tolmetin sodium Form II is further characterized by IR with absorption bands at 3478, 3029, 2921, 1623, 1607, 1586, 1508, 1490, 1454, 1406, 1374, 1343, 1307, 1271, 1222, 1179, 1151, 1133, 1043, 980, 915, 886, 834, 742, 723, 688, 591, 549 and 483 cm “1 as depicted in Fig. 12 and by its TGA data as shown in Fig. 13.
  • the crystalline Form II is also characterized by its differential scanning calorimetry as shown in Fig 14.
  • the temperature of the reaction mixture was raised to 40-45°C and maintained. Organic layer was separated and extract aqueous layer twice with dichloromethane. Combine all dichloromethane fractions and washed with water twice (300 ml each). Dichloromethane was distilled out to get the residue, to which methanol (250 ml) was added. The reaction mass as stirred at 0-5°C for 1 hour, filtered and washed with cold methanol to obtain 80-100 g of crystalline methyl 5-(p-methylbenzoyl)-l- methylpyrrole-2-acetate characterized by PXRD as shown in Fig. 1.
  • the tolmetin sodium (25 g) was dissolved in water (250 ml) at 20-25°C.
  • the pH of reaction mixture was adjusted to 1.5 to 4.0 at 20-25°C and then reaction mixture was maintained for 60 minutes at 20-25°C.
  • the solid obtained was filtered and washed with 2 x 50 ml water and dried under vacuum at 45°C for 10-12 hours to obtained 15-20 g crystalline tolmetin characterized by PXRD as shown in Fig. 4.
  • Tolmetin sodium obtained from example 6 was further dried at 60°C for 24 hours.
  • the solid obtained from heating crystalline form I is crystalline form II.

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Abstract

The present invention relates to novel process for the preparation of tolmetin sodium, by employing easily available starting material and suitable reaction conditions. This invention is further related to novel crystalline forms of tolmetin methyl ester, tolmetin and tolmetin sodium and their process for the preparation.

Description

PROCESS FOR PRODUCING 2-[l-METHYL-5-(4-METHYLBENZOYL)- PYRROL-2-YL]ACETIC ACID OR SALT THEREOF
Field of the Invention This invention in general relates to the field of 2-[l-methyl-5-(4- methylbenzoyl)pyrrol-2-yl]acetic acid. More particularly the present invention provides a novel process for producing 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2- yljacetic acid or salt thereof.
Background of the Invention 2-[l-Methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid (Tolmetin) or salt thereof (Tolmetin Sodium) is effectively used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, treatment of acute flares and the long-term management of the chronic disease as well as in the treatment of juvenile rheumatoid arthritis. Tolmetin as a product and its process is first disclosed in US Patent No.
3,752,826. The disclosed process comprises the reaction of N- methylpyrroleacetonitrile with p-methyl benzoylchloride in the presence of anhydrous aluminium chloride in carbon disulfide solvent yielded l-methyl-5-(p-toluoyl)pyrrole- 2-acetonitrile, which on hydrolysis with sodium hydroxide in a mixture of ethanol and water leads to the formation of sodium salt of Tolmetin.
According to the process disclosed in '826, the use of aluminium chloride and carbon disulfide as reagent or solvent at industrial level is very difficult due to hygroscopic nature of the anhydrous aluminium chloride. Whereas, the solvent carbon disulfide employed in Friedel Craft acylation reaction is stored under water to avoid vapor loss and fire hazard because of its low flash point. Hence, it requires much caution to employ carbon disulfide at commercial scale.
US Patent No. 3,846,447 ('447) reveals the process wherein, the treatment of l-methylpyrrole-2-acetonitrile with phosgene in ether to afford 5-chlorcarbonyl-l- methylpyrrole-2-acetonitrile, which is further, hydrolyzed and esterified to yield ethyl-5-chlorocarbonyl-l-methylpyrrolacetate. The ethyl-5-chlorocarbonyl-l- methylpyrrolacetate further undergoes Grignard reaction with p- toluylmagnesiumbromide at -600C in dry toluene, followed by acid base treatment lead to a product. This final product is purified through column chromatography, crystallized in methanol to afford pure ethyl- l-methyl-5-(p-toluoyl) pyrroleacetate, which is further, subjected to hydrolysis in aqueous ethanolic sodium hydroxide solution to afford Tolmetin sodium.
According to the process disclosed in US Patent No. 3,846,447, it employs phosgene and ether at low temperature for conducting the Grignard reaction at industrial scale, wherein, it requires a lot of safety precaution methods to take of the poisonous nature of the phosgene gas and hence increased production cost of the Tolmetin. Moreover, the low flash point of the ether is prone to have fire hazard, therefore, it is very difficult to handle the ether at industrial scale in view of safety requirements. Additionally, the process herein, it requires -600C to perform the Grignard reaction, which is also a limiting parameter in view of industrial scalability.
Therefore, there is a need to develop a economically viable, safe and industrially feasible process for the preparation of Tolmetin or its pharmaceutically acceptable salts thereof. Present invention bridges this gap and reveals novel and industrially feasible process wherein, it eliminates the use of poisonous, fire hazardous, hygroscopic reagents and low flash point solvents for the preparation of the desired Tolmetin or its pharmaceutically acceptable salts thereof.
Object and Summary of the Invention It is, therefore, a principal object of the present invention to provide a novel way for producing 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid or salt thereof overcoming the limitations faced in the prior art. These and other objects are attained in accordance with the present invention wherein there is provided several embodiments of the process for producing tolmetin or its pharmaceutically acceptable salts thereof employing easily available starting material and suitable reaction conditions.
In accordance with one preferred embodiment of the present invention, there is provided a novel process for producing tolmetin or its pharmaceutically acceptable salts thereof employing toluoyl morpholide as an intermediate in a way to improve the yield and purity and obviate the formation of byproducts. In accordance with another preferred embodiment of the present invention, there is provided a novel process for producing tolmetin or its pharmaceutically acceptable salts thereof, wherein the intermediate toluoyl morpholide is condensed with methyl ester of l-methylpyrrole-2-acetic acid in the presence of halogenating agent followed by basic hydrolysis.
In accordance with yet another preferred embodiment of the present invention, there is provided a novel process for producing tolmetin or its pharmaceutically acceptable salts thereof. The process comprises the condensation of an intermediate toluoyl morpholide with methyl ester of l-methylpyrrole-2-acetic acid in the presence of halogenating agent and then treated with acid to get tolmetin free base which is further treated with base to get tolmetin sodium.
In accordance with yet another preferred embodiment of the present invention there is provided a novel process for producing tolmetin which is further converted to its salt by conventional method. The process comprises the condensation of toluoyl morpholide with methyl ester of l-methylpyrrole-2-acetic acid in presence of halogenating agent followed by acid hydrolysis.
In accordance with yet another preferred embodiment of the present invention, there is provided a novel process for producing methyl 5-(4-methylbenzoyl)-l- methylpyrrole-2-acetate used in the production of tolmetin or its pharmaceutically acceptable salts thereof. The process comprises the condensation of toluoyl morpholide with methyl ester of l-methylpyrrole-2-acetic acid in presence of halogenating agent. In yet another preferred embodiment of the present invention, the process for producing tolmetin or its pharmaceutically acceptable salts thereof is provided and crystalline tolmetin sodium Form I and Form II characterized by powder X-ray diffraction, differential scanning calorimetry (DSC) and thermo gravemetric analysis (TGA). In still another preferred embodiment of the present invention, there is provided a crystalline tolmetin characterized by powder X-ray diffraction, differential scanning calorimetry (DSC) and thermo gravemetric analysis (TGA).
In still another preferred embodiment of the present invention, there is provided a crystalline methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate characterized by powder X-ray diffraction, differential scanning calorimetry (DSC) and thermo gravemetric analysis (TGA).
In accordance with still another preferred embodiment of the present invention, the process for producing methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2- acetate used in the production of tolmetin or its pharmaceutically acceptable salts thereof is provided and the crystalline methyl 5-(4-methylbenzoyl)-l-methylpyrrole- 2-acetate is characterized by powder X-ray diffraction, differential scanning calorimetry (DSC) and thermo gravemetric analysis (TGA). In yet another specific embodiment, the present invention provides a process for producing 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid or salt thereof, wherein the process comprises:
(a) condensing toluoyl morpholide with methyl ester of 1-methylpyπτole- 2-acetic acid in presence of halogenating agent to obtain the compound methyl 5-(4-methylbenzoyl)- 1 -methylpyrrole-2-acetate;
(b) hydrolyzing the compound methyl 5-(4-methylbenzoyl)-l- methylpyrrole-2-acetate in the presence of base in a solvent; and
(c) isolating 2-[l-methyl-5-(4-methylbenzoyl)-pyrrol-2-yl] acetic acid or salt thereof. In another specific embodiment, the present invention provides a process for producing 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid or salt thereof, wherein the process comprises:
(a) condensing toluoyl morpholide with methyl ester of 1- methylpyrrrole-2-acetic acid in presence of halogenating agent to obtain the compound methyl 5-(4-methylbenzoyl)-l -methylpyrrole-2-acetate;
(b) treating the compound methyl 5-(4-methylbenzoyl)-l- methylpyrrole-2-acetate with base in water and then with acid to 2-[l-methyl- 5-(4-methylbenzoyl)-pyrrol-2-yl] acetic acid;
(c) isolating the 2-[ 1 -methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid; and
(d) optionally converting the 2-[l-methyl-5-(4- methylbenzoyl)pyrrol-2-yl] acetic acid to its pharmaceutically acceptable salt. In yet another preferred embodiment, the presenst invention provides a process for producing methyl 5-(4-methylbenzoyl)-l -methylpyrrole-2-acetate used for production of 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid or salt thereof wherein the process comprises:
(a) treating morpholine with 4-methylbenzoyl chloride in presence of base and an organic solvent to obtain toluoyl morpholide; (b) isolating the resultant toluoyl morpholide; and
(c) condensing toluoyl morpholide with methyl ester of 1- methylpyrrrole-2-acetic acid in the presence of halogenating agent to obtain methyl 5-(4-methylbenzoyl)- 1 -methylpyrrole-2-acetate. The present invention also provides a crystalline Form I of sodium salt of 2-
[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid obtained by the process of the present invention, wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 4.13, 8.29, 11.39, 11^91, 12.46, 12.77, 15.36, 16.67, 18.33, 18.50, 19.81, 20.15, 21.33, 22.06, 22.52, 22.96, 23.51, 24.93, 25.14, 25.71, 26.25, 27.83, 28.08, 28.92, 29.33, 31.11, 31.81, 32.33, 33.54, 34.13, 34.64, 35.3, 37.2, 37.62, 38.86 and 39.81 + 0.2 2Θ values.
In another embodiment, the invention provides a crystalline Form I of sodium salt of 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid obtained by the process of the present invention, wherein said form is characterized by having IR absorption bands at 3512, 3106, 2295, 1676, 1597, 1488, 1453, 1414, 1370, 1342, 1306, 1279, 1229, 1191, 1179, 1152, 1133, 1043, 979, 889, 835, 789, 749, 728, 705, 647 and 485 cm'1.
In another embodiment, the invention provides a further process of heating the crystalline Form I of sodium salt of 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2- yl] acetic acid or salt thereof to produce crystalline Form II of said compound.
The invention also provides a crystalline Form II of sodium salt of 2-[l- methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid obtained by the process of the present invention, wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 4.09, 5.40, 9.21, 10.86, 12.20, 15.35, 16.08, 16.45, 18.77, 21.51, 22.83, 23.53, 24.19, 26.44, 26.99, 27.53, 28.11, 29.66, 29.93, 31.99, 33.55, 34.40, 37.30, 38.26, 39.47, 42.16 and 45.81 ± 0.2 2Θ values.
In another embodiment, there is provided a crystalline Form II of sodium salt of 2-[l-methyl-5-(4-methylbenzoyl)-pyrrol-2-yl] acetic acid, wherein said form is characterized by having IR absorption bands at 3478, 3029, 2921, 1623, 1607, 1586, 1508, 1490, 1454, 1406, 1374, 1343, 1307, 1271, 1222, 1179, 1151, 1133, 1043, 980,
915, 886, 834, 742, 723, 688, 591, 549 and 483 cm"1.
Also provided is a crystalline form of 2-[l-methyl-5-(4-methylbenzoyl)pyrrol- 2-yl] acetic acid, wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 3.58, 4.57, 5.84, 7.19, 8.56, 9.16, 9.85, 10.80, 11.77, 13.81, 14.30, 15.19, 15.67, 17.08, 17.51, 18.48, 19.81, 21.13, 21.34, 21.67, 22.53, 23.97, 25.34, 26.18, 27.14, 28.05, 28.84, 30.61, 34.46, 35.75, 38.09 and 40.47 ± 0.2 2Θ values. In another embodiment, there is provided a crystalline form of 2-[l-methyl-5-
(4-methylbenzoyl)pyrrol-2-yl]acetic acid, wherein said form is characterized by having IR absorption bands at 3217, 3029, 2958, 2920, 2737, 2633, 1732, 1701, 1617, 1568, 1486, 1459, 1427, 1406, 1374, 1267, 1237, 1195, 1177, 1154, 1045, 977, 931, 886, 831, 780, 746, 719, 676, 661, 566, 536 and 482 cm"1. The invention also provides for a crystalline Methyl 5-(p-methylbenzoyl)-l- methylpyrrole-2-acetate, wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 5.42, 10.13, 10.90, 13.88, 16.41, 17.17, 18.02, 18.54, 20.39, 20.98, 21.95, 22.71, 23.20, 23.59, 24.02, 25.11, 26.47, 27.25, 28.01, 28.19, 29.77, 30.47, 30.82, 31.66, 32.655, 33.45, 34.35, 35.19, 36.27, 37.60, 38.17, 38.95, 39.94, 40.45, 41.52, 42.86, 44.59 and 45.70 ± 0.2 2Θ values.
In another embodiment, the invention provides a crystalline methyl 5-(p- methylbenzoyl)-l-methylpyrrole-2-acetate, wherein said form is characterized by having IR absorption bands at 3444, 3030, 3001, 2954, 2923, 2851, 1925, 1723, 1624,
1606, 1486, 1459, 1439, 1405, 1375, 1355, 1331, 1262, 1214, 1182, 1152, 1039, 1002, 973, 885, 834, 763, 745, 722, 686, 622, 577 and 481 cm"1.
Brief Description of the Drawings
Further object of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:
Fig. 1 shows a characteristic X-ray powder diffraction pattern for crystalline tolmetin methyl ester.
Fig. 2 shows a characteristic infrared absorption spectrum of crystalline tolmetin methyl ester in potassium bromide. [Vertical axis: Transmission (5); horizontal axis: wave number (cm"1)].
Fig. 3 gives thermo gravimetric analysis of crystalline tolmetin methyl ester. Fig. 4 shows a characteristic X-ray powder diffraction pattern for crystalline tolmetin. Fig. 5 shows a characteristic infrared absorption spectrum of crystalline tolmetin in potassium bromide. [Vertical axis: Transmission (5); horizontal axis: wave number (cm"1)].
Fig. 6 gives thermo gravimetric analysis of crystalline tolmetin. Fig. 7 shows a characteristic X-ray powder diffraction pattern for crystalline tolmetin sodium Form I.
Fig. 8 shows a characteristic infrared absorption spectrum of crystalline tolmetin sodium Form I in potassium bromide. [Vertical axis: Transmission (5); horizontal axis: wave number (cm"1)]. Fig. 9 gives thermo gravimetric analysis of crystalline tolmetin sodium Form
I.
Fig. 10 shows differential scanning calorimetry thermogram of crystalline tolmetine sodium Form I.
Fig. 11 shows a characteristic X-ray powder diffraction pattern for crystalline tolmetin sodium Form II.
Fig. 12 shows a characteristic infrared absorption spectrum of crystalline tolmetin sodium Form II in potassium bromide. [Vertical axis: Transmission (5); horizontal axis: wave number (cm"1)].
Fig. 13 gives thermo gravimetric analysis of crystalline tolmetin sodium Form II.
Fig. 14 shows differential scanning calorimetry thermogram of crystalline tolmetin sodium Form II.
Description of the Invention
The disclosed embodiment of the present invention deals with a process for producing tolmetin or its pharmaceutically acceptable salts thereof by using easily available starting material and suitable reaction conditions.
The present invention in its aspect is a new, improved, economical and industrially feasible method for producing tolmetin or its pharmaceutically acceptable salts thereof. The process for the preparation of tolmetin or its pharmaceutically acceptable salts thereof is outlined in scheme 1 and comprises the condensation of toluoyl morpholide (I) with methyl ester of l-methylpyrrole-2-acetic acid (II) in presence of halogenating agent to get methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2- acetate (III). Further methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate (III) either treated with base in a solvent to get the tolmetin or its pharmaceutically acceptable salts thereof or first treated with base in water to get tolmetin which is further converted to its salt by conventional methods.
Figure imgf000009_0001
(IV)
The process for the preparation of tolmetin or its pharmaceutically acceptable salt, the 4-methylbenzoyl chloride is first treated with morpholine in presence of base and solvent to get the toluoyl morpholide (I) intermediate as a product. The base used herein is selected from the group consisting of but not limited to sodium carbonate, potassium carbonate, potassium tert-butoxide, triethylamine, trimethylamine, diethyl amine, dimethyl amine preferably triethyl amine. The reaction is carried out in a solvent selected from the group consisting of but not limited to aromatic hydrocarbon such as toluene, benzene, xylene; ester such as ethyl acetate, methyl acetate, preferably toluene. The reaction is carried out at a temperature from O0C to 4O0C, preferably 25-350C.
The intermediate toluoyl morpholide (I) is then condensed with methyl ester of l-methylpyrrole-2-acetic acid (II) to get crude methyl 5-(4-methylbenzoyl)-l- methylpyrrole-2-acetate (III). In general the condensation reaction is carried out in presence of halogenating agent and inert atmosphere. The halogenating agent used herein is selected from the group consisting of but not limited to POCl3, POBr3, preferably POCl3. The condensation is carried out with or without solvent, wherein solvent is selected from the group consisting of halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, preferably dichloromethane. The reaction is carried out at a temperature from 10-350C, preferably at 25-3O0C for a time period of 10-40 hrs preferably 15-40 hrs. The crude product is then treated with organic solvent selected from the group consisting of methanol, ethanol and isopropyl alcohol, preferably methanol to get the pure compound of formula III.
Methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate (III) obtained from the above process is crystalline in nature and well characterized by powder X-ray diffraction pattern as shown in Fig. 1 with peaks at 5.42, 10.13, 10.90, 13.88, 16.41, 17.17, 18.02, 18.54, 20.39, 20.98, 21.95, 22.71, 23.20, 23.59, 24.02, 25.11, 26.47, 27.25, 28.01, 28.19, 29.77, 30.47, 30.82, 31.66, 32.655, 33.45, 34.35, 35.19, 36.27, 37.60, 38.17, 38.95, 39.94, 40.45, 41.52, 42.86, 44.59 and 45.70 ± 0.2 2Θ values. Crystalline methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate (III) is further characterized by IR with absorption bands at 3444, 3030, 3001, 2954, 2923, 2851, 1925, 1723, 1624, 1606, 1486, 1459, 1439, 1405, 1375, 1355, 1331, 1262, 1214, 1182, 1152, 1039, 1002, 973, 885, 834, 763, 745, 722, 686, 622, 577 and 481 cm"1 as depicted in Fig. 2 and by TGA data as shown in Fig. 3. Methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2 -acetate (III) is further converted to tolmetin or its pharmaceutically acceptable salt directly by treating it with base in a solvent to get the tolmetin or its pharmaceutically acceptable salt. The base used herein is selected from the group consisting of hydroxide, carbonate, alkoxide of alkali metal such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium t-butoxide; alkaline earth metal hydroxide such magnesium hydroxide, calcium hydroxide, preferably sodium hydroxide. The solvent used herein is selected from the group consisting of but not limited to alcohol such as methanol, ethanol, isopropyl alcohol, n-propanol; ketone such as acetone, methyl ethyl ketone; water or mixture thereof, preferably ethanol and water mixture. The reaction is carried out at ambient temperature to 4O0C.
Tolmetin or its pharmaceutically acceptable salt can also be prepared from methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate (III) by first converting it to tolmetin (IV) and then transform it into its salt by conventional methods. In this process methyl 5-(4-methylbenzoyl)-l-rnethylpyrrole-2-acetate (III) is first treated with base in water at ambient temperature and then by acid to get the tolmetin (IV). The base used herein is selected from the group consisting of but not limited to hydroxide, carbonate and alkoxide of alkali metal such as, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium t-butoxide, preferably sodium hydroxide. The acid used herein is selected from the group consisting of but not limited to hydrochloric acid, sulfuric acid, acetic acid, preferably hydrochloric acid. The reaction is carried out at a temperature of 15-4O0C, preferably 20-300C. Tolmetin (FV) obtained from the above process is crystalline in nature and well characterized by powder X-ray diffraction pattern as shown in Fig. 4 with peaks at 3.58, 4.57, 5.84, 7.19, 8.56, 9.16, 9.85, 10.80, 11.77, 13.81, 14.30, 15.19, 15.67, 17.08, 17.51, 18.48, 19.81, 21.13, 21.34, 21.67, 22.53, 23.97, 25.34, 26.18, 27.14, 28.05, 28.84, 30.61, 34.46, 35.75, 38.09 and 40.47 ± 0.2 2Θ values. Crystalline tolmetin is further characterized by IR with absorption bands at
3217, 3029, 2958, 2920, 2737, 2633, 1732, 1701, 1617, 1568, 1486, 1459, 1427, 1406, 1374, 1267, 1237, 1195, 1177, 1154, 1045, 977, 931, 886, 831, 780, 746, 719, 676, 661, 566, 536 and 482 cm"1 as depicted in Fig. 5 and by TGA data as shown in Fig. 6. The tolmetin (IV) obtained is further treated with base to get the tolmetin or its pharmaceutically acceptable salts by conventional methods. The base used herein is selected from the group consisting of hydroxide, carbonate, alkoxide of alkali metal such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium t-butoxide; alkaline earth metal hydroxide such magnesium hydroxide, calcium hydroxide, preferably sodium hydroxide.
The above mentioned process for the preparation of tolmetin or its pharmaceutically acceptable salts is preferably leads to the formation of tolmetin sodium as a product, which is crystalline in nature and designated as Form I. The crystalline Form I is well characterized by its powder X-ray diffraction pattern as shown in Fig. 7 with peaks at 4.13, 8.29, 11.39, 11.91, 12.46, 12.77, 15.36, 16.67, 18.33, 18.50, 19.81, 20.15, 21.33, 22.06, 22.52, 22.96, 23.51, 24.93, 25.14, 25.71, 26.25, 27.83, 28.08, 28.92, 29.33, 31.11, 31.81, 32.33, 33.54, 34.13, 34.64, 35.3, 37.2, 37.62, 38.86 and 39.81 ± 0.2 2Θ values.. Crystalline tolmetin sodium Form I is further characterized by IR with absorption bands at 3512, 3106, 2295, 1676, 1597, 1488, 1453, 1414, 1370, 1342, 1306, 1279, 1229, 1191, 1179, 1152, 1133, 1043, 979, 889, 835, 789, 749, 728, 705, 647 and 485 cm'1 as depicted in Fig. 8 as well as characterized by differential scanning calorimetry as shown in Fig. 10. The crystalline Form I is having the water content of 10-12.5% which clearly indicated from its TGA data as shown in Fig. 9
Tolmetin sodium obtained from above process is when heated further then it is converted into novel crystalline tolmetin sodium Form II.
The crystalline tolmetin sodium Form II is well characterized by powder X- ray diffraction pattern as shown in Fig. 11 with peaks at 4.09, 5.40, 9.21, 10.86, 12.20, 15.35, 16.08, 16.45, 18.77, 21.51, 22.83, 23.53, 24.19, 26.44, 26.99, 27.53, 28.11, 29.66, 29.93, 31.99, 33.55, 34.40, 37.30, 38.26, 39.47, 42.16 and 45.81 ± 0.2 2Θ values.
Crystalline tolmetin sodium Form II is further characterized by IR with absorption bands at 3478, 3029, 2921, 1623, 1607, 1586, 1508, 1490, 1454, 1406, 1374, 1343, 1307, 1271, 1222, 1179, 1151, 1133, 1043, 980, 915, 886, 834, 742, 723, 688, 591, 549 and 483 cm"1 as depicted in Fig. 12 and by its TGA data as shown in Fig. 13. The crystalline Form II is also characterized by its differential scanning calorimetry as shown in Fig 14. Having thus described about various methods for the preparation of tolmetin or its pharmaceutically acceptable salts of the present invention, the following examples are provided to illustrate specific embodiments of the present invention. They are however, not intended to be limiting the scope of present invention in any way: Example-1
Preparation of Toluoyl morpholide
In a mixture of toluene (800 ml) and morpholine (67.6 g), triethyl amine (78.4 g) was added at temperature 0-5°C. To this reaction mixture toluoyl chloride (100 g) was added. The temperature of the reaction mixture was raised to 25-350C and maintained till reaction completes. Triethyl amine hydrochloride salt was filtered and washed with toluene (200 ml). Combined toluene layer was washed with acidic water. The toluene layer was distilled out to get the residue which on crystallization in n-hexane (600ml) gave 100-130 gram of title compound. Example -2 Preparation of Methyl 5-(p-methylbenzoyl)-l-metliylpyrrole-2-acetate
In a flask containing the toluoyl morpholide (147.4 g), phosphorous oxychloride (243.6 g) was added at a temperature 15-25°C in an inert atmosphere. The temperature of the reaction mixture was raised to 25-30°C and maintained till complete formation of complex. After the formation of complex, pyrrole acetate (100 g) was added to the reaction mixture and stirred. At the completion of the reaction, dichloromethane (800 ml) was added to reaction mixture and followed by transferring it to pre-cooled sodium hydroxide solution (200 g NaOH in 1200 ml water). The pH of reaction mass was adjusted to 5.5- 6.5 with sodium hydroxide solution. The temperature of the reaction mixture was raised to 40-45°C and maintained. Organic layer was separated and extract aqueous layer twice with dichloromethane. Combine all dichloromethane fractions and washed with water twice (300 ml each). Dichloromethane was distilled out to get the residue, to which methanol (250 ml) was added. The reaction mass as stirred at 0-5°C for 1 hour, filtered and washed with cold methanol to obtain 80-100 g of crystalline methyl 5-(p-methylbenzoyl)-l- methylpyrrole-2-acetate characterized by PXRD as shown in Fig. 1.
Example -3 Preparation of Methyl 5-(p-methylbenzoyl)-l-methylpyrrole-2-acetate
In a flask containing the toluoyl morpholide (29.47 g), phosphorous oxychloride (48.72 g) was added at a temperature 10-15°C in inert atmosphere. The temperature of the reaction mixture was raised to 25-30°C and maintained till complete formation of complex. After the formation of complex, pyrrole acetate (20 g) was added to the reaction mixture and stirred. At the completion of the reaction, water (150 ml) was added at 5-25°C. The reaction mass was cooled to 10°C followed by the addition of 50 % sodium hydroxide solution to adjust pH between 6-7. The reaction mass was stirred at 20-25°C to get the crude product. The obtained crude product successively washed with water for 3-4 times. The crude product upon crystallization in methanol gave 15-20 g of the pure crystalline methyl 5-(p- methylbenzoyl)-l-methylpyrrole-2-acetate characterized by PXRD as shown in Fig. 1. Example 4 Preparation of 5-(p-methy-benzoyl)-l-methylpyrrole-2-acetic acid (Tolmetin)
To a mixture of water (250 ml) and methyl 5-(p-methylbenzoyl)-l- methylpyrrole-2-acetate (Tolmetin ester) (25 g), sodium hydroxide solution (4.42 g dissolved in 50 ml water) was added at 20-25°C. The temperature of the reaction mixture was maintained for 6-10 hours for complete hydrolysis. The reaction mass was filtered through filter cloth. The pH of filtrate was adjusted to 1.5 to 4.0 at 20- 25 °C and maintained for 60 minutes. The obtained product was filtered and washed with 2 X 50 ml water and dried under vacuum at 45°C for 10-12 hours to obtain 15-20 g crystalline Tolmetin characterized by PXRD as shown in Fig. 4.
Example 5 Preparation of 5-(/7-methylbenzoyl)-l-methylpyrrole-2-acetic acid (Tolmetin)
The tolmetin sodium (25 g) was dissolved in water (250 ml) at 20-25°C. The pH of reaction mixture was adjusted to 1.5 to 4.0 at 20-25°C and then reaction mixture was maintained for 60 minutes at 20-25°C. The solid obtained was filtered and washed with 2 x 50 ml water and dried under vacuum at 45°C for 10-12 hours to obtained 15-20 g crystalline tolmetin characterized by PXRD as shown in Fig. 4.
Example 6 Preparation of tolmetin sodium In a flask containing methyl 5-(p-methylbenzoyl)-l-methylpyrrole-2-acetate
(20 g), methanol (160 ml) was added at ambient temperature. The sodium hydroxide (3.1 g dissolved in 40 ml water) was added to the reaction mixture and the temperature was raised to 30-35°C and maintained. After complete hydrolysis methanol was completely distilled out which is followed by the addition of water (100 ml). The reaction mass was washed with a mixture of organic solvent (Toluene/ MDC/ Ethyl acetate) and followed by the treatment of aqueous layer with activated charcoal. After charcoal treatment the aqueous layer was filtered and distilled out till around 50 ml mass remains undistilled. To this absolute ethanol (10 ml) was added and maintained at 20-25°C for a period of time and then further added absolute ethanol (10 ml) and cooled to 0-5 °C. Filtered the solid obtained and washed with cold ethanol to obtained 13-15 g Tolmetin sodium, which is crystalline Form I and having the water content of 10-12.5%. Example 7 Preparation of tolmetin sodium
Tolmetin sodium obtained from example 6 was further dried at 60°C for 24 hours. The solid obtained from heating crystalline form I is crystalline form II.
Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

Claims

We Claim:
1. A process for producing 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2- yl] acetic acid or salt thereof, the process comprising: (a) condensing toluoyl morpholide with methyl ester of 1- methylpyπτole-2-acetic acid in presence of halogenating agent to obtain the compound methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate;
(b) hydrolyzing the compound methyl 5-(4-methylbenzoyl)-l- methylpyrrole-2-acetate in the presence of base in a solvent; and (c) isolating 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid or salt thereof.
2. The process according to claim 1, wherein the halogenating agent is selected from POCl3 and POBr3.
3. The process according to claim 1, wherein the base is selected from the group comprising hydroxide, carbonate, and alkoxide of alkali metal.
4. The process according to claim 3, wherein the base is preferably hydroxide of alkaline earth metal.
5. The process according to claim 4, wherein the base is selected from the group comprising sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and potassium /-butoxide.
6. The process according to claim 1, wherein the solvent is selected from the group comprising alcohol, ketone, water and mixtures thereof.
7. The process according to claim 6, wherein the solvent is selected from methanol, ethanol, isopropyl alcohol, n-propanol, acetone, methyl ethyl ketone and water or mixture thereof.
8. The process according to claim 7, wherein the solvent is preferably ethanol or water or mixture thereof.
9. A process for producing 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2- yl]acetic acid or salt thereof, the process comprising:
(a) condensing toluoyl morpholide with methyl ester of 1- methylpyrrrole-2-acetic acid in presence of halogenating agent to obtain the compound methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate;
(b) treating the compound methyl 5-(4-methylbenzoyl)-l- methylpyrrole-2-acetate with base in water and then with acid to obtain 2-[l- methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid;
(c) isolating the 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid; and
(d) optionally, converting the 2-[l-methyl-5-(4- methylbenzoyl)pyrrol-2-yl]acetic acid to its pharmaceutically acceptable salt.
10. The process according to claim 9, wherein the halogenating agent is selected from POCl3 and POBr3.
11. The process according to claim 9, wherein the base is selected from the group comprising hydroxide, carbonate, and alkoxide of alkali metal.
12. The process according to claim 11, wherein the base is selected from the group comprising sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and potassium t-butoxide.
13. The process according to claim 12, wherein the base is preferably sodium hydroxide.
14. The process according to claim 9, wherein the acid is selected from hydrochloric acid, sulfuric acid and acetic acid.
15. A process for producing methyl 5-(4-methylbenzoyl)-l-methylpyrrole- 2-acetate used for production of 2- [l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl] acetic acid or salt thereof according to claim 1 or 9, the process comprising:
(a) treating morpholine with 4-methylbenzoyl chloride in presence of base and an organic solvent to obtain toluoyl morpholide;
(b) isolating the resultant toluoyl morpholide; and
(c) condensing toluoyl morpholide with methyl ester of 1- methylpyrrrole-2-acetic acid in the presence of halogenating agent to obtain methyl 5-(4-methylbenzoyl)-l -methylpyrrole-2-acetate.
16. The process according to claim 15, wherein the base used is selected from the group comprising sodium carbonate, potassium carbonate, potassium tert- butoxide, triethylamine, trimethylamine, diethyl amine and dimethyl amine.
17. The process according to claim 16, wherein the base is preferably triethyl amine.
18. The process according to claim 15, wherein the organic solvent is selected from aromatic hydrocarbon and ester.
19. The process according to claim 18, wherein the organic solvent is selected from toluene, benzene, xylene, ethyl acetate and methyl acetate.
20. The process according to claim 19, wherein the organic solvent is preferably toluene.
21. The process according to claim 15, wherein the halogenating agent is selected from POCl3 and POBr3.
22. A process according to claim 15, further comprising recrystallization of the compound methyl 5-(4-methylbenzoyl)-l -methylpyrrole-2-acetate in a solvent.]
23. The process according to claim 22, wherein the solvent used is methanol, ethanol, and isopropyl alcohol.
24. A crystalline Form I of sodium salt of 2-[l-methyl-5-(4- methylbenzoyl)pyrrol-2-yl]acetic acid obtained according to claim 1, wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 4.13, 8.29, 11.39, 11.91, 12.46, 12.77, 15.36, 16.67, 18.33, 18.50, 19.81, 20.15, 21.33, 22.06, 22.52, 22.96, 23.51, 24.93, 25.14,. 25.71, 26.25, 27.83, 28.08, 28.92, 29.33, 31.11, 31.81, 32.33, 33.54, 34.13, 34.64, 35.3, 37.2, 37.62, 38.86 and 39.81 ± 0.2 2Θ values.
25. A crystalline Form I of sodium salt of 2-[l-methyl-5-(4- methylbenzoyl)pyrrol-2-yl]acetic acid obtained according to claim 1, wherein said form is characterized by having IR absorption bands at 3512, 3106, 2295, 1676, 1597, 1488, 1453, 1414, 1370, 1342, 1306, 1279, 1229, 1191, 1179, 1152, 1133, 1043, 979, 889, 835, 789, 749, 728, 705, 647 and 485 cm'1.
26. The process according to any of the claims lor 9, further comprising heating the resultant compound 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid or salt thereof to produce crystalline Form II of said compound.
27. A crystalline Form II of the salt of 2-[l-methyl-5-(4- methylbenzoyl)pyrrol-2-yl]acetic acid obtained according to claim 26, wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 4.09, 5.40, 9.21, 10.86, 12.20, 15.35, 16.08, 16.45, 18.77, 21.51, 22.83, 23.53, 24.19, 26.44, 26.99, 27.53, 28.11, 29.66, 29.93, 31.99, 33.55, 34.40, 37.30, 38.26, 39.47, 42.16 and 45.81 ± 0.2 2Θ values.
28. A crystalline Form II of the salt of 2-[l-methyl-5-(4- methylbenzoyl)pyrrol-2-yl]acetic acid obtained according to claim 26, wherein said form is characterized by having IR absorption bands at 3478, 3029, 2921, 1623, 1607, 1586, 1508, 1490, 1454, 1406, 1374, 1343, 1307, 1271, 1222, 1179, 1151, 1133, 1043, 980, 915, 886, 834, 742, 723, 688, 591, 549 and 483 cm"1.
29. A crystalline form of 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2- yl]acetic acid obtained according to claim 9, wherein said form is characterized by having an X-ray powder diffraction pattern peaks at 3.58, 4.57, 5.84, 7.19, 8.56, 9.16, 9.85, 10.80, 11.77, 13.81, 14.30, 15.19, 15.67, 17.08, 17.51, 18.48, 19.81, 21.13, 21.34, 21.67, 22.53, 23.97, 25.34, 26.18, 27.14, 28.05, 28.84, 30.61, 34.46, 35.75, 38.09 and 40.47 ± 0.2 2Θ values.
30. A crystalline form of 2-[l-methyl-5-(4-methylbenzoyl)pyrrol-2- yl]acetic acid obtained according to claim 9, wherein said form is characterized by having IR absorption bands at 3217, 3029, 2958, 2920, 2737, 2633, 1732, 1701, 1617, 1568, 1486, 1459, 1427, 1406, 1374, 1267, 1237, 1195, 1177, 1154, 1045, 977, 931, 886, 831, 780, 746, 719, 676, 661, 566, 536 and 482 cm'1.
31. A crystalline methyl 5-(p-methylbenzoyl)-l-methylpyrrole-2-acetate obtained according to claim 15, wherein said form is characterized by having an X- ray powder diffraction pattern peaks at 5.42, 10.13, 10.90, 13.88, 16.41, 17.17, 18.02, 18.54, 20.39, 20.98, 21.95, 22.71, 23.20, 23.59, 24.02, 25.11, 26.47, 27.25, 28.01, 28.19, 29.77, 30.47, 30.82, 31.66, 32.655, 33.45, 34.35, 35.19, 36.27, 37.60, 38.17, 38.95, 39.94, 40.45, 41.52, 42.86, 44.59 and 45.70 ± 0.2 2Θ values.
32. A crystalline methyl 5-(p-methylbenzoyl)-l-methylpyrrole-2-acetate obtained according to claim 15, wherein said form is characterized by having IR absorption bands at 3444, 3030, 3001, 2954, 2923, 2851, 1925, 1723, 1624, 1606, 1486, 1459, 1439, 1405, 1375, 1355, 1331, 1262, 1214, 1182, 1152, 1039, 1002, 973, 885, 834, 763, 745, 722, 686, 622, 577 and 481 cm"1.
PCT/IN2008/000231 2007-12-07 2008-04-08 Process for producing 2-[1-methyl-5-(4-methylbenzoyl)- pyrrol-2- yl]acetic acid or salt thereof WO2009072139A1 (en)

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