WO2015033357A2 - An improved process for the preparation of pyrrole derivatives - Google Patents

An improved process for the preparation of pyrrole derivatives Download PDF

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Publication number
WO2015033357A2
WO2015033357A2 PCT/IN2014/000584 IN2014000584W WO2015033357A2 WO 2015033357 A2 WO2015033357 A2 WO 2015033357A2 IN 2014000584 W IN2014000584 W IN 2014000584W WO 2015033357 A2 WO2015033357 A2 WO 2015033357A2
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Prior art keywords
compound
formula
acid
hydroxide
sodium
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PCT/IN2014/000584
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English (en)
French (fr)
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WO2015033357A3 (en
Inventor
Shri Prakash Dhar Dwivedi
Ramesh Chandra SINGH
Jagdish Maganlal PATEL
Vikas PATEL
Vishwadeepak Rama Pati TRIPATHI
Pranav Jitendra Gangwar
Jigar Mukundbhai RAVAL
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Cadila Healthcare Limited
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Priority to US14/916,402 priority Critical patent/US10112898B2/en
Publication of WO2015033357A2 publication Critical patent/WO2015033357A2/en
Publication of WO2015033357A3 publication Critical patent/WO2015033357A3/en

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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
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • 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

Definitions

  • the present invention relates to an improved process for the preparation of pyrroles derivatives having hypolipidemic and hypocholesteremic activities.
  • the invention relates to an improved process for the preparation of 2- ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy) phenyl)propanoate and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof.
  • the invention also relates to an improved process for the preparation of mesylate compound (A 1 ).
  • Pyrrole derivative of present invention is chemically 2-ethoxy-3-(4-(2-(2-methyl- 5-(4-(methylthio) phenyl)- lH-pyrrol-l-yl)ethoxy)phenyl)propanoate, which may be optically active or racemic and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof.
  • the INN name for pyrrole derivative is Saroglitazar® which is magnesium salt of pyrrole compound of Formula (I), having below chemical structure.
  • the compound of Formula (I) lower or modulate triglyceride levels and/or cholesterol levels and/or lower density lipoproteins (LDL) and raise HDL plasma levels and hence are useful in combating different medical conditions, where such lowering (and raising) is beneficial.
  • LDL lower density lipoproteins
  • the compound of Formula (I) are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions selected from arteriosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders.
  • U.S. Patent No. 6,987, 123 B2 discloses novel heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine.
  • the US ⁇ 23 patent discloses five reaction pathways for the synthesis of pyrrole derivatives. In route- 1 the compound of Formula (la) and (lb) are reacted under Paal-Knoor conditions to obtain compound (1) as shown below:
  • U.S. PG-Pub. No. 201 1/0275669 Al discloses the process for the preparation of pyrrole derivative of general Formula (1) prepared by the five reaction pathways as disclosed herein abpve.
  • polymorphs affect important pharmaceutical parameters selected from storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e. g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e. g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic.
  • chemical reactivity e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
  • mechanical changes e. g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more
  • the physical properties of the crystalline form to that of an amorphous form may be important in pharmaceutical processing.
  • an amorphous form may provide better bioavailability than the crystalline form.
  • a present amorphous form may be useful for formulations which can have better stability, solubility, storage, compressibility etc important for formulation and product manufacturing and doesn't degrade to crystalline forms of saroglitazar.
  • the present amorphous form of saroglitazar may provide atleast a suitable alternative for development of finished formulations.
  • M is hydrogen or a pharmaceutically acceptable cation, the process comprising: (a) reacting a hydroxy compound (A) with; a mesylate compound (Al) to obtain alkoxy ester compound of Formula (II);
  • M is hydrogen or a pharmaceutically acceptable cation selected from sodium (Na), potassium (K), lithium (Li), calcium (Ca), barium (Ba), strontium (Sr) and zinc (Zn);
  • M is hydrogen or a pharmaceutically acceptable cation selected from sodium (Na), potassium (K), lithium (Li), calcium (Ca), barium (Ba), strontium (Sr) and zinc (Zn);
  • M is hydrogen or a pharmaceutically acceptable cation selected from sodium (Na), potassium (K), lithium (Li), calcium (Ca), barium (Ba), strontium (Sr) and zinc (Zn);
  • FIG. 1 discloses the x-ray diffractogram (XRD) of the substantially amorphous form of saroglitazar magnesium.
  • FIG. 2 discloses the x-ray diffractogram (XRD) of mesylate compound (Al).
  • FIG. 3 discloses the x-ray diffractogram (XRD) of mesylate compound (Al) as per example-3.
  • the above and other objects of the present invention are achieved by the process of the present invention, which leads to substantially amorphous saroglitazar magnesium suitable for pharmaceutical use and having greater stability.
  • the invention provides an improved process for preparing substantially amorphous form of saroglitazar magnesium in a single solvent.
  • the solution prior to any solids formation, can be filtered to remove any undissolved solids, solid impurities and the like prior to removal of the solvent.
  • Any filtration system and filtration techniques known in the art can be used.
  • substantially amorphous herein means amorphous form of saroglitazar having percentage crystallinity less than 25%, particularly, less than 20%.
  • DMF refers to N,N-dimethylforamide.
  • DMAc refers to N,N-dimethylacetamide.
  • DMSO refers to N,N-dimethylsulfoxide.
  • NMP refers to N-methylpyrrolidone.
  • THF tetrahydrofuran.
  • MTBE refers to methyl tert-butyl ether.
  • TAA triethylamine
  • TAA refers to tert-butyl amine
  • DIPEA diisopropyl ethylamine
  • DBU refers to l ,8-diazabicyclo[5.4.0]undec-7-ene.
  • DABCO refers to l,4-diazabicyclo[2.2.2]octane.
  • DBN refers to l ,5-Diazabicyclo[4.3.0]non-5-ene
  • HPLC refers to high performance liquid chromatography.
  • M is hydrogen or a pharmaceutically acceptable cation
  • reaction of hydroxy compound (A) with the mesylate compound (Al) is performed in one or more of organic solvents in the presence of a base and optionally in the presence of a phase transfer catalyst.
  • the organic solvent comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether or mixture thereof.
  • alcohols selected from methanol, ethanol, isopropanol, 2-propanol,
  • the phase transfer catalyst comprises one or more of tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium iodide (TBAI), benzyl triethyl ammonium chloride (TEBAC), polyethylene Glycol (PEG-200, 400, 600, 800, 1000), crown ethers like 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18- crown-6, and diaza-18-crown-6.
  • the phase transfer catalyst may be l8-crown-6.
  • hydrolysis of alkoxy ester compound of Formula (II) is performed with an acid to obtain a compound of Formula (IB), wherein M is hydrogen or with a base to obtain a compound of Formula (IB), wherein M is a pharmaceutically acceptable cation.
  • the acid comprises of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, triflouroacetic acid, and formic acid.
  • reaction of the hydroxy compound (A) and the mesylate compound (Al) may be performed under heating at 35°C to about reflux temperature of solvents.
  • the reaction may be heated at 75°C to 85°C till the completion of the reaction.
  • the reaction may be heated for 25 hours to 40 hours, preferably 36 hours.
  • the obtained alkoxy ester (II) may be proceeded further without isolating. Therefore, the alkoxy ester (II) may be further hydrolyzed as in step (b) in-situ.
  • the base for hydrolyzing alkoxy ester (II) comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, strontium hydroxide, magnesium hydroxide, zinc hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, magnesium acetate, potassium tert-butoxide, and sodium pentoxide.
  • alkoxy ester of Formula (II) provides compound (IB), wherein M is a pharmaceutically acceptable cation comprises of sodium (Na), potassium (K), lithium (Li), calcium (Ca), barium (Ba), magnesium (Mg), strontium (Sr) and zinc (Zn).
  • M is a pharmaceutically acceptable cation comprises of sodium (Na), potassium (K), lithium (Li), calcium (Ca), barium (Ba), magnesium (Mg), strontium (Sr) and zinc (Zn).
  • the pharmaceutically acceptable cation compound (IB) may optionally be neutralized to obtain the compound of Formula (IB), wherein M is hydrogen.
  • the neutralization may be performed by addition of an acid comprising hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, triflouroacetic acid, and formic acid.
  • the pH of reaction mixture may be adjusted to 2-3 to have acidic pH.
  • the compound of Formula (IB) wherein M is hydrogen may be further converted to compound of Formula (IB) wherein M is a pharmaceutically acceptable cation.
  • the pharmaceutically acceptable cation comprises to alkali or alkaline earth metal cations.
  • the pharmaceutically acceptable cations comprises of alkali or alkaline earth metal selected from sodium, potassium, lithium, calcium, strontium, barium, magnesium and zinc.
  • M is hydrogen or a pharmaceutically acceptable cation selected from sodium (Na), potassium (K), lithium (Li), calcium (Ca), barium (Ba), strontium (Sr) and zinc (Zn); (c) optionally, neutralizing the compound of Formula (IB) wherein M is a pharmaceutically acceptable cation to obtain a compound of Formula (IB), wherein M is hydrogen; and
  • the compound of Formula (IB), wherein M is hydrogen or pharmaceutically acceptable cation may be prepared by the process as disclosed herein above.
  • alkoxy ester compound of Formula (II) is performed with an acid to obtain a compound of Formula (IB), wherein is hydrogen or with a base to obtain a compound of Formula (IB), wherein M is a pharmaceutically acceptable cation.
  • the pharmaceutically acceptable cation compound of Formula (IB) may optionally be neutralized to obtain a compound of Formula (IB), wherein M is hydrogen.
  • the neutralization may be performed by addition of an acid.
  • the acid comprising hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, triflouroacetic acid, and formic acid.
  • the pH of the reaction mixture may be adjusted to 2-3 to have an acidic pH.
  • the base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, strontium hydroxide, zinc hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide.
  • the compound (IB) wherein M is hydrogen may be reacted with a magnesium source to obtain saroglitazar magnesium of Formula (I).
  • the magnesium source comprises of magnesium hydroxide, magnesium methoxide, magnesium acetate, magnesium chloride, and magnesium metal.
  • the magnesium source may be magnesium acetate tetrahydrate.
  • the saroglitazar magnesium (I) may be obtained by the process comprising:
  • the product saroglitazar magnesium (I) thus obtained may be filtered and dried under vacuum tray drier, sieved and milled to obtain a particle size range.
  • the milled product may be further dried till constant weight may be obtained to obtain substantially amorphous saroglitazar (I) free from residual solvents.
  • the organic solvent used for extraction comprises one or more of chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene.
  • the anti-solvent comprises one or more of aliphatic hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tertbutyl ether.
  • the anti-solvent is n-heptane.
  • the anti-solvent may be diluted with one or more another solvent comprising esters selected from ethyl acetate, isopropyl acetate, n-butyl acetate, t- butyl acetate, and isobutyl acetate.
  • esters selected from ethyl acetate, isopropyl acetate, n-butyl acetate, t- butyl acetate, and isobutyl acetate.
  • n-butyl acetate may be used.
  • the product thus obtained may be obtained by the removal of anti-solvent by the known technique in the art selected from filtration, centrifugation, decantation, a rotational distillation device such as a Buchi Rotavapor, spray dyring, agitated thin film drying (“ATFD”), and freeze drying (lyophilization) or any other known techniques.
  • a rotational distillation device such as a Buchi Rotavapor, spray dyring, agitated thin film drying (“ATFD”), and freeze drying (lyophilization) or any other known techniques.
  • the sieving of product may be done through 0.5 sieve followed by milling.
  • milling include various makes of ball mills, roller mills, gyratory mills, multi-mills, Jet-mills, and the like.
  • a mill such as a Micros Super Fine Mill (available from Nara Machinery Co. Ltd or Tokyo, Japan), Multi-Mill Sr. No. G. 1.132 (available from Grooves International Pharmaceutical & Chemical Machinery), Jet-Mill from Midas Micronizer M-100 Aerosol (No. 154/07-08 (available from microtech Enginering Company) or a common mixer grinder can be used.
  • a common mixer grinder can be used.
  • another commercially available milling machine can be used.
  • M is hydrogen or a pharmaceutically acceptable cation selected from sodium (Na), potassium (K), lithium (Li), calcium (Ca), barium (Ba), strontium (Sr) and zinc (Zn);
  • the compound of Formula (IB), wherein M is hydrogen or pharmaceutically acceptable cation may be prepared by the process as disclosed herein above.
  • alkoxy ester compound of Formula (II) is performed with an acid to obtain a compound of Formula (IB), wherein is hydrogen or with a base to obtain a compound of Formula (IB), wherein M is a pharmaceutically acceptable cation.
  • the pharmaceutically acceptable cation compound of Formula (IB) may optionally be neutralized to obtain a compound of Formula (IB), wherein M is hydrogen.
  • the neutralization may be performed by addition of an acid comprising hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, triflouroacetic acid, and formic acid.
  • the pH of the reaction mixture may be adjusted to 2-3 to have an acidic pH.
  • the base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, strontium hydroxide, zinc hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide.
  • the compound of Formula (IB), wherein M is hydrogen may be further reacted with organic amine to obtain the compound of Formula (IC).
  • the organic amine comprises of ammonia, methylamine, dimethylamine, ethylamine, diethylamine, 1,2-ethanediamine, n-propylamine, isopropylamine, diisopropylamine, N-methyl isopropylamine, n-butylamine, t-butylamine, 2-butamine, 1 ,2-ethahediamine, N- methylglucamine, N N-trimethylethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4- aminobutyl)- guanidine dicyclohexylamine, benzenemethanamine, ethanolamine, diethanolarnine, tris(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benz
  • the compound (IC) may optionally be neutralized to obtain a compound of Formula (IB), wherein M is hydrogen.
  • the neutralization may be performed by addition of an acid comprising hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, triflouroacetic acid and formic acid.
  • the pH of reaction mixture may be adjusted to 2-3 to have acidic pH.
  • the compound (IB) wherein M is hydrogen may be reacted with a magnesium source to obtain saroglitazar magnesium of Formula (I).
  • the magnesium source comprises magnesium hydroxide, magnesium methoxide, magnesium acetate, magnesium chloride and magnesium metal.
  • the magnesium source may be magnesium acetate tetrahydrate.
  • the saroglitazar magnesium (I) may be obtained by extracting the reaction mixture with one or more of organic solvent followed by washing the organic layer and removal of the organic solvent to obtain a residue.
  • the residue may be treated with same solvent and added into an anti-solvent to obtain saroglitazar magnesium (I).
  • the product thus obtained may be' filtered and dried under vacuum tray drier, sieved and milled to obtained suitable particle size range. The milled product may be further dried till constant weight may be obtained to obtain substantially amorphous saroglitazar (I) free from residual solvents.
  • the organic solvent used for extraction comprises one or more of chlorinated. hydrocarbons selected from methylene dichloride, ethylene dichloride and chlorobenzene; aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene.
  • the anti-solvent comprises one or more of aliphatic hydrocarbons selected from pentane, hexane, heptane and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tertbutyl ether.
  • the anti-solvent may be n-heptane.
  • the anti-solvent may be diluted with one or more of another solvent comprises of esters selected from ethyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and isobutyl acetate.
  • esters selected from ethyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and isobutyl acetate.
  • n-butyl acetate may be used.
  • M is hydrogen or a pharmaceutically acceptable cation selected from sodium (Na), potassium (K), lithium (Li), calcium (Ca), barium (Ba), strontium (Sr) and zinc (Zn);
  • the organic solvent comprises one or more of esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; hydrocarbons selected from toluene, xylene, ethyl benzene, heptane, hexane, and cyclohexane; chlorinated solvents selected from methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, and carbon tetrachloride.
  • esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate
  • hydrocarbons selected from toluene, xylene, ethyl benzene, heptane, hexane, and cyclohexane
  • chlorinated solvents selected from methylene dichloride, ethylene dichloride, chlorobenzen
  • the base in step (a) comprises one or more of alkali or alkaline earth metals hydroxide, carbonates, bicarbonates, hydrides, alkoxides etc.
  • alkali or alkaline earth metals hydroxide carbonates, bicarbonates, hydrides, alkoxides etc.
  • the embodiments of the process may further comprise of in-situ hydrolyzing the compound (Dl) without isolating from step (a) as the scope of the invention.
  • the compound (Dl) may be hydrolyzed with same or different bases.
  • the base for hydrolysis comprises one or more of alkali or alkaline earth metals hydroxide, carbonates, bicarbonates, hydrides, alkoxides etc.
  • the reaction mixture may be preferably diluted with one or more of another solvent.
  • the another solvent comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate.
  • methanol may be used.
  • the compound (CI) may be obtained by decarboxylation of carboxylic acid derivative obtained in-situ which may be not isolated.
  • the compound (Bl) may be obtained by treating the diketo compound (CI) with ethanolamine under Paal-Knoor conditions in presence of an acid.
  • the acid comprising acetic acid, hydrochloric acid, sulfuric acid,, formic acid, hydrobromic acid, trifluoroacetic acid, and pivalic acid.
  • the pivalic acid may be used.
  • the compound (Bl) may be in-situ proceed for further reaction.
  • the solvent system may be same.
  • the solvent for further reaction may be toluene.
  • the compound (Bl) obtained in step (c) may be reacted with methane sulphonyl chloride in toluene in the presence of a base to obtain mesylate compound (Al).
  • the base for step (d) comprises one or more of alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, and lithium hydroxide; alkali metal carbonates selected from sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal bicarbonates selected from sodium bicarbonate, and potassium bicarbonate; ammonia or its aqueous solution; organic bases selected from methyl amine, ethyl amine, TEA, TBA, DIP A, DIPEA, pyridine, piperidine, morpholine, DBU, DABCO and DBN.
  • TEA may be used.
  • the mesylate compound (Al) may be in-situ reacted with the hydroxy compound (A) in the presence of a base and optionally in the presence of a phase transfer catalyst.
  • the base comprises of alkali or alkaline earth metals hydroxide, carbonates, bicarbonates, hydrides, alkoxides etc.
  • the phase transfer catalyst comprises of tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium iodide (TBAI), benzyl triethyl ammonium chloride (TEBAC), polyethylene Glycol (PEG-200, 400, 600, 800, 1000), crown ethers like 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, diaza-18-crown-6 and the like.
  • the phase transfer catalyst may be 18-crown-6.
  • the reaction of hydroxy compound (A) and mesylate compound (Al) may be performed under heating at 35°C to about reflux temperature of solvents.
  • the reaction may be heated at 75°C to 85°C till the completion of the reaction.
  • the reaction may be heated for 25 hours to 40 hours, preferably 36 hours.
  • the hydrolysis of alkoxy ester compound of Formula (II) obtained is performed with an acid to obtain a compound of Formula (IB) wherein M is hydrogen or with a base to obtain a compound of Formula (IB) wherein M is a pharmaceutically acceptable cation.
  • the acid comprising hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, triflouroacetic acid, and formic acid.
  • the base for hydrolyzing alkoxy ester (II) comprises of alkali or alkaline earth metals hydroxide, carbonates, bicarbonates, hydrides etc.
  • alkali or alkaline earth metals hydroxide carbonates, bicarbonates, hydrides etc.
  • sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydride sodium hydroxide may be used.
  • the compound (IB) wherein M is hydrogen may be reacted with a magnesium source to obtain saroglitazar magnesium of Formula (I).
  • the magnesium source comprises magnesium hydroxide, magnesium methoxide, magnesium acetate, magnesium chloride, and magnesium metal.
  • the magnesium source may be magnesium acetate tetrahydrate.
  • the saroglitazar magnesium (I) may be obtained by extracting the reaction mixture with one or more of organic solvent followed by washing the organic layer and removal of the organic solvent. The residue may be treated with the same solvent and added into an anti-solvent to obtain the saroglitazar magnesium (I).
  • the product thus obtained may be filtered and dried under vacuum tray drier, sieved and milled to obtained suitable particle size range.
  • the milled product may be further dried till constant weight may be obtained to obtain substantially amorphous saroglitazar (I) free from residual solvents.
  • the organic solvent comprises one or more of toluene, xylene, ethyl acetate and methylene dichloride.
  • the saroglitazar magnesium of Formula (I) may be obtained by removal of solvent and treatment with an anti-solvent.
  • the anti-solvent comprises one or more of aliphatic hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, " and methyl tertbutyl ether.
  • the anti-solvent may be n-heptane.
  • the anti-solvent may ;be diluted with one or more of another solvent comprising esters selected from ethyl acetate, isopropyl acetate, n-butyl acetate, t- butyl acetate, and isobutyl acetate.
  • another solvent comprising esters selected from ethyl acetate, isopropyl acetate, n-butyl acetate, t- butyl acetate, and isobutyl acetate.
  • n-butyl acetate may be used.
  • the reaction of 4-(methylthio)benzaldehyde and methylvinylketone is performed in the presence of a stetter catalyst.
  • the stetter catalyst comprises of alkylthiazolium halide of Formula (C),
  • R Ci-Ci 2 alkyl like methyl, ethyl, propyl, butyl, and dodecyl;
  • X halide like chloride, fluoride, bromide, and iodide.
  • the stetter catalyst is 5-(2-hydroxyethyl)-3,4-dimethylthiazol-3-ium iodide (C-stetter).
  • the reaction may be performed in the presence or absence of organic solvent.
  • the organic solvent comprises one or more of esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; hydrocarbons selected from toluene, xylene, ethyl benzene, heptane, hexane, and cyclohexane; chlorinated solvents selected from methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, and carbontetrachloride.
  • the base in step (a) comprises one or more of alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metai carbonates selected from sodium carbonate and potassium carbonate; alkali metal bicarbonates selected from sodium bicarbonate and potassium bicarbonate; ammonia or its aqueous solution; organic bases selected from methyl amine, ethyl amine, TEA, TBA, DIP A, DIPEA, pyridine, piperidine, morpholine, DBU, DABCO and DBN.
  • TEA may be used.
  • the compound (Bl) may be obtained by treating the diketo compound (CI) with ethanolamine under Paal- noor conditions in presence of an acid.
  • the acid comprises of acetic acid, hydrochloric acid, sulfuric acid, formic acid, hydrobromic acid, trifluoroacetic acid, and pivalic acid.
  • the pivalic acid may be used.
  • the compound (Bl) may be in-situ proceed for further reaction.
  • the solvent system may be same.
  • the suitable solvent for further reaction may be toluene.
  • the compound (B l) obtained in step (b) may be reacted with methane sulphonyl chloride in toluene in the presence of base to obtain mesylate compound (Al).
  • the base for step (c) comprises one or more of alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates selected from sodium carbonate and potassium carbonate' alkali metal bicarbonates selected from sodium bicarbonate and potassium bicarbonate; ammonia or its aqueous solution; rganic bases selected from methyl amine, ethyl amine, TEA, TBA, DIP A, DIPEA, pyridine, piperidine, morpholine, DBU, DABCO and DBN.
  • TEA may be used.
  • the compound (Al) may be isolated by removal of toluene by distillation followed by treating the residue with methanol and removal of methanol to obtain wet-cake.
  • the wet product may be dried in vacuum tray dryer to obtain constant weight.
  • the compound (Al) obtained may be characterized by x-ray powder diffraction as crystalline.
  • the crystalline mesylate compound (Al) is crystalline Form-I characterized by x-ray powder diffraction having characteristic peaks at about 12.4, 15.0, 17.7 and 23.2 ⁇ 0.2° 2 ⁇ and x-ray powder diffraction pattern substantially as shown as in FIG.2.
  • the compound (A 1) may be optionally purified in one or more of organic solvent.
  • the organic solvent comprises of esters selected from ethyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, and isobutyl acetate; alcohols selected from methanol, ethanol, isopropanol, n-butanol, and t-butanol; ketones selected from acetone, methyl isobutyl ketone, and methyl ethyl ketone, or mixtures thereof.
  • the mixture of ethyl acetate and methanol may be used.
  • the crystalline mesylate compound (Al) obtained by purification is crystalline Form-II characterized by x-ray powder diffraction having characteristic peaks at about 9.7, 16.4, 17.3, 17.7, 19.0, 19.7, 20.6, 20.9, 21.9, 25.1, 25.9 and 29.4 ⁇ 0.2° 2 ⁇ and x-ray powder diffraction pattern substantially as shown as in FIG.3.
  • crystalline mesylate compound (Al) for the preparation of substantially amorphous saroglitazar magnesium.
  • substantially amorphous saroglitazar magnesium substantially free from residual solvents.
  • the substantially amorphous saroglitazar magnesium is characterized by powder diffraction pattern substantially as depicted FIG.l.
  • Powder X-ray Diffraction of saroglitazar magnesium and mesylate compound (Al) can be obtained under following conditions.
  • Powder X-ray Diffraction X-ray powder diffraction spectrum was observed on a MF 2100 2 W X-ray Powder diffractometer of make Rigaku having a Copper ⁇ -radiation at a voltage of 40kV and 30mA. Approximately 150 mg sample was gently flattened on a quartz plate without further processing (e.g. Grinding and sieving) and scanned from 4° to 40° at 0.010° sampling width and 4.000° per minute.
  • saroglitazar magnesium alongwith its intermediates may be prepared by the reaction scheme- 1, scheme-2 and scheme-3 as shown below, which is also the scope of the present invention.
  • compositions comprising saroglitazar of the invention.
  • pharmaceutical compositions includes pharmaceutical formulations like tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • a pharmaceutical composition comprising substantially amorphous saroglitazar magnesium prepared by the process of the present invention together with one or more of pharmaceutically acceptable carriers, excipients Or diluents.
  • the present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention.
  • reaction mixture was filtered and pivalic acid (57.3 g) and ethanol amine (143.9 g) were added and heated to 105° to 1 15°C for removing water azeotropically.
  • the toluene layer was separated and triethyl amine (271.85 g) was added at 25° to 35°C and the reaction mixture was cooled to 10° to 20°C.
  • Methane sulphonyl chloride (282.5 g) was added dropwise, and stirred for 2 hours and heated to 35° to 45°C.
  • the reaction mixture was filtered and washed with toluene. Toluene was distilled out completely under the vacuum to obtain the residue. The residue was dissolved in toluene (1500 mL) and used for further process.
  • the reaction mixture was stirred for 2 hours at 25°C and cooled to 0°C.
  • the product precipitated was filtered and washed with methanol to obtain crystalline compound (Al).
  • the compound (Al) was characterized as crystalline solid by x- ray powder diffraction (FIG.3).
  • the separated organic layer was washed with water (600.0 ml) and characoalized with HP-120 (5.0 g) charcoal and stirred for 30 min and filtered.
  • the filtrate was added sodium hydroxide 20.14 g solution in water (200.0 ml) and the reaction mixture was stirred for 3 hours.
  • the reaction mixture was diluted with water (1800.0 ml) and stirred for 15 min.
  • the separated aqueous layer was washed with n-butyl acetate.
  • the separated aqueous layer was added magnesium acetate tetrahydrate solution (90.0 g) in water (100.0 ml) and stirred for 1 hour.
  • the aqueous layer was extracted with methylene dichloride (2000 ml).
  • the separated organic layer was washed with sodium chloride solution and charcoalized.
  • the charcoalized solution was filtered and filtrate was distilled to remove toluene completely.
  • the residue was diluted with toluene (1000 ml) and stirred for 30 min.
  • the organic solution was added into n-heptane (1500 mL) and stirred for 3 hours.
  • the product was filtered and washed with n-heptane and dried in vacuum tray dryer at 25°C to 30°C for 3 hours.
  • the product was sieved through 0.5 mm sieve and milled through jet-milled.
  • the product was further dried in vacuum tray drier at 40°C to 50°C for 6 hours followed by drying at 55°C to 65°C for 40 hours to obtain amorphous saroglitazar magnesium (I).
  • the compound is characterized by x-ray power diffraction (FIG.l).
  • reaction of methanesulfonic acid 2-[2-methyl-5-(4-methylsulfanyl-phenyl)- pyrrol-l-yl]-ethyl ester (Al) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (A) may also be performed in similar manner as above in absence of phase transfer catalyst 18-Crown-6.
  • the separated aqueous layer was washed with isopropyl acetate.
  • the combined organic layer was treated with (S)-(-)-phenyl ethylamine (55.94 g) and stirred for 2 hours at 25°C and 30 min at 45°C.
  • the reaction mixture was cooled to 0°C and stirred for 2 hours, filtered and washed with isopropyl acetate.
  • the wet-cake was dried to obtain saroglitazar phenyl ethylamine salt.
  • the separated aqueous layer was treated with magnesium acetate tetrahydrate (2.29 g) in water (5 mL) solution and stirred for 60 min.
  • the reaction mixture was extracted with methylene dichloride (800 mL).
  • the methylene dichloride was complete removed by distillation under vacuum below 40°C to obtain the residue.
  • the residue was diluted with methylene dichloride (50 ml) and stirred for 30 min.
  • the organic solution was added into n-heptane (1500 mL) and stirred for 3 hours.
  • the product was filtered and washed with n-heptane and dried in vacuum tray dryer at 25°C to 30°C for 3 hours.
  • the product was sieved through 0.5 mm sieve and milled through jet-milled.
  • the product was further dried in vacuum tray drier at 40°C to 50°C for 6 hours followed by drying at 55°C to 65°C for 40 hours to obtain substantially amorphous saroglitazar magnesium (I).
  • the compound is characterized by x-ray power diffraction (FIG.l).

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