WO2015177801A1 - Nouveau procede pour la preparation d'un compose contenant du lactame - Google Patents

Nouveau procede pour la preparation d'un compose contenant du lactame Download PDF

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WO2015177801A1
WO2015177801A1 PCT/IN2014/000347 IN2014000347W WO2015177801A1 WO 2015177801 A1 WO2015177801 A1 WO 2015177801A1 IN 2014000347 W IN2014000347 W IN 2014000347W WO 2015177801 A1 WO2015177801 A1 WO 2015177801A1
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formula
iodophenyl
solvent
solid state
ethyl
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PCT/IN2014/000347
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English (en)
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Dodda Mohan Rao
Dodda SPANDANA
Janagam CHANDANA REDDY
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Symed Labs Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel, commercially viable and industrially advantageous process for the preparation of Apixaban and its intermediates, in high yield and with high purity, using a novel intermediate 3-chloro-l-(4-iodophenyl)-5,6- dihydropyridin-2(lH)-one.
  • U.S. Patent No. 6,967,208 (hereinafter referred to as the '208 patent), assigned to Bristol-Myers Squibb Pharma, discloses a variety of lactam-containing compounds and derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds are anticoagulants which inhibit the coagulation factor Xa with increased selectivity.
  • Apixaban l-(4- Methoxyphenyl)-7-oxo-6-[4-(2-oxo- 1 -piperidinyl)phenyl]-4,5,6,7-tetrahydro- 1 H-pyrazole- [3,4-c]pyridine-3-carboxamide, acts as an inhibitor of clotting factor Xa and which is used as an agent for the prophylaxis and/or treatment of thromboembolic disorders.
  • Apixaban is represented by the following structural formula 1 :
  • Apixaban is sold by Bristol-Myers Squibb under the brand name Eliquis® and is orally administered as tablets containing 2.5 mg and 5 mg of Apixaban.
  • apixaban is prepared by the following sequence of reaction steps:
  • step-(c) the 4-iodophenyl compound obtained in step-(c) is condensed with ⁇ -valerolactam in the presence of potassium carbonate and copper iodide in dimethylsulfoxide, followed by column chromatographic purifications on silica gel to produce ethyl l-(4- methoxyphenyl)-7-oxo-6- [4-(2-oxo- 1 -piperidinyl)phenyl]-4,5 ,6,7-tetrahydro- 1 H- pyrazolo[3,4-c]pyridine-3-carboxylate as a tan foam; and
  • step-(d) the ethyl ester compound obtained in step-(d) is then reacted with ammonia in ethylene glycol at 120°C in a sealed vessel, followed by column chromatographic purifications on silica gel to produce apixaban.
  • apixaban is prepared by reacting 3-chloro-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)-one with ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate in the presence of triethylamine in toluene, followed by multiple extractions and tedious workup procedures to produce ethyl 1 -(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro- 1 H-pyrazolo[3,4- c]pyridine-3-carboxylate, which is then subjected to catalytic hydrogenation using Pd/C catalyst under pressure of 3,100 mmHg in tetrahydrofuran, followed by tedious workup procedures to produce ethyl 6-(4-aminophenyl)-l
  • the resulting aminophenyl intermediate is then reacted with 5-bromovalerylchloride in the presence of aqueous potassium carbonate and sodium metabisulfite, followed by tedious and cumbersome workup procedures to produce a bromoamide compound, which is then subjected to cyclization by means of potassium ethoxide in tetrahydrofuran, followed by tedious and cumbersome workup procedures to produce l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro- 1 H-pyrazolo[3,4-c]pyridine-3-carboxylate.
  • the resulting ester compound is then subjected to amidation either by means of anhydrous ammonia and propylene glycol or by reacting with formamide in dimethylformamide to produce Apixaban.
  • U.S. Patent No. 6,919,451 discloses two synthetic routes for the preparation of apixaban.
  • the first synthetic route of apixaban described in the US'451 patent is shown in the below scheme-3:
  • apixaban is prepared by reacting ethyl 2-chloro-2-(2-(4-methoxyphenyl) hydrazono)acetate with 3-morpholin-4-yl-5,6-dihydro-lH-pyridin-2-one in the presence of triethylamine in ethyl acetate, followed by tedious workup procedures and column chromatographic purifications to produce ethyl l-(4-methoxy-phenyl)-7a-morpholin-4-yl- 7-oxo-3a,4,5,6,7,7a-hexahydro-lH-pyrazolo[3,4-c]pyridin-3-carboxylate, which is then reacted with trifluoroacetic acid in methylene chloride, followed by column chromatographic purifications to produce ethyl l-(4-methoxy-pheny
  • This intermediate compound is reacted with l-(4-iodophenyl)-piperidin-2-one in the presence of potassium carbonate, copper iodide and 8-hydroxyquinoline in dimethylsulfoxide under nitrogen atmosphere, followed by treatment with ammonium hydroxide and subjecting to tedious workup procedures to produce ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidin-l-yl)- phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid, which is then reacted with iso-butyl chloroformate in the presence of triethylamine to produce a mixed anhydride intermediate, followed by treatment with ammonium hydroxide to produce apixaban.
  • apixaban is prepared by reacting the ⁇ , ⁇ -dichlorolactam with morpholine in excess at reflux to produce l-(4-iodophenyl)-3-morpholino-5,6-dihydro-2H-pyridin-2-one, which is then reacted with piperidin-2-one in the presence of Cu(PPh 3 )3Br catalyst and cesium carbonate, followed by tedious workup procedures and column chromatographic purifications to produce 3-morpholin-4-yl-l-[4-(2-oxo-piperidin-l-yl)-phenyl]-5,6-dihydro- lH-pyridin-2-one.
  • This intermediate compound is then reacted with ethyl 2-chloro-2-(2-(4- methoxyphenyl)hydrazono)acetate in the presence of triethylamine to produce a morpholine substituted pyrazolo-pyridine compound, which is then treated with aqueous hydrochloric acid solution, followed by tedious workup procedures and column chromatographic purifications to produce ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo- piperidin-l-yl)-phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate.
  • Desirable process properties include non-hazardous conditions, environmentally friendly and easy to handle reagents, reduced process steps, reduced reaction time periods, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of apixaban and its intermediates in high purity and with high yield.
  • ethyl 6-(4- iodophenyl)- 1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro- 1 H-pyrazolo[3,4-c]pyridine-3- carboxylate of formula 3, which is a key intermediate in the synthesis of Apixaban can be prepared advantageously with high purity and with high yield, by reacting 3,3-dichloro-l- (4-iodophenyl)-piperidin-2-one of formula 6 with lithium chloride in the presence of lithium carbonate to produce a novel intermediate compound 3-chloro-l-(4-iodophenyl)- 5,6-dihydropyridin-2(lH)-one of formula 5, which is then reacted with ethyl 2-chloro-2-(2- (4-methoxyphenyl)hydrazono)acetate of formula 4 in the presence of an organic base to produce ethyl
  • Apixaban can be prepared with high purity and with high overall yield by using the compound of formula 3 obtained by the processes disclosed herein, by known methods.
  • the novel process solves the drawbacks associated with the prior processes and is commercially viable for preparing Apixaban and its intermediates thereof.
  • provided herein are efficient, industrially advantageous and environmentally friendly processes for the preparation of Apixaban and its key intermediate ethyl 6-(4-iodophenyl)- 1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro- 1 H- pyrazolo[3,4-c]pyridine-3-carboxylate of formula 3, in high overall yield and with high purity using novel intermediate compound.
  • apixaban intermediates including 5-bromo-pentanoic acid-(4-iodophenyl)amide; 1 -(4-Iodophenyl)- piperidin-2-one; 3,3-dichloro-l-(4-iodophenyl)-piperidin-2-one; 3-chloro-l-(4- iodophenyl)-5,6-dihydropyridin-2(lH)-one; ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)- 7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate; and ethyl l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]-4,5,
  • the process avoids the use of highly flammable solvents like tetrahydrofuran, hexane, and dimethylsulfoxide;
  • the process avoids the use of additional and corrosive acids like hydrochloric acid and trifluoroacetic acid; v) the process avoids the use of expensive and toxic reagents and/or catalysts like cesium carbonate, palladium on carbon, Cu(PPh 3 ) 3 Br, iso-butyl chloroformat and sodium metabisulfite;
  • the process avoids the use of tedious and cumbersome procedures like prolonged reaction times, multiple extractions using different solvents, multiple process steps, column chromatographic purifications, expensive catalytic hydrogenation steps, multiple isolation/recrystallizations;
  • the processes involve, easy work-up methods and simple isolation processes, and there is a reduction in chemical waste.
  • Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of solid state form of 3 -chloro- 1 -(4-iodophenyl)-5,6-dihydropyridin-2( 1 H)-one.
  • XRPD X-ray diffraction
  • Figure 2 is a characteristic powder X-ray diffraction (XRPD) pattern of solid state form of ethyl 6-(4-iodophenyl)- 1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro- 1 H-pyrazolo[3,4- c]pyridine-3 -carboxylate.
  • XRPD X-ray diffraction
  • Figure 3 is a characteristic powder X-ray diffraction (XRPD) pattern of solid state form of 5-bromo-pentanoic acid-(4-iodophenyl)amide.
  • Figure 4 is a characteristic powder X-ray diffraction (XRPD) pattern of solid state form of 1 -(4-Iodophenyl)-piperidin-2-one.
  • Figure 5 is a characteristic powder X-ray diffraction (XRPD) pattern of solid state form of 3 ,3 -dichloro- 1 -(4-iodophenyl)-piperidin-2-one.
  • XRPD X-ray diffraction
  • Figure 6 is a characteristic powder X-ray diffraction (XRPD) pattern of solid state form of ethyl 1 -(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo- 1 -piperidinyl)phenyl]-4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c]pyridine-3-carboxylate.
  • XRPD characteristic powder X-ray diffraction
  • the reaction in step-(a) is carried out in the presence of a reaction inert solvent.
  • the solvent used in step-(a) is selected from the group consisting of dimethylformamide, dimethylacetamide and mixtures thereof, and a most specific solvent is dimethylformamide.
  • the suitable reagent used in step-(a) is selected from the group consisting of lithium chloride, lithium carbonate, and a combination thereof. Specifically, the reagent used in step-(a) is the combination of lithium chloride and lithium carbonate.
  • the reaction in step-(a) is carried out at a temperature of about 25°C to the 120°C, specifically at a temperature of about 45°C to 110°C, and more specifically at 110°C.
  • the reaction time may vary between about 2 hours to about 8 hours, and most specifically about 3 hours to about 5 hours.
  • reaction mass containing the 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin- 2(lH)-one of formula 5 obtained in step-(a) may be subjected to usual work up, followed by isolation from a suitable solvent by conventional methods such as cooling, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
  • reaction mass containing the 3-chloro-l-(4- iodophenyl)-5,6-dihydropyridin-2(lH)-one of formula 5 obtained in step-(a) is quenched with water, followed by stirring the resulting mass and then collecting the separated solid in a highly pure form.
  • the reaction in step-(b) is carried out in the presence of a reaction inert solvent.
  • exemplary solvents used in step-(b) include, but are not limited to, an aromatic hydrocarbon solvent, an ester solvent, a ketone solvent, a nitrile solvent, and mixtures thereof.
  • the solvent used in step-(b) is selected from the group consisting of toluene, ethyl acetate, butyl acetate, acetonitrile, methylisobutyl ketone and mixtures thereof, and a most specific solvent is toluene or ethyl acetate.
  • the suitable base used in step-(b) is an organic or inorganic base, and most specifically an organic base.
  • organic bases include, but are not limited to, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N- methylmorpholine and 1 -alkylimidazole.
  • a most specific organic base is triethylamine.
  • the reaction in step-(b) is carried out at a temperature of about 25°C to the reflux temperature of the solvent used, specifically at a temperature of about 50°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used.
  • the reaction time may vary between about 1 hour to about 5 hours, and most specifically about 2 hours to about 3 hours.
  • reaction mass containing the ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7- oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of formula 3 obtained in step-(b) may be subjected to usual work up such as a washing, an extraction, carbon treatment, an evaporation, a pH adjustment, a layer separation etc., followed by isolation from a suitable solvent by conventional methods such as cooling, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
  • the solvent used to isolate the compound of formula 3 is selected from the group consisting of water, a ketone, an alcohol, an ether, an ester, a hydrocarbon solvent, a chlorinated hydrocarbon, and mixtures thereof.
  • a most specific solvent is toluene, acetone, or a combination thereof.
  • the solid obtained in any of the above process steps may be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
  • the isolation of the compound of formula 5 is carried out as per the process exemplified in example 4.
  • the solid state form of the 3-chloro-l-(4-iodophenyl)-5,6- dihydropyridin-2(lH)-one of formula 5, obtained by the process exemplified herein, is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 9.16, 14.76, 15.23, 17.99, 19.41, 19.94, 20.50, 21.50, 21.73, 22.02, 23.85, 25.40, 25.84, 27.36, 28.40, 28.82, 29.25, 29.56, 30.11, 30.71, 31.70, 33.85, 34.58, 36.31, 36.90, 36.97, 37.27, 37.35, 38.39, 39.11, 39.86, 44.80, 47.09 and 48.05 ⁇ 0.2 degrees 2-theta substantially in accordance with Figure 1.
  • the isolation of the compound of formula 3 is carried out as per the process exemplified in example 6.
  • the solid state form of ethyl 6-(4-iodophenyl)-l-(4- methoxyphenyl)-7-oxo-4,5 ,6,7-tetrahydro- 1 H-pyrazolo [3 ,4-c]pyridine-3 -carboxylate of formula 3, obtained by the process exemplified herein, is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 6.81, 9.87, 10.81, 12.40, 13.66, 13.95, 14.50, 15.50, 17.44, 19.04, 19.62, 19.98, 20.54, 21.15, 21.69, 22.96, 23.39, 24.79, 24.96, 25.54, 26.25, 27.78, 28.36 and 32.84 ⁇ 0.2 degrees 2-theta substantially in accordance with Figure 2.
  • step- (b) The conversion of the ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of formula 3 into Apixaban in step- (b) can be carried out either as per the methods described in the prior art, for example, as per the processes described in the US Patent Nos. US 6,967,208, US 7,396,932 and US 6,919,451 ; or as per the processes described hereinafter.
  • reaction steps-(a) and (b) are carried out by using the methods, conditions and reagents as described hereinabove.
  • the reaction in step-(c) is carried out in the presence of a reaction inert solvent.
  • the solvent used in step-(c) is an aromatic hydrocarbon solvent, and a most specific solvent is toluene.
  • the suitable reagent used in step-(c) is selected from the group consisting of cuprous iodide, 8-hydroxyquinoline, and a combination thereof. Specifically, the reagent used in step-(c) is the combination of cuprous iodide and 8- hydroxyquinoline.
  • the reaction in step-(c) is carried out in the presence of a base.
  • the base used in the above reaction is an organic or inorganic base, and specifically an inorganic base.
  • Exemplary inorganic bases include, but are not limited to, tripotassium phosphate; hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals.
  • a most specific inorganic base is sodium carbonate or potassium carbonate.
  • reaction in step-(c) is carried out at a temperature of about 25°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used.
  • reaction mass containing the ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl] -4,5,6,7-tetrahydro- 1 H-pyrazolo [3 ,4-c]pyridine-3 -carboxylate of formula 2 obtained in step-(c) may be subjected to usual work up such as a washing, an extraction, carbon treatment, an evaporation, a pH adjustment, a layer separation etc., followed by isolation from a suitable solvent by conventional methods such as cooling, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
  • the solvent used to isolate the compound of formula 2 is selected from the group as described hereinabove.
  • a most specific solvent is toluene.
  • the solid obtained in any of the above process steps may be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
  • the isolation of the compound of formula 2 is carried out as per the process exemplified in example 7.
  • the solid state form of the ethyl l-(4-methoxyphenyl)-7- oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3- carboxylate of formula 2, obtained by the process exemplified herein, is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 5.14, 6.67, 7.42, 9.25, 10.20, 10.83, 13.34, 14.82, 15.31, 15.64, 17.09, 17.50, 18.09, 18.66, 20.33, 20.99, 22.30, 22.68, 23.05, 24.66 and 25.28 ⁇ 0.2 degrees 2-theta substantially in accordance with Figure 6.
  • the reaction in step-(d) is carried out in the presence of a solvent.
  • the solvent used in step-(d) is selected from the group consisting of ethylene glycol, propylene glycol, dimethylformamide, an alcohol, a ketone, a nitrile solvent, an ester solvent, and mixtures thereof.
  • the suitable reagent used in step-(d) is selected from the group consisting of anhydrous ammonia, ammonium hydroxide, formamide, sodium methoxide, and a combination thereof.
  • reaction in step-(d) is carried out at a temperature of about 25°C to the reflux temperature of the solvent used, and most specifically at 120°C.
  • reaction mass containing the apixaban of formula 1 obtained in step-(d) may be subjected to usual work up, followed by isolation from a suitable solvent by conventional methods as described hereinabove.
  • the solvent used for isolating/recrystallizing pure apixaban of formula 1 is selected from the group consisting of water, acetone, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, dichloromethane, toluene, N,N-dimethyformamide, acetonitrile, and mixtures thereof.
  • the solid obtained in any of the above process steps may be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
  • the intermediate compounds of formulae 2, 3, 4, 5 and 6 obtained by the process described herein are isolated as solid state forms in substantially pure form.
  • substantially pure refers to the intermediates compounds of formulae 2, 3, 4, 5 and 6 synthesized herein, having a purity of greater than about 95 wt%, specifically greater than about 98 wt%, more specifically greater than about 99 wt%, and still more specifically greater than about 99.5 wt%.
  • the purity is preferably measured by High Performance Liquid Chromatography (HPLC).
  • HPLC High Performance Liquid Chromatography
  • the purity of the intermediate compounds of formulae 2, 3, 4, 5 and 6 obtained by the processes disclosed herein is about 97% to about 99.9% as measured by HPLC.
  • the 3,3-dichloro-l-(4-iodophenyl)-piperidin-2-one of formula 6 is prepared by reacting 4-iodoaniline with 5-bromovaleryl chloride in the presence of triethylamine in dimethylformamide to produce 5-bromo-pentanoic acid-(4-iodophenyl)amide, which is then treated with a base to produce l-(4-Iodophenyl)-piperidin-2-one to produce 3,3- dichloro- 1 -(4-iodophenyl)-piperidin-2-one of formula 6.
  • the isolation of 5-bromo-pentanoic acid-(4-iodophenyl)amide is carried out as per the process exemplified in example 1.
  • the solid state form of the 5-bromo-pentanoic acid-(4-iodophenyl)amide, obtained by the process exemplified herein is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 6.38, 12.81, 19.30, 19.83, 22.71, 23.67, 24.53, 24.72, 25.82, 27.00, 29.44, 32.07, 32.43, 39.16 and 40.53 ⁇ 0.2 degrees 2-theta substantially in accordance with Figure 3.
  • the isolation of l-(4-Iodophenyl)-piperidin-2-one is carried out as per the process exemplified in example 2.
  • the solid state form of the l-(4-Iodophenyl)-piperidin-2-one, obtained by the process exemplified herein is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 13.77, 14.55, 15.65, 18.60, 18.89, 20.59, 23.18, 23.69, 24.28, 24.64, 27.34, 27.64, 28.94, 35.68, 37.25, 38.18 and 41.32 ⁇ 0.2 degrees 2-theta substantially in accordance with Figure 4.
  • the isolation of 3, 3 -dichloro- l-(4-iodophenyl)-piperidin-2-one of formula 6 is carried out as per the process exemplified in example 3.
  • the solid state form of the 3,3-dichloro-l-(4-iodophenyl)-piperidin-2-one of formula 6, obtained by the process exemplified herein, is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 8.83, 11.79, 12.63, 15.15, 16.60, 17.73, 20.12, 22.56, 22.90, 23.87, 23.97, 24.21, 24.40, 24.64, 26.78, 27.85, 28.07, 29.40, 29.53, 30.60, 31.32, 32.30, 34.54, 36.37, 42.03 and 45.37 ⁇ 0.2 degrees 2-theta substantially in accordance with Figure 5.
  • the apixaban of formula 1 and its intermediates thereof obtained by the process disclosed herein may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
  • ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
  • the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 90°C.
  • the drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like.
  • the Apixaban obtained by the processes disclosed herein has a purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC.
  • reflux temperature means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
  • room temperature or "RT” refer to a temperature of about 15°C to about 35°C.
  • RT can refer to a temperature of about 20°C to about 30°C.
  • the X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X- ray powder diffractometer equipped with a Cu-anode (copper- ⁇ radiation). Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 38 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
  • Step-1 Preparation of l-(4-Iodophenyl)-3-morpholine-5,6-dihydro-2H-pyridin-2-one 3,3-Dichloro-l-(4-iodophenyl)-piperidin-2-one (100 g) was added to morpholine (352 g) at room temperature, followed by heating the mixture at reflux and then stirring for 2-3 hours at the same temperature. The reaction mass was cooled to room temperature, followed by drop- wise addition of water (1056 ml) over a period of 1 hour at the same temperature and then stirring the mass for 30 minutes at room temperature.
  • Step-2 Ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH- py razolo [3,4-c] py ridine-3-carboxy late
  • the resulting toluene layer was washed with water (200 ml x 2), followed by distillation of toluene layer under vacuum at 90°C to obtain a residue (164 g).
  • 4N Hydrochloric acid (79.2 g) and dichloromethane (315 ml) were added to the resulting residue and then stirred for 2 hours at room temperature.
  • the reaction mass was washed with 2% sodium bicarbonate solution (200 ml), followed by washing with water (200 ml) and then adjusting the pH to 6.
  • the resulting dichloromethane layer was treated with carbon (10 g), followed by distillation under vacuum at 55°C to obtain a residue (175 g).
  • Chloroform 200 ml was added to l-(4-iodophenyl)-piperidin-2-one (100 g) at room temperature to form a clear solution, followed by the addition of phosphorous pentachloride (242.4 g) at the same temperature. The resulting mixture was stirred for 2 hours at reflux and then cooled the mass to room temperature. The reaction mass was added to ice, followed by separation of the layers. The resulting aqueous layer was extracted thrice with chloroform (200 ml x 3). The combined organic layer was washed subsequently with 20% sodium bicarbonate (100 ml) solution and water (100 ml + 50 ml).
  • Piperidin-2-one (95.5 g) was added to toluene (2000 ml) and the mixture was heated to reflux while removing the collected water through Dean-Stark apparatus under nitrogen atmosphere. The reaction mass was cooled to room temperature and then stirred for 15 minutes under nitrogen atmosphere at the same temperature, followed by the addition of ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridine-3-carboxylate (100 g). The resulting mixture was stirred for 15 minutes under nitrogen atmosphere, followed by the addition of potassium carbonate (28.5 g) and then stirring for 15 minutes under nitrogen atmosphere.
  • Cuprous iodide (14.6 g) and 8- hydroxyquinoline (11.2 g) were added to the reaction mass and then heated to reflux under nitrogen atmosphere, followed by portion-wise addition of potassium carbonate (28.5 g x 3) for every 5 hours.
  • the reaction mass was filtered and then washed with toluene (200 ml x 2).
  • the resulting filtrate was washed with 30% aqueous hypo solution (2 x 100 ml).
  • Aqueous ammonia (100 ml) was added to the resulting toluene layer and then stirred for 3 hours at room temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Nouveau procédé commercialement viable et industriellement avantageux pour la préparation de 1- (4-méthoxyphényl)-7-oxo-6-[4- (2-oxo -1-pipéridinyl) phényl]-4,5,6,7-tétrahydro-1 H-pyrazole-[3,4-c] pyridine-3-carboxamide, à rendement élevé et présentant une grande pureté, à l'aide d'un nouvel intermédiaire 3-chloro-1-(4-iodophényl)-5,6-dihydropyridine-2 (1H)-one.
PCT/IN2014/000347 2014-05-23 2014-05-23 Nouveau procede pour la preparation d'un compose contenant du lactame WO2015177801A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112409355A (zh) * 2020-12-29 2021-02-26 南京法恩化学有限公司 一种阿哌沙班的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6919451B2 (en) * 2001-12-10 2005-07-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
US20060069258A1 (en) * 2004-09-28 2006-03-30 Rafael Shapiro Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones
US20120201816A1 (en) * 2001-09-21 2012-08-09 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor xa inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120201816A1 (en) * 2001-09-21 2012-08-09 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor xa inhibitors
US6919451B2 (en) * 2001-12-10 2005-07-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
US20060069258A1 (en) * 2004-09-28 2006-03-30 Rafael Shapiro Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112409355A (zh) * 2020-12-29 2021-02-26 南京法恩化学有限公司 一种阿哌沙班的制备方法
CN112409355B (zh) * 2020-12-29 2022-04-05 南京法恩化学有限公司 一种阿哌沙班的制备方法

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