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WO2018127936A1 - Novel economic metal free process for apixaban - Google Patents

Novel economic metal free process for apixaban Download PDF

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Publication number
WO2018127936A1
WO2018127936A1 PCT/IN2018/050003 IN2018050003W WO2018127936A1 WO 2018127936 A1 WO2018127936 A1 WO 2018127936A1 IN 2018050003 W IN2018050003 W IN 2018050003W WO 2018127936 A1 WO2018127936 A1 WO 2018127936A1
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compound
formula
halogen
optionally substituted
alkyl
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French (fr)
Inventor
Swapnil MOHILE
Manoj Patil
Ravindra LANDGE
Sandeep TAPKIR
Shivaji GUGALE
R. Sridharan
Sudhir Nambiar
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Hikal Ltd
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Hikal Ltd
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel, economical, efficient, metal free, environment friendly and commercially viable process for preparation of Apixaban with high yield and high chemical purity.
  • Apixaban is chemically known as l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide and was found potent as direct inhibitor of factor Xa.
  • Apixaban is commercially available as Eliquis in the form of pharmaceutical preparation. It is an anticoagulant useful for treatment of venous thromboembolic event also indicated the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
  • the structure of Apixaban of formula (I) is represented below.
  • Apixaban is disclosed in US Patent US 6,967,208B2 (henceforth the US '208) and the said patent further discloses a series of coagulation factor Xa inhibitors and is developed for oral administration in a variety of indications that require the use of an antithrombotic agent.
  • the International (PCT) publication WO 2003/026652A1 discloses the process for the preparation of pyrazole-pyridine derivatives.
  • the said US '208 is a family equivalent of WO '652.
  • Another synthetic process described in the said patent family involves expensive aryl iodide intermediates and rarely used or unusual ligands such as bromotris(triphenylphosphine)copper ligand. Use of such ligands and expensive aryl iodides are not preferred for industrial synthesis.
  • the PCT publication WO2014/072884 A 1 discloses a process for the preparation of Apixaban and novel intermediates useful in the synthesis of Apixaban.
  • the disclosed synthesis involves the use of expensive key starting material, flammable and toxic ethyl oxalyl chloride and use of ethylene glycol as a solvent in final step, which is difficult to remove.
  • the final step in this process involves higher temperature reaction (115°C to 120°C) in pressure reactor, which is difficult to achieve on industrial scale production.
  • the main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is simple, economical, user- friendly and commercially viable.
  • Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale and to avoid excessive use of reagent(s) and organic solvent(s), which makes the present invention eco-friendly as well.
  • Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a high yield with high chemical purity.
  • the present invention provides an improved process for the preparation of Apixaban of formula (I) which comprises the steps of:
  • Formula (I) a) obtaining a compound of formula (IV) by reacting a compound of formula (II) with compound of formula (III) in the presence of a suitable base in a suitable solvent or mixture thereof at a suitable temperature;
  • a compound of formula (VI) by reacting a compound of formula (V) with a suitable halogenating agent at a suitable temperature in a suitable solvent followed by amidation using a suitable source of ammonia in a suitable solvent or mixture thereof; d) obtaining a compound of formula (VIII) by reacting a compound of formula (VI) with a compound of formula (VII) in the presence of a suitable organometallic coupling agent or base or Lewis acid at a suitable temperature in a suitable solvent or mixture thereof;
  • j) optionally obtaining a compound of formula (I) by reacting a compound of formula (X) in presence of a suitable halogenating agent at a suitable temperature followed by coupling with a compound of formula (VII) in presence or absence of coupling agent, in a suitable base and suitable solvent or mixture of solvents thereof.
  • the compound of formula (IV) of step (a) is obtained by cycloaddition of compound of formula (II) with compound of formula (III), wherein the substituent "R" appeared in compounds (III) and (IV) may be selected from the group consisting of Ci-C 6 alkyl chain, branched, substituted or containing a double bond, optionally with non-substituted aromatic ring or a group containing C7-C 10 alkyl, aryloptionally substituted by any heteroatomin presence of suitable base in a suitable solvent.
  • the said solvent used in step (a) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, ethyl acetate, 1,4-dioxane, ethylene dichloride, chloroform, methyl tert-butyl ether, cyclohexane, toluene, xylene, tetrahydrofuran, dichloromethane, 1,2- dichloroethane and the like or mixture of solvents thereof; most preferably toluene.
  • step (a), step (b) and step (e) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, ⁇ , ⁇ -diisopropylethylamine, imidazole, l,8diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, 1,5- diazabicyclo[4.3.0]non-5-ene, 4-dimethylaminopyridine, pyridine, morpholine, N-methyl morpholine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; most preferably triethyl amine, potassium carbonate.
  • mono, di and tri alkyl amine such as triethyl amine, ⁇ , ⁇ -diisopropylethylamine,
  • step (a) and step (b) are preferably carried out at 0°C to ambient temperature or to reflux temperature; more preferably at ambient to reflux temperature.
  • the crude compound of formula (IV) of the step (a) is preferably used as such or may be purified by distillation or crystallization or by different purification techniques well understood by those skilled in the art.
  • the said acid used in step (b) is preferably selected from group consisting of cone.
  • step (b) wherein the said acid strength for hydrolysis of step (b) is preferably selected from 0.1N-12.0N, more preferably 0.1N- 6. ON and most preferably from 4.0N-6.0N.
  • the said solvent used in step (b) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, isopropyl acetate, dimethyl sulfoxide, acetic acid, dichloromethane, chloroform, tetrahydrofuran,2-methyltetrahydrofuran, dimethylformamide, 1,4-dioxane, methyl tert-butyl ether, cyclohexane and the like or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, dimethyl sulfoxide, acetic acid, tetrahydrofuran, 1,4-dioxane, chloroform and the like or mixture thereof; most preferably water.
  • the said halogenating agent used in step (c) is preferably selected from the group of sulphur halide oxides such as thionyl chloride, thionyl bromide, a-halo acids such as oxalyl chloride, oxalyl bromide or phosphorous (V) halides, phosphorous (III) halides, phosphorous oxyhalides, hydrohalic acids, cyanuric chloride, bromine, chlorine, iodine, N-bromosuccinimide(NBS), N- iodosuccinimide(NIS), N-chlorosuccinimide(NCS), triphenyl phosphine or suitable halogenating agent, more preferably oxalyl chloride, oxalyl bromide, thionyl chloride, phosphorous (V) halides and the like; most preferably thionyl chloride.
  • sulphur halide oxides such as
  • the said ammonia source used in step (c) is preferably selected from ammonia gas, aqueous ammonia solutions, ammonium carbonates, ammonium carbamates, ammonium bicarbonate and ammonium acetates and the like; most preferably aq. ammonia.
  • the said solvent used in step (c) is preferably selected from the group consisting of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, methyl tert-butyl ether, cyclohexane or any halogenated solvent and the mixture thereof; more preferably toluene, tetrahydrofuran and more preferably dichloromethane, 1,2- dichloroethane, chloroform or carbon tetrachloride and the like or mixture of solvents thereof; most preferably dichloromethane.
  • step (c), step (g) and step (i) is preferably carried out at 0°C to ambient temperature to reflux temperature; more preferably at 0°C to reflux temperature.
  • the said solvent used in step (d) is preferably selected from the group consisting of ethyl acetate, 1,4-dioxane, 1,2- dichloroethane, chloroform, dichloromethane, methyl tert-butyl ether, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide,2-methyltetrahydrofuran, ethers and the like or mixture of solvents thereof; most preferably toluene.
  • the said organometallic coupling agent is a Lewis acid or a base used in step (d) which is preferably selected from the group of trialkyl aluminium, dialkyl aluminium, aluminium trihalides, or group consisting of alkyl lithium agents such as n-butyllithium, sec-butyllithium, i-butyllithium and the mixture thereof, more preferably trimethyl aluminium or n-butyllithium; most preferably trimethyl aluminium.
  • reaction temperature of step (d) is preferably carried out at -10°C to ambient temperature or reflux temperature, more preferably at -10°C to reflux temperature in an open or self-generated pressure reaction condition.
  • the said protecting group used in step (e) is preferably selected from the group consisting of acetic anhydride, trifluoroacetic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, camphor sulfonyl chloride, p-benzenesulfonyl chloride,p-trifluoromethyl benzenesulfonyl chloride; most preferably methanesulfonyl chloride.
  • the said solvent used in step (e) is preferably selected from the group consisting of water, ethyl acetate, 1,4-dioxane, 1,2- dichloroethane, chloroform, dichloromethane, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, 2- methyltetrahydrofuran, ethers and the like or mixture of solvents thereof; most preferably dichloromethane .
  • step (e), step (f) and step (h) is preferably carried out at 0°C to ambient temperature to reflux temperature, more preferably at 0°C to ambient temperature.
  • alkali or alkaline earth metal hydroxides may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, caesium hydroxide (CsOH), Calcium hydroxide (Ca(OH) 2 ), magnesium hydroxide (Mg(OH) 2 ), barium hydroxide (Ba(OH) 2 ), Ci-Csquaternary ammonium hydroxide, tetrabutyl ammonium hydroxide, metal Ci-C 6 straight or branched chain alkoxide or suitable basic resins or related compounds having strength for hydrolysis; most preferably sodium hydroxide, potassium hydroxide.
  • the said solvent used in step (f) is preferably selected from the group consisting of water, alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isopropyl acetate, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane and the like or mixture of solvents thereof; most preferably methanol.
  • alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isopropyl acetate, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane and the like or mixture of solvents thereof; most preferably methanol.
  • the said halogenating agent used in step (g), step (h) and step j) is preferably selected from the group consisting of sulphur dihalide oxides such as thionyl chloride, thionyl bromide, a-halo acids such as oxalyl chloride, oxalyl bromide or phosphorous (V) halides, phosphorous (III) halides, phosphorous oxyhalides, hydrohalic acids, cyanuric chloride, bromine, chlorine, iodine, n- bromosuccinimide, n-chlorosuccinimide, n-iodosuccinimide, triphenyl phosphine and the like; most preferably thionyl chloride.
  • sulphur dihalide oxides such as thionyl chloride, thionyl bromide
  • a-halo acids such as oxalyl chloride, oxalyl bromide
  • the said base of step (g) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, ⁇ , ⁇ -diisopropylethylamine, l,8-Diazabicyclo[5.4.0]undec-7-ene, 1,5- Diazabicyclo[4.3.0]non-5-ene, 1,5-Diazabicyclo [4.3.0]non-5-ene, imidazole, 4- dimethylaminopyridine, pyridine, metal Ci-C 6 straight or branched chain alkoxide, potassium carbonate, potassium ie/t-butoxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate and / or alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide; most preferably triethyl amine or 4-dimethylaminopyridine.
  • mono, di and tri alkyl amine such as triethyl amine, ⁇ , ⁇ -di
  • the substituent "X" appeared in compounds (XI), (XII) and (XIII) is preferably selected from any halogenating group such as chloride, bromide, iodide, and fluoride.
  • step (g) and step (h) is preferably selected from the group consisting of propylphosphonic anhydride(T 3 P) ,hydroxybenzotriazole(HOB t) , 1 -Ethyl- 3 - (3 - dimethylaminopropyl)carbodiimide(EDCI), 1 -[Bis(dimethylamino)methylene]- 1H- 1 ,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate(HATU), benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate(Py-BOP), (Benzotriazol- 1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent), ⁇ , ⁇ '- Dicyclohexylcarbodiimide(DCC),
  • the said base of step (g) and (h) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, N, N-diisopropylethylamine, ⁇ , ⁇ -diisopropylamine, l,8-diazabicyclo[5.4.0]undec-7- ene, l,5-diazabicyclo[4.3.0]non-5-ene, 1,5-diazabicyclo [4.3.0]non-5-ene, imidazole, 4- dimethylaminopyridine, pyridine, morpholine, n-methyl morpholinein presence of suitable additives such as hydroxybenzotriazole, 4-dimethylaminopyridine; most preferably triethyl amine, 4-dimethylaminopyridine.
  • mono, di and tri alkyl amine such as triethyl amine, N, N-diisopropylethylamine,
  • the said solvent used in step (g) and (h) is preferably selected from the group consisting of water, ethyl acetate, 1,4-dioxane, 1,2-dichloroethane, chloroform, dichloromethane, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethers and the like or mixture of solvents thereof; most preferably acetonitrile, 2-methyltetrahydrofuran, ethyl acetate, dichloromethane .
  • step (b), step (c), step (d), step (e), step (f), step (g) and step (h) is preferably used as such or more preferably purified by distillation or by different purification techniques well understood by those skilled in the art.
  • step (i) and step j) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, N,N-diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, 1,5-diazabicyclo [4.3.0]non-5-ene, imidazole, 4-dimethylaminopyridine, pyridine, metal Ci-C 6 straight or branched chain alkoxide such as sodium methoxide, potassium methoxide, potassium t- butoxide, sodium, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or al
  • step (i) and step (j) is preferably selected from the group consisting of water, alcohols ethyl acetate, 1,4-dioxane, 1,2-dichloroethane, chloroform, dichloromethane, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethers and the like or mixture of solvents thereof; more preferably toluene, xylene, tetrahydrofuran, 1,2-dichloroethane, chloroform, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone, alcohols and the like or mixture of solvents thereof
  • the crude compound of formula (I) is purified by recrystallization or purified by acid-base treatment by reacting with suitable acids to form salts which further converted into Apixaban.
  • suitable acid is preferably selected from group consisting of hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, succinic acid, oxalic acid, formic acid, acetic acid, p-toluene sulfonic acid, p-benzene sulfonic acid and the like.
  • the crude compound of formula (I) is preferably purified by crystallization in different solvents like alkanes such as hexanes, heptanes, pentane, cyclohexane, cyclopentane cycloheptane, acetates such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ethers such as methyl tert-butyl ether, diisopropyl ether, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran alcohols such as methanol, ethanol, propanol, isopropanol, isobutanol, n-butanol, isoamyl alcohol, hexanol, allyl alcohol, sulfolane, ⁇ , ⁇ ' -dimethyl acet
  • Example 1 Preparation of ethyl l-(4-methoxyphenvi)-7-oxo-lH,4H,5H,7H- pyrano[3,4-c1pyrazole-3-carboxylate (IV) .
  • Example 1.1 To a stirred solution of compound II (8.0g, 0.0452 moles) and compound III (13.16g, 0.0542 moles) in toluene (60mL), triethylamine (18.90mL, 0.1355 moles) was added and heated the reaction mixture to reflux temperature for 6 to 8h. The reaction mixture was allowed to cool to 25°C to 30°C and quenched by water (80mL), stirred for lh, filtered and suck dried.
  • Example 1.2 To a stirred solution of compound II (8.0g, 0.0452 moles) and compound III (11.6g, 0.0452 moles) in toluene (80mL), potassium carbonate(31.23g, 0.226 moles) and KI (0.75g, 0.00452 moles) was added at 25°C to 30°C and heated the reaction mixture to reflux temperature for lOh. The reaction mixture was allowed to cool to 25°C to 30°C, quenched by water (160mL) and extracted with ethyl acetate (240mL). The organic layer was evaporated under reduced pressure to yield crude compound. Crude compound was purified using methyl tert-butyl ether: methanol, filtered and suck dried to yield pale yellow to brown solid compound of formula IV (7.0 g, 50% yield).
  • Example 2.1 A stirred solution compound of formula IV (30g, 0.0948 moles) in 6N aq. hydrochloric acid (300mL) was heated to reflux temperature for 6 to 12h. The reaction mixture was allowed to cool to 20°C to 25 °C and then to 10°C to 15°C. The reaction mixture was stirred at 10°C to 15°C for lh, filtered and washed with water (300mL). The water was removed by azeotropic distillation using toluene at 110°C for 2 to 5h and dried under reduced pressure at 50°C to 55°C to yield off white to brown solid compound of formula V (23g, 85% yield) with HPLC purity 98.43%,LCMS: 289 [M+H] + ,
  • Example 2.2 A stirred solution compound of formula IV (250g, 0.790 moles) in 4N aq. hydrochloric acid (3.75L) was heated to 90°C to 95°C for 12 to 24h. The reaction mixture was allowed to cool to 20°C to 25°C and stirred for additional lh. Filtered and washed with water (750mL). The water was removed by azeotropic distillation using toluene at 110°C for 2 to 5h and dried under reduced pressure at 50°C to 55°C to yield off white to brown solid compound of formula V (209g, 91.7% yield) with HPLC purity 96.71%.
  • Example 3.1 To a stirred solution of compound V (15g, 0.0520 moles) in dimethylformamide (0.06mL), dichloromethane (225mL), thionyl chloride (19.8g, 0.1665 moles) was added dropwise at 20°C to 30°C and heated the reaction mixture to reflux temperature for 4 to 5h. The reaction mixture was cooled to 10°C to 15°C under nitrogen atmosphere and aq. ammonia (75mL) was added below 25°C and stirred for 2 to 3h (pH was maintained at 11 to 12).
  • Example 3.2 To a stirred solution of compound V (103g, 0.3572 moles) in dimethylformamide (lmL), dichloromethane (3L), thionyl chloride (63.8g, 0.535 moles) was added dropwise at 20°C to 30°C and heated the reaction mixture to reflux temperature for 5 to 8h. The reaction mixture was gradually cooled to 20°C to 25°C under nitrogen purging, further cooled to 10°C to 15°C and ammonia gas was purged through the reaction mixture for 3 to 5h. Water (1L) was added below 25°C and stirred for 15 to 20 min. The reaction mixture was filtered, washed with water (3L) and dried under reduced pressure at 50°C to 55°C to yield off white to brown solid compound VI (88g, 85.7% yield) with HPLC purity 98.22%.
  • Example 4 Preparation of 4-(2-hvdroxyethyl)-l-(4-methoxyphenyl)-5-N-[4-(2 oxopiperidin-l-yl)phenyl1-lH-pyrazole-3,5-dicarboxamide.
  • Example 6.1 To a stirred solution of compound VI (3.0g, 0.0144 moles) in methanol (15mL)aq. KOH solution (1.16 g, 0.0432 moles in 15 mL water) was added dropwise at 20°to 25°C for 10 to 15min. and maintained for 1 to 2h. The reaction mixture was evaporated under reduced pressure, water (50mL) was added and allowed to cool to 10°C to 15°C. The pH maintained at 1.0 to 2.0 using 50% aq. hydrochloric acid solution and further stirred for lh.
  • Example 6.2 To a stirred solution of compound VI (50.0g, 0.1736 moles) in methanol (250mL) at 0 to 5 °C, aq. NaOH solution (13.88 g, 0.3472 moles in 250 mL water) was added dropwise below 10°C and maintained for 2 to 3h at 15°C to 20°C. The reaction mixture was again cooled to 0°C to 5°C and adjusted the pH of reaction mass at 1.0 to 2.0 using 1 N aq. hydrochloric acid solution and further stirred for 0.5h.
  • aq. NaOH solution 13.88 g, 0.3472 moles in 250 mL water
  • reaction mixture was filtered, washed with water and removed traces of water by azeotropic distillation using toluene followed by dried under reduced pressure at 50°C to 55°C to yield off white to brown solid compound X (49.0g, 92% yield) with HPLC purity 98.82%.
  • Example 7.2 To a stirred solution of compound X (200. Og, 0.6551 moles) in 2-MeTHF (3.0 L, 15 V), thionyl chloride (187. lg, 1.5722 moles) was added in one lot at 20°C to 30°C and further heated for 5 to 6h at 75°C to 85°C. The reaction mixture was concentrated under reduced pressure at 45°C to 50°C followed by stripping with toluene (10V). Filtered the solid obtained, washed with toluene (400mL, 2V) and dried under reduced pressure at 40°C to 50°C to yield off white to brown solid compound XII (206g, 97% yield) with HPLC purity 96.86%.
  • Example 8 Preparation of 4-(2-chloroethyl)-l-(4-methoxyphenyl)-5-N-[4-(2 oxopiperidin-l-yl) phenyll-lH-pyrazole-3,5-dicarboxamide.
  • Example 8.1 To a stirred solution of compound XII(0.05g, 0.1544 mmoles), compound VII(0.029g,0.1544 mmoles), triethyl amine (0.23g, 0.2316 mmoles), 4- dimethylaminopyridine (5mg,0.04632 mmoles) in dichloromethane (lmL,20 V), the ⁇ , ⁇ '- dicyclohexylcarbodiimide (0.035g, 0.1698 mmoles) in dichloromethane (l.OmL, 20 V) solution was added dropwise at 0°C to 5°C. The reaction mixture was stirred at 25°C to 30°C for 12h and quenched using saturated brine solution (2mL).
  • Example 8.2 To a stirred solution of compound XII (O. lg, 0.3088 mmoles) in ethyl acetate (2mL), thionyl chloride(0.32g,2.78 mmoles) was added at 20°C to 30°C and reflux for 5 to 6h. The reaction mixture was evaporated under reduced pressure resulted into unstable compound XI (without any isolation) which subsequently dissolved in dichloromethane (2mL). To this reaction mixture triethylamine (0.12mL,0.9264 mmoles) and compound VII (0.06 g, 0.3088 mmoles) was added at 20°C to 30°C stirred at 25°C for 6h.
  • Example 8.3 To a stirred solution of compound XII (50. Og, 0.1544 moles) in tetrahydrofuran(350mL),N,N,N N'-Tetramethyl-O-(lH-benzotriazol-l- yl)uroniumhexafluorophosphate(74.35g, 0.231 moles i.e. TBTU), triethylamine (26 mL, 0.185 moles) and Compound VII (52.88 g, 0.278 moles) was added sequentially under stirring at 20°C to 30°C and maintained for next 24h. Filtered the solid, washed with water (500mL) and dried under reduced pressure at 50°C to yield crude compound XIII.
  • the crude compound was purified by crystallization in mixture of toluene: methanol (4: 1, 5V).
  • Example 9 Preparation of 4-(2-chloroethyl)-l-(4-methoxyphenyl)-5-N-[4-(2 oxopiperidin-l-yl)phenyl1-lH-pyrazole-3,5-dicarboxamide.
  • the crude compound was purified using ternary system of solvent [(Acetonitrile (10V):Dichloromethane (8V):Methanol (6V)] to yield off white to brown solid coloured compound XIII(0.733g, 65% yield) with HPLC purity 98.90%,
  • Example 10 Preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l yl)phenyll-4,5,6,7-tetrahydro-lH-pyrazolor3,4-cl pyridine-3-carboxamide.
  • Example 12 Preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyll-4,5,6,7-tetrahydro-lH-pyrazolor3,4-cl pyridine-3-carboxamide,
  • Example 12.1 To a stirred solution of compound XIII (lOg, 0.02016 moles) in dichloromethane(150niL, 15 V), potassium t-butoxide (6.78g, 0.06048 moles) was added lotwise for 15 min. at 10°C to 15°C. The reaction mixture was stirred at 20°C to 25°C for 3 to 6h, evaporated under reduced pressure at 40°C to 45°C and water (lOOmL) was added, stirred for additional lh. The reaction mixture was filtered, washed with water (50mL), dried under reduced pressure to yield crude compound I.
  • potassium t-butoxide 6.78g, 0.06048 moles
  • Example 12.2 To a stirred solution of aq. NaOH (115g, 2.87 moles) in 1.78L water and 1.78L methanol was added compound XIII (178g, 0.3591 moles) at 25°C to 30 °C. The resultant mixture was heated to 30°C to 35 °C for 4 to 6h. Water (1.78L, 10V) was then added at 20°C to 25 °C, stirred for additional 10 min, filtered the reaction mixture and washed with water twice (3.56L, 10V), dried under reduced pressure to yield crude compound I. The crude compound was purified by recrystallisation in mixture of toluene: methanol (2: 1, 15V) to yield off white to white solid of compound (I) (118g, 72% yield) with HPLC purity 99.88%.
  • Reaction mixture was then concentrated under reduced pressure at 50°C till 3 V followed by addition of 1.18L water and stirred for additional 30 min, filtered the reaction mixture and washed with water 1.18L twice, dried under reduced pressure at 50°C to 60°C to yield white solid of compound (I)(114g, 97% yield) with desired (N-l) form and HPLC purity 99.90%.

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Abstract

The present invention relates to provide an improved and novel process for the preparation of Apixaban of formula (I), which is simple, economical, metal-free, efficient, user and environment friendly, moreover commercially viable.

Description

NOVEL ECONOMIC METAL FREE PROCESS FOR APIXABAN
FIELD OF THE INVENTION
The present invention relates to a novel, economical, efficient, metal free, environment friendly and commercially viable process for preparation of Apixaban with high yield and high chemical purity.
BACKGROUND OF THE INVENTION
Apixaban is chemically known as l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide and was found potent as direct inhibitor of factor Xa. Apixaban is commercially available as Eliquis in the form of pharmaceutical preparation. It is an anticoagulant useful for treatment of venous thromboembolic event also indicated the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. The structure of Apixaban of formula (I) is represented below.
Figure imgf000002_0001
Formula (I)
Apixaban is disclosed in US Patent US 6,967,208B2 (henceforth the US '208) and the said patent further discloses a series of coagulation factor Xa inhibitors and is developed for oral administration in a variety of indications that require the use of an antithrombotic agent. The International (PCT) publication WO 2003/026652A1 (henceforth the WO '652) discloses the process for the preparation of pyrazole-pyridine derivatives. The said US '208 is a family equivalent of WO '652.
The International (PCT) publication WO 2003/049681 and its corresponding US Patent US 6,919,451B2 and US Patent US 7,153,960B2 discloses the process for the preparation of pyrazole-pyridine derivatives including the Apixaban. The said process is described in Scheme (I) and (II). The process disclosed in the said patents involves δ- valerolactum which underwent dichlorination followed by elimination resulting to chloro derivative, which further underwent cycloaddition reaction with ethyl (2Z)-chloro[(4- methoxyphenyl)hydrazo no] acetate followed by alkylation/arylation using aryl iodide derivative. The resulting intermediate is underwent amidation via mixed anhydride of acid to give Apixaban. The arylation of amide relatively requires harsh conditions i.e. higher temperature.
Another synthetic process described in the said patent family involves expensive aryl iodide intermediates and rarely used or unusual ligands such as bromotris(triphenylphosphine)copper ligand. Use of such ligands and expensive aryl iodides are not preferred for industrial synthesis.
Sche
Figure imgf000003_0001
Schem
Figure imgf000003_0002
Another synthetic process is described in CN102675314A; which discloses the process for preparation of Apixaban by cyclization of /?-nitroaniline with 5-halopentanoyl chloride, resulting into l-(4-nitrophenyl)-2-piperidinone which underwent dichlorination followed by elimination, resulting into 3-chloro-5,6-dihydro-l-(4-nitrophenyl)- 2(lH)-pyridinone which further underwent reaction with ethyl (2Z)-chloro[(4- methoxyphenyl)hydrazono]acetate, the resulting ethyl 4,5,6,7-tetrahydro-l-(4- methoxyphenyl)-6-(4-nitrophenyl)-7-oxo- lH-yrazolo[3,4-c] pyridine-3-carboxylate is underwent reduction followed by cyclization with 5-halovalaroyl chloride and the resulting intermediate further underwent amidation to give Apixaban. The synthesis involves the use of excess of 5-bromopentanoyl chloride and phosphorus pentachloride which tend to be unstable and difficult to handle intermediates, expensive palladium carbon conditions and use of dimethylformamide (DMF) as a solvent in final step which remain in residual form. The same is difficult to remove and hence resulted the lower purity of the final product. Another drawback of the said process that the synthesis route is difficult to achieve large scale industrial production of Apixaban. Similar synthesis is subsequently reported in CN104262338A. The said process is described in Scheme (III) and scheme (IV) respectively.
Scheme III:
Figure imgf000004_0001
Scheme IV:
Figure imgf000005_0001
The PCT publication WO2014/072884 A 1 discloses a process for the preparation of Apixaban and novel intermediates useful in the synthesis of Apixaban. However, the disclosed synthesis involves the use of expensive key starting material, flammable and toxic ethyl oxalyl chloride and use of ethylene glycol as a solvent in final step, which is difficult to remove. Moreover, the final step in this process involves higher temperature reaction (115°C to 120°C) in pressure reactor, which is difficult to achieve on industrial scale production.
Accordingly, based on the drawbacks mentioned in all the prior arts which involves the complex synthesis, use of expensive, hazardous reagents, drastic reaction conditions etc. Therefore, there is an urgent need for commercial and economical viable process of highly pure Apixaban of formula (I). Thus, the present inventors motivated to pursue the process development research which involves the use of efficient, environment friendly and less hazardous reagents to obviate from the aforesaid drawbacks associated with the prior arts.
OBJECT OF THE INVENTION
The main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is simple, economical, user- friendly and commercially viable.
Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale and to avoid excessive use of reagent(s) and organic solvent(s), which makes the present invention eco-friendly as well. Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a high yield with high chemical purity.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of Apixaban of formula (I) which comprises the steps of:
Figure imgf000006_0001
Formula (I) a) obtaining a compound of formula (IV) by reacting a compound of formula (II) with compound of formula (III) in the presence of a suitable base in a suitable solvent or mixture thereof at a suitable temperature;
b) obtaining a compound of formula (V) by hydrolyzing ester group of formula (IV) with a suitable acid or a base at a suitable temperature in aqueous or organic solvent or a mixture thereof;
c) obtaining a compound of formula (VI) by reacting a compound of formula (V) with a suitable halogenating agent at a suitable temperature in a suitable solvent followed by amidation using a suitable source of ammonia in a suitable solvent or mixture thereof; d) obtaining a compound of formula (VIII) by reacting a compound of formula (VI) with a compound of formula (VII) in the presence of a suitable organometallic coupling agent or base or Lewis acid at a suitable temperature in a suitable solvent or mixture thereof;
e) converting a compound of formula (VIII) to form a compound of formula (IX) by treating with a suitable protecting group in the presence of a suitable base at a suitable temperature in an aqueous or organic solvent or mixture thereof;
f) optionally converting a compound of formula (VI) to a compound of formula (X) by hydrolyzing with a suitable alkali, an alkaline earth metal base at a suitable temperature in an aqueous or an organic solvent or mixture thereof;
g) optionally obtaining a compound of formula (XIII) by reacting a compound of formula (X) with a suitable halogenating agent with a suitable base in the presence ofa suitable solvent to a compound of formula (XI) followed by coupling with a compound of formula (VII) in presence of a base or in the presence of a suitable coupling agent at a suitable temperature in a suitable solvent or mixture thereof;
h) obtaining alternatively a compound of formula (XIII) by reacting a compound of formula (X) with a suitable halogenating agent in a suitable solvent to a compound of formula (XII) followed by coupling with a compound of formula (VII) in presence of suitable coupling agent, suitable base at a suitable temperature in a suitable solvent or mixture thereof;
i) converting a compound of formula (IX) or a compound of formula (XIII) to Apixaban of formula (I) by treating with a suitable base at a suitable temperature in a suitable organic solvent or mixture thereof; and
j) optionally obtaining a compound of formula (I) by reacting a compound of formula (X) in presence of a suitable halogenating agent at a suitable temperature followed by coupling with a compound of formula (VII) in presence or absence of coupling agent, in a suitable base and suitable solvent or mixture of solvents thereof.
Figure imgf000008_0001
DETAILED DESCRIPTION OF THE INVENTION
The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms "a", "an", "the", include plural referents unless the context clearly indicates otherwise.
In accordance with the objectives, wherein the present invention provides an improved process for the preparation of Apixaban of formula (I) via novel synthetic approach.
Accordingly, in an embodiment of the present invention, wherein the compound of formula (IV) of step (a) is obtained by cycloaddition of compound of formula (II) with compound of formula (III), wherein the substituent "R" appeared in compounds (III) and (IV) may be selected from the group consisting of Ci-C6 alkyl chain, branched, substituted or containing a double bond, optionally with non-substituted aromatic ring or a group containing C7-C 10 alkyl, aryloptionally substituted by any heteroatomin presence of suitable base in a suitable solvent.
In an another embodiment of the present invention, wherein the said solvent used in step (a) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, ethyl acetate, 1,4-dioxane, ethylene dichloride, chloroform, methyl tert-butyl ether, cyclohexane, toluene, xylene, tetrahydrofuran, dichloromethane, 1,2- dichloroethane and the like or mixture of solvents thereof; most preferably toluene.
In an another embodiment of the present invention, wherein the said base used in
step (a), step (b) and step (e) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, Ν,Ν-diisopropylethylamine, imidazole, l,8diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, 1,5- diazabicyclo[4.3.0]non-5-ene, 4-dimethylaminopyridine, pyridine, morpholine, N-methyl morpholine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; most preferably triethyl amine, potassium carbonate.
In an another embodiment of the present invention, wherein the said reaction of step (a) and step (b) is preferably carried out at 0°C to ambient temperature or to reflux temperature; more preferably at ambient to reflux temperature.
In an another embodiment of the present invention, wherein the crude compound of formula (IV) of the step (a) is preferably used as such or may be purified by distillation or crystallization or by different purification techniques well understood by those skilled in the art.
In an another embodiment of the present invention, wherein the said acid used in step (b) is preferably selected from group consisting of cone. Hydrochloric acid (HC1), cone, sulfuric acid (H2S04), nitric acid (HNO3), phosphoric acid (H3P04), boric acid (H3B03), hydrogen fluoride (HF), hydrogen bromide (HBr), hydrogen iodide (HI), perchloric acid (HC104) or the said acid may be an acid cationic resins or related compounds having strength for hydrolysis; most preferably cone, hydrochloric acid.
In another embodiment of the present invention, wherein the said acid strength for hydrolysis of step (b) is preferably selected from 0.1N-12.0N, more preferably 0.1N- 6. ON and most preferably from 4.0N-6.0N.
In an another embodiment of the present invention, wherein the said solvent used in step (b) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, isopropyl acetate, dimethyl sulfoxide, acetic acid, dichloromethane, chloroform, tetrahydrofuran,2-methyltetrahydrofuran, dimethylformamide, 1,4-dioxane, methyl tert-butyl ether, cyclohexane and the like or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, dimethyl sulfoxide, acetic acid, tetrahydrofuran, 1,4-dioxane, chloroform and the like or mixture thereof; most preferably water.
In an another embodiment of the present invention, wherein the said halogenating agent used in step (c) is preferably selected from the group of sulphur halide oxides such as thionyl chloride, thionyl bromide, a-halo acids such as oxalyl chloride, oxalyl bromide or phosphorous (V) halides, phosphorous (III) halides, phosphorous oxyhalides, hydrohalic acids, cyanuric chloride, bromine, chlorine, iodine, N-bromosuccinimide(NBS), N- iodosuccinimide(NIS), N-chlorosuccinimide(NCS), triphenyl phosphine or suitable halogenating agent, more preferably oxalyl chloride, oxalyl bromide, thionyl chloride, phosphorous (V) halides and the like; most preferably thionyl chloride.
In an another embodiment of the present invention, wherein the said ammonia source used in step (c) is preferably selected from ammonia gas, aqueous ammonia solutions, ammonium carbonates, ammonium carbamates, ammonium bicarbonate and ammonium acetates and the like; most preferably aq. ammonia.
In an another embodiment of the present invention, wherein the said solvent used in step (c) is preferably selected from the group consisting of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, methyl tert-butyl ether, cyclohexane or any halogenated solvent and the mixture thereof; more preferably toluene, tetrahydrofuran and more preferably dichloromethane, 1,2- dichloroethane, chloroform or carbon tetrachloride and the like or mixture of solvents thereof; most preferably dichloromethane.
In an another embodiment of the present invention, wherein the reaction of step (c), step (g) and step (i) is preferably carried out at 0°C to ambient temperature to reflux temperature; more preferably at 0°C to reflux temperature.
In an another embodiment of the present invention, wherein the said solvent used in step (d) is preferably selected from the group consisting of ethyl acetate, 1,4-dioxane, 1,2- dichloroethane, chloroform, dichloromethane, methyl tert-butyl ether, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide,2-methyltetrahydrofuran, ethers and the like or mixture of solvents thereof; most preferably toluene.
In an another embodiment of the present invention, wherein the said organometallic coupling agent is a Lewis acid or a base used in step (d) which is preferably selected from the group of trialkyl aluminium, dialkyl aluminium, aluminium trihalides, or group consisting of alkyl lithium agents such as n-butyllithium, sec-butyllithium, i-butyllithium and the mixture thereof, more preferably trimethyl aluminium or n-butyllithium; most preferably trimethyl aluminium.
In an another embodiment of the present invention, wherein the reaction temperature of step (d) is preferably carried out at -10°C to ambient temperature or reflux temperature, more preferably at -10°C to reflux temperature in an open or self-generated pressure reaction condition.
In an another embodiment of the present invention, wherein the said protecting group used in step (e) is preferably selected from the group consisting of acetic anhydride, trifluoroacetic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, camphor sulfonyl chloride, p-benzenesulfonyl chloride,p-trifluoromethyl benzenesulfonyl chloride; most preferably methanesulfonyl chloride.
In an another embodiment of the present invention, wherein the said solvent used in step (e) is preferably selected from the group consisting of water, ethyl acetate, 1,4-dioxane, 1,2- dichloroethane, chloroform, dichloromethane, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, 2- methyltetrahydrofuran, ethers and the like or mixture of solvents thereof; most preferably dichloromethane .
In an another embodiment of the present invention, wherein the reaction temperature of step (e), step (f) and step (h) is preferably carried out at 0°C to ambient temperature to reflux temperature, more preferably at 0°C to ambient temperature.
In an another embodiment of the present invention, wherein the said base used in step (f) is preferably selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, alkali or alkaline earth metal hydroxides may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, caesium hydroxide (CsOH), Calcium hydroxide (Ca(OH)2), magnesium hydroxide (Mg(OH)2), barium hydroxide (Ba(OH)2), Ci-Csquaternary ammonium hydroxide, tetrabutyl ammonium hydroxide, metal Ci-C6 straight or branched chain alkoxide or suitable basic resins or related compounds having strength for hydrolysis; most preferably sodium hydroxide, potassium hydroxide.
In an another embodiment of the present invention, wherein the said solvent used in step (f) is preferably selected from the group consisting of water, alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isopropyl acetate, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane and the like or mixture of solvents thereof; most preferably methanol.
In an another embodiment of the present invention, wherein the said halogenating agent used in step (g), step (h) and step j) is preferably selected from the group consisting of sulphur dihalide oxides such as thionyl chloride, thionyl bromide, a-halo acids such as oxalyl chloride, oxalyl bromide or phosphorous (V) halides, phosphorous (III) halides, phosphorous oxyhalides, hydrohalic acids, cyanuric chloride, bromine, chlorine, iodine, n- bromosuccinimide, n-chlorosuccinimide, n-iodosuccinimide, triphenyl phosphine and the like; most preferably thionyl chloride. In an another embodiment of the present invention, wherein the said base of step (g) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, Ν,Ν-diisopropylethylamine, l,8-Diazabicyclo[5.4.0]undec-7-ene, 1,5- Diazabicyclo[4.3.0]non-5-ene, 1,5-Diazabicyclo [4.3.0]non-5-ene, imidazole, 4- dimethylaminopyridine, pyridine, metal Ci-C6straight or branched chain alkoxide, potassium carbonate, potassium ie/t-butoxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate and / or alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide; most preferably triethyl amine or 4-dimethylaminopyridine.
The substituent "X" appeared in compounds (XI), (XII) and (XIII) is preferably selected from any halogenating group such as chloride, bromide, iodide, and fluoride.
In an another embodiment of the present invention, wherein the said coupling agent used in step (g) and step (h) is preferably selected from the group consisting of propylphosphonic anhydride(T3P) ,hydroxybenzotriazole(HOB t) , 1 -Ethyl- 3 - (3 - dimethylaminopropyl)carbodiimide(EDCI), 1 -[Bis(dimethylamino)methylene]- 1H- 1 ,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate(HATU), benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate(Py-BOP), (Benzotriazol- 1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent), Ν,Ν'- Dicyclohexylcarbodiimide(DCC), o-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate(TBTU), N,N,N',N'-Tetramethyl-o-(lH-benzotriazol-l-yl)uronium hexafluorophosphate(HBTU) or using suitable Ci-C6 alkyl haloformates such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, 2,2,2-trifluoroethyl chloroformate more preferably propylphosphonic anhydride, hydroxybenzotriazole, Ν,Ν'- dicyclohexylcarbodiimide, l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, ethyl chloroformate, methyl chloroformate; most preferably N,N'-dicyclohexylcarbodiimide, o-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate.
In an another embodiment of the present invention, wherein the said base of step (g) and (h) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, N, N-diisopropylethylamine, Ν,Ν-diisopropylamine, l,8-diazabicyclo[5.4.0]undec-7- ene, l,5-diazabicyclo[4.3.0]non-5-ene, 1,5-diazabicyclo [4.3.0]non-5-ene, imidazole, 4- dimethylaminopyridine, pyridine, morpholine, n-methyl morpholinein presence of suitable additives such as hydroxybenzotriazole, 4-dimethylaminopyridine; most preferably triethyl amine, 4-dimethylaminopyridine.
In an another embodiment of the present invention, wherein the said solvent used in step (g) and (h) is preferably selected from the group consisting of water, ethyl acetate, 1,4-dioxane, 1,2-dichloroethane, chloroform, dichloromethane, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethers and the like or mixture of solvents thereof; most preferably acetonitrile, 2-methyltetrahydrofuran, ethyl acetate, dichloromethane .
In an another embodiment of the present invention, wherein the crude compound of step (b), step (c), step (d), step (e), step (f), step (g) and step (h) is preferably used as such or more preferably purified by distillation or by different purification techniques well understood by those skilled in the art.
In another embodiment of the present invention, wherein the compound of formula (IX) or a compound of formula (XIII) converted into Apixaban of formula (I) via intramolecular cyclization, wherein the said base of step (i) and step j) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, N,N-diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, 1,5-diazabicyclo [4.3.0]non-5-ene, imidazole, 4-dimethylaminopyridine, pyridine, metal Ci-C6straight or branched chain alkoxide such as sodium methoxide, potassium methoxide, potassium t- butoxide, sodium, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide; most preferably potassium t-butoxide, sodium hydroxide.
In an another embodiment of the present invention, wherein the said solvent used in step (i) and step (j) is preferably selected from the group consisting of water, alcohols ethyl acetate, 1,4-dioxane, 1,2-dichloroethane, chloroform, dichloromethane, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethers and the like or mixture of solvents thereof; more preferably toluene, xylene, tetrahydrofuran, 1,2-dichloroethane, chloroform, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone, alcohols and the like or mixture of solvents thereof; most preferably toluene or dichloromethane .
In an another embodiment of the present invention, wherein the crude compound of formula (I) is purified by recrystallization or purified by acid-base treatment by reacting with suitable acids to form salts which further converted into Apixaban. The suitable acid is preferably selected from group consisting of hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, succinic acid, oxalic acid, formic acid, acetic acid, p-toluene sulfonic acid, p-benzene sulfonic acid and the like.
The crude compound of formula (I) is preferably purified by crystallization in different solvents like alkanes such as hexanes, heptanes, pentane, cyclohexane, cyclopentane cycloheptane, acetates such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ethers such as methyl tert-butyl ether, diisopropyl ether, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran alcohols such as methanol, ethanol, propanol, isopropanol, isobutanol, n-butanol, isoamyl alcohol, hexanol, allyl alcohol, sulfolane, Ν,Ν' -dimethyl acetamide, ethylene glycol, propylene glycol, acetone, dimethylformamide, dimethyl sulfoxide, alcohols, water, dichloromethane, 1,2- dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, chlorobenzene, 1,2- dichlorobenzene, acetonitrile, propionitrile, butyronitrile, methyl ethyl ketone, methyl isobutyl ketone, acetic acid, formic acid and the like or mixture of solvents thereof.
In an another embodiment of the present invention, wherein one or all the steps may be performed in in-situ manner.
The list of starting material and key intermediates used in the current invention as follows.
Figure imgf000016_0001
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
Examples
Example 1: Preparation of ethyl l-(4-methoxyphenvi)-7-oxo-lH,4H,5H,7H- pyrano[3,4-c1pyrazole-3-carboxylate (IV) .
Figure imgf000016_0002
Example 1.1: To a stirred solution of compound II (8.0g, 0.0452 moles) and compound III (13.16g, 0.0542 moles) in toluene (60mL), triethylamine (18.90mL, 0.1355 moles) was added and heated the reaction mixture to reflux temperature for 6 to 8h. The reaction mixture was allowed to cool to 25°C to 30°C and quenched by water (80mL), stirred for lh, filtered and suck dried. The obtained wet cake washed with water (80mL), methyl tert-butyl ether (80mL) and suck dried to yield pale yellow to brown solid of compound IV(9.0g, 63%yield) with HPLC purity 97.47%,LCMS: 317 [M+H]+,
1H NMR: (DMSO, 400 MHz): 1.318 (3H, t), 3.170 (2H, t), 3.833 (3H, S), 4.346 (2H, q), 4.614 (2H, t), 7.070 (2H, d), 7.550 (2H, d).
Example 1.2: To a stirred solution of compound II (8.0g, 0.0452 moles) and compound III (11.6g, 0.0452 moles) in toluene (80mL), potassium carbonate(31.23g, 0.226 moles) and KI (0.75g, 0.00452 moles) was added at 25°C to 30°C and heated the reaction mixture to reflux temperature for lOh. The reaction mixture was allowed to cool to 25°C to 30°C, quenched by water (160mL) and extracted with ethyl acetate (240mL). The organic layer was evaporated under reduced pressure to yield crude compound. Crude compound was purified using methyl tert-butyl ether: methanol, filtered and suck dried to yield pale yellow to brown solid compound of formula IV (7.0 g, 50% yield).
1H NMR (DMSO, 400 MHz): 1.318 (3H, t), 3.170 (2H, t), 3.833 (3H, S), 4.346 (2H, q), 4.614 (2H, t), 7.070 (2H, d), 7.550 (2H, d).
Example 2: Preparation of l-(4-methoxypheiryi)-7-oxo-lH,4H,5H,7H pyrano[3,4 clpyrazole-3-carboxylic acid (V)
Figure imgf000017_0001
Example 2.1: A stirred solution compound of formula IV (30g, 0.0948 moles) in 6N aq. hydrochloric acid (300mL) was heated to reflux temperature for 6 to 12h. The reaction mixture was allowed to cool to 20°C to 25 °C and then to 10°C to 15°C. The reaction mixture was stirred at 10°C to 15°C for lh, filtered and washed with water (300mL). The water was removed by azeotropic distillation using toluene at 110°C for 2 to 5h and dried under reduced pressure at 50°C to 55°C to yield off white to brown solid compound of formula V (23g, 85% yield) with HPLC purity 98.43%,LCMS: 289 [M+H]+,
1H NMR (DMSO, 400 MHz):3.156 (2H, t), 3.831 (3H, s), 4.60 (2H, t), 7.07 (2H, d), 7.56 (2H, d), 13.33 (1H, s). D20: 3.150 (2H, t), 3.822 (3H, s), 4.59 (2H, t), 7.060 (2H, d), 7.548 (2H, d).
Example 2.2: A stirred solution compound of formula IV (250g, 0.790 moles) in 4N aq. hydrochloric acid (3.75L) was heated to 90°C to 95°C for 12 to 24h. The reaction mixture was allowed to cool to 20°C to 25°C and stirred for additional lh. Filtered and washed with water (750mL). The water was removed by azeotropic distillation using toluene at 110°C for 2 to 5h and dried under reduced pressure at 50°C to 55°C to yield off white to brown solid compound of formula V (209g, 91.7% yield) with HPLC purity 96.71%.
Example 3: Preparation of l-(4-methoxyphenyl)-7-oxo-lH,4H,5H,7H-pyranor3,4- clpyrazole-3-carboxamide
Figure imgf000018_0001
(V) (VI)
Example 3.1: To a stirred solution of compound V (15g, 0.0520 moles) in dimethylformamide (0.06mL), dichloromethane (225mL), thionyl chloride (19.8g, 0.1665 moles) was added dropwise at 20°C to 30°C and heated the reaction mixture to reflux temperature for 4 to 5h. The reaction mixture was cooled to 10°C to 15°C under nitrogen atmosphere and aq. ammonia (75mL) was added below 25°C and stirred for 2 to 3h (pH was maintained at 11 to 12). The reaction mixture was filtered, washed with water (150mL) and dried under reduced pressure at 50°C to 55°C to yield off white to brown solid compound VI (22g, 70% yield)with HPLC purity 95.94%, LCMS: 286 [M-H]~, 1H NMR (DMSO, 400 MHz): 3.16 (2H, t), 3.829 (3H, s), 4.584 (2H, t), 7.071 (2H, d), 7.52 (1H, d), 7.57 (2 H, d), 7.81 (1H, d). D20: 3.174 (2H, t), 3.833 (3H, s), 4.596 (2H, t), 7.061 (2H, d), 7.562 (2H, d).
Example 3.2: To a stirred solution of compound V (103g, 0.3572 moles) in dimethylformamide (lmL), dichloromethane (3L), thionyl chloride (63.8g, 0.535 moles) was added dropwise at 20°C to 30°C and heated the reaction mixture to reflux temperature for 5 to 8h. The reaction mixture was gradually cooled to 20°C to 25°C under nitrogen purging, further cooled to 10°C to 15°C and ammonia gas was purged through the reaction mixture for 3 to 5h. Water (1L) was added below 25°C and stirred for 15 to 20 min. The reaction mixture was filtered, washed with water (3L) and dried under reduced pressure at 50°C to 55°C to yield off white to brown solid compound VI (88g, 85.7% yield) with HPLC purity 98.22%.
Example 4: Preparation of 4-(2-hvdroxyethyl)-l-(4-methoxyphenyl)-5-N-[4-(2 oxopiperidin-l-yl)phenyl1-lH-pyrazole-3,5-dicarboxamide.
Figure imgf000019_0001
In a stirred heterogeneous mixture of compound VI (5.0g, 0.1740 moles) and compound VII (3.3 lg, 0.1740 moles) in toluene (50mL, 10 V), 25% trimethyl aluminium solution in hexane (2.5g. 0.1740 moles) was added dropwise within 10 min at 0°C to 5 °C. The reaction mixture was heated at 100°C to 110°C for 2 to 6h, allowed to cool to 0°C to 5°C, quenched using IN hydrochloric acid (lOOmL) and maintained pH 2. The reaction mixture was stirred at 10°C to 15°C for 2h, allowed to warm at 25°C to 30°C, extracted with dichloromethane (90mL) and washed with all IN hydrochloric acid (25mL). The organic layer dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield crude compound (7.0g). The crude compound was purified by using column chromatography to yield beige coloured solid compound VIII(4.0g, 49% yield) with HPLC purity 95.57%, LCMS: 478 [M+H]+, 1H NMR (DMSO, 400 MHz): 1.834 (4H, t), 2.371 (2H, t), 3.04 (2H, t), 3.56 (2H, t), 3.726 (2H, t), 3.80 (3H, s), 5.58 (1H, s), 7.033 (2H, dd), 7.22 (2H, dd), 7.38 (1H, d), 7.45 (2H, dd), 7.58 (2H, dd), 7.69 (1H, d)l l. l l (1H, s).
Example 5: Preparation of 2-[3-carbamoyl-l-(4-methoxyphenyl)-5-|[4-(2-oxopiperidin- l-yl)phenyl1carbamoyl|-lH-pyrazol-4-yl1ethyl methane sulfonate,
Figure imgf000020_0001
To a stirred solution of compound VIII (7.6g, 0.0159 moles), triethylamine (6.43g. 0.06366 moles) in dichloromethane (1140mL, 150 V), methanesulfonyl chloride (5.46g. 0.0477 moles) was added slowly for 30min at 0°to 5 °C. The reaction mixture was allowed to warm to 10°to 15 °C for 2h and water (lOOmL) was added stirred for 30 min. The organic layer was separated, washed with saturated sodium bicarbonate solution (200mL), water (lOOmL) and dried over anhydrous sodium sulphate, and evaporated under reduced pressure to yield off white to brown solid compound IX (8.84g, 96% yield) with HPLC purity 89.07%,LCMS: 554 [M-H]~,
1H NMR (CDC13, 400 MHz): 1.94 (4H, t), 2.54 (2H, t), 2.99 (3H, s), 3.38 (2H, t), 3.60 (2H, t), 3.83 (3H, s), 3.73 (2H, t), 5.46 (1H, s), 6.95-6.97 (3H, m), 7.21 (2H, dd), 7.45 (2H, dd), 7.65 (2H, dd), 8.42 (1H, s).
Example 6: Preparation of 3-carbamoyl-4-(2-hvdroxyethyl)-l-(4-methoxyphenyl)-lH- pyrazole-5-carboxylic acid,
Figure imgf000020_0002
Example 6.1: To a stirred solution of compound VI (3.0g, 0.0144 moles) in methanol (15mL)aq. KOH solution (1.16 g, 0.0432 moles in 15 mL water) was added dropwise at 20°to 25°C for 10 to 15min. and maintained for 1 to 2h. The reaction mixture was evaporated under reduced pressure, water (50mL) was added and allowed to cool to 10°C to 15°C. The pH maintained at 1.0 to 2.0 using 50% aq. hydrochloric acid solution and further stirred for lh. The reaction mixture was filtered, washed with water dried under reduced pressure at 50°C to 55°C to yield off white to brown solid compound X (3.18g, 91% yield) with HPLC purity 98.6%,LCMS: 306 [M+H]+,
1H NMR (DMSO, 400 MHz): 3.167 (2H, t), 3.563 (2H, t), 3.813 (3H, s), 4.795 (1H, s) 7.030 (2H, d), 7.348-7.378 (3H, m), 7.676 (1H, s), 13.439 (1H, s). D20: 3.175 (2H, t), 3.594 (3H, t), 3.820 (3H, s), 7.056 (2H, d), 7.380 (2H, d).
Example 6.2: To a stirred solution of compound VI (50.0g, 0.1736 moles) in methanol (250mL) at 0 to 5 °C, aq. NaOH solution (13.88 g, 0.3472 moles in 250 mL water) was added dropwise below 10°C and maintained for 2 to 3h at 15°C to 20°C. The reaction mixture was again cooled to 0°C to 5°C and adjusted the pH of reaction mass at 1.0 to 2.0 using 1 N aq. hydrochloric acid solution and further stirred for 0.5h. The reaction mixture was filtered, washed with water and removed traces of water by azeotropic distillation using toluene followed by dried under reduced pressure at 50°C to 55°C to yield off white to brown solid compound X (49.0g, 92% yield) with HPLC purity 98.82%.
Example7: Preparation of 3-carbamoyl-4-(2-chloroethyl)-l-(4-methoxyphenyl)-lH- pyrazole-5-arboxylic acid,
Figure imgf000021_0001
(X) (XII) Example 7.1: To a stirred solution of compound X (0.1g,0.000327 moles) in acetonitrile (2mL), thionyl chloride (0.5mL, 0.000327 moles) was added dropwise at 20°C to 30°C and further stirred for 3 to 4h at 20°C to 25 °C. The reaction mixture was filtered, washed with acetonitrile (2mL) and dried under reduced pressure at 40°C to 50°C to yield off white to brown solid compound XII (0.09g, 85% yield).
1H NMR (DMSO, 400 MHz): 3.46 (2H, t), 3.77-3.82 (5H, m), 7.034 (2H, t), 7.373-7.414 (3H, m), 7.70 (1H, s), 13.553 (1H, s). D20: 3.419 (2H, t), 3.756 (5H, m), 7.012 (2H, d), 7.348 (2H, d).
Example 7.2: To a stirred solution of compound X (200. Og, 0.6551 moles) in 2-MeTHF (3.0 L, 15 V), thionyl chloride (187. lg, 1.5722 moles) was added in one lot at 20°C to 30°C and further heated for 5 to 6h at 75°C to 85°C. The reaction mixture was concentrated under reduced pressure at 45°C to 50°C followed by stripping with toluene (10V). Filtered the solid obtained, washed with toluene (400mL, 2V) and dried under reduced pressure at 40°C to 50°C to yield off white to brown solid compound XII (206g, 97% yield) with HPLC purity 96.86%.
Example 8: Preparation of 4-(2-chloroethyl)-l-(4-methoxyphenyl)-5-N-[4-(2 oxopiperidin-l-yl) phenyll-lH-pyrazole-3,5-dicarboxamide.
Figure imgf000022_0001
(XII) (XIII)
Example 8.1: To a stirred solution of compound XII(0.05g, 0.1544 mmoles), compound VII(0.029g,0.1544 mmoles), triethyl amine (0.23g, 0.2316 mmoles), 4- dimethylaminopyridine (5mg,0.04632 mmoles) in dichloromethane (lmL,20 V), the Ν,Ν'- dicyclohexylcarbodiimide (0.035g, 0.1698 mmoles) in dichloromethane (l.OmL, 20 V) solution was added dropwise at 0°C to 5°C. The reaction mixture was stirred at 25°C to 30°C for 12h and quenched using saturated brine solution (2mL). The organic layer was separated dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield brown coloured crude compound and further purified using ternary system of solvent [Acetonitrile (10V):Dichloromethane (8V):Methanol (6V)] to yield, off white to brown solid coloured compound XIII(0.04g, 52% yield) with HPLC purity 98.90%,
LCMS: 496 [M+H]+,
1H NMR (DMSO, 400 MHz): 1.847 (4H, m), 2.371 (2H, t), 3.161 (2H, d), 3.269 (2H, t), 3.563 (2H, t), 3.80 (3H, s), 7.050 (2H, dd), 7.212 (2H, dd), 7.478 (3H, m), 7.541 (2H, dd), 7.77 (2H, dd), 10.779 (1H, s). D20: 1.850 (4H, m), 2.371 (2H, t), 3.161 (2H, d), 3.260 (2H, t), 3.563 (2H, t), 3.809 (3H, s), 7.052 (2H, dd), 7.218 (2H, dd), 7.479 (2H, dd), 7.542 (2H, dd).
Example 8.2: To a stirred solution of compound XII (O. lg, 0.3088 mmoles) in ethyl acetate (2mL), thionyl chloride(0.32g,2.78 mmoles) was added at 20°C to 30°C and reflux for 5 to 6h. The reaction mixture was evaporated under reduced pressure resulted into unstable compound XI (without any isolation) which subsequently dissolved in dichloromethane (2mL). To this reaction mixture triethylamine (0.12mL,0.9264 mmoles) and compound VII (0.06 g, 0.3088 mmoles) was added at 20°C to 30°C stirred at 25°C for 6h. The organic layer was evaporated at under reduced pressure to yield crude compound which was purified using ternary system of solvent [Acetonitrile (10V): Dichloromethane (8V): Methanol (6V)] to yield off white to brown solid compound XIII (0.09g, 60% yield), LCMS: 496 [M+H]+, 1H NMR (DMSO, 400 MHz): 1.847 (4H, m), 2.371 (2H, t), 3.161 (2H, d), 3.269 (2H, t), 3.563 (2H, t), 3.80 (3H, s), 7.050 (2H, dd), 7.212 (2H, dd), 7.478 (3H, m), 7.541 (2H, dd), 7.77 (2H, dd), 10.779 (1H, s). D20: 1.850 (4H, m), 2.371 (2H, t), 3.161 (2H, d), 3.260 (2H, t), 3.563 (2H, t), 3.809 (3H, s), 7.052 (2H, dd), 7.218 (2H, dd), 7.479 (2H, dd), 7.542 (2H, dd).
Example 8.3: To a stirred solution of compound XII (50. Og, 0.1544 moles) in tetrahydrofuran(350mL),N,N,N N'-Tetramethyl-O-(lH-benzotriazol-l- yl)uroniumhexafluorophosphate(74.35g, 0.231 moles i.e. TBTU), triethylamine (26 mL, 0.185 moles) and Compound VII (52.88 g, 0.278 moles) was added sequentially under stirring at 20°C to 30°C and maintained for next 24h. Filtered the solid, washed with water (500mL) and dried under reduced pressure at 50°C to yield crude compound XIII. The crude compound was purified by crystallization in mixture of toluene: methanol (4: 1, 5V). The repeat purification of the obtained compound in mixture of toluene: methanol (6:4, 10V) to yield off white to brown solid of compound XIII (55.5g, 72% yield) with HPLC purity 97.11%.
Example 9: Preparation of 4-(2-chloroethyl)-l-(4-methoxyphenyl)-5-N-[4-(2 oxopiperidin-l-yl)phenyl1-lH-pyrazole-3,5-dicarboxamide.
Figure imgf000024_0001
(X) (xm)
To a stirred solution of compound X (0.7g, 0.0229 moles) in ethyl acetate (7mL)thionyl chloride (0.65g, 0.055 moles) was added at 20°C to 30°C. The reaction mixture was heated at 60°C for 3h, solvent was evaporated under reduced pressure, dichloromethane (14.0mL, 20V) and compound VII (0.88g,0.0458 moles) was added at 25°C to 30°C which further heated to reflux temperature for 6h. The reaction mixture was quenched using water (5mL) at 25°C to 30°C, filtered, dried under reduced pressure at 40°C to 50°C to yield crude compound. The crude compound was purified using ternary system of solvent [(Acetonitrile (10V):Dichloromethane (8V):Methanol (6V)] to yield off white to brown solid coloured compound XIII(0.733g, 65% yield) with HPLC purity 98.90%,
LCMS: 496 [M+H]+,
1H NMR (DMSO, 400 MHz): 1.847 (4H, m), 2.371 (2H, t), 3.161 (2H, d), 3.269 (2H, t), 3.563 (2H, t), 3.80 (3H, s), 7.050 (2H, dd), 7.212 (2H, dd), 7.478 (3H, m), 7.541 (2H, dd), 7.77 (2H, dd), 10.779 (1H, s). D20: 1.850 (4H, m), 2.371 (2H, t), 3.161 (2H, d), 3.260 (2H, t), 3.563 (2H, t), 3.809 (3H, s), 7.052 (2H, dd), 7.218 (2H, dd), 7.479 (2H, dd), 7.542 (2H, dd).
Example 10: Preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l yl)phenyll-4,5,6,7-tetrahydro-lH-pyrazolor3,4-cl pyridine-3-carboxamide.
Figure imgf000025_0001
(X)
To a stirred solution of compound X (0.05g, 0.1637mmoles) thionyl chloride (0.25mL, 5V) was added at 20°C to 30°C. The reaction mixture was heated at 75°C for 3h, solvent was evaporated under reduced pressure, toluene (l.OmL), potassium t-butoxide (0.11g,0.4913 mmoles) and compound VII (0.03 lg, 0.1637 mmoles) was added at 20°C to 30°C, stirred for 15h at 25°C. The reaction mixture was quenched using water (5mL), extracted with ethyl acetate (lOmL), dried over an hydrous sodium sulphate and organic layer evaporated under reduced pressure to yield crude compound. The crude compound was purified using column chromatography to yield off white to white solid compound of formula (I)(0.033g, 45% yield)with HPLC purity 99.87%, LCMS: 477[M+H20]+,
1H-NMR (DMSO, 400 MHz): 1.841-1.851 (4H, m), 2.383 (2H, m), 3.20 (2H, m), 3.59 (2H, m), 3.80 (3H, s), 4.05 (2H, m),7.00 (2H, m), 7.26 (2H, m), 7.35 (2H, m), 7.44 (1H, d), 7.51 (2H, m), 7.72 (1H, s).
Example 11; Preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyll-4,5,6,7-tetrahydro-lH-pyrazolor3,4-cl pyridine-3-carboxamide,
Figure imgf000025_0002
To a stirred solution of compound IX (2.9g, 0.0052 moles) in toluene (290mL), potassium t- butoxide (3.5g, 0.0313 moles) was added lot wise for 1.5h at 20°C to 25°C. The reaction mixture was stirred at 20°C to 25°C for 6 to 8h, quenched using water (200mL), stirred for additional lh and filtered, washed with water (50mL), dried under reduced pressure to yield crude compound. The crude compound was purified by recrystallization using in acetone: water (8:2, 25V) to yield off white to white solid of compound (I) (2.0g, 83% yield), with HPLC purity 99.93%,LCMS: 477 [M+H20]+,
1H-NMR (DMSO, 400 MHz): 1.841-1.851 (4H, m), 2.383 (2H, m), 3.20 (2H, m), 3.59 (2H, m), 3.80 (3H, s), 4.05 (2H, m), 7.00 (2H, m), 7.26 (2H, m), 7.35 (2H, m), 7.44 (1H, d), 7.51 (2H, m), 7.72 (1H, s).
Example 12: Preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyll-4,5,6,7-tetrahydro-lH-pyrazolor3,4-cl pyridine-3-carboxamide,
Figure imgf000026_0001
Example 12.1: To a stirred solution of compound XIII (lOg, 0.02016 moles) in dichloromethane(150niL, 15 V), potassium t-butoxide (6.78g, 0.06048 moles) was added lotwise for 15 min. at 10°C to 15°C. The reaction mixture was stirred at 20°C to 25°C for 3 to 6h, evaporated under reduced pressure at 40°C to 45°C and water (lOOmL) was added, stirred for additional lh. The reaction mixture was filtered, washed with water (50mL), dried under reduced pressure to yield crude compound I. The crude compound was purified by recrystallization in mixture of toluene: methanol (2: 1, 20V) to yield off white to white solid of compound (I)(6.5g, 70% yield) with HPLC purity 99.87%,LCMS: 477 [M+H20]+,
1H-NMR (DMSO, 400 MHz): 1.841-1.851 (4H, m), 2.383 (2H, m), 3.20 (2H, m), 3.59 (2H, m), 3.80 (3H, s), 4.05 (2H, m), 7.00 (2H, m), 7.26 (2H, m), 7.35 (2H, m), 7.44 (1H, d), 7.51 (2H, m), 7.72 (1H, s).
Example 12.2:To a stirred solution of aq. NaOH (115g, 2.87 moles) in 1.78L water and 1.78L methanol was added compound XIII (178g, 0.3591 moles) at 25°C to 30 °C. The resultant mixture was heated to 30°C to 35 °C for 4 to 6h. Water (1.78L, 10V) was then added at 20°C to 25 °C, stirred for additional 10 min, filtered the reaction mixture and washed with water twice (3.56L, 10V), dried under reduced pressure to yield crude compound I. The crude compound was purified by recrystallisation in mixture of toluene: methanol (2: 1, 15V) to yield off white to white solid of compound (I) (118g, 72% yield) with HPLC purity 99.88%.
Example 13: Preparation of (N-l) form of Apixaban:
To a stirred solution of 1.18L ethyl alcohol and 10 % mixture of acetonitrile in water (~ 5 to 8V) was added compound I (118g, 0.2567 moles) at 25°C to 30 °C. The resultant mixture was heated to reflux and maintained reflux for additional lh. The seed (1.18g, -1%) material was added to the clear pale-yellow solution upon cooling at 60°C to 70°C. Further cooled reaction mixture to 40°C to 50°C and stirred for next lh. Reaction mixture was then concentrated under reduced pressure at 50°C till 3 V followed by addition of 1.18L water and stirred for additional 30 min, filtered the reaction mixture and washed with water 1.18L twice, dried under reduced pressure at 50°C to 60°C to yield white solid of compound (I)(114g, 97% yield) with desired (N-l) form and HPLC purity 99.90%.

Claims

Claims
1. An improved process for the reparation of Apixaban of formula (I)
Figure imgf000028_0001
Formula (I) comprising the steps of: a) obtaining a compound of formula (IV) by reacting a compound of formula (II) with compound of formula (III) in the presence of a suitable base in a suitable solvent or mixture thereof at a suitable temperature;
Figure imgf000028_0002
wherein R is H, Ci-C6alkyl chain, branched, substituted or containing a double bond, optionally with non-substituted aromatic ring or a group containing C7-C10 alkyl, aryloptionally substituted by any heteroatom; b) obtaining a compound of formula (V) by hydrolyzing ester group of formula (IV) with a suitable acid or a base at a suitable temperature in aqueous or organic solvent or a mixture thereof; (V)
c) obtaining a compound of formula (VI) by reacting a compound of formula (V) with a suitable halogenating agent at a suitable temperature in a suitable solvent followed by amidation using a suitable source of ammonia in a suitable solvent or mixture thereof;
Figure imgf000029_0001
(VI)
wherein Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7-C10 alkyl, aryl optionally substituted by atoms selected from N, O, S, halogen, Si or any heteroatom; d) obtaining a compound of formula (VIII) by reacting a compound of formula (VI) with a compound of formula (VII) in the presence of a suitable organometallic coupling agent or base or Lewis acid at a suitable temperature in a suitable solvent or mixture thereof;
Figure imgf000029_0002
(VII) (VIII wherein Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7-C10 alkyl, aryl optionally substituted by atoms selected from N, 0,S, halogen, Si or any heteroatom; e) converting a compound of formula (VIII) to form a compound of formula (IX) by treating with a suitable protecting group in the presence of a suitable base at a suitable temperature in an aqueous or organic solvent or mixture thereof;
Figure imgf000030_0001
(IX)
wherein Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7-C10 alkyl, aryl optionally substituted by atoms selected from N, O, S, halogen, Si or any heteroatom and P is R3O-CO- or R tS ; R3 is Ci-C6 alkyl group optionally substituted with one or more atoms selected from among halogen (F, CI), S, O, Si or a group containing C7-C15 alkyl, aryl (monocyclic or polycyclic) optionally substituted by one or more atom(s) selected from N, O, S, halogen, Si or any heteroatom and R4 is C6-Cio aryl or heteroaryl group optionally substituted with F, CI, N02 and X is halogen(Cl, Br, I), CH3S02, PhS02, 4-Me- PhS02; f) optionally converting a compound of formula (VI) to a compound of formula (X) by hydrolyzing with a suitable alkali or alkaline earth metal base at a suitable temperature in an aqueous or an organic solvent or mixture thereof; wherein Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7-C10 alkyl, aryl optionally substituted by atoms selected from N, O, S, halogen, Si or any heteroatom; g) optionally obtaining a compound of formula (XIII) by reacting a compound of formula (X) with a suitable halogenating agent with a suitable base in the presence of a suitable solvent to a compound of formula (XI) followed by coupling with a compound of formula (VII) in presence of a base or in the presence of a suitable coupling agent at a suitable temp
Figure imgf000031_0001
(XI) (XIII)
wherein X is halogen (F, CI, Br, I), As, S, O, Si and Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7-C10 alkyl, aryl optionally substituted by atoms selected from N, O, S, halogen, Si or any heteroatom; h) alternatively obtaining a compound of formula (XIII) by reacting a compound of formula (X) with a suitable halogenating agent in a suitable solvent to a compound of formula (XII) followed by coupling with a compound of formula (VII) in presence of suitable coupling agent, suitable base at a suitable temperature in a suitable solvent or mixture thereof; wherein Xis halogen (CI, Br, I) As, S, O, Si and Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7-C 10 alkyl, aryl optionally substituted by atoms selected from N, O, S, halogen, Si or any heteroatom; converting a compound of formula (IX) or a compound of formula (XIII) to Apixaban of formula (I) by treating with a suitable base at a suitable temperature in a suitable organic solvent or mixture thereof;
Figure imgf000032_0001
Formula (I)
optionally obtaining a compound of formula (I) by reacting a compound of formula (X) in presence of a suitable halogenating agent at a suitable temperature followed by coupling with a compound of formula (VII) in presence or absence of coupling agent, in a suitable base and suitable solvent or mixture of solvents thereof.
2. The process as claimed in claim 1, wherein the said solvent used in step (a) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, ethyl acetate, 1,4-dioxane, ethylene dichloride, chloroform, methyl tert-butyl ether, cyclohexane, toluene, xylene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane or mixture of solvents thereof; most preferably toluene.
3. The process as claimed in claim 1, wherein the said base used in step (a), step (b) and step (e) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, N,N-diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7- ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,5-diazabicyclo[4.3.0]non-5-ene, imidazole, 4-dimethylaminopyridine, pyridine, morpholine, N-methyl morpholine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide; most preferably triethyl amine, potassium carbonate.
4. The process as claimed in claim 1, wherein the said acid used in step (b) which is preferably selected from group consisting of cone, hydrochloric acid, cone, sulfuric acid, nitric acid, phosphoric acid, boric acid, hydrogen fluoride, hydrogen bromide, hydrogen iodide, perchloric acid or the said acid is an acid cationic resin or related compounds having strength for hydrolysis; most preferably cone, hydrochloric acid.
5. The process as claimed in claim 1 and claim 4, wherein the said acid strength for hydrolysis of step (b) is preferably selected from 2.0 N-12.0 N, most preferably from 4.0 N-6.0 N.
6. The process as claimed in claim 1, wherein the said solvent used in step (b) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, isopropyl acetate, dimethyl sulfoxide, acetic acid, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, 1,4- dioxane, methyl tert-butyl ether, cyclohexane or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, dimethyl sulfoxide, acetic acid, tetrahydrofuran, 1,4-dioxane, chloroform or mixture thereof; most preferably water.
7. The process as claimed in claim 1, wherein the said halogenating agent used in step (c) is preferably selected from the group of sulphur halide oxides such as thionyl chloride, thionyl bromide, a-halo acids such as oxalyl chloride, oxalyl bromide or phosphorous (V) halides, phosphorous (III) halides, phosphorous oxyhalides, hydrohalic acids, cyanuric chloride, bromine, chlorine, iodine, N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide, triphenyl phosphine or suitable halogenating agent, more preferably oxalyl chloride, oxalyl bromide, thionyl chloride, phosphorous (V) halides; most preferably thionyl chloride.
8. The process as claimed in claim 1, wherein the said ammonia source used in step (c) is preferably selected from ammonia gas, aqueous ammonia solutions, ammonium carbonates, ammonium carbamates, ammonium bicarbonate and ammonium acetates; most preferably aq. ammonia.
9. The process as claimed in claim 1, wherein the said solvent used in step (c) is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, methyl tert-butyl ether, cyclohexane or any halogenated solvent and the mixture of solvents thereof; most preferably dichloromethane.
10. The process as claimed in claim 1, wherein the said solvent used in step (d) is preferably selected from the group consisting of ethyl acetate, 1,4-dioxane, 1,2- dichloroethane, chloroform, dichloromethane, methyl tert-butyl ether, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, 2-methyltetrahydrofuran, ethers and mixture of solvents thereof; most preferably toluene.
11. The process as claimed in claim 1, wherein the said organometallic coupling agent is a Lewis acid or a base used in step (d) which is preferably selected from the group of trialkyl aluminium, dialkyl aluminium, aluminium trihalides, or group consisting of alkyl lithium agents such as n-butyllithium, sec-butyllithium, i-butyllithium and the mixture thereof; more preferably trimethyl aluminium or n-butyllithium; most preferably trimethyl aluminium.
12. The process as claimed in claim 1, wherein the said protecting group used in step (e) is preferably selected from the group consisting of acetic anhydride, trifluoroacetic anhydride, methanesulfonyl chloride,p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, camphor sulfonyl chloride, p-benzenesulfonyl chloride, p-trifluoromethyl benzenesulfonyl chloride; most preferably methanesulfonyl chloride.
13. The process as claimed in claim 1, wherein the said solvent used in step (e) is preferably selected from the group consisting of water, ethyl acetate, 1,4-dioxane, 1,2- dichloroethane, chloroform, dichloromethane, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, 2-methyltetrahydrofuran, ethers or mixture of solvents thereof; most preferably dichloromethane.
14. The process as claimed in claim 1, wherein the said base used in step (f) is preferably selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, Ci- C5 quaternary ammonium hydroxide, tetrabutyl ammonium hydroxide, metal Ci-C6 straight or branched chain alkoxide or suitable basic resins or related compounds having strength for hydrolysis; most preferably sodium hydroxide, potassium hydroxide.
15. The process as claimed in claim 1, wherein the said solvent used in step (f) is preferably selected from the group consisting of water, alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isopropyl acetate, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane or mixture of solvents thereof; most preferably methanol.
16. The process as claimed in claim 1, wherein the said halogenating agent used in step (g), step (h) and step j) is preferably selected from the group consisting of sulphur dihalide oxides such as thionyl chloride, thionyl bromide, a-halo acids such as oxalyl chloride, oxalyl bromide or phosphorous (V) halides, phosphorous (III) halides, phosphorous oxyhalides, hydrohalic acids, cyanuric chloride, bromine, chlorine, iodine, n-bromosuccinimide, n-chlorosuccinimide, n-iodosuccinimide, triphenyl phosphine; most preferably thionyl chloride.
17. The process as claimed in claim 1, wherein the said base of step (g) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, Ν,Ν-diisopropylethylamine, l,8-Diazabicyclo[5.4.0]undec-7-ene, 1,5- Diazabicyclo[4.3.0]non-5-ene, 1,5-Diazabicyclo [4.3.0]non-5-ene, imidazole, 4- dimethylaminopyridine, pyridine, metal Ci-C6 straight or branched chain alkoxide, potassium carbonate, potassium ie/ -butoxide sodium carbonate, sodium bicarbonate, potassium bicarbonate and / or alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide; most preferably triethyl amine or4- dimethylaminopyridine.
18. The process as claimed in claim 1, wherein the said coupling agent used in step (g) and step (h) is preferably selected from the group consisting of propylphosphonic anhydride, hydroxybenzotriazole, l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1- [Bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxide hexafluorophosphate, benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate, (Benzotriazol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, Ν,Ν'-Dicyclohexylcarbodiimide, 0-(Benzotriazol- 1-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate, N,N,N',N'-Tetramethyl-o-( 1H- benzotriazol-l-yl)uronium hexafluorophosphateor using suitable Ci-C6 alkyl haloformates such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, 2,2,2-trifluoroethyl chloroformate more preferably propylphosphonic anhydride, hydroxybenzotriazole, Ν,Ν'-dicyclohexylcarbodiimide, 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, ethyl chloroformate, methyl chloroformate; most preferably Ν,Ν'- dicyclohexylcarbodiimide, 0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate .
19. The process as claimed in claim 1, wherein the said base of step (g) and (h) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, N, N-diisopropylethylamine, N,N-diisopropylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, 1,5-diazabicyclo [4.3.0]non-5-ene, imidazole, 4-dimethylaminopyridine, pyridine, morpholine, n- methyl morpholine in presence of suitable additives such as hydroxybenzotriazole, 4- dimethylaminopyridine; most preferably triethyl amine, 4-dimethylaminopyridine.
20. The process as claimed in claim 1, wherein the said solvent used in step (g) and (h) is preferably selected from the group consisting of water, ethyl acetate, 1,4-dioxane, 1,2- dichloroethane, chloroform, dichloromethane, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethers or mixture of solvents thereof; more preferably acetonitrile, 2-methyltetrahydrofuran, ethyl acetate, dichloromethane .
21. The process as claimed in claim 1, wherein the said base of step (i) and step (j) is preferably selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, Ν,Ν-diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, 1,5- diazabicyclo[4.3.0]non-5-ene, 1,5-diazabicyclo [4.3.0]non-5-ene, imidazole, 4- dimethylaminopyridine, pyridine, metal Ci-C6 straight or branched chain alkoxide such as sodium methoxide, potassium methoxide, potassium t-butoxide, sodium, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide; most preferably potassium t-butoxide, sodium hydroxide.
22. The process as claimed in claim 1, wherein the said solvent used in step (i) and step (j) is preferably selected from the group consisting of water, alcohols ethyl acetate, 1,4-dioxane, 1,2-dichloroethane, chloroform, dichloromethane, cyclohexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethers or mixture of solvents thereof; more preferably toluene, xylene, tetrahydrofuran, 1,2- dichloroethane, chloroform, dichloromethane, tetrahydrofuran, 2- methyltetrahydrofuran, acetonitrile, acetone, alcohols or mixture of solvents thereof; most preferably toluene or dichloromethane.
23. The process as claimed in claim 1, wherein the crude compound of formula (I) is preferably purified by recrystallization or acid-base treatment by reacting with suitable acids to form salts which further converted into Apixaban.
24. The process as claimed in claim 23, wherein the suitable acid is preferably selected from group consisting of hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, succinic acid, oxalic acid, formic acid, acetic acid, p-toluene sulfonic acid, p-benzene sulfonic acid or mixture thereof.
25. The process as claimed in claim 23, wherein solvents for crystallization is preferably selected from alkanes such as hexanes, heptanes, pentane, cyclohexane, cyclopentane cycloheptane, acetates such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ethers such as methyl tert-butyl ether, diisopropyl ether, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, alcohols such as methanol, ethanol, propanol, isopropanol, isobutanol, n-butanol, isoamyl alcohol, hexanol, allyl alcohol, sulfolane, Ν,Ν' -dimethyl acetamide, ethylene glycol, propylene glycol, acetone, dimethylformamide, dimethyl sulfoxide, alcohols, water, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, acetonitrile, propionitrile, butyronitrile, methyl ethyl ketone, methyl isobutyl ketone, acetic acid, formic acid or mixture of solvents thereof; more preferably mixture of methanol, acetonitrile and water.
26. The process as claimed in claim 1, wherein one or all the steps are performed in in- situ manner.
27. The compound of formula IV
Figure imgf000038_0001
(IV)
wherein R is H, C2-C6alkyl chain, branched, substituted or containing a double bond optionally with non-substituted aromatic ring or a group containing C7-C10 alkyl, aryl optionally substituted by any heteroatom.
28. The compound of formula (VI)
Figure imgf000038_0002
(VI) wherein Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7-C10 alkyl, aryl optionally substituted by atoms selected from N, O, S, halogen, Si or any heteroatom.
29. The compound of formula (VIII)
Figure imgf000039_0001
wherein Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7-C10 alkyl, aryl optionally substituted by atoms selected from N, 0,S, halogen, Si or any heteroatom.
30. The compound of formula (IX)
Figure imgf000039_0002
wherein Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7-C10 alkyl, aryl optionally substituted by atoms selected from N, O, S, halogen, Si or any heteroatom and P isR30- CO- or R4S02-; R3 is Ci-C6 alkyl group optionally substituted with one or more atoms selected from among any halogen (F, CI), S, O, Si or a group containing C7-C15 alkyl, aryl (monocyclic or polycyclic) both the types are optionally substituted by one or more atom(s) selected from N, O, S, halogen, Si or any heteroatom and R4 is C6-Cio aryl or heteroaryl group optionally substituted with F, CI, N02 and X is halogen (CI, Br, I), CH3S02, PhS02, 4-Me-PhS02.
31. The compound of formula
Figure imgf000040_0001
wherein Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7-Cioalkyl, aryl optionally substituted by atoms selected from N, O, S, halogen, Si or any heteroatom.
32. The compound of formula (XIII)
Figure imgf000040_0002
(XIII)
wherein Xis halogen (F, CI, Br, I), As, S, O, Si and Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7-C10 alkyl, aryl optionally substituted by atoms selected from N, O, S, halogen, Si or any heteroatom.
wherein X is halogen (CI, Br, I), As, S, O, Si and Riis H, Ci-C6 alkyl group containing a double bond optionally substituted with halogen (CI, Br, I), S, O, Si or a group containing C7- Cio alkyl, aryl optionally substituted by atoms selected from N, O, S, halogen, Si or any heteroatom.
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WO2020085616A1 (en) * 2018-10-24 2020-04-30 하나제약 주식회사 Method for preparing apixaban

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Publication number Priority date Publication date Assignee Title
WO2014203275A2 (en) * 2013-06-18 2014-12-24 Cadila Healthcare Limited An improved process for the preparation of apixaban and intermediates thereof
WO2016079549A1 (en) * 2014-11-19 2016-05-26 Egis Gyógyszergyár Zrt. Process and intermediate for the preparation of apixaban

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Publication number Priority date Publication date Assignee Title
WO2014203275A2 (en) * 2013-06-18 2014-12-24 Cadila Healthcare Limited An improved process for the preparation of apixaban and intermediates thereof
WO2016079549A1 (en) * 2014-11-19 2016-05-26 Egis Gyógyszergyár Zrt. Process and intermediate for the preparation of apixaban

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020085616A1 (en) * 2018-10-24 2020-04-30 하나제약 주식회사 Method for preparing apixaban
CN112771044A (en) * 2018-10-24 2021-05-07 合娜制药株式会社 Preparation method of apixaban

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