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WO2018127936A1 - Nouveau procédé économique sans métal pour apixaban - Google Patents

Nouveau procédé économique sans métal pour 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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Prior art keywords
compound
formula
halogen
optionally substituted
alkyl
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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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré et nouveau pour la préparation d'Apixaban de formule (I), qui est simple, économique, sans métal, effiace et respectueux des utilisateurs et de l'environnement, et de plus commercialement viable.
PCT/IN2018/050003 2017-01-05 2018-01-04 Nouveau procédé économique sans métal pour apixaban Ceased WO2018127936A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020085616A1 (fr) * 2018-10-24 2020-04-30 하나제약 주식회사 Procédé de préparation d'apixaban

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014203275A2 (fr) * 2013-06-18 2014-12-24 Cadila Healthcare Limited Procédé amélioré pour la préparation d'apixaban et de ses intermédiaires
WO2016079549A1 (fr) * 2014-11-19 2016-05-26 Egis Gyógyszergyár Zrt. Procédé et intermédiaire pour la préparation d'apixaban

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014203275A2 (fr) * 2013-06-18 2014-12-24 Cadila Healthcare Limited Procédé amélioré pour la préparation d'apixaban et de ses intermédiaires
WO2016079549A1 (fr) * 2014-11-19 2016-05-26 Egis Gyógyszergyár Zrt. Procédé et intermédiaire pour la préparation d'apixaban

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020085616A1 (fr) * 2018-10-24 2020-04-30 하나제약 주식회사 Procédé de préparation d'apixaban
CN112771044A (zh) * 2018-10-24 2021-05-07 合娜制药株式会社 阿哌沙班的制备方法

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