WO2018158620A1 - Preparation of active pharmaceutical ingredients and intermediates thereof - Google Patents
Preparation of active pharmaceutical ingredients and intermediates thereof Download PDFInfo
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- WO2018158620A1 WO2018158620A1 PCT/IB2017/053183 IB2017053183W WO2018158620A1 WO 2018158620 A1 WO2018158620 A1 WO 2018158620A1 IB 2017053183 W IB2017053183 W IB 2017053183W WO 2018158620 A1 WO2018158620 A1 WO 2018158620A1
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- dihydropyridin
- phenyl
- morpholin
- oxo
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- LBFAEOWNWSDWRZ-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1N(CCC=C1N2CCOCC2)C1=O)=O Chemical compound [O-][N+](c(cc1)ccc1N(CCC=C1N2CCOCC2)C1=O)=O LBFAEOWNWSDWRZ-UHFFFAOYSA-N 0.000 description 3
- 0 CCOC(C(*)=NNc(cc1)ccc1OC)=O Chemical compound CCOC(C(*)=NNc(cc1)ccc1OC)=O 0.000 description 2
- YUGIGSPFTMLIMA-UHFFFAOYSA-N Nc(cc1)ccc1N(CCC=C1N2CCOCC2)C1=O Chemical compound Nc(cc1)ccc1N(CCC=C1N2CCOCC2)C1=O YUGIGSPFTMLIMA-UHFFFAOYSA-N 0.000 description 2
- SCVWQFDPLBFZAP-UHFFFAOYSA-N O=C(CCCC1)N1c(cc1)ccc1N(CCC=C1N2CCOCC2)C1=O Chemical compound O=C(CCCC1)N1c(cc1)ccc1N(CCC=C1N2CCOCC2)C1=O SCVWQFDPLBFZAP-UHFFFAOYSA-N 0.000 description 2
- QNZCBYKSOIHPEH-UHFFFAOYSA-N COc(cc1)ccc1-[n]1nc(C(N)=O)c(CCN2c(cc3)ccc3N(CCCC3)C3=O)c1C2=O Chemical compound COc(cc1)ccc1-[n]1nc(C(N)=O)c(CCN2c(cc3)ccc3N(CCCC3)C3=O)c1C2=O QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- C07D201/00—Preparation, separation, purification or stabilisation of unsubstituted lactams
- C07D201/02—Preparation of lactams
- C07D201/08—Preparation of lactams from carboxylic acids or derivatives thereof, e.g. hydroxy carboxylic acids, lactones or nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
-
- 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
Definitions
- the present invention provides processes for the preparation of active
- the present invention provides the use of an aqueous designer smart surfactant solution for synthesizing active pharmaceutical ingredients and intermediates thereof. Summary of the Invention
- the present invention provides ecofriendly, cost-effective, and industrially advantageous process for the preparation of active pharmaceutical ingredients and intermediates thereof using an aqueous designer smart surfactant solution.
- the designer smart surfactants used in the processes of the present invention differ from conventional surfactants in that the former have specifically engineered functional groups that generate micelles of appropriate size and shape so as to enhance the reaction rate.
- the present invention provides the use of an aqueous designer smart surfactant solution for carrying out a wide range of organic reactions selected from carbon-carbon coupling, amide synthesis, nitro reduction, Knoevenagel reaction, ester hydrolysis, amination of alcohols, oxidation of alcohols, aza lactone formation, Suzuki- Miyaura coupling, silylation, C-H activation, Negishi coupling, Buchwald-Hartwig amination, benzylic couplings, Pd-catalyzed couplings, Zn-mediated coupling, Heck coupling, CuH-catalyzed asymmetric hydrosilylation, Sonogashira coupling, borylation of aryl halides, aerobic oxidation in nanomicelles of aryl alkynes, asymmetric 1 ,4-additions, aldol condensation, nucleophilic aromatic substitution reactions, olefin metathesis, allylic animations, transition metal catalyzed organic reactions, N-arylation and N-al
- the present invention provides the use of an aqueous designer smart surfactant solution for preparing active pharmaceutical ingredients selected from those used as antidiabetics; antibiotics; antimicrobials; analgesics; anti-allergics; antiasthmatics; anticancer drugs; CNS drugs such as antidepressants, antianxiety drugs, anti- Parkinson's drugs, antiepileptics and neuroleptic drugs; cardiovascular drugs such as diuretics, hypolipidemics, antiarrhythmics, vasodilators, anti-anginals, and
- antihypertensives include sympathomimetics; antiemetics; anti-inflammatory drugs; anti- histaminic drugs; antitussives; antivirals; antimigraine drugs; immunosuppressants;
- cholinomemetic drugs adrenergic drugs; antimuscarinic drugs; antispasmodic drugs; skeletal muscle relaxants; expectorants, dermatological drugs; drugs for treating attention deficit hyperactive disorders (ADHD); and drugs for treating gastrointestinal disorders.
- ADHD attention deficit hyperactive disorders
- the present invention provides the use of an aqueous designer smart surfactant solution for preparing apixaban and intermediates thereof. Detailed Description of the Invention
- a first aspect of the present invention provides the use of an aqueous designer smart surfactant solution for carrying out organic reactions selected from C-C coupling, amide synthesis, ester hydrolysis, amination of alcohols, oxidation of alcohols, aza lactone formation, Suzuki-Miyaura coupling, silylation, C-H activation, Negishi coupling,
- a second aspect of the present invention provides the use of an aqueous designer smart surfactant solution for preparing active pharmaceutical ingredients selected from those used as antidiabetics; antibiotics; antimicrobials; analgesics; anti- allergies; antiasthmatics; anticancer drugs; CNS drugs such as antidepressants, antianxiety drugs, anti- Parkinson's drugs, antiepileptics and neuroleptic drugs; cardiovascular drugs such as diuretics, hypolipidemics, antiarrhythmics, vasodilators, anti-anginals, and
- antihypertensives include sympathomimetics; antiemetics; anti-inflammatory drugs; anti- histaminic drugs; antitussives; antivirals; antimigraine drugs; immunosuppressants;
- cholinomemetic drugs adrenergic drugs; antimuscarinic drugs; antispasmodic drugs; skeletal muscle relaxants; expectorants; dermatological drugs; drugs for treating attention deficit hyperactive disorders (ADHD); and drugs for treating gastrointestinal disorders.
- ADHD attention deficit hyperactive disorders
- a third aspect of the present invention provides the use of an aqueous designer smart surfactant solution for reparing apixaban of Formula I
- a fourth aspect of the present invention provides a process for preparing apixaban of Formula I
- steps i) to iii) are carried out in an aqueous designer smart surfactant solution.
- a fifth aspect of the present invention provides a process for preparing apixaban of Formula I
- steps i) to iv) are carried out in an aqueous designer smart surfactant solution.
- a sixth aspect of the present invention provides a process for preparing apixaban of Formula I
- steps i) to v) are carried out in an aqueous designer smart surfactant solution.
- a seventh aspect of the present invention provides a process for preparing l-(4- arninophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III
- An eighth aspect of the present invention provides a process for preparing apixaban of Formula I
- a ninth aspect of the present invention provides a process for preparing 5-halo-N- ⁇ 4-[5- ⁇ 1 ⁇ -4- ⁇ 1)-6- ⁇ -3,6- ⁇ - 1 (2H)-yl]phenyl jpentanamide of Formula IV
- a tenth aspect of the present invention provides a process for preparing apixaban of Formula I
- An eleventh aspect of the present invention provides a process for the preparation of 3-(mo holin-4-yl)-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6-dihydropyridin-2(lH)-one of Formula V
- a twelfth aspect of the present invention provides a process for preparing apixaban of Formula I
- a thirteenth aspect of the present invention provides a process for the preparation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII
- a fourteenth aspect of the present invention provides a process for preparing apixaban of Formula I
- a fifteenth aspect of the present invention provides a one pot process for the preparation of apixaban of Formula I
- a sixteenth aspect of the present invention provides a process for preparing 3- (morpholin-4-yl)- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] -5 ,6-dihydropyridin-2( lH)-one of Formula V
- steps i) to iii) are carried out in an aqueous designer smart surfactant solution.
- a seventeenth aspect of the present invention provides a process for apixaban of Formula I
- steps i) to iii) are carried out in an aqueous designer smart surfactant solution.
- ambient temperature refers to the temperature in the range of about 20°C to about 35°C.
- halogen refers to fluorine, chlorine, bromine, or iodine.
- pure refers to an active pharmaceutical ingredient or an intermediate thereof having a high performance liquid chromatographic (HPLC) purity of greater than or equal to about 80%. In an embodiment of the present invention, the HPLC purity is greater than or equal to about 90%. In another embodiment of the present invention, the HPLC purity is greater than or equal to about 99%.
- HPLC high performance liquid chromatographic
- surfactant refers to a surface active agent or a mixture of agents that lower the interfacial tension between a solid and a liquid, or two liquids.
- designer smart surfactant refers to specially designed nonionic surfactants such as those disclosed in U.S. Patent No. 8,785,665; Green Chem., 2016, 18, 14-19; and Green Chem., 2015, 17, 644-683.
- aqueous designer smart surfactant solutions examples include PTS, TPGS- 750M, SPGS-550M (Nok), Triton ® X-100, Tergitol ® TMN-6, Tergitol ® 15S40, Tergitol ® 15S7, Brij ® -35, Tween ® 80, and PTS-7.
- Examples of organic reactions include C-C coupling, amide synthesis, ester hydrolysis, amination of alcohols, oxidation of alcohols, aza lactone formation, Suzuki- Miyaura coupling, silylation, C-H activation, Negishi coupling, Buchwald-Hartwig amination, benzylic couplings, Pd-catalyzed couplings, Zn-mediated coupling, Heck coupling, CuH-catalyzed asymmetric hydrosilylation, Sonogashira coupling, borylation of aryl halides, aerobic oxidation in nanomicelles of aryl alkynes, asymmetric 1,4-additions, aldol condensation, nucleophilic aromatic substitution reactions, olefin metathesis, allylic animations, transition metal catalyzed organic reactions, N-arylation and N-alkylation, O- alkylation of aromatic and aliphatic alcohols, reductive amination, asymmetric reduction of ketones, Diels-Al
- active pharmaceutical ingredient refers to a substance used in a finished pharmaceutical product (FPP) intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.
- the active pharmaceutical ingredient may be present in the form of a free base or a pharmaceutically acceptable salt thereof.
- active pharmaceutical ingredient(s) Polymorphs and solvates of the active pharmaceutical ingredient(s) are also included within the scope of the present invention.
- active pharmaceutical ingredient(s) include those used as antidiabetics; antibiotics; antimicrobials; analgesics; anti- allergies; anti-asthmatics;
- anticancer drugs such as anticancer drugs, CNS drugs such as antidepressants, antianxiety drugs, anti-Parkinson's drugs, antiepileptics and neuroleptic drugs; cardiovascular drugs such as diuretics, hypolipidemics, antiarrhythmics, vasodilators, anti-anginals, and antihypertensives; sympathomimetics; antiemetics; anti-inflammatory drugs; anti-histaminic drugs;
- antitussives ; antivirals; antimigraine drugs; immunosuppressants; cholinomemetic drugs; adrenergic drugs; antimuscarinic drugs; antispasmodic drugs; skeletal muscle relaxants; expectorants, dermatological drugs; drugs for treating attention deficit hyperactive disorders; and drugs for treating gastrointestinal disorders.
- active pharmaceutical ingredient examples include apixaban, rivaroxaban, edoxaban, dabigatran etexilate, eluxadoline, canagliflozin, dapagliflozin, empagliflozin, pazopanib, fexofenadine, febuxostat, ciprofloxacin, amoxicillin, moxifloxacin, valacyclovir, vaganciclovir, acyclovir, ganciclovir, asenapine, abiraterone, ambrisentan, palbociclib, linagliptin, vildagliptin, sitagliptin, alogliptin, saxagliptin, omarigliptin, liraglutide, losartan, irbesartan, eprosartan, valsartan, amantadine, sertraline, sevelamer,
- intermediate refers to an organic compound that is formed at any stage during the preparation of an active pharmaceutical ingredient.
- substrate refers to a material on which a process is conducted.
- substrate may also be used interchangeably with the term “reagent” or "reactant”.
- the present invention provides processes for the preparation of apixaban of Formula I and intermediates thereof in an aqueous designer smart surfactant solution, without using any organic solvent.
- reducing agents include sodium sulphide, sodium hydrosulphite, iron, ammonium chloride, zinc, tin (II) chloride, platinum oxide, Fe/NFUCl, Zn/NFUCl, formic acid in presence of a metal catalyst, pyridinium zinc complex, and trihalosilanes.
- l-(4-Arninophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III may be isolated from the reaction mixture, or the reaction mixture may be carried out as such to the next step.
- Isolation of l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III may be accomplished by filtration, decantation, extraction, distillation, evaporation, precipitation, centrifugation, concentration, or a combination thereof, followed by optional washing with de-ionized water, and optional drying.
- Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying.
- 5-halovaleryl halides include 5-chlorovaleryl chloride, 5- bromovaleryl chloride, and 5-chlorovaleryl bromide.
- bases include organic and inorganic bases selected from ethyl amine, ammonia, triethyl amine, N-methylrr ⁇ holine, isobutylamine, tributyl amine, diisopropyl amine, diisopropylethylamine, triisopropylamine, pyridine, 4-dimethylaminopyridine (DMAP), potassium tert-butoxide, 4-ethylrr ⁇ holine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane, 2,6-di-tert-butyl-4-dimethylaminopyridine, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium bicarbonate, magnesium bicarbonate, and potassium bicarbonate.
- organic and inorganic bases selected from eth
- reaction of l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide is carried out at a temperature of about 0°C to about 50°C, for example, at a temperature of about 15°C to about 40°C.
- reaction of l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide is carried out for about 15 minutes to about 4 hours, for example, for about 30 minutes to about 3 hours.
- 5-Halo-N- ⁇ 4-[5-(mo holin-4-yl)-6-oxo-3,6-dihydropyridin-l(2H)- yl]phenyl ⁇ pentanamide of Formula IV may be isolated from the reaction mixture, or the reaction mixture may be carried out as such to the next step.
- Isolation of 5-halo-N- ⁇ 4-[5- ⁇ 1 ⁇ 1 ⁇ -4 ⁇ 1)-6- ⁇ -3,6- ⁇ 1 ⁇ - 1 (2H)- yl]phenyl ⁇ pentanamide of Formula IV may be accomplished by filtration, decantation, extraction, distillation, evaporation, precipitation, centrifugation, concentration, or a combination thereof, followed by optional washing with de-ionized water, and optional drying.
- Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying.
- bases include organic and inorganic bases selected from ethyl amine, ammonia, triethyl amine, N-methylrr ⁇ holine, isobutylamine, tributyl amine, diisopropyl amine, diisopropylethylamine, triisopropylamine, pyridine, 4-dimethylaminopyridine
- DMAP potassium tert-butoxide
- DBU 4-ethylrr ⁇ holine
- DBU l,4-diazabicyclo[2.2.2]octane
- 2,6-di-tert-butyl-4-dimethylaminopyridine lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium bicarbonate, magnesium bicarbonate, and potassium bicarbonate.
- catalysts include tetra butylammonium iodide, terra butylammonium bromide, potassium iodide, and potassium bromide.
- the cyclization of 5-halo-N- ⁇ 4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl ⁇ pentanamide of Formula IV is carried out at a temperature of about 15°C to about 60°C, for example, at about 20°C to about 40°C.
- Isolation of 3-(morpholin-4-yl)- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] -5 ,6- dihydropyridin-2(lH)-one of Formula V may be accomplished by filtration, decantation, extraction, distillation, evaporation, precipitation, centrifugation, concentration, or a combination thereof, followed by optional washing with de-ionized water, and optional drying.
- Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying.
- Ethyl 1 -(4-methoxyphenyl)-7-oxo-6- [4-(2-oxopiperidin- 1 -yl)phenyl] -4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII may be isolated from the reaction mixture, or it may be carried out as such to the next step without isolation.
- Isolation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII may be accomplished by filtration, decantation, extraction, distillation, evaporation, precipitation, centrifugation, concentration, or a combination thereof, followed by optional washing with de-ionized water, and optional drying.
- Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying.
- Isolation of apixaban of Formula I may be accomplished by filtration, decantation, extraction, distillation, evaporation, precipitation, centrifugation, concentration, or a combination thereof, followed by optional washing with de-ionized water, and drying.
- Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying.
- Example 1 Preparation of l-(4-aminophenyl)-3-(mo ⁇ holin-4-yl)-5,6-dihvdropyridin- 2(lH)-one (Formula III) using an organic solvent
- Example 1 Preparation of l-(4-aminophenyl)-3-(mo ⁇ holin-4-yl)-5,6-dihvdropyridin- 2(lH)-one (Formula III) in an aqueous designer smart surfactant solution
- Example 2 Preparation of l-(4-aminophenyl)-3-(mo ⁇ holin-4-yl)-5,6-dihvdropyridin- 2(lH)-one (Formula III) in an aqueous designer smart surfactant solution
- Formula III was added to a reaction vessel containing an aqueous solution of TPGS-750- M (2 wt. % in 40 mL water) at ambient temperature.
- the reaction mixture was cooled to 5°C to 10°C.
- N-methyl morpholine (4 g) was added followed by the slow addition of 5- bromovaleryl chloride (6 g) to the reaction mixture.
- the reaction mixture was stirred at ambient temperature for 1 hour to 2 hours.
- the reaction mixture was filtered, washed with de-ionized water (30 mL), and then dried in an air oven at 45°C to 50°C to obtain the title compound.
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention provides processes for the preparation of active pharmaceutical ingredients and intermediates thereof in an aqueous designer smart surfactant solution.
Description
PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS AND INTERMEDIATES THEREOF
Field of the Invention
The present invention provides processes for the preparation of active
pharmaceutical ingredients and intermediates thereof in an aqueous designer smart surfactant solution.
Background of the Invention
Most pharmaceutical compounds are synthesized using organic solvents as the reaction medium and as extraction solvents. This is due to the solubility of most of the organic substrates, reagents, and catalysts in organic solvents. Thus, organic solvents make up most of the organic waste created during synthesis. In view of growing concerns over Environmental Health and Safety (EHS) and stringent rules regulating the use and disposal of organic solvents, there is a need for developing non-hazardous alternatives for synthesizing pharmaceutical compounds. A way forward in this regard is to use water as a solvent instead of organic solvents, as this will radically reduce the use of organic solvents. However, the use of water as a solvent is in itself limited due to the insolubility of most of the organic substrates in water, and in most of the cases, either the reaction does not take place at all, or the reaction yield is low. The use of conventional surfactants such as sodium dodecylsulfate, cetyltrimethylammonium chloride, dodecyltrimethylammonium chloride, and sodium dodecyl benzene sulphonate for increasing the solubility of organic substrates in water is described in Green Chem., 2015, 17, 644-683. Although the use of such conventional surfactants increases the solubility of organic substrates in water by lowering the interfacial tension between the substrate and water, they often disperse the reactants resulting in slow reaction rates. Thus, there exists a need in the art for developing faster and high yielding processes for the synthesis of active pharmaceutical ingredients and intermediates thereof using water as the solvent. U.S. Patent No.
8,785,665; Green Chem., 2016, 18, 14-19; and Green Chem., 2015, 17, 644-683, in general, describe the use of specifically designed aqueous, designer smart surfactant solutions developed by Lipshutz and coworkers for carrying out various chemical reactions, without providing specific examples of any active pharmaceutical ingredients.
The present invention provides the use of an aqueous designer smart surfactant solution for synthesizing active pharmaceutical ingredients and intermediates thereof.
Summary of the Invention
The present invention provides ecofriendly, cost-effective, and industrially advantageous process for the preparation of active pharmaceutical ingredients and intermediates thereof using an aqueous designer smart surfactant solution. The designer smart surfactants used in the processes of the present invention differ from conventional surfactants in that the former have specifically engineered functional groups that generate micelles of appropriate size and shape so as to enhance the reaction rate.
Specifically, the present invention provides the use of an aqueous designer smart surfactant solution for carrying out a wide range of organic reactions selected from carbon-carbon coupling, amide synthesis, nitro reduction, Knoevenagel reaction, ester hydrolysis, amination of alcohols, oxidation of alcohols, aza lactone formation, Suzuki- Miyaura coupling, silylation, C-H activation, Negishi coupling, Buchwald-Hartwig amination, benzylic couplings, Pd-catalyzed couplings, Zn-mediated coupling, Heck coupling, CuH-catalyzed asymmetric hydrosilylation, Sonogashira coupling, borylation of aryl halides, aerobic oxidation in nanomicelles of aryl alkynes, asymmetric 1 ,4-additions, aldol condensation, nucleophilic aromatic substitution reactions, olefin metathesis, allylic animations, transition metal catalyzed organic reactions, N-arylation and N-alkylation, O- alkylation of aromatic and aliphatic alcohols, reductive amination, asymmetric reduction of ketones, Diels-Alder reaction, and ring-closing metathesis.
More specifically, the present invention provides the use of an aqueous designer smart surfactant solution for preparing active pharmaceutical ingredients selected from those used as antidiabetics; antibiotics; antimicrobials; analgesics; anti-allergics; antiasthmatics; anticancer drugs; CNS drugs such as antidepressants, antianxiety drugs, anti- Parkinson's drugs, antiepileptics and neuroleptic drugs; cardiovascular drugs such as diuretics, hypolipidemics, antiarrhythmics, vasodilators, anti-anginals, and
antihypertensives; sympathomimetics; antiemetics; anti-inflammatory drugs; anti- histaminic drugs; antitussives; antivirals; antimigraine drugs; immunosuppressants;
cholinomemetic drugs; adrenergic drugs; antimuscarinic drugs; antispasmodic drugs; skeletal muscle relaxants; expectorants, dermatological drugs; drugs for treating attention deficit hyperactive disorders (ADHD); and drugs for treating gastrointestinal disorders.
Most specifically, the present invention provides the use of an aqueous designer smart surfactant solution for preparing apixaban and intermediates thereof.
Detailed Description of the Invention
A first aspect of the present invention provides the use of an aqueous designer smart surfactant solution for carrying out organic reactions selected from C-C coupling, amide synthesis, ester hydrolysis, amination of alcohols, oxidation of alcohols, aza lactone formation, Suzuki-Miyaura coupling, silylation, C-H activation, Negishi coupling,
Buchwald-Hartwig amination, benzylic couplings, Pd-catalyzed couplings, Zn-mediated coupling, Heck coupling, CuH-catalyzed asymmetric hydrosilylation, Sonogashira coupling, borylation of aryl halides, aerobic oxidation in nanomicelles of aryl alkynes, asymmetric 1,4-additions, aldol condensation, nucleophilic aromatic substitution reactions, olefin metathesis, allylic animations, transition metal catalyzed organic reactions, N- arylation and N-alkylation, O-alkylation of aromatic and aliphatic alcohols, reductive amination, asymmetric reduction of ketones, Diels-Alder reaction, and ring-closing metathesis.
A second aspect of the present invention provides the use of an aqueous designer smart surfactant solution for preparing active pharmaceutical ingredients selected from those used as antidiabetics; antibiotics; antimicrobials; analgesics; anti- allergies; antiasthmatics; anticancer drugs; CNS drugs such as antidepressants, antianxiety drugs, anti- Parkinson's drugs, antiepileptics and neuroleptic drugs; cardiovascular drugs such as diuretics, hypolipidemics, antiarrhythmics, vasodilators, anti-anginals, and
antihypertensives; sympathomimetics; antiemetics; anti-inflammatory drugs; anti- histaminic drugs; antitussives; antivirals; antimigraine drugs; immunosuppressants;
cholinomemetic drugs; adrenergic drugs; antimuscarinic drugs; antispasmodic drugs; skeletal muscle relaxants; expectorants; dermatological drugs; drugs for treating attention deficit hyperactive disorders (ADHD); and drugs for treating gastrointestinal disorders.
A third aspect of the present invention provides the use of an aqueous designer smart surfactant solution for reparing apixaban of Formula I
Formula I
and intermediates thereof.
A fourth aspect of the present invention provides a process for preparing apixaban of Formula I
Formula I
comprising:
reducing 3-(morpholin-4-yl)- 1 -(4-nitrophenyl)-5,6-dihydropyridin- of Formula II
Formula II
to obtain l-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III;
Formula III
ii) reacting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide to obtain 5-halo-N-{4-[5-(morpholin- 4-yl)-6-oxo-3,6-dihydropyridin-l(2H)-yl]phenyl}pentanamide of Formula IV;
Formula IV (wherein X = halogen)
iii) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV to obtain 3-^ο 1ιο1ίη-4^1)-1-[4-(2- oxopiperidin-l-yl)phen l]-5,6-dihydropyridin-2(lH)-one of Formula V;
Formula V
iv) reacting 3-(morpholin-4-yl)- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] -5 ,i dihydropyridin-2(lH)-one of Formula V with ethyl (2Z)-halo[2-(4- methoxyphenyl)hydrazinylidene]ethanoate of Formula VI
Formula VI (wherein X = halogen)
to obtain ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII; and
Formula VII
v) amidating ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII to obtain apixaban of Formula I,
wherein steps i) to iii) are carried out in an aqueous designer smart surfactant solution.
A fifth aspect of the present invention provides a process for preparing apixaban of Formula I
Formula I
comprising:
i) reducing 3-(morpholin-4-yl)- 1 -(4-nitrophenyl)-5,6-dihydropyridin- one of Formula II
Formula II
to obtain l-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III;
Formula III
ii) reacting l-(4-anήnophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide to obtain 5-halo-N-{4-[5-(morpholin- 4-yl)-6-oxo-3,6-dihydro ridin-l(2H)-yl]phenyl}pentanamide of Formula IV;
Formula IV (wherein X = halogen)
iii) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl} pentanamide of Formula IV to obtain 3-(morpholin-4-yl)-l-[4- (2-oxopiperidin-l-yl) henyl]-5,6-dihydropyridin-2(lH)-one of Formula V;
Formula V
iv) reacting 3-(morpholin-4-yl)- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] -5 ,t dihydropyridin-2(lH)-one of Formula V with ethyl (2Z)-halo[2-(4- methoxyphenyl) hydrazinylidenejethanoate of Formula VI
Formula VI (wherein X = halogen)
to obtain ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII; and
Formula VII
v) amidating ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII to obtain apixaban of Formula I,
wherein steps i) to iv) are carried out in an aqueous designer smart surfactant solution.
A sixth aspect of the present invention provides a process for preparing apixaban of Formula I
Formula I
comprising:
reducing 3-(morpholin-4-yl)- 1 -(4-nitrophenyl)-5,6-dihydropyridin- of Formula II
Formula II
to obtain l-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III;
Formula III
ii) reacting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide to obtain 5-halo-N-{4-[5-(morpholin- 4-yl)-6-oxo-3,6-dih dropyridin-l(2H)-yl]phenyl}pentanamide of Formula IV;
Formula IV (wherein X = halogen)
iii) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl} pentanamide of Formula IV to obtain 3-(morpholin-4-yl)-l-[4- (2-oxopiperidin-l-yl) henyl]-5,6-dihydropyridin-2(lH)-one of Formula V;
Formula V
iv) reacting 3-(mo holin-4-yl)-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,ί dihydropyridin-2(lH)-one of Formula V with ethyl (2Z)-halo[2-(4- methoxyphenyl) hydrazinylidenejethanoate of Formula VI
Formula VI (wherein X = halogen) to obtain ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII; and
Formula VII
v) amidating ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII to obtain apixaban of Formula I,
wherein steps i) to v) are carried out in an aqueous designer smart surfactant solution.
A seventh aspect of the present invention provides a process for preparing l-(4- arninophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III
Formula III
comprising reducing 3-(mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)-one of Formula II
Formula II
in the presence of a reducing agent in an aqueous designer smart surfactant solution.
An eighth aspect of the present invention provides a process for preparing apixaban of Formula I
Formula I
comprising:
reducing 3-(morpholin-4-yl)- 1 -(4-nitrophenyl)-5,6-dihydropyridin- of Formula II
Formula II
in the presence of a reducing agent in an aqueous designer smart surfactant solution to obtain l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin- 2(lH)-one of Formula III; and
Formula III
ii) converting 1-(4- ηιίηορ1ΐ6ηγ1)-3-(ηιο 1ιο1ίη-4-γ1)-5,6-(1ί1ιγάΓοργΓί(1ίη- 2(lH)-one of Formula III into apixaban of Formula I.
A ninth aspect of the present invention provides a process for preparing 5-halo-N- { 4-[5-^οφηο1ίη-4-ν1)-6-οχο-3,6-άώνάΓορνΓίάίη- 1 (2H)-yl]phenyl jpentanamide of Formula IV
Formula IV (wherein X = halog
comprising reacting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III
Formula III
with 5-halovaleryl halide in an aqueous designer smart surfactant solution.
A tenth aspect of the present invention provides a process for preparing apixaban of Formula I
Formula I
comprising:
reacting 1 -(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin- of Formula III
Formula III
with 5-halovaleryl halide in an aqueous designer smart surfactant solution to obtain
5-halo-N- { 4- [5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- 1 (2H)- yl]phenyl}pentanamide of Formula IV; and
Formula IV (wherein X = halogen)
ii) converting 5-halo-N-{4-[5-(mo holin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV into apixaban of Formula I.
An eleventh aspect of the present invention provides a process for the preparation of 3-(mo holin-4-yl)-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6-dihydropyridin-2(lH)-one of Formula V
Formula V
comprising cyclizing 5-halo-N-{4-[5-(mo holin-4-yl)-6-oxo-3,6-dihydropyridin■ yl]phenyl} pentanamide of Formula IV
Formula IV (wherein X = halogen)
in an aqueous designer smart surfactant solution.
A twelfth aspect of the present invention provides a process for preparing apixaban of Formula I
Formula I
comprising:
i) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl} pentanamide of Formula IV
Formula IV (wherein X = halogen)
in an aqueous designer smart surfactant solution to obtain 3-^οφ1ιο1ίη-4^1)-1-[4- (2-oxopiperidin-l-yl)phenyl]-5,6-dihydropyridin-2(lH)-one of Formula V; and
Formula V
ii) converting 3-(ηιο 1ιο1ίη-4-γ1)-1-[4-(2-οχορίρ6Γί(ϋη-1-γ1)ρ1ΐ6ηγ1]-5,6- dihydropyridin-2(lH)-one of Formula V into apixaban of Formula I.
A thirteenth aspect of the present invention provides a process for the preparation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII
Formula VII
comprising reacting 3-(mo holin-4-yl)-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6- dihydropyridin-2(lH)-one of Formula V
Formula V
with ethyl (2Z)-halo[2-(4-methoxyphenyl)hydrazinylidene]ethanoate of Formula VI
Formula VI (wherein X = halogen)
in an aqueous designer smart surfactant solution.
A fourteenth aspect of the present invention provides a process for preparing apixaban of Formula I
Formula I
comprising:
i) reacting 3-(morpholin-4-yl)- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] -5 ,t dihydropyridin-2( 1 H)-one of Formula V
Formula V
with ethyl (2Z)-halo[2-(4-methoxyphenyl)hydrazinylidene]ethanoate of Formula VI
Formula VI (wherein X = halogen)
in an aqueous designer smart surfactant solution to obtain ethyl l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII; and
Formula VII
ii) converting ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII into apixaban of Formula I.
A fifteenth aspect of the present invention provides a one pot process for the preparation of apixaban of Formula I
Formula I
using aqueous designer smart surfactant solution.
A sixteenth aspect of the present invention provides a process for preparing 3- (morpholin-4-yl)- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] -5 ,6-dihydropyridin-2( lH)-one of Formula V
Formula V
comprising:
reducing 3-(morpholin-4-yl)- 1 -(4-nitrophenyl)-5,6-dihydropyridin- of Formula II
Formula II
to obtain l-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III;
Formula III
ii) reacting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide to obtain 5-halo-N-{4-[5-(morpholin- 4-yl)-6-oxo-3,6-dihydropyridin-l(2H)-yl]phenyl}pentanamide of Formula IV; and
Formula IV (wherein X = halogen)
iii) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV to obtain 3-^ο 1ιο1ίη-4^1)-1-[4-(2- oxopiperidin-l-yl)phenyl]-5,6-dihydropyridin-2(lH)-one of Formula V,
wherein steps i) to iii) are carried out in an aqueous designer smart surfactant solution.
A seventeenth aspect of the present invention provides a process for apixaban of Formula I
Formula I
comprising:
reducing 3-(morpholin-4-yl)- 1 -(4-nitrophenyl)-5,6-dihydropyridin- of Formula II
Formula II
to obtain l-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III;
Formula III
ii) reacting l-(4-anήnophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide to obtain 5-halo-N-{4-[5-(morpholin- 4-yl)-6-oxo-3,6-dihydro ridin-l(2H)-yl]phenyl}pentanamide of Formula IV; and
Formula IV (wherein X = halogen)
iii) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV to obtain 3-^οφ1ιο1ίη-4^1)-1-[4-(2- oxopiperidin-l-yl)phen l]-5,6-dihydropyridin-2(lH)-one of Formula V; and
Formula V
iv) converting 3-(morpholin-4-yl)- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] -5 ,6- dihydropyridin-2(lH)-one of Formula V into apixaban of Formula I,
wherein steps i) to iii) are carried out in an aqueous designer smart surfactant solution.
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term "ambient temperature," as used herein, refers to the temperature in the range of about 20°C to about 35°C.
The term "halogen", as used herein, refers to fluorine, chlorine, bromine, or iodine.
The term "pure," as used herein, refers to an active pharmaceutical ingredient or an intermediate thereof having a high performance liquid chromatographic (HPLC) purity of greater than or equal to about 80%. In an embodiment of the present invention, the HPLC purity is greater than or equal to about 90%. In another embodiment of the present invention, the HPLC purity is greater than or equal to about 99%.
The term "surfactant," as used herein, refers to a surface active agent or a mixture of agents that lower the interfacial tension between a solid and a liquid, or two liquids.
The term "designer smart surfactant," as used herein, refers to specially designed nonionic surfactants such as those disclosed in U.S. Patent No. 8,785,665; Green Chem., 2016, 18, 14-19; and Green Chem., 2015, 17, 644-683.
Examples of aqueous designer smart surfactant solutions include PTS, TPGS- 750M, SPGS-550M (Nok), Triton® X-100, Tergitol® TMN-6, Tergitol® 15S40, Tergitol® 15S7, Brij®-35, Tween® 80, and PTS-7.
Examples of organic reactions include C-C coupling, amide synthesis, ester hydrolysis, amination of alcohols, oxidation of alcohols, aza lactone formation, Suzuki- Miyaura coupling, silylation, C-H activation, Negishi coupling, Buchwald-Hartwig amination, benzylic couplings, Pd-catalyzed couplings, Zn-mediated coupling, Heck coupling, CuH-catalyzed asymmetric hydrosilylation, Sonogashira coupling, borylation of aryl halides, aerobic oxidation in nanomicelles of aryl alkynes, asymmetric 1,4-additions, aldol condensation, nucleophilic aromatic substitution reactions, olefin metathesis, allylic animations, transition metal catalyzed organic reactions, N-arylation and N-alkylation, O- alkylation of aromatic and aliphatic alcohols, reductive amination, asymmetric reduction of ketones, Diels-Alder reaction, and ring-closing metathesis.
The term "active pharmaceutical ingredient," as used herein, refers to a substance used in a finished pharmaceutical product (FPP) intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings. The active pharmaceutical ingredient may be present in the form of a free base or a pharmaceutically acceptable salt thereof.
Polymorphs and solvates of the active pharmaceutical ingredient(s) are also included within the scope of the present invention.
Examples of active pharmaceutical ingredient(s) include those used as antidiabetics; antibiotics; antimicrobials; analgesics; anti- allergies; anti-asthmatics;
anticancer drugs; CNS drugs such as antidepressants, antianxiety drugs, anti-Parkinson's drugs, antiepileptics and neuroleptic drugs; cardiovascular drugs such as diuretics, hypolipidemics, antiarrhythmics, vasodilators, anti-anginals, and antihypertensives; sympathomimetics; antiemetics; anti-inflammatory drugs; anti-histaminic drugs;
antitussives; antivirals; antimigraine drugs; immunosuppressants; cholinomemetic drugs; adrenergic drugs; antimuscarinic drugs; antispasmodic drugs; skeletal muscle relaxants; expectorants, dermatological drugs; drugs for treating attention deficit hyperactive disorders; and drugs for treating gastrointestinal disorders.
Some specific examples of active pharmaceutical ingredient include apixaban, rivaroxaban, edoxaban, dabigatran etexilate, eluxadoline, canagliflozin, dapagliflozin, empagliflozin, pazopanib, fexofenadine, febuxostat, ciprofloxacin, amoxicillin, moxifloxacin, valacyclovir, vaganciclovir, acyclovir, ganciclovir, asenapine, abiraterone, ambrisentan, palbociclib, linagliptin, vildagliptin, sitagliptin, alogliptin, saxagliptin, omarigliptin, liraglutide, losartan, irbesartan, eprosartan, valsartan, amantadine, sertraline, sevelamer, gabapentin, atorvastatin, mesalamine, orlistat, lansoprazole, pantoprazole, esomeprazole, sodium oxybate, loratadine, desloratadine, isotretinoin, tretinoin, acetretin, doxycycline, allantoin, pimavanserin, ivacaftor, venetoclax, ribociclib, masitinib, baricitinib, sunitinib, sorafenib, ibrutinib, apremilast, ixazomib, tofacitinib, dolutegravir, sofosbuvir, rifaximin, and LCZ696.
The term "intermediate," as used herein, refers to an organic compound that is formed at any stage during the preparation of an active pharmaceutical ingredient.
The term "substrate," as used herein, refers to a material on which a process is conducted. The term "substrate," may also be used interchangeably with the term "reagent" or "reactant".
The present invention provides processes for the preparation of apixaban of Formula I and intermediates thereof in an aqueous designer smart surfactant solution, without using any organic solvent.
The reduction of 3-(mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)- one of Formula II to obtain l-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-
2(lH)-one of Formula III is carried out in the presence of a reducing agent in an aqueous designer smart surfactant solution.
Examples of reducing agents include sodium sulphide, sodium hydrosulphite, iron, ammonium chloride, zinc, tin (II) chloride, platinum oxide, Fe/NFUCl, Zn/NFUCl, formic acid in presence of a metal catalyst, pyridinium zinc complex, and trihalosilanes.
The reduction of 3-(mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)- one of Formula II is carried out at ambient temperature to a temperature of about 70°C, for example, at a temperature of about 40°C to about 60°C.
The reduction of 3-(mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)- one of Formula II is carried out for about 30 minutes to about 8 hours, for example, for about 1 hour to about 6 hours.
l-(4-Arninophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III may be isolated from the reaction mixture, or the reaction mixture may be carried out as such to the next step.
Isolation of l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III may be accomplished by filtration, decantation, extraction, distillation, evaporation, precipitation, centrifugation, concentration, or a combination thereof, followed by optional washing with de-ionized water, and optional drying.
Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying.
The reaction of l-(4-aminophenyl)-3-(moφholin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide is carried out in the presence of a base in an aqueous designer smart surfactant solution.
Examples of 5-halovaleryl halides include 5-chlorovaleryl chloride, 5- bromovaleryl chloride, and 5-chlorovaleryl bromide.
Examples of bases include organic and inorganic bases selected from ethyl amine, ammonia, triethyl amine, N-methylrr ^holine, isobutylamine, tributyl amine, diisopropyl amine, diisopropylethylamine, triisopropylamine, pyridine, 4-dimethylaminopyridine (DMAP), potassium tert-butoxide, 4-ethylrr ^holine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane, 2,6-di-tert-butyl-4-dimethylaminopyridine, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate,
potassium carbonate, barium carbonate, sodium bicarbonate, magnesium bicarbonate, and potassium bicarbonate.
The reaction of l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide is carried out at a temperature of about 0°C to about 50°C, for example, at a temperature of about 15°C to about 40°C.
The reaction of l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide is carried out for about 15 minutes to about 4 hours, for example, for about 30 minutes to about 3 hours.
5-Halo-N-{4-[5-(mo holin-4-yl)-6-oxo-3,6-dihydropyridin-l(2H)- yl]phenyl}pentanamide of Formula IV may be isolated from the reaction mixture, or the reaction mixture may be carried out as such to the next step.
Isolation of 5-halo-N- { 4-[5-^ο 1ιο1ίη-4^1)-6-οχο-3,6-άί1^π^Γίάίη- 1 (2H)- yl]phenyl}pentanamide of Formula IV may be accomplished by filtration, decantation, extraction, distillation, evaporation, precipitation, centrifugation, concentration, or a combination thereof, followed by optional washing with de-ionized water, and optional drying.
Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying.
The cyclization of 5-halo-N- {4- [5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV to obtain 3-^οφ1ιο1ίη-4^1)-1-[4-(2- oxopiperidin-l-yl)phenyl]-5,6-dihydropyridin-2(lH)-one of Formula V is carried out in the presence of a base and a catalyst in an aqueous designer smart surfactant solution.
Examples of bases include organic and inorganic bases selected from ethyl amine, ammonia, triethyl amine, N-methylrr ^holine, isobutylamine, tributyl amine, diisopropyl amine, diisopropylethylamine, triisopropylamine, pyridine, 4-dimethylaminopyridine
(DMAP), potassium tert-butoxide, 4-ethylrr ^holine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane, 2,6-di-tert-butyl-4-dimethylaminopyridine, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium bicarbonate, magnesium bicarbonate, and potassium bicarbonate.
Examples of catalysts include tetra butylammonium iodide, terra butylammonium bromide, potassium iodide, and potassium bromide.
The cyclization of 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV is carried out at a temperature of about 15°C to about 60°C, for example, at about 20°C to about 40°C.
The cyclization of 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV is carried out for about 5 hours to about 15 hours, for example, for about 7 hours to about 12 hours.
3-(Mo holin-4-yl)-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6-dihydropyridin-2(lH)- one of Formula V may be isolated from the reaction mixture, or the reaction mixture may be carried out as such to the next step.
Isolation of 3-(morpholin-4-yl)- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] -5 ,6- dihydropyridin-2(lH)-one of Formula V may be accomplished by filtration, decantation, extraction, distillation, evaporation, precipitation, centrifugation, concentration, or a combination thereof, followed by optional washing with de-ionized water, and optional drying.
Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying.
The reaction of 3-(mo holin-4-yl)-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6- dihydropyridin-2(lH)-one of Formula V with ethyl (2Z)-halo[2-(4- methoxyphenyl)hydrazinylidene]ethanoate of Formula VI to obtain ethyl l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII may be carried out in an aqueous designer smart surfactant solution.
Ethyl 1 -(4-methoxyphenyl)-7-oxo-6- [4-(2-oxopiperidin- 1 -yl)phenyl] -4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII may be isolated from the reaction mixture, or it may be carried out as such to the next step without isolation.
Isolation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII may be accomplished by filtration, decantation, extraction, distillation, evaporation, precipitation,
centrifugation, concentration, or a combination thereof, followed by optional washing with de-ionized water, and optional drying.
Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying.
The amidation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII to obtain apixaban of Formula I may be carried out in an aqueous designer smart surfactant solution.
The conversion of 3-(mo holin-4-yl)-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6- dihydropyridin-2(lH)-one of Formula V into apixaban of Formula I may be carried out by processes known in the art such as by the process disclosed in U.S. Patent No. 7,396,932, which is incorporated herein by reference at least for the disclosure of such a process.
Isolation of apixaban of Formula I may be accomplished by filtration, decantation, extraction, distillation, evaporation, precipitation, centrifugation, concentration, or a combination thereof, followed by optional washing with de-ionized water, and drying.
Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
Method
Chromatographic purity of the samples were determined by HPLC using an Agilent® 1200 Series HPLC system with G1322A Degasser, G1311A Quaternary pump, G1329A Autosampler and G1314B Detector.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Comparative Examples:
Example 1 : Preparation of l-(4-aminophenyl)-3-(moφholin-4-yl)-5,6-dihvdropyridin- 2(lH)-one (Formula III) using an organic solvent
3-(Morpholin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)-one (100 g; Formula
II) was added into a reaction vessel containing methanol (1500 mL) and water 1000 (mL). Sodium sulphide (120 g) was added. The reaction mixture was stirred at 45 °C to 50°C. On completion, de-ionized water (100 mL) was added into the reaction mixture. The reaction mixture was cooled to 10°C to 15°C, and stirred for 1 hour. Dichloromethane (700 mL) was added, and the reaction mixture was stirred for 10 minutes. The reaction mixture was allowed to settle for 10 minutes. Layers were separated and dichloromethane (500 mL) was added to the aqueous layer at 10°C to 20°C. The contents were stirred for 10 minutes, and then allowed to settle for 10 minutes. Layers were separated and dichloromethane (300 mL) was again added to the aqueous layer at 10°C to 20°C. The contents were stirred for 10 minutes, and then allowed to settle for 10 minutes. Layers were separated. De-ionized water (300 mL) was added to the combined organic layers. The contents were stirred for 5 minutes and then allowed to settle for 10 minutes. The organic layer was evaporated under reduced pressure at a temperature not exceeding 40°C to obtain a residue. Dichloromethane (1000 mL) was added to the residue. The contents were stirred for 15 minutes, and taken as such to the next step (water content at this stage should not be more than 0.15 % w/w).
Example 2: Preparation of 5-bromo-N-{4-Γ5-(moφholin-4-yl)-6-oxo-3,6-dihvdropyridin- l(2H)-yllphenyl¾pentanamide (Formula IV; when X = Br) using an organic solvent
The organic layer containing l-(4-Aminophenyl)-3-(morpholin-4-yl)-5,6- dihydropyridin-2(lH)-one (Formula III) obtained from Example 1 was cooled to -10°C to -5°C. Triethylamine (70 g) and 5-bromo valeryl chloride (72.6 g) were added at -10°C to 0°C over a period of 30 minutes. The reaction mixture was stirred for 30 minutes. After completion, de-ionized water (500 mL) was added at a temperature of not more than 30°C. The reaction mixture was stirred for 10 minutes, and then allowed to settle for 20 minutes. The layers were separated and the organic layer was taken as such to the next step.
Example 3: Preparation of 3-(ηιοφ1ιο1ίη-4-ν1)-1-Γ4-(2-οχορίρ6Γί(ϋη-1-ν1)ρ1ΐ6ην11-5,6- dihydropyridin-2(lH)-one (Formula V) using an organic solvent
The organic layer containing 5-bromo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6- dihydropyridin-l(2H)-yl]phenyl}pentanamide (Formula IV; when X = Br) obtained from Example 2 was cooled to 0°C to 10°C. Aqueous potassium hydroxide solution (40 g potassium hydroxide in 100 mL water) was added. The reaction mixture was refluxed for 8 hours to 12 hours. On completion, the reaction mixture was cooled to 25°C to 30°C. De-ionized water (500 mL) was added. The reaction mixture was stirred for 15 minutes. The layers were separated. De-ionized water (500 mL) was added to the organic layer. The reaction mixture was stirred for 15 minutes. The layers again were separated. The organic layer was dried under reduced pressure at a temperature of not more than 40°C to obtain the title compound.
HPLC Purity: 85.58%
Working Examples
Example 1 : Preparation of l-(4-aminophenyl)-3-(moφholin-4-yl)-5,6-dihvdropyridin- 2(lH)-one (Formula III) in an aqueous designer smart surfactant solution
3-(Mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)-one (10 g;
Formula II) was added to a reaction vessel containing an aqueous solution of SPGS-550M (20 mL, 2 wt. % in water) at ambient temperature. Sodium sulphide (20 g) was added. The reaction mixture was heated to 50°C to 55°C and stirred for 3 hours to 4 hours. The reaction mixture was cooled to ambient temperature. The reaction mixture was filtered, washed with de-ionized water (30 mL), and then dried in an air oven at 45°C to 50°C to obtain the title compound.
Yield: 94%
Example 2: Preparation of l-(4-aminophenyl)-3-(moφholin-4-yl)-5,6-dihvdropyridin- 2(lH)-one (Formula III) in an aqueous designer smart surfactant solution
3-(Mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)-one (5 g; Formula II) was added to a reaction vessel containing an aqueous solution of Triton X 100 (2.5 g in 50 mL water) at ambient temperature. Sodium sulphide (10 g) was added. The reaction mixture was heated to 50°C to 55°C and stirred for 3 hours to 4 hours. The reaction
mixture was cooled to ambient temperature. The reaction mixture was filtered, washed with de-ionized water (30 mL), and then dried in an air oven at 45°C to 50°C to obtain the title compound.
Yield: 77%
Example 3: Preparation of 5-bromo-N-ί4-Γ5-(moφholin-4-yl')-6-oxo-3,6-dihvdropyridin- l(2H)-yl1phenyl¾pentanamide (Formula IV; when X = Br) in an aqueous designer smart surfactant solution
l-(4-Aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one (4 g;
Formula III) was added to a reaction vessel containing an aqueous solution of TPGS-750- M (2 wt. % in 40 mL water) at ambient temperature. The reaction mixture was cooled to 5°C to 10°C. N-methyl morpholine (4 g) was added followed by the slow addition of 5- bromovaleryl chloride (6 g) to the reaction mixture. The reaction mixture was stirred at ambient temperature for 1 hour to 2 hours. The reaction mixture was filtered, washed with de-ionized water (30 mL), and then dried in an air oven at 45°C to 50°C to obtain the title compound.
Yield: 80%
Example 4: Preparation of 5-bromo-N-{4-Γ5-(moφholin-4-yl)-6-oxo-3,6-dihvdropyridin- l(2H)-yllphenyl¾pentanamide (Formula IV; when X = Br) in an aqueous designer smart surfactant solution
l-(4-Aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one (1 g;
Formula III) was added to a reaction vessel containing an aqueous solution of TPGS-750- M (2 wt. % in 10 mL water) at ambient temperature. The reaction mixture was cooled to 5°C to 10°C. Triethylamine (0.923 g) was added into the reaction mixture followed by the slow addition of 5-bromovaleryl chloride (1.5 g). The reaction mixture was stirred at ambient temperature for 1 hour to 2 hours. The reaction mixture was filtered, washed with de-ionized water (30 mL), and then dried in an air oven at 45 °C to 50°C to obtain the title compound.
Yield: 64%
Example 5: Preparation of 3-(ηιοφ1ιο1ίη-4-ν1)-1-Γ4-(2-οχορίρ6Γί(ϋη- 1-ν1)ρ1ΐ6ην11-5,6- dihydropyridin-2(lH)-one (Formula V) in an aqueous designer smart surfactant solution
5-Bromo-N- { 4- [5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- 1 (2H)-yl]phenyl } pentanamide (0.75 g; Formula IV when X = Br) was added to a reaction vessel containing an aqueous solution of SPGS-550M (2 wt. % in 10 mL water) at ambient temperature.
Potassium tert-butoxide (0.3 g) and potassium iodide (0.05 g) were added into the reaction mixture. The reaction mixture was stirred at 35°C to 40°C for 9 hours to 10 hours. The reaction mixture was filtered, washed with de-ionized water (10 mL), and then dried in an air oven at 45 °C to 50°C to obtain the title compound.
Yield: 64%
HPLC Purity: 94.12%
Claims
We claim:
1. Use of an aqueous designer smart surfactant solution for preparing apixaban of Formula I
Formula I
and intermediates thereof.
2. The use according to the claim 1 , wherein the aqueous designer smart surfactant solution is selected from the group consisting of PTS, TPGS-750M, SPGS-550M (Nok), Triton™ X- 100, Tergitol® TMN-6, Tergitol® 15S40, Tergitol® 15S7, Brij®-35, Tween® 80, and PTS-7.
3. A process for preparing apixaban of Formula I
Formula I
comprising:
i) reducing 3-(mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)- one of Formula II
Formula II
to obtain l-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III;
Formula III
ii) reacting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide to obtain 5-halo-N-{4-[5-(morpholin- 4-yl)-6-oxo-3,6-dih dropyridin-l(2H)-yl]phenyl}pentanamide of Formula IV;
Formula IV (wherein X = halogen)
iii) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV to obtain 3-^οφ1ιο1ίη-4^1)-1-[4-(2- oxopiperidin-l-yl)phen l]-5,6-dihydropyridin-2(lH)-one of Formula V;
Formula V
iv) reacting 3-(morpholin-4-yl)- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] -5 ,6- dihydropyridin-2(lH)-one of Formula V with ethyl (2Z)-halo[2-(4- methoxyphenyl)hydrazinylidene]ethanoate of Formula VI
Formula VI (wherein X = halogen) to obtain ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII; and
Formula VII
v) amidating ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII to obtain apixaban of Formula I,
wherein steps i) to iii) are carried out in an aqueous designer smart surfactant solution.4. A process for preparing apixaban of Formula I
Formula I
comprising:
i) reducing 3-(mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)- one of Formula II
Formula II
to obtain l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III;
Formula III
ii) reacting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide to obtain 5-halo-N-{4-[5-(morpholin- 4-yl)-6-oxo-3,6-dihydro ridin-l(2H)-yl]phenyl}pentanamide of Formula IV;
iii) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV to obtain 3-^ο 1ιο1ίη-4^1)-1-[4-(2- oxopiperidin-l-yl)phen l]-5,6-dihydropyridin-2(lH)-one of Formula V;
Formula V
iv) reacting 3-(morpholin-4-yl)- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] -5 ,6- dihydropyridin-2(lH)-one of Formula V with ethyl (2Z)-halo[2-(4- methoxyphenyl)hydrazinylidene]ethanoate of Formula VI
Formula VI (wherein X = halogen)
to obtain ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII; and
Formula VII
v) amidating ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII to obtain apixaban of Formula I,
wherein steps i) to- iv) are carried out in an aqueous designer smart surfactant solution. 5. A process for preparing apixaban of Formula I
Formula I
comprising:
i) reducing 3-(mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)- one of Formula II
Formula II
to obtain l-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III;
Formula III
ii) reacting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide to obtain 5-halo-N-{4-[5-(morpholin- 4-yl)-6-oxo-3,6-dihydropyridin-l(2H)-yl]phenyl}pentanamide of Formula IV;
Formula IV (wherein X = halogen)
iii) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV to obtain 3-^ο 1ιο1ίη-4^1)-1-[4-(2- oxopiperidin-l-yl)phen l]-5,6-dihydropyridin-2(lH)-one of Formula V;
Formula V
iv) reacting 3-(morpholin-4-yl)- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] -5 ,i dihydropyridin-2(lH)-one of Formula V with ethyl (2Z)-halo[2-(4- methoxyphenyl)hydrazinylidene]ethanoate of Formula VI
Formula VI (wherein X = halogen)
to obtain ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII; and
Formula VII
v) amidating ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII to obtain apixaban of Formula I,
wherein steps i) to v) are carried out in an aqueous designer smart surfactant solution. 6. A process for preparing l-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin- 2(lH)-one of Formula III
Formula III
comprising reducing 3-(mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin- 2( 1 H) -one of Formula II
Formula II
in the presence of a reducing agent in an aqueous designer smart surfactant solution.
7. A process for preparing apixaban of Formula I
Formula I
comprising:
i) reducing 3-(mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)- one of Formula II
Formula II
in the presence of a reducing agent in an aqueous designer smart surfactant solution to obtain l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin- 2(lH)-one of Formula III; and
Formula III
ii) converting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin- 2(lH)-one of Formula III into apixaban of Formula I.
8. A process for preparing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6- dihydropyridin-l(2H)-yl]phenyl}pentanamide of Formula IV
Formula IV (wherein X = halogen)
comprising reacting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin- 2(lH)-one of Formula III
Formula III
with 5-halovaleryl halide in an aqueous designer smart surfactant solution.
A process for preparing apixaban of Formula I
Formula I
comprising:
i) reacting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III
Formula III
with 5-halovaleryl halide in an aqueous designer smart surfactant solution to obtain 5-halo-N- { 4- [5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- 1 (2H)- yl]phenyl}pentanamide of Formula IV; and
Formula IV (wherein X = halogen)
ii) converting 5-halo-N-{4-[5-(mo holin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV into apixaban of Formula I.
10. A process for the preparation of 3-(morpholin-4-yl)-l-[4-(2-oxopiperidin-l- yl)phenyl]-5,6-dihydropyridin-2(lH)-one of Formula V
Formula V
comprising cyclizing 5-halo-N-{4-[5-(mo holin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV
Formula IV (wherein X = halogen)
in an aqueous designer smart surfactant solution.
11. A process for preparing apixaban of Formula I
Formula I
comprising:
i) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV
Formula IV (wherein X = halogen)
in an aqueous designer smart surfactant solution to obtain 3-(morpholin-4-yl)-l-[4- (2-oxopiperidin-l-yl) henyl]-5,6-dihydropyridin-2(lH)-one of Formula V; and
Formula V
ii) converting 3-(mo holin-4-yl)-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6- dihydropyridin-2(lH)-one of Formula V into apixaban of Formula I.
12. A process for the preparation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII
Formula VII
comprising reacting 3-(mo holin-4-yl)-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6- dihydropyridin-2(lH)-one of Formula V
Formula V
with ethyl (2Z)-halo[2-(4-methoxyphen l)hydrazinylidene]ethanoate of Formula VI
Formula VI (wherein X = halogen)
in an aqueous designer smart surfactant solution.
13. A process for preparing apixaban of Formula I
Formula I
comprising:
i) reacting 3-^ο 1ιο1ίη-4-γ1)-1-[4-(2-οχορίρ6Γί(ϋη-1-γ1)ρ1ΐ6ηγ1]-5,6- dihydropyridin-2( 1 H)-one of Formula V
Formula V
with ethyl (2Z)-halo[2-(4-methoxyphenyl)hydrazinylidene]ethanoate of Formula
Formula VI (wherein X = halogen) in an aqueous designer smart surfactant solution to obtain ethyl l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII; and
Formula VII
ii) converting ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate of Formula VII into apixaban of Formula I.
14. A one pot process for the preparation of apixaban of Formula I
Formula I
using aqueous designer smart surfactant solution.
15. A process for preparing 3-(morpholin-4-yl)-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,( dihydropyridin-2( 1 H)-one of Formula V
Formula V
comprising:
i) reducing 3-(ηιο 1ιο1ίη-4-γ1)-1-(4-ηίΐΓορ1ΐ6ηγ1)-5,6-άί1ιγάΓοργΓίάίη-2(1Η)- one of Formula II
Formula II
to obtain l-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III;
Formula III
ii) reacting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide to obtain 5-halo-N-{4-[5-(morpholin- 4-yl)-6-oxo-3,6-dihydro ridin-l(2H)-yl]phenyl}pentanamide of Formula IV; and
Formula IV (wherein X = halogen)
iii) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV to obtain 3-^οφ1ιο1ίη-4^1)-1-[4-(2- oxopiperidin-l-yl)phenyl]-5,6-dihydropyridin-2(lH)-one of Formula V, wherein steps i) to iii) are carried out in an aqueous designer smart surfactant solution. 16. A process for apixaban of Formula I
Formula I
comprising:
i) reducing 3-(mo holin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)- one of Formula II
Formula II
to obtain l-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III;
Formula III
ii) reacting l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)- one of Formula III with 5-halovaleryl halide to obtain 5-halo-N-{4-[5-(morpholin- 4-yl)-6-oxo-3,6-dihydro ridin-l(2H)-yl]phenyl}pentanamide of Formula IV; and
iii) cyclizing 5-halo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin- l(2H)-yl]phenyl}pentanamide of Formula IV to obtain 3-^οφ1ιο1ίη-4^1)-1-[4-(2- oxopiperidin-l-yl)phen l]-5,6-dihydropyridin-2(lH)-one of Formula V; and
Formula V
iv) converting 3-(mo holin-4-yl)-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6- dihydropyridin-2(lH)-one of Formula V into apixaban of Formula I,
wherein steps i) to iii) are carried out in an aqueous designer smart surfactant solution. 17. The processes according to any one of claims 3-16, wherein the aqueous designer smart surfactant solution is selected from the group consisting of PTS, TPGS-750M, SPGS-550M (Nok), Triton X-100, Tergitol® TMN-6, Tergitol® 15S40, Tergitol® 15S7, Brij®-35, Tween® 80, and PTS-7.
18. The processes according to any one of claims 3, 4, 5, 15, or 16, wherein the reduction of 3-(morpholin-4-yl)-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)-one of Formula II to obtain l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III is carried out in the presence of a reducing agent.
19. The processes according to any one of claims 3-7, 15, or 16, wherein the reducing agent is selected from the group consisting of sodium sulphide, sodium hydrosulphite, iron, ammonium chloride, zinc, tin (II) chloride, platinum oxide, Fe/NF Cl, Zn/NFUCl, formic acid in presence of a metal catalyst, pyridinium zinc complex, and trihalosilanes. 20. The processes according to any one of claims 3, 4, 5, 8, 9, 15, or 16, wherein the reaction of l-(4-aminophenyl)-3-(mo holin-4-yl)-5,6-dihydropyridin-2(lH)-one of Formula III with 5-halovaleryl halide is carried out in the presence of a base.
21. The processes according to claim 20, wherein the base is selected from the group consisting of ethyl amine, ammonia, triethyl amine, N-methylrr ^holine, isobutylamine, tributyl amine, diisopropyl amine, diisopropylethylamine, triisopropylamine, pyridine, 4-
dimethylaminopyridine (DMAP), potassium tert-butoxide, 4-ethylmorpholine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l ,4-diazabicyclo[2.2.2]octane, 2,6-di-tert-butyl-4- dimethylaminopyridine, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium bicarbonate, magnesium bicarbonate, and potassium bicarbonate.
22. The processes according to any one of claims 3, 4, 5, 8, 9, 15, or 16, wherein the 5- halovaleryl halide is selected from the group consisting of 5-chlorovaleryl chloride, 5- bromovaleryl chloride, and 5-chlorovaleryl bromide.
23. The processes according to any one of claims 3, 4, 5, 10, 11 , 15, or 16, wherein the cyclization of 5-halo-N-{4-[5-(mo holin-4-yl)-6-oxo-3,6-dihydropyridin-l(2H)- yl]phenyl}pentanamide of Formula IV to obtain 3-^οφηο1ίη-4^1)-1-[4-(2-οχορίρεΓίάίη- l-yl)phenyl]-5,6-dihydropyridin-2(lH)-one of Formula V is carried out in the presence of a base and a catalyst.
24. The processes according to claim 23, wherein the base is selected from the group consisting of ethyl amine, ammonia, triethyl amine, N-methylmorpholine, isobutylamine, tributyl amine, diisopropyl amine, diisopropylethylamine, triisopropylamine, pyridine, 4- dimethylaminopyridine (DMAP), potassium tert-butoxide, 4-emylmorpholine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l ,4-diazabicyclo[2.2.2]octane, 2,6-di-tert-butyl-4- dimethylaminopyridine, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium bicarbonate, magnesium bicarbonate, and potassium bicarbonate.
25. The processes according to claim 23, wherein the catalyst is selected from the group consisting of tetra butylammonium iodide, tetra butylammonium bromide, potassium iodide, and potassium bromide.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116444514A (en) * | 2022-01-05 | 2023-07-18 | 浙江华海药业股份有限公司 | A kind of preparation method of apixaban ethyl ester |
| CN119552160A (en) * | 2024-11-29 | 2025-03-04 | 济南健丰化工有限公司 | A kind of preparation method of apixaban |
| WO2025114271A1 (en) * | 2023-11-29 | 2025-06-05 | Lonza Bend Inc. | Nucleophilic aromatic substitution in an aqueous medium in the presence of a surfactant |
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| US20150353541A1 (en) * | 2013-01-09 | 2015-12-10 | Srinivasan Thirumalai Rajan | Novel intermediate and polymorphs of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetra hydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and process thereof |
| US20160244440A1 (en) * | 2013-11-18 | 2016-08-25 | Chengdu Easton Biopharmaceutical Co., Ltd. | Pyridine derivative and medical use thereof |
| US20160280646A1 (en) * | 2013-08-02 | 2016-09-29 | Shanghai Syncores Technologies Inc. Ltd | Novel method for synthesizing key intermediate of apixaban |
| US20170015663A1 (en) * | 2014-09-05 | 2017-01-19 | Unichem Laboratories Limited | Process for the preparation of apixaban and intermediates thereof |
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2017
- 2017-05-30 WO PCT/IB2017/053183 patent/WO2018158620A1/en not_active Ceased
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150353541A1 (en) * | 2013-01-09 | 2015-12-10 | Srinivasan Thirumalai Rajan | Novel intermediate and polymorphs of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetra hydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and process thereof |
| US20160280646A1 (en) * | 2013-08-02 | 2016-09-29 | Shanghai Syncores Technologies Inc. Ltd | Novel method for synthesizing key intermediate of apixaban |
| US20160244440A1 (en) * | 2013-11-18 | 2016-08-25 | Chengdu Easton Biopharmaceutical Co., Ltd. | Pyridine derivative and medical use thereof |
| US20170015663A1 (en) * | 2014-09-05 | 2017-01-19 | Unichem Laboratories Limited | Process for the preparation of apixaban and intermediates thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116444514A (en) * | 2022-01-05 | 2023-07-18 | 浙江华海药业股份有限公司 | A kind of preparation method of apixaban ethyl ester |
| WO2025114271A1 (en) * | 2023-11-29 | 2025-06-05 | Lonza Bend Inc. | Nucleophilic aromatic substitution in an aqueous medium in the presence of a surfactant |
| CN119552160A (en) * | 2024-11-29 | 2025-03-04 | 济南健丰化工有限公司 | A kind of preparation method of apixaban |
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