[go: up one dir, main page]

WO2018158620A1 - Préparation d'ingrédients pharmaceutiques actifs et intermédiaires de ceux-ci - Google Patents

Préparation d'ingrédients pharmaceutiques actifs et intermédiaires de ceux-ci Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
dihydropyridin
phenyl
morpholin
oxo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2017/053183
Other languages
English (en)
Inventor
Pankaj Kumar Singh
Mukesh Kumar Madhra
Mohan Prasad
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Pharmaceutical Industries Ltd
Original Assignee
Sun Pharmaceutical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Pharmaceutical Industries Ltd filed Critical Sun Pharmaceutical Industries Ltd
Publication of WO2018158620A1 publication Critical patent/WO2018158620A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de préparation d'ingrédients pharmaceutiques actifs et d'intermédiaires de ceux-ci dans une solution aqueuse de tensioactifs à conception intelligente.
PCT/IB2017/053183 2017-02-28 2017-05-30 Préparation d'ingrédients pharmaceutiques actifs et intermédiaires de ceux-ci Ceased WO2018158620A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201711007134 2017-02-28
IN201711007134 2017-02-28

Publications (1)

Publication Number Publication Date
WO2018158620A1 true WO2018158620A1 (fr) 2018-09-07

Family

ID=63370647

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/053183 Ceased WO2018158620A1 (fr) 2017-02-28 2017-05-30 Préparation d'ingrédients pharmaceutiques actifs et intermédiaires de ceux-ci

Country Status (1)

Country Link
WO (1) WO2018158620A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116444514A (zh) * 2022-01-05 2023-07-18 浙江华海药业股份有限公司 一种阿哌沙班乙酯化物的制备方法
CN119552160A (zh) * 2024-11-29 2025-03-04 济南健丰化工有限公司 一种阿哌沙班的制备方法
WO2025114271A1 (fr) * 2023-11-29 2025-06-05 Lonza Bend Inc. Substitution aromatique nucléophile en milieu aqueux en présence d'un tensioactif

Citations (4)

* Cited by examiner, † Cited by third party
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
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116444514A (zh) * 2022-01-05 2023-07-18 浙江华海药业股份有限公司 一种阿哌沙班乙酯化物的制备方法
WO2025114271A1 (fr) * 2023-11-29 2025-06-05 Lonza Bend Inc. Substitution aromatique nucléophile en milieu aqueux en présence d'un tensioactif
CN119552160A (zh) * 2024-11-29 2025-03-04 济南健丰化工有限公司 一种阿哌沙班的制备方法

Similar Documents

Publication Publication Date Title
CN101910143B (zh) 稠合的氨基二氢噻嗪衍生物
TWI680128B (zh) 二氫吡咯並吡啶衍生物
EP2262804B1 (fr) Dérivés polysubstitues de 6-heteroaryle-imidazo[1,2-a]pyridines, leur préparation et leur application en thérapeutique
EP2958915B1 (fr) Composés d'azabenzimidazole en tant qu'inhibiteurs d'isozymes pde4 pour le traitement de troubles du snc et d'autres affections
EP3126361B1 (fr) Chromène et 1,1a,2,7b-tétrahydrocyclopropa[c]chromène pyridopyrazinediones comme modulateurs de gamma-sécrétase
TW201326182A (zh) 六氫哌喃並［３，４－ｄ］［１，３］噻□－２－胺化合物類
CN118696035A (zh) 作为补体因子b抑制剂的螺环哌啶基衍生物及其用途
WO2018158620A1 (fr) Préparation d'ingrédients pharmaceutiques actifs et intermédiaires de ceux-ci
CN1374957A (zh) 苯并吡喃衍生物
TW202003491A (zh) 哌嗪氮雜螺衍生物
US10738063B2 (en) 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide compounds
AU2016214102B2 (en) Novel cyclopropabenzofuranyl pyridopyrazinediones
US7671209B2 (en) Regiospecific synthesis of nicotine derivatives
JP2016531880A (ja) ガンマセクレターゼモジュレーターとしての新規二環式ピリジノン
WO2017027343A1 (fr) Antagonistes du récepteur cgrp
DK2616460T3 (en) HETEROCYCLIC COMPOUNDS FOR TREATMENT OR PREVENTION OF DISEASES CAUSED BY decreased neurotransmission of serotonin, norepinephrine or dopamine
CN120641420A (zh) 经取代的二氢吡咯并[3,4-d]嘧啶化合物及其在治疗医学病状中的用途
CN120548312A (zh) 经取代的四氢吡咯并-吡啶酮化合物及其在治疗医学病状中的用途
CN1141940C (zh) 多环噻唑体系用于制备预防或治疗肥胖的药物的用途
AU728147B2 (en) Method for the preparation of alpha-bromo-lactam derivatives
CN101910175A (zh) N-苯基咪唑并[1，2-a]吡啶-2-甲酰胺化合物、其制备方法和治疗用途
CN101081853A (zh) 4－(羟甲基)－2,6－二甲氧基苯基硼酸化合物
JP3874073B2 (ja) テキシル基を有するクロロシラン化合物の製造方法
HK40058692A (en) 6,7-dihydro-5h-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide compounds
CN1982316A (zh) 作为药物的新氨基吲唑衍生物与含有它们的药物组合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17898920

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17898920

Country of ref document: EP

Kind code of ref document: A1