AR118649A1 - Opciones sintéticas hacia la fabricación de (6r,10s)-10-{4-[5-cloro-2-(4-cloro-1h-1,2,3-triazol-1-il)fenil]-6-oxo-1(6h)-pirimidinil}-1-(difluorometil)-6-metil-1,4,7,8,9,10-hexahidro-11,15-(meteno)pirazol[4,3-b][1,7]diazaciclotetradecin-5(6h)-ona - Google Patents

Opciones sintéticas hacia la fabricación de (6r,10s)-10-{4-[5-cloro-2-(4-cloro-1h-1,2,3-triazol-1-il)fenil]-6-oxo-1(6h)-pirimidinil}-1-(difluorometil)-6-metil-1,4,7,8,9,10-hexahidro-11,15-(meteno)pirazol[4,3-b][1,7]diazaciclotetradecin-5(6h)-ona

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Publication number
AR118649A1
AR118649A1 ARP200101024A ARP200101024A AR118649A1 AR 118649 A1 AR118649 A1 AR 118649A1 AR P200101024 A ARP200101024 A AR P200101024A AR P200101024 A ARP200101024 A AR P200101024A AR 118649 A1 AR118649 A1 AR 118649A1
Authority
AR
Argentina
Prior art keywords
compound
formula
alkyl
produce
chloro
Prior art date
Application number
ARP200101024A
Other languages
English (en)
Inventor
Ham Cyril Ben
Sbastien Franois Emmanuel Lemaire
Kostiantyn Chernichenko
Duy Chi Trung Cao
Diego Fernando Domenico Broggini
Simon Albert Wagschal
Bin Zheng
Changxia Yuan
Yi Xiao
Carolyn S Wei
Amarjit Singh
Eric M Simmons
Subha Mukherjee
Sergei Kolotuchin
Yu Fan
Nicolas Cuniere
Original Assignee
Bristol Myers Squibb Co
Janssen Pharmaceutica Nv
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 Bristol Myers Squibb Co, Janssen Pharmaceutica Nv filed Critical Bristol Myers Squibb Co
Publication of AR118649A1 publication Critical patent/AR118649A1/es

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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
    • C07D471/12—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 three hetero rings
    • C07D471/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Se proporcionan métodos altamente eficientes para preparar intermedios clave en la síntesis del Compuesto de fórmula (I), que son ampliamente aplicables y pueden proporcionar componentes seleccionados que tienen una variedad de grupos sustituyentes. Reivindicación 1: Un proceso para la preparación del Compuesto de fórmula (I) que comprende los pasos de 1) hacer reaccionar el Compuesto 1 de la estructura de fórmula (1) con el Compuesto 2 de la fórmula (2) en donde X se selecciona a partir de CI, Br e I; Y se selecciona a partir de OR⁹, NHOC₁₋₃ alquilo, CI, Br e I; y R⁹ se selecciona de alquilo C₁₋₃, hidroxialquilo C₁₋₃, fenilo sustituido y bencilo sustituido; en un disolvente adecuado para producir los Compuestos 3a o 3b de la fórmula (3a) ó (3b); 2) convertir el Compuesto 3a o 3b en el Compuesto 4 de la fórmula (4) en presencia de un ácido; 3) hacer reaccionar posteriormente el Compuesto 4 en un disolvente alcohólico con un ortoformiato de tri-alquilo para proporcionar el Compuesto 5 de la fórmula (5) en donde R¹ es alquilo C₁₋₆; y R³’ se selecciona a partir de alquilo C₁₋₆, opcionalmente fenilo y bencilo sustituido; 4) hidrolizar en un éster en condiciones básicas o someter a hidrogenólisis cuando R³ se sustituye por bencilo al Compuesto 6 de la fórmula (6) en donde R¹ y X son como se definen anteriormente; 5) activar posteriormente la fracción carboxílica del Compuesto 6 y hacerla reaccionar con un auxiliar quiral para formar el Compuesto 6a de la fórmula (6a) donde Xa es un auxiliar quiral y R¹ y X son como se definieron anteriormente; 6) luego hace reaccionar el Compuesto 6a con una base en presencia de un donante de metilo tal como haluros de alquilo en presencia de un auxiliar quiral al Compuesto 7 de la fórmula (6b) en donde R¹, X y Xa son como se definen anteriormente; 7) eliminar Xa para obtener el Compuesto 7 de la fórmula (7) en donde R¹ y X son como se definen anteriormente; 8) hacer reaccionar posteriormente el Compuesto 7 en presencia de un catalizador metálico con el Compuesto 8 de la estructura de fórmula (8) para producir el Compuesto 9 de fórmula (9); 9) reducir el grupo nitro en el Compuesto 9 al Compuesto 10 de la fórmula (10); 10) ciclar el Compuesto 10 con un agente de acoplamiento adecuado para producir el Compuesto 11 de fórmula (11); 11) desenmascarar la funcionalidad de la cetona en presencia de un ácido para producir el Compuesto 12 de fórmula (12); 12a) reducir el Compuesto 12 con un amoniaco equivalente en presencia de un agente reductor o 12b) una enzima transaminasa en presencia de una fuente de amina, diferentes sistemas de reciclaje y un cofactor para generar el centro estereogénico de aminas presente en el Compuesto 13 de fórmula (13); 13) que luego se acopla con el Compuesto 14 de la estructura de fórmula (14), para producir Compuesto de fórmula (I).
ARP200101024A 2019-04-11 2020-04-13 Opciones sintéticas hacia la fabricación de (6r,10s)-10-{4-[5-cloro-2-(4-cloro-1h-1,2,3-triazol-1-il)fenil]-6-oxo-1(6h)-pirimidinil}-1-(difluorometil)-6-metil-1,4,7,8,9,10-hexahidro-11,15-(meteno)pirazol[4,3-b][1,7]diazaciclotetradecin-5(6h)-ona AR118649A1 (es)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US201962832614P 2019-04-11 2019-04-11

Publications (1)

Publication Number Publication Date
AR118649A1 true AR118649A1 (es) 2021-10-20

Family

ID=70457148

Family Applications (1)

Application Number Title Priority Date Filing Date
ARP200101024A AR118649A1 (es) 2019-04-11 2020-04-13 Opciones sintéticas hacia la fabricación de (6r,10s)-10-{4-[5-cloro-2-(4-cloro-1h-1,2,3-triazol-1-il)fenil]-6-oxo-1(6h)-pirimidinil}-1-(difluorometil)-6-metil-1,4,7,8,9,10-hexahidro-11,15-(meteno)pirazol[4,3-b][1,7]diazaciclotetradecin-5(6h)-ona

Country Status (16)

Country Link
US (1) US20220144836A1 (es)
EP (2) EP3953334B1 (es)
JP (1) JP2022526659A (es)
KR (1) KR20220045105A (es)
CN (1) CN114375290A (es)
AR (1) AR118649A1 (es)
AU (1) AU2020272973A1 (es)
BR (1) BR112021020368A2 (es)
CA (1) CA3132365A1 (es)
EA (1) EA202192807A1 (es)
ES (1) ES2969253T3 (es)
IL (1) IL287102A (es)
MX (1) MX2021012286A (es)
SG (1) SG11202111132WA (es)
TW (1) TW202104188A (es)
WO (1) WO2020210613A1 (es)

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EP4133064A4 (en) 2020-04-10 2024-07-24 Codexis Inc GENETICALLY ENGINEERED TRANSAMINASE POLYPEPTIDES
TW202229280A (zh) * 2020-10-12 2022-08-01 美商必治妥美雅史谷比公司 （６ｒ，１０ｓ）－１０－｛４－［５－氯－２－（４－氯－１ｈ－１，２，３－三唑－１－基）苯基］－６－側氧基－１（６ｈ）－嘧啶基｝－１－（二氟甲基）－６－甲基－１，４，７，８，９，１０－六氫－１１，１５－（亞甲橋基）吡唑并［４，３－ｂ］［１，７］二氮雜環十四炔－５（６ｈ）－酮之製備方法

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CA2830234A1 (en) * 2011-03-15 2012-09-20 Abbvie Inc. Nuclear hormone receptor modulators
RS57659B1 (sr) 2014-01-31 2018-11-30 Bristol Myers Squibb Co Makrociklusi sa heterocikličnim p2' grupama kao inhibitori faktora xia
US9453018B2 (en) 2014-10-01 2016-09-27 Bristol-Myers Squibb Company Pyrimidinones as factor XIa inhibitors
NO2721243T3 (es) * 2014-10-01 2018-10-20
CN105294496A (zh) * 2015-09-28 2016-02-03 中山大学 一种西酞普兰中间体的制备方法
CN110062757B (zh) * 2017-01-18 2022-03-04 广东东阳光药业有限公司 凝血因子XIa抑制剂及其用途
AU2020257911B2 (en) * 2019-04-16 2023-01-05 China Resources Biopharmaceutical Company Limited Macrocyclic derivatives acting as XIa factor inhibitor
WO2021013209A1 (zh) * 2019-07-23 2021-01-28 南京明德新药研发有限公司 作为XIa因子抑制剂的大环衍生物
IL296983A (en) * 2020-04-10 2022-12-01 Codexis Inc Carboxyesterase polypeptides for kinetic separation

Also Published As

Publication number Publication date
BR112021020368A2 (pt) 2021-12-07
EP3953334B1 (en) 2023-11-22
ES2969253T3 (es) 2024-05-17
AU2020272973A1 (en) 2021-12-02
CN114375290A (zh) 2022-04-19
MX2021012286A (es) 2022-04-06
CA3132365A1 (en) 2020-10-15
SG11202111132WA (en) 2021-11-29
US20220144836A1 (en) 2022-05-12
IL287102A (en) 2021-12-01
EP4234555A2 (en) 2023-08-30
WO2020210613A1 (en) 2020-10-15
EA202192807A1 (ru) 2022-02-24
KR20220045105A (ko) 2022-04-12
EP4234555A3 (en) 2024-01-03
EP3953334A1 (en) 2022-02-16
JP2022526659A (ja) 2022-05-25
TW202104188A (zh) 2021-02-01

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