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HRP20191641T1 - Postupak dobivanja spojeva korisnih kao inhibitora atr kinaze - Google Patents

Postupak dobivanja spojeva korisnih kao inhibitora atr kinaze Download PDF

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Publication number
HRP20191641T1
HRP20191641T1 HRP20191641T HRP20191641T1 HR P20191641 T1 HRP20191641 T1 HR P20191641T1 HR P20191641 T HRP20191641 T HR P20191641T HR P20191641 T1 HRP20191641 T1 HR P20191641T1
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Croatia
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compound
formula
conditions
solvent
process according
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Jean-Damien Charrier
John Studley
Francoise Yvonne Theodora Marie Pierard
Steven John Durrant
Benjamin Joseph Littler
Robert Michael Hughes
David Andrew Siesel
Paul Angell
Armando Urbina
Yi Shi
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Vertex Pharma
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Publication of HRP20191641T1 publication Critical patent/HRP20191641T1/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Catalysts (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Claims (20)

1. Postupak dobivanja spoja formule I-2: ili njegove soli, naznačen time, da obuhvaća korak reakcije spoja formule 4-iv: sa spojem sljedeće strukture: pod pogodnim uvjetima spajanja kako bi se dobio spoj formule 5-i: i uklanjanje zaštite spoja formule 5-i pod pogodnim uvjetima Boc deprotekcije, pri čemu pogodni uvjeti umrežavanja uključuju kombiniranje odgovarajućeg paladijskog katalizatora s odgovarajućom bazom u odgovarajućem otapalu i pri čemu je pogodni paladij katalizator odabran između Pd[P(tBu)3]2, Pd(dtbpf)Cl2, Pd(PPh3)2Cl2, Pd(PCy3)2Cl2, Pd(dppf)Cl2 i Pd(dppe)Cl2; pogodno otapalo je izabrano između jednog ili više od sljedećih otapala: toluen, MeCN, voda, EtOH, IPA, 2-Me-THF ili IPAc; i pogodna baza je odabrana između K2CO3, Na2CO3 ili K3PO4.
2. Postupak u skladu s patentnim zahtjevom 1, naznačen time, da nadalje obuhvaća korak pripreme spoja formule 4-iv: reakcijom spoja formule 4-iii: sa spojem formule 4-ii: pod pogodnim uvjetima cikloadicije.
3. Postupak u skladu s patentnim zahtjevom 2, naznačen time, da pogodni ciklusi razdvajanja sadržavaju pogodnu bazu odabranu između piridina, DIEA, TEA, t-BuONa ili K2CO3 i pogodno otapalo odabrano između acetonitrila, tetrahidrofurana, 2-metiltetrahidrofurana, MTBE, EtOAc, i -PrOAc, DCM, toluena, DMF i metanola.
4. Postupak u skladu s patentnim zahtjevom 2, naznačen time, da nadalje obuhvaća korak pripreme spoja formule 4-ii: reakcijom spoja formule 4-i: pod pogodnim uvjetima stvaranja klorooksima.
5. Postupak u skladu s patentnim zahtjevom 4, naznačen time, da pogodni uvjeti stvaranja klorooksima obuhvaćaju dodavanje HCl u dioksanu otopini spoja formule 4-i u prisutnosti NCS-a u pogodnom otapalu odabranom od neprotonskih otapala, aromatskih ugljikovodika i alkil acetata.
6. Postupak u skladu s patentnim zahtjevom 5, naznačen time, da je otapalo neprotonsko otapalo izabrano između DCM, DCE, THF i dioksana.
7. Postupak u skladu s patentnim zahtjevom 5, naznačen time, da je otapalo aromatski ugljikovodik odabran između toluena i ksilena.
8. Postupak u skladu s patentnim zahtjevom 5, naznačen time, da je otapalo alkil acetat odabran između izopropil acetata i etil acetata.
9. Postupak u skladu s patentnim zahtjevom 4, naznačen time, da nadalje obuhvaća korak pripreme spoja formule 4-i: reakcijom spoja formule 3b: pod pogodnim uvjetima formiranja oksima.
10. Postupak u skladu s patentnim zahtjevom 9, naznačen time, da se odgovarajući uvjeti za tvorbu oksima sastoje ili iz niza koraka ili iz dva koraka.
11. Postupak u skladu s patentnim zahtjevom 10, naznačen time, da pogodni uvjeti za tvorbu oksima sadržavaju sekvencu u jednom koraku koja uključuje obradu spoja formule 3b s NH2OH-HCl u smjesi THF-a i vode.
12. Postupak u skladu s patentnim zahtjevom 11, naznačen time, da se 1 ekvivalent spoja formule 3b kombinira sa 1,1 ekvivalenta NH2OH-HCl u 10 : 1 v / v mješavini THF / voda.
13. Postupak u skladu s patentnim zahtjevom 10, naznačen time, da pogodni uvjeti stvaranja oksima sadržavaju sekvencu u dva koraka, pri čemu sekvenca u dva koraka sadržava prvi korak uklanjanja zaštite ketalne skupine u spoju formule 3b: pod pogodnim zaštitnim uvjetima da se dobije odgovarajući aldehid, i drugi korak podvrgavanja odgovarajućeg aldehida pogodnim uvjetima stvaranja oksima.
14. Postupak u skladu s patentnim zahtjevom 9, naznačen time, da nadalje obuhvaća korak pripreme spoja formule 3b: reakcijom spoja formule 2b: pod pogodnim Boc uvjetima zaštite.
15. Postupak u skladu s patentnim zahtjevom 14, naznačen time, da nadalje obuhvaća korak pripreme spoja formule 2b: reakcijom spoja formule 1b: s metilaminom u pogodnim reduktivnim aminacijskim uvjetima.
16. Postupak u skladu s patentnim zahtjevom 15, naznačen time, da pogodni reduktivni uvjeti aminacije uključuju dodavanje reduciranog sredstva odabranog između NaBH4, NaBH3CN i NaBH (OAc)3 u prisutnosti otapala odabranog između diklorometana (DCM), dikloroetana (DCE), metanola, etanola, 1-propanola i izopropanola, dioksana, tetrahidrofurana i 2-metiltetrahidrofurana.
17. Postupak iz zahtjeva 16, naznačen time, da pogodni reduktivni uvjeti aminacije nadalje sadržavaju bazu odabranu između trietilamina i diizopropiletilamina.
18. Postupak u skladu sa zahtjevom 17, naznačen time, da pogodni reduktivni uvjeti aminacije obuhvaćaju dodavanje 1,2 ekvivalenta NaBH4 kapleta u prisutnosti trimetilamina u metanolu.
19. Postupak u skladu s patentnim zahtjevom 1, naznačen time, da pogodni Boc zaštitni uvjeti uključuju dodavanje odgovarajućeg Boc sredstva za uklanjanje zaštite odabranog između TMS-Cl, HCl, TBAF, H3PO4 ili TFA, a prikladno otapalo je odabrano između acetona, toluena, metanola, etanola, 1-propanola, izopropanola, CH2Cl2, EtOAc, izopropil acetata, tetrahidrofurana, 2-metiltetrahidrofurana, dioksana ili dietiletera.
20. Postupak u skladu s patentnim zahtjevom 19, naznačen time, da je prikladno sredstvo za uklanjanje zaštite Boc HCl ili TFA, a pogodno otapalo je aceton ili CH2Cl2.
HRP20191641 2011-09-30 2019-09-12 Postupak dobivanja spojeva korisnih kao inhibitora atr kinaze HRP20191641T1 (hr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161541865P 2011-09-30 2011-09-30
EP15151822.2A EP2940017B1 (en) 2011-09-30 2012-09-28 Process for making compounds useful as inhibitors of ATR kinase

Publications (1)

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HRP20191641T1 true HRP20191641T1 (hr) 2019-12-13

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US (4) US9035053B2 (hr)
EP (4) EP3608316A1 (hr)
JP (4) JP6212045B2 (hr)
KR (2) KR102184246B1 (hr)
CN (2) CN103987709B (hr)
AR (1) AR088092A1 (hr)
AU (3) AU2012315615A1 (hr)
BR (1) BR112014007721B1 (hr)
CA (2) CA3124539A1 (hr)
ES (1) ES2751741T3 (hr)
HK (2) HK1201259A1 (hr)
HR (1) HRP20191641T1 (hr)
HU (1) HUE046429T2 (hr)
IL (3) IL231771A0 (hr)
IN (1) IN2014KN00929A (hr)
MX (1) MX353461B (hr)
PL (1) PL2940017T3 (hr)
PT (1) PT2940017T (hr)
RS (1) RS59337B1 (hr)
RU (2) RU2677292C2 (hr)
SG (2) SG11201401093WA (hr)
TW (3) TWI625324B (hr)
WO (1) WO2013049726A2 (hr)
ZA (1) ZA201402625B (hr)

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