SI2538785T1 - Postopki za sintezo spojin diariltiohidantoina in diarilhidantoina - Google Patents

Postopki za sintezo spojin diariltiohidantoina in diarilhidantoina Download PDF

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SI2538785T1
SI2538785T1 SI201131468T SI201131468T SI2538785T1 SI 2538785 T1 SI2538785 T1 SI 2538785T1 SI 201131468 T SI201131468 T SI 201131468T SI 201131468 T SI201131468 T SI 201131468T SI 2538785 T1 SI2538785 T1 SI 2538785T1
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compound
formula
polar solvent
process according
amount
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SI201131468T
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English (en)
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Andrew Thompson
Carol Lamberson
Scott Greenfield
Rajendra Parasmal Jain
Remy Angelaud
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Medivation Prostate Therapeutics Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems

Claims (23)

  1. POSTOPKI ZA SINTEZO SPOJIN DIARILTIOHIDANTOINA IN DIARILHIDANTOINA PATENTNI ZAHTEVKI
    1. Postopek priprave spojine s formulo (I):
    pri čemer navedeni postopek zajema reagiranje spojine s formulo D:
    značilne po tem, da je R6 Ci-Cs alkil; s spojino s formulo (F):
  2. 2. Postopek po zahtevku 1, ki zajema mešanje spojine D s spojino F v polarnem topilu ali v mešanici prvega polarnega topila in drugega polarnega topila ter segrevanje na 60-100 °C za 1 do 48 ur.
  3. 3. Postopek po zahtevku 2, značilen po tem, da se reakcijska mešanica nadalje ohladi na 15 do 30 °C in združi z vodo, čemur sledi ekstrakcija želenega produkta s polarnim topilom ali z mešanico tretjega polarnega topila in četrtega polarnega topila.
  4. 4. Postopek po zahtevku 2 ali 3, v katerem je polarno topilo izbrano ali so prvo, drugo, tretje in četrto polarno topilo izbrani iz skupine, ki jo sestavljajo dimetilsulfoksid (DMSO), dimetilformamid (DMF), N-metilpirolidon (NMP), dimetilacetamid (DMA), izopropil acetat (IPAc), MeCN in izopropil alkohol (IPA).
  5. 5. Postopek po katerem koli od zahtevkov 2 do 4, ki zajema mešanje spojine s formulo D s spojino s formulo F v mešanici prvega polarnega topila, ki je izopropil acetat (IPAc), in drugega polarnega topila, kije dimetilsulfoksid (DMSO).
  6. 6. Postopek po zahtevku 1, ki zajema mešanje spojine D s spojino F v mešanici prvega polarnega topila in drugega polarnega topila ter segrevanje, nato ohlajanje mešanice in združitev z vodo ter ekstrakcijo želenega produkta z mešanico tretjega polarnega topila in četrtega polarnega topila.
  7. 7. Postopek po zahtevku 6, v katerem so prvo, drugo, tretje in četrto polarno topilo izbrani iz skupine, ki jo sestavljajo dimetilsulfoksid (DMSO), dimetilformamid (DMF), N-metilpirolidon (NMP), dimetilacetamid (DMA), izopropil acetat (IPAc) in izopropil alkohol (IPA).
  8. 8. Postopek po zahtevku 3 ali zahtevku 6, v katerem je prvo polarno topilo izopropil acetat (IPAc), drugo polarno topilo je dimetilsulfoksid (DMSO), tretje polarno topilo je IPAc in četrto polarno topilo je izopropil alkohol (IPA).
  9. 9. Postopek po zahtevku 1, ki zajema reagiranje spojine s formulo D-1
    s spojino s formulo F
    v prisotnosti DMSO.
  10. 10. Postopek po katerem koli zahtevku 1 do 9, ki nadalje zajema reagiranje spojine s formulo A:
    značilen po tem, da je LG izstopajoča skupina, Br ali I; s spojino s formulo B:
    za pridobitev spojine s formulo C:
    reagiranje spojine s formulo C s spojino s formulo R6-LG v alkilirajočih razmerah ali spojine s formulo R6-OH v esterifikacijskih razmerah, da nastane spojina s formulo D:
  11. 11. Postopek po zahtevku 10, značilen po tem, da se reagiranje spojine s formulo A s spojino s formulo B, da nastane spojina s formulo C, izvede v prisotnosti katalitične količine bakrovega (I) klorida 0,05-0,35 ekvivalentov glede na spojino A in acetilcikloheksanona v količini, ki je približno enaka količini uporabljenega bakrovega (I) klorida.
  12. 12. Postopek po zahtevku 10 ali 11, značilen po tem, da se korak spremembe spojine s formulo C v spojino s formulo D izvede z alkiliranjem spojine s formulo C z alkil halidom.
  13. 13. Postopek po zahtevku 12, značilen po tem, da je alkil halid metil metil jodid.
  14. 14. Postopek po zahtevku 12 ali 13, značilen po tem, da se alkiliranje izvede v prisotnosti anorganske baze.
  15. 15. Postopek po zahtevku 14, značilen po tem, da je anorganska baza kalijev karbonat.
  16. 16. Postopek po katerem koli od zahtevkov 10 do 15, značilen po tem, da se po spremembi spojine s formulo C v spojino s formulo D spojina s formulo D izolira z dodajanjem vode v reakcijsko mešanico za precipitacijo spojine s formulo D.
  17. 17. Postopek po zahtevkih 12, 13, 14, 15 in 16, značilen po tem, da se reakcijski mešanici v obdobju 1 ure dodaja 10-18 volumnov vode za precipitacijo spojine s formulo D.
  18. 18. Postopek po zahtevku 17, značilen po tem, da se spojina s formulo D ponovno suspendira ali ponovno raztopi v vodi, temu pa sledi ponovna izolacija spojine s formulo D.
  19. 19. Postopek po zahtevku 17 ali 18, značilen po tem, da je količina preostanka kalija ali količina preostanka baze v spojini s formulo D manj kot ali enaka 500 ppm.
  20. 20. Postopek po zahtevku 18, značilen po tem, da se spojina s formulo D po ponovni izolaciji posuši.
  21. 21. Postopek po zahtevku 20, značilen po tem, da je količina preostanka vlage spojine s formulo D manj kot ali enaka 0,1 %.
  22. 22. Postopek po zahtevku 20, značilen po tem, da je količina preostanka vlage spojine s formulo D manj kot ali enaka 0,1 % in da je količina preostanka kalija ali količina preostanka baze v spojini s formulo D manj kot ali enaka 500 ppm.
  23. 23. Postopek po katerem koli od predhodnih zahtevkov, ki zajema pripravo spojine s formulo I in oblikovanje farmacevtskega pripravka, ki vsebuje navedeno spojino in farmacevtsko sprejemljiv nosilec ali pomožno snov.
SI201131468T 2010-02-24 2011-02-24 Postopki za sintezo spojin diariltiohidantoina in diarilhidantoina SI2538785T1 (sl)

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US30779610P 2010-02-24 2010-02-24
EP11748095.4A EP2538785B1 (en) 2010-02-24 2011-02-24 Processes for the synthesis of diarylthiohydantoin and diarylhydantoin compounds
PCT/US2011/026135 WO2011106570A1 (en) 2010-02-24 2011-02-24 Processes for the synthesis of diarylthiohydantoin and diarylhydantoin compounds

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KR (1) KR101514659B1 (sl)
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