DK1755596T3 - Fremgangsmåde til fremstilling af atazanavirbisulfat og hidtil ukendte former - Google Patents

Fremgangsmåde til fremstilling af atazanavirbisulfat og hidtil ukendte former Download PDF

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DK1755596T3
DK1755596T3 DK05744537.1T DK05744537T DK1755596T3 DK 1755596 T3 DK1755596 T3 DK 1755596T3 DK 05744537 T DK05744537 T DK 05744537T DK 1755596 T3 DK1755596 T3 DK 1755596T3
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crystals
free base
atazanavir
sulfuric acid
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Soojin Kim
Bruce T Lotz
Mary F Malley
Jack Z Gougoutas
Martha Davidovich
Sushil K Srivastava
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Bristol Myers Squibb Holdings Ireland
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    • 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
    • C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/127—Preparation from compounds containing pyridine rings
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

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  • Chemical & Material Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
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Claims (27)

  1. FREMGANGSMÅDE TIL FREMSTILLING AF ATAZANAVIRBISULFAT OG HIDTIL UKENDTE FORMER
    1. Fremgangsmåde til fremstilling af atazanavirbisulfat i form af Form A-krystaller, hvilken fremgangsmåde omfatter omsætning af en opløsning af atazanavir fri base i et organisk opløsningsmiddel, der er acetone eller en blanding af acetone og N-methylpyrrolidon, med en første del af koncentreret svovlsyre i en mængde til at omsætte med mindre end ca. 15 vægt-% atazanavir fri base, tilsætning afkom af Form A-krystaller af atazanavirbisulfat til reaktionsblandingen, mens krystaller af atazanavirbisulfat dannes, tilsætning af supplerende koncentreret svovlsyre i flere trin ved en tiltagende rytme ifølge følgende ligning
    hvor Vtid = svovlsyrevolumen tilsat i det forløbne tidsrum Vtotai= totalt syrevolumen, der repræsenterer ladningen på 90 % tid = forløbet krystalliseringstid tidtotal = forløbet krystalliseringstid i alt eller tid i alt for syreladning for at bevirke dannelse af atazanavirbisulfatkrystaller og tørring af atazanavirbisulfatet for at danne Form A-krystaller.
  2. 2. Fremgangsmåde ifølge krav 1, hvor opløsningen af atazanavir fri base initialt omsættes med fra 5 til 15 vægt-% af den totale mængde anvendt svovlsyre.
  3. 3. Fremgangsmåde ifølge krav 1, hvor opløsningen af atazanavir fri base initialt omsættes med fra 8 til 12 vægt-% af den totale mængde anvendt svovlsyre.
  4. 4. Fremgangsmåde ifølge krav 1, hvor atazanavir fri base omsættes med den første svovlsyredel ved en temperatur inden for intervallet fra 35 til 55 °C.
  5. 5. Fremgangsmåde ifølge krav 1, hvor opløsningen af atazanavir fri base opvarmes til en temperatur inden for intervallet fra 35 til 55 °C, inden den omsættes med svovlsyre.
  6. 6. Fremgangsmåde ifølge krav 1, hvor reaktionsblandingen af atazanavir fri base og svovlsyre podes med fra 0,1 til 80 vægt-% Form A-krystaller baseret på vægten af atazanavir fri base.
  7. 7. Fremgangsmåde ifølge krav 1, hvor den podede reaktionsblanding opvarmes til en temperatur inden for intervallet fra 35 til 55 °C.
  8. 8. Fremgangsmåde ifølge krav 1, hvor det organiske opløsningsmiddel til atazanavir fri base er en blanding af acetone og N-methylpyrro lidon.
  9. 9. Fremgangsmåde til fremstilling af atazanavirbisulfat Mønster C-materialet, hvilken fremgangsmåde omfatter udsættelse af Form A-krystaller af atazanavirbisulfat for en høj relativ fugtighed på mindst ca. 95 % RH i mindst 24 timer og derefter tørring.
  10. 10. Fremgangsmåde til fremstilling af atazanavirbisulfat Mønster C-materiale, hvilken fremgangsmåde omfatter (a) omsætning af en opløsning af atazanavir fri base i et organisk opløsningsmiddel, der er acetone eller en blanding af acetone og N-methylpyrrolidon, med en første del af koncentreret svovlsyre i en mængde til at omsætte med mindre end ca. 15 vægt-% atazanavir fri base, tilsætning afkom af Form A-krystaller af atazanavirbisulfat til reaktionsblandingen, mens krystaller af atazanavirbisulfat dannes, tilsætning af supplerende koncentreret svovlsyre i flere trin ved en tiltagende rytme ifølge
    hvor Vtid = svovlsyrevolumen tilsat i det forløbne tidsrum Vt0tai = totalt syrevolumen, der repræsenterer ladningen på 90 % tid = forløbet krystalliseringstid tidtotai = forløbet krystalliseringstid i alt eller tid i alt for syreladning for at bevirke dannelse af atazanavirbisulfatkrystaller, og tørring af atazanavirbisulfat for at danne Form A-krystaller; (b) suspension af krystallerne af Form A atazanavirbisulfat fra trin (a) i vand og tørring af suspensionen for at danne Mønster C-materiale; eller (c) udsættelse af krystaller af Form A atazanavirbisulfat fra trin (a) for en høj relativ fugtighed på mere end 95 % RH i mindst 24 timer for at danne Mønster C-materiale eller (d) blanding af Form A-krystaller fra trin (a) med en eller flere formuleringsexcipienser og vådgranulering af den resulterende blanding for direkte at danne Mønster C-materiale i blanding med excipienseme.
  11. 11. Fremgangsmåde ifølge krav 1 til fremstilling af atazanavirbisulfat
    i form af Form A-krystaller, hvilken fremgangsmåde omfatter fremstilling af et triaminsalt med strukturen
    og uden isolering af triaminsaltet, omsætning af triaminsaltet med en aktiv ester af en syre med strukturen
    og en base i tilstedeværelse af et organisk opløsningsmiddel for at danne en opløsning af atazanavir fri base med strukturen
    og omdannelse af den frie base til det tilsvarende bisulfatsalt ved behandling af en opløsning af fri base i methylenchlorid med N-methylpyrrolidon og acetone, opvarmning af ovenstående blanding for at ijeme methylenchlorid og behandling af ovenstående blanding med svovlsyre for at danne bisulfatsaltet af den fri base, hvor svovlsyren tilsættes ved en tiltagende rytme ifølge følgende ligning
    hvor Vtid = svovlsyrevolumen tilsat i det forløbne tidsrum Vtotai= totalt syrevolumen, der repræsenterer ladningen på 90 % tid = forløbet krystalliseringstid tidtotai = forløbet krystalliseringstid i alt eller tid i alt for syreladning
  12. 12. Fremgangsmåde ifølge krav 11, hvor triaminsaltet er hydrochloridsaltet
  13. 13. Fremgangsmåde ifølge krav 11, hvor syrens aktive ester har strukturen
  14. 14. Fremgangsmåde ifølge krav 11, hvor basen er et alkalimetalhydroxid, et alkalisk jordmetalhydroxid, et alkalimetalcarbonat, et alkalisk jordmetalearbonat, et alkalimetalphosphat, et alkalisk jordmetalphosphat eller en organisk base.
  15. 15. Fremgangsmåde ifølge krav 14, hvor basen er NaOH, KOH, Mg(OH)2, K2HP04, MgC03, Na2C03, K2C03, triethylamin, diisopropylethylamin eller N-methylmorpholin og det organiske opløsningsmiddel er methylenchlorid, ethylacetat, dichlorethan, tetrahydrofuran, acetonitril eller N,N-dimethylformamid.
  16. 16. Fremgangsmåde ifølge krav 11, hvor triaminsaltet og den aktive ester omsættes ved en temperatur inden for intervallet fra 30 til 40 °C.
  17. 17. Fremgangsmåde ifølge krav 16, hvor triaminsaltet og den aktive ester omsættes i tilstedeværelse af K2HP04 som basen og methylenchlorid som opløsningsmidlet.
  18. 18. Fremgangsmåde ifølge krav 11, hvilken fremgangsmåde indbefatter trinnet med podning af blandingen af fri base, acetone og N-methylpyrrolidon med krystaller af atazanavirbisulfat.
  19. 19. Fremgangsmåde til fremstilling af atazanavirbisultat,
    hvilken fremgangsmåde omfatter fremstilling af et triaminhydrogenchloridsalt med strukturen
    omsætning af triaminhydrogenchloridsaltet med en aktiv ester med strukturen
    og K2HPO4 i tilstedeværelse af methylenchlorid for at danne en opløsning af den frie base med strukturen
    i methylenchlorid og omdannelse af den frie base til det tilsvarende bisulfatsalt via en kubisk krystalliseringsteknik, hvor svovlsyren tilsættes ved en tiltagende rytme ifølge følgende ligning
    hvor Vtid = svovlsyrevolumen tilsat i det forløbne tidsrum Vtotai = totalt syrevolumen, der repræsenterer ladningen på 90 % tid = forløbet krystalliseringstid tidtotal = forløbet krystalliseringstid i alt eller tid i alt for syreladning
  20. 20. Form E3 af atazanavirbisulfat.
  21. 21. Forbindelse ifølge krav 20 fremstillet som et triethanolatsolvat af atazanavirbisulfat.
  22. 22. Forbindelse ifølge krav 20 kendetegnet ved et røntgenpulverdiffraktionsmønster i alt væsentligt som det, der vises i figur 9.
  23. 23. Forbindelse ifølge krav 20 med krystalstrukturen i alt væsentligt, som den der vises i figur 10.
  24. 24. Forbindelse ifølge krav 20, der er kendetegnet ved fraktionsatomkoordinater i alt væsentligt som de, der er opført i tabel 6.
  25. 25. Forbindelse ifølge krav 20, der er kendetegnet ved krystallografiske data, der i alt væsentligt svarer til følgende: Celledimensioner: a =10,749(5) Å b = 13,450(4) A c = 9,250(2) Å a = 98,33(2)° β = 95,92(3)° γ= 102,82(3)° Afstandsgruppe PI Molekyler/asymmetrisk enhed 1 hvor den krystallinske form er ved ca. -23 °C.
  26. 26. Forbindelse ifølge krav 20, der er kendetegnet ved differentiel scanningskalorimetriske termogramdata, der i alt væsentligt stemmer overens med de data, der vises i figur 11.
  27. 27. Forbindelse ifølge krav 20, der er kendetegnet ved en termogravimetrisk analysekurve, der i alt væsentligt, stemmer overens med den kurve, der vises i figur 11.
DK05744537.1T 2004-05-04 2005-05-03 Fremgangsmåde til fremstilling af atazanavirbisulfat og hidtil ukendte former DK1755596T5 (da)

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US56804304P 2004-05-04 2004-05-04
US60753304P 2004-09-07 2004-09-07
US11/119,558 US7829720B2 (en) 2004-05-04 2005-05-02 Process for preparing atazanavir bisulfate and novel forms
PCT/US2005/015333 WO2005108349A2 (en) 2004-05-04 2005-05-03 Process for preparing atazanavir bisulfate and novel forms

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DK1755596T5 DK1755596T5 (da) 2016-05-23

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EP (3) EP2980074A1 (da)
JP (1) JP5086069B2 (da)
KR (1) KR101153606B1 (da)
AU (2) AU2005240622B2 (da)
BR (1) BRPI0509595B8 (da)
CA (2) CA2777216A1 (da)
CY (1) CY1116919T1 (da)
DK (1) DK1755596T5 (da)
ES (1) ES2552219T3 (da)
HR (1) HRP20150962T2 (da)
HU (1) HUE026242T2 (da)
IL (1) IL178965A (da)
MX (1) MXPA06012612A (da)
NO (1) NO341013B1 (da)
PL (1) PL1755596T3 (da)
PT (1) PT1755596E (da)
RS (1) RS54284B1 (da)
SI (1) SI1755596T1 (da)
WO (1) WO2005108349A2 (da)

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CA2565629A1 (en) 2005-11-17
EP1755596A4 (en) 2010-12-29
AU2010201538A1 (en) 2010-05-13
JP5086069B2 (ja) 2012-11-28
DK1755596T5 (da) 2016-05-23
AU2005240622B2 (en) 2010-02-11
IL178965A (en) 2011-05-31
US8513428B2 (en) 2013-08-20
EP2669273A1 (en) 2013-12-04
WO2005108349A2 (en) 2005-11-17
BRPI0509595B8 (pt) 2021-05-25
AU2005240622A1 (en) 2005-11-17
KR20070006935A (ko) 2007-01-11
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CA2777216A1 (en) 2005-11-17
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IL178965A0 (en) 2007-03-08
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