HRP20192152T1 - Postupak priprave inhibitora pde4 - Google Patents

Postupak priprave inhibitora pde4 Download PDF

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HRP20192152T1
HRP20192152T1 HRP20192152TT HRP20192152T HRP20192152T1 HR P20192152 T1 HRP20192152 T1 HR P20192152T1 HR P20192152T T HRP20192152T T HR P20192152TT HR P20192152 T HRP20192152 T HR P20192152T HR P20192152 T1 HRP20192152 T1 HR P20192152T1
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formula
compound
process according
carried out
ether
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Alessandro Falchi
Emilio Lutero
Emanuele Ferrari
Fausto Pivetti
Rocco Bussolati
Edoardo Mariani
Orsola Vecchi
Erhard Bappert
Caterina Ventrici
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Chiesi Farmaceutici S.P.A.
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Claims (26)

1. Postupak priprave spojeva formule (XI) gdje n jest 0 ili 1 te R1 i R2, su neovisno odabrani u skupinu koju čine H, linearni ili razgranati (C1-C6) alkil, opcionalno supstituiran jednim ili više supstituenata odabranih iz skupine koju čine: atomi halogena, (C3-C7) cikloalkil, te linearni ili razgranati (C2-C6) alkinil, koji postupak obuhvaća: (a) reakciju spoja formule (X) u kojoj n jest 0 ili 1, sa spojem formule (III) gdje je X odabran od -NHSO2Me i -NO2 i Z je odabran od -OH, klor, brom, linearni ili razgranati (C1-C6)alkoksi, ariloksi, arilalkoksi, (C1-C6)alkilkarboniloksi, arilkarboniloksi te aril(C1-C6) alkilkarboniloksi čime nastaje spoj formule (XI) u kojoj n jest 0 ili 1 ili spoj formule (XII) gdje R1, R2 i n imaju gore naznačena značenja; te, kad je spoj formule (XII) dobiven u koraku (a): (b) njegovu redukciju u odgovarajući spoj formule (XIII) gdje R1, R2 i n imaju gore naznačena značenja, te njegovom reakcijom s metansulfonil-halogenidom nastaje spoj formule (XI) gdje n ima gore naznačena značenja; te gdje je spoj formule (X) u koraku (a) dobiven prema bilo kojem od alternativnih koraka (c1) ili (c2): c1) oksidacijom spoja formule (XIV) gdje n jest 0 ili 1 čime nastaje spoj formule (XV) gdje n jest 0 ili 1, a zatim njegovom enantioselektivnom redukcijom dobiva se spoj formule (X) gdje n ima gore naznačena značenja; ili c2) kromatografsko odvajanje spoja formule (XIV) u kojoj n jest 0 ili 1, čime nastaju oba spoj formule (X) i spoj formule (XVI) gdje n ima gore naznačena značenja; te opcionalno oksidacija spoja formule (XVI) dobivenog u koraku (c2) u odgovarajući spoj formule (XV) koji se zatim reducira u spoj formule (XIV) gdje n jest 0 ili 1 i reprocesuira u slijedećem kromatografskom postupku odvajanja; te pri čemu se svi spojevi formule (XI), (X), (XII), (XIII), (XIV), (XV) ili (XVI) gdje n jest 1 mogu dobiti oksidacijom odgovarajućih spojeva u kojima n jest 0.
2. Postupak priprave spoja formule (I) prema patentnom zahtjevu 1 gdje n jest 0 ili 1, koji postupak obuhvaća: a) reakciju spoja formule (II) gdje n jest 0 ili 1, sa spojem formule (III) pri čemu je X odabran od -NHSO2Me i -NO2 te Z je odabran od -OH, klor, brom, linearni ili razgranati (C1-C6)alkoksi, ariloksi, arilalkoksi, (C1-C6)alkilkarboniloksi, arilkarboniloksi i aril(C1-C6) alkilkarboniloksi čime nastaje spoj formule (I) u kojoj n jest 0 ili 1 ili spoj formule (IV) u kojoj n ima gore naznačena značenja te X je -NO2; te kada je spoj formule (IV) dobiven u koraku a): b) njegovu redukciju u odgovarajući spoj formule (V) gdje n jest 0 ili 1, te njegovu reakciju s metansulfonil-halogenidom u kojoj nastaje spoj formule (I) gdje n ima gore naznačena značenja; te gdje je spoj formule (II) u koraku a) dobiven prema bilo kojem od alternativnih koraka (c1) ili (c2): c1) oksidacijom spoja formule (VI) gdje n jest 0 ili 1 čime nastaje spoj formule (VII) gdje n jest 0 ili 1, a zatim se njegovom enantioselektivnom redukcijom dobiva spoj formule (II) gdje n ima gore naznačena značenja; ili c2) kromatografskim odvajanjem spoja formule (VI) u kojoj n jest 0 ili 1, pri čemu nastaju oba spoj formule (II) i spoj formule (VIII) gdje n ima gore naznačena značenja; te opcionalno oksidacija spoja formule (VIII) dobivenog u koraku (c2) u odgovarajući spoj formule (VII) koji se zatim reducira u spoj formule (VI) gdje n jest 0 ili 1 i reprocesuira u kromatografskom postupku odvajanja; te gdje se svi spojevi formule (I), (II), (IV), (V), (VI), (VII) ili (VIII) gdje n jest 1 mogu dobiti oksidacijom odgovarajućih spojeva u kojima n jest 0.
3. Postupak prema patentnom zahtjevu 2, koji obuhvaća reakciju, u koraku a), spoja formule (II) sa spojem formule (III) gdje X jest -NHSO2Me.
4. Postupak prema patentnom zahtjevu 2, koji obuhvaća reakciju, u koraku a), spoja formule (II) sa spojem formule (III) gdje X jest -NO2 čime nastaje spoj formule (IV) te, u koraku b), redukciju (IV) u odgovarajući amino-derivat formule (V) koji zatim reagira s metansulfonil-halogenidom čime se dobiva spoj formule (I).
5. Postupak prema patentnom zahtjevu 2, koji obuhvaća reakciju spoja formule (II) koji je dobiven po koraku c1), oksidacijom spoja formule (VI) u spoj formule (VII) te enantioselektivnom redukcijom ovog potonjeg u spoj formule (II).
6. Postupak prema patentnom zahtjevu 2, koji obuhvaća reakciju spoja formule (II) koji je dobiven po koraku c2), kromatografskim odvajanjem spoja formule (VI) čime se dobivaju oba spoj formule (II) te spoj formule (VIII).
7. Postupak prema patentnom zahtjevu 2, koji obuhvaća oksidaciju spoja formule (I) u kojoj n jest 0.
8. Postupak prema bilo kojem od patentnih zahtjeva 2 do 4 za pripravu spoja formule (I) ili formule (IV) koji obuhvaća reakciju spoja formule (II) sa spojem formule (III) gdje Z jest -OH u prisutnosti reagensa za spajanje odabranog od DCC, CDI, HATU, HBTU, TBTU, DMTMM, COMU, EDCI, sa ili bez HOBt, sa ili bez organske baze kao što su TEA, DIPEA, NMM, DBU, DBO, piridin i DMAP, u otapalu odabranom iz skupine koju čine dimetil sulfoksid, sulfolan, dimetil-formamid, dimetil-acetamid, N-metil pirolidon, toluen, benzen, ksilen, aceton, izopropil-keton, meti-etil-keton, metil-izobutil-keton, THF, dioksan, 2-metoksietil-eter, dietil-eter, izopropil-eter, t-butil-metil-eter, etil-acetat, izopropil-acetat, acetonitril, diklormetan, kloroform, klorobenzen, i njihove smjese.
9. Postupak prema patentnim zahtjevima 2 ili 3, proveden s CDI i DBU u etil-acetatu.
10. Postupak prema patentnim zahtjevima 2 ili 4, proveden s EDCI i DMAP u DMF.
11. Postupak prema patentnim zahtjevima 2 ili 4, naznačeno time da je redukcija od (IV) u koraku b) provedena sa sredstvom za redukciju odabranom iz skupine koju čine vodik, cikloheksadien, amonijev formijat, mravlja kiselina, željezo, kositrov diklorid, kositar, niklov klorid, nikal, litijev aluminijev hidrid, natrijev aluminijev hidrid, litijev borov hidrid, natrijev borov hidrid, kalijev borov hidrid i natrijev hidrosulfit.
12. Postupak prema patentnom zahtjevu 11, naznačeno time da je sredstvo za redukciju odabrano od vodik, cikloheksadien, amonijev formijat i mravlja kiselina, provodi se u prisutnosti katalizatora odabranog od katalizatora zasnovanog na paladiju, platini ili niklu, ili je odabran iz skupine koju čine paladij na ugljku, paladij sa sulfidom na ugljiku, paladij na barijevom sulfatu, paladij na kalcijevom karbonatu, platina na ugljenu.
13. Postupak prema patentnom zahtjevu 11, naznačeno time da je sredstvo za redukciju mravlja kiselina, provodi se u prisutnosti amonijaka ili amina, preferirano trietilamina, u otapalu odabranom iz skupine koju čine voda, metanol, etanol, izopropanol, n-butanol, t-butanol, dimetilformamid, dimetilacetamid, N-metil pirolidon, toluen, benzen, ksilen, THF, dioksan, 2-metoksietil-eter, dietil-eter, izopropil-eter, t-butil-metil-eter, etil-acetat, izopropil-acetat, acetonitril i njihove smjese.
14. Postupak prema patentnom zahtjevu 11, proveden s vodikom uz 5% paladij na aktiviranom ugljenom prašku, tipa A103038, s dodanim sulfidom u etil-acetatu.
15. Postupak prema patentnim zahtjevima 2 ili 4 naznačeno time da je reakcija od (V) s metansulfonil-halogenidom provedena u prisutnosti jednog ili više otapala odabranog od toluen, benzen, ksilen, tetrahidrofuran, dioksan, 2-metoksietil-eter, dietil-eter, izopropil-eter, t-butil-metil-eter, etil-acetat, izopropil-acetat, acetonitril, diklormetan, kloroform, klorbenzen i njihove smjese te je baza preferirano odabrana iz skupine koju čine natrijev hidroksid, natrijev karbonat, natrijev bikarbonat, natrijev hidrid, kalijev hidroksid, kalijev karbonat, kalijev bikarbonat, litijev hidroksid, litijev karbonat, cezijev hidroksid, cezijev karbonat, cezijev bikarbonat, TEA, DIPEA, NMM, DBO, piridin i DMAP te kad se koristi piridin u suvišku, ostala otapalo se mogu izbjeći.
16. Postupak prema patentnim zahtjevima 2 ili 5 naznačeno time da se oksidacija od (VI) u kojoj se dobiva (VII) provodi u prisutnosti sredstva za oksidaciju odabranog od metalnog oksida kao što je MnO2, hipervalentni jod, kao što je 2-jodoksibenzojeva kiselina (IBX) ili Dess-Martinov perjodinan, oksidansi zasnovani na dimetilsulfoksidu (Swern) kao što je kompleks sumporova trioksida i piridina, u otapalu odabranom iz skupine koju čine voda, dimetilformamid, dimetilacetamid, N-metilpirolidon, dimetilsulfoksid, sulfolan, toluen, benzen, ksilen, aceton, izopropil- keton, metil-etil-keton, metil-izobutil keton, etil-acetat, izopropil-acetat, acetonitril, diklormetan, THF, dioksan i njihove smjese.
17. Postupak prema patentnim zahtjevima 2 ili 5 naznačeno time da je enantioselektivna redukcija od (VII) u (II) provedena sa sredstvom za redukciju odabranom od vodika u prisutnosti kiralnog kompleksa teškog metala nastalog prethodno ili nastalog in situ, pri čemu in situ tvorba može biti reakcijom kompleksa Ru, Rh ili Ir kao što je RuCl2(PPh3)3, [Ru(p-cimen)Cl2]2, [RhCI2(Cp*)]2 ili [IrCI2(Cp*)]2 s kiralnim ligandom kao što je SL-N004-1((R)-4-tert-butil-2-[(R)-2-(bis(1-fenil)fosfino)ferocen-1-il]oksazolin), SL-N003-1((R)-4-izopropil-2-[(R)-2-(difenilfosfino)-ferocen-1-il]oksazolin), (S,S)-Ts-DPEN((1S,2S)-(-)-N-p-tosil-1,2-difeniletilenediamin), (S,S)-Ms-DPEN((1S,2S)-(-)-N-mezil-1,2-difeniletilenediamin), (R)-DAIPEN ((2R)-(-)-1,1-bis(4-metoksifenil)-3-metil-1,2-butanediamin), (1R,2S)-1-amino-2-indanol.
18. Postupak prema patentnom zahtjevu 17 naznačeno time da je enantioselektivna redukcija provedena u prisutnosti baze odabrane iz skupine koju čine natrijev hidroksid, natrijev karbonat, natrijev C1-C4 alkoholati, natrijev bikarbonat, natrijev hidrid, kalijev hidroksid, kalijev karbonat, kalijev C1-C4 alkoholati, kalijev bikarbonat, litijev hidroksid, litijev karbonat, litijev C1-C4 alkoholati, cezijev hidroksid, cezijev karbonat, cezijev bikarbonat, trietilamin, piridin i 4-dimetilaminopiridin.
19. Postupak prema patentnim zahtjevima 2 ili 5 naznačeno time da je enantioselektivna redukcija provedena u prisutnosti sredstva za redukciju odabanog od kiralnog kompleksa borana kao što je diizopinokamfeilboran (npr. alil-diizopinokamfeilboran, klordiizopinokamfeil-boran, diizopinokamfeil-metoksi-boran) ili oksazaborolidini (npr. 2-metil-CBS-oksazaborolidin, 2-butil-CBS-oksazaborolidin, o-tolil-CBS-oksazaborolidin, gdje CBS označava Corey-Bakshi-Shibata oksazaborolidinski katalizator).
20. Postupak prema patentnom zahtjevu 17 naznačeno time da je enantioselektivna redukcija provedena u otapalu odabranom iz skupine koju čine voda, metanol, etanol, izopropanol, n-butanol, t-butanol, dimetilformamid, dimetilacetamid, N-metil pirolidon, toluen, benzen, ksilen, THF, dioksan, 2-metoksietil-eter, dietil-eter, izopropil-eter, t-butil-metil-eter, etil-acetat, izopropil-acetat, acetonitril i njihove smjese.
21. Postupak prema patentnim zahtjevima 2 ili 5 naznačeno time da je enantioselektivna redukcija provedena s kompleksom nastalim in situ reakcijom RuCl2(PPh3)3 i kiralnog liganda SL-N004-1, u toluenu te u prisutnosti vodenog natrijeva hidroksida.
22. Postupak prema patentnom zahtjevu 1, naznačeno time da je bilo koji od koraka a), b), c1) i c2) proveden prema bilo kojem od prethodnih patentnih zahtjeva.
23. Intermedijarni spojevi formule (XII) i (XIII) gdje n jest 0 ili 1 te R1 i R2, su neovisno odabrani u skupinu koju čine H, linearni ili razgranati (C1-C6) alkil, opcionalno supstituiran jednim ili više supstituenata odabranih iz skupine koju čine: atomi halogena, (C3-C7) cikloalkil, te linearni ili razgranati (C2-C6) alkinil.
24. Intermedijarni spojevi prema patentnom zahtjevu 23 koji imaju formulu (IV) i (V) gdje n jest 0 ili 1
25. Postupak prema patentnom zahtjevu 2 naznačeno time da je spoj formule (I) pročišćen kristalizacijom ili usitnjavanjem u jednom ili više otapala odabranih iz skupine koju čine voda, metanol, etanol, izopropanol, n-butanol, t-butanol, toluen, benzen, ksilen, aceton, izopropil-keton, metil-etil-keton, metil-izobutil-keton, THF, dioksan, 2-metoksietil-eter, dietil-eter, izopropil-eter, t-butil-metil-eter, etil-acetat, izopropilacetat, diklormetan, alifatski ili aromatski ugljikovodik, preferirano odabran iz skupine koju čine pentan, heksan, heptan, cikloheksan i metilcikloheksan ili njihove smjese.
26. Postupak prema patentnom zahtjevu 25 proveden u etil-acetatu s n-heptanom za pripravu kristala Oblika A spoja formule (I) gdje n je 1 naznačeno time da su slijedeći karakteristični XRPD signali: 7,48; 7,93; 10,15; 10,32; 12,72; 13,51; 16,18; 16,46; 18,08; 18,53; 18,94; 8,55; 17,79; 19,89; 19, 1; 20,2; 21,37; 22,96; 23,63; 24,87; 26,51; 28,09;28,61 te 25,82 ± 0.2 stupnjeva /2 theta (CuKα2).
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