HRP20192340T1 - Postupci za proizvodnju spojeva pirimidinilciklopentana - Google Patents

Postupci za proizvodnju spojeva pirimidinilciklopentana Download PDF

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HRP20192340T1
HRP20192340T1 HRP20192340TT HRP20192340T HRP20192340T1 HR P20192340 T1 HRP20192340 T1 HR P20192340T1 HR P20192340T T HRP20192340T T HR P20192340TT HR P20192340 T HRP20192340 T HR P20192340T HR P20192340 T1 HRP20192340 T1 HR P20192340T1
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kred
formula
compound
nadph
alkyl
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Hans Iding
Reinhard Reents
Michelangelo Scalone
Francis Gosselin
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F. Hoffmann - La Roche Ag
Genentech, Inc.
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    • C07—ORGANIC CHEMISTRY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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    • 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
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    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
    • C07C269/02—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 from isocyanates with formation of carbamate groups
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C12P17/165—Heterorings having nitrogen atoms as the only ring heteroatoms
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers
    • 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
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pyridine Compounds (AREA)

Claims (38)

1. Postupak za proizvodnju spoja formule (I), ili njegovih soli, naznačen time, da on obuhvaća reakciju spajanja spoja formule (II) sa spojem formule (III) pri čemu R1 je amino-zaštitna skupina odabrana s popisa koji čine: benzil, benziloksikarbonil (karbobenziloksi, CBZ), 9-fluorenilmetiloksikarbonil (Fmoc), p-metoksibenziloksikarbonil, p-nitrobenziloksikarbonil, tert-butoksikarbonil (BOC) i trifluoroacetil. R2 je amino-zaštitna skupina odabrana s popisa koji čine: benzil, benziloksikarbonil (karbobenziloksi, CBZ), 9-fluorenilmetiloksikarbonil (Fmoc), p-metoksibenziloksikarbonil, p-nitrobenziloksikarbonil, tert-butoksikarbonil (BOC) i trifluoroacetil. M je metalni ion odabran s popisa koji čine: ion alkalijskog metala, ion zemnoalkalijskog metala i ion tranzicijskog metala.
2. Postupak u skladu s patentnim zahtjevom 1, naznačen time, da R1 je tert-butoksikarbonil (BOC).
3. Postupak u skladu s patentnim zahtjevom 1 ili 2, naznačen time, da R2 je tert-butoksikarbonil (BOC).
4. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 3, naznačen time, da M je Na+.
5. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 4, naznačen time, da on obuhvaća sljedeće reakcijske korake: a) odstranjivanje zaštite spoja formule (III) u otapalu pod kiselim uvjetima; b) usklađivanje na alkalijski pH uporabom lužine; c) dodatak otopine koja sadrži spoj formule (II) u otapalu; d) dodatak otopine koja sadrži sredstvo za spajanje u otapalu.
6. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 5, naznačen time, da je lužina u koraku b) odabrana od N-etil-morfolina (NEM), trietilamina (TEA), tri(n-propil)amina (TPA), diizopropiletilamina (DIPEA), piridina i lutidina.
7. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 6, naznačen time, da sredstvo za spajanje koje se koristi u koraku d) je propilfosfonski anhidrid (T3P).
8. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 7, naznačen time, da nadalje obuhvaća postupak za proizvodnju spojeva formule (II) koji obuhvaća asimetrično hidrogeniranje spoja formule (IV) uporabom katalizatora (C) od metalnog kompleksa, pri čemu su R1 i M kao što su određeni u bilo kojem od patentnih zahtjeva 1 do 4.
9. Postupak u skladu s patentnim zahtjevom 8, naznačen time, da je katalizator (C) od metalnog kompleksa katalizator od rutenijskog kompleksa koji je odabran od spoja s formulama (C1), (C2) ili (C3): Ru(Z)2D (C1) [Ru(Z)2-p(D)(L)m](Y)p (C2) Ru(E)(E')(D)(F) (C3) gdje: D je kiralni fosfinski ligand; L je neutralni ligand koji je odabran od C2-7 alkena, ciklooktena, 1,3-heksadiena, norbornadiena, 1,5-ciklooktadiena, benzena, heksametilbenzena, 1,3,5-trimetilbenzena, p-cimena, tetrahidrofurana, dimetilformamida, acetonitrila, benzonitrila, acetona, toluena i metanola; Z je anionski ligand koji je odabran od hidrida, fluorida, klorida, bromida, η5-2,4-pentadienila, η5-2,4-dimetil-pentadienila, ili skupine A-COO-, uz uvjet da kada su dva Z priključena na atom Ru, tada oni mogu biti ili isti ili različiti; A je C1-7 alkil, C1-7 haloalkil, aril ili haloaril; Y je ne-koordinirajući anion koji je odabran od fluorida, klorida, bromida, BF4-, ClO4-, SbF6-, B(fenila)4-, B(3,5-di-trifluorometil-fenila)4-, CF3SO3- i C6H5SO3-; F je jedan opcionalno kiralni diamin; E i E' su oba dva ioni halogena, ili E je hidrid a E' je BH4-; m je 1, 2, 3 ili 4; i p je 1 ili 2.
10. Postupak u skladu s patentnim zahtjevom 9, naznačen time, da je anionski ligand (Z) neovisno odabran od sljedećih: klorid, bromid, jodid, OAc i TFA.
11. Postupak u skladu s patentnim zahtjevom 9, naznačen time, da ne-koordinirajući anion (Y) je BF4-.
12. Postupak u skladu s patentnim zahtjevom 9, naznačen time, da kiralni diamin F je (1S, 2S)-1,2-difeniletilendiamin (S,S-DPEN).
13. Postupak u skladu s patentnim zahtjevom 9, naznačen time, da je kiralni fosfinski ligand D odabran od spoja s formulama od (D1) do (D12):
pri čemu: R11 je C1-7 alkil, C1-7 alkoksi, hidroksi ili C1-7 alkil-C(O)O-; svaki od R12 i R13 je neovisno vodik, C1-7 alkil, C1-7 alkoksi ili di(C1-7 alkil)amino; ili R11 i R12 koji su priključeni na istu fenilnu skupinu, ili R12 i R13 koji su priključeni na istu fenilnu skupinu, kada se uzimaju zajedno, predstavljaju –X-(CH2)r-Y-, gdje X je –O- ili –C(O)O-, Y je –O-, -N(niži alkil)- ili -CF2-, dok je r cijeli broj od 1 do 6; ili su dva R11 kada se uzimaju zajedno, sljedeći: -O-(CH2)s-(O)- ili –O-CH(CH3)-(CH2)s-CH(CH3)-O-, pri čemu je s cijeli broj od 1 do 6; ili R11 i R12, ili R12 i R13, zajedno s ugljikovim atomima na koje su priključeni, tvore naftil, tetrahidronaftil ili dibenzofuran-prsten; svaki od R14 i R15 je neovisno C1-7 alkil, C3-8 cikloalkil, fenil, naftil ili heteroaril, opcionalno supstituirani s jednim do sedam supstituenata koji su neovisno odabrani iz skupine koja se sastoji od sljedećih: C1-7 alkil, C1-7 alkoksi, di(C1-7 alkil)amino, morfolinil, fenil, tri(C1-7 alkil)silil, C1-7 alkoksikarbonil, hidroksikarbonil, hidroksisulfonil, (CH2)t-OH i (CH2)t-NH2, gdje je t cijeli broj od 1 do 6; R16 je C1-7 alkil; R17 je C1-7 alkil; i R18 je neovisno aril, heteroaril, C3-8 cikloalkil ili C1-7 alkil.
14. Postupak u skladu s patentnim zahtjevom 9 ili 13, naznačen time, da kiralni fosfinski ligand (D) je (S)-BINAP.
15. Postupak u skladu s patentnim zahtjevom 9, naznačen time, da je katalizator od rutenijskog kompleksa odabran iz skupine koju čine: Ru(TFA)2((R)-3,5-Xyl-BINAP), Ru(OAc)2((S)-2-furil-MeOBIPHEP), Ru(OAc)2((S)-BINAP), [Ru(OAc)2((S)-BINAP)]AlCl3, Ru(TFA)2((S)-BINAP), Ru(TFA)2((S)-BINAPHANE), Ru(TFA)2((S)-BIPHEMP), Ru(OAc)2((S)-MeOBIPHEP), Ru(TFA)2((S)-TMBTP), Ru(TFA)2((S,S)-iPr-DUPHOS), [Ru((R)-BINAP)(pCym)(AN)](BF4)2, [RuBr((S)-BINAP)(C6H6)]Br, [RuCl((S)-BINAP)(C6H6)]BF4, [RuI((S)-BINAP)(C6H6)]I, [Ru((S)-BINAP)(AN))4](BF4)2, i RuCl2((S)-pTol-BINAP)(S,S-DPEN).
16. Postupak u skladu s patentnim zahtjevom 9, naznačen time, da katalizator od rutenijskog kompleksa je Ru(TFA)2((S)-BINAP).
17. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 7, naznačen time, da nadalje obuhvaća postupak za proizvodnju spojeva formule (III) , koji obuhvaća asimetrično reduciranje spoja formule (V) koji je kataliziran putem oksidoreduktaze, gdje je R2 kao što je određen u bilo kojem od patentnih zahtjeva 1 i 3.
18. Postupak u skladu s patentnim zahtjevom 17, naznačen time, da oksidoreduktaza katalizira asimetričnu redukciju spoja formule (V) u spoj formule (III) s dijastereoselektivnošću od najmanje 95% dijastereomernog viška (de).
19. Postupak u skladu s patentnim zahtjevom 17, naznačen time, da se asimetrična redukcija spoja formule (V) u spoj formule (III) katalizira putem oksidoreduktaze u prisutnosti zajednički djelujućeg faktora (kofaktora).
20. Postupak u skladu s patentnim zahtjevom 19, naznačen time, da se kod kofaktora koji se oksidira u asimetričnoj redukciji spoja formule (V) u spoj formule (III), radi o NADH ili NADPH.
21. Postupak u skladu s patentnim zahtjevom 19, naznačen time, da se kofaktor in situ regenerira pomoću: (a) regeneracije kofaktora spojene s enzimom uz uporabu glukoze i glukozne dehidrogenaze kao zajedničke podloge (kosupstrata); ili (b) regeneracije kofaktora spojene sa supstratom uz uporabu sekundarnog alkohola kao kosupstrata.
22. Postupak u skladu s patentnim zahtjevom 21, naznačen time, da je sekundarni alkohol kao kosupstrat za regeneraciju spojenu sa supstratom, odabran od sljedećih: 2-propanol, 2-butanol, butan-1,4-diol, 2-pentanol, pentan-1,5-diol, 4-metil-2-pentanol, 2-heksanol, heksan-1,5-diol, 2-heptanol ili 2-oktanol.
23. Postupak u skladu s patentnim zahtjevom 17, naznačen time, da se kod oksidoreduktaze radi o oksidoreduktazi koja je ovisna o dijastereoselektivnom NADPH odabranom s popisa koji čine: KRED-NADPH-111, KRED-NADPH-112, KRED-NADPH-113, KRED-NADPH-114, KRED-NADPH-115, KRED-NADPH-121, KRED-NADPH-123, KRED-NADPH-145, KRED-NADPH-155, A231, KRED-NADPH-136, KRED-X1, KRED-X2, KRED-X1-PIB06, KRED-X1.1-P1F01, KRED-X1.1-P1H10, KRED-X1.1-P1G11, KRED-X1.1-P1C04, KRED-X1.1-P1C11 i KRED-X1.1-P1C08.
24. Postupak u skladu s patentnim zahtjevom 17, naznačen time, da se kod oksidoreduktaze radi o oksidoreduktazi koja je ovisna o dijastereoselektivnom NADPH odabranom s popisa koji čine: KRED-X1, KRED-X2, KRED-X1-P1B06, KRED-X1.1-P1F01, KRED-X1.1-P1H10, KRED-X1.1-P1G11, KRED-X1.1-P1C04, KRED-X1.1-P1C11 i KRED-X1.1-P1C08.
25. Postupak u skladu s patentnim zahtjevom 17, naznačen time, da se asimetrično reduciranje spoja formule (V) u spoj formule (III) izvodi u vodenom mediju u prisutnosti jednog ili više organskih zajednički djelujućih otapala (kootapala).
26. Postupak u skladu s patentnim zahtjevom 25, naznačen time, da se organska kootapala nalaze u ukupnoj koncentraciji od 1 do 50 %V.
27. Postupak u skladu s patentnim zahtjevom 25, naznačen time, da su organska kootapala odabrana s popisa koji čine: glicerol, 2-propanol, dietileter, tert-butilmetileter, diizopropileter, dibutileter, metiltetrahidrofuran, etilacetat, butilacetat, toluen, heptan, heksan, cikloheksan i njihove mješavine.
28. Postupak u skladu s patentnim zahtjevom 17, naznačen time, da se asimetrično reduciranje spoja formule (V) u spoj formule (III) izvodi u vodenom puferu.
29. Postupak u skladu s patentnim zahtjevom 28, naznačen time, da se kod pufera radi o 2-(N-morfolino)etansulfonskoj kiselini (MES) ili kalijevom divodikovom fosfatu (PBS).
30. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 7, naznačen time, da nadalje obuhvaća postupak za proizvodnju spojeva formule (VI) ili njihovih farmaceutski prihvatljivih soli, pri čemu je spoju formule (I) odstranjena zaštita gdje je R1 kao što je određen u bilo kojem od patentnih zahtjeva 1 do 2.
31. Postupak u skladu s patentnim zahtjevom 30, naznačen time, da obuhvaća sljedeće reakcijske korake: i) odstranjivanje zaštite spoju formule (I) u otopini pod kiselim uvjetima; ii) prilagođavanje pH-vrijednosti uporabom lužine u otopini; iii) opcionalno kristaliziranje spoja formule (VI).
32. Postupak u skladu s patentnim zahtjevom 31, naznačen time, da se odstranjivanje zaštite u koraku i) izvodi uporabom klorovodične kiseline, sumporne kiseline, trifluorooctene kiseline ili bromovodične kiseline.
33. Postupak u skladu s patentnim zahtjevom 31, naznačen time, da se otopina koja se koristi za odstranjivanje zaštite u koraku i) odabire od n-propanola, izopropanola i mješavine n-propanola i vode u omjeru 1:1.
34. Postupak u skladu s patentnim zahtjevom 31, naznačen time, da se kristaliziranje u koraku iii) izvodi pomoću promjene otapala u kristalizacijsko otapalo koje je pogodno za kristaliziranje spoja formule (VI).
35. Postupak u skladu s patentnim zahtjevom 34, naznačen time, da se kristalizacijsko otapalo u koraku iii) odabire od toluena, heptana, tetrahidrofurana, 2-propanona, 2-butanona, etilen-glikol-dimetil-etera, etilacetata, butilacetata, izopropilacetata i njihovih mješavina.
36. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 35, naznačen time, da nadalje obuhvaća formuliranje spoja u farmaceutski pripravak.
37. Spoj, naznačen time, da je predstavljen formulom (II) u kojoj R1 i M su kao što su određeni prema bilo kojem od patentnih zahtjeva 1 do 4.
38. Spoj formule (II) u skladu s patentnim zahtjevom 37, naznačen time, da je to natrij-(S)-3-(tert-butoksikarbonil(izopropil)amino)-2-(4-klorofenil)propanoat.
HRP20192340TT 2013-11-15 2019-12-30 Postupci za proizvodnju spojeva pirimidinilciklopentana HRP20192340T1 (hr)

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