NO340743B1 - Fremgangsmåte for syntese av organiske forbindelser - Google Patents
Fremgangsmåte for syntese av organiske forbindelser Download PDFInfo
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- NO340743B1 NO340743B1 NO20080157A NO20080157A NO340743B1 NO 340743 B1 NO340743 B1 NO 340743B1 NO 20080157 A NO20080157 A NO 20080157A NO 20080157 A NO20080157 A NO 20080157A NO 340743 B1 NO340743 B1 NO 340743B1
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- Prior art keywords
- phenyl
- alkyl
- alkylamino
- formula
- group
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- 238000000034 method Methods 0.000 title claims description 18
- 230000015572 biosynthetic process Effects 0.000 title description 5
- 238000003786 synthesis reaction Methods 0.000 title description 5
- 150000002894 organic compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- -1 bulky alkyllithium Inorganic materials 0.000 claims description 3
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Steroid Compounds (AREA)
Description
Den foreliggende oppfinnelsen tilveiebringer en ny fremgangsmåte for å fremstille forbindelser med formel (I):
der
RI er fenyl substituert med trifluormetyl og eventuelt en ytterligere substituent valgt fra gruppen bestående av hydroksy-Ci-C6-alkyl, Ci-C6-alkylamino, hydroksy-Ci-C6-alkylamino, di-Ci-C6-alkylamino, l#-imidazolyl, Ci-C6-alkyl-l#-imidazolyl, karbamoyl, Ci-C6-alkykarbamoyl, pyrrolidino, piperidino, piperazino, Ci-C6-alkylpiperazino, morfolino, Ci-C6-alkoksy, trifluor-Ci-C6-alkoksy, fenyl, pyridyl og halogenyl;
R2 er hydrogen; og
R4 er metyl.
Forbindelser med formel (I) er beskrevet i W. Breitenstein et al., WO 04/005281 som ble publisert 15. januar 2004, hvorved beskrivelsen her er innarbeidet ved referanse. En foretrukken forbindelse med formel ( X) er 4-metyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-iV-[5-(4-metyl-li7-imidazol-1 -yl)-3-(trifluormetyl)fenyl] benzamid (Ia). Forbindelser med formel (I) er vist å hemme en eller flere tyrosinkinaser, slik som c-Abl, Bcr-Abl, reseptor tyrosinkinasene PDGF-R, Flt3, VEGF-R, EGF-R og c-Kit. Som sådan kan forbindelser med formel (I) benyttes for behandling av visse neoplastiske sykdommer, slik som leukemi.
Tidligere syntese av forbindelser med formel (I), og spesifikt (Ia), involverer en hydrolyse av en etylester til en karboksylsyre, som så reageres med et anilin, og å benytte dietylcyanofosfonat som et koblingsmiddel som vist i skjema 1.
Denne fremgangsmåten gir lave og ujevne utbytter. Videre er dietylcyanofosfonat et kostbart reagens. Således er det et behov for en alternativ fremgangsmåte som er billigere, konsistent, effektiv og som frembringer forbindelser (I) i høye utbytter.
Det er et formål ved denne oppfinnelsen å tilveiebringe en alternativ fremgangsmåte for å fremstille forbindelser med formel (I) på en effektiv måte med høye og konsistente utbytter.
Det er et ytterligere formål ved denne oppfinnelsen å fremstille forbindelser med formel (I) fra lavkostreagenser.
Det er enda et ytterligere formål ved denne oppfinnelsen å tilveiebringe en fremgangsmåte for å fremstille forbindelser med formel (I) som benytter tryggere reagenser.
Den foreliggende oppfinnelsen overvinner problemene som man støter på ved den tidligere syntesen som er beskrevet i skjema 1 og resulterer typisk i et økt samlet utbytte på fra 54-86 %.
Den foreliggende oppfinnelsen tilveiebringer en ny fremgangsmåte for å fremstille forbindelser med formel (I): som omfatter den følgende reaksjonen:
der
RI er fenyl substituert med trifluormetyl og eventuelt en ytterligere substituent valgt fra gruppen bestående av hydroksy-Ci-C6-alkyl, Ci-C6-alkylamino, hydroksy-Ci-C6-alkylamino, di-Ci-C6-alkylamino, l#-imidazolyl, Ci-C6-alkyl-l#-imidazolyl, karbamoyl, Ci-C6-alkykarbamoyl, pyrrolidino, piperidino, piperazino, Ci-C6-alkylpiperazino, morfolino, Ci-C6-alkoksy, trifluor-Ci-C6-alkoksy, fenyl, pyridyl og halogenyl;
R2 er hydrogen;
R4 er metyl; og
R3 er Ci-C6-alkyl, fenyl, fenyl- Ci-C6-alkyl eller substituert fenyl.
Direkte kondensasjon av ester (II) med anilin (IV) katalyseres av en base, slik som kalium ferf-butoksid for å fremstille forbindelser med formel (I). Fremgangsmåten utføres ved en temperatur på mellom -50°C til 50°C i et organisk løsningsmiddel av tetrahydrofuran, dimetylformamid, toluen eller iV-metylpyrrolidon.
Detaljert beskrivelse av oppfinnelsen
Det generelle reaksjonsskjemaet ifølge oppfinnelsen kan illustreres som følger:
der
RI er fenyl substituert med trifluormetyl og eventuelt en ytterligere substituent valgt fra gruppen bestående av hydroksy-Ci-C6-alkyl, Ci-C6-alkylamino, hydroksy-Ci-C6-alkylamino, di-Ci-C6-alkylamino, l#-imidazolyl, Ci-C6-alkyl-l#-imidazolyl, karbamoyl, Ci-C6-alkykarbamoyl, pyrrolidino, piperidino, piperazino, Ci-C6-alkylpiperazino, morfolino, Ci-C6-alkoksy, trifluor-Ci-C6-alkoksy, fenyl, pyridyl og halogenyl;
R2 er hydrogen;
R4 er metyl; og
R3 er Ci-C6-alkyl, fenyl, fenyl- Ci-C6-alkyl eller substituert fenyl.
Direkte kondensasjon av ester (II) med anilin (IV) kan katalyseres av en sterk base slik som kalium fert-butoksid til å fremstille forbindelser med formel (I) i godt utbytte og med høy renhet uten noen kromatografi eller omkrystallisasjonsrensing. Andre baser, slik som metallhydrid, bulky alkyllitium, metall-alkoksid, metall-6z's(trimetylsilyl)amid eller litiumdialkylamid, kan også benyttes. Metallet kan være litium, natrium eller kalium. Fremgangsmåten utføres ved temperatur på mellom -50°C til 50°C i et organisk løsningsmiddel av tetrahydrofuran, dimetylformamid, toluen eller iV-metylpyrrolidon.
Ved en foretrukken utførelsesform omfatter fremgangsmåten den følgende reaksjon:
der R3er Ci-C6-alkyl, fenyl, fenyl- Ci-C6-alkyl eller substituert fenyl.
Forbindelsen med formel (IVa) kan fremstilles ved å benytte fremgangsmåter som er beskrevet i patentsøknadene U.S. SN 60/688,920 og SN 60/688,976, som begge har tittelen "Process for the Synthesis of Organic Compounds", som ble innlevert samtidig med denne. Beskrivelsene av disse søknadene er her innarbeidet som referanse.
Den mest foretrukne utførelsesformen omfatter fremgangsmåten den følgende reaksjon:
Slik det er benyttet i denne søknaden, dersom ikke annet uttrykkelig er angitt her, skal hver av de følgende betegnelsene ha betydningen som er angitt nedenfor.
Alkyl omfatter 1-6 karbonatomer, og er lineær eller forgrenet; foretrukne alkyl enheter er butyl, slik som w-butyl, sec-butyl, isobutyl, tert- butyl, propyl, slik som w-propyl eller isopropyl, etyl eller metyl. Særlig foretrukne alkylenheter er metyl, etyl, «-propyl eller tert- butyl.
Halogen er fluor, klor, brom eller iod, spesielt fluor, klor eller brom.
De følgende eksemplene illustrerer mer spesifikt den foreliggende oppfinnelsen, men begrenser ikke oppfinnelsen på noen måte.
Eksempel 1
Syntese av forbindelse med formel (Ia)
Til en 1-L kolbe, utstyrt med en mekanisk rører, temperatursensor, tilbakeløpskondensator, tilsetningstrakt og nitrogeninnløp-utløp under en nitrogenatmosfære ved 23°C, fylles forbindelser (lic) (16 g), (IVa) (12 g) og THF (300 mL). Blandingen røres i 15 minutter ved 23°C og avkjøles til -20°C til -15°C. En løsning av 1 M kalium f-butoksid i THF (275 ml) tilsettes ved -20°C til -10°C. Etter tilsetningen varmes blandingen til 18-23°C. Når reaksjonen er fullført i henhold til HPLC, avkjøles blandingen til 5°C. En løsning av 15 % vandig natriumklorid (500 ml) tilsettes til blandingen, og temperaturen holdes under 15°C. Produktet ekstraheres over i isopropylacetat (500 ml) og vaskes sekvensielt med 15 % vandig natriumkloridløsning (500 ml) og vann (500 ml). Den organiske fasen destilleres under atmosfærisk trykk ved en indre temperatur på 75-85°C inntil restvolumet er omtrent 200 ml. Den oppnådde suspensjonen avkjøles til 70 ± 5°C og fylles med etanol (250 ml) og vann (30 ml). Blandingen varmes til tilbakeløp (78°C) i 1 time og avkjøles deretter til -10°C til -15°C. Suspensjonen røres i ytterligere 30 minutter ved -10°C til -15°C. Fast stoff samles opp ved filtrering, fylles med kald (5°C) etanol (85 ml) og tørkes under vakuum (10-20 torr/1,3-2,7 kPa) ved 55-60°C med nitrogenlufting (8-16 timer) for å oppnå AMN107 (17,4 g, 67 % utbytte) som et hvitt faststoff.
^NMR 300 MHz, DMSO-d6), 5 10,5 (s, 1H), 9,15 (s, 1H), 9,05 (s, 1H), 8,60 (s, 1H), 8,45 (d, 1H), 8,35 (d, 1H), 8,22 (d, 2H), 8,10 (d, 2H), 7,65 (m, 2H), 7,45 (m, 4H), 2,25 (s, 3H), 2,05 (s, 3H).
Claims (6)
1.
Fremgangsmåte for fremstilling av forbindelser med formel (I)
som omfatter å reagere forbindelser:
med Ri-NH-R2,
der
Ri er fenyl substituert med trifluormetyl og eventuelt en ytterligere substituent valgt fra gruppen bestående av hydroksy-Ci-C6-alkyl, Ci-C6-alkylamino, hydroksy-Ci-C6-alkylamino, di-Ci-C6-alkylamino, l#-imidazolyl, Ci-C6-alkyl-l#-imidazolyl, karbamoyl, Ci-C6-alkykarbamoyl, pyrrolidino, piperidino, piperazino, Ci-C6-alkylpiperazino, morfolino, Ci-C6-alkoksy, trifluor-Ci-C6-alkoksy, fenyl, pyridyl og halogenyl;
R2er hydrogen;
R4er metyl; og
R3er Ci-C6-alkyl, fenyl, fenyl-Ci-C6-alkyl eller substituert fenyl,
og der fremgangsmåten katalyseres av en base i et organisk løsningsmiddel.
2.
Fremgangsmåte ifølge krav 1, for fremstilling av en forbindelse med formel (Ia)
som omfatter å reagere forbindelsen:
der R3er Ci-C6-alkyl, fenyl, fenyl-Ci-C6-alkyl eller substituert fenyl, med forbindelsen 5-(4-metyl-l#-imidazol-l-yl)-3-(trifluormetyl)-benzenamm med strukturen (IVa):
og der fremgangsmåten katalyseres av en base i et organisk løsningsmiddel.
3.
Fremgangsmåte ifølge et hvilke som helst av kravene 1-2, der basen er valgt fra gruppen bestående av metallhydrid, bulky alkyllitium, metall-alkoksid, metall-6z's(trimetylsilyl)amid og litiumdialkylamid.
4.
Fremgangsmåte ifølge krav 3, der metallet er valgt fra gruppen bestående av litium, natrium og kalium.
5.
Fremgangsmåte ifølge krav 3, der basen er kalium ferr-butoksid.
6.
Fremgangsmåte ifølge et hvilke som helst av kravene 1-2, der det organiske løsningsmidlet er valgt fra gruppen bestående av tetrahydrofuran, dimetylformamid, toluen og iV-metylpyrrolidon.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68897705P | 2005-06-09 | 2005-06-09 | |
| US70559005P | 2005-08-04 | 2005-08-04 | |
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| GT200600316A (es) * | 2005-07-20 | 2007-04-02 | Sales de 4-metilo-n-(3-(4-metilo-imidazol-1-ilo)-5-trifluorometilo-fenilo)-3-(4-piridina-3-ilo-pirimidina-2-iloamino)- benzamida. | |
| US8242271B2 (en) | 2007-06-04 | 2012-08-14 | Avila Therapeutics, Inc. | Heterocyclic compounds and uses thereof |
| EP2305667A3 (en) | 2008-07-17 | 2011-05-11 | Teva Pharmaceutical Industries Ltd. | Nilotinib intermediates and preparation thereof |
| EP2530081A3 (en) | 2008-11-05 | 2013-04-10 | Teva Pharmaceutical Industries, Ltd. | Nilotinib HCI crystalline forms |
| WO2010060074A1 (en) * | 2008-11-24 | 2010-05-27 | Teva Pharmaceutical Industries Ltd. | Preparation of nilotinib and intermediates thereof |
| US20110053968A1 (en) * | 2009-06-09 | 2011-03-03 | Auspex Pharmaceuticals, Inc. | Aminopyrimidine inhibitors of tyrosine kinase |
| JO3634B1 (ar) | 2009-11-17 | 2020-08-27 | Novartis Ag | طريقة لعلاج اضطرابات تكاثرية وحالات مرضية أخرى متوسطة بنشاط كيناز bcr-abl، c-kit، ddr1، ddr2، أو pdgf-r |
| JP5841234B2 (ja) | 2011-03-31 | 2016-01-13 | ザ プロクター アンド ギャンブルカンパニー | フケ／脂漏性皮膚炎の治療に有効な皮膚活性剤を特定及び評価するためのシステム、モデル、及び方法 |
| AR086913A1 (es) * | 2011-06-14 | 2014-01-29 | Novartis Ag | 4-metil-3-[[4-(3-piridinil)-2-pirimidinil]-amino]-n-[5-(4-metil-1h-imidazol-1-il)-3-(trifluoro-metil)-fenil]-benzamida amorfa, forma de dosificacion que la contiene y metodo para prepararlas |
| WO2013120852A1 (en) | 2012-02-13 | 2013-08-22 | Grindeks, A Joint Stock Company | Intermediates for a novel process of preparing imatinib and related tyrosine kinase inhibitors |
| US9920357B2 (en) | 2012-06-06 | 2018-03-20 | The Procter & Gamble Company | Systems and methods for identifying cosmetic agents for hair/scalp care compositions |
| WO2015092624A1 (en) | 2013-12-16 | 2015-06-25 | Ranbaxy Laboratories Limited | Nilotinib mono-oxalate and its crystalline form |
| CN103694176B (zh) | 2014-01-07 | 2015-02-18 | 苏州立新制药有限公司 | 尼洛替尼中间体的制备方法 |
| EP3095782A1 (en) | 2015-05-18 | 2016-11-23 | Esteve Química, S.A. | New method for preparing 3-(4-methyl-1h-imidazol-1-yl)-5-(trifluoromethyl)benzenamine |
| US11666888B2 (en) | 2018-02-05 | 2023-06-06 | Bio-Rad Laboratories, Inc. | Chromatography resin having an anionic exchange-hydrophobic mixed mode ligand |
| JP7409696B2 (ja) | 2018-06-15 | 2024-01-09 | ハンダ ファーマシューティカルズ インコーポレイテッド | キナーゼ阻害剤の塩およびその組成物 |
| JP2020007240A (ja) * | 2018-07-04 | 2020-01-16 | 住友化学株式会社 | ベンズアミド化合物の製造方法 |
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| DE69901379T2 (de) | 1999-03-09 | 2002-11-07 | Sigma Tau Ind Farmaceuti | Camptothecin-Derivate mit Antitumor-Wirkung |
| IT1306129B1 (it) | 1999-04-13 | 2001-05-30 | Sigma Tau Ind Farmaceuti | Esteri della l-carnitina o di alcanoil l-carnitine utilizzabili comelipidi cationici per l'immissione intracellulare di composti |
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| WO2004005281A1 (en) * | 2002-07-05 | 2004-01-15 | Novartis Ag | Inhibitors of tyrosine kinases |
| EP1532138B1 (en) * | 2002-07-05 | 2008-11-19 | Novartis AG | Inhibitors of tyrosine kinases |
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