HRP20171528T1 - Soli 2-fluoro-n-metil-4-[7-(kinolin-6-il-metil)-imidazo[1,2-b][1,2,4] triazin-2-il]benzamida i postupci povezani s njihovom pripremom - Google Patents
Soli 2-fluoro-n-metil-4-[7-(kinolin-6-il-metil)-imidazo[1,2-b][1,2,4] triazin-2-il]benzamida i postupci povezani s njihovom pripremom Download PDFInfo
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- HRP20171528T1 HRP20171528T1 HRP20171528TT HRP20171528T HRP20171528T1 HR P20171528 T1 HRP20171528 T1 HR P20171528T1 HR P20171528T T HRP20171528T T HR P20171528TT HR P20171528 T HRP20171528 T HR P20171528T HR P20171528 T1 HRP20171528 T1 HR P20171528T1
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- 150000003839 salts Chemical class 0.000 title claims 26
- 238000000034 method Methods 0.000 title claims 18
- 230000008569 process Effects 0.000 title claims 13
- 150000001875 compounds Chemical class 0.000 claims 43
- 238000006243 chemical reaction Methods 0.000 claims 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 9
- 229910052794 bromium Inorganic materials 0.000 claims 9
- 229910052801 chlorine Inorganic materials 0.000 claims 9
- 239000000460 chlorine Substances 0.000 claims 9
- 238000002360 preparation method Methods 0.000 claims 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 5
- 229910052740 iodine Chemical group 0.000 claims 5
- 239000011630 iodine Chemical group 0.000 claims 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 4
- 239000002253 acid Substances 0.000 claims 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 4
- 239000012453 solvate Substances 0.000 claims 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 3
- 125000000217 alkyl group Chemical group 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 230000002140 halogenating effect Effects 0.000 claims 3
- 239000000203 mixture Substances 0.000 claims 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical group CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims 2
- LIOLIMKSCNQPLV-UHFFFAOYSA-N 2-fluoro-n-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide Chemical class C1=C(F)C(C(=O)NC)=CC=C1C1=NN2C(CC=3C=C4C=CC=NC4=CC=3)=CN=C2N=C1 LIOLIMKSCNQPLV-UHFFFAOYSA-N 0.000 claims 2
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo(3.3.1)nonane Chemical compound C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 claims 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 238000002441 X-ray diffraction Methods 0.000 claims 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 2
- 239000007822 coupling agent Substances 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 238000002844 melting Methods 0.000 claims 2
- 230000008018 melting Effects 0.000 claims 2
- 229910052763 palladium Inorganic materials 0.000 claims 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims 2
- 239000000843 powder Substances 0.000 claims 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- -1 (benzotriazol-1-yloxyl)tripyrrolidinophosphonium hexafluorophosphate Chemical compound 0.000 claims 1
- MJIWQHRXSLOUJN-UHFFFAOYSA-N 1,2,4-triazin-3-amine Chemical compound NC1=NC=CN=N1 MJIWQHRXSLOUJN-UHFFFAOYSA-N 0.000 claims 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims 1
- ZTNPHABKLIJXTL-UHFFFAOYSA-N 2-fluoro-n-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;dihydrochloride Chemical group Cl.Cl.C1=C(F)C(C(=O)NC)=CC=C1C1=NN2C(CC=3C=C4C=CC=NC4=CC=3)=CN=C2N=C1 ZTNPHABKLIJXTL-UHFFFAOYSA-N 0.000 claims 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims 1
- 206010003571 Astrocytoma Diseases 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims 1
- 206010005003 Bladder cancer Diseases 0.000 claims 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims 1
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- 208000024172 Cardiovascular disease Diseases 0.000 claims 1
- 206010008342 Cervix carcinoma Diseases 0.000 claims 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims 1
- 206010009944 Colon cancer Diseases 0.000 claims 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 1
- 201000008808 Fibrosarcoma Diseases 0.000 claims 1
- 206010016654 Fibrosis Diseases 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 208000007766 Kaposi sarcoma Diseases 0.000 claims 1
- 208000008839 Kidney Neoplasms Diseases 0.000 claims 1
- 208000018142 Leiomyosarcoma Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 206010025323 Lymphomas Diseases 0.000 claims 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 claims 1
- 206010027406 Mesothelioma Diseases 0.000 claims 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims 1
- 208000034578 Multiple myelomas Diseases 0.000 claims 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 1
- 206010033128 Ovarian cancer Diseases 0.000 claims 1
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims 1
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
- 206010038389 Renal cancer Diseases 0.000 claims 1
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 1
- 208000000389 T-cell leukemia Diseases 0.000 claims 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 claims 1
- 210000001744 T-lymphocyte Anatomy 0.000 claims 1
- 208000024770 Thyroid neoplasm Diseases 0.000 claims 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 claims 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 1
- 208000008383 Wilms tumor Diseases 0.000 claims 1
- 230000000172 allergic effect Effects 0.000 claims 1
- 208000010668 atopic eczema Diseases 0.000 claims 1
- 208000026106 cerebrovascular disease Diseases 0.000 claims 1
- 201000010881 cervical cancer Diseases 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 208000006990 cholangiocarcinoma Diseases 0.000 claims 1
- 208000029742 colonic neoplasm Diseases 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000008482 dysregulation Effects 0.000 claims 1
- 201000004101 esophageal cancer Diseases 0.000 claims 1
- 230000004761 fibrosis Effects 0.000 claims 1
- 206010017758 gastric cancer Diseases 0.000 claims 1
- 208000005017 glioblastoma Diseases 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 201000010536 head and neck cancer Diseases 0.000 claims 1
- 208000014829 head and neck neoplasm Diseases 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims 1
- 208000027866 inflammatory disease Diseases 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- 201000010982 kidney cancer Diseases 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000019423 liver disease Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 201000008026 nephroblastoma Diseases 0.000 claims 1
- 210000000056 organ Anatomy 0.000 claims 1
- 201000008968 osteosarcoma Diseases 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 208000005069 pulmonary fibrosis Diseases 0.000 claims 1
- 230000009467 reduction Effects 0.000 claims 1
- 230000008929 regeneration Effects 0.000 claims 1
- 238000011069 regeneration method Methods 0.000 claims 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims 1
- 230000019491 signal transduction Effects 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- 201000011549 stomach cancer Diseases 0.000 claims 1
- 206010042863 synovial sarcoma Diseases 0.000 claims 1
- 201000002510 thyroid cancer Diseases 0.000 claims 1
- 201000005112 urinary bladder cancer Diseases 0.000 claims 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61P13/00—Drugs for disorders of the urinary system
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- A61P35/02—Antineoplastic agents specific for leukemia
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three 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
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Claims (21)
1. Sol naznačena time da je sol 2-fluoro-N-metil-4-[7-(kinolin-6-ilmetil)imidazo[1,2-b][1,2,4]triazin-2-il]benzamid dihidrokloridne kiseline, ili njezin hidrat ili solvat.
2. Hidrat prema zahtjevu 1, koji je naznačen time da ima točku taljenja od 220 do 224 °C, poželjno 222 °C.
3. Hidrat prema zahtjevu 2, naznačen time da je kristalan.
4. Hidrat prema zahtjevu 2 koji ima DSC termogram koji je naznačen time da ima endotermni vršak kod 222 °C, ili DSC termogram uglavnom kao što je prikazano na slici 2, ili TGA uglavnom kao što je prikazano na slici 3.
5. Hidrat prema zahtjevu 2, naznačen time da ima uzorak difrakcije X-zraka na prahu koji obuhvaća karakteristične vrške izražene u stupnjevima 2θ kod 26.0, 24.7, 18.2, 29.3, i 7.8.
6. Sol koja je sol 2-fluoro-N-metil-4-[7-(kinolin-6-ilmetil)imidazo[1,2-b][1,2,4]triazin-2-il]benzamid dibenzensulfonske kiseline, ili njezin hidrat ili solvat.
7. Sol prema zahtjevu 6, naznačen time da navedena sol je bezvodna.
8. Sol prema zahtjevu 6, koja je naznačena time da ima točku taljenja od 268 do 272 °C, poželjno 270 °C.
9. Sol prema zahtjevu 6, naznačena time da je kristalna.
10. Sol prema zahtjevu 9, koja ima DSC termogram koji je naznačen time da ima endotermni vršak kod 270 °C, ili DSC termogram uglavnom kao što je prikazano na slici 5.
11. Sol prema zahtjevu 6, naznačen time da ima uzorak difrakcije X-zraka na prahu koji obuhvaća karakteristične vrške izražene u stupnjevima 2θ kod 15.0, 16.3, 18.3, 20.2, 23.8, i 4.9.
12. Pripravak naznačen time da sadrži sol, ili njegov hidrat ili solvat, prema bilo kojem od zahtjeva 1-11 i barem jedan farmaceutski prihvatljiv nosač.
13. Sol prema bilo kojem od zahtjeva 1-11, ili njegov hidrat ili solvat, za uporabu za liječenje bolesti povezane s disregulacijom puta signalizacije HGF/c-MET, naznačen time da je navedena bolest poželjno rak, ateroskleroza, fibroza pluća, fibroza i regeneracija bubrega, bolest jetre, alergijski poremećaj, upalna bolest, autoimuni poremećaj, cerebrovaskularna bolest, kardiovaskularna bolest, ili stanje povezano s transplantacijom organa, poželjnije rak mokraćnog mjehura, rak dojke, rak grlića maternice, kolangiokarcinom, rak debelog crijeva, rak jednjaka, rak želuca, rak glave i vrata, rak bubrega, rak jetre, rak pluća, rak nazofarinksa, rak jajnika, rak gušterače, rak prostate, rak štitnjače, osteosarkom, sinovijalni sarkom, rabdomiosarkom, MFH/fibrosarkom, leiomiosarkom, Kapozijev sarkom, multipli mijelom, limfom, leukemija zrelih T stanica, akutna mijelogena leukemija, kronična mijeloična leukemija, glioblastoma, astrocitom, melanoma, mezoteliom, ili Wilmsov tumor.
14. Postupak za pripremanje hidrata prema zahtjevu 2, naznačen time da sadrži:
a) reakciju prve smjese koja sadrži 2-fluoro-N-metil-4-[7-(kinolin-6-ilmetil)imidazo[1,2-b][1,2,4]triazin-2-il]benzamid i vodu s barem dva ekvivalenta klorovodične kiseline u otapalu koje sadrži vodu tako da nastane druga smjesa; i
b) miješanje druge smjese s metil tert-butil eterom.
15. Postupak za pripremanje spoja s formulom I:
[image]
ili njegove soli;
naznačen time da obuhvaća reakciju spoja s formulom II:
[image]
sa spojem s formulom III:
[image]
da se dobije spoj s formulom I, ili njegova sol;
pri čemu X1 je klor, brom, ili jod.
16. Postupak za dobivanje spoja s formulom V i njegovih soli
[image]
naznačen time da sadrži
(a) reakciju spoja s formulom II:
[image]
pri čemu X1 je klor, brom, ili jod,
sa spojem s formulom III:
[image]
da se dobije spoj s formulom I, ili njegova sol; i
[image]
(b) reakciju navedenog spoja s formulom I, ili njegove soli, s koncentriranom klorovodičnom kiselinom da se dobije spoj s formulom IV ili njegova sol; i
[image]
(c) reakciju spoja s formulom IV, ili njegove soli, s CH3NH2 u prisutnosti barem jednog sredstva za spajanje da se dobije spoj s formulom V:
[image]
ili njegova sol, pri čemu je navedeno sredstvo za spajanje odabrano od 1-etil-3-(3-dimetilaminopropil)karbodiimida, N-hidroksibenzotriazola, (benzotriazol-1-iloxil)tripirolidinofosfonij heksaflurofosfata, te njegove soli, ili
(d) (i) reakciju spoja s formulom IV ili njegove soli,
[image]
sa sredstvom za halogeniranje, da se dobije spoj s formulom VI ili njegova sol;
[image]
pri čemu X2 je halogen i navedeno sredstvo za halogeniranje je poželjno tionil klorid; i
(d) (ii) reakciju navedenog spoja s Formulom VI, ili njegove soli, s CH3NH2 da se dobije spoj s formulom V ili njegova sol.
17. Postupak prema zahtjevu 15 ili zahtjevu 16, naznačen time da dodatno sadrži pripremanje spoja s formulom II:
[image]
postupkom koji obuhvaća reakciju spoja s formulom IIa:
[image]
sa spojem s formulom IIb:
[image]
tijekom vremena prikladnog za pripremanje spoja s formulom II,
pri čemu X1 je klor, brom, ili jod, poželjno u prisutnosti prolina,
pri čemu postupak poželjno nadalje obuhvaća korake:
pripremanje spoja s formulom IIa:
[image]
postupkom koji obuhvaća reakciju spoja s formulom IIc:
[image]
s prop-2-en-1-olom u prisutnosti paladijevog katalizatora i baze;
pri čemu X3 je klor, brom, ili jod, ili
pripremanje spoja s formulom IIa:
[image]
postupkom koji obuhvaća reakciju spoja s formulom IId:
[image]
s kiselinom prema formuli HX';
pri čemu X' je klor, brom, ili jod.
18. Postupak prema zahtjevu 17, naznačen time da dodatno sadrži pripremanje spoja s formulom IId:
[image]
postupkom koji obuhvaća redukciju spoja s formulom IIe:
[image]
s plinovitim vodikom u prisutnosti paladija-na-ugljiku, pri čemu navedeni postupak poželjno nadalje sadrži pripremanje spoja s formulom IIe postupkom koji obuhvaća reakciju spoja s formulom IIc sa spojem s formulom IIf:
[image]
u prisutnosti paladijevog acetata i CuI i baze; ili
poželjno nadalje sadrži pripremanje spoja s formulom IId:
[image]
postupkom koji obuhvaća reakciju spoja s formulom IIg:
[image]
s 9-borabiciklo[3.3.1]nonanom, nakon čega slijedi reakcija sa spojem s formulom IIc:
[image]
u prisutnosti paladijevog (II) diacetata da se dobije spoj s formulom IId;
pri čemu X3 je klor, brom, ili jod.
19. Postupak prema bilo kojem od zahtjeva 15 do 18, naznačen time da nadalje sadrži pripremanje spoja s formulom III postupkom koji obuhvaća reakciju spoja s formulom IIIa:
[image]
sa spojem s formulom IIIb:
[image]
u prisutnosti paladijevog katalizatora i baze; pri čemu:
X4 je klor, brom ili jod; i
svaki Ra je, neovisno, C1-6 alkil; ili
svaki Ra, zajedno s dva kisikova atoma i borovim atomom tvori 5- ili 6-člani heterociklički prsten; pri čemu je navedeni heterociklički prsten proizvoljno supstituiran s 1, 2, 3, ili 4 neovisno odabrane skupine C1-4 alkil, poželjno pri čemu spoj s formulom IIIb ima formulu IIIb-1:
[image]
navedeni postupak čak poželjnije nadalje sadrži pripremanje spoja s formulom IIIb-1 postupkom koji obuhvaća:
a) reakciju spoja s formulom IIIc:
[image]
reagensa s formulom R1MgY, nakon čega slijedi reakcija sa spojem s formulom B(OR2)3 da se dobije spoj s formulom IIId:
[image]
i
b) nakon reakcije u koraku a), reakciju spoja s formulom IIId s kiselinom, nakon čega slijedi reakcija s pinakolom da se dobije spoj s formulom IIIb-1;
pri čemu:
R1 je C1-6 alkil;
svaki R2 je, neovisno, C1-6 alkil; i
X5 je klor, brom, ili jod.
20. Postupak prema zahtjevu 19, naznačen time da dodatno sadrži pripremanje spoja s formulom IIIa reakcijom 1,2,4-triazin-3-amina sa sredstvom za halogeniranje.
21. Spoj s formulom III:
[image]
ili njegova sol, ili
spoj s formulom II:
[image]
naznačen time da X1 je klor, jod, ili brom.
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| US5499508P | 2008-05-21 | 2008-05-21 | |
| PCT/US2009/044622 WO2009143211A2 (en) | 2008-05-21 | 2009-05-20 | Salts of 2-fluoro-n-methyl-4-[7-(quinolin-6-yl-methyl)- imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| EP09751439.2A EP2300455B1 (en) | 2008-05-21 | 2009-05-20 | Salts of 2-fluoro-n-methyl-4-[7-(quinolin-6-yl-methyl)- imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
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