PT109598A - N-(1,2,3-triazolmetil)-3-hidroxi-3-ariloxindoles quirais não-racémicos - Google Patents
N-(1,2,3-triazolmetil)-3-hidroxi-3-ariloxindoles quirais não-racémicos Download PDFInfo
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- PT109598A PT109598A PT109598A PT10959816A PT109598A PT 109598 A PT109598 A PT 109598A PT 109598 A PT109598 A PT 109598A PT 10959816 A PT10959816 A PT 10959816A PT 109598 A PT109598 A PT 109598A
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- alkoxy
- polyvinylpyrrolidone
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- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 claims description 7
- 101150035983 str1 gene Proteins 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- ZHGWWQGQWUUIBK-UHFFFAOYSA-N 1,1-dichloroethane;ethoxyethane Chemical compound CC(Cl)Cl.CCOCC ZHGWWQGQWUUIBK-UHFFFAOYSA-N 0.000 claims 1
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims 1
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 1
- 239000011261 inert gas Substances 0.000 claims 1
- 210000003127 knee Anatomy 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 229920002717 polyvinylpyridine Polymers 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 238000001356 surgical procedure Methods 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 6
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003112 inhibitor Substances 0.000 abstract description 5
- 239000002243 precursor Substances 0.000 abstract description 4
- 229910052723 transition metal Inorganic materials 0.000 abstract description 4
- 150000003624 transition metals Chemical class 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 2
- 229910052796 boron Inorganic materials 0.000 abstract description 2
- 201000011510 cancer Diseases 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 abstract 1
- 238000006254 arylation reaction Methods 0.000 abstract 1
- 238000007036 catalytic synthesis reaction Methods 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- -1 1,2,3-triazol-3-yl Chemical group 0.000 description 15
- 229910052740 iodine Inorganic materials 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- YHWMUKQFHPVCRR-UHFFFAOYSA-N 3-(4-chlorophenyl)-3-hydroxy-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 YHWMUKQFHPVCRR-UHFFFAOYSA-N 0.000 description 2
- PCGPECDBGKABHI-UHFFFAOYSA-N 4-(4-bromophenyl)-1H-indole-2,3-dione Chemical compound C1=CC(Br)=CC=C1C1=CC=CC2=C1C(=O)C(=O)N2 PCGPECDBGKABHI-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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- QTYUSOHYEPOHLV-FNORWQNLSA-N 1,3-Octadiene Chemical compound CCCC\C=C\C=C QTYUSOHYEPOHLV-FNORWQNLSA-N 0.000 description 1
- PUUONSHOOPBHHW-UHFFFAOYSA-N 1-[(1-benzyltriazol-4-yl)methyl]indole-2,3-dione Chemical compound C12=CC=CC=C2C(=O)C(=O)N1CC(N=N1)=CN1CC1=CC=CC=C1 PUUONSHOOPBHHW-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- CVGGOCHTMCUPOI-UHFFFAOYSA-N 5-bromo-1-prop-2-ynylindole-2,3-dione Chemical compound BrC1=CC=C2N(CC#C)C(=O)C(=O)C2=C1 CVGGOCHTMCUPOI-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241000125205 Anethum Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 229940116211 Vasopressin antagonist Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000012650 click reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 239000003038 vasopressin antagonist Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
-
- 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
- C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
- C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
A PRESENTE INVENÇÃO REFERE-SE A SÍNTESE CATALÍTICA ASSIMÉTRICA DE NOVOS N- (1,2,3-TRIAZOLMETIL)- 3-HIDROXI-3-ARILOXINDOLES QUIRAIS A PARTIR DE PRECURSORES DERIVADOS DA ISATINA, UTILIZANDO CATALISADORES DE METAIS DE TRANSIÇÃO QUIRAIS. ESTES COMPOSTOS FORAM PLANEADOS E SINTETIZADOS COM FUTURA APLICAÇÃO COMO INIBIDORES BIOLÓGICOS. ESTES COMPOSTOS QUIRAIS N-(1,2,3-TRIAZOLMETIL)-3-HIDROXI-3-ARILOXINDOLESL DE FÓRMULA (I) SÃO OBTIDOS ENANTIOSELECTIVAMENTE A PARTIR DE PRECURSORES DE FÓRMULA (11) ATRAVÉS DE UMA EFICIENTE REAÇÃO DE ARILAÇÃO UTILIZANDO REAGENTES DE BORO OU DERIVADOS E UM CATALISADOR DE METAL DE TRANSIÇÃO QUIRAL, SOB CONDIÇÕES REACIONAIS SUAVES. A PRESENTE APLICAÇÃO DESCREVE A PREPARAÇÃO DOS COMPOSTOS N- (1,2,3-TRIAZOLMETI1)-3-HIDROXI-3-ARILOXINDOES QUIRAIS DE FÓRMULA (I), OS QUAIS DEVEM SER BONS INIBIDORES NUMA SÉRIE DE ALVOS BIOLÓGICOS, EM ESPECIAL NA DOENÇA DE ALZHEIMER E CANCRO.
Description
D E S C R I Ç Ã O "N~ (1,2,3-triazolmetil)-3~hidroxi-3-ariloxindoles quirais não-r®cèmxcos"
Domínio Técnico Ά presente aplicação refere-se à síntese de novos 11-11,2,3-triatoimetild-3-lD-dr00ti“3-ariloxind.ol:es quitais a partir cie precursores derivados da i satins utilizando catai is adores de metais de transição. Estes compostos foram planeados s sintetirados com futura aplicaçao corno inibidores b i òi0 Q1 c o s *
Estado da arte h presente invenção: refere-se à sxPtese: de novos :21-(1,2,3-triaaõlmetiii) “3~fiidroni"3“ariloxindoles quirais a partir: de precursores derivados da ísatina ntilisando catalisadores; de: restais de transição. Estes compostos foram, planeados e sintetirados: com futura aplicação como ioibídores:
PiolcgiC os , dos dias de boje, a maior parte dos fármaeos existentes no mercado ou em desenvolvimento sao quirais, emistindo geraImante apenas numa forma enantiomeriea, pois na maioria dos casos apenas um dos enantíomefos é eficae., Em: alguns çasos: o outro enantiomer o anula o efeito do: primeiro, ou poderá mesmo ser bastante prejudicial aõ organismo (EG, 2004), 3~H i.drox.1 ox' ndo ies 3-substituidos exibem ama boa gama áe atividades biológicas:, nos quais podamos incluir SSR~li941o, um composto não pepi. idi co, ativo oraimente, um recetor antagonista de vasopressina (Sai et ai. 29(12), ÃG-G41R, um. recetor antagonista de gastrina/CEK-S, eficiente na reparação de cartilagem (Ochí et a 1. 2001), um derivado N~ metilo-espiro [2,3' ] -oxindolespiro[3,2/ ' ] -5,6-d.imetoxi-l' ' -1 nd a n on a - 4 - {a r i 1 o - s u bs t 1 t u i d o..} ~ p ;i r r o 1 i d i ri a qu e £ o i ideniifioado corno um inibi dor de acetiIcoiinesterase íkChE) ;; (A.1.1 let!! 11ÍIIÍ ΜΪβΐΙΙ NITDG09, urn candidato p|||i!!!fâiliabó: antimalarico (Rottmann et al. 2010). Desenvolvemos uma família de derivados de οκ índoles 2~subst ítuidos~2~h.idroz.U o ãqu:di ma n 1 f e s t a r a in bo a inibi cão em | {Tot. obe.na za r a e t a 1 ·, 2 016} *
Por outro lado, a unidade 1,2,3-tríazoie está presente em 1:111 |í|; j. tos compos tos bib 1 o gi ca mente at i vos f. Bu r jgi||p Marques ::1!!|| 2015, Thirumurugan et al. 2013, Trone et al. 2007 and Totobenezara and Burke 201,5.) « Por exemplo, ea-r box i amid o -ill:iiit:|tlçiiiii (CAI} , um itiibidor de transduçâo de sinal uti 1 ízÍ4d!!l::: no tratamento do cancro (Perafoo ei al. 2004). o antibiótico !!|-l:|:dt:|r|Í!! tlpóbipturi:.......; Yang !;!;^!ti:!:!!^!!t .99). e a cefalcsporina 'ã!||| ! !cii.i,£'|il.r i,a..zl;.n:|!!i bed|!i;ii|li; Fu '1:1:7 lllliss............ ç!i/i! félo!!l nds#:l !!iónhedl::iÍ:|t.o:í mollill; |:| |i'o 4¾ !:Í!'.! !: ítsqrliiieto | Ipates '!:!:!:$;§ rffiacó£'diÍ|||!Í ..........Mill,2,13¾ !f i!:!' it r :li:lbd.me ti-11:1- 3 -- h id r ifi ~ 3 - a r I ΙόΙίΒΐΐ Í;ii|f: '::!!||:| | fá t u.f iitentdlllt lii .dilld-nbecidif , J|>esa.|i|po seu 'é:iilif!:!ifferreia:|!!i:p:fapefiiα:ό:>·li: :IÍÍl|Í:fi:t:ãG, a fitléetllilii.ntif ção d i éf iiiiiiiiiica· a sdlltepe .Él n:tif:éil!!i, ,:!:! f arní 1:11::3 1 :ie .!!!::fi:i:ivá::|:d.s de !!!!i|IÉÍiiií^ :,· éT^^iijb.i-I) H:!“:|!!!!!l::: ,::lÍ:l:df |ÍÍ:l::o:llia:.|:l:l||:;ipd§i.es. de | qf.If||.s. r' á o .............................:l:Í:f:ÍÍll:lÍ::|:Í | ά:|:|!!!|41:1:®^!!βο e.spel:|:l p:d|ltil|tiiÍ!!:ÉG:d:i::: iillvidadis ^7!!ΐ,όία1όρ:Ι:1::|:| !éi!!::i:lv:d|!!:çf:lulaxes: liiipecliudis.!!!!!
Sumário :1::11 :i '1; óbfitívcl festa aplXcfçio é a !^|ss-çir !!l:!!|i|m:í.i:f|:s f fe :r::||:ilfii.|:DS' de ilàe í 1 ::: | s de !!!:£ρ:1ιτΐύ1ρ !!!1|1|1 !ijdlra.l|i!!!!lll;:;:; ::: !r|::cem:.i|:|.s 1 iifat |§i$|i$i|d$ :i|ataX;isa||!?r|l: d:|: .rffliii :dé: !iitra|||i||:||l!|. dos quais se espera possuírem boas atividades biológicas em alvos ceIuXares espeCifi oos
Sotâo:, esta aplicação: descreve compostos de formula (I)
m nos quais, R, Hl, Ra & Ed representam:: í-í, grupos alquilo, aril o:, vinílo, aiilo, aicdxido, halogénios (F, B.r, Cl), OH, CM, CHO e CO.çi, R^ represe:;ca um. grupo alquilo: linear com Ιο carbonos, um grupo c.ío.1 oheteroa iqu Mo, como:
um grupo arílo ou heteroarilo, que incluí, um grupo feníip substituído (contendo aicóxido, haíogénio (F, Br, Cl), OH, CM, CHO, CCgH) , 2~ e i-pirldina, pirimidina, pitIdarlna:, tiofeno,·furano, pirano, benzollo, pir.role.
Um grupo Penai lo ou derivado,
onde R' é aicóxido, dalogenio (F, Br, Cl),; OH, CM, CHO e
Co-sU
Sv -ν' .·! ! -qr RS representa um grupo arilo.
Todos estes compostos podem ser obtidos: numa uni ca £q riria, enar-.t ornér A ca - para: ou enriquecida .
Os compostos de formula (I) são ofótidos a partir dos compostos de formula (11)
CU5 h introdução da unidade 1,2,3~tnazole em (II) é facilmente conseguida utilizando a reação click de Suarpless-Mc1 da 1, Pasta n t e a f i o 1 en te,
Esperamos obter elevada atividade biológica com estes compostos tendo em conta possuirem dois potentes f armaooforos, nomeadamente as unidades 3-ar 1. i o~3~ nídroxioxíndole e 1,. 2 f 3~triazole, e aièm disso, eles existem na sua forma: enantiornericements pura: ou estado enrique eido.
Descrição geral
Esta aplicação tem como objetivo reportar o desenvolvimento^ de novas famílias de derivados de P-íl,2,líp-friazolem;etild~ d-Pidrcsilc-d-ariioKindoles de formula (I) quitais não rncómicos, esperando otter boa atividade pioiógies em. pQ:tencias a 1 vos biú 1 ógicas: chave.
Os compostos de: fórmula (I) são obtidos a partir de precursores derivados de isatina de fórmula (II) , através: da adi câo do ácidos: aril o-boroni o os, esteres ou reagentes do tipo 1 r ifluorofoorato, numa. reação cataiiçada por metaisr de transição^ (Burke e Marques 2015) .
Os substratos de fórmula {II} sâQ: obtidos a partir de ll!!pied||s:c|lillllÍ:Í q !l|j|d|bS|ÍÍ! reação ; click dipolar de cic lo-adi cão de. Sha rpleS'S-'Mel.dal com os áridos orgânicos apropriados (Rostovtsev et al. 2002, Tornoe llllt III Ι||:|1Ι;1Ι:| IÍst;Í;l|||i:eipG:||;:: lio realizadas jf catalisadores de cobre (Burke e Marques 2015) (Esquema 1).
Escpiema 1 III A ia ação I cllliliil métri c s:|:|l||;|i;:||||pa ra 1| é reo I irada ;f utilizando um catalisador apropriado de metal de transição., .....................IIP*;·.......Ru,.................]£yy:;.....As reações.......ΐ;:; |||ilOrmil:pe:t||i|| (ii aliza:da.s| || pli|a||| ólóplllílil.alipIp :ΐ1||ρ||ΐ'' pré- jf i:||||a:ta|::iii;||||| dill! Ο I iga r|d| ........a Q Idlil!!|:t :1::.. l;i||||:|' if: If :||ϊ ............fÓ:b:Çl::|:. 'Í|||||:|iul|:|)â.l.ã:0 C^i3|b |;M ::::||:rÍÍ:é:ÚÇa Çp ,1 ííilll.......lia#edlefil! bdli e ||ma J&l-affl .................... (|:|||Ιρ:.1#ρθΡ||#| |p|||:h é Ut i.l í z:ãd#: Corld:::. 1 isa(dd:ií| .f ||||í:-tiC#1i.fp|ii::::das::;:iÓ:|;giiÍ lsfis di spol çóirseliiilsidéll.el |í ffffffÊt|::!!ÍfI!iz«dos::tddid| |||} cloro- {f§ ||;f Idlf iót:a:|:|édij|i|Í f||111Rb |||d) Cl] p, l§ffCQD} OH] a, f Rh c:|bd.jÍÍ||g, ·§φ§ ff l2S:l IPX |;:Í:|Í| RÓ-. (-ÓXá:|p:Í s :||||||;::{:00^:|:) § ità }" ||||: l|||::ê]::|^Íf 11ld%desslé::: p r a:|.f I a |1||||Ι1|1ΙΙδ| f rm 1 lllli .ilÉlf I Gl I! ||::l|Vf;i I!.i .r:a.l|||iu.e pf J em|| s ο:|||μt í 1 iffdqe' £ópi:®i|if··· 11:111 ff |í ffff^ffff:ffff^ff 1:11 Jiwl|||xRói:f| :| r|:b#|!!!||:;:: : j|J Jiy||.....x.yl||-p-|dl(l,|' .# ..............UI t|||||:; |p.j|||||j|||| ||j|||llfc;ap|lg| ff J: ff li |f f Jfff f f| 'r|||||í.oa:|| aiff ff f §f||ÍIIÍ||^^ B'ffÊffffffÍf ff “1ύ'-ι Walpbos, Josíphos, Nau d, SchmalzPhos, QuinNap, derj.vados de fosforamidite (MonoPhosÓ etc, NHCs quirais, disíios, como; 3icic 1 o [2.2.2 j octad.ieno cie siraetrie O e ligandos quirais tier i vados de sui firiarnida-ai ceno e i igandos | ........Ρ^ρφί || ^|iiB:op||| lÉ: dpi fit jÉÍÍÍ!lde:l!lÉ:gqnd© qU:|iii-l| ip-ia· eífife || :p: ;;;; ;i;;;;;;;;;.;;; i;
No case da base, podem sei. u l. í 1 i radas qeraiuieni.e as
|||||::. bases: .......... ί::ΐΦΐΐ:Χ: I 0:Í::ÍÍÍif ’ KKip.* l|| CSiCCq ©i |K0 ||t|||||||||| i...;qaanliÉÍiÍ.......tie- . baile iipiajiliifee 1 a 3 |@:quiii3di|:les J f .............idÉiiniiin. pbppn· se.r irtiliplpdoilli. toli^pol 1 ibilll. | lllllditiet Hi©iillliter... dietll:l|llfi, dleXoroetanlbX:.:,,Xi;pfl......::l:v:iip-ididppi 11 111 s raetÍÍÍÍll etanoltlll: i s o p r o p a η o .1., |; IrP'iil l|:;dlllllii||:nó>||||MÉ........e NMP.
As reações são realizadas sob atmosfera inerte (isto é, sob la till!!!!! de |:a;iiti::. seio ou -â-3iii|[o-n:) ;i; II lAlIliliililii slid li|aX.i:lad:S:s.........geralmente a temperaturas na damdli,. 1 |ie 2 5 °C :e;ll|:01:d, PÍ;|lp iiier oblillas ^ί||ίΡίίίί>'ί^ίβ;|ϊί9:% I <1 iSiijii ri t.i- ^^ijÉi^ip-^iiãiiii:: 191111111¾) . WÈi và^liÍiiiiiiiíííííí(l | iniiie IQllllp.iillher'iillll | f p.O|§elil |Í;Í i|iÍil§3S: iiiiili ·|1 f.i <£$§'«( '1,
Esquema 2.
Figura 1
Exemplos
Sintese de substratos N-prapargilo-isatina agitada durante 10 minutos, Uai a sol. ação da ear roxa pede ser vista no balia reáeional, á mistura lai deixada1 em agi tadio à temperatura ambiente durante ama hora, e dopais a brometo de pr eparei Ia (1,1 equi va i et t e t is foi a d iai opa do qata-g-a;ota, Ά mistura xsacional foi deixada em agitaçao durante Os horas â temperatura ambí eu te:. O DihF foi reaiavido sob pressão redusídSa OS foi adicionado AcOut e HuS. A fano aquosa boi extraída cam hcOEt (;3*l3Q mi,) e as. fases orglinicas juntas foram 1 amadas com brine, secas sob Mgsun e evaporadas no rod ao apor para se obterem os der 1. vários b-propargi lo dose j a:doa, I-(Prop-2-inilo)indoline-2,3-diona
Sói ido laranja. (905 de rendi.mento) . 2H RMN (CDCls, 400 MH 2} δ:; 2:. 3,2-:2.33 ;m, IH, Cd) , 3.35 (s, 2H, íOHjb , 7,14-1.21 (m, 2H, Ar), 7.64-7.68 (m, 2H, hr:. 13C BMN (CDCI3, 100 MHz) δ: 2 9.:56, 75.45, IStSb, 111.21, 117,79, 124.327 125. SI, 139.56, 149.72, 157.27, 132,65. 5-Mefcilo-l-(prop-2—inilo)indoline-2,3-diona
sólido laranja (211 de rendimento). -H RMN {CDC13, 400 MH2} δ; 2,2 9 (s, 1H, C H:} , 2.35 (e * 3 h, 6¾) , 4,51 (a, 2 h, C }fe ) , 7.01-7.03 (d, d- 3 Ha, In, Ar) , 7.43-7.43 (m, 2H, Ar), i3:C mm {CDCI3, 100 MHz) δ: 20.86, 29.56, 73.33, 75.93, 111..02, 117.53, 125.93, 134,2 3, 13:8.98, 147.37, 157,4o, 192.94. 5-Bromo-l-(prop-2-inilo)indoline-2,3-diona
Solido laranja (30% de rendimento). XH RMN (CDC1;,, 400 MHz) S; 2.3'3 ÍS, IH, SM; , 4.53 ísf 2:H, CM;;) , 7, 04-7. 26 (d, 3: lia, I.H., Sr) ( 3.:23-7..:3:5 fm, 111, Ar), ISIS (a, lit, Ar), 13C RMN (CDC13, 100 MHz) δ; 29.5 1, 7 3.91, 7 3,3 5, 112,93, 117.29, 11:9.95, 128133, 149.78, 148.40, 106.53, 181.01.
Sintese dos subs tratos N~ (1,2,3-Triazolmet.ilo) -isatina ilrmoedi.ífraá to gera 1
Oum bulao de fundo Redondo forars adieidnsAos os derivados de A-propargilo ísatína, os áridos (1 equivalente) , Cal (101)2 equivalentes) ., DIPEA 10.03 édUi velentes), MQÂe (D. 04 equivalentes:) e CMtGls. A mistura foi deixada em agitação 1 temperatura: ambiente durente 18 horas e monitorizada per CCF. A mi stura r oaclonal foi t11trade util isando um funil de: placa porosa eqm uma camada de oeiite e lavado com ClpClu. 0 solvente foi evaporado no rota vapor e a: mistura crude roi purifieada numa coluna crcmatcgráfica de vidre cem silica gel g s a n d o h e x a n ο/A c0E t (5/1) - (1/1) -Ac0Et; como a ra d f e n t e d o solventes, 1-((1-Benzila-lH-l,2,3-triazoi-4-ilo)raetilo)indoline-2,3-diona
Sólido isMísIa (3Ô8 d© rwuàimaKto} , p. f7- 13? .2-135*8O. ΓιΗ RMN { (CD3)2CO, 400 ΜΗζ) δ: 5.02 is, 20, CH;·) , 0.60 ;e, 20, Çtb), 7 013-5.17 ft, 2- 3 Hr, 1.H, Ar) , 7,22-7.24 (d, 2- 8 Ha, lH:, Ar), 7.32-?.. 36 {&,· 511, Ar), 7.54--7.:56 {d, J- 6 0r, 10, Ar), 7,62-7,6:6 (0, Jr 8 Ha, 1H, Ar), 8,74 (a, 10, -CH) . ;3C RMN {(CD3)2CO, 100 MHa) δ: 36.06, 54.26, 1 12.21, 11)70, 12:4.74, 124,29, 125.14, 128.67, 1:27.11, 129.66, 1:36.86, 138 ., 93, 14 5,0 6, 151.67 , X 5 8.5 3, 184,13. 1- { (1-Butilo-lH-l, 2,3~triazol~4~ilo) taetilo) xndoline~2,3~ diona
Sólido Laranla (203 de rsadlosoto) . p .£. .104,2-105.7 °G . XH mm ({CD:5)jCO, 400 ΜΗζ) δ: 0.8 6-9,90 (t, J- 8 0 r, 30, CH·,) , 1,25-1,31 Cq, 2= 8 Hr, 20, CiiC , 1,79-1.66 (m, 20, 20:2, 7.16 (t, lii, Ar),· 7.25-7:,2 5 (d, 2- 8 Hr, 111, Ar),: 7.53-7.55 is, 10, -CH) . l3C mos {<CD3)2CO, 100 ΜΗζ) δ: 18.65 (CHC , 29.18 ICHíO , 32.8® (2169 , 36.09 ICO;®, 59,36 ICHj), :1:12,28. (CH), 116,60 1C), 123.73 OCO) , 124.28 (CH) , 12 5.13 (CH), :138 .:84 (20), 142.51 (C)151.64 1C) , 152.49 (C-C) , 184.16 iC-O) . EM {ESI) m/z: 285.0 [MJ*·. 1~ { (l-Ciclahexilo-lH-l, 2,3~triazol"4-ila} rnetxlo) indoline-2,3-di.ona·
S61 icfc la sadia (10% de seRllaRntsB , R RMN { {CDR ;;S0, 400 MHz) δi 1.:17-1.13 Hr 12, CM.?} , 1.24-1.37 tra, 22, CBR, 1.82- I > 7 0 {m>. MB, CBR, 1.38-2:.01 (2, 111, €:3.R , 8.33-4.42 Cm., RI, CB3 , 4.34 (R 22, 2HR 3. 10-?. 17 ;;s, 22, 7lR , 7.52-7.37 (d, J>- 8 Η*, 111, àr} , 7-,81-7,23 ?;t, ζ::; 8 MR, IE, Asr 82 20 R,. 12, :····0Ηί. 1 ;iC HMN { (CDs) 2SO, 100 MHz) 5: 24.54 RR, R 24.27
ÍCH2 f 32.83 sCllR, 23,17 (CHR , 53.85 Γ2Η3 , 111,1? (CBR II 7,82 (C) , 121.52 (8:B i , 12 3.38 < C5) , 12 4,4 5 t R i i , 133,8 3 8ÇHR 141.16 (OR 120.25 (Cr IB7.85 RBRR , 18 3.15 3(>Q1 . EM (ESI) m/z: 311.1 RRl. 1-((1-((18, 2R, SS) -2- Isopropilo-S-metilciclohexilo} -1E-1,2,3“triazol“4-ilo)metilc) indoline-2,3-diona.
Odlddo laranja 333% de RsiutiszaRor p .£. 123.. 2-135 >7°iR lB mm (CDC13, 400 MHz) δ: 0.69-0.71 id, J=== 8 Hz, IB, CRB, 0 275-0,78 id, d- g Hz, 3H, CBR, 3.81-0,83 (5:, R=- 5 Hz, 3B, CBR, 0,37-1.,04 (τα, 2H, CIO:R 1,31-1,4 3 (IS, 22, CBR, i . 85-1,68 (Si, 15, CH) , 1,7 2-1.33 (Ts, 42,- CB>, Oil}, 4,37 vR la, ν.·ϊ" ; , 4 , > tCi'j- r -.-:-:0 > ' * '-·' ,. X X \t X-X/ : -- / ,· / . 3 '·: . :: X \ X ., X " v- r *' ··- f - -X i -X X ; / - * X *-·: ” / * ·; : X / 4 X-X í t ·-' - 4· X : 4 r 1.3:., 13C RMN (CDC13, lOO MHz) 5: .:10. -13 :CHo, 21,1-1 (COM, iCH'.) > 117,03 (1(0 124,04 (CD , 12 0,33 (Cl) , 103.30 (CD, 140,00 (1) , 1 OIL 4 3 /€} , 103.00 (COOC, 1.33.34 (COID EM (ESI) m/z : 3 6:7,3 Ϊ [311", 1-{<l-Benzilo~lH~l, 2,3~triazol~4~ilo)metilo)~5-metilo-indoline-2,3-diona
BoliOo Israrn a (37% de renDo-oOo) . p. £. : 143.1~144 , £r·C . lU SMN (CDCls, 400 MHz) δ: 2.30 {&, 31, OHd , 4.06 is, 21% 160:-, 2, -: ·-' :. , .4 1-,/ -.-.1,- : , .' > .:. 3™ -,: , O'" 6 X:,-.. / X-IX / -iX: , ' -: > -X 3 0- 4 / ; -- ϊ -XX Ϊ > X - - 2 -' X' X .: -X / : > : . X f Xl, " , Rífií (CDCls, 100 MHz) δ; 20.00 ÇCHs) , 30.32 OHO, 54.04 (CD), (Cl), 120,11 (OK) , 12 3,2 0: (13), 134,:02 (0(), 1.34.13 (C ) ,
(1-0.:. EM (ESI) m/z: 332. X (MjO 1-{{l-Bensilo-lH-l,2,3~tríazol~4-ilo)metíla)™5-bromo~ indoline-2,3~diona
So lido larang a {52%· de randimenttO , p. £. 173.1 -175, 0*0:, ;H RMN (CDCl.i, 400 MHa) δ: 7 , 98 3, 2M, CHS , 3.77 ia, 2H, CKo ; 7., 34 -73.2¾ end 3H, '&±\ f. 7.35 (m, 311, M) , 7,52 (a, 1H, -CHd, 7.66-7.59 ru, 2H, Ar). :3C RMN (C0C13, 100 MHz) δ: 33.131 (O'ibd , 53.57 (€3-5:3, 113.54 (CM) , 11.7,07' (C) , 118.75 (2) , 122.9 7 (CM } , 12 8,14 ; CM3 , 128 . 4 3 (CM j , '129 . 17 (€51) , 1 28,3'7 (CHS, 134.04 (C).., 140,33 (CM), 141.90 (C) , 149,05 €2), 157,27 {2=-==0) , 152:.08 (C=::P; . EM (ESI) m/z: 39 7.0 ÍRp',
Sirxtese catalítica assimétrica de N~ (1,2 ,. 3-triasolmetilo} -3-hidroxi-3~ariloxindoles quirais não-racémicos
Pro ce-bime n to go ra i dam. bg.Iao dr fundo .Redondo fox adio longest! sob autoatoaxa
Inerte M h Oa o acx) (Cdft;.;? (1..2 st;g, 0,005 .noxo:.i, 3 Col id, i&}~ MCMAF (5.3 sag, 0,010 mooi, 9 roll) o COdCOd· (I ml,), A mistura foi agitado â temperatura ggSdiattte dafa;nte 1 Mora,. Mods a dual o ooleente fox removido: uo xo earn par, Sots at or: of e ta inner te foi adi :0 faltado sag:ueno.ialaventa: go balão feacional o a:ubst rato PA-t ala tola isatiexa (0,10 mmol ] , c âoldo afitbofPnion (0-,.32 mmol, 2 égaiv.},: metanol (2 of; o DXMEA (14..0: at, 0.. 08 rraol, 0.5 egglv, ) . 31 misr.ata fox -ag it safes a 60 7 C bat ante 13 horas. C mot ha no 1, foi eraporado no ratavapor. Fata detaradnao: o reisdirsento do· produto: preiandido, a midtor a crude foi ptri.fica.da par eromaltografig de coluna am silica gel, utilizando trexauc/lCsllCt (1/1) domo eluants, ísbtetuio--sB o prodasm prmtapdido (1)-(12) . Para deter imitar a opnversso, a mistura crude ísri filtrada ruas funil da placa porosa eamstendc uma camada: ce cai I te e uma camada da ai. li ca. çel, 0 s mistura eiultía com. EtaO. 0 solvente foi evaporado ao: notavapor e a mistura crude analisado cor «22(1. 1-{(1.-Benzi lo--1H-1, 2 s 3-triazol~4-ilo)mat±lo)~3-hidroxi~3-~ feni 1 indol;in~2 -ona (1)
Sólido Cr as Cd . p. £. 1 5 0 - 3 - d 3 ? ,7 ° C . ::K RMN (CDCI3, 400 MH z} δ: 3.47 tá Pt, ia, OH), 4,39 (s, 3:2, Ci-P) , 13 7 -~S .29 fd, C-: 16 IP, 2 H, CelS) ,. 7.04-7.07 (t, 2H, Ãr)f 7.10--0.34 fm, X3M, /dm, 7 . 4 2 (a, Ui, :::CH í , I3C RMN (CDClp, 100 MHz) δ; 33.82, a 4,33, 7 § . 0 0, 110.18, 12 2.22, l i 7.2 S, 12 S . 0 3, 12 5 . i 1, 13 3 . .21, 1.2:8.43, 12 3.7 3, 12 3 . id , 122.27 , 1.3 Ô . 14, 131.53/ 1.34.33., 140,01, 14 2,13 , 14 3.0 0 , 177.34 . EM&R (ESI) : 2/ s ca l. cd pS:r a CçsHstPrQ330.13303 , eη ooa 11 a do pa r a C»c.Hf32 Ο;: ( d) a 3 871,.10590. HPLC: l/aíoei Chiralpak: In, n-fcaxano/i-ptapiusal -8 Q / 2 8, 1.0 m I, /m in, 220 nm, tempo s de r e:t e nç do: 22.7 0 7 m 7. u (tseu o r3 , 5 3.833 mi u fma 1 o r) . 1" < (I-Benzilo-IH-X , 2,3-triasoI~4~-ilo) met.iXo) ~3~bidroxi~3~ (naftalsn-2-ilo}xndolin-S-ana (2)
Solido Izranje cloro, p. f „ 7 S , 4 - 7 6 . 0'C . 1H KHN (CDCX,, 400 MHz) δ: 5, 03 (s, :1H, Clip), h. < 38 Os jor, lily llH}, 5,37-5,48^ (q, 8- 13 Hz, 2R, CHH, 7.03..7.0:8:: 1.0, Hi, Ar], 7,13-7.35 .(}&, OH, Ari, 7.44-7,4 g 4¾. 3íi, Ar), 7,04---7.71 -qf ,4. q qx., χ 44, At}, 7..70-7.78 pe, 2.H, Ar},. 7,8« Is, 177, Hill .> i;iC RMN (CDC1H, 100 ΜΗ») δ.:: 35.80, 54.3 0, 7:8..21, 110:.25:, 1..22.05:, 173.15, lzH 93, 124.48, 188..12, log, 49, 123,54, 127,71, 128.:22, 12 8,4 2, 12 3.7 3, 12 8.3 7 , 12 9.2 8 , 13 0,2 7, 131 . 50, 1 3 3,1 <,, 13.3... 21, 134.,. 38 , 1B7.30, 14.2 .28, 143.02, 17? . 3j EH (ESI) m/z: 4 47,2: [14; 78 HPLC: Dsxcel Ohlralpzk: IA, n-5,anans/1 - propOFiól :::: 30720, 1.8 nlL/ízin, 210 nx, tempo® de retmtçáo; 35.013 mie: {manor}, 30.00? min (maior). 1-<(1-Benzilo-1H-1,2,3-triazol~4~xlo)metilo)~3~hxdroxi-3~ p ~ toll1i ndolin-2-ona (3)
ardido branco, p. £. .; 5 3 . M. r 5.0 - C. lfit (CDC13, 400 MHz) δ: 2:,30 (s, 3H, CHa) ,. 4..36 Ϊ®, OH, .ClbO ,. 5 > 34---5 . m (q, .7- IS Ife, 2H, CH:;d :, 7.0:2-7198 (!P, 3K, or), 7.14-2.33 in;, lOi-i, 7V;p) , :.ll :s, i H, -CM). ;5C ffi® (CDCOh, 100 MHz) 5: 11.23., 35.79, S 4.34 7 7 >89, 110.2,8, ill. 05, 2 2 3,3 0, 12 4,97 , 12 5,3 0, 122.12, 123.91, 12 9.2 4, 129.11, 2 32* 9 3- 131,09, 1. 31,4 3, 137 . 57 , 132.2-5:, 14 2.1 3, 1 4 3.0 4 . 17 7,4 7 . EM (SSI} m/ z : 41 1 , 2 [Mj-, HPLC: Dalcal Cioiralpak 12, a-lb;aáano/i--p.rcoana'l - 2()/2 0, 1.0 iaL/cVlii, 210 rim, tedpob ole rerraapaa: 221273 cin (denon:/, 2 2.52 0 rp i n. Í f :;a 1 c- e; . 1-((1-Benzilo-lH-l,2,3-triazol-4-xIo)metilo)-3-(4~ bromofenilo)-3-hidroxindolxn-2-ona (4)
Sólido amarelo claro. p,£.== 1 32.1 -153 . CM . ^ MJ (CDCls, 400 MHz) :5c 4,97 (s, 2.M, CBb), 5.38-5.39 lq, .7- 16 Hr, 211, CBnk, 7,05-7.019 it, J-· 8 Hz, Hi, Ar} , 7.16-7.22 (m, 6H, Ar) , 713.1-7.11 (m, 7H, Ar) . i3C RMN (CDCla, 100 MHz) δ: 35.81, 54.4 6, 7 ?. 6 £, 110.32, 12:2:.54, 12 2.. 63:, 124.02, 124.96, 127.29, 12 8.27, 129.0 7, 12 2.3 3 > 130.44, 131 ,0 9, 131.0 9, 12 4:. 3 3 , 13 9 .. 0 3 , 142,10 , 142.9 4 , 170.7 9 . EM (ESI) m/z : 4:7 7.1 [2 ] ; . HELiSi Dalicel Chiral pale 1A, n-hesano/i-propariol - 90/20, .1.0 mllmin, 210 nre, tempos 3 a retaeçâQ.: 2 5.140 ma (meter), 27,453 run (maior 5 . 1-((1-benzilo-lH-l,2,3-triazol-4~ilo)metilo)-3-(4-fluorofenilo)-3~hidroxindolin-2-ana (5)
óleo laranja claro. :ίΗ RMN ( <CD3)2CO, 400 MHz) δ; 4.91-5,07 (q;, ,1= 16 H?; 2H, CH:?), 5.59 is, 2H, CRH, 5-8 9 (a hr, 1M, OHO, 7.61-7.0 6 (m, 3H, Ar) , 7.17-712 2 (rtq 2.H;, Ar) , 7.29-7.35 (m, 6H, Ar), 7.41-7.:4 4 (m, 2H, At), 7.92 (: g/ lip «CH) . i3C RMN ( (CD3)2CO, 100 MHz) δ; 35.39, 54 . 15, 7 7.65, 110.93, 115.46 , 115. ? 6, 12,3.7 5, 123.7 7 , 12 5.36, 12 9.3 3, 12 3,62 , 123.7' :6 , 1.2 9 < 0 4,, 120.6 9, 1 3 0.2 6, 1 3 3., 41. * 13:6 . ? 0 , 13 S , 2 9, 138,32, 143.40,: 143:.57, 1:61.86, 164 .20, 177.03, EM (ESI) m/z: 915.1 |h ] t, HPLC: [laical Chi ralpafc IA, n-Hesarío/í-propanol - 0 07201 1.0 ml/mla , 210 nti, tempos de retenção: 13.673 isln imenorl , 23.127 ml a (maior) . 1- ( (l~Benzilo~lH-l, 2,3-fcriazol-4-ilo) meti Ιο) --3 - - (4 clorofenilo) ~3~hidroxindolin~2 ~ cma. (6)
S1 .1 d o a :-a r e1 o c i a r o . p. f . 14 1 . 4 - I 4 2 . >P C . : H RMN < CDC13 , 400 MBz) δ: 4.08 Os, 211, Cm) , 5.39-3.50 Up 2- 12 .Hm, 211, 22¾} , 2 , .-35-72 89 (t,, U- 8 Ha, 1H, Ãr) , 2,21-7,22 Oa, 8H, Ar) , 7,8:1-1.35 írn, 4H, Ar), 7,41 (s, id, -PH) . i3CRMN (CDC1;5, 100 MHz) δ: 3:3.82, 54.48, 7 7.33, 118,32, 122:.54, 124.0,1, 124.97, 12 6,33,: 123,20, 123,30, 123 > 07 , 123, 3.3-, 138 , 43, 131.14 , 134.33, 1 94,4 5, 138.30, 142.19, .142:. 88, 176.8 7 . EM (ESI) m/z: 431,1 [PU. HPLC: Daicel GHlr.UpaU 171, rv---heoa77o7i- propanol -- 80/20, 1,0 mU/miru 210 nm, t,®mpd3: d® reteapOlo; 20,447 min (nmUorí, 23,687 mim PmiooT). 1- ( (1-Benzilo-lH-l, 2, 3~tria»oX-~4~ilo) xtte-fcilo) -3~kidraxi~3-(4-metoxifeniio)indolín-S-ona (7}
Sólido laranja claro, p.f. === 130.4~I31.827- RMN ((CDs^SO, 400 MHz) δ: 0.71 is, 38, OMe), 4.87--3.712 (q, 2- IS Hz, 2H, Ciia) , 5'. 57 ia,: 2H, C H;8 , 6.68 (a, 1B, 012, 6,82-2.8.4 (d, ,2 8 Hz, 2 H, Ar), 7,01-7,0:4 (t, 1.H, 820, 7..13-7,15 0m, «H, Ar)·, 7.20-7,.37 ms éH, Ari.., 8.10 ia, 1H, ==8:H). i;3C RMN ( <CD3)íSO, 100' MHz) δ * 34,. 31, 82.7 5, 5 8 .1X , 76.60:, 109,40, 11 3.8 0 , 122.77, 123..52,: 124,0.5,. 126.7 4,: 127,87, 128... 16, 126:.76, 129.1:0, 138.13, 138.267 136.03, 142.067 142.31, 158.73, 176,533 EM (ESI) m/z: 427,1 [M]% HPLC: Da.íocl Chiralpa5 10, n-hcaano/i-propanQl - 80/207 1.0 fíiL/ain, 24 0 nm, tempos de retenção: 32.7 67 raia (3::31163) , 38,027 rdn (Palor;, 1- ( {l-Benzilo-lH-l, 2,3~t.riazol-4-i.lo) metilo) ~3-hidroJti-3~ (tiofen-3~ilo)indolin~2~ona (8)
Sólido branco, p.f.- li 7 . B-I 4 8 . 327 . XH RMN (CDCls, 400 MHz) δ.: 4,98 (s:, 211, CH2, 5,38-5.:5.0 tq, 2 1.6 Rp 28, £H?J , 7.06- 7 vr (rvi . ?[-? Άτ) 7 17-3 91 f-m 13 Ar·)· Ί <fi-7 âv (o 7R Ar). 13C BMN (CDC13, 100 MHz) δ: 85.85, 54.43, 75.96, 110.27, 22 2.57, 123.14, 12 3.77, 124,88, 1:25.65, 12 7.06, 12:8,24, -: a ç , -í , i <· a · ,'.:-,: 113 . ,. : 3 ο . < r -3r > 5 , nil, / 6, i n i, 3 a , 143.0:07 17 6.54, EM (ESI) ra/zo 423.1 ill] c HPLC: Da ice 1 CMlalpaC ΙΑ, n-he Sane/1.- prop aro 1 - SO /20, 1.0 ml, 8m in, 210 rip, tempos be retemçâC: 26.960 min (menor), 34.227 8:1.h (raaibr) . 1- { (l-Benzilo-lH-l, 2,3~t.riazol-4-ilo) metilo} ~3~hidroxi~3“ {3 -hidroxifenilo} indalin - 2 *ona (9).
Sólido brsnco, p.f.- / ./.: ··, : : . 10 o . lK RMN < {CD.j) ,sS0, 400 MHd) δ: 4.28:--2,01 (q, 0- lb 2H, CH?) .* 2-57 ( e, 211,, ¢11½¾ , : t b . C'O \b/ .ί / / ( Ο , O b \ f 1 > ,'b 1 , , : · b O )0 > ;‘bl ) , ' , ·, : : ," : : , <-·>') t Λ i } , , , ./.· Ό"' * b .·' ' : b f On, bbl ) , b b ,· 1H t OH; , 9.:11) G.:, 1H, OH). :SC RMN ( <CD3)íSO, 100 MHz) 5: -- * 2b -O f --· O'. ·. V / ··' --V ‘ V·' V' / -2 y ‘o * O; f X. ·χ. ,½. * .0 90 f A Ò Hr » :-ϊ .·' f χ. X y . .·'·' o f A <G,cG < 7 O y
i 3:3.17, lib„ 01, 14 2.13 , 1,4 3., 2 3 , 142.3 9:, '1 57.19 , 1 ? 8 , 3 0 , EM (ESI) m/i: 413,1 ÍMJ O HPLC: Daiool Chiralpak là, noh.exãts,o/ 1,--- 1-(( l-Butilo-lH-l, 2,3-triazol-~4-il0}metxl0} ~3~hxdroxi~3-fenilindolin-2 ~ ana (10}
ό.: fco vs ca re 1 o c i ar o, lB RM» ( (CD.*) sCO, 400 MHz} δ : 0 . 6 8 -0 . 3 j. v f ···' ^ t } / v 3.14.:. » -3 .-:7 0 t --.Κ / > 27 ·; f Λ * * 7' >) ·.!.: t Cl / x.- j jV: ? y .: t ·.-'·* v \ Ο.; λ--’-- y ···'M / \·?Π;· / ‘ ' V ·' '" ··' * 4' -7 s- f v Π ··· y λ Õ / /4 ·' 1 y J- 8 H z , 2::, Dr), 7.8? !s, 12:, -CH) . :!:?C RMN {{CD3};'C0, 100 MH z) δ : 13 , €2, 20 -13, 3 2 . .8 6, 32- 2 3, 30-21, 73, 3 2, 110.3 2 ,· 133,72, 132,20, 143,13, 143.43, 177,23- EM {ESI) m/z: 363,2 [Mj ', HPI..C : Deice! Chi ral pa k ID, n-heOá no/i.-propanol. 30/20, 1- { {1 -Bensilo- 1H-1,2,3-triazol-4~ilo} nietilo) -3~hidroxi~5“ rae tilo-3~ fen i 1 i ndo 1 in-2-ona {II)
3611 do branco, p.f.- 163.7 ~ 1 64.:071 . XH RMN {CDCI;;, 400 MHz} &: 2.2 5 (a, Oil, 2Ho) , 3.44 (a be, 111, Oil), 4,36 !.», 22, 0002), . J: ; , ; , V". ,. , ., > . 0 ; . ..: v.:: ,: w S.S , S- ; , . — Λ , .>> , .ί. M , : .: . ^ 0 RMN {CDCls, 100 MHz) δ: 21.16, 33.36, 14,36, 73.14, 13)9.53, 12 9,25, 13 6.40, 131- 54, 13 3,5 91 X 3 4,4 2, 13 5.71, 14 5,19, 19 3,16, 1 77.32. EM {ESI} m/z: 411.2 [DjO. HFLC: Dai cel nm,. tempos da re tad® Acs 2 4.72 7 mi a , 34..020 ala (malar}... I-({1-Benzilo-lH-l,2,3~triazol~4~ilo)mefcilo)-5-bromo-3-hidroxi-3- feni 1 i ndo I in-2-on a {.12}·
Sólido a :···,:; ao. p . £. 149 31 - 1 0 0.0 "33 !H RM£J (CDC13, 400 MHz) δ: 4. 38-4 093 Id, 16 Hz, 2!lf 302)., 5130-3,47 ml, 10 Ha, 2A, Clfej , 7.00-7.16 id, 3- 3 Η®, 1H, Am7, 7,20-7,21 im., 2H, A a; , 7.20 pa, 4H, Ar] , 7.34 (m, 4M,: Ar) , 7741-7,42 (a:, 2M, A r, -ÇH.) ., 7. B 6 -7.34 it, 7- 0: lid. 111, Id, 0.2 4-0.26 id, d- 3 HZ, Hi, Ari. ;;<C RMN (CDC1,, 100 MHz) 6: 7· 7 . 1'6, .01.40, 7 2.9:2:, 1;]. 1.7 9, 116:.. 3 9, 12 0,02, 12 3.12 , 12:8.2 6, 12 0.71, 12 #:. 0 7 , 12 li. 0 3, 12 9,30, 132.06, 133.62, 134,22, 13 &. ? 6, 1.39 v 3?, 141,1B:, :142 , SO, 17 6., 88., EM (ESI) m/z: 4 7:1,1 [M} *.. U&liC : Da iceI C:hiralpak ΙΑ, ndoemano/i -p-rpp&nol 86220, 1.0 mldmin, 216 am, tempos da retaapdo; 24.347 min 1menor i , 4 7,026 min ima.idxO ,
Abreviaturas :03 PDA Di i soprop i 1 a Pi lamina DMA Dlmati lardtamAda. DMF 0 dme® 1 I f a ra:am i dd DM 3D Od met 21s η11&ido
ee Escasso ard:dtiom:éx'iGO MHG ii quedos carbéhG M-heteróGÍolicos "HM p M- M® 111 p i p e r 1 ei i n a ΤΗΓ Tet rabi d ror tirano t. a . temperatura ãmbiéríte GCF Cromatogratia de Camada idná. RMN Ressonância magnét ica nuclear EH Espectro de massa EGAs Espectro de massa de alta resolução
Referências Π, h. AH, R. Ismail, T, S. Choon, Y. K, Yoon, A., Q, Wê.l>- S* Pandian, A. S. Huraar, 11, Osman, E. Manogarãn, Bioerç. Mèd. €h&m> Lmtt. 2010, 20J 7D64.
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Claims (3)
- REIVINDICÃÇÕES X - C opípe :S t o a goíTí a t X ei d a d e fe X ei5 g 1 ca c cm f: o r m u 1 a (I.) , ae n do que0) aos quads,· R, Bl, ec o rd uepre.ap.ntaaa:: IX, grupos alquile, arile, ciailo, aiilo, a lx:cx ide, halcqáaics Ir, Br, ÇI.) , PH, CP, CHO o CCCH, sd representa cm grupe alquile iinear com 1-€ Parade uca, ara grape- cieieiaaXrXrcalPuilOj eome; r'"i dd O d"? psP .N-A AC ca >·' >f" .,-0., ,.. R . R ..··· \ r> f V í 9 Ç V« X ' N'-R ^ Λ /a ^^ .Av,d ^ ^ >W .......d·...../ '.....N ΛΧ N'R \ .....<d......n-r Vvv« Vytr . iy v- \ / ·...../ Η N C,,c '·'....... '· Η H: c.m grupo exilo eu. ha&êxoarllo, qas inclui, um grupe tanile eadstityide (centaedo aledaidc, .h&Içq&iiiç (F, Br, Cl), OH, C®, CHO, CXXCB) , 2- e i-piridina., piriuddica, pi ri. da a lua a, tief enp, fagána, pi rane, bapeei lp, pi. r rela, Urs grupe Penai lo oti. deriaedo,onda Cd é a lodaido, ha I open i, o CF, Br, Cl), OB, C®, C.HQ e COaix, XO representa up. grupo atilo.
- 2. Geppostoa cds aUieidade drolqqioa cós dorsala il) , que coutes peio mouse us ceatrs quiról e podes ssx obtidos nu topsa dou enarXtidseroK surge, esp adutora erpni quedida op up dos erarpióseros ou usa. rai o tora r a oésice:, t Processe para produção de despcstos dg tórsula il) , oarecter1radoe por tratas anuo de ora eosposto dó tors ui a ; IX ) , es que ,033 E, Rn, rd o Ed .tepresoritapd H, grupos alquilo, siri Io, vintleq asilo, aloésido, dalogéniop \f, Br, Ci) , OH, CXi, CHO d COsp .Pd· representa us prop o alquilo linear coo X-δ car bonds, us g r upo c X cl arde t e t ca l:d o i. lo, doso. íUs grupo ariXo: ou n et o roar il o, quo ineXoi, as grupo fanilo snbetitdido {oootondo: aXeôxldo;, Palogèaio (F, Er, Cd.)í , Ou,· :BH, CHO, CCPBX , X - 0: â~pirl.dina, pX r iíPidina , pi ri da alua, t i o f e no, £ ur ato, p X. r a η o, bend ο X i o, p 1 r r o i e, as grupo bone X Io o o cio ripado.,11 Illlilllill é l|l||ii;|'d.c?íf |h|^||illi|lp|! Br , |ίί,| ΐΦΙΐΙ PPl....................11 '11 11 |0:lll 1Ι|τη Í(P ΰ Tá|ríi iii :;;; 1| 11 jj|r!i p&ira fibililx IPii:çiiiêí·.J;dl:^i;^:Í|:ia;^ll::^vο ίψΐ/ρίψί,§ urn 1 iqaudo, 11 |m|ll|ii;|:|. a;p!'!;i^p:;iiÍia[:áÊ 1^:1 f-e^psi«Uirfl Is a p r. opr i ad a n uma a t in o s f e r a i n e r. t e .
- 4. Processo p'ara produção de compostos de Formula. (1)., de acoxdo com a 3* reinvindacao, car.ac-ter.i-7.a-do pela ucilizagao de urn complexo de ròdio, como por exemplo, ródiο (I) cloroll! 1 , 5-ciciooctadieno) - idipiprollllll ||ί1ί:;£#ΐ!ρ|: ]'|:/| l|:l|l yGffi} .........lill '11^11 fR& í c|§4:} 2c.l j 111 ||>|(%dIoi ll||l 2 e |1 111h Í apÉdlllili}:llllht!llllàrl|.rí|i;|da de: pl|e va r Í4 WWk^^lllllP:|i '& Pills!!!' 5 . lllllllli'essso liit'll $Íb4i&ç4É de 'clftipospos! :4i: lpl||!ia!!iis):..:if :::;:|p:,ssi; acordo corn a 3a reinvináaçrác, caracterizado pela utilização lllliiillllpr ligando, corno por exemplo, 8!NAP, TolBIMAP,..... D1 ϋP, DIPAPIP, D.loxPhos, DeguPhos, Xylyi-F-Phos, {R) -Phanephos, iR)-Shi F, ( R) -SIPH0S, íR, R) -Chiraρh0s, C -TunePh0s, ...............liEllil,M§pPk<lnePh0111 Sy npB|:41|!!|dail||-0 !lll4::i|ll441!!illilp401,l|ll4.ud||i. $c!!§fàl zllfos* .lilnllpls:,.. derivaboSllldb Μ !1||:|:|;0Χ'ά'ΐΤΐ.141(111111:Μbblllpefl: %tW, lies qúl|l|ÍS, d(ísiipd::!!!14ppip::|!:' Bíciclo[2.2.2]octadieno de simetria €2 e ligandos quirals derivados de suif inamida-aioen.o o. ligandos derivados de oxazolina, como: PyBox, Pyrox, Quinox, numa quantidade que ........;.........faria........iittl........|sssgi:'|'lll||||! 11 11111, lll'oo eS'Sqll|a.:| â|p:rl||;ç:| d!.. dq lsiií|p;gp|:p;| êfy dsiss Ji acordo com a 3“ reiuvíndação, caracterirado pela utillzaçàG de uma base, como por exemplo, trietilamina, K2CO··, NarCQv., ..................pi|3y..........|f;|iifls,;.........IpiprWilill k|:|1I, mmm, d||| Ikoi, tFjlllfccIl 111 !!!l! K|;|||;!ll|:uma. 4|4::n|idadell|d|; llllta entre | M | iildlldiilillsll Ti ProcOece p-aía produção do compostos: de formaia {I1 , de acordo com a 3 a rei:rom.nda:eao, car ao ter irado pela: utilização de um soaioante^ cot@: por estsmplo, teljceuP^ éitel: dimettiled, éter dietildco, diocoroetano:, 3'SlF'f 1, imáíocanm, acetona, ame t. o íi: í,1 r i. 1. o, met a η o 1, e t a no 1 r loop r: o p a no i, 1.2 -· dicletdetano, DMF, DMa e NMF, id trocésco para producio de iDOxspdatoa do- formula: (1), de acordo com a 3 a reirru indaga o, oar act eriçado peia utilicaçao de uma temperatura: ma pama de Pd^C c 100 a Cd d . Processe para pí ;.-ducâc de coíapéstoâ1 de formula H), €íB âjCordo com a 3a peingindaçap* car:acterirado: peia ati 1 i rapam: de uma. atmosfera inerte criado por um gáa inerte como por enempio, nitrogénio ou árgon.
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