NO327849B1 - 2-iminopyrrolidin-derivater, deres anvendelse samt farmakologisk preparat - Google Patents

Info

Publication number

NO327849B1

NO327849B1 NO20034632A NO20034632A NO327849B1 NO 327849 B1 NO327849 B1 NO 327849B1 NO 20034632 A NO20034632 A NO 20034632A NO 20034632 A NO20034632 A NO 20034632A NO 327849 B1 NO327849 B1 NO 327849B1

Authority

NO

Norway

Prior art keywords

compound

reaction

solvent

butyl

tert

Prior art date

2001-04-19

Links

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• 238000002360 preparation method Methods 0.000 title claims description 35
• NJBMZYSKLWQXLJ-UHFFFAOYSA-N 3,4-dihydro-2h-pyrrol-5-amine Chemical class NC1=NCCC1 NJBMZYSKLWQXLJ-UHFFFAOYSA-N 0.000 title abstract description 4
• 230000000144 pharmacologic effect Effects 0.000 title description 2
• 150000003839 salts Chemical class 0.000 claims abstract description 34
• 150000001875 compounds Chemical class 0.000 claims description 804
• 238000004519 manufacturing process Methods 0.000 claims description 148
• -1 pyrrolidyl Chemical group 0.000 claims description 102
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 91
• 239000001257 hydrogen Substances 0.000 claims description 79
• 229910052739 hydrogen Inorganic materials 0.000 claims description 79
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 43
• 125000003545 alkoxy group Chemical group 0.000 claims description 26
• 102000003790 Thrombin receptors Human genes 0.000 claims description 20
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
• 108090000166 Thrombin receptors Proteins 0.000 claims description 19
• 229910052736 halogen Inorganic materials 0.000 claims description 18
• 150000002367 halogens Chemical class 0.000 claims description 18
• 210000004027 cell Anatomy 0.000 claims description 15
• 239000003795 chemical substances by application Substances 0.000 claims description 15
• 239000003856 thrombin receptor antagonist Substances 0.000 claims description 13
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 10
• 201000011510 cancer Diseases 0.000 claims description 9
• 102100032341 PCNA-interacting partner Human genes 0.000 claims description 8
• 101710196737 PCNA-interacting partner Proteins 0.000 claims description 8
• 208000007536 Thrombosis Diseases 0.000 claims description 8
• 239000003112 inhibitor Substances 0.000 claims description 8
• 210000000329 smooth muscle myocyte Anatomy 0.000 claims description 8
• 210000002889 endothelial cell Anatomy 0.000 claims description 7
• 230000035755 proliferation Effects 0.000 claims description 7
• 230000002792 vascular Effects 0.000 claims description 7
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
• 210000002950 fibroblast Anatomy 0.000 claims description 6
• 208000037803 restenosis Diseases 0.000 claims description 6
• 206010028980 Neoplasm Diseases 0.000 claims description 5
• 210000000663 muscle cell Anatomy 0.000 claims description 5
• 210000003360 nephrocyte Anatomy 0.000 claims description 5
• 210000004498 neuroglial cell Anatomy 0.000 claims description 5
• 201000008968 osteosarcoma Diseases 0.000 claims description 5
• 125000004043 oxo group Chemical group O=* 0.000 claims description 5
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
• 206010051055 Deep vein thrombosis Diseases 0.000 claims description 4
• 206010018364 Glomerulonephritis Diseases 0.000 claims description 4
• 206010020772 Hypertension Diseases 0.000 claims description 4
• 208000012902 Nervous system disease Diseases 0.000 claims description 4
• 208000025966 Neurological disease Diseases 0.000 claims description 4
• 208000001132 Osteoporosis Diseases 0.000 claims description 4
• 208000010378 Pulmonary Embolism Diseases 0.000 claims description 4
• 206010047249 Venous thrombosis Diseases 0.000 claims description 4
• 208000006673 asthma Diseases 0.000 claims description 4
• 208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 4
• 208000019622 heart disease Diseases 0.000 claims description 4
• 208000027866 inflammatory disease Diseases 0.000 claims description 4
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
• DLTOJMSKWYCCDR-UHFFFAOYSA-N 1-(3-tert-butyl-4-methoxy-5-piperazin-1-ylphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1h-isoindol-2-yl)ethanone;dihydrochloride Chemical compound Cl.Cl.N=C1C=2C(F)=C(OCC)C(OCC)=CC=2CN1CC(=O)C(C=C(C=1OC)C(C)(C)C)=CC=1N1CCNCC1 DLTOJMSKWYCCDR-UHFFFAOYSA-N 0.000 claims description 3
• 230000002776 aggregation Effects 0.000 claims description 3
• 238000004220 aggregation Methods 0.000 claims description 3
• 239000005557 antagonist Substances 0.000 claims description 3
• 229940127218 antiplatelet drug Drugs 0.000 claims description 3
• 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 3
• 230000003449 preventive effect Effects 0.000 claims description 3
• 239000002464 receptor antagonist Substances 0.000 claims description 3
• 229940044551 receptor antagonist Drugs 0.000 claims description 3
• 230000001225 therapeutic effect Effects 0.000 claims description 3
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
• 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 2
• UNMBLVOFOAGGCG-UHFFFAOYSA-N 1-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1h-isoindol-2-yl)ethanone;hydrobromide Chemical compound Br.N=C1C=2C(F)=C(OCC)C(OCC)=CC=2CN1CC(=O)C(C=C(C=1OC)C(C)(C)C)=CC=1N1CCOCC1 UNMBLVOFOAGGCG-UHFFFAOYSA-N 0.000 claims description 2
• DRKSEQYPXLAOCN-UHFFFAOYSA-N 1-[3-tert-butyl-5-[4-(2-hydroxyacetyl)piperazin-1-yl]-4-methoxyphenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1h-isoindol-2-yl)ethanone;hydrobromide Chemical compound Br.N=C1C=2C(F)=C(OCC)C(OCC)=CC=2CN1CC(=O)C(C=C(C=1OC)C(C)(C)C)=CC=1N1CCN(C(=O)CO)CC1 DRKSEQYPXLAOCN-UHFFFAOYSA-N 0.000 claims description 2
• UUHSJXNGSZYRKE-UHFFFAOYSA-N 2-[4-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1h-isoindol-2-yl)acetyl]-2-methoxyphenyl]piperazin-1-yl]acetic acid;dihydrochloride Chemical compound Cl.Cl.N=C1C=2C(F)=C(OCC)C(OCC)=CC=2CN1CC(=O)C(C=C(C=1OC)C(C)(C)C)=CC=1N1CCN(CC(O)=O)CC1 UUHSJXNGSZYRKE-UHFFFAOYSA-N 0.000 claims description 2
• JSBBMMHTNIUVTC-UHFFFAOYSA-N 2-hydroxyethanone Chemical group OC[C]=O JSBBMMHTNIUVTC-UHFFFAOYSA-N 0.000 claims description 2
• 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims description 2
• 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims description 2
• 125000004069 aziridinyl group Chemical group 0.000 claims description 2
• 125000002883 imidazolyl group Chemical group 0.000 claims description 2
• 125000005880 oxathiolanyl group Chemical group 0.000 claims description 2
• 125000000466 oxiranyl group Chemical group 0.000 claims description 2
• 125000005545 phthalimidyl group Chemical group 0.000 claims description 2
• 125000005936 piperidyl group Chemical group 0.000 claims description 2
• 125000005494 pyridonyl group Chemical group 0.000 claims description 2
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
• 125000005195 alkyl amino carbonyloxy group Chemical group 0.000 claims 1
• 208000010125 myocardial infarction Diseases 0.000 claims 1
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 abstract description 2
• JKPOPBAIEHSKDF-UHFFFAOYSA-N 1-(3-tert-butyl-4-methoxy-5-piperazin-1-ylphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1h-isoindol-2-yl)ethanone Chemical compound N=C1C=2C(F)=C(OCC)C(OCC)=CC=2CN1CC(=O)C(C=C(C=1OC)C(C)(C)C)=CC=1N1CCNCC1 JKPOPBAIEHSKDF-UHFFFAOYSA-N 0.000 abstract 1
• MCSPUQNLRAUDSC-UHFFFAOYSA-N 2-[4-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1h-isoindol-2-yl)acetyl]-2-methoxyphenyl]piperazin-1-yl]acetic acid Chemical compound N=C1C=2C(F)=C(OCC)C(OCC)=CC=2CN1CC(=O)C(C=C(C=1OC)C(C)(C)C)=CC=1N1CCN(CC(O)=O)CC1 MCSPUQNLRAUDSC-UHFFFAOYSA-N 0.000 abstract 1
• QWKAUGRRIXBIPO-UHFFFAOYSA-N Atopaxar Chemical compound N=C1C=2C(F)=C(OCC)C(OCC)=CC=2CN1CC(=O)C(C=C(C=1OC)C(C)(C)C)=CC=1N1CCOCC1 QWKAUGRRIXBIPO-UHFFFAOYSA-N 0.000 abstract 1
• MLZNVXAZRKOMGP-UHFFFAOYSA-N ethyl 2-[4-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1h-isoindol-2-yl)acetyl]-2-methoxyphenyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1C1=CC(C(=O)CN2C(C3=C(F)C(OCC)=C(OCC)C=C3C2)=N)=CC(C(C)(C)C)=C1OC MLZNVXAZRKOMGP-UHFFFAOYSA-N 0.000 abstract 1
• 238000006243 chemical reaction Methods 0.000 description 531
• 239000002904 solvent Substances 0.000 description 238
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 224
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 189
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 169
• 238000000034 method Methods 0.000 description 162
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 152
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 123
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
• 239000000203 mixture Substances 0.000 description 104
• WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 92
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 87
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 86
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
• 125000000547 substituted alkyl group Chemical group 0.000 description 79
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 78
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 75
• 235000019441 ethanol Nutrition 0.000 description 73
• 230000002829 reductive effect Effects 0.000 description 62
• 125000001424 substituent group Chemical group 0.000 description 62
• 238000001308 synthesis method Methods 0.000 description 61
• 238000005160 1H NMR spectroscopy Methods 0.000 description 56
• 239000000243 solution Substances 0.000 description 56
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 52
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 49
• 239000011541 reaction mixture Substances 0.000 description 47
• 238000010898 silica gel chromatography Methods 0.000 description 47
• 101150041968 CDC13 gene Proteins 0.000 description 46
• 238000010992 reflux Methods 0.000 description 46
• 229910001868 water Inorganic materials 0.000 description 46
• 125000000217 alkyl group Chemical group 0.000 description 43
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
• 239000012044 organic layer Substances 0.000 description 39
• 229910000027 potassium carbonate Inorganic materials 0.000 description 39
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 38
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 37
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 37
• 238000010438 heat treatment Methods 0.000 description 37
• 230000029936 alkylation Effects 0.000 description 36
• 238000005804 alkylation reaction Methods 0.000 description 36
• 238000001816 cooling Methods 0.000 description 35
• 239000013078 crystal Chemical group 0.000 description 34
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
• 239000012267 brine Substances 0.000 description 33
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
• 239000002585 base Substances 0.000 description 32
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 30
• 150000002431 hydrogen Chemical class 0.000 description 29
• 239000003153 chemical reaction reagent Substances 0.000 description 27
• 238000006722 reduction reaction Methods 0.000 description 27
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 26
• 239000012312 sodium hydride Substances 0.000 description 26
• 229910000104 sodium hydride Inorganic materials 0.000 description 26
• 239000004743 Polypropylene Substances 0.000 description 25
• 238000003786 synthesis reaction Methods 0.000 description 25
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
• 230000015572 biosynthetic process Effects 0.000 description 24
• 238000000605 extraction Methods 0.000 description 24
• 230000002194 synthesizing effect Effects 0.000 description 24
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 23
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 23
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
• 125000005415 substituted alkoxy group Chemical group 0.000 description 23
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
• 150000002148 esters Chemical class 0.000 description 22
• 230000009467 reduction Effects 0.000 description 22
• 108090000190 Thrombin Proteins 0.000 description 21
• 239000003921 oil Substances 0.000 description 21
• 235000019198 oils Nutrition 0.000 description 21
• 238000003756 stirring Methods 0.000 description 21
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 20
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 19
• 239000007787 solid Substances 0.000 description 19
• 229960004072 thrombin Drugs 0.000 description 19
• 239000003054 catalyst Substances 0.000 description 18
• ISWNAMNOYHCTSB-UHFFFAOYSA-N methanamine;hydrobromide Chemical compound [Br-].[NH3+]C ISWNAMNOYHCTSB-UHFFFAOYSA-N 0.000 description 17
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 17
• 239000012046 mixed solvent Substances 0.000 description 17
• 125000006239 protecting group Chemical group 0.000 description 17
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 17
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 17
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 16
• VFHWCZMTMRVBAN-UHFFFAOYSA-N acetaldehyde hydrobromide Chemical compound Br.CC=O VFHWCZMTMRVBAN-UHFFFAOYSA-N 0.000 description 16
• 125000003277 amino group Chemical group 0.000 description 16
• 239000000706 filtrate Substances 0.000 description 16
• 230000003647 oxidation Effects 0.000 description 15
• 238000007254 oxidation reaction Methods 0.000 description 15
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 15
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
• 230000009435 amidation Effects 0.000 description 14
• 238000007112 amidation reaction Methods 0.000 description 14
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 14
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 13
• 150000001350 alkyl halides Chemical class 0.000 description 13
• 150000001412 amines Chemical class 0.000 description 13
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 13
• 229910052794 bromium Inorganic materials 0.000 description 13
• 230000000694 effects Effects 0.000 description 13
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
• 239000000843 powder Substances 0.000 description 13
• 239000012279 sodium borohydride Substances 0.000 description 13
• 229910000033 sodium borohydride Inorganic materials 0.000 description 13
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
• DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 12
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 12
• 238000005893 bromination reaction Methods 0.000 description 12
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 12
• 229910000024 caesium carbonate Inorganic materials 0.000 description 12
• 230000003197 catalytic effect Effects 0.000 description 12
• 238000006138 lithiation reaction Methods 0.000 description 12
• 150000003222 pyridines Chemical class 0.000 description 12
• 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 12
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 11
• 230000031709 bromination Effects 0.000 description 11
• 125000000753 cycloalkyl group Chemical group 0.000 description 11
• 238000010511 deprotection reaction Methods 0.000 description 11
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 11
• 229910052757 nitrogen Inorganic materials 0.000 description 11
• 239000007858 starting material Substances 0.000 description 11
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 10
• 229910052731 fluorine Inorganic materials 0.000 description 10
• 239000010410 layer Substances 0.000 description 10
• 239000003960 organic solvent Substances 0.000 description 10
• 229910052763 palladium Inorganic materials 0.000 description 10
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
• 239000005909 Kieselgur Substances 0.000 description 9
• GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 9
• 125000002252 acyl group Chemical group 0.000 description 9
• 150000001408 amides Chemical class 0.000 description 9
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
• 150000003857 carboxamides Chemical class 0.000 description 9
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 9
• 239000005457 ice water Substances 0.000 description 9
• 239000000543 intermediate Substances 0.000 description 9
• UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 9
• 230000009466 transformation Effects 0.000 description 9
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
• 150000001299 aldehydes Chemical class 0.000 description 8
• YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 8
• 230000032050 esterification Effects 0.000 description 8
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• 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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• DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
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• 238000011426 transformation method Methods 0.000 description 1
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• STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 description 1
• 230000001960 triggered effect Effects 0.000 description 1
• WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
• JGWFUSVYECJQDT-UHFFFAOYSA-N trimethyl(2-trimethylsilyloxyethoxy)silane Chemical compound C[Si](C)(C)OCCO[Si](C)(C)C JGWFUSVYECJQDT-UHFFFAOYSA-N 0.000 description 1
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• IARSSOVWSJAVSZ-UHFFFAOYSA-N tris(dimethylamino)sulfanium Chemical compound CN(C)[S+](N(C)C)N(C)C IARSSOVWSJAVSZ-UHFFFAOYSA-N 0.000 description 1
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• GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
• 239000002076 α-tocopherol Substances 0.000 description 1
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