EA038744B1 - 3-ЗАМЕЩЕННЫЕ 5-АМИНО-6H-ТИАЗОЛО[4,5-d]ПИРИМИДИН-2,7-ДИОНОВЫЕ СОЕДИНЕНИЯ, ОБЛАДАЮЩИЕ АГОНИСТИЧЕСКОЙ АКТИВНОСТЬЮ В ОТНОШЕНИИ TOLL-ПОДОБНОГО РЕЦЕПТОРА TLR7, ДЛЯ ЛЕЧЕНИЯ И ПРОФИЛАКТИКИ ВИРУСНЫХ ИНФЕКЦИЙ - Google Patents

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Publication number

EA038744B1

EA038744B1 EA201791011A EA201791011A EA038744B1 EA 038744 B1 EA038744 B1 EA 038744B1 EA 201791011 A EA201791011 A EA 201791011A EA 201791011 A EA201791011 A EA 201791011A EA 038744 B1 EA038744 B1 EA 038744B1

Authority

EA

Eurasian Patent Office

Prior art keywords

amino

thiazolo

tetrahydrofuran

pyrimidine

hydroxy

Prior art date

2014-12-08

Links

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• 230000000694 effects Effects 0.000 title claims abstract description 13
• -1 3-SUBSTITUTED 5-AMINO-6H-THIAZOLO[4,5-d]PYRIMIDINE-2,7-DIONE COMPOUNDS Chemical class 0.000 title claims description 170
• 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 title abstract description 23
• 102100039390 Toll-like receptor 7 Human genes 0.000 title abstract description 21
• 230000008484 agonism Effects 0.000 title abstract 2
• 238000011282 treatment Methods 0.000 title description 35
• 208000015181 infectious disease Diseases 0.000 title description 9
• 241000700605 Viruses Species 0.000 title description 4
• 238000011321 prophylaxis Methods 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 330
• 150000003839 salts Chemical class 0.000 claims abstract description 49
• 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 claims abstract description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
• 239000013543 active substance Substances 0.000 claims abstract description 5
• 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 85
• 239000001257 hydrogen Substances 0.000 claims description 39
• 229910052739 hydrogen Inorganic materials 0.000 claims description 39
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 36
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 34
• 125000000217 alkyl group Chemical group 0.000 claims description 33
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 31
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 25
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 24
• HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 claims description 23
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 18
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 18
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
• 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 claims description 14
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 14
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 14
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 14
• 229920002554 vinyl polymer Polymers 0.000 claims description 14
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 9
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 9
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 9
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
• VWMOKZVZPAXOGK-CWWJLMTASA-N 5-amino-3-[(2R,3R,5S)-5-[cyclopentyl(hydroxy)methyl]-3-hydroxyoxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(O)C1CCCC1)=O VWMOKZVZPAXOGK-CWWJLMTASA-N 0.000 claims description 7
• ONQSMTMFFXEKNN-MOEZTCPLSA-N [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxyoxolan-2-yl]propyl] acetate Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@H]1[C@@H](C[C@H](O1)[C@H](CC)OC(C)=O)O)=O ONQSMTMFFXEKNN-MOEZTCPLSA-N 0.000 claims description 7
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
• 239000000556 agonist Substances 0.000 claims description 7
• FYYAXSGIFXZSLJ-DQSPEZDDSA-N (2R,3S,5S)-2-(5-amino-2,7-dioxo-6H-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)oxolane-3-carbonitrile Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1C#N)CO)=O FYYAXSGIFXZSLJ-DQSPEZDDSA-N 0.000 claims description 6
• HLRVJBJIXWVBPC-BAJZRUMYSA-N N-[(2R,3R,5S)-2-(5-amino-2,7-dioxo-6H-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)oxolan-3-yl]acetamide Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1NC(C)=O)CO)=O HLRVJBJIXWVBPC-BAJZRUMYSA-N 0.000 claims description 6
• FIJZDCCBNWALLX-OBXARNEKSA-N N-[(2R,3R,5S)-2-(5-amino-2,7-dioxo-6H-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)oxolan-3-yl]methanesulfonamide Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1NS(=O)(=O)C)CO)=O FIJZDCCBNWALLX-OBXARNEKSA-N 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 125000001544 thienyl group Chemical group 0.000 claims description 6
• BAPUBUNRCUYTJG-RUFHJGMRSA-N C[C@H](O)[C@@H]1C[C@@H](C)[C@@H](O1)N1C(=O)SC2C1=NC(N)=NC2=O Chemical compound C[C@H](O)[C@@H]1C[C@@H](C)[C@@H](O1)N1C(=O)SC2C1=NC(N)=NC2=O BAPUBUNRCUYTJG-RUFHJGMRSA-N 0.000 claims description 5
• YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 5
• 229940090181 propyl acetate Drugs 0.000 claims description 5
• GEVVIXVISDEXBL-JOAULVNJSA-N 5-amino-3-[(2R,3R,5S)-5-(hydroxymethyl)-3-pyrrolidin-1-yloxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1N1CCCC1)CO)=O GEVVIXVISDEXBL-JOAULVNJSA-N 0.000 claims description 4
• ZMTKCUWAZUIQSB-TZVDFBJISA-N 5-amino-3-[(2R,3R,5S)-5-[cyclopropyl(hydroxy)methyl]-3-hydroxyoxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(O)C1CC1)=O ZMTKCUWAZUIQSB-TZVDFBJISA-N 0.000 claims description 4
• 108010060825 Toll-Like Receptor 7 Proteins 0.000 claims description 4
• 102000008236 Toll-Like Receptor 7 Human genes 0.000 claims description 4
• XDFJFHCSLJOEFB-MRCNFZFLSA-N [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxyoxolan-2-yl]propyl] 2-methylpropanoate Chemical compound CC(C(=O)O[C@@H](CC)[C@H]1O[C@H]([C@@H](C1)O)N1C(SC2=C1N=C(NC2=O)N)=O)C XDFJFHCSLJOEFB-MRCNFZFLSA-N 0.000 claims description 4
• CSCCBXFBWDXYLV-BAJZRUMYSA-N 5-amino-3-[(2R,3R,5S)-3-(2-fluoropropan-2-yl)-5-(hydroxymethyl)oxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1C(C)(C)F)CO)=O CSCCBXFBWDXYLV-BAJZRUMYSA-N 0.000 claims description 3
• RLLOHXQIPZNMEJ-GHPRUCIASA-N 5-amino-3-[(2R,3R,5S)-3-azido-5-(1-hydroxypropyl)oxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1N=[N+]=[N-])C(CC)O)=O RLLOHXQIPZNMEJ-GHPRUCIASA-N 0.000 claims description 3
• VLMYBVQWGNHTKE-GHPRUCIASA-N 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-(1-hydroxy-2-methoxyethyl)oxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(COC)O)=O VLMYBVQWGNHTKE-GHPRUCIASA-N 0.000 claims description 3
• AVQFGCZUSKVJKK-YNVXMBFESA-N 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-(1-hydroxypropyl)oxolan-2-yl]-[1,3]thiazolo[4,5-d]pyrimidin-2-one Chemical compound NC=1N=CC2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(CC)O AVQFGCZUSKVJKK-YNVXMBFESA-N 0.000 claims description 3
• ITEJEZHUERWUHO-HSGQIBGNSA-N 5-amino-3-[(2R,3R,5S)-5-(1-hydroxypropyl)-3-methylsulfanyloxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1SC)C(CC)O)=O ITEJEZHUERWUHO-HSGQIBGNSA-N 0.000 claims description 3
• DAXWDTFMGNGWDN-MPGRNQODSA-N [(2R,3R,5S)-2-(5-amino-2-oxo-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-5-(1-hydroxypropyl)oxolan-3-yl] acetate Chemical compound CCC(O)[C@@H]1C[C@@H](OC(C)=O)[C@@H](O1)N1C(=O)SC2=C1N=C(N)N=C2 DAXWDTFMGNGWDN-MPGRNQODSA-N 0.000 claims description 3
• ZYPFNBPDNCWMMN-UPBCOZELSA-N [(S)-[(2S,4R,5R)-5-(5-amino-2-oxo-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxyoxolan-2-yl]-cyclopropylmethyl] acetate Chemical compound NC=1N=CC2=C(N=1)N(C(S2)=O)[C@H]1[C@@H](C[C@H](O1)[C@H](C1CC1)OC(C)=O)O ZYPFNBPDNCWMMN-UPBCOZELSA-N 0.000 claims description 3
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
• 150000002431 hydrogen Chemical class 0.000 claims description 3
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
• BBAITXSLHSPQQE-OPMNTLCASA-N 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-(1-hydroxyethyl)oxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(C)O)=O BBAITXSLHSPQQE-OPMNTLCASA-N 0.000 claims description 2
• RFHAKLORKVEFPL-XWXUBSDMSA-N 5-amino-3-[(2R,3R,5S)-5-[cyclopropyl(hydroxy)methyl]-3-hydroxyoxolan-2-yl]-[1,3]thiazolo[4,5-d]pyrimidin-2-one Chemical compound NC=1N=CC2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(O)C1CC1 RFHAKLORKVEFPL-XWXUBSDMSA-N 0.000 claims description 2
• ZCJZGIGROVUOPX-RTRLNWJGSA-N [(2R,3R,5S)-2-(5-amino-2,7-dioxo-6H-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-5-(1-hydroxypropyl)oxolan-3-yl] acetate Chemical compound CCC(O)[C@@H]1C[C@@H](OC(C)=O)[C@@H](O1)N1C(=O)SC2=C1N=C(N)NC2=O ZCJZGIGROVUOPX-RTRLNWJGSA-N 0.000 claims description 2
• UEOONJPGATTXIY-CWWJLMTASA-N [[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxyoxolan-2-yl]-cyclopropylmethyl] acetate Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@H]1[C@@H](C[C@H](O1)C(C1CC1)OC(C)=O)O)=O UEOONJPGATTXIY-CWWJLMTASA-N 0.000 claims description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
• RBBVFTMXRGQVLB-JHMXTYEHSA-N 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-(1-hydroxyprop-2-ynyl)oxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(C#C)O)=O RBBVFTMXRGQVLB-JHMXTYEHSA-N 0.000 claims 2
• SIFTXVZNXXHTES-OBXARNEKSA-N 5-amino-3-[(2R,3R,5S)-5-(hydroxymethyl)-3-methylsulfanyloxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1SC)CO)=O SIFTXVZNXXHTES-OBXARNEKSA-N 0.000 claims 2
• PHEUKDFCZMUHJE-MOEZTCPLSA-N 5-amino-3-[(2R,3R,5S)-5-[(1S)-1-hydroxybut-2-ynyl]-3-methyloxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1C)[C@H](C#CC)O)=O PHEUKDFCZMUHJE-MOEZTCPLSA-N 0.000 claims 2
• CJXQWQPKUPDFBA-IZRASGFBSA-N 5-amino-3-[(2R,3R,5S)-5-[(S)-cyclopropyl(hydroxy)methyl]-3-methyloxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1C)[C@@H](O)C1CC1)=O CJXQWQPKUPDFBA-IZRASGFBSA-N 0.000 claims 2
• BTRQBSPYFHKFKC-UFFDXJJYSA-N 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-(1-hydroxy-2-phenylethyl)oxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(CC1=CC=CC=C1)O)=O BTRQBSPYFHKFKC-UFFDXJJYSA-N 0.000 claims 1
• RPTVVEXHXBYUJC-IPQYHECASA-N 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-(1-hydroxy-3-methylbutyl)oxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(CC(C)C)O)=O RPTVVEXHXBYUJC-IPQYHECASA-N 0.000 claims 1
• TZUYSXKALNLZMX-DFODGGNXSA-N 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-[hydroxy(thiophen-2-yl)methyl]oxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(C=1SC=CC=1)O)=O TZUYSXKALNLZMX-DFODGGNXSA-N 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 242
• 239000000243 solution Substances 0.000 description 196
• 238000001819 mass spectrum Methods 0.000 description 124
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
• 235000019439 ethyl acetate Nutrition 0.000 description 120
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 109
• 239000000203 mixture Substances 0.000 description 88
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 82
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 78
• 238000002360 preparation method Methods 0.000 description 73
• 239000012044 organic layer Substances 0.000 description 72
• 238000005160 1H NMR spectroscopy Methods 0.000 description 64
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 63
• 239000000741 silica gel Substances 0.000 description 63
• 229910002027 silica gel Inorganic materials 0.000 description 63
• 239000007787 solid Substances 0.000 description 61
• 238000004440 column chromatography Methods 0.000 description 59
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 54
• 239000011541 reaction mixture Substances 0.000 description 54
• 239000003208 petroleum Substances 0.000 description 53
• 239000011734 sodium Substances 0.000 description 49
• 238000002953 preparative HPLC Methods 0.000 description 48
• WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 45
• 229920006395 saturated elastomer Polymers 0.000 description 45
• 239000012267 brine Substances 0.000 description 39
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 37
• 241000700721 Hepatitis B virus Species 0.000 description 35
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 30
• 238000005481 NMR spectroscopy Methods 0.000 description 29
• 238000006243 chemical reaction Methods 0.000 description 29
• 239000012043 crude product Substances 0.000 description 29
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 28
• 238000000746 purification Methods 0.000 description 28
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 24
• 238000003756 stirring Methods 0.000 description 23
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 22
• 239000000651 prodrug Substances 0.000 description 22
• 229940002612 prodrug Drugs 0.000 description 22
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
• 239000002904 solvent Substances 0.000 description 18
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
• 210000004027 cell Anatomy 0.000 description 17
• 239000000460 chlorine Substances 0.000 description 17
• 239000003921 oil Substances 0.000 description 17
• FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 17
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• BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
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• CYIUFVYZGOCGEV-UHFFFAOYSA-N tributyl(2-methylprop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC(C)=C CYIUFVYZGOCGEV-UHFFFAOYSA-N 0.000 description 1
• YLGRTLMDMVAFNI-UHFFFAOYSA-N tributyl(prop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC=C YLGRTLMDMVAFNI-UHFFFAOYSA-N 0.000 description 1
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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• GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
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