HUT67288A - Process for producing cyclic imino derivatives and pharmaceutical compositions comprising them - Google Patents

Info

Publication number

HUT67288A

HUT67288A HU913455A HU345591A HUT67288A HU T67288 A HUT67288 A HU T67288A HU 913455 A HU913455 A HU 913455A HU 345591 A HU345591 A HU 345591A HU T67288 A HUT67288 A HU T67288A

Authority

HU

Hungary

Prior art keywords

group

formula

compound

pyrrolidinone

methyl

Prior art date

1990-11-02

Links

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• Global Dossier
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• 238000000034 method Methods 0.000 title claims abstract description 18
• 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
• 230000008569 process Effects 0.000 title abstract description 8
• 150000001875 compounds Chemical class 0.000 claims abstract description 202
• 150000003839 salts Chemical class 0.000 claims abstract description 32
• 238000002360 preparation method Methods 0.000 claims abstract description 23
• 150000007524 organic acids Chemical class 0.000 claims abstract description 7
• 150000007522 mineralic acids Chemical class 0.000 claims abstract description 6
• -1 phenylsulfenyl Chemical group 0.000 claims description 330
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 184
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 77
• 229910052757 nitrogen Inorganic materials 0.000 claims description 64
• 125000000217 alkyl group Chemical group 0.000 claims description 60
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 52
• 239000002253 acid Substances 0.000 claims description 49
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 39
• 239000011541 reaction mixture Substances 0.000 claims description 38
• 125000003545 alkoxy group Chemical group 0.000 claims description 37
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 36
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 35
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 32
• 238000006243 chemical reaction Methods 0.000 claims description 29
• HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 28
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 27
• 239000001257 hydrogen Substances 0.000 claims description 26
• 229910052739 hydrogen Inorganic materials 0.000 claims description 26
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 23
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 23
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 23
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 19
• 125000003277 amino group Chemical group 0.000 claims description 19
• 239000000460 chlorine Substances 0.000 claims description 19
• 229910052801 chlorine Inorganic materials 0.000 claims description 17
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 17
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 16
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
• 239000002585 base Substances 0.000 claims description 16
• 229910052717 sulfur Inorganic materials 0.000 claims description 16
• 150000002148 esters Chemical class 0.000 claims description 15
• 229910052760 oxygen Inorganic materials 0.000 claims description 15
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 14
• 239000001301 oxygen Substances 0.000 claims description 14
• 125000002947 alkylene group Chemical group 0.000 claims description 13
• 125000003118 aryl group Chemical group 0.000 claims description 13
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 13
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 13
• 230000009467 reduction Effects 0.000 claims description 13
• 238000005917 acylation reaction Methods 0.000 claims description 12
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
• 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 12
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
• 230000010933 acylation Effects 0.000 claims description 11
• 125000004647 alkyl sulfenyl group Chemical group 0.000 claims description 11
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
• 150000001721 carbon Chemical group 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000004432 carbon atom Chemical group C* 0.000 claims description 11
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 10
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
• 229910052794 bromium Inorganic materials 0.000 claims description 10
• 125000005842 heteroatom Chemical group 0.000 claims description 10
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 9
• 150000001412 amines Chemical class 0.000 claims description 9
• 125000004122 cyclic group Chemical group 0.000 claims description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 9
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
• 125000001424 substituent group Chemical group 0.000 claims description 9
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
• 125000003282 alkyl amino group Chemical group 0.000 claims description 8
• 239000011737 fluorine Substances 0.000 claims description 8
• 229910052731 fluorine Inorganic materials 0.000 claims description 8
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 8
• 239000011593 sulfur Substances 0.000 claims description 8
• 125000002252 acyl group Chemical group 0.000 claims description 7
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 7
• 230000029936 alkylation Effects 0.000 claims description 7
• 238000005804 alkylation reaction Methods 0.000 claims description 7
• 125000004467 aryl imino group Chemical group 0.000 claims description 7
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
• 125000004185 ester group Chemical group 0.000 claims description 7
• 150000003951 lactams Chemical group 0.000 claims description 7
• 125000004957 naphthylene group Chemical group 0.000 claims description 7
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 7
• 125000006239 protecting group Chemical group 0.000 claims description 7
• HMXQIFUGFZEJEO-UHFFFAOYSA-N 1,2-dihydropyrrol-3-one Chemical group O=C1CNC=C1 HMXQIFUGFZEJEO-UHFFFAOYSA-N 0.000 claims description 6
• KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 6
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 6
• 239000005977 Ethylene Substances 0.000 claims description 6
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 6
• 125000005277 alkyl imino group Chemical group 0.000 claims description 6
• 150000001408 amides Chemical class 0.000 claims description 6
• 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 6
• 238000007327 hydrogenolysis reaction Methods 0.000 claims description 6
• 230000007062 hydrolysis Effects 0.000 claims description 6
• 238000006460 hydrolysis reaction Methods 0.000 claims description 6
• 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 6
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
• 229920002554 vinyl polymer Polymers 0.000 claims description 6
• 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 5
• OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
• 229910052783 alkali metal Inorganic materials 0.000 claims description 5
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 5
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
• 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 5
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 5
• 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 5
• ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 5
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
• 125000005835 indanylene group Chemical group 0.000 claims description 5
• 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 5
• 230000003647 oxidation Effects 0.000 claims description 5
• 238000007254 oxidation reaction Methods 0.000 claims description 5
• 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 5
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
• 125000006828 (C2-C7) alkoxycarbonyl group Chemical group 0.000 claims description 4
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
• 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 description 4
• 125000001931 aliphatic group Chemical group 0.000 claims description 4
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
• 150000001409 amidines Chemical class 0.000 claims description 4
• 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 claims description 4
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
• 125000001246 bromo group Chemical group Br* 0.000 claims description 4
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 125000005567 fluorenylene group Chemical group 0.000 claims description 4
• 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 4
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
• 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 claims description 4
• 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 4
• 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 4
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
• 125000002071 phenylalkoxy group Chemical group 0.000 claims description 4
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
• 238000006277 sulfonation reaction Methods 0.000 claims description 4
• 238000001149 thermolysis Methods 0.000 claims description 4
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
• MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
• 238000010306 acid treatment Methods 0.000 claims description 3
• 150000001340 alkali metals Chemical class 0.000 claims description 3
• 125000004414 alkyl thio group Chemical group 0.000 claims description 3
• 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 3
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 3
• 230000015572 biosynthetic process Effects 0.000 claims description 3
• 239000004305 biphenyl Substances 0.000 claims description 3
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
• 230000032050 esterification Effects 0.000 claims description 3
• 238000005886 esterification reaction Methods 0.000 claims description 3
• 125000005560 phenanthrenylene group Chemical group 0.000 claims description 3
• 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 3
• 125000004434 sulfur atom Chemical group 0.000 claims description 3
• 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 2
• LLIULJSIRLAGTK-UHFFFAOYSA-N CC1C(N(CC1)CCCC1=CC=CC=C1)=O Chemical compound CC1C(N(CC1)CCCC1=CC=CC=C1)=O LLIULJSIRLAGTK-UHFFFAOYSA-N 0.000 claims description 2
• 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
• XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 2
• 238000000297 Sandmeyer reaction Methods 0.000 claims description 2
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
• 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
• 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 2
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 2
• 125000002431 aminoalkoxy group Chemical group 0.000 claims description 2
• 125000005121 aminocarbonylalkoxy group Chemical group 0.000 claims description 2
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
• 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 2
• 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
• 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
• 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
• 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
• 238000006114 decarboxylation reaction Methods 0.000 claims description 2
• 125000005805 dimethoxy phenyl group Chemical group 0.000 claims description 2
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
• 125000004997 halocarbonyl group Chemical group 0.000 claims description 2
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
• 125000004076 pyridyl group Chemical group 0.000 claims description 2
• 230000002829 reductive effect Effects 0.000 claims description 2
• 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 2
• 150000003568 thioethers Chemical class 0.000 claims description 2
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
• ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims 1
• RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical group C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 claims 1
• XOGSILNRNDISMC-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C=C1)C1=CC=C(C=C1)OCN1C(C(CC1)CC(=O)O)=O Chemical compound C(N)(=N)C1=CC=C(C=C1)C1=CC=C(C=C1)OCN1C(C(CC1)CC(=O)O)=O XOGSILNRNDISMC-UHFFFAOYSA-N 0.000 claims 1
• OYDDSGPBMVDMJQ-UHFFFAOYSA-N [1-(1-carbamimidoyl-4-phenylcyclohexa-2,4-dien-1-yl)-5-oxopyrrolidin-3-yl]methylphosphonic acid Chemical compound C(N)(=N)C1(CC=C(C=C1)C1=CC=CC=C1)N1C(CC(C1)CP(=O)(O)O)=O OYDDSGPBMVDMJQ-UHFFFAOYSA-N 0.000 claims 1
• DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims 1
• 150000001342 alkaline earth metals Chemical class 0.000 claims 1
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
• 239000000969 carrier Substances 0.000 claims 1
• 230000001413 cellular effect Effects 0.000 claims 1
• 235000019788 craving Nutrition 0.000 claims 1
• 125000002993 cycloalkylene group Chemical group 0.000 claims 1
• ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 1
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims 1
• XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical group O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims 1
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
• WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims 1
• ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Chemical group C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 claims 1
• BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
• 230000002776 aggregation Effects 0.000 abstract description 5
• 238000004220 aggregation Methods 0.000 abstract description 5
• 235000005985 organic acids Nutrition 0.000 abstract description 4
• 230000000144 pharmacologic effect Effects 0.000 abstract description 3
• 230000002401 inhibitory effect Effects 0.000 abstract description 2
• 239000003814 drug Substances 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 581
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 543
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 448
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 325
• 239000000741 silica gel Substances 0.000 description 324
• 229910002027 silica gel Inorganic materials 0.000 description 324
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 222
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 133
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 132
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 129
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 120
• 229910001868 water Inorganic materials 0.000 description 120
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 106
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 103
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 102
• 239000000203 mixture Substances 0.000 description 102
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 86
• 239000002904 solvent Substances 0.000 description 85
• 239000000243 solution Substances 0.000 description 84
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 64
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 61
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 55
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