PL191330B1 - Nowe pochodne chromanu, sposób ich wytwarzania, ich zastosowanie i środek farmaceutyczny - Google Patents

Info

Publication number

PL191330B1

PL191330B1 PL319995A PL31999597A PL191330B1 PL 191330 B1 PL191330 B1 PL 191330B1 PL 319995 A PL319995 A PL 319995A PL 31999597 A PL31999597 A PL 31999597A PL 191330 B1 PL191330 B1 PL 191330B1

Authority

PL

Poland

Prior art keywords

dimethylchroman

group

hydrogen

product

ethylsulfonyl

Prior art date

1996-05-15

Links

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• Global Dossier
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• 238000000034 method Methods 0.000 title claims description 36
• 238000004519 manufacturing process Methods 0.000 title claims description 3
• ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical class [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 78
• 150000003839 salts Chemical class 0.000 claims abstract description 18
• 229910052801 chlorine Inorganic materials 0.000 claims abstract description 11
• JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims abstract description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
• 229910052740 iodine Inorganic materials 0.000 claims abstract description 4
• -1 CpF2p + 1 Chemical group 0.000 claims description 53
• 239000001257 hydrogen Substances 0.000 claims description 47
• 229910052739 hydrogen Inorganic materials 0.000 claims description 47
• 150000002431 hydrogen Chemical class 0.000 claims description 26
• 238000011282 treatment Methods 0.000 claims description 26
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
• 238000006243 chemical reaction Methods 0.000 claims description 23
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
• 239000000126 substance Substances 0.000 claims description 18
• VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical class C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims description 16
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 15
• 125000001153 fluoro group Chemical group F* 0.000 claims description 15
• 239000003814 drug Substances 0.000 claims description 13
• 206010003119 arrhythmia Diseases 0.000 claims description 11
• 230000006793 arrhythmia Effects 0.000 claims description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
• 239000004480 active ingredient Substances 0.000 claims description 9
• 229940124530 sulfonamide Drugs 0.000 claims description 9
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
• 238000002360 preparation method Methods 0.000 claims description 7
• 150000003456 sulfonamides Chemical class 0.000 claims description 7
• 230000002401 inhibitory effect Effects 0.000 claims description 6
• 230000002265 prevention Effects 0.000 claims description 6
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
• 239000000460 chlorine Substances 0.000 claims description 5
• 230000027119 gastric acid secretion Effects 0.000 claims description 5
• PDCRFMGZSHARMR-UHFFFAOYSA-N n-(6-cyano-2,2-dimethyl-3,4-dihydrochromen-4-yl)-n-methylethanesulfonamide Chemical compound C1=C(C#N)C=C2C(N(C)S(=O)(=O)CC)CC(C)(C)OC2=C1 PDCRFMGZSHARMR-UHFFFAOYSA-N 0.000 claims description 5
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
• 210000002784 stomach Anatomy 0.000 claims description 5
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
• 206010012735 Diarrhoea Diseases 0.000 claims description 4
• 206010042434 Sudden death Diseases 0.000 claims description 4
• 239000002168 alkylating agent Substances 0.000 claims description 4
• 238000005804 alkylation reaction Methods 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
• 230000005284 excitation Effects 0.000 claims description 4
• 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 4
• CXNJGGIJHOTNPR-UHFFFAOYSA-N methyl 4-[ethylsulfonyl(methyl)amino]-2,2-dimethyl-3,4-dihydrochromene-6-carboxylate Chemical compound C1=C(C(=O)OC)C=C2C(N(C)S(=O)(=O)CC)CC(C)(C)OC2=C1 CXNJGGIJHOTNPR-UHFFFAOYSA-N 0.000 claims description 4
• MYVCBFZXIKNCGB-UHFFFAOYSA-N n-(7-chloro-6-fluoro-2,2-dimethyl-3,4-dihydrochromen-4-yl)-n-methylethanesulfonamide Chemical compound ClC1=C(F)C=C2C(N(C)S(=O)(=O)CC)CC(C)(C)OC2=C1 MYVCBFZXIKNCGB-UHFFFAOYSA-N 0.000 claims description 4
• VTICUGOJGKDYJD-UHFFFAOYSA-N n-butyl-n-(6-cyano-2,2-dimethyl-3,4-dihydrochromen-4-yl)ethanesulfonamide Chemical compound C1=C(C#N)C=C2C(N(CCCC)S(=O)(=O)CC)CC(C)(C)OC2=C1 VTICUGOJGKDYJD-UHFFFAOYSA-N 0.000 claims description 4
• XSGQFTYHLOBXJW-UHFFFAOYSA-N n-methyl-n-(2,2,6-trimethyl-3,4-dihydrochromen-4-yl)ethanesulfonamide Chemical compound C1=C(C)C=C2C(N(C)S(=O)(=O)CC)CC(C)(C)OC2=C1 XSGQFTYHLOBXJW-UHFFFAOYSA-N 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 229910052708 sodium Inorganic materials 0.000 claims description 4
• 208000025865 Ulcer Diseases 0.000 claims description 3
• 206010047281 Ventricular arrhythmia Diseases 0.000 claims description 3
• 229940100198 alkylating agent Drugs 0.000 claims description 3
• 210000001198 duodenum Anatomy 0.000 claims description 3
• 238000007336 electrophilic substitution reaction Methods 0.000 claims description 3
• 210000001035 gastrointestinal tract Anatomy 0.000 claims description 3
• ABXLWUGDSGBHAE-UHFFFAOYSA-N n-(6,7-dichloro-2,2-dimethyl-3,4-dihydrochromen-4-yl)-n-methylethanesulfonamide Chemical compound ClC1=C(Cl)C=C2C(N(C)S(=O)(=O)CC)CC(C)(C)OC2=C1 ABXLWUGDSGBHAE-UHFFFAOYSA-N 0.000 claims description 3
• WCSSTKFXFSZDMA-UHFFFAOYSA-N n-(6-cyano-2,2-dimethyl-3,4-dihydrochromen-4-yl)-n-(4,4,4-trifluorobutyl)ethanesulfonamide Chemical compound C1=C(C#N)C=C2C(N(CCCC(F)(F)F)S(=O)(=O)CC)CC(C)(C)OC2=C1 WCSSTKFXFSZDMA-UHFFFAOYSA-N 0.000 claims description 3
• ZFWWYFNVKJPHEH-UHFFFAOYSA-N n-(6-fluoro-2,2-dimethyl-3,4-dihydrochromen-4-yl)-n-hexylethanesulfonamide Chemical compound C1=C(F)C=C2C(N(CCCCCC)S(=O)(=O)CC)CC(C)(C)OC2=C1 ZFWWYFNVKJPHEH-UHFFFAOYSA-N 0.000 claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 claims description 3
• 125000001424 substituent group Chemical group 0.000 claims description 3
• 238000006467 substitution reaction Methods 0.000 claims description 3
• 231100000397 ulcer Toxicity 0.000 claims description 3
• 230000002861 ventricular Effects 0.000 claims description 3
• 208000003663 ventricular fibrillation Diseases 0.000 claims description 3
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
• 125000006313 (C5-C8) alkyl group Chemical group 0.000 claims description 2
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
• 206010042600 Supraventricular arrhythmias Diseases 0.000 claims description 2
• 230000029936 alkylation Effects 0.000 claims description 2
• 125000004429 atom Chemical group 0.000 claims description 2
• 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
• 229910052744 lithium Inorganic materials 0.000 claims description 2
• 229910052751 metal Inorganic materials 0.000 claims description 2
• 239000002184 metal Substances 0.000 claims description 2
• OHHVOTBTEBRMAO-UHFFFAOYSA-N n-(6-ethyl-2,2-dimethyl-3,4-dihydrochromen-4-yl)-n-(4,4,4-trifluorobutyl)ethanesulfonamide Chemical compound O1C(C)(C)CC(N(CCCC(F)(F)F)S(=O)(=O)CC)C2=CC(CC)=CC=C21 OHHVOTBTEBRMAO-UHFFFAOYSA-N 0.000 claims description 2
• 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
• 125000005936 piperidyl group Chemical group 0.000 claims description 2
• 150000003458 sulfonic acid derivatives Chemical class 0.000 claims description 2
• 150000002641 lithium Chemical group 0.000 claims 1
• 125000004436 sodium atom Chemical group 0.000 claims 1
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 18
• 229910052794 bromium Inorganic materials 0.000 abstract description 4
• 125000002252 acyl group Chemical group 0.000 abstract description 2
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 2
• 125000000217 alkyl group Chemical group 0.000 abstract 6
• 125000004422 alkyl sulphonamide group Chemical group 0.000 abstract 1
• 125000003368 amide group Chemical group 0.000 abstract 1
• 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
• 150000002148 esters Chemical class 0.000 abstract 1
• 125000003709 fluoroalkyl group Chemical group 0.000 abstract 1
• 229910052736 halogen Inorganic materials 0.000 abstract 1
• 150000002367 halogens Chemical class 0.000 abstract 1
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 abstract 1
• 239000000047 product Substances 0.000 description 256
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
• 238000002844 melting Methods 0.000 description 59
• 230000008018 melting Effects 0.000 description 59
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 55
• 239000002904 solvent Substances 0.000 description 54
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
• 239000013078 crystal Substances 0.000 description 48
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 39
• 239000000203 mixture Substances 0.000 description 39
• WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 36
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 36
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
• 108091006146 Channels Proteins 0.000 description 33
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
• 239000000243 solution Substances 0.000 description 30
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 27
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 25
• 239000012312 sodium hydride Substances 0.000 description 25
• 229910000104 sodium hydride Inorganic materials 0.000 description 25
• 239000003921 oil Substances 0.000 description 22
• 235000019198 oils Nutrition 0.000 description 22
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 20
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 20
• 238000009903 catalytic hydrogenation reaction Methods 0.000 description 20
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 19
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
• 239000002178 crystalline material Substances 0.000 description 16
• 239000000725 suspension Substances 0.000 description 16
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 239000000741 silica gel Substances 0.000 description 15
• 229910002027 silica gel Inorganic materials 0.000 description 15
• AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 14
• FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 14
• LNDGACQEAYKNOI-UHFFFAOYSA-N 1,1,1-trifluoro-4-iodobutane Chemical compound FC(F)(F)CCCI LNDGACQEAYKNOI-UHFFFAOYSA-N 0.000 description 12
• 238000004587 chromatography analysis Methods 0.000 description 11
• UAXWPLCLDSMHRF-UHFFFAOYSA-N 2,2-dimethyl-6-hydroxychroman-4-one Natural products OC1=CC=C2OC(C)(C)CC(=O)C2=C1 UAXWPLCLDSMHRF-UHFFFAOYSA-N 0.000 description 10
• ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 10
• 230000000694 effects Effects 0.000 description 10
• 239000011541 reaction mixture Substances 0.000 description 10
• 238000003756 stirring Methods 0.000 description 10
• IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 9
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• 238000002425 crystallisation Methods 0.000 description 9
• 230000008025 crystallization Effects 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• 230000008569 process Effects 0.000 description 9
• PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
• 239000003480 eluent Substances 0.000 description 8
• 239000012053 oil suspension Substances 0.000 description 8
• 239000007787 solid Substances 0.000 description 8
• ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
• 230000009471 action Effects 0.000 description 7
• 229910021529 ammonia Inorganic materials 0.000 description 7
• 239000002585 base Substances 0.000 description 7
• 239000012230 colorless oil Substances 0.000 description 7
• 230000007062 hydrolysis Effects 0.000 description 7
• 238000006460 hydrolysis reaction Methods 0.000 description 7
• HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 7
• 239000007788 liquid Substances 0.000 description 7
• 150000002923 oximes Chemical class 0.000 description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
• PTOMGSWLGSRLCK-UHFFFAOYSA-N 2,2-dimethyl-4-oxo-3h-chromene-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2OC(C)(C)CC(=O)C2=C1 PTOMGSWLGSRLCK-UHFFFAOYSA-N 0.000 description 6
• ZCZUDOBLRMXOGV-UHFFFAOYSA-N 2,3-Dihydro-6-methoxy-2,2-dimethyl-4H-1-benzopyran-4-one Chemical compound O1C(C)(C)CC(=O)C2=CC(OC)=CC=C21 ZCZUDOBLRMXOGV-UHFFFAOYSA-N 0.000 description 6
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
• TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
• 150000001412 amines Chemical class 0.000 description 6
• KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 6
• UHMZHYUCMREDRI-UHFFFAOYSA-N ethyl thiohypochlorite Chemical compound CCSCl UHMZHYUCMREDRI-UHFFFAOYSA-N 0.000 description 6
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
• 239000002244 precipitate Substances 0.000 description 6
• OHBAWAXGKXWFAZ-UHFFFAOYSA-N 2,2-dimethyl-3,4-dihydrochromen-4-amine;hydrochloride Chemical compound Cl.C1=CC=C2OC(C)(C)CC(N)C2=C1 OHBAWAXGKXWFAZ-UHFFFAOYSA-N 0.000 description 5
• 229910000564 Raney nickel Inorganic materials 0.000 description 5
• 230000003288 anthiarrhythmic effect Effects 0.000 description 5
• 230000000903 blocking effect Effects 0.000 description 5
• 239000003054 catalyst Substances 0.000 description 5
• 238000001816 cooling Methods 0.000 description 5
• 238000000354 decomposition reaction Methods 0.000 description 5
• 239000005457 ice water Substances 0.000 description 5
• IFUDNQFEYVTYQW-UHFFFAOYSA-N methyl 4-amino-2,2-dimethyl-3,4-dihydrochromene-6-carboxylate Chemical compound O1C(C)(C)CC(N)C2=CC(C(=O)OC)=CC=C21 IFUDNQFEYVTYQW-UHFFFAOYSA-N 0.000 description 5
• 239000012074 organic phase Substances 0.000 description 5
• 230000000144 pharmacologic effect Effects 0.000 description 5
• 238000000746 purification Methods 0.000 description 5
• 238000010992 reflux Methods 0.000 description 5
• OSKGYRIYNMZFSJ-UHFFFAOYSA-N (3,4-dichlorophenyl) acetate Chemical compound CC(=O)OC1=CC=C(Cl)C(Cl)=C1 OSKGYRIYNMZFSJ-UHFFFAOYSA-N 0.000 description 4
• AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 4
• KOFFXZYMDLWRHX-UHFFFAOYSA-N 1-(5-fluoro-2-hydroxyphenyl)ethanone Chemical compound CC(=O)C1=CC(F)=CC=C1O KOFFXZYMDLWRHX-UHFFFAOYSA-N 0.000 description 4
• ANOOTOPTCJRUPK-UHFFFAOYSA-N 1-iodohexane Chemical compound CCCCCCI ANOOTOPTCJRUPK-UHFFFAOYSA-N 0.000 description 4
• PLEFHPWZHDJYFJ-UHFFFAOYSA-N 4-amino-2,2-dimethyl-3,4-dihydrochromene-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2OC(C)(C)CC(N)C2=C1 PLEFHPWZHDJYFJ-UHFFFAOYSA-N 0.000 description 4
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
• 241000283973 Oryctolagus cuniculus Species 0.000 description 4
• 239000007868 Raney catalyst Substances 0.000 description 4
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
• 229940079593 drug Drugs 0.000 description 4
• 239000007789 gas Substances 0.000 description 4
• 210000001156 gastric mucosa Anatomy 0.000 description 4
• 210000004907 gland Anatomy 0.000 description 4
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
• 230000005764 inhibitory process Effects 0.000 description 4
• NOEMMKIWQGWBKJ-UHFFFAOYSA-N n-(6-fluoro-2,2-dimethyl-3,4-dihydrochromen-4-yl)-n-methylethanesulfonamide Chemical compound C1=C(F)C=C2C(N(C)S(=O)(=O)CC)CC(C)(C)OC2=C1 NOEMMKIWQGWBKJ-UHFFFAOYSA-N 0.000 description 4
• ANTKQOZUPWHVCP-UHFFFAOYSA-N n-butyl-n-(6-fluoro-2,2-dimethyl-3,4-dihydrochromen-4-yl)ethanesulfonamide Chemical compound C1=C(F)C=C2C(N(CCCC)S(=O)(=O)CC)CC(C)(C)OC2=C1 ANTKQOZUPWHVCP-UHFFFAOYSA-N 0.000 description 4
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