CA1291134C - Process for preparing 1,5-benzothiazepine derivatives - Google Patents
Process for preparing 1,5-benzothiazepine derivativesInfo
- Publication number
- CA1291134C CA1291134C CA000526793A CA526793A CA1291134C CA 1291134 C CA1291134 C CA 1291134C CA 000526793 A CA000526793 A CA 000526793A CA 526793 A CA526793 A CA 526793A CA 1291134 C CA1291134 C CA 1291134C
- Authority
- CA
- Canada
- Prior art keywords
- lower alkyl
- compound
- cis
- group
- methanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- KJFRSZASZNLCDF-UHFFFAOYSA-N 1,5-benzothiazepine Chemical class S1C=CC=NC2=CC=CC=C12 KJFRSZASZNLCDF-UHFFFAOYSA-N 0.000 title claims abstract 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 125000002252 acyl group Chemical group 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 29
- -1 alkyl quaternary ammonium compound Chemical class 0.000 claims description 27
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 150000008051 alkyl sulfates Chemical class 0.000 claims description 4
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 208000018152 Cerebral disease Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 claims description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 239000012024 dehydrating agents Substances 0.000 claims description 2
- 208000019622 heart disease Diseases 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 6
- 230000029936 alkylation Effects 0.000 claims 4
- 230000000304 vasodilatating effect Effects 0.000 abstract description 3
- 208000001953 Hypotension Diseases 0.000 abstract description 2
- 230000002490 cerebral effect Effects 0.000 abstract description 2
- 208000021822 hypotensive Diseases 0.000 abstract description 2
- 230000001077 hypotensive effect Effects 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 2
- 230000003389 potentiating effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000000047 product Substances 0.000 description 41
- 239000000203 mixture Substances 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- 239000002904 solvent Substances 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000007858 starting material Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000002168 alkylating agent Substances 0.000 description 8
- 229940100198 alkylating agent Drugs 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000012458 free base Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 4
- 229940085242 benzothiazepine derivative selective calcium channel blockers with direct cardiac effects Drugs 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000005189 Embolism Diseases 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 150000007657 benzothiazepines Chemical class 0.000 description 3
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 208000001435 Thromboembolism Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 125000005228 aryl sulfonate group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- CKRLOOLWVKHPPE-RPBOFIJWSA-N benzyl n-[2-[(2s,3s)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-5-yl]ethyl]-n-methylcarbamate Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](O)C(=O)N(CCN(C)C(=O)OCC=2C=CC=CC=2)C2=CC=C(Cl)C=C2S1 CKRLOOLWVKHPPE-RPBOFIJWSA-N 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- YKNYRRVISWJDSR-UHFFFAOYSA-N methyl oxirane-2-carboxylate Chemical compound COC(=O)C1CO1 YKNYRRVISWJDSR-UHFFFAOYSA-N 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- ZDMPBVMYGNRJCM-RPBOFIJWSA-N (2s,3s)-5-[2-[benzyl(methyl)amino]ethyl]-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4-one Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](O)C(=O)N(CCN(C)CC=2C=CC=CC=2)C2=CC=C(Cl)C=C2S1 ZDMPBVMYGNRJCM-RPBOFIJWSA-N 0.000 description 1
- DQYDVJXPTXYTOL-JSOSNVBQSA-N (2s,3s)-5-[2-[benzyl(methyl)amino]ethyl]-8-chloro-3-hydroxy-2-(4-phenylmethoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4-one Chemical compound C1=CC([C@@H]2SC3=CC(Cl)=CC=C3N(C([C@@H]2O)=O)CCN(C)CC=2C=CC=CC=2)=CC=C1OCC1=CC=CC=C1 DQYDVJXPTXYTOL-JSOSNVBQSA-N 0.000 description 1
- SLGQXZDAILNTQU-SJORKVTESA-N (2s,3s)-8-chloro-3-hydroxy-2-(4-hydroxyphenyl)-5-[2-(methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4-one Chemical compound C1([C@@H]2SC3=CC(Cl)=CC=C3N(C([C@@H]2O)=O)CCNC)=CC=C(O)C=C1 SLGQXZDAILNTQU-SJORKVTESA-N 0.000 description 1
- VOJBMVZEUCIAIV-MSOLQXFVSA-N (2s,3s)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4-one Chemical compound C1([C@@H]2SC3=CC(Cl)=CC=C3N(C([C@@H]2O)=O)CCNC)=CC=C(OC)C=C1 VOJBMVZEUCIAIV-MSOLQXFVSA-N 0.000 description 1
- VDEXLXXWSBFGHU-MSOLQXFVSA-N (2s,3s)-8-chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4-one Chemical compound C1([C@@H]2SC3=CC(Cl)=CC=C3N(C([C@@H]2O)=O)CCN(C)C)=CC=C(O)C=C1 VDEXLXXWSBFGHU-MSOLQXFVSA-N 0.000 description 1
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 description 1
- TYRZAGMAVZESQX-UHFFFAOYSA-N 2-amino-5-chlorobenzenethiol Chemical compound NC1=CC=C(Cl)C=C1S TYRZAGMAVZESQX-UHFFFAOYSA-N 0.000 description 1
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 1
- WQMAANNAZKNUDL-UHFFFAOYSA-N 2-dimethylamino-1-chloro-ethane hydrochloride Natural products CN(C)CCCl WQMAANNAZKNUDL-UHFFFAOYSA-N 0.000 description 1
- LQLJZSJKRYTKTP-UHFFFAOYSA-N 2-dimethylaminoethyl chloride hydrochloride Chemical compound Cl.CN(C)CCCl LQLJZSJKRYTKTP-UHFFFAOYSA-N 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- UINRCHSSGCCNDO-UHFFFAOYSA-N 7-chloro-1,5-benzothiazepine Chemical compound S1C=CC=NC2=CC(Cl)=CC=C21 UINRCHSSGCCNDO-UHFFFAOYSA-N 0.000 description 1
- VPHKBEKDKIKTIY-UHFFFAOYSA-N 8-chloro-3,5-dihydro-2H-1,5-benzothiazepin-4-one oxalic acid Chemical compound C(C(=O)O)(=O)O.ClC1=CC2=C(NC(CCS2)=O)C=C1 VPHKBEKDKIKTIY-UHFFFAOYSA-N 0.000 description 1
- UNCLRGCBQRNLAH-UHFFFAOYSA-N 8-chloro-3-hydroxy-2-(4-phenylmethoxyphenyl)-3,5-dihydro-2h-1,5-benzothiazepin-4-one Chemical compound S1C2=CC(Cl)=CC=C2NC(=O)C(O)C1C(C=C1)=CC=C1OCC1=CC=CC=C1 UNCLRGCBQRNLAH-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- DSYDPJOSIJLTMJ-FTJBHMTQSA-N [(2S,3S)-5-[2-[benzyl(methyl)amino]ethyl]-8-chloro-2-(4-hydroxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate Chemical compound OC1=CC=C(C=C1)[C@@H]1SC2=C(N(C([C@@H]1OC(C)=O)=O)CCN(C)CC1=CC=CC=C1)C=CC(=C2)Cl DSYDPJOSIJLTMJ-FTJBHMTQSA-N 0.000 description 1
- QWYMPDUGHGXMNN-VMXYRSAXSA-N [(2S,3S)-5-[2-[benzyl(methyl)amino]ethyl]-8-chloro-4-oxo-2-(4-phenylmethoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate oxalic acid Chemical compound C(C(=O)O)(=O)O.C(C1=CC=CC=C1)OC1=CC=C(C=C1)[C@@H]1SC2=C(N(C([C@@H]1OC(C)=O)=O)CCN(C)CC1=CC=CC=C1)C=CC(=C2)Cl QWYMPDUGHGXMNN-VMXYRSAXSA-N 0.000 description 1
- KBZDZTFKFVPAGB-UHFFFAOYSA-N [hydroxy(dimethyl)-lambda4-selanyl]methane Chemical compound C[Se](C)(C)O KBZDZTFKFVPAGB-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- QRLHGYSWLXZWKE-UHFFFAOYSA-N dimethyl 2-oxopropane-1,3-disulfonate Chemical compound COS(=O)(=O)CC(=O)CS(=O)(=O)OC QRLHGYSWLXZWKE-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- SDIXRDNYIMOKSG-UHFFFAOYSA-L disodium methyl arsenate Chemical compound [Na+].[Na+].C[As]([O-])([O-])=O SDIXRDNYIMOKSG-UHFFFAOYSA-L 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- CRSMROBXMKUTAY-UHFFFAOYSA-N n,n-dimethylmethanamine;4-methylbenzenesulfonic acid Chemical compound C[NH+](C)C.CC1=CC=C(S([O-])(=O)=O)C=C1 CRSMROBXMKUTAY-UHFFFAOYSA-N 0.000 description 1
- PYIXYEMKFUOLDQ-UHFFFAOYSA-N n-benzyl-2-chloro-n-methylethanamine;hydrochloride Chemical compound [Cl-].ClCC[NH+](C)CC1=CC=CC=C1 PYIXYEMKFUOLDQ-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- VTVJMWZZVJSEMO-UHFFFAOYSA-N pyrrolidine-2-carbonyl chloride Chemical compound ClC(=O)C1CCCN1 VTVJMWZZVJSEMO-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- HADKRTWCOYPCPH-UHFFFAOYSA-M trimethylphenylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C1=CC=CC=C1 HADKRTWCOYPCPH-UHFFFAOYSA-M 0.000 description 1
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61001845A JPS62161776A (ja) | 1986-01-07 | 1986-01-07 | １，５−ベンゾチアゼピン誘導体の製法 |
| JP1845/1986 | 1986-01-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1291134C true CA1291134C (en) | 1991-10-22 |
Family
ID=11512884
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000526793A Expired - Lifetime CA1291134C (en) | 1986-01-07 | 1987-01-06 | Process for preparing 1,5-benzothiazepine derivatives |
Country Status (14)
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5580867A (en) * | 1994-09-09 | 1996-12-03 | Universite De Montreal | Myocardial protection during ischemia and reperfusion |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57169476A (en) * | 1981-04-13 | 1982-10-19 | Hamari Yakuhin Kogyo Kk | Novel preparation of benzothiazepine derivative |
| JPS57175182A (en) * | 1981-04-22 | 1982-10-28 | Hamari Yakuhin Kogyo Kk | Novel preparation of benzothiazepin derivative |
| JPS58113186A (ja) * | 1981-12-28 | 1983-07-05 | Hamari Yakuhin Kogyo Kk | ベンゾチアゼピン誘導体の新規な製造法 |
| JPS58116476A (ja) * | 1981-12-29 | 1983-07-11 | Hamari Yakuhin Kogyo Kk | ベンゾチアゼピン誘導体の新規製造法 |
| US4567175A (en) * | 1983-06-03 | 1986-01-28 | Tanabe Seiyaku Co., Ltd. | 8-Chloro-1,5-benzothiazepine derivatives |
| US4585768A (en) * | 1984-04-10 | 1986-04-29 | Tanabe Seiyaku Co., Ltd. | 1,5-benzothiazepine derivatives and processes for preparing the same |
-
1986
- 1986-01-07 JP JP61001845A patent/JPS62161776A/ja active Granted
- 1986-12-15 IE IE326986A patent/IE59359B1/en not_active IP Right Cessation
- 1986-12-19 IL IL81039A patent/IL81039A/xx not_active IP Right Cessation
- 1986-12-29 PT PT84036A patent/PT84036B/pt not_active IP Right Cessation
- 1986-12-29 ES ES8603613A patent/ES2003642A6/es not_active Expired
- 1986-12-30 FI FI865343A patent/FI865343L/fi not_active Application Discontinuation
-
1987
- 1987-01-06 SU SU874028773A patent/SU1544187A3/ru active
- 1987-01-06 CA CA000526793A patent/CA1291134C/en not_active Expired - Lifetime
- 1987-01-06 DD DD87299117A patent/DD257426A5/de not_active IP Right Cessation
- 1987-01-06 KR KR1019870000022A patent/KR910002879B1/ko not_active Expired
- 1987-01-06 BG BG077954A patent/BG46747A3/xx unknown
- 1987-01-07 HU HU8752A patent/HU198031B/hu not_active IP Right Cessation
- 1987-01-07 CN CN87100139A patent/CN1030388C/zh not_active Expired - Fee Related
- 1987-01-07 AT AT0001687A patent/AT394367B/de not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PT84036A (en) | 1987-01-01 |
| FI865343A0 (fi) | 1986-12-30 |
| IL81039A0 (en) | 1987-03-31 |
| HUT45242A (en) | 1988-06-28 |
| JPS62161776A (ja) | 1987-07-17 |
| IE59359B1 (en) | 1994-02-09 |
| KR870007147A (ko) | 1987-08-17 |
| IL81039A (en) | 1991-07-18 |
| IE863269L (en) | 1987-07-07 |
| CN1030388C (zh) | 1995-11-29 |
| FI865343A7 (fi) | 1987-07-08 |
| ATA1687A (de) | 1991-09-15 |
| CN87100139A (zh) | 1987-08-12 |
| FI865343L (fi) | 1987-07-08 |
| BG46747A3 (bg) | 1990-02-15 |
| SU1544187A3 (ru) | 1990-02-15 |
| PT84036B (pt) | 1989-01-17 |
| DD257426A5 (de) | 1988-06-15 |
| JPH0573749B2 (enrdf_load_stackoverflow) | 1993-10-15 |
| AT394367B (de) | 1992-03-25 |
| KR910002879B1 (ko) | 1991-05-09 |
| ES2003642A6 (es) | 1988-11-01 |
| HU198031B (en) | 1989-07-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |