CN116348470A - Method for producing octahydrothienoquinoline compound and intermediate therefor - Google Patents
Method for producing octahydrothienoquinoline compound and intermediate therefor Download PDFInfo
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- CN116348470A CN116348470A CN202180068464.4A CN202180068464A CN116348470A CN 116348470 A CN116348470 A CN 116348470A CN 202180068464 A CN202180068464 A CN 202180068464A CN 116348470 A CN116348470 A CN 116348470A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 187
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 19
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 238000001953 recrystallisation Methods 0.000 claims description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 26
- 150000003892 tartrate salts Chemical class 0.000 abstract description 14
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 abstract description 6
- 229960003638 dopamine Drugs 0.000 abstract description 3
- POMVSFNBRWJNLM-UHFFFAOYSA-N cyclohexane-1,4-dione;ethane-1,2-diol Chemical compound OCCO.O=C1CCC(=O)CC1 POMVSFNBRWJNLM-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000018 receptor agonist Substances 0.000 abstract description 2
- 229940044601 receptor agonist Drugs 0.000 abstract description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- 239000002904 solvent Substances 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 39
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- -1 benzenesulfonyloxy Chemical group 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 239000002585 base Substances 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000001816 cooling Methods 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 11
- 239000012442 inert solvent Substances 0.000 description 11
- 239000012046 mixed solvent Substances 0.000 description 11
- 239000010410 layer Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000003287 optical effect Effects 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- 150000002430 hydrocarbons Chemical class 0.000 description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 6
- 229940011051 isopropyl acetate Drugs 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000004210 ether based solvent Substances 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- ULKSWZAXQDJMJT-UHFFFAOYSA-M magnesium;2,2,6,6-tetramethylpiperidin-1-ide;chloride Chemical compound [Cl-].CC1(C)CCCC(C)(C)N1[Mg+] ULKSWZAXQDJMJT-UHFFFAOYSA-M 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000003759 ester based solvent Substances 0.000 description 3
- GNWXVOQHLPBSSR-UHFFFAOYSA-N oxolane;toluene Chemical compound C1CCOC1.CC1=CC=CC=C1 GNWXVOQHLPBSSR-UHFFFAOYSA-N 0.000 description 3
- 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 2
- KWNBXZAMABGMIA-BFYDXBDKSA-N (3r,4ar,8ar)-n-[2-(dimethylamino)ethylcarbamoyl]-1-methyl-6-oxo-n-propyl-2,3,4,4a,5,7,8,8a-octahydroquinoline-3-carboxamide Chemical compound C1C(=O)CC[C@H]2N(C)C[C@H](C(=O)N(C(=O)NCCN(C)C)CCC)C[C@@H]21 KWNBXZAMABGMIA-BFYDXBDKSA-N 0.000 description 2
- RNGXCKSKLBTDLH-UHFFFAOYSA-N 1'-methyl-n-propylspiro[1,3-dioxolane-2,6'-2,3,4,4a,5,7,8,8a-octahydroquinoline]-3'-carboxamide Chemical compound C1CC2N(C)CC(C(=O)NCCC)CC2CC21OCCO2 RNGXCKSKLBTDLH-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 125000005947 C1-C6 alkylsulfonyloxy group Chemical group 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 208000005793 Restless legs syndrome Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010568 chiral column chromatography Methods 0.000 description 2
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 description 2
- PFIPAWLCLBWISL-UHFFFAOYSA-N ethyl 1'-methylspiro[1,3-dioxolane-2,6'-2,3,4,5,7,8-hexahydroquinoline]-3'-carboxylate Chemical compound C1C(C(=O)OCC)CN(C)C(CC2)=C1CC12OCCO1 PFIPAWLCLBWISL-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000005453 ketone based solvent Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000005440 p-toluyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C(*)=O)C([H])([H])[H] 0.000 description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- VKRKCBWIVLSRBJ-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decan-8-one Chemical compound C1CC(=O)CCC21OCCO2 VKRKCBWIVLSRBJ-UHFFFAOYSA-N 0.000 description 1
- DRZKVOXHHKGXOH-UHFFFAOYSA-N 2-bromopropane;magnesium Chemical compound [Mg].CC(C)Br DRZKVOXHHKGXOH-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical class [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- NGYHNWRKMRIRFH-UHFFFAOYSA-N N-(1,5,6,7-tetrahydroindol-4-ylidene)hydroxylamine Chemical compound ON=C1CCCC2=C1C=CN2 NGYHNWRKMRIRFH-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- MTCMFVTVXAOHNQ-UHFFFAOYSA-N ethyl 2-(bromomethyl)prop-2-enoate Chemical compound CCOC(=O)C(=C)CBr MTCMFVTVXAOHNQ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 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
- 239000011261 inert gas Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- QNRUKMBLUVIEBO-UHFFFAOYSA-L lithium;magnesium;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-] QNRUKMBLUVIEBO-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a composition suitable for use as dopamine D 2 A novel process for industrially producing a compound (P) useful as a receptor agonist or a pharmacologically acceptable salt thereof, and a novel production intermediate. The present invention provides a method for producing a compound (P) or a pharmacologically acceptable salt thereof from 1, 4-cyclohexanedione monoethylene glycol ketal (2) via a compound (AA) or the like as a production intermediate.
Description
Technical Field
The invention relates to a composition with dopamine D 2 A method for producing an optically active octahydrothienoquinoline compound which acts as an acceptor agonist, an optically active compound useful as a production intermediate, and a method for producing the same.
Background
The compound represented by the formula (P) (hereinafter referred to as compound (P)) or a pharmacologically acceptable salt thereof has excellent dopamine D 2 Receptor agonists are therefore reported to be useful as therapeutic or prophylactic agents for parkinson's disease, restless leg syndrome, hyperlactinemia, and the like (see, for example, patent documents 1 and 2).
Patent documents 1 to 3 report a method for producing the compound (P). For example, patent document 3 describes that compound (IV) is produced from compound (II) as a starting material, and then, by performing reduction and direct optical resolution using chiral column chromatography, compound (V) can be separated into optically active substances, and then, compound (XIII) corresponding to compound (P) of the present invention can be produced using the obtained optically active compound (V) (see schemes (Scheme) 1 and 2).
Scheme 1
Scheme 2
(wherein R is 1 、R 2 、R 10 、R 11 、X 1 And X 2 The same definition as that described in patent document 3
Prior art literature
Patent literature
Patent document 1: international publication 2012/124649 pamphlet
Patent document 2: japanese patent laid-open No. 2014-74013 specification
Patent document 3: japanese patent laid-open No. 2014-88362 specification
Disclosure of Invention
Problems to be solved by the invention
In addition to the direct optical resolution of the compound (V) by using chiral column chromatography, the method for producing the compound (P) described in patent documents 1 to 3 involves a plurality of steps requiring complicated operations such as purification by column chromatography, and has problems in terms of industrially producing the compound (P) or a pharmacologically acceptable salt thereof.
The purpose of the present invention is to provide a novel production method and a novel production intermediate which are suitable for the industrial production of a compound (P) or a pharmacologically acceptable salt thereof.
Means for solving the problems
The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found a method for producing a compound represented by formula (P) or a pharmacologically acceptable salt thereof, which is suitable for industrial production, by producing a compound (6) containing a compound (6B) described later as a starting material, then producing a compound (optically active tartrate salt, preferably L-tartrate salt) represented by formula (AA), separating the compound, and using the compound represented by formula (AA) as a production intermediate without requiring complicated operations such as chiral column purification and column purification.
(wherein TA is an optically active tartaric acid derivative, preferably L-tartaric acid)
That is, the present invention relates to the following [1] to [17] and the like.
[1] A process for producing a compound represented by the formula (AA),
[ wherein TA is an optically active tartaric acid derivative ]
The method comprises the following steps:
step 1: a step of producing a compound represented by the formula (4) by reacting a compound represented by the formula (2) with methylamine and a compound represented by the formula (3),
[ wherein X is 1 R is a leaving group 1 Is C 1-6 Alkyl group]
[ formula, R 1 The same as the previous definition]；
Step 2: a step of producing a compound represented by the formula (5) by reducing the compound represented by the formula (4) with a reducing agent in the presence of an acid,
[ formula, R 1 The same as the previous definition]；
Step 3: a step of producing a compound represented by the formula (6) by reacting the compound represented by the formula (5) with n-propylamine in the presence of a base,
Step 4: a step of producing the compound represented by the formula (AA) by reacting the compound represented by the formula (6) with an optically active tartaric acid derivative.
[2] The manufacturing method according to the aforementioned [1], further comprising a step 4P of: a step of purifying the compound represented by the aforementioned formula (AA) by recrystallization.
[3] The production method according to the above [1] or [2], wherein the compound represented by the above formula (AA) is a compound represented by the formula (6A),
the optically active tartaric acid derivative is L-tartaric acid.
[4]According to the above [1]]～[3]The production method according to any one of, wherein X 1 Is a halogen atom.
[5] The production method according to any one of the above [1] to [4], wherein the acid in the step 2 is methanesulfonic acid and the reducing agent is sodium borohydride.
[6] The production method according to any one of the above [1] to [5], wherein the base in the above step 3 is sodium methoxide.
[7] A compound represented by formula (AA).
[ wherein TA is an optically active tartaric acid derivative ]
[8] A compound represented by the formula (6A).
[9] A process for producing a compound represented by the formula (P) or a pharmacologically acceptable salt thereof,
the method is characterized by using a compound represented by the formula (AA).
[ wherein TA is an optically active tartaric acid derivative ]
[10] A process for producing a compound represented by the formula (P) or a pharmacologically acceptable salt thereof,
the method is characterized by using a compound represented by the formula (6A).
[11] A process for producing a compound represented by the formula (P) or a pharmacologically acceptable salt thereof,
the method comprises the following steps:
step 5: a step of producing a compound represented by the formula (6B) by reacting a compound represented by the formula (AA) with a base,
[ wherein TA is an optically active tartaric acid derivative ]
Step 9: a step of producing a compound represented by the above formula (P) by reacting a compound represented by the formula (10) with sulfur and malononitrile, and separating the compound in a solid state.
[12] A process for producing a compound represented by the formula (P) or a pharmacologically acceptable salt thereof,
the method comprises the following steps:
step 5: a step of producing a compound represented by the formula (6B) by reacting the compound represented by the formula (6A) with a base,
Step 9: a step of producing a compound represented by the above formula (P) by reacting a compound represented by the formula (10) with sulfur and malononitrile, and separating the compound in a solid state.
[13] The production method according to the aforementioned [11] or [12], further comprising step 6: a step of producing a compound represented by formula (8) by reacting a compound represented by formula (6B) with a compound represented by formula (7).
R 2 -OC(O)-X 2 (7)
[ wherein X is 2 Is a chlorine atom or a bromine atom, R 2 Phenyl which is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of halogen atoms and nitro groups]
[ formula, R 2 The same as the previous definition]
[14] The method of manufacturing according to the aforementioned [13], further comprising step 7: a step of producing a compound represented by the formula (9) by reacting the compound represented by the formula (8) with N, N-dimethylethylenediamine.
[15] The method of manufacturing according to the aforementioned [14], further comprising step 8: and (3) a step of hydrolyzing the compound represented by the formula (9) to produce a compound represented by the formula (10).
[16] The manufacturing method according to the aforementioned [15], further comprising a step 9P of: a step of purifying the compound represented by the aforementioned formula (P) by recrystallization as needed.
[17] The manufacturing method according to the aforementioned [16], further comprising step 10: a step of converting the compound represented by the aforementioned formula (P) into a pharmacologically acceptable salt of the compound represented by the formula (P) as required.
Effects of the invention
According to the production method of the present invention, there can be provided a novel production method of a compound represented by the formula (P) or a pharmacologically acceptable salt thereof, which is suitable for industrial production without requiring complicated operations such as chiral column purification and column purification, and a production intermediate thereof.
Detailed Description
In the present specification, the following terms have the following meanings unless specifically stated otherwise.
Examples of the "optically active tartaric acid derivative" include di (p-toluoyl) -L-tartaric acid, dibenzoyl-L-tartaric acid, and L-tartaric acid. L-tartaric acid is preferred.
“C 1-6 The alkyl group "means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, hexyl, and isohexyl.
"leaving group" may be taken to mean C 1-6 Alkylsulfonyloxy, arylsulfonyloxy, a halogen atom, and the like. Halogen atoms are preferred.
"halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
“C 1-6 Alkylsulfonyloxy "means C 1-6 alkyl-SO 2 Examples of the group represented by-O-include methanesulfonyloxy and the like.
"arylsulfonyloxy" is phenyl-SO 2 -O-represents a group, the phenyl group being unsubstituted or selected from C 1-6 Alkyl, halogen atomsExamples of the phenyl group substituted with a group selected from the group consisting of nitro groups include tosyloxy and benzenesulfonyloxy.
"phenyl group substituted with 1 to 3 groups independently selected from the group consisting of a halogen atom and a nitro group" means phenyl group substituted with 1 to 3 groups independently selected from the group consisting of a halogen atom and a nitro group, and examples thereof include p-chlorophenyl group, p-nitrophenyl group and the like.
The following abbreviations are used in this specification.
Positive (n-) indicates normal (normal), and tertiary (tert-) indicates tertiary (tert).
Me represents methyl, pr represents propyl.
TMPMgCl.LiCl represents a 2, 6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex.
The position numbers of ring atoms in the compounds represented by the formulas (AA), (5B), (6A), (6B), (8), (9) and (10) are labeled in the following manner.
The position numbers of ring atoms in the compounds represented by the formula (P) are labeled in the following manner.
The compounds of formulae (5) and (6) are meant to include mixtures of up to 8 diastereomers based on asymmetric carbon atoms in the 3, 4a and 8a positions of the decahydroquinoline ring.
The compounds represented by the formulas (5) and (6) include, for example, compounds represented by the following formulas (5B) and (6B), respectively.
[ formula, R 1 The same as the previous definition]
Represented by the formulae (4) and (5)In the compound (C), R 1 The present invention includes any one of a compound having an asymmetric carbon atom in the R configuration, a compound having an asymmetric carbon atom in the S configuration, and any combination thereof.
The compounds represented by the formula (AA) and the formula (6A) also include hydrates and solvates with solvents such as ethanol, respectively.
The compound represented by the formula (P) or a pharmacologically acceptable salt thereof also includes a hydrate, a solvate with a pharmaceutically acceptable solvent such as ethanol.
The following describes the production method of the present invention.
When the raw materials and the reagent compounds for each step are commercially available, the commercially available products can be used as they are.
The compound represented by the formula (P) or a pharmacologically acceptable salt thereof can be produced by the steps shown in scheme 3 and scheme 4 below.
Scheme 3
(wherein X is 1 R is a leaving group 1 Is C 1-6 Alkyl, TA is an optically active tartaric acid derivative)
(step 1)
The compound (4) is obtained by subjecting 1, 4-cyclohexanedione monoethylene glycol ketal (2), methylamine and the compound (3) to dehydration condensation in an inactive solvent.
The reaction is preferably azeotropically dehydrated using a dean-stark apparatus or the like.
Examples of the inert solvent include hydrocarbon solvents such as toluene and xylene, and carboxylic ester solvents such as isopropyl acetate.
The methylamine used is preferably a methanol solution. The amount of methylamine is generally about 2 to about 4 equivalents relative to compound (2).
The amount of compound (3) is generally about 1 to about 2 equivalents relative to compound (2).
The reaction temperature is usually-10℃to the reflux temperature.
The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., and is usually 1 to 24 hours.
Examples of the compound (3) include ethyl 2- [ [ [ (4-methylphenyl) sulfonyl ] oxy ] methyl ] -2-acrylate, ethyl 2- [ [ (methylsulfonyl) oxy ] methyl ] -2-acrylate, ethyl 2- (bromomethyl) -2-acrylate, ethyl 2- (chloromethyl) -2-acrylate, and the like.
(step 2)
The compound (4) is reduced with a reducing agent such as sodium cyanoborohydride or sodium borohydride in an inert solvent in the presence of an acid to obtain a compound (5) containing the compound (5B).
The amount of reducing agent is generally about 1 to about 2 equivalents relative to compound (4).
Examples of the inert solvent include tetrahydrofuran, methanol, ethanol, ethyl acetate, 1, 4-dioxane, and a mixed solvent thereof.
Examples of the acid include hydrogen chloride, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, and formic acid.
The amount of acid is generally about 1 to about 2 equivalents relative to compound (4).
The reaction temperature is usually-50℃to 50℃and preferably-10℃to 30 ℃.
The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., and is usually 10 minutes to 12 hours.
(step 3)
Compound (6) containing compound (6B) is obtained by reacting compound (5) containing compound (5B) with n-propylamine in the presence of a base in an inactive solvent. Examples of the inert solvent used in the reaction include an ether solvent such as tetrahydrofuran, diisopropyl ether, t-butyl methyl ether, cyclopentyl methyl ether, and 1, 2-dimethoxyethane, a hydrocarbon solvent such as toluene, and xylene, and a mixed solvent thereof.
The amount of n-propylamine is generally about 1 to about 6 equivalents relative to compound (5).
Examples of the base include alkali metal alkoxides such as sodium methoxide.
The amount of base is generally about 0.2 to about 0.5 equivalent relative to compound (5).
The reaction temperature is usually from 0℃to 100℃and preferably from 0℃to 30 ℃.
The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., and is usually 1 to 24 hours.
In this step, epimerization of the 3-position on the decahydroquinoline ring is also performed.
After the completion of the reaction, the compound (6B) may be isolated and purified before the next step, but may be used in the next step without isolation in the state of a mixture of the compounds (6) containing the compound (6B) after the conventional work-up.
(step 4)
The compound (6B) can be optically resolved from the compound (6) containing the compound (6B) by forming a salt with an optically active tartaric acid derivative by a conventional method.
For example, the compound (6) containing the compound (6B) is reacted with an optically active tartaric acid derivative such as L-tartaric acid in an inactive solvent to form a salt, thereby obtaining the optically active compound (AA).
As a preferable mode of step 4, compound (AA) may be isolated in a solid state by reacting compound (6) containing compound (6B) with an optically active tartaric acid derivative in an inactive solvent to form optically active compound (AA), and then cooling the reaction mixture to 25 ℃. The obtained solid was washed with a mixture of an inactive solvent and a poor solvent, and dried under reduced pressure, whereby compound (AA) was obtained.
The equivalent of the optically active tartaric acid derivative was about 1.0 equivalent to the compound (6).
As the inert solvent, any solvent may be used as long as it does not interfere with salt formation, and for example, alcohol solvents such as methanol, ethanol, 1-propanol, and 2-propanol, amide solvents such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone, water, and a mixed solvent thereof, and the like can be used.
The reaction temperature is usually from 0℃to the reflux temperature, preferably from 20℃to 65℃and more preferably from 55℃to 65 ℃.
As the poor solvent, ether solvents such as methyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, and diethoxymethane, ketone solvents such as acetone and methyl ethyl ketone, carboxylic acid ester solvents such as ethyl acetate and isopropyl acetate, nitrile solvents such as acetonitrile, hydrocarbon solvents such as hexane, heptane, and toluene, and mixed solvents thereof can be used.
The cooling temperature is usually 0 to room temperature, and the cooling time varies depending on the solvent used, the cooling temperature, and the like, and is usually 1 to 24 hours.
As another embodiment of the present invention, examples of the optically active tartaric acid derivative include di (p-toluoyl) -L-tartaric acid, dibenzoyl-L-tartaric acid, and L-tartaric acid. L-tartaric acid is preferred.
(step 4P)
The compound (AA) obtained in step 4 may be purified by recrystallization as needed. The recrystallization solvent includes the inactive solvent and the poor solvent of the step 4.
Scheme 4
(wherein TA is as defined above and X 2 Is a chlorine atom or a bromine atom, R 2 Phenyl which is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of halogen atoms and nitro groups
(step 5)
Compound (AA) is reacted with a base in a mixed solvent of water and an inactive solvent to obtain compound (6B).
Examples of the inert solvent include hydrocarbon solvents such as toluene and xylene, carboxylic acid ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate, ether solvents such as diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane and diethoxymethane, and mixed solvents thereof.
Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, and the like.
The amount of the base to be used may be in the range of 0.5 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2 equivalents, relative to the compound (AA).
The reaction temperature is usually in the range of 0℃to 40℃and preferably in the range of 0℃to 30 ℃.
After the completion of the reaction, the compound (6B) may be isolated and purified before the next step, but may be used in the next step without purification after the conventional work-up.
(step 6)
The aryl carbamate compound (8) is obtained by reacting the compound (6B) with the aryl haloformate compound (7) in an inert solvent in the presence of a base.
Examples of the inert solvent include hydrocarbon solvents such as toluene and xylene, ether solvents such as tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether and 1, 2-dimethoxyethane, and mixed solvents thereof.
As the aryl haloformate compound (7), 4-nitrophenyl chloroformate, 2-chlorophenyl chloroformate, phenyl chloroformate and the like can be mentioned.
The amount of the aryl haloformate compound (7) is usually about 1 to about 5 equivalents relative to the compound (6B).
Examples of the base include sodium hexamethyldisilazide, lithium hexamethyldisilazide, magnesium isopropylbromide, TMPMgCl and LiCl.
The amount of base is generally about 1 to about 5 equivalents relative to compound (6B).
The reaction temperature is usually-78℃to 50℃and preferably-40℃to 20 ℃.
The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., and is usually 15 minutes to 24 hours.
(step 7)
The ureide compound (9) is obtained by reacting the aryl carbamate compound (8) with N, N-dimethylethylenediamine or a salt thereof in an inactive solvent in the presence or absence of a base.
Examples of the inert solvent include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol, ether solvents such as tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, and 1, 2-dimethoxyethane, and mixtures thereof.
Regarding the amount of N, N-dimethylethylenediamine, it is usually about 1 to about 5 equivalents with respect to the compound (8).
Examples of the base include inorganic bases such as potassium carbonate, and organic amines such as triethylamine, N-diisopropylethylamine, pyridine, N-methylmorpholine and N, N-dimethylaniline. Of these bases, triethylamine or N, N-diisopropylethylamine can be preferably used.
The amount of base is generally 0 to about 10 equivalents relative to compound (8).
The reaction temperature is usually from 0℃to 150℃and preferably from 0℃to 60 ℃.
The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., and is usually 15 minutes to 24 hours.
(step 8)
Acid hydrolysis of the ureide compound (9) is carried out in an inactive solvent, thereby obtaining a 6-oxo-decahydroquinoline compound (10).
Examples of the inert solvent include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol, tetrahydrofuran, dimethoxyethane, 1, 4-dioxane, water, and a mixed solvent thereof.
Examples of the acid include sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, and the like. Among these acids, hydrochloric acid is preferably used.
The amount of acid is generally about 5 to about 15 equivalents relative to compound (9).
The reaction temperature is usually-10℃to 100℃and preferably 0℃to 40 ℃.
The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., and is usually 10 minutes to 24 hours.
After the completion of the reaction, the compound (10) may be isolated and purified before the next step, but may be used in the next step without purification after the conventional work-up.
(step 9)
The octahydrothienoquinoline compound (P) is obtained by reacting the 6-oxo-decahydroquinoline compound (10) with sulfur and malononitrile in an inactive solvent in the presence or absence of a base.
Examples of the inert solvent include 2-propanol, ethanol, and methanol.
The amount of sulfur is generally about 1 to about 2 equivalents relative to compound (10).
The amount of malononitrile is generally about 1 to about 3 equivalents relative to compound (10).
Examples of the base include organic amines such as morpholine, piperidine and triethylamine.
The amount of base is generally 0 to about 3 equivalents relative to compound (10).
The reaction temperature is usually 0 to reflux temperature, and the reaction time is usually 15 minutes to 24 hours, depending on the raw material used, the solvent, the reaction temperature, and the like.
The compound (P) obtained can be isolated by curing by a conventional method. For example, the compound (P) can be isolated in a solid state by cooling the reaction mixture after the completion of the reaction and adding a poor solvent. The obtained solid was washed with a mixture of an inactive solvent and a poor solvent, whereby compound (P) was obtained.
Examples of the poor solvent include hydrocarbon solvents such as hexane and heptane, water, and the like.
The cooling temperature is usually 0 to room temperature, and the cooling time varies depending on the solvent used, the cooling temperature, and the like, and is usually 1 to 24 hours.
(step 9P)
If necessary, the compound (P) obtained in step 9 may also be purified by performing recrystallization. Examples of the good solvent for recrystallization include the inactive solvent in the above step 9, and ketone solvents such as acetone and methyl ethyl ketone. As the poor solvent for recrystallization, the poor solvent of the above step 9 can be mentioned.
(step 10)
The compound (P) may be reacted with an inorganic acid or an organic acid in an inactive solvent according to need by a conventional method or a method described in pamphlet of international publication No. 2012/124649 to prepare a pharmacologically acceptable salt thereof. Examples of such salts include: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; acid addition salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, and the like.
(step 10P)
The pharmacologically acceptable salt of the compound (P) obtained in step 10 may also be purified by performing recrystallization, if necessary. Examples of the recrystallization solvent include an acetone-water mixed solvent, a methanol-water mixed solvent, and an ethanol-water mixed solvent.
The following examples illustrate the invention in further detail.
The present invention is not limited to these, and may be modified within the scope of the present invention.
Examples
1 H-NMR was measured by Fourier transform type NMR.
Regarding the chemical purity of examples, experiments were performed by gas chromatography in examples 4 and 5, and experiments were performed by liquid chromatography in examples 10 and 11, calculated from the respective peak areas.
The optical purity of the examples was measured by liquid chromatography and calculated from the peak areas of the respective samples.
Example 1
1 '-methyl-2', 3',4',5',7',8 '-hexahydro-1' H-spiro [1, 3-dioxolane-2, 6 '-quinoline ] -3' -carboxylic acid ethyl ester (Compound (4-1))
To a mixture of ethyl 2- (bromomethyl) acrylate (81.6 g) and toluene (660 g), a mixture of 40% methylamine-methanol solution (89.4 g) and toluene (156 g) was added dropwise at 1 to 20℃and stirred at 2 to 8℃for 1 hour. To the reaction mixture, 1, 4-cyclohexanedione monoethylene ketal (60.0 g) and toluene (24 g) were added in this order at 2 to 4℃and azeotropically dehydrated at about 110℃for 9 hours. The reaction mixture was cooled to below 30 ℃ and then allowed to stand overnight. Water (140 g) was added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed with water (140 g), and concentrated under reduced pressure at 50 ℃. After cooling the residue to 30℃or lower, methanol (30 g) was added to give a methanol solution of the title compound (168 g, the next step was performed in 100% yield).
Example 2
1 '-methyl octahydro-1' H-spiro [1, 3-dioxolane-2, 6 '-quinoline ] -3' -carboxylic acid ethyl ester (Compound (5-1))
Tetrahydrofuran (300 g) and methanol (62 g) were added to a methanol solution of ethyl 1 '-methyl-2', 3',4',5',7',8 '-hexahydro-1' H-spiro [1, 3-dioxolane-2, 6 '-quinoline ] -3' -carboxylate obtained in example 1, methanesulfonic acid (38.8 g) and tetrahydrofuran (8.4 g) were sequentially added dropwise at 1 to 7℃and stirred under ice-cooling for 30 minutes. Then, a mixture of sodium borohydride (10.9 g) and a 0.1M aqueous sodium hydroxide solution (130 g) and water (12 g) were sequentially added dropwise at 1 to 10℃and stirred at 5 to 16℃for 2 hours. To the reaction mixture, 20% aqueous potassium carbonate solution (240 g) was added at 5 to 11℃and stirred at 11 to 14℃for 30 minutes. After allowing the reaction mixture to stand overnight, the aqueous layer was removed. The organic layer was diluted with toluene (480 g), stirred at room temperature for 30 minutes, and then the aqueous layer was removed. The organic layer was washed with water (170 g) and 16% brine (170 g) in this order, and concentrated under reduced pressure at 50 ℃. After cooling the residue to 30℃or lower, toluene (90 g) was added to obtain a toluene solution of the title compound (225 g, the next step was performed in 100% yield).
Example 3
1 '-methyl-N-propyloctahydro-1' H-spiro [1, 3-dioxolane-2, 6 '-quinoline ] -3' -carboxamide (Compound (6))
To a toluene solution of ethyl 1 '-methyl octahydro-1' H-spiro [1, 3-dioxolane-2, 6 '-quinoline ] -3' -carboxylate obtained in example 2, 1-propylamine (136 g) and toluene (30 g) were added at 22 to 25℃followed by dropwise addition of 28% sodium methoxide in methanol (37.1 g) and tetrahydrofuran (6.0 g) at 2 to 5 ℃. The reaction mixture was stirred at 19 to 23℃for 4 hours and then allowed to stand overnight. To the reaction mixture, acetic acid (11.5 g) and isopropyl acetate (6.0 g) were sequentially added dropwise at 17 to 20℃and then 16% brine (360 g) and isopropyl acetate (350 g) were sequentially added at 18 to 27℃to separate an aqueous layer. Isopropyl acetate (210 g) was added to the aqueous layer for extraction. The organic layers were combined, allowed to stand overnight, and concentrated at 50℃under reduced pressure. To the residue was added 1-propanol (190 g), and the mixture was concentrated under reduced pressure at 60 ℃. To the residue was added 1-propanol (60 g), and the insoluble matter was filtered and washed with 1-propanol (99 g) to give a 1-propanol solution of the title compound (251 g, next step was performed in 100% yield).
Example 4
(3 ' R,4' aR,8' aR) -1' -methyl-N-propyloctahydro-1 ' H-spiro [1, 3-dioxolane-2, 6' -quinoline ] -3' -carboxamide L-tartrate (crude compound (6A))
To the 1-propanol solution of 1 '-methyl-N-propyloctahydro-1' H-spiro [1, 3-dioxolane-2, 6 '-quinoline ] -3' -carboxamide obtained in example 3 was added 1-propanol (30 g), followed by heating to 60 ℃. L-tartaric acid (28.8 g) was added at 61 to 64℃and stirred at that temperature for 5 minutes, and then L-tartaric acid (28.8 g) was further added at 59 to 60℃and stirred at 59 to 61℃for 30 minutes. Acetone (100 g) was added dropwise to the reaction mixture at 56 to 59℃and then cooled to 45℃over 20 minutes. Next, the reaction mixture was cooled to 25℃over 100 minutes, and then acetone (490 g) was added dropwise at 24 to 25 ℃. The reaction mixture was stirred at 24 to 25℃for 1 hour and then allowed to stand overnight. The suspension was heated to 50℃and stirred at 49 to 52℃for 30 minutes. Then, the suspension was cooled to 29℃and stirred at 27 to 29℃for 1.5 hours. After the suspension was filtered, the obtained solid was washed 2 times with a mixture of 1-propanol (12 g) and acetone (36 g), and dried under reduced pressure at 70℃to obtain the title compound (26.7 g) (yield 16%, optical purity 98.3% ee, chemical purity 97.6%).
Example 5
(3 ' R,4' aR,8' aR) -1' -methyl-N-propyloctahydro-1 ' H-spiro [1, 3-dioxolane-2, 6' -quinoline ] -3' -carboxamide L-tartrate (Compound (6A))
To (3 ' R,4' aR,8' aR) -1' -methyl-N-propyloctahydro-1 ' H-spiro [1, 3-dioxolane-2, 6' -quinoline ] -3' -carboxamide L-tartrate (20.0 g) obtained in example 4 was added methanol (48 g), followed by heating to 60 ℃. After stirring at 60-62℃for 30 minutes, the solution was filtered while it was still hot, and the insoluble matter was washed with methanol (16 g). After the filtrate was stirred at 26 to 30℃for 1 hour, acetone (260 g) was added at 22 to 26 ℃. The suspension was heated to 50℃and stirred at 51 to 53℃for 30 minutes. The suspension was further cooled to 26℃for 30 minutes, stirred at this temperature for 30 minutes, and left to stand overnight. The suspension was cooled to 0 to 10℃and stirred at 3 to 6℃for 1 hour. The suspension was filtered, and the obtained solid was washed 2 times with a mixture of methanol (14 g) and acetone (28 g), and then dried under reduced pressure at 70℃to give the title compound (15.8 g) (yield 79%, optical purity >99.8% ee, chemical purity 99.5%).
1 H-NMR(CD 3 OD)δppm：0.91(3H,t,J＝7.4Hz),1.38-1.94(9H,m),1.95-2.12(1H,m),2.15-2.30(1H,m),2.70-2.80(1H,m),2.86(3H,s),2.90-3.00(1H,m),3.01-3.19(3H,m),3.48-3.57(1H,m),3.88-3.98(4H,m),4.43(2H,s)
Example 6
(3 ' R,4' aR,8' aR) -1' -methyl-N-propyloctahydro-1 ' H-spiro [1, 3-dioxolane-2, 6' -quinoline ] -3' -carboxamide (Compound (6B))
To a mixture of (3 ' R,4' aR,8' aR) -1' -methyl-N-propyloctahydro-1 ' H-spiro [1, 3-dioxolane-2, 6' -quinoline ] -3' -carboxamide L-tartrate (130 g, 97.3% ee in optical purity, 97.4% ee in chemical purity), toluene (1300 g) and water (250 g) was added potassium carbonate (130 g) and water (39 g) at 25-30 ℃. After removing the aqueous layer of the reaction mixture, it was concentrated under reduced pressure at an external temperature of 60 ℃. After cooling the residue to 30℃or lower, tetrahydrofuran (770 g) and toluene (86 g) were added to give a tetrahydrofuran-toluene solution of the title compound (923 g, the next step was performed in 100% yield).
Example 7
N- { [ (3 ' R,4' aR,8' aR) -1' -methyl octahydro-1 ' H-spiro [1, 3-dioxolan-2, 6' -quinolin ] -3' -yl ] carbonyl } -N-propylcarbamic acid phenyl ester (compound (8-1))
Tetrahydrofuran-toluene solution of (3 ' R,4' aR,8' aR) -1' -methyl-N-propyloctahydro-1 ' H-spiro [1, 3-dioxolane-2, 6' -quinoline ] -3' -carboxamide obtained in example 6 (815 g, 76.3g in terms of compound (6B)) was added dropwise to tetrahydrofuran-toluene solution of TMPMgCl. LiCl (17.5% in terms of TMPMgCl, 471 g) at-13 to-10℃under an inert gas atmosphere, and stirred for 20 minutes at-15 to-10 ℃. To the reaction mixture was added phenyl chloroformate (52.4 g) at-15 to-10℃and stirred at that temperature for 30 minutes. To the reaction mixture was added 20% aqueous ammonium chloride solution (840 g) at-15 to 16℃and the mixture was warmed to room temperature. To the reaction mixture was added tert-butyl methyl ether (730 g), and the aqueous layer was separated. The organic layer was washed with water (660 g), and concentrated under reduced pressure at an external temperature of 50 ℃. To the residue was added 2-propanol (1200 g), and the mixture was concentrated under reduced pressure at an external temperature of 50℃until the content of the mixture reached 485g, to give a 2-propanol solution of the title compound (yield 88%, title compound 93.9 g).
Example 8
1- { [ (3 ' R,4' aR,8' aR) -1' -methyl octahydro-1 ' H-spiro [1, 3-dioxolan-2, 6' -quinolin ] -3' -yl ] carbonyl } -3- [2- (dimethylamino) ethyl ] -1-propylurea (compound (9))
To a 2-propanol solution of phenyl N- { [ (3 ' R,4' aR,8' aR) -1' -methyl octahydro-1 ' H-spiro [1, 3-dioxolan-2, 6' -quinolin ] -3' -yl ] carbonyl } -N-propylcarbamate obtained in example 7 was added 2-propanol (248 g). N, N-dimethylethylenediamine (87.4 g) was added to the mixture at 57 to 60℃and stirred at 55 to 57℃for 4 hours. After cooling the reaction mixture to room temperature, it was used directly in the next step in 100% yield.
Example 9
1- { [ (3R, 4aR,8 aR) -1-methyl-6-oxodecahydroquinolin-3-yl ] carbonyl } -3- [2- (dimethylamino) ethyl ] -1-propylurea (compound (10))
To the reaction mixture of example 8 (containing 1- { [ (3 ' R,4' aR,8' aR) -1' -methyl octahydro-1 ' H-spiro [1, 3-dioxolan-2, 6' -quinolin-3 ' -yl ] carbonyl } -3- [2- (dimethylamino) ethyl ] -1-propylurea), 2mol/L hydrochloric acid (1100 mL) was added at 20-39℃and stirred at 50-59℃for 3 hours. After the reaction mixture was cooled to room temperature, t-butyl methyl ether (630 g) was added to the reaction mixture, and an organic layer was separated. To the aqueous layer was added t-butyl methyl ether (630 g) for washing. After 40% aqueous potassium carbonate (850 g) was added to the aqueous layer, toluene (820 g) was added, and the aqueous layer was separated. The organic layer was concentrated under reduced pressure at an external temperature of 60℃until the content of the mixture reached 146 g. To the residue was added 2-propanol (1500 g), and the mixture was concentrated under reduced pressure at 60℃to give a 2-propanol solution (278 g) of the title compound (yield 64%, 52.8g of the title compound).
Example 10
1- { [ (4 aR,6R,8 aR) -2-amino-3-cyano-8-methyl-4, 4a,5,6,7, 8a, 9-octahydrothieno [3,2-g ] quinolin-6-yl ] carbonyl } -3- [2- (dimethylamino) ethyl ] -1-propylurea (crude compound (P))
To a solution of 1- { [ (3R, 4aR,8 aR) -1-methyl-6-oxodecahydroquinolin-3-yl ] carbonyl } -3- [2- (dimethylamino) ethyl ] -1-propylurea in 2-propanol (25.1 g, containing 4.77g as compound (10)) obtained in example 9, sulfur (438 mg), malononitrile (919 mg) and 2-propanol (6.37 g) were added in this order at room temperature, and stirred at 50℃for 2.5 hours.
After cooling the reaction mixture to room temperature, it was left to stand overnight. The reaction mixture was heated at an external temperature of 56 ℃ to dissolve the solid. After cooling the reaction mixture to 22 ℃, it was stirred at 22-23 ℃ for 1 hour. To the reaction mixture, water (33 g) was added dropwise at 23 to 24℃and then stirred at 24℃for 2 hours. To the mixture, water (33 g) was added dropwise at this temperature, followed by stirring at this temperature for 1 hour and stirring under ice-cooling for 1.5 hours. The suspension was filtered, and the obtained solid was washed 4 times with a mixture of ice-cooled 2-propanol (2.5 g) and water (6.2 g), and then dried under reduced pressure at an external temperature of 50℃or lower to give the title compound (4.09 g) (yield 70%, optical purity 99.7% ee, chemical purity 97.6%).
Example 11
1- { [ (4 aR,6R,8 aR) -2-amino-3-cyano-8-methyl-4, 4a,5,6,7, 8a, 9-octahydrothieno [3,2-g ] quinolin-6-yl ] carbonyl } -3- [2- (dimethylamino) ethyl ] -1-propylurea (compound (P))
To 1- { [ (4 ar,6r,8 ar) -2-amino-3-cyano-8-methyl-4, 4a,5,6,7, 8a, 9-octahydrothieno [3,2-g ] quinolin-6-yl ] carbonyl } -3- [2- (dimethylamino) ethyl ] -1-propylurea (4.00 g, 98.6% ee in optical purity, 98.4% in chemical purity) was added acetone (22 g) at room temperature and stirred at 50 ℃ until dissolved.
After cooling the mixture to 20℃water (28 g) was added dropwise. After the mixture was stirred at 20℃for 1 hour, water (28 g) was added dropwise at this temperature. The mixture was stirred at 20℃for 1 hour, and under ice-cooling for 1 hour. The suspension was filtered, and the obtained solid was washed with a mixture of ice-cooled acetone (3.2 g) and water (8.0 g), and then dried under reduced pressure at an external temperature of 50℃to give the title compound (3.70 g) (yield 93%, optical purity >99.8% ee, chemical purity 99.4%).
Industrial applicability
The present invention enables the industrial production of the compound (P) or a pharmacologically acceptable salt thereof, which is useful as a therapeutic or prophylactic agent for parkinson's disease, restless leg syndrome or hypercrolactonemia, without requiring complicated procedures such as chiral column purification or column purification.
Claims (8)
1. A process for producing a compound represented by the formula (6A),
the method comprises the following steps:
step 1: a step of producing a compound represented by the formula (4) by reacting a compound represented by the formula (2) with methylamine and a compound represented by the formula (3),
in the formula (3), X 1 R is a leaving group 1 Is C 1-6 An alkyl group, a hydroxyl group,
in the formula (4), R 1 The same as defined above;
step 2: a step of producing a compound represented by formula (5) by reducing the compound represented by formula (4) with a reducing agent in the presence of an acid,
in the formula (5), R 1 The same as defined above;
step 3: a step of producing a compound represented by formula (6) by reacting the compound represented by formula (5) with n-propylamine in the presence of a base,
Step 4: and a step of producing the compound represented by the formula (6A) by reacting the compound represented by the formula (6) with L-tartaric acid, and separating the compound in a solid state.
2. The manufacturing method according to claim 1, further comprising step 4P: and (3) purifying the compound represented by the formula (6A) by recrystallization.
3. The production method according to claim 1 or 2, wherein X 1 Is a halogen atom.
4. The production process according to any one of claims 1 to 3, wherein the acid in step 2 is methanesulfonic acid and the reducing agent is sodium borohydride.
5. The production process according to any one of claims 1 to 4, wherein the base in step 3 is sodium methoxide.
6. A compound represented by the formula (6A),
7. a process for producing a compound represented by the formula (P) or a pharmacologically acceptable salt thereof,
the method is characterized by using a compound represented by the formula (6A),
8. a process for producing a compound represented by the formula (P) or a pharmacologically acceptable salt thereof,
the method comprises the following steps:
step 5: a step of producing a compound represented by the formula (6B) by reacting the compound represented by the formula (6A) with a base,
step 6: a step of producing a compound represented by formula (8) by reacting the compound represented by formula (6B) with a compound represented by formula (7),
R 2 -OC(O)-X 2 (7)
in the formula (7), X 2 Is a chlorine atom or a bromine atom, R 2 Phenyl which is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of halogen atoms and nitro groups,
in the formula (8), R 2 The same as defined above;
step 7: a step of producing a compound represented by the formula (9) by reacting the compound represented by the formula (8) with N, N-dimethylethylenediamine,
step 8: a step of producing a compound represented by the formula (10) by hydrolyzing the compound represented by the formula (9),
step 9: a step of producing the compound represented by the formula (P) by reacting the compound represented by the formula (10) with sulfur and malononitrile, and separating the compound in a solid state;
step 9P: a step of purifying the compound represented by the formula (P) by recrystallization as needed; and
step 10: further converting the compound represented by the formula (P) into a pharmacologically acceptable salt of the compound represented by the formula (P) as needed.
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| JP6166990B2 (en) * | 2012-09-12 | 2017-07-19 | キッセイ薬品工業株式会社 | Process for producing octahydrothienoquinoline derivative and its intermediate |
| US9585885B2 (en) * | 2012-12-10 | 2017-03-07 | Kissei Pharmaceutical Co., Ltd. | Substituted pyrido[2,3-g]quinazolines as dopamine D2 receptor agonists |
| WO2014112492A1 (en) * | 2013-01-17 | 2014-07-24 | キッセイ薬品工業株式会社 | Novel octahydroquinoline derivative, pharmaceutical composition containing same, and use thereof |
| JP2014172873A (en) * | 2013-03-11 | 2014-09-22 | Kissei Pharmaceutical Co Ltd | Novel octahydroquinoline derivatives, pharmaceutical compositions containing the same, and their applications |
| JP2016011291A (en) * | 2014-06-04 | 2016-01-21 | キッセイ薬品工業株式会社 | Novel dopamine D2 receptor agonist |
| JP2016160206A (en) * | 2015-03-02 | 2016-09-05 | キッセイ薬品工業株式会社 | New ureide carbonyl octahydroquinoline derivative, pharmaceutical composition containing the same and application thereof |
-
2021
- 2021-10-06 CN CN202180068464.4A patent/CN116348470A/en active Pending
- 2021-10-06 TW TW110137109A patent/TW202229290A/en unknown
- 2021-10-06 WO PCT/JP2021/036912 patent/WO2022075347A1/en active Application Filing
- 2021-10-06 JP JP2022555521A patent/JPWO2022075347A1/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| TW202229290A (en) | 2022-08-01 |
| JPWO2022075347A1 (en) | 2022-04-14 |
| WO2022075347A1 (en) | 2022-04-14 |
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