JP2012506847A - シナカルセトを調製するためのプロセス - Google Patents
シナカルセトを調製するためのプロセス Download PDFInfo
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- JP2012506847A JP2012506847A JP2011532599A JP2011532599A JP2012506847A JP 2012506847 A JP2012506847 A JP 2012506847A JP 2011532599 A JP2011532599 A JP 2011532599A JP 2011532599 A JP2011532599 A JP 2011532599A JP 2012506847 A JP2012506847 A JP 2012506847A
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- formula
- represented
- cinacalcet
- compound represented
- compound
- Prior art date
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- VDHAWDNDOKGFTD-MRXNPFEDSA-N cinacalcet Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 VDHAWDNDOKGFTD-MRXNPFEDSA-N 0.000 title claims abstract description 107
- 229960003315 cinacalcet Drugs 0.000 title claims abstract description 102
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims description 158
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 46
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- ABXGMGUHGLQMAW-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(C(F)(F)F)=C1 ABXGMGUHGLQMAW-UHFFFAOYSA-N 0.000 claims description 23
- -1 N-methyl-N-methylenemethanaminium halide Chemical class 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 230000002829 reductive effect Effects 0.000 claims description 9
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000012024 dehydrating agents Substances 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 230000002152 alkylating effect Effects 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000000543 intermediate Substances 0.000 abstract description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 99
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- WFYGIZJPNJFYOP-IQIBNGDESA-N (e)-n-[(1r)-1-naphthalen-1-ylethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)C\C=C\C1=CC=CC(C(F)(F)F)=C1 WFYGIZJPNJFYOP-IQIBNGDESA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- 235000019441 ethanol Nutrition 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 16
- IYGDLMZKWOUQOJ-UHFFFAOYSA-N 3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]propan-1-one;hydrochloride Chemical compound Cl.CN(C)CCC(=O)C1=CC=CC(C(F)(F)F)=C1 IYGDLMZKWOUQOJ-UHFFFAOYSA-N 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- 238000006722 reduction reaction Methods 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000010992 reflux Methods 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- BTANRVKWQNVYAZ-UHFFFAOYSA-N Sec-butyl alcohol Natural products CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- QANQWUQOEJZMLL-PKLMIRHRSA-N cinacalcet hydrochloride Chemical compound Cl.N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 QANQWUQOEJZMLL-PKLMIRHRSA-N 0.000 description 7
- 229960000478 cinacalcet hydrochloride Drugs 0.000 description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 101150003085 Pdcl gene Proteins 0.000 description 6
- 239000004280 Sodium formate Substances 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 6
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 6
- 235000019254 sodium formate Nutrition 0.000 description 6
- 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 5
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 5
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- XJAOTJGPBORSLL-XFULWGLBSA-N 3-[[(1r)-1-naphthalen-1-ylethyl]amino]-1-[3-(trifluoromethyl)phenyl]propan-1-one;hydrochloride Chemical compound Cl.N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCC(=O)C1=CC=CC(C(F)(F)F)=C1 XJAOTJGPBORSLL-XFULWGLBSA-N 0.000 description 4
- WWSUKIRCFAWJOJ-OAQYLSRUSA-N 3-[benzyl-[(1r)-1-naphthalen-1-ylethyl]amino]-1-[3-(trifluoromethyl)phenyl]propan-1-one Chemical compound C=1C=CC=CC=1CN([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCC(=O)C1=CC=CC(C(F)(F)F)=C1 WWSUKIRCFAWJOJ-OAQYLSRUSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- KSBWHDDGWSYETA-SNAWJCMRSA-N (E)-3-(trifluoromethyl)cinnamic acid Chemical compound OC(=O)\C=C\C1=CC=CC(C(F)(F)F)=C1 KSBWHDDGWSYETA-SNAWJCMRSA-N 0.000 description 3
- YLTJJMIWCCJIHI-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]propanoic acid Chemical compound OC(=O)CCC1=CC=CC(C(F)(F)F)=C1 YLTJJMIWCCJIHI-UHFFFAOYSA-N 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- CWUNPFVHATZKFE-MRXNPFEDSA-N cinacalcet carbamate Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)C(=O)OCCCC1=CC=CC(C(F)(F)F)=C1 CWUNPFVHATZKFE-MRXNPFEDSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- DMDSCGYIKXUOGG-UHFFFAOYSA-M trimethyl-[3-oxo-3-[3-(trifluoromethyl)phenyl]propyl]azanium;iodide Chemical compound [I-].C[N+](C)(C)CCC(=O)C1=CC=CC(C(F)(F)F)=C1 DMDSCGYIKXUOGG-UHFFFAOYSA-M 0.000 description 3
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 2
- QWXKQVIMGVVIBX-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]propan-1-ol Chemical compound OCCCC1=CC=CC(C(F)(F)F)=C1 QWXKQVIMGVVIBX-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- 102000013830 Calcium-Sensing Receptors Human genes 0.000 description 2
- 108010050543 Calcium-Sensing Receptors Proteins 0.000 description 2
- 101150065749 Churc1 gene Proteins 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- 102100038239 Protein Churchill Human genes 0.000 description 2
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- VVDUZZGYBOWDSQ-UHFFFAOYSA-M eschenmoser's salt Chemical compound [I-].C[N+](C)=C VVDUZZGYBOWDSQ-UHFFFAOYSA-M 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- GDEHAOJGPHEOSO-OAHLLOKOSA-N n-[(1r)-1-naphthalen-1-ylethyl]-3-[3-(trifluoromethyl)phenyl]propanamide Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)C(=O)CCC1=CC=CC(C(F)(F)F)=C1 GDEHAOJGPHEOSO-OAHLLOKOSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-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
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 2
- GOOYPHDQKHMZHR-OAHLLOKOSA-N (1r)-n-benzyl-1-naphthalen-1-ylethanamine Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CC1=CC=CC=C1 GOOYPHDQKHMZHR-OAHLLOKOSA-N 0.000 description 1
- KCLJDAVYFCDIDY-XFULWGLBSA-N (1r)-n-benzyl-1-naphthalen-1-ylethanamine;hydrochloride Chemical compound Cl.N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CC1=CC=CC=C1 KCLJDAVYFCDIDY-XFULWGLBSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- KWEKXPWNFQBJAY-UHFFFAOYSA-N (dimethyl-$l^{3}-silanyl)oxy-dimethylsilicon Chemical compound C[Si](C)O[Si](C)C KWEKXPWNFQBJAY-UHFFFAOYSA-N 0.000 description 1
- OBTFEAIGXISQSS-UHFFFAOYSA-N 1-amino-1-[3-(trifluoromethyl)phenyl]propan-1-ol Chemical compound NC(CC)(O)C1=CC(=CC=C1)C(F)(F)F OBTFEAIGXISQSS-UHFFFAOYSA-N 0.000 description 1
- NNMBNYHMJRJUBC-UHFFFAOYSA-N 1-bromo-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(Br)=C1 NNMBNYHMJRJUBC-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- XBPDAKZKYMDZJH-UHFFFAOYSA-N 3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]propan-1-one Chemical compound CN(C)CCC(=O)C1=CC=CC(C(F)(F)F)=C1 XBPDAKZKYMDZJH-UHFFFAOYSA-N 0.000 description 1
- IPXTWKCDCXMGLF-UHFFFAOYSA-N 3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]propan-1-one;hydroiodide Chemical compound I.CN(C)CCC(=O)C1=CC=CC(C(F)(F)F)=C1 IPXTWKCDCXMGLF-UHFFFAOYSA-N 0.000 description 1
- APCCHYPQHODSBD-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]propanal Chemical compound FC(F)(F)C1=CC=CC(CCC=O)=C1 APCCHYPQHODSBD-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N Butanol Natural products CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- 0 C[C@@](*CCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12 Chemical compound C[C@@](*CCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12 0.000 description 1
- OQAFZFFHFYUKIC-AUTVTPELSA-N C[C@H](/C(/C=C)=C(\C=CC=C1)/C1=C\C)NCCC(c1cc(C(F)(F)F)ccc1)=O Chemical compound C[C@H](/C(/C=C)=C(\C=CC=C1)/C1=C\C)NCCC(c1cc(C(F)(F)F)ccc1)=O OQAFZFFHFYUKIC-AUTVTPELSA-N 0.000 description 1
- VWVCDYANVNDQIN-XPFLVSTFSA-N C[C@H](c1cccc2ccccc12)NC/C=C/C(C1)=CC=CC1C(F)(F)F Chemical compound C[C@H](c1cccc2ccccc12)NC/C=C/C(C1)=CC=CC1C(F)(F)F VWVCDYANVNDQIN-XPFLVSTFSA-N 0.000 description 1
- HBNXNENVPBYUJL-XESZBRCGSA-N C[C@H](c1cccc2ccccc12)NCCCC(c1cc(C(F)(F)F)ccc1)O Chemical compound C[C@H](c1cccc2ccccc12)NCCCC(c1cc(C(F)(F)F)ccc1)O HBNXNENVPBYUJL-XESZBRCGSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 150000003975 aryl alkyl amines Chemical class 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 230000002092 calcimimetic effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000852 hydrogen donor Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000002934 lysing effect Effects 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
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- VDHAWDNDOKGFTD-UHFFFAOYSA-N n-(1-naphthalen-1-ylethyl)-3-[3-(trifluoromethyl)phenyl]propan-1-amine Chemical compound C=1C=CC2=CC=CC=C2C=1C(C)NCCCC1=CC=CC(C(F)(F)F)=C1 VDHAWDNDOKGFTD-UHFFFAOYSA-N 0.000 description 1
- GDEHAOJGPHEOSO-UHFFFAOYSA-N n-(1-naphthalen-1-ylethyl)-3-[3-(trifluoromethyl)phenyl]propanamide Chemical compound C=1C=CC2=CC=CC=C2C=1C(C)NC(=O)CCC1=CC=CC(C(F)(F)F)=C1 GDEHAOJGPHEOSO-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 230000028327 secretion Effects 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
a)式(II):
b)上述の式(II)で表される化合物を、
(i)次式:
HNR1R2
(式中、R1及びR2は独立して水素又はC1〜C5のアルキルを表わし、R1及びR2の一方が水素の場合、他方は水素ではなく、或いは、R1及びR2が共にC4〜C7のアルキレンブリッジを形成し、これらに結合している窒素原子を含めて複素環を形成し、C4〜C7のアルキレンブリッジの1個の−CH2−基はホルムアルデヒドの存在下で−O−に置換されていてもよい)で表される化合物、又は
(ii)次式:
(CH3)2N+=CH2 Hal-
(式中、Halはハロゲン原子である)で表されるN−メチル−N−メチレンメタンアミニウムハライド
と反応させて式(IV):
c)次式:
R3−X、CO(OR3)2、SO2(OR3)2、PO(OR3)3、CH3PO(OR3)2及び(4−NO2C6H4O)PO(OR3)2(式中、R3はC1〜C4のアルキルであり、XはI、Br、OSO2CF3又はOSO2Fである)で表される化合物から成る群から選択されるアルキル化剤を用いて式(IV)で表される化合物をアルキル化して、式(IVa):
d)式(IVa)で表される化合物を式(III)で表される(R)−(1−ナフチル)エチルアミンと結合させる工程とを含むプロセスを提供する。
e)還元剤の存在下、又は接触水素化プロセスによって式(V)で表される化合物を還元する工程を含む調製を提供する。
f)脱水剤を用いて式(Va)で表される化合物を脱水する工程、又は
g)上述の式(V)で表される化合物を酸の存在下、Znを用いて還元して、式(VI)で表される化合物を式(I)で表されるシナカルセトとの混合物として得る工程を含む調製を提供する。
h)式(VI)で表される化合物の二重結合を還元して、式(I)で表される化合物を得る工程を含む調製を提供する。
a)式(II):
e)還元剤の存在下、又は接触水素化プロセスによって式(V)で表される化合物を還元して、式(Va):
f)脱水剤を用いて式(Va)で表される化合物を脱水して、式(VI):
h)式(VI)で表される化合物を還元して、式(I)で表されるシナカルセトを得る工程とを含む。
a)式(II):
g)上述の式(V)で表される化合物を酸の存在下、Znを用いて還元して、式(VI):
h)式(VI)で表される化合物を還元して、式(I)で表されるシナカルセトを得る工程とを含む。
b)上述の式(II)で表される化合物を、
(i)次式:
HNR1R2
(式中、R1及びR2は独立して水素又はC1〜C5のアルキルを表わし、R1及びR2の一方が水素の場合、他方は水素ではなく、或いは、R1及びR2が共にC4〜C7のアルキレンブリッジを形成し、これらに結合している窒素原子を含めて複素環を形成し、C4〜C7のアルキレンブリッジの1個の−CH2−基はホルムアルデヒドの存在下で−O−に置換されていてもよい)で表される化合物、又は
(ii)次式:
(CH3)2N+=CH2 Hal-
(式中、Halはハロゲン原子である)で表されるN−メチル−N−メチレンメタンアミニウムハライドと反応させて式(IV):
c)次式:
R3−X、CO(OR3)2、SO2(OR3)2、PO(OR3)3、CH3PO(OR3)2及び(4−NO2C6H4O)PO(OR3)2(式中、R3はC1〜C4のアルキルであり、XはI、Br、OSO2CF3又はOSO2Fである)で表される化合物から成る群より選択されるアルキル化剤を用いて、式(IV)で表される化合物をアルキル化して式(IVa):
d)式(IVa)で表される化合物を式(III)で表される(R)−(1−ナフチル)エチルアミンと結合させて、式(V):
e)還元剤の存在下、又は接触水素化プロセスによって式(V)で表される化合物を還元して、式(Va):
f)脱水剤を用いて式(Va)で表される化合物を脱水して、式(VI):
h)式(VI)で表される化合物を還元して、式(I)で表されるシナカルセトを得る工程とを含む。
b)上述の式(II)で表される化合物を、
(i)次式:
HNR1R2
(式中、R1及びR2は独立して水素又はC1〜C5のアルキルを表わし、R1及びR2の一方が水素の場合、他方は水素ではなく、或いは、R1及びR2が共にC4〜C7のアルキレンブリッジを形成し、これらに結合している窒素原子を含めて複素環を形成し、C4〜C7のアルキレンブリッジの1個の−CH2−基はホルムアルデヒドの存在下で−O−に置換されていてもよい)で表される化合物、又は
(ii)次式:
(CH3)2N+=CH2 Hal-
(式中、Halはハロゲン原子である)で表されるN−メチル−N−メチレンメタンアミニウムハライドと反応させて式(IV):
c)次式:
R3−X、CO(OR3)2、SO2(OR3)2、PO(OR3)3、CH3PO(OR3)2及び(4−NO2C6H4O)PO(OR3)2(式中、R3はC1〜C4のアルキルであり、XはI、Br、OSO2CF3又はOSO2Fである)で表される化合物から成る群より選択されるアルキル化剤を用いて、式(IV)で表される化合物をアルキル化して式(IVa):
d)式(IVa)で表される化合物を式(III)で表される(R)−(1−ナフチル)エチルアミンと結合させて、式(V):
g)上述の式(V)で表される化合物を酸の存在下、Znを用いて還元して、式(VI):
h)式(VI)で表される化合物の二重結合を還元して、式(I)で表される化合物を得る工程とを含む。
j)上述の式(IVa)で表される化合物を式(IIIa):
k)式(Vb)で表される化合物を式(I)で表されるシナカルセトに還元し、必要に応じて、式(I)で表されるシナカルセトを、式(I)で表される化合物との塩の生成に適した薬学的に許容される酸と反応させる工程を含む調製を提供する。
(R)−3−(1−(ナフタレン−1−イル)エチルアミノ)−1−(3−(トリフルオロメチル)フェニル)プロパン−1−オン塩酸塩(V)の合成
方法A
1H NMR (400 MHz, DMSO-d6),δ(ppm, TMS): 10.00 (1H, br s; -NH2 +-), 9.24 (1H, br s; -NH2 +-), 8.31 (1H, d, J = 8.4; ArH), 8.23 (1H, d, J = 8.0 Hz; ArH), 8.16 (1H, br s; ArH), 8.08-7.96 (4H, m; ArH), 7.82 (1H, t, J = 8.0 Hz; ArH), 7.69-7.58 (3H, m; ArH), 5.47-5.36 (1H, m; -CH(CH3)-), 3.70-3.54 (2H, m; -CH2-), 3.41-3.26 (2H, m; -CH2-), 1.72 (3H, m, J = 6.4 Hz; -CH(CH3)-).
塩酸(R)−(1−ナフチル)エチルアミン(III)(1.5g)、パラホルムアルデヒド(0.3g)、3−(トリフルオロメチル)アセトフェノン(II)(1.8g)、30%w/w塩酸水溶液(0.1g)、エタノール(4.5g)及び水(1.5g)を攪拌下で反応器に投入し、HPLCによって充分な転化が確認されるまでマイクロ波照射(最大250W)下で5分間反応させた。次に、水(10.0g)及びトルエン(3.0g)を添加し、得られた懸濁液を25℃で攪拌した。室温での濾過により標記化合物(1.6g)を単離し、水及びメチル2−プロパノールで洗浄し、50℃で乾燥した。
3−(ジメチルアミノ)−1−(3−(トリフルオロメチル)フェニル)プロパン−1−オン塩酸塩(IV)の合成
3−(ジメチルアミノ)−1−(3−(トリフルオロメチル)フェニル)プロパン−1−オンヨウ化水素酸塩(IV)の合成
N,N,N−トリメチル−3−オキソ−3−(3−(トリフルオロメチル)フェニル)プロパン−1−アミニウムヨウ化物(IVa)の合成
(R)−3−(1−(ナフタレン−1−イル)エチルアミノ)−1−(3−(トリフルオロメチル)フェニル)プロパン−1−オン塩酸塩(V)の合成
(R,E)−N−(1−(ナフタレン−1−イル)エチル)−3−(3−(トリフルオロメチル)フェニル)プロパ−2−エン−1−アミン(VI)及び(R)−N−(1−(ナフタレン−1−イル)エチル)−3−(3−(トリフルオロメチル)フェニル)プロパン−1−アミン(I)の混合物の合成
(R)−及び(S)−3−((R)−1−(ナフタレン−1−イル)エチルアミノ−1−(3−(トリフルオロメチル)フェニル)プロパン−1−オール(Va)の合成
(R,E)−N−(1−(ナフタレン−1−イル)エチル)−3−(3−(トリフルオロメチル)フェニル)プロパ−2−エン−1−アミン(VI)の合成
1H NMR (400 MHz, CDCl3),δ(ppm, TMS): 8.21-8.17 (1H, m; ArH), 7.92-7.86 (1H, m; ArH), 7.78 (1H, d, J = 8.0 Hz; ArH), 7.72 (1H, d, J = 7.2 Hz; ArH), 7.58-7.45 (6H, m; ArH), 7.43-7.37 (1H, m; ArH), 6.48 (1H, d, J = 16.0 Hz; -ArCH=CHCH2-), 6.39 (1H, dt, J = 16.0, 6.0 Hz; -ArCH=CHCH2-), 4.76 (1H, q, J = 6.6 Hz; -CH(CH3)-), 3.46-3.33 (2H, m; -CH2-), 1.57 (3H, d, J = 6.6; -CH(CH3)-).
シナカルセト遊離塩基(I)の合成
シナカルセト遊離塩基(I)の合成
((R)−3−(ベンジル(1−(ナフタレン−1−イル)エチル)アミノ)−1−(3−(トリフルオロメチル)フェニル)プロパン−1−オン(Vb)の合成
1H NMR (400 MHz, DMSO-d6),δ(ppm, TMS): 8.19 (1H, d, J = 8.4 Hz; ArH), 7.92-7.86 (3H, m; ArH), 7.86-7.83 (1H, m; ArH), 7.74 (1H, d, J = 8.4 Hz; ArH), 7.64-7.56 (2H, m; ArH), 7.45-7.36 (3H, m; ArH), 7.20-7.19 (4H, m; ArH), 7.19-7.11 (1H, m; ArH), 4.69 (1H, q, J = 6.8; -CH(CH3)-), 3.73 (1H, d, J = 14.0 Hz; PhCH2-), 3.58 (1H, d, J = 14.0 Hz; PhCH2-), 3.24-3.01 (2H, m; -CH2-), 3.00-2.89 (2H, m; -CH2-), 1.48 (3H, d, J = 6.8; -CH(CH3)-).
Claims (17)
- 請求項1に記載の式(V)で表されるシナカルセト中間体を調製するためのプロセスであって、次の工程:
b)式(II):
(i)次式:
HNR1R2
(式中、R1及びR2は独立して水素又はC1〜C5のアルキルを表わし、R1及びR2の一方が水素の場合、他方は水素ではなく、或いは、R1及びR2が共にC4〜C7のアルキレンブリッジを形成し、これらに結合している窒素原子を含めて複素環を形成し、C4〜C7のアルキレンブリッジの1個の−CH2−基はホルムアルデヒドの存在下で−O−に置換されていてもよい)で表される化合物、又は
(ii)次式:
(CH3)2N+=CH2 Hal-
(式中、Halはハロゲン原子である)で表されるN−メチル−N−メチレンメタンアミニウムハライド
と反応させて式(IV):
c)次式:
R3−X、CO(OR3)2、SO2(OR3)2、PO(OR3)3、CH3PO(OR3)2及び(4−NO2C6H4O)PO(OR3)2(式中、R3はC1〜C4のアルキルであり、XはI、Br、OSO2CF3又はOSO2Fである)で表される化合物から成る群より選択されるアルキル化剤を用いて式(IV)で表される化合物をアルキル化して、式(IVa):
d)式(IVa)で表される化合物を式(III):
- 請求項2に記載の式(Va)で表されるシナカルセト中間体を調製するためのプロセスであって、次の工程:
e)還元剤の存在下、又は接触水素化プロセスによって、請求項1に記載の式(V)で表される化合物を還元して、式(Va)で表される化合物を得る工程を含むプロセス。 - 請求項7に記載の式(Va)で表されるシナカルセト中間体を調製するためのプロセスであって、請求項4又は5に記載の式(V)で表される化合物を調製する工程を含むプロセス。
- 請求項10に記載の式(VI)で表されるシナカルセト中間体を調製するためのプロセスであって、請求項7又は8に記載の式(Va)で表される化合物を調製する工程を含むプロセス。
- 請求項10に記載の式(VI)で表されるシナカルセト中間体を調製するためのプロセスであって、請求項4又は5に記載の式(V)で表される化合物を調製する工程を含むプロセス。
- 式(I):
a)式(II):
e)還元剤の存在下、又は接触水素化プロセスによって、式(V)で表される化合物を還元して、式(Va):
f)脱水剤を用いて式(Va)で表される化合物を脱水して、式(VI):
h)式(VI)で表される化合物を還元して、式(I)で表されるシナカルセトを得る工程とを含み、必要に応じてシナカルセトを薬学的に許容される塩に転化する工程を含むプロセス。 - 式(I):
a)式(II):
g)上述の式(V)で表される化合物を酸の存在下、Znを用いて還元して、式(VI):
h)式(VI)で表される化合物を還元して、式(I)で表されるシナカルセトを得る工程とを含み、必要に応じてシナカルセトを薬学的に許容される塩に転化する工程を含むプロセス。 - 式(I):
b)式(II):
(i)次式:
HNR1R2
(式中、R1及びR2は独立して水素又はC1〜C5のアルキルを表わし、R1及びR2の一方が水素の場合、他方は水素ではなく、或いは、R1及びR2が共にC4〜C7のアルキレンブリッジを形成し、これらに結合している窒素原子を含めて複素環を形成し、C4〜C7のアルキレンブリッジの1個の−CH2−基はホルムアルデヒドの存在下で−O−に置換されていてもよい)で表される化合物、又は
(ii)次式:
(CH3)2N+=CH2 Hal-
(式中、Halはハロゲン原子である)で表されるN−メチル−N−メチレンメタンアミニウムハライド
と反応させて式(IV):
c)次式:
R3−X、CO(OR3)2、SO2(OR3)2、PO(OR3)3、CH3PO(OR3)2及び(4−NO2C6H4O)PO(OR3)2(式中、R3はC1〜C4のアルキルであり、XはI、Br、OSO2CF3又はOSO2Fである)で表される化合物から成る群より選択されるアルキル化剤を用いて式(IV)で表される化合物をアルキル化して、式(IVa):
d)式(IVa)で表される化合物を式(III)で表される(R)−(1−ナフチル)エチルアミンと結合させて、式(V):
e)還元剤の存在下、又は接触水素化プロセスによって、式(V)で表される化合物を還元して、式(Va):
f)脱水剤を用いて式(Va)で表される化合物を脱水して、式(VI):
h)式(VI)で表される化合物を還元して、式(I)で表されるシナカルセトを得る工程とを含み、必要に応じてシナカルセトを薬学的に許容される塩に転化する工程を含むプロセス。 - 式(I):
b)上述の式(II)で表される化合物を、
(i)次式:
HNR1R2
(式中、R1及びR2は独立して水素又はC1〜C5のアルキルを表わし、R1及びR2の一方が水素の場合、他方は水素ではなく、或いは、R1及びR2が共にC4〜C7のアルキレンブリッジを形成し、これらに結合している窒素原子を含めて複素環を形成し、C4〜C7のアルキレンブリッジの1個の−CH2−基はホルムアルデヒドの存在下で−O−に置換されていてもよい)で表される化合物、又は
(ii)次式:
(CH3)2N+=CH2 Hal-
(式中、Halはハロゲン原子である)で表されるN−メチル−N−メチレンメタンアミニウムハライドと反応させて式(IV):
c)次式:
R3−X、CO(OR3)2、SO2(OR3)2、PO(OR3)3、CH3PO(OR3)2及び(4−NO2C6H4O)PO(OR3)2(式中、R3はC1〜C4のアルキルであり、XはI、Br、OSO2CF3又はOSO2Fである)で表される化合物から成る群より選択されるアルキル化剤を用いて式(IV)で表される化合物をアルキル化して、式(IVa):
d)式(IVa)で表される化合物を式(III)で表される(R)−(1−ナフチル)エチルアミンと結合させて、式(V):
g)上述の式(V)で表される化合物を酸の存在下、Znを用いて還元して、式(VI):
h)式(VI)で表される化合物の二重結合を還元して、式(I)で表されるシナカルセトを得る工程とを含み、必要に応じてシナカルセトを薬学的に許容される塩に転化する工程を含むプロセス。
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