JP2021536471A - メチル6−(2,4−ジクロロフェニル)−5−[4−[(3s)−1−(3−フルオロプロピル)ピロリジン−3−イル]オキシフェニル]−8,9−ジヒドロ−7h−ベンゾ[7]アンヌレン−2−カルボキシレートの塩およびその製造方法 - Google Patents
メチル6−(2,4−ジクロロフェニル)−5−[4−[(3s)−1−(3−フルオロプロピル)ピロリジン−3−イル]オキシフェニル]−8,9−ジヒドロ−7h−ベンゾ[7]アンヌレン−2−カルボキシレートの塩およびその製造方法 Download PDFInfo
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- JP2021536471A JP2021536471A JP2021512678A JP2021512678A JP2021536471A JP 2021536471 A JP2021536471 A JP 2021536471A JP 2021512678 A JP2021512678 A JP 2021512678A JP 2021512678 A JP2021512678 A JP 2021512678A JP 2021536471 A JP2021536471 A JP 2021536471A
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- Prior art keywords
- compound
- solvent
- pyrrolidine
- salt
- reaction
- Prior art date
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- Granted
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- 150000003839 salts Chemical class 0.000 title claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 title claims description 21
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 title abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title abstract description 9
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 title abstract description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims description 135
- -1 6- (2,4-dichlorophenyl) -5- {4- [1- (3-fluoro-propyl) -pyrrolidine-3-yloxy] -phenyl} -8,9-dihydro-7H-benzocycloheptene- 2-Carboxylic acid methyl ester oxalate Chemical compound 0.000 claims description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 15
- 229940011051 isopropyl acetate Drugs 0.000 claims description 15
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- 235000006408 oxalic acid Nutrition 0.000 claims description 5
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 claims description 4
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- NTBIYBAYFBNTCD-UHFFFAOYSA-N dibenzoyl 2,3-dihydroxybutanedioate Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C(O)C(O)C(=O)OC(=O)C1=CC=CC=C1 NTBIYBAYFBNTCD-UHFFFAOYSA-N 0.000 abstract description 11
- 239000000126 substance Substances 0.000 abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 55
- 238000006243 chemical reaction Methods 0.000 description 26
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 239000003153 chemical reaction reagent Substances 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 15
- 238000006069 Suzuki reaction reaction Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 230000037361 pathway Effects 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- AXDYGPIMKPWMQH-UHFFFAOYSA-N methyl 5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene-2-carboxylate Chemical compound C1CCCC(=O)C=2C1=CC(C(=O)OC)=CC=2 AXDYGPIMKPWMQH-UHFFFAOYSA-N 0.000 description 7
- 239000012429 reaction media Substances 0.000 description 7
- 238000007127 saponification reaction Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000004949 mass spectrometry Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229910052796 boron Inorganic materials 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 238000005660 chlorination reaction Methods 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 150000002148 esters Chemical group 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 4
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 3
- ISHYFWKKWKXXPL-UHFFFAOYSA-N 1-bromo-2,4-dichlorobenzene Chemical compound ClC1=CC=C(Br)C(Cl)=C1 ISHYFWKKWKXXPL-UHFFFAOYSA-N 0.000 description 3
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QNEGDGPAXKYZHZ-UHFFFAOYSA-N (2,4-dichlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1Cl QNEGDGPAXKYZHZ-UHFFFAOYSA-N 0.000 description 2
- 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
- URBUZQPPQLQHBZ-UHFFFAOYSA-N 1-fluoro-3-iodopropane Chemical compound FCCCI URBUZQPPQLQHBZ-UHFFFAOYSA-N 0.000 description 2
- ZQKJCBDCOGLKCQ-UHFFFAOYSA-N 2,4-dichloro-1-iodobenzene Chemical compound ClC1=CC=C(I)C(Cl)=C1 ZQKJCBDCOGLKCQ-UHFFFAOYSA-N 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
- BICZJRAGTCRORZ-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(O)C=C1 BICZJRAGTCRORZ-UHFFFAOYSA-N 0.000 description 2
- LSAUHWRNBBMZIC-UHFFFAOYSA-N 4-sulfanyl-1h-triazine-6-thione Chemical compound SC1=CC(=S)NN=N1 LSAUHWRNBBMZIC-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- ZLXABOVOCSRKAL-KRWDZBQOSA-N FCCCN1C[C@H](CC1)OC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C Chemical compound FCCCN1C[C@H](CC1)OC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C ZLXABOVOCSRKAL-KRWDZBQOSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000005228 aryl sulfonate group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- IIJREXIVDSIOFR-UHFFFAOYSA-N dichloromethane;heptane Chemical compound ClCCl.CCCCCCC IIJREXIVDSIOFR-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 102000015694 estrogen receptors Human genes 0.000 description 2
- 108010038795 estrogen receptors Proteins 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- AEDZDSTZWLDMAR-UHFFFAOYSA-N methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate Chemical compound ClC1=C(C=CC(=C1)Cl)C1=C(C2=C(CCC1)C=C(C=C2)C(=O)OC)OS(=O)(=O)C(F)(F)F AEDZDSTZWLDMAR-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 150000002940 palladium Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical compound F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 2
- APCBTRDHCDOPNY-SSDOTTSWSA-N tert-butyl (3r)-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](O)C1 APCBTRDHCDOPNY-SSDOTTSWSA-N 0.000 description 2
- SGHPXNIINLLSMV-KRWDZBQOSA-N tert-butyl (3s)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC1=CC=C(B2OC(C)(C)C(C)(C)O2)C=C1 SGHPXNIINLLSMV-KRWDZBQOSA-N 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- ZLXABOVOCSRKAL-UHFFFAOYSA-N 1-(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine Chemical compound FCCCN1CC(CC1)OC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C ZLXABOVOCSRKAL-UHFFFAOYSA-N 0.000 description 1
- HVKCZUVMQPUWSX-UHFFFAOYSA-N 1-bromo-2,3-dichlorobenzene Chemical compound ClC1=CC=CC(Br)=C1Cl HVKCZUVMQPUWSX-UHFFFAOYSA-N 0.000 description 1
- WLRMIOGKWITDNU-UHFFFAOYSA-N 2-methoxy-6,7,8,9-tetrahydrobenzo[7]annulen-5-one Chemical compound C1CCCC(=O)C=2C1=CC(OC)=CC=2 WLRMIOGKWITDNU-UHFFFAOYSA-N 0.000 description 1
- VSCBATMPTLKTOV-UHFFFAOYSA-N 2-tert-butylimino-n,n-diethyl-1,3-dimethyl-1,3,2$l^{5}-diazaphosphinan-2-amine Chemical compound CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C VSCBATMPTLKTOV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910018072 Al 2 O 3 Inorganic materials 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- MKUJUQWPQBXXEM-AWEZNQCLSA-N CC1(OB(OC1(C)C)C1=CC=C(O[C@@H]2CNCC2)C=C1)C Chemical compound CC1(OB(OC1(C)C)C1=CC=C(O[C@@H]2CNCC2)C=C1)C MKUJUQWPQBXXEM-AWEZNQCLSA-N 0.000 description 1
- BHVCZKSVHXCBNQ-UHFFFAOYSA-N CCCCCCC.CCl Chemical compound CCCCCCC.CCl BHVCZKSVHXCBNQ-UHFFFAOYSA-N 0.000 description 1
- 0 COC(c(cc1CCC2)ccc1C(*)=C2c(c(Cl)c1)ccc1Cl)=O Chemical compound COC(c(cc1CCC2)ccc1C(*)=C2c(c(Cl)c1)ccc1Cl)=O 0.000 description 1
- MGHONVIXIACLEQ-UHFFFAOYSA-N COC(c(cc1CCCC2c(ccc(Cl)c3)c3Cl)ccc1C2=O)=O Chemical compound COC(c(cc1CCCC2c(ccc(Cl)c3)c3Cl)ccc1C2=O)=O MGHONVIXIACLEQ-UHFFFAOYSA-N 0.000 description 1
- KOKLVESEZTUZTG-BMWKDGKBSA-N C[C@H]1C=CC=CC1C(O)OCC(C([O]=C)=O)OCC1=CC=CCC1 Chemical compound C[C@H]1C=CC=CC1C(O)OCC(C([O]=C)=O)OCC1=CC=CCC1 KOKLVESEZTUZTG-BMWKDGKBSA-N 0.000 description 1
- YDCDQLPZRXYIRX-UQKRIMTDSA-N Cl.CC1(OB(OC1(C)C)C1=CC=C(O[C@@H]2CNCC2)C=C1)C Chemical compound Cl.CC1(OB(OC1(C)C)C1=CC=C(O[C@@H]2CNCC2)C=C1)C YDCDQLPZRXYIRX-UQKRIMTDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229940102550 Estrogen receptor antagonist Drugs 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- QZUPHAGRBBOLTB-UHFFFAOYSA-N NSC 244302 Chemical compound C=1C=CC=CC=1P(C(C)(C)C)C1=CC=CC=C1 QZUPHAGRBBOLTB-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- VSWDORGPIHIGNW-UHFFFAOYSA-N Pyrrolidine dithiocarbamic acid Chemical compound SC(=S)N1CCCC1 VSWDORGPIHIGNW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000007983 Tris buffer Substances 0.000 description 1
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 description 1
- DZJXKISLUDYJSV-UHFFFAOYSA-N [N].C1CCNC1 Chemical compound [N].C1CCNC1 DZJXKISLUDYJSV-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 150000001638 boron Chemical class 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-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
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- MUJOVVKDDICVMS-UHFFFAOYSA-N diazaphosphinine Chemical compound C1=CN=NP=C1 MUJOVVKDDICVMS-UHFFFAOYSA-N 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 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
- 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
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005003 perfluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000005009 perfluoropropyl group Chemical group FC(C(C(F)(F)F)(F)F)(F)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- CTYRPMDGLDAWRQ-UHFFFAOYSA-N phenyl hydrogen sulfate Chemical compound OS(=O)(=O)OC1=CC=CC=C1 CTYRPMDGLDAWRQ-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 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
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 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
- PVNUIRUAPVSSOK-UHFFFAOYSA-N tert-butylimino(tripyrrolidin-1-yl)-$l^{5}-phosphane Chemical compound C1CCCN1P(N1CCCC1)(=NC(C)(C)C)N1CCCC1 PVNUIRUAPVSSOK-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/1616—Coordination complexes, e.g. organometallic complexes, immobilised on an inorganic support, e.g. ship-in-a-bottle type catalysts
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/06—Oxalic acid
- C07C55/07—Salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Health & Medical Sciences (AREA)
- Pyrrole Compounds (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
− エステル型溶媒、エーテル型溶媒、およびトルエンから選択される溶媒中で、化合物(2)にシュウ酸を添加する工程を含む、前記化合物(2)のシュウ酸塩の製造方法;ならびに
− トルエンとヘプタンとの混合物中で、化合物(2)にジベンゾイル酒石酸を添加する工程を含む、前記化合物(2)のジベンゾイル酒石酸塩の製造方法、
がさらに提供される。
特に、本発明による塩は、本明細書において以降でスキーム3および4に表される特許出願国際公開第2017/140669号に記載の合成経路に従って得ることができる。塩を得る前の工程は、以下のスキームによって表される。
本明細書では、上記で述べる塩形態:
n=1〜4である式−O−SO2−CnF(2n+1)の脱離基、より特定すると、トリフレート(n=1の場合)またはノナフレート(n=4の場合)、または
臭素またはヨウ素から選択されるハロゲン原子、
を表すことができる。
− アルキル基:直鎖状または分岐鎖状の飽和炭化水素ベースの脂肪族基で、特に断りのない限り、1〜6個の炭素原子を含む(「(C1〜C6)−アルキル」と記載)。例えば、限定されないが、メチル、エチル、プロピル、n−プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、イソペンチル、ヘキシル、およびイソヘキシル基などが言及される。前記基は、フッ素原子によって部分的にまたは完全に置換することができ、限定されないが、ペルフルオロメチル、ペルフルオロエチル、ペルフルオロプロピル、ペルフルオロブチルなどが挙げられる;
− アリール基:フェニル、ナフチル、または置換フェニルであり、ここで、置換フェニルは、水素の1つまたはそれ以上が:ハロゲン原子、アルキル、ニトロ、シアノ、アルコキシ、アリール、ヘテロアリール、およびトリフルオロメチル基などが挙げられるがこれらに限定されない同じまたは異なる置換基によって置き換えられたフェニル基として定義される。
本明細書において以降で述べる塩化工程は、両方の合成経路(国際公開第2017/140669号経路および改善された経路)において実行することができる。
本明細書で述べる化合物(2)の合成方法の鈴木カップリング工程で有用である試薬(1)の製造を、特許出願国際公開第2017/140669号から再現して以下のスキーム5に示す。
1H NMR(400 MHz, DMSO-d6, δ ppm): 1.27 (s, 12H); 1.39 (s, 9H); 2.05 (m, 1H); 2.14 (m, 1H); 3.37 (3H); 3,55 (m, 1H); 5.05 (s, 1H); 6.94 (d, J = 8.4 Hz, 2H); 7.61 (d, J = 8.4 Hz, 2H).
1H NMR(400 MHz, DMSO-d6, δ ppm): 1.28 (s : 12H); 2.10 (m : 1H); 2.21 (m : 1H); 3.31 (3H); 3.48 (m, : 1H); 5.19 (m : 1H); 6.97 (d , J = 8.4 Hz : 2H); 7.63 (d , J = 8.4 Hz : 2H); 9.48 (s : 1H); 9.71 (s : 1H).
LC/MS (m/z, MH+): 290
1H NMR(400 MHz, DMSO-d6, δ ppm): 1.27 (s, 12H); 1.77 (m, 2H); 1.84 (m, 1H); 2.27 (m, 1H); 2.41 (m, 1H); 2.49 (2H); 2.62 (dd, J = 2,6 and 10,4Hz, 1H); 2.69 (m, 1H); 2.83 (dd, J = 6.2 and 1.4Hz, 1H); 4.47 (td, J = 6.2 and 47Hz, 2H); 4.99 (m, 1H); 6.77 (d, J = 8.4 Hz, 2H); 7.58 (d, J = 8.4 Hz, 2H).
LC/MS (m/z, MH+): 350
中間体および最終化合物(2)、(3’)、(4)、および(5)のナンバリングは、上記で述べたスキーム2を参照する。
メチル5−オキソ−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アンヌレン−2−カルボキシレート(5)(40g)、炭酸カリウム(K2CO3、40〜101g、すなわち、1.5〜4当量)、ブロモ−ジクロロベンゼン(62.1g)、キサントホス(21.2g)、およびPd2dba3(8.39g)の脱気した混合物を、窒素下、激しく撹拌しながら、反応が完了するまでトルエン(320ml)中で還流した。
1H NMR (400 MHz, DMSO-d6 in ppm) of the isolated compound (4): 1.77 (m, 1 H) 2.00 (m, 1 H); 2.18 (m, 2 H); 3.08 (m, 1 H); 3.20 (m, 1 H); 3.89 (s, 3 H); 4.46 (dd, J=11.3, 3.7 Hz, 1 H); 7.46 (m, 2 H); 7.59 (d, J=2.0 Hz, 1 H); 7.64 (d, J=7.9 Hz, 1 H); 7.91 (dd, J=8.0, 1.4 Hz, 1 H); 7.94 (s, 1 H).
LC/MS ([M+H]+): 363
1H NMR (400 MHz, DMSO-d6 in ppm): 2.18 (m, 2 H); 2.41 (m, 2 H); 2.95 (m, 2 H); 3.90 (s, 3 H); 7.55 (m, 2 H); 7.68 (d, J=8 Hz, 1 H); 7.80 (d, J=1.8 Hz, 1 H) 8.01 (m, 2 H).
LC/MS (EI m/z): 494 +
化合物(3’)の純度:99.0%、HPLCで測定:
− 移動相:水/アセトニトリル/HCOOH;
− 固定相:XSelect CSH C18−3.5μm(Waters)または同等物;
− カラム長さ:100mm;
− カラム内径:4.6mm;
− 流量:1mL/分;
− 注入量:10μL;
− 検出:254nm(UV)。
トリフレート(3’)(20g)、ボロン酸エステル「試薬(1)」(14.1g)、Cs2CO3(19.7g)、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド(1.4g)、水(100ml)、およびアセトニトリル(260ml)の脱気した混合物を、窒素下、40℃で撹拌した。変換の完了後、反応媒体を室温まで冷却し、酢酸イソプロピル(100ml)を添加し、水相を分離した。有機相を、希NaCl水溶液(0.3M;2×200ml)で洗浄し、酢酸イソプロピルの共沸蒸留によって乾燥し、エチレンジアミン、チャコール、およびジメルカプトトリアジンをグラフトしたシリカ、で順に処理して、残留パラジウムを除去した。
LC/MS ([M+H]+): 568
3.1:代替法1
ナトリウムtert−ブトキシドの2M THF溶液(19.48ml)を、化合物(5)(5g)、1−ブロモ−2,4−ジクロロベンゼン(7.76g)、酢酸パラジウム(257mg)、キサントホス(660mg)、およびTHF(20ml)を含有する脱気した混合物に60℃で滴下した。この反応物を、反応完了まで60℃で加熱し、室温まで冷却し、モルのKH2PO4水溶液でクエンチした。酢酸エチルによる抽出、水による洗浄、およびシリカゲルクロマトグラフィによる精製の後、化合物(4)を、収率70%、純度92%で単離した。
1H NMR (400 MHz, DMSO-d6 in ppm): 1.78 (m, 1 H); 2.01 (m, 1 H); 2.19 (m, 2 H); 3.10 (m, 1 H); 3.22 (m, 1 H); 3.89 (s, 3 H); 4.47 (dd, J=11.3, 3.6 Hz, 1 H); 7.47 (m, 2 H); 7.61 (d, J=1.8 Hz, 1 H); 7.65 (d, J=7.9 Hz, 1 H); 7.92 (d, J=7.7 Hz, 1 H); 7.95 (s, 1 H).
LC/MS ([M+H]+): 363
化合物(5)(0.5g)、1−ヨード−2,4−ジクロロベンゼン(0.76ml)、トルエン(9ml)、水(1ml)、Cs2CO3(1.05g)、酢酸パラジウム(50mg)、およびキサントホス(250mg)を含有する脱気した混合物を、約22時間にわたって加熱還流した。室温まで冷却した後、有機相をジクロロメタンで希釈し、水で洗浄し、シリカゲル上でのクロマトグラフィで精製して、白色固体730mg(87%)を得た。
1H NMR (400 MHz, DMSO-d6 in ppm): 1.78 (m, 1 H); 2.01 (m, 1 H); 2.19 (m, 2 H); 3.09 (m, 1 H); 3.21 (m, 1 H); 3.89 (s, 3 H); 4.47 (dd, J=11.3, 3.7 Hz, 1 H); 7.47 (m, 2 H); 7.60 (d, J=2.0 Hz, 1 H); 7.64 (d, J=8.1 Hz, 1 H); 7.92 (dd, J=7.9, 1.5 Hz, 1 H); 7.95 (s, 1 H).
3.1:代替法1
カリウムビス−トリメチルシリルアミドの0.5MのTHF溶液(7.70ml)を、THF(18ml)中の化合物(4)(1g)およびN−フェニルビス−トリフルイミド(1.22g)の混合物に、−50℃で滴下した。室温まで加温後、反応媒体を0〜5℃の水でクエンチし、ジクロロメタンで、続いて酢酸エチルで抽出し、シリカゲルクロマトグラフィ(溶出液:ジクロロメタン−ヘプタン)で精製して、所望される化合物(3’)を、収率80%およびLC/MSで測定した純度90%で得た。
1H NMR (400 MHz, DMSO-d6 in ppm): 2.18 (m, 2 H); 2.41 (m, 2 H); 2.95 (m, 2 H); 3.89 (s, 3 H); 7.55 (m, 2 H); 7.68 (d, J=8.1 Hz, 1 H); 7.80 (d, J=1.7 Hz, 1 H); 8.01 (m, 2 H).
LC/MS ([M+H]+): 494
DBU(247μl)を、アセトニトリル(2ml)中に化合物(4)(500mg)およびN,N−ビス(トリフルオロメチルスルホニル)アニリン(639mg)を含有する懸濁液に、0〜5℃で滴下した。室温で22時間撹拌後の変換率は、約80%であった。反応混合物を、0〜5℃まで冷却し、水素化ナトリウム(オイル中の60%分散体27.5mg)を添加した。室温で1.5時間撹拌した後、変換率は、約100%であった。得られた懸濁液を0〜5℃まで冷却し、ろ過し、予め冷却しておいたアセトニトリル(0.5ml)で、続いて水(2ml)で洗浄して、化合物(3’)460mgを、LC/MSで測定した純度98%で、白色粉末として得た(収率:67.5%)。
1H NMR (400 MHz, DMSO-d6 in ppm): 2.18 (m, 2 H); 2.42 (m, 2 H); 2.95 (m, 2 H); 3.90 (s, 3 H); 7.55 (m, 2 H); 7.68 (d, J=7.9 Hz, 1 H); 7.82 (s, 1 H); 8.02 (m, 2 H).
メチル8−ブロモ−9−(4−{[(3S)−1−(3−フルオロプロピル)ピロリジン−3−イル]オキシ}フェニル)−6,7−ジヒドロ−5H−ベンゾ[7]アンヌレン−3−カルボキシレート臭化水素酸塩(25.0g)、2,4−ジクロロフェニルボロン酸(9.9g)、K2CO3(11.9g)、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド(1.4g)、水(75ml)、および1,4−ジオキサン(206ml)の脱気した混合物を、窒素下、60℃で撹拌した。次に、2,4−ジクロロフェニルボロン酸(9.9g)を、水と1,4−ジオキサン(25ml)との混合物中に溶解し、添加した。変換の完了後、反応媒体を室温まで冷却し、水(50ml)中のピロリジンジチオカルバメート(1.4g)を添加した。混合物を20℃で撹拌し、ろ過した。フィルターをトルエンで洗浄し、水相を分離した。有機相を、希NaCl水溶液(2M、3×75ml)で洗浄した。次に、チャコール(2.5g)およびAl2O3(50.1g)を20℃で添加した。混合物をろ過し、フィルターをトルエンで洗浄した(3×50ml)。有機相を、1,4−ジオキサンの一部を除去するために1.8容量に濃縮した。
RMN 1H (400 MHz, DMSO-d6in ppm): 1,82-1,98 (m, 3 H); 2,09-2,30 (m, 5 H); 2,89-3,22 (m , 7 H); 3,39 (m, 1 H); 3,86 (s, 3 H); 4,39 (td, J=5,9 and 47,4 Hz, 2 H); 4,87 (m, 1 H); 5,76 (s, 2 H); 6,67 (d, J=8,9 Hz, 2 H); 6,75 (d, J=8,9 Hz, 2 H); 6,90 (d, J=8,1 Hz, 1 H); 7,20 (d, J=8,4 Hz, 1 H); 7,29 (dd, J=2,0 and 8,4 Hz, 1 H); 7,54 (t, J=7,9 Hz, 4 H); 7,60 (d, J=2,0 Hz, 1 H); 7,68 (tt, J=1,3 and 7,9 Hz, 2 H); 7,79 (dd, J=1,8 and 8,1 Hz, 1 H); 7,96 (d, J=1,8 Hz, 1 H); 7,98 (t, J=7,9 Hz, 4 H); 10,70 (m spread, 1 H) ; 13,00 (m spread, 1 H).
質量分析の分析データ
M+=568g.mol−1
M’(塩)=358g.mol−1
質量分析器:Waters UPLC−SQD、エレクトロスプレーイオン化(ES+/−)
クロマトグラフィ条件:
カラム:ACQUITY UPLC CSH C18−1.7μm−2.1×50mm
溶媒:A:H2O(+0.1%ギ酸)B:CH3CN(+0.1%ギ酸)
カラム温度:45℃
流量:0.85ml/分
勾配(2.5分):2.5分間で5%から100%のB;2.40分間の100%B;0.05分間で100%から5%のB
UV:190〜380nm
結果:
・1.12分(UV純度31%):[M’−H]−に相当するES−におけるm/z=357
・1.17分(UV純度67%):[M]+に相当するES+におけるm/z=568
化合物(2)ジベンゾイル酒石酸塩の純度:93.2%、HPLCで測定
化合物(2)のシュウ酸塩およびジベンゾイル酒石酸塩は、反応媒体から析出、結晶化して、反応媒体からの化合物(2)の塩の回収を可能とする点において、特に有利である。化合物(2)の塩基形態では、試験したいずれの溶媒および温度でも、生成物を反応媒体から単離することができなかった。以下の表1に示すように、化合物(2)で試験した様々な塩の中で、シュウ酸塩およびジベンゾイル酒石酸塩だけが、容易に析出可能であった。
Claims (8)
- エステル型溶媒は、酢酸エステル溶媒、特に酢酸エチルまたは酢酸イソプロピルである、請求項3に記載の方法。
- エーテル型溶媒は、メチル−tertブチルエーテルおよびジイソプロピルエーテルから選択される、請求項3に記載の方法。
- エステル型溶媒は、酢酸イソプロピルである、請求項3または4に記載の方法。
- 酢酸イソプロピル中、加熱下で、特に60℃から80℃の間で、より特定すると70℃で行われる、請求項6に記載の方法。
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Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
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EP3434272A1 (en) | 2017-07-25 | 2019-01-30 | Sanofi | Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid |
IL281191B (en) | 2018-09-07 | 2022-07-01 | Sanofi Sa | Salts of methyl 6-(4,2-dichlorophenyl)-5-[4-[(s3)-1-(3-fluoropropyl)pyrrolidine-3-yl]oxyphenyl]-9,8-dihydro-h7-benzo[7 ]anolane-2-carboxylate and processes for their preparation |
CA3160897A1 (en) | 2019-12-09 | 2021-06-17 | Sanofi | Crystalline form of a 7h-benzo[7]annulene-2-carboxylic acid derivative |
JP7419575B2 (ja) | 2020-06-28 | 2024-01-22 | メッドシャイン ディスカバリー インコーポレイテッド | 縮合環インダゾール系化合物 |
JP2023545552A (ja) | 2020-10-19 | 2023-10-30 | サノフイ | 置換6,7-ジヒドロ-5h-ベンゾ[7]アヌレン化合物およびそれらの誘導体、それらの製造のための方法ならびにそれらの治療的使用 |
CA3196103A1 (en) | 2020-10-19 | 2022-04-28 | Patrick Bernardelli | Substituted 6,7-dihydro-5h-benzo[7]annulene compounds and their derivatives, processes for their preparation and therapeutic uses thereof |
WO2023125700A1 (zh) | 2021-12-28 | 2023-07-06 | 南京明德新药研发有限公司 | 四氢环庚吲唑化合物的盐型、晶型 |
WO2023187086A1 (en) | 2022-03-31 | 2023-10-05 | Sanofi | Amorphous solid form of amcenestrant |
WO2023198903A1 (en) | 2022-04-15 | 2023-10-19 | Sanofi | Novel substituted fluorinated n-propyl-pyrrolidine and n‑propyl-azetidine compounds, processes for their preparation and therapeutic uses thereof |
WO2023198904A1 (en) * | 2022-04-15 | 2023-10-19 | Sanofi | Substituted 6,7-dihydro-5h-benzo[7]annulene derivatives, processes for their preparation and therapeutic uses thereof |
WO2023198879A1 (en) | 2022-04-15 | 2023-10-19 | Sanofi | Novel substituted fluorinated n-propyl-pyrrolidine compounds, processes for their preparation and therapeutic uses thereof |
WO2023198905A1 (en) | 2022-04-15 | 2023-10-19 | Sanofi | Novel substituted fluorinated vinyl-n-propyl-pyrrolidine compounds, processes for their preparation and therapeutic uses thereof |
WO2023198901A1 (en) | 2022-04-15 | 2023-10-19 | Sanofi | Novel substituted 4-amino-4-oxo-but-2-enyl derivatives, processes for their preparation and therapeutic uses thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017140669A1 (en) * | 2016-02-15 | 2017-08-24 | Sanofi | 6,7-dihydro-5h-benzo[7]annulene derivatives as estrogen receptor modulators |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992015579A1 (en) | 1991-03-08 | 1992-09-17 | Rhone-Poulenc Rorer International (Holdings) Inc. | Multicyclic tertiary amine polyaromatic squalene synthetase inhibitors |
DE19833786A1 (de) | 1998-07-18 | 2000-01-20 | Schering Ag | Benzocycloheptene, Verfahren zu ihrer Herstellung, pharmazeutische Präparate, die diese enthalten, sowie deren Verwendung zur Herstellung von Arzneimitteln |
EP1229036B1 (en) | 2001-01-24 | 2005-01-12 | CHIESI FARMACEUTICI S.p.A. | 2H-1-benzopyran derivatives, processes for their preparation and pharmaceutical compositions thereof |
US6927224B2 (en) | 2001-08-11 | 2005-08-09 | Bristol Myers Squibb Company | Selective estrogen receptor modulators |
WO2003091239A1 (en) | 2002-04-24 | 2003-11-06 | Merck & Co., Inc. | Estrogen receptor modulators |
WO2004058682A1 (ja) | 2002-12-26 | 2004-07-15 | Eisai Co., Ltd. | 選択的エストロゲン受容体モジュレーター |
EP1765803B1 (en) | 2004-06-25 | 2016-03-09 | Janssen Pharmaceutica NV | Quaternary salt ccr2 antagonists |
CA2611712C (en) | 2005-06-14 | 2014-05-13 | Baylor University | Combretastatin analogs with tubulin binding activity |
US8127618B1 (en) | 2007-05-18 | 2012-03-06 | Pacesetter, Inc. | Implantable micro-electromechanical system sensor |
EP2048126A1 (de) | 2007-10-11 | 2009-04-15 | Bayer Schering Pharma AG | Benzocycloheptanderivate als selektiv wirksame Estrogene |
WO2009101634A2 (en) | 2008-02-13 | 2009-08-20 | Lupin Limited | A novel process for the preparation of eszopiclone |
DE102010030538A1 (de) | 2010-06-25 | 2011-12-29 | Bayer Schering Pharma Aktiengesellschaft | 6,7-Dihydro-5H-benzo[7]annulen-Derivate, Verfahren zu ihrer Herstellung, pharmazeutische Präparate die diese enthalten, sowie deren Verwendung zur Herstellung von Arzneimitteln |
GB2483736B (en) | 2010-09-16 | 2012-08-29 | Aragon Pharmaceuticals Inc | Estrogen receptor modulators and uses thereof |
US20120130129A1 (en) | 2010-11-16 | 2012-05-24 | Baylor University | Efficient Method for Preparing Functionalized Benzosuberenes |
EP2655367B1 (en) | 2010-12-24 | 2016-07-06 | Merck Sharp & Dohme B.V. | N-substituted azetidine derivatives |
DE102011087987A1 (de) | 2011-12-08 | 2013-06-13 | Bayer Intellectual Property Gmbh | 6,7-Dihydro-5H-benzo[7]annulen-Derivate, Verfahren zu ihrer Herstellung, pharmazeutische Präparate die diese enthalten, sowie deren Verwendung zur Herstellung von Arzneimitteln |
CN102584687A (zh) | 2011-12-30 | 2012-07-18 | 北京赛林泰医药技术有限公司 | 作为选择性雌激素受体调节剂的乙烯衍生物 |
WO2013097773A1 (en) | 2011-12-30 | 2013-07-04 | Centaurus Biopharma Co., Ltd. | Novel arylalkene derivatives and use thereof as selective estrogen receptor modulators |
US20160184311A1 (en) | 2013-08-14 | 2016-06-30 | Novartis Ag | Combination Therapy for the Treatment of Cancer |
WO2015028409A1 (de) | 2013-08-27 | 2015-03-05 | Bayer Pharma Aktiengesellschaft | 6,7-dihydro-5h-benzo[7]annulen-derivate, verfahren zu ihrer herstellung, pharmazeutische präparate die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln |
AU2014358850A1 (en) | 2013-12-06 | 2016-06-16 | F. Hoffmann-La Roche Ag | Estrogen receptor modulator for the treatment of locally advanced or metastatic estrogen receptor positive breast cancer |
EA032311B1 (ru) | 2014-12-18 | 2019-05-31 | Ф. Хоффманн-Ля Рош Аг | Тетрагидро-пиридо[3,4-b]индоловые модуляторы эстрогеновых рецепторов и их применение |
CN107406424B (zh) | 2014-12-18 | 2020-08-25 | 豪夫迈·罗氏有限公司 | 雌激素受体调节剂及其用途 |
IL255261B2 (en) | 2015-04-29 | 2024-03-01 | Radius Pharmaceuticals Inc | A combination of an m-TOR inhibitor and RAD1901 for use in a method to inhibit cancer growth or to produce tumor regression in patients with resistance to the drug and/or patients with cancer positive for an estrogen receptor alpha mutation |
CN106924210A (zh) | 2015-12-29 | 2017-07-07 | 北京新领先医药科技发展有限公司 | 一种含有帕布昔利布的胶囊剂及其制备方法 |
SG11201903908PA (en) | 2016-11-17 | 2019-05-30 | Sanofi Sa | Novel substituted n-(3-fluoropropyl)-pyrrolidine compounds, processes for their preparation and therapeutic uses thereof |
EP3434272A1 (en) | 2017-07-25 | 2019-01-30 | Sanofi | Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid |
IL281191B (en) | 2018-09-07 | 2022-07-01 | Sanofi Sa | Salts of methyl 6-(4,2-dichlorophenyl)-5-[4-[(s3)-1-(3-fluoropropyl)pyrrolidine-3-yl]oxyphenyl]-9,8-dihydro-h7-benzo[7 ]anolane-2-carboxylate and processes for their preparation |
US20200155521A1 (en) | 2018-11-16 | 2020-05-21 | Arqule, Inc. | Pharmaceutical combination for treatment of cancer |
BR112021022216A2 (pt) | 2019-05-09 | 2021-12-28 | Sanofi Sa | Ácido 6-(2,4-diclorofenil)-5-[4-[(3s)-1-(3-fluoropropil)pirrolidin-3-il]oxifenil]-8,9-di-hidro-7h-benzo[7]anuleno-2-carboxílico para uso em pacientes com câncer de mama metastático ou avançado |
JP2022541938A (ja) * | 2019-07-22 | 2022-09-28 | サン・ファーマ・アドバンスド・リサーチ・カンパニー・リミテッド | 選択的エストロゲン受容体分解剤 |
BR112022008520A2 (pt) * | 2019-11-04 | 2022-07-26 | Recurium Ip Holdings Llc | Sais e formas de um modulador de receptor de estrogênio |
CA3160897A1 (en) * | 2019-12-09 | 2021-06-17 | Sanofi | Crystalline form of a 7h-benzo[7]annulene-2-carboxylic acid derivative |
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