CN100412053C - 苯乙酸衍生物的制备方法 - Google Patents
苯乙酸衍生物的制备方法 Download PDFInfo
- Publication number
- CN100412053C CN100412053C CNB008133972A CN00813397A CN100412053C CN 100412053 C CN100412053 C CN 100412053C CN B008133972 A CNB008133972 A CN B008133972A CN 00813397 A CN00813397 A CN 00813397A CN 100412053 C CN100412053 C CN 100412053C
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- methyl
- chloro
- fluorine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 63
- 230000008569 process Effects 0.000 title abstract description 5
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 238000002360 preparation method Methods 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 150000002148 esters Chemical class 0.000 claims abstract description 15
- 229940002612 prodrug Drugs 0.000 claims abstract description 10
- 239000000651 prodrug Substances 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract 4
- 239000002253 acid Substances 0.000 claims description 58
- 239000011737 fluorine Substances 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 23
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 17
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 16
- 239000000460 chlorine Substances 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- -1 methoxyl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 230000029936 alkylation Effects 0.000 claims description 5
- 238000005804 alkylation reaction Methods 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 230000008707 rearrangement Effects 0.000 claims description 4
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000005179 haloacetyl group Chemical group 0.000 claims description 3
- 230000002452 interceptive effect Effects 0.000 claims description 3
- 230000004044 response Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 239000002243 precursor Substances 0.000 abstract 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 abstract 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 abstract 1
- 229940124639 Selective inhibitor Drugs 0.000 abstract 1
- 150000003951 lactams Chemical class 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 153
- 239000000203 mixture Substances 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- 229960001866 silicon dioxide Drugs 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 20
- 238000001704 evaporation Methods 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- 239000000377 silicon dioxide Substances 0.000 description 15
- 235000012239 silicon dioxide Nutrition 0.000 description 15
- HRXZRAXKKNUKRF-UHFFFAOYSA-N 4-ethylaniline Chemical compound CCC1=CC=C(N)C=C1 HRXZRAXKKNUKRF-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 230000008878 coupling Effects 0.000 description 13
- 238000010168 coupling process Methods 0.000 description 13
- 238000005859 coupling reaction Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- URFPRAHGGBYNPW-UHFFFAOYSA-N 1-bromo-4-ethylbenzene Chemical compound CCC1=CC=C(Br)C=C1 URFPRAHGGBYNPW-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 235000011167 hydrochloric acid Nutrition 0.000 description 8
- 229910052740 iodine Inorganic materials 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000011630 iodine Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- 229940117389 dichlorobenzene Drugs 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 6
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- WFNLHDJJZSJARK-UHFFFAOYSA-N 2-chloro-6-methylaniline Chemical compound CC1=CC=CC(Cl)=C1N WFNLHDJJZSJARK-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N pentanoic acid group Chemical group C(CCCC)(=O)O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- CSCLMFNQXZSBGQ-UHFFFAOYSA-N 2,3,4,6-tetrafluoro-n-(4-methylphenyl)aniline Chemical compound C1=CC(C)=CC=C1NC1=C(F)C=C(F)C(F)=C1F CSCLMFNQXZSBGQ-UHFFFAOYSA-N 0.000 description 3
- LKAZLRVMFGEKEH-UHFFFAOYSA-N 2,6-dichloro-n-(4-methylphenyl)aniline Chemical compound C1=CC(C)=CC=C1NC1=C(Cl)C=CC=C1Cl LKAZLRVMFGEKEH-UHFFFAOYSA-N 0.000 description 3
- AEBQXUBWNRRHKZ-UHFFFAOYSA-N 2-chloro-n-(2,6-dichlorophenyl)-n-(4-methylphenyl)acetamide Chemical compound C1=CC(C)=CC=C1N(C(=O)CCl)C1=C(Cl)C=CC=C1Cl AEBQXUBWNRRHKZ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 125000005907 alkyl ester group Chemical group 0.000 description 3
- 238000005660 chlorination reaction Methods 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
- 238000004440 column chromatography Methods 0.000 description 3
- 125000000596 cyclohexenyl group Chemical class C1(=CCCCC1)* 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- FMBNMGDVELSOJQ-UHFFFAOYSA-N n-(4-ethylphenyl)-2,3,5,6-tetrafluoroaniline Chemical compound C1=CC(CC)=CC=C1NC1=C(F)C(F)=CC(F)=C1F FMBNMGDVELSOJQ-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 3
- 238000007738 vacuum evaporation Methods 0.000 description 3
- WUYUSIOFCKTMRZ-UHFFFAOYSA-N 1-(2-chloro-6-methylphenyl)-5-ethyl-3h-indol-2-one Chemical compound O=C1CC2=CC(CC)=CC=C2N1C1=C(C)C=CC=C1Cl WUYUSIOFCKTMRZ-UHFFFAOYSA-N 0.000 description 2
- LYTJUQLAYSVAEX-UHFFFAOYSA-N 2-chloro-6-fluoro-n-(4-methylphenyl)aniline Chemical compound C1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl LYTJUQLAYSVAEX-UHFFFAOYSA-N 0.000 description 2
- QIAQIYQASAWZPP-UHFFFAOYSA-N 2-chloro-6-fluorophenol Chemical compound OC1=C(F)C=CC=C1Cl QIAQIYQASAWZPP-UHFFFAOYSA-N 0.000 description 2
- BOXIRPSKMKAVNY-UHFFFAOYSA-N 2-chloro-n-(4-ethylphenyl)-6-methylaniline Chemical compound C1=CC(CC)=CC=C1NC1=C(C)C=CC=C1Cl BOXIRPSKMKAVNY-UHFFFAOYSA-N 0.000 description 2
- NBVBURRXINMCJB-UHFFFAOYSA-N 2-chloro-n-(4-methylphenyl)-n-(2,3,4,6-tetrafluorophenyl)acetamide Chemical compound C1=CC(C)=CC=C1N(C(=O)CCl)C1=C(F)C=C(F)C(F)=C1F NBVBURRXINMCJB-UHFFFAOYSA-N 0.000 description 2
- OHDCGQURSOVSIP-UHFFFAOYSA-N 5-methyl-1-(2,3,4,6-tetrafluorophenyl)-3h-indol-2-one Chemical compound O=C1CC2=CC(C)=CC=C2N1C1=C(F)C=C(F)C(F)=C1F OHDCGQURSOVSIP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- MUGDLCRNVHHISG-UHFFFAOYSA-N CCC(CCC1=O)CC1=CCOC(C)=O Chemical compound CCC(CCC1=O)CC1=CCOC(C)=O MUGDLCRNVHHISG-UHFFFAOYSA-N 0.000 description 2
- FYAUCLDUDNJWMR-UHFFFAOYSA-N ClC1=C(C(=CC(=C1)F)CN)NC1=CC=C(C=C1)C Chemical compound ClC1=C(C(=CC(=C1)F)CN)NC1=CC=C(C=C1)C FYAUCLDUDNJWMR-UHFFFAOYSA-N 0.000 description 2
- NOXQKDYYKMDGQA-UHFFFAOYSA-N ClC1=C(C(=CC=C1)CN)N(C1=CC=C(C=C1)CC)C(CCl)=O Chemical compound ClC1=C(C(=CC=C1)CN)N(C1=CC=C(C=C1)CC)C(CCl)=O NOXQKDYYKMDGQA-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 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
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-YYWVXINBSA-N N,N-dimethylformamide-d7 Chemical compound [2H]C(=O)N(C([2H])([2H])[2H])C([2H])([2H])[2H] ZMXDDKWLCZADIW-YYWVXINBSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012018 catalyst precursor Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000002243 cyclohexanonyl group Chemical class *C1(*)C(=O)C(*)(*)C(*)(*)C(*)(*)C1(*)* 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- BRRWYVHGUAIKBY-UHFFFAOYSA-N n-(4-ethylphenyl)-2,3,6-trifluoroaniline Chemical compound C1=CC(CC)=CC=C1NC1=C(F)C=CC(F)=C1F BRRWYVHGUAIKBY-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 150000002941 palladium compounds Chemical class 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011734 sodium Substances 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
- URLVCROWVOSNPT-XOTOMLERSA-N (2s)-4-[(13r)-13-hydroxy-13-[(2r,5r)-5-[(2r,5r)-5-[(1r)-1-hydroxyundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]-2-methyl-2h-furan-5-one Chemical compound O1[C@@H]([C@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 URLVCROWVOSNPT-XOTOMLERSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- LFXMCCUTBWQOJG-UHFFFAOYSA-N 1-(2-chloro-6-fluorophenyl)-5-methyl-3h-indol-2-one Chemical compound O=C1CC2=CC(C)=CC=C2N1C1=C(F)C=CC=C1Cl LFXMCCUTBWQOJG-UHFFFAOYSA-N 0.000 description 1
- IPWBFGUBXWMIPR-UHFFFAOYSA-N 1-bromo-2-fluorobenzene Chemical class FC1=CC=CC=C1Br IPWBFGUBXWMIPR-UHFFFAOYSA-N 0.000 description 1
- SBYRHTZJKKWEMP-UHFFFAOYSA-N 2,3,4,6-tetrafluoroaniline Chemical compound NC1=C(F)C=C(F)C(F)=C1F SBYRHTZJKKWEMP-UHFFFAOYSA-N 0.000 description 1
- SPSWJTZNOXMMMV-UHFFFAOYSA-N 2,3,5,6-tetrafluoroaniline Chemical compound NC1=C(F)C(F)=CC(F)=C1F SPSWJTZNOXMMMV-UHFFFAOYSA-N 0.000 description 1
- AQJFATAFTQCRGC-UHFFFAOYSA-N 2-Chloro-4-methylphenol Chemical class CC1=CC=C(O)C(Cl)=C1 AQJFATAFTQCRGC-UHFFFAOYSA-N 0.000 description 1
- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 description 1
- PLTNCEGFKZZXEI-UHFFFAOYSA-N 2-chloro-4-fluoro-6-methylaniline Chemical compound CC1=CC(F)=CC(Cl)=C1N PLTNCEGFKZZXEI-UHFFFAOYSA-N 0.000 description 1
- ZJLAWMDJTMMTQB-UHFFFAOYSA-N 2-chloro-6-fluoroaniline Chemical compound NC1=C(F)C=CC=C1Cl ZJLAWMDJTMMTQB-UHFFFAOYSA-N 0.000 description 1
- ILRBTKGCACIETD-UHFFFAOYSA-N 2-chloro-n-(2-chloro-6-fluorophenyl)-n-(4-ethylphenyl)acetamide Chemical compound C1=CC(CC)=CC=C1N(C(=O)CCl)C1=C(F)C=CC=C1Cl ILRBTKGCACIETD-UHFFFAOYSA-N 0.000 description 1
- SVCPNJWCSAOMAH-UHFFFAOYSA-N 2-chloro-n-(2-chloro-6-fluorophenyl)-n-(4-methylphenyl)acetamide Chemical compound C1=CC(C)=CC=C1N(C(=O)CCl)C1=C(F)C=CC=C1Cl SVCPNJWCSAOMAH-UHFFFAOYSA-N 0.000 description 1
- XXNJYZYKTNBAPC-UHFFFAOYSA-N 2-chloro-n-(4-ethylphenyl)-n-(2,3,5,6-tetrafluorophenyl)acetamide Chemical compound C1=CC(CC)=CC=C1N(C(=O)CCl)C1=C(F)C(F)=CC(F)=C1F XXNJYZYKTNBAPC-UHFFFAOYSA-N 0.000 description 1
- YDVSVULRCYRFBS-UHFFFAOYSA-N 2-chloro-n-(4-ethylphenyl)-n-(2,3,6-trifluorophenyl)acetamide Chemical compound C1=CC(CC)=CC=C1N(C(=O)CCl)C1=C(F)C=CC(F)=C1F YDVSVULRCYRFBS-UHFFFAOYSA-N 0.000 description 1
- HXQDSHSATAEREW-UHFFFAOYSA-N 5-methyl-1,3-dihydroindol-2-one Chemical compound CC1=CC=C2NC(=O)CC2=C1 HXQDSHSATAEREW-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZSSFQLTWLYHWSF-UHFFFAOYSA-N ClC1=C(C(=CC(=C1)F)CN)N(C1=CC=C(C=C1)C)C(CCl)=O Chemical compound ClC1=C(C(=CC(=C1)F)CN)N(C1=CC=C(C=C1)C)C(CCl)=O ZSSFQLTWLYHWSF-UHFFFAOYSA-N 0.000 description 1
- URPGCNWVHOGYNC-UHFFFAOYSA-N ClC1=C(C(=CC=C1)CN)NC1=CC=C(C=C1)C Chemical compound ClC1=C(C(=CC=C1)CN)NC1=CC=C(C=C1)C URPGCNWVHOGYNC-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- FEIILCFCRJUVPS-UHFFFAOYSA-N FCC1=C(C(=CC=C1CF)CF)O Chemical compound FCC1=C(C(=CC=C1CF)CF)O FEIILCFCRJUVPS-UHFFFAOYSA-N 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N Glyoxylic acid Natural products OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QUHYUSAHBDACNG-UHFFFAOYSA-N acerogenin 3 Natural products C1=CC(O)=CC=C1CCCCC(=O)CCC1=CC=C(O)C=C1 QUHYUSAHBDACNG-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- URLVCROWVOSNPT-QTTMQESMSA-N desacetyluvaricin Natural products O=C1C(CCCCCCCCCCCC[C@@H](O)[C@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 URLVCROWVOSNPT-QTTMQESMSA-N 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical class CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical class C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- UAIZDWNSWGTKFZ-UHFFFAOYSA-L ethylaluminum(2+);dichloride Chemical class CC[Al](Cl)Cl UAIZDWNSWGTKFZ-UHFFFAOYSA-L 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 150000002411 histidines Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- OSXGBILCTZUOGO-UHFFFAOYSA-N n-(5-fluoro-2-methylphenyl)acetamide Chemical compound CC(=O)NC1=CC(F)=CC=C1C OSXGBILCTZUOGO-UHFFFAOYSA-N 0.000 description 1
- SHLTXWFNRJQZTQ-UHFFFAOYSA-N n-chloro-2-methylaniline Chemical compound CC1=CC=CC=C1NCl SHLTXWFNRJQZTQ-UHFFFAOYSA-N 0.000 description 1
- KUDPGZONDFORKU-UHFFFAOYSA-N n-chloroaniline Chemical compound ClNC1=CC=CC=C1 KUDPGZONDFORKU-UHFFFAOYSA-N 0.000 description 1
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 description 1
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/54—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings
- C07C211/56—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
- C07C235/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Pain & Pain Management (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
Abstract
用于制备式I化合物、或其药学可接受的盐、或其药学可接受的前药酯的方法,包括用碱分裂式II内酰胺,其中符号定义如上;以及所用前体和前体的制备方法。式I化合物是药学活性化合物,是环加氧酶(II)的选择性抑制剂。
Description
本发明涉及2-苯基氨基-5-烷基苯乙酸(下述式I化合物)、其中间体和其药学可接受的盐及其药学可接受的前药酯的制备方法:
其中R是甲基或乙基;
R1是氯或氟;
R2是氢或氟;
R3是氢、氟、氯、甲基、乙基、甲氧基、乙氧基或羟基;
R4是氢或氟;且
R5是氯、氟、三氟甲基或甲基,
条件是R1,R2,R4和R5在R是乙基和R3是H时不全为氟。
因此,在本发明的第一方面提供了一种制备式I化合物、或其药学可接受盐、或其药学可接受并可生理学分裂的前药酯的方法,包括用碱分裂式II内酰胺,
其中的符号定义如上。
如果需要,上述方法可包括暂时保护任何干扰性反应基团和随后分离所得到的本发明化合物;和,如果需要,将式I化合物的游离羧酸转化为其药学可接受的酯衍生物;和/或,如果需要,将式I的游离酸转化为盐或将得到的盐转化为游离酸或另一种盐。
上述方法可在本领域已知的内酰胺水解分裂条件下、优选使用诸如氢氧化钠水溶液(例如NaOH的30%的水溶液)等强碱、任选存在诸如乙醇或甲醇等水可混溶的有机溶剂、优选在例如约50-100℃范围内的升高的温度下进行(例如US专利3,558,690中一般性描述的)。得到的反应混合物用酸方便地中和,例如用无机酸,诸如盐酸,得到式I的游离酸产物,其可通过结晶回收,例如通过将反应混合冷却到环境温度并过滤。
药学可接受的前药酯是酯衍生物,其通过溶剂分解作用或在生理条件下可转化成式I的游离羧酸。这类酯是例如低级烷基酯(诸如甲酯或乙酯)、羧甲基酯等羧基低级烷基酯、硝基氧基低级烷基酯(诸如4-硝基氧基丁酯)等。
药学可接受的盐是金属盐,诸如碱金属盐,例如钠、钾、镁或钙盐,以及铵盐,它们例如通过使用氨或一或二烷基胺形成,诸如二乙基铵盐,以及用氨基酸形成,诸如精氨酸和组氨酸盐。
可根据本发明方法制备的优选的式I化合物包括:
5-甲基-2-(2’,4’-二氯-6’-甲基苯胺基)苯乙酸;
5-甲基-2-(2’,3’,5’,6’-四氟苯胺基)苯乙酸;
5-甲基-2-(2’,3’,4’,6’-四氟苯胺基)苯乙酸;
5-甲基-2-(2’,6’-二氯苯胺基)苯乙酸;
5-甲基-2-(2’,6’-二氯苯胺基)苯乙酸,钾盐;
5-甲基-2-(2’,6’-二氯苯胺基)苯乙酸,钠盐;
5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸;
5-甲基-2-(2’,6’-二氯-4’-甲基苯胺基)苯乙酸;
5-甲基-2-(2’-氯-6’-甲基苯胺基)苯乙酸;
5-甲基-2-(2’,4’-二氟-6’-氯苯胺基)苯乙酸;
5-甲基-2-(2’-氟-4’,6’-二氯苯胺基)苯乙酸;
5-甲基-2-(2’-氯-4’-氟-6’-甲基苯胺基)苯乙酸;
5-乙基-2-(2’-氟-6’-氯苯胺基)苯乙酸;
5-乙基-2-(2’-氯-6’-甲基苯胺基)苯乙酸;
5-乙基-2-(2’,3’,6’-三氟苯胺基)苯乙酸;
5-乙基-2-(2’,3’,5’,6’-四氟-4’-乙氧基苯胺基)苯乙酸;
5-乙基-2-(2’-氯-4’,6’-二氟苯胺基)苯乙酸;
5-乙基2-(2’,4’-二氯-6’-氟苯胺基)苯乙酸;
5-乙基-2-(2’,4’-二氯-6’-甲基苯胺基)苯乙酸;
5-乙基-2-(2’-氟-4’-氯-6’-甲基苯胺基)苯乙酸;
5-乙基-2-(2’,4’-二氟-6’-甲基苯胺基)苯乙酸;
5-乙基-2-(2’-氯-4’-氟-6’-甲基苯胺基)苯乙酸;
5-甲基-2-(2’-氯-4’-羟基-6’-氟苯胺基)苯乙酸;
5-甲基-2-(2’-氟-6’-三氟甲基苯胺基)苯乙酸,和
5-甲基-2-(2’,4’-二氯-6’-三氟甲基苯胺基)苯乙酸,
及其药学可接受的盐;和其药学可接受的前药酯。
可根据本发明制备的特别优选的式I化合物包括:
5-甲基-2-(2’,3’,4’,6’-四氟苯胺基)苯乙酸;
5-甲基-2-(2’,6’-二氯苯胺基)苯乙酸;
5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸;
5-甲基-2-(2’,6’-二氯-4’-甲基苯胺基)苯乙酸;
5-甲基-2-(2’-氯-6’-甲基苯胺基)苯乙酸;
5-甲基-2-(2’-氯-4’-氟-6’-甲基苯胺基)苯乙酸;
5-乙基-2-(2’-氟-6’-氯苯胺基)苯乙酸;
5-乙基-2-(2’-氯-6’-甲基苯胺基)苯乙酸;
5-乙基-2-(2’,3’,6’-三氟苯胺基)苯乙酸,和
5-乙基-2-(2’,4’-二氯-6’-甲基苯胺基)苯乙酸,
及其药学可接受的盐;和其药学可接受的前药酯。
这样,还优选本发明方法可用于制备式I化合物或其药学可接受的盐或其药学可接受的前药酯,其中R是甲基或乙基;R1是氯或氟;R2是氢;R3是氢、氟、氯、甲基或羟基;R4是氢;R5是氯、氟或甲基。
式II的内酰胺可通过氧化式III内酰胺制备:
其中符号定义如上。
可使用标准的温和氧化条件,诸如在例如二甲苯等适合的溶剂中与催化量的负载在炭上的钯一起加热。
式III的内酰胺可通过式IV的苯胺衍生物
其中符号定义如上,与式Va的环己酮衍生物或式Vb的氨基取代的环己烯衍生物偶联制备,
其中R是乙基或甲基,R’是低级烷基等。
IV与Va和Vb的偶联通常涉及水或仲胺HNR’2的消去,例如在酸性条件下。
Vb可通过式Vb’的氨基取代的环己烯衍生物
其中R和R’定义如上,与乙醛酸甲酯或乙醛酸乙酯反应制备。Vb可通过水解转化为Va,如下文在实施例中所述。
或者,通过环化式VII的化合物得到式II的内酰胺
其中符号的定义如上。
环化过程方便地在Friedel-Crafts烷基化条件下,例如在诸如氯化铝或二氯化乙基铝等Friedel-Crafts催化剂存在下,优选在例如约100-约180℃的升高的温度下进行。环化反应可在诸如二氯苯的惰性溶剂存在下进行,或优选将熔化的是VII化合物与Friedel-Crafts催化剂一起加热。
式VII化合物通过式VIII的二苯胺
其中符号定义如上,与卤代乙酰氯的N-酰化反应制备。
例如,式VIII化合物和氯乙酰氯一起被加热到例如约80℃。可通过用例如2-丙醇等溶剂稀释反应混合物并结晶来回收产物。
式VIII化合物可通过式IX化合物的重排和水解制备,
其中符号定义如上。
式IX化合物方便地用有机碱处理,例如碱金属醇盐,诸如甲醇钠,优选同时加热,例如加热到至少约75℃的温度。在此过程中,式X中间产物,
其中符号定义如上,作为最初重排反应的产物而形成,但在占优势的反应条件下进行直接分裂,得到式VIII二苯胺化合物。
或者,VIII的二苯胺化合物可通过相应的式XI卤代苯衍生物,
其中X是卤素,例如I或Br,其它符号定义如上,与对甲苯胺或4-乙基苯胺偶联得到。
这种偶联反应可采用Buchwald化学进行。例如式XI化合物和对甲苯胺或4-乙基苯胺与例如叔丁醇钠等有机碱和例如BINAP等适合的配体在诸如甲苯等有机溶剂中混合;加入钯化合物或诸如Pd(dba)2等催化剂前体,加热反应混合物。冷却并用例如HCl等酸处理后,从反应混合物的有机相回收式VIII的二苯胺产物。
再或者,式VIII的二苯胺化合物可通过偶联定义如上的相应的式IV苯胺衍生物
和4-溴甲苯或1-乙基-4-溴苯得到。这种偶联反应可类似地采用Buchwald化学进行。例如,式IV的化合物和4-溴甲苯或1-乙基-4-溴苯与例如叔丁醇钠等有机碱在诸如甲苯等有机溶剂中混合;向该反应混合物中加入钯化合物或例如Pd(dba)2等催化剂前体和例如P(tBu)3或BINAP等配体,然后在例如110℃的升高的温度搅拌直到反应完成,例如搅拌过夜。类似地,例如在冷却并用例如HCl等酸处理后,可从反应混合物的有机相回收式VIII的二苯胺产物。
式IX的化合物可通过用2-氯-N-(4-甲基苯基)乙酰胺或2-氯-N-(4-乙基苯基)乙酰胺烷基化相应的式XII酚衍生物制备,
其中符号定义如上。例如式XII的化合物和2-氯-N-(4-甲基苯基)乙酰胺或2-氯-N-(4-乙基苯基)乙酰胺在诸如2-丙醇等有机溶剂中在例如K2CO3等碱存在下混合,反应混合物沸腾直至反应完成,例如沸腾4小时。例如可通过4-甲基-或4-乙基苯胺与氯乙酰氯的反应就地制备2-氯-N-(4-甲基苯基)乙酰胺和2-氯-N-(4-乙基苯基)乙酰胺。如果需要,可从反应混合物中回收式IX化合物。但是优选不分离式IX化合物,而是通过对式XII化合物烷基化得到的产物反应混合物进行上述重排和水解将其转化为式VIII化合物。
或者,可通过氧化相应的式XIII化合物(或其互变异构体)制备式VIII的二苯胺化合物,
其中符号定义如上。
可用标准的方法进行脱氢反应,例如用碘,例如在THF/AcOH中的I2处理。
式XIII的化合物可通过偶联1-甲氧基-4-甲基环己-1,4-二烯或1-甲氧基-4-乙基环己-1,4-二烯和如上定义的式IV的苯胺衍生物制备。
该偶联反应在诸如TiCl4等催化剂存在下、在例如THF和氯苯等有机溶剂中进行,优选冷却到例如约-40℃。
可通过Brich还原将4-甲基茴香醚或4-乙基茴香醚部分还原制备1-甲氧基-4-甲基环己-1,4-二烯或1-甲氧基-4-乙基环己-1,4-二烯,例如用在液氨中的Na处理,如Subba Rao等人,AustralianJournal of Chemistry 1992,45,p.187-203所述。
适宜的是不分离式XIII化合物,而是在式IV化合物和1-甲氧基-4-甲基环己-1,4-二烯或1-甲氧基-4-乙基环己-1,4-二烯之间的偶联反应之后进行氧化,得到式VIII的二苯胺衍生物。
在以前述方法转化为式I至XIII化合物的起始化合物和中间体中,存在的官能基,如氨基、羟基和羧基,可任选用合成有机化学中常规的传统保护基保护。被保护的羟基、氨基和羧基是在温和条件下可转化为游离氨基、羟基和羧基而不发生其它不希望的副反应的那些。例如羟基保护基优选是苄基或取代的苄基。
上述制备2-苯基氨基-5-烷基苯乙酸衍生物的方法在下页示意表示。
2-芳基氨基-芳基乙酸(COX-2抑制剂)合成工艺概述
上述式II,III,VII,VIII,IX,X和XIII化合物的制备方法包括在本发明范围内。
因此,本发明进一步包括选自下列的方法:
a)制备式II内酰胺的方法,
其包括氧化式III的内酰胺
b)制备上述式II内酰胺的方法,其包括环化式VII的化合物
c)制备上述式III化合物的方法,包括将式IV苯胺衍生物
与式Va的环己酮衍生物或式Vb的氨基取代的环己烯衍生物偶联,
其中R是乙基或甲基,R’是低级烷基等;
d)制备式VII化合物的方法,其包括用卤代乙酰氯N-酰化式VIII的二苯胺
e)制备式VIII化合物的方法,包括重排和水解式IX化合物
f)制备式VIII化合物的方法,其包括式XI的卤代苯衍生物与对甲苯胺或4-乙基苯胺偶联,
其中X是卤素;
g)制备式VIII化合物的方法,其包括式IV的苯胺衍生物与4-溴甲苯或1-乙基-4-溴苯偶联;
h)制备式VIII化合物的方法,其包括分裂式X化合物
i)制备式X化合物的方法,其包括重排式IX化合物;
j)制备式IX化合物的方法,其包括用2-氯-N-(4-甲基苯基)乙酰胺或2-氯-N-(4-乙基苯基)乙酰胺烷基化式XII化合物;
k)制备式VIII化合物的方法,其包括用2-氯-N-(4-甲基苯基)乙酰胺或2-氯-N-(4-乙基苯基)乙酰胺烷基化式XII化合物,然后将式IX中间体化合物重排和分裂;
l)制备式VIII化合物的方法,包括相应的式XIII化合物(或其互变异构体)的氧化
m)制备式XIII化合物的方法,包括将1-甲氧基-4-甲基环己-1,4-二烯或1-甲氧基-4-乙基环己-1,4-二烯与上述式IV苯胺衍生物偶联;和
n)制备式VIII化合物的方法,包括将1-甲氧基-4-甲基环己-1,4-二烯或1-甲氧基-4-乙基环己-1,4-二烯与上述式IV苯胺衍生物偶联,然后脱氢;
其中所有使用的符号定义如上。
上述a)-n)的一个或多个方法可以以适当的顺序(参见上述给出的反应方案)用于式I化合物的制备。
因此,本发明还提供一种制备式I化合物的方法,
其中符号定义如上,其包括一个或多个选自上述定义的方法a)至n)的方法,任选与根据本发明第一方面的方法结合。
当用包括一个或多个上述定义的a)至n)方法的方法、优选与本发明第一方面的方法一起制备时,本发明还提供了式I化合物、或其药学可接受盐、或其药学可接受前药酯。
式II,III,VII,VIII,IX,X和XIII化合物本身包括在本发明范围内。
因此,本发明的另一方面提供了选自下列的化合物:
a)式II化合物
b)式III化合物
c)式VII化合物
d)式VI II化合物
e)式IX化合物
f)式X化合物
和
g)式XIII化合物,或其互变异构体
其中符号定义如上。
其中R1或R5之一是氯且另一个是氟的式XII化合物可通过本领域已知的酚氯化方法制备,优选存在催化量的仲胺,例如二异丙基胺。在根据本发明的一个优选实施方案中,氯化反应包括将氯和酚同时加入反应混合物中,优选使用己烷组分作为溶剂。已经发现,在所需产物的制备中同时将至少一部分、优选大部分氯和酚加入反应混合物得到了与不希望的副产物相比提高了的产率和选择性。另外,己烷组分的使用使得可以通过结晶以高纯度(例如,99%)分离所需的酚产物。
在下述实施例中仅以举例说明的方式进一步表述本发明。
实施例
式VIII的二苯胺化合物
通过下面实施例1和2所述的Buchwald化学,或者按实施倒1所述将式IV的苯胺衍生物
与4-溴甲苯或1-乙基-4-溴苯偶联制备,或如实施例2所述将式XI的卤代苯衍生物
与对甲苯胺或4-乙基苯胺偶联制备。这样得到的式VIII化合物可通过下述方法转化为相应的式I化合物。
实施例1a N-(2’,3’,4’,6’-四氟苯基)-4-甲基苯胺
2,3,4,6-四氟苯胺(0.72g,4.4mmol)、4-溴甲苯(0.8g,4.7mmol)、甲苯(55ml)、叔丁醇钠(0.8g,8.3mmol)、三叔丁基膦(130mg,0.64mmol)和双-二亚苄基丙酮-钯(0)(125mg,0.2mmol)的混合物在氮气下加热到85℃3小时。冷却后,加入水(50ml)、浓盐酸(10ml)和hyflo(1g),继续搅拌约1小时,然后过滤。有机相用水洗涤2次,蒸发,在二氧化硅(45g)上使用庚烷/甲苯(2∶1)作为洗脱液对残留物进行快速色谱提纯,得到N-(2’,3’,4’,6’-四氟苯基)-4-甲基苯胺油(0.92g,3.6mmol),其结晶(mp.64-65℃)。
1H-NMR(400MHz,DMSO-d6):2.20(s,3H,CH3);6.63[d,8.2Hz,2H,HC(2),HC(6)];6.99[d,8.2Hz,2H,HC(3),HC(5)];7.56[对称的m,1H,HC(5’)];7.84(s,1H,NH).
N,N-二-对甲苯基-2,3,4,6-四氟苯胺作为副产物分离,mp:94.96℃。
实施例1b:N-(2’,3’,5’,6’-四氟苯基)-4-乙基苯胺
2,3,5,6-四氟苯胺(4.5g,27.3mmol)、4-乙基溴苯(5.0g,27mmol)、甲苯(50ml)、叔丁醇钠(4.67g,48mmol)、三叔丁基膦(217mg,1.07mmol)和双-二亚苄基丙酮-钯(0)(260mg,0.45mmol)的混合物在氮气下加热到85℃15.5小时。混合物冷却到室温,加入水(30ml)、浓盐酸(20ml)和hyflo。搅拌45分钟后,过滤混合物,有机相用水洗涤3次。真空蒸发溶剂,残留物在二氧化硅上使用己烷/甲苯(9∶1至3∶1)进行色谱,得到N-(2’,3’,5’,6’-四氟苯基)-4-乙基苯胺液体。
1H-NMR(400MHz,CDCl3):1.26(t,3H,CH3);2.65(q,2H,CH2);5.65(s,1H,NH);6.73[tt,1H,H-C(4’)];6.88[d,2H,H-C(2,6)];7.15[d,2H,H-C(3,5)].
MS,m/z:268(M-H),248(M-HF).
实施例1c:N-(2’-氯-4’-氟-6’-甲基苯基)-4-甲基苯胺
3.08g(19.3mmol)of 2-氯-4-氟-6-甲基苯胺(由N-乙酰基-4-氟-2-甲基苯胺通过氯化然后水解制备)、3.48g (20.3mmol)4-溴甲苯溶于55ml甲苯中,加入3.43g(36mmol)叔丁醇钠、166mg(0.82mmol)三叔丁基膦和460mg(0.8mmol)双-二亚苄基丙酮-钯(0)后,混合物在氮气下加热至90℃40分钟同时搅拌。通常的酸性水溶液处理(50ml水,10ml浓HCl,1g hyflo,过滤,用水洗涤有机相,干燥,蒸发)得到5.5g粗产物,其可用快速色谱提纯,使用二氧化硅并用庚烷作为洗脱液,得到3.52g N-(2’-氯-4’-氟-6’-甲基苯基)-4-甲基苯胺油状物质。
1H-NMR(400MHz,DMSO-d6):2.18(s,3H,CH3);6.37(d,2H,H-C(2,6)];6.92[d,2H,H-C(3,5)];7.19(dd,1H,H-C(5’));7.32(s,1H,NH);7.35(dd,1H,HC(3’)).
实施例1d:N-(2’-氯-6’-甲基苯基)-4-甲基苯胺
1.02g(7.2mmol)2-氯-6-甲基苯胺、1.23g(7.2mmol)4-溴甲苯、1.15g(12mmol)叔丁醇钠、160mg(0.7mmol)三叔丁基膦和130mg(0.23mmol)双-二亚苄基丙酮-钯(0)在50ml甲苯中在氮气下在90℃反应20分钟,并在60℃加热过夜。水处理(3N HCl,与hyflo一起,用水洗涤有机相)和在二氧化硅上使用庚烷/甲苯(4∶1)作为洗脱液的快速色谱提纯得到1.49g N-(2’-氯-6’-甲基苯基)-4-甲基苯胺。
1H-NMR(400MHz,CDCl3):2.21(s,3H,C-6’-CH3);2.29(s,3H,C-4-CH3);5.61(s,br,1H,NH);6.57[d,2H,HC(2,6)];7.04[d,2H,HC(3,5)];7.07[t,在7.04的信号下,1H,HC(4’)];7.16[d,2H,H(C5’)];7.33[d,1H,H(C3’)].
N,N-二-对甲苯基-2-氯-6-甲基苯胺(9mg)作为副产物分离。
实施例1e:N-(2’-氯-6’-甲基苯基)-4-乙基苯胺
向5.2g(37mmol)of 2-氯-6-甲基苯胺和6.95g(37.6mmol)4-乙基溴苯在50ml甲苯中的溶液加入6.5g(68mmol)叔丁醇钠、180mg(0.89mmol)三叔丁基膦(溶于2ml甲苯中)和300mg(0.52mmol)双-二亚苄基丙酮-钯(0)。混合物在氮气下加热到90℃3小时,然后冷却至室温。加入Hyflo(1g)、水(30ml)和浓盐酸(10ml),搅拌30分钟后将混合物过滤。用水(30ml)洗涤有机相2次,蒸发。残留物进行快速色谱,在二氧化硅(75g)上用庚烷洗脱,得到5.3g(21.6mmol,58%)N-(2’-氯-6’-甲基苯基)-4-乙基苯胺几乎无色的液体。
1H-NMR(300MHz,CDCl3):1.10(t,3H,CH 3 -CH2-);2.10[s,3H,CH3-C(6’)];2.50(q,2H,CH3-CH 2 -);5.54(s,br,1H,NH);6.48[d,2H,HC(2,6)];6.93[t,1H,H(C4’)];6.95[d,2H,HC(3,5)];7.05[d,1H,HC(5’)];7.22[d,1H,HC(3’)].
实施例1f:N-(2’,4’-二氯-6’-甲基苯基)-4-乙基苯胺
2,4-二氯-6-甲基苯胺(3.313g,18.8mmol)、4-乙基溴苯(3.64g,20mmol)、叔丁醇钠(3.41g,35mmol)、外消旋BINAP(0.274g,0.44mmol)、双-二亚苄基丙酮-钯(0)(250mg,0.43mmol)和甲苯(50ml)的混合物在氮气下回流22小时。冷却混合物,用水(40ml)、浓HCl(10ml)、hyflo(1.7g)处理,再搅拌30分钟,过滤。有机相用水洗涤2次,蒸发。粗产物(6.88g)用快速色谱提纯(二氧化硅,甲苯),得到2.93g of N-(2’,4’-二氯-6’-甲基苯基)-4-乙基苯胺。
1H-NMR(300MHz,CDCl3):1.15(t,3H,CH 3 -CH2-Ar);2.08(s,3H,C-6’-CH3);2.50(q,2H,CH3-CH 2 -Ar);5.42(s,br.,1H,NH);6.50[d,2H,HC(2,6,)];6.96[d,2H,HC(3,5)];7.10[s,1H,HC(5’)];7.25[s,1H,HC(3’)].
当用三叔丁基膦代替BINAP时,反应即使在85℃也进行得很快;但是当使用过量的4-乙基溴苯时,N,N-二-(4-乙基苯基)-2’,4’-二氯-6’-甲基苯胺以相当大的量作为副产物生成。该副产物可作为固体分离,mp:74-75℃;1H-NMR(400MHz,CDCl3):1.24(t,6H,CH2-CH 3 );2.09(s,3H,C-6’-CH3);2.61(q,4H,CH 2 -CH3);6.89[d,4H,HC(2,6)];7.06[d,4H,HC(3,5)];7.20[s,1H,HC(5’)];7.36[s,1H,HC(3’)];MS:383(M+),368(M-CH3),354(M-CH2CH3).
实施例2:N-(2’,3’,6’-三氟苯基)-4-乙基苯胺
向1.21g 4-乙基苯胺、1.10g 2,3,6-三氟-溴苯在10g甲苯的溶液中连续加入350mg BINAP和在3ml甲苯中的300mg双-二亚苄基丙酮-钯(0)(Pd(dba)2)以及在3ml甲苯中的0.9g叔丁醇钠。用氮气冲洗混合物,回流加热6小时。冷却至室温后,加入水(30ml)、浓盐酸(10ml)和hyflo(1g),连续搅拌1小时。过滤混合物,滤液分相。有机相用水洗涤3次,用硫酸镁干燥,蒸发至干燥。残留物本身用于后继步骤,或用快速色谱提纯,在二氧化硅上使用甲苯作为洗脱液,得到1.13g N-(2’,3’,6’-三氟苯基)-4-乙基苯胺。
1H-NMR(300MHz,CDCl3):1.14(t,7.7Hz,3H,CH 3 -CH2-Ar);2.53(q,7.7Hz,2H,CH3-CH 2 -Ar);5.29(br.s,1H,NH);6.7-6.81[m,2H,C-4’-H,HC(5’)];6.75[d,2H,HC(2,6)];7.02[d,8.5Hz,2H,HC(3,5)].
式VIII的二苯胺化合物,例如在上述实施例1和2中制备的,如实施例3所述转化为相应的式VII化合物。
实施例3a N-(2’,3’,4’,6’-四氟苯基)-N-氯乙酰基-4-甲基苯胺
N-(2’,3’,4’,6’-四氟苯基)-4-甲基苯胺(0.82g,3.2mmol)和氯乙酰氯(1.6g)的混合物在搅拌下在氮气下加热至90℃1.3小时。为了破坏过量的酰基氯,加入2-丙醇和水(分别为2ml),继续在室温搅拌过夜。加入甲苯(20ml)后,混合物用碳酸氢钠萃取,有机相用硫酸镁干燥并蒸发至干燥。用快速色谱(二氧化硅,甲苯)提纯残留物,得到N-(2’,3’,4’,6’-四氟苯基)-N-氯乙酰基-4-甲基苯胺油(0.98g,2.95mmol)。
实施例3b:N-(2’,3’,5’,6’-四氟苯基)-N-氯乙酰基-4-乙基苯胺
不使用溶剂,混合N-(2’,3’,5’,6’-四氟苯基)-4-乙基苯胺(2.05g)和氯乙酰氯(1.99g)并在搅拌下在氮气下加热至90℃20小时。冷却后加入四氢呋喃(10ml)和碳酸氢钠水溶液并继续搅拌约1小时。用甲苯稀释有机相,用水洗涤3次,用硫酸镁干燥。蒸发并用色谱提纯残留物(二氧化硅,甲苯),得到N-(2’,3’,5’,6’-四氟苯基)-N-氯乙酰基-4-乙基苯胺(1.84g)固体,其从庚烷中重结晶,mp.:72℃。
1H-NMR(400MHz,DMF-d7,140℃):1.25(t,3H,CH3);2.70(q,2H,CH2);4.28(s,2H,CH2-CO);7.35[d,2H,HC(3,5)];7.43[d,2H,HC(2,6)];7.65[tt,1H,HC(4’)].
实施例3c:N-(2’-氯-4’-氟-6’-甲基苯基)-N-氯乙酰基-4-甲基苯胺
1.32g N-(2’-氯-4’-氟-6’-甲基苯基)-4-甲基苯胺与氯乙酰氯(1.76g)在90℃反应30分钟。冷却的混合物与甲苯(20ml)和碳酸钠水溶液一起搅拌30分钟,蒸发有机相。残留物用在二氧化硅上使用甲苯的快速色谱提纯,得到1.04g N-(2’-氯-4’-氟-6’-甲基苯基)-N-氯乙酰基-4-甲基苯胺固体,其从庚烷/2-丙醇(9∶1)重结晶,mp.:96-97℃。
1H-NMR(400MHz,DMF-d7,120℃,所有峰表现为变宽或分裂):2.43(s,3H,CH3);4.31(s,2H,Cl-CH2-CO);7.31[d,1H,HC(5’)];7.32和7.40[AB,4H,C-HC(2,6)和HC(3,5)];7.45[s,1H,HC(3’)].
实施例3d:N-(2’-氯-6’-甲基苯基)-N-氯乙酰基-4-甲基苯胺
N-(2’-氯-6’-甲基苯基)-4-甲基苯胺(1.4g)在2.21g氯乙酰氯中的溶液加热到90℃4小时。混合物用甲苯(25ml)稀释,冷却至室温,用碳酸钠水溶液洗涤。干燥有机相,蒸发,残留物进行快速色谱[57g二氧化硅,甲苯和甲苯/乙酸乙酯(98∶2)],得到1.45gN-(2’-氯-6’-甲基苯基)-N-氯乙酰基-4-甲基苯胺,其从庚烷重结晶,mp:113-114℃。
实施例3e:N-(2’-氯-6’-甲基苯基)-N-氯乙酰基-4-乙基苯胺
N-(2’-氯-6’-甲基苯基)-N-4-乙基苯胺(4.95g,20mmol)用氯乙酰氯(3.23g,28.5mmol)处理,混合物在搅拌下在氮气下加热到95℃40分钟。加入2-丙醇(5ml)后,冷却至室温,混合物用甲苯稀释,用碳酸氢钠水溶液萃取。有机相用水洗涤并蒸发至于燥。快速色谱在二氧化硅(55g)上使用甲苯作为洗脱剂得到5.66g(17.6mmol,88%)N-(2’-氯-6’-甲基苯基)-N-氯乙酰基-4-乙基苯胺粘性液体。
1H-NMR(400MHz,DMF-d7,140℃):1.22(t,3H,CH 3 -CH2-),2.32(s,3H,CH3-C6’);2.65(q,2H,CH3-CH 2 -);4.12,4.18(AB,2H,CH2-Cl);7.22和7.31[每个d,每个2H,HC(2,6)和HC(3,5)];7.3-7.5[m,3H,HC(3’,4’,5’)].
实施例3f:N-(2’,4’-二氯-6’-甲基苯基)-N-氯乙酰基-4-乙基苯胺
N-(2’,4’-二氯-6’-甲基苯基)-4-乙基苯胺(4.83g作为与副产物N,N-二-(4-乙基苯基)-2’,4’-二氯-6’-甲基苯胺的混合物)溶解在4.18g氯乙酰氯中,加热至100℃ 1.5小时。冷却混合物,用甲苯稀释(50ml)并用碳酸氢钠水溶液萃取。蒸发有机相至干燥,用在二氧化硅(75g)上使用甲苯洗脱的色谱提纯,得到非反应的N,N-二-(4-乙基苯基)-2’,4’-二氯-6’-甲基苯胺和N-(2’,4’-二氯-6’-甲基苯基)-N-氯乙酰基-4-乙基苯胺(2.95g)。结晶的样品在83-84℃熔化。
1H-NMR(400MHz,DMF-d7,140℃):1.22(t,3H,CH 3 -CH2);2.31(s,3H,C-6’-CH3);2.56(q,2H,CH3-CH 2 );4.20(s,分裂,2H,Cl-CH2-CO);7.35,7.42[AB,4H,分别为HC(2,6)和HC(3,5)];7.40[s,br.1H,HC(5’)],7.53[s,br,1H,HC(3’)].
或者,式VIII化合物可通过如下程序制备:将1-甲氧基-4-甲基环己-1,4-二烯或1-甲氧基-4-乙基环己-1,4-二烯与上面定义的式IV苯胺衍生物偶联,得到式XIII的中间体化合物(或其互变异构体),
其不经分离就进行氧化,得到式VIII化合物,如下文实施例4所述。
实施例4a):N-(2’,6’-二氯苯基)-4-甲基苯胺
a)将4.35g 2,6-二氯-苯胺在4ml四氢呋喃和35ml氯苯中的溶液冷却到-40至-45℃。在该温度,向溶液中加入5.09g四氯化钛,然后加入5.0g 1-甲氧基-4-甲基环己-1,4-二烯。反应混合物温热至约-35℃并在该温度搅拌2小时。然后向反应混合物中滴加10.18g碘在20ml四氢呋喃和2.3ml乙酸中的溶液,并将温度温热至0℃。混合物在0℃搅拌1小时,在25℃搅拌16小时。然后向反应混合物中加入3.4g碘,在25℃继续再搅拌24小时。最后通过将反应混合物倾入250ml亚硫酸氢钠(38-40%)和400ml碳酸钠饱和水溶液的混合物中淬灭反应。水相用乙酸乙酯萃取(1×200ml和2×100ml),合并乙酸乙酯相并用100ml水洗涤。用无水硫酸钠干燥有机相,真空蒸发,得到11.44g深色淤浆。淤浆溶解在己烷/叔丁基甲基醚,在硅胶上过滤溶液,蒸发溶剂后得到5.75g粗产物。产物可直接用于下一步骤。或者,可用例如柱色谱提纯,在硅胶上用己烷/叔丁基甲基醚(9∶1)作为洗脱液,得到纯N-(2’,6’-二氯苯基)-4-甲基苯胺。
1H-NMR(CDCl3,400MHz,300K)δ2.31(s,3H,CH3),3.6-4.8(宽峰,1H,NH),6.68(d,J=8Hz,2H,H-C(2)和H-C(6)),7.02-7.12(m,3H,H-C(3),H-C(5)和H-C(4’)),7.38(d,J=8Hz,2H,H-C(3’)和H-C(5’)).
MS(EI):m/z 251(M+),216(M-Cl)+,181(M-2Cl)+
实施例4b):N-(2’-氯-6’-氟-苯基)-4-甲基苯胺
3.91g 2-氯-6-氟-苯胺在4ml四氢呋喃和35ml氯苯中的溶液冷却到-40至-45℃。在该温度向溶液中加入5.09g四氯化钛,然后加入5.0g 1-甲氧基-4-甲基环己-1,4-二烯。反应混合物温热至约-35℃并在该温度搅拌2小时。随后将10.18g碘在20ml四氢呋喃和2.3ml乙酸中的溶液滴加到反应混合物中,随后温度温热至0℃。混合物在0℃搅拌1小时并在25℃搅拌16小时。然后向反应混合物中加入3.4g碘,在25℃继续再搅拌24小时。最后通过将反应混合物倾入250ml亚硫酸氢钠(38-40%)和400ml碳酸钠饱和水溶液的混合物中淬灭反应。水相用乙酸乙酯萃取(1×200ml和2×100ml),合并乙酸乙酯相并用100ml水洗涤。用无水硫酸钠干燥有机相,真空蒸发,得到黄色粘性液体。液体溶于己烷/叔丁基甲基醚中,在硅胶上过滤溶液,蒸发溶剂后得到4.33g粗产物。产物可直接用于下一步骤。或者,可用例如柱色谱提纯,在硅胶上用己烷/叔丁基甲基醚(9∶1)作为洗脱液,得到纯N-(2’-氯-6’-氟-苯基)-4-甲基苯胺。
1H-NMR(DMSO-d6,500MHz,300K)δ2.17(s,3H,CH3);6.53[dd,J=8.5Hz,JH-F=1.5Hz,2H,HC(2)和HC(6)],6.94[d,J=8.0Hz,2H,HC(3)和HC(5)],7.16[ddd,J=8.0Hz,JH-F=6.0Hz,1H,HC(4’)],7.25[ddd,J=8.0,1.5Hz,JH-F=8.0,1H,HC(5’)];7.34[ddd,J=8.0,1.5Hz,JH-F=1.5,1H,HC(3’)];7.63(s,1H,NH).
MS(EI)m/z 235(100,M+),200(35,(M-Cl)+),185(55)
实施例4c):N-(2’-氯-6’-甲基-苯基)-4-乙基苯胺
3.0g 2-氯-6-甲基-苯胺在3.5ml四氢呋喃和31ml氯苯中的溶液冷却到-40至-45℃。在该温度,向溶液中加入4.01g的四氯化钛,然后加入6.18g 1-甲氧基-4-乙基环己-1,4-二烯。反应混合物温热至约-35℃并在该温度搅拌3小时。向反应混合物中加入8.06g碘在16.4ml四氢呋喃和1.8ml乙酸中的溶液并温热至0℃。混合物在0℃搅拌30分钟,在25℃搅拌2小时。然后向反应混合物中加入2.68g碘并在25℃继续再搅拌24小时。再加入2.68g碘并在25℃继续再搅拌72小时。最后通过将反应混合物倾入250ml亚硫酸氢钠(38-40%)和450ml碳酸钠饱和水溶液的混合物中淬灭反应。水相用乙酸乙酯萃取(1×200ml和2×100ml),合并乙酸乙酯相并用100ml盐水洗涤。用无水硫酸钠干燥有机相,真空蒸发,得到深色粘性液体。液体溶于庚烷/甲苯中,在硅胶上过滤溶液,蒸发溶剂后得到2.0g粗产物。产物可直接用于下一步骤。或者,可用例如柱色谱提纯,在硅胶上用庚烷/甲苯(7∶3)作为洗脱液,得到纯N-(2’-氯-6’-甲基-苯基)-4-乙基苯胺。
1H-NMR(CDCl3,400MHz,300K)δ1.24(t,J=7.5Hz,3H,H3C(8)),2.22(s,3H,H3C-C(2’)),2.61(q,J=7.5Hz,2H,H2C(7)),4.0-5.5(宽峰,1H,NH),6.60(d-状,J=8Hz,2H,H-C(2)和H-C(6)),7.02-7.10(m,3H,H-C(3),H-C(5)和H-C(4’)),7.10-7.20(m,1H,H-C(3’)),7.33(d-状,J=9Hz,1H,H-C(5’)).
MS:m/z 245(M+),230,214,194,180.
用于实施例4的1-甲氧基-4-甲基环己-1,4-二烯和1-甲氧基-4-乙基环己-1,4-二烯起始原料根据已知的文献中的方法制备。
1-甲氧基-4-甲基环己-1,4-二烯
根据已知文献中的工艺制备:
G.S.R.Subba Rao,D.K.Banerjee,L.Uma Devi和UmaSheriff,Australian Journal of Chemistry 1992,45,p.187-203
1-甲氧基-4-乙基环己-1,4-二烯
根据上述为1-甲氧基-4-甲基环己-1,4-二烯所给出的相同文献制备化合物4。
实施例4的产物转化为相应的式VII化合物,例如上文实施例3和下文实施例5所述的。
实施例5:N-(2’,6’-二氯苯基)-N-氯乙酰基-4-甲基苯胺
N-(2’,6’-二氯苯基)-4-甲基苯胺(4.86g)与氯乙酰氯(3.92g)在90℃反应2小时。用甲苯稀释后,混合物用碳酸钠水溶液洗涤2次,用40%亚硫酸氢钠和水洗涤。干燥有机相(MgSO4)并蒸发。残留物用乙醇(12g)重结晶,得到N-(2’,6’-二氯苯基)-N-氯乙酰基-4-甲基苯胺(2.83g),mp:129.5-130℃.
另一替代方法中,式VI I化合物可通过如下方法制备:式IX化合物的Smiles型重排
得到上文定义的式VIII中间产物,其不经分离就转化为式VII化合物,如下面的实施例所述。
实施例6a):N-(2’,6’-二氯-4’-甲基苯基)-N-氯乙酰基-4-甲基 苯胺
12g(67mmol)2,6-二氯-4-甲酚溶于25ml 2-丙醇,然后加入10.5g(76mmol)碳酸钾和12.8g(70mmol)2-氯-N-(4-甲基苯基)乙酰胺。混合物回流4小时。此时,形成了A:2-(2’,6’-二氯-4’-甲基苯氧基)-N-(4-甲基苯基)乙酰胺。缓慢地加入13.6ml甲醇钠在甲醇中的30%溶液,温度通过蒸馏25ml溶剂升高到约85℃。混合物再搅拌2小时,形成B。在70℃加入25ml水得到两相溶液。弃去下层。上层用20ml庚烷馏分稀释,用2×20ml水洗涤。分离有机相并在真空中浓缩,得到N-(2’,6’-二氯-4’-甲基苯基)-4-甲基苯胺粗油。
GC/MS:265(100,M+),195(130).
该油加热到90℃并用6.5ml氯乙酰氯处理。2小时后混合物用60ml2-丙醇稀释,冷却至约20℃并加入晶种。沉淀后的悬浮液冷却到0℃。过滤分离晶体,用冷2-丙醇洗涤,干燥,得到N-(2’,6’-二氯-4’-甲基苯基)-N-氯乙酰基-4-甲基苯胺。Mp:140-141℃.
1H-NMR(DMF-d7,413K,400Mz)2.33(s,3H,CH3);2.40(s,3H,CH3);4.18(s,2H,CH2);7.22[d,2H,HC(5)和HC(3)];7.38[d,2H,HC(2)和HC(6)];7.42[s,2H,HC(3’)和HC(5’)].
实施例6b):N-(2’-氯-6’-氟苯基)-N-氯乙酰基-4-甲基苯胺
与实施例6a的方法类似,从2-氯-6-氟苯酚开始。
Mp:80-82℃.
1H-NMR(DMF-d7,393K,400Mz)2.4(s,3H,CH3);4.3(s,2H,CH2);7.35[d,2H,HC(3)和HC(5)];7.43[ddd,1H,HC(5’)];7.48[d,2H,HC(2)和HC(6)];7.55[d,1H,HC(3’)];7.6[ddd,1H,HC(4’)].
实施例6c):N-(2’,3’,6’-三氟苯基)-N-氯乙酰基-4-乙基苯胺
与实施例6a的方法类似,从2,3,6-三氟苯酚和2-氯-N-(4-乙基苯基)乙酰胺开始。粗中间体N-(2’,3’,6’-三氟苯基)-4-乙基苯胺用过滤粗提纯,在二氧化硅上用甲苯作为洗脱液。
Mp:49-50℃.1H-NMR(DMF-d7,413K,400MHz)1.24(t,3H,CH3);2.70(q,2H,CH2-CH3);4.25(s,2H,CH2-Cl);7.20[m,1H,HC(5’)];7.34[d,2H,HC(3)和HC(5)];7.42[d,2H,HC(2)和HC(6)];7.46[m,1H,HC(4’)].
实施例6d):N-(2’-氯-6’-氟苯基)-N-氯乙酰基-4-乙基苯胺
与实施例6a的方法类似,从2-氯-6-氟苯酚和2-氯-N-(4-乙基苯基)乙酰胺开始。
Mp:67-68℃.1H-NMR(DMF-d7,413K,500MHz)1.23(t,3H,CH3);2.68(q,2H,CH2-CH3);4.20(s,2H,CH2-Cl);7.29[d,2H,HC(3)和HC(5)];7.34[m,1H,HC(5’)];7.43[d,2H,HC(2)和HC(6)];7.48[m,2H,HC(3’)和HC(4’)].
实施例6e):N-(2’,6’-二氯苯基)-N-氯乙酰基-4-甲基苯胺
与实施例6a的方法类似,从2,6-二氯苯酚和2-氯-N-(4-甲基苯基)乙酰胺开始。乙酰化反应结束后混合物用少量甲苯(0.2份)稀释防止固化。
Mp:129-130℃.1H-NMR(DMF-d7,393K,500Mz)2.40(s,3H,CH3);4.28(s,2H,CH2-Cl);7.30[d,2H,HC(3)和HC(5)];7.46[d,2H,HC(2)和HC(6)];7.54[m,1H,HC(4’)];7.67[d,2H,HC(3’)和HC(5’)].
如实施例7所述,环化式VII化合物得到式II内酰胺。
实施例7a):N-(2’,6’-二氯-4’-甲基苯基)-5-甲基羟吲哚
6.85g(20mmol)N-(2’,6’-二氯-4’-甲基苯基)-N-氯乙酰基-4-甲基苯胺和3.36g(26mmol)氯化铝的混合物缓慢加热至160-170℃并在该温度保持3-4小时。在此期间,连续将氮气鼓入熔化物。混合物用20ml甲苯稀释,加入20ml温水。分离有机层,用水洗涤,蒸发。残留物用20ml 2-丙醇洗涤,得到N-(2’,6’-二氯-4’-甲基苯基)-5-甲基羟吲哚。Mp:153-154℃.
1H-NMR(DMSO-d6,500Mz,300K)2.29[s,3H,CH3-C(5)];2.41[s,3H,CH3-C(4’)];3.81(s,2H,CH2);6.27[d,1H,HC(7)];7.00[d,1H,HC(6)];7.19[s,1H,HC(4)];7.58[s,2H,HC(3’)和HC(5’)].
实施例7b):N-(2’-氯-6’-氟苯基)-5-甲基羟吲哚
与实施例7a相同的方法。
Mp:137-138℃.1H-NMR(DMSO-d6,500MHz,300K)2.27(s,3H,CH3)3.83(s,2H,CH2)6.35[d,1H,HC(7)];7.01[d,1H,HC(6)];7.19[s,1H,HC(4)];7.52[d,1H,HC(5’)];7.60[d,1H,HC(3’)],7.63[d,1H,HC(4’)].
实施例7c):N-(2’,3’,6’-三氟苯基)-5-乙基羟吲哚
与实施例7a相同的方法。反应4小时后,再加入10%氯化铝。总反应时间:6小时。
Mp:171-172℃.1H-NMR(DMSO-d6,500Mz,300K)1.18(t,3H,CH3);2.60[q,2H,CH2-CH3];3.89[s,2H,CH2-CO];6.62[d,1H,HC(7)];7.09[d,1H,HC(6)];7.25[s,1H,HC(4)];7.46[m,1H,HC(5’)];7.76[m,1H,HC(4’)].
实施例7d):N-(2’-氯-6’-氟苯基)-5-乙基羟吲哚
与实施例7c相同的方法。
Mp:129-130℃.1H-NMR(DMSO-d6,300K,500Mz)1.18(t,3H,CH3);2.59[q,2H,CH2-CH3];3.86(s,2H,CH2-CO);6.39[d,1H,HC(7)];7.05[d,1H,HC(6)];7.24[s,1H,HC(4)],7.59[m,1H,HC(5’)];7.64[m,2H,HC(3’)和HC(4’)].
实施例7e):N-(2’,6’-二氯苯基)-5-甲基羟吲哚
与实施例7a相同的方法
1H-NMR(DMSO-d6,500MHz,300K)2.30(s,3H,CH3);3.85(s,2H,CH2);6.29[d,1H,HC(7)];7.02[d,1H,HC(6)];7.22[s,1H,HC(4)],7.62[t,1H,HC(4’)];7.76[d,2H,HC(3’)和HC(5’)].
实施例7f):N-(2’,3’,4’,6’-四氟苯基)-5-甲基羟吲哚
将N-(2’,3’,4’,6’-四氟苯基)-N-氯乙酰基-4-甲基苯胺(0.97g,2.97mmol)在氯苯(2.5g)中的溶液用三氯化铝(1.05g,7.8mmol)处理,混合物在搅拌下在油浴中(155℃)加热5小时同时用氮气冲洗烧瓶。加入甲苯(30ml)和水(20ml),在室温继续搅拌30分钟。分离各相,有机相用盐酸(2N)和水洗涤。减压蒸发,得到固体(0.84g,2.85mmol),用2-丙醇重结晶得到纯N-(2’,3’,4’,6’-四氟苯基)-5-甲基羟吲哚,mp.172-173℃.
1H-NMR(300MHz,300K,CDCl3):2.28(s,3H,CH3);3.65[s,2H,H2C(3)];6.39[d,7.5Hz,1H,HC(7)];6.85-7.0[m,1H,HC(5’)];6.98üd,7.5Hz,1H,HC(6)];7.09[s,1H,HC(4)].
实施例7g):N-(2’-氯-6’-甲基苯基)-5-乙基羟吲哚
在烧瓶中混合N-(2’-氯-6’-甲基苯基)-N-氯乙酰基-4-乙基苯胺(2.08g)和三氯化铝(1.16g),混合物用氮气冲洗。将烧瓶置于油浴中(155-160℃),在氮气流下搅拌混合物4.5小时。稍微将混合物冷却到约100℃,用甲苯(30ml)和1N HCl(20ml)处理,搅拌30分钟,同时温度逐渐下降。相分离后,有机相用1N HCl和水洗涤,干燥(硫酸镁)并蒸发。在二氧化硅上(86g)用色谱处理残留物,使用含有5-20%乙酸异丙酯的甲苯作为洗脱液,得到标题化合物。
Mp:125-126℃
在另一种可替代方案中式II内酰胺通过氧化不饱和的式III内酰胺制备,
例如,其可以如实施例8所述进行制备。
实施例8:(5-乙基-2-吗啉-4-基-亚环己-2-烯基)-乙酸乙酯
91.6g 4-乙基-环己酮、73.6g吗啉和2g对甲苯磺酸一水合物溶于400ml甲苯。混合物加热至回流,形成的水通过水分离器除去。反应约24小时后,反应混合物冷却到100℃,加入2g对甲苯磺酸,然后用30分钟加入157.22g乙醛酸乙酯。混合物再次加热至回流5小时,冷却至22℃。真空蒸发溶剂,粗产物在真空在140-150℃/9.5-2mbar蒸馏。
1H-NMR(CDCl3,500MHz,277K)δ0.896ppm(t,J=7Hz,3H,H3C(17)),1.277(t,J=7Hz,3H,H3C(10)),1.20-1.45(m,2H,H2C(16)),1.50-1.62(m,1H,H-C(4)),1.876(ddd,J1=18Hz,J2=9Hz,J3=3Hz,1H,H-C(3)),2.13(m,1H,H-C(5)),2.35(dt,J1=17Hz,J2=5Hz,1H,H-C(3)),2.55-2.65(m,2H,H-C(12)和H-C(15)),2.72-2.80(m,2H,H-C(12)和H-C(15)),3.55(dm,J=15Hz,1H,H-C(5)),3.74(m,4H,H2C(13)和H2C(14)),4.152(q,J=7Hz,2H,H2C(9)),5.46(dd,J1=5Hz,J2=3Hz,1H,H-C(2)),6.17(宽s,1H,H-C(7))。赋值相应于结构式上给出的数字。
IR(膜):在2960,1710,1624,1609,1191,1156和1120cm-1有强吸收。.
MS(EI):m/z 279(M+),250(M-C2H5)+,234,206(M-CO2C2H5)+,176,164,135,84.
b).合成(5-乙基-2-氧代-亚环己基)-乙酸乙酯
10g[5-乙基-2-吗啉-4-基-亚环己-2-烯基]-乙酸乙酯溶于20ml甲苯。在强烈搅拌下滴加12ml 6M HCl,反应混合物在22℃再搅拌60分钟。分离有机层并用25ml水洗涤2次。合并的水相用25ml甲苯萃取。合并的甲苯层用无水硫酸钠干燥,真空蒸发溶剂,得到6.72g [5-乙基-2-氧代-亚环己基]-乙酸乙酯油。
1H-NMR(CDCl3,500MHz,277K)δ0.935ppm(t,J=7Hz,3H,H3C(12)),1.259(t,J=7Hz,3H,H3C(10)),1.31-1.45(m,2H,H2C(11)),1.46-1.55(m,1H,H-C(5)),1.59-1.69(m,1H,H-C(4)),1.97-2.04(m,1H,H-C(5)),2.296(ddd,J=17Hz,11Hz和3Hz,1H,H-C(3)),2.383(m,1H,H-C(6)),2.615(dt,J=17和4Hz,1H,H-C(6)),3.57(dm,J=17Hz,1H,H-C(3)),4.17(q,J=7Hz,2H,H2C(9)),6.42(m,1H,H-C(7)).赋值相应于结构式上给出的数字。
IR(膜):在1719,1698和1200cm-1有强吸收.
MS(EI):m/z 210(M+),164(M-C2H5OH)+,135.
c).合成1-(2-氯-6-甲基-苯基)-5-乙基-1,4,5,6-四氢吲哚-2-酮
3.45g 2-氯-6-甲基-苯胺溶于26ml甲苯。加入0.227g对甲苯磺酸(一水合物),混合物加热至回流。用75分钟滴加5.0g(5-乙基-2-氧代-亚环己基)-乙酸乙酯在13ml甲苯中的溶液,用水分离器收集形成的水。反应混合物加热至回流15小时,在此期间频繁出去凝结的溶剂并用新鲜甲苯代替。处理时,混合物冷却到22℃,用70ml饱和碳酸氢钠水溶液在强烈搅拌下处理。分离各层,甲苯相用5%柠檬酸水溶液洗涤,最后用10%氯化钠水溶液洗涤。水相用70ml甲苯萃取,合并甲苯相。真空蒸发溶剂,得到7.1g粗产物高度黏稠的油。粗产物的分析样品可在硅胶上用色谱提纯,用甲苯/乙酸乙酯(9∶1)作为洗脱液,得到纯1-(2-氯-6-甲基-苯基)-5-乙基-1,4,5,6-四氢吲哚-2-酮。
1H-NMR(d6-DMSO,400MHz,300K)δ0.894ppm(t,J=7Hz,3H,H3C(11)),1.34-1.43(m,2H,H2C(10)),1.70-1.82(m,1H,H-C(5)),1.90-2.02(m,1H,H-C(6)),2.038(s,3H,H3C(6’)),2.28-2.40(m,2H,H-C(4)和H-C(6)),2.87(dd,J1=17Hz和J2=4Hz,1H,H-C(4)),5.14(m,1H,H-C(7)),5.96(宽s,1H,H-C(3)),7.3-7.5(m,3H,H-C(3’),H-C(4’),H-C(5’)).赋值相应于结构式上给出的数字。
IR(膜):在1703,1660和1476cm-1有强吸收。
MS(EI):m/z 287(M+),272(M-CH3)+,258(M-C2H5)+,252(M-Cl)+.
d):合成N-(2-氯-6-甲基-苯基)-5-乙基-羟吲哚
1-(2-氯-6-甲基-苯基)-5-乙基-1,4,5,6-四氢吲哚-2-酮可用常规方法,例如用10%Pd-C在回流的二甲苯中氧化,得到N-(2-氯-6-甲基-苯基)-5-乙基-羟吲哚。
1H-NMR和MS谱见实施例7g.
上述定义的式II内酰胺转化为上述定义的式I化合物,例如如下面的实施例9所述。
实施例9a):5-甲基-2-(2’,6’-二氯-4’-甲基苯胺基)苯乙酸
1.5g N-(2’,6’-二氯-4’-甲基苯基)-5-甲基羟吲哚、18ml乙醇和1ml水的混合物加热至回流。缓慢加入1.9g 30%氢氧化钠溶液,继续回流4-5小时。将溶液冷却到约40℃并缓慢地用1.5g浓盐酸在12ml水中的溶液处理直到pH 3-4。得到的悬浮液冷却到20℃。过滤收集结晶,用水洗涤,干燥,得到5-甲基-2-(2’,6’-二氯-4’-甲基苯胺基)苯乙酸。
Mp:179-182℃.1H-NMR(DMSO-d6,300K,500Mz)2.22[s,3H,CH3-C(5)];2.32[s,3H,CH3-C(4’)];3.67(s,2H,CH2);6.18[d,1H,HC(3)],6.87[s,d,1H,HC(4)];6.97(s,1H,NH);7.02[s,1H,HC(6)];7.36[s,2H,HC(3’)和HC(5’)];12.68(br.s,1H,COOH).
实施例9b):5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸
与9a相同的方法。
Mp:152-154℃ 1H-NMR(DMSO-d6,500MHz,300K)δ2.21(s,3H,CH3),3.64(s,2H,CH2);6.42[dd,1H,HC(3)],6.90[dd,1H,HC(4)],7.01[d,1H,HC(6)],7.09(s,1H,NH),7.09[ddd,1H,HC(4’)],7.23[ddd,1H,HC(5’)],7.34[ddd,1H,HC(3’)],12.67(s,1H,COOH).
实施例9c):5-甲基-2-(2’,3’,4’,6’-四氟苯胺基)-苯乙酸
350mg N-(2’,3’,4’,6’-四氟苯基)-5-甲基羟吲哚在20ml乙醇和5ml水中的悬浮液通过通入氮气1.5小时脱气。然后加入260mg30%氢氧化钠水溶液,混合物加热至回流6.5小时。然后蒸馏除去大部分乙醇,冷却混合物至室温,随后缓慢加入1N盐酸(1.05g)至pH为约3。过滤沉淀,用乙醇/水(1∶1)洗涤,在室温真空干燥,得到标题产物。
Mp:145-146℃.
1H-NMR(300MHz,DMSO-d6):2.23(s,3H,CH3);3.65(s,2H,CH2-COO);6.55[s,1H,HC(3)];6.92[d,1H,HC(4)];7.00[s,1H,HC86]];7.20(s,1H,NH);7.50[m,1H,HC(5’)].
基本如上所述,类似地将其它式II内酰胺转化为式I化合物。
Claims (8)
2. 用于制备式I化合物、或其药学可接受的盐、或其药学可接受的前药酯的方法,
其中R是甲基或乙基;
R1是氯或氟;
R2是氢或氟;
R3是氢、氟、氯、甲基、乙基、甲氧基、乙氧基或羟基;
R4是氢或氟;且
R5是氯、氟、三氟甲基或甲基,
条件是R1,R2,R4和R5在R是乙基和R3是H时不全为氟;
该方法包括步骤:
(a)重排和水解式IX化合物
产生式VIII化合物
(b)用卤代乙酰氯N-酰化式VIII化合物,以产生式VII化合物
(c)环化式VII化合物,以产生式II的内酰胺
和
(d)用碱分裂式II的内酰胺,
并且在上述方法中,任选地,暂时保护任何干扰性反应基团和随后分离所得到的化合物;和,任选地,将式I化合物的游离羧酸转化为其药学可接受的酯衍生物;和/或,任选地,将式I的游离羧酸转化为药学上可接受的盐或将得到的盐转化为游离羧酸或另一种药学上可接受的盐。
3. 权利要求1或2的方法,包括暂时保护任何干扰性反应基团和随后分离所得到的化合物的另外的步骤。
4. 权利要求2的方法,包括将式I化合物的游离羧酸转化为其药学可接受的酯衍生物的另外的步骤。
5. 权利要求2的方法,包括将式I的游离羧酸转化为药学可接受的盐或将得到的盐转化为游离羧酸或另一种药学可接受的盐的另外的步骤。
7. 根据权利要求2的方法,用于制备选自下列的化合物:
5-甲基-2-(2’,3’,4’,6’-四氟苯胺基)苯乙酸;
5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸;
5-甲基-2-(2’,6’-二氯-4’-甲基苯胺基)苯乙酸;
及其药学可接受的盐;和其药学可接受的前药酯。
8. 根据权利要求1或2的方法,其中
R是甲基;
R1是氯;
R2、R3和R4是氢,且
R5是氟。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9922830.6A GB9922830D0 (en) | 1999-09-27 | 1999-09-27 | Processes |
GB9922830.6 | 1999-09-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1377337A CN1377337A (zh) | 2002-10-30 |
CN100412053C true CN100412053C (zh) | 2008-08-20 |
Family
ID=10861676
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB008133972A Expired - Fee Related CN100412053C (zh) | 1999-09-27 | 2000-09-25 | 苯乙酸衍生物的制备方法 |
Country Status (34)
Country | Link |
---|---|
US (2) | US20080249318A1 (zh) |
EP (2) | EP1216226B1 (zh) |
JP (1) | JP2003510303A (zh) |
KR (1) | KR100745341B1 (zh) |
CN (1) | CN100412053C (zh) |
AR (2) | AR031529A1 (zh) |
AT (1) | ATE447547T1 (zh) |
AU (1) | AU775416B2 (zh) |
BR (1) | BR0014314A (zh) |
CA (1) | CA2379553C (zh) |
CO (1) | CO5210865A1 (zh) |
CY (1) | CY1110539T1 (zh) |
CZ (1) | CZ20021027A3 (zh) |
DE (1) | DE60043261D1 (zh) |
DK (1) | DK1216226T3 (zh) |
EC (2) | ECSP003680A (zh) |
ES (1) | ES2338209T3 (zh) |
GB (1) | GB9922830D0 (zh) |
HK (1) | HK1047739A1 (zh) |
HU (1) | HUP0202728A3 (zh) |
IL (2) | IL148330A0 (zh) |
MY (1) | MY125201A (zh) |
NO (1) | NO327912B1 (zh) |
NZ (1) | NZ517461A (zh) |
PE (1) | PE20010644A1 (zh) |
PL (1) | PL207777B1 (zh) |
PT (1) | PT1216226E (zh) |
RU (1) | RU2273628C2 (zh) |
SI (1) | SI1216226T1 (zh) |
SK (1) | SK287241B6 (zh) |
TR (1) | TR200200745T2 (zh) |
TW (1) | TWI270540B (zh) |
WO (1) | WO2001023346A2 (zh) |
ZA (1) | ZA200202367B (zh) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0209257D0 (en) * | 2002-04-23 | 2002-06-05 | Novartis Ag | Organic compounds |
AU2003248642A1 (en) | 2002-06-11 | 2003-12-22 | Nitromed, Inc. | Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use |
GB0224198D0 (en) * | 2002-10-17 | 2002-11-27 | Novartis Ag | Organic compounds |
AR042206A1 (es) | 2002-11-26 | 2005-06-15 | Novartis Ag | Acidos fenilaceticos y derivados |
US7161026B1 (en) | 2005-07-08 | 2007-01-09 | Property Development Corporation International, Ltd, Inc. | Method of preparation of methyl-benzyl-ketone |
AR061623A1 (es) | 2006-06-26 | 2008-09-10 | Novartis Ag | Derivados de acido fenilacetico |
US8227451B2 (en) | 2008-11-12 | 2012-07-24 | Auspex Pharmaceuticals | Phenylacetic acid inhibitors of cyclooxygenase |
CN102311355B (zh) * | 2011-09-26 | 2014-02-05 | 扬州天和药业有限公司 | 罗本考昔的一种制备方法 |
CN107721901A (zh) * | 2017-11-12 | 2018-02-23 | 刘磊 | 一种2‑[2‑(2,3,5,6‑四氟苯胺基)苯基]乙酸的制备方法 |
EA202190330A1 (ru) | 2018-07-27 | 2021-06-04 | КРКА, д.д., НОВО МЕСТО | Способ получения полиморфной формы робенакоксиба |
CN116621715A (zh) * | 2018-08-03 | 2023-08-22 | 日产化学株式会社 | 氟化芳族仲胺化合物的制造方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3558690A (en) * | 1965-04-08 | 1971-01-26 | Gelgy Chemical Corp | Substituted derivatives of 2-anilinophenylacetic acids and a process of preparation |
JPH0977664A (ja) * | 1995-09-13 | 1997-03-25 | Yakult Honsha Co Ltd | シクロオキシゲナーゼ−2特異的阻害剤及び抗炎症剤 |
WO1999011605A1 (en) * | 1997-08-28 | 1999-03-11 | Novartis Ag | Certain 5-alkyl-2-arylaminophenylacetic acids and derivatives |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1097265B (it) | 1978-06-23 | 1985-08-31 | Acraf | Nouva sintesi di un acido fenilacetico |
JPS5677246A (en) * | 1980-11-27 | 1981-06-25 | Nissan Chem Ind Ltd | Production of substituted phenylacetic acid |
DE3404401C2 (de) | 1984-02-08 | 1994-02-10 | Hoechst Ag | Verwendung von Aryloxy-Verbindungen als Antidots |
FR2578836B1 (fr) | 1985-03-12 | 1987-04-17 | Rhone Poulenc Spec Chim | Procede de chloration selective de composes phenoliques |
ES2065928T3 (es) | 1989-01-27 | 1995-03-01 | Heumann Pharma Gmbh & Co | Procedimiento para la fabricacion de derivados de acido 2,6-diclorodifenilaminacetico. |
IT1248032B (it) * | 1991-06-11 | 1995-01-05 | Laboratorio Chimico Int Spa | Procedimento per la preparazione della n- (2,6-diclorofenil) -n-fenil-n-(cloroacetil)-ammina. |
CN1091420A (zh) * | 1993-02-25 | 1994-08-31 | 永信药品工业股份有限公司 | 二苯胺衍生物的制备方法 |
JPH0789951A (ja) | 1993-06-03 | 1995-04-04 | Sterling Winthrop Inc | インターロイキン−1β転換酵素阻害剤 |
US5475139A (en) | 1993-10-22 | 1995-12-12 | Yung Shin Pharm. Ind. Co., Ltd. | Method for the preparation of substituted derivatives of diphenyl amine |
CA2189036A1 (en) | 1994-04-29 | 1995-11-09 | Roland E. Dolle | Halomethyl amides as il-1.beta. protease inhibitors |
US5576460A (en) | 1994-07-27 | 1996-11-19 | Massachusetts Institute Of Technology | Preparation of arylamines |
US6355680B1 (en) | 1996-02-20 | 2002-03-12 | Exocell, Inc. | Albumin-binding compounds that prevent nonenzymatic glycation and that may be used for treatment of glycation-related pathologies |
US6034266A (en) | 1996-03-11 | 2000-03-07 | Fundacao Oswaldo Cruz-Fiocruz | Gem-difluoro derivative of phenylacetamide and phenylacetic acid and their pharmaceutical uses |
BR9600975A (pt) * | 1996-03-11 | 1997-12-30 | Fundacao Oswaldo Cruz | Derivados do ácido gem-difluorfenilacético e de gem-difluorfenilacetamida processo de sua preparação e suas aplicações farmacêuticas |
CA2208900C (en) | 1996-07-18 | 2006-08-01 | Lonza Ag | Process for preparing 2-pyrimidinecarboxylates |
US5817877A (en) | 1996-09-23 | 1998-10-06 | Yale University | Metal-catalyzed amination of organic sulfonates to organic amines |
-
1999
- 1999-09-27 GB GBGB9922830.6A patent/GB9922830D0/en not_active Ceased
-
2000
- 2000-09-25 ES ES00969292T patent/ES2338209T3/es not_active Expired - Lifetime
- 2000-09-25 PL PL365994A patent/PL207777B1/pl unknown
- 2000-09-25 AU AU79067/00A patent/AU775416B2/en not_active Ceased
- 2000-09-25 AT AT00969292T patent/ATE447547T1/de active
- 2000-09-25 BR BR0014314-6A patent/BR0014314A/pt not_active IP Right Cessation
- 2000-09-25 DE DE60043261T patent/DE60043261D1/de not_active Expired - Lifetime
- 2000-09-25 RU RU2002109239/04A patent/RU2273628C2/ru not_active IP Right Cessation
- 2000-09-25 NZ NZ517461A patent/NZ517461A/en not_active IP Right Cessation
- 2000-09-25 CA CA2379553A patent/CA2379553C/en not_active Expired - Fee Related
- 2000-09-25 DK DK00969292.2T patent/DK1216226T3/da active
- 2000-09-25 HU HU0202728A patent/HUP0202728A3/hu unknown
- 2000-09-25 EP EP00969292A patent/EP1216226B1/en not_active Expired - Lifetime
- 2000-09-25 JP JP2001526501A patent/JP2003510303A/ja active Pending
- 2000-09-25 EP EP09171648A patent/EP2275403A1/en not_active Withdrawn
- 2000-09-25 KR KR1020027003901A patent/KR100745341B1/ko not_active IP Right Cessation
- 2000-09-25 PE PE2000001007A patent/PE20010644A1/es not_active Application Discontinuation
- 2000-09-25 IL IL14833000A patent/IL148330A0/xx active IP Right Grant
- 2000-09-25 AR ARP000105014A patent/AR031529A1/es active IP Right Grant
- 2000-09-25 SI SI200031050T patent/SI1216226T1/sl unknown
- 2000-09-25 PT PT00969292T patent/PT1216226E/pt unknown
- 2000-09-25 CN CNB008133972A patent/CN100412053C/zh not_active Expired - Fee Related
- 2000-09-25 EC EC2000003680A patent/ECSP003680A/es unknown
- 2000-09-25 WO PCT/EP2000/009346 patent/WO2001023346A2/en active IP Right Grant
- 2000-09-25 CZ CZ20021027A patent/CZ20021027A3/cs unknown
- 2000-09-25 TR TR2002/00745T patent/TR200200745T2/xx unknown
- 2000-09-25 SK SK414-2002A patent/SK287241B6/sk not_active IP Right Cessation
- 2000-09-26 MY MYPI20004481 patent/MY125201A/en unknown
- 2000-09-27 CO CO00073348A patent/CO5210865A1/es not_active Application Discontinuation
- 2000-09-27 TW TWPROCESSFA patent/TWI270540B/zh not_active IP Right Cessation
-
2002
- 2002-02-21 IL IL148330A patent/IL148330A/en not_active IP Right Cessation
- 2002-03-19 NO NO20021368A patent/NO327912B1/no not_active IP Right Cessation
- 2002-03-25 ZA ZA200202367A patent/ZA200202367B/en unknown
- 2002-12-23 HK HK02109296.0A patent/HK1047739A1/xx not_active IP Right Cessation
-
2003
- 2003-01-10 AR ARP030100070A patent/AR042404A2/es unknown
-
2007
- 2007-08-16 US US11/893,481 patent/US20080249318A1/en not_active Abandoned
-
2009
- 2009-01-13 EC EC2009003680A patent/ECSP093680A/es unknown
- 2009-05-07 US US12/436,991 patent/US7906677B2/en not_active Expired - Fee Related
-
2010
- 2010-02-03 CY CY20101100105T patent/CY1110539T1/el unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3558690A (en) * | 1965-04-08 | 1971-01-26 | Gelgy Chemical Corp | Substituted derivatives of 2-anilinophenylacetic acids and a process of preparation |
JPH0977664A (ja) * | 1995-09-13 | 1997-03-25 | Yakult Honsha Co Ltd | シクロオキシゲナーゼ−2特異的阻害剤及び抗炎症剤 |
WO1999011605A1 (en) * | 1997-08-28 | 1999-03-11 | Novartis Ag | Certain 5-alkyl-2-arylaminophenylacetic acids and derivatives |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100412053C (zh) | 苯乙酸衍生物的制备方法 | |
JP4770174B2 (ja) | グルタミン酸誘導体及びピログルタミン酸誘導体の製造方法並びに新規製造中間体 | |
JP2003292484A (ja) | γ−ヒドロキシアミノ酸誘導体及びモナティン類の製造方法 | |
JPS6327471A (ja) | 光学活性なベンゼンスルホンアミド誘導体の製造法 | |
JP2001504125A (ja) | シクロプロピルアミンの製造法 | |
US20130338360A1 (en) | Method for the preparation of high-purity pharmaceutical intermediates | |
CN1225625A (zh) | α-氨基酸酰胺,其制备方法及其治疗用途 | |
JPH0848661A (ja) | グリコロイルアニリド類の製造方法 | |
JP2005512986A (ja) | 置換1h−キノキサリン−2−オン化合物ならびに置換4−アリール−および4−ヘテロアリールシクロヘキサン化合物 | |
US4614806A (en) | Process for the asymmetric synthesis of chiral indoline-2-carboxylic acids | |
US20120253051A1 (en) | Process for the preparation of ropinirole and salts thereof | |
WO2012165607A1 (ja) | プロリン化合物の製造方法 | |
SK286425B6 (sk) | Spôsob výroby R-(+)-6-karboxamido-3-N-metylamino-1,2,3,4- tetrahydrokarbazolu a použitie kyseliny L-pyroglutámovej | |
JP4032127B2 (ja) | (R)−2−アミノ−1−(m−クロロフェニル)エタノールの製造法 | |
WO2008026678A1 (fr) | Derive de diester d'acide succinique, procede de production associe et utilisation de ce derive dans la production d'une preparation pharmaceutique | |
CA2211930A1 (en) | 7-(n-substituted amino)-2-phenylheptanoic acid derivative and process for manufacturing the same | |
JP2003226677A (ja) | 光学活性2−(1−アミノアルキル)アニリン類およびその光学活性な酒石酸類との塩、並びにそれらの製造方法 | |
JP3144921B2 (ja) | ベンジルエステル誘導体及びその製造方法 | |
US4644081A (en) | Process for the asymmetric synthesis of chiral indoline-2-carboxylic acids | |
JP3144920B2 (ja) | α−アシルアミノケトン誘導体、その製造方法及びその利用 | |
JP2001226328A (ja) | カプシアミドの中間体およびカプシアミドの改良製造法 | |
JPH08183779A (ja) | 光学活性ピペラジン誘導体の製造方法および製造の中間体 | |
JP2004067525A (ja) | ペンタフルオロサルファー置換アントラニル酸誘導体の製造方法およびペンタフルオロサルファー置換アントラニル酸誘導体 | |
JP2000128840A (ja) | シス−2−アミノシクロヘキサンカルボン酸およびシス−2−ベンズアミドシクロヘキサンカルボン酸の製造方法 | |
JP2003238521A (ja) | 4−ヒドロキシベンゼンスルホンアニリドの製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1047739 Country of ref document: HK |
|
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080820 Termination date: 20120925 |