TWI409260B - 製造非類固醇抗發炎劑之方法及該抗發炎劑之中間物 - Google Patents
製造非類固醇抗發炎劑之方法及該抗發炎劑之中間物 Download PDFInfo
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- TWI409260B TWI409260B TW100126242A TW100126242A TWI409260B TW I409260 B TWI409260 B TW I409260B TW 100126242 A TW100126242 A TW 100126242A TW 100126242 A TW100126242 A TW 100126242A TW I409260 B TWI409260 B TW I409260B
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- 238000004519 manufacturing process Methods 0.000 title abstract description 7
- 239000000543 intermediate Substances 0.000 title abstract description 3
- 238000000034 method Methods 0.000 title description 18
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 title 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 title 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- -1 chloro, bromo, hydroxy, methoxy, ethoxy Chemical group 0.000 abstract description 4
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 3
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- XVMGLGWOAQFCJM-UHFFFAOYSA-N 2-hydroxy-4-methyl-2-(trifluoromethyl)pent-3-enoic acid Chemical compound CC(C)=CC(O)(C(O)=O)C(F)(F)F XVMGLGWOAQFCJM-UHFFFAOYSA-N 0.000 description 19
- 239000000203 mixture Substances 0.000 description 17
- 108090001060 Lipase Proteins 0.000 description 13
- 102000004882 Lipase Human genes 0.000 description 13
- 239000004367 Lipase Substances 0.000 description 13
- 235000019421 lipase Nutrition 0.000 description 13
- 239000002904 solvent Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 108090000371 Esterases Proteins 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 5
- 125000005907 alkyl ester group Chemical group 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 230000007071 enzymatic hydrolysis Effects 0.000 description 4
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 4
- YWSTUXQXABOCLM-UHFFFAOYSA-N ethyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pent-3-enoate Chemical compound CCOC(=O)C(O)(C(F)(F)F)C=C(C)C YWSTUXQXABOCLM-UHFFFAOYSA-N 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 150000007517 lewis acids Chemical class 0.000 description 4
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 4
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- UNSLQFMTPYHZDA-UHFFFAOYSA-N 2-methylquinolin-5-amine Chemical compound NC1=CC=CC2=NC(C)=CC=C21 UNSLQFMTPYHZDA-UHFFFAOYSA-N 0.000 description 3
- JYVLIDXNZAXMDK-UHFFFAOYSA-N 2-pentanol Substances CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004157 Hydrolases Human genes 0.000 description 3
- 108090000604 Hydrolases Proteins 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- KBDMNBWTHOKXQA-UHFFFAOYSA-N 1-methylisoquinolin-5-amine Chemical compound C1=CC=C2C(C)=NC=CC2=C1N KBDMNBWTHOKXQA-UHFFFAOYSA-N 0.000 description 2
- SSJOWWYMHNQEMM-UHFFFAOYSA-N 2,6-dimethylquinolin-5-amine Chemical compound NC1=C(C)C=CC2=NC(C)=CC=C21 SSJOWWYMHNQEMM-UHFFFAOYSA-N 0.000 description 2
- SVNCRRZKBNSMIV-UHFFFAOYSA-N 3-Aminoquinoline Chemical compound C1=CC=CC2=CC(N)=CN=C21 SVNCRRZKBNSMIV-UHFFFAOYSA-N 0.000 description 2
- ADRXTTZQSFNWGU-UHFFFAOYSA-N 4-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid Chemical compound OC(=O)C(O)(C(F)(F)F)CC(C)(C)C1=CC(F)=CC2=C1OCC2 ADRXTTZQSFNWGU-UHFFFAOYSA-N 0.000 description 2
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 2
- ORLGLBZRQYOWNA-UHFFFAOYSA-N 4-methylpyridin-2-amine Chemical compound CC1=CC=NC(N)=C1 ORLGLBZRQYOWNA-UHFFFAOYSA-N 0.000 description 2
- TVOSOIXYPHKEAR-UHFFFAOYSA-N 4-piperidin-1-ylaniline Chemical compound C1=CC(N)=CC=C1N1CCCCC1 TVOSOIXYPHKEAR-UHFFFAOYSA-N 0.000 description 2
- RGOCAJHJUPXFMV-UHFFFAOYSA-N 5-amino-2-methylisoquinolin-1-one Chemical compound C1=CC=C2C(=O)N(C)C=CC2=C1N RGOCAJHJUPXFMV-UHFFFAOYSA-N 0.000 description 2
- DTVYNUOOZIKEEX-UHFFFAOYSA-N 5-aminoisoquinoline Chemical compound N1=CC=C2C(N)=CC=CC2=C1 DTVYNUOOZIKEEX-UHFFFAOYSA-N 0.000 description 2
- LAXPLKHRIWVALF-UHFFFAOYSA-N 6-chloro-2-methylquinolin-5-amine Chemical compound NC1=C(Cl)C=CC2=NC(C)=CC=C21 LAXPLKHRIWVALF-UHFFFAOYSA-N 0.000 description 2
- YOQADHGBMFCUMX-UHFFFAOYSA-N 6-fluoro-2-methylquinolin-5-amine Chemical compound NC1=C(F)C=CC2=NC(C)=CC=C21 YOQADHGBMFCUMX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229950011175 aminopicoline Drugs 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 229960004979 fampridine Drugs 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 2
- XMIAFAKRAAMSGX-UHFFFAOYSA-N quinolin-5-amine Chemical compound C1=CC=C2C(N)=CC=CC2=N1 XMIAFAKRAAMSGX-UHFFFAOYSA-N 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- XVMGLGWOAQFCJM-ZCFIWIBFSA-N (2r)-2-hydroxy-4-methyl-2-(trifluoromethyl)pent-3-enoic acid Chemical compound CC(C)=C[C@@](O)(C(O)=O)C(F)(F)F XVMGLGWOAQFCJM-ZCFIWIBFSA-N 0.000 description 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 description 1
- PLUVIWXTXMIJER-UHFFFAOYSA-N 2-(trifluoromethyl)pent-2-enoic acid Chemical compound FC(F)(F)C(C(=O)O)=CCC PLUVIWXTXMIJER-UHFFFAOYSA-N 0.000 description 1
- PFGKECMMYOMMSF-UHFFFAOYSA-N 2-(trifluoromethyl)pentanal Chemical compound CCCC(C=O)C(F)(F)F PFGKECMMYOMMSF-UHFFFAOYSA-N 0.000 description 1
- USEGQJLHQSTGHW-UHFFFAOYSA-N 3-bromo-2-methylprop-1-ene Chemical compound CC(=C)CBr USEGQJLHQSTGHW-UHFFFAOYSA-N 0.000 description 1
- XMTMIKDGIZFCBZ-UHFFFAOYSA-N 4-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol Chemical compound OCC(O)(C(F)(F)F)CC(C)(C)C1=CC(F)=CC2=C1OCC2 XMTMIKDGIZFCBZ-UHFFFAOYSA-N 0.000 description 1
- PAVTXINZFWRQOD-UHFFFAOYSA-N 5-fluoro-2,3-dihydro-1-benzofuran Chemical compound FC1=CC=C2OCCC2=C1 PAVTXINZFWRQOD-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 102100021851 Calbindin Human genes 0.000 description 1
- 241000222175 Diutina rugosa Species 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 101000898082 Homo sapiens Calbindin Proteins 0.000 description 1
- 101710098556 Lipase A Proteins 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 101710099648 Lysosomal acid lipase/cholesteryl ester hydrolase Proteins 0.000 description 1
- 102100026001 Lysosomal acid lipase/cholesteryl ester hydrolase Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101001021643 Pseudozyma antarctica Lipase B Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- YIYBQIKDCADOSF-UHFFFAOYSA-N alpha-Butylen-alpha-carbonsaeure Natural products CCC=CC(O)=O YIYBQIKDCADOSF-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- KJHQVUNUOIEYSV-UHFFFAOYSA-N ethyl 3,3,3-trifluoro-2-oxopropanoate Chemical compound CCOC(=O)C(=O)C(F)(F)F KJHQVUNUOIEYSV-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108010043393 protease N Proteins 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YIYBQIKDCADOSF-ONEGZZNKSA-N trans-pent-2-enoic acid Chemical compound CC\C=C\C(O)=O YIYBQIKDCADOSF-ONEGZZNKSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/08—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing alicyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
-
- 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
- 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
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero 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
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/02—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2
- C07D317/06—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2 condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Description
本發明之目的係提供一種適於醫藥生產之新穎方法,其特徵在於藉由相同的或較少數目的步驟數獲得較高的總產率。本發明之目的藉由此處所述之方法實現。
本申請案主張早期申請的歐洲專利申請案EP 07090075.8(2007年4月18日申請)與EP 07008931.3(2007年5月9日申請)之優先權以及美國申請案60/912,596(2007年4月18日)的所有權益。
通式VIII之化合物
被描述為強效抗發炎劑(例如WO 98/54159、WO 00/32584、WO 02/10143、WO 03/082827、WO 03/082280、WO 2004/063163與WO 2006/050998),其中基團X1
、X2
、X3
之至少一者係選自氟基、氯基、溴基、羥基、甲氧基、乙氧基、三氟甲基、胺基,而X1
、X2
、X3
之其他基團具有氫原子之意義,其中基團Z1
、Z2
、Z3
之至少一者係選自-O-、-S-、-NH-、-N(-CH3)-,而Z1
、Z2
、Z3
之其他基團具有-CH2
-基團之意義,其中Ar係芳族基團。
然而,用於製造通式VIII之化合物之方法具有相當多的步驟,導致整個反應鏈的產率較低,並不適於大規模生產。
此處所述合成路徑之基本要素係通式I之化合物
其中基團X1
、X2
、X3
之至少一者係選自氟基、氯基、溴基、羥基、甲氧基、乙氧基、三氟甲基、胺基,而X1
、X2
、X3
之其他基團具有氫原子之意義,其中基團Z1
、Z2
、Z3
之至少一者係選自-O-、-S-、-NH-、-N(-CH3
)-,而Z1
、Z2
、Z3
之其他基團具有-CH2
-基團之意義。
本發明之另一態樣係一製造方法,依此方法可製得對映體純形式之通式VIII之化合物(對映體過量值ee80%)。該技術之專家明瞭先前技術之化合物在當用作醫藥時通常係為對映體純形式。因此,開發一種能生產對映體純形式之通式VIII化合物的製造路徑極為重要。此目的亦藉由本發明達到。此處所述方法之起始原料(2-羥基-4-甲基-2-(三氟甲基)戊烯酸)可以對映體純形式用於所述之方法,隨後產生對映體純形式之最終化合物。
化合物2-羥基-4-甲基-2-(三氟甲基)戊烯酸可根據Mikami所述之方法生成(Tetrahedron: Asymmetry 15(2004) 3885-3889)。亦可使用外消旋2-羥基-4-甲基-2-(三氟甲基)-戊烯酸烷酯或其游離酸並藉由酶催化水解分離對映體。因此,本發明之目的係提供一方法,其中所需的對映體純形2-羥基-4-甲基-2-(三氟甲基)戊烯酸經由酶催化水解與不需要的對映體分離。
利用對映體純形或濃集(ee80%) 2-羥基-4-甲基-2-(三氟甲基)戊烯酸作為起始原料產生通式VIII之對映體純形化合物。所述的由對映體純形或濃集2-羥基-4-甲基-2-(三氟甲基)戊烯酸起始的反應之優點係其避免合成不需要的對映體且避免將該不需要的對映體帶入以後的步驟,因此避免了在隨後階段(或即使在最終產品中)分離對映體,因此更為有效。
經由通式I之化合物產生通式VIII之化合物之一般方法如下詳細描述。此技術之專家完全瞭解反應路徑可有許多不背離本發明之一般教示的變化形式。例如,可不分離合成路徑的所有中間體。
由通式IV之化合物起始製造方法
其中X1
、X2
、X3
、Z1
、Z2
、Z3
具有前文所述之意義。
通式IV之化合物與2-羥基-4-甲基-2-(三氟-甲基)戊烯酸反應
(2-羥基-4-甲基-2-(三氟-甲基)戊烯酸)以產生通式II之化合物
其中X1
、X2
、X3
、Z1
、Z2
、Z3
具有前文所述之意義。
前述反應在路易士酸存在下在有機溶劑中進行。適合的溶劑係(例如)極性溶劑或鹵化溶劑,較佳的溶劑包括二氯甲烷與二氯乙烷。路易士酸可為氯化鋁、BF3
、HF或磷酸。
在一本發明之較佳實施例中,式IV之化合物溶解在一鹵化溶劑(例如CH2
Cl2
),加入AlCl3
,最終將2-羥基-4-甲基-2-(三氟甲基)戊烯酸加入攪拌的溶液中。在一更佳的實施例中,AlCl3
與2-羥基-4-甲基-2-(三氟甲基)戊烯酸之添加係在0-5℃下進行,使該混合物達到室溫,且該混合物在室溫下繼續攪拌4-120小時。
此外,使用1.5當量的式IV之化合物,2當量的AlCl3
與1.0當量的2-羥基-4-甲基-2-(三氟甲基)戊烯酸係較佳。
用對映體純形2-羥基-4-甲基-2-(三氟甲基)戊烯酸進行前述反應。對映體純形2-羥基-4-甲基-2-(三氟甲基)戊烯酸可在如Mikami述及(參見前文)的不對稱催化下進行合成或該消旋型可進行酶水解。
不對稱水解可在水中進行。如有必要可加入極性有機溶劑(例如二甲亞碸、低碳醇)以提高受質之溶解度。反應混合物可加以緩衝(磷酸鹽或類似適合的緩衝劑)以使該反應混合物之pH保持在個別酶所需的固定水準。
相當多的酶可用於酶水解。其等包括水解酶(EC3.水解酶)之子類EC3.1(特別是羧酸酯水解)。
上述水解酶可從不同來源購得,例如
1. 英國Alphamerics Limited
脂酶C1、脂酶C2、脂酶A、脂酶AS1、脂酶AN、脂酶PC、脂酶PF、脂酶(CALB)
2. 日本Amano Enzyme Inc.
脂酶AH、脂酶AK、脂酶AYS、脂酶PS、蛋白酶K、蛋白酶N、蛋白酶P
3. 美國Biocatalytics Incorporated
ICR-101、ICR-102、ICR-103、ICR-104、ICR-105、ICR-106、ICR-107、ICR-108、ICR-109、ICR-110、ICR-111、ICR-112、ICR-113、ICR-114、ICR-115、ICR-116、ICR-117、ICR-118、ICR-119、ICR-120、IMW-102、IMW-105
4. 德國Julich Chiral Solutions
酯酶BS1、酯酶BS2、酯酶BS3、酯酶PF2、酯酶PL
5. NovoNordisk/Novozyme(丹麥)
Duramyl、Novozyme 868、Novozyme 525L、Novozyme 388、營養酶0、Liopoase
6. 德國Sigma
來自豬胰臟的脂酶Typ II、來自豬肝的酯酶、來自皺褶假絲酵母(candida rugosa)的脂酶。
此技術之專家瞭解可獲得相同結果的另外的酶。
酶水解如下進行:使用外消旋2-羥基-4-甲基-2-(三氟甲基)戊烯酸烷酯作為起始原料。烷基可為C1
-C5
烷基,其可為直鏈或支鏈。該烷基最好係乙基。在水中將其乳化,調整pH,在約10-約60℃溫度下加入酶。溫度、pH與反應時間可根據個別酶而變化。反應時間可最長達300小時。反應條件必須在控制之下(GC控制)進行測試以找到最適條件。
根據本發明之方法之有利特點係無須皂化步驟。在2-羥基-4-甲基-2-(三氟甲基)戊烯酸烷酯與式IV之化合物反應產生化合物II之烷基酯之方法中需要皂化。
令熟習此項技術的專家驚奇的係式IV之化合物與2-羥基-4-甲基-2-(三氟-甲基)-戊烯酸在路易士酸存在下之反應產生通式II之化合物。更令人驚奇的係式IV之化合物與2-羥基-4-甲基-2-(三氟-甲基)-戊烯酸在路易士酸存在下(即在Friedel Craft條件下)之反應進行至多快10倍,產率高於用烷基酯之反應。
可藉由(例如)氫化鋰鋁或硼氫化鋰將通式II之化合物還原至通式I之關鍵化合物。
通式I之對映體純形化合物係本方法之關鍵化合物,因此係本發明之另一目的。式I之化合物之較佳實施例係具有下列取代模式中之一:
在本發明之上下文中對映體純形指對映體過量值(ee)>80%。根據本發明應理解合成ee>90%、ee>95%、ee>97%甚至ee>99%之化合物係可能的。
然後將通式I之化合物氧化以形成通式V之醛。
其中X1
、X2
、X3
、Z1
、Z2
、Z3
具有前文所述之意義。
氧化可藉由SO3
/吡啶複合物或用草醯氯/DMSO(Swern氧化反應)進行。此技術之專家瞭解其他將式I之醇氧化至式V之醛之可能性。
通式V之醛隨後與通式VI之芳族胺反應
H2
N-Ar
(VI)
其中Ar係芳族基團。
通式VI之化合物可係任何芳族胺。通式VI之化合物之較佳實施例係選自以下列表:
1-胺基-2-甲基-苯
1-胺基-4-甲基-苯
2-胺基-4-甲基吡啶
2-胺基-吡啶
2-按基-嘧啶
3-胺基-喹啉
4-胺基-吡啶
4-胺基-嘧啶
5-胺基-異喹啉
5-胺基-1-甲基-異喹啉
5-胺基-2,6-二甲喹啉
5-胺基-2-甲基-吲哚
5-胺基-2-甲基-異喹啉-1(2H)-酮
5-胺基-2-甲基喹啉
5-胺基-6-氯-2-甲基喹啉
5-胺基-6-氟-2-甲基喹啉
5-胺基-異喹啉-2(1H)-酮
5-胺基-喹啉
胺苯
N-(4-胺苯基)-哌啶。
所產生的下式VII之亞胺隨後被還原以產生通式VIII之化合物(VII),其中X1
、X2
、X3
、Z1
、Z2
、Z3
具有前文所述之意義。
該反應可藉由硼氫化鈉在醇溶液中(或在THF中)進行,其亦可藉由H2
/Ni進行。
與現代的合成相比,本發明的主要優點係其避免化合物II之烷基酯之純化。上述烷基酯(其為2-羥基-4-甲基-2-(三氟甲基)戊烯酸烷酯與式IV之化合物反應之產物)需要藉由結晶從原料化合物IV中分離。根據本發明,可在化合物II階段(即利用游離酸2-羥基-4-甲基-2-(三氟甲基)戊烯酸作為起始原料)對化合物IV進行必要的分離。在化合物II階段,可利用酸鹼萃取(其比化合物II之烷基酯之結晶更有效)與化合物IV分離。
如上所述,此技術之專家知道許多此處所述之方法步驟之變化與偏差。因此,很明顯請求項中所述之本發明包含對於此項技術的專家顯而易見或可由此項技術之專家輕易識別而無發明之需要的其他變化形式與偏差。
在以下實例中進一步描述前述方法步驟,該等實例非意欲以任何方式限制本發明。
將0.27 mol Mn與0.01 mol ZnCl2
在THF中的懸浮液加熱至回流。將0.01 mol 3-溴-2-甲基-1-丙烯加入沸騰的混合物中,在30分鐘後將0.11 mmol乙基-三氟丙酮酸與0.18 mol 2-溴-2-甲基-1-丙烯在90 ml THF中的溶液在2.5小時內滴入反應混合物中。在回流下3小時後,該混合物在室溫下攪拌19小時。該反應混合物倒至90 ml飽和的NH4
Cl與冰之混合物上。在劇烈攪拌30分鐘後,該混合物用每次各110 ml MTBE萃取四次。結合的有機萃取物用30 ml鹽水清洗,經硫酸鎂乾燥並在真空中濃縮。殘餘物質在減壓下蒸餾。以73%之產率獲得2-羥基-4-甲基-2-(三氟甲基)戊烯酸乙酯。
使用2-羥基-4-甲基-2-(三氟甲基)戊烯酸乙酯作為起始原料。27.1 g(120 mmol)2-羥基-4-甲基-2-(三氟甲基)戊烯酸乙酯在60 mL水中乳化,用氫氧化鈉溶液將pH調整至8.0,該溶液在室溫下攪拌。在室溫下加入6 g酶(Novozyme 388)。該混合物在GC控制下攪拌10小時。
該水溶液用100 mL MTBE萃取兩次。用HCl溶液將水相酸化至pH 1,用矽藻土與MTBE處理,並將其過濾。將水相分離且用MTBE萃取三次。將有機相蒸乾以獲得淺褐色固體。粗製2-羥基-4-甲基-2-(三氟甲基)戊烯酸從正庚烷結晶。(R)-2-羥基-4-甲基-2-(三氟甲基)戊烯酸之產率係25%。
反應條件必須針對個別酶藉由改變溶劑、緩衝劑、pH、溫度、反應時間來加以調整,以獲得所需(R)-或(S)-2-羥基-4-甲基-2-(三氟甲基)戊烯酸之最佳結果。
將0.07 mol 5-氟-2,3-二氫-苯并呋喃在21 ml二氯甲烷之溶液冷卻至3℃。在30分鐘期間內將0.1 mol AlCl3
加入此溶液中。在此添加之後,以30分鐘逐滴加入0.05 mol 2-羥基-4-甲基-2-(三氟甲基)戊烯酸。將該混合物在回流條件下攪拌至少6小時。完全反應後,將溶液倒於冰(50 ml)與1 M HCl(10 ml)的混合物上並攪拌至少1小時。水相用51 ml乙酸乙酯萃取三次。結合的有機相用水、飽和氯化鈉溶液(鹽水)清洗,並經硫酸鎂乾燥。溶劑在真空下蒸發。產物可從正庚烷再結晶。因為標題化合物以高純度形式生產,再結晶沒有必要。該標題化合物可直接使用以開始下一步。
前文所述之相同反應可用其他式IV之化合物進行
其中X1
、X2
、X3
、Z1
、Z2
、Z3
具有根據下表之意義:
將6.6 mol 4-(5-氟-2,3-二氫-苯并呋喃-7-基)-2-羥-4-甲基-2-(三氟甲基)戊酸在77 ml THF中的溶液冷卻至4℃。將12 mmol氫化鋰鋁分批加入該溶液中。將混合物在4℃下攪拌60分鐘,在回流條件下攪拌8-9小時。在完全反應後(TLC控制),將該混合物冷卻至4℃並用1 ml飽和NaHCO3
溶液處理。將該混合物攪拌至少2小時,此時混合物的顏色由灰色變為白色。將沉澱的鋁鹽濾出,用10 ml熱THF清洗。在真空下蒸發溶劑。殘餘物質藉由從二氯甲烷與正庚烷中再結晶進行純化。(產率73.7%)。
利用根據實例3中表格的化合物,可於同等產率下生產其他衍生物。
使用R-或S-2-羥-4-甲基-2-(三氟甲基)戊烯酸與前文所述之通式IV之化合物一起開始反應序列,可以製得映體純形式之下列式I化合物:
在25℃下將2.28 g 5-胺基-2-甲基-喹啉加入3.84 g 4-(氟-2,3-二氫苯并-呋喃-7-基)-4-甲基-2-(三氟甲基)戊醛在7 ml乙酸中之溶液中。將50 ml甲苯加入該溶液中,並在Dean-Stark分水器下回流至少12小時。完全反應之後(TLC控制),該溶劑在真空下蒸發。藉由與甲苯共沸蒸餾移除乙酸。將蒸發殘餘物(產率88.7%)溶於乙醇中,並進一步處理。
可在相似條件下用下列胺進行反應,具有相當的結果:
1-胺基-2-甲基-苯
1-胺基-4-甲基-苯
2-胺基-4-甲基吡啶
2-胺基-吡啶
2-胺基-嘧啶
3-胺基-喹啉
4-胺基-吡啶
4-胺基-嘧啶
5-胺基-異喹啉
5-胺基-1-甲基-異喹啉
5-胺基-2,6-二甲喹啉
5-胺基-2-甲基-吲哚
5-胺基-2-甲基-異喹啉-1(2H)-酮
5-胺基-2-甲基喹啉
5-胺基-6-氯-2-甲基喹啉
5-胺基-6-氟-2-甲基喹啉
5-胺基-異喹啉-2(1H)-酮
5-胺基-喹啉
胺苯
N-(4-胺苯基)-哌啶
將10 mmol 1,1,1-三氟-4-(5-氟-2,3-二氫苯并呋喃-7-基)-4-甲基-2-{[(2-甲基-5-喹啉-5-基-亞胺基]甲基}戊烷-2-醇)溶於255 ml乙醇中。將5 mmol重碳酸鈉加入此溶液中。該混合物在25℃下攪拌20分鐘。於溫度保持0至10℃下在10分鐘期間將34 mmol氫硼化鈉加入此溶液中。將混合物攪拌6小時,在溫度保持25℃下以10分鐘將另一份34 mmol硼氫化鈉加入該溶液中。然後將該混合物在室溫下攪拌6小時(TLC控制)。完成之後,在溫度保持25℃下以10分鐘加入飽和重碳酸鈉溶液。將該混合物攪拌60分鐘,最後將該溶劑在真空下蒸發。將殘餘物質用水稀釋,並用150 ml乙酸乙酯萃取兩次。將該溶劑蒸發,藉由從乙醇再結晶將所得的殘餘物質純化(產率71.2%)。
利用實例5之反應中的其他胺(例如實例5中所列的胺),利用式I的其他化合物(例如實例3之表格中所列的化合物)可使用此處所述之方法產生大量通式VIII之化合物。
根據前述實例,以6個步驟合成如通式VIII之化合物係可能的,而先前技術之方法需要13個步驟。此種通式VIII之化合物之6步合成之總產率為14.3%,而使用先前技術方法總產率為8.7%。
此外,整體合成路徑可以對映體純形式進行,即僅產生所需的通式VIII之對映體。利用掌性2-羥基-4-甲基-2-(三氟甲基)戊烯酸係可能的。
重要的是瞭解使用2-羥基-4-甲基-2-(三氟甲基)戊烯酸之總產率約保持在14%,而先前技術之方法由於化合物VIII對映體之必要的分離,故總產率下降至5%以下。
此外,根據所述步驟之反應條件適於工業規模的生產。過量的化合物(例如化合物IV)可再分離與再循環。
Claims (5)
- 一種對映體純形式之式I之化合物,
- 如請求項1之化合物,其中該對映體純形式之式I化合物之對映體過量值(ee)>80%。
- 如請求項1之化合物,其中該對映體純形式之式I化合物之對映體過量值(ee)>90%。
- 如請求項1之化合物,其中該對映體純形式之式I化合物之對映體過量值(ee)>95%。
- 如請求項1之化合物,其中該對映體純形式之式I化合物之對映體過量值(ee)>97%。
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US20060116396A1 (en) * | 2004-11-12 | 2006-06-01 | Stefan Jaroch | 5-Substituted quinoline and isoquinoline derivatives, a process for their production and their use as anti-inflammatory agents |
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US20060116396A1 (en) * | 2004-11-12 | 2006-06-01 | Stefan Jaroch | 5-Substituted quinoline and isoquinoline derivatives, a process for their production and their use as anti-inflammatory agents |
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BRPI0810448A2 (pt) | 2014-10-14 |
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IL200970A0 (en) | 2010-05-17 |
US8071796B2 (en) | 2011-12-06 |
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WO2008128750A2 (en) | 2008-10-30 |
HK1141525A1 (zh) | 2010-11-12 |
TW201139423A (en) | 2011-11-16 |
US20140200354A1 (en) | 2014-07-17 |
WO2008128750A3 (en) | 2009-01-08 |
SG182950A1 (en) | 2012-08-30 |
TWI356057B (en) | 2012-01-11 |
JP2010524878A (ja) | 2010-07-22 |
CN101679247B (zh) | 2014-02-19 |
CA2683512A1 (en) | 2008-10-30 |
EP2142503A2 (en) | 2010-01-13 |
US20120035371A1 (en) | 2012-02-09 |
CN101679247A (zh) | 2010-03-24 |
AU2008240936B8 (en) | 2014-08-14 |
KR20090129480A (ko) | 2009-12-16 |
AR066216A1 (es) | 2009-08-05 |
IL223343A0 (en) | 2013-02-03 |
IL200970A (en) | 2015-02-26 |
MX2009011253A (es) | 2009-12-02 |
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