US20120035371A1 - Process for the manufacture of non-steroidal anti-inflammatory agents and intermediates thereof - Google Patents
Process for the manufacture of non-steroidal anti-inflammatory agents and intermediates thereof Download PDFInfo
- Publication number
- US20120035371A1 US20120035371A1 US13/273,472 US201113273472A US2012035371A1 US 20120035371 A1 US20120035371 A1 US 20120035371A1 US 201113273472 A US201113273472 A US 201113273472A US 2012035371 A1 US2012035371 A1 US 2012035371A1
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- Prior art keywords
- amino
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- compound
- methyl
- Prior art date
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- Abandoned
Links
- 238000000034 method Methods 0.000 title claims description 39
- 238000004519 manufacturing process Methods 0.000 title abstract description 9
- 239000000543 intermediate Substances 0.000 title abstract description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 title 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 title 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 34
- -1 chloro, bromo, hydroxy, methoxy, ethoxy Chemical group 0.000 claims abstract description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 70
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- UNSLQFMTPYHZDA-UHFFFAOYSA-N 2-methylquinolin-5-amine Chemical compound NC1=CC=CC2=NC(C)=CC=C21 UNSLQFMTPYHZDA-UHFFFAOYSA-N 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 150000002466 imines Chemical class 0.000 claims description 4
- TVOSOIXYPHKEAR-UHFFFAOYSA-N 4-piperidin-1-ylaniline Chemical compound C1=CC(N)=CC=C1N1CCCCC1 TVOSOIXYPHKEAR-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 239000001257 hydrogen Substances 0.000 claims 4
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 1
- WELYLZBFTUUYRL-UHFFFAOYSA-N aniline;quinolin-5-amine Chemical compound NC1=CC=CC=C1.C1=CC=C2C(N)=CC=CC2=N1 WELYLZBFTUUYRL-UHFFFAOYSA-N 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract description 2
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 2
- 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
- 238000006243 chemical reaction Methods 0.000 description 19
- 108090001060 Lipase Proteins 0.000 description 12
- 102000004882 Lipase Human genes 0.000 description 12
- 239000004367 Lipase Substances 0.000 description 12
- 235000019421 lipase Nutrition 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 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
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 108090000371 Esterases Proteins 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 125000005907 alkyl ester group Chemical group 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
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- UWEDJYGUAHJAES-UHFFFAOYSA-N CC1=C(C)C(C(C)(C)CC(C)(O)CO)=C2CCCC2=C1C Chemical compound CC1=C(C)C(C(C)(C)CC(C)(O)CO)=C2CCCC2=C1C UWEDJYGUAHJAES-UHFFFAOYSA-N 0.000 description 4
- 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 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
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 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
- 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
- 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 3
- 102000004157 Hydrolases Human genes 0.000 description 3
- 108090000604 Hydrolases Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DYKMNPDMJIYFIK-UHFFFAOYSA-N [H]N([Ar])CC(C)(O)CC(C)(C)C1=C2CCCC2=C(C)C(C)=C1C Chemical compound [H]N([Ar])CC(C)(O)CC(C)(C)C1=C2CCCC2=C(C)C(C)=C1C DYKMNPDMJIYFIK-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000001953 recrystallisation Methods 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
- JQULCCZIXYRBSE-UHFFFAOYSA-N 2-methyl-1h-indol-5-amine Chemical compound NC1=CC=C2NC(C)=CC2=C1 JQULCCZIXYRBSE-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
- 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
- FFAAWJOWXLOVGV-SRZZPIQSSA-N CC1=C(C)C(C(C)(C)CC(C)(O)/C=N/[Ar])=C2CCCC2=C1C Chemical compound CC1=C(C)C(C(C)(C)CC(C)(O)/C=N/[Ar])=C2CCCC2=C1C FFAAWJOWXLOVGV-SRZZPIQSSA-N 0.000 description 2
- XCDLVJDXLFEPDH-UHFFFAOYSA-N CC1=C(C)C(C(C)(C)CC(C)(O)C=O)=C2CCCC2=C1C Chemical compound CC1=C(C)C(C(C)(C)CC(C)(O)C=O)=C2CCCC2=C1C XCDLVJDXLFEPDH-UHFFFAOYSA-N 0.000 description 2
- VYZLSVPLUSVXQE-UHFFFAOYSA-N CC1=C(C)C(C)=C2CCCC2=C1 Chemical compound CC1=C(C)C(C)=C2CCCC2=C1 VYZLSVPLUSVXQE-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229950011175 aminopicoline Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229940093499 ethyl acetate Drugs 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 229960004979 fampridine Drugs 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 229960003390 magnesium sulfate Drugs 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 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
- 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
- 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
- XVMGLGWOAQFCJM-LURJTMIESA-N (2s)-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-LURJTMIESA-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
- 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- LMOFGCCPQWNEAQ-UHFFFAOYSA-N C=C(C)CC(C)(O)C(=O)O Chemical compound C=C(C)CC(C)(O)C(=O)O LMOFGCCPQWNEAQ-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C)(CC(CO)(C(F)(F)F)O)c(c(*)c1*)c(**I)c(*)c1I Chemical compound CC(C)(CC(CO)(C(F)(F)F)O)c(c(*)c1*)c(**I)c(*)c1I 0.000 description 1
- XBOBVUWIIOIICJ-UHFFFAOYSA-N CC1=C(C)C(C(C)(C)CC(C)(O)C(=O)O)=C2CCCC2=C1C Chemical compound CC1=C(C)C(C(C)(C)CC(C)(O)C(=O)O)=C2CCCC2=C1C XBOBVUWIIOIICJ-UHFFFAOYSA-N 0.000 description 1
- HFBJEYXQVGKRAM-VWLOTQADSA-N CC1=NC2=C(C=C1)C(CC[C@](O)(CC(C)(C)C1=C3OCCC3=CC(F)=C1)C(F)(F)F)=CC=C2 Chemical compound CC1=NC2=C(C=C1)C(CC[C@](O)(CC(C)(C)C1=C3OCCC3=CC(F)=C1)C(F)(F)F)=CC=C2 HFBJEYXQVGKRAM-VWLOTQADSA-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
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 101000898082 Homo sapiens Calbindin Proteins 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 101710098556 Lipase A Proteins 0.000 description 1
- 101710098554 Lipase B 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 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
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- MOOAHMCRPCTRLV-UHFFFAOYSA-N boron sodium Chemical compound [B].[Na] MOOAHMCRPCTRLV-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 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
- 238000007429 general method Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 108010009355 microbial metalloproteinases Proteins 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
- 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
- 108010043393 protease N Proteins 0.000 description 1
- 238000000746 purification Methods 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
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 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
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
-
- 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
- C07D405/12—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 chain containing hetero atoms as chain links
Definitions
- Another aspect of the invention is a manufacturing method according to which the compounds of general formula VIII can be produced in an enantiomerically pure form (enantiomeric excess ee>>80%). It is clear to the expert in the art that the compounds of the prior art are—when used as pharmaceuticals—usually in an enantiomerically pure form. It is therefore important to develop a manufacturing route that is able to produce the compounds of general formula VIII in enantiomerically pure form. This object is also achieved by the present invention.
- the starting materials of the process described herein (2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid) may be used in the described processes in enantiomerically pure form, subsequently yielding the final compound in enantiomerically pure form.
- the compound 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid may be generated according to the method described by Miami (Tetrahedron: Asymmetry 15 (2004) 3885-3889). It is also possible to use racemic alkyl 2-hydroxy-4-methyl-2-(trifluoromethyl)-pentenoate or the free acid thereof and separate the enantiomers by enzymatic hydrolysis.
- the reaction described above is carried out in a organic solvent in the presence of a lewis acid.
- Suitable solvents are e.g. polar solvents or halogenated solvents, the preferred solvents include dichloromethane and dichloroethane.
- the lewis acid may be aluminium chloride, BF 3 , HF, or phosphoric acid.
- the compound according to formula IV is solved in a halogenated solvent (e.g. CH 2 Cl 2 ) AlCl 3 is added and finally the 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is added to the stirred solution.
- a halogenated solvent e.g. CH 2 Cl 2
- AlCl 3 is added and finally the 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is added to the stirred solution.
- the addition of AlCl 3 and the 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is carried out at 0-5° C., the mixture is allowed to come to room temperature and the mixture is continued to stir for 4-120 hours at room temperature.
- the reaction described above can be carried out with enantiomerically pure 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid.
- the enantiomeric pure 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid may be synthesized under asymmetric catalysis as described by Mikami (see above) or the racemic form may be enzymatically hydrolized.
- the asymmetric hydrolysis may be carried out in water. If necessary polar organic solvents (e.g. DMSO, lower alcohols) may be added to enhance solubility of the substrate.
- polar organic solvents e.g. DMSO, lower alcohols
- the reaction mixture may be buffered (phosphate or similar suitable buffers) to keep the pH of the reaction mixture at constant level as required by the individual enzyme.
- hydrolases EC3.hydrolases
- EC3.1. carboxylic esterhydrolasis in particular
- hydrolases are commercially available from various sources, e.g.
- the enzymatic hydrolysis is carried out as follows: Racemic alkyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is used as starting material.
- the alkyl group may be a C 1 -C 5 alkyl group which may be a straight chain or branched.
- Preferably the alkyl group is an ethyl group. It is emulsified in water, the pH is adjusted, the enzyme is added at temperature from about 10° C. to about 60° C. Temperature, pH and reaction time may vary depending on the individual enzyme. The reaction time may be up to 300 hours.
- the reaction conditions have to be tested under control (e.g. GC control) to find the optimum.
- a saponification is needed in a process in which alkyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate bis reacted with a compound of formula IV yielding an alkyl ester of compound II.
- the compound of general formula II may be reduced to the key compound of general formula I
- lithium aluminium hydride or lithium borohydride by e.g. lithium aluminium hydride or lithium borohydride.
- Enantiomerically pure compounds of general formula I are key compounds of the process, and are therefore a further object of the invention.
- Preferred embodiments of the compounds of formula I are those which have one of the following substitution patterns:
- the oxidation may be carried out by SO 3 /pyridin complex or with oxalylchloride/DMSO (Swern oxidation).
- SO 3 /pyridin complex or with oxalylchloride/DMSO (Swern oxidation).
- oxalylchloride/DMSO Dissolved oxidation
- the compound according to general formula VI may be any aromatic amine.
- Preferred embodiments of the compounds of general formula VI are selected from the following list:
- the reaction may be carried out by sodium borohydride in alcoholic solution (or in THF), it may also be carried out by H 2 /Ni.
- a key advantage of the present invention compared to state of the art synthesis that it avoids the purification of an alkyl ester of compound II.
- Such alkyl ester (which is the product of the reaction of alkyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate with a compound of formula IV) needs to be separated from the starting compound IV by crystallization.
- the necessary separation of compound IV can be made at the stage of compound. II (i.e. by using free acid 2-hydroxy-4-methyl-2-(trifluoromethyl)-pentenoic acid as the starting material).
- the separation from compound IV can be made using acid-base-extraction (which is more efficient compared to crystallization of the alkyl ester of compound II).
- a suspension of 0.27 mol Mn and 0.01 mol ZnCl 2 in 105 ml THF is heated to reflux.
- 0.01 mol 3-bromo-2-methyl-1-propene is added to the boiling mixture and after 30 minutes a solution of 0.11 mmol ethyl-trifluoropyruvate and 0.18 mol 2-bromo-2-methyl-1-propene in 90 ml THF is dropped to the reaction mixture within 2.5 hours. After 3 hours under reflux the mixture is stirred for 19 hours at room temperature.
- the reaction mixture is poured on 90 ml of a saturated NH 4 Cl and ice mixture. After vigorous stirring for 30 minutes the mixture is extracted four times with 110 ml of MTBE each.
- Ethyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is used as starting material.
- 27.1 g (120 mmole) ethyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is emulsified in 60 mL water, the pH is adjusted to 8.0 with sodium hydroxide solution, the solution is stirred at room temperature.
- 6 g of the enzyme (Novozyme 388) is added at room temperature. The mixture is stirred for 10 hours under GC control.
- the aqueous solution is extracted two times with 100 mL of MTBE.
- the aqueous phase is acidified to pH 1 with HCl solution, treated with diatomaceous earth and MTBE and filtered.
- the aqueous is was separated and extracted three times with MTBE.
- the organic phase is evaporated to dryness to obtain a light brownish solid.
- the crude 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is crystallized from n-heptane.
- the yield of (R)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is 25%.
- reaction conditions have to adapted to the individual enzyme by changing solvent, buffer, pH, temperature, reaction time in order to achieve optimum results for the desired (R)- or (S)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid.
- the combined organic phases are washed with water, saturated sodium chloride solution (brine) and dried over magnesiumsulfate.
- the solvent is evaporated under vacuum.
- the product may be recrystallized from n-heptane. As the title compound is yielded in highly pure form the recrystallization is not necessary.
- the title compound may be used directly to start the next step.
- the precipitated aluminium salts are filtered off and washed with 10 ml of hot THF.
- the solvent is evaporated under vacuum.
- the residue is purified by recrystallization from dichloromethane and n-heptane. (yield 73.7%).
- reaction may be carried out under similar conditions with the amines listed below with comparable results:
- the whole synthetic route can be carried out in enantiomerically pure form, i.e. generating only the desired enantiomer of general formula VIII. This is possible in using chiral 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid.
- reaction conditions according to the described steps are moreover suitable for production at industrial scale.
- Excess compounds e.g. compound IV
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Abstract
The current invention describes novel chiral synthetic routes and intermediates for the manufacture of chiral anti-inflammatory agents of general formula VIII
in which at least one of the groups X1, X2, X3 is selected from
- fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, trifluoromethyl, amino
- whereas the other groups X1, X2, X3 have the meaning of a hydrogen atom,
- in which at least one of the groups Z1, Z2, Z3 is selected from
- —O—, —S—, —NH—, —N(—CH3)—,
- whereas the other groups Z1, Z2, Z3 have the meaning of a —CH2— group,
and in which Ar is an aromatic group.
Description
- This application claims the priorities of earlier filed European patent applications EP 07090075.8 (filed Apr. 18, 2007) and EP 07008931.3 (filed May 9, 2007) as well as all benefits of U.S. application 60/912,596 (filed Apr. 18, 2007).
- Compounds of general formula VIII
- in which at least one of the groups X1, X2, X3 is selected from
fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, trifluoromethyl, amino
whereas the other groups X1, X2, X3 have the meaning of a hydrogen atom,
in which at least one one of the groups Z′, Z2, Z3 is selected from - whereas the other groups Z1, Z2, Z3 have the meaning of a —CH2— group,
and in which Ar is an aromatic group
are described as powerful anti-inflammatory agents (e.g. WO 98154159, WO 00/32584, WO 02110143, WO 03/082827, WO 03/082280, WO 2004/063163 and WO 2006/050998). - However, the processes for the manufacturing of the compounds of general formula VIII have quite a number of steps, resulting in low yields of the whole chain of reactions and are not suitable for large scale productions.
- It is therefore the object of the invention to make available a novel process characterized a higher total yield achieved by the same or lower number of steps which is suitable for pharmaceutical production. The object of the invention is achieved by the processes described herein.
- An essential element of the synthetic route described herein is the compound of general formula I
- in which at least one of the groups X1, X2, X3 is selected from
fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, trifluoromethyl, amino
whereas the other groups X1, X2, X3 have the meaning of a hydrogen atom,
and in which at least one of the groups Z1, Z2, Z3 is selected from - whereas the other groups Z1, Z2, Z3 have the meaning of a —CH2— group.
- Another aspect of the invention is a manufacturing method according to which the compounds of general formula VIII can be produced in an enantiomerically pure form (enantiomeric excess ee>>80%). It is clear to the expert in the art that the compounds of the prior art are—when used as pharmaceuticals—usually in an enantiomerically pure form. It is therefore important to develop a manufacturing route that is able to produce the compounds of general formula VIII in enantiomerically pure form. This object is also achieved by the present invention. The starting materials of the process described herein (2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid) may be used in the described processes in enantiomerically pure form, subsequently yielding the final compound in enantiomerically pure form.
- The compound 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid may be generated according to the method described by Miami (Tetrahedron: Asymmetry 15 (2004) 3885-3889). It is also possible to use racemic alkyl 2-hydroxy-4-methyl-2-(trifluoromethyl)-pentenoate or the free acid thereof and separate the enantiomers by enzymatic hydrolysis.
- It is therefore an object of the present invention to provide a process in which the desired enantiomerically pure 2-hydroxy-4-methyl-2-(trifluormethyl)pentenoic acid is separated from the undesired enantiomer by way of enzymatic hydrolysis.
- Using enantiomerically pure or enriched (ee>>80%) 2-hydroxy-4-methyl-2-(trifluormethyl)pentenoic acid as the starting materials results in an enantiomerically pure compound of general formula VIII. The advantage of the described reaction starting with enantiomerically pure or enriched 2-hydroxy-4-methyl-2-(trifluormethyl)pentenoic acid is that it avoids the synthesis of an undesired enantiomer and it avoids carrying the same through following steps, therefore avoiding the separation of the enantiomers at a later stage (or even in the final product) and therefore being much more efficient.
- The general method for the production of the compounds of general formula VIII via the compound of general formula I is described below in detail. The expert in the art is fully aware of the fact that a number of variants of the reaction route are possible without deviating from the general teaching of the present invention. It is for example possible to not isolate all intermediates of the synthetic route.
- The process for the manufacturing starts with a compound of general formula IV
- in which X1, X2, X3, Z1, Z2, Z3 have meaning described above.
- The compound of general formula IV is reacted with 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid
- to yield a compound of general formula II
- in which X1, X2, X3, Z1, Z2, Z3 have the above described meaning.
- The reaction described above is carried out in a organic solvent in the presence of a lewis acid. Suitable solvents are e.g. polar solvents or halogenated solvents, the preferred solvents include dichloromethane and dichloroethane. The lewis acid may be aluminium chloride, BF3, HF, or phosphoric acid.
- In a preferred embodiment of the invention the compound according to formula IV is solved in a halogenated solvent (e.g. CH2Cl2) AlCl3 is added and finally the 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is added to the stirred solution. In an even more preferred embodiment the addition of AlCl3 and the 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is carried out at 0-5° C., the mixture is allowed to come to room temperature and the mixture is continued to stir for 4-120 hours at room temperature.
- It is furthermore preferred that 1.5 equivalents of the compound according to formula IV are used, 2 equivalents AlCl3 and 1.0 equivalent of 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid.
- The reaction described above can be carried out with enantiomerically pure 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid. The enantiomeric pure 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid may be synthesized under asymmetric catalysis as described by Mikami (see above) or the racemic form may be enzymatically hydrolized.
- The asymmetric hydrolysis may be carried out in water. If necessary polar organic solvents (e.g. DMSO, lower alcohols) may be added to enhance solubility of the substrate. The reaction mixture may be buffered (phosphate or similar suitable buffers) to keep the pH of the reaction mixture at constant level as required by the individual enzyme.
- Quite a number of enzymes are possible for the enzymatic hydrolysis. These include the hydrolases (EC3.hydrolases) of the subclasses EC3.1. (carboxylic esterhydrolasis in particular).
- Such hydrolases are commercially available from various sources, e.g.
-
-
- Lipase C1, Lipase C2, Lipase A, Lipase AS1, Lipase AN, Lipase PC, Lipase PF, Lipase B (CALB)
-
-
- Lipase AH, Lipase AK, Lipase AYS, Lipase PS, Protease K, Protease N, Protease P
-
-
- 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
-
-
- Esterase BS1, Esterase BS2, Esterase BS3, Esterase PF2, Esterase PL
-
-
- Duramyl, Novozyme 868, Novozyme 525L, Novozyme 388, Neutrase 0, Liopoase
-
-
- Lipase from porcine pancreas Typ II, Esterase porcine liver, Lipase candida rugosa.
The expert in the art is aware of further enzymes that may achieve the same result.
- Lipase from porcine pancreas Typ II, Esterase porcine liver, Lipase candida rugosa.
- The enzymatic hydrolysis is carried out as follows: Racemic alkyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is used as starting material. The alkyl group may be a C1-C5 alkyl group which may be a straight chain or branched. Preferably the alkyl group is an ethyl group. It is emulsified in water, the pH is adjusted, the enzyme is added at temperature from about 10° C. to about 60° C. Temperature, pH and reaction time may vary depending on the individual enzyme. The reaction time may be up to 300 hours. The reaction conditions have to be tested under control (e.g. GC control) to find the optimum.
- It is an advantageous feature of the process according to the invention that no saponification step is needed. A saponification is needed in a process in which alkyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate bis reacted with a compound of formula IV yielding an alkyl ester of compound II.
- It is surprising for the expert skilled in the art that the reaction of the compound of formula IV with 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid in the presence of a lewis acid yields the compound of general formula II.
- It is even more surprising that the reaction of the compound of formula IV with 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid in the presence of a lewis acid (i.e. under Friedel-Craft conditions) is carried out up to 10 times faster and with higher yields than with alkyl esters.
- The compound of general formula II may be reduced to the key compound of general formula I
- by e.g. lithium aluminium hydride or lithium borohydride.
- Enantiomerically pure compounds of general formula I are key compounds of the process, and are therefore a further object of the invention. Preferred embodiments of the compounds of formula I are those which have one of the following substitution patterns:
-
enan- Z1 Z2 Z3 X1 X2 X3 tiomer a) O F R b) O F R c) O F R d) NH F R e) O F R f) S F R g) NH Cl R h) NH Cl R i) S Cl R j) S CF3 R k) S CF3 R l) O CF3 R m) O O—CH3 R n) O O—CH3 R o) O O O—CH3 R p) O F R q) NH F R r) NH NH2 R s) NH NH2 R t) O Br R u) O F S v) O F S w) O F S x) NH F S y) O F S z) S F S aa) NH Cl S bb) NH Cl S cc) S Cl S dd) S CF3 S ee) S CF3 S ff) O CF3 S gg) O O—CH3 S hh) O O—CH3 S ii) O O O—CH3 S jj) O F S kk) NH F S ll) NH NH2 S mm) NH NH2 S nn) O Br S
Enantiomerically pure in the context of this invention means an enantiomeric excess (ee)>80%. It has to be understood that according to the present invention it is possible to synthesize compounds of ee>90%, ee>95%, ee>97% and even ee>99%. - The compound of general formula I is then oxydized to form the aldehyde of general formula V
- in which X1, X2, X3, Z1, Z2, Z3 have the meaning described above.
- The oxidation may be carried out by SO3/pyridin complex or with oxalylchloride/DMSO (Swern oxidation). The expert in the art is aware of other possibilities to oxydize the alcohol of formula Ito the aldehyd of formula V.
- The aldehyde of general formula V is then reacted with an aromatic amine of general formula VI
-
H2N—Ar (VI) - in which Ar is an aromatic group.
- The compound according to general formula VI may be any aromatic amine. Preferred embodiments of the compounds of general formula VI are selected from the following list:
- 1-amino-2-methyl-benzene
- 1-amino-4-methyl-benzene
- 2-amino-4-methylpyridine
- 2-amino-pyridine
- 2-amino-pyrimidine
- 3-amino-quinoline
- 4-amino-pyridine
- 4-amino-pyrimidine
- 5-amino-isoquinoline
- 5-amino-1-methyl-isoquinoline
- 5-amino-2,6-di-methylquinoline
- 5-amino-2-methyl-indole
- 5-amino-2-methyl-isoquinol-1(2H)-one
- 5-amino-2-methylquinoline
- 5-amino-6-chloro-2-methylquinoline
- 5-amino-6-fluoro-2-methylquinoline
- 5-amino-isoquinol-2(1H)-one
- 5-amino-quinoline
- amino-benzene
- N-(4-aminophenyl)-piperidine.
- The generated imine of formula VII
- in which X1, X2, X3, Z1, Z2, Z3 and Ar have the meaning described above is subsequently reduced in order to yield the compound according to general formula VIII.
- The reaction may be carried out by sodium borohydride in alcoholic solution (or in THF), it may also be carried out by H2/Ni.
- A key advantage of the present invention compared to state of the art synthesis that it avoids the purification of an alkyl ester of compound II. Such alkyl ester (which is the product of the reaction of alkyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate with a compound of formula IV) needs to be separated from the starting compound IV by crystallization. According to the present invention the necessary separation of compound IV can be made at the stage of compound. II (i.e. by using free acid 2-hydroxy-4-methyl-2-(trifluoromethyl)-pentenoic acid as the starting material). At the stage of compound II the separation from compound IV can be made using acid-base-extraction (which is more efficient compared to crystallization of the alkyl ester of compound II).
- As described above the expert in the art knows a number of variations and deviations from the process steps described herein. It is therefore clear that the invention described in the claims encompasses further variants and deviations which are obvious to the expert in the art or can easily be identified by the expert in the art without any need to be inventive.
- The process steps described above are furthermore described in the following examples which are not meant to limit the invention in any way.
- A suspension of 0.27 mol Mn and 0.01 mol ZnCl2 in 105 ml THF is heated to reflux. 0.01 mol 3-bromo-2-methyl-1-propene is added to the boiling mixture and after 30 minutes a solution of 0.11 mmol ethyl-trifluoropyruvate and 0.18 mol 2-bromo-2-methyl-1-propene in 90 ml THF is dropped to the reaction mixture within 2.5 hours. After 3 hours under reflux the mixture is stirred for 19 hours at room temperature. The reaction mixture is poured on 90 ml of a saturated NH4Cl and ice mixture. After vigorous stirring for 30 minutes the mixture is extracted four times with 110 ml of MTBE each. The combined organic extracts are washed with 30 ml of brine, dried over magnesiumsulfate and concentrated in vacuo. The residue is destilled under reduced pressure. ethyl-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is obtained in 73% yield.
- Ethyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is used as starting material. 27.1 g (120 mmole) ethyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is emulsified in 60 mL water, the pH is adjusted to 8.0 with sodium hydroxide solution, the solution is stirred at room temperature. 6 g of the enzyme (Novozyme 388) is added at room temperature. The mixture is stirred for 10 hours under GC control.
- The aqueous solution is extracted two times with 100 mL of MTBE. The aqueous phase is acidified to pH 1 with HCl solution, treated with diatomaceous earth and MTBE and filtered. The aqueous is was separated and extracted three times with MTBE. The organic phase is evaporated to dryness to obtain a light brownish solid. The crude 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is crystallized from n-heptane. The yield of (R)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is 25%.
- The reaction conditions have to adapted to the individual enzyme by changing solvent, buffer, pH, temperature, reaction time in order to achieve optimum results for the desired (R)- or (S)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid.
- A solution of 0.07 mol 5-fluoro-2,3-dihydro-benzofurane in 21 ml of dichloromethane is cooled to 3° C. To this solution 0.1 mol of AlCl3 is added over a period of 30 minutes. After this addition 0.05 mol of 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is added dropwise over 30 minutes. The mixture is stirred for at least 6 h under reflux conditions. After complete reaction the solution is poured on a mixture of ice (50 ml) and 1M HCl (10 ml) and stirred for at least 1 hour. The aqueous phase is extracted three times with 51 ml of ethylacetate. The combined organic phases are washed with water, saturated sodium chloride solution (brine) and dried over magnesiumsulfate. The solvent is evaporated under vacuum. The product may be recrystallized from n-heptane. As the title compound is yielded in highly pure form the recrystallization is not necessary. The title compound may be used directly to start the next step.
- The same reaction described above may be carried out with other compounds according to formula IV
- wherein X1, X2, X3, Z1, Z2, Z3 have the meaning according to the following table:
-
Z1 Z2 Z3 X1 X2 X3 A O F B O F C O F D NH F E O F F S F G NH Cl H NH Cl I S Cl J S CF3 K S CF3 L O CF3 M O O—CH3 N O O—CH3 O O O O—CH3 P O F Q NH F R NH NH2 S NH NH2 T O Br - A solution of 6.6 mol 4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid in 77 ml of THF is cooled to 4° C. 12 mmol of lithium aluminiumhydride is added portionwise to the solution. The mixture is stirred at 4° C. for 60 minutes, and stirred for 8-9 hours under reflux conditions. After complete reaction (TLC control) the mixture is cooled to 4° C. and treated with 1 ml of saturated NaHCO3 solution. The mixture is stirred for at least 2 hours whereupon the colour of the mixture turns from grey to white. The precipitated aluminium salts are filtered off and washed with 10 ml of hot THF. The solvent is evaporated under vacuum. The residue is purified by recrystallization from dichloromethane and n-heptane. (yield 73.7%).
- Using the compounds according to the table in example 3 further derivatives may be produced in comparable yields.
- Starting the reaction sequence with R- or S-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid in combination with the compounds of general formula IV as described above the following compounds according to formula I may be produced in enantiomerically pure form:
-
enan- Z1 Z2 Z3 X1 X2 X3 tiomer a) O F R b) O F R c) O F R d) NH F R e) O F R f) S F R g) NH Cl R h) NH Cl R i) S Cl R j) S CF3 R k) S CF3 R l) O CF3 R m) O O—CH3 R n) O O—CH3 R o) O O O—CH3 R p) O F R q) NH F R r) NH NH2 R s) NH NH2 R t) O Br R u) O F S v) O F S w) O F S w) NH F S y) O F S z) S F S aa) NH Cl S bb) NH Cl S cc) S Cl S dd) S CF3 S ee) S CF3 S ff) O CF3 S gg) O O—CH3 S hh) O O—CH3 S ii) O O O—CH3 S jj) O F S kk) NH F S ll) NH NH2 S mm) NH NH2 S nn) O Br S - To a solution of 3.84 g 4-(fluoro-2,3-dihydrobenzo-furan-7-yl)-4-methyl-2-(trifluoromethyl)pentanal] in 7 ml of acetic acid is added 2.28 g of 5-amino-2-methyl-quinoline at 25° C. 50 ml of toluene is added to the solution and refluxed under Dean-Stark trap for at least 12 hours. After complete reaction (TLC control) the solvent is evaporated under vacuum. Acetic acid is removed by aceotropic destillation with toluene. The evaporation residue (Yield 88.7%) is dissolved in alcohol and further processed.
- The reaction may be carried out under similar conditions with the amines listed below with comparable results:
- 1-amino-2-methyl-benzene
- 1-amino-4-methyl-benzene
- 2-amino-4-methylpyridine
- 2-amino-pyridine
- 2-amino-pyrimidine
- 3-amino-quinoline
- 4-amino-pyridine
- 4-amino-pyrimidine
- 5-amino-isoquinoline
- 5-amino-1-methyl-isoquinoline
- 5-amino-2,6-di-methylquinoline
- 5-amino-2-methyl-indole
- 5-amino-2-methyl-isoquinol-1(2H)-one
- 5-amino-2-methylquinoline
- 5-amino-6-chloro-2-methylquinoline
- 5-amino-6-fluoro-2-methylquinoline
- 5-amino-isoquinol-2(1H)-one
- 5-amino-quinoline
- amino-benzene
- N-(4-aminophenyl)-piperidine
- 10 mmol 1,1,1 trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-{[(2-methyl-5-quinoline-5-ylimino]methyl}pentane-2-ol) are dissolved in 255 ml of ethanol. To this solution 5 mmol of sodium bicarbonate is added. The mixture is stirred at 25° C. for 20 minutes. 34 mmol of sodium boronhydride are added to this solution during 10 minutes maintaining the temperature at 0-10° C. The mixture is stirred for 6 hours and another 34 mmol portion of sodium borohydride is added to the solution over 10 minutes maintaining the temperature at 25° C. Then the mixture is stirred at room temperature for 6 hours (TLC control). After completion saturated sodium bicarbonate solution is added over 10 minutes keeping the temperature at 25° C. The mixture is stirred for 60 minutes, and finally the solvent is evaporated under vacuum. The residue is diluted with water and extracted two times with 150 ml of ethyl acetate each. The solvent is evaporated and the residue obtained is purified by recrystallization from ethanol (yield 71.2%).
- Using other amines in the reaction of example 5 (e.g. those listen in example 5) and using the other compounds of formula I (e.g. those listed in the table in example 3) quite a number of compounds of general formula VIII may be generated using the methods described herein.
- According to the examples described above, it is possible to synthesize the compound according to general formula VIII in 6 steps, whereas the prior art methods needed 13 steps. The overall yield of the present 6 steps synthesis of compounds of general formula VIII is 14.3% whereas it is 8.7% using the prior art methods.
- Moreover, the whole synthetic route can be carried out in enantiomerically pure form, i.e. generating only the desired enantiomer of general formula VIII. This is possible in using chiral 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid.
- It is important to understand that the total yield using chiral 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid remains approximately 14% whereas it drops to less than 5% according to prior art methods due to the necessary separation of the enantiomers of compound VIII.
- The reaction conditions according to the described steps are moreover suitable for production at industrial scale. Excess compounds (e.g. compound IV) can be re-isolated and recycled.
Claims (27)
1.-18. (canceled)
19. A process for producing a compound according to formula VIII
in which at least one of the groups X1, X2, X3 is fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, trifluoromethyl or amino
and the other groups X1, X2, X3 are hydrogen,
and in which at least one of the groups Z1, Z2, Z3 is —O—, —S—, —NH—, or —N(—CH3)—, and the other groups Z1, Z2, Z3 are —CH2— groups
and in which Ar stands for an aromatic group
comprising reducing an enantiomerically pure imine of formula VII
in which
at least one of the groups X1, X2, X3 is fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, trifluoromethyl or amino and the other groups X1, X2, X3 are hydrogen,
and in which at least one of the groups Z1, Z2, Z3 is —O—, —S—, —NH— or —N(—CH3)—, and the other groups Z1, Z2, Z3 are —CH2— groups
and in which Ar stands for an aromatic group.
21. The process according to claim 20 , wherein said compound of formula V is obtained by oxidizing an enantiomerically pure compound according to formula I
in which at least one of the groups X1, X2, X3 is fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, trifluoromethyl or amino and the other groups X1, X2, X3 are hydrogen, and in which at least one of the groups Z1, Z2, Z3 is —O—, —S—, —NH—, or —N(—CH3)—, and the other groups Z1, Z2, Z3 are —CH2—.
22. A process according to claim 21 , wherein the compound of formula I is reacted with SO3/pyridine complex to form the aldehyde of formula V.
23. A process according to claim 20 , wherein, in producing the compound of formula VII the compound of formula V is dissolved in acetic acid, the amine of formula VI is added at room temperature, toluene is added and the mixture is refluxed for 5-50 h to yield the imine of formula VII.
24. A process according to claim 20 , wherein the amine of formula VI is:
1-amino-2-methyl-benzene
1-amino-4-methyl-benzene
2-amino-4-methylpyridine
2-amino-pyridine
2-amino-pyrimidine
3-amino-quinoline
4-amino-pyridine
4-amino-pyrimidine
5-amino-isoquinoline
5-amino-1-methyl-isoquinoline
5-amino-2,6-di-methylquinoline
5-amino-2-methyl-indole
5-amino-2-methyl-isoquinol-1(2H)-one
5-amino-2-methylquinoline
5-amino-6-chloro-2-methylquinoline
5-amino-6-fluoro-2-methylquinoline
5-amino-isoquinol-2(1H)-one
5-amino-quinoline
amino-benzene or
N-(4-aminophenyl)-piperidine
25. A process according to claim 24 , wherein the amine of formula VI is 5-amino-2-methylquinoline.
26. A process according to claim 19 , wherein the imine of formula VII is reacted with sodium borohydride in alcoholic solution to yield the compound according to formula VIII.
27. A process according to claim 19 , wherein the compound of formula VIII is:
1,1,1 trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-{[(2-methyl-5-quinoline-5-ylimino]methyl}pentane-2-ol).
28. A process according to claim 19 , wherein the compound of formula VIII is:
1,1,1 trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-{[(2-methyl-5-quinolinyl]methyl}pentane-2-ol).
29. A process according to claim 21 , wherein the enantiomerically pure compound of formula I is:
30. A process according to claim 19 , wherein one of the groups X1, X2, X3 is fluoro and the other groups X1, X2, X3 are hydrogen.
31. A process according to claim 19 , wherein one of the groups Z1, Z2, Z3 is —O— and the others are —CH2— groups.
32. A process according to claim 19 , wherein Ar is 5-amino 2-methylquinoline.
33. A process according to claim 19 , wherein X1 is H, X2 is fluoro, X3 is H, Z1 is CH2, Z2 is CH2, and Z3 is O.
35. A process according to claim 29 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>80%.
36. A process according to claim 35 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>90%.
37. A process according to claim 36 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>95%.
38. A process according to claim 37 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>97%.
39. An enantiomerically pure compound of formula I
wherein:
40. A compound according to claim 39 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>80%.
41. A compound according to claim 39 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>90%.
42. A compound according to claim 39 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>95%.
43. A compound according to claim 39 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>97%.
44. A process according to claim 29 , wherein
one of the groups X1, X2, X3 is F, Cl, CF3, OCH3, NH2 or Br and the other groups X1, X2, X3 are each H;
and
one of the groups Z1, Z2, Z3 is O, S or NH and the other groups Z1, Z2, Z3 are each —CH2—.
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US13/273,472 US20120035371A1 (en) | 2007-04-18 | 2011-10-14 | Process for the manufacture of non-steroidal anti-inflammatory agents and intermediates thereof |
US14/212,422 US20140200354A1 (en) | 2007-04-18 | 2014-03-14 | Process for the Manufacture of Non-Steroidal Anti-Inflammatory Agents and Intermediates Thereof |
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EP07008931 | 2007-05-03 | ||
EP07008931.3 | 2007-05-09 | ||
US12/104,772 US8071796B2 (en) | 2007-04-18 | 2008-04-17 | Process for the manufacture of non-steroidal anti-inflammatory agents and intermediates thereof |
US13/273,472 US20120035371A1 (en) | 2007-04-18 | 2011-10-14 | Process for the manufacture of non-steroidal anti-inflammatory agents and intermediates thereof |
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