WO2000047560A2 - Process for the preparation of asymmetrical 1,4-dihydro-pyridine-dicarboxylic acid esters - Google Patents
Process for the preparation of asymmetrical 1,4-dihydro-pyridine-dicarboxylic acid esters Download PDFInfo
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- WO2000047560A2 WO2000047560A2 PCT/HU2000/000012 HU0000012W WO0047560A2 WO 2000047560 A2 WO2000047560 A2 WO 2000047560A2 HU 0000012 W HU0000012 W HU 0000012W WO 0047560 A2 WO0047560 A2 WO 0047560A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- general formula
- methyl
- compound
- stands
- ethyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- SYHPGXUWPYJXOO-UHFFFAOYSA-N 1,4-dihydropyridine-2,3-dicarboxylic acid Chemical class OC(=O)C1=C(C(O)=O)NC=CC1 SYHPGXUWPYJXOO-UHFFFAOYSA-N 0.000 title claims abstract description 10
- -1 benzyloxymethyl group Chemical group 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 229910052736 halogen Chemical group 0.000 claims abstract description 10
- 150000002367 halogens Chemical group 0.000 claims abstract description 10
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims abstract description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 52
- 238000006243 chemical reaction Methods 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 17
- 238000009835 boiling Methods 0.000 claims description 12
- 239000007858 starting material Substances 0.000 claims description 7
- FBRUPCDQCFCJRG-UHFFFAOYSA-N 1-(2,3-dichlorophenyl)-n-[(2,3-dichlorophenyl)-[(2,3-dichlorophenyl)methylideneamino]methyl]methanimine Chemical compound ClC1=CC=CC(C=NC(N=CC=2C(=C(Cl)C=CC=2)Cl)C=2C(=C(Cl)C=CC=2)Cl)=C1Cl FBRUPCDQCFCJRG-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- QPEWTRLOOVQAMO-UHFFFAOYSA-N 4-(2-chlorophenyl)-5-ethyl-2,3-dimethyl-6-(phenylmethoxymethyl)piperidine-3,5-dicarboxylic acid Chemical compound N1C(C)C(C)(C(O)=O)C(C=2C(=CC=CC=2)Cl)C(CC)(C(O)=O)C1COCC1=CC=CC=C1 QPEWTRLOOVQAMO-UHFFFAOYSA-N 0.000 claims description 4
- MWUKXKUVZNUXFK-UHFFFAOYSA-N CCC1(C(O)=O)C(COCCN2C(C3=CC=CC=C3C2=O)=O)NC(C)C(C)(C(O)=O)C1C1=CC=CC=C1Cl Chemical compound CCC1(C(O)=O)C(COCCN2C(C3=CC=CC=C3C2=O)=O)NC(C)C(C)(C(O)=O)C1C1=CC=CC=C1Cl MWUKXKUVZNUXFK-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- OEBFVKDPQVFAPH-LUAWRHEFSA-N ethyl (z)-3-amino-4-[2-(1,3-dioxoisoindol-2-yl)ethoxy]but-2-enoate Chemical compound C1=CC=C2C(=O)N(CCOCC(/N)=C/C(=O)OCC)C(=O)C2=C1 OEBFVKDPQVFAPH-LUAWRHEFSA-N 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 230000001131 transforming effect Effects 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 8
- XKORCTIIRYKLLG-ARJAWSKDSA-N methyl (z)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(\C)N XKORCTIIRYKLLG-ARJAWSKDSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 7
- OMGKAWIKWIBLGX-UHFFFAOYSA-N 1-(2-chlorophenyl)-n-[(2-chlorophenyl)-[(2-chlorophenyl)methylideneamino]methyl]methanimine Chemical compound ClC1=CC=CC=C1C=NC(C=1C(=CC=CC=1)Cl)N=CC1=CC=CC=C1Cl OMGKAWIKWIBLGX-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 4
- 239000002050 international nonproprietary name Substances 0.000 description 4
- PVHUJELLJLJGLN-UHFFFAOYSA-N nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- DXUTWLTWGKEWJA-UHFFFAOYSA-N ethyl 3-oxo-4-phenylmethoxybutanoate Chemical compound CCOC(=O)CC(=O)COCC1=CC=CC=C1 DXUTWLTWGKEWJA-UHFFFAOYSA-N 0.000 description 3
- MPKBVLNKYXFHSS-UHFFFAOYSA-N ethyl 4-(1,3-dioxoisoindol-2-yl)-4-ethoxy-3-oxobutanoate Chemical compound C(C)OC(CC(=O)C(N1C(C=2C(C1=O)=CC=CC2)=O)OCC)=O MPKBVLNKYXFHSS-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 229960005425 nitrendipine Drugs 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- CJAZREGQWKYVSL-OUKQBFOZSA-N (E)-3-amino-4-(1,3-dioxoisoindol-2-yl)-2-ethoxyhex-2-enoic acid Chemical compound CCC(/C(=C(/C(=O)O)\OCC)/N)N1C(=O)C2=CC=CC=C2C1=O CJAZREGQWKYVSL-OUKQBFOZSA-N 0.000 description 2
- UFKZLUSJYMJIFQ-UHFFFAOYSA-N 1-(2-nitrophenyl)-n-[(2-nitrophenyl)-[(2-nitrophenyl)methylideneamino]methyl]methanimine Chemical compound [O-][N+](=O)C1=CC=CC=C1C=NC(C=1C(=CC=CC=1)[N+]([O-])=O)N=CC1=CC=CC=C1[N+]([O-])=O UFKZLUSJYMJIFQ-UHFFFAOYSA-N 0.000 description 2
- LPJCZBANVUTVOH-UHFFFAOYSA-N 1-(3-nitrophenyl)-n-[(3-nitrophenyl)-[(3-nitrophenyl)methylideneamino]methyl]methanimine Chemical compound [O-][N+](=O)C1=CC=CC(C=NC(N=CC=2C=C(C=CC=2)[N+]([O-])=O)C=2C=C(C=CC=2)[N+]([O-])=O)=C1 LPJCZBANVUTVOH-UHFFFAOYSA-N 0.000 description 2
- LLMLNAVBOAMOEE-UHFFFAOYSA-N 2,3-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1Cl LLMLNAVBOAMOEE-UHFFFAOYSA-N 0.000 description 2
- KYTJTKMOZQPKAB-UHFFFAOYSA-N 2-(2-chloroethoxymethyl)-4-(2-chlorophenyl)-3-ethyl-5,6-dimethylpiperidine-3,5-dicarboxylic acid Chemical compound CCC1(C(O)=O)C(COCCCl)NC(C)C(C)(C(O)=O)C1C1=CC=CC=C1Cl KYTJTKMOZQPKAB-UHFFFAOYSA-N 0.000 description 2
- VEKNYWJNNHCOBA-UHFFFAOYSA-N 2-(chloromethyl)-4-(2-chlorophenyl)-3-ethyl-5,6-dimethylpiperidine-3,5-dicarboxylic acid Chemical compound CCC1(C(O)=O)C(CCl)NC(C)C(C)(C(O)=O)C1C1=CC=CC=C1Cl VEKNYWJNNHCOBA-UHFFFAOYSA-N 0.000 description 2
- ZKXXQEPSUGGWJP-UHFFFAOYSA-N 4-(2-chlorophenyl)-3-ethyl-2-(hydroxymethyl)-5,6-dimethylpiperidine-3,5-dicarboxylic acid Chemical compound CCC1(C(O)=O)C(CO)NC(C)C(C)(C(O)=O)C1C1=CC=CC=C1Cl ZKXXQEPSUGGWJP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- MCYBNDPENPDKMO-WQLSENKSSA-N ethyl (z)-3-amino-4-phenylmethoxybut-2-enoate Chemical compound CCOC(=O)\C=C(/N)COCC1=CC=CC=C1 MCYBNDPENPDKMO-WQLSENKSSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 2
- 229960000227 nisoldipine Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- QFAFIESIRDVQFP-VOTSOKGWSA-N (E)-3-amino-4-chloro-2-ethoxyhex-2-enoic acid Chemical compound CCC(/C(=C(/C(=O)O)\OCC)/N)Cl QFAFIESIRDVQFP-VOTSOKGWSA-N 0.000 description 1
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- ZKGFMZJIENXHDL-UHFFFAOYSA-N 1,2-dihydropyridine-2,3-dicarboxylic acid Chemical class OC(=O)C1NC=CC=C1C(O)=O ZKGFMZJIENXHDL-UHFFFAOYSA-N 0.000 description 1
- YCMCDCJBGLNQTO-UHFFFAOYSA-N 2,3,6-trimethyl-5-(2-methylpropyl)-4-(2-nitrophenyl)piperidine-3,5-dicarboxylic acid Chemical compound CC(C)CC1(C(O)=O)C(C)NC(C)C(C)(C(O)=O)C1C1=CC=CC=C1[N+]([O-])=O YCMCDCJBGLNQTO-UHFFFAOYSA-N 0.000 description 1
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 1
- RZDWUAGEAUZJHQ-UHFFFAOYSA-N 4-(2-chloroethoxy)-3-oxobutanoic acid Chemical compound OC(=O)CC(=O)COCCCl RZDWUAGEAUZJHQ-UHFFFAOYSA-N 0.000 description 1
- ZYQJWEICXWITIW-UHFFFAOYSA-N 4-(2-chlorophenyl)-2-methyl-6-(phenylmethoxymethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound N1C(C)=C(C(O)=O)C(C=2C(=CC=CC=2)Cl)C(C(O)=O)=C1COCC1=CC=CC=C1 ZYQJWEICXWITIW-UHFFFAOYSA-N 0.000 description 1
- NTJPEQNLFCLKAR-UHFFFAOYSA-N 6-methyl-3-oxoheptanoic acid Chemical compound CC(C)CCC(=O)CC(O)=O NTJPEQNLFCLKAR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- YPMPTULBFPFSEQ-PLNGDYQASA-N ethyl (z)-3-aminobut-2-enoate Chemical compound CCOC(=O)\C=C(\C)N YPMPTULBFPFSEQ-PLNGDYQASA-N 0.000 description 1
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 1
- NZJBBKAVCWXTPT-UHFFFAOYSA-N ethyl 4-hydroxy-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CO NZJBBKAVCWXTPT-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- VCDOXKMVZZSCQK-ARJAWSKDSA-N methyl (z)-2-aminobut-2-enoate Chemical compound COC(=O)C(\N)=C\C VCDOXKMVZZSCQK-ARJAWSKDSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical class OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
Abstract
The invention relates to an improved process for the preparation of asymmetrical 1,4-dihydro-pyridine-dicarboxylic acid esters of general Formula (I) (wherein R?1 and R2¿ each stands for lower alkyl or an ethyl group substituted by methosy or cyano, with the proviso that R?1 and R2¿ are different; R¿3? stands for lower alkyl optionally substituted by hydroxy or halogen, or a benzyloxymethyl group or a group of the general Formula -CH2-O-CH2-CH2-X; X stands for halogen, azido or -NR?4R5; R4 and R5¿ are identical or different and each stands for hydrogen or lower alkyl, or R?4 and R5¿ together with the nitrogen atom, they are attached to, form a phthaloyl group; A is nitro or halogen and n is 1 or 2).
Description
Process for the preparation of asymmetrical 1,4- -dihydro-pyridine-dicarboxylic acid esters
Field of the invention
This invention relates to a new process for the preparation of asymmetrical 1 ,4-dihydro-pyridine-dicarboxylic acid esters. Technical background
It is known that 3,5-dimethyl-1 ,4-dihydro-2,6-dimethyl-4- -(2-nitro-phenyl)-pyhdine-3,5-dicarboxylate having the INN (International Non-proprietary Name) "nifedipine" can be prepared by the reaction of 1-(2-nitro-phenyl)-N,N'-bis-(2-nitro- -benzylidene)-methylene-diamine, methyl acetoacetate and methyl-3-amino-crotonate (HU 201 ,912). According to prior art a process of this type is only suitable for the preparation of symmetrical 1 ,4-dihydro-pyridine-dicarboxylic acid esters. It is also known that when preparing asymmetrical 1 ,4-dihydro- -pyridine-dicarboxylic acid esters by this reaction route - i.e. by a method in which the aldehyde component is present in the reaction mixture in "protected" form (in this case in form of the so-called "benzylidene" compound) - symmetrical esters are also formed which contaminate the product (EP 534,520).
It is also known that e.g. in the preparation of a mixed ester having the INN "nitrendipine" symmetrical esters are formed in a competitive reaction and contaminate the product to a large extent; this applies if the aldehyde is used either in free or protected form [Lyubomir D. Raev, Ivo C. Ivanov Arch
Pharm. (Weinheim) 322, 253-256 (1989)].
Pursuant to prior art asymmetrical 1 ,4-dihydro-pyridine- -dicarboxylic acid esters can be prepared by three types of reactions.
H. H. Fox et al [J. Org. Chem. 16, 1259 (1951)] describe the reaction of aldehydes, beta-oxo-carboxylic acid esters and enamino-carboxylic acid esters.
E. Knoevenagel [Ber. Dtsch. Chem. Ges. 31, 743 (1898)] discloses the reaction of benzylidene derivatives of beta-oxo-carboxylic acid esters with enamino carboxylic acid esters.
According to DOS 2,117,571 asymmetrical esters of pyridine dicarboxylic acids are prepared by reacting the corresponding benzylidene compound, beta-oxo-ester and ammonia. The latter process gives only a low yield for asymmetrical esters because due to the free ammonia content of the system undesired side-reactions can take place and by- -products contaminating the end-product are formed.
The chemical entity 3-ethyl-5-methyl-2-[(2-amino- -ethoxy)-methyl]-6-methyl-4-(2-chloro-phenyl)-1 ,4-dihydro- -pyridine-3,5-dicarboxylate (INN "amlodipine") is an effective coronary dilatory and antihypertensive agent. According to EP 89,167 this compound can be prepared by removing the phthaloyl group from 3-ethyl-5-methyl-2-[(2-phthalimido- -ethoxy)-methyl]-6-methyl-4-(2-chloro-phenyl)-1 ,4-dihydro- -pyridine-3,5-dicarboxylate. The phthaloyl group can be split off preferably with the aid of hydrazine. The above phthalimido
compound can be prepared by means of the method of Hantzsch by reacting phthalimido-ethoxy-acetoacetate, 2- -chloro-benzaldehyde and methyl-3-amino-crotonate. In EP 89,167 no yield is disclosed for the above cyclisation reaction. According to J. Med. Chem. 29, 1696-1702 (1986) the yield reported for said reaction is not higher than 25 %. Summary of the invention
It is the object of the present invention to provide a process for the preparation of a broad range of mixed esters of 1 ,4-dihydro-pyridine-dicarboxylic acid esters which can be carried out with high yields and gives a pure product.
The above object is solved by the process of the present invention.
According to the present invention there is provided a process for the preparation of asymmetrical 1 ,4-dihydro- -pyridine-dicarboxylic acid esters of the general Formula
(wherein
R1 and R2 each stands for lower alkyl or an ethyl group substituted by methoxy or cyano, with the proviso that
R1 and R2 are different; R3 stands for lower alkyl optionally substituted by hydroxy
or halogen, or a benzyloxymethyl group or a group of the general Formula -CH2-0-CH2-CH2-X; X stands for halogen, azido or -NR4R5; R4 and R5 are identical or different and each stands for hydrogen or lower alkyl, or R4 and R5 together with the nitrogen atom, they are attached to, form a phthaloyl group; A is nitro or halogen and n is 1 or 2) which comprises a) reacting a compound of the general Formula
( A ) n (wherein A and n are as stated above) with a compound of the general Formula
R1OOC — CH2 — C — CH3 Ml
II o and an amino crotonic acid ester of the general Formula
R2OOC — CH =C R3 V|
NH2
(wherein R1, R2 and R3 are as stated above); or b) reacting a compound of the general Formula II with
a beta-keto-carboxylic acid ester of the general Formula
R2OOC — CH2 — C R3 i
II o and an amino-crotonic acid ester of the general Formula
R1OOC — CH = C — CH_
I v
NH2
(wherein R1, R2 and R3 are as stated above) and if desired transforming a compound of the general Formula I thus obtained into another compound of the general Formula I.
Detailed description of the invention
The present invention is based on the recognition that on reacting compounds of the general Formula II either with compounds of the general Formulae III and VI, or with compounds of the general Formulae IV and V the desired mixed esters of the general Formula I are obtained with high yields and in pure form, practically free of by-products. This recognition is so much the more surprising as in spite of the complicated reaction mechanism the process of the present invention provides the desired mixed esters in highly pure form and no symmetrical esters are formed in the reaction. It could not be aforeseen that the mixed esters of the general Formula I would be formed in pure form and free of symmetrical esters.
The definitions used throughout the patent specification and the claims are to be interpreted as follows:
The term "lower alkyl" relates to straight or branched chained saturated hydrocarbon groups having 1-4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, π-butyl, secondary butyl etc.).
The term "halogen" encompasses the fluorine, chlorine, bromine and iodine atoms and stands preferably for chlorine or bromine, particularly for chlorine.
The term "amino protective group" relates to groups generally known from prior art for the protection of the amino group. Such groups may be e.g. alkylsulfonyloxy (e.g. methanesulfonyloxy), benzenesulfonyloxy, p-toluenesulfonyloxy, aralkyl (e.g. benzyl) or acyl (e.g. lower alkanoyl such as acetyl; or aroyl e.g. benzoyl) etc.
According to a preferred embodiment of the process of the present invention compounds of the general Formula I are prepared in which A stands for chlorine in position 2, or nitro in position 2 or 3; n is 1 ; R1 stands for methyl; R2 represents ethyl or 2-methyl-propyl and R3 stands for methyl, hydroxymethyl, chloromethyl, phthalimido-ethoxy-methyl, benzyloxymethyl or 2-chloro-ethoxy-methyl.
According to a particularly preferred embodiment of the process of the present invention 3-ethyl-5-methyl-2-[(2- phthaiimido-ethoxy)-methyl]-6-methyl-4-(2-chloro-phenyl)-1 ,4- -dihydro-pyridine-3,5-dicarboxylate is prepared.
The process of the present invention is suitable for the preparation of calcium antagonists widespreadly used in therapy (e.g. nitrendipin, nisoldipin, felodipin, nimodipin etc.).
According to the process of the present invention valuable pharmaceutical intermediates can also be prepared. Thus the process of the present invention is suitable for the preparation of 3-ethyl-5-methyl-2-[(2-phthalimido-ethoxy)- -methyl]-6-methyl-4-(2-chloro-phenyl)-1 ,4-dihydro-pyridine-3,5- -dicarboxylate which can be used as intermediate in the manufacture of amlodipin (EP 89,167).
According to a further aspect of the present invention there is provided 3-ethyl-5-methyl-2-(benzyloxymethyl)-6- -methyl-4-(2-chloro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylate which is a new compound of the general Formula I, never described in prior art.
According to process a) of the process of the present invention 1 mole of a compound of the general Formula II is reacted with 3-4.5 moles of a compound of the general Formula III and 3-4.5 moles of a compound of the general Formula VI. It is preferred to use 3 moles of a compound of the general Formula III and 3 moles of a compound of the general Formula VI, related to 1 mole of a compound of the general Formula II. The reaction is carried out in an inert organic solvent. As reaction medium polar protic solvents, preferably lower alkanols (e.g. methanol, ethanol, propanol, isopropanol or isobutanol), water or amides (e.g. formamide, dimethyl formamide) or dipolar aprotic solvents (e.g. acetonitrile, dimethyl sulfoxide, nitro benzene, etc.) or mixtures thereof can be used. One may work preferably by using a lower alkanol as reaction medium.
The reaction temperature can be varied between wide ranges. The reaction can be performed at a temperature between room temperature and 120°C, preferably at 30-90°C. One may work preferably at the boiling point of the solvent used as reaction medium (preferably a lower alkanol).
The reaction time may also be varied between wide ranges, depending on the reaction temperature. The reaction takes generally 1-50 hours. According to an advantageous form of realization of the process of the present invention the reaction is carried out in alkanol as medium, at the boiling point of the reaction mixture, for 10-25 hours.
The reaction conditions used for process b) of the present invention are similar to those applied for process a) (e.g. solvent, temperature, reaction time).
The reaction mixture may be worked up by methods known per se. A reaction product poorly soluble in the cold in the solvent used can be separated by cooling and subsequent filtration or centrifuging. In this case generally a second generation of the product can be recovered by evaporating the solvent. If the desired product is in solution at the end of the reaction, it can be isolated in crystalline or oily form by evaporating the solvent. The oil thus obtained can be generally crystallized. Alternatively the desired product can be precipitated from the reaction mixture by adding water or an aqueous acid. The product thus obtained can be purified, if desired, by conventional methods (e.g. recrystallization or chromatographical separation).
The compounds of the general Formula I contain a chiral carbon atom. The present invention encompasses the preparation of all optical isomers of the compound of the general Formula 1 and optional ratio mixtures thereof, including the racemates.
A compound of the general Formula I obtained by the process of the present invention can be optionally converted into another compound of the general Formula I.
Said subsequent transformations can be carried out in a known manner.
Thus e.g. a compound of the general Formula I, wherein R3 stands for benzyloxymethyl, can be converted by hydrogenation into a compound of the general Formula I wherein R3 stands for hydroxymethyl. The reaction can be carried out by catalytic hydrogenation; as catalyst e.g. palladium or platinum can be used. Hydrogenation can be performed in a solvent (e.g. acetic acid) under a pressure of 2-6 atm and at room temperature.
According to another optional subsequent transformation the phthaloyl group is removed from a compound of the general Formula I, wherein R3 stands for phthalimido-ethoxy-methyl, to yield the corresponding compound of the general Formula I wherein R3 stands for 2- -amino-ethoxy-methyl. The phthaloyl group can be removed e.g. by treatment with hydrazine.
The starting materials of the general Formula II are generally known compounds. However, 1-(2,3-dichloro-
-phenyl)-N,N'-bis-(2,3-dichloro-benzylidene)-methylene-diamine of the general Formula II is a new compound.
According to a further aspect of the present invention there is provided 1-(2,3-dichloro-phenyl)-N,N'-bis-(2,3- dichloro-benzylidene)-methylene-diamine of the general Formula II.
The preparation of 1-(2,3-dichloro-phenyl)-N,N'-bis- (2,3-dichloro-benzylidene)-methylene-diamine is carried out by reacting 2,3-dichloro-benzaldehyde with ammonia. The desired compound is obtained within a short reaction time, with high yields and in pure form. The reaction may be carried out in an aliphatic alcohol (preferably ethanol) as medium at room temperature.
The beta-keto-esters of the general Formulae III and IV used as starting material are commercially available compounds.
The starting materials of the general Formulae V and VI are also known, except the following two compounds of the general Formula VI: ethyl-4-(phthalimido-ethoxy)-3-amino-crotonate; ethyl-4-benzyloxy-3-amino-chrotonate.
According to a further feature of the present invention there are provided the following compounds of the general Formula VI: ethyl-4-(phthalimido-ethoxy)-3-amino-crotonate; ethyl-4-benzyloxy-3-amino-chrotonate.
The above two new compounds of the general Formula
VI can be prepared by reacting ammonia with ethyl-4- -phthalimido-ethoxy-acetoacetate or ethyl-4-benzyloxy- -acetoacetate, respectively. The reaction may be carried out in an aliphatic alcohol (preferably ethanol or isopropanol) as medium under heating. The reaction provides high yields.
The advantage of the process of the present invention is that the desired mixed asymmetrical 1,4-dihydro-pyridine- -dicarboxylic acid esters of the general Formula I can be obtained with good yields, in highly pure form, free of by-products. The process is suitable for industrial scale manufacture, is readily feasible and requires no special apparatus.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples.
Examples
I
Preparation of new starting materials of the general
Formula II
Example 1
1-(2,3-dichloro-phenyl)-N,N'-bis-(2,3-dichloro-benzylidene)- -methylene-diamine
8.75 g (0.05 mole) of 2,3-dichloro-benzaldehyde are stirred in 20 ml of ethanol containing 5-7 % by weight of ammonia at room temperature for 5 hours. The precipitated product is filtered, washed with ethanol and dried. Thus 8.25 g of 1-(2,3-dichloro-phenyl)-N,N'-bis-(2,3-dichloro-benzylidene)- -methylene-diamine are obtained, yield 98 %, mp.: 160-162°C. Analysis: for the Formula C21H12CI6N2 (505.063) calc: C%=49.94; H%=2.39; N%=5.55; Cl%=42.17; found: C%=49.51 ; H%=2.43; N%=5.32; Cl%=42.01.
II Preparation of new starting materials of compounds of the general Formula VI
Example 2
Ethyl-4-phthalimido-ethoxy-3-amino-crotonate
37 g (0.116 mole) of ethyl-4-phthalimido-ethoxy- -acetoacetate are heated to boiling in 240 ml of ethanol containing 9.5 % by weight of ammonia for 19 hours. The
reaction mixture is evaporated. The residual oil is crystallized at 0-5°C from isopropanol, filtered, washed with a small amount of isopropanol and dried. Thus 28.47 g of ethyl-4- -phthalimido-ethoxy-3-amino-crotonate are obtained in the form of light beige crystals. Yield 77.2 %, mp.: 77-78°C. Analysis: for the Formula Cι6H18N205 (318.331) calc: C%=60.37; H%=5.70; N%=8.79; found: C%=59.99; H%=5.78; N%=9.08. Example 3 Ethyl-4-benzyloxy-3-amino-crotonate
2.36 g (10 millimoles) of ethyl-4-benzyloxy-acetoacetate are reacted in 12 ml of ethanol containing 5-7 % by weight of ammonia at 40°C for 9 hours. The reaction mixture is evaporated. Thus 2.26 g of ethyl-4-benzyloxy-3-amino-crotonate are obtained in the form of a faint yellow oil. Yield 95.7 %. n20 = 1.5356.
D
III
Preparation of dihydro-pyridine-dicarboxylic acid esters of the general Formula I
Example 4
3-ethyl-5-methyl-2-f(2-phthalimido-ethoxy)-methvπ-6-methyl-4-
-(2-chloro-phenyl)-1 ,4-dihvdro-pyridine-3,5-dicarboxylate
Method a)
A mixture of 11.31 g (0.028 mole) of 1-(2-chloro-
-phenyl)-N,N'-bis-(2-chloro-benzylidene)-methylene-diamine, 9.8 g (0.084 mole) of methyl acetoacetate, 27 g (0,84 mole) of
ethyl-4-phthalimidoethoxy-3-amino-crotonate and 230 ml of isopropanol is heated to boiling for 26 hours. The reaction mixture is evaporated. The residual oil is crystallized from acetic acid at 5-10°C, filtered and suspended in cold (0-5°C) methanol. Thus 17.66 g of 3-ethyl-5-methyl-2-[(2-phthalimido- -ethoxy)-methyl]-6-methyM-(2-chloro-phenyl)-1,4-dihydro-pyridine- -3,5-dicarboxylate are obtained, yield 38.8 %, mp.: 147-149°C. Analysis: for the Formula C28H27CIN207 (538.986) calc: C%=62.39; H%=5.05; Cl%=6.58; N%=5.19; found: C%=62.42; H%=5.14; Cl%=6.32; N%=5.09. Method b)
A mixture of 8.86 g (0.022 mole) of 1-(2-chloro-phenyl)- N,N'-bis-(2-chloro-benzylidene)-methylene-diamine, 7.61 g (0.066 mole) of methyl-amino-crotonate, 21 g (0.066 mole) of ethyl-4-phthalimido-ethoxy-acetoacetate and 140 ml of isopropanol is heated to boiling for 26 hours. The reaction mixture is evaporated. The residual oil is worked up as described in method a). Thus 10.22 g of 3-ethyl-5-methyl-2- -[(2-phthalimido-ethoxy)-methyl]-6-methyl-4-(2-chloro-phenyl)- -1 ,4-dihydro-pyridine-3,5-dicarboxylate are obtained, yield 28.7 %. Mp.: 145-147°C.
Analysis: for the Formula C28H27CIN207 (538.986) calc: C%=62.39; H%=5.05; Cl%=6.58; N%=5.19; found: C%=63.05; H%=4.98; Cl%=6.47; N%=5.04.
Example 5
3-ethyl-5-methyl-2,6-dimethyl-4-(3-nitro-phenyl)-1 ,4-dihvdro- pyridine-3,5-dicarboxylate (nitrendipin) Method a)
A mixture of 4.33 g (10 millimoles) of 1-(3-nitro-phenyl)- -N,N'-bis-(3-nitro-benzylidene)-methylene-diamine, 5.18 g (45 millimoles) of methyl-3-amino-crotonate, 5.86 g (45 millimoles) of ethyl acetoacetate and 30 ml of isopropanol is stirred and heated under reflux for 15 hours. The solution is cooled to 0°C. After 30 minutes the precipitated crystals are filtered. The mother-lye is evaporated in vacuo and the crystals are filtered. The united crystalline product is washed with cold isopropanol and dried. Thus 9.3 g of 3-ethyl-5-methyl-2,6-dimethyl-4-(3- -nitro-phenyl)-1 ,4-dihydro-pyridine-3,5-dicarboxylate are obtained, yield 86.0 %, mp.: 156-158°C. Analysis: for the Formula Cι8H20N2O6 (360.369) calc: C%=59.99; H%=5.59; N%=7.77; found: C%=59.76; H%=5.61 ; N%=7.83. Method b)
A mixture of 4.33 g (10 millimoles) of 1-(3-nitro-phenyl)- -N,N'-bis-(3-nitro-benzylidene)-methylene-diamine, 5.81 g (45 millimoles) of ethyl-3-amino-crotonate and 5.22 g (45 millimoles) of methyl-acetoacetate are reacted in an analogous manner to method a). Thus 9.19 g of 3-ethyl-5-methyl-2,6-dimethyl-4-(3- -nitro-phenyl)-1 ,4-dihydro-pyridine-3,5-dicarboxylate are obtained, yield 85.0 %, mp.: 155-157°C.
Example 6
3-(2-methyl-propyl)-5-methyl-2,6-dimethyl-4-f2-nitro-phenyl)- -1 ,4-dihvdro-pyridine-3,5-dicarboxylate (nisoldipin)
A mixture of 4.33 g (10 millimoles) of 1-(2-nitro-phenyl)- -N,N'-bis-(2-nitro-benzylidene)-methylene-diamine, 3.45 g (30 millimoles) of methyl-3-amino-crotonate, 4,75 g (30 millimoles) of 2-methyl-propyl-acetoacetate and 30 ml of n-butanol is stirred and heated under reflux for 20 hours. The solution is evaporated in vacuo. The oily residue is purified by flash chromatography on Kieselgel 60 and elution with a 6:4 mixture of ethyl acetate and n-hexane. A warm 1 :1 mixture of ethyl acetate and n-hexane (20 ml) is poured on the oil thus obtained, whereupon the product crystallized on cooling is filtered, washed with cold ethanol and dried. Thus 2.9 g of 3- -(2-methyl-propyl)-5-methyl-2,6-dimethyl-4-(2-nitro-phenyl)-1,4- -dihydro-pyridine-3,5-dicarboxylate are obtained, yield 25 %, mp.: 142-143°C. Example 7
3-ethyl-5-methyl-2-benzyloxymethyl-6-methyl-4-(2-chloro-phenyl)- -1 ,4-dihvdro-pyridine-3.5-dicarboxylate
A mixture of 8.64 g (20 millimoles) of 1-(2-chloro- -phenyl)-N,N'-bis-(2-chloro-benzylidene)-methylene-diamine, 6.69 g (60 millimoles) of methyl-3-amino-crotonate, 13.7 g (60 millimoles) of ethyl-4-benzyloxy-acetoacetate and 200 ml of methanol is heated to boiling for 27 hours. The reaction mixture can be worked up by two methods. a) The reaction mixture is evaporated to one-third of
the original volume in vacuo and crystallized at a temperature between 0°C and 5°C. The precipitated crystals are filtered and recrystallized from methanol. Thus 11.7 g of 3-ethyl-5- -methyl-2-benzyloxymethyl-6-methyl-4-(2-chloro-phenyl)-1,4- -dihydro-pyridine-3,5-dicarboxylate are obtained, yield 40 %, mp.: 113-115°C. b) The reaction mixture is cooled to a temperature of 10°C below the boiling point, whereupon a mixture of 110 ml of 12 N hydrochloric acid, 110 ml of water and 220 ml of methanol is added dropwise within 20 minutes. The mixture is stirred at room temperature for 3 hours and allowed to stand in a refrigerator for 48 hours. After filtration 13.5 g of 3-ethyl-5- methyl-2-benzyloxymethyl-6-methyl-4-(2-chloro-phenyl)-1 ,4- -dihydro-pyridine-3,5-dicarboxylate are obtained, yield 46 %. Mp.: 111-113°C
Analysis: for the Formula C25H26CIN05 (454.932) calc: C%=66.00; H%=5.76; N%=3.08; Cl%=7.79; found: C%=66.04; H%=5.78; N%=3.13; Cl%=7.85. Example 8
3-ethyl-5-methyl-2-hvdroxymethyl-6-methyl-4-(2-chloro-phenv0- -1 ,4-dihydro-pyridine-3,5-dicarboxylate Method a)
. A mixture of 2.0 g (5 millimoles) of 1-(2-chloro-phenyl)- -N,N'-bis-(2-chloro-benzylidene)-methylene-diamine, 1.71 g (15 millimoles) of methyl-3-amino-crotonate, 2.19 g (15 millimoles) of ethyl-4-hydroxy-acetoacetate and 50 ml of methanol is heated to boiling for 20 hours. After clarification
the solution is evaporated, the residual oil is subjected to column chromatography on Kieselgel 60 and eluted with a 4:6 mixture of n-hexane and ethyl acetate. The oily residue obtained after evaporation is crystallized from diisopropyl ether. Thus 3.4 g of 3-ethyl-5-methyl-2-hydroxymethyl-6- -methyl-4-(2-chloro-phenyl)-1 ,4-dihydro-pyridine-3,5-dicarboxylate are obtained in the form of a faint yellow solid substance. Yield 62 %, mp.: 131-133°C. Method b)
7.97 g (18 millimoles) of 2-benzyloxymethyl-6-methyl-4- -(2-chloro-phenyl)-1 ,4-dihydro-pyridine-3,5-dicarboxylate are dissolved in 120 ml of ethyl acetate, whereupon 1.54 g of a Selcat-Q type palladium-charcoal catalyst and 6 drops of acetic acid are added and the mixture is hydrogenated under a pressure of 6 atm at room temperature. The catalyst is filtered off and the filtrate is evaporated. The residual yellow oil is dissolved in hot acetic acid, cooled and poured into icecold water under stirring. The precipitated yellow powder is filtered, washed, dried, suspended in diisopropyl ether, filtered and dried again. Thus 5.8 g of 3-ethyl-5-methyl-2-hydroxymethyl-6- -methyl-4-(2-chloro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylate are obtained, yield 90.6 %. Mp.: 134-136°C. Analysis: for the Formula C18H20CINO5 (365.814) calc: C%=59.10; H%=5.51 ; N%=3.83; Cl%=9.69; found: C%=57.36; H%=5.55; N%=3.87; Cl%=9.64.
Example 9
S-ethyl-δ-methyl^-chloromethyl-e-methyl^-^-chloro-phenyl)-
-1 ,4-dihydro-pyridine-3,5-dicarboxylate
Method a)
A mixture of 2.0 g (5 millimoles) of 1-(2-chloro-phenyl)- -N,N'-bis-(2-chloro-benzylidene)-methylene-diamine, 1.71 g (15 millimoles) of methyl-3-amino-crotonate, 2.47 g (15 millimoles) of ethyl-4-chloro-acetoacetate and 50 ml of methanol is heated to boiling for 32 hours. After clarification the solution is evaporated in vacuo. The residual oil is subjected to column chromatography on Kieselgel 60 and eluted with a 4:6 mixture of n-hexane and ethyl acetate. Thus 0.57 g of 3-ethyl-5-methyl-2-chloromethyl-6-methyl-4-(2-chloro- -phenyl)-1 ,4-dihydro-pyridine-3,5-dicarboxylate are obtained in the form of an oil. Method b)
A mixture of 0.4 g (1 millimole) of 1-(2-chloro-phenyl)- -N,N'-bis-(2-chloro-benzylidene)-methylene-diamine, 0.35 g (3 millimoles) of methyl-acetoacetate and 1.0 g (3 millimoles) of ethyl-4-chloro-ethoxy-3-amino-crotonate and 7 ml of isopropanol is heated to boiling for 24 hours. The reaction mixture is clarified and evaporated. The residue is purified as described in method a). Thus 0.56 g of 3-ethyl-5-methyl-2- -chloromethyl-6-methyl-4-(2-chloro-phenyl)-1 ,4-dihydro-pyridine- -3,5-dicarboxylate are obtained, mp.: 142-144°C.
Example 10
3-ethyl-5-methyl-2-(2-chloroethoxy-methyl)-6-methyl-4-(2- -chloro-phenyl)-1 ,4-dihydro-pyridine-3,5-dicarboxylate
A mixture of 2.4 g (6 millimoles) of 1-(2-chloro-phenyl)- N,N'-bis-(2-chloro-benzylidene)-methylene-diamine, 2.7 g (18 millimoles) of methyl-3-amino-crotonate, 3.75 g (18 millimoles) of 4-(2-chloro-ethoxy)-acetoacetate and 45 ml of isopropanol is heated to boiling for 15 hours. The reaction mixture is cooled, the precipitated crystalline product is filtered, washed with cold isopropanol and diisopropyl ether and dried. The crude product is recrystallized from methanol. Thus 2.47 g of 3-ethyl-5-methyl-2-(2-chloro-ethoxy-methyl)-6-methyl-4-(2-chloro- -phenyl)-1 ,4-dihydro-pyridine-3,5-dicarboxylate are obtained in the form of butter-coloured crystals. Yield 32 %, mp.: 152- 153°C.
Analysis: for the Formula C20H23CI2NO5 (428.320) calc: C%=56.08; H%=5.41 ; Cl%=16.56; N%=3.27; found: C%=56.10; H%=5.42; Cl%=16.18; N%=3.37.
Claims
1. Process for the preparation of asymmetrical 1 ,4- -dihydro-pyridine-dicarboxylic acid esters of the general Formula
(wherein
R1 and R2 each stands for lower alkyl or an ethyl group substituted by methoxy or cyano, with the proviso that
R1 and R2 are different; R3 stands for lower alkyl optionally substituted by hydroxy or halogen, or a benzyloxymethyl group or a group of the general Formula -CH2-0-CH2-CH2-X; X stands for halogen, azido or -NR4R5; R4 and R5 are identical or different and each stands for hydrogen or lower alkyl, or R4 and R5 together with the nitrogen atom, they are attached to, form a phthaloyl group; A is nitro or halogen and n is 1 or 2) which comprises a) reacting a compound of the general Formula 
A „
(wherein A and n are as stated above) with a compound of the general Formula
R1OOC — CH, — C — CH, Ml
II o and an amino crotonic acid ester of the general Formula R2OOC — CH =c R3 i
I
NH2
(wherein R1, R2 and R3 are as stated above); or b) reacting a compound of the general Formula II with a beta-keto-carboxylic acid ester of the general Formula
R2OOC — CH2 — C R3 |v
II o and an amino-crotonic acid ester of the general Formula
R1OOC — CH = C — CH3
NH2
(wherein R1, R2 and R3 are as stated above) and if desired transforming a compound of the general Formula I thus obtained into an other compound of the general Formula I.
2. Process according to Claim 1 for the preparation of compounds of the general Formula I wherein A stands for chlorine in position 2, or nitro in position 2 or 3; n is 1 ; R1 stands for methyl; R2 represents ethyl or 2-methyl-propyl and R3 stands for methyl, hydroxymethyl, chloromethyl, phthalimido-ethoxy-methyl, benzyloxymethyl or 2-chloro- -ethoxy-methyl which comprises using the corresponding starting materials.
3. Process according to Claim 1 for the preparation of 3-ethyl-5-methyl-2-[(2-phthalimido-ethoxy)-methyl]-6-methyl-4- -(2-chloro-phenyl)-1 ,4-dihydro-pyridine-3,5-dicarboxylate which comprises using the corresponding starting materials.
4. Process according to process a) of Claim 1 which comprises reacting 1 mole of a compound of the general Formula II with 3-4.5 moles, preferably 3 moles of a compound of the general Formula III and 3-4.5 moles, preferably 3 moles of a compound of the general Formula VI.
5. Process according to process b) of Claim 1 which comprises reacting 1 mole of a compound of the general Formula II with 3-4.5 moles, preferably 3 moles of a compound of the general Formula IV and 3-4.5 moles, preferably 3 moles of a compound of the general Formula V.
6. Process according to Claim 1 which comprises carrying out the reaction in a polar protic or dipolar aprotic solvent or a mixture thereof.
7. Process according to Claim 7 which comprises carrying out the reaction in an aliphatic alcohol, preferably methanol, ethanol, propanol, isopropanol or isobutanol; or water, formamide, dimethyl formamide, acetonitrile, dimethyl sulfoxide or nitro benzene.
8. Process according to Claim 7 which comprises carrying out the reaction in a lower aliphatic alcohol.
9. Process according to Claim 1 which comprises carrying out the reaction at a temperature between room temperature and 120°C, preferably at 30-90°C.
10. Process according to Claim 8 or 9 which comprises carrying out the reaction at the boiling point of the lower aliphatic alcohol.
11. Process according to Claim 1 which comprises carrying out the reaction for 1-50 hours, preferably 10-25 hours.
12. Process according to Claim 1 which comprises converting a compound of the general Formula I, wherein R3 stands for benzyloxymethyl by hydrogenation into the corresponding compound of the general Formula I, wherein R3 stands for hydroxymethyl.
13. Process according to Claim 1 which comprises removing the phthaloyl group from a compound of the general Formula I, wherein R3 stands for phthalimido-ethoxy-methyl, to yield a compound of the general Formula I, wherein R3 stands for 2-amino-ethoxy-methyl.
14. 3-ethyl-5-methyl-2-(benzyloxymethyl)-6-methyl-4- -(2-chloro-phenyl)-1 ,4-dihydro-pyridine-3,5-dicarboxylate of the general Formula I.
15. 1-(2,3-dichloro-phenyl)-N,N'-bis-(2,3-dichloro- -benzylidene)-methylene-diamine of the general Formula II.
16. The following compounds of the general Formula VI: ethyl-4-(phthalimido-ethoxy)-3-amino-crotonate; ethyl-4-benzyloxy-3-amino-chrotonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU28195/00A AU2819500A (en) | 1999-02-15 | 2000-02-15 | Process for the preparation of asymmetrical 1,4-dihydro-pyridine-dicarboxylic acid esters |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP9900353 | 1999-02-15 | ||
| HU9900353A HUP9900353A3 (en) | 1999-02-15 | 1999-02-15 | Process for producing asymmetric esters of 1,4-dihydropyridine-dicarboxylic acids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000047560A2 true WO2000047560A2 (en) | 2000-08-17 |
| WO2000047560A3 WO2000047560A3 (en) | 2000-11-02 |
Family
ID=89997785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2000/000012 WO2000047560A2 (en) | 1999-02-15 | 2000-02-15 | Process for the preparation of asymmetrical 1,4-dihydro-pyridine-dicarboxylic acid esters |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2819500A (en) |
| HU (1) | HUP9900353A3 (en) |
| WO (1) | WO2000047560A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7671208B2 (en) | 2007-03-30 | 2010-03-02 | Esteve Quimica, S.A. | Acetone solvate of phthaloyl amlodipine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3907508A1 (en) * | 1988-03-08 | 1989-09-21 | Egyt Gyogyszervegyeszeti Gyar | PROCESS AND INTERMEDIATE PRODUCTS, IF N N SUBSTITUTED, (2- (NITRO) -PHENYL) METHYLENIMINE FOR THE PRODUCTION OF 1,4-DI- (HYDRO) -2,6-DI- (METHYL) -4- (2 '- ( NITRO) -PHENYL) -PYRIDINE-3,5-DI- (CARBONIC ACID DIMETHYL ESTER) AND METHOD FOR PRODUCING THIS INTERMEDIATE PRODUCTS |
| EP0534520A2 (en) * | 1991-09-13 | 1993-03-31 | Merck & Co. Inc. | Process for the preparation of 4-substituted-1,4-dihydropyridines |
-
1999
- 1999-02-15 HU HU9900353A patent/HUP9900353A3/en unknown
-
2000
- 2000-02-15 WO PCT/HU2000/000012 patent/WO2000047560A2/en active Application Filing
- 2000-02-15 AU AU28195/00A patent/AU2819500A/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3907508A1 (en) * | 1988-03-08 | 1989-09-21 | Egyt Gyogyszervegyeszeti Gyar | PROCESS AND INTERMEDIATE PRODUCTS, IF N N SUBSTITUTED, (2- (NITRO) -PHENYL) METHYLENIMINE FOR THE PRODUCTION OF 1,4-DI- (HYDRO) -2,6-DI- (METHYL) -4- (2 '- ( NITRO) -PHENYL) -PYRIDINE-3,5-DI- (CARBONIC ACID DIMETHYL ESTER) AND METHOD FOR PRODUCING THIS INTERMEDIATE PRODUCTS |
| EP0534520A2 (en) * | 1991-09-13 | 1993-03-31 | Merck & Co. Inc. | Process for the preparation of 4-substituted-1,4-dihydropyridines |
Non-Patent Citations (1)
| Title |
|---|
| LEVAI, L. ET AL: "Nucleophilic substitution in the azomethine series: an improved synthesis of 1,4- dihydropyridines" SYNTH. COMMUN. (1992), 22(1), 47-61 , XP000929356 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7671208B2 (en) | 2007-03-30 | 2010-03-02 | Esteve Quimica, S.A. | Acetone solvate of phthaloyl amlodipine |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2819500A (en) | 2000-08-29 |
| HU9900353D0 (en) | 1999-04-28 |
| HUP9900353A2 (en) | 2001-03-28 |
| WO2000047560A3 (en) | 2000-11-02 |
| HUP9900353A3 (en) | 2002-01-28 |
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