JPH02212474A - Production of optically active 1,4-dihydropyridine derivative - Google Patents
Production of optically active 1,4-dihydropyridine derivativeInfo
- Publication number
- JPH02212474A JPH02212474A JP3000489A JP3000489A JPH02212474A JP H02212474 A JPH02212474 A JP H02212474A JP 3000489 A JP3000489 A JP 3000489A JP 3000489 A JP3000489 A JP 3000489A JP H02212474 A JPH02212474 A JP H02212474A
- Authority
- JP
- Japan
- Prior art keywords
- group
- optically active
- dihydropyridine
- formula
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title claims description 33
- 238000004519 manufacturing process Methods 0.000 title claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- -1 benzylidene acetoacetate derivative Chemical class 0.000 claims description 30
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000000129 anionic group Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 abstract description 23
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 abstract description 22
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 150000002148 esters Chemical class 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 239000012442 inert solvent Substances 0.000 abstract description 3
- 150000001450 anions Chemical class 0.000 abstract description 2
- PAWSVPVNIXFKOS-IHWYPQMZSA-N (Z)-2-aminobutenoic acid Chemical class C\C=C(/N)C(O)=O PAWSVPVNIXFKOS-IHWYPQMZSA-N 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- 239000000047 product Substances 0.000 description 26
- 239000000203 mixture Substances 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 238000000034 method Methods 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- 239000002904 solvent Substances 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 230000003287 optical effect Effects 0.000 description 11
- 230000000704 physical effect Effects 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 10
- 239000005695 Ammonium acetate Substances 0.000 description 10
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 10
- 229940043376 ammonium acetate Drugs 0.000 description 10
- 235000019257 ammonium acetate Nutrition 0.000 description 10
- 238000011914 asymmetric synthesis Methods 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 241001448862 Croton Species 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CUNSUQKHHZVKMU-UHFFFAOYSA-N 1,4-dihydropyridine-2-carboxylic acid Chemical compound OC(=O)C1=CCC=CN1 CUNSUQKHHZVKMU-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VNMMLNVSLPRZDK-UHFFFAOYSA-N 3-oxo-5-phenylpent-4-enoic acid Chemical class OC(=O)CC(=O)C=CC1=CC=CC=C1 VNMMLNVSLPRZDK-UHFFFAOYSA-N 0.000 description 3
- JPXPPUOCSLMCHK-UHFFFAOYSA-N 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid Chemical compound COC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 JPXPPUOCSLMCHK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- OFILYROTVDAUGT-UHFFFAOYSA-N 5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid Chemical compound COC(=O)C1=CNC=C(C(O)=O)C1 OFILYROTVDAUGT-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002327 cardiovascular agent Substances 0.000 description 2
- 229940125692 cardiovascular agent Drugs 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910000372 mercury(II) sulfate Inorganic materials 0.000 description 2
- LYUBYLJQOZIBQB-XFFZJAGNSA-N methyl (2z)-2-[(3-nitrophenyl)methylidene]-3-oxobutanoate Chemical compound COC(=O)C(\C(C)=O)=C/C1=CC=CC([N+]([O-])=O)=C1 LYUBYLJQOZIBQB-XFFZJAGNSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- BWSIKGOGLDNQBZ-UHFFFAOYSA-N 2-(methoxymethyl)pyrrolidin-1-amine Chemical group COCC1CCCN1N BWSIKGOGLDNQBZ-UHFFFAOYSA-N 0.000 description 1
- VVXFDFQEIRGULC-UHFFFAOYSA-N 2-fluoro-5-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(F)C(C=O)=C1 VVXFDFQEIRGULC-UHFFFAOYSA-N 0.000 description 1
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 102000052583 Anaphase-Promoting Complex-Cyclosome Apc8 Subunit Human genes 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000003445 Hantzsch reaction Methods 0.000 description 1
- 101000912124 Homo sapiens Cell division cycle protein 23 homolog Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- GSBJXOIVIOYPOW-SNVBAGLBSA-N [(1r)-1-phenylethyl] 3-oxobutanoate Chemical compound CC(=O)CC(=O)O[C@H](C)C1=CC=CC=C1 GSBJXOIVIOYPOW-SNVBAGLBSA-N 0.000 description 1
- GSBJXOIVIOYPOW-JTQLQIEISA-N [(1s)-1-phenylethyl] 3-oxobutanoate Chemical compound CC(=O)CC(=O)O[C@@H](C)C1=CC=CC=C1 GSBJXOIVIOYPOW-JTQLQIEISA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 201000001034 autosomal recessive chronic granulomatous disease cytochrome b-positive type III Diseases 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KIVHHEUXDIMERT-QMMMGPOBSA-N butyl (2s)-2-amino-3-methylbutanoate Chemical compound CCCCOC(=O)[C@@H](N)C(C)C KIVHHEUXDIMERT-QMMMGPOBSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- WOWBFOBYOAGEEA-UHFFFAOYSA-N diafenthiuron Chemical compound CC(C)C1=C(NC(=S)NC(C)(C)C)C(C(C)C)=CC(OC=2C=CC=CC=2)=C1 WOWBFOBYOAGEEA-UHFFFAOYSA-N 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- RSJUPDUDZRGVRW-UHFFFAOYSA-N ethyl 4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidine-6-carboxylate Chemical compound N1C=NC(=O)C2=C1NC(C(=O)OCC)=C2 RSJUPDUDZRGVRW-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- JYVHOGDBFNJNMR-UHFFFAOYSA-N hexane;hydrate Chemical compound O.CCCCCC JYVHOGDBFNJNMR-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- DLENDKSMPIEGPF-UHFFFAOYSA-N lithium piperidine Chemical compound [Li+].C1CCNCC1 DLENDKSMPIEGPF-UHFFFAOYSA-N 0.000 description 1
- AHNJTQYTRPXLLG-UHFFFAOYSA-N lithium;diethylazanide Chemical compound [Li+].CC[N-]CC AHNJTQYTRPXLLG-UHFFFAOYSA-N 0.000 description 1
- DHNYUSXLKLFHTB-UHFFFAOYSA-N lithium;piperazine Chemical compound [Li].C1CNCCN1 DHNYUSXLKLFHTB-UHFFFAOYSA-N 0.000 description 1
- BRPMJMJJONIAHU-UHFFFAOYSA-N lithium;pyrrolidine Chemical compound [Li].C1CCNC1 BRPMJMJJONIAHU-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- LYUBYLJQOZIBQB-YRNVUSSQSA-N methyl (2e)-2-[(3-nitrophenyl)methylidene]-3-oxobutanoate Chemical compound COC(=O)C(\C(C)=O)=C\C1=CC=CC([N+]([O-])=O)=C1 LYUBYLJQOZIBQB-YRNVUSSQSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- RJBVJBGFJIHJSZ-ZETCQYMHSA-N tert-butyl (2s)-2-amino-3-methylbutanoate Chemical compound CC(C)[C@H](N)C(=O)OC(C)(C)C RJBVJBGFJIHJSZ-ZETCQYMHSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
Abstract
Description
【発明の詳細な説明】
（１）産業上の利用分野
本発明は光学活性な１，４−ジヒドロピロリジン誘導体
の製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION (1) Industrial Application Field The present invention relates to a method for producing optically active 1,4-dihydropyrrolidine derivatives.
更に詳細には、循環器系医薬品として臨床上有用な１．
４−ジヒドロピリジン系化合物の光学活性体、並びにそ
れらを製造するだめの重要中間体である光学活性な１，
４−ジヒドロピリジン誘導体の製造方法に関する。More specifically, 1. which is clinically useful as a cardiovascular drug.
Optically active forms of 4-dihydropyridine compounds, as well as optically active 1, which is an important intermediate for producing them.
The present invention relates to a method for producing a 4-dihydropyridine derivative.
（２）従来技術
従来、多数の１，４−ジヒドロピリジン誘導体が知られ
ており、それらのあるものは、光学異性体間で薬理活性
が質的にも量的にも異なることが知られている［に汀ａ
ｍａＺａＷａ ｅｔ ａ］ ： Ｊ、Ｈｅｄ、 Ｃｈｅ
ｍ、 。(2) Prior art A large number of 1,4-dihydropyridine derivatives have been known in the past, and it is known that the pharmacological activity of some of them differs both qualitatively and quantitatively between optical isomers. [Ni 汀a
maZaWaet a]: J, Hed, Che
m.
ｖｏｌ、２９．２５０４−２５１１ （１９８６）参照
］。vol. 29.2504-2511 (1986)].
かかる光学活性な１，４−ジヒドロピリジン誘導体を製
造するに当り、重要中間体として、光学活性な１．４−
ジヒドロピリジンカルボン酸が用いられる。その製造方
法としては、例えばラセミ体の１−エトキシメチル−２
，６−シメチルー１．４−ジヒドロピリジン−３，５−
ジカルボン酸ジメチルを、苛酷なアルカリ性条件下で加
水分解して得られる１−エトキシメチル−２，６−シメ
チルー３−メトキシカルボニル−１，４−ジヒドロピリ
ジン−５−カルボン酸を光学活性アミン類を用いて光学
分割する方法が知られている［Ｔ、 ｓｈｉｂａｎｕｍ
ａ ｅｔ ａ］：Ｃｈｅｍ、 Ｐｈａｒｍ、 Ｂｕｌｌ
、、 ｖｏｌ、２８．２８０９−２８１２ （１９８０
）参照］。又、同様に、ラセミ体の１，４−ジヒドロピ
リジンカルボン酸に光学活性な２−メ１ヘキシー２−フ
ェニルエタノールを縮合して１ｑられる一対のジアステ
レオマーをクロマトグラフィー等によって分割し、１ｑ
られたＣ４位の絶対配置が異なるそれぞれのジアステレ
オマーと、所望のエステル残基に対応するアルコール類
とでエステル交換せしめて目的とする光学活性な１，４
−ジヒドロピリジン誘導体を製造している（Ｊ、Ｅ、Ａ
ｒｒｏｗｓｍｉｔｈ ｅｔａ］、 Ｊ、 Ｈｅｄ、
Ｃｈｅｍ、ｖｏｌ、２９． １６９６−１７０２ （１
９８６） 。In producing such optically active 1,4-dihydropyridine derivatives, optically active 1,4-dihydropyridine derivatives are used as important intermediates.
Dihydropyridine carboxylic acid is used. As a method for producing it, for example, racemic 1-ethoxymethyl-2
,6-dimethyl-1,4-dihydropyridine-3,5-
1-ethoxymethyl-2,6-dimethyl-3-methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid obtained by hydrolyzing dimethyl dicarboxylate under harsh alkaline conditions using optically active amines. A method of optical resolution is known [T, shibanum
a et a]: Chem, Pharm, Bull
,, vol, 28.2809-2812 (1980
)reference]. Similarly, a pair of diastereomers obtained by condensing racemic 1,4-dihydropyridinecarboxylic acid with optically active 2-meth-hexy-2-phenylethanol are separated by chromatography or the like to obtain 1q.
The desired optically active 1,4 diastereomers having different absolute configurations at the C4 position are transesterified with alcohols corresponding to the desired ester residues.
- Dihydropyridine derivatives are produced (J, E, A
rrowsmith eta], J. Hed,
Chem, vol, 29. 1696-1702 (1
986).
特開昭５８−１８０４８３ 、特開昭５９−５１８３
、特開昭５６−３６４５５等参照）。しかしながら、こ
れらの方法においては、エステル交換反応が重要であり
、反応選択性が、導入するアルコールの種類や３位のエ
ステル基の種類に大きく依存し、その−膜性には著しい
限界があ・る。JP-A-58-180483, JP-A-59-5183
, JP-A-56-36455, etc.). However, in these methods, the transesterification reaction is important, and the reaction selectivity largely depends on the type of alcohol introduced and the type of ester group at the 3-position, and there are significant limits to the membrane properties. Ru.
一方本発明者らはさきに下記式［ＩＶ］で表わされる１
、４−ジヒドロピリジン誘導体類において、Ｒ２が単一
の絶対配置である一対のジアステレオマーの混合物を分
離し、得られるＣ４位が単一の絶対配置である光学活性
な１，４−ジヒドロピリジン誘導体を用い、Ｒ２エステ
ル基を開裂すると、Ｃ４位が単一の絶対配置でおる光学
活性な１．４−ジヒドロピロリジンカルボン酸誘導体類
（下記式［Ｖ］）が得られることを見いだしている。On the other hand, the present inventors first demonstrated that 1 represented by the following formula [IV]
, in 4-dihydropyridine derivatives, a mixture of a pair of diastereomers in which R2 has a single absolute configuration is separated, and the resulting optically active 1,4-dihydropyridine derivative in which the C4 position has a single absolute configuration is obtained. It has been found that when the R2 ester group is cleaved using the above method, optically active 1,4-dihydropyrrolidinecarboxylic acid derivatives (formula [V] below) in which the C4 position has a single absolute configuration can be obtained.
この方法により簡便でかつ効率的に、高い光学純度をも
つ１，４−ジヒドロピリジンカルボン酸が得られる［特
願昭６２−１８３６２８号及び特願昭６３−１８０４１
７号参照］
このようにして得られた上記式［Ｖ］で表わされる光学
活性な１．４−ジヒドロピリジンカルボン酸をエステル
化することにより優れた薬理作用をもつ光学活性な１．
４−ジヒドロピリジン誘導体またはその塩が製造される
。By this method, 1,4-dihydropyridinecarboxylic acid with high optical purity can be obtained simply and efficiently [Japanese Patent Application No. 183628/1982 and Japanese Patent Application No. 18041/1983]
See No. 7] By esterifying the thus obtained optically active 1,4-dihydropyridinecarboxylic acid represented by the above formula [V], an optically active 1,4-dihydropyridinecarboxylic acid having an excellent pharmacological effect can be obtained.
A 4-dihydropyridine derivative or a salt thereof is produced.
更に光学活性な１，４−ジヒドロピリジン誘導体を不斉
合成法により立体選択的に製造する方法も知られている
。Furthermore, a method for stereoselectively producing optically active 1,4-dihydropyridine derivatives by an asymmetric synthesis method is also known.
例えば１．４−ジヒドロピリジン誘導体の一般合成方法
である）ｉｏｄｉｆｉｅｄ ＨａｎｔＺＳＣｈ合成反応
において、原料として用いる３−アミノクロトン酸エス
テルのエステル残基に不斉源を導入すると、Ｃ４位の一
方の絶対配置をもつ１，４−ジヒドロピリジン誘導体が
優先的に生成することが知られている（ドイツ国特許出
願公開明細書第２９３５４５１号 参照）。For example, in the iodified HantZSCh synthesis reaction (which is a general synthesis method for 1,4-dihydropyridine derivatives), when an asymmetric source is introduced into the ester residue of the 3-aminocrotonic acid ester used as a raw material, it is possible to generate a compound with one absolute configuration at the C4 position. It is known that 1,4-dihydropyridine derivatives are preferentially produced (see German Patent Application No. 2935451).
同様に３−アミノクロトン酸エステルのアミノ基部分に
光学活性な１−アミノ−２−メトキシメチルピロリジン
基を有する光学活性な３−アミノクロトン酸エステル誘
導体を用いることにより、１．４−ジヒドロピリジン誘
導体の０４位に不斉合成反応が誘起されることが知られ
ている［Ｄ。Similarly, by using an optically active 3-aminocrotonic acid ester derivative having an optically active 1-amino-2-methoxymethylpyrrolidine group in the amino group moiety of the 3-aminocrotonic acid ester, a 1,4-dihydropyridine derivative can be prepared. It is known that an asymmetric synthesis reaction is induced at position 04 [D.
Ｅｎｄ（！ｒｓら、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ
ｅｒｓ： ｖｏｌ ２４． ４９６７−４９７０ （１
９１３３）及び特開昭６１−１２６６３号公報参照］。End (!rs, Tetrahedron Lett
ers: vol 24. 4967-4970 (1
9133) and Japanese Unexamined Patent Publication No. 12663/1982].
又、３−アミノクロトン酸エステルのアミノ基部分に光
学活性なバリンエステルを導入した誘導体を用いると光
学活性な１，４−ジヒドロピリジン誘導体が１ｑられる
ことも知られている（特開昭６３−２０８５７３号公報
参照］。It is also known that 1q of optically active 1,4-dihydropyridine derivatives can be obtained by using a derivative in which optically active valine ester is introduced into the amino group of 3-aminocrotonic acid ester (JP-A-63-208573). Please refer to the publication].
かかる不斉合成反応を用いることにより、一方の絶対配
置を有する１、４−ジヒドロピリジン誘導体を、優先的
に製造することができる。この方法は前述の光学分割方
法に比べてはるかに効率的に所望の光学活性な１，４−
ジヒドロピリジン誘導体を製造することができる。By using such an asymmetric synthesis reaction, a 1,4-dihydropyridine derivative having one absolute configuration can be preferentially produced. This method is much more efficient than the optical resolution methods described above and allows the desired optically active 1,4-
Dihydropyridine derivatives can be produced.
ところが、光学分割方法はそれを繰り返すことにより最
終的には光学的に完全に純粋な所望の光学活性体を得る
ことができるが、不斉合成反応を用いる方法では、その
反応の不斉誘導能により生成物の光学ｌｌ１１度が決定
され、現在までのところ光学的に完全に純粋な生成物を
与える不斉合成反応は知られていない。かくして、不斉
合成反応により得られた生成物を光学的に純粋にするた
めには困難が伴う。However, in the optical resolution method, it is possible to finally obtain a completely optically pure desired optically active substance by repeating the process, but in the method using an asymmetric synthesis reaction, the asymmetric induction ability of the reaction is limited. The optical 11 degrees of the product was determined by the method, and to date, no asymmetric synthesis reaction is known that yields an optically completely pure product. Thus, it is difficult to make the product obtained by the asymmetric synthesis reaction optically pure.
事実前掲の参考文献の実例においても不斉合成反応によ
って光学的に完全に純粋な光学活性体すなわち単一の絶
対配置を持つ１，４−ジヒドロピリジン誘導体が得られ
た例はない。In fact, even in the examples cited in the above-mentioned references, there is no example in which an optically completely pure optically active substance, that is, a 1,4-dihydropyridine derivative having a single absolute configuration, was obtained by an asymmetric synthesis reaction.
換言すれば公知の方法には一長一短があり、光学分割方
法では光学的に純粋な目的物が得られるが製造効率は低
り、不斉合成反応による方法では製造効率は高いが光学
的に純粋な目的物を製造するのが困難である。In other words, the known methods have advantages and disadvantages; optical resolution methods yield optically pure target products but have low production efficiency; methods using asymmetric synthesis reactions have high production efficiency but produce optically pure target products. It is difficult to manufacture the desired product.
本発明者はかかる光学活性な１，４−ジヒドロピリジン
誘導体の製造方法について鋭意研究を重ね、効率的であ
り且つ光学的に完全に純粋な１．４−ジヒドロピリジン
誘導体の製造方法を見い出し本発明に到達した。The present inventor has conducted extensive research into methods for producing such optically active 1,4-dihydropyridine derivatives, and has found an efficient and optically completely pure method for producing 1,4-dihydropyridine derivatives, thereby achieving the present invention. did.
（３）発明の目的
本発明の目的は、光学活性な１，４−ジヒドロピリジン
誘導体の製造方法を提供することにある。(3) Purpose of the Invention An object of the present invention is to provide a method for producing an optically active 1,4-dihydropyridine derivative.
本発明の製造方法によって提供される光学活性な１．４
−ジヒドロピリジン誘導体は・、そのまま循環器系医薬
品として臨床上有用な１．４−ジヒドロピリジン系化合
物として利用することができる。Optically active 1.4 provided by the production method of the present invention
-Dihydropyridine derivatives can be used as they are as 1,4-dihydropyridine compounds that are clinically useful as cardiovascular drugs.
あるいは本発明の製造方法によって提供される光学活性
な１，４−ジヒドロピリジン誘導体を重要製造中間体と
して、優れた薬理作用を有する１、４−ジヒドロピリジ
ン系化合物（例えば、特開昭６１−５７５５６号）の光
学活性体を提供するために利用できる。Alternatively, the optically active 1,4-dihydropyridine derivative provided by the production method of the present invention is used as an important production intermediate to produce a 1,4-dihydropyridine compound with excellent pharmacological action (e.g., JP-A-61-57556). can be used to provide an optically active form of.
（４）発明の構成及び効果
すなわち本発明は、
（１）下記式［Ｉ］
で表わされるベンジリデンアセト酢酸エステル誘導体と
下記式［ＩＩ］
ＣＨ３−Ｃ＝ ＣＨＣＯ２Ｒ２
Ｈ
・ｃ！：ＨｃｏｚＲ４
・・・［ｆｆ］
で表わされる光学活性な３−アミノクロトン酸エステル
誘導体とをリチウムアミドの存在下で反応させ、次いで
加水分解し、ひきつづいて、Ｈ４−１
・・・［Ｉ［［］
［Ｌは１価の陰イオン基を表わす。］
で表わされるアンモニウム塩と反応させることを特徴と
する下記式［ＩＶ］
で表わされる光学活性な１，４−ジヒドロピリジン誘導
体の製造方法を提供する。(4) Structure and effect of the invention, that is, the present invention, (1) A benzylideneacetoacetate derivative represented by the following formula [I] and the following formula [II] CH3-C= CHCO2R2 H ・c! :HcozR4...[ff] is reacted with an optically active 3-aminocrotonic acid ester derivative represented by the following in the presence of lithium amide, and then hydrolyzed, followed by H4-1...[I[[ ] [L represents a monovalent anionic group. ] Provided is a method for producing an optically active 1,4-dihydropyridine derivative represented by the following formula [IV], which comprises reacting with an ammonium salt represented by the following formula [IV].
本発明の製造方法により提供される１、４−ジヒドロピ
リジン誘導体は光学活性体である。すなわち、上記式［
ＩＶ］で表わされる１、４−ジヒドロピリジン誘導体は
、０４位とエステル残基Ｒ２とに不斉炭素を有しており
、可能な４種の光学異性体のうちのいずれか１つの光学
異性体またはジアステレオマーを表わす。The 1,4-dihydropyridine derivative provided by the production method of the present invention is an optically active derivative. That is, the above formula [
The 1,4-dihydropyridine derivative represented by IV] has an asymmetric carbon at the 04-position and the ester residue R2, and can be any one of the four possible optical isomers or Represents diastereomers.
本発明の製造方法によれば、効率的に且つ高い光学純度
を有する単一の絶対配置をもっ１，４−ジヒドロピリジ
ン誘導体を提供することができる。According to the production method of the present invention, it is possible to efficiently provide a 1,4-dihydropyridine derivative having a single absolute configuration and having high optical purity.
本発明によれば上記式［ＩＩで表わされるベンジリデン
アセト酢酸エステル誘導体において、Ｘ。According to the present invention, in the benzylidene acetoacetate derivative represented by the above formula [II], X.
Ｙ及びＺは同一もしくは異なって水素原子：例えばフッ
素原子、塩素原子等のハロゲン原子；またはニトロ基を
表わす。但し、Ｘ、Ｙ及びＺが同時に水素原子を表わす
ことはない。Y and Z are the same or different and represent a hydrogen atom; for example, a halogen atom such as a fluorine atom or a chlorine atom; or a nitro group. However, X, Y and Z do not represent hydrogen atoms at the same time.
又、Ｒ１の低級アルキル基とし“ては、例えば、メチル
基、エチル基、プロピル基、イソプロピル基。Examples of the lower alkyl group for R1 include methyl group, ethyl group, propyl group, and isopropyl group.
ブチル基、 ５ｅｃ−ブチル基、 ｔｅｒｔ−ブチル基
等の直鎖または分岐した低級アルキル基が挙げられる。Straight-chain or branched lower alkyl groups such as a butyl group, a 5ec-butyl group, a tert-butyl group, and the like can be mentioned.
またＲ１の置換基としては、例えばフッ素原子、塩素原
子等のハロゲン原子；メトキシ基、エトキシ基等の０１
〜Ｃ６のアルコキシ基；（置換）アミン基等があげられ
る。Examples of substituents for R1 include halogen atoms such as fluorine and chlorine; 01 such as methoxy and ethoxy groups;
~C6 alkoxy group; (substituted) amine group, etc.
上記式［ＩＩで表わされるベンジリデンアセト酢酸エス
テル誘導体は２つの幾何異性体、すなわち７体とＥ体の
いずれか一方の幾何異性体または両者の混合物を表わす
。The benzylidene acetoacetate derivative represented by the above formula [II represents one of two geometric isomers, ie, heptad and E-forms, or a mixture of both.
本発明における上記式［ＩＩ］で表わされる光学活性な
３−アミノクロトン酸エステル誘導体において、Ｒ２は
上記式［１−ａ］で表わされる置換アルキル基である。In the optically active 3-aminocrotonic acid ester derivative represented by the above formula [II] in the present invention, R2 is a substituted alkyl group represented by the above formula [1-a].
上記式［ＩＩ−ａ］においてＲ５の低級アルキル基とし
ては、メチル基、エチル基等、低級アルキルオキシ基と
しては、メトキシ基、エトキシ基、プロポキシ基等が挙
げられる。Ｒ６の置換もしくは非置換のフェニル基とし
てはメチル基、メトキシ基。In the above formula [II-a], examples of the lower alkyl group for R5 include a methyl group and an ethyl group, and examples of the lower alkyloxy group include a methoxy group, an ethoxy group, a propoxy group, and the like. The substituted or unsubstituted phenyl group for R6 is a methyl group or a methoxy group.
ハロゲン原子等で置換されているかもしくは置換基のな
いフェニル基が挙げられる。これらのうちでもＲ５は低
級アルキル基、なかでもメチル基が好ましく、Ｒ６は非
置換のフェニル基が好ましい。A phenyl group substituted with a halogen atom or the like or having no substituent is exemplified. Among these, R5 is preferably a lower alkyl group, especially a methyl group, and R6 is preferably an unsubstituted phenyl group.
上記式［１１ｒｌにおいてＲ３およびＲ４は低級アルキ
ル基を表わし、例えばメチル基、エチル基、プロピル基
、イソプロピル基、ブチル基、イソブチル基、 ５ｅｃ
−ブチル基、 ｔｅｒｔ−ブチル基、ペンチル基、シク
ロヘキシル基などが挙げられる。なかでもＲ３がイソプ
ロピル基、Ｒ４がｔｅｒｔ−ブチル基が好ましい。In the above formula [11rl, R3 and R4 represent lower alkyl groups, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 5ec
-butyl group, tert-butyl group, pentyl group, cyclohexyl group, etc. Among these, R3 is preferably an isopropyl group, and R4 is preferably a tert-butyl group.
上記式［ＩＩ］で表わされる３−アミノクロトン酸エス
テル誘導体には２つの不斉炭素が存在し、可能な４種の
光学異性体のうちいずれか１種の光学異性体を表わす。The 3-aminocrotonic acid ester derivative represented by the above formula [II] has two asymmetric carbon atoms, and represents any one of the four possible optical isomers.
かかる光学活性な３−アミノクロトン酸エステル誘導体
の製造方法は公知であり、例えば特願昭６２−１８３６
２８号の明細書にはアセト酢酸（Ｓｋｌフェニルエチル
の製造方法が開示されている。このような光学活性なア
セト酢酸エステルと光学活性なアミノ酸エステルとを用
いて公知の方法に準じて縮合することにより製造するこ
とができる［特開昭６１−１３７８４７号公報及びに、
Ｔｏｍｉｏｋａ ｅｔ ａｔ ：Ｊ、 Ａｍ、 Ｃｈ
ｅｍ、 Ｓｏｃ、、 Ｖｏｌ １０６． ２７１Ｂ−
２７１９（１９８４）参照］。Methods for producing such optically active 3-aminocrotonic acid ester derivatives are known, for example, as disclosed in Japanese Patent Application No. 1836/1983.
The specification of No. 28 discloses a method for producing acetoacetic acid (Skl phenylethyl). Using such an optically active acetoacetate and an optically active amino acid ester, condensation is carried out according to a known method. [Unexamined Japanese Patent Publication No. 61-137847 and
Tomioka et at: J, Am, Ch
em, Soc,, Vol 106. 271B-
2719 (1984)].
本発明の上記式［１１１］で表わされるアンモニウム塩
において、Ｌは１価の陰イオン基を表わす。In the ammonium salt represented by the above formula [111] of the present invention, L represents a monovalent anion group.
ＮＨ４・Ｌとしては例えば酢酸アンモニウム、塩化アン
モニウム、臭化アンモニウム、リン酸アンモニウム、硫
酸アンモニウム、四フッ化ホウ素酸アンモニウム等が挙
げられる。これらのなかでも好ましくは酢酸アンモニウ
ムが挙げられる。Examples of NH4.L include ammonium acetate, ammonium chloride, ammonium bromide, ammonium phosphate, ammonium sulfate, and ammonium tetrafluoroborate. Among these, ammonium acetate is preferred.
本発明においては、まず上記式［ＩＩ畳表わされるベン
ジリデンアセト酢酸エステル誘導体と上記式［ＩＩ］で
られされる光学活性な３−アミノクロトン酸エステル誘
導体とをリチウムアミドの存在下で反応させる。In the present invention, first, the benzylideneacetoacetate derivative represented by the above formula [II] and the optically active 3-aminocrotonic acid ester derivative represented by the above formula [II] are reacted in the presence of lithium amide.
かかる反応に用いるリチウムアミドとしては、リチウム
ジイソプロピルアミド（ＬＤＡ）、リチウムジエチルア
ミド、リチウムピペリジンアミド。Lithium amides used in such reactions include lithium diisopropylamide (LDA), lithium diethylamide, and lithium piperidine amide.
リチウムピペラジンアミド、リチウムピロリジンアミド
等があげられる。なかでもしＤＡが好ましい。かかる反
応は、’−８０℃ないし３０℃の温度範囲、好ましくは
一８０℃ないし一７０℃の温度範囲で、不活性溶媒中で
反応せしめるのが好ましい。Examples include lithium piperazine amide and lithium pyrrolidine amide. Among them, DA is preferable. The reaction is preferably carried out in an inert solvent at a temperature range of -80°C to 30°C, preferably -80°C to -70°C.
かかる不活性溶媒としては、テトラヒドロフラン（ＴＨ
Ｆ）、ジオキサン、ジエチルエーテル。Such inert solvents include tetrahydrofuran (TH
F), dioxane, diethyl ether.
ジメトキシエタン、エチレングリコールジメチルエーテ
ル、ベンゼン、トルエン、ジメチルホルムアミド（ＤＭ
Ｆ）、ヘキサメチルホスホリックアミド（ＨＭＰＡ）等
のアブロティツク溶媒（非水素系溶媒）等が挙げられる
。なかでもＴＨＥが好ましい。Dimethoxyethane, ethylene glycol dimethyl ether, benzene, toluene, dimethylformamide (DM
F), abrotic solvents (non-hydrogen solvents) such as hexamethylphosphoric amide (HMPA), and the like. Among them, THE is preferred.
本発明においては、上記反応の後、次いで加水分解し、
ひきつづき上記式［Ｉ［１］で表わされるアンモニウム
塩と反応させると所望の上記式［ＩＶ ］で表わされる
１、４−ジヒドロピリジンの１対のジアステレオマーの
うちの一つの光学異性体が優先的に製造される。加水分
解は、有機酸、無機酸等の酸、アルカリ存在下で行うこ
とができるが、なかでも塩酸等の鉱酸の存在下で行うの
が好ましい。In the present invention, after the above reaction, hydrolysis is performed,
Subsequently, when the reaction is carried out with the ammonium salt represented by the above formula [I[1], one optical isomer of the pair of diastereomers of the desired 1,4-dihydropyridine represented by the above formula [IV] becomes preferential. Manufactured in Hydrolysis can be carried out in the presence of an acid such as an organic acid or an inorganic acid, or an alkali, but it is preferably carried out in the presence of a mineral acid such as hydrochloric acid.
上記アンモニウム塩との反応は室温下でアルコール類、
ハロゲン化炭化水素類、エーテル類等の溶媒の存在下で
行うのが好ましい。かかる反応に用いるアンモニウム塩
の量は、出発物質に対し、１〜５０当量、好ましくは５
〜１０当量である。The reaction with the above ammonium salt is carried out at room temperature with alcohols,
It is preferable to carry out the reaction in the presence of a solvent such as a halogenated hydrocarbon or an ether. The amount of ammonium salt used in this reaction is 1 to 50 equivalents, preferably 5 equivalents, based on the starting material.
~10 equivalents.
本発明によれば、上記式［■］で表わされるベンジリデ
ンアセト酢酸エステル誘導体と上記式［ＩＩ］で表わさ
れる光学活性な３−アミノクロトン酸エステル誘導体と
の反応は、３−アミノクロトン酸エステル誘導体の２つ
の不斉基の効果によって１，４−ジヒドロピリジン誘導
体の０４位に立体選択的反応が誘起し、光学活性な１，
４−ジヒドロピリジン誘導体が製造される。驚くべきこ
とにはこの立体選択率は９３％ｄ、 ｅ、にも到達する
のである。According to the present invention, the reaction between the benzylideneacetoacetate derivative represented by the above formula [■] and the optically active 3-aminocrotonic acid ester derivative represented by the above formula [II] A stereoselective reaction is induced at the 04-position of the 1,4-dihydropyridine derivative due to the effect of the two asymmetric groups of the optically active 1,
A 4-dihydropyridine derivative is produced. Surprisingly, this stereoselectivity reaches 93% d, e.
本発明によれば、本立体選択的反応はベンジリデンアセ
ト酢酸エステル誘導体の幾何異性体によってほとんど影
響を受けない。すなわちその７体とＥ体間に立体選択率
の差が小さいのである。ベンジリデンアセト酢酸エステ
ル誘導体は、７体またはＥ体のいずれか一方の幾何異性
体または両者の混合物が用いられる。According to the invention, the stereoselective reaction is hardly influenced by the geometric isomer of the benzylideneacetoacetate ester derivative. In other words, the difference in stereoselectivity between the 7-isomer and the E-isomer is small. As the benzylidene acetoacetate derivative, either a heptad or E geometric isomer or a mixture of the two is used.
更に驚くべきことには、ここで得られた１、４−ジヒド
ロピリジン誘導体の一対のジアステレオマーの混合物を
単に再結晶するのみで高い回収率をもって、光学的に完
全に純粋な単一の絶対配置をもつ１，４−ジヒドロピリ
ジン誘導体が得られる。Even more surprisingly, by simply recrystallizing the mixture of a pair of diastereomers of the 1,4-dihydropyridine derivative obtained here, optically completely pure single absolute configuration can be obtained with a high recovery rate. A 1,4-dihydropyridine derivative having the following formula is obtained.
かかる反応を実施した後得られた１、４−ジヒドロピリ
ジン誘導体は、更に単離精製することによって、より純
粋なものとすることができる。かかる精製方法の詳細は
、例えば特願昭６３−１８０４１７号に開示されている
。The 1,4-dihydropyridine derivative obtained after carrying out such a reaction can be made more pure by further isolation and purification. Details of this purification method are disclosed, for example, in Japanese Patent Application No. 180417/1983.
（５）実施例 以下、実施例をもって本発明を具体的に説明する。(5) Examples The present invention will be specifically explained below with reference to Examples.
参考例１
無水ベンゼン（７５ｄ）に（Ｓ） −（−） −１−フ
ェニルエチルアルコール（８，５４ｇ）とトリエチルア
ミン（７，２ｄ）とを溶解し、浴温度７０℃で、ジケテ
ン（７，３＋１１）を滴下し、３０分間加温した。Reference Example 1 Dissolve (S) -(-) -1-phenylethyl alcohol (8.54 g) and triethylamine (7,2 d) in anhydrous benzene (75 d) and dissolve diketene (7,3+11 ) was added dropwise and heated for 30 minutes.
エーテルを加え、ＩＮＨα（５ｄ）、飽和食塩水で洗浄
後、ＨｇＳＯ４で乾燥し、溶媒を減圧下に留去し、残留
物をシリカゲルカラムクロマトグラフィーに付し、ヘキ
サン−酢酸エチル（９：１）で溶出される両分を集める
と、目的物のアセト酢酸（Ｓ）−１−フェニルエチル（
１４０（１１）が得られた［ｂｐ ８０’ （０，
４５ｍｍ１ｇ） 、 ［α］、 −８４，４° （Ｃ
＝１．ＯＯ，エタノール）］。After adding ether and washing with INHα (5d) and saturated brine, drying with HgSO4, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and purified with hexane-ethyl acetate (9:1). Collecting both eluted fractions yields the target product (S)-1-phenylethyl acetoacetate (
140 (11) was obtained [bp 80' (0,
45mm1g), [α], -84,4° (C
=1. OO, ethanol)].
（ｑられたアセト酢酸（Ｓ）−１−フェニルエチル（５
，４２ｇ）とＬ−バリンｔ−ブチルエステル（５，０１
ｇ）とを混合し室温下で一夜攪拌した。次いでベンゼン
（２０ｄ）を加えてＨｇＳＯ４で乾燥後、溶媒を宙去し
た。残留物をシリカゲルカラムクロマトグラフィーに付
し、ｎ−へキサンと酢酸エチルの混液で溶出される両分
を集めると目的とする無色油状の３− （（Ｓ）−１−
ｔ−ブトキシカルボニル−２−メチルプロピルアミノ）
クロトンＭ（Ｓ）−１−フェニルエチル（９，３５ｇ、
収率９８％）が得られた。このものの物性値は以下のと
おり。(q) acetoacetate (S)-1-phenylethyl (5
, 42g) and L-valine t-butyl ester (5,01
g) and stirred overnight at room temperature. Next, benzene (20d) was added, and after drying with HgSO4, the solvent was evaporated. The residue was subjected to silica gel column chromatography, and both fractions eluted with a mixture of n-hexane and ethyl acetate were collected to yield the desired colorless oily 3-((S)-1-
t-butoxycarbonyl-2-methylpropylamino)
Croton M(S)-1-phenylethyl (9.35g,
A yield of 98%) was obtained. The physical properties of this material are as follows.
’Ｈ−ＮＭＲδＩ）ｌ）Ｉｆｆ （ＣＤＣ２３） ：１
．００（ｄ、６Ｈ，Ｊ＝４．４）、 １．４１（Ｓ、９
旧。'H-NMRδI)l)Iff (CDC23): 1
．． 00 (d, 6H, J=4.4), 1.41 (S, 9
Old.
１．５１（ｄ、３Ｈ，Ｊ＝６．６）、 １．８５（Ｓ
、３Ｎ）。1.51 (d, 3H, J=6.6), 1.85 (S
, 3N).
２．１５（ｍ、ＩＨ）、 ３．７３（ｄｄ、１Ｎ、Ｊ＝
９．７． Ｊ＝５．９）。2.15 (m, IH), 3.73 (dd, 1N, J=
9.7. J=5.9).
４．５１３（Ｓ、ｌ１１）、 ５．９３（Ｑ、ＩＨ，Ｊ
＝６．６）。4.513 (S, l11), 5.93 (Q, IH, J
=6.6).
７．２−７．５（ｍ、５Ｈ）、 ８．７８（ｄ、１Ｎ、
Ｊ＝９．７）。7.2-7.5 (m, 5H), 8.78 (d, 1N,
J=9.7).
ｅａｔ
ＩＲν Ｃｍ’ ：
光ル×
３０００、 １７４０． １６６０． １６１０． １
２Ｂ０． １１４０゜参考例２
Ｌ−バリン−１−ブチルエステル（１，９２（１）とア
セト酢酸 （Ｒ）−１−フェニルエチル（２，２８ｇ）
とを混合し、室温下で一夜攪拌した。ベンゼン（１０ｄ
）を加えて、Ｈ（１３０４で乾燥後、溶媒を減圧留去し
、残留物をエタノールから再結晶して、無色柱状晶の３
− （（Ｓ）−１−ｔ−ブトキシカルボニル−２−メチ
ルプロピルアミノ）クロトン酸（Ｒ）−１−フェニルエ
チル（３，０８Ｑ 、収率７８％）が得られた。物性値
は以下のとおり。eat IRν Cm': light x 3000, 1740. 1660. 1610. 1
2B0. 1140° Reference Example 2 L-valine-1-butyl ester (1,92(1) and (R)-1-phenylethyl acetoacetate (2,28 g)
and stirred overnight at room temperature. Benzene (10d
) and dried with H (1304), the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 3 colorless columnar crystals.
-(R)-1-phenylethyl ((S)-1-t-butoxycarbonyl-2-methylpropylamino)crotonate (3,08Q, yield 78%) was obtained. The physical property values are as follows.
ｍ、ｐ、 ５９℃（エタノール）
１Ｈ−ＮＭＲ６ｐｐｍ （ＣＤｃｉ２３） ：０、９８
（ｄ、 ６１１． Ｊ＝６．８）、 １．４７（Ｓ、
９１）。m, p, 59°C (ethanol) 1H-NMR6ppm (CDci23): 0,98
(d, 611. J=6.8), 1.47 (S,
91).
１．５２（ｄ、３Ｈ，Ｊ＝６．８）、 １．８５（Ｓ
、３Ｈ）。1.52 (d, 3H, J=6.8), 1.85 (S
, 3H).
２．１８（ｍ、ＩＨ）、 ３．７４（ｄｄ、１Ｈ，Ｊ＝
９．７． Ｊ＝５．７）。2.18 (m, IH), 3.74 (dd, 1H, J=
9.7. J=5.7).
４．５８（Ｓ、ＩＨ）、 ５．９４（Ｑ、ＩＨ，Ｊ＝６
．８）。4.58 (S, IH), 5.94 (Q, IH, J=6
．． 8).
７゜２−７．５（ｍ、５Ｈ）、 ８゜８（ｄ、 １Ｈ，
Ｊ＝１０）。7゜2-7.5 (m, 5H), 8゜8 (d, 1H,
J=10).
Ｂｒ
ＩＲν ｃｎｒｌ ：
η込べ
３０００、 １７３５． １Ｂ６０． １６００． １
２７０． １１４０゜ノ
ｈ
参考例３
参考例４
参考例１と同様にして３− （（Ｒ） −１−ｔ−ブト
キシカルボニル−２−メチルプロピルアミノ）クロトン
酸 （Ｒ１１−フェニルエチルが得られた。物性値は以
下のとおり。Br IRν cnrl: η included 3000, 1735. 1B60. 1600. 1
270. 1140°h Reference Example 3 Reference Example 4 3-((R)-1-t-butoxycarbonyl-2-methylpropylamino)crotonic acid (R11-phenylethyl) was obtained in the same manner as in Reference Example 1. Physical properties The values are as follows.
［α］２５＋４３．０” （Ｃ＝１．００．エタノー
ル）２−フルオロ−５−二トロベンズアルデヒド（８５
２ｎ＋ａ）とアセト酢酸メチル（６０３ｍｇ ）をトル
エン＜５ｄ＞に溶解し、メタンスルホン酸（７００ｍｇ
）を加えて、０℃で２時間攪拌した。水（５ｄ）を加え
析出した結晶をン戸取し、得られた結晶を水、ｎ−ヘキ
サンで順次洗浄した後乾燥し、目的とする（Ｚ）−２−
（２−フルオロ−５−二トロペンジリデン）アセト酢酸
メチルＢ１４ｍｇ 、収率５３％〉が１９られた。物性
値は以下のとおり。[α]25+43.0” (C=1.00.ethanol) 2-fluoro-5-nitrobenzaldehyde (85
2n+a) and methyl acetoacetate (603mg) were dissolved in toluene <5d>, and methanesulfonic acid (700mg
) and stirred at 0°C for 2 hours. Add water (5d) and collect the precipitated crystals, wash the obtained crystals sequentially with water and n-hexane, and then dry to obtain the desired (Z)-2-
Methyl (2-fluoro-5-nitropenzylidene) acetoacetate B (14 mg, yield 53%) was obtained. The physical property values are as follows.
ｍ、ｐ、 １０９°−１１０” （酢酸エチル）１Ｈ
−ＮＭＲδｐｉ）ｍ （ＣＤ（ｆｆ１３） ：２．４６
（Ｓ、３８）、 ３．８９（Ｓ、３Ｈ）。m, p, 109°-110” (ethyl acetate) 1H
-NMRδpi)m (CD(ff13): 2.46
(S, 38), 3.89 (S, 3H).
７．２９（ｄｄ、ｉｔｌ、Ｊ＝９． Ｊ＝８）、 ７．
６７（ｓ、ｌｔり。7.29 (dd, itl, J=9. J=8), 7.
67(s,ltri.
８．２−８．４（０１，２Ｈ）。8.2-8.4 (01, 2H).
ＩＲシ志Ｃｍ−１ ：
１７３６、 １６５６． １５３２． １３５２． １
２５２゜Ｘ線結晶構造解析により７体であることが確定
された。IR Shishi Cm-1: 1736, 1656. 1532. 1352. 1
Seven bodies were confirmed by 252° X-ray crystal structure analysis.
Ｏ２
００２ＣＨ３
（７体）
参考例５
ヱ旦Σ肛剪久工四
Ｏ−ニトロベンズアルデヒド（５，０ｇ）とアセト酢酸
メチル（５，５ｇ）をベンゼン（３０ｍｆｆｉ）に溶解
し、酢酸（０，５ｒｆＪｌ）ピペリジン（０，５ｍ）を
加え室温下−夜攪拌した。析出した沈澱を塩化メチレン
（１５０ｄ＞に溶解し、飽和炭酸水素ナトリウム。O2 002CH3 (7 bodies) Reference example 5 O-nitrobenzaldehyde (5.0g) and methyl acetoacetate (5.5g) were dissolved in benzene (30mffi), and acetic acid (0.5rfJl) was dissolved. Piperidine (0.5m) was added and the mixture was stirred at room temperature overnight. The precipitate was dissolved in methylene chloride (150 ml) and saturated sodium bicarbonate.
ＩＮ ＮａＯＨ水溶液、水で順次洗浄し、Ｈ！ＪＳＯ
４で乾燥、溶媒を留去し、得られた結晶をアセトンより
２回再結晶すると（Ｚ）−２−（３−ニトロベンジリデ
ン）アセト酢酸メチル（５，７８ｇ、収率７０．３％）
が得られた。Washed with IN NaOH aqueous solution and water sequentially, and H! J.S.O.
4, the solvent was distilled off, and the obtained crystals were recrystallized twice from acetone to give methyl (Z)-2-(3-nitrobenzylidene)acetoacetate (5.78 g, yield 70.3%).
was gotten.
再結晶母液をシリカゲルカラムクロマトグラフィーに付
し、ｎ−ヘキサン−酢酸エチルより溶出される両分を集
めると（Ｅ）−２−（３−ニトロベンジリデン）アセト
酢酸メチル（１７２ｍｇ）が得られた。物性値は下記の
とおり。The recrystallized mother liquor was subjected to silica gel column chromatography, and both fractions eluted from n-hexane-ethyl acetate were collected to obtain methyl (E)-2-(3-nitrobenzylidene)acetoacetate (172 mg). The physical property values are as follows.
ＣＺ） −２−（３−ニトロベンジリデン）アセト酢酸
メチル
ｍ、ｐ、 １５３〜１５４℃（アセトン）１Ｈ−ＮＭＲ
６ｐｐＩＩＩ （ＣＤＣＪｈ ） ：２．４５（Ｓ、３
Ｎ）、 ３．８９（Ｓ、３Ｈ）。CZ) -2-(3-nitrobenzylidene)methyl acetoacetate m, p, 153-154°C (acetone) 1H-NMR
6ppIII (CDCJh): 2.45 (S, 3
N), 3.89 (S, 3H).
７．６（）（Ｓ、１旧、 ７．５−７．８（ｍ、２Ｍ）
。7.6 () (S, 1 old, 7.5-7.8 (m, 2M)
.
８、２−８．３５ （ｍ、 ２Ｈ）。8, 2-8.35 (m, 2H).
ＣＯｚ ＣＨ３
（７体）
（Ｅ）−２−（３−ニトロベンジリデン）アセト酢酸メ
チル
ｍ、ｐ、 １７〜７８℃（アセトン）
１ＨＮＭＲ６９１）ｍ （ＣＤＣＪｈ ） ：２．３８
（ｓ、３Ｈ）、 ３．８９（ｓ、３Ｈ）。COz CH3 (7 bodies) (E)-2-(3-nitrobenzylidene) methyl acetoacetate m, p, 17-78°C (acetone) 1HNMR691) m (CDCJh): 2.38
(s, 3H), 3.89 (s, 3H).
７．６９（Ｓ、ｉＨ）、 ７．４−７．８（Ｉｌｌ、２
＋１）。7.69 (S, iH), 7.4-7.8 (Ill, 2
+1).
８、２−８．３（１１１，２８）。8, 2-8.3 (111, 28).
実施例１
４Ｒ−２，６−シメチルー４−２−フルオロ−５ニトロ
フエニル）−１４−ジヒ゛ロピリジンー３．５−ジカル
ボン酸メチル （Ｓ）−１−フェニルエチル
３−（（Ｓ）−１−ｔ−ブトキシカルボニル−２−メチ
ルプロピルアミノ）クロトンＭ（Ｓ）−１−フェニルエ
チル（１６，９７ｇ）を乾燥したＴＨＦ（８０７りに溶
解し、反応液を一７８℃に冷却し、これにリチウムジイ
ソプロピルアミド（ＬＤＡ）（１，２当量）を添加した
。１時間攪拌した後、（Ｚ）−２−（２−フルオロ−５
−ニトロベンジリデン）アセト酢酸メチル（１２，５５
（１）の乾燥ＴＨＦ溶液（１００ｄ）をゆっくり滴下し
た。この温度で３時間攪拌後、ＩＮ Ｈα（１２０ｍ
）を加えて室温にもどした。有機層と分離し、２Ｎ
）（（ｆｆｌ（１２０ｒｊ！！りを加えて室温で一夜攪
拌後、ベンゼンで抽出し、抽出液を乾燥し、溶媒を留去
し、得られた橙色の残留物をエタノール（２００ｄ＞に
溶かし、酢酸アンモニウム（１８，１！７）を加えて室
温下で３時間攪拌した。溶媒を留去し、残留物を酢酸エ
チルに溶かし、飽和炭酸水素ナトリウム、水で順次洗浄
し、ＭｇＳＯ４で乾燥後、溶媒を留去した。Example 1 Methyl 4R-2,6-dimethyl-4-2-fluoro-5nitrophenyl)-14-dihydropyridine-3,5-dicarboxylate (S)-1-phenylethyl 3-((S)-1-t-butoxy Carbonyl-2-methylpropylamino)croton M(S)-1-phenylethyl (16.97 g) was dissolved in dry THF (807 g), the reaction mixture was cooled to -78°C, and lithium diisopropylamide ( LDA) (1,2 eq.) was added. After stirring for 1 hour, (Z)-2-(2-fluoro-5
-nitrobenzylidene)methyl acetoacetate (12,55
A dry THF solution (100d) of (1) was slowly added dropwise. After stirring at this temperature for 3 hours, IN Hα (120 m
) and allowed to return to room temperature. Separate the organic layer and add 2N
)((ffl(120rj!!) was added and stirred overnight at room temperature, then extracted with benzene, the extract was dried, the solvent was distilled off, and the resulting orange residue was dissolved in ethanol (200d>). Ammonium acetate (18,1!7) was added and stirred at room temperature for 3 hours. The solvent was distilled off, the residue was dissolved in ethyl acetate, washed successively with saturated sodium bicarbonate and water, and dried over MgSO4. The solvent was distilled off.
残留物をシリカゲルカラムクロマトグラフィーに付し、
ｎ−ヘキサン−酢酸エチル混液で溶出される両分を集め
ると、目的とする２、６−シメチルー４−（２−フルオ
ロ−５−ニトロフェニル）−１゜４−ジヒドロピリジン
−３，５−ジカルボン酸メチル （Ｓ）−１−フェニル
エチルのジアステレオマーの混合物（１Ｂ、７ａ 、収
率７１．２％）が得られた。The residue was subjected to silica gel column chromatography,
When both fractions eluted with a mixture of n-hexane and ethyl acetate are collected, the desired 2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1°4-dihydropyridine-3,5-dicarboxylic acid is obtained. A mixture of diastereomers of methyl (S)-1-phenylethyl (1B, 7a, 71.2% yield) was obtained.
ＬｉＣｈｒＯ３Ｏｒｂｏｓｉ６０をカラムとしてＨＰＬ
Ｃにて分析した（ｎ−ベキサン：イソプロピルアルコー
ル＝１９：’ｌ）。その結果このジアステレオマー混合
物は（４Ｒ−３）体が主成分で微量の（４３−３）体が
含まれており９２６９％ｄ、 ｅ、であった。更に得ら
れた目的物を酢酸エチル−ヘキサンから１回再結晶して
ＨＰＬＣで完全に単一のピークを示す（４Ｒ）−２゜６
−シメチルー４−（２−フルオロ−５−二トロフェニル
）−１，４−ジヒドロピリジン−３，５−ジカルボン酸
メチル （Ｓ）−１−フェニルエチル得られた。このも
のの物性値は以下のとおり。HPL using LiChrO3Orbosi60 as a column
(n-bexane:isopropyl alcohol=19:'l). As a result, this diastereomer mixture contained the (4R-3) isomer as a main component and a trace amount of the (43-3) isomer, and was 9269% d, e. Furthermore, the obtained target product was recrystallized once from ethyl acetate-hexane and showed a completely single peak on HPLC (4R)-2゜6.
-Simethyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl (S)-1-phenylethyl was obtained. The physical properties of this material are as follows.
−、１）、 １４７−１４９’″
［α］Ｄ＋１６６° ｃｃ＝ｉ，ｏｏ，エタノール）１
Ｈ−ＮＭＲ６ｐｌ）ｍ （ＣＤＣＲ．＋ ） ：１、５
４（ｄ，３）１，Ｊ＝６．６）、 ２．３１（Ｓ，３Ｈ
）。-, 1), 147-149''' [α]D+166° cc=i, oo, ethanol) 1
H-NMR6pl)m (CDCR.+): 1, 5
4(d,3)1, J=6.6), 2.31(S,3H
).
２、３４（Ｓ，３Ｈ）、 ３．６２（Ｓ，３１１）、
５．３２（Ｓ，ＩＨ）。2, 34 (S, 3H), 3.62 (S, 311),
5.32 (S, IH).
５、８５（Ｑ，１８， Ｊ＝６．６）、 ５．９（Ｓ，
ＩＨ）。5, 85 (Q, 18, J=6.6), 5.9 (S,
IH).
６、９−７．３（Ｉｌｌ，６旧， ７．９−８．２（ｍ
，２Ｈ）。6, 9-7.3 (Ill, 6 old, 7.9-8.2 (m
, 2H).
ＩＲ νに８ｒＣＩＩ−１ニ
ヤφボ
３３５０、 １６９５， １６８０， １４９０
， １３４５。IR ν to 8rCII-1 φbo 3350, 1695, 1680, 1490
, 1345.
実施例２
エチル
３− （（Ｓ）−１−ｔ−ブトキシカルボニル−２−メ
チルプロピルアミン）クロトンＭ（Ｒ）−１−フェニル
エチル（７２２ｍｖ）のＴＨＦ溶液を一１８℃に冷却し
、これにＬＤＡ（１．２当量）を加え、１時間攪拌した
後（Ｚ）−２−（２−フルオロ−５−二トロペンジリデ
ン）アセト酸メチル（５３４ｍｇ）のＴＨＦ溶液を加え
、３時間攪拌後、１Ｎ）１０２１１０ｍｊ）を加えて室
温にもどした。有機層を分離し２Ｎ Ｈα（ １０ｄ
）を加えて室温下で一夜攪拌した。Example 2 A THF solution of ethyl 3-((S)-1-t-butoxycarbonyl-2-methylpropylamine)croton M(R)-1-phenylethyl (722mv) was cooled to -18°C and added to it. After adding LDA (1.2 equivalents) and stirring for 1 hour, a THF solution of methyl (Z)-2-(2-fluoro-5-nitropenzylidene)acetoate (534 mg) was added, and after stirring for 3 hours, 1N) 102110mj) was added and the temperature was returned to room temperature. Separate the organic layer and add 2N Hα (10d
) and stirred overnight at room temperature.
実施例１と同様に処理したのち、生成物をエタノールに
溶解し酢酸アンモニウム（７７１ｍｇ）を加えて室温下
で３時間攪拌した。溶媒を留去し、残留物を酢酸エチル
に溶解し、洗浄，乾燥，溶媒を留去し、残留物をシリカ
ゲルカラムクロマトグラフィーに付して、ヘキサン−酢
酸エチル混液で溶出される画分を染めると目的とする２
，６−シメチルー４− （２−フルオロ−５−二トロフ
ェニル）−１、４−ジヒドロピリジン−３，５−ジカル
ボン酸メチル （１？）−１−フェニルエチルのジアス
テレオマーの混合物（６９４ｍｇ 、収率６９％）が得
られた。After treatment in the same manner as in Example 1, the product was dissolved in ethanol, ammonium acetate (771 mg) was added, and the mixture was stirred at room temperature for 3 hours. The solvent is distilled off, the residue is dissolved in ethyl acetate, washed, dried, the solvent is distilled off, the residue is subjected to silica gel column chromatography, and the fraction eluted with a hexane-ethyl acetate mixture is stained. and aim 2
,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1?)-1-phenylethyl diastereomer mixture (694 mg, yield 69%) was obtained.
ＨＰＬＣで分析した結果、２つのジアステレオマー （
（４Ｒ−Ｒ）体と（４Ｓ−Ｒ）体）の比は８６．５
： １３．５（７３％ｄ．ｅ、）であった。As a result of HPLC analysis, two diastereomers (
The ratio of (4R-R) body and (4S-R) body) is 86.5
: 13.5 (73% de,).
このジアステレオマーの混合物を酢酸エチル−〇ーヘキ
サンより再結晶して（４Ｒ）−２．６−シメチルー４−
（２−フルオロ−５−ニトロフェニル）−１，４−ジ
ヒドロピリジン−３，５−ジカルボン酸メチル （Ｒ）
−１−フェニルエチルが１ｑられた。This diastereomer mixture was recrystallized from ethyl acetate-〇-hexane and (4R)-2,6-dimethyl-4-
Methyl (2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (R)
1q of -1-phenylethyl was obtained.
物性値は以下のとおり。The physical property values are as follows.
ｍ．９． １７０−１７２℃
’！ー１ーＮＭＲδｐｐｍ （ＣＤＣＲ３） ：１、３
４（ｄ，３Ｈ，Ｊ＝６．６）、 ２．３１（Ｓ，６１）
。m. 9. 170-172℃'! -1-NMRδppm (CDCR3): 1, 3
4 (d, 3H, J=6.6), 2.31 (S, 61)
.
３Ｊ３（Ｓ，３Ｈ）、 ５．３７（Ｓ，１旧， ５．８
（Ｑ，１Ｈ，Ｊ＝６．６）。3J3 (S, 3H), 5.37 (S, 1 old, 5.8
(Q, 1H, J=6.6).
５、９（ｓ，ＩＨ）、 ７．０−７．３（ｍ，６Ｈ）、
８．２−８．３（ｍ，２旧。5, 9 (s, IH), 7.0-7.3 (m, 6H),
8.2-8.3 (m, 2 old.
ＩＲ シＫＢ’ｃｍー１ ニ
ジいグ
３３Ｂ０， １γ１０， １６９０， １４９０
， １３５０。IR ShiKB'cm-1 Nijiig33B0, 1γ10, 1690, 1490
, 1350.
Ｏｚ
Ｈ
実施例３
３− （（Ｓ） −１−ｔ−ブトキシカルボニル−２−
メチルプロピルアミノ）クロトン酸 （Ｓ）−’１−フ
ェニルエチル（３６０ｍａ）と（Ｚ）−２−（３−ニト
ロベンジリデン）アセト酢酸メチル（２４９ｍｇ）をＬ
ＤＡ （１，２当量）存在下ＴＨＥ溶液中−７８℃で３
時間攪拌した。次いで２Ｎ Ｈαを加えて室温下、処
理し、得られた生成物をエタノール中酢酸アンモニウム
（３８５ｍａ）と室温下３時間攪拌した。Oz H Example 3 3- ((S) -1-t-butoxycarbonyl-2-
Methylpropylamino)crotonic acid (S)-'1-phenylethyl (360ma) and methyl (Z)-2-(3-nitrobenzylidene)acetoacetate (249mg) in L
3 at −78 °C in THE solution in the presence of DA (1,2 eq.)
Stir for hours. 2N Hα was then added and treated at room temperature, and the resulting product was stirred with ammonium acetate (385 ma) in ethanol at room temperature for 3 hours.
生成物をシリカゲルカラムクロマトグラフィーに付し、
目的とする２、６−シメチルー４−（３−二トロフェニ
ル）−１，４−ジヒドロピリジン−３，５−ジカルボン
酸メチル （Ｓ）−１−フェニルエチル（３ｔｉｍｇ、
収率７１％）のジアステレオマー（（４Ｒ・Ｓ）体と（
４Ｓ−３）体）の混合物が得られた。The product was subjected to silica gel column chromatography,
Target methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (S)-1-phenylethyl (3timg,
(yield 71%) diastereomer ((4R・S) body and (
A mixture of 4S-3) was obtained.
’Ｈ−ＮＭＲ（ＣＤα３）における（Ｓ）−１−フェニ
ルエチル基のメチルピーク（（４Ｒ−３）体δ１．５４
（４Ｓ−Ｓ）体δ１．４０）の積分によりその比を求
めると、９３．６：６．４ （８７％ｄ、ｅ、） テ
アッた。コノ混合物をエタノールから再結晶するとＮＭ
Ｒ的に純粋で、ＨＰＬＣで単一のピークを示す（４Ｒ）
−２゜６−シメチルー４−（３−ニトロフェニル）−１
゜４−ジヒドロピリジン−３，５−ジカルボン酸メチル
（Ｓ）−１−フェニルエチルが得られた。そのものの
物性値は下記のとおり。'H-NMR (CDα3) methyl peak of (S)-1-phenylethyl group ((4R-3) form δ1.54
When the ratio was determined by integrating the (4S-S) body δ1.40), it was 93.6:6.4 (87% d, e,). When the mixture is recrystallized from ethanol, NM
R-pure, showing a single peak on HPLC (4R)
-2゜6-dimethyl-4-(3-nitrophenyl)-1
゜Methyl (S)-1-phenylethyl 4-dihydropyridine-3,5-dicarboxylate was obtained. Its physical properties are as follows.
ｍ、ｐ、 １５６−１５７℃（エタノール）ｆα］、＋
１２３° （Ｃ＝１．ＯＯ，メタノール）１Ｈ−ＮＭＲ
（ＣＤＧ３ ）δｐｐｍ ：１．５４（ｄ、３Ｈ，Ｊ＝
６．５）、 ２．３３（ｓ、３Ｈ）。m, p, 156-157℃ (ethanol) fα], +
123° (C=1.OO, methanol) 1H-NMR
(CDG3) δppm: 1.54 (d, 3H, J=
6.5), 2.33(s, 3H).
２．３７（Ｓ、３Ｎ）、 ３．６５（Ｓ、３Ｎ）。2.37 (S, 3N), 3.65 (S, 3N).
５、１２（ｓ、 １旧、 ５．７１（ｂｓ、１旧。5, 12 (s, 1 old, 5.71 (bs, 1 old.
５．８０（Ｑ、ＩＨ，Ｊ＝６．５）、 ６．９−７．３
（ｍ、６１１）。5.80 (Q, IH, J=6.5), 6.9-7.3
(m, 611).
７．５３（ｄ、ｌｔｌ、 Ｊ＝７）、 ７．８−８．１
（ｍ、２旧。7.53 (d, ltl, J=7), 7.8-8.1
(m, 2 old.
ＩＲｖＫＢ’ｃｍ−１：
ｒＡグ
３３４０、１６７５．１５３０．１４９５．１３５０．
１２２０゜実施例４
３− （（Ｓ）−１−ｔ−ブトキシカルボニル−２−メ
チルプロピルアミン）クロトンＩ（Ｒ）−ｉ−フェニル
エチル（７２２ｍａ）と（Ｚ）−２−（３−ニトロベン
ジリデン）アセト酢酸メチル（４９８ｍａ）をＬＤＡ（
１，２当量）の存在下ＴＨＦ中で一１８℃で３時間攪拌
した。次いでＩＮ ）（（ｌｆｔ（６ｄ）を加えて室
温下処理し、得られた生成物をエタノール中で酢酸アン
モニウム（７７１ｍｇ）と室温下３時間攪拌した。生成
物をシリカゲルカラムクロマトグラフィーに付し、目的
とする２、６−シメチルー４−（３−ニトロフェニル）
−１，４−ジヒドロピリジン−３，５−ジカルボン酸メ
チル （Ｒ）−１−フェニルエチル（６０２ｍｇ、収率
６９％）のジアステレオマー（（４Ｒ−Ｒ）体と（４８
−Ｒ）休）の混合物が得られた。’Ｈ−ＮＭＲによる分
析の結果、その比（（４Ｒ−Ｒ）体： （４３−Ｒ）体
）は７６．２ ： ２３．８ （５２％ｄ、ｅ、）であ
った。IRvKB'cm-1: rAg3340, 1675.1530.1495.1350.
1220° Example 4 3-((S)-1-t-butoxycarbonyl-2-methylpropylamine)croton I(R)-i-phenylethyl (722ma) and (Z)-2-(3-nitrobenzylidene) ) Methyl acetoacetate (498ma) was converted into LDA (
The mixture was stirred for 3 hours at -18° C. in THF in the presence of 1.2 equivalents). Then, IN )((lft (6d) was added and treated at room temperature, and the obtained product was stirred in ethanol with ammonium acetate (771 mg) at room temperature for 3 hours. The product was subjected to silica gel column chromatography, Target 2,6-dimethyl-4-(3-nitrophenyl)
Methyl -1,4-dihydropyridine-3,5-dicarboxylate (R)-1-phenylethyl (602 mg, yield 69%) diastereomers ((4R-R) and (48
-R) mixture was obtained. As a result of 'H-NMR analysis, the ratio ((4R-R) form: (43-R) form) was 76.2:23.8 (52% d, e,).
このものをエタノールより再結晶すると１Ｈ−ＮＭＲで
純粋でありＨＬＰＣで単一のピークを示す（４Ｒ）−２
，６−シメチルー４−（３−ニトロフェニル）−１，４
−ジヒドロピリジン−３，５−ジカルボン酸メチル （
Ｒ）−１−フェニルエチルが得られた。そのものの物性
値は下記のとおり。When this product is recrystallized from ethanol, it is pure in 1H-NMR and shows a single peak in HLPC (4R)-2
,6-dimethyl-4-(3-nitrophenyl)-1,4
-Methyl dihydropyridine-3,5-dicarboxylate (
R)-1-phenylethyl was obtained. Its physical properties are as follows.
１日−ＮＭＲ（ＣＤＣＪ２３ ＞ δｐｐｎ ：１．
４０（ｄ、３Ｈ，Ｊ＝６．６）、 ２．３４（Ｓ、６Ｈ
）。1 day - NMR (CDCJ23 > δppn: 1.
40 (d, 3H, J=6.6), 2.34 (S, 6H
).
３．６４（Ｓ、３Ｈ）、 ５．１４（Ｓ、１８）。3.64 (S, 3H), 5.14 (S, 18).
５．８１（ｂｓ、１旧、 ５．８４（Ｑ、ＩＨＪ＝６．
６）。5.81 (BS, 1 old, 5.84 (Q, IHJ=6.
6).
７．２−７゜５（ｍ、６Ｈ）、７．６５（ｄ、ＩＨ，Ｊ
・７．７）。7.2-7゜5 (m, 6H), 7.65 (d, IH, J
・7.7).
８．０２（ｄ、ＩＨ，Ｊ＝６．６）、 ８．１４（ｓ、
１Ｎ）。8.02 (d, IH, J=6.6), 8.14 (s,
1N).
Ｏ２
実施例５
３−（（Ｓ）−１−ｔ−ブトキシカルボニル−２−メチ
ルプロピルアミノ）クロトン酸（Ｓ）−１−フェニルエ
チル（１８０ｍｇ）と（Ｅ）−２−（３−ニトロベンジ
リデン）アセト酢酸メチル（１２５ｍｇ）をＬＤＡ（１
，２当量）の存在下ＴＨＦ中で一７８℃で３時間攪拌し
た。次いで１Ｎ ＨＣ２（６ｒｄ）を加えて室温下処理
し、得られた生成物をエタノール中で酢酸アンモニウム
（１９２ｍｇ）と室温下３時間攪拌した。生成物をシリ
カゲルカラムクロマトグラフィーに付し、目的とする２
、６−シメチルー４−（３−ニトロフェニル）−１，４
−ジヒドロピリジン−３，５−ジカルボン酸メチル （
Ｓ）−１−フェニルエチル（ｔ６９ｍｇ 、収率７７．
８％）のジアステレオマーの混合物が得られた。’Ｈ−
ＮＭＲによる分析の結果、（４Ｒ−３）体と（４３−３
）体）の比は９１．８：８．２ （８３，６％ｄ、ｅ
、） テあった。O2 Example 5 (S)-1-phenylethyl 3-((S)-1-t-butoxycarbonyl-2-methylpropylamino)crotonate (180 mg) and (E)-2-(3-nitrobenzylidene) Methyl acetoacetate (125 mg) was dissolved in LDA (1
, 2 equivalents) in THF at -78°C for 3 hours. Then, 1N HC2 (6rd) was added and treated at room temperature, and the obtained product was stirred in ethanol with ammonium acetate (192 mg) at room temperature for 3 hours. The product was subjected to silica gel column chromatography to obtain the desired 2
, 6-dimethyl-4-(3-nitrophenyl)-1,4
-Methyl dihydropyridine-3,5-dicarboxylate (
S)-1-phenylethyl (t69mg, yield 77.
A mixture of diastereomers (8%) was obtained. 'H-
As a result of NMR analysis, (4R-3) and (43-3)
) body) ratio is 91.8:8.2 (83.6%d, e
,) There was te.
このものをエタノールから再結晶すると、１日−ＮＭＲ
で純粋でありＨＬＰＧで単一のピークを示す（４Ｒ）−
２，６−シメチルー４−（３−ニトロフェニル）−１，
４−ジヒドロピリジン−３，５−ジカルボン酸メチル
（Ｓ）−１−フェニルエチルが得られ、このものは、実
施例３の化合物と同じ物性値を示した。When this product is recrystallized from ethanol, 1 day-NMR
(4R)- is pure and shows a single peak in HLPG.
2,6-dimethyl-4-(3-nitrophenyl)-1,
Methyl 4-dihydropyridine-3,5-dicarboxylate
(S)-1-phenylethyl was obtained, which showed the same physical properties as the compound of Example 3.
実施例６
３−（（Ｓ）−１−１−ブトキシカルボニル−メヂルプ
ロビルアミノ）クロトンｉｌｆ（Ｒ）−１−フェニルエ
チル（１８０ｍｏ）と（Ｅ）−２−（３−ニトロベンジ
リデン）アセト酢酸メチル（１２５ｍｏ）をＬＤＡ （
１。２当量）の存在下、ＴＨＦ中で一７８℃で３時間攪
拌した。次いでＩＮ ＋−（Ｃｆ２（５ｄ＞を加えて
室温下処理し、生成物をエタノール中で酢酸アンモニウ
ム（１９２ｍｇ）と室温下３時間攪拌した。Example 6 3-((S)-1-1-butoxycarbonyl-medylpropylamino)croton ilf(R)-1-phenylethyl (180 mo) and (E)-2-(3-nitrobenzylidene)acetate Methyl acetate (125mo) was converted into LDA (
1.2 equivalents) in THF at -78°C for 3 hours. IN+-(Cf2(5d) was then added and treated at room temperature, and the product was stirred with ammonium acetate (192 mg) in ethanol at room temperature for 3 hours.
生成物をシリカゲルカラムクロマトグラフィーに付し、
目的とする２，６−シメチルー４−（３−二トロフェニ
ル）−１．４−ジヒドロピリジン−３．５−ジカルボン
酸メチル （Ｒｉｌ−フェニルエチル（１４２ｍｇ，収
率６５。１％）のジアステレオマーの混合物が得られた
。１Ｈ−ＮＭＲによる分析の結果、（４Ｒ−Ｒ）体と（
４３−Ｒ）体）の比はａｉ．ｏ ： １９．０（６２％
ｄ．ｅ．）であった。The product was subjected to silica gel column chromatography,
Target diastereomer of methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Ril-phenylethyl (142 mg, yield 65.1%) A mixture of (4R-R) and (
The ratio of 43-R) is ai. o: 19.0 (62%
d. e. )Met.
このものをエタノールから再結晶すると、（４Ｒ）−２
．６−シメチルー４−（３−ニトロフェニル）−１，４
−ジヒドロピリジン−３，５−ジカルボン酸メチル （
Ｒ）−１−フェニルエチルが得られ、このものは実施例
４と一致した。When this product is recrystallized from ethanol, (4R)-2
．． 6-Simethyl-4-(3-nitrophenyl)-1,4
-Methyl dihydropyridine-3,5-dicarboxylate (
R)-1-phenylethyl was obtained, which was consistent with Example 4.
実施例７
エチル
３−（（Ｒ）−１ − ｔ−ブトキシカルボニル−メチ
ルプロピルアミノ）クロトン酸（Ｒ）−１−フェニルエ
チル（１８０ｍｇ）と（Ｚ） −２− （２−フルオロ
−５−ニトロベンジリデン）アセト酢酸メチル（１３５
ｍｇ）をＬＤＡ（１．２当量）とをＴＨＦ中で一７８℃
で攪拌し、次いで１Ｎ ＨＣｕ（５ｄ）を加えて室温
下処理し、生成物をエタノール中で室温下、酢酸アンモ
ニウム（１９３ｍｇ）と攪拌した。生成物をシリカゲル
カラムクロマトグラフィーに付し、目的とする２、６−
シメチルー４−（２−フルオロ−５−ニトロフェニル）
−１，４−ジヒドロピリジン−３，５−ジカルボン酸メ
チル （Ｒ）−１−フェニルエチル（１６０１１１ｇ）
のジアステレオマーの混合物が得られた。）−ＩＰＬＣ
で分析した結果、（４Ｓ・Ｒ）体がほとんどで微量の（
４Ｒ−Ｒ）体が含まれていた（９３％ｄ、ｅ、）このも
のを酢酸エチル−ｎ−ヘキザン再結晶するとＨＰＬＣで
単一のピークを示す（４Ｓ）−２，６−シメチルー４−
（２−フルオロ−５ニトロフエニル）−１，４−ジヒド
ロピリジン−３，５−ジカルボン酸メチル （Ｒ）−１
−フェニルエチルが得られた。このものの物性値は下記
のとおり。Example 7 (R)-1-phenylethyl ethyl 3-((R)-1-t-butoxycarbonyl-methylpropylamino)crotonate (180 mg) and (Z)-2-(2-fluoro-5-nitro benzylidene) methyl acetoacetate (135
mg) and LDA (1.2 eq.) in THF at -78°C.
and then treated with 1N HCu (5d) at room temperature, and the product was stirred with ammonium acetate (193 mg) in ethanol at room temperature. The product was subjected to silica gel column chromatography to obtain the desired 2,6-
Cymethyl-4-(2-fluoro-5-nitrophenyl)
Methyl -1,4-dihydropyridine-3,5-dicarboxylate (R)-1-phenylethyl (160111g)
A mixture of diastereomers was obtained. )-IPLC
As a result of analysis with
When this product containing 4R-R) form (93% d, e,) was recrystallized from ethyl acetate-n-hexane, it showed a single peak on HPLC (4S)-2,6-dimethyl-4-
(2-Fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl (R)-1
-Phenylethyl was obtained. The physical properties of this product are as follows.
ｍ、ｐ、 １４７−１４９℃
’ｌ−１−ＮＭｌ−１−Ｎ （ＣＤα３）＝１．５４（
ｄ、Ｊ＝６．６．３８＞、 ２．３１（Ｓ、３）１）。m, p, 147-149℃'l-1-NMl-1-N (CDα3) = 1.54 (
d, J=6.6.38>, 2.31(S,3)1).
２．３４（Ｓ、３Ｈ）、 ３．６２（Ｓ、３Ｈ）。2.34 (S, 3H), 3.62 (S, 3H).
５．３２（Ｓ、ＩＮ）、 ５．８５（Ｑ、Ｊ＝６．６．
１旧。5.32 (S, IN), 5.85 (Q, J=6.6.
1 old.
５．９（ｓ、１Ｍ）、 ６．９−７．３（ｍ、６０）。5.9 (s, 1M), 6.9-7.3 (m, 60).
７、７−８．２ （ｍ、 ２旧。7, 7-8.2 (m, 2 old.
ＩＲシＫＢ’ｃｍ−１ ：
慎ルに
３３５０、１６９５．１＆８０．１４９０．１３４５、
Ｏ２
トｌ
実施例８
３−（（Ｓ）−１−ｔ−ブトキシカルボニル−メチルプ
ロピルアミノ）クロトンｉｍ（Ｓ）−１−７ ｘニルエ
ｆル（３６１ｍｇ）、！＝（Ｚ） − ２−（ ３−ニ
トロベンジリデン）アセト酢酸メチル（２４９１１１０
）とをＬＤＡ（１．２当量）の存在下でＴＨＦ中−１５
℃で３時間攪拌した。２Ｎ Ｈα（５ｄ）を加えて室
温下処理し、得られた生成物をエタノール中で酢酸アン
モニウム（３８５ｍａ）と室温下３時間攪拌した。IR ShiKB'cm-1: Shinru 3350, 1695.1 & 80.1490.1345,
O2 Tol Example 8 3-((S)-1-t-butoxycarbonyl-methylpropylamino)croton im(S)-1-7xNylefl (361 mg),! =(Z)-2-(3-nitrobenzylidene)methyl acetoacetate (2491110
) and -15 in THF in the presence of LDA (1.2 eq.)
The mixture was stirred at ℃ for 3 hours. 2N Hα (5d) was added and treated at room temperature, and the resulting product was stirred in ethanol with ammonium acetate (385 ma) at room temperature for 3 hours.
生成物をシリカゲルカラムクロマトグラフィーに付し、
目的とする２，６−シメチルー４−（３−二トロフェニ
ル）−１．４−ジヒドロピリジン−３，５−ジカルボン
酸メチル （Ｓ）−１−フェニルエチルのジアステレオ
マーの混合物（２８８ｍｇ 、収率６６％）が得られた
。ＮＭＲによる分析の結果、（４Ｒ−Ｓ）と（４３−３
）の比は８５，２ ： １４．８ （７０％ｄ．ｅ．）
であった。The product was subjected to silica gel column chromatography,
Target mixture of diastereomers of methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (S)-1-phenylethyl (288 mg, yield 66%) was obtained. As a result of NMR analysis, (4R-S) and (43-3
) ratio is 85.2:14.8 (70% de.e.)
Met.
Claims (4)
ゲン原子又はニトロ基を表わす。 但し、Ｘ、Ｙ及びＺが同時に水素原子を表わすことはな
い。Ｒ＾１は置換もしくは非置換の低級アルキル基を表
わす。］ で表わされるベンジリデンアセト酢酸エステル誘導体と
下記式［II］ ▲数式、化学式、表等があります▼・・・［II］ 式中Ｒ＾２は下記式 ▲数式、化学式、表等があります▼・・・［II−ａ］ を表わす。Ｒ＾５は低級アルキル基又は低級アルキルオ
キシ基を表わし、Ｒ＾６は置換もしくは非置換のフェニ
ル基を表わす。ｎは０又は１を表わす。Ｒ＾３およびＲ
＾４は低級アルキル基を表わす。＊はキラル中心点を表
わす。 で表わされる光学活性な３−アミノクロトン酸エステル
誘導体とをリチウムアミドの存在下で反応させ、次いで
加水分解し、ひきつづいて、ＮＨ＿４・Ｌ・・・［III
］ ［Ｌは１価の陰イオン基を表わす。］ で表わされるアンモニウム塩と反応させることを特徴と
する下記式［IV］ ▲数式、化学式、表等があります▼・・・［IV］ 〔式中、Ｘ、Ｙ、Ｚ、Ｒ＾１およびＲ＾２、＊は前記式
［ I ］、［II］の定義に同じである。〕 で表わされる光学活性な１，４−ジヒドロピリジン誘導
体の製造方法。(1) The following formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼... [I] In the formula, X, Y, and Z are the same or different and represent a hydrogen atom, a halogen atom, or a nitro group. However, X, Y and Z do not represent hydrogen atoms at the same time. R^1 represents a substituted or unsubstituted lower alkyl group. ] The benzylidene acetoacetate derivative represented by the following formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[II] In the formula, R^2 is the following formula▲There are mathematical formulas, chemical formulas, tables, etc.▼・...represents [II-a]. R^5 represents a lower alkyl group or a lower alkyloxy group, and R^6 represents a substituted or unsubstituted phenyl group. n represents 0 or 1. R^3 and R
^4 represents a lower alkyl group. * represents the chiral center point. The optically active 3-aminocrotonic acid ester derivative represented by
] [L represents a monovalent anionic group. ] The following formula [IV] is characterized by reacting with an ammonium salt represented by ^2, * are the same as the definitions of the above formulas [I] and [II]. ] A method for producing an optically active 1,4-dihydropyridine derivative represented by:
素原子であり、Ｚが水素原子又はフッ素原子である請求
項１記載の製造方法。(2) The manufacturing method according to claim 1, wherein in the above formula [I], X is a nitro group, Y is a hydrogen atom, and Z is a hydrogen atom or a fluorine atom.
５が低級アルキル基である請求項１記載の製造方法。(3) In the above formula [II-a], n is 0 and R^
The manufacturing method according to claim 1, wherein 5 is a lower alkyl group.
であり、Ｒ＾４がｔｅｒｔ−ブチル基である請求項１記
載の製造方法。(4) The manufacturing method according to claim 1, wherein in the above formula [II], R^3 is an isopropyl group and R^4 is a tert-butyl group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3000489A JPH02212474A (en) | 1989-02-10 | 1989-02-10 | Production of optically active 1,4-dihydropyridine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3000489A JPH02212474A (en) | 1989-02-10 | 1989-02-10 | Production of optically active 1,4-dihydropyridine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02212474A true JPH02212474A (en) | 1990-08-23 |
Family
ID=12291749
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3000489A Pending JPH02212474A (en) | 1989-02-10 | 1989-02-10 | Production of optically active 1,4-dihydropyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02212474A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112679416A (en) * | 2020-12-31 | 2021-04-20 | 济南朗科医药技术有限公司 | Preparation method of benidipine hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63208573A (en) * | 1986-10-09 | 1988-08-30 | Fujirebio Inc | Production of optically active 1,4-dihydropyridine derivative |
| JPS6429359A (en) * | 1987-07-24 | 1989-01-31 | Teijin Ltd | 1,4-dihydropyridine derivative and production thereof |
-
1989
- 1989-02-10 JP JP3000489A patent/JPH02212474A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63208573A (en) * | 1986-10-09 | 1988-08-30 | Fujirebio Inc | Production of optically active 1,4-dihydropyridine derivative |
| JPS6429359A (en) * | 1987-07-24 | 1989-01-31 | Teijin Ltd | 1,4-dihydropyridine derivative and production thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112679416A (en) * | 2020-12-31 | 2021-04-20 | 济南朗科医药技术有限公司 | Preparation method of benidipine hydrochloride |
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