CN104768930B - The manufacture method of optical activity bicyclic urea compounds - Google Patents
The manufacture method of optical activity bicyclic urea compounds Download PDFInfo
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- CN104768930B CN104768930B CN201380056395.0A CN201380056395A CN104768930B CN 104768930 B CN104768930 B CN 104768930B CN 201380056395 A CN201380056395 A CN 201380056395A CN 104768930 B CN104768930 B CN 104768930B
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- -1 bicyclic urea compounds Chemical class 0.000 title claims abstract description 59
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 35
- 230000003287 optical Effects 0.000 title claims abstract description 12
- 150000004703 alkoxides Chemical class 0.000 claims abstract description 33
- YGYAWVDWMABLBF-UHFFFAOYSA-N phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229910052751 metal Inorganic materials 0.000 claims abstract description 23
- 239000002184 metal Substances 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 150000001447 alkali salts Chemical class 0.000 claims abstract description 15
- 150000001412 amines Chemical class 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000010936 titanium Substances 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 10
- 239000011777 magnesium Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 229910052782 aluminium Inorganic materials 0.000 claims description 9
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 9
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical group [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 9
- 239000001110 calcium chloride Substances 0.000 claims description 9
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- RTAQQCXQSZGOHL-UHFFFAOYSA-N titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 7
- 229910052719 titanium Inorganic materials 0.000 claims description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- VBJZVLUMGGDVMO-UHFFFAOYSA-N Hafnium Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052735 hafnium Inorganic materials 0.000 claims description 4
- QCWXUUIWCKQGHC-UHFFFAOYSA-N zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052726 zirconium Inorganic materials 0.000 claims description 4
- DTYCRHCCLVCUDT-UHFFFAOYSA-J calcium;magnesium;tetrachloride Chemical compound [Mg+2].[Cl-].[Cl-].[Cl-].[Cl-].[Ca+2] DTYCRHCCLVCUDT-UHFFFAOYSA-J 0.000 claims 4
- 238000005886 esterification reaction Methods 0.000 claims 2
- 150000001263 acyl chlorides Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 239000002253 acid Substances 0.000 abstract description 8
- 239000003513 alkali Substances 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 102000006635 beta-Lactamases Human genes 0.000 abstract description 2
- 108020004256 beta-Lactamases Proteins 0.000 abstract description 2
- 230000002633 protecting Effects 0.000 abstract description 2
- 239000000837 restrainer Substances 0.000 abstract 1
- 239000002585 base Substances 0.000 description 41
- 239000002904 solvent Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000000376 reactant Substances 0.000 description 12
- 238000007792 addition Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 4
- AUHZEENZYGFFBQ-UHFFFAOYSA-N Mesitylene Chemical compound CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 241000534944 Thia Species 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 239000008079 hexane Substances 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKDQKPLMQBXTNH-UHFFFAOYSA-N N,N-dimethyl-2H-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- YYIQGSYCCNQAGV-UHFFFAOYSA-N benzyl 4-aminopiperidine-1-carboxylate Chemical class C1CC(N)CCN1C(=O)OCC1=CC=CC=C1 YYIQGSYCCNQAGV-UHFFFAOYSA-N 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 229960000539 carbamide Drugs 0.000 description 3
- 235000013877 carbamide Nutrition 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 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 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-Tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N Cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- IRXSLJNXXZKURP-UHFFFAOYSA-N Fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 210000002356 Skeleton Anatomy 0.000 description 2
- JMXKSZRRTHPKDL-UHFFFAOYSA-N Titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 238000009835 boiling Methods 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
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium monoxide Chemical compound [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 239000002035 hexane extract Substances 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- DBUJFULDVAZULB-UHFFFAOYSA-N 1-methoxypentane Chemical compound CCCCCOC DBUJFULDVAZULB-UHFFFAOYSA-N 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- HYTSWLKLRKLRHK-UHFFFAOYSA-N 7-oxo-6-phenylmethoxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Chemical compound NC(=O)C1CCC2CN1C(=O)N2OCC1=CC=CC=C1 HYTSWLKLRKLRHK-UHFFFAOYSA-N 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- WGEFECGEFUFIQW-UHFFFAOYSA-L Calcium bromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L Magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N O-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N Titanium isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atoms 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
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- ABBZJHFBQXYTLU-UHFFFAOYSA-N but-3-enamide Chemical compound NC(=O)CC=C ABBZJHFBQXYTLU-UHFFFAOYSA-N 0.000 description 1
- IXGDPRSVHMKXER-UHFFFAOYSA-N butyl acetate;dichloromethane Chemical compound ClCCl.CCCCOC(C)=O IXGDPRSVHMKXER-UHFFFAOYSA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 229910001622 calcium bromide Inorganic materials 0.000 description 1
- 229940059251 calcium bromide Drugs 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N diazomethane Chemical group C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005842 heteroatoms Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000004346 phenylpentyl group Chemical group C1(=CC=CC=C1)CCCCC* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Abstract
The present invention provides a kind of method conveniently and efficiently manufacturing the optical activity bicyclic urea compounds being used as beta lactamase restrainer intermediate.In the present invention, the ester compounds and amine reaction by making regulation in the presence of metal alkoxide and/or alkali salt manufactures the amide compound of correspondence.Next so that it is react with phosgene or phosgene equivalent and utilize acid or alkali to process as required, optical activity bicyclic urea compounds is thus manufactured.Thus, catalyst or the condensing agent etc. of high price can not used and without protecting or conveniently and efficiently manufacturing optical activity bicyclic urea compounds with high-optical-purity in the case of deprotection operation.
Description
Technical field
The present invention relates to a kind of optical activity as pharmaceuticals intermediate, particularly beta-lactamase inhibitor intermediates
The manufacture method of bicyclic urea compounds.
Background technology
As the manufacture method of the optical activity bicyclic urea compounds for beta-lactamase inhibitor intermediates, the most
Know there is method (patent documentation 1, particularly PREPARATIVE EXAMPLE 1, Example 1A) as described below.
Prior art literature
Patent documentation
Patent documentation 1:WO2009/091856
Summary of the invention
The problem that the invention solves the problems that
From the standpoint of the reagent that operation length and use palladium or dehydrating condensation agent etc. are expensive, the method that patent documentation 1 is recorded
Have problems in terms of commercial scale enforcement.
For solving the technical scheme of problem
In consideration of it, the present inventor etc. are concentrated on studies, it was found that by metal alkoxide and/or alkaline-earth metal
In the presence of salt, make ester compounds and the amine reaction of regulation, manufacture the amide compound of correspondence, further, by making this acyl
Amines utilizes acid to process after reacting with phosgene or phosgene equivalent, can be converted into optical activity dicyclo urea chemical combination
Thing, so that completing the present invention.
That is, the present application relates to the manufacture method of the amide compound shown in following formula (4), and the method includes: under
State in the presence of the metal alkoxide shown in formula (1) and/or alkali salt, make the ester compounds shown in following formula (2) and following
Amine reaction shown in formula (3).
M(OR1)X (1)
(in formula, M is any one in magnesium, aluminum, titanium, zirconium or hafnium.R1Represent the alkyl of C1～12.X represent 1～4 whole
Number.)
(in formula, R2、R3Separately represent the alkyl of C1～12, the thiazolinyl of C2～12, the cycloalkyl of C3～12, C7～
Any one in the aryl of aralkyl, C6～12 of 12.N is 1 or 2.)
R4NH2 (3)
(in formula, R4Represent hydrogen atom, the alkyl of C1～12, the thiazolinyl of C2～12, the cycloalkyl of C3～12, C7～12
Any one in the aryl of aralkyl, C6～12.)
(in formula, R3、R4, n and described R3、R4, n identical.)
Described amide compound can be by reacting with phosgene or phosgene equivalent and formed shown in following formula (5)
Chemism bicyclic urea compounds.
The effect of invention
The method according to the invention, can not use catalyst or the condensing agent etc. of high price and without protection or de-
Conveniently and efficiently it is used as pharmaceuticals intermediate, particularly beta-lactamase with high-optical-purity manufacture in the case of protection operation
The optical activity bicyclic urea compounds of inhibitor intermediate.
Detailed description of the invention
First, the initiation material in the present invention is illustrated.
Ester compounds used in the present invention is represented by following formula (2).
Here, R2、R3Separately represent the alkyl of C1～12, the thiazolinyl of C2～12, the cycloalkyl of C3～12, C7～
Any one in the aryl of aralkyl, C6～12 of 12.
These groups optionally have the substituent group of more than 1.As above-mentioned substituent group, such as, can enumerate: fluorine atom, chlorine
The halogen atoms such as atom, bromine atoms, atomic iodine；Hydroxyl；The alkoxyl such as methoxyl group, ethyoxyl；Methyl mercapto；Trifluoromethyl；Acetyl
Base；Benzoyl；Cyano group；Nitro；Carboxyl；The alkoxy carbonyl such as methoxycarbonyl, ethoxy carbonyl etc..
For abovementioned alkyl, such as, can enumerate: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, secondary
The straight or brancheds such as butyl, the tert-butyl group, n-pentyl, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl
Alkyl.The carbon number of alkyl is more preferably 1～7, and more preferably 1～5, particularly preferably 1～3.
As above-mentioned thiazolinyl, such as, can enumerate: vinyl, pi-allyl, 1-acrylic, isopropenyl, 3-cyclobutenyl, 1-
Methacrylic etc..Wherein, the thiazolinyl of the thiazolinyl of preferably C2～C5, more preferably C2～C4, more preferably pi-allyl.
Above-mentioned cycloalkyl is defined as from the carbon atom of more than 1 (preferably 1) optionally by hetero atom (such as nitrogen-atoms, oxygen
Atom, sulphur atom etc.) substituted cycloalkane removes 1 hydrogen atom and the group that obtains.Therefore, the carbon atom in this cycloalkyl
Number refers to carbon and heteroatomic total exactly, and the constitution element number being equivalent to ring skeleton (that is, refers to ternary in the case of C3
Ring).Specifically, as the cycloalkyl of C3～12, such as, can illustrate: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cycloheptyl
The ring type saturated hydrocarbyls such as base, ring octyl group, cyclo-dodecyl；Azirine-2-base, azetidine-2-base, azetidine-3-base, pyrroles
Alkane-2-base, pyrrolidin-3-yl, piperidin-2-yl, piperidines-3-base, piperidin-4-yl, azepan-2-base, azepan-
The nitrogenous saturated heterocyclics such as 3-base, azepan-4-base；Oxirane-2-base, oxetanes-2-base, oxetanes-
3-base, tetrahydrofuran-2-base, tetrahydrofuran-3-base,Alkane-2-base,Alkane-3-base,Alkane-4-base, oxa-ring
The oxygen-containing saturated heterocyclics such as heptane-2-base, oxepane-3-base, oxepane-4-base；Thiirane-2-base, thia ring
Butane-2-base, Thietane-3-base, tiacyclopentane-2-base, tiacyclopentane-3-base, thianthrene-2-base, thianthrene-3-
The sulfur-bearing saturated heterocyclics etc. such as base, thianthrene-4-base, thia cycloheptane-2-base, thia cycloheptane-3-base, thia cycloheptane-4-base.
The constitution element number of the ring skeleton of cycloalkyl is 3～12, preferably 5～7, more preferably 6 (hexatomic rings).
It addition, in the case of above-mentioned cycloalkyl is nitrogenous saturated heterocyclic, the nitrogen-atoms of this heterocycle is optionally protected by protection group
Protect.As the protection group of nitrogen-atoms, such as, can enumerate: tert-butoxycarbonyl (Boc yl), methoxycarbonyl (Moc yl), 9-fluorenes
The substituted or unsubstituted alkoxy carbonyl of the carbon numbers 1～15 such as ylmeth-oxycarbonyl (Fmoc yl)；Benzyloxycarbonyl (Cbz
Base), substituted or unsubstituted aromatic alkoxy carbonyl to the carbon numbers such as methoxybenzyloxycarbonyl 7～12；Acetyl group, benzene first
The substituted or unsubstituted acyl group of the carbon numbers such as acyl group 2～12.Wherein, preferably tert-butoxycarbonyl (Boc yl), methoxyl group
Carbonyl (Moc yl), 9-fluorenylmethoxycarbonyl groups (Fmoc yl), benzyloxycarbonyl (Cbz yl), acetyl group, more preferably uncle
Butoxy carbonyl (Boc yl), benzyloxycarbonyl (Cbz yl).
As above-mentioned aralkyl, such as, can enumerate: benzyl, 1-phenethyl, 2-phenethyl, phenyl propyl, phenyl butyl,
Phenylpentyl etc..Wherein, the aralkyl of preferably C7～10, the aralkyl of more preferably C7～8.
As above-mentioned aryl, such as, can enumerate: phenyl, tolyl, xylyl, sym-trimethylbenzene. base, tetramethylphenyl, 1-
Naphthyl etc..
As R2、R3, specifically, preferably enumerate: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, secondary
The alkyl (alkyl of preferably C1～5) of the C1～8 such as butyl, the tert-butyl group, n-pentyl；The C3 such as cyclopropyl, cyclobutyl, cyclohexyl～
The cycloalkyl (cycloalkyl of preferably C3～5) of 7；The thiazolinyls such as pi-allyl；The aralkyl of the C7～12 such as benzyl, 1-phenethyl is (excellent
Elect the aralkyl of C7～9 as)；The aryl such as phenyl, 1-naphthyl.
As R2, the more preferably alkyl of C1～3, pi-allyl or the benzyl such as methyl, ethyl, isopropyl, further preferably
For benzyl.
As R3, more preferably pi-allyl or benzyl, more preferably benzyl.
N is 1 or 2, the piperidine derivative of preferably n=2.
Above-claimed cpd (2) can according to WO2002/010172 and CHEMICAL COMMUNICAT IONS, 1996,349.
Method described in is easily manufactured.Specifically, the method manufacture shown in following formula can be passed through.More specifically, paddy ammonia is made
Acid derivative reacts with Azimethylene. etc. and synthesizes corresponding diazo-ketones, uses rhodium catalyst etc. to carry out intramolecular cyclization.Connect down
Come, utilize reducing agent (sodium borohydride etc.) by after carbonyl reduction, the protection group of N is carried out deprotection, thus can manufacture above-mentionedization
Compound (2).This deprotection such as can be carried out by following operation: is converted into trifluoroacetyl group from Boc protecting group,
The alcohol body obtained is carried out triflated after, utilize benzyloxy amine to carry out substitution reaction.
Then, the amide compound as product is illustrated.
The amide compound obtained in the present invention is represented by following formula (4).
In formula, R3, R4, n and described R3, R4, n identical.
R4Represent hydrogen atom, the alkyl of C1～12, the thiazolinyl of C2～12, the cycloalkyl of C3～12, the aralkyl of C7～12,
Any one in the aryl of C6～12.They optionally have the substituent group of more than 1.As above-mentioned substituent group and each functional group,
Can enumerate and above-mentioned R2、R3The same substituent group of situation and functional group.
As R4, it may be more preferable to enumerate: optionally there is the C1 of substituent group～the alkyl of 5；The thiazolinyl of C2～C4；Optionally have
The ring type saturated hydrocarbyl of the C3～6 of substituent group；Optionally have substituent group, the optional protected C3～6 of nitrogen-atoms containing nitrification
Heterocycle；Optionally there is the C7 of substituent group～the aralkyl of 8；Optionally there is the C6 of substituent group～the aryl of 12.
As R4, specifically, can enumerate: hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, cyclopropyl, positive fourth
Base, isobutyl group, sec-butyl, the tert-butyl group, cyclobutyl, n-pentyl, cyclohexyl, pi-allyl, benzyl, 1-phenethyl, phenyl, 1-naphthalene
Base, p-methoxyphenyl, 1-(tert-butoxycarbonyl) piperidin-4-yl, 1-(benzyloxycarbonyl) piperidin-4-yl etc..
As R4, particularly preferably hydrogen atom, pi-allyl, benzyl, p-methoxyphenyl, 1-(tert-butoxycarbonyl) piperazine
Pyridine-4-base or 1-(benzyloxycarbonyl) piperidin-4-yl, more preferably hydrogen atom or 1-(benzyloxycarbonyl) piperidines-4-
Base.
It follows that it is double to the optical activity making above-mentioned amide compound and phosgene or phosgene equivalent react and obtain
Ring carbamide compound illustrates.
The optical activity dicyclo urea obtained in the present invention is represented by following formula (5).
Here, R3、R4, n and above-mentioned R3、R4, n identical.
Hereinafter, the manufacture method of above-claimed cpd (4) is illustrated.
Above-claimed cpd (4) can be by making in the presence of the metal alkoxide shown in following formula (1) and/or alkali salt
Amine reaction shown in above-claimed cpd (2) and following formula (3) manufactures.
M(OR1)X (1)
R4NH2 (3)
In above-mentioned metal alkoxide (1), M is the arbitrary metal in magnesium, aluminum, titanium, zirconium or hafnium.It is preferably magnesium, aluminum or titanium,
More preferably aluminum or titanium.If aluminum or titanium, then can implement this reaction with the such high yield of yield more than 80%.It addition, it is special
Be not M be that the response time can significantly be foreshortened to less than 10 hours by the metal alkoxide (1) of aluminum, therefore, reaction can be implemented efficiently,
Therefore preferably.
R1Represent the alkyl of C1～12.Specifically, can enumerate: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl,
Isobutyl group, sec-butyl, the tert-butyl group, n-pentyl.It is preferably the alkyl of C1～5, more preferably methyl, ethyl, isopropyl, tertiary fourth
Base.R1It is preferably branched, more preferably isopropyl.
X represents the integer of 1～4, determines according to the kind of metal.
As metal alkoxide (1), preferably Ti (OMe)4、Ti(OEt)4、Ti(OiPr)4、Al(OMe)3、Al(OEt)3、Al
(OiPr)3、Mg(OMe)2、Mg(OEt)2、Hf(OtBu)4、Zr(OnBu)4, more preferably Ti (OMe)4、Ti(OEt)4、Ti
(OiPr)4、Al(OMe)3、Al(OEt)3、Al(OiPr)3、Mg(OMe)2、Mg(OEt)2, more preferably Ti (OiPr)4, or Al
(OiPr)3。
It addition, in this operation, alkali salt also can replace above-mentioned metal alkoxide (1) or in above-mentioned metal alkoxide (1)
On the basis of be used as catalyst.In the present invention so-called " alkali salt " in comprise alkaline-earth halide or alkaline-earth metal oxygen
Compound, such as, can illustrate: calcium chloride, calcium oxide, calcium bromide, magnesium chloride, magnesium bromide, magnesium oxide, preferably calcium chloride, chlorination
Magnesium, particularly preferably calcium chloride.It addition, in the case of wanting to obtain the compound (4) as product using high yield, preferably
Use magnesium chloride.
As above-mentioned metal alkoxide (1), the lower limit of the respective usage amount of alkali salt, relative to above-claimed cpd (2) 1
Mole it is more than 0.1 mole, preferably more than 0.5 mole, more preferably more than 1.0 moles, as the upper limit, relative to above-mentionedization
Compound (2) 1 moles is less than 10 moles, preferably less than 5 moles, more preferably less than 2 moles.
In above-mentioned amine (3), R4With above-mentioned R4Identical.As amine (3), preferably ammonia, allyl amine, benzyl amine, to methoxy
Base aniline, 4-amino-1-(tert-butoxycarbonyl) piperidines, 4-amino-1-(benzyloxycarbonyl) piperidines, more preferably ammonia,
Or 4-amino-1-(benzyloxycarbonyl) piperidines.
As the lower limit of the usage amount of above-mentioned amine (3), it is more than 0.5 mole relative to above-claimed cpd (2) 1 moles, excellent
Electing more than 0.8 mole as, more preferably more than 1 mole, as the upper limit, be 50 to rub relative to above-claimed cpd (2) 1 moles
Below Er, preferably less than 20 moles, more preferably less than 10 moles.
As the reaction dissolvent of this operation, as long as reaction not impact is just not particularly limited, such as hydrocarbon system can be used
Solvent, ether series solvent, halogen series solvent etc..Specifically, such as can enumerate: pentane, hexane, heptane, Pentamethylene., hexamethylene
The hydrocarbon system solvents such as alkane, cycloheptane, benzene,toluene,xylene, sym-trimethylbenzene.；Ether, Di Iso Propyl Ether, cyclopentyl-methyl ether, tertiary fourth
Ylmethyl ether, oxolane, 1,4-bis-The ether series solvent such as alkane, ethylene glycol dimethyl ether；Dichloromethane, 1,2-dichloroethanes,
The halogen series solvents, the preferably aromatic series such as benzene,toluene,xylene, sym-trimethylbenzene. hydrocarbon system such as 1,1-dichloroethanes, sym-tetrachloroethane are molten
Agent；The dialkyl ethers such as ether, Di Iso Propyl Ether, cyclopentyl-methyl ether, t-butyl methyl ether；Oxolane, 1,4-bis-Alkane,
The cyclic ethers such as ethylene glycol dimethyl ether, more preferably toluene, oxolane.
As the usage amount of above-mentioned reaction dissolvent, if too much, then from the standpoint of cost and post processing, the most preferably, because of
This, be below 50 weight portions preferably with respect to above-claimed cpd (2) 1 weight portion, more preferably below 20 weight portions.Separately
Outward, lower limit is not particularly limited, and is more than 0.5 weight portion preferably with respect to above-claimed cpd (2) 1 weight portion, further preferably
It it is more than 1 weight portion.
As the reaction temperature of this operation, as long as being just not particularly limited more than the freezing point of solvent and below boiling point,
As long as suitably determining, as lower limit, it is preferably more than-78 DEG C, more preferably more than-50 DEG C, more preferably-30 DEG C
Above, particularly preferably more than 15 DEG C, as the upper limit, preferably less than 150 DEG C, more preferably less than 100 DEG C, the most excellent
Elect less than 50 DEG C as.
As the response time of this operation, it is more than 0.5 hour and less than 100 hours, preferably less than 50 hours.Separately
Outward, if the metal alkoxide (1) using M to be aluminum, then it is also contemplated that and the response time is significantly foreshortened to less than 10 hours.
As the order of addition of the reagent of this operation, it is not particularly limited, can depend in the solution of above-claimed cpd (3)
Secondary interpolation metal alkoxide and/or alkali salt and above-claimed cpd (2), it is also possible at metal alkoxide and/or alkali salt
Solution in add above-claimed cpd (3) and above-claimed cpd (2), it is also possible in the solution of above-claimed cpd (2) in interpolation
State compound (3) and metal alkoxide and/or alkali salt.It addition, adding metal alkoxide and/or alkali salt, above-mentioned
When compound (2) and (3), it is also possible to be suitably dissolved in solvent and add.
As the reacted process of this operation, as long as carrying out the general process for obtaining product from reactant liquor
?.Specifically, in reactant liquor, such as add water and add toluene, ethyl acetate, isopropyl acetate, methyl tertbutyl
The organic solvent such as ether, hexane extracts.From the extract obtained, organic solvent is distilled off by operations such as heating under reduced pressure,
The most separable object.It addition, in the case of insoluble matter separates out, aforesaid operations can be carried out after filtering out insoluble matter.
Although the object as above obtained has the sufficient purity that can be used for subsequent handling, but is used as partial crystallization, respectively distillation, post
The general process for purification such as chromatography improve purity further.
It addition, the R as above obtained3=Bn, R4=H, the compound (6) of n=2 are the compound that document is unknown.
Hereinafter, the manufacture method of above-claimed cpd (5) is illustrated.
Above-claimed cpd (5) can react by making above-claimed cpd (4) manufacture with phosgene or phosgene equivalent.
As above-mentioned phosgene equivalent, can enumerate: double phosgenes, three phosgenes, carbonyl dimidazoles etc..
As phosgene or the lower limit of the usage amount of phosgene equivalent, it is 0.3 relative to above-claimed cpd (4) 1 moles
More than mole, preferably more than 0.5 mole, more preferably more than 0.8 mole, be less than 10 moles as the upper limit, and preferably 5 rub
Below Er, more preferably less than 3 moles.
As the reaction dissolvent of this operation, as long as reaction not impact is just not particularly limited, can use hydrocarbon system solvent,
Ether series solvent, ester series solvent, halogen series solvent etc., nitrile series solvent etc..Specifically, such as can enumerate: pentane, hexane, heptan
The hydrocarbon system solvents such as alkane, Pentamethylene., hexamethylene, cycloheptane, benzene,toluene,xylene, sym-trimethylbenzene.；Ether, Di Iso Propyl Ether, ring
Amyl methyl ether, t-butyl methyl ether, oxolane, 1,4-bis-The ether series solvent such as alkane, ethylene glycol dimethyl ether；Acetic acid first
The ester series solvents such as ester, ethyl acetate, isopropyl acetate, butyl acetate；Dichloromethane, 1,2-dichloroethanes, 1,1-dichloroethanes,
The halogen series solvents such as sym-tetrachloroethane；The nitrile series solvents such as acetonitrile, preferably toluene, oxolane, dichloromethane, acetonitrile, further
It is preferably toluene, oxolane, dichloromethane, acetonitrile.
As the reaction temperature of this operation, as long as being just not particularly limited more than the freezing point of solvent and below boiling point,
As long as suitably determining, as lower limit, it is preferably more than-78 DEG C, more preferably more than-50 DEG C, particularly preferably-30
More than DEG C, as the upper limit, preferably less than 150 DEG C, more preferably less than 100 DEG C, more preferably less than 50 DEG C, the most excellent
Elect less than 20 DEG C as.
As the response time of this operation, preferably more than 0.1 hour, more preferably more than 0.5 hour, further preferably
It is more than 0.7 hour, preferably less than 50 hours, more preferably less than 20 hours, more preferably less than 10 hours, especially
It is preferably less than 5 hours.
As the order of addition of the reagent of this operation, phosgene or phosgene can be added in the solution of compound (4)
Equivalent, it is also possible to add compound (4) in the solution of phosgene or phosgene equivalent.
It addition, in the present reaction, by above-claimed cpd (4) and phosgene or the reaction of phosgene equivalent, sometimes produce
Compound shown in raw following formula (7) or following formula (8):
(X represents phosgene or the residue of phosgene equivalent).In this case, by utilizing acid or alkali to instead
Liquid is answered to process, available above-claimed cpd (5).
As above-mentioned acid, can enumerate: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, citric acid etc..These are preferably with water
The form of solution uses.It is preferably phosphoric acid.
As the lower limit of the usage amount of above-mentioned acid, it is more than 0.3 mole relative to above-claimed cpd (4) 1 moles, is preferably
More than 0.5 mole, more preferably more than 0.8 mole, be less than 10 moles as the upper limit, preferably less than 5 moles, more preferably
Less than 3 moles.
As above-mentioned alkali, can enumerate: pyridine, triethylamine, diisopropylethylamine, N, N-dimethyl aminopyridine, carbon
Acid hydrogen sodium, potassium bicarbonate, sodium carbonate, potassium carbonate etc..It is preferably N, N-dimethyl aminopyridine.Usage amount as above-mentioned alkali
Lower limit, is more than 0.3 mole relative to above-claimed cpd (4) 1 moles, preferably more than 0.5 mole, more preferably 0.8 mole
Above, it is less than 10 moles as the upper limit, preferably less than 5 moles, more preferably less than 3 moles.
Acid or alkali can carry out rank to a certain degree in the reaction of compound (4) and phosgene or phosgene equivalent
Section adds.Or, phosgene or phosgene equivalent can be added in compound (4) and the solution of alkali.
As the reacted process of this operation, as long as carrying out the general process for obtaining product from reactant liquor
?.Specifically, in reactant liquor, such as add water and add toluene, ethyl acetate, isopropyl acetate, methyl tertbutyl
The organic solvent such as ether, hexane extracts.From the extract obtained, organic solvent is distilled off by operations such as heating under reduced pressure,
The most separable object.
As above the object obtained can use the general process for purification such as partial crystallization, respectively distillation, column chromatography to improve further
Purity.
The application advocates Japanese patent application filed in 1 day November in 2012 the 2012-242227th and in 2013 years
The priority of Japanese patent application filed in January 29 the 2013-014760th.The application quotes application on November 1st, 2012
Japanese patent application the 2012-242227th and at Japanese patent application 2013-filed in 29 days January in 2013
The full content of the description of No. 014760 is as reference.
Embodiment
Below, it is shown that the present invention is illustrated by embodiment in further detail, but the present invention is not by these embodiments
Any restriction.
In the present embodiment, the yield of each compound, generation are than using high performance liquid chromatography and in condition set forth below
Under be analyzed.
(efficient liquid phase chromatographic analysis condition)
Post: Phenomenex Luna 5C18 (2) 4.6 × 250mm
Mobile phase A: 0.1 weight % phosphate aqueous solution, Mobile phase B: acetonitrile
Flow velocity: 1.0mL/min
Gradient condition
0.00 minute mobile phase A: Mobile phase B=80:20
30.00 minutes mobile phase A: Mobile phase B=20:80
40.00 minutes mobile phase A: Mobile phase B=20:80
40.01 minutes mobile phase A: Mobile phase B=80:20
53.00 minute stopping
Column temperature: 35 DEG C
Detection wavelength: 210nm
(embodiment 1) 4-[({ (2S, 5R)-5-[(benzyloxy) amino] piperidin-2-yl } carbonyl) amino] piperidines-1-carboxylic acid
The manufacture method of benzyl ester
By 4-amino-1-(benzyloxycarbonyl) piperidines (6.31g, 26.9mmol) and Ti (OiPr)4(7.61g、
26.8mmol) it is incorporated in oxolane (30mL), stirs 1 hour at 25 DEG C.(2S, 5R)-5-benzyl is added in this reactant liquor
Epoxide amino-piperadine-2-benzyl carboxylate (7.57g, 22.3mmol), stirs 23 hours at 35 DEG C.Add water (38mL), saturated
Sodium bicarbonate aqueous solution (20mL), filters out the insoluble matter of precipitation.After filtrate separatory, carry out washing (20mL) by organic layer.
Organic layer is evaporated to 31g, after adding hexane (50mL) at 50 DEG C, is cooled to 0 DEG C.After stirring 1 hour, filter and separate out
Solid.The solid hexane (40mL) that will filter out cleans, and drying under reduced pressure at 40 DEG C thus obtains title compound
(8.38g, yield 81%).
(embodiment 2) 4-({ [(2S, 5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo [3.2.1] octane-2-
Base] carbonyl } amino) manufacture method of piperidines-1-benzyl carboxylate
The compound (8.07g, 17.3mmol) obtained in embodiment 1 middle addition diisopropylethylamine (7.19g,
55.7mmol), dichloromethane (144mL), be cooled to-10 DEG C.Three phosgenes (4.11g, 13.9mmol) are added in reactant liquor,
Stir 1 hour.In reactant liquor, add 3 weight % phosphate aqueous solutions (45g), after stirring 21 hours at 25 DEG C, carry out separatory.
The organic layer sodium bicarbonate aqueous solution (40mL) of 5 weight %, water (40mL) are carried out.By organic layer concentrating under reduced pressure,
To title compound (8.25g, yield 97%).
The manufacture method of (embodiment 3) (2S, 5R)-5-benzyloxyamino-piperidines-2-carboxylic acid amide
Calcium chloride is added in (2S, 5R)-5-benzyloxyamino-piperidines-2-carboxylic acid, ethyl ester (278mg, 1mmol)
(111mg, 1.00mmol), 20 weight % methanolic ammonia solutions (860mg), stir 4 hours at 25 DEG C.If utilizing high-efficient liquid phase color
Reactant liquor is carried out quantitatively, then generating title compound with yield 86% by spectrum.After reactant liquor concentrating under reduced pressure, add acetic acid second
Ester (20mL), water (2mL), filter precipitate.After precipitate is cleaned by ethyl acetate (2mL), carry out drying under reduced pressure, thus obtain
To title compound (154mg, yield 62%).
1H NMR(500MHz、CDCl3): 7.27-7.35 (m, 5H), 4.65 (s, 2H), 3.74 (dd, 1H, 12.0,
3.5Hz)、3.51(ddd、1H、12.0、4.0、1.5Hz)、3.15-3.21(m、1H)、2.78(t、1H、12.0Hz)、2.30(dq、
1H、14.0Hz、3.5Hz)、1.98-2.03(m、1H)、1.75(dq、1H、12.0Hz、3.5Hz)
The manufacture method of (embodiment 4) (2S, 5R)-5-benzyloxyamino-piperidines-2-carboxylic acid amide
Calcium chloride is become magnesium chloride, in addition, implements similarly to Example 3.Utilize high performance liquid chromatography to instead
Answering liquid to be analyzed, result generates title compound with yield 99%.
The manufacturer of (embodiment 5) 7-oxo-6-benzyloxy-1,6-diazabicyclo [3.2.1] octane-2-carboxylic acid amide
Method
By (2S, 5R)-5-benzyloxyamino-piperidines-2-carboxylic acid amide (118mg, 0.475mmol), potassium carbonate potassium
(372mg, 2.69mmol), dichloromethane (10mL) are cooled to-10 DEG C and add three phosgenes (117mg, 0.394mmol).-
After stirring 1 hour at 10 DEG C, add N, N-dimethyl aminopyridine (2.3mg, 0.019mmol), be stirred at room temperature 1 day.Will
After reactant liquor concentrates, add ethyl acetate (10mL), water (2mL), carry out separatory.Organic layer is dried with anhydrous sodium sulfate,
Concentrating under reduced pressure, thus obtains title compound (83.3mg, yield 64%).
1H NMR(500MHz、CDCl3): 7.34-7.44 (m, 5H), 6.69 (s, 1H), 6.20 (s, 1H), 5.05 (d, J=
11.5Hz, 1H), 4.91 (d, J=11.5Hz, 1H), 3.94 (d, J=8.5Hz, 1H), 3.32 (s, 1H), 3.03 (d, J=
11.5Hz, 1H), 2.78 (d, J=11.5Hz, 1H), 2.33 (dd, J=14.5,7.0Hz, 1H), 1.88-2.02 (m, 2H),
1.58-1.64(m、1H)
The manufacture method of (embodiment 6) (2S, 5R)-5-benzyloxyamino-piperidines-2-carboxylic acid allyl amide
By allyl amine (46.8mg, 0.820mmol), Al (OiPr)3(156mg, 0.764mmol), oxolane (1mL)
After stirring 1 hour at 60 DEG C, interpolation (2S, 5R)-5-benzyloxyamino-piperidines-2-benzyl carboxylate (171mg,
0.504mmol), after stirring 5 hours, utilizing high performance liquid chromatography to carry out reactant liquor quantitatively, result generates with yield 92%
Title compound.
1H NMR(500MHz、CDCl3): 7.28-7.35 (m, 5H), 6.86 (s (br), 1H), 5.82 (ddt, J=17.0,
10.5,5.5Hz, 1H), 5.11-5.19 (m, 2H), 4.68 (s, 2H), 3.87 (tt, J=5.5,1.5Hz, 2H), 3.30 (ddd, J
=11.0,4.0,1.5Hz, 1H), 3.17 (dd, J=11.0,3.5Hz, 1H), 2.96 (tt, J=10.0,4.0Hz, 1H), 2.46
(dd, J=11.5,10.0Hz, 1H), 2.11 (dq, J=13.0,4.0Hz, 1H), 1.88-1.94 (m, 1H), 1.42-1.50 (m,
1H)、1.23-1.31(m、1H)
(embodiment 7) 4-[({ (2S, 5R)-5-[(benzyloxy) amino] piperidin-2-yl } carbonyl) amino] piperidines-1-carboxylic acid
The manufacture method of benzyl ester
Use Al (OiPr)3Replace Ti (OiPr)4, in addition, under conditions of similarly to Example 1, carry out 4 hours instead
Should.Utilizing high performance liquid chromatography to be analyzed, result generates title compound with yield 90%.
(embodiment 8) 4-[({ (2S, 5R)-5-[(benzyloxy) amino] piperidin-2-yl } carbonyl) amino] piperidines-1-carboxylic acid
The manufacture method of benzyl ester
Use Zr (OnBu)4Replace Ti (OiPr)4, in addition, carry out under conditions of similarly to Example 1 27 hours
Reaction.Utilizing high performance liquid chromatography to be analyzed, result generates title compound with yield 38%.
(embodiment 9) 4-[({ (2S, 5R)-5-[(benzyloxy) amino] piperidin-2-yl } carbonyl) amino] piperidines-1-carboxylic acid
The manufacture method of benzyl ester
Use Hf (OtBu)4Replace Ti (OiPr)4, in addition, carry out under conditions of similarly to Example 1 21 hours
Reaction.Utilizing high performance liquid chromatography to be analyzed, result generates title compound with yield 51%.
The manufacture method of (comparative example 1) (2S, 5R)-5-benzyloxyamino-piperidines-2-carboxylic acid amide
20 weight % ammonia first are added in (2S, 5R)-5-benzyloxyamino-piperidines-2-carboxylic acid, ethyl ester (278mg, 1mmol)
Alcoholic solution (860mg), stirs 14 hours at 45 DEG C.Utilizing high performance liquid chromatography to be analyzed reactant liquor, result is with yield
20% generates title compound.
Claims (12)
1. the manufacture method of the amide compound shown in following formula (4), the method includes:
In the presence of the metal alkoxide shown in following formula (1) and/or alkali salt, the esterification shown in following formula (2) is made to close
Amine reaction shown in thing and following formula (3),
M(OR1)X (1)
In formula (1), M is any one in magnesium, aluminum, titanium, zirconium or hafnium, R1Represent C1～12 alkyl, X represent 1～4 whole
Number,
In formula (2), R2、R3Separately represent the alkyl of C1～12, the thiazolinyl of C2～12, the cycloalkyl of C3～12, C7～
Any one in the aryl of aralkyl, C6～12 of 12, n is 1 or 2,
R4NH2 (3)
In formula (3), R4Represent hydrogen atom, the alkyl of C1～12, the thiazolinyl of C2～12, the cycloalkyl of C3～12, the virtue of C7～12
Any one in the aryl of alkyl, C6～12,
In formula (4), R3、R4, n and above-mentioned R3、R4, n identical.
Manufacture method the most according to claim 1, wherein, described metal alkoxide is Ti (OiPr)4Or Al (OiPr)3。
Manufacture method the most according to claim 1, wherein, described alkali salt is calcium chloride or magnesium chloride.
Manufacture method the most according to claim 1, wherein, described R2For methyl, ethyl, isopropyl, pi-allyl or benzyl,
R3For benzyl, n is 2.
Manufacture method the most according to claim 1, wherein, described R4For hydrogen atom, pi-allyl or benzyl.
Manufacture method the most according to claim 1, wherein, described metal alkoxide is Ti (OiPr)4Or Al (OiPr)3,
Described alkali salt is calcium chloride or magnesium chloride,
Described R2For methyl, ethyl, isopropyl, pi-allyl or benzyl, R3For benzyl, n is 2,
Described R4For hydrogen atom, pi-allyl or benzyl.
7. the manufacture method of the amide compound shown in following formula (4), the method includes:
In the presence of the metal alkoxide shown in following formula (1) and/or alkali salt, the esterification shown in following formula (2) is made to close
Amine reaction shown in thing and following formula (3),
M(OR1)X (1)
In formula (1), M is any one in magnesium, aluminum, titanium, zirconium or hafnium, R1Represent C1～12 alkyl, X represent 1～4 whole
Number,
In formula (2), R2、R3Separately represent the alkyl of C1～12, the thiazolinyl of C2～12, the cycloalkyl of C3～12, C7～
Any one in the aryl of aralkyl, C6～12 of 12, n is 1 or 2,
R4NH2 (3)
In formula (3), R4Represent 1-(tert-butoxycarbonyl) piperidin-4-yl or 1-(benzyloxycarbonyl) piperidin-4-yl,
In formula (4), R3、R4, n and above-mentioned R3、R4, n identical.
Manufacture method the most according to claim 7, wherein, described metal alkoxide is Ti (OiPr)4Or Al (OiPr)3。
Manufacture method the most according to claim 7, wherein, described alkali salt is calcium chloride or magnesium chloride.
Manufacture method the most according to claim 7, wherein, described R2For methyl, ethyl, isopropyl, pi-allyl or benzyl
Base, R3For benzyl, n is 2.
11. manufacture methods according to claim 7, wherein, described metal alkoxide is Ti (OiPr)4Or Al (OiPr)3,
Described alkali salt is calcium chloride or magnesium chloride,
Described R2For methyl, ethyl, isopropyl, pi-allyl or benzyl, R3For benzyl, n is 2.
12. according to the manufacture method according to any one of claim 1～11, wherein, makes described compound (4) and carbon further
Acyl chlorides or the reaction of phosgene equivalent, form the optical activity bicyclic urea compounds shown in following formula (5),
In formula (5), R3、R4, n and described R3、R4, n identical.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012242227 | 2012-11-01 | ||
| JP2012-242227 | 2012-11-01 | ||
| JP2013-014760 | 2013-01-29 | ||
| JP2013014760 | 2013-01-29 | ||
| PCT/JP2013/078918 WO2014069351A1 (en) | 2012-11-01 | 2013-10-25 | Method for producing optically active bicyclic urea compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104768930A CN104768930A (en) | 2015-07-08 |
| CN104768930B true CN104768930B (en) | 2016-11-30 |
Family
ID=
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012133486A1 (en) * | 2011-03-31 | 2012-10-04 | 株式会社カネカ | Process for preparing cyclic amine compounds |
| WO2013038330A1 (en) * | 2011-09-13 | 2013-03-21 | Wockhardt Limited | Nitrogen containing compounds and their use |
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012133486A1 (en) * | 2011-03-31 | 2012-10-04 | 株式会社カネカ | Process for preparing cyclic amine compounds |
| WO2013038330A1 (en) * | 2011-09-13 | 2013-03-21 | Wockhardt Limited | Nitrogen containing compounds and their use |
Non-Patent Citations (1)
| Title |
|---|
| Design,Synthesis,and Biological Evaluation of Matrix Metalloproteinase Inhibitors Derived from a Modified Proline Scaffold;Menyan Cheng et al;《J. Med. Chem》;19990912;第42卷;5426-5436 * |
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