JPH0615526B2 - 3-Aminomethylpyrrolidine derivative and its salt - Google Patents
3-Aminomethylpyrrolidine derivative and its saltInfo
- Publication number
- JPH0615526B2 JPH0615526B2 JP60215628A JP21562885A JPH0615526B2 JP H0615526 B2 JPH0615526 B2 JP H0615526B2 JP 60215628 A JP60215628 A JP 60215628A JP 21562885 A JP21562885 A JP 21562885A JP H0615526 B2 JPH0615526 B2 JP H0615526B2
- Authority
- JP
- Japan
- Prior art keywords
- benzyl
- cis
- compound
- added
- spectrum
- 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.)
- Expired - Lifetime
Links
- 150000003839 salts Chemical class 0.000 title claims description 10
- OQCUGPQOZNYIMV-UHFFFAOYSA-N pyrrolidin-3-ylmethanamine Chemical class NCC1CCNC1 OQCUGPQOZNYIMV-UHFFFAOYSA-N 0.000 title claims description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 84
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 72
- 150000001875 compounds Chemical class 0.000 description 63
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 239000000243 solution Substances 0.000 description 44
- -1 monochloroacetyl group Chemical group 0.000 description 29
- 238000002329 infrared spectrum Methods 0.000 description 28
- 238000001819 mass spectrum Methods 0.000 description 28
- 239000000203 mixture Substances 0.000 description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 27
- 239000007788 liquid Substances 0.000 description 27
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 26
- 239000003921 oil Substances 0.000 description 26
- 239000002904 solvent Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000010410 layer Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 235000011121 sodium hydroxide Nutrition 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 238000010992 reflux Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 7
- 235000011054 acetic acid Nutrition 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RNWBPOAFKSKZSF-VXGBXAGGSA-N (3S,4S)-3-(azidomethyl)-1-benzyl-4-fluoropyrrolidine Chemical compound C1[C@@H](CN=[N+]=[N-])[C@H](F)CN1CC1=CC=CC=C1 RNWBPOAFKSKZSF-VXGBXAGGSA-N 0.000 description 2
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 description 2
- VLKCHXWEIFACKS-UHFFFAOYSA-N 3-(azidomethyl)-1-benzyl-3-fluoropyrrolidine Chemical compound C1C(F)(CN=[N+]=[N-])CCN1CC1=CC=CC=C1 VLKCHXWEIFACKS-UHFFFAOYSA-N 0.000 description 2
- MWTGBAURSCEGSL-UHFFFAOYSA-N 3-(benzylamino)propanenitrile Chemical compound N#CCCNCC1=CC=CC=C1 MWTGBAURSCEGSL-UHFFFAOYSA-N 0.000 description 2
- WPWGDRFCVLQTBF-UHFFFAOYSA-N 4-(azidomethyl)-1-benzylpyrrolidin-3-ol Chemical compound C1C(CN=[N+]=[N-])C(O)CN1CC1=CC=CC=C1 WPWGDRFCVLQTBF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- MOOAHMCRPCTRLV-UHFFFAOYSA-N boron sodium Chemical compound [B].[Na] MOOAHMCRPCTRLV-UHFFFAOYSA-N 0.000 description 2
- 239000003518 caustics Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- OBDFQUSHNJZDSN-UHFFFAOYSA-N n-ethylethanamine;1,1,2,3,3,3-hexafluoroprop-1-ene Chemical compound CCNCC.FC(F)=C(F)C(F)(F)F OBDFQUSHNJZDSN-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- WQBXDWCSXGTIBZ-UHFFFAOYSA-N (1-benzyl-3-fluoropyrrolidin-3-yl)methanamine Chemical compound C1C(CN)(F)CCN1CC1=CC=CC=C1 WQBXDWCSXGTIBZ-UHFFFAOYSA-N 0.000 description 1
- FPCRQLQBOSVYQA-UHFFFAOYSA-N (1-benzyl-3-fluoropyrrolidin-3-yl)methanol Chemical compound C1C(CO)(F)CCN1CC1=CC=CC=C1 FPCRQLQBOSVYQA-UHFFFAOYSA-N 0.000 description 1
- ORRHJFKSGZLNGY-UHFFFAOYSA-N (1-benzyl-4-fluoropyrrolidin-2-yl)methanamine Chemical compound NCC1CC(F)CN1CC1=CC=CC=C1 ORRHJFKSGZLNGY-UHFFFAOYSA-N 0.000 description 1
- MBMBUSUISIGXCG-UHFFFAOYSA-N (1-benzyl-4-hydroxypyrrolidin-3-yl)methyl methanesulfonate Chemical compound C1C(O)C(COS(=O)(=O)C)CN1CC1=CC=CC=C1 MBMBUSUISIGXCG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CGXLVFZJJOXEDF-UHFFFAOYSA-N 1,8-naphthyridine-3-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CN=C21 CGXLVFZJJOXEDF-UHFFFAOYSA-N 0.000 description 1
- 150000005058 1,8-naphthyridines Chemical class 0.000 description 1
- QTKGPIMTYKXKPS-UHFFFAOYSA-N 1-benzyl-3-methoxypyrrolidine Chemical compound C1C(OC)CCN1CC1=CC=CC=C1 QTKGPIMTYKXKPS-UHFFFAOYSA-N 0.000 description 1
- DHGMDHQNUNRMIN-UHFFFAOYSA-N 1-benzylpyrrolidin-3-one Chemical compound C1C(=O)CCN1CC1=CC=CC=C1 DHGMDHQNUNRMIN-UHFFFAOYSA-N 0.000 description 1
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 1
- RBYQYPQIZQKEFL-UHFFFAOYSA-N 1-methoxypyrrolidine Chemical compound CON1CCCC1 RBYQYPQIZQKEFL-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- SHGPKKOJRMHXDW-UHFFFAOYSA-N 3-(azidomethyl)-1-benzyl-4-chloropyrrolidine Chemical compound C1C(CN=[N+]=[N-])C(Cl)CN1CC1=CC=CC=C1 SHGPKKOJRMHXDW-UHFFFAOYSA-N 0.000 description 1
- SIMYCJOGGRXQIY-UHFFFAOYSA-N 3-chloropyrrolidine Chemical compound ClC1CCNC1 SIMYCJOGGRXQIY-UHFFFAOYSA-N 0.000 description 1
- CDDGNGVFPQRJJM-UHFFFAOYSA-N 3-fluoropyrrolidine Chemical compound FC1CCNC1 CDDGNGVFPQRJJM-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- YTOKWAKFIPMZJV-OQPBUACISA-N 7-[(3r,4r)-3-(aminomethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C1[C@H](F)[C@H](CN)CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 YTOKWAKFIPMZJV-OQPBUACISA-N 0.000 description 1
- FHVGMLMMBNMNKI-PRHODGIISA-N 7-[(3r,4s)-3-(aminomethyl)-4-chloropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C1[C@@H](Cl)[C@H](CN)CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 FHVGMLMMBNMNKI-PRHODGIISA-N 0.000 description 1
- KPHNEBJBODMCQA-UHFFFAOYSA-N 7-[3-(aminomethyl)-3-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C1CC1N2C=C(C(=O)C3=CC(=C(N=C32)N4CCC(C4)(CN)F)F)C(=O)O KPHNEBJBODMCQA-UHFFFAOYSA-N 0.000 description 1
- RAIWMQAKDWDWOG-UHFFFAOYSA-N 7-[3-(aminomethyl)-3-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride Chemical compound C1CC1N2C=C(C(=O)C3=CC(=C(N=C32)N4CCC(C4)(CN)F)F)C(=O)O.Cl RAIWMQAKDWDWOG-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- SHGPKKOJRMHXDW-VXGBXAGGSA-N C1[C@@H](CN=[N+]=[N-])[C@H](Cl)CN1CC1=CC=CC=C1 Chemical compound C1[C@@H](CN=[N+]=[N-])[C@H](Cl)CN1CC1=CC=CC=C1 SHGPKKOJRMHXDW-VXGBXAGGSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 239000005973 Carvone Substances 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
- LZFYGNDEDCIKSP-UHFFFAOYSA-N N-[(1-benzyl-3-fluoropyrrolidin-3-yl)methyl]acetamide Chemical compound C1C(CNC(=O)C)(F)CCN1CC1=CC=CC=C1 LZFYGNDEDCIKSP-UHFFFAOYSA-N 0.000 description 1
- MGJSUYPIWXENBZ-UHFFFAOYSA-N N-[(1-benzyl-4-fluoropyrrolidin-3-yl)methyl]acetamide Chemical compound C1C(F)C(CNC(=O)C)CN1CC1=CC=CC=C1 MGJSUYPIWXENBZ-UHFFFAOYSA-N 0.000 description 1
- RXRFWBUVXVBXLY-UHFFFAOYSA-N N-[(3-fluoropyrrolidin-3-yl)methyl]acetamide Chemical compound CC(=O)NCC1(CCNC1)F RXRFWBUVXVBXLY-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- GLFBPDDMMVIVQJ-DGCLKSJQSA-N [(3R,4S)-1-benzyl-4-methylpyrrolidin-3-yl]methanamine Chemical compound C[C@@H]1CN(Cc2ccccc2)C[C@H]1CN GLFBPDDMMVIVQJ-DGCLKSJQSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- SEJYFISUUHLFAB-UHFFFAOYSA-N ethyl 2-[benzyl(2-cyanoethyl)amino]acetate Chemical compound CCOC(=O)CN(CCC#N)CC1=CC=CC=C1 SEJYFISUUHLFAB-UHFFFAOYSA-N 0.000 description 1
- STOTYTBCQWUTQI-UHFFFAOYSA-N ethyl 4-oxo-2,3-dihydro-1h-1,8-naphthyridine-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)CNC2=N1 STOTYTBCQWUTQI-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012458 free base Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- RIARYQRDUOZXEX-UHFFFAOYSA-N n-[(1-benzyl-4-chloropyrrolidin-3-yl)methyl]acetamide Chemical compound C1C(Cl)C(CNC(=O)C)CN1CC1=CC=CC=C1 RIARYQRDUOZXEX-UHFFFAOYSA-N 0.000 description 1
- RIARYQRDUOZXEX-ZIAGYGMSSA-N n-[[(3r,4s)-1-benzyl-4-chloropyrrolidin-3-yl]methyl]acetamide Chemical compound C1[C@@H](Cl)[C@H](CNC(=O)C)CN1CC1=CC=CC=C1 RIARYQRDUOZXEX-ZIAGYGMSSA-N 0.000 description 1
- MGJSUYPIWXENBZ-ZIAGYGMSSA-N n-[[(3r,4s)-1-benzyl-4-fluoropyrrolidin-3-yl]methyl]acetamide Chemical compound C1[C@@H](F)[C@H](CNC(=O)C)CN1CC1=CC=CC=C1 MGJSUYPIWXENBZ-ZIAGYGMSSA-N 0.000 description 1
- USOGGYDQFOUYRH-NKWVEPMBSA-N n-[[(3s,4s)-4-chloropyrrolidin-3-yl]methyl]acetamide Chemical compound CC(=O)NC[C@@H]1CNC[C@H]1Cl USOGGYDQFOUYRH-NKWVEPMBSA-N 0.000 description 1
- MCMONGRBVLPZDE-NKWVEPMBSA-N n-[[(3s,4s)-4-fluoropyrrolidin-3-yl]methyl]acetamide Chemical compound CC(=O)NC[C@@H]1CNC[C@H]1F MCMONGRBVLPZDE-NKWVEPMBSA-N 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- VMPYTOIPVPQDNX-UHFFFAOYSA-N pyrrolidin-1-ylmethanamine Chemical class NCN1CCCC1 VMPYTOIPVPQDNX-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
【発明の詳細な説明】 本発明は、優れた抗菌活性を有するピリドンカルボン酸
誘導体の製造における、価値ある中間体である新規３−
アミノメチルピロリジン誘導体およびその塩に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention is a novel 3- intermediate which is a valuable intermediate in the production of pyridonecarboxylic acid derivatives having excellent antibacterial activity.
The present invention relates to aminomethylpyrrolidine derivatives and salts thereof.
本発明の化合物は、下記一般式 （式中、Ｒ１は水素原子または低級アルキル基を意味
し、 Ｒ２はハロゲン原子で置換されていてもよいアシル基，
水素原子または低級アルキル基を意味し、Ｒ３はシハロ
ゲン原子，低級アルキル基または低級アルコキシ基を意
味し、かつピロリジン環の３位または４位に位置する。The compound of the present invention has the following general formula: (In the formula, R 1 represents a hydrogen atom or a lower alkyl group, and R 2 is an acyl group optionally substituted with a halogen atom,
It means a hydrogen atom or a lower alkyl group, R 3 means a cyhalogen atom, a lower alkyl group or a lower alkoxy group, and is located at the 3-position or 4-position of the pyrrolidine ring.
但し、Ｒ３がピロリジン環の４位に位置し、かつ低級ア
ルキル基であるとき、 で示される基はアミノ基またはモノ低級アルキル置換ア
ミノ基以外の基を意味する。） で表わされる新規３−アミノメチルピロリジン誘導体お
よびその塩である。Provided that when R 3 is located at the 4-position of the pyrrolidine ring and is a lower alkyl group, The group represented by means a group other than an amino group or a mono-lower alkyl-substituted amino group. ) Is a novel 3-aminomethylpyrrolidine derivative and a salt thereof.
本明細書において低級アルキル基および低級アルコキシ
基とは炭素原子１ないし６個を有するアルキル基および
アルコキシ基を意味し、ハロゲン原子とはフッ素，塩素
または臭素を意味する。またアシル基とは炭素原子１な
いし６個を有するアシル基を意味する。ハロゲン原子で
置換されていてもよいアシル基としては、例えばホルミ
ル基，アセチル基，プロピオニル基，ピバロイル基，モ
ノクロロアセチル基，ジクロロアセチル基，トリクロロ
アセチル基，トリフルオロアセチル基等が挙げられる。In the present specification, the lower alkyl group and the lower alkoxy group mean an alkyl group and an alkoxy group having 1 to 6 carbon atoms, and the halogen atom means fluorine, chlorine or bromine. Further, the acyl group means an acyl group having 1 to 6 carbon atoms. Examples of the acyl group which may be substituted with a halogen atom include a formyl group, an acetyl group, a propionyl group, a pivaloyl group, a monochloroacetyl group, a dichloroacetyl group, a trichloroacetyl group and a trifluoroacetyl group.
本発明の化合物の塩とは、例えば酢酸，乳酸，コハク
酸，シュウ酸，メタンスルホン酸等の有機酸との塩ある
いは塩酸，リン酸，硫酸等の無機酸との塩等が挙げられ
る。Examples of the salt of the compound of the present invention include salts with organic acids such as acetic acid, lactic acid, succinic acid, oxalic acid and methanesulfonic acid, and salts with inorganic acids such as hydrochloric acid, phosphoric acid and sulfuric acid.
本発明の化合物はピロリジン環上に不斉炭素原子を有す
るので光学活性体として存在しうる。従ってこれらの光
学活性体は本発明の化合物に包含される。Since the compound of the present invention has an asymmetric carbon atom on the pyrrolidine ring, it can exist as an optically active substance. Therefore, these optically active substances are included in the compound of the present invention.
更にまた、本発明の化合物の中には、ピロリジン環上に
複数個の不斉炭素原子を有するものがあり、それらは異
なる立体異性体として存在しうる。これらの立体異性体
およびその混合物もまた本発明の化合物に包含される。Furthermore, some of the compounds of this invention have multiple asymmetric carbon atoms on the pyrrolidine ring, which may exist as different stereoisomers. These stereoisomers and mixtures thereof are also included in the compound of the present invention.
本発明の化合物の製造法につき以下に説明する。The production method of the compound of the present invention is described below.
(1)一般式［Ｉ］においてＲ２が水素原子または低級ア
ルキル基である本発明の化合物は、下記一般式 （式中、Ｚは−ＣＨ２Ｎ３または−ＣＮを意味し、Ｒは
水素原子または保護基を意味し、Ｒ３は前掲と同じ。） で表わされる化合物［II］、あるいは下記一般式 （式中、Ｒ′２はアシル基を意味し、Ｒ，Ｒ１およびＲ
３は前掲と同じ。） で表わされる化合物［III］を還元し、Ｒが保護基であ
る場合には、常法により保護基を除去することによって
製造することができる。(1) In the general formula [I], R 2 is a hydrogen atom or a lower alkyl group. (In the formula, Z means —CH 2 N 3 or —CN, R means a hydrogen atom or a protecting group, and R 3 is the same as the above.), Or a compound represented by the following general formula: (In the formula, R ′ 2 means an acyl group, and R, R 1 and R
3 is the same as above. ) Can be produced by reducing the compound [III] represented by the formula (3) and removing R by a conventional method when R is a protecting group.
本反応は、原料化合物を溶媒中還元剤の存在下に、０〜
80℃で30分〜24時間攪拌することにより実施できる。This reaction is carried out by mixing the raw material compound in a solvent in the presence of a reducing agent with 0 to
It can be carried out by stirring at 80 ° C for 30 minutes to 24 hours.
還元剤としては、例えばパラジウム炭素，ラネーニッケ
ル，酸化白金等の触媒の存在下における水素，リチウム
アルミニウムヒドリド，ナトリウムビス（２−メトキシ
エトキシ）アルミニウムヒドリド等が使用される。As the reducing agent, for example, hydrogen in the presence of a catalyst such as palladium carbon, Raney nickel, platinum oxide, lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, or the like is used.
溶媒は原料化合物や使用する還元剤等により適宜選択す
ればよいが、エーテル，テトラヒドロフラン，トルエ
ン，メタノール，エタノール，酢酸，水等が使用され
る。The solvent may be appropriately selected depending on the raw material compound, the reducing agent used, etc., but ether, tetrahydrofuran, toluene, methanol, ethanol, acetic acid, water, etc. are used.
原料化合物［II］は参考例に記載の方法あるいはこれに
準じた方法で製造することができる。The starting compound [II] can be produced by the method described in Reference Example or a method analogous thereto.
原料化合物［III］は後記反応(3)により製造することが
できる。The starting compound [III] can be produced by the reaction (3) described below.
(2)一般式［Ｉ］において、Ｒ３がハロゲン原子である
本発明の化合物は、下記一般式 （式中、Ｒ，Ｒ１，Ｒ２は前掲と同じ。） で表わされる化合物［IV］の水酸基をハロゲン原子と置
換し、Ｒが保護基である場合には、常法により保護基を
除去することによって製造することができる。(2) In the general formula [I], the compound of the present invention in which R 3 is a halogen atom has the following general formula (In the formula, R, R 1 and R 2 are the same as the above.) The hydroxyl group of the compound [IV] is replaced with a halogen atom, and when R is a protecting group, the protecting group is removed by a conventional method. Can be manufactured.
本反応は、式［IV］の化合物とハロゲン化剤（例えば、
塩化チオニル，三塩化リン，三臭化リン，ヘキサフルオ
ロプロペン−ジエチルアミン，ジエチルアミノスルファ
トリフルオライド等）を溶媒中または無溶媒下、０〜15
0℃で20分〜５時間反応させることにより実施できる。
溶媒としては、エーテル，ジクロロメタン，クロロホル
ム，ベンゼン，トルエン等が使用される。This reaction involves the compound of formula [IV] and a halogenating agent (eg,
Thionyl chloride, phosphorus trichloride, phosphorus tribromide, hexafluoropropene-diethylamine, diethylaminosulfatrifluoride, etc.) in a solvent or without solvent, 0 to 15
It can be carried out by reacting at 0 ° C. for 20 minutes to 5 hours.
As the solvent, ether, dichloromethane, chloroform, benzene, toluene or the like is used.
原料化合物［IV］は参考例に記載の方法あるいはこれに
準ずる方法で製造することができる。The raw material compound [IV] can be produced by the method described in Reference Example or a method analogous thereto.
(3)一般式［Ｉ］において、Ｒ２がアシル基である本発
明の化合物は、下記一般式 （式中、Ｒ′は保護基を意味し、Ｒ１およびＲ３は前掲
と同じ。） で表わされる化合物［Ｖ］をアシル化した後、保護基を
常法により除去することによって製造することができ
る。(3) In the general formula [I], the compound of the present invention in which R 2 is an acyl group has the following general formula: (In the formula, R'means a protecting group, R 1 and R 3 are the same as those mentioned above.) After acylating the compound [V], the protecting group is removed by a conventional method. You can
本反応は、式［Ｖ］の化合物とアシル化剤を溶媒中また
は無溶媒下、０〜150℃で10分〜12時間反応させること
により実施できる。アシル化剤としては、例えば無水酢
酸や無水トリフルオロ酢酸の如き酸無水物，塩化アセチ
ルの如き酸塩化物，等の通常用いられるアシル化剤が挙
げられる。溶媒としては、クロロホルム，アセトン，テ
トラヒドロフラン，アセトニトリル，トルエン，ピリジ
ン，水，等が使用される。また本反応は、苛性アルカ
リ，炭酸アルカリ，重炭酸アルカリ，トリエチルアミ
ン，ピリジン，等の酸受容体の存在下に行ってもよい。This reaction can be carried out by reacting the compound of formula [V] with an acylating agent in a solvent or without solvent at 0 to 150 ° C. for 10 minutes to 12 hours. Examples of the acylating agent include commonly used acylating agents such as acid anhydrides such as acetic anhydride and trifluoroacetic anhydride and acid chlorides such as acetyl chloride. As the solvent, chloroform, acetone, tetrahydrofuran, acetonitrile, toluene, pyridine, water or the like is used. Further, this reaction may be carried out in the presence of an acid acceptor such as caustic alkali, alkali carbonate, alkali bicarbonate, triethylamine, pyridine and the like.
原料化合物［Ｖ］は前記反応(1)あるいは(2)により製造
することができる。The raw material compound [V] can be produced by the above reaction (1) or (2).
上記の各反応において使用される保護基は、反応条件に
より適宜選択すればよいが、例えばβ−ラクタム系抗生
物質，ペプチド，または核酸の化学において通常用いら
れる保護基が使用される。The protecting group used in each reaction described above may be appropriately selected depending on the reaction conditions, and for example, a protecting group usually used in the chemistry of β-lactam antibiotics, peptides, or nucleic acids is used.
この様にして製造される本発明の化合物は、常法に従い
単離、精製され、その条件によって塩の形や遊離塩基の
形で得られるが、これらは目的に応じて相互に変換さ
れ、目的とする形の本発明の化合物が製造される。The compound of the present invention produced in this manner is isolated and purified according to a conventional method, and is obtained in the form of a salt or a free base depending on the conditions. A form of the compound of the invention is prepared.
かくして得られる化合物［Ｉ］はいずれも新規化合物で
あり、優れた抗菌活性を有するビリドンカルボン酸誘導
体製造の中間体として価値あるものである。The compound [I] thus obtained is a novel compound and is valuable as an intermediate for the production of a viridonecarboxylic acid derivative having excellent antibacterial activity.
本発明の化合物の1,8−ナフチリジン誘導体を例にと
り、ピリドンカルボン酸誘導体の製造を図示すると次の
通りである。Taking the 1,8-naphthyridine derivative of the compound of the present invention as an example, the production of a pyridonecarboxylic acid derivative is illustrated as follows.
この反応式によれば、本発明の化合物［Ｉ］に化合物
［VI］を反応させて式［VII］のエステル体を得、これ
をさらに加水分解してカルボン酸［VIII］を製造するこ
とができる。 According to this reaction scheme, the compound [I] of the present invention can be reacted with the compound [VI] to obtain an ester of the formula [VII], which can be further hydrolyzed to produce a carboxylic acid [VIII]. it can.
ここに得られる式［VIII］の化合物は極めて優れた抗菌
力を有し、抗菌剤、特に注射用抗菌剤として価値ある化
合物である。The compound of the formula [VIII] obtained here has extremely excellent antibacterial activity and is a valuable compound as an antibacterial agent, particularly as an injectable antibacterial agent.
次に実施例および参考例を挙げて本発明の化合物の製造
法について説明する。Next, the production method of the compound of the present invention will be described with reference to Examples and Reference Examples.
参考例１ (1)１−ベンジル−３−ヒドロキシ−４−ヒドロキシメ
タルピロリジン110ｇ，トリエチルアミン53.7ｇ，クロ
ロホルム１の混合物を氷冷下攪拌しながら、これにメ
タンスルホニルクロリド60.9ｇのクロロホルム（60ml）
溶液を３〜６℃で滴下する。１時間攪拌した後、飽和重
炭酸ナトリウム水溶液200mlを加えてクロロホルム層を
分ける。クロロホルム層を10％酢酸水溶液で抽出し、水
層を氷冷下に50％苛性ソーダ水溶液でアルカリ性とした
後、クロロホルムで抽出する。乾燥後、溶媒を留去し
て、１−ベンジル−３−ヒドロキシ−４−メチルスルホ
ニルオキシメチルピロリジン81ｇを油状物として得る。Reference Example 1 (1) A mixture of 110 g of 1-benzyl-3-hydroxy-4-hydroxymetalpyrrolidine, 53.7 g of triethylamine and chloroform 1 was stirred under ice-cooling, and 60.9 g of methanesulfonyl chloride in chloroform (60 ml) was added thereto.
The solution is added dropwise at 3-6 ° C. After stirring for 1 hour, 200 ml of saturated aqueous sodium bicarbonate solution is added and the chloroform layer is separated. The chloroform layer is extracted with a 10% aqueous acetic acid solution, the aqueous layer is made alkaline with a 50% aqueous sodium hydroxide solution under ice cooling, and then extracted with chloroform. After drying, the solvent is distilled off to obtain 81 g of 1-benzyl-3-hydroxy-4-methylsulfonyloxymethylpyrrolidine as an oil.
IRスペクトル（液膜）cm-1：3370，1350，1170． マス・スペクトルｍ／ｚ：285（Ｍ＋），208，190，9
1． NMRスペクトル（ＣＤＣｌ３）δ：3.0（３Ｈ，ｓ，ＳＯ
２ＣＨ３），7.32（５Ｈ，ｓ，Ｃ６Ｈ５）． (2)上記化合物50ｇをジメチルホルムアミド200mlに溶か
し、アジ化ナトリウム22.8ｇを加えて120〜130℃で2.5
時間加熱攪拌する。溶媒を減圧下に留去し、残渣に水を
加えてエーテルで抽出する。エーテル層を水洗後乾燥し
濃縮して、３−アジドメチル−１−ベンジル−４−ヒド
ロキシピロリジン30ｇを油状物として得る。IR spectrum (liquid film) cm −1 : 3370, 1350, 1170. Mass spectrum m / z: 285 (M + ), 208, 190, 9
1. NMR spectrum (CDCl 3 ) δ: 3.0 (3H, s, SO
2 CH 3), 7.32 (5H , s, C 6 H 5). (2) Dissolve 50 g of the above compound in 200 ml of dimethylformamide, add 22.8 g of sodium azide, and add 2.5 at 120-130 ° C.
Heat and stir for hours. The solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with ether. The ether layer is washed with water, dried and concentrated to give 30 g of 3-azidomethyl-1-benzyl-4-hydroxypyrrolidine as an oil.
IRスペクトル（液膜）cm-1：3350，2100，1450，1265． マス・スペクトルｍ／ｚ：232（Ｍ＋），175，158，9
1． NMRスペクトル（ＣＤＣｌ３）δ：3.36（２Ｈ，ｄ，Ｊ
＝７Hz，ＣＨ２Ｎ３），3.58（２Ｈ，ｓ，ＣＨ２Ｐ
ｈ），7.31（５Ｈ，ｓ，Ｃ６Ｈ５）． (3)上記化合物8.0ｇをクロロホルム60mlに溶かし、攪拌
下に塩化チオニル10.0ｇを滴下する。この反応混合物を
2.5時間加熱還流した後、減圧で濃縮する。残渣に水と
酢酸エチルを加え、40％苛性ソーダ水溶液でpHを9.0以
上とした後、有機層を分ける。乾燥後溶媒を留去し、残
渣をカラムクロマトグラフィで分離精製して、３−アジ
ドメチル−１−ベンジル−４−クロロピロリジンのトラ
ンス体0.9ｇおよびシス体4.6ｇをそれぞれ油状物として
得る。IR spectrum (liquid film) cm −1 : 3350, 2100, 1450, 1265. Mass spectrum m / z: 232 (M + ), 175, 158, 9
1. NMR spectrum (CDCl 3 ) δ: 3.36 (2H, d, J
= 7 Hz, CH 2 N 3 ), 3.58 (2H, s, CH 2 P
h), 7.31 (5H, s , C 6 H 5). (3) 8.0 g of the above compound is dissolved in 60 ml of chloroform, and 10.0 g of thionyl chloride is added dropwise with stirring. This reaction mixture
After heating under reflux for 2.5 hours, concentrate under reduced pressure. Water and ethyl acetate are added to the residue, the pH is adjusted to 9.0 or higher with 40% aqueous sodium hydroxide solution, and the organic layer is separated. After drying, the solvent is distilled off, and the residue is separated and purified by column chromatography to give 0.9 g of trans form of 3-azidomethyl-1-benzyl-4-chloropyrrolidine and 4.6 g of cis form as oils.
トランス体：IRスペクトル（液膜）cm-1：2800，2100，
740，700． マス・スペクトルｍ／ｚ：250（Ｍ＋），158，91． NMRスペクトル（ＣＤＣｌ３）δ：3.66（２Ｈ，ｓ，Ｃ
Ｈ２Ｐｈ），4.05（１Ｈ，ｍ，Ｃ４−Ｈ），7.34（５
Ｈ，ｓ，Ｃ６Ｈ５）． シス体：IRスペクトル（液膜）cm-1：2880，2100，74
0，700． マス・スペクトルｍ／ｚ：250（Ｍ＋），158，91． NMRスペクトル（ＣＤＣｌ３）δ：3.72（２Ｈ，ｓ，Ｃ
Ｈ２Ｐｈ），4.5（１Ｈ，ｍ，Ｃ４−Ｈ），7.34（５
Ｈ，ｓ，Ｃ６Ｈ５）． 実施例１ (1)ナトリウムビス（２−メトキシエトキシ）アルミニ
ウムヒドリドの70％のトルエン溶液16.6mlをトルエン15
mlに溶かし、氷冷しながらこれにシス−３−アジドメチ
ル−１−ベンジル−４−クロロピロリジン7.2ｇのトル
エン（15ml）溶液を滴下して室温で２時間攪拌する。反
応液に氷水を加え、次いで20％苛性ソーダ水溶液でアル
カリ性とした後、トルエン層を分け、乾燥濃縮して、シ
ス−３−アミノメチル−１−ベンジル−４−クロロピロ
リジンを油状物として得る。Trans form: IR spectrum (liquid film) cm −1 : 2800, 2100,
740, 700. Mass spectrum m / z: 250 (M + ), 158, 91. NMR spectrum (CDCl 3 ) δ: 3.66 (2H, s, C
H 2 Ph), 4.05 (1H , m, C 4 -H), 7.34 (5
H, s, C 6 H 5 ). Cis: IR spectrum (liquid film) cm −1 : 2880, 2100, 74
0,700. Mass spectrum m / z: 250 (M + ), 158, 91. NMR spectrum (CDCl 3 ) δ: 3.72 (2H, s, C
H 2 Ph), 4.5 (1H , m, C 4 -H), 7.34 (5
H, s, C 6 H 5 ). Example 1 (1) 16.6 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene was added to toluene 15
It is dissolved in ml, and a solution of 7.2 g of cis-3-azidomethyl-1-benzyl-4-chloropyrrolidine in toluene (15 ml) is added dropwise thereto while cooling with ice, and the mixture is stirred at room temperature for 2 hours. Ice water was added to the reaction solution, which was then made alkaline with a 20% aqueous sodium hydroxide solution, the toluene layer was separated, dried and concentrated to obtain cis-3-aminomethyl-1-benzyl-4-chloropyrrolidine as an oil.
同様にして、トランス−３−アジドメチル−１−ベンジ
ル−４−クロロピロリジンからトランス−３−アミノメ
チル−１−ベンジル−４−クロロピロリジンを得る。Similarly, trans-3-aminomethyl-1-benzyl-4-chloropyrrolidine is obtained from trans-3-azidomethyl-1-benzyl-4-chloropyrrolidine.
(2)上記化合物（シス体）をトルエン50mlに溶かし、こ
れに氷水と20％苛性ソーダ水溶液を加えてpHを9.0以上
とした後、無水酢酸5.9ｇを添加する。30分後、有機層
を分け、２Ｎ塩酸で抽出する。水層を40％苛性ソーダ水
溶液でアルカリ性とした後、酢酸エチルで抽出する。酢
酸エチル溶液を乾燥後、減圧で濃縮して、シス−３−ア
セチルアミノメチル−１−ベンジル−４−クロロピロリ
ジン5.8ｇを油状物として得る。(2) The above compound (cis form) is dissolved in 50 ml of toluene, and ice water and 20% caustic soda aqueous solution are added to adjust the pH to 9.0 or more, and then 5.9 g of acetic anhydride is added. After 30 minutes, the organic layer is separated and extracted with 2N hydrochloric acid. The aqueous layer is made alkaline with 40% aqueous sodium hydroxide solution and then extracted with ethyl acetate. The ethyl acetate solution was dried and then concentrated under reduced pressure to obtain 5.8 g of cis-3-acetylaminomethyl-1-benzyl-4-chloropyrrolidine as an oil.
IRスペクトル（液膜）cm-1：3300，1650，700． マス・スペクトルｍ／ｚ：266（Ｍ＋），158，91． NMRスペクトル（ＣＤＣｌ３）δ：3.6（２Ｈ，ｓ，ＣＨ
２ＰＨ），4.1（１Ｈ，ｍ，Ｃ４−Ｈ），7.3（５Ｈ，
ｓ，Ｃ６Ｈ５）． 同様にして、上記化合物（トランス体）からトランス−
３−アセチルアミノメチル−１−ベンジル−４−クロロ
ピロリジンを油状物として得る。IR spectrum (liquid film) cm −1 : 3300, 1650, 700. Mass spectrum m / z: 266 (M + ), 158, 91. NMR spectrum (CDCl 3 ) δ: 3.6 (2H, s, CH
2 PH), 4.1 (1H, m, C 4 -H), 7.3 (5H,
s, C 6 H 5). Similarly, from the above compound (trans form), trans-
3-Acetylaminomethyl-1-benzyl-4-chloropyrrolidine is obtained as an oil.
IRスペクトル（液膜）cm-1：3300，1650，700． マス・スペクトルｍ／ｚ：266（Ｍ＋），158，91． NMRスペクトル（ＣＤＣｌ３）δ：3.71（２Ｈ，ｓ，Ｃ
Ｈ２ＰＨ），4.48（１Ｈ，ｍ，Ｃ４−Ｈ），7.33（５
Ｈ，ｓ，Ｃ６Ｈ５）． (3)上記化合物（シス体）17.7ｇを酢酸50mlに溶かし、
５％パラジウム−炭素400mgを加えて水蒸気流下に加水
素分解する。酢酸を減圧で留去した後、アセトニトリル
を加えて放置する。析出する結晶を濾取して、シス−３
−アセチルアミノメチル−４−クロロピロリジン・酢酸
塩７ｇを得る。IR spectrum (liquid film) cm −1 : 3300, 1650, 700. Mass spectrum m / z: 266 (M + ), 158, 91. NMR spectrum (CDCl 3 ) δ: 3.71 (2H, s, C
H 2 PH), 4.48 (1H , m, C 4 -H), 7.33 (5
H, s, C 6 H 5 ). (3) Dissolve 17.7 g of the above compound (cis form) in 50 ml of acetic acid,
5% Palladium-carbon (400 mg) is added and hydrogenolysis is performed under a steam flow. After acetic acid was distilled off under reduced pressure, acetonitrile was added and the mixture was allowed to stand. The precipitated crystals are collected by filtration to give cis-3.
7 g of -acetylaminomethyl-4-chloropyrrolidine acetic acid salt are obtained.
ｍ．ｐ．136〜137℃． 同様にして、上記化合物（トランス体）から、トランス
−３−アセチルアミノメチル−４−クロロピロリジンを
得る。m. p. 136-137 ° C. Similarly, trans-3-acetylaminomethyl-4-chloropyrrolidine is obtained from the above compound (trans form).
参考例２ ３−アジドメチル−１−ベンジル−４−ヒドロキシピロ
リジン32ｇのクロロホルム（300ml）溶液にヘキサフル
オロプロペン−ジエチルアミン64ｇを加えて攪拌下に２
時間加熱還流する。減圧で溶媒を留去し、残渣を酢酸エ
チルに溶かし、15％塩酸で抽出する。水層を冷却しなが
ら20％苛性ソーダ水溶液でアルカリ性とし、酢酸エチル
で抽出する。抽出液を乾燥後濃縮し、残渣（29ｇ）をカ
ラムクロマトグラフィで分離精製して、次の化合物を油
状物として得る。Reference Example 2 To a solution of 3-azidomethyl-1-benzyl-4-hydroxypyrrolidine (32 g) in chloroform (300 ml) was added hexafluoropropene-diethylamine (64 g), and the mixture was stirred to give 2
Heat to reflux for hours. The solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate and extracted with 15% hydrochloric acid. While cooling the aqueous layer, make it alkaline with a 20% aqueous sodium hydroxide solution and extract with ethyl acetate. The extract is dried and concentrated, and the residue (29 g) is separated and purified by column chromatography to give the following compound as an oil.
トランス−３−アジドメチル−１−ベンジル−４−フル
オロピロリジン：3.5ｇ IRスペクトル（液膜）cm-1：2100，1450，1270． マス・スペクトルｍ／ｚ：234（Ｍ＋），177，91． NMRスペクトル（ＣＤＣｌ３）δ：3.64（２Ｈ，ｓ，Ｃ
Ｈ２Ｐｈ），4.5，5.2（１Ｎ，br，C4-H），7.30（５
Ｈ，ｓ，Ｃ６Ｈ５）． シス−３−アジドメチル−１−ベンジル−４−フルオロ
ピロリジン：3.0ｇ IRスペクトル（液膜）cm-1：2100，1450，1270． マス・スペクトルｍ／ｚ：234（Ｍ＋），177，91． NMRスペクトル（ＣＤＣｌ３）δ：3.68（２Ｈ，ｓ，Ｃ
Ｈ２Ｐｈ），4.75，5.45（１Ｈ，br，Ｃ４−Ｈ），7.30
（５Ｈ，ｓ，Ｃ６Ｈ５）． シス体とトランス体の混合物：7.3ｇ 実施例２ (1)実施例１(1)と同様にして、トランス−３−アジドメ
チル−１−ベンジル−４−フルオロピロリジン3.1ｇか
ら得たトランス−３−アミノメチル−１−ベンジル−４
−フルオロピロリジンと無水酢酸７mlを実施例１(2)と
同様に反応処理して、トランス−３−アセチルアミノメ
チル−１−ベンジル−４−フルオロピロリジン2.2ｇを
油状物として得る。Trans-3-azidomethyl-1-benzyl-4-fluoropyrrolidine: 3.5 g IR spectrum (liquid film) cm −1 : 2100, 1450, 1270. Mass spectrum m / z: 234 (M + ), 177, 91. NMR spectrum (CDCl 3 ) δ: 3.64 (2H, s, C
H 2 Ph), 4.5, 5.2 (1N, br, C 4 -H), 7.30 (5
H, s, C 6 H 5 ). Cis-3-azidomethyl-1-benzyl-4-fluoropyrrolidine: 3.0 g IR spectrum (liquid film) cm −1 : 2100, 1450, 1270. Mass spectrum m / z: 234 (M + ), 177, 91. NMR spectrum (CDCl 3 ) δ: 3.68 (2H, s, C
H 2 Ph), 4.75, 5.45 (1H, br, C 4 -H), 7.30
(5H, s, C 6 H 5). Mixture of cis and trans isomers: 7.3 g Example 2 (1) Trans-3-obtained from 3.1 g of trans-3-azidomethyl-1-benzyl-4-fluoropyrrolidine in the same manner as in Example 1 (1). Aminomethyl-1-benzyl-4
-Fluoropyrrolidine and 7 ml of acetic anhydride were treated in the same manner as in Example 1 (2) to give trans-3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine (2.2 g) as an oil.
IRスペクトル（液膜）cm-1：3270，1650，1550． マス・スペクトルｍ／ｚ：250（Ｍ＋），158，91． NMRスペクトル（ＣＤＣｌ３）δ：1.96（３Ｈ，ｓ，Ｃ
ＯＣＨ３），3.61（２Ｈ，ｓ，ＣＨ２Ｐｈ），4.52，5.
22（１Ｈ，br，Ｃ４−Ｈ），7.30（５Ｈ，ｓ，Ｃ
６Ｈ５）． 同様にして、シス−３−アジドメチル−１−ベンジル−
４−フルオロピロリジンから、シス−３−アセチルアミ
ノメチル−１−ベンジル−４−フルオロピロリジンを油
状物として得る。IR spectrum (liquid film) cm −1 : 3270, 1650, 1550. Mass spectrum m / z: 250 (M + ), 158, 91. NMR spectrum (CDCl 3 ) δ: 1.96 (3H, s, C
OCH 3), 3.61 (2H, s, CH 2 Ph), 4.52,5.
22 (1H, br, C 4 -H), 7.30 (5H, s, C
6 H 5 ). Similarly, cis-3-azidomethyl-1-benzyl-
From 4-fluoropyrrolidine, cis-3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine is obtained as an oil.
IRスペクトル（液膜）cm-1：3270，1650，1550． マス・スペクトルｍ／ｚ：250（Ｍ＋），158，91． NMRスペクトル（ＣＤＣｌ３）δ：1.98（３Ｈ，ｓ，Ｃ
ＯＣＨ３），3.66（２Ｈ，ｓ，ＣＨ２Ｐｈ），4.75，5.
48（１Ｈ，br，Ｃ４−Ｈ），7.31（５Ｈ，ｓ，Ｃ
６Ｈ５）． (2)実施例２と同様にして、シス−およびトランス−３
−アセチルアミノメチル−１−ベンジル−４−フルオロ
ピロリジンからシス−およびトランス−３−アセチルア
ミノメチル−４−フルオロピロリジンを得る。IR spectrum (liquid film) cm −1 : 3270, 1650, 1550. Mass spectrum m / z: 250 (M + ), 158, 91. NMR spectrum (CDCl 3 ) δ: 1.98 (3H, s, C
OCH 3), 3.66 (2H, s, CH 2 Ph), 4.75,5.
48 (1H, br, C 4 -H), 7.31 (5H, s, C
6 H 5 ). (2) In the same manner as in Example 2, cis- and trans-3.
-Acetylaminomethyl-1-benzyl-4-fluoropyrrolidine gives cis- and trans-3-acetylaminomethyl-4-fluoropyrrolidine.
参考例３ (1)窒素気流下に攪拌しながらヨー化トリメチルスルホ
キソニウム145ｇをジメチルスルホキシド600mlに溶か
し、これに63％水素化ナトリウム25ｇを15分で加える。
10分後、反応液に１−ベンジル−３−オキソピロリジン
105ｇのジメチルスルホキシド（100ml）溶液を10分で滴
下し、さらにトルエン700ml，水600mlを加える。トルエ
ン層を分け、乾燥後減圧で濃縮する。残渣を減圧蒸留し
て、５−ベンジル−１−オキサ−５−アザスピロ［2,
4］ヘプタン78ｇを得る。Reference Example 3 (1) 145 g of trimethylsulfoxonium iodide was dissolved in 600 ml of dimethyl sulfoxide while stirring under a nitrogen stream, and 25 g of 63% sodium hydride was added thereto in 15 minutes.
After 10 minutes, 1-benzyl-3-oxopyrrolidine was added to the reaction solution.
A solution of 105 g of dimethyl sulfoxide (100 ml) was added dropwise over 10 minutes, and 700 ml of toluene and 600 ml of water were further added. The toluene layer is separated, dried and concentrated under reduced pressure. The residue was distilled under reduced pressure to give 5-benzyl-1-oxa-5-azaspiro [2,
4] Obtain 78 g of heptane.
ｂ．ｐ．130〜135℃／3.5mmHg． IRスペクトル（液膜）cm-1：2980，2800，1130，700． マス・スペクトルｍ／ｚ：189（Ｍ＋），159，91． (2)上記化合物60ｇを氷冷攪拌下に70％フッ化水素−ピ
リジン120ml中に10分で滴下する。５時間後反応液を氷
水400ml中に注ぎ30％苛性ソーダ水溶液100mlを加えてア
ルカリ性とする。析出物を濾去し濾液をクロロホルムで
抽出する。抽出液を乾燥後濃縮して、１−ベンジル−３
−フルオロ−３−ヒドロキシメチルピロリジンと１−ベ
ンジル−３−フルオロメチル−３−ヒドロキシピロリジ
ンの混合物65ｇを得る。この混合物をピリジン中無水酢
酸14.4ｇでアセチル化して油状物68ｇを得る。これをカ
ラムクロマトグラフィで分離精製して、３−アセチルオ
キシメチル−１−ベンジル−３−フルオロピロリジン36
ｇを得る。この化合物にメタノール100mlと10％苛性ソ
ーダ100mlを加え10分間加熱還流する。反応液に水100ml
とクロロホルム300mlを加えた後クロロホルム層を分け
濃縮する。残渣を減圧蒸留して、１−ベンジル−３−フ
ルオロ−３−ヒドロキシメチルピロリジン18.6ｇを得
る。b. p. 130-135 ℃ / 3.5mmHg. IR spectrum (liquid film) cm −1 : 2980, 2800, 1130, 700. Mass spectrum m / z: 189 (M + ), 159, 91. (2) 60 g of the above compound was added dropwise to 120 ml of 70% hydrogen fluoride-pyridine over 10 minutes while stirring with ice cooling. After 5 hours, the reaction solution is poured into 400 ml of ice water and 100 ml of 30% aqueous sodium hydroxide solution is added to make the mixture alkaline. The precipitate is filtered off and the filtrate is extracted with chloroform. The extract was dried and concentrated to give 1-benzyl-3.
65 g of a mixture of -fluoro-3-hydroxymethylpyrrolidine and 1-benzyl-3-fluoromethyl-3-hydroxypyrrolidine are obtained. This mixture is acetylated with 14.4 g of acetic anhydride in pyridine to give 68 g of an oil. This is separated and purified by column chromatography to give 3-acetyloxymethyl-1-benzyl-3-fluoropyrrolidine 36
get g. To this compound, 100 ml of methanol and 100 ml of 10% caustic soda are added, and the mixture is heated under reflux for 10 minutes. 100 ml of water in the reaction solution
And 300 ml of chloroform are added, and the chloroform layer is separated and concentrated. The residue is distilled under reduced pressure to obtain 18.6 g of 1-benzyl-3-fluoro-3-hydroxymethylpyrrolidine.
ｂ．ｐ．133〜137℃／１mmHg IRスペクトル（液膜）cm-1：3350，1050，700． マス・スペクトルｍ／ｚ：209（Ｍ＋），132，91． (3)上記化合物2.6ｇのクロロホルム（20ml）溶液に、氷
冷下トリエチルアミン1.26ｇとメタンスルホニルクロリ
ド1.2ｇを加え16時間攪拌する。反応液に水20mlを加え
てクロロホルム層を分け、乾燥後濃縮し、残渣をカラム
クロマトグラフィで分離精製して、１−ベンジル−３−
フルオロ−３−メチルスルホニルオキシメチルピロリジ
ン3.2ｇを油状物として得る。b. p. 133-137 ℃ / 1mmHg IR spectrum (liquid film) cm −1 : 3350, 1050, 700. Mass spectrum m / z: 209 (M + ), 132, 91. (3) To a solution of 2.6 g of the above compound in chloroform (20 ml), 1.26 g of triethylamine and 1.2 g of methanesulfonyl chloride were added under ice cooling, and the mixture was stirred for 16 hours. 20 ml of water was added to the reaction solution, the chloroform layer was separated, dried and concentrated, and the residue was separated and purified by column chromatography to give 1-benzyl-3-
3.2 g of fluoro-3-methylsulfonyloxymethylpyrrolidine are obtained as an oil.
IRスペクトル（液膜）cm-1：1350，1270，700． マス・スペクトルｍ／ｚ：287（Ｍ＋），192，91． NMRスペクトル（ＣＤＣｌ３）δ：3.05（３Ｈ，ｓ，Ｓ
Ｏ２ＣＨ３），3.65（２Ｈ，ｓ，ＣＨ２Ｐｈ）． (4)上記化合物3.1ｇ，アジ化ナトリウム1.4ｇ，ジメチ
ルホルムアミド30mlの混合物を120〜130℃で３時間攪拌
する。析出物を濾去し濾液を減圧濃縮する。残渣に水20
mlとクロロホルム20mlを加えた後クロロホルム層を分け
乾燥濃縮する。残渣をカラムクロマトグラフィで分離精
製して、３−アジドメチル−１−ベンジル−３−フルオ
ロピロリジン2.0ｇに油状物として得る。IR spectrum (liquid film) cm −1 : 1350, 1270, 700. Mass spectrum m / z: 287 (M + ), 192, 91. NMR spectrum (CDCl 3 ) δ: 3.05 (3H, s, S
O 2 CH 3), 3.65 ( 2H, s, CH 2 Ph). (4) A mixture of 3.1 g of the above compound, 1.4 g of sodium azide and 30 ml of dimethylformamide is stirred at 120 to 130 ° C. for 3 hours. The precipitate is filtered off and the filtrate is concentrated under reduced pressure. Water on the residue 20
ml and chloroform 20 ml are added, and the chloroform layer is separated and dried and concentrated. The residue is separated and purified by column chromatography to give 2.0 g of 3-azidomethyl-1-benzyl-3-fluoropyrrolidine as an oil.
IRスペクトル（液膜）cm-1：1350，1270，700． マス・スペクトルｍ／ｚ：287（Ｍ＋），210，91． NMRスペクトル（ＣＤＣｌ３）δ：3.05（３Ｈ，ｓ，Ｓ
Ｏ２ＣＨ３），3.65（２Ｈ，ｓ，ＣＨ２Ｐｈ），7.30
（５Ｈ，ｓ，Ｃ６Ｈ５）． 実施例３ (1)３−アジドメチル−１−ベンジル−３−フルオロピ
ロリジン2.0ｇとナトリウムビス（２−メトキシエトキ
シ）アルミニウムヒドリドの70％トルエン溶液20mlを用
い、実施例１(1)と同様に反応処理して、３−アミノメ
チル−１−ベンジル−３−フルオロピロリジンを得る。IR spectrum (liquid film) cm −1 : 1350, 1270, 700. Mass spectrum m / z: 287 (M + ), 210, 91. NMR spectrum (CDCl 3 ) δ: 3.05 (3H, s, S
O 2 CH 3 ), 3.65 (2H, s, CH 2 Ph), 7.30
(5H, s, C 6 H 5). Example 3 (1) The same reaction as in Example 1 (1) was performed using 2.0 g of 3-azidomethyl-1-benzyl-3-fluoropyrrolidine and 20 ml of 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride. Work-up gives 3-aminomethyl-1-benzyl-3-fluoropyrrolidine.
(2)上記化合物と無水酢酸1.1ｇを実施例１(2)と同様に
反応処理した後、カラムクロマトグラフィで分離精製し
て、３−アセチルアミノメチル−１−ベンジル−３−フ
ルオロピロリジン1.7ｇを油状物として得る。(2) The above compound and 1.1 g of acetic anhydride were treated in the same manner as in Example 1 (2), and then separated and purified by column chromatography to give 1.7 g of 3-acetylaminomethyl-1-benzyl-3-fluoropyrrolidine. Obtained as an oil.
IRスペクトル（液膜）cm-1：3150，1650，1550，700． マス・スペクトルｍ／ｚ：250（Ｍ＋），230，91． NMRスペクトル（ＣＤＣｌ３）δ：1.98（３Ｈ，ｓ，Ｃ
ＯＣＨ３），3.66（２Ｈ，ｓ，ＣＨ２Ｐｈ），7.30（５
Ｈ，ｓ，Ｃ６Ｈ５）． (3)上記化合物3.7ｇのアルコール（80ml）溶液に５％パ
ラジウム−炭素300mgを加え、水素気流下50〜60℃で加
水素分解する。触媒を濾去し溶媒を留去して、３−アセ
チルアミノメチル−３−フルオロピロリジン2.3ｇを得
る。IR spectrum (liquid film) cm −1 : 3150, 1650, 1550, 700. Mass spectrum m / z: 250 (M + ), 230, 91. NMR spectrum (CDCl 3 ) δ: 1.98 (3H, s, C
OCH 3 ), 3.66 (2H, s, CH 2 Ph), 7.30 (5
H, s, C 6 H 5 ). (3) To a solution of 3.7 g of the above compound in alcohol (80 ml), 300 mg of 5% palladium-carbon was added, and hydrogenolysis was carried out at 50-60 ° C under a hydrogen stream. The catalyst is filtered off and the solvent is distilled off to obtain 2.3 g of 3-acetylaminomethyl-3-fluoropyrrolidine.
ｍ．ｐ．122〜125℃． 参考例４ トランス−３−アジドメチル−１−ベンジル−４−ヒド
ロキシピロリジン10ｇをテトラヒドロフラン50mlに溶か
し、氷冷下に60％水素化ナトリウム2.1ｇとヨー化メチ
ル7.3ｇを加える。２時間攪拌した後、水を加えエーテ
ルで抽出し、エーテルを留去後、残渣をカラムクロマト
グラフィで分離精製して、トランス−３−アジドメチル
−１−ベンジル−４−メトキシピロリジン4.7ｇを油状
物として得る。m. p. 122-125 ° C. Reference Example 4 10 g of trans-3-azidomethyl-1-benzyl-4-hydroxypyrrolidine is dissolved in 50 ml of tetrahydrofuran, and 2.1 g of 60% sodium hydride and 7.3 g of methyl iodide are added under ice cooling. After stirring for 2 hours, water was added, the mixture was extracted with ether, the ether was evaporated, and the residue was separated and purified by column chromatography to give trans-3-azidomethyl-1-benzyl-4-methoxypyrrolidine (4.7 g) as an oil. obtain.
IRスペクトル（液膜）cm-1：2100． マス・スペクトルｍ／ｚ：246（Ｍ＋），158． NMRスペクトル（ＣＤＣｌ３）δ：3.30（３Ｈ，ｓ，Ｏ
ＣＨ３），3.60（２Ｈ，ｓ，ＣＨ２Ｐｈ），7.28（５
Ｈ，ｓ，Ｃ６Ｈ５）． 実施例４ (1)トランス−３−アジドメチル−１−ベンジル−４−
メトキシピロリジン4.7ｇとナトリウムビス（２−メト
キシエトキシ）アルミニウムヒドリドの70％のトルエン
溶液15mlを用い、実施例１(1)と同様に反応処理して、
トランス−３−アミノメチル−１−ベンジル−４−メト
キシピロリジンを得る。IR spectrum (liquid film) cm -1 : 2100. Mass spectrum m / z: 246 (M + ), 158. NMR spectrum (CDCl 3 ) δ: 3.30 (3H, s, O
CH 3 ), 3.60 (2H, s, CH 2 Ph), 7.28 (5
H, s, C 6 H 5 ). Example 4 (1) trans-3-azidomethyl-1-benzyl-4-
Using 4.7 g of methoxypyrrolidine and 15 ml of a 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride, a reaction treatment was carried out in the same manner as in Example 1 (1),
Trans-3-aminomethyl-1-benzyl-4-methoxypyrrolidine is obtained.
(2)上記化合物と無水酢酸5.6ｇを実施例１(2)と同様に
反応処理して、トランス−３−アセチルアミノメチル−
１−ベンジル−４−メトキシピロリジン4.4ｇを油状物
として得る。(2) The above compound and 5.6 g of acetic anhydride were treated in the same manner as in Example 1 (2) to give trans-3-acetylaminomethyl-
4.4 g of 1-benzyl-4-methoxypyrrolidine are obtained as an oil.
IRスペクトル（液膜）cm-1：3300． マス・スペクトルｍ／ｚ：262（Ｍ＋），171，158． NMRスペクトル（ＣＤＣｌ３）δ：1.98（３Ｈ，ｓ，Ｃ
ＯＣＨ３），3.28（３Ｈ，ｓ，ＯＣＨ３），3.60（２
Ｈ，ｓ，ＣＨ２Ｐｈ），7.25（５Ｈ，ｓ，Ｃ６Ｈ５）． (3)実施例２と同様にして、トランス−３−アセチルア
ミノメチル−１−ベンジル−４−メトキシピロリジンか
らトランス−３−アセチルアミノメチル−４−メトキシ
ピロリジンを得る。IR spectrum (liquid film) cm -1 : 3300. Mass spectrum m / z: 262 (M + ), 171, 158. NMR spectrum (CDCl 3 ) δ: 1.98 (3H, s, C
OCH 3 ), 3.28 (3H, s, OCH 3 ), 3.60 (2
H, s, CH 2 Ph) , 7.25 (5H, s, C 6 H 5). (3) Trans-3-acetylaminomethyl-4-methoxypyrrolidine was obtained from trans-3-acetylaminomethyl-1-benzyl-4-methoxypyrrolidine in the same manner as in Example 2.
参考例５ (1)Ｎ−（２−シアノエチル）ベンジルアミン32ｇをア
セトニトリル120mlに溶かしこれに炭酸ナトリウム32ｇ
とクロロ酢酸エチルを加えて攪拌下に13時間加熱還流す
る。不溶物を濾去した後溶媒を留去し、残渣にトルエン
200mlと水を加える。トルエン層を分け、10％酢酸水溶
液で洗い、乾燥後溶媒を留去して、Ｎ−エトキシカルボ
ニルメチル−Ｎ−（２−シアノエチル）ベンジルアミン
41ｇを得る。Reference Example 5 (1) 32 g of N- (2-cyanoethyl) benzylamine was dissolved in 120 ml of acetonitrile, and 32 g of sodium carbonate was added thereto.
And ethyl chloroacetate are added and the mixture is heated under reflux for 13 hours with stirring. The insoluble material was filtered off, the solvent was distilled off, and the residue was toluene.
Add 200 ml and water. The toluene layer was separated, washed with 10% acetic acid aqueous solution, dried and the solvent was distilled off to give N-ethoxycarbonylmethyl-N- (2-cyanoethyl) benzylamine.
41 g are obtained.
(2)上記化合物28ｇをトルエン200mlに溶かし、室温でナ
トリウムエトキシドの28％のメタノール溶液28mlを滴下
する。70℃で１時間加熱した後冷却する。析出する結晶
を濾取しトルエンで洗って、１−ベンジル−３−シアノ
−４−オキソピロリジンのナトリウム塩20ｇを得る。(2) 28 g of the above compound is dissolved in 200 ml of toluene, and 28 ml of a 28% methanol solution of sodium ethoxide is added dropwise at room temperature. Heat at 70 ° C. for 1 hour and then cool. The precipitated crystals are collected by filtration and washed with toluene to obtain 20 g of 1-benzyl-3-cyano-4-oxopyrrolidine sodium salt.
ｍ．ｐ．207〜210℃（分解） IRスペクトル（ＫＢｒ）cm-1：2170，1560． (3)上記化合物100ｇと水150mlの混合物に12〜15℃でナ
トリウムボロンヒドリド16ｇを含む１Ｎ苛性ソーダ水溶
液（100ml）を加える。酢酸56mlと水200mlの混液を滴下
しクロロホルムで抽出する。抽出液を乾燥し濃縮した
後、残渣にイソプロピルアルコール150mlとヘキサン200
mlを加えて４℃で17時間放置する。析出する結晶を濾去
し、濾液を濃縮して、トランス−１−ベンジル−４−ヒ
ドロキシ−３−シアノピロリジン50ｇを油状物として得
る。（本品は約10％のシス体を含む。） IRスペクトル（液膜）cm-1：3430，2240，700． マス・スペクトルｍ／ｚ：202（Ｍ＋），91，42． (4)上記化合物50ｇをアルコール150mlと12％アルコール
性アンモニア100ml中で、ラネーニッケル13mlを触媒と
して接触還元する。触媒を濾去し濾液を減圧濃縮して、
トランス−３−アミノメチル−１−ベンジル−４−ヒド
ロキシピロリジン48ｇを油状物として得る。m. p. 207-210 ° C (decomposition) IR spectrum (KBr) cm -1 : 2170, 1560. (3) To a mixture of 100 g of the above compound and 150 ml of water, at 12 to 15 ° C., an aqueous 1N caustic soda solution (100 ml) containing 16 g of sodium boron hydride is added. A mixed solution of 56 ml of acetic acid and 200 ml of water is added dropwise and extracted with chloroform. After the extract was dried and concentrated, the residue was added with 150 ml of isopropyl alcohol and 200 ml of hexane.
Add ml and leave at 4 ° C for 17 hours. Precipitated crystals are filtered off and the filtrate is concentrated to obtain 50 g of trans-1-benzyl-4-hydroxy-3-cyanopyrrolidine as an oil. (This product contains about 10% of cis isomer.) IR spectrum (liquid film) cm −1 : 3430, 2240, 700. Mass spectrum m / z: 202 (M + ), 91, 42. (4) 50 g of the above compound is catalytically reduced in 150 ml of alcohol and 100 ml of 12% alcoholic ammonia using 13 ml of Raney nickel as a catalyst. The catalyst was filtered off, the filtrate was concentrated under reduced pressure,
48 g of trans-3-aminomethyl-1-benzyl-4-hydroxypyrrolidine are obtained as an oil.
２シュウ酸塩：ｍ．ｐ．167〜171℃． 実施例５ (1)塩化チオニル53mlをクロロホルム300mlに溶かし、こ
れにトランス−３−アミノメチル−１−ベンジル−４−
ヒドロキシピロリジン50ｇのクロロホルム（200ml）溶
液を80℃で滴下する。攪拌下に約3.5時間加熱還流した
後反応液を約半量に濃縮し、これに水200mlを滴下す
る。水層を分け、50％の苛性ソーダ水溶液でアルカリ性
とし、酢酸エチルで抽出する。抽出液を乾燥後濃縮し
て、シス−３−アミノメチル−１−ベンジル−４−クロ
ロピロリジン48ｇを得る。Dioxalate: m.p. p. 167-171 ° C. Example 5 (1) Thionyl chloride (53 ml) was dissolved in chloroform (300 ml), and trans-3-aminomethyl-1-benzyl-4- was added thereto.
A solution of 50 g of hydroxypyrrolidine in chloroform (200 ml) is added dropwise at 80 ° C. After heating and refluxing for about 3.5 hours with stirring, the reaction solution is concentrated to about half volume, and 200 ml of water is added dropwise thereto. Separate the aqueous layer, make alkaline with 50% aqueous sodium hydroxide and extract with ethyl acetate. The extract is dried and concentrated to give 48 g of cis-3-aminomethyl-1-benzyl-4-chloropyrrolidine.
本品をジオキサンと水の混合溶媒中でシュウ酸塩とし、
再結晶して、シス−３−アミノメチル−１−ベンジル−
４−クロロピロリジン・２シュウ酸塩74ｇを得る。Make this product an oxalate salt in a mixed solvent of dioxane and water,
Recrystallize to give cis-3-aminomethyl-1-benzyl-
74 g of 4-chloropyrrolidine dioxalate are obtained.
ｍ．ｐ．156〜159℃． (2)シス−３−アミノメチル−１−ベンジル−４−クロ
ロピロリジン・２シュウ酸塩14.6ｇを水に懸濁させ、こ
れに苛性カリウム12ｇを含む水溶液を加えてクロロホル
ムで抽出する。抽出液を乾燥した後無水酢酸4.4ｇを加
える。反応液を10％塩酸で抽出し、抽出液を40％苛性ソ
ーダ水溶液でアルカリ性とした後、クロロホルムで抽出
する。クロロホルム溶液を乾燥した後濃縮して、シス−
３−アセチルアミノメチル−１−ベンジル−４−クロロ
ピロリジン7.7ｇを得る。本品は実施例１(2)で得たもの
と同一であった。m. p. 156-159 ° C. (2) 14.6 g of cis-3-aminomethyl-1-benzyl-4-chloropyrrolidine dioxalate is suspended in water, an aqueous solution containing 12 g of potassium caustic is added thereto, and the mixture is extracted with chloroform. After drying the extract, 4.4 g of acetic anhydride is added. The reaction mixture is extracted with 10% hydrochloric acid, the extract is made alkaline with 40% aqueous sodium hydroxide solution, and then extracted with chloroform. The chloroform solution was dried and then concentrated to give cis-
7.7 g of 3-acetylaminomethyl-1-benzyl-4-chloropyrrolidine are obtained. This product was the same as that obtained in Example 1 (2).
(3)シス−３−アミノメチル−１−ベンジル−４−クロ
ロピロリジン・２シュウ酸塩10ｇを水60mlに懸濁し、パ
ラジウム炭素を用いて60℃で加水素分解する。触媒を濾
去し濃縮後アルコールを加える。析出する結晶を濾取し
て、シス−３−アミノメチル−４−クロロピロリジン・
２シュウ酸塩5.6ｇを得る。(3) 10 g of cis-3-aminomethyl-1-benzyl-4-chloropyrrolidine dioxalate is suspended in 60 ml of water, and hydrogenolysis is carried out at 60 ° C. using palladium carbon. The catalyst is filtered off, concentrated and alcohol is added. The precipitated crystals were collected by filtration to give cis-3-aminomethyl-4-chloropyrrolidine.
5.6 g of dioxalate are obtained.
ｍ．ｐ．199〜201℃（分解） NMRスペクトル（ＤＭＳＯ−ｄ６）δ：4.95（１Ｈ，b
s，Ｃ４−Ｈ）． 参考例６ (1)Ｎ−（２−シアノエチル）ベンジルアミン40ｇ，ト
リエチルアミン56ｇ，アセトニトリル300mlの混合物に
クロロアセトン46ｇのアセトニトリル（80ml）溶液を滴
下する。滴下後６時間加熱還流し、析出物を濾去する。
溶媒を留去した後、残渣をクロロホルムに溶かし、１Ｎ
塩酸で抽出する。塩酸層を20％苛性ソーダ水溶液でアル
カリ性とし、クロロホルムで抽出する。乾燥後、溶媒を
留去して、Ｎ−アセトニル−Ｎ−（２−シアノエチル）
ベンジルアミン30ｇを油状物として得る。m. p. 199-201 ° C (decomposition) NMR spectrum (DMSO-d 6 ) δ: 4.95 (1H, b
s, C 4 -H). Reference Example 6 (1) To a mixture of 40 g of N- (2-cyanoethyl) benzylamine, 56 g of triethylamine and 300 ml of acetonitrile, a solution of 46 g of chloroacetone in 80 ml of acetonitrile was added dropwise. After the dropping, the mixture is heated under reflux for 6 hours, and the precipitate is filtered off.
After distilling off the solvent, the residue was dissolved in chloroform and
Extract with hydrochloric acid. The hydrochloric acid layer is made alkaline with a 20% aqueous sodium hydroxide solution and extracted with chloroform. After drying, the solvent was distilled off to give N-acetonyl-N- (2-cyanoethyl).
30 g of benzylamine are obtained as an oil.
IRスペクトル（液膜）cm-1：2250，1710，740． マス・スペクトルｍ／ｚ：216（Ｍ＋），197，91． NMRスペクトル（ＣＤＣｌ３）δ：2.10（３Ｈ，ｓ，Ｃ
ＯＣＨ３）． (2)上記化合物9.0ｇのメタノール（150ml）溶液にナト
リウムボロンヒドリド0.9ｇを加え、一夜放置する。溶
媒を留去し、クロロホルムおよび水を加え、クロロホル
ム層を分け乾燥する。溶媒を留去し、残渣をカラムクロ
マトグラフィで分離精製して、Ｎ−（２−シアノエチ
ル）−Ｎ−（２−ヒドロキシプロピル）ベンジルアミン
7.3ｇを油状物として得る。IR spectrum (liquid film) cm −1 : 2250, 1710, 740. Mass spectrum m / z: 216 (M + ), 197, 91. NMR spectrum (CDCl 3 ) δ: 2.10 (3H, s, C
OCH 3). (2) To a solution of 9.0 g of the above compound in methanol (150 ml) was added 0.9 g of sodium boron hydride, and the mixture was allowed to stand overnight. The solvent is distilled off, chloroform and water are added, and the chloroform layer is separated and dried. The solvent was distilled off, and the residue was separated and purified by column chromatography to give N- (2-cyanoethyl) -N- (2-hydroxypropyl) benzylamine.
7.3 g are obtained as an oil.
マス・スペクトルｍ／ｚ：218（Ｍ＋），173，91． NMRスペクトル（ＣＤＣｌ３）δ：1.12（３Ｈ，ｄ，Ｊ
＝７Hz， 7.30（５Ｈ，ｓ，Ｃ６Ｈ５）． (3)上記化合物27.5ｇのクロロホルム（300ml）溶液に塩
化チオニル30ｇを滴下し１時間加熱還流する。冷後氷水
を加え、50％苛性ソーダ水溶液でアルカリ性としクロロ
ホルム層を分ける。乾燥後クロロホルムを留去して、Ｎ
−（２−クロロプロピル）−２−シアノエチルベンジル
アミン24ｇを油状物として得る。Mass spectrum m / z: 218 (M + ), 173, 91. NMR spectrum (CDCl 3 ) δ: 1.12 (3H, d, J
= 7Hz, 7.30 (5H, s, C 6 H 5). (3) Thionyl chloride (30 g) was added dropwise to a solution of the compound (27.5 g) in chloroform (300 ml), and the mixture was heated under reflux for 1 hour. After cooling, add ice water, make alkaline with 50% caustic soda solution, and separate the chloroform layer. After drying, the chloroform is distilled off and N
24 g of-(2-chloropropyl) -2-cyanoethylbenzylamine are obtained as an oil.
IRスペクトル（液膜）cm-1：2250，1450，740． マス・スペクトルｍ／ｚ：236（Ｍ＋），196，91． NMRスペクトル（ＣＤＣｌ３）δ：1.50（３Ｈ，ｄ，Ｊ
＝７Hz， 3.70（２Ｈ，ｓ，ＣＨ２Ｐｈ），7.30（５Ｈ，ｓ，Ｃ６
Ｈ５）． (4)ジメチルスルホキシド100mlとトルエン200mlの混液
にカリウムｔ−プトキシド16ｇを溶かし、これに上記化
合物26ｇのトルエン（300ml）溶液を滴下した後一夜放
置する。水を加えトルエン層を分け、水洗後乾燥する。
溶媒を留去し、残渣をカラムクロマトグラフィで分離精
製して、次の化合物を油状物として得る。IR spectrum (liquid film) cm −1 : 2250, 1450, 740. Mass spectrum m / z: 236 (M + ), 196, 91. NMR spectrum (CDCl 3 ) δ: 1.50 (3H, d, J
= 7Hz, 3.70 (2H, s, CH 2 Ph), 7.30 (5H, s, C 6
H 5). (4) 16 g of potassium t-ptoxide was dissolved in a mixed solution of 100 ml of dimethyl sulfoxide and 200 ml of toluene, and a solution of 26 g of the above compound in toluene (300 ml) was added dropwise thereto, and the mixture was allowed to stand overnight. Water is added and the toluene layer is separated, washed with water and dried.
The solvent is distilled off, and the residue is separated and purified by column chromatography to obtain the next compound as an oily substance.
トランス−１−ベンジル−３−シアノ−４−メチルピロ
リジン：3.13ｇ IRスペクトル（液膜）cm-1：2240，1450，700． マス・スペクトルｍ／ｚ：200（Ｍ＋），133，91． NMRスペクトル（ＣＤＣｌ３）δ：1.15（３Ｈ，ｄ，Ｊ
＝６Hz， 3.60（２Ｈ，ｓ，ＣＨ２Ｐｈ），7.30（５Ｈ，ｓ，Ｃ６
Ｈ５）． シス−１−ベンジル−３−シアノ−４−メチルピロリジ
ン：1.0ｇ IRスペクトル（液膜）cm-1：2240，1450，700． マス・スペクトルｍ／ｚ：200（Ｍ＋），133，91． NMRスペクトル（ＣＤＣｌ３）δ：1.21（３Ｈ，ｄ，Ｊ
＝６Hz， 3.60（２Ｈ，ｓ，ＣＨ２Ｐｈ），7.30（５Ｈ，ｓ，Ｃ６
Ｈ５）． トランス体とシス体の混合物：11ｇ 実施例６ (1)シス−１−ベンジル−３−シアノ−４−メチルピロ
リジン1.0ｇをアルコール30ml中、ラネーニッケル１ml
を触媒として加水素分解する。触媒を濾去した後溶媒を
留去して、シス−３−アミノメチル−１−ベンジル−４
−メチルピロリジンを油状物として得る。Trans-1-benzyl-3-cyano-4-methylpyrrolidine: 3.13 g IR spectrum (liquid film) cm −1 : 2240, 1450, 700. Mass spectrum m / z: 200 (M + ), 133, 91. NMR spectrum (CDCl 3 ) δ: 1.15 (3H, d, J
= 6Hz, 3.60 (2H, s, CH 2 Ph), 7.30 (5H, s, C 6
H 5). Cis-1-benzyl-3-cyano-4-methylpyrrolidine: 1.0 g IR spectrum (liquid film) cm −1 : 2240, 1450, 700. Mass spectrum m / z: 200 (M + ), 133, 91. NMR spectrum (CDCl 3 ) δ: 1.21 (3H, d, J
= 6Hz, 3.60 (2H, s, CH 2 Ph), 7.30 (5H, s, C 6
H 5). Mixture of trans form and cis form: 11 g Example 6 (1) 1.0 g of cis-1-benzyl-3-cyano-4-methylpyrrolidine in 1 ml of Raney nickel in 30 ml of alcohol
Is used as a catalyst for hydrogenolysis. After the catalyst was filtered off, the solvent was distilled off to give cis-3-aminomethyl-1-benzyl-4.
-Methylpyrrolidine is obtained as an oil.
同様にして、トランス−１−ベンジル−３−シアノ−４
−メチルピロリジンからトランス−３−アミノメチル−
１−ベンジル−４−メチルピロリジンを得る。Similarly, trans-1-benzyl-3-cyano-4
-Methylpyrrolidine to trans-3-aminomethyl-
1-benzyl-4-methylpyrrolidine is obtained.
(2)上記化合物（シス体）をクロロホルム20mlにとか
し、無水酢酸0.7mlを加える。１時間後10％苛性ソーダ
水溶液を加えてクロロホルム層を分け、乾燥後クロロホ
ルムを留去して、シス−３−アセチルアミノメチル−１
−ベンジル−４−メチルピロリジン1.2ｇを油状物とし
て得る。(2) The above compound (cis form) is dissolved in 20 ml of chloroform, and 0.7 ml of acetic anhydride is added. After 1 hour, 10% aqueous caustic soda solution was added to separate the chloroform layer, and after drying, chloroform was distilled off to give cis-3-acetylaminomethyl-1.
1.2 g of -benzyl-4-methylpyrrolidine are obtained as an oil.
IRスペクトル（液膜）cm-1：3300，1650，1550，700． マス・スペクトルｍ／ｚ：246（Ｍ＋），174，91． NMRスペクトル（ＣＤＣｌ３）δ：0.95（３Ｈ，ｄ，Ｊ
＝７Hz， 1.94（３Ｈ，ｓ，ＣＯＣＨ３），7.25（５Ｈ，ｓ，Ｃ６
Ｈ５）． 同様にして、上記化合物（トランス体）から、トランス
−３−アセチルアミノメチル−１−ベンジル−４−メチ
ルピロリジンを油状物として得る。IR spectrum (liquid film) cm −1 : 3300, 1650, 1550, 700. Mass spectrum m / z: 246 (M + ), 174, 91. NMR spectrum (CDCl 3 ) δ: 0.95 (3H, d, J
= 7Hz, 1.94 (3H, s, COCH 3 ), 7.25 (5H, s, C 6
H 5). Similarly, trans-3-acetylaminomethyl-1-benzyl-4-methylpyrrolidine is obtained as an oil from the above compound (trans form).
IRスペクトル（液膜）cm-1：3300，1650，1550，700． マス・スペクトルｍ／ｚ：246（Ｍ＋），159，91． NMRスペクトル（ＣＤＣｌ３）δ：1.05（３Ｈ，ｄ，Ｊ
＝６Hz， 1.95（３Ｈ，ｓ，ＣＯＣＨ３），7.28（５Ｈ，ｓ，Ｃ６
Ｈ５）． (3)実施例２と同様にして、シス−およびトランス−３
−アセチルアミノメチル−１−ベンジル−４−メチルピ
ロリジンからシス−およびトランス−３−アセチルアミ
ノメチル−４−メチルピロリジンを得る。IR spectrum (liquid film) cm −1 : 3300, 1650, 1550, 700. Mass spectrum m / z: 246 (M + ), 159, 91. NMR spectrum (CDCl 3 ) δ: 1.05 (3H, d, J
= 6Hz, 1.95 (3H, s, COCH 3 ), 7.28 (5H, s, C 6
H 5). (3) In the same manner as in Example 2, cis- and trans-3.
-Acetylaminomethyl-1-benzyl-4-methylpyrrolidine gives cis- and trans-3-acetylaminomethyl-4-methylpyrrolidine.
実施例７ (1)シス−９−アジドメチル−１−ベンジル−４−フル
オロピロリジン4.5ｇをナトリウムビス（２−メトキシ
エトキシ）アルミニウムヒドリドの70％のトルエン溶液
35mlとトルエン50mlの混合物中に氷冷下で滴下する。室
温で２日間放置した後、これに氷水および20％苛性ソー
ダ水溶液３mlを加える。トルエン層を分け、乾燥後濃縮
して、シス−３−アミノメチル−１−ベンジル−４−フ
ルオロピロリジン５ｇを油状物として得る。Example 7 (1) 4.5 g of cis-9-azidomethyl-1-benzyl-4-fluoropyrrolidine was added to a 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride.
It is added dropwise to a mixture of 35 ml and 50 ml of toluene under ice cooling. After standing at room temperature for 2 days, ice water and 3 ml of 20% aqueous sodium hydroxide solution are added thereto. The toluene layer is separated, dried and concentrated to give 5 g of cis-3-aminomethyl-1-benzyl-4-fluoropyrrolidine as an oil.
(2)100％蟻酸20mlを氷冷し、これに無水酢酸12mlを加え
る。この混合物に上記化合物５ｇを加えて約１時間攪拌
する。減圧下に濃縮し、飽和重炭酸ソーダ水溶液を加え
てアルカリ性とした後、クロロホルムで抽出する。抽出
液を乾燥し濃縮して、シス−１−ベンジル−４−フルオ
ロ−３−ホルミルアミノメチルピロリジン４ｇを得る。(2) 20 ml of 100% formic acid is cooled with ice, and 12 ml of acetic anhydride is added thereto. 5 g of the above compound is added to this mixture and stirred for about 1 hour. Concentrate under reduced pressure, add saturated aqueous sodium bicarbonate to make it alkaline, and then extract with chloroform. The extract is dried and concentrated to give 4 g of cis-1-benzyl-4-fluoro-3-formylaminomethylpyrrolidine.
IRスペクトル（液膜）cm-1：3300，1670，700． マス・スペクトルｍ／ｚ：236（Ｍ＋），158，91． NMRスペクトル（ＣＤＣｌ３）δ：3.65（２Ｈ，ｓ，Ｃ
Ｈ２Ｐｈ），5.12（１Ｈ，brｄ，Ｊ＝56Hz），7.30（５
Ｈ，ｓ，Ｃ６Ｈ５）． (3)上記化合物４ｇをトルエン20mlに溶かす。ナトリウ
ムビス（２−メトキシエトキシ）アルミニウムヒドリド
の70％のトルエン溶液30mlとトルエン30mlの混合液を氷
冷し、これに上の溶液を滴下する。室温で一夜放置後、
氷水および20％苛性ソーダ水溶液を加え、トルエン層を
分け、乾燥後濃縮して、シス−１−ベンジル−４−フル
オロ−３−メチルアミノメチルピロリジンを油状物とし
て得る。IR spectrum (liquid film) cm −1 : 3300, 1670, 700. Mass spectrum m / z: 236 (M + ), 158, 91. NMR spectrum (CDCl 3 ) δ: 3.65 (2H, s, C
H 2 Ph), 5.12 (1H, brd, J = 56Hz), 7.30 (5
H, s, C 6 H 5 ). (3) Dissolve 4 g of the above compound in 20 ml of toluene. A mixture of 30 ml of 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride and 30 ml of toluene is ice-cooled, and the above solution is added dropwise thereto. After standing overnight at room temperature,
Ice water and a 20% aqueous sodium hydroxide solution were added, the toluene layer was separated, dried and concentrated to give cis-1-benzyl-4-fluoro-3-methylaminomethylpyrrolidine as an oil.
(4)上記化合物をトルエン50mlに溶かし、氷冷しながら
無水トリフルオロ酢酸８mlを加えて約１時間放置する。
反応液を飽和重炭酸ナトリウム水溶液で洗った後、溶媒
を減圧下留去し、残渣をカラムクロマトグラフィで分離
精製して、シス−１−ベンジル−４−フルオロ−３−
（Ｎ−トリフルオロアセチル）メチルアミノメチルピロ
リジン2.4ｇを油状物として得る。(4) Dissolve the above compound in 50 ml of toluene, add 8 ml of trifluoroacetic anhydride while cooling with ice, and leave it for about 1 hour.
The reaction mixture was washed with saturated aqueous sodium bicarbonate solution, the solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography to give cis-1-benzyl-4-fluoro-3-.
2.4 g of (N-trifluoroacetyl) methylaminomethylpyrrolidine are obtained as an oil.
IRスペクトル（液膜）cm-1：1690，1190，700． マス・スペクトルｍ／ｚ：318（Ｍ＋），241，91． NMRスペクトル（ＣＤＣｌ３）δ：3.15（３Ｈ，br，Ｎ
−ＣＨ３），3.68（２Ｈ，ｓ，ＣＨ２Ｐｈ），7.30（５
Ｈ，ｓ，Ｃ６Ｈ５）． (5)実施例２と同様にして、シス−１−ベンジル−４−
フルオロ−３−（Ｎ−トリフルオロアセチル）メチルア
ミノメチルピロリジンからシス−４−フルオロ−３−
（Ｎ−トリフルオロアセチル）メチルアミノメチルピロ
リジンを得る。IR spectrum (liquid film) cm −1 : 1690, 1190, 700. Mass spectrum m / z: 318 (M + ), 241, 91. NMR spectrum (CDCl 3 ) δ: 3.15 (3H, br, N
-CH 3), 3.68 (2H, s, CH 2 Ph), 7.30 (5
H, s, C 6 H 5 ). (5) In the same manner as in Example 2, cis-1-benzyl-4-
From fluoro-3- (N-trifluoroacetyl) methylaminomethylpyrrolidine to cis-4-fluoro-3-
(N-trifluoroacetyl) methylaminomethylpyrrolidine is obtained.
実施例８ (1)３−アセチルアミノメチル−１−ベンジル−４−フ
ルオロピロリジン3.0ｇとナトリウムビス（２−メチキ
シエトキシ）アルミニウムヒドリドの70％トルエン溶液
30mlを用い、実施例７(3)と同様に反応処理して、シス
−１−ベンジル−３−エチルアミノメチル−４−フルオ
ロピロリジンを得る。Example 8 (1) 3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine (3.0 g) and sodium bis (2-methoxyethoxy) aluminum hydride in 70% toluene solution
The reaction is carried out in the same manner as in Example 7 (3) using 30 ml to obtain cis-1-benzyl-3-ethylaminomethyl-4-fluoropyrrolidine.
(2)上記化合物と無水トリフルオロ酢酸６mlから実施例
７(4)と同様にして、シス−１−ベンジル−４−フルオ
ロ−３−（Ｎ−トリフルオロアセチル）エチルアミノメ
チルピロリジン2.4ｇを得る。(2) From the above compound and 6 ml of trifluoroacetic anhydride, cis-1-benzyl-4-fluoro-3- (N-trifluoroacetyl) ethylaminomethylpyrrolidine (2.4 g) was obtained in the same manner as in Example 7 (4). .
IRスペクトル（液膜）cm-1：1690，1140． マス・スペクトルｍ／ｚ：332（Ｍ＋），255，91． NMRスペクトル（ＣＤＣｌ３）δ：5.10（１Ｈ，brｄ，
Ｊ＝60Hz，Ｃ４−Ｈ），7.33（５Ｈ，ｓ，Ｃ６Ｈ５）． (3)実施例２と同様にして、シス−１−ベンジル−４−
フルオロ−３−（Ｎ−トリフルオロアセチル）エチルア
ミノメチルピロリジンからシス−４−フルオロ−３−
（Ｎ−トリフルオロアセチル）エチルアミノメチルピロ
リジンを得る。IR spectrum (liquid film) cm -1 : 1690, 1140. Mass spectrum m / z: 332 (M + ), 255, 91. NMR spectrum (CDCl 3 ) δ: 5.10 (1H, brd,
J = 60Hz, C 4 -H) , 7.33 (5H, s, C 6 H 5). (3) In the same manner as in Example 2, cis-1-benzyl-4-
Fluoro-3- (N-trifluoroacetyl) ethylaminomethylpyrrolidine to cis-4-fluoro-3-
(N-trifluoroacetyl) ethylaminomethylpyrrolidine is obtained.
参考例７ (1)シス−３−アセチルアミノメチル−１−ベンジル−
４−クロロピロリジン3.5ｇから、実施例１(3)と同様に
して得られるシス−３−アセチルアミノメチル−４−ク
ロロピロリジンをアセトニトリル50mlに溶かす。これに
７−クロロ−１−シクロプロピル−６−フルオロ−1,4
−ジヒドロ−４−オキソ−1,8−ナフチリジン−３−カ
ルボン酸エチル3.3ｇとトリエチルアミン８mlを加え１
時間加熱還流する。一夜室温で放置後、析出結晶を濾取
する。この結晶を水とクロロホルムの混液に溶かし振と
う後、クロロホルム層を分け、乾燥した後クロロホルム
を留去する。残渣をアセトニトリルから再結晶して、７
−（シス−３−アセチルアミノメチル−４−クロロ−１
−ピロリジニル）−１−シクロプロピル−６−フルオロ
−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン−３
−カルボン酸エチル4.6ｇを得る。Reference Example 7 (1) cis-3-Acetylaminomethyl-1-benzyl-
Cis-3-Acetylaminomethyl-4-chloropyrrolidine obtained in the same manner as in Example 1 (3) from 3.5 g of 4-chloropyrrolidine is dissolved in 50 ml of acetonitrile. 7-chloro-1-cyclopropyl-6-fluoro-1,4
Add 3.3 g of ethyl dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 8 ml of triethylamine and add 1
Heat to reflux for hours. After standing overnight at room temperature, the precipitated crystals are collected by filtration. The crystals are dissolved in a mixed solution of water and chloroform and shaken. The chloroform layer is separated, dried and the chloroform is distilled off. The residue was recrystallized from acetonitrile to give 7
-(Cis-3-Acetylaminomethyl-4-chloro-1
-Pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-4.6 g of ethyl carboxylate are obtained.
ｍ．ｐ．213〜214℃ (2)この化合物2.0ｇに20％塩酸20mlを加えて２時間加熱
還流する。減圧下に塩酸を留去し、残渣にエタノールを
加える。析出結晶を濾取して、７−（シス−３−アミノ
メチル−４−クロロ−１−ピロリジニル）−１−シクロ
プロピル−６−フルオロ−1,4−ジヒドロ−４−オキソ
−1,8−ナフチリジン−３−カルボン酸塩酸塩1.55ｇを
得る。 ｍ．ｐ．243〜248℃（分解）． (3)この化合物1.0ｇを水に溶かし、これに飽和炭酸水素
ナトリウム水溶液を加えてpH7.5〜8.0とし冷却する。結
晶を濾取し、クロロホルム−メタノール混液から再結晶
して、７−（シス−３−アミノメチル−４−クロロ−１
−ピロリジニル）−１−シクロプロピル−６−フルオロ
−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン−３
−カルボン酸0.7ｇを得る。m. p. 213-214 ° C (2) To 2.0 g of this compound is added 20 ml of 20% hydrochloric acid, and the mixture is heated under reflux for 2 hours. Hydrochloric acid is distilled off under reduced pressure, and ethanol is added to the residue. The precipitated crystals were collected by filtration to give 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-. 1.55 g of naphthyridine-3-carboxylic acid hydrochloride are obtained. m. p. 243-248 ° C (decomposition). (3) 1.0 g of this compound is dissolved in water, and saturated aqueous sodium hydrogen carbonate solution is added to adjust the pH to 7.5 to 8.0, followed by cooling. The crystals were collected by filtration and recrystallized from a chloroform-methanol mixture to give 7- (cis-3-aminomethyl-4-chloro-1).
-Pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-0.7 g of carboxylic acid is obtained.
ｍ．ｐ．174〜177℃． 同様にして以下の化合物を得る。m. p. 174-177 ° C. Similarly, the following compounds are obtained.
参考例８ トランス−３−アセチルアミノメチル−４−クロロ−１
−ピロリジンから次の化合物を得る。Reference Example 8 trans-3-acetylaminomethyl-4-chloro-1
-The following compounds are obtained from pyrrolidine.
(1)７−（トランス−３−アセチルアミノメチル−４−
クロロ−１−ピロリジニル）−１−シクロプロピル−６
−フルオロ−1,4−ジヒドロ−４−オキソ−1,8−ナフチ
リジン−３−カルボン酸エチル，ｍ．ｐ．203〜206℃． (2)７−（トランス−３−アミノメチル−４−クロロ−
１−ピロリジニル）−１−シクロプロピル−６−フルオ
ロ−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン−
３−カルボン酸， ｍ．ｐ．222〜224℃（分解）． 参考例９ シス−３−アセチルアミノメチル−４−フルオロ−１−
ピロリジンから次の化合物を得る。(1) 7- (trans-3-acetylaminomethyl-4-
Chloro-1-pyrrolidinyl) -1-cyclopropyl-6
Ethyl -fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. p. 203-206 ° C. (2) 7- (trans-3-aminomethyl-4-chloro-
1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic acid, m. p. 222-224 ° C (decomposition). Reference Example 9 cis-3-acetylaminomethyl-4-fluoro-1-
The following compounds are obtained from pyrrolidine.
(1)７−（シス−３−アセチルアミノメチル−４−フル
オロ−１−ピロリジニル）−１−シクロプロピル−６−
フルオロ−1,4−ジヒドロ−４−オキソ−1,8−ナフチリ
ジン−３−カルボン酸エチル，ｍ．ｐ．179〜181℃， (2)７−（シス−３−アミノメチル−４−フルオロ−１
−ピロリジニル）−１−シクロプロピル−６−フルオロ
−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン−３
−カルボン酸塩酸塩， ｍ．ｐ．284〜286℃（分解）． (3)７−（シス−３−アミノメチル−４−フルオロ−ピ
ロリジニル）−１−シクロプロピル−６−フルオロ−1,
4−ジヒドロ−４−オキソ−1,8−ナフチリジン−３−カ
ルボン酸， ｍ．ｐ．217〜218℃． 参考例１０ トランス−３−アセチルアミノメチル−４−フルオロ−
１−ピロリジンから次の化合物を得る。(1) 7- (cis-3-acetylaminomethyl-4-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-
Ethyl fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. p. 179-181 ° C, (2) 7- (cis-3-aminomethyl-4-fluoro-1
-Pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
A carboxylic acid hydrochloride salt, m. p. 284-286 ° C (decomposition). (3) 7- (cis-3-aminomethyl-4-fluoro-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m. p. 217-218 ° C. Reference Example 10 trans-3-acetylaminomethyl-4-fluoro-
The following compound is obtained from 1-pyrrolidine.
(1)７−（トランス−３−アセチルアミノメチル−４−
フルオロ−１−ピロリジニル）−１−シクロプロピル−
６−フルオロ−1,4−ジヒドロ−４−オキソ−1,8−ナフ
チリジン−３−カルボン酸エチル，ｍ．ｐ．211〜213
℃． (2)７−（トランス−３−アミノメチル−４−フルオロ
−１−ピロリジニル）−１−シクロプロピル−６−フル
オロ−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン
−３−カルボン酸塩酸塩，ｍ．ｐ．269〜272℃（分
解）． 参考例１１ ３−アセチルアミノメチル−３−フルオロ−１−ピロリ
ジンから次の化合物を得る。(1) 7- (trans-3-acetylaminomethyl-4-
Fluoro-1-pyrrolidinyl) -1-cyclopropyl-
Ethyl 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. p. 211 ~ 213
° C. (2) 7- (trans-3-aminomethyl-4-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carvone Hydrochloride, m. p. 269-272 ° C (decomposition). Reference Example 11 The following compound is obtained from 3-acetylaminomethyl-3-fluoro-1-pyrrolidine.
(1)７−（３−アセチルアミノメチル−３−フルオロ−
１−ピロリジニル）−１−シクロプロピル−６−フルオ
ロ−1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン−
３−カルボン酸エチル，ｍ．ｐ．214〜215℃． (2)７−（３−アミノメチル−３−フルオロ−１−ピロ
リジニル）−１−シクロプロピル−６−フルオロ−1,4
−ジヒドロ−４−オキソ−1,8−ナフチリジン−３−カ
ルボン酸塩酸塩， ｍ．ｐ．272〜279℃． (3)７−（３−アミノメチル−３−フルオロ−１−ピロ
リジニル）−１−シクロプロピル−６−フルオロ−1,4
−ジヒドロ−４−オキソ−1,8−ナフチリジン−３−カ
ルボン酸， ｍ．ｐ．229〜232℃．(1) 7- (3-acetylaminomethyl-3-fluoro-
1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-
Ethyl 3-carboxylate, m.p. p. 214-215 ° C. (2) 7- (3-aminomethyl-3-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4
-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride, m.p. p. 272 to 279 ° C. (3) 7- (3-aminomethyl-3-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4
-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m. p. 229-232 ° C.
Claims (3)
し、 Ｒ２はハロゲン原子で置換されていてもよいアシル基，
水素原子または低級アルキル基を意味し、Ｒ３はハロゲ
ン原子，低級アルキル基または低級アルコキシ基を意味
し、かつピロリジン環の３位または４位に位置する。 但し、Ｒ３がピロリジン環の４位に位置し、かつ低級ア
ルキル基であるとき、 で示される基はアミノ基またはモノ低級アルキル置換ア
ミノ基以外の基を意味する。） で表わされる３−アミノメチルピロリジン誘導体および
その塩。1. A general formula (In the formula, R 1 represents a hydrogen atom or a lower alkyl group, and R 2 is an acyl group optionally substituted with a halogen atom,
It means a hydrogen atom or a lower alkyl group, R 3 means a halogen atom, a lower alkyl group or a lower alkoxy group, and is located at the 3-position or 4-position of the pyrrolidine ring. Provided that when R 3 is located at the 4-position of the pyrrolidine ring and is a lower alkyl group, The group represented by means a group other than an amino group or a mono-lower alkyl-substituted amino group. ) A 3-aminomethylpyrrolidine derivative represented by: and a salt thereof.
請求の範囲第１項記載の３−アミノメチルピロリジン誘
導体およびその塩。2. A 3-aminomethylpyrrolidine derivative and a salt thereof according to claim 1, wherein R 3 is located at the 4-position of the pyrrolidine ring.
第２項記載の３−アミノメチルピロリジン誘導体および
その塩。3. A 3-aminomethylpyrrolidine derivative or a salt thereof according to claim 2, wherein R 3 is a halogen atom.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60215628A JPH0615526B2 (en) | 1985-09-27 | 1985-09-27 | 3-Aminomethylpyrrolidine derivative and its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60215628A JPH0615526B2 (en) | 1985-09-27 | 1985-09-27 | 3-Aminomethylpyrrolidine derivative and its salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6272660A JPS6272660A (en) | 1987-04-03 |
| JPH0615526B2 true JPH0615526B2 (en) | 1994-03-02 |
Family
ID=16675549
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60215628A Expired - Lifetime JPH0615526B2 (en) | 1985-09-27 | 1985-09-27 | 3-Aminomethylpyrrolidine derivative and its salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0615526B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2603638B2 (en) * | 1987-07-08 | 1997-04-23 | 第一製薬株式会社 | Analysis and preparative methods for optical isomers |
| DE4104870A1 (en) * | 1991-02-17 | 1992-08-27 | Bayer Ag | USE OF 3, (4) SUBSTITUTED PYRROLIDINES AS CATALYSTS FOR THE POLYISOCYANATE POLYADDITION METHOD, METHOD FOR THE PRODUCTION THEREOF AND METHOD FOR THE PRODUCTION OF POLYURETHANE (UREA) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4665079A (en) * | 1984-02-17 | 1987-05-12 | Warner-Lambert Company | Antibacterial agents |
-
1985
- 1985-09-27 JP JP60215628A patent/JPH0615526B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6272660A (en) | 1987-04-03 |
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