JPH04270272A - Production of aminoalkylmorpholine derivative - Google Patents
Production of aminoalkylmorpholine derivativeInfo
- Publication number
- JPH04270272A JPH04270272A JP5395391A JP5395391A JPH04270272A JP H04270272 A JPH04270272 A JP H04270272A JP 5395391 A JP5395391 A JP 5395391A JP 5395391 A JP5395391 A JP 5395391A JP H04270272 A JPH04270272 A JP H04270272A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- formula
- alkyl
- aralkyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 239000005708 Sodium hypochlorite Substances 0.000 abstract description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- ZKWFSTHEYLJLEL-UHFFFAOYSA-N morpholine-4-carboxamide Chemical class NC(=O)N1CCOCC1 ZKWFSTHEYLJLEL-UHFFFAOYSA-N 0.000 abstract description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- -1 2- (N-Methyl-N-benzylaminomethyl)-4-ethylmorpholin-5-one Chemical compound 0.000 description 30
- 239000000203 mixture Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine 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
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- CKZVBXBEDDAEFE-UHFFFAOYSA-N (4-benzylmorpholin-2-yl)methanamine Chemical compound C1COC(CN)CN1CC1=CC=CC=C1 CKZVBXBEDDAEFE-UHFFFAOYSA-N 0.000 description 2
- ZYXIOXNUKBMPQJ-UHFFFAOYSA-N 2-(4-benzylmorpholin-4-ium-2-yl)acetate Chemical compound C1COC(CC(=O)O)CN1CC1=CC=CC=C1 ZYXIOXNUKBMPQJ-UHFFFAOYSA-N 0.000 description 2
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical compound OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 description 2
- GVWRZZNYCOTWNN-UHFFFAOYSA-N 4-benzyl-2-(chloromethyl)morpholine Chemical compound C1COC(CCl)CN1CC1=CC=CC=C1 GVWRZZNYCOTWNN-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- WZFOBUJYPANZMG-UHFFFAOYSA-N ethyl 2-(4-benzylmorpholin-2-yl)acetate Chemical compound C1COC(CC(=O)OCC)CN1CC1=CC=CC=C1 WZFOBUJYPANZMG-UHFFFAOYSA-N 0.000 description 2
- LTGXGCGDXHMONY-UHFFFAOYSA-N ethyl n-(morpholin-2-ylmethyl)carbamate Chemical compound CCOC(=O)NCC1CNCCO1 LTGXGCGDXHMONY-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- OPELDSFLVQSDPM-UHFFFAOYSA-N 1,2,5-trifluoro-4-oxoquinoline-3-carboxylic acid Chemical compound FC1=C2C(C(=C(N(C2=CC=C1)F)F)C(=O)O)=O OPELDSFLVQSDPM-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- IMCDTSZTCIFXNN-UHFFFAOYSA-N 2-(4-benzylmorpholin-2-yl)acetonitrile Chemical compound C1COC(CC#N)CN1CC1=CC=CC=C1 IMCDTSZTCIFXNN-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FXAHCXPEXLCFFY-UHFFFAOYSA-N 4-(chloromethyl)morpholine Chemical compound ClCN1CCOCC1 FXAHCXPEXLCFFY-UHFFFAOYSA-N 0.000 description 1
- GVWBJJLCTWNTRU-UHFFFAOYSA-N 4-benzylmorpholine Chemical compound C=1C=CC=CC=1CN1CCOCC1 GVWBJJLCTWNTRU-UHFFFAOYSA-N 0.000 description 1
- MVKGRIHKSLEKTE-UHFFFAOYSA-N 7-[2-(aminomethyl)morpholin-4-yl]-1-cyclopropyl-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1COC(CN)CN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F MVKGRIHKSLEKTE-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 238000006105 Hofmann reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- DZTHIGRZJZPRDV-LBPRGKRZSA-N N-acetyl-L-tryptophan Chemical compound C1=CC=C2C(C[C@H](NC(=O)C)C(O)=O)=CNC2=C1 DZTHIGRZJZPRDV-LBPRGKRZSA-N 0.000 description 1
- DZTHIGRZJZPRDV-UHFFFAOYSA-N Nalpha-Acetyltryptophan Natural products C1=CC=C2C(CC(NC(=O)C)C(O)=O)=CNC2=C1 DZTHIGRZJZPRDV-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910000435 bromine oxide Inorganic materials 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 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
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- POCFBDFTJMJWLG-UHFFFAOYSA-N dihydrosinapic acid methyl ester Natural products COC(=O)CCC1=CC(OC)=C(O)C(OC)=C1 POCFBDFTJMJWLG-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl 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])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- WHQLQYRFIHPMNA-UHFFFAOYSA-N ethyl acetate;oxolane Chemical compound C1CCOC1.CCOC(C)=O WHQLQYRFIHPMNA-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 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
- 125000000623 heterocyclic group 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
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- OXYALYJRWGRVAM-UHFFFAOYSA-N morpholin-2-ylmethanamine Chemical compound NCC1CNCCO1 OXYALYJRWGRVAM-UHFFFAOYSA-N 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 229940116191 n-acetyltryptophan Drugs 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 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 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004079 stearyl 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])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
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Abstract
Description
【０００１】0001
【産業上の利用分野】本発明は医薬品の合成中間体とし
て有用なアミノアルキルモルホリン誘導体の製造法に関
する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing aminoalkylmorpholine derivatives useful as synthetic intermediates for pharmaceuticals.
【０００２】0002
【従来の技術】特開平２−１３８２７８号公報には従来
のピリドンカルボン酸抗菌剤に比較してグラム陽性菌に
対しｉｎ ｖｉｔｒｏおよびｉｎ ｖｉｖｏ で増強さ
れた効力と広い抗菌作用を有し、実験動物への経口投与
によってより優れた吸収を示し、問題となる副作用がほ
とんどなく、低毒性を示す１−シクロプロピル−６，８
−ジフルオロ−１，４−ジヒドロ−７−〔２−（アミノ
メチル）モルホリノ〕−４−オキソ−３−キノリンカル
ボン酸が開示されており、この化合物は臨床的により優
れた有用性が期待されている。２−アミノメチルモルホ
リンおよびその誘導体はその合成中間体として有用であ
り、この中間体の工業的な合成法の確立が望まれている
。従来、アミノアルキルモルホリン誘導体の合成法とし
て、特開昭５３−９０２７５号公報には、例えば、２−
（Ｎ−メチル−Ｎ−ベンジルアミノメチル）−４−エチ
ルモルホリン−５−オンを水素化アルミニウムリチウム
にて還元させて、２−（Ｎ−メチル−Ｎ−ベンジルアミ
ノメチル）−４−エチルモルホリンを得ることが記載さ
れている。特開昭６２−２２８０８２号公報には、４−
ベンジル−２−クロロメチルモルホリンにカリウムフタ
ルイミドを反応させ、得られたフタルイミド体をヒドラ
ジンなどで処理することにより、２−アミノメチル−４
−ベンジルモルホリンを製造する方法が記載されている
。また、特開昭６３−２６４４６７号公報には、先のフ
タルイミドを用いる方法とともに、４−ベンジル−２−
クロロメチルモルホリンにアジ化ナトリウムを反応させ
、得られたアジド体を水素化ビス（２−メトキシエトキ
シ）アルミニウムナトリウムなどで還元することにより
、２−アミノメチル−４−ベンジルモルホリンを製造す
る方法が開示されている。さらに、ヨーロッパ公開特許
第３１１９４８号公報には、４−ベンジル−２−クロロ
メチルモルホリンなどの活性エステル体に一般式[Prior Art] JP-A No. 2-138278 discloses that it has enhanced efficacy and broad antibacterial activity against Gram-positive bacteria in vitro and in vivo compared to conventional pyridonecarboxylic acid antibacterial agents, and that it has a broad antibacterial effect on experimental animals. 1-Cyclopropyl-6,8 exhibits superior absorption, almost no problematic side effects, and low toxicity when administered orally.
-difluoro-1,4-dihydro-7-[2-(aminomethyl)morpholino]-4-oxo-3-quinolinecarboxylic acid is disclosed, and this compound is expected to have better clinical utility. There is. 2-aminomethylmorpholine and its derivatives are useful as intermediates for their synthesis, and it is desired to establish an industrial synthesis method for this intermediate. Conventionally, as a method for synthesizing aminoalkylmorpholine derivatives, for example, 2-
(N-Methyl-N-benzylaminomethyl)-4-ethylmorpholin-5-one was reduced with lithium aluminum hydride to produce 2-(N-methyl-N-benzylaminomethyl)-4-ethylmorpholine. It is stated that you can get JP-A-62-228082 discloses 4-
By reacting benzyl-2-chloromethylmorpholine with potassium phthalimide and treating the obtained phthalimide with hydrazine etc., 2-aminomethyl-4
- A method for producing benzylmorpholine is described. In addition, JP-A No. 63-264467 describes the method using phthalimide as well as 4-benzyl-2-
Discloses a method for producing 2-aminomethyl-4-benzylmorpholine by reacting chloromethylmorpholine with sodium azide and reducing the resulting azide with sodium bis(2-methoxyethoxy)aluminum hydride. has been done. Furthermore, in European Patent Publication No. 311948, there is a general formula for active esters such as 4-benzyl-2-chloromethylmorpholine.
【化３】
（式中、Ｒ３ 、Ｒ４ は水素、低級アルキル、ベンジ
ルを示すか、Ｒ３ 、Ｒ４ は互いに結合して隣接する
窒素原子とともに複素環を形成する基を示す。）により
表されるアミノ化剤によりアミノ化し、次いで脱ベンジ
ル化反応に付すことを特徴とするアミノアルキルモルホ
リン誘導体の製造法が記載されている。(In the formula, R3 and R4 represent hydrogen, lower alkyl, or benzyl, or R3 and R4 represent a group bonding to each other to form a heterocycle with the adjacent nitrogen atom.) A method for producing an aminoalkylmorpholine derivative is described, which comprises amination with a converting agent and then subjecting it to a debenzylation reaction.
【０００３】0003
【発明が解決しようとする課題】上述の特開昭５３−９
０２７５号、同６２−２８０８２号および同６３−２６
４４６７号公報の方法を工業的に利用するに際し、発火
の危険性のある水素化アルミニウムリチウムや、爆発の
危険性のあるアジ化カリウムおよびアジ化ナトリウムま
たはそれらとの反応により得られるアジド化合物などを
取り扱う必要があり、さらにフタルイミドカリウムなど
高価な原料、中間体を使用する必要がある。また、いず
れも合成の工程数が長いなどの欠点も有していた。さら
に、ヨーロッパ公開特許第３１１９４８号公報のアミノ
化剤を用いる方法では、そのアミノ化反応において高温
、高圧の条件が必要で工業経済上の不利益を有するもの
であった。[Problem to be solved by the invention] The above-mentioned Japanese Patent Application Laid-open No. 53-9
No. 0275, No. 62-28082 and No. 63-26
When the method of Publication No. 4467 is used industrially, lithium aluminum hydride, which has a risk of ignition, potassium azide and sodium azide, which have a risk of explosion, or azide compounds obtained by reaction with them, etc. must be used. In addition, it is necessary to use expensive raw materials and intermediates such as potassium phthalimide. In addition, all of them also had drawbacks such as a long number of synthesis steps. Furthermore, the method using an aminating agent disclosed in European Patent Publication No. 311,948 requires conditions of high temperature and high pressure in the amination reaction, which is disadvantageous in terms of industrial economy.
【０００４】0004
【課題を解決するための手段】本発明者らはアミノアル
キルモルホリン誘導体の工業的な合成法について鋭意研
究した結果、容易に入手可能なカルバモイルモルホリン
誘導体をホフマン反応に付すことにより、高収率および
安全にアミノアルキルモルホリン誘導体を製造すること
ができることを見いだし、本発明を完成するに至った。
即ち、本発明は、 一般式[Means for Solving the Problems] As a result of intensive research into industrial synthesis methods for aminoalkylmorpholine derivatives, the present inventors have found that by subjecting readily available carbamoylmorpholine derivatives to the Hoffmann reaction, high yield and The present inventors have discovered that aminoalkylmorpholine derivatives can be produced safely and have completed the present invention. That is, the present invention has the following general formula:
【化４】
（式中、Ｒはアルキル、アラルキル、アシル、アルコキ
シカルボニル、アラルキルオキシカルボニルまたは置換
基を有していてもよいフェニルを、ｎは１〜３の整数を
示す。）により表される化合物をホフマン反応に付し、
必要であれば、脱保護反応に付することを特徴とする、
一般式embedded image (wherein R represents alkyl, aralkyl, acyl, alkoxycarbonyl, aralkyloxycarbonyl, or phenyl which may have a substituent, and n represents an integer of 1 to 3) Subjecting the compound to a Hoffmann reaction,
characterized by subjecting it to a deprotection reaction if necessary,
general formula
【化５】
〔式中、Ｒ’は水素、アルキル、アラルキル、アシル、
アルコキシカルボニル、アラルキルオキシカルボニルま
たは置換基を有していてもよいフェニルを、Ｒ１ は水
素もしくは−ＣＯＯＲ２ （ここで、Ｒ２ はアルキル
またはアラルキルを示す。）を示し、ｎは前記と同義で
ある。〕により表わされるアミノアルキルモルホリン化
合物を製造することができる。[In the formula, R' is hydrogen, alkyl, aralkyl, acyl,
alkoxycarbonyl, aralkyloxycarbonyl or phenyl which may have a substituent, R1 represents hydrogen or -COOR2 (here, R2 represents alkyl or aralkyl), and n has the same meaning as above. An aminoalkylmorpholine compound represented by the following formula can be produced.
【０００５】本明細書中、アルキルとはメチル、エチル
、プロピル、イソプロピル、ブチル、イソブチル、第三
級ブチル、ペンチル、ヘキシル、ヘプチル、オクチル、
デシル、ドデシル、オクタデシルなどの炭素数１〜１８
個のアルキルを、アラルキルとは芳香環上にフッ素、塩
素、臭素、ヨウ素などのハロゲン、アルキル、メトキシ
、エトキシ、プロポキシなどのアルコキシ、トリフルオ
ロメチル、水酸基、ニトロ、アミノから選ばれる置換基
の１〜３個を有していてもよいベンジル、フェニルエチ
ル、フェニルプロピル、フェニルブチル、ナフチルメチ
ルなどを、アシルとはホルミル、アセチル、プロピオニ
ル、ブチリル、バレリル、ピバロイルなどの炭素数１〜
５個のアシルを、アルコキシカルボニルとは炭素数１〜
４個のアルコキシ部を有するものであってメトキシカル
ボニル、エトキシカルボニル、プロポキシカルボニル、
イソプロポキシカルボニル、ブトキシカルボニル、イソ
ブトキシカルボニル、第３級ブトキシカルボニルなどを
、アラルキルオキシカルボニルとは芳香族環上にフッ素
、塩素、臭素、ヨウ素などのハロゲン、アルキル、、メ
トキシ、エトキシ、プロポキシなどのアルコキシ、トリ
フルオロメチル、水酸基、ニトロ、アミノから選ばれる
置換基の１〜３個を有していてもよいベンジルオキシカ
ルボニル、フェニルエトキシカルボニル、フェニルプロ
ポキシカルボニル、フェニルブトキシカルボニル、ナフ
チルメチルオキシカルボニルなどを示す。また、置換基
を有していてもよいフェニルの置換基とはハロゲン、ア
ルキル、アルコキシ、トリフルオロメチル、水酸基、ニ
トロ、アミノなどを挙げることができる。In this specification, alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl,
1 to 18 carbon atoms such as decyl, dodecyl, octadecyl, etc.
Aralkyl is a substituent on an aromatic ring selected from halogens such as fluorine, chlorine, bromine, and iodine, alkyls, alkoxys such as methoxy, ethoxy, and propoxy, trifluoromethyl, hydroxyl groups, nitro, and amino. Acyl refers to benzyl, phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, etc., which may have 1 to 3 carbon atoms, and acyl refers to formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, etc., which may have 1 to 3 carbon atoms.
5 acyl, alkoxycarbonyl has 1 to 1 carbon atoms
Those having four alkoxy moieties, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, etc., and aralkyloxycarbonyl include halogens such as fluorine, chlorine, bromine, and iodine, alkyl, methoxy, ethoxy, propoxy, etc. on the aromatic ring. benzyloxycarbonyl, phenylethoxycarbonyl, phenylpropoxycarbonyl, phenylbutoxycarbonyl, naphthylmethyloxycarbonyl, etc., which may have 1 to 3 substituents selected from alkoxy, trifluoromethyl, hydroxyl, nitro, and amino; show. Furthermore, examples of the substituent of phenyl which may have a substituent include halogen, alkyl, alkoxy, trifluoromethyl, hydroxyl, nitro, and amino.
【０００６】本発明方法において、ホフマン反応は、次
亜塩素酸ナトリウム、次亜臭素酸ナトリウムあるいは臭
素と水酸化ナトリウムとの混合物などの試薬の存在下、
適当な溶媒〔水、アルコール類（メタノール、エタノー
ル、プロピルアルコール、ブチルアルコール、第三級ブ
チルアルコール、ベンジルアルコールなど）、テトラヒ
ドロフラン、ジオキサン、ジグライム、ジメチルスルホ
キシドなどが挙げられ、これらを単独または混合して使
用することができる〕中、−３０〜２００℃、好ましく
は０〜１００℃の温度で、１〜４８時間かけて行うこと
により進行する。また、〔化２〕の化合物のうちＲ’が
水素の化合物は、〔化２〕の化合物のうちＲ’が水素以
外の化合物を酸またはアルカリ条件下に加水分解するか
、接触還元させることにより得る事ができる。In the method of the present invention, the Hofmann reaction is carried out in the presence of a reagent such as sodium hypochlorite, sodium hypobromite or a mixture of bromine and sodium hydroxide.
Appropriate solvents (including water, alcohols (methanol, ethanol, propyl alcohol, butyl alcohol, tertiary butyl alcohol, benzyl alcohol, etc.), tetrahydrofuran, dioxane, diglyme, dimethyl sulfoxide, etc. alone or in combination) can be used] at a temperature of -30 to 200°C, preferably 0 to 100°C, for 1 to 48 hours. In addition, compounds of [Chemical formula 2] in which R' is hydrogen can be obtained by hydrolyzing the compounds of [Chemical formula 2] in which R' is other than hydrogen under acidic or alkaline conditions or by catalytic reduction. You can get it.
【０００７】このようにして得られる〔化２〕の化合物
は再結晶、クロマトグラフィーなどのそれ自体公知の方
法により、反応混合物から分離、精製することができる
。また、〔化２〕の化合物においては、不斉炭素が存在
するので、それに基づく光学異性体が存在する。したが
って、〔化２〕の化合物がラセミ体である場合には、酒
石酸、リンゴ酸、Ｎ−アセチルトリプトファン、１０−
カンファスルホン酸、マンデル酸、ジベンゾイル酒石酸
などの酸性光学分割剤を用いることによって対応する光
学異性体に分割することができる。さらに、これらの光
学異性体は、対応する光学活性な原料化合物を使用する
ことによっても製造でき、個々の光学異性体は再結晶、
クロマトグラフィーなどのそれ自体公知の方法により精
製することができる。The compound of formula 2 thus obtained can be separated and purified from the reaction mixture by methods known per se such as recrystallization and chromatography. Moreover, in the compound of [Chemical formula 2], since an asymmetric carbon exists, optical isomers based on the asymmetric carbon exist. Therefore, when the compound of [Chemical formula 2] is a racemate, tartaric acid, malic acid, N-acetyltryptophan, 10-
It can be resolved into corresponding optical isomers by using an acidic optical resolving agent such as camphorsulfonic acid, mandelic acid, dibenzoyltartaric acid, etc. Furthermore, these optical isomers can also be produced by using corresponding optically active raw material compounds, and individual optical isomers can be produced by recrystallization,
It can be purified by methods known per se, such as chromatography.
【０００８】このようにして得られる〔化２〕の化合物
は必要に応じ、常法にて塩酸、臭化水素酸、硫酸、燐酸
などの無機酸との塩、メタンスルホン酸、パラトルエン
スルホン酸、乳酸、酢酸、マレイン酸、クエン酸、酒石
酸などの有機酸との塩とすることができる。[0008] The compound of [Chemical formula 2] thus obtained can be converted into a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, methanesulfonic acid, para-toluenesulfonic acid, etc., according to a conventional method. , salts with organic acids such as lactic acid, acetic acid, maleic acid, citric acid, and tartaric acid.
【０００９】なお、本発明の出発原料として用いた〔化
１〕の化合物は新規物質であって、例えば、一般式[0009] The compound [Formula 1] used as a starting material for the present invention is a new substance, and for example, the compound of the general formula
【化
６】
〔式中、Ｒ５ は水酸基、ハロゲン（塩素、臭素、ヨウ
素、フッ素）、アルコキシ（メトキシ、エトキシ、プロ
ポキシ、ブトキシなど）、または−ＯＲ６ （ここでＲ
６ はアシル、アルコキシカルボニルまたはアラルキル
オキシカルボニルを示す。）を示し、Ｒ、ｎは前記と同
義である。〕により表わされる新規なカルボン酸および
その反応性誘導体（エステル、酸クロリドまたは酸無水
物など）をアンモニアと反応させることにより製造する
ことができる。（但し、〔化６〕のＲ５ がエトキシの
化合物はＳｙｎｔｈｅｔｉｃ Ｃｏｍｍｕｎ．，第１０
巻、５９頁、１９８０年により公知である。）これらの
反応は、〔化６〕の化合物に対し、アンモニアを１〜５
０倍モル使用し、無溶媒あるいは適当な溶媒の存在下、
０〜２００℃、好ましくは０〜１００℃の温度で１〜４
８時間かけて行う。適当な溶媒としては水、アルコール
類、テトラヒドロフランなどが使用できる。また、〔化
１〕の化合物は、一般式[In the formula, R5 is a hydroxyl group, halogen (chlorine, bromine, iodine, fluorine), alkoxy (methoxy, ethoxy, propoxy, butoxy, etc.), or -OR6 (where R
6 represents acyl, alkoxycarbonyl or aralkyloxycarbonyl. ), and R and n have the same meanings as above. ] and its reactive derivatives (esters, acid chlorides, acid anhydrides, etc.) can be produced by reacting them with ammonia. (However, compounds in which R5 of [Chemical formula 6] is ethoxy are referred to in Synthetic Commun., No. 10
Vol. 59, 1980. ) These reactions involve adding 1 to 5 ammonia to the compound of [Chemical formula 6].
Using 0 times the mole, without solvent or in the presence of an appropriate solvent,
1 to 4 at a temperature of 0 to 200°C, preferably 0 to 100°C
It takes 8 hours. Water, alcohols, tetrahydrofuran, etc. can be used as suitable solvents. Moreover, the compound of [Chemical formula 1] has the general formula
【化７】
（式中、各記号は前記と同義である。）により表わされ
る化合物（Ｊ． Ｍｅｄ． Ｃｈｅｍ．， 第３３巻、
１４０６頁（１９９０年））を加水分解させることによ
っても製造することができる。A compound represented by (wherein each symbol has the same meaning as above) (J. Med. Chem., Vol. 33,
1406 (1990)).
【００１０】0010
【実施例】以下、参考例および実施例により本発明を具
体的に説明するが、本発明はこれらによって何ら限定さ
れるものではない。EXAMPLES The present invention will be specifically explained below with reference to Reference Examples and Examples, but the present invention is not limited by these in any way.
【００１１】参考例１
４−ベンジルモルホリン−２−酢酸エチルエステル１３
．２ｇ、水酸化カリウム５ｇと７０％含水メタノール１
５０ｍｌの溶液を一夜放置する。希塩酸で中和後、濃縮
乾固させ、エタノールを加える。不溶物を除去し、濃縮
して、４−ベンジルモルホリン−２−酢酸１１ｇを得る
。ＮＭＲ（ＣＤＣｌ３ ），δ（ｐｐｍ）： １．７
〜２．９（６Ｈ，ｍ）， ３．４７（２Ｈ，ｓ），３．
４〜４．１（３Ｈ，ｍ）， ７．２６（５Ｈ，ｓ）Reference Example 1 4-benzylmorpholine-2-acetic acid ethyl ester 13
．． 2g, potassium hydroxide 5g and 70% aqueous methanol 1
Leave 50 ml of the solution overnight. After neutralizing with dilute hydrochloric acid, concentrate to dryness and add ethanol. Insoluble materials were removed and concentrated to obtain 11 g of 4-benzylmorpholine-2-acetic acid. NMR (CDCl3), δ (ppm): 1.7
~2.9 (6H, m), 3.47 (2H, s), 3.
4-4.1 (3H, m), 7.26 (5H, s)
【０
０１２】参考例２
五塩化リン９．６ｇと塩化メチレン８０ｍｌの混合物に
、４−ベンジルモルホリン−２−酢酸１０ｇと塩化メチ
レン３０ｍｌの溶液を氷冷下に滴下する。１０℃で３時
間撹拌した後、減圧下に濃縮して、４−ベンジルモルホ
リン−２−酢酸クロリドを得る。得られた酸クロリドを
２８％アンモニア水に加え、室温で１時間撹拌する。
クロロホルムで抽出し、水洗、乾燥後、減圧下に濃縮し
て、４−ベンジルモルホリン−２−アセタミド４．０ｇ
を得る。 融点 ９７〜１００℃0
Reference Example 2 A solution of 10 g of 4-benzylmorpholine-2-acetic acid and 30 ml of methylene chloride was added dropwise to a mixture of 9.6 g of phosphorus pentachloride and 80 ml of methylene chloride under ice cooling. After stirring at 10° C. for 3 hours, it is concentrated under reduced pressure to obtain 4-benzylmorpholine-2-acetic acid chloride. The obtained acid chloride was added to 28% aqueous ammonia and stirred at room temperature for 1 hour. Extracted with chloroform, washed with water, dried, and concentrated under reduced pressure to obtain 4.0 g of 4-benzylmorpholine-2-acetamide.
get. Melting point 97-100℃
【００１３】参考例３
エタノール１００ｍｌにアンモニアを飽和させ、４−ベ
ンジルモルホリン−２−酢酸エチルエステル５．２７ｇ
を加える。封管中、室温で３日間放置し、溶媒を濃縮し
、４−ベンジルモルホリン−２−アセタミドを得る。
融点は参考例２で得られた物と一致した。Reference Example 3 100 ml of ethanol was saturated with ammonia, and 5.27 g of 4-benzylmorpholine-2-acetic acid ethyl ester was added.
Add. The mixture is left in a sealed tube at room temperature for 3 days, and the solvent is concentrated to obtain 4-benzylmorpholine-2-acetamide. The melting point was consistent with that obtained in Reference Example 2.
【００１４】参考例４
４−ベンジルモルホリン−２−アセトニトリル８．６５
ｇに、濃硫酸１１ｍｌを加え、４０℃で４時間撹拌する
。氷水中に注ぎ、中和後、酢酸エチルエステル−テトラ
ヒドロフラン混合溶媒で抽出、水洗、乾燥後、減圧下に
濃縮して、４−ベンジルモルホリン−２−アセタミド８
．０ｇを得る。融点は参考例２で得られた物と一致した
。Reference Example 4 4-benzylmorpholine-2-acetonitrile 8.65
11 ml of concentrated sulfuric acid was added to the mixture, and the mixture was stirred at 40°C for 4 hours. Pour into ice water, neutralize, extract with acetic acid ethyl ester-tetrahydrofuran mixed solvent, wash with water, dry, and concentrate under reduced pressure to obtain 4-benzylmorpholine-2-acetamide 8.
．． Obtain 0g. The melting point was consistent with that obtained in Reference Example 2.
【００１５】実施例１
４−ベンジルモルホリン−２−アセタミド５．０ｇとエ
タノール１２０ｍｌの溶液に、氷冷下、１２％次亜塩素
酸ナトリウム水溶液２８ｍｌを加え、同温度で１時間、
更に、６０℃にて１．５時間撹拌する。水中に注ぎ、ク
ロロホルムで抽出し、有機層を水洗、乾燥後、減圧下に
濃縮して４−ベンジル−２−エトキシカルボニルアミノ
メチルモルホリンを油状物として得る。ＮＭＲ（ＣＤＣ
ｌ３ ），δ（ｐｐｍ）： １．２４（３Ｈ，ｔ，Ｊ＝
７）， １．７６ 〜２．３６（２Ｈ，ｍ），２．５
〜２．８（２Ｈ，ｍ）， ２．９〜３．３５（２Ｈ，
ｍ）， ３．５１（２Ｈ，ｓ）， ３．５ 〜３．９（
３Ｈ，ｍ）， ４．１０（２Ｈ，ｑ，Ｊ＝７）， ４．
９（１Ｈ，ｂｓ）， ７．３１（５Ｈ，ｓ）Example 1 To a solution of 5.0 g of 4-benzylmorpholine-2-acetamide and 120 ml of ethanol, 28 ml of a 12% aqueous sodium hypochlorite solution was added under ice cooling, and the mixture was heated at the same temperature for 1 hour.
Further, the mixture was stirred at 60°C for 1.5 hours. The organic layer was poured into water, extracted with chloroform, washed with water, dried, and concentrated under reduced pressure to obtain 4-benzyl-2-ethoxycarbonylaminomethylmorpholine as an oil. NMR (CDC
l3 ), δ (ppm): 1.24 (3H, t, J=
7), 1.76 ~ 2.36 (2H, m), 2.5
~2.8 (2H, m), 2.9 ~ 3.35 (2H,
m), 3.51 (2H, s), 3.5 ~ 3.9 (
3H, m), 4.10 (2H, q, J=7), 4.
9 (1H, bs), 7.31 (5H, s)
【００１６】実施例２
４−ベンジル−２−エトキシカルボニルアミノメチルモ
ルホリン５５．７ｇとイソプロピルアルコール３００ｍ
ｌの溶液に１０％パラジウム−炭素１０ｇ、次いで、ヒ
ドラジン一水和物１２ｇを加え、１．５時間還流する。
触媒を除き、減圧下に濃縮して、２−エトキシカルボニ
ルアミノメチルモルホリンを得る。融点９７〜９８℃Example 2 55.7 g of 4-benzyl-2-ethoxycarbonylaminomethylmorpholine and 300 m of isopropyl alcohol
10 g of 10% palladium-carbon and then 12 g of hydrazine monohydrate are added to the solution of 1 ml of the mixture, and the mixture is refluxed for 1.5 hours. The catalyst is removed and concentrated under reduced pressure to obtain 2-ethoxycarbonylaminomethylmorpholine. Melting point 97-98℃
【
００１７】実施例３
４−ベンジルモルホリン−２−アセタミドを水中、実施
例１と同様にして、２−アミノメチル−４−ベンジルモ
ルホリンを得た。 沸点１５０〜１６０℃／０．５ｍ
ｍＨｇ[
Example 3 4-Benzylmorpholine-2-acetamide was added to water in the same manner as in Example 1 to obtain 2-aminomethyl-4-benzylmorpholine. Boiling point 150-160℃/0.5m
mHg
【００１８】実施例４
４−ベンジルモルホリン−２−アセタミドとメタノール
より、実施例１と同様にして、４−ベンジル−２−メト
キシカルボニルアミノメチルモルホリンを得た。ＮＭＲ
（ＣＤＣｌ３ ），δ（ｐｐｍ）： １．７５〜２．３
５（２Ｈ，ｍ）， ２．５ 〜２．８（２Ｈ，ｍ），
２．９〜３．３５（２Ｈ，ｍ）， ３．４９（２Ｈ，ｓ
）， ３．５ 〜３．９（３Ｈ，ｍ）， ３．６８（３
Ｈ，ｓ）， ５．１（１Ｈ，ｂｓ）， ７．３０（５Ｈ
，ｓ）Example 4 4-Benzyl-2-methoxycarbonylaminomethylmorpholine was obtained from 4-benzylmorpholine-2-acetamide and methanol in the same manner as in Example 1. NMR
(CDCl3), δ (ppm): 1.75 to 2.3
5 (2H, m), 2.5 ~ 2.8 (2H, m),
2.9-3.35 (2H, m), 3.49 (2H, s
), 3.5 to 3.9 (3H, m), 3.68 (3
H, s), 5.1 (1H, bs), 7.30 (5H
,s)
【００１９】実施例５
４−ベンジル−２−メトキシカルボニルアミノメチルモ
ルホリンより、実施例２と同様にして、２−メトキシカ
ルボニルアミノメチルモルホリンを得た。ＮＭＲ（ＣＤ
Ｃｌ３ ），δ（ｐｐｍ）： ２．２（１Ｈ，ｂｓ），
２．４ 〜４．０（９Ｈ，ｍ）， ３．７０（３Ｈ，
ｓ）， ５．１（１Ｈ，ｂｓ）Example 5 2-methoxycarbonylaminomethylmorpholine was obtained from 4-benzyl-2-methoxycarbonylaminomethylmorpholine in the same manner as in Example 2. NMR (CD
Cl3), δ (ppm): 2.2 (1H, bs),
2.4 ~ 4.0 (9H, m), 3.70 (3H,
s), 5.1 (1H, bs)
【００２０】実施例６
４−ベンジルモルホリン−２−アセタミドとベンジルア
ルコールより、実施例１と同様にして、４−ベンジル−
２−ベンジルオキシカルボニルアミノメチルモルホリン
を得た。ＮＭＲ（ＣＤＣｌ３ ），δ（ｐｐｍ）： １
．７４〜２．３４（２Ｈ，ｍ）， ２．５ 〜２．８（
２Ｈ，ｍ）， ２．９〜３．３５（２Ｈ，ｍ）， ３．
４９（２Ｈ，ｓ）， ３．５ 〜３．９（３Ｈ，ｍ），
５．０２（２Ｈ，ｓ）， ５．５（１Ｈ，ｂｓ），
７．３０（１０Ｈ，ｓ）Example 6 From 4-benzylmorpholine-2-acetamide and benzyl alcohol, 4-benzyl-
2-benzyloxycarbonylaminomethylmorpholine was obtained. NMR (CDCl3), δ (ppm): 1
．． 74 ~ 2.34 (2H, m), 2.5 ~ 2.8 (
2H, m), 2.9-3.35 (2H, m), 3.
49 (2H, s), 3.5 ~ 3.9 (3H, m),
5.02 (2H, s), 5.5 (1H, bs),
7.30 (10H, s)
【００２１】実施例７
４−ベンジルモルホリン−２−アセタミドと第３級ブタ
ノールより、実施例１と同様にして、４−ベンジル−２
−（第３級ブトキシカルボニルアミノメチル）モルホリ
ンを得た。ＮＭＲ（ＣＤＣｌ３ ），δ（ｐｐｍ）：
１．４８（９Ｈ，ｓ）， １．７５〜２．３５（２Ｈ，
ｍ）， ２．５ 〜２．８（２Ｈ，ｍ）， ２．９〜３
．３５（２Ｈ，ｍ）， ３．４９（２Ｈ，ｓ）， ３．
５ 〜３．９（３Ｈ，ｍ）， ５．３（１Ｈ，ｂｓ），
７．３０（５Ｈ，ｓ）Example 7 4-Benzylmorpholine-2-acetamide and tertiary butanol were prepared in the same manner as in Example 1.
-(tert-butoxycarbonylaminomethyl)morpholine was obtained. NMR (CDCl3), δ (ppm):
1.48 (9H, s), 1.75-2.35 (2H,
m), 2.5 to 2.8 (2H, m), 2.9 to 3
．． 35 (2H, m), 3.49 (2H, s), 3.
5 ~ 3.9 (3H, m), 5.3 (1H, bs),
7.30 (5H, s)
【００２２】[0022]
【発明の効果】本発明方法により経済的に得られる〔化
２〕の化合物は医薬品の中間体として有用である。例え
ば、実施例２で得られる２−エトキシカルボニルアミノ
メチルモルホリンと１−シクロプロピル−６，７，８−
トリフルオロ−１，４−ジヒドロ−４−オキソ−３−キ
ノリンカルボン酸とを縮合させ、さらに、エトキシカル
ボニル基を除去することによって、１−シクロプロピル
−６，８−ジフルオロ−１，４−ジヒドロ−７−［２−
（アミノメチル）モルホリノ］−４−オキソ−３−キノ
リンカルボン酸（以下、化合物Ａと称する）、融点１８
３〜１８５℃に導くことができる。このようにして得ら
れた化合物Ａはグラム陰性菌に対する抗菌力を維持しつ
つ、グラム陽性菌に対して従来のピリドンカルボン酸化
合物にくらべて著しく強い抗菌力を有すること、実験動
物に経口的に投与したとき極めて良好な吸収を示し、そ
の結果、ｉｎ ｖｉｔｒｏの抗菌力をそのまま反映して
、マウスなどの全身感染実験において経口投与で十分な
感染防御効果を示すこと、さらに、経口および非経口的
投与において特に問題となる副作用を示さないなど極め
て有用な医薬品である。[Effects of the Invention] The compound of formula 2, which can be obtained economically by the method of the present invention, is useful as an intermediate for pharmaceuticals. For example, 2-ethoxycarbonylaminomethylmorpholine obtained in Example 2 and 1-cyclopropyl-6,7,8-
By condensing trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and further removing the ethoxycarbonyl group, 1-cyclopropyl-6,8-difluoro-1,4-dihydro -7- [2-
(aminomethyl)morpholino]-4-oxo-3-quinolinecarboxylic acid (hereinafter referred to as compound A), melting point 18
3-185°C. Compound A obtained in this way maintains antibacterial activity against Gram-negative bacteria, and has significantly stronger antibacterial activity against Gram-positive bacteria than conventional pyridonecarboxylic acid compounds, and can be administered orally to experimental animals. It exhibits extremely good absorption when administered, and as a result, it directly reflects its in vitro antibacterial activity, and shows sufficient infection-protective effects when administered orally in systemic infection experiments such as in mice. It is an extremely useful drug that does not exhibit any problematic side effects during administration.
Claims (1)
シカルボニル、アラルキルオキシカルボニルまたは置換
基を有していてもよいフェニルを、ｎは１〜３の整数を
示す。）により表わされる化合物をホフマン反応に付し
、必要であれば、脱保護反応に付すことを特徴とする、
一般式 【化２】 〔式中、Ｒ’は水素、アルキル、アラルキル、アシル、
アルコキシカルボニル、アラルキルオキシカルボニルま
たは置換基を有していてもよいフェニルを、Ｒ１ は水
素もしくは−ＣＯＯＲ２ （ここでＲ２ はアルキルま
たはアラルキルを示す。）を示し、ｎは前記と同義であ
る。〕により表わされるアミノアルキルモルホリン誘導
体の製造法。Claim 1: General formula [Formula 1] (wherein R is alkyl, aralkyl, acyl, alkoxycarbonyl, aralkyloxycarbonyl, or phenyl which may have a substituent, and n is an integer of 1 to 3. ) is subjected to a Hoffmann reaction and, if necessary, a deprotection reaction,
General formula [Formula 2] [In the formula, R' is hydrogen, alkyl, aralkyl, acyl,
alkoxycarbonyl, aralkyloxycarbonyl or phenyl which may have a substituent, R1 represents hydrogen or -COOR2 (herein, R2 represents alkyl or aralkyl), and n has the same meaning as above. ] A method for producing an aminoalkylmorpholine derivative represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5395391A JPH04270272A (en) | 1991-02-25 | 1991-02-25 | Production of aminoalkylmorpholine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5395391A JPH04270272A (en) | 1991-02-25 | 1991-02-25 | Production of aminoalkylmorpholine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04270272A true JPH04270272A (en) | 1992-09-25 |
Family
ID=12957086
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5395391A Pending JPH04270272A (en) | 1991-02-25 | 1991-02-25 | Production of aminoalkylmorpholine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04270272A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994022843A1 (en) * | 1993-03-26 | 1994-10-13 | Schering Corporation | 2-substituted morpholine and thiomorpholine derivatives as gaba-b antagonists |
| JP2004509953A (en) * | 2000-09-29 | 2004-04-02 | グラクソ グループ リミテッド | Compounds useful for treating inflammatory diseases |
| JP2005525390A (en) * | 2002-03-28 | 2005-08-25 | グラクソ グループ リミテッド | N-{[(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methyl} -2- {3-[(methylsulfonyl) as a CCR3 antagonist for the treatment of inflammatory conditions ) Amino] phenyl} acetamide |
-
1991
- 1991-02-25 JP JP5395391A patent/JPH04270272A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994022843A1 (en) * | 1993-03-26 | 1994-10-13 | Schering Corporation | 2-substituted morpholine and thiomorpholine derivatives as gaba-b antagonists |
| JP2004509953A (en) * | 2000-09-29 | 2004-04-02 | グラクソ グループ リミテッド | Compounds useful for treating inflammatory diseases |
| JP2005525390A (en) * | 2002-03-28 | 2005-08-25 | グラクソ グループ リミテッド | N-{[(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methyl} -2- {3-[(methylsulfonyl) as a CCR3 antagonist for the treatment of inflammatory conditions ) Amino] phenyl} acetamide |
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