JPS6332073B2 - - Google Patents
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- Publication number
- JPS6332073B2 JPS6332073B2 JP56060368A JP6036881A JPS6332073B2 JP S6332073 B2 JPS6332073 B2 JP S6332073B2 JP 56060368 A JP56060368 A JP 56060368A JP 6036881 A JP6036881 A JP 6036881A JP S6332073 B2 JPS6332073 B2 JP S6332073B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- general formula
- reaction
- acid
- 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
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- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 17
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- -1 N-protected lysine Chemical class 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 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
- 235000001014 amino acid Nutrition 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- JRLUQGSODQQBFK-UHFFFAOYSA-N phenyl n-(1,3-benzothiazol-2-yl)carbamate Chemical compound N=1C2=CC=CC=C2SC=1NC(=O)OC1=CC=CC=C1 JRLUQGSODQQBFK-UHFFFAOYSA-N 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
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- UHGULLIUJBCTEF-UHFFFAOYSA-N 2-aminobenzothiazole Chemical class C1=CC=C2SC(N)=NC2=C1 UHGULLIUJBCTEF-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- RHYBFKMFHLPQPH-UHFFFAOYSA-N N-methylhydantoin Chemical compound CN1CC(=O)NC1=O RHYBFKMFHLPQPH-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 description 1
- XPNCYFXBJGEJFY-UHFFFAOYSA-N 2-(1,3-benzothiazol-2-ylcarbamoylamino)acetic acid Chemical compound C1=CC=C2SC(NC(=O)NCC(=O)O)=NC2=C1 XPNCYFXBJGEJFY-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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- SREKYKXYSQMOIB-UHFFFAOYSA-N N-carbamoylsarcosine Chemical compound NC(=O)N(C)CC(O)=O SREKYKXYSQMOIB-UHFFFAOYSA-N 0.000 description 1
- VDIPNVCWMXZNFY-UHFFFAOYSA-N N-methyl-beta-alanine Chemical compound CNCCC(O)=O VDIPNVCWMXZNFY-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 244000000005 bacterial plant pathogen Species 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- NGNUXOCKVMKGQL-UHFFFAOYSA-N methyl 3-(methylamino)propanoate Chemical compound CNCCC(=O)OC NGNUXOCKVMKGQL-UHFFFAOYSA-N 0.000 description 1
- BFGNHBBJJWESFT-UHFFFAOYSA-N n,n-dimethylformamide;ethoxyethane Chemical compound CCOCC.CN(C)C=O BFGNHBBJJWESFT-UHFFFAOYSA-N 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
Description
本発明は一般式〔Ｉ〕
〔式中、Ｘは同一もしくは異なつて、低級アルキ
ル基、低級アルコキシ基、ハロゲン原子、ニトロ
基を示し、R1は水素、低級アルキル基、低級ア
ルカノイル基、低級アルコキシカルボニル基を示
し、R2は同一もしくは異なつて水素、低級アル
キル基、メチルチオエチル基、アラルキル基を示
す。R1とR2が一体となつて、―（CH2）p―（式
中、ｐは３または４である。）を形成してもよい。
ｍは０または１〜４の整数を示す。ｎは１または
２の整数を示す。〕で表わされる新規なベンゾチ
アゾール誘導体およびその製造法に関する。
本発明の化合物は血小板凝集阻害作用、血圧降
下作用を有し、また除草作用、植物病原菌に対し
て殺菌作用を示すので、医薬、農薬として有用な
化合物である。
以下に本発明を詳細に説明する。本発明の化合
物〔Ｉ〕は一般式〔〕
（式中、Ｘ、R1、R2、ｍおよびｎは前記と同様
の意義を有する。）で示される化合物を環化させ
ることによつて得ることができる。
上記一般式〔〕で示される化合物は以下に示
す方法により得ることができる。すなわち、一般
式〔〕
The present invention is based on the general formula [I] [In the formula, X is the same or different and represents a lower alkyl group, a lower alkoxy group, a halogen atom, or a nitro group, R 1 represents hydrogen, a lower alkyl group, a lower alkanoyl group, or a lower alkoxycarbonyl group, and R 2 represents They may be the same or different and represent hydrogen, lower alkyl group, methylthioethyl group, or aralkyl group. R 1 and R 2 may be combined to form -(CH 2 ) p - (wherein p is 3 or 4).
m represents 0 or an integer of 1-4. n represents an integer of 1 or 2. This invention relates to a novel benzothiazole derivative represented by the following formula and a method for producing the same. The compound of the present invention has a platelet aggregation inhibiting effect and a blood pressure lowering effect, and also exhibits a herbicidal effect and a bactericidal effect against plant pathogenic bacteria, so it is a useful compound as a medicine and an agrochemical. The present invention will be explained in detail below. The compound [I] of the present invention has the general formula [] (In the formula, X, R 1 , R 2 , m and n have the same meanings as above.) It can be obtained by cyclizing the compound represented by the formula. The compound represented by the above general formula [] can be obtained by the method shown below. In other words, the general formula []
【式】（式中、Ｘ、ｍは前記
と同様の意義を有する。）で示される２―アミノ
ベンゾチアゾール類と一般式〔〕2-Aminobenzothiazoles represented by [Formula] (wherein, X and m have the same meanings as above) and general formula []
【式】（式中、Ｚはハロゲン原
子を示し、Ｙは水素、ハロゲン、低級アルキル
基、低級アルコキシ基、ニトロ基を示す。）で表
わされるハロ炭酸フエニル類を、塩化メチレン、
クロロホルム、酢酸エチル、ジオキサン、テトラ
ハイドロフラン、Ｎ，Ｎ―ジメチルホルムアミド
などの溶媒中、ピリジン、トリエチルアミン、
Ｎ，Ｎ―ジメチルアニリン、Ｎ―メチルモルホリ
ンなどの存在下に反応させて、一般式〔Ｖ〕
（式中、Ｘ、Ｙ、ｍは前記と同様の意義を有す
る。）で示される化合物を合成する。使用する塩
基の量は基本的には反応系中に存在する酸塩、さ
らには反応中に生成するハロゲン化水素を中和す
るに必要な量を用いる。一般式〔〕の化合物は
一般式〔〕の化合物に対して１〜1.5倍モル量
使用する。反応は−20℃から使用する溶媒の間で
実施されるが、より好ましくは０℃から30℃の間
で行なわれる。反応は通常、12時間から36時間の
間で終了する。ついで、上記反応によつて得られ
た一般式〔Ｖ〕の化合物と一般式〔〕
（式中、R1、R2は前記と同様の意義を有する。
Ｒは水酸基、低級アルコキシ基を示す。）で表わ
されるアミノ酸あるいはこれらの誘導体とを反応
させることによつて、一般式〔〕
（式中、Ｘ、R1、R2、Ｒ、ｍおよびｎは前記と
同様の意義を有する。）で示される化合物を合成
する。
一般式〔〕で示される化合物は、一般的に、
公知化合物ないしは公知の方法で製造される化合
物である。一般式〔〕において、Ｒ＝−OHで
あるときは、一般式〔〕で示される化合物はア
ミノ酸であり、Ｒが低級アルコキシ基であるとき
は、アミノ酸を一般的公知のエステル化法によつ
てエステル化することによつて一般式〔〕で示
される化合物が得られる。一般式〔〕で表わさ
れる化合物としては、グリシン、ザルコシン、ア
ラニン、β―アラニン、Ｎ―メチル―β―アラニ
ン、４―アミノ―ｎ―酪酸、４―Ｎ―メチルアミ
ノ―ｎ―酪酸、バリン、ロイシン、イソロイシ
ン、メチオニン、フエニルアラニン、プロリン、
ピペコリン酸、ニペコチン酸、４―ピペリジンカ
ルボン酸、N〓―保護リジン、N〓―保護オルニチ
ン、ヒスチジン、トリプトフアン、スレオニンな
どのアミノ酸およびそれらの低級アルキルエステ
ルがあげられる。ここでリジンおよびオルニチン
側鎖のアミノ基の保護基としてはアセチル基、ベ
ンジルオキシカルボニル基、トシル基などが用い
られる。またグルタミン酸およびアスパラギン酸
の側鎖のカルボキシル基は遊離の形あるいは低級
アルキルエステルあるいはベンジルエステルの形
で用いられる。システインの―SHの保護基とし
てはベンジルオキシカルボニル基あるいはベンジ
ル基が用いられる。本発明のアミノ酸は光学活性
体、光学不活性体のいずれも使用できる。一般式
〔〕で表わされる化合物は酸塩、たとえば塩酸、
硫酸、臭化水素酸のような無機酸の塩、トリフル
オロ酢酸のような有機酸の塩の型で反応に使用す
ることもできる。酸塩を用いるときは、反応に際
し、等モルの塩酸を用いて遊離の型にしてから反
応を行なうことが望ましい。一般式〔Ｖ〕の化合
物と一般式〔〕の化合物の反応は適当な有機溶
媒中実施されるが、反応に用いられる有機溶媒と
しては、反応に直接関与しない不活性溶媒はいず
れも使用できるが、好ましくは、ベンゼン、トル
エン、キシレンなどの芳香族炭化水素類、ジオキ
サン、テトラハイドロフランなどのエーテル類、
Ｎ，Ｎ―ジメチルホルムアミドなどのアミド類、
酢酸エチルなどのエステル類、クロロホルム、塩
化メチレンなどが使用される。使用される原料化
合物である一般式〔〕で表わされる化合物は、
一般式〔Ｖ〕で表わされる化合物に対し、等モル
ないし３倍モルの間で使用することが望ましい。
反応は室温から反応溶媒の沸点の間で実施される
が、好ましくは50〜70℃の範囲で行なわれる。反
応は通常１時間〜５日間で終了する。
一般式〔〕中Ｒが水酸基である化合物は一般
式〔〕で表わされる化合物である。Ｒが低級ア
ルコキシ基である場合、一般式〔〕で表わされ
る化合物をアルカリの存在下に加水分解すること
により、一般式〔〕の化合物に導くことができ
る。
上記方法によつて得られた一般式〔〕で表わ
される化合物を環化させて、一般式〔Ｉ〕で示さ
れる化合物を得ることができる。環化反応は通常
カルボキシル基の活性化に使用する方法、たとえ
ば酸塩化物法、アジド法、混合酸無水物法、活性
エステル法により目的を達成することもできる。
しかし、本発明者らは種々検討した結果、無水酢
酸を使用することにより、非常に高収率に目的物
を得ることができることを見出し、本発明を完成
した。すなわち、ジオキサン、テトラハイドロフ
ランなどのエーテル類、ベンゼン、トルエン、キ
シレンなどの芳香族炭化水素類、Ｎ，Ｎ―ジメチ
ルホルムアミドなどのアミド類、酢酸エチルなど
のエステル類などの溶媒中、あるいは無溶媒の状
態で、無水酢酸で処理することにより、一般式
〔Ｉ〕の化合物を高収率に得ることができた。本
反応に使用する無水酢酸の量は、使用する原料化
合物一般式〔〕の化合物に対して約２倍モルか
ら大過剰の状態で使用される。反応温度は室温か
ら使用する反応溶媒の沸点の間で実施されるが、
好ましくは室温から70℃の間で実施される。反応
時間は反応温度によつても異なるが、通常１時間
〜５日の間で反応は完結する。
また一般式〔Ｉ〕において、R1が低級アルカ
ノイル基、低級アルコキシカルボニル基で示され
る化合物は、一般式〔Ｉ〕において、R1が水素
である化合物を適当な有機溶媒中、たとえば、酢
酸エチル、酢酸ブチル、アセトニトリル、ベンゼ
ン、トルエン、ジオキサン、クロロホルム、塩化
メチレンなどの溶媒中、−10℃〜50℃、好ましく
は０〜30℃の温度で適当な有機塩基、たとえばト
リエチルアミン、トリブチルアミンなどの存在下
に、一般式〔〕
（式中、Halはハロゲン原子を表わし、R3は低級
アルコキシ基を示す。）で示される化合物を反応
させることによつて得ることができる。反応は１
時間〜３日の間で終了する。
次に本発明の目的化合物を単離するには、通常
有機合成化学の分野で一般に実施されている単
離、精製方法、たとえば濃縮、抽出、再結晶、ク
ロマトグラフイー等により単離することができ
る。
以下に本発明を実施例をもつて、本発明の態様
をさらに具体的に説明するが、本発明はこれらに
よつて限定されるものではない。
実施例 １
３―〔２―（６―エトキシベンゾチアゾリル）〕
―１―メチルヒダントイン（化合物No.46）の合
成
Ｎ―〔２―（６―エトキシベンゾチアゾリル）〕
アミノカルボニルザルコシン（化合物No.10）5.5g
（0.018モル）に無水酢酸200mlを加え70℃で２時
間撹拌する。その後、減圧濃縮し残渣をエーテル
50mlにより結晶化させると、淡黄色針状晶として
目的物4.70g（収率90.7％）を得た。
融点 191〜193℃
元素分析 Ｃ(%) Ｈ(%) Ｎ(%)
実測値 53.42 4.35 14.32
計算値 53.60 4.50 14.42
（C13H13N3O3Sとして）
PMR （CDCl3−d6−DMSO）δppm 7.83（1H、
ｄ、Ｊ＝９Hz）、7.55（1H、ｄ、Ｊ＝２
Hz）、7.07（1H、dd、Ｊ＝２Hz、Ｊ＝９
Hz）、4.17（2H、ｓ）、4.08（2H、ｑ、Ｊ
＝７Hz）、2.97（3H、ｓ）、1.37（3H、ｔ、
Ｊ＝７Hz）
IR （KBr）νmax 3420、2920、1790、1740、
1600
実施例１と同様な操作により第１表に示す化合
物（No.47〜72）を合成した。[Formula] (wherein, Z represents a halogen atom, and Y represents hydrogen, halogen, lower alkyl group, lower alkoxy group, or nitro group), methylene chloride,
In a solvent such as chloroform, ethyl acetate, dioxane, tetrahydrofuran, N,N-dimethylformamide, pyridine, triethylamine,
By reacting in the presence of N,N-dimethylaniline, N-methylmorpholine, etc., the general formula [V] A compound represented by the formula (wherein X, Y, and m have the same meanings as above) is synthesized. The amount of base used is basically the amount necessary to neutralize the acid salts present in the reaction system as well as the hydrogen halide generated during the reaction. The compound of general formula [] is used in an amount of 1 to 1.5 times the molar amount of the compound of general formula []. The reaction is carried out between -20°C and the solvent used, more preferably between 0°C and 30°C. The reaction is usually completed within 12 to 36 hours. Then, the compound of the general formula [V] obtained by the above reaction and the general formula [] (In the formula, R 1 and R 2 have the same meanings as above.
R represents a hydroxyl group or a lower alkoxy group. ) by reacting with an amino acid represented by the general formula [] A compound represented by the formula (wherein X, R 1 , R 2 , R, m and n have the same meanings as above) is synthesized. The compound represented by the general formula [] is generally
It is a known compound or a compound produced by a known method. In the general formula [], when R=-OH, the compound represented by the general formula [] is an amino acid, and when R is a lower alkoxy group, the amino acid is esterified by a generally known esterification method. By esterification, a compound represented by the general formula [] is obtained. Compounds represented by the general formula [] include glycine, sarcosine, alanine, β-alanine, N-methyl-β-alanine, 4-amino-n-butyric acid, 4-N-methylamino-n-butyric acid, valine, Leucine, isoleucine, methionine, phenylalanine, proline,
Examples include amino acids such as pipecolic acid, nipecotic acid, 4-piperidinecarboxylic acid, N-protected lysine, N-protected ornithine, histidine, tryptophan, and threonine, and lower alkyl esters thereof. Here, an acetyl group, a benzyloxycarbonyl group, a tosyl group, etc. are used as the protecting group for the amino group of the lysine and ornithine side chains. Further, the side chain carboxyl group of glutamic acid and aspartic acid is used in a free form or in the form of a lower alkyl ester or benzyl ester. A benzyloxycarbonyl group or a benzyl group is used as the protecting group for --SH of cysteine. The amino acid of the present invention can be used in either an optically active form or an optically inactive form. The compound represented by the general formula [] is an acid salt, such as hydrochloric acid,
It can also be used in the reaction in the form of an inorganic acid salt such as sulfuric acid or hydrobromic acid, or an organic acid salt such as trifluoroacetic acid. When using an acid salt, it is desirable to convert it into a free form using equimolar hydrochloric acid before the reaction. The reaction between the compound of general formula [V] and the compound of general formula [] is carried out in a suitable organic solvent, but any inert solvent that does not directly participate in the reaction can be used as the organic solvent used in the reaction. , preferably aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dioxane and tetrahydrofuran;
Amides such as N,N-dimethylformamide,
Esters such as ethyl acetate, chloroform, methylene chloride, etc. are used. The compound represented by the general formula [], which is the raw material compound used, is
It is preferable to use the compound in an amount equal to or 3 times the mole of the compound represented by the general formula [V].
The reaction is carried out between room temperature and the boiling point of the reaction solvent, preferably in the range of 50 to 70°C. The reaction usually completes in 1 hour to 5 days. A compound in which R in the general formula [] is a hydroxyl group is a compound represented by the general formula []. When R is a lower alkoxy group, the compound represented by the general formula [] can be led to the compound represented by the general formula [] by hydrolyzing it in the presence of an alkali. The compound represented by the general formula [] obtained by the above method can be cyclized to obtain the compound represented by the general formula [I]. The purpose of the cyclization reaction can also be achieved by a method normally used for activating a carboxyl group, such as an acid chloride method, an azide method, a mixed acid anhydride method, or an active ester method.
However, as a result of various studies, the present inventors have found that the desired product can be obtained in a very high yield by using acetic anhydride, and have completed the present invention. That is, in a solvent such as ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene, amides such as N,N-dimethylformamide, and esters such as ethyl acetate, or without a solvent. By treating with acetic anhydride in this state, the compound of general formula [I] could be obtained in high yield. The amount of acetic anhydride used in this reaction is from about 2 times the mole to a large excess relative to the starting material compound of general formula []. The reaction temperature is between room temperature and the boiling point of the reaction solvent used,
It is preferably carried out at a temperature between room temperature and 70°C. Although the reaction time varies depending on the reaction temperature, the reaction is usually completed within 1 hour to 5 days. In addition, in the general formula [I], a compound in which R 1 is a lower alkanoyl group or a lower alkoxycarbonyl group is prepared by adding a compound in which R 1 is hydrogen in a suitable organic solvent, for example, ethyl acetate. , butyl acetate, acetonitrile, benzene, toluene, dioxane, chloroform, methylene chloride, etc., in the presence of a suitable organic base, such as triethylamine, tributylamine, etc., at a temperature of -10°C to 50°C, preferably 0 to 30°C. Below is the general formula [] (In the formula, Hal represents a halogen atom, and R 3 represents a lower alkoxy group.) It can be obtained by reacting a compound represented by the following formula. The reaction is 1
It will be completed within 3 days. Next, the target compound of the present invention can be isolated by isolation and purification methods commonly practiced in the field of organic synthetic chemistry, such as concentration, extraction, recrystallization, chromatography, etc. can. The present invention will be described in more detail below with reference to Examples, but the present invention is not limited thereto. Example 1 3-[2-(6-ethoxybenzothiazolyl)]
-Synthesis of 1-methylhydantoin (compound No. 46) N-[2-(6-ethoxybenzothiazolyl)]
Aminocarbonylsarcosine (compound No.10) 5.5g
Add 200 ml of acetic anhydride to (0.018 mol) and stir at 70°C for 2 hours. Then, concentrate under reduced pressure and convert the residue into ether.
When crystallized from 50 ml, 4.70 g (yield: 90.7%) of the desired product was obtained as pale yellow needle-like crystals. Melting point 191-193℃ Elemental analysis C(%) H(%) N(%) Actual value 53.42 4.35 14.32 Calculated value 53.60 4.50 14.42 (as C 13 H 13 N 3 O 3 S) PMR (CDCl 3 −d 6 −DMSO ) δppm 7.83 (1H,
d, J=9Hz), 7.55(1H, d, J=2
Hz), 7.07 (1H, dd, J=2Hz, J=9
Hz), 4.17 (2H, s), 4.08 (2H, q, J
=7Hz), 2.97 (3H, s), 1.37 (3H, t,
J=7Hz) IR (KBr) νmax 3420, 2920, 1790, 1740,
1600 Compounds (Nos. 47 to 72) shown in Table 1 were synthesized by the same operation as in Example 1.
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】
実施例 ２
３―（２―ベンゾチアゾリル）―１―エトキシ
カルボニルヒダントインの合成（化合物No.73）
３―（２―ベンゾチアゾリル）ヒダントイン
（化合物No.48）5.9g（0.025モル）およびクロルギ
酸エチル5.5g（0.051モル）を塩化メチレン200ml
に加え、氷冷撹拌下トリエチルアミン5.2gを塩化
メチレン50mlに溶解した溶液を２時間で滴下す
る。滴下終了後、室温で２日間撹拌したのち、１
規定塩酸100mlで２回、水100mlで２回、５％炭酸
水素ナトリウム100mlで３回、水100mlで４回それ
ぞれ洗浄する。ついで無水硫酸ナトリウムで乾燥
したのち、減圧濃縮し、濃縮残渣をクロロホルム
により結晶化させると、無色針状晶として標題化
合物が3.75g（収率48.6％）得られる。
PMR （CDCl3）δppm 8.2〜7.25（4H、ｍ）、
4.52（2H、ｓ）、4.38（2H、ｑ、Ｊ＝７
Hz）、1.37（3H、ｔ、Ｊ＝７Hz）
実施例２と同様な操作により第２表に示す化合
物（No.74、75）を合成した。[Table] Example 2 Synthesis of 3-(2-benzothiazolyl)-1-ethoxycarbonylhydantoin (Compound No. 73) 5.9 g (0.025 mol) of 3-(2-benzothiazolyl)hydantoin (Compound No. 48) and 5.5 g (0.051 mol) of ethyl chloroformate were added to 200 ml of methylene chloride.
In addition to this, a solution of 5.2 g of triethylamine dissolved in 50 ml of methylene chloride was added dropwise over 2 hours while stirring on ice. After the completion of the dropwise addition, after stirring at room temperature for 2 days, 1
Wash twice with 100 ml of normal hydrochloric acid, twice with 100 ml of water, three times with 100 ml of 5% sodium bicarbonate, and four times with 100 ml of water. After drying over anhydrous sodium sulfate, the mixture is concentrated under reduced pressure, and the concentrated residue is crystallized from chloroform to obtain 3.75 g (yield: 48.6%) of the title compound as colorless needles. PMR ( CDCl3 ) δppm 8.2-7.25 (4H, m),
4.52 (2H, s), 4.38 (2H, q, J=7
Hz), 1.37 (3H, t, J=7Hz) Compounds (No. 74, 75) shown in Table 2 were synthesized by the same operation as in Example 2.
【表】
参考例 １
２―フエノキシカルボニルアミノベンゾチアゾ
ール（化合物No.１）
２―アミノベンゾチアゾール50g（0.333モル）
に塩化メチレン400mlおよびピリジン32g（0.406モ
ル）を加え室温で撹拌する。ついでクロル炭酸フ
エニル62g（0.396モル）を塩化メチレン400mlに溶
解した溶液を45分で滴下する。その後室温で17時
間撹拌後過し、得られた固体を塩化メチレン
500ml、ついで水５で２回に分けて洗浄すると
白色固体として標題化合物が81.6g（90.7％）得ら
れる。このものは酢酸エチルにより結晶化し無色
針状晶となる。
融点 237℃（分解）
元素分析値 Ｃ(%) Ｈ(%) Ｎ(%)
実測値 61.99 3.48 10.54
計算値 62.21 3.73 10.36
（C14H10N2O2Sとして）
IR （KBr）νmax 3450、2900、1740、1610
PMR （d6―DMSO）δppm 7.8（9H、ｍ）、3.5
（1H、bs）
参考例１と同様な操作により第３表に示す化合
物（No.２〜７）を合成した。[Table] Reference example 1 2-phenoxycarbonylaminobenzothiazole (compound No. 1) 2-Aminobenzothiazole 50g (0.333mol)
Add 400 ml of methylene chloride and 32 g (0.406 mol) of pyridine to the mixture and stir at room temperature. Then, a solution of 62 g (0.396 mol) of phenyl chlorocarbonate dissolved in 400 ml of methylene chloride was added dropwise over 45 minutes. Thereafter, after stirring at room temperature for 17 hours, it was filtered, and the obtained solid was diluted with methylene chloride.
Washing with 500 ml and then 2 portions with 5 portions of water gives 81.6 g (90.7%) of the title compound as a white solid. This product crystallizes into colorless needle crystals with ethyl acetate. Melting point 237℃ (decomposition) Elemental analysis value C (%) H (%) N (%) Actual value 61.99 3.48 10.54 Calculated value 62.21 3.73 10.36 (as C 14 H 10 N 2 O 2 S) IR (KBr) νmax 3450, 2900, 1740, 1610 PMR (d 6 - DMSO) δppm 7.8 (9H, m), 3.5
(1H, bs) Compounds (Nos. 2 to 7) shown in Table 3 were synthesized by the same operation as in Reference Example 1.
【表】【table】
【表】
参考例 ２
Ｎ―（２―ベンゾチアゾリル）アミノカルボニ
ルグリシン（化合物No.８）
２―フエノキシカルボニルアミノベンゾチアゾ
ール20g（0.074モル）およびグリシン11g（0.147モ
ル）をピリジン400mlに加え、70℃で48時間撹拌
する。ついで別し、液を減圧下に濃縮し、得
られた淡黄色固体に水600mlおよびトリエチルア
ミン40mlを加え溶解したのち、酢酸エチル100ml
で４回洗浄する。その後、氷冷撹拌下に濃塩酸で
PH２に調整し、生じた白色沈殿を取し、200ml
の水で洗浄すると、標題化合物が15.6g（収率83.9
％）得られる。このものはDMF―エーテルより
結晶化し無色針状晶となる。
融点 190℃（分解）
元素分析値 Ｃ(%) Ｈ(%) Ｎ(%)
実測値 47.86 3.44 16.46
計算値 47.80 3.61 16.72
（C10H9N3O3Sとして）
IR （KBr）νmax 3390、3280、1680、（br）、
1600
PMR （CDCl3―d6―DMSO）δppm 7.4（4H、
ｍ）
参考例 ３
Ｎ―（２―ベンゾチアゾリル）アミノカルボニ
ル―Ｎ―メチル―β―アラニンメチルエステル
（化合物No.19）
２―フエノキシカルボニルアミノベンゾチアゾ
ール15g（0.055モル）およびＮ―メチル―β―ア
ラニンメチルエステル7.8g（0.067モル）に酢酸エ
チル200mlを加え96時間還流する。その後過し、
液を１規定塩酸100mlで３回、５％炭酸水素ナ
トリウム100mlで２回、水50mlで５回洗浄したの
ち、無水硫酸ナトリウムで乾燥する。硫酸ナトリ
ウムを去後、液を減圧濃縮し、濃縮残渣を０
℃に放置すると、標題化合物が無色針状晶として
7.36g（収率50.4％）得られる。
融点 89.5〜90.5℃
元素分析 Ｃ(%) Ｈ(%) Ｎ(%)
実測値 53.31 5.14 14.02
計算値 53.23 5.15 14.32
（C13H15N3O3Sとして）
PMR （CDCl3）δppm 9.33（1H、bs）、7.47
（4H、ｍ）、3.67（3H、ｓ）、3.67（2H、
ｔ、Ｊ＝６Hz）、3.00（3H、ｓ）、2.63
（2H、ｔ、Ｊ＝６Hz）
IR （PCHCl3）νmax 3430、3260、2960、
1735、1680、1600
参考例２または参考例３と同様な操作により第
４表に示す化合物（No.９〜38）を合成した。[Table] Reference example 2 N-(2-benzothiazolyl)aminocarbonylglycine (compound No. 8) 20 g (0.074 mol) of 2-phenoxycarbonylaminobenzothiazole and 11 g (0.147 mol) of glycine are added to 400 ml of pyridine and stirred at 70° C. for 48 hours. The liquid was then separated and concentrated under reduced pressure. 600 ml of water and 40 ml of triethylamine were added to the obtained pale yellow solid to dissolve it, and then 100 ml of ethyl acetate was added.
Wash 4 times with Then, add concentrated hydrochloric acid while stirring on ice.
Adjust the pH to 2, remove the white precipitate, and add 200ml.
After washing with water, 15.6 g of the title compound (yield 83.9
%)can get. This substance crystallizes from DMF-ether to form colorless needle-shaped crystals. Melting point 190℃ (decomposition) Elemental analysis value C (%) H (%) N (%) Actual value 47.86 3.44 16.46 Calculated value 47.80 3.61 16.72 (as C 10 H 9 N 3 O 3 S) IR (KBr) νmax 3390, 3280, 1680, (br),
1600 PMR (CDCl 3 - d 6 - DMSO) δppm 7.4 (4H,
m) Reference example 3 N-(2-benzothiazolyl)aminocarbonyl-N-methyl-β-alanine methyl ester (compound No. 19) 200 ml of ethyl acetate was added to 15 g (0.055 mol) of 2-phenoxycarbonylaminobenzothiazole and 7.8 g (0.067 mol) of N-methyl-β-alanine methyl ester, and the mixture was refluxed for 96 hours. After that,
The solution is washed three times with 100 ml of 1N hydrochloric acid, twice with 100 ml of 5% sodium bicarbonate, and five times with 50 ml of water, and then dried over anhydrous sodium sulfate. After removing the sodium sulfate, the liquid was concentrated under reduced pressure to reduce the concentration residue to 0.
When left at ℃, the title compound forms colorless needle crystals.
7.36g (yield 50.4%) is obtained. Melting point 89.5-90.5℃ Elemental analysis C(%) H(%) N(%) Actual value 53.31 5.14 14.02 Calculated value 53.23 5.15 14.32 (as C 13 H 15 N 3 O 3 S) PMR (CDCl 3 ) δppm 9.33 (1H , bs), 7.47
(4H, m), 3.67 (3H, s), 3.67 (2H,
t, J=6Hz), 3.00 (3H, s), 2.63
(2H, t, J=6Hz) IR (PCHCl 3 ) νmax 3430, 3260, 2960,
1735, 1680, 1600 Compounds (Nos. 9 to 38) shown in Table 4 were synthesized in the same manner as in Reference Example 2 or 3.
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】
参考例 ４
Ｎ―〔２―（６―エトキシ）ベンゾチアゾリ
ル〕アミノカルボニル―Ｎ―メチル―β―アラ
ニン（化合物No.39）
Ｎ―〔２―（６―エトキシ）ベンゾチアゾリ
ル〕アミノカルボニル―Ｎ―メチル―β―アラニ
ン（化合物No.20）12.1gのメチルアルコール50ml
を加え、氷冷撹拌下に５％水酸化ナトリウム水溶
液300mlを30分で滴下する。その後過し、液
を酢酸エチル50mlで２回洗浄し、濃塩酸でPH２に
調整する。生じた沈殿を取し、水２で洗浄す
ると標題化合物が10.98g（収率94.7％）得られる。
本物質はDMF―水により結晶化し、無色針状晶
を与える。
融点 191〜193℃（分解）
元素分析 Ｃ(%) Ｈ(%) Ｎ(%)
実測値 52.15 5.19 12.71
計算値 52.00 5.30 12.99
（C14H17N3O4Sとして）
PMR （PCDCl3）―d6―DMSO）δppm 11.6
（2H、bs）、7.45（1H、ｄ、Ｊ＝９Hz）、
7.18（1H、ｄ、Ｊ＝３Hz）、6.92（1H、
dd、Ｊ＝３Hz、Ｊ＝９Hz）、4.07（2H、
ｑ、Ｊ＝７Hz）、3.67（2H、ｔ、Ｊ＝７
Hz）、3.03（3H、ｓ）、2.55（2H、ｔ、Ｊ
＝７Hz）、1.2（3H、ｔ、Ｊ＝７Hz）
IR （KBr）νmax 3400、3200、2450、1675、
1605
参考例４と同様な操作により第５表に示す化合
物（No.40〜45）を合成した。[Table] Reference example 4 N-[2-(6-ethoxy)benzothiazolyl]aminocarbonyl-N-methyl-β-alanine (Compound No. 39) 12.1 g of N-[2-(6-ethoxy)benzothiazolyl]aminocarbonyl-N-methyl-β-alanine (Compound No. 20) 50 ml of methyl alcohol
was added, and 300 ml of 5% aqueous sodium hydroxide solution was added dropwise over 30 minutes while stirring on ice. Thereafter, it is filtered, the liquid is washed twice with 50 ml of ethyl acetate, and the pH is adjusted to 2 with concentrated hydrochloric acid. The resulting precipitate is collected and washed with 2 portions of water to obtain 10.98 g (yield: 94.7%) of the title compound.
This substance crystallizes in DMF-water to give colorless needle-shaped crystals. Melting point 191-193℃ (decomposition) Elemental analysis C (%) H (%) N (%) Actual value 52.15 5.19 12.71 Calculated value 52.00 5.30 12.99 (as C 14 H 17 N 3 O 4 S) PMR (PCDCl 3 ) - d 6 - DMSO) δppm 11.6
(2H, bs), 7.45 (1H, d, J=9Hz),
7.18 (1H, d, J = 3Hz), 6.92 (1H,
dd, J=3Hz, J=9Hz), 4.07(2H,
q, J = 7Hz), 3.67 (2H, t, J = 7
Hz), 3.03 (3H, s), 2.55 (2H, t, J
= 7Hz), 1.2 (3H, t, J = 7Hz) IR (KBr) νmax 3400, 3200, 2450, 1675,
1605 Compounds (Nos. 40 to 45) shown in Table 5 were synthesized by the same operation as in Reference Example 4.
【表】【table】
Claims (1)
ル基、低級アルコキシ基、ハロゲン原子、ニトロ
基を示し、R1は水素、低級アルキル基、低級ア
ルカノイル基、低級アルコキシカルボニル基を示
し、R2は同一もしくは異なつて、水素、低級ア
ルキル基、メチルチオエチル基、アラルキル基を
示す。R1とR2が一体となつて、―（CH2）p―
（式中、ｐは３または４である。）を形成してもよ
い。ｍは０または１〜４の整数を示す。ｎは１ま
たは２の整数を示す。〕で表わされる新規なベン
ゾチアゾール誘導体。[Claims] 1. General formula [] [In the formula, X is the same or different and represents a lower alkyl group, a lower alkoxy group, a halogen atom, or a nitro group, R 1 represents hydrogen, a lower alkyl group, a lower alkanoyl group, or a lower alkoxycarbonyl group, and R 2 represents They are the same or different and represent hydrogen, lower alkyl group, methylthioethyl group, or aralkyl group. When R 1 and R 2 are combined, ―(CH 2 ) p ―
(wherein p is 3 or 4). m represents 0 or an integer of 1-4. n represents an integer of 1 or 2. ] A novel benzothiazole derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6036881A JPS57175189A (en) | 1981-04-21 | 1981-04-21 | Benzothiazole derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6036881A JPS57175189A (en) | 1981-04-21 | 1981-04-21 | Benzothiazole derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57175189A JPS57175189A (en) | 1982-10-28 |
| JPS6332073B2 true JPS6332073B2 (en) | 1988-06-28 |
Family
ID=13140120
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6036881A Granted JPS57175189A (en) | 1981-04-21 | 1981-04-21 | Benzothiazole derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57175189A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012514032A (en) * | 2008-12-29 | 2012-06-21 | コリア・インスティテュート・オブ・サイエンス・アンド・テクノロジー | Benzoarylureido compound and composition for preventing or treating neurodegenerative brain disease containing the same |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5179207A (en) * | 1991-08-19 | 1993-01-12 | Eastman Kodak Company | Substituted 2-amino-5-maleimido thiophenes and substituted 2-amino-maleimido thiazoles |
| US5235047A (en) * | 1991-08-19 | 1993-08-10 | Eastman Kodak Company | Bathochromic azo dyes derived from 2-aminothiophenes and 2-aminothiazoles |
| US6410484B1 (en) * | 1999-11-01 | 2002-06-25 | Sumitomo Chemical Company, Limited | 6-Hydroxy-5,6-dihydrouracil compound and herbicidal composition containing thereof |
| IL151045A0 (en) | 2000-02-07 | 2003-04-10 | Abbott Gmbh & Co Kg | 2-benzothiazolyl urea derivatives and their use as protein kinase inhibitors |
| TW200407324A (en) * | 2002-05-17 | 2004-05-16 | Bristol Myers Squibb Co | Bicyclic modulators of androgen receptor function |
| MX2012000178A (en) | 2009-07-02 | 2012-02-28 | Novartis Ag | 2-carboxamide cycloamino ureas useful as pi3k inhibitors. |
| GB201711555D0 (en) * | 2017-07-18 | 2017-08-30 | Kent Innovation & Entpr | Antibacterial compounds |
| JPWO2023008472A1 (en) * | 2021-07-28 | 2023-02-02 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS535163A (en) * | 1976-05-20 | 1978-01-18 | Velsicol Chemical Corp | 11benzothiazolyllimidazolidianes |
| JPS55133381A (en) * | 1979-03-02 | 1980-10-17 | Velsicol Chemical Corp | Tetrahydrobenzothiazolylimidazolidinone |
-
1981
- 1981-04-21 JP JP6036881A patent/JPS57175189A/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS535163A (en) * | 1976-05-20 | 1978-01-18 | Velsicol Chemical Corp | 11benzothiazolyllimidazolidianes |
| JPS55133381A (en) * | 1979-03-02 | 1980-10-17 | Velsicol Chemical Corp | Tetrahydrobenzothiazolylimidazolidinone |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012514032A (en) * | 2008-12-29 | 2012-06-21 | コリア・インスティテュート・オブ・サイエンス・アンド・テクノロジー | Benzoarylureido compound and composition for preventing or treating neurodegenerative brain disease containing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57175189A (en) | 1982-10-28 |
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