JPS6236038B2 - - Google Patents
Info
- Publication number
- JPS6236038B2 JPS6236038B2 JP56067136A JP6713681A JPS6236038B2 JP S6236038 B2 JPS6236038 B2 JP S6236038B2 JP 56067136 A JP56067136 A JP 56067136A JP 6713681 A JP6713681 A JP 6713681A JP S6236038 B2 JPS6236038 B2 JP S6236038B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- formula
- lower alkyl
- alkyl group
- 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
Links
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 150000007514 bases Chemical class 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- -1 cephalosporin compound Chemical class 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 238000007033 dehydrochlorination reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005868 electrolysis reaction Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 125000000094 2-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
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940088710 antibiotic agent Drugs 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
- 239000012267 brine Substances 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Description
本発明は新規なチアゾリノアゼチジノン誘導体
及びその製造法に関する。
本発明のチアゾリノアゼチジノン誘導体は文献
未載の新規化合物であり、下記一般式〔〕で表
わされる。
〔式中R1はアリール基又はアリールオキシ基
を示す。R2はフエニル環上にニトロ基を有する
ことのあるアリール低級アルキル基、フエニル環
上にニトロ基を有することのあるアリールオキシ
低級アルキル基又はハロゲン原子を置換基として
有することのある低級アルキル基を示す。X1及
びX2は水素原子又はハロゲン原子を示す。〕
上記一般式〔〕で表わされるチアゾリノアゼ
チジノン誘導体はペニシリン系、セフアロスポリ
ン系抗生物質を合成するための中間体として有用
な化合物である。例えば下記反応式に従い本発明
の化合物から抗菌剤として有用なセフアロスポリ
ン系化合物〔a〕又は〔b〕に誘導し得る。
〔式中R1,R2,X1及びX2は前記に同じ。〕
上記一般式〔〕で表わされるチアゾリノアゼ
チジノン誘導体は種々の方法により製造される
が、その好ましい一例を挙げれば例えば一般式
〔式中R1,R2,X1及びX2は前記に同じ。〕で表
わされる塩素化チアゾリノアゼチジノン誘導体に
塩基性化合物を作用させることにより製造され
る。
本発明において、R1で示されるアリール基と
しては例えばフエニル基、トリル基、キシリル
基、ナフチル基、p−クロルフエニル基、p−メ
トキシフエニル基、p−ニトロフエニル基、p−
ヒドロキシフエニル基等を挙げることができ、ま
たアリールオキシ基としては例えばフエノキシ
基、トリルオキシ基、キシリルオキシ基、ナフチ
ルオキシ基、p−クロルフエニルオキシ基、p−
メトキシフエニルオキシ基、p−ニトロフエニル
オキシ基、p−ヒドロキシフエニルオキシ基等を
挙げることができる。R2で示されるフエニル環
上にニトロ基を有することのあるアリール低級ア
ルキル基としては例えばベンジル基、p−ニトロ
ベンジル基、ジフエニルメチル基、2−フエニル
エチル基、2−(p−ニトロフエニル)エチル
基、3−フエニルプロピル基、3−(p−ニトロ
フエニル)プロピル基等を挙げることができ、フ
エニル環上にニトロ基を有することのあるアリー
ルオキシ低級アルキル基としては例えばフエノキ
シメチル基、p−ニトロフエノキシメチル基、2
−フエノキシエチル基、2−(p−ニトロフエノ
キシ)エチル基、3−フエノキシプロピル基、3
−(p−ニトロフエノキシ)プロピル基等を挙げ
ることができ、またハロゲン原子を置換基として
有することのある低級アルキル基としては例えば
メチル基、エチル基、n−プロピル基、イソプロ
ピル基、n−ブチル基、tert−ブチル基、2−ク
ロロエチル基、2,2,2−トリクロロエチル基
等を挙げることができる。またX1及びX2で示さ
れるハロゲン原子としては例えば塩素原子、臭素
原子、弗素原子等を挙げることができる。
本発明において出発原料として用いられる一般
式〔〕で表わされる塩素化チアゾリノアゼチジ
ノン誘導体は新規化合物であり、例えば下記反応
式に示す方法により製造される。
〔式中R1,R2,X1及びX2は前記に同じ。〕
一般式〔〕で表わされる化合物の電解ハロゲ
ン化は、例えば水と酢酸メチル、酢酸エチル、ギ
酸メチル、プロピオン酸エチル、クロロホルム、
四塩化炭素等の有機溶媒との混合溶媒中、公知の
ハロゲン酸及び/又はハロゲン化物の存在下に一
般式〔〕で表わされる化合物を電解処理すれば
よい。電解処理の条件としては、通常約5〜
500mA/cm2の範囲の電流密度で約2〜50F/mol
の電気量を通電し、約20〜100℃の範囲の温度で
電解を行なえばよい。
一般式〔〕で表わされる化合物と塩素との反
応は、光照射下適当な有機溶媒中にて行なわれ
る。使用される有機溶媒としては塩素に対して不
活性な溶媒をいずれも使用でき、例えばジクロル
メタン、ジブロムエタン、ジクロルエタン、クロ
ロホルム、四塩化炭素等のハロゲン化炭化水素
類、酢酸メチル、酢酸エチル、ギ酸メチル、酢酸
ブチル、プロピオン酸エチル等のエステル類、ジ
エチルエーテル、ジブチルエーテル、テトラヒド
ロフラン、ジオキサン等のエーテル類、アセトニ
トリル、ブチロニトリル等のニトリル類、ペンタ
ン、ヘキサン、シクロヘキサン等の炭化水素類、
ベンビン、トルエン、キシレン、クロルベンゼン
等の芳香族炭化水素、二硫化炭素又はこれらの混
合溶媒等を挙げることができる。塩素としては通
常分子状塩素が用いられる。一般式〔〕で表わ
される化合物と塩素との使用割合としては特に限
定がなく、広い範囲内にて適宜選択することがで
きるが、通常前者に対して後者を0.5〜10倍モル
量、好ましくは1〜5倍モル量用いるのがよい。
該反応は通常−20〜100℃程度にて行なわれる。
一般式〔〕で表わされる化合物に塩基性化合
物を作用させると脱塩酸反応が起こり一般式
〔〕で表わされる本発明の化合物が生成する。
塩基性化合物としては従来公知のものを広く使用
できるが、有機アミン類を用いるのが好ましく、
具体的にはジメチルアミン、ジエチルアミン、ト
リエチルアミン、エチルジイソプロピルアミン、
ピペリジン、ルチジン、ピリジン、1,5−ジア
ザビシクロ〔5,4,0〕ウンデセン−5,1,
5−ジアザビククロ〔4,3,0〕ノネン−5等
を例示できる。塩基性化合物の使用量としては特
に限定がなく広い範囲内で適宜選択することがで
きるが、通常一般式〔〕で表わされる化合物に
対して0.5〜10倍モル量、好ましくは1〜5倍モ
ル量用いられる。この脱塩酸反応は有機溶媒中で
行なつてもよいし、或いは使用する塩基性化合物
を溶媒として使用することもできる。有機溶媒と
しては原料化合物、目的化合物及び塩基性化合物
に対して不活性な溶媒を広く使用でき、例えば塩
化メチレン、クロロホルム、四塩化炭素、ジクロ
ルエタン、ジブロムエタン等のハロゲン化炭化水
素類、ジエチルエーテル、ジブチルエーテル、テ
トラヒドロフラン、ジオキサン等のエーテル類、
ペンタン、ヘキサン、ヘプタン、オクタン等の炭
化水素類、ベンゼン、クロルベンゼン、トルエ
ン、キシレン等の芳香族炭化水素類等を挙げるこ
とができる。該反応は室温下、加温下及び冷却下
のいずれでも行なわれるが、通常−20〜80℃の範
囲内で行なうのがよい。
斯くして得られる本発明の化合物は通常行なわ
れている分離手段、例えば溶媒抽出、カラムクロ
マトグラフイー等の手段により反応混合物から容
易に単離精製される。
本発明の化合物に構造上類似する化合物として
は式
で示される化合物がJ.A.C.S.,97,5008(1975)
やPure Appl.Chem.,43,423(1975)に記載さ
れており、該化合物は下記反応式に従い合成され
る。
式〔〕の化合物から式〔〕の化合物を得る
反応はN−ブロモサクシンイミド及びラジカル開
始剤を用いて加熱、紫外線照射下に行なわれる。
このブロム化は3位にメトキシ基を有している式
〔〕の化合物であるからこそ可能であつたので
あり、メトキシ基の代りに水素原子で置換された
化合物の場合にはブロム化は進行しない。
これに対して本発明の方法によれば、特殊な試
薬を使用することなく、温和な条件下に簡便に且
つ高収率で目的化合物を収得し得る。しかも目的
物の分離、精製も容易であり、副生物等の廃棄物
の問題がなく、工業的にも極めて有利な方法であ
る。
以下に参考例及び実施例を挙げる。
参考例 1
塩化ナトリウム1gを水3mlに溶解し、これに
濃硫酸0.07ml、塩化メチレン5ml及び化合物
〔〕(R1=フエニル、R2=メチル)50mgを加え
電解液を調製する。3cm2の白金板電極を装入し
30mA定電流、1.6〜1.8V、25℃で約2時間電解を
行う。電解終了後塩化メチレン(30ml)で抽出を
行う。抽出液は亜硫酸ナトリウム水、重ソウ水、
食塩水で洗浄後無水硫酸ナトリウムで乾燥し、溶
媒を除去して淡黄色の液体74mgを得た。このもの
をシリカゲルカラムを用い、ベンゼン:酢酸エチ
ル(5:1)の混合溶媒で展開すると目的化合物
〔〕(R1=フエニル、R2=メチル、X1=X2=
Cl)が62.5mg(収率96%)得られた。
(IR) 1780,1745cm-1
NMR(CDCl3)
3.75(3H,s,COOH3)
3.81(2H,s,−CH2Cl)
5.14(2H,s,C=CH2)
5.41(1H,s,
The present invention relates to a novel thiazolinoazetidinone derivative and a method for producing the same. The thiazolinoazetidinone derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula []. [In the formula, R 1 represents an aryl group or an aryloxy group. R 2 is an aryl lower alkyl group that may have a nitro group on the phenyl ring, an aryloxy lower alkyl group that may have a nitro group on the phenyl ring, or a lower alkyl group that may have a halogen atom as a substituent. show. X 1 and X 2 represent a hydrogen atom or a halogen atom. ] The thiazolinoazetidinone derivative represented by the above general formula [ ] is a compound useful as an intermediate for synthesizing penicillin and cephalosporin antibiotics. For example, a cephalosporin compound [a] or [b] useful as an antibacterial agent can be derived from the compound of the present invention according to the following reaction formula. [In the formula, R 1 , R 2 , X 1 and X 2 are the same as above. ] The thiazolinoazetidinone derivative represented by the above general formula [] can be produced by various methods. [In the formula, R 1 , R 2 , X 1 and X 2 are the same as above. ] is produced by reacting a basic compound with a chlorinated thiazolinoazetidinone derivative. In the present invention, examples of the aryl group represented by R 1 include phenyl group, tolyl group, xylyl group, naphthyl group, p-chlorophenyl group, p-methoxyphenyl group, p-nitrophenyl group, p-
Examples of aryloxy groups include phenoxy, tolyloxy, xylyloxy, naphthyloxy, p-chlorophenyloxy, and p-chlorophenyloxy groups.
Examples include methoxyphenyloxy group, p-nitrophenyloxy group, and p-hydroxyphenyloxy group. Examples of the aryl lower alkyl group that may have a nitro group on the phenyl ring represented by R2 include benzyl group, p-nitrobenzyl group, diphenylmethyl group, 2-phenylethyl group, 2-(p-nitrophenyl)ethyl group, Examples of aryloxy lower alkyl groups that may have a nitro group on the phenyl ring include 3-phenylpropyl group and 3-(p-nitrophenyl)propyl group, such as phenoxymethyl group and p-nitrophenyl group. dimethyl group, 2
-Phenoxyethyl group, 2-(p-nitrophenoxy)ethyl group, 3-phenoxypropyl group, 3
-(p-nitrophenoxy)propyl group, and examples of lower alkyl groups that may have a halogen atom as a substituent include methyl group, ethyl group, n-propyl group, isopropyl group, and n-butyl group. , tert-butyl group, 2-chloroethyl group, 2,2,2-trichloroethyl group, and the like. Examples of the halogen atom represented by X 1 and X 2 include a chlorine atom, a bromine atom, and a fluorine atom. The chlorinated thiazolinoazetidinone derivative represented by the general formula [] used as a starting material in the present invention is a new compound, and is produced, for example, by the method shown in the reaction formula below. [In the formula, R 1 , R 2 , X 1 and X 2 are the same as above. ] Electrolytic halogenation of the compound represented by the general formula [ ] can be carried out using, for example, water and methyl acetate, ethyl acetate, methyl formate, ethyl propionate, chloroform,
The compound represented by the general formula [] may be electrolytically treated in the presence of a known halogen acid and/or halide in a mixed solvent with an organic solvent such as carbon tetrachloride. The conditions for electrolytic treatment are usually about 5~
Approximately 2-50F/mol at current density in the range of 500mA/ cm2
It is sufficient to conduct electrolysis at a temperature in the range of about 20 to 100°C by applying an amount of electricity. The reaction between the compound represented by the general formula [] and chlorine is carried out in a suitable organic solvent under irradiation with light. As the organic solvent used, any solvent inert to chlorine can be used, such as dichloromethane, dibromoethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, methyl acetate, ethyl acetate, methyl formate, Esters such as butyl acetate and ethyl propionate; ethers such as diethyl ether, dibutyl ether, tetrahydrofuran, and dioxane; nitriles such as acetonitrile and butyronitrile; hydrocarbons such as pentane, hexane, and cyclohexane;
Examples include aromatic hydrocarbons such as benbin, toluene, xylene, and chlorobenzene, carbon disulfide, and mixed solvents thereof. Molecular chlorine is usually used as chlorine. The ratio of the compound represented by the general formula [] and chlorine to be used is not particularly limited and can be appropriately selected within a wide range, but the latter is usually 0.5 to 10 times the molar amount of the former, preferably It is preferable to use 1 to 5 times the molar amount.
The reaction is usually carried out at about -20 to 100°C. When a basic compound is allowed to act on the compound represented by the general formula [], a dehydrochlorination reaction occurs to produce the compound of the present invention represented by the general formula [].
Although a wide range of conventionally known basic compounds can be used, it is preferable to use organic amines.
Specifically, dimethylamine, diethylamine, triethylamine, ethyldiisopropylamine,
piperidine, lutidine, pyridine, 1,5-diazabicyclo[5,4,0]undecene-5,1,
Examples include 5-diazabicucro[4,3,0]nonene-5. The amount of the basic compound to be used is not particularly limited and can be appropriately selected within a wide range, but it is usually 0.5 to 10 times the molar amount, preferably 1 to 5 times the molar amount of the compound represented by the general formula []. amount used. This dehydrochlorination reaction may be carried out in an organic solvent, or the basic compound used may be used as a solvent. As the organic solvent, a wide range of solvents can be used that are inert to the starting compound, target compound, and basic compound, such as halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and dibromoethane, diethyl ether, and Ethers such as butyl ether, tetrahydrofuran, dioxane,
Examples include hydrocarbons such as pentane, hexane, heptane, and octane, and aromatic hydrocarbons such as benzene, chlorobenzene, toluene, and xylene. The reaction may be carried out at room temperature, under heating or under cooling, but is preferably carried out usually within the range of -20 to 80°C. The compound of the present invention thus obtained can be easily isolated and purified from the reaction mixture by conventional separation means such as solvent extraction and column chromatography. Compounds structurally similar to the compounds of the present invention include the formula The compound shown in JACS, 97, 5008 (1975)
and Pure Appl.Chem., 43 , 423 (1975), and the compound is synthesized according to the following reaction formula. The reaction for obtaining the compound of formula [] from the compound of formula [] is carried out using N-bromosuccinimide and a radical initiator under heating and ultraviolet irradiation.
This bromination was possible because the compound of the formula [] has a methoxy group at the 3-position; in the case of a compound in which a hydrogen atom is substituted for the methoxy group, bromination can proceed. do not. In contrast, according to the method of the present invention, the target compound can be obtained simply and in high yield under mild conditions without using any special reagents. Moreover, separation and purification of the target product are easy, there is no problem of waste such as by-products, and this method is extremely advantageous from an industrial perspective. Reference examples and examples are listed below. Reference Example 1 1 g of sodium chloride is dissolved in 3 ml of water, and 0.07 ml of concentrated sulfuric acid, 5 ml of methylene chloride, and 50 mg of the compound [] (R 1 = phenyl, R 2 = methyl) are added to prepare an electrolytic solution. Insert a 3 cm 2 platinum plate electrode.
Electrolyze at 30 mA constant current, 1.6 to 1.8 V, and 25°C for about 2 hours. After the electrolysis is complete, extract with methylene chloride (30ml). Extract liquid is sodium sulfite water, hydrogenated sodium water,
After washing with brine and drying over anhydrous sodium sulfate, the solvent was removed to obtain 74 mg of a pale yellow liquid. When this product was developed using a silica gel column with a mixed solvent of benzene:ethyl acetate (5:1), the target compound [] (R 1 = phenyl, R 2 = methyl, X 1 = X 2 =
Cl) was obtained in an amount of 62.5 mg (yield 96%). (IR) 1780, 1745cm -1 NMR (CDCl 3 ) 3.75 (3H, s, COOH 3 ) 3.81 (2H, s, -CH 2 Cl) 5.14 (2H, s, C=CH 2 ) 5.41 (1H, s,
【式】 6.05(2H,s,【formula】 6.05(2H,s,
【式】
7.3〜7.9(5H,m,フエニル)
参考例 2
化合物〔〕(R1=フエニル、R2=メチル、X1
=X2=Cl)50mgを塩化メチレン0.5mlに溶解し、
塩素の飽和した塩化メチレン溶液1.5mlを加え
る。直ちに750Wタングステンランプを用いて光
照射しながら20〜27℃の範囲で1時間反応を行
う。反応終了後反応液を氷水に注ぎ、塩化メチレ
ン層を分離する。チオ硫酸ナトリウム水溶液、飽
和食塩水で洗浄した後、無水硫酸ナトリウムで乾
燥する。減圧下溶媒を除去し、残渣をベンゼン−
酢酸エチル(9:1)を溶媒としてシリカゲルカ
ラムで分離、精製すると50.05mgの化合物〔〕
R1=フエニル、R2=メチル、X1=X2=Cl)を得
る。収率86%
IR(cm-1)1770、1760
NMR(CDCl3δ)
3.80(s,3H)、3.98(bs,2H)
4.12(s,2H)、5.12(s,1H)
6.10(d,1H)、6.28(d,1H)
7.2〜7.5(m,3H)
7.5〜7.8(m,2H)
実施例 1
化合物〔〕(R1=フエニル、R2=メチル、X1
=X2=H)55mgを塩化メチル0.6mlに溶解し、こ
れにトリエチルアミン88μを加え、室温で撹拌
する。2時間反応を行つた後エーテル5mlを加
え、次に水を加えて洗浄する。続いて10%塩酸、
飽和食塩水で洗浄する。エーテル層を無水硫酸ナ
トリウムで乾燥し、減圧下溶媒を除去する。残渣
をシリカゲルカラムで精製すると、無色油状物と
して目的物〔〕(R1=フエニル、R2=メチル、
X1=X2=H)を得る。収率98%
IR(cm-1) 1770,1720
NMR(CDCl3δ)
3.76(s,3H)、3.90(s,2H)
4.07(bs,2H)、4.63(bs,2H)
5.83(d,1H)、6.30(bd,1H)
7.25(s,5H)
実施例 2〜7
実施例1と同様の操作、処理を行う。結果を第
1〜2表に示す。尚表中Phはフエニル基を意味
する。
[Formula] 7.3-7.9 (5H, m, phenyl) Reference example 2 Compound [] (R 1 = phenyl, R 2 = methyl, X 1
=X 2 =Cl) 50mg was dissolved in methylene chloride 0.5ml,
Add 1.5 ml of chlorine saturated methylene chloride solution. Immediately, reaction is carried out for 1 hour at 20 to 27°C while irradiating with light using a 750W tungsten lamp. After the reaction is completed, the reaction solution is poured into ice water and the methylene chloride layer is separated. After washing with an aqueous sodium thiosulfate solution and saturated saline, drying with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in benzene.
Separation and purification with a silica gel column using ethyl acetate (9:1) as a solvent yielded 50.05 mg of the compound []
R 1 = phenyl, R 2 = methyl, X 1 = X 2 = Cl). Yield 86% IR (cm -1 ) 1770, 1760 NMR (CDCl 3 δ) 3.80 (s, 3H), 3.98 (bs, 2H) 4.12 (s, 2H), 5.12 (s, 1H) 6.10 (d, 1H) ), 6.28 (d, 1H) 7.2-7.5 (m, 3H) 7.5-7.8 (m, 2H) Example 1 Compound [] (R 1 = phenyl, R 2 = methyl, X 1
=X 2 =H) 55mg is dissolved in 0.6ml of methyl chloride, 88μ of triethylamine is added thereto, and the mixture is stirred at room temperature. After 2 hours of reaction, 5 ml of ether was added and then water was added for washing. followed by 10% hydrochloric acid,
Wash with saturated saline. The ether layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. When the residue was purified with a silica gel column, the desired product [] (R 1 = phenyl, R 2 = methyl,
X 1 =X 2 =H) is obtained. Yield 98% IR (cm -1 ) 1770, 1720 NMR (CDCl 3 δ) 3.76 (s, 3H), 3.90 (s, 2H) 4.07 (bs, 2H), 4.63 (bs, 2H) 5.83 (d, 1H ), 6.30 (bd, 1H) 7.25 (s, 5H) Examples 2 to 7 The same operations and processes as in Example 1 are performed. The results are shown in Tables 1 and 2. In addition, Ph in the table means a phenyl group.
【表】【table】
【表】【table】
【表】
実施例 8〜19
実施例1と同様の操作、処理を行う。結果を第
3表に示す。尚表中Phはフエニル基を意味す
る。[Table] Examples 8 to 19 The same operations and treatments as in Example 1 were performed. The results are shown in Table 3. In addition, Ph in the table means a phenyl group.
【表】【table】
Claims (1)
を示す。R2はフエニル環上にニトロ基を有する
ことのあるアリール低級アルキル基、フエニル環
上にニトロ基を有することのあるアリールオキシ
低級アルキル基又はハロゲン原子を置換基として
有することのある低級アルキル基を示す。X1及
びX2は水素原子又はハロゲン原子を示す。〕で表
わされるチアゾリノアゼチジノン誘導体。 2 一般式 〔式中R1はアリール基又はアリールオキシ基
を示す。R2はフエニル環上にニトロ基を有する
ことのあるアリール低級アルキル基、フエニル環
上にニトロ基を有することのあるアリールオキシ
低級アルキル基又はハロゲン原子を置換基として
有することのある低級アルキル基を示す。X1及
びX2は水素原子又はハロゲン原子を示す。〕で表
わされるチアゾリノアゼチジノン誘導体に塩基性
化合物を作用させて一般式 〔式中R1,R2,X1及びX2は前記に同じ。〕で表
わされるチアゾリノアゼチジノン誘導体を得るこ
とを特徴とするチアゾリノアゼチジノン誘導体の
製造法。[Claims] 1. General formula [In the formula, R 1 represents an aryl group or an aryloxy group. R 2 is an aryl lower alkyl group that may have a nitro group on the phenyl ring, an aryloxy lower alkyl group that may have a nitro group on the phenyl ring, or a lower alkyl group that may have a halogen atom as a substituent. show. X 1 and X 2 represent a hydrogen atom or a halogen atom. ] A thiazolinoazetidinone derivative represented by 2 General formula [In the formula, R 1 represents an aryl group or an aryloxy group. R 2 is an aryl lower alkyl group that may have a nitro group on the phenyl ring, an aryloxy lower alkyl group that may have a nitro group on the phenyl ring, or a lower alkyl group that may have a halogen atom as a substituent. show. X 1 and X 2 represent a hydrogen atom or a halogen atom. ] By reacting a basic compound with a thiazolinoazetidinone derivative represented by [In the formula, R 1 , R 2 , X 1 and X 2 are the same as above. A method for producing a thiazolinoazetidinone derivative, which comprises obtaining a thiazolinoazetidinone derivative represented by the formula:
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP56067136A JPS57183794A (en) | 1981-05-01 | 1981-05-01 | Thiazolinoazetidinone derivative and its preparation |
US06/370,034 US4482491A (en) | 1981-05-01 | 1982-04-20 | Thiazolinoazetidinone derivatives and process for the preparation of the same |
GB08212330A GB2101986B (en) | 1981-05-01 | 1982-04-28 | Thiazolinoazetidinone derivatives |
FR8207398A FR2504927B1 (en) | 1981-05-01 | 1982-04-29 | THIAZOLINOAZETIDINONE DERIVATIVES, METHODS FOR THEIR PREPARATIONS AND THEIR USE IN THE PREPARATION OF CEPHALOSPORINS |
DE3249934A DE3249934C2 (en) | 1981-05-01 | 1982-04-30 | |
DE3216256A DE3216256A1 (en) | 1981-05-01 | 1982-04-30 | THIAZOLINOAZETIDINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
DE3249933A DE3249933C2 (en) | 1981-05-01 | 1982-04-30 | Process for the preparation of 2- [4- (aryl or heteroaryldithio) -2-azetidinon-1-yl] -3-halomethyl-3-butenoic acid derivatives |
FR8220933A FR2522662B1 (en) | 1981-05-01 | 1982-12-14 | PROCESS FOR THE PREPARATION OF CEPHALOSPORINS |
US06/625,621 US4603014A (en) | 1981-05-01 | 1984-06-28 | Thiazolinoazetidinone derivatives and process for the preparation of the same |
GB08418485A GB2144418B (en) | 1981-05-01 | 1984-07-19 | Thiazolinoazetidinone derivatives and process for the preparation of the same |
GB08500025A GB2152051B (en) | 1981-05-01 | 1985-01-02 | Process for the preparation of azetidinone derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP56067136A JPS57183794A (en) | 1981-05-01 | 1981-05-01 | Thiazolinoazetidinone derivative and its preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS57183794A JPS57183794A (en) | 1982-11-12 |
JPS6236038B2 true JPS6236038B2 (en) | 1987-08-05 |
Family
ID=13336177
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP56067136A Granted JPS57183794A (en) | 1981-05-01 | 1981-05-01 | Thiazolinoazetidinone derivative and its preparation |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS57183794A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS57185295A (en) * | 1981-05-08 | 1982-11-15 | Otsuka Chem Co Ltd | Thiazolinoazetidinone derivative and its preparation |
-
1981
- 1981-05-01 JP JP56067136A patent/JPS57183794A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS57183794A (en) | 1982-11-12 |
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