JPH0231080B2 - - Google Patents
Info
- Publication number
- JPH0231080B2 JPH0231080B2 JP54106807A JP10680779A JPH0231080B2 JP H0231080 B2 JPH0231080 B2 JP H0231080B2 JP 54106807 A JP54106807 A JP 54106807A JP 10680779 A JP10680779 A JP 10680779A JP H0231080 B2 JPH0231080 B2 JP H0231080B2
- Authority
- JP
- Japan
- Prior art keywords
- methoxy
- conh
- carboxylic acids
- methanol
- salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 78
- -1 alkali metal salt Chemical class 0.000 claims description 23
- 229910052783 alkali metal Inorganic materials 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 230000002140 halogenating effect Effects 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 22
- 238000000034 method Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- 150000003839 salts Chemical class 0.000 description 15
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 8
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 7
- IKWLIQXIPRUIDU-ZCFIWIBFSA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical class OC(=O)C1=CCS[C@@H]2CC(=O)N12 IKWLIQXIPRUIDU-ZCFIWIBFSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 6
- 229910052744 lithium Inorganic materials 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 150000003573 thiols Chemical class 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000006198 methoxylation reaction Methods 0.000 description 3
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 description 2
- 229960003585 cefmetazole Drugs 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- IOMZQBUUXIFYSA-UHFFFAOYSA-N cyanomethylthiourea hydrochloride Chemical compound Cl.C(#N)CNC(S)=N IOMZQBUUXIFYSA-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- HSPSCWZIJWKZKD-UHFFFAOYSA-N n-chloroacetamide Chemical compound CC(=O)NCl HSPSCWZIJWKZKD-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- JJXJBRYXFBBXRW-OGFXRTJISA-N CN1N=NN=C1SCC=1CS[C@H]2N(C1C(=O)O)C(C2)=O.C(C)(=O)N Chemical compound CN1N=NN=C1SCC=1CS[C@H]2N(C1C(=O)O)C(C2)=O.C(C)(=O)N JJXJBRYXFBBXRW-OGFXRTJISA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- CHQQOIATOXROGV-UHFFFAOYSA-N [Li+].C[O-].[Li+].C[O-] Chemical compound [Li+].C[O-].[Li+].C[O-] CHQQOIATOXROGV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000003946 cyclohexylamines Chemical class 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical class CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Inorganic materials Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- CHVZPRDGLWBEMJ-UHFFFAOYSA-N n-chlorobenzenesulfonamide Chemical compound ClNS(=O)(=O)C1=CC=CC=C1 CHVZPRDGLWBEMJ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 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
- 239000000126 substance Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、7α―メトキシ―7β―
R2SCH2CONH―△3―セフエム―４―カルボン
酸類（R2はシアノメチル基を意味する）の中間
体である、7α―メトキシ―7β―
R1SO3CH2CONH―△3―セフエム―４―カルボ
ン酸類（R1はアリール基又は低級アルキル基を
意味する）の製造法に関するものである。
本発明方法によつて得られる7α―メトキシ―
7β―R2SCH2CONH―△3―セフエム―４―カル
ボン酸類（R2は前と同じ）は医薬上非常に有用
であり、例えば、本発明により製造される7α―
メトキシ―7β―シアノメチルチオアセトアミド
―３―（１―メチル―1H―テトラゾール―５―
イル）チオメチル―３―セフエム―４―カルボン
酸（一般名：セフメタゾール）は特開昭50―
83383に示される如く広範囲にわたり非常に強い
抗菌スペクトルを有する化合物として広く知られ
ている。
7α―メトキシ―7β―R2SCH2CONH―△3―セ
フエム―４―カルボン酸類の製造法については、
これまで数多く検討されてきた。たとえば特開昭
51―59890号公報およびJ.Antibiotics，29，969
（1976）に記載の方法では、次の製造工程
に従つて７―アミノ―３―（１―メチル―1H―
テトラゾール―５―イル）チオメチル―３―セフ
エム―４―カルボン酸〔〕から３段階を経て
7α―メトキシ―7β―アミノ体〔〕とし、これ
に酸塩化物法等により一般式〔〕
で示される化合物に導びくというものであるが、
この方法は反応工程がやや長く、また実際に追試
してみると中間体の〔〕がやや不安定であるた
めにその取り扱い方法が難かしいということが判
明した。また、特開昭50―50394号公報およびJ.
Antibiotice，29，554（1976）に記載の方法のよ
うに、〔〕の４位カルボン酸をエステルで保護
し、７―メトキシ化する方法では、反応工程がさ
らに長くなり、４位カルボン酸のエステル化およ
び脱エステル化に際して、かなりの純分の損失が
さけられない。
このように、いずれも製造工程が長いとか、収
率が悪いとか、7α位にメトキシ基のない未反応
物が多く残存してくるなどの理由で工業的製造法
として満足のいくものはなく簡便かつ高収率に行
ないうる製造法の出現が待ち望まれていた。
そこで本発明者等は、７位のメトキシ化が容易
に進行する７位アミノ基の保護基を用い、しかも
その保護基は、7α―メトキシ化の後も除去する
ことなく、直接、7α―メトキシ―7β―
R2SCH2CONH―△3―セフエム―４―カルボン
酸類に容易に導びくことの出来る製造法を見い出
す目的で鋭意研究を重ねた結果、本発明方法を完
成するに至つた。
本発明において用いられる7β―
R1SO3CH2CONH―△3―セフエム―４―カルボ
ン酸類とは7β位側鎖がR1SO3CH2CONHであり、
通常、反応に関与しない基で置換されている△3
―セフエム―４―カルボン酸およびその塩を表わ
し、たとえば、一般式
で示される化合物類を表わす。ここでR1はメチ
ル，エチル，プロピル等の低級アルキル基，置換
又は無置換のフエニル，ナフチル等のアリール基
を示し、それらの置換基としては、メチル，ニト
ロがあげられる。またＡで示される有機残基は、
反応に関与しないものであれば何でもよいが、一
般的には、水素原子、クロル等のハロゲン原子、
メチル、エチル、プロピル等のアルキル基、水酸
基、メトキシ、エトキシ、プロポキシ等のアルコ
キシ基、アセトオキシメチル基、複素環チオメチ
ル基等を示すが、その複素環チオメチルの複素環
としては、例えばテトラゾール、チアジアゾー
ル、チアゾール、イソチアゾール、オキサジアゾ
ール、トリアゾール、オキサゾール、イミダゾー
ル等であり、それはメチル、エチル等の低級アル
キル基で置換されていてもよい。また、その低級
アルキル基は、カルボキシル基、スルホン酸基、
アミノ基等の置換基を有していても良い。また−
COOWはカルボン酸又はその塩を表わし、塩類
としては、ナトリウム塩、カリウム塩等のアルカ
リ金属塩、マグネシウム塩、カルシウム塩等のア
ルカリ土類金属塩等の無機塩基との塩類、トリエ
チルアミン塩、ジシクロヘキシルアミン塩、シク
ロヘキシルアミン塩、ジメチルベンジルアミン塩
等の有機アミン塩もしくはキノリン塩等の有機塩
基との塩類を表わす。
また、7α―メトキシ―7β―R1SO3CH2CONH
―△3―セフエム―４―カルボン酸類とは7β―
R1SO3CH2CONH―△3―セフエム―４―カルボ
ン酸類の7α―位の水素原子をメトキシ基で置換
した化合物類を表わし、他の位置については7β
―R1SO3CH2CONH―△3―セフエム―４―カル
ボン酸類と同様の意味を示す。たとえば、一般式
で示される化合物類を表わし、R1およびＡは前
記と同じ意味を示す。W′は前記Ｗで規定した範
囲内の意味を示すが、W′とＷとは必ずしも同じ
でなくてもよい。
また、7α―メトキシ―7β―R2SCH2CONH―
△3―セフエム―４―カルボン酸類とは、7α―メ
トキシ―7β―R1SO3CH2CONH―△3―セフエム
―４―カルボン酸類のR1SO3基をR2S基で置換し
た化合物類を表わし、他の位置については7α―
メトキシ―7β―R1SO3CH2CONH―△3―セフエ
ム―４―カルボン酸類と同様の意味を示す。たと
えば式
で示される化合物類を表わし、Ａは前記と同じ意
味を示す。W″は前記Ｗで規定した範囲内の意味
を示すが、W″とＷは必ずしも同じでなくてもよ
い。
また、7α―メトキシ―7β―R1SO3CH2CONH
―△3―セフエム―４―カルボン酸類と反応させ
るチオール類またはその塩類とは、式R2SHで示
される化合物またはその塩類を表わし、R2は上
記と同じ意味を表わし、その塩類としては、7β
―R1SO3CH2CONH―△3―セフエム―４―カル
ボン酸類で述べた塩類と同じ意味を表わす。
本発明は、7β―R1SO3CH2CONH―△3―セフ
エム―４―カルボン酸類で表わされる化合物を不
活性乾燥溶媒中−95〜−10℃のあいだの温度でメ
タノールのアルカリ金属塩と反応させ、次に反応
溶液中に同温度で陽性ハロゲンを発生し得るハロ
ゲン化剤を加える。反応時間は特に制限されない
が、一般に比較的短時間で進行し、約５分ない
し、２時間で完了する。反応の方法としては、メ
タノールのアルカリ金属塩およびハロゲン化剤の
添加を２回以上に分割して加えてもよく、特に反
応物および生成物がメタノールのアルカリ金属塩
によつて分解を受けやすい場合には、２回以上に
分割した方が好ましい結果を与える。次にこのよ
うにして、メタノールのアルカリ金属塩とハロゲ
ン化剤で処理した反応液中にカルボン酸たとえば
蟻酸または酢酸等を加え過剰のメタノールのアル
カリ金属塩を分解する。過剰のハロゲン化剤が存
在している場合には必要に応じて還元剤たとえば
亜リン酸トリメチル、トリフエニルホスフイン、
チオ硫酸ソーダ等をカルボン酸を加える前または
後に加えることによつてハロゲン化剤を分解し、
7α―メトキシ―7β―R1SO3CH2CONH―△3―セ
フエム―４―カルボン酸類で得ることが出来る。
本方法において使用できるメタノールのアルカリ
金属塩は、たとえば、リチウムメトキサイド、ナ
トリウムメトキサイド、カリウムメトキサイド等
があげられるが、好ましくはリチウムメトキサイ
ドがあげられる。一般にメタノールのアルカリ金
属塩は不活性溶媒中過剰量のメタノールの存在
下、アルカリ金属塩を加えることによりあるい
は、メタノール溶液中にアルカリ金属を加えるこ
とにより製造される。得られたメタノールのアル
カリ金属塩は必ずしも単離する必要はなく、この
溶液を7β―R1SO3CH2CONH―△3―セフエム―
４―カルボン酸類の溶液中に添加することによつ
て本発明の目的は達せられる。本方法に使用でき
るメタノールのアルカリ金属塩の量は、原料のセ
フアロスポリンに対して約２〜10当量のアルカリ
金属塩が使用されるが前にも述べたように反応物
または生成物がアルカリ金属塩によつて分解をう
けやすい場合には、過剰のアルカリ金属塩を用い
ることは好ましくなく、場合によつては２回以上
に分割してメタノールのアルカリ金属塩およびハ
ロゲン化剤を添加することが好ましい。
7β―R1SO3CH2CONH―△3―セフエム―４―
カルボン酸類は、一般に本発明方法に用いられる
有機溶媒に対する溶解度が非常に良く、本反応に
は非常に好都合であるが、ジシクロヘキシルアミ
ン塩のような比較的難溶性の塩類の場合には、ｐ
―トルエンスルホン酸等の酸を当モル加えて溶解
させた後、本発明の通常方法により反応させるこ
とが出来る。本反応に適当な溶媒としては、ジメ
チルホルムアミド、ジメチルアセトアミド、ヘキ
サメチルホスホルトリアミド、メタノール、酢酸
エチル、トルエン、テトラヒドロフラン、二塩化
エチレン、アセトニトリル、アセトン、クロロホ
ルム等通常の有機反応に使用できる不活性溶媒が
あげられ、必要に応じてこれらまたは他の不活性
溶媒を２種以上の混合溶媒として用いてもよい。
本反応に使用できるハロゲン化剤は一般に陽性ハ
ロゲンを発生し得るものであり、この様なハロゲ
ン化剤としては、たとえば塩素、臭素、Ｎ―ハロ
アミド類、たとえばＮ―クロロアセトアミド、Ｎ
―ブロムアセトアミド；Ｎ―ハロイミド類、たと
えばＮ―クロロサクシンイミド、Ｎ―ブロムサク
シンイミド；Ｎ―ハロスルホンアミド類たとえば
Ｎ―クロロベンゼンスルホンアミド；または次亜
塩素酸ｔ―ブチルの如き次亜塩素酸アルキルがあ
げられるが、次亜塩素酸ｔ―ブチルが特に好まし
く、必要に応じて酢酸エチル等の不活性溶媒で希
釈して用いてもよい。この様にして得られた7α
―メトキシ―7β―R1SO3CH2CONH―△3―セフ
エム―４―カルボン酸類を好ましくは塩基の存在
下でチオール類またはその塩類と反応させれば、
目的とする7α―メトキシ―7β―R2SCH2CONH
―△3―セフエム―４―カルボン酸類を得ること
が出来る。この反応は一般に溶媒中塩基の存在下
で行なわれるが、7α―メトキシ―7β―
R1SO3CH2CONH―△3―セフエム―４―カルボ
ン酸類またはチオール類が、その塩類として用い
られる場合には塩基を特別に加えなくても好まし
い結果が得られる。この反応における反応温度は
特に限定されないが、通常室温以下で反応させる
ことが好ましい。また、反応溶媒としては、ジメ
チルホルムアミド、ジメチルアセトアミド、水、
アセトン、ジオキサン、アセトニトリル、塩化メ
チレン、クロロホルム、テトラヒドロフラン、ジ
クロルエタン、ベンゼン、トルエン、ピリジン、
酢酸エチル等、その他この発明の反応に悪影響を
与えない一般溶媒があげられ、２種類以上の溶媒
を混合して用いてもよい。また、この反応は7β
―R1SO3CH2CONH―△3―セフエム―４―カル
ボン酸類で示される化合物をメタノールのアルカ
リ金属塩とメタノールの存在下ハロゲン化剤で処
理して7α―メトキシ―7β―R1SO3CH2CONH―
△3―セフエム―４―カルボン酸類を得、これを
単離してからチオール類またはその塩類と反応さ
せてもよいし、また、単離せずに、その反応液中
にチオール類またはその塩類を加えることによつ
ても目的とする7α―メトキシ―7β―
R2SCH2CONH―△3―セフエム―４―カルボン
酸類を好収率で得ることが出来る。
本発明方法により7α―メトキシ―7β―シアノ
メチルチオアセトアミド―３―（１―メチル―
1H―テトラゾール―５―イル）チオメチル―３
―セフエム―４―カルボン酸（一般名：セフメタ
ゾール）などは、特に簡便かつ好収率で得ること
が出来、本発明は、工業的製法として、おおいに
価値のある方法である。
このようにして得られた7α―メトキシ―7β―
R2SCH2CONH―△3―セフエム―４―カルボン
酸類は、一般に、セフアロスポリナーゼに対して
安定であり、且つ広範囲抗菌スペクトルを有する
優れた抗生物質である。
本発明方法を、R1SO3基を有する原料化合物に
代えて塩素原子を有する化合物を用いる方法と対
比させ、２つの工程にわけて以下に説明する。
〔第１工程〕
The present invention provides 7α-methoxy-7β-
R 2 SCH 2 CONH-△ 3-7α -methoxy-7β-, which is an intermediate of cefem-4-carboxylic acids (R 2 means a cyanomethyl group)
This invention relates to a method for producing R 1 SO 3 CH 2 CONH-△ 3 -cephem-4-carboxylic acids (R 1 means an aryl group or a lower alkyl group). 7α-methoxy obtained by the method of the present invention
7β-R 2 SCH 2 CONH-△ 3 -Cefem-4-carboxylic acids (R 2 is the same as before) are very useful pharmaceutically, for example, 7α-
Methoxy-7β-cyanomethylthioacetamide-3-(1-methyl-1H-tetrazole-5-
il) thiomethyl-3-cefem-4-carboxylic acid (generic name: cefmetazole) was disclosed in Japanese Patent Application Publication No. 1973-
As shown in No. 83383, it is widely known as a compound that has a very strong antibacterial spectrum over a wide range. Regarding the production method of 7α-methoxy-7β-R 2 SCH 2 CONH-△ 3 -cefem-4-carboxylic acids,
Many studies have been done so far. For example, Tokukai Sho
51-59890 and J. Antibiotics, 29 , 969
(1976), the following manufacturing steps According to 7-amino-3-(1-methyl-1H-
After three steps from tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid []
7α-methoxy-7β-amino body [], and then the general formula [] by acid chloride method etc. This leads to the compound shown by
This method requires a rather long reaction process, and additional trials revealed that the intermediate [ ] is somewhat unstable, making it difficult to handle. In addition, Japanese Patent Application Laid-Open No. 50-50394 and J.
Antibiotice, 29 , 554 (1976), in which the 4-position carboxylic acid of [] is protected with an ester and 7-methoxylated, the reaction step is even longer, During the oxidation and deesterification, considerable losses of pure matter are unavoidable. In this way, none of these methods is satisfactory as an industrial production method, and is simple because the production process is long, the yield is poor, and a large amount of unreacted material without a methoxy group at the 7α-position remains. The emergence of a manufacturing method that can be carried out with high yield has been awaited. Therefore, the present inventors used a protecting group for the amino group at the 7-position, which facilitates the methoxylation of the 7-position, and furthermore, the protecting group can be directly used for 7α-methoxylation without being removed even after the 7α-methoxylation. ―7β―
As a result of intensive research aimed at finding a manufacturing method that can easily lead to R 2 SCH 2 CONH-△ 3 -cephem-4-carboxylic acids, the method of the present invention was completed. 7β- used in the present invention
R 1 SO 3 CH 2 CONH―△ 3 -Cefem-4-carboxylic acids have the side chain at the 7β position as R 1 SO 3 CH 2 CONH.
Usually substituted with a group that does not participate in the reaction △ 3
-Cefem-4-carboxylic acid and its salts, for example, the general formula Represents the compounds represented by. Here, R 1 represents a lower alkyl group such as methyl, ethyl or propyl, or a substituted or unsubstituted aryl group such as phenyl or naphthyl, and examples of substituents thereof include methyl and nitro. In addition, the organic residue indicated by A is
Any substance that does not participate in the reaction may be used, but generally hydrogen atoms, halogen atoms such as chlorine,
Examples include alkyl groups such as methyl, ethyl, and propyl, hydroxyl groups, alkoxy groups such as methoxy, ethoxy, and propoxy, acetoxymethyl groups, and heterocyclic thiomethyl groups. Examples of the heterocyclic thiomethyl include tetrazole and thiadiazole. , thiazole, isothiazole, oxadiazole, triazole, oxazole, imidazole, etc., which may be substituted with lower alkyl groups such as methyl, ethyl, etc. In addition, the lower alkyl group is a carboxyl group, a sulfonic acid group,
It may have a substituent such as an amino group. Also-
COOW represents a carboxylic acid or a salt thereof, and salts include salts with inorganic bases such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, triethylamine salts, and dicyclohexylamine salts. salts, organic amine salts such as cyclohexylamine salts and dimethylbenzylamine salts, or salts with organic bases such as quinoline salts. Also, 7α-methoxy-7β-R 1 SO 3 CH 2 CONH
―△ 3 ―What is Cefem-4-carboxylic acids? 7β―
R 1 SO 3 CH 2 CONH―△ 3 - Represents compounds in which the hydrogen atom at the 7α-position of cefem-4-carboxylic acids is substituted with a methoxy group, and 7β for other positions.
―R 1 SO 3 CH 2 CONH―△ 3 ―Cefem-4-Carboxylic acids. For example, the general expression represents the compounds represented by, and R 1 and A have the same meanings as above. W' indicates a meaning within the range defined by W, but W' and W do not necessarily have to be the same. Also, 7α-methoxy-7β-R 2 SCH 2 CONH-
△ 3 -Cefem-4-carboxylic acids are compounds in which the R 1 SO 3 group of 7α-methoxy-7β-R 1 SO 3 CH 2 CONH-△ 3 -Cefem- 4 -carboxylic acids is replaced with an R 2 S group. 7α- for other positions.
Methoxy-7β-R 1 SO 3 CH 2 CONH-△ 3 -Same meaning as cefem-4-carboxylic acids. For example, the expression represents the compounds represented by, and A has the same meaning as above. W'' indicates a meaning within the range defined by W, but W'' and W do not necessarily have to be the same. Also, 7α-methoxy-7β-R 1 SO 3 CH 2 CONH
The thiols or salts thereof to be reacted with the -△ 3 -cefem-4-carboxylic acids refer to compounds represented by the formula R 2 SH or salts thereof, where R 2 has the same meaning as above, and the salts include: 7β
―R 1 SO 3 CH 2 CONH―△ 3 ―Cefem-4- Expresses the same meaning as the salts mentioned in carboxylic acids. The present invention relates to the treatment of compounds represented by 7β-R 1 SO 3 CH 2 CONH-△ 3 -cephem-4-carboxylic acids with an alkali metal salt of methanol at a temperature between -95 and -10°C in an inert dry solvent. A halogenating agent capable of generating a positive halogen at the same temperature is added to the reaction solution. Although the reaction time is not particularly limited, it generally proceeds in a relatively short time and is completed in about 5 minutes to 2 hours. As a reaction method, the alkali metal salt of methanol and the halogenating agent may be added in two or more portions, especially when the reactants and products are susceptible to decomposition by the alkali metal salt of methanol. , it is better to divide the process into two or more times for better results. Next, a carboxylic acid such as formic acid or acetic acid is added to the reaction solution treated with the alkali metal salt of methanol and the halogenating agent to decompose the excess alkali metal salt of methanol. If an excess of halogenating agent is present, a reducing agent such as trimethylphosphite, triphenylphosphine,
Decompose the halogenating agent by adding sodium thiosulfate etc. before or after adding the carboxylic acid,
It can be obtained from 7α-methoxy-7β-R 1 SO 3 CH 2 CONH-△ 3 -cephem-4-carboxylic acids.
Examples of the alkali metal salt of methanol that can be used in this method include lithium methoxide, sodium methoxide, and potassium methoxide, with lithium methoxide being preferred. Generally, alkali metal salts of methanol are prepared by adding the alkali metal salt in the presence of an excess amount of methanol in an inert solvent or by adding the alkali metal to a methanol solution. The obtained alkali metal salt of methanol does not necessarily need to be isolated, and this solution is converted into 7β-R 1 SO 3 CH 2 CONH-
The object of the present invention is achieved by adding it to a solution of 4-carboxylic acids. The amount of alkali metal salt of methanol that can be used in this method is about 2 to 10 equivalents to cephalosporin as a raw material. In cases where the methanol is susceptible to decomposition, it is not preferable to use an excess of the alkali metal salt, and in some cases it is preferable to add the alkali metal salt of methanol and the halogenating agent in two or more portions. . 7β―R 1 SO 3 CH 2 CONH―△ 3 ―CEFEM―4―
Carboxylic acids generally have very good solubility in the organic solvent used in the method of the present invention and are very convenient for this reaction, but in the case of relatively sparingly soluble salts such as dicyclohexylamine salt, p
- After adding and dissolving the same mole of acid such as toluenesulfonic acid, the reaction can be carried out by the usual method of the present invention. Suitable solvents for this reaction include inert solvents that can be used in ordinary organic reactions, such as dimethylformamide, dimethylacetamide, hexamethylphosphortriamide, methanol, ethyl acetate, toluene, tetrahydrofuran, ethylene dichloride, acetonitrile, acetone, and chloroform. These or other inert solvents may be used as a mixed solvent of two or more, if necessary.
The halogenating agent that can be used in this reaction is generally capable of generating a positive halogen, and examples of such halogenating agents include chlorine, bromine, N-haloamides, such as N-chloroacetamide, N-chloroacetamide, and
- Bromoacetamide; N-haloimides such as N-chlorosuccinimide, N-bromsuccinimide; N-halosulfonamides such as N-chlorobenzenesulfonamide; or alkyl hypochlorite such as t-butyl hypochlorite Among them, t-butyl hypochlorite is particularly preferred, and it may be used after being diluted with an inert solvent such as ethyl acetate, if necessary. 7α obtained in this way
-Methoxy-7β-R 1 SO 3 CH 2 CONH -△ 3 -Cefem-4-carboxylic acids are reacted with thiols or their salts preferably in the presence of a base,
Target 7α-methoxy-7β-R 2 SCH 2 CONH
-△ 3 - Cefem-4-carboxylic acids can be obtained. This reaction is generally carried out in the presence of a base in a solvent, but 7α-methoxy-7β-
When R 1 SO 3 CH 2 CONH-△ 3 -cephem-4-carboxylic acids or thiols are used as their salts, favorable results can be obtained without the special addition of a base. The reaction temperature in this reaction is not particularly limited, but it is usually preferable to carry out the reaction at room temperature or lower. In addition, as a reaction solvent, dimethylformamide, dimethylacetamide, water,
Acetone, dioxane, acetonitrile, methylene chloride, chloroform, tetrahydrofuran, dichloroethane, benzene, toluene, pyridine,
Other common solvents such as ethyl acetate that do not adversely affect the reaction of the present invention may be used, and two or more solvents may be used in combination. Also, this reaction is 7β
―R 1 SO 3 CH 2 CONH―△ 3 ―Cefem-4-carboxylic acids are treated with a halogenating agent in the presence of an alkali metal salt of methanol and methanol to form 7α-methoxy-7β-R 1 SO 3 CH 2 CONH―
△ 3 -Cefem-4-carboxylic acids may be obtained, isolated and then reacted with thiols or their salts, or thiols or their salts may be added to the reaction solution without isolation. Especially the target 7α-methoxy-7β-
R 2 SCH 2 CONH-△ 3 -cephem-4-carboxylic acids can be obtained in good yield. By the method of the present invention, 7α-methoxy-7β-cyanomethylthioacetamide-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-3
-Cefem-4-carboxylic acid (generic name: cefmetazole) can be obtained particularly easily and in a good yield, and the present invention is a highly valuable method as an industrial production method. 7α-methoxy-7β- thus obtained
R 2 SCH 2 CONH-Δ 3 -Cefem-4-carboxylic acids are generally stable against cephalosporinase and are excellent antibiotics with a broad antibacterial spectrum. The method of the present invention will be explained below in two steps in comparison with a method using a compound having a chlorine atom instead of a raw material compound having an R 1 SO 3 group. [First step]
【表】
上記の表から明らかなように、本発明方法によ
り、特開昭54―103887号公報に記載のハロゲン化
合物を用いる方法からはとうてい予測できない高
収率で目的生成物を得ることができる。しかし、
得られる生成物の純度は高く、本発明方法１では
純度97％、本発明方法２では純度99％（いずれも
HPLC法）の目的生成物が得られた。
次に本発明を実施例及び参考例によつて更に詳
細に説明するが、この実施例によつて本発明はな
んら限定されるものではない。
実施例 １
7β―〔２―（ｐ―トルエンスルホニルオキシ）
アセトアミド〕セフアロスポラン酸ジシクロヘキ
シルアミン塩10.7ｇをジメチルホルムアミド40
ml、テトラヒドロフラン16mlおよび酢酸エチル40
mlの混合溶液にｐ―トルエンスルホン酸2.75ｇを
加えて撹拌溶解した。この溶液を−60℃に冷却
し、金属リチウム0.48ｇとメタノール26mlから調
製したリチウムメトキサイド溶液を20分かけて滴
下した。滴下終了後−60℃で30分間撹拌し、さら
に次亜塩素酸ｔ―ブチル3.75ｇを酢酸エチル26ml
で希釈した液を25分間で滴下した。さらに10分間
−60℃のまま撹拌後、トリフエニルホスフイン13
ｇを酢酸エチル60mlに溶解した液および酢酸2.1
mlを加えて反応を停止させた。５℃まで40分間で
昇温し、生じた不溶物を別し、不溶物をアセト
ン50mlで洗い液とあわせ、この中に酢酸エチル
600mlを加えると結晶が析出した。この結晶を
取し、酢酸エチルで洗浄後減圧乾燥して、7α―
メトキシ―7β―〔２―（ｐ―トルエンスルホニ
ルオキシ）アセトアミド〕セフアロスポラン酸リ
チウム塩を得た。
IR（nujol）：νC′=O 1780cm-1（β―ラクタム）
NMR（CF3COOH）：δ
2.30（3H，Ｓ）、2.55（3H，Ｓ）、3.60（2H，
ブロードＳ）、3.73（3H，ｓ）、4.86（2H，
ｓ）、5.3〜5.5（3H，ｍ）、7.40〜8.10（4H，
ｑ）、8.50（1H，Ｓ）
参考例 １
シアノメチルイソチオ尿素塩酸塩0.61ｇをジメ
チルホルムアミド３ml中で撹拌し、−35℃に冷却
した。この中へ金属ナトリウム0.18ｇとメタノー
ル４mlから調製したナトリウムエトキサイド溶液
を滴下した、得られたNC CH2SNa溶液を10分
間の撹拌後、7α―メトキシ―7β―〔２―（ｐ―
トルエンスルホニルオキシ）アセトアミド〕セフ
アロスポラン酸リチウム塩2.09ｇをジメチルホル
ムアミド８ml中に溶解した液に−35℃で加え、同
温度で１時間撹拌した。酢酸0.5mlを加えてから、
反応液を蒸留水150ml中に注ぎ、１規定塩酸でPH
2.5としてから酢酸エチル50mlで４回抽出した。
抽出液を飽和食塩水30mlで洗浄後無水硫酸マグネ
シウムで脱水した。過後反応液を減圧下で濃縮
し、残渣をイソプロピルアルコールに溶解させ、
２―エチルヘキサン酸ナトリウム0.66ｇによりナ
トリウム塩として結晶化させた。結晶を取後、
イソプロピルアルコールで洗浄し、減圧下で乾燥
させ、7α―メトキシ―7β―シアノメチルチオア
セトアミド―セフアロスポラン酸ナトリウムを得
た。
IR（nujol）：1775cm-1
NMR（CF3CO2H）：δ
2.27（3H，Ｓ）、3.55〜3.85（6H、ピークの
重なりの為に不明瞭）、3.72（3H，Ｓ）、
5.12〜5.56（2H，ｑ）、5.31（1H，Ｓ）、8.43
（1H，Ｓ）
実施例 ２
7β―〔２―（ｐ―トルエンスルホニルオキシ）
アセトアミド〕―３―（１―メチル―1H―テト
ラゾール―５―イル）チオメチル―３―セフエム
―４―カルボン酸ジシクロヘキシルアミン塩23.1
ｇおよびｐ―トルエンスルホン酸5.5ｇをジメチ
ルホルムアミド80ml、テトラヒドロフラン30mlお
よび酢酸エチル80ml中で撹拌溶解させた後、温度
を−60℃に下げた。この溶液中に、金属リチウム
0.67ｇとメタノール42mlから調製したリチウムメ
トキサイドをゆつくりと滴下し、滴下終了後30分
間同温度で撹拌した。ついで次亜塩素数ｔ―ブチ
ル6.95ｇを酢酸エチル48mlで希釈して滴下した。
30分間の撹拌後、金属リチウム0.22ｇとメタノー
ル14mlから調製したリチウムメトキサイドをゆつ
くりと滴下し、10分後次亜塩素酸ｔ―ブチル1.74
ｇを酢酸エチル12mlで希釈して滴下した。10分
後、さらに金属リチウム0.06ｇとメタノール４ml
から調製したリチウムメトキサイドを滴下し10分
後次亜塩素酸ｔ―ブチル0.88ｇを酢酸エチル６ml
で希釈して滴下した。30分間撹拌した後、トリフ
エニルホスフイン13ｇを酢酸エチル60mlに溶解し
た液を加えさらに３規定塩酸32mlを加えてからた
だちに酢酸エチル600mlと氷水800ｇの混合液中に
注ぎ３規定塩酸でPH３として分液した。酢酸エチ
ル300mlで２回抽出して最初の抽出液と合わせ、
飽和食塩水100mlで２回洗浄後無水硫酸マグネシ
ウムで脱水し、減圧下で濃縮した。残渣を２―エ
チルヘキサン酸ナトリウム5.32ｇによりイソプロ
ピルアルコール中から結晶化させた。結晶を取
しイソプロピルアルコールで洗浄後減圧乾燥して
7α―メトキシ―7β―〔２―（ｐ―トルエンスル
ホニルオキシ）アセトアミド〕―３―（１―メチ
ル―1H―テトラゾール―５―イル）チオメチル
―３―セフエム―４―カルボン酸ナトリウム塩を
得た。
IR（nujol）：νC=O 1775cm-1
NMR（CF3COOH）：δ
2.53（3H，Ｓ）、3.65（2H，ブロードＳ）、
3.68（3H，Ｓ）、4.15（3H，Ｓ）、4.63（2H，
ブロードＳ）、4.80（2H，ブロードｓ）、
5.27（1H，Ｓ）、7.45〜7.95（4H，ｑ）、8.30
（1H，Ｓ）
参考例 ２
実施例２と同様に反応して7α―メトキシ―7β
―〔２―（ｐ―トルエンスルホニルオキシ）アセ
トアミド〕―３―（１―メチル―1H―テトラゾ
ール―５―イル）チオメチル―３―セフエム―４
―カルボン酸ナトリウム塩から7α―メトキシ―
7β―シアノメチルチオアセトアミド―３―（１
―メチル―1H―チトラゾール―５―イル）チオ
メチル―３―セフエム―４―カルボン酸ナトリウ
ムを得た。
IR（nujol）：1760cm-1
NMR（CF3CO2H）：δ
3.6〜3.8（6H重なりの為不明瞭）、3.70
（3H，Ｓ）、4.15（3H，Ｓ）、4.4〜4.8（2H，
ｑ）、5.28（1H，Ｓ）、8.35（1H，Ｓ）
実施例 ３
7β―〔２―（ｐ―トルエンスルホニルオキシ）
アセトアミド〕―３―（１―メチル―1H―テト
ラゾール―５―イル）チオメチル―３―セフエム
―４―カルボン酸2.16ｇをジメチルホルムアミド
24ml中で撹拌溶解させ温度を−50℃に冷却した。
金属リチウム0.056ｇとメタノール４mlから調製
したリチウムメトキサイド溶液をゆつくりと滴下
し、30分間の撹拌後次亜塩素酸ｔ―ブチル0.434
ｇを滴下した。20分間撹拌してから、金属リチウ
ム0.028ｇとメタノール２mlから調製したリチウ
ムメトキサイド溶液をゆつくりと滴下し、30分後
次亜塩素酸ｔ―ブチル0.434ｇを滴下した。20分
後、シアノメチルイソチオ尿素塩酸塩1.82ｇをジ
メチルホルムアミド９ml中で撹拌し、リチウムメ
トキサイド（金属リチウム0.17ｇとメタノール12
mlから調製）により−30℃で発生させた
NCCH2SLi溶液を加え、反応液を−30℃で1.5時
間さらに−10℃で20分間撹拌した。酢酸２mlを加
えてから蒸留水200mlと酢酸エチル100mlの混合液
中に注ぎ２規定塩酸でPH2.5として分液した。さ
らに酢酸エチル50mlで２回抽出し、有機層を合わ
せて飽和食塩水で２回洗浄後無水硫酸マグネシウ
ムで脱水し、活性炭処理をした。減圧下で濃縮後
イソプロピルアルコール中から２―エチルヘキサ
ン酸ナトリウムにより、結晶化させ、結晶を取
後減圧乾燥して、7α―メトキシ―7β―シアノメ
チルチオアセトアミド―３―（１―メチル―1H
―テトラゾール―５―イル）チオメチル―３―セ
フエム―４―カルボン酸ナトリウムを得た。この
もののIRおよびNMRスペクトルは参考例２のも
のと完全に一致した。
実施例１または実施例２に従つてそれぞれ下記
の化合物を得た。[Table] As is clear from the above table, the method of the present invention allows the desired product to be obtained in a high yield that is completely unpredictable from the method using a halogen compound described in JP-A-54-103887. . but,
The purity of the product obtained is high, with 97% purity in method 1 of the present invention and 99% purity in method 2 of the present invention (in both cases, the purity is 97%).
HPLC method) desired product was obtained. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these Examples in any way. Example 1 7β-[2-(p-toluenesulfonyloxy)
Acetamide] 10.7 g of cephalosporanic acid dicyclohexylamine salt and 40 g of dimethylformamide
ml, tetrahydrofuran 16ml and ethyl acetate 40ml
2.75 g of p-toluenesulfonic acid was added to ml of the mixed solution and dissolved with stirring. This solution was cooled to -60°C, and a lithium methoxide solution prepared from 0.48 g of metallic lithium and 26 ml of methanol was added dropwise over 20 minutes. After dropping, stir at -60℃ for 30 minutes, then add 3.75g of t-butyl hypochlorite to 26ml of ethyl acetate.
The diluted solution was added dropwise over 25 minutes. After stirring for an additional 10 minutes at -60°C, triphenylphosphine 13
g dissolved in 60 ml of ethyl acetate and acetic acid 2.1
ml was added to stop the reaction. The temperature was raised to 5℃ for 40 minutes, the resulting insoluble matter was separated, the insoluble matter was combined with the washing solution with 50 ml of acetone, and ethyl acetate was added to this.
When 600 ml was added, crystals precipitated. The crystals were collected, washed with ethyl acetate, dried under reduced pressure, and 7α-
Methoxy-7β-[2-(p-toluenesulfonyloxy)acetamide]cephalosporanic acid lithium salt was obtained. IR (nujol): ν C ′ =O 1780cm -1 (β-lactam) NMR (CF 3 COOH): δ 2.30 (3H, S), 2.55 (3H, S), 3.60 (2H,
Broad S), 3.73 (3H, s), 4.86 (2H,
s), 5.3-5.5 (3H, m), 7.40-8.10 (4H,
q), 8.50 (1H, S) Reference Example 1 0.61 g of cyanomethylisothiourea hydrochloride was stirred in 3 ml of dimethylformamide and cooled to -35°C. A sodium ethoxide solution prepared from 0.18 g of sodium metal and 4 ml of methanol was added dropwise to this solution. After stirring the resulting NC CH 2 SNa solution for 10 minutes, 7α-methoxy-7β-[2-(p-
To a solution of 2.09 g of lithium salt of toluenesulfonyloxy)acetamide]cephalosporanate dissolved in 8 ml of dimethylformamide was added at -35°C, and the mixture was stirred at the same temperature for 1 hour. Add 0.5ml of acetic acid and then
Pour the reaction solution into 150ml of distilled water and adjust the pH with 1N hydrochloric acid.
2.5 and extracted four times with 50 ml of ethyl acetate.
The extract was washed with 30 ml of saturated saline and then dehydrated with anhydrous magnesium sulfate. After filtration, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in isopropyl alcohol.
It was crystallized as a sodium salt from 0.66 g of sodium 2-ethylhexanoate. After removing the crystal,
Washing with isopropyl alcohol and drying under reduced pressure gave sodium 7α-methoxy-7β-cyanomethylthioacetamide-cephalosporanate. IR (nujol): 1775 cm -1 NMR (CF 3 CO 2 H): δ 2.27 (3H, S), 3.55-3.85 (6H, unclear due to peak overlap), 3.72 (3H, S),
5.12-5.56 (2H, q), 5.31 (1H, S), 8.43
(1H,S) Example 2 7β-[2-(p-toluenesulfonyloxy)
Acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid dicyclohexylamine salt 23.1
After stirring and dissolving 5.5 g of g and p-toluenesulfonic acid in 80 ml of dimethylformamide, 30 ml of tetrahydrofuran and 80 ml of ethyl acetate, the temperature was lowered to -60°C. In this solution, metallic lithium
Lithium methoxide prepared from 0.67 g and 42 ml of methanol was slowly added dropwise, and after the addition was completed, the mixture was stirred at the same temperature for 30 minutes. Then, 6.95 g of t-butyl hypochlorite was diluted with 48 ml of ethyl acetate and added dropwise.
After stirring for 30 minutes, lithium methoxide prepared from 0.22 g of metallic lithium and 14 ml of methanol was slowly added dropwise, and after 10 minutes, 1.74 g of t-butyl hypochlorite was added.
g was diluted with 12 ml of ethyl acetate and added dropwise. After 10 minutes, add 0.06 g of metallic lithium and 4 ml of methanol.
After 10 minutes, 0.88 g of t-butyl hypochlorite was added dropwise to 6 ml of ethyl acetate.
It was diluted with water and added dropwise. After stirring for 30 minutes, add a solution of 13 g of triphenylphosphine in 60 ml of ethyl acetate, add 32 ml of 3N hydrochloric acid, and immediately pour into a mixture of 600 ml of ethyl acetate and 800 g of ice water. It liquefied. Extract twice with 300 ml of ethyl acetate and combine with the first extract.
After washing twice with 100 ml of saturated brine, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from isopropyl alcohol with 5.32 g of sodium 2-ethylhexanoate. The crystals were collected, washed with isopropyl alcohol, and dried under reduced pressure.
7α-methoxy-7β-[2-(p-toluenesulfonyloxy)acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt was obtained. IR (nujol): ν C=O 1775cm -1 NMR (CF 3 COOH): δ 2.53 (3H, S), 3.65 (2H, broad S),
3.68 (3H, S), 4.15 (3H, S), 4.63 (2H,
Broad S), 4.80 (2H, Broad S),
5.27 (1H, S), 7.45-7.95 (4H, q), 8.30
(1H,S) Reference Example 2 Reacted in the same manner as in Example 2 to form 7α-methoxy-7β
-[2-(p-toluenesulfonyloxy)acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4
-7α-methoxy from carboxylic acid sodium salt-
7β-cyanomethylthioacetamide-3-(1
Sodium -methyl-1H-titrazol-5-yl)thiomethyl-3-cephem-4-carboxylate was obtained. IR (nujol): 1760 cm -1 NMR (CF 3 CO 2 H): δ 3.6 to 3.8 (unclear due to 6H overlap), 3.70
(3H, S), 4.15 (3H, S), 4.4~4.8 (2H,
q), 5.28 (1H, S), 8.35 (1H, S) Example 3 7β-[2-(p-toluenesulfonyloxy)
[Acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.16 g) in dimethylformamide
The mixture was stirred and dissolved in 24 ml, and the temperature was cooled to -50°C.
A lithium methoxide solution prepared from 0.056 g of metallic lithium and 4 ml of methanol was slowly added dropwise, and after stirring for 30 minutes, 0.434 t-butyl hypochlorite was added.
g was added dropwise. After stirring for 20 minutes, a lithium methoxide solution prepared from 0.028 g of metallic lithium and 2 ml of methanol was slowly added dropwise, and after 30 minutes, 0.434 g of t-butyl hypochlorite was added dropwise. After 20 minutes, 1.82 g of cyanomethylisothiourea hydrochloride was stirred in 9 ml of dimethylformamide, and lithium methoxide (0.17 g of lithium metal and 12 g of methanol) was stirred in 9 ml of dimethylformamide.
prepared from ml) at −30°C.
NCCH 2 SLi solution was added and the reaction was stirred at -30°C for 1.5 hours and at -10°C for 20 minutes. After adding 2 ml of acetic acid, the mixture was poured into a mixture of 200 ml of distilled water and 100 ml of ethyl acetate, and the mixture was separated with 2N hydrochloric acid to adjust the pH to 2.5. Further, the mixture was extracted twice with 50 ml of ethyl acetate, and the organic layers were combined, washed twice with saturated brine, dehydrated with anhydrous magnesium sulfate, and treated with activated carbon. After concentrating under reduced pressure, it was crystallized from isopropyl alcohol with sodium 2-ethylhexanoate, and the crystals were collected and dried under reduced pressure to give 7α-methoxy-7β-cyanomethylthioacetamide-3-(1-methyl-1H
Sodium -tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate was obtained. The IR and NMR spectra of this product completely matched those of Reference Example 2. The following compounds were obtained according to Example 1 or Example 2, respectively.
【表】【table】
【表】
さらに参考例１に従つて7α―メトキシ―7β―
R1SO3CH2CONH―△3―セフエム―４―カルボ
ン酸類から7α―メトキシ―7β―R2SCH2CONH
―△3―セフエム―カルボン酸類を得た。[Table] Furthermore, according to Reference Example 1, 7α-methoxy-7β-
R 1 SO 3 CH 2 CONH―△ 3 -Cefem-4-carboxylic acids to 7α-methoxy-7β―R 2 SCH 2 CONH
-△ 3 -Cefem-carboxylic acids were obtained.
【表】【table】
【表】【table】
Claims (1)
―カルボン酸類（R1はアリール基又は低級アル
キル基を意味する）をメタノールのアルカリ金属
塩とメタノールの存在下、ハロゲン化剤で処理す
ることによる7α―メトキシ―7β―
R1SO3CH2CONH―△3―セフエム―４―カルボ
ン酸類（R1は前と同じ）の製造法。1 7β―R 1 SO 3 CH 2 CONH―△ 3 ―Cefm―4
-7α-methoxy-7β- by treating carboxylic acids (R 1 means an aryl group or lower alkyl group) with a halogenating agent in the presence of an alkali metal salt of methanol and methanol.
R 1 SO 3 CH 2 CONH―△ 3 -Production method of Cefem-4-carboxylic acids (R 1 is the same as before).
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10680779A JPS5630987A (en) | 1979-08-21 | 1979-08-21 | Preparation of 7alpha-methoxycephalosporin |
| CA000358275A CA1152980A (en) | 1979-08-21 | 1980-08-14 | PROCESS FOR PRODUCING 7-.alpha.-METHOXYCEPHALOSPORINS |
| IT49520/80A IT1146168B (en) | 1979-08-21 | 1980-08-19 | PROCEDURE FOR PRODUCING 7-METHOXY CEPHALOSPORINE |
| HU802068A HU184815B (en) | 1979-08-21 | 1980-08-19 | Process for preparing 7alpha-methoxy-7beta-/cyano-methyl-acetamido-3-cefem-4-carboxylic acid derivatives |
| ES494868A ES8106532A1 (en) | 1979-08-21 | 1980-08-20 | Preparation of 7alphaamethoxycephalosporin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10680779A JPS5630987A (en) | 1979-08-21 | 1979-08-21 | Preparation of 7alpha-methoxycephalosporin |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18314786A Division JPS6242989A (en) | 1986-08-04 | 1986-08-04 | Production of 7alpha-methoxycephalosporin compound |
| JP1703290A Division JPH02270882A (en) | 1990-01-26 | 1990-01-26 | Production of 7alpha-methoxycephalosporin compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5630987A JPS5630987A (en) | 1981-03-28 |
| JPH0231080B2 true JPH0231080B2 (en) | 1990-07-11 |
Family
ID=14443116
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10680779A Granted JPS5630987A (en) | 1979-08-21 | 1979-08-21 | Preparation of 7alpha-methoxycephalosporin |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS5630987A (en) |
| CA (1) | CA1152980A (en) |
| ES (1) | ES8106532A1 (en) |
| HU (1) | HU184815B (en) |
| IT (1) | IT1146168B (en) |
-
1979
- 1979-08-21 JP JP10680779A patent/JPS5630987A/en active Granted
-
1980
- 1980-08-14 CA CA000358275A patent/CA1152980A/en not_active Expired
- 1980-08-19 IT IT49520/80A patent/IT1146168B/en active
- 1980-08-19 HU HU802068A patent/HU184815B/en unknown
- 1980-08-20 ES ES494868A patent/ES8106532A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IT8049520A0 (en) | 1980-08-19 |
| HU184815B (en) | 1984-10-29 |
| JPS5630987A (en) | 1981-03-28 |
| CA1152980A (en) | 1983-08-30 |
| IT1146168B (en) | 1986-11-12 |
| ES494868A0 (en) | 1981-09-01 |
| ES8106532A1 (en) | 1981-09-01 |
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