CN1042130C - 4－氧代氮杂环丁烷－2－磺酰胺及其盐,其制备方法和应用 - Google Patents
4－氧代氮杂环丁烷－2－磺酰胺及其盐,其制备方法和应用 Download PDFInfo
- Publication number
- CN1042130C CN1042130C CN93117362A CN93117362A CN1042130C CN 1042130 C CN1042130 C CN 1042130C CN 93117362 A CN93117362 A CN 93117362A CN 93117362 A CN93117362 A CN 93117362A CN 1042130 C CN1042130 C CN 1042130C
- Authority
- CN
- China
- Prior art keywords
- methyl
- hydrogen
- phenyl
- oxo
- conh
- 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 - Fee Related
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title abstract description 14
- MBVWZZYHNWLOIK-UHFFFAOYSA-N 4-oxoazetidine-2-sulfonamide Chemical compound NS(=O)(=O)C1CC(=O)N1 MBVWZZYHNWLOIK-UHFFFAOYSA-N 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229940124530 sulfonamide Drugs 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- -1 isoxazolyl carbonylamino Chemical group 0.000 claims description 21
- 239000011541 reaction mixture Substances 0.000 claims description 21
- 238000007254 oxidation reaction Methods 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 13
- 230000003647 oxidation Effects 0.000 claims description 11
- 125000005544 phthalimido group Chemical group 0.000 claims description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000012286 potassium permanganate Substances 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 2
- 229910052794 bromium Inorganic materials 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 230000000903 blocking effect Effects 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 150000003952 β-lactams Chemical class 0.000 abstract description 2
- 238000011203 antimicrobial therapy Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- 239000000460 chlorine Substances 0.000 description 35
- 235000019439 ethyl acetate Nutrition 0.000 description 32
- 239000000243 solution Substances 0.000 description 28
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 27
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 20
- 238000006297 dehydration reaction Methods 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 230000018044 dehydration Effects 0.000 description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- 239000011734 sodium Substances 0.000 description 14
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 14
- 125000001091 aminosulfinyl group Chemical group [H]N([H])S(*)=O 0.000 description 12
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 12
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 11
- 239000000284 extract Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- NHNUFAASKXPOQA-UHFFFAOYSA-N (3-acetamido-2-hydroxyphenyl)arsonic acid Chemical compound C(C)(=O)NC=1C(=C(C=CC1)[As](O)(=O)O)O NHNUFAASKXPOQA-UHFFFAOYSA-N 0.000 description 9
- FKPXGNGUVSHWQQ-UHFFFAOYSA-N 5-methyl-1,2-oxazol-3-amine Chemical compound CC1=CC(N)=NO1 FKPXGNGUVSHWQQ-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- PIZNQHDTOZMVBH-UHFFFAOYSA-N thionylimide Chemical compound N=S=O PIZNQHDTOZMVBH-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 229960001866 silicon dioxide Drugs 0.000 description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 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 5
- 239000012043 crude product Substances 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 239000012452 mother liquor Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000013375 chromatographic separation Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000008241 heterogeneous mixture Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 159000000000 sodium salts Chemical group 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JBZRLVKMCLOFLG-UHFFFAOYSA-N O=S=Cl Chemical compound O=S=Cl JBZRLVKMCLOFLG-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 150000003217 pyrazoles Chemical class 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- FCZNNHHXCFARDY-WQRUCBPWSA-N (2s,5r,6r)-3,3-dimethyl-4,7-dioxo-6-[(2-phenylacetyl)amino]-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2=O)(C)C)C(O)=O)C(=O)CC1=CC=CC=C1 FCZNNHHXCFARDY-WQRUCBPWSA-N 0.000 description 1
- ZVNYYNAAEVZNDW-UHFFFAOYSA-N 2-phenylpyrazol-3-amine Chemical compound NC1=CC=NN1C1=CC=CC=C1 ZVNYYNAAEVZNDW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- 101100232929 Caenorhabditis elegans pat-4 gene Proteins 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 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 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 1
- 229960003644 aztreonam Drugs 0.000 description 1
- XKXHCNPAFAXVRZ-UHFFFAOYSA-N benzylazanium;chloride Chemical compound [Cl-].[NH3+]CC1=CC=CC=C1 XKXHCNPAFAXVRZ-UHFFFAOYSA-N 0.000 description 1
- FCWGIFCVCCHGTK-UHFFFAOYSA-N butane-2-sulfonamide Chemical compound CCC(C)S(N)(=O)=O FCWGIFCVCCHGTK-UHFFFAOYSA-N 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 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
- 239000012453 solvate Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
- C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
通式I所示的4-氧代氮杂环丁烷-2-磺酰胺及其盐，
其中各基团见说明书所述。
其制备方法及其在β-内酰胺类似物合成中作为中间化合物的应用或作为制造抗菌治疗制剂的有效物质的应用。
Description
本发明涉及新的4-氧代氮杂环丁烷-2-磺酰胺及其盐，其制备方法及其制备药物的应用。
文献中记载了一些4-氧代氮杂环丁烷磺酸，最为人们所知的是4-氧代氮杂环丁烷-1-磺酸[Chemistry in Britain(1983)3O2]；属于这类化合物的有β-内酰胺抗生Aztreonam[Drugs of the Future8(1983)295]。
还已知一些经双环分子开环[Angew./Chem.95(1983)91.2]，或经相应的4-氧代氮杂环丁烷-2-磺酸衍生物氧化[YU专利申请P-24O/91、YU专利申请P-1390/91及EU专利申请92102335.4/92]得到的4-氧代氮杂环丁烷-2-磺酸。
同样，还已知一些4-氧代氮杂环丁烷-2-磺酸衍生物，例如其酰氯[DE专利申请255671/76]其酯[Croat,Chem,Acta62(1989)521-527]及其硫酯[J.Chem,Soc.Chem.Commun.23(1972)1304-1305]。
根据本申请人对现有技术的一些了解，4-氧代氮杂环丁烷-2-磺酰胺及其盐还未为人们所知。
本发明的主题是通式Ⅰ的新的4-氧代氮杂环丁烷-2-磺酰胺及其盐，
式中各基团的含义如R1为氢、卤素，R2为氢、卤素、NH2、苯基-CH2CONH、苯基OCH2CONH、苯二酰亚氨基、o-MeNHCOC6H4CONH、异噁唑基羰基氨基，R3为氢、Me2C=C-COOMe、H2C=C(Me)-CH-COOMe、Me2C=C-COOC H2苯基、H2C=C(Me)-CH-COOCH2C6H4NO2-p、Me2C=C-COOCH2C6H4NO2-p、Me2C=C-COOCH2C6H4Me-m、H2C=C(Me)-CHO-OCH2C6H4Me-m、Me2C=C-COOH，R4为氢或钠，以及R5为氢、烷基、苄基或一个杂环如异噁唑、吡唑等。
本发明的另一个主题，是制备通式Ⅰ所示的新的4-氧代氨杂环丁烷-2-磺酰胺的方法，式中所引用的基团具有上文所述的含义，该方法借助通式Ⅱ所示的4-氧代氮杂环丁烷-2-磺酰胺的氧化来进行，
式中各基团的含义R1为氢或卤素，R2为氢、卤素、NH2、苯基-CH2CONH、苯基OCH2CONH、苯二酰亚氩基、o-MeNHCOC6H4CONH、异噁唑基羰基氨基，R3为Me2C=C-COOMe、H2C=C(Me)-CH-COOMe、Me2C=C-COOCH2苯基、H2C=C(Me)-CH-COOCH2C6H4NO2-p、Me2C=C-COOCH2C6H4NO2-p、Me2C=C-COOCH2C6H4Me-m、H2C=C(Me)-CHCOOCH2C6H4Me-m，R4为氢，以及R5为氢、烷基、苄基或一个杂环如异噁唑、吡唑等。
该氧化反应在有机化学已知氧化反应中通常的氧化剂如过氧化氢、过乙酰乙酸、m-氯代过苯甲酸及高锰酸钾中，在一种酸性或中性的水或水-有机介质中，在0-100℃的温度下进行。所有反应均以常规反应条件、摩尔比并借助标准分离步骤进行。取决于不同氧化剂种类，这些摩尔比及反应温度，会得到不同的4-氧代氮杂环丁烷-2-磺酰胺的衍生物，例如在各实施例中所述及。取决于不同方式及分离方法，4-氧代氮杂环丁烷-2-磺酰胺可以游离酰胺或其无机酸盐的形式制得。氨基及羧基保护基团则以常规的已知方法加以脱除。
如美国专利US4,052,387(1977)中所述，通式Ⅱ所示的磺酰胺通过相应的亚磺酰氯与胺的反应来制备。这种亚磺酰氯以青霉素亚砜[如美国专利US4,O81,440(1978)中所述]或以亚磺酸[如Croat,Chem,Acta62(1989)521中所述]为原料现用现制备。
本发明的另一主题，是本发明的新化合物在制备各种β-内酰胺类化合物，尤其是制备新双环体系时作为中间化合物的应用。
本发明的另一主题，是本发明化合物制造具抗菌药效制剂中的有效物质的应用。
下面以实施例来阐明本发明。
实施例1
(2R,3R)1-(1’-甲氧羰基-2’-甲基-丙-1’-烯基)-2-苄基氨基磺酰基-3-苯氧基乙酰氨基-4-氧代氮杂环丁烷
在(5R,6R)6-苯氧基乙酰氨基青霉烷酸-亚砜-甲基酯(1.9g,5mMol)溶于无水甲苯(215ml)所成的溶液中，加入氧化钙(1.65g,28.4mMol)及N-氯代琥珀酰亚胺(0.85g,6.4mMol)，并将该反应混合物在氮气流中，在沸点温度下搅拌1.5小时。将其冷至0℃、加入苄胺(2.26g,21mMol)，并再搅拌2小时。过滤反应混合物，用水(2×90ml)洗涤母液，脱水(Na2SO4)，过滤并真空浓缩。在硅胶柱用二氯甲烷∶甲醇溶剂混合液(20∶1)洗脱残留物。将所得到的立体异构的(2R,3R)1-(1’-甲氧氧羰基-2’-甲基-丙-1’烯基)-2-苄基-氨基亚磺酰-3-苯氧基乙酰氨基-4-氧代氮杂环丁烷混合物(1.8g,74.4％)[大量异构体
1H NMR(CDCl3)δ:2.13及2.26(6H 2s,CMe2),3.75(3H,s,OMe),4.13-4.50(5H,m,CH2N,CH2O,SNH),4.95(1H,d,J 5.0Hz,C2H),5.87(1H,dd,J 5.0及10.0Hz,C3H),6.75-7.37(5H,m,C6H5O),8.47(1H,d,J 10.0Hz CONH)ppm]
溶于二氯甲烷(35ml)及甲酸(7ml)中，加入含水(30％)H2O2溶液(28ml)，并在室温下搅拌反应混合物6小时。分离出有机萃取物，用水洗涤，脱水(Na2SO4)，过滤并浓缩。剩下的是一种泡沫状产物(1.98g,95％)：
Rf0.55(CH2Cl2∶MeOH=20∶1)；IR(KBr)3420-3230m,1785s,1735m,1690s,1605m,1530s,1495m,1440m,1370m,1335m,1225s,1162s,1065s,995wcm-1；
1H NMR(CDCl3)δ:2.09及2.25(6H,2s,CMe2),3.69(3H,s,OMe),4.09-4.41(5H,m,CH2N,CH2O,SNH),4.80(1H,d,J 5,3Hz,C2H),5.83(1H,dd,J及10.8Hz,C3H),6.87-7.44(5H,m,C6H5O),7.77(1H,d,J 10.8Hz,CONH)ppm。
实施例2
(2R,3R)1-(1’-甲氧羰基-2’-甲基-丙-2’-烯基)-2-[(5’-甲基-异噁唑-3’-基)]氨基磺酰基-3-苯氧基乙酰氨基-4-氧代氮杂环丁烷
使(5R,6R)6-苯氧基乙酰氨基青霉烷酸-亚砜-甲基酯(1.9g,5mMol)与N-氯代琥珀酰亚胺，如实施例1所述那样进行反应，尔后以3-氨基-5-甲基异噁唑(2.06g,21mMol)代替苄基胺加入其中。经搅拌并处理反应混合物后，分离(2R,3R)1-(1’-甲氧羰基-2’-甲基-丙-2’-烯基)-2-[(5′-甲基-异噁唑-3’-基)]氨基亚磺酰基]-3-苯氧基乙酰氨基-4-氧代氮杂环丁烷的立体异构混合物。浓缩甲苯溶液后，熔点为185-190℃的异构体结晶出来
[1H NMR(CDCl3)δ:1.99(3H,s,Me),2.15(3H,s,Me-异噁唑),3.85(3H,s,OMe),4.43(2H,bs,OCH2),5.05(1H,s,NCHCO),5.09及5.27(2H,2bs,=CH2),5.37(1H,d,J 4.5Hz,C2H),5.79(1H,s,CH-异噁唑),5.84(1H,dd,J 4.5及9.5Hz,C3H),6.95-7.34(5H,m,C6H5O),7.70(1H,d,J 9.5Hz,CONH),8.29(1H,s,SNH)ppm；Anal.C21H23O8N4S；gef.:C,52.42；H,5.82；N,12.02；S,6.34％；ber.:C,52.93；H,5.08；N,11.76；S,6.73％]。
将吸出的结晶溶于二氯甲烷及甲酸，并如实施例1中所提及的那样，用过氧化氢进行氧化，此时制得泡沫状产物：Rf为0.20(CH2Cl2∶MeOH=20∶1)；
IR(KBr)3400-3000m,1795vs,1750s,1690m,1620m,1605m,1535-1494s,1465m,1440m,1245s,1165s,cm-1；
1H NMR(CDCl3)δ:1.91(3H,s,Me),2.18(3H,s,Me-异噁唑),3.79(3H,s,OMe),4.44(2H,bs,OCH2),4.90(1H,s,NCHCO),5.00及5.17(2H,2bs,=CH2),5.46(1H,d,J 5.0Hz,C2H),6.01(1H,dd,J 5.0及10.3Hz,C3H),6.82-7.41(5H,m,C6H5O),7.75(1H,d,J 10.3Hz,CONH)ppm。
实施例3
(2R,3R)1-(1’-甲氧羰基-2’-甲基-丙-1’烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基磺酰基]-3-苯氧基乙酰氨基-4-氧代氮杂环丁烷
将按实施例2制得的亚磺胺(熔点185-190℃)溶于二氯甲烷，并在室温下同三乙基胺一起搅拌2小时。经处理反应混合物后，以硅胶柱色谱分离得(2R,3R)1-(1’-甲氧羰基-2’-甲基-丙-1’-烯基)-2-[5’-甲基-异噁唑-3’-基)-氨基亚磺酰基]-3-苯氧基乙酰氨基-4-氧代氮杂环丁烷(收率为80％)：
1H NMR(CDCl3)δ:2.06及2.19(6H,2s,CMe2),2.25(3H,s,Me-异噁唑),3.76(3H,s,OMe),4.31及4.40(2H,ABq,J 15.0Hz,OCH2),5.34(1H,d,J 5.0Hz,C2H),5.80(1H,s,CH-异噁唑),5.60(1H,dd,J 5.0及8.8Hz,C3H),6.84-7.32(5H,m,C6H5O=,7.92(1H,d,J 8.8Hz,CONH),8.43(1H,s,SNH=ppm]，
接着如实施例1中所述，将其用H2O2氧化。得泡沫状产物，收率为85％。
Rf0.24(CH2Cl2∶MeOH=20∶1)；
IR(KBr)1790s,1735m,1700s,1620m,1540-1495s,1465m,1440m,1380m,1230s,1165scm-1；
1HNMR(CDCl3)δ:2.09及2.22(6H2s,CMe2),2.26(3H,s,Me-异噁唑)3.71(3H,s,OMe),4.46及4.57(2H,ABq J 15.0Hz,OCH2),4.57(1H,s,SNH)5.54(1H,d,J 5.2Hz,C2H),6.07(1H,s,CH-异噁唑),6.06(1H,dd,J5.2及10.4Hz,C3H),6.95-7.37(5H,m,C6H5O),7.76(1H,d,J 10.4Hz,CONH),ppm。
实施例4
(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-2’-烯基)-2-[(5’-甲基异唑-3’-基)氨基磺酰基]-3-苯二酰亚氨基-4-氧代氮杂环丁烷
如实施例1中所述,使(5R,6R)6-苯二酰亚氨基青霉烷酸-亚砜-p-硝基苄基酯(1.5g,3mMol)与N-氯代琥珀酰亚胺(0.4g,3mMol)反应，尔后加入3-氨基-5-甲基-异噁唑(1.18g,12mMol)，并在10℃下将反应混合物搅拌4小时。滗出甲苯溶液，用水洗涤，脱水，过滤并真空浓缩。在二氯甲烷∶乙酸乙酯溶剂体系(4∶1)中，用硅胶柱色谱分离得0.88g(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-2’-烯基)-2-[5’-甲基-异噁唑-3’-基)氨基亚磺酰基]-3-苯二酰亚氨基-4-氧代氮杂环丁烷：
[1H NMR(CDCl3)δ:1.90(3H,s,Me),2.27(3H,s Me-异噁唑),4.76(1H,bs,NCHCO)；4.92及5.06(2H,2bs,=CH2),5.25(2H,bs,OCH2),5.67(1H,d,J 5.4Hz,C2H),6.09(1H,d,J 5.4,Hz,C3H),7.20(1H,bs,CH-异噁唑),7.52及8.20(4H,2d,J 9.04Hz,C6H4NO2),7.71-7.95(4H,m，苯二酰亚氨基)，及8.05(1H,bs,SNH)ppm]。
如实施例1中所述，在二氯甲烷(15ml)及甲酸(2ml)中与H2O2(12ml,30％水溶液)反应，生成0.63g磺酰胺：
Rf0.58(CH2Cl2∶MeOH=9∶1)；
IR(KBr)1805s,1790s,1735vs,1615m,1525m,1475m,1390s,1350s,1270w,1170w,1110w,720m cm-1；
1H NMR(CDCl3)δ:2.02(3H,s,Me),2.22(3H,s,Me-异噁唑),4.98(1H,s,NCHCO),5.09-5.35(4H,m,=CH2,OCH2),5.57(1H,d,J 4.5Hz C2H),5.76(1H,d,J 4.5Hz,C3H),5.97(1H,s,CH-异噁唑),7.51及8.15(4H,2d,J 8.4Hz,C6H4NO2),7.69-8.05(4H,m,苯二酰亚氨基)ppm]。
实施例5
(2R,3R)-2-苄基氨基磺酰基-3-苯基乙酰氨基-4-氧代氮杂环丁烷
如实施例1中所述，使(5R,6R)6-苯基乙酰氨基青霉烷酸-亚砜-p-硝基苄基酯(2.10g,4.3mMol)与N-氯代琥珀酰亚胺(0.72g,5.4mMol)进行反应，接着用苄基胺(1.5ml)制备(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-苄基-氨基-亚磺酰基-3-苯基乙酰氨基-4-氧代氮杂环丁烷的立体异构混合物(1.78g,69.4％)：[大量立体异构体 1H NMR(DMSO-d6)δ:2.11及2.25(6H,2s,CMe2),3.53(2H,s,CH2CO),3.81-4.36(3H,m,SNHCH2),4.78(1H,d,J5.4Hz,C2H),5.24(2H,bs,OCH2),5.70(1H,dd,J 5.4及9.0Hz,C3H),6.65(1H,d,J 9.0Hz,CONH),7.07-7.35(10H,m,2C6H5),7.44及8.17(4H,2d,J将该产物溶于乙酸乙酯(25ml)及80％乙酸(25ml)中，并在0℃下，在1小时时间内滴加4％高锰酸钾水溶液(50ml)。滴加30％H2O2溶液，至高锰酸盐颜色消失。分离出有机萃取物，用NaHCO3水溶液和水洗涤，脱水(Na2SO4)并真空浓缩。以硅胶柱色谱法用二氯甲烷∶乙酸乙酯溶剂体系(4∶1)洗脱，分离得0.3g(23.5％)熔点为135-137℃的磺酰胺：
Rf0.92(n-BuOH∶HOAc∶H2O=4∶1∶1)；
IR(KBr)3360m,3290m,1770vs,1655s,1515m,1320s,1135s,720scm-1；
1H NMR(DMSO-d6)δ:3.56(2H,bs,CH2CO),4.15-4.20(2H,m,NCH2),4.85(1H,d,J 4.7Hz,C2H),5.57(1H,dd,J 4.7及9.5Hz,C3H),7.25及7.38(10H,2bs,2C6H5),7.87-7.93(1H,m,SNE),8.49(1H,d,J 9.5Hz,CONH)9.24(1H,bs,N1H)ppm；分析：C18H19N3O4S实测：C57.70,H5.90,N11.74,S8.47％计算：C57.89,H5.13,N11.25,S8.59％。
实施例6
(2R,3R)1-(1’-羧基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基-磺酰基]-3-苯基乙酰氨基-4-氧代氮杂环丁烷
如实施例1中所述，使(5R,6R)6-苯基乙酰氨基青霉烷酸-亚砜-p-硝基苄酯(3.0g,6.2mMol)与N-氯代琥珀酰亚胺(1.0g,7.5mMol)进行反应，而后加入3-氨基-5-甲基-异噁唑(2.4g,25mMol)，并在5℃下将反应混合物搅拌3小时。滗出甲苯溶液，用水洗涤，脱水并真空浓缩。得1.43g(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-2’-烯基)-2-[5’-甲基-异噁唑-3’-基)氨基亚磺酰基]-3-苯乙酰亚氨基-4-氧代氮杂环丁烷[熔点：157-160℃；
1H NMR(CDCl3)δ:1.93(3H,s,Me),2.35(3H,s,Me-异噁唑),3.61(2H,s,CH2CO),4.94(1H,bs,NCHCO),5.07及5.19(2H,2bs,=CH2),5.13(1H,d,J 4.8Hz,C2H),5.28(2H,bs,OCH2),5.57(1H,bs,CH-异噁唑),5.77(1H,dd,J 4.8及9.0Hz,C3H),7.22(5H,bs,C6H5),7.44(1H,d,J 9.0Hz,CONH),7.49及8.21(4H,2d,J 8.8Hz,C6H4NO2)ppm],
它在三乙胺及二氯甲烷中，经搅拌转化为(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基亚磺酰基]-3-苯乙酰氨基-4-氧代氮杂环丁烷
[1H NMR(CDCl3)δ:2.18及2.22(6H,2s,CMe2),2.34(3H,s,Me-异噁唑),3.61(2H,s,CH2CO),5.11(1H,d,J 4.9Hz,C2H),5.25(2H,s,OCH2),5.64(1H,dd,J 5.0及8.4Hz,C3H),5.63(1H,s,CH-异噁唑),7.24(5H,s,C6H5),7.26(1H,d,J 8.4Hz,CONH),7.47及8.18(4H,2d,J 8.5Hz,C6H4NO2)ppm]。
将所得的亚磺酰胺，如实施例1中所述，用H2 O2氧化成(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-[5’-甲基异噁唑-3’-基)氨基磺酰基-3-苯乙酰氨基-4-氧代氮杂环丁烷。
[Rf0.57(CH2Cl2∶MeOH=8∶1)IR(KBr)3680-2500m,1785s,1730m,1665s,1615m,1520s,1350s,1215m,1160m cm-1；1H NMR(CDCl3)δ:1.99及2.15(6H,2s,CMe2),2.28(3H,s,Me-异噁唑),3.59(2H,s,CH2CO),5.19(2H,s,OCH2),5.44(1H,d,J 5.3Hz,C2H),5.81(1H,s,CH-异噁唑),5.84(1H,dd,J 5.3及9.9Hz,C3H),6.84(1H,d,J 9.9Hz,CONH),7.28(5H,s,C6H5),7.45及8.17(4H,2d,J 8.9Hz,C6H4NO2)ppm]。
接着，将所得的磺酰胺溶于甲醇(25ml)，并在2.4巴压力下，用10％披钯炭(50mg)氢化2小时。将反应混合物过滤，真空浓缩母液。使残留物溶于二氯甲烷(20ml)及水(20ml)，添加NaHCO3)将pH值调至8.5。分离出水萃取物，用新鲜二氯甲烷振摇萃取，再加入一份二氯甲烷(15ml)，并添加盐酸，将pH值调至2.2。分离出有机萃取物，脱水(Na2SO4)，过滤并真空蒸发。得0.14g(52.4％)产物。
Rf0.48(CH2Cl2∶MeOH=3∶2)
IR(KBr)3660-2300bm,2910m,1790s,1680bs,1620s,1465m,1270m,1165m,930w cm-1；
1H NMR(CDCl3)δ:1.93及2.07(6H,2s,CMe2),2.35(3H,s,Me-异噁唑),3.67(2H,s,CH2CO),5.68(1H,d,J 5.2Hz,C2H),6.0(1H,dd,J 5.2及9.3Hz,C3H),6.12(1H,s,CH-异噁唑),6.63(1H,d,J 9.3Hz,CONH),7.27-7.31(5H,m,C6H5)ppm。
实施例7
(2R,3R)1-(1’-m-甲基苄氧羰基-2’-甲基-丙-2’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氮基磺酰基]-3-[(3’-o-氯代苯基-5’-甲基-异噁唑-4’-基)羧基酰氨基]-4-氧代氮杂环丁烷
如实施例1中所述，使(5R,6R)6-(3’-o-氯代苯基-5’-甲基异噁唑-4-基)羧基酰氨基青霉烷酸-亚砜-m-甲基苄基酯(2.0g,3.6mMol)与N-氯代琥珀酰亚胺反应，而后加入3-氨基-5-甲基异噁唑(1.1g,11mMol),并在室温下搅拌反应混合物3小时。过滤该混合物，用水(3×60ml)萃取母液，脱水(Na2SO4)，过滤并真空浓缩。制得1.92g(2R,3R)1-(1’-m-甲基-苄氧羰基-2’-甲基-丙-2’-烯基)-2-[5’-甲基-异噁唑-3’-基)氨基亚磺酰基]-3-[3’-o-氯代苯基-5’-甲基-异噁唑-4’-基)羧基酰氨基]-4-氧代氮杂环丁烷的立体异构物混合物[Rf为0.40及0.26，在二氯甲烷∶乙酸乙酯(4∶1)中]。将该产物溶于二氯甲烷及甲酸，并如实施例1中所述，用H2O2氧化。将粗产物在硅胶柱上并经用二氯甲烷∶乙酸乙酯溶剂混合液洗脱来进行色谱分离。制得0.62g(44％)磺酰胺：
Rf0.55(CH2Cl2∶MeOH=10∶1)；
IR(KBr)3405w,1795vs,1745s,1680vs,1620s,1520s,1465s,1385m,1340m,1265m,1160m,770mcm-1；
1H NMR(CDCl3)δ:1.79(3H,s,Me),2.31(3H,s,苯基-Me),2.35及2.72(6H,2s,2Me-异噁唑)4.85(1H,s,NCHCO),4.90及5.10(2H,2s,=CH2),5.08及5.13(2H,ABq,J 120Hz,OCH2),5.44(1H,d,J 5.0Hz,C2H),5.95(1H dd,J 5.0及9.6Hz,C3H),6.04(1H,s,CH-异噁唑),6.37(1H,d,J 9.6Hz,CONH),7.01-7.26及7.41-7.55(8H,2m,2C6H4)ppm。
实施例8
(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-苄基氨基磺酰基-3,3-二溴-4-氧代氮杂环丁烷
使(5R)6,6-二溴青霉烷酸-亚砜-苄基酯
(7.0g,15mMol)如实施例1所述那样，与N-氯代琥珀酰亚胺进行反应，而后用苄胺(4ml,37.5mMol)使反应继续进行，抽出反应混合物，用水洗涤母液，脱水(Na2SO4)，过滤并真空浓缩。粗产物在硅胶柱上经用二氯甲烷∶乙酸乙酯(6∶1)溶剂混合液洗脱进行色谱分离，得3.08g(36％)(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2苄基氨基-亚磺酰基-3,3-二溴-4-氧代氮杂环丁烷
[1H NMR(CDCl3)d:1.84及2.26(6H,2s,CMe2),3.68-4.40(3H,m,SNHCH2),5.07及5.24(2H,ABq,J12Hz,OCH2),5.09(1H,s,C2H),7.10-7.30(10H,m,2C6H5)ppm],
将其在氯仿中用m-氯代过苯酸(1.2g,6mMol)氧化。该反应混合物在-10℃下搅拌20分钟，接着在室温下搅拌1小时。加入1M亚硫酸氢钠溶液(36ml,6mMol)，分离出有机层，用水洗涤，脱水(Na2SO4)，过滤并真空浓缩。
使残留物溶于二氯甲烷，并使之通过硅胶柱，制得2.1g(59％)熔点为120-122℃的白色结晶状产物：
Rf0.88(CH2Cl2/EtOAc=4∶1)；
IR(KBr):3250vs,1780vs,1730vs,1640s,1444vs,1370b,1255s,1200s,1165vs,1055vs,755vs,700vs cm-1；
1H NMR(CDCl3)δ:2.09及2.28(6H,2s,CMe2),4.09(2H,d,J 5.8Hz,NCH2-苯基),4.63(1H,t,J 5.8Hz,SNH),5.08及5.34(2H,ABq,J 11.7Hz,OCH2),5.32(1H,s,C2H),7.29-7.35(10H,m,2C6H5),ppm。
实施例9
(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异噁唑-3’-基)-氨基-磺酰基]-3,3-二溴-4-氧代氮杂环丁烷
a)使(5R)6,6-二溴青霉烷酸-亚砜-苄基酯(7.0g,15mMol)如实施例1中所述，与N-氯代琥珀酰亚胺反应，接着，加入3-氨基-5-甲基-异噁唑(4.47g,45mMol)，并在20℃温度下，将该反应混合物搅拌3小时。吸出沉淀物，使之干燥，将其溶于二氯甲烷(30ml)，并在20℃温度下同三乙胺(1.5ml)一起搅拌1小时。将反应混合物用0.1N盐酸(pH值为1-2)及水洗涤，对有机萃取物脱水(Na2SO4)，过滤并真空浓缩。残留物由1.85g(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基-亚磺酰基]-3,3-二溴-4-氧代氮杂环丁烷组成[熔点：58-60℃；
Rf0.51(CH2Cl2∶EtOAc=4∶1)；1H NMR(CDCl3)δ:1.88及2.13(6H,2s,CMe2),2.31(3H,s,Me-异噁唑),5.13(2H,s,OCH2),5,56(1H,s,C2H),5.67(1H,s,CH-异噁唑),7.35(5H,s,C6H5)及8.32(1H,s,SNH)ppm],
将其如实施例8中所述，用m-氯代过苯酸氧化。将粗产物在硅胶柱上，用二氯甲烷∶乙酸乙酯(4∶1)溶剂混合液洗脱来进行色谱分离，得熔点为168-170℃的白色结晶状产物(52.6％)：
Rf0.25(CH2Cl2∶EtOAc=4∶1)；
IR(KBr):3160m,1780vs,1765vs,1625s,1500s,1395vs,1383s,1220s,1175vscm-1；
1H NMR(CDCl3)δ:2.06及2.15(6H,2s,CMe2),2.37(3H,s,Me-异噁唑),5.05(2H,s,OCH2),5.70(1H,s,C2H),6.07(1H,s,CH-异噁唑),7.31(5H,s,C6H5)ppm。
b)将按上述方法制得的亚磺酰胺(0.85g,1.5mMol)溶于二氯甲烷(5ml)及甲酸(5ml)，并在沸点温度下，在1小时时间内，用H2O2(0.56ml)将其氧化。在冷却后的反应混合物中加入水，分离出有机层，用5％NaHCO3溶液及水振摇萃取，脱水(Na2SO4)，过滤并浓缩。制得同方法a)中完全相同的产物。
实施例10
(2R)1-(1’-羧基-2’-甲基-丙-1’-烯基)-2-苄基氨基磺酰基-3,3-二溴-4-氧代氮杂环丁烷
在氮气流下，向用冰冷却的三氯化铝(0.4g,3mMol)二氯甲烷(15ml)悬浮液中，加入由(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-苄基氨基磺酰基-3,3-二溴-4-氧代氮杂环丁烷(0.59g,1mMol)及苯甲醚(0.65g,6mMol)溶于二氯甲烷(15ml)所成的溶液，并在室温下搅拌30分钟。向该反应溶液中掺加乙酸乙酯(15ml)及0.1N盐酸(5ml)。分离两层溶液，并用5％NaHCO3溶液(2×20ml)萃取乙酸乙酯层。再将各层分离开。水萃取物用0.1N盐酸将pH值调至1，加入新鲜乙酸乙酯(20ml)，加入NaCl，并充分振摇。分离出乙酸乙酯层，再用饱和盐溶液洗涤，接着，脱水并真空浓缩。得0.49g(98％)熔点为47-50℃的产物：
Rf0.66(EtOAc∶MeOH=3∶1)；
IR(Film):3300m,2960-2930m,1805vs,1700s,1625m,1425m,1350s,1160s cm-1；1H NMR(DMSO-d6)δ:1.98及2.23(6H,2s,CMe2),4.09及4.20(2H,ABX,J 5.7,6.0及15.2Hz,CH2Ph),5.51(1H,s,C2H),7.29-7.39(5H,m,C6H5),8.49(1H,dd,J 5.7及6.0Hz,NH),13.5(1H,b,COOH)ppm。
实施例11
(2R)1-(1’-羧基-2’-甲基-丙-1’-烯基)-2-苄基氨基磺酰基-4-氧代氮杂环丁烷
将(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-4-氧代氮杂环丁烷-2-亚磺酸(3.23g,10mMol)溶于亚硫酰二氯(20ml)，并在25℃下，将该溶液搅拌1小时。减压下，浓缩过量亚硫酰二氯，直至产生油状残留物，将残留物溶于二氯甲烷(50ml)，将所成溶液冷至10℃，并在搅拌及冷却条件下，加入5％苄胺的二氯甲烷溶液，直至pH值达7.0，并在该温度下继续搅拌30分钟。吸出所沉淀的苄胺盐酸盐，并用二氯甲烷洗涤之。母液中加入水(50ml)，用10％盐酸使该混合物酸化至pH值为1.3，并使各层分离，有机层重又用水洗涤，用Na2SO4脱水并蒸发至干。得到Rf值为0.64及0.72(CH2Cl2∶EtOAc=2∶1)的(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-苄基氨基亚磺酰基-4-氧代氮杂环丁烷立体异构体混合物(3.85g,93％)，用硅胶柱色谱法将该混合物分离。[Rf值为0.64的物质：
IR(CH2Cl2):3020vs,2980s,1760vs,1700m,1415m,1260vs,1210s,1070m,900s,cm-1,1H NMR(CDCl3)δ:1.95及2.24(6H,2s,CMe2),3.11(1H,dd,J5.0及153Hz,αC3H),3.39(1H,dd,J2.6及15.3Hz,βC3H),4.0-4.3(3H,m,NHCH2),4.77(1H,2d,J2.6及5.0Hz,C2H),5.08及5.29(2H,ABq,J 12.0Hz,CH2苯基),7.32(10H,s,2C6H5)ppm；[Rf-值为0.72的物质IR(CH2Cl2):3025vs,2980s,1755vs,1700m,1420m,1260vs,1210s,1075m,900s cm-1；1H NMR(CDCl3)δ:2.08及2.21(6H,2s,CMe2),2.94及3.16(2H,2d,J 3.2及4.7Hz,βC3H及αC3H),4.19(3H,b,NHCH2),4.77(1H,dd,J 3.2及4.7Hz,C2H)5.06 und 5.28(2H,ABq,J 12.3Hz,CH2苯基),7.32(10H,s,2C6H5)ppm]。
使该亚磺酰胺(Sulfinamid)(1.65g,4mMol)如实施例5中所述，与高锰酸钾反应。经短时间保持高锰酸钾颜色不变后，反应结束。经在硅胶柱上以CH2Cl2∶EtOAc=2∶1溶剂混合液洗脱进行色谱分离后，制得1.32g(77％)(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-苄基氨基磺酰基-4-氧代氮杂环丁烷。
[Rf0.62(苯∶EtOAc=2∶1)；熔点：92-94℃；IR(KBr):3300vs,1775vs,1650vs,1430m,1350s,1335s,1290vs,1200m,1150s,1070w cm-1；1H NMR(CDCl3)δ:2.05及2.23(6H,2s,CMe2),3.16(2H,d,J 3.8Hz,αC3H及βC3H),4.08(2H,d,J 5.9Hz,NCH2),4.50(1H,t,J 5.9Hz,NH),4.89(1H,t,J 3.8Hz,C2H),5.09及5.18(2H,ABq,J 12.0Hz,CH2-苯基),7.25及7.34(10H,2s,2C6H5)ppm]。
将所得磺酰胺(0.4g,1.16mMol)如实施例6所述，加以氢化及处理，得0.36g相应酸：
Rf0.88(n-BuOH∶HAc∶H2O=4∶1∶1)；
IR(KBr):3260s,1760vs,1700s,1630m,1430m,1330s,1170s,1070m cm-1；
1H NMR(CDCl3)δ:2.09及2.26(6H,2s,CMe2),3.17(2H,d,J 4.1Hz,C3H),4.26(2H,s,NCH2),4.98(1H,t,J 4.1Hz C2H),7.30(5H,s,C6H5)ppm。
实施例12
(2R)2-苄基氨基磺酰基-4-氧代氮杂环丁烷
a)将(2R)1-(1’-甲氧羰基-2’-甲基-丙-1’-烯基)-4-氧代氮杂环丁烷-2-亚磺酸(5.0g,20mMol)溶于亚硫酰二氯(20ml)，并如实施例11中所述加以处理。制得Rf值为0.20及0.27(CH2Cl2∶EtOAc=2∶1)的(2R)1-(1’-甲氧羰基-2’-甲基-丙-1’-烯基)-2-苄基氨基亚磺酰基-4-氧代氮杂环丁烷的立体异构体混合物(5.4g,80.4％)，该混合物以色谱法在硅胶柱上予以分离[Rf值为0.2的物质：
IR(CH2Cl2):3200-3300m,2930m,1760vs,1715s,1220s,1080s cm-1；1H NMR(CDCl3)δ:1.99及2.23(6H,2s,CMe2),3.17(1H,d,J5.0及15.2Hz,αC3H),3.46(1H,dd,J 2.6及15.2Hz,βC3H),3.75(3H,s,OCH3),4.15-4.30(1H,b,NH),4.23(2H,s,CH2苯基),4.92(1H,2d,C2H J 2.6及5.0Hz),7.31(5H,s,C6H5)ppm；Rf-为0.27:IR(CH2Cl2):3300m,2950m,1775vs,1720s,1360s,1220s,1080s cm-1；1HNMR(CDCl3)δ:2.07及2.20(6H,2s,CMe2),2.97(1H,dd,J 3.1及15.5Hz,βC3H),3.25(1H,dd,J 5.0及15.5Hz,αC3H),3.73(3H,s,OCH3),4.15-4.33(1H,b,NH),4.26(2H,s,CH2Ph),4.83(1H,2d,J 3.1及5.0Hz,C2H),7.32(5H,s,C6H5)ppm]。
使亚磺酰胺(3.36g,10mMol)如实施例5中所述，与高锰酸钾反应。在油状产物(2.5g)中加入乙醚(30ml)，并在室温下将所得的凝胶状物质搅拌8小时。吸出所沉淀的结晶状产物，并用乙醚洗涤之。
熔点：111-130℃；Rf0.10(Benzol∶EtOAc=3∶1)；
IR(KBr):3300vs,1790vs,1740vs,1430s,1330s,1300s,1120s,1070s cm-1；1HNMR(DMSO-d6)δ:2.96(3H,dd,J 2.1及15.2Hz,βC3H),3.29(1H,dd,J4.7及15.2Hz,αC3H),4.23(2H,d,J 5.9Hz,NCH2),4.71(1H,dd,J 2.1及4.7Hz,C2H),7.33(5H,s,C6H5),7.96(1H,t,J 5.9Hz,SNH),8.92(1H,s,N1H)ppm。
b)如实施例11中所述制备的(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-苄基氨基磺酰基-4-氧代氮杂环丁烷，相似于方法a)，与高锰酸钾反应，制得完全相同的产物。
实施例13
(2R)1-(1’-羧基-2’-甲基-丙-1’-烯基)-2-[(5’甲基-异噁唑-3’-基)氨基磺酰基]-4-氧代氮杂环丁烷
将(2R)1-(1’-苄基氧羰基-2’-甲基-丙-1’-烯基)-4-氧代氮杂环丁烷-2-亚磺酸(3.23g,10mMol)溶于亚硫酰二氯(10ml)，将该溶液在25℃搅拌1小时。减压下浓缩过量亚硫酰二氯，得油状残留物。将该残留物溶于二氯甲烷(50ml)，加入3-氨基-5-甲基-异噁唑(2.94g,30mMol)，并室温下搅拌3小时。反应混合物中掺入水(50ml)，并用10％盐酸将pH值调整至1.5。分离各层。有机层再用水(50ml)洗涤。再向有机层掺入水(50ml)，并以饱和NaHCO3溶液调节pH值至8.0。分离各相，再用水洗涤有机层，用Na2SO4脱水，并蒸发至干。制得Rf值为0.29及0.35(CH2Cl2∶EtOAc=2∶1)的(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基亚磺酰基]-4-氧代氮杂环丁烷的立体异构体混合物(3.8g,92.6％)，该两种物质以硅胶柱色谱法加以分离。
[Rf值为0.29的物质：
IR(CH2Cl2)1780vs,1720m,1620s,1465s,1360s,1290m,1215s,1100s,1080m cm-1；1H NMR(CDCl3)δ:1.98及2.20(6H,2s,CMe2),234(3H,s,Me-异噁唑),3.28(1H,dd,J 4.7及15.5Hz,αC3H),3.54(1H,dd,J2.6及15.5Hz,βC3H),5.06(1H,dd,J 2.6及4.7Hz,C2H)5.19(2H,s,CH2苯基),5.82(1H,s,CH-异噁唑),7.33(5H,s,C6H5),8.40(1H,s,NH)ppm；Rf:0.35；IR(CH2Cl2)1780vs,1725m,1630s,1470s,1360m,1290m,1220s,1100s cm-1；1H NMR(CDCl3)δ:2.09及2.24(6H,2s,CMe2),2.36(3H,s,Me-异噁唑),3.04(1H,dd,J 2.9及15.5Hz,βC3H),3.30(1H,dd,J 5.0及15.5Hz,αC3H),5.11(1H,dd,J 2.9及J 5.0Hz,C2H),5.21(2H,s,CH2Ph),5.80(1H,s,CH-异噁唑),7.26(5H,s)ppm]。
在室温下，将由亚磺酰胺(4.03g,10mMol)、m-氯代过苯酸(4.30g,25mMol)及乙酸乙酯(50ml)组成的溶液搅拌24小时。反应结束后，滴入硫代硫酸钠水溶液(15mMol)，并再搅拌30分钟。用5％NaHCO3水溶液，将该反应混合物的pH值调至8.5，并分离各层。水相以NaCl饱和，并用乙酸乙酯萃取(3×30ml)。将汇集后的有机层用盐水(30m洗涤，用Na2SO4脱水，并蒸发至干。制得钠盐形式的粗产物(3.5g，79％)。将粗产物溶于水，并用10％盐酸溶液酸化至pH为2.0，得(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基磺酰基]-4-氧代氮杂环丁烷[熔点：141-143℃(从乙醚中结晶出来)；
Rf0.40(CH2Cl2∶EtOAc=2∶1)；IR(KBr):3200s,1790vs,1720vs,1620s,1465s,1395s,1300s,1175s cm-1；1H NMR(CDCl3)δ:2.02及2.14(6H,2s,CMe2),2.37(3H,s,Me-异噁唑),3.32(2H,d,J 3.5Hz,αC3H及βC3H),5.10(2H,s,CH2Ph),5.28(1H,t,J 3.5Hz,C2H),6.10(1H,s,CH-异噁唑),7.25(5H,s,C6H5)ppm.Anal:C19H21N3O6S；Gef.:C,54.21；H,5.34；N,9.96,S,8.23％；Ber.:C,54.41,H,5.05,N,10.02,S,7.64％]。
如实施例6中所述,将所得磺酰胺(419mg,1mMol)氢化,并加以处理。得227mg(69％)产物：
Rf0.91(n-BuOH∶HAc∶H2O=4∶1∶1)；
IR(KBr):3600-3000b,3175s,1795s,1760s,1680vs,1620vs,1520m,1470vs,1400vs,1310s,1270m,1180vs,1080m,1045m,cm-1；
1H NMR (DMSO-d6)δ:1.89及2.13(6H,2s,CMe2),2.35(3H,s,Me-异噁唑),3.21(1H,dd,J 1.8及15.3Hz,βC3H),3.55(1H,dd,J 4.5及15.3Hz,αC3H),5.34(1H,dd,J 1.8及4.5Hz,C2H),6.07(1H,s,CH-异噁唑),11.32(1H,bs,NH),13.05(1H,b,COOH)ppm。
实施例14
(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-[3’,4’-二甲基-异噁唑-5’-基)氨基磺酰基]-4-氧代氮杂环丁烷
将(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-4-氧代氮杂环丁烷-2-亚磺酸(3.23g,10mMol)溶于亚硫酰二氯(10ml)。在25℃下，将该溶液搅拌1小时。减压浓缩过量亚硫酰二氯，得油状残留物。使浓缩后的残留物溶于二氯甲烷(50ml)，加入5-氨基-3,4-二甲基-异噁唑(3.78g,30mMol)，并如实施例13中所述进行处理。制得Rf值为0.31及0.38(CH2Cl2∶EtOAc=2∶1)的(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-[3’,4’-二甲基-异噁唑-5’-基)氨基-亚磺酰基]-4-氧代氮杂环丁烷立体异构体混合物(3.20g,76.7％)，该混合物以硅胶柱色谱法进行分离[Rf值为0.31的物质：
IR(KBr):1790vs,1730m,1710s,1650s,1370m,1300m,1225vs,1100m cm-1；1H NMR(CDCl3)δ:1.82,1.97,2.16,2.20(12H,4s,4Me),3.17(1H,d,J 4.1Hz,αC3H),3.45(1H,d,J 3.2Hz,βC3H),5.04(1H,dd,J3.2及4.1Hz,C2H),5.24(2H,s,CH2Ph),7.35(5H,s,C6H5),7.87(1H,s,NH)ppm；Rf-值为0.38的物质：IR(KBr):1785vs,1730s,1700s,1650s,1370m,1300m,1230s,1100s cm-1；1H NMR(CDCl3)δ:1.81,2.10,2.17,2.24(12H,4s,4Me),3.09(1H,d,J 2.9Hz,βC3H),3.34(1H,d,J 5.0Hz,αC3H),5.05(1H,dd,J 2.9及5.0Hz,C2H),5.20-5.30(3H,m,CH2苯基及NH),7.35(5H,s,C6H5),ppm]。
在室温下，将由亚磺酰胺(4.17,10mMol),m-氯代过苯酸(4.3g,25mMol)及乙酸乙酯(50ml)组成的溶液搅拌24小时，并如实施例13中所述加以处理。制得3.2g(70％)熔点为160℃的钠盐形式产物：
Rf0.44(EtOAc)；
IR(CH2Cl2):1790vs,1730m,1365s,1220s,1170s,1070m cm-1；1H NMR(CDCl3)δ:1.90,2.03,2.21,2.23(12H,4s,4Me),3.29 (2H,d,J 4.0Hz,αC3H及βC3H),5.17(1H,t,J 4.0Hz,C2H),5.24(2H,s,CH2苯基)，7.35(5H,s,C6H5)ppm。
实施例15
(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(2’-苯基-吡唑-3’-基)氨基磺酰基]-4-氧代氮杂环丁烷
将(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-4-氧代氮杂环丁烷-2-亚磺酸(10mMol)溶于亚硫酰二氯(3.23g,10mMol)，并如实施例13中所述，进行处理，其中添加2-苯基-3-氨基吡唑(4.77g,30mMo1)来代替3-氨基-5-甲基异噁唑。制得Rf值为0.44及0.50(CH2Cl2∶EtOAc=2∶1)的(2R)1-(1’-苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(2’苯基-吡唑-3’-基)氨基亚磺酰基]-4-氧代氮杂环丁烷立体异构体的混合物(4.04g,86％)，将该混合物以硅胶柱色谱法进行分离[Rf值为0.44的物质：
IR(KBr):1780vs,1720s,1600m,1500s,1455m,1360m,1290m,1215vs,1080m cm-1；1H NMR(CDCl3)δ:1.93及2.16(6H,2s,CMe2),2.96(1H,dd,J 4.9及15.3Hz,αC3H),3.07(1H,dd,J 2.5及15.3Hz,βC3H),4.79(1H,dd,J 2.5及4.9Hz,C2H),5.14(2H,s,CH2苯基),6.22及7.57(2H,2d,J1.9Hz,=CH-CH=),7.26-7.45(10H,m,2C6H5)ppm；Rf-值为0.50的物质：IR(KBr):1780vs,1720s,1600m,1500s,1455m,1385m,1360m,1290m,1220s,1100s,1070m cm-1；1H NMR(CDCl3)δ:2.01及2.13(6H,2s,CMe2),2.80(1H,dd,J 2.3及15.5Hz,βC3H),2.92(1H,dd,J 5.3及15.5Hz,αC3H),4.80(2H,b,C2H),5.09及5.18(2H,ABq,J 12.4Hz,CH2苯基),6.21及7.58(2H,2d,J 1.6Hz=CH-CH=),7.20-7.40(10H,m,2C6H5)ppm。
在室温下，将由亚磺酰胺(4.64g,10mMol)、m-氯代过苯酸(4.3g,25mMol)及乙酸乙酯(50ml)组成的溶液搅拌24小时，并如实施例13中所述进行处理。制得钠盐形式的产物3.4g(67％):
Rf0.47(EtOAc)；
IR(CH2Cl2):3340w,1785s,1725m,1700m,1500s,1390s,1360s,1290m,1215s,1170s,1075m cm-1,
1H NMR(CDCl3)δ:1.96及2.16(6H,2s,CMe2),2.88(1H,dd,J 5.2及15.5Hz,αC3H),3,00(1H,dd,J 2.3及15.5Hz,βC3H),4.92(1H,dd,J 2.3及5.2,C2H),5.07及5.18(2H,ABq,J 12.1Hz,CH2苯基),6.20及7.56(2H,2d,J1.7Hz,=CH-CH=),7.20-7.40(10H,m,2C6H5)ppm。
实施例16
(2R,3R)1-(1’-m-甲基苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异唑-3’-基)氨基磺酰基]-3-[(3’-o-氯代苯基-5’-甲基-异噁唑-4’-基)羧基酰氨基]-4-氧代氮杂环丁烷
将按实施例7所述方法制备的亚磺酰胺立体异构混合物(2.24g)溶于二氯甲烷(10ml)，并在室温下，同三乙胺(0.48ml)一起搅拌2小时。先用0.1N盐酸(5ml)，再用水(10ml)进行萃取，并将有机萃取物脱水(Na2SO4)，过滤并真空浓缩。制得产物2.23g(99.5％)，从中经硅胶柱色谱法，以CH2Cl2∶EtOAc溶液混合液洗脱，得(2R,3R)1-(1’-m-甲基苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基亚磺酰基]-3-[(3’-o-氯代苯基-5’-甲基-异噁唑-4’-基)羧基酰氨基]-4-氧代氮杂环丁烷
[Rf0.21(CH2Cl2∶EtOAc=4∶1)；熔点94-96℃；1H NMR(CDCl3)δ:1.95 und 2.22(6H,2s,CMe2),2.33及2.35(6H,2s,2Me-I异噁唑),2.77(3H,s,Me-苯基),4.96(1H,d,J 4.5Hz,C2H),5.13(2H,bs,OCH2),5.61(1H,dd,J 4.5及8.5Hz,C3H),5.72(1H,s,CH-异噁唑),6.69(1H,d,J 8.5Hz,CONH),7.04-7.55(8H,m,2C6H4)ppm],
接着将其按实施例1中所述，用H2O2氧化。以85.8％的收率制得该磺酰胺：
Rf0.55(CH2Cl2∶MeOH=10∶1)；
IR(Film)3410w,3160vw,3070vw,1795vs,1735w,1685bs,1620s,1640m,1580bs,1420w,1300m,1270m,1220m,1170m,1120m,1060m,770m,740m cm-1；
1H NMR(CDCl3)δ:1.84及2.11(6H,2s,CMe2),2.26及2.33(6H,2s,2Me-异噁唑),2.72(3H,s,Me-苯基),5.01(2H,bs,OCH2),5.36(1H,d,J 5.0-Hz,C2H),5.71-5.92(2H,m,C3H及CH-异噁唑),6.41(1H,d,J 10Hz,CONH),7.01-7.62(8H,m,2C6H4)ppm。
实施例17
(2R,3R)1-(1’-羧基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基异噁唑-3’-基)氨基磺酰基]-3-苯二酰亚氨基-4-氧代氮杂环丁烷
a)将按实施例4制得的(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-2’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基亚磺酰基]-3-苯二酰亚氨基-4-氧代氮杂环丁烷溶于二氯甲烷，并同三乙胺一起搅拌，以此制得(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基亚磺酰基]-3-苯二酰亚氨基-4-氧代氮杂环丁烷
[1H NMR(CDCl3)δ:2.14(6H,bs,CMe2),2.31(3H,s,Me-异噁唑),5.08 und 5.23(2H,ABq,J 13.5Hz,OCH2),5.58(1H,d,J 5.4Hz,C2H),5.71(1H,bs,CH-异噁唑),6.0(1H,d,J5.4Hz,C3H),7.45及8.16(4H,2d,J 9.0Hz,C6H4NO2),7.70-7.94(4H,m,苯二酰亚氨基)ppm]
它在如实施例1中所述那样用过氧化氢氧化时生成(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基磺酰基]-3-苯二酰亚氨基-4-氧代氮杂环丁烷
[Rf0.60(CH2Cl2∶MeOH=9∶1)；IR(KBr):1790bs,1730vs,1615m,1520m,1465m,1385s,1350m,1290w cm-1；1HNMR(CDCl3)δ:2.12及2.26(6H,2s,CMe2),2.32(3H,s,Me-异噁唑),5.21(2H,bs,OCH2),5.73(1H,d,J 5.4Hz,C2H),5.83(1H,d,J 5.4Hz,C3H),6.05(1H,bs,CH-异噁唑),7.50及8.18(4H,2d,J 9.0Hz,C6H4NO2),7.60-7.86(4H,m，苯二酰亚氨基)ppm]。将该磺酰胺(840mg,1.38mMol)溶于甲醇(25ml)，氢化并如实施例6中所述加以处理。以室温下搅拌有机萃取物，即沉淀出熔点为160-165℃的这种酸(490mg,75％):
IR(KBr3515m,3200m,1795s,1780s,1735vs,1685m,1625m,1525w,1475m,1415m,1390vs,1310w,1180m cm-1；
1H NMR (DMSO-d6)δ:2.17(6H,s,CMe2),2.27(3H,s,Me-异噁唑),3.31(2H,bs,SNH,COOH,HOH),5.68(1H,d,J 4.9Hz,C2H),5.82(1H,d,J 4.9Hz,C3H),5.89(1H,s,CH-异噁唑),7.92(4H,s，苯二酰亚氨基)ppm。
b)将按实施例4制备的磺酰胺(0.63g)溶于二氯甲烷(10ml)，并在10℃中，同三乙胺(0.1g)一起搅拌5小时。经硅胶柱色谱法，由浓缩后所得残留物制得0.57g磺酰胺，它完全同上面a)中所述，并能经氢解释出该磺酸。
实施例18
(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基磺酰基]-3氨基-4-氧代氮杂环丁烷
使按实施例17制备的磺酰胺与硫化钠反应，然后与二环己基碳酰亚胺反应，接着再如Croat,Chem./Acta49(1977)中所记载的那样，与甲基肼反应。得泡沫状产物，它能产生水合茚三酮阳性反应：
Rf0.48(CH2Cl2∶MeOH=9∶1)
IR(KBr)1785s,1735m,1710m,1620m,1525s,1465w,1400w,1150s,1300w,1275w,1220m,1165m cm-1；
1H NMR(CDCl3)δ:2.13及2.25(6H,2s,CMe2),2.39(3H,s,Me-异噁唑),4.66(1H,d,J 5.2Hz,C2H),5.21(1H,d,J 5.2Hz,C3H),5.22及5.29(2H,ABq,J 12.8Hz,OCH2),6.12(1H,s,CH-异噁唑),7.49及8.22(4H,2d,J 8.5Hz,C6H4NO2)ppm。
实施例19
(2R,3R)1-(1’-羧基-2’-甲基-丙-1’-烯基)-2-甲基氨基磺酰基-3-o-甲基-氨基羰基苯基碳酰胺基-4-氧代氮杂环丁烷
使(5R,6R)6-苯二酰亚胺基青霉烷酸-亚砜-p-硝基苄基酯(1.5g,3mMol)如实施例1中所述，与N-氯代琥珀酰亚胺(0.4g,3mMol)反应，而后将反应溶液冷至5℃，并加入甲胺(1ml)溶于甲苯(4ml)所成的溶液。在5℃下，将反应混合物搅拌3小时，并真空浓缩之。将残留物悬浮在二氯甲烷(15ml)中；吸出未溶解的那部分物质，并真空浓缩母液。制得由1.53g(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-甲基氨基亚磺酰基-3-o-甲基氨基羰基苯基碳酰氨基-4-氧代氮杂环丁烷组成的立体异构混合物。
[IR(Film):3250bm,3065w,2950w,1780s,1730sh,1715vs,1650m,1605w,1525s,1350s,1295m,1220m,1185s,1060m,855w,820w,740mcm-1],
将该混合物如实施例1中所述，用H2O2氧化。
得1.23g(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-甲基氨基磺酰基-3-o-甲基-氨基羰基苯基碳酰氨基-4-氧代氮杂环丁烷
[Rf0.81(CH2Cl2∶MeOH=9∶1)；1H NMR(CDCl3)δ:2.15及2.31(6H,2s,CMe2),2.86(3H,d,J 4,5Hz,CONMe),2.98(3H,d,J 4.9Hz,SO2NMe),5.16(1H,d,J 4.9Hz,C2H),5.31及5.38(2H,ABq,J 13.2Hz,OCH2),5.94(1H,dd,J 4.9及10.4Hz,C3H),6.38(1H,m,SO2NH),6.97(1H,d,J 10.4Hz,CONH),7,18(1H,q,J 4.9Hz,CONH),7.44-7.52(4H,m,OCC6H4CO),7.54及8.25(4H,2d,J 8.7Hz,C6H4NO2)ppm],
它通过如实施例17中所述的氢解，产生熔点为142℃(分解)的酸0.68g。
IR(KBr):3410m,3370m,3170m,2960m,1785vs,1720s,1680s,1615s,1600w,1560w,1515m,1440w,1415w,1375w,1330s,1315s,1285s,1210s,1185w,1155w,1080m,735m,700m cm-1；
1H NMR(DMSO-d6)δ:2.01及2.19(6H,2s,CMe2),2.64(3H,d,J 4.5Hz,CONMe),2.75(3H,d,J 4.7Hz,SO2NMe),5.24(1H,d,J 5.0Hz,C2H),5.65(1H,dd,J 5.0及8.7Hz,C3H),7.17(1H,q,J 4.7Hz,SO2NH),7.48-7.56(4H,m,C6H4),8.38(1H,q,J 4.5Hz,CONH),9.07(1H,d,J,8.7Hz,CONH)ppm。
实施例20
(2R,3R)1-(1’-羧基-2’-甲基-丙-1’-烯基)-2-苄基氨基磺酰基-3-苯基-乙酰氨基-4-氧代氮杂环丁烷
使(5R,6R)6-苯基乙酰氨基青霉烷酸-亚砜-p-硝基苄基酯(3.0g,6.2mMol)如实施例1中所述，同N-氯代琥珀酰亚胺(1.0g,75mMol)进行反应，而后加入苄基胺(1.3ml，12.4mMol)，并在5℃下，将反应混合物搅拌2小时。滗析甲苯溶液，用水洗涤，脱水并真空浓缩之。添加乙酸乙酯，制得(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-2’-烯基)-2-苄基氨基-亚磺酰基-3-苯基-乙酰氨基-4-氧代氮杂环丁烷
[1H NMR(CDCl3)δ:1.91(3H,s,Me),3.48(2H,s,CH2CO),3.95-4.32(3H,m,SNHCH2),4.80-5.14(4H,m,NCHCO=CH2,C2H),5.26(2H,bs,OCH2),5.87(1H,dd,J 5.0 und 9.8Hz,C3H),6.52(1H,d,J 9.8Hz,CONH),7.12-7.37(10H,m,2C6H5),7.47 und 8.22(4H,2d,J 8.8Hz,C6H4NO2)ppm],
将其吸收(1.82g)，用三乙胺溶于二氯甲烷所成的溶液使之异构化，变成(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-苄基-氨基-亚磺酰基-3-苯基乙酰氨基-4-氧代氮杂环丁烷(1.66g)，并用H2O2如实施例1中所述，将其氧化。得(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-苄基氨基磺酰基-3-苯基乙酰氨基-4-氧代氮杂环丁烷(1.57g):Rf0.60(CH2Cl2∶EtOAc=4∶1)；[1H NMR(CDCl3)δ:2.06及2.24(6H,2s,CMe2),3.59-3.98(5H,m,CH2CO,SNHCH2),4.67(1H,d,J5.0Hz,C2H)5.21(2H,bs,OCH2),5.73(1H,dd,J 5.0及10.3Hz,C3H),6.68(1H,d,J 10.3Hz,CONH),7.00-7.36(10H,m,2C6H5),7.42 und 8.19(4H,2d,J 8.8Hz,C6H4NO2)ppm],
接着将其如实施例6中所述，加以氢化。分离出0.91g产物：
Rf0.38(CH2Cl2∶MeOH=4∶1)；
IR(Film):3500-2300bm,1785s,1740-1600bs,1525m,1340s,1270m,1210m,1160s,1070m,740m,705s cm-1；
1H NMR(CDCl3)δ:2.07及2.25(6H,2s,CMe2),3.56及3.64(2H,ABq,J14.8Hz,CH2CO),3.98-4.02(3H,m,SNHCH2),4.94(1H,d,J 5.2Hz,C2H),5.84(1H,dd,J 5.2及10.3Hz,C3H)6.77(1H,d,J 10.3Hz,CONH),7.11-7.37(10Hm,2C6H5)ppm。
实施例21
(2R,3R)1-(1’-羧基-2’-甲基-丙-1’-烯基)-2-甲基氨基磺酰基-3-苯基乙酰氨基-4-氧代氮杂环丁烷
使(5R,6R)6-苯基乙酰基青霉烷酸-亚砜-p-硝基苄基酯(3.0g,6.2mMol)与N-氯代琥珀酰亚胺(1.0g,7.5mMol)，如实施例1所述那样进行反应，而后加入甲基胺(1ml)，并将反应混合物在5℃下搅拌2小时。吸出沉淀物，用水洗涤母液，脱水并真空浓缩。硅胶柱色谱分离得到(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-甲基-氨基-亚磺酰基-3-苯基乙酰氨基-4-氧代氮杂环丁烷(1.63g)
1HNMR(CDCl3)δ:2.12及2.26(6H,2s,CMe2),2.47(3H,d,J 5.4Hz,NMe),3.63(2H,ABq,J 14.9Hz,CH2CO),4.68(1H,d,J 5.0Hz,C2H),5.28(2H,s,OCH2),5.80(1H,dd,J,5.0及9.9Hz,C3H),7.19(1H,d,J 9.9Hz,CONH),7.26-7.38(5H,m,C6H5),7.50及8.24(4H,2d,J 8.7Hz,C6H4NO2)ppm],接着如实施例1中所述，用H2O2将其氧化。得(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-甲基氨基-磺酰基-3-苯基-乙酰氨基-4-氧代氮杂环丁烷(0.98g)
[IR(KBr):3460-3140bw,1785s,1730m,1700-1675bm,1610w,1525s,1350s,1220m,1155m,1070m,850w cm-1；1H NMR(CDCl3)δ:2.09及2.26(6H,2s,CMe2),2.46(3H,d,J 5.0Hz,NMe),3.17(1H,q,J 5Hz,SNH),3.55及3.69(2H,ABq,J 14.5Hz,CH2CO),4.97(1H,d,J 5.0Hz,C2H)5.27及5.33(2H,ABq,J 13.2Hz,OCH2),5.80(1H,dd,J,5.2及10.3Hz,C3H),6.58(1H,d,J 10.3Hz,CONH),7.32-7.51(5H,m,C6H5),7.50及8.23(4H,2d,J 8.7Hz,C6H4NO2)ppm]。
将所得的磺酰胺如实施例6中所述，加以氢化，并分离经氢化而产生的酸(0.43g):
IR(KBr):3660-2440bm,1785s,1740-1620bm,1335m,1160m,1075w,740w,705wcm-1；
1H NMR(CDCl3)δ:2.07及2.25(6H,2s,CMe2),2.53(3H,d,J 4.5Hz,NMe),3.63(2H,ABq,J 15.1Hz,CH2CO),4.16(1H,m,SNH),5.24(1H,d,J 5.2Hz,C2H),5.88(1H,dd,J 5.2及10.3Hz,C3H),6.84(1H,d,J 10.3Hz,CONH),7.26-7.40(5H,m,C6H5)ppm。
实施例22
(2R,3R)1-(1’-羧基-2’-甲基-丙-1’-烯基)-2-[(5’-甲基-异噁唑-3-基)氨基磺酰基]-3-苯氧基乙酰氨基-4-氧代氮杂环丁烷
使(5R,6R)6-苯氧基乙酰氨基青霉烷酸-亚砜-p-硝基苄基酯(5.0g,10mMol)与N-氯代琥珀酰亚胺(1.7g,13mMol)如实施例1所述进行反应，而后加入3-氨基-5-甲基-异噁唑(4.1g,40mMol)，并在0℃下，将反应混合物搅拌2小时。滗析甲苯溶液，用水洗涤，脱水，并真空浓缩。得由(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-2’-烯基)-2-[(5’-甲基-异噁唑-3’-基)氨基亚磺酰基]-3-苯氧基乙酰氨基-4-氧代氮杂环丁烷组成的立体异构体混合物(5.0g；83.6％)[占大部分的立体异构体，熔点为196-198℃；IR(KBr):3310w,1775s,1755m,1665m,1625m,1520s,1350s,1240m,1170m,1100s,915w,855w,755w cm-1；1H NMR(CDCl3)δ:2.02(3H,s,Me),2.25(3H,s,Me-异噁唑),4.45及4.54(2H,ABq,J 15.1,OCH2CO),5.07(1H,bs,NCHCO),5.07及5.19(2H,2bs=CH2),5.39(1H,d,J 5.1Hz,C2H),5.35(2H,bs,OCH2),5.76(1H,bs,CH-异噁唑),5.85(1H,dd,j 5.0及9.0Hz,C3H),6.91-7.36(5H,m,C6H5),7.49(1H,d,CONH),7.49及8.21(4H,2d,J 8.8Hz,C6H4NO2)ppm]。
所得立体异构体混合物用H2O2如实施例1中所述那样予以氧化，并用三乙胺溶于二氯甲烷所成的溶液，使之异构化，而后制得3.5g(68.2g)(2R,3R)1-(1’-p-硝基苄氧羰基-2’-甲基-丙-1’-烯基)-2-(5’-甲基-异噁唑-3’-基)氨基磺酰基-3-苯氧基乙酰氨基-4-氧代氮杂环丁烷：[Rf0.67CH2Cl2∶MeOH=9∶1)；IR(KBf):3410-2700m,1795s,1735m,1700s,1620m,1525s,1500m,1465m,1400m,1355s,1300m,1220s,1165m,1065-1110mcm-1；1H NMR(CDCl3)δ:2.11及2.20(6H,2s,CMe2),2.24(3H,s,Me-异噁唑),4.35及4.50(2H,ABq,J 15.1Hz,OCH2CO),5.26(2H,s,OCH2),5.59(1H,d,J 5.2Hz,C2H),6.00(1H,s,CH-异噁唑),6.03(1H,dd,J 5.2及10.5Hz,C3H),6.90-7.35(5H,s,OC6H5),7.52及8.22(4H,2d,J 8.8Hz,C6H4NO2)ppm]。
接着，使所得的磺酰胺(0.56g,0.91mMol)进行如实施例6中所述的氢解，并分离出0.23g(52.5％)产物：
Rf值为0.35(CH2Cl2∶MeOH=1.5∶1.0)
IR(KBr)3600-2400bm,1795s,1700bs,1620m,1500-1550s,1235s,1170s,1065-1090m,940m cm-1；
1H NMR(CDCl3)δ:2.05及2.19(6H,2s,CMe2),2.27(3H,s,Me-异噁唑),4.50及4.59(2H,ABq,J15.0Hz,OCH2CO),5.78(1H,d,J 4.8HzC2H),6.09(1H,dd,J 4.8及10.5Hz,C3H),6.23(1H,s,CH-异噁唑),6.91-7.40(5H,m,OC6H5),7.78(1H,d,J 10.5Hz,CONH)ppm。
Claims (12)
1、通式Ⅰ所示的4-氧代氮杂环丁烷-2-磺酰胺及其盐，
式中各基团的含义如下：R1为氢、卤素，R2为氢、卤素、NH2、苯基-CH2CONH、苯基OCH2CONH、苯二酰亚氨基、o-MeNHCOC6H4CONH、异噁唑基羰基氨基，R3为Me2C=C-COOH,R4为氢，以及R5为氢、烷基、苄基或一个杂环基。
2、权利要求1所述的化合物，其特征在于，R1为氢，R2为苯基-CH2CONH，以及R5为甲基-异噁唑-3-基。
3、权利要求1所述的化合物，其特征在于，R1为氢，R2为氢，以及R5为苯基-CH2。
4、权利要求1所述的化合物，其特征在于，R1为氢，R2为苯二酰亚氨基，以及R5为5-甲基-异噁唑-3-基。
5、权利要求1所述的化合物，其特征在于，R1为氢，R2为o-MeNHCOC6H4CONH,以及R5为甲基。
6、权利要求1所述的化合物，其特征在于，R1为氢，R2为苯基-CH2CONH，以及R5为苯基-CH2。
7、权利要求1所述的化合物，其特征在于，R1为氢，R2为苯基-CH2CONH，以及R5为甲基。
8、权利要求1所述的化合物，其特征在于，R1为氢，R2为氢，以及R5为5-甲基-异噁唑-3-基。
9、权利要求1所述的化合物，其特征在于，R1为溴，R2为溴，以及R5为苯基-CH2。
10、权利要求1所述的化合物，其特征在于，R1为氢，R2为苯基-OCH2CONH，以及R5为5-甲基-异噁唑-3-基。
11、制备通式Ⅰ所示4-氧代氮杂环丁烷-2-磺酰胺及其盐的方法，式中各基团的含义同权利要求1所述，其特征在于，使通式Ⅱ所示的4-氧代氮杂环丁烷-2-亚磺酰胺，
其中：R1为氢或卤素，R2为氢、卤素、苯基CH2CONH、苯基OCH2CONH、苯二酰亚氨基、o-MeNHCOC6H4CONH、异噁唑基羰基氨基，R3为Me2C=C-COOMe、Me2C=C-COOCH2苯基、Me2C=C-COOCH2C6H4NO2-p、Me2C=C-COOCH2C6H4Me-m，R4为氢，以及R5为氢、烷基、苄基或一个杂环基，在一种通用的氧化剂的存在下，于酸性或中性的水或水-有机介质中，在0-100℃的温度下进行氧化，接着以常规方法解离保护基团，处理反应混合物，并分离产物。
12、如权利要求11所述的方法，其中的氧化剂选自过氧化氢、过乙酰乙酸、间-氯代过苯甲酸或高锰酸钾。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4230053A DE4230053A1 (de) | 1992-09-08 | 1992-09-08 | 4-Oxo-azetidin-2-sulfonsäureamide und ihre Salze, Verfahren zu deren Herstellung und ihre Verwendung |
| DEP4230053.3 | 1992-09-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1099750A CN1099750A (zh) | 1995-03-08 |
| CN1042130C true CN1042130C (zh) | 1999-02-17 |
Family
ID=6467533
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93117362A Expired - Fee Related CN1042130C (zh) | 1992-09-08 | 1993-09-08 | 4－氧代氮杂环丁烷－2－磺酰胺及其盐,其制备方法和应用 |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US5466686A (zh) |
| EP (1) | EP0659177B1 (zh) |
| JP (1) | JPH08501093A (zh) |
| CN (1) | CN1042130C (zh) |
| AT (1) | ATE187441T1 (zh) |
| BG (1) | BG62135B1 (zh) |
| CA (1) | CA2142275A1 (zh) |
| CZ (1) | CZ54595A3 (zh) |
| DE (2) | DE4230053A1 (zh) |
| ES (1) | ES2142350T3 (zh) |
| GR (1) | GR3032702T3 (zh) |
| HR (1) | HRP930613A2 (zh) |
| HU (1) | HU217979B (zh) |
| PL (1) | PL173895B1 (zh) |
| PT (1) | PT659177E (zh) |
| RO (1) | RO115256B1 (zh) |
| RU (1) | RU2124003C1 (zh) |
| SK (1) | SK29295A3 (zh) |
| WO (1) | WO1994005632A1 (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HRP921292A2 (en) * | 1992-11-17 | 1994-08-31 | Pliva Pharm & Chem Works | 5-thia-1,4-diazabicyclo (4.2.0.)octane -3,8-dioxo analogs of beta-lactams, the process for the preparation and use thereof |
| HRP970146A2 (en) * | 1997-03-13 | 1998-10-31 | Mice Kovacevic | Epoxi-azetidines, preparation and use |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2556045A1 (de) * | 1974-12-24 | 1976-07-08 | Lilly Co Eli | Verfahren zur herstellung von 3-methylencephamsulfoxiden |
| EP0095764A2 (en) * | 1982-05-31 | 1983-12-07 | Takeda Chemical Industries, Ltd. | 2-Oxoazetidinone derivatives, their production and use |
| EP0499232A2 (en) * | 1991-02-12 | 1992-08-19 | PLIVA Handels GmbH | 4-Oxo-azetidine-2-sulfonic acids and their salts, processes for the preparation thereof and their use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4436596A (en) * | 1982-11-16 | 1984-03-13 | Eli Lilly And Company | N-Substituted-2-(R)-(sulfinic acid)-3-(S)-(acylamido)-4-oxo-azetidines and process |
-
1992
- 1992-09-08 DE DE4230053A patent/DE4230053A1/de not_active Withdrawn
-
1993
- 1993-03-30 HR HRP4230053.3A patent/HRP930613A2/xx not_active Application Discontinuation
- 1993-09-03 US US08/115,538 patent/US5466686A/en not_active Expired - Fee Related
- 1993-09-08 CZ CZ95545A patent/CZ54595A3/cs unknown
- 1993-09-08 SK SK292-95A patent/SK29295A3/sk unknown
- 1993-09-08 WO PCT/EP1993/002428 patent/WO1994005632A1/de not_active Application Discontinuation
- 1993-09-08 EP EP93919299A patent/EP0659177B1/de not_active Expired - Lifetime
- 1993-09-08 ES ES93919299T patent/ES2142350T3/es not_active Expired - Lifetime
- 1993-09-08 JP JP6506898A patent/JPH08501093A/ja active Pending
- 1993-09-08 PT PT93919299T patent/PT659177E/pt unknown
- 1993-09-08 DE DE59309898T patent/DE59309898D1/de not_active Expired - Fee Related
- 1993-09-08 RU RU95111375A patent/RU2124003C1/ru active
- 1993-09-08 RO RO95-00477A patent/RO115256B1/ro unknown
- 1993-09-08 HU HU9500694A patent/HU217979B/hu not_active IP Right Cessation
- 1993-09-08 AT AT93919299T patent/ATE187441T1/de not_active IP Right Cessation
- 1993-09-08 CN CN93117362A patent/CN1042130C/zh not_active Expired - Fee Related
- 1993-09-08 CA CA002142275A patent/CA2142275A1/en not_active Abandoned
- 1993-09-08 PL PL93307851A patent/PL173895B1/pl unknown
-
1994
- 1994-12-28 BG BG99296A patent/BG62135B1/bg unknown
-
2000
- 2000-02-18 GR GR20000400400T patent/GR3032702T3/el unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2556045A1 (de) * | 1974-12-24 | 1976-07-08 | Lilly Co Eli | Verfahren zur herstellung von 3-methylencephamsulfoxiden |
| EP0095764A2 (en) * | 1982-05-31 | 1983-12-07 | Takeda Chemical Industries, Ltd. | 2-Oxoazetidinone derivatives, their production and use |
| EP0499232A2 (en) * | 1991-02-12 | 1992-08-19 | PLIVA Handels GmbH | 4-Oxo-azetidine-2-sulfonic acids and their salts, processes for the preparation thereof and their use |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0659177B1 (de) | 1999-12-08 |
| BG99296A (bg) | 1995-12-29 |
| RO115256B1 (ro) | 1999-12-30 |
| BG62135B1 (bg) | 1999-03-31 |
| HRP930613A2 (en) | 1998-06-30 |
| HU217979B (hu) | 2000-05-28 |
| PT659177E (pt) | 2000-04-28 |
| PL307851A1 (en) | 1995-06-26 |
| RU95111375A (ru) | 1997-03-20 |
| HUT73528A (en) | 1996-08-28 |
| GR3032702T3 (en) | 2000-06-30 |
| JPH08501093A (ja) | 1996-02-06 |
| WO1994005632A1 (de) | 1994-03-17 |
| CN1099750A (zh) | 1995-03-08 |
| HU9500694D0 (en) | 1995-04-28 |
| DE59309898D1 (de) | 2000-01-13 |
| EP0659177A1 (de) | 1995-06-28 |
| ES2142350T3 (es) | 2000-04-16 |
| CZ54595A3 (en) | 1995-12-13 |
| RU2124003C1 (ru) | 1998-12-27 |
| PL173895B1 (pl) | 1998-05-29 |
| ATE187441T1 (de) | 1999-12-15 |
| CA2142275A1 (en) | 1994-03-17 |
| SK29295A3 (en) | 1995-09-13 |
| US5466686A (en) | 1995-11-14 |
| DE4230053A1 (de) | 1994-03-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1169791C (zh) | 新颖的乙酰胺衍生物和蛋白酶抑制剂 | |
| CN1308326C (zh) | 吲哚满酮衍生物的制备方法 | |
| CN1075718A (zh) | 金属醇盐 | |
| CN1275122A (zh) | 制备噁唑烷酮的方法 | |
| CN1688544A (zh) | 作为蕈毒碱受体拮抗剂的含氟代和磺酰氨基的3,6－二取代的氮杂双环(3.1.0)己烷衍生物 | |
| CN1146204A (zh) | 噁唑类杂环芳香族化合物及其用途 | |
| CN1882541A (zh) | N－[苯基(烷基－2－哌啶基)甲基]苯甲酰胺衍生物,其制备和治疗用途 | |
| CN1080256C (zh) | 新的β－内酰胺类及制备紫杉烷的方法 | |
| CN1175246A (zh) | 用于治疗动脉粥样硬化的取代的氮杂环丁－2－酮 | |
| CN1826335A (zh) | 1,2,4－三唑化合物的制造方法以及其中间体 | |
| CN1197452A (zh) | 用于治疗动脉粥样硬化的氮杂环丁烷酮衍生物 | |
| CN1927830A (zh) | 光学纯亚磺酰胺化合物及其应用 | |
| CN1931838A (zh) | 一种氮杂环丁酮衍生物及其合成方法 | |
| CN1034077C (zh) | 新的吡啶并[2，3-f][1，4]硫代吖庚因的制备方法 | |
| CN1219932A (zh) | 用作选择性凝血酶抑制剂的芳族脒衍生物 | |
| CN100349867C (zh) | 制备r,r(或s,s)构型的格隆铵－立体异构体的方法 | |
| CN1042130C (zh) | 4－氧代氮杂环丁烷－2－磺酰胺及其盐,其制备方法和应用 | |
| CN1043425C (zh) | 亚水杨基氨基过渡金属配合物及其制法 | |
| CN1168713C (zh) | 制备鼻病毒蛋白酶抑制剂的合成路线以及关键的中间体 | |
| CN1852885A (zh) | 腈化合物、羧酸化合物或羧酸酯化合物的制备方法 | |
| CN101054355A (zh) | 光学纯双亚磺酰胺化合物及其应用 | |
| CN1042224C (zh) | 制备2-亚氨基噻唑啉衍生物的方法 | |
| CN1216039A (zh) | 制备紫杉酚的方法 | |
| CN1377269A (zh) | 玻璃体结合蛋白受体拮抗剂 | |
| CN1551871A (zh) | 制备噻唑ppar-配体及其多晶型物的方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |