CN86106583B - 抗菌素的制备方法 - Google Patents
抗菌素的制备方法 Download PDFInfo
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- CN86106583B CN86106583B CN86106583A CN86106583A CN86106583B CN 86106583 B CN86106583 B CN 86106583B CN 86106583 A CN86106583 A CN 86106583A CN 86106583 A CN86106583 A CN 86106583A CN 86106583 B CN86106583 B CN 86106583B
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 239000003242 anti bacterial agent Substances 0.000 title description 2
- 229940088710 antibiotic agent Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 31
- 239000000126 substance Substances 0.000 claims description 30
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000002091 cationic group Chemical group 0.000 claims description 4
- 239000000460 chlorine Chemical group 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 241001597008 Nomeidae Species 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- -1 pivaloyloxymethyl esters Chemical class 0.000 abstract description 25
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- 150000003839 salts Chemical class 0.000 abstract description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
- 239000000047 product Substances 0.000 description 42
- 239000000203 mixture Substances 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 238000001228 spectrum Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000001301 oxygen Substances 0.000 description 16
- 229910052760 oxygen Inorganic materials 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- 239000000376 reactant Substances 0.000 description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 11
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 10
- 208000035126 Facies Diseases 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 239000003292 glue Substances 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- MANJIGKYCYWWBD-UHFFFAOYSA-N 2-chloro-2-oxoacetic acid Chemical compound OC(=O)C(Cl)=O MANJIGKYCYWWBD-UHFFFAOYSA-N 0.000 description 3
- RRKMWVISRMWBAL-UHFFFAOYSA-N 3,4-dihydroxy-5-methoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(O)=C1O RRKMWVISRMWBAL-UHFFFAOYSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 3
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- QCEUHAVJXFDJQC-UHFFFAOYSA-N 2-fluoro-2-oxoacetic acid Chemical compound OC(=O)C(F)=O QCEUHAVJXFDJQC-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- USQOVYLRWBOSQC-HNNXBMFYSA-N CCCCCCNC(=O)Oc1cccc(c1)-c1ccc(cc1F)[C@H](C)C(O)=O Chemical compound CCCCCCNC(=O)Oc1cccc(c1)-c1ccc(cc1F)[C@H](C)C(O)=O USQOVYLRWBOSQC-HNNXBMFYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- SMDGVPQREIZILS-UHFFFAOYSA-N $l^{1}-oxidanylmethylbenzene Chemical compound [O]CC1=CC=CC=C1 SMDGVPQREIZILS-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- CPKISUMKCULUNR-UHFFFAOYSA-N 2-methoxy-2-oxoacetic acid Chemical compound COC(=O)C(O)=O CPKISUMKCULUNR-UHFFFAOYSA-N 0.000 description 1
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 1
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- PSEJBIODJNSJNT-UHFFFAOYSA-N CCCCC([O])=O Chemical compound CCCCC([O])=O PSEJBIODJNSJNT-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- YOZSRQSUXWJLEU-UHFFFAOYSA-N benzyl 2-chloro-2-oxoacetate Chemical compound ClC(=O)C(=O)OCC1=CC=CC=C1 YOZSRQSUXWJLEU-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- QDHCHVWSKUMZDZ-UHFFFAOYSA-N ethyl dihydrogen phosphite Chemical compound CCOP(O)O QDHCHVWSKUMZDZ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 125000002217 penem group Chemical group 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 230000035943 smell Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- 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
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Abstract
3R,4R-4-乙酸基-3-[1R-1-(甲硅烷氧基)乙基]-2-氮杂环丁烷酮转化成抗菌的5R,6S-6(1R-1-羟乙基)-2-(1-氧代-3-硫羟烷基硫代)-2-青霉烯-3-羧酸及其医药上可接受的盐和新戊酰氧甲酯的方法和中间体。
Description
本发明涉及制备式(Ⅰ)所示的5R,6S-6-(1R-1-羟乙基)-2-(1-氧代-3-硫羟烷基硫代)-2-青霉烯-3-羧酸,或其在医药上可接受的阳离子盐或新戊酰氧甲酯的改进的方法及其中间体。尤其是其盐或酯,这些盐或酯为非对映异构体近似1∶1的混合物,混合物中青霉烯2-取代基是(顺式-1-氧代-3-硫羟烷基硫代),即硫羟烷环取代基之间互为顺式关系。式(Ⅰ)化学式为:
在欧洲专利申请130025的说明书中,首次叙述了这些化合物,该申请案进一步公开了用这些化合物作为抗菌剂的方法。
在欧洲专利EP130025中公开的合成方法是非常通用的,很容易做到各种各样类似物的合成。然而,对于个别的化合物,尤其是上述顺式化合物及其新戊酰氧甲酯,极需要一种包括较少化学步骤的直接合成方法。
对上述化学式(Ⅰ)化合物的一种引人注意的前体是式(A)所示的3R,4R-4-乙酸基-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-2-氮杂环丁烷酮,其化学式为:
由6-氨基-青霉烷酸可以有效地制备这种出化合物,例如采用Leanza等人在《四面体》39卷2505~2513页(1983)中提出的方法。在合成方案的第一阶段,Leanza等人提出的氮杂环丁烷酮被转化为新的化合物,其化学式为:
然而,对于随后将这种化合物与酰基氯反应的建议却无实用性,因为酰基氯优先与硫羟烷亚砜基起反应而产生无用产品。但是,意想不到,以酰基氟代替酰基氯,导致在氮原子上的选择酰化作用,而形成先前无法得到的下文所示的化学式(Ⅲb)化合物。因而,给下文所示化学式(Ⅲa)化合物确定一种有用的前体,并且通过进一步转化,提供更有价值的下述化学式(Ⅱ)的中间体。虽然上述二甲基-叔-丁基甲硅烷基羟基保护基是最佳的,当然其它的甲硅烷基羟基保护基也可代用。
因此,本发明的目的在于如下化学式的化合物:
(a) F-C-C-OR3 <math><msup><mi></mi><msub><mi>‖</mi></msup><mi>O</mi></msub></math> <math><msup><mi></mi><msub><mi>‖</mi></msup><mi>O</mi></msub></math>
其中,R3是-CH2-C=CH2或-CH-O-C-C(CH3)3 <math><msup><mi></mi><msub><mi>|</mi></msup><mi>X</mi></msub></math> <math><msup><mi></mi><msub><mi>‖</mi></msup><mi>O</mi></msub></math>
X是氢或氯;
其中,R3含义同上;
R2是氢或一般的甲硅烷基羟基保护基(最好是二甲基-叔-丁基硅烷基)。但条件为,当R3是新戊酰氧甲基时,R2不是氢;
其中,R1是一般的甲硅烷基羟基保护基(最好是二甲基-叔-丁基甲硅烷基),R是氢或-C-C-OR3 <math><msup><mi></mi><msub><mi>‖</mi></msup><mi>O</mi></msub></math> <math><msup><mi></mi><msub><mi>‖</mi></msup><mi>O</mi></msub></math>
其中,R3定义同上。
本发明还包括制备化学式(Ⅲb)化合物的方法
其中,R1和R3含义如上所述。该方法包括下述化学式(Ⅲa)的化合物与化学式(Ⅳ)所示的酰基氟的酰化作用。
F-C-C-OR3 ---(Ⅳ) <math><msup><mi></mi><msub><mi>‖</mi></msup><mi>O</mi></msub></math> <math><msup><mi></mi><msub><mi>‖</mi></msup><mi>O</mi></msub></math>
该作用在0~-80℃时,在有叔胺存在和在反应惰性溶剂中进行。较低的温度例如-20~-70℃为最佳。该方法还包括通过化学式(Ⅱ)化合物把产物(Ⅲb)转化为上述化学式(Ⅰ)化合物的常规方法。
最后,当R3是新戊酰氧甲基时,本发明的目标是,用氟亚磺酸钾为试剂,把相应的酰基氯转化为酰基氟的方法。
“反应惰性溶剂”一词是指一种不会以对产品的产率有不利影响的方式来与试剂、中间体或产物相互作用的溶剂。
本发明也包括上述化学式(Ⅱ)的化合物转化为上述化学式(Ⅰ)的化合物或者它在医药上可接受的阳离子盐的方法,化学式(Ⅱ)中R2是氢,R3不是新戊酰氧甲基。
熟悉本技术领域的人员将知道苄基或对-硝基苄基酯可以代替上述烯丙基或2-氯烯丙基酯,于是,通过一般氢解方法,最终可除去保护基。
在本合成方法的第一阶段,外消旋顺式-或反式-3-(乙酰硫代)硫醇烷1-氧化物在反应惰性溶剂如异丙醇中,于绝对无水条件下通过碱金属醇盐如甲醇钠的作用转化成硫醇盐。转化过程最好在低温(例如-5°~-45℃)下进行,以-20~-30℃为最佳。保持无水和低温的相同条件,硫醇盐(C)与二硫化碳反应,生成下述化学式(D)所示的盐。
该盐接着与具有如上述化学式(A)的氮杂环丁烷酮反应,一般在稍高温度(例如-20~20℃),最好在-5~+5℃下生成上述化学式(Ⅲa)的化合物。每一种由此产生的顺式和反式产品皆由一对近似等量的非对映异构体组成。
然后,化学式(Ⅲa)的化合物与化学式(Ⅳ)的酰基氟在一般所述的条件和以上概述的条件下进行反应,最佳的初始温度为-45~-60℃,最大提高到-15~-25℃。理想的反应惰性溶剂是二氯甲烷,理想的叔胺是N,N-二异丙基乙胺。
本合成的第二阶段是在反应惰性溶剂(例如不含乙醇氯仿)中,由亚磷酸三烷基酯(例如亚磷酸三乙基酯)对化学式(Ⅲb)化合物的作用而形成含有完整青霉烯环系的化学式(Ⅱ)化合物,式中R2是一个甲硅烷基保护基。上述反应对温度要求不严格,但一般在室温以上,例如40~80℃之间,当溶剂是氯仿时,可方便地达到回流温度。
在最后或次末阶段,用标准方法除去甲硅烷基保护基,例如就二甲基-叔-丁基甲硅烷基来说,可通过乙酸和四丁基氟化铵在无水四氢呋喃中的作用,以生成式(Ⅰ)的新戊酰氧甲酯形式的化合物或R2是氢的化学式(Ⅱ)化合物。
最后,当R3是烯丙基或2-氯烯丙基时,酯被水解,生成所需要的化学式(Ⅰ)的青霉烯,其形式为酸或其在医药上可接受的阳离子盐,通常应用无水条件来避免β-内酰胺降解,最佳条件是在有催化量的三苯膦和四(三苯膦)钯(例如,前者大约为0.15摩尔当量,后者大约为0.075摩尔当量)的情况下,在无水反应惰性溶剂中(例如二氯甲烷和(或)乙酸乙酯),采用1~1.1摩尔当量的亲油羧酸的碱金属盐(例如2-乙基己酸钠)。尽管温度要求不严格,但反应仍适宜在室温下进行。
所需的酰基氟(Ⅳ)由相应的酰基氯以上述用于该目的的试剂来制备,或由无水氟化铯制取(通常在室温或接近室温时进行,而初始与试剂化合是在较低温度例如0~-30℃),或是由氟亚磺酸钾制取(FSO2K,通常在较热的温度例如45~85℃时进行)。出乎意料的是当R3是新戊酰氧甲基时,只有后一个试剂和条件会得到满意的酰基氟产率。
关于本发明方法所需的起始原料,3R,4R-4-乙酸基-3-〔1R-1-(甲硅烷氧基)乙基〕-2-氮杂环丁烷酮可根据上面引述的Leanza等人的方法容易得到。按照上面引述的欧洲专利申请的方法,每种外消旋顺式-和反式-3-(乙酰硫代)硫醇烷1-氧化物是可以得到的。根据Afonso等人在《美国化学学会杂志》104卷6138~6139页(1982)提出的方法,烯丙基乙二酸一酰基氯化物是可以得到的。根据下文详述的方法,2-氯烯丙基乙二酸一酰基氯化物可从2-氯烯丙基醇和草酰氯中得到。新戊酰氧甲基乙二酸一酰基氯化物可通过一系列步骤从草酸的苄基半酯和氯甲基新戊酸酯中制得,这也在下文中详述。
下述实施例用作说明本发明,但不能认作对本发明的限制,在本发明范围和精神内对本发明进行多方面的改变是允许的。
实施例1
3S,4R-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-4-〔顺式-1-氧代-3-硫羟烷基硫代(硫代羰基)硫代〕-2-氮杂环丁烷酮
配有机械搅拌器、滴液漏斗和低温温度计的经火焰干燥的三颈瓶,在氮气气氛下,装有外消旋顺式-3-(乙酰基硫代)硫醇烷1-氧化物(4.26克,23.9毫摩尔)和90毫升异丙醇。该反应混合物被冷却到液温-20℃时,甲醇钠(1.18克,21.9毫摩尔)以一次添加。在-20~-25℃搅拌90分钟,然后温热到-10℃。该反应混合物再被冷却到-30℃,并且通过半小时的时间逐滴加入溶于30毫升异丙醇的二硫化碳溶液(7.96克,104毫摩尔),然后在-25~-30℃搅拌40分钟。再通过30分钟的时间逐滴地加进溶于54毫升异丙醇的3R,4R-4-乙酸基-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-2-氮杂环丁烷酮的溶液〔6克,20.9毫摩尔,Leanza等人在《四面体》39卷,2505~2513页(1983)提出〕,该反应混合物在-20℃时搅拌30分钟,接着升温到0℃,并且在0~1℃搅拌90分钟。用150毫升饱和氯化铵溶液使该反应骤冷,然后添加200毫升乙酸乙酯,将该混合物转移到分液漏斗,同时加进150毫升盐水。有机相被分离而水相添加200毫升乙酸乙酯萃取,所合并的乙酸乙酯萃取物用100毫升一份的盐水洗涤两次。有机相被冷却到5℃并用硫酸镁干燥,然后过滤并在真空下浓缩,得到粘性油。该油与50毫升一份的二氯甲烷共沸四次,在高真空下泵送,得到8.32克(90.5%)黄色泡沫体,该泡沫体包括两种标题非对映异构体混合物。
将上述泡沫胶试样与异丙基醚搅拌两小时,借此制得分析试样。将黄色固体过滤并干燥。其熔点为85~89℃(分解)。
分析C16H29O3NS4Si
计算值:C,43.69%;H,6.65%;N,3.19%。
实测值:C,43.41%;H,6.38%;N,3.06%。
红外线(KBr)厘米-11770
1H-核磁共振谱(CDCl3)δ(ppm):0.072(s,3H,CH3Si),0.077(s,3H,CH3Si),0.877(s,9H,叔-丁基),1.21(d,J=6.1Hz,3H,CH3),2.74~3.24(m,6H,3CH2),3.78(m,1H,CHS),4.29(dd,J=6.1、3.7Hz,1H,CH),4.55(m,1H,CHO),5.65(m,1H,CHS),6.65(bs,1H,NH)。
实施例2
3S,4R-N-〔(2-氯烯丙基氧基)草酰〕-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-4〔顺式-1-氧代-3-硫羟烷基硫代(硫代羰基)硫代〕-2-氮杂环丁烷酮
配备有滴液漏斗和低温温度计的经火焰干燥的三颈烧瓶,在氮气气氛下,装有上述实施例的产品(52.2克,118.7毫摩尔)和975毫升无水二氯甲烷(通过中性的氧化铝)。该反应混合物冷却到液温-50~-55℃,通过20分钟时间逐滴地加进2-氯烯丙基乙二酸一酰基氟化物(24.7克,148.4毫摩尔),在-50~-55℃另搅拌10分钟。通过65分钟时间逐滴加进16.1克(124.6毫摩尔)N,N-二异丙基乙胺溶液。在-50~-55℃搅拌75分钟。该反应混合物可温热到-20℃,然后用900毫升水使它缓慢地冷却。有机相被分离,并用另外的900毫升水和900毫升盐水洗涤。用硫酸镁干燥有机相,过滤后真空浓缩,得到65.6克(94%)两种非对映异构体混合物的黄色泡沫胶。
1H-核磁共振谱(CDCl3)δ(ppm):0.33(S,3H,CH3Si),0.095(S,3H,CH3Si),0.86(s,9H,叔-丁基),1.24(d,J=6.4Hz,3H,CH3),2.75~3.77(m,7H,硫醇烷),4.43(m,1H,CH),4.66(m,1H,CHO),4.84(s,2H,CH2),5.47(d,1H,乙烯基CH),5.56(d,1H,乙烯基CH),6.7和6.74(2d,J=3.7Hz,1H,NCHS)。
红外线(KBr)厘米-11820,1762,1708。
实施例3
5R,6S-6-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-2-(顺式-1-氧代-3-硫羟烷基硫代)-2-青霉烯-3-羧酸-2-氯烯丙基酯。
配备有冷凝器和平衡附加漏斗的经火焰干燥的三颈烧瓶,在氮气气氛下,装有上述实施例的产品(15.6克,26.6毫摩尔)和800毫升不含乙醇的氯仿。该反应混合物被加热到和缓的回流,于是通过8小时的时间逐滴加入亚磷酸三乙酯(9.3克,56毫摩尔)的不含乙醇的氯仿(70毫升)溶液。反应混合物在和缓回流中再加热8小时。然后冷却到室温,用真空浓缩。剩余物与冷的异丙醚一起搅拌,过滤及干燥,得到6.23克(43%)两种非对映异构体混合物,该混合物为米色固体,熔点为138~140℃。
分析 C21H32O5NS3ClSi
计算值:C,46.86%;H,5.99%;N,2.60%;S,17.87%;
实测值:C,46.71%;H,5.94%;N,2.46%;S,17.73%;
1H-核磁共振谱(CDCl3)δ(ppm):0.064(s,6H,2CH3Si),0.87(s,9H,叔-丁基),1.24(d,J=6.4Hz,3H,CH3),2.70~4.05(m,8H,CHCO,硫醇烷),4.25(m,1H,CH),4.74(q,J〈`;;AB`〉=14.1Hz,2H,CH2),5.38(d,J=0.5Hz,1H,CHS),5.66(m,2H,乙烯基CH2)。
红外线(KBr)厘米-11784。
实施例4
5R,6S-6-(1R-1-羟乙基)-2-(顺式-1-氧代-3-硫羟烷基硫代-2-青霉烯-3-羧酸-2-氯烯丙基酯
配备有温度计和两个附加漏斗的经火焰干燥的三颈瓶,在氮气气氛下,装有上述实施例的产品(22.7克,42毫摩尔)和65毫升无水四氢呋喃。该反应混合物被冷却到液温5℃,并且通过15分钟时间逐滴加进25.2克(420毫摩尔)冰醋酸,保持其液温5℃。通过1小时的时间,逐滴加入四丁基氟化铵的四氢呋喃(1M,126毫升)的溶液保持液温5℃。该反应混合物可以慢慢地温热至室温,并在室温下搅拌16小时。注入2000毫升冰冻水,用1000毫升(每次)乙酸乙酯萃取三次。合并的有机相萃取物用650毫升(每次)水洗涤三次、650毫升(每次)碳酸氢钠饱和溶液洗涤两次以及用650毫升(每次)盐水洗涤两次,然后用硫酸钠干燥,过滤并真空浓缩,得到14.14克(79%)两种非对映异构体混合物,该混合物为黄色固体。把部分试样加入乙酸乙酯中研磨而制得标准试样,熔点为145~149℃(分解)。
1H-核磁共振谱(二甲基亚砜-d6)δ(ppm):1.17(d,J=6.8Hz,3H,CH3),2.38~4.04(m,9H,CHCO,CHO,硫醇烷),4.78(q,JAB=14.1Hz,2H,CH2),5.25(d,J=4.4Hz1H,0H),5.48(s,1H,CHS),5.76(d,2H,乙烯基CH2)。
红外线(KBr)厘米-11769。
分析C15H18O5NS3Cl
计算值:C,42.49%;H,4.28%;N,3.31%。
实测值:C,42.79%;H,4.39%;N,3.28%。
实施例5
5R,6S-6-(1R-1-羟乙基)-2-(顺式-1-氧代-3-硫羟烷基硫代)-2-青霉烯-3-羧酸钠
在氩气气氛下,于包在铝箔中的经火焰干燥的烧瓶中,加入上述实施例的产品(18.2克,43毫摩尔)的脱气二氯甲烷溶液(400毫升)、三苯膦(1.69克,6.5毫摩尔)、2-乙基己酸钠(在60毫升0.82M乙酸乙酯中,49毫摩尔)和四(三苯膦)钯(3.69克,3.2毫摩尔)。该反应混合物在室温下搅拌70分钟,补加350毫克四(三苯膦)钯,反应混合物在室温下再搅拌25分钟。通过6分钟时间加入脱气乙酸乙酯(275毫升)。该反应混合物在室温下搅拌30分钟,过滤,固体稍为风干,然后用180毫升丙酮调搅30分钟,使其成浆状,再过滤和干燥,得到15.3克(97%)两种非对映异构体混合物,该混合物为黄色固体产品,相当于欧洲专利申请号130025说明书的第20页实施例2的顺式-1-氧代-3-硫羟烷基异构体。
用同样方法,可将下文实施例9的产品转化成相同产率的同样标题产品。
实施例6
5R,6S-6-(1R-1-羟乙基)-2-(顺式-1-氧代-3-硫羟烷基硫代)-2-青霉烯-3-羧酸
将上述实施例的钠盐(1克)溶解在10毫升水中,用3毫升(每次)丁醇萃取三次,再用3毫升(每次)乙酸乙酯萃取两次。水相与750毫克活性炭在0~5℃下搅拌45分钟,然后过滤。滤液用3毫升(每次)丁醇萃取三次,再用3毫升(每次)乙酸乙酯萃取两次。水相与750毫克活性炭在0~5℃下搅拌90分钟,然后进行过滤和冻干,得到696毫克浅褐色固体。该固体溶解在1.2毫升水中,冷却到0~5℃,用1N盐酸酸化成pH2.6,在0~5℃下搅拌45分钟,过滤,用少量水洗涤,再干燥,得到374毫克两种非对映异构体混合物,该混合物为白色固体,熔点178~181℃(分解)。
红外线(KBr)厘米-11778,1745
1H-核磁共振谱(二甲基亚砜-d6)δ(ppm):1.16(d,J=5.6Hz,3H,CH3),2.38~4.00(m,9H,CHCO,CHO,硫醇烷),5.25(bs,1H,OH),5.72(s,1H,CHS)。
分析C12H15O5NS3
计算值:C,41.24%;H,4.33%;N,4.01%。
实测值:C,41.32%;H,4.24%;N,4.82%。
实施例7
3S,4R-N-(烯丙基氧基草酰)-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-4-〔顺式-1-氧代-3-硫羟烷基硫代(硫代羰基)硫代〕-2-氮杂环丁烷酮
除了使反应混合物保持在-50℃3.5小时,以及在冷却之前不温热到-20℃以外,其它采取实施例2的步骤,使实施例1的标题产品(1.00克,0.00227摩尔)与烯丙基乙二酸一酰基氟化物(0.37克,0.00283摩尔)反应,得到1.19克黄色粘性油状的本标题产品。
1H-核磁共振谱(CDCl3)300MHzδ:0.04(s,3H),0.10(s,3H),0.86(s,9H),1.24(d,3H,J=6.3Hz),2.74(m,3H),2.84(m,1H),3.17(m,1H),3.58(m,1H),3.79(dd,1H,J=8.8,14.7Hz),4.40(m,1H),4.79(d,2H,J=5.9Hz),5.32(dd,1H,J=1,10.5Hz),5.40(dd,1H,J=1,17.2Hz),5.94(ddt,1H,J=5.9,10.5,17.2Hz),6.70和6.72(2d,1H,J=3.5Hz)。
实施例8
5R,6S-6-〔1R-1-(二甲基-叔-丁基甲硅烷基氧基)乙基〕-2-(顺式-1-氧代-3-硫羟烷基硫代)-2-青霉烯-3-羧酸烯丙基酯
采用实施例3的步骤,使上述实施例的产品(1.19克,0.00216摩尔)转化成本标题产品,用0.73克戊烷研磨,不用异丙醚研磨。通过硅胶层析,用乙酸乙酯作为洗脱液进一步纯化,得到0.415克本标题产品。薄层层析,比移值为0.3(乙酸乙酯)。
1H-核磁共振谱(CDCl3)300Hzδ:0.08(s,6H),0.88(s,9H),1.25(d,3H,J=6.3MHz),2.6~2.9(m,4H),3.13(m,1H),3.64(m,1H),3.70和3.72(2dd,1H,J=1.5,4.7Hz),3.84和3.97(2dd,1H,J=8.4,14.2Hz),4.24(m,1H),4.70(m,2H),5.24(dd,1H,J=1.3,10.5Hz),5.40(dd,1H,J=1.3,17.1Hz),5.63和5.65(2d,1H,J=1.5Hz),5.93(ddt,1H,J=5.6,10.5,17.1Hz)。
实施例9
5R,6S-6-(1R-1-羟乙基)-2-(顺式-1-氧代-3-硫羟烷基硫代)-2-青霉烯-3-羧酸烯丙基酯
采用实施例4的步骤,使上述实施例的产品(200毫克,0.397毫摩尔)转化成本标题产品。通过硅胶层析,用CH3OH∶乙酸乙酯为1∶19的洗脱液纯化得到1.33毫克本标题产品。
1H-核磁共振谱(CDCl3)300MHz:1.36(d,3H,J=6.2Hz,2.46和2.51(2br d,1H),2.6~2.9(m,4H),3.14(m,1H),3.6~3.8(m,2H),3.81和3.93(2dd,1H,J=8,14Hz,4.23(m,1H),4.66(dd,1H,J=5.6,13Hz),4.77(dd,1H,J=5.6,13Hz),5.25(d,1H,J=10.5Hz),5.41(d,1H,J=17.1Hz),5.67和5.70(2s,1H),5.94(ddt,1H,J=5.6,10.5,17.1)。
红外线(KBr)厘米-13233,1767,1681,1495,1316,1201,1124。
实施例10
3S,4R-N-新戊酰氧甲基氧草酰)-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-4-〔顺式-1-氧代-3-硫羟烷基硫代(硫代羰基)硫代〕-2-氮杂环丁烷酮
将实施例1的产品(4.65克,0.0106摩尔)溶解在21.1毫升无水二氯甲烷中,并冷却到-30℃。加入新戊酰氧甲基草酰氟化物(4.36克,0.0211摩尔),使该混合物冷却到-50℃,通过注射器于5分钟时间加进N,N-二异丙基乙胺(1.63克,2.21毫升,0.0127摩尔)。在此期间,该反应因化学反应放热温度升至-35℃,35分钟后在-35~-50℃,依次用125毫升无水二氯甲烷,185毫升水稀释该混合物。分离二氯甲烷层,用185毫升新水洗涤一次,然后用硫酸钠干燥,移去硫酸钠,得到7.06克本标题产品,虽有酰基氟污染,但对于下一步骤来说纯度是足够的。薄层层析,比移值为0.3(乙酸乙酯)
1H-核磁共振谱(CDCl3,90MHz)δ(ppm):0.04(s,3H),0.10(s,3H),0.88(s,9H),1.21和1.2~1.6(s和m,12H),2.6~3.4(m,5H),3.6~4(m,2H),4.4~4.8(m,2H),5.85(S,2H),7.2(m,1H)。
实施例11
5R,6S-6-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-2-(顺式-1-氧代-3-硫羟烷基硫代)-2-青霉烯-3-羧酸新戊酰氧甲基酯
采用实施例3的步骤,使上述实施例的产品(6.98克粗产品,6.52克合格产品,0.0104摩尔)转化成本标题的粗产品(11.8克)。不用研磨,而将其溶解在480毫升正己烷和90毫升二氯甲烷中,用300毫升(每次)水洗涤四次来进一步提纯,然后用硫酸钠干燥,移去硫酸钠得到仍有亚磷酸三乙酯气味的黄色油(8.71克)。使亚磷酸三乙酯自乙酸乙酯(12毫升,用于溶解)和正己烷(165毫升到浊点,在三小时持续迟滞期间需300多毫升)中结晶,得到2.50克纯净的本标题产品。薄层层析,比移值为0.15(乙酸乙酯)。
1H-核磁共振谱(CDCl3)δ(ppm):0.1(s,6H),0.9(s,9H),1.2(m,12H),2.4~4.5(m,9H),5.7(dd,1H),5.9(q,2H)。
实施例12
5R,6S-6-(1R-1-羟乙基)-2-(顺式-1-氧代-3-硫羟烷基硫代)-2-青霉烯-3-羧酸新戊酰氧甲基酯
采用实施例4的步骤使上述实施例的产品(1.88克,3.25毫摩尔)转化成本标题产品,即先用500毫升乙酸乙酯稀释该反应混合物,然后用150毫升(每次)盐水洗涤三次,用硫酸钠干燥并移去硫酸钠,借此达到初步分离。剩余物用200毫升乙酸乙酯再溶解,用150毫升(每次)水洗涤两次,每次都添加足够的盐水以破坏乳状液,所合并的含水萃取液则用乙酸乙酯回洗,并且与原来的有机相合并。用硫酸钠干燥此有机相混合液,再移去硫酸钠,得到泡沫胶,泡沫胶从乙酸乙酯和乙醚中结晶,得到1.34克纯净的本标题产品。
红外线(KBr)2.96,5.60,5.69,5.91和6.75微米。
1H-核磁共振谱(CDCl3,250MHz)δ(ppm):1.23(s,9H),1.35(d,3H),2.5(bc,1H),2.6~2.9(C,4H),3.16(m,1H),3.62~4.0(C,3H),4.25(m,1H),5.7和5.72(2d,1H),5.88(q,2H)。
制备方法1
2-氯烯丙基乙二酸一酰基氟化物
〔(2-氯烯丙基氧基)草酰氟〕
CH2=CClCH2O(CO)COF
在干燥氮气下,经火焰干燥的玻璃装置中,把氟化铯(167克,1.1摩尔)装入1升单颈瓶中,并且置于高真空条件下,用火焰慢慢地加热,直至固体变得能自由流动,然后冷却到室温。加入从CaH2(183毫升)中蒸馏出的乙腈,该混合物被冷却到液温-20℃。并通过30分钟时间逐滴加进2-氯烯丙基乙二酸一酰基氯化物(183克,1.0摩尔),缓慢地温热到室温,在室温下搅拌16小时,副产物氟化铯,通过过滤用乙腈洗涤来回收。滤液和洗涤液合并移去,残余物在低温下蒸馏,得到129克(77%)所要求的产品,沸点62~64℃/22毫米。
红外线(KBr)厘米-11770,1870
1H-核磁共振谱(CDCl3)δ(ppm):4.80(s,2H),5.4~5.6(m,2H)。
制备方法2
烯丙基乙二酸一酰基氟化物
〔烯丙基草酰氟〕
CH2=CHCH2O(CO)COF
通过上述制备方法,将烯丙基乙二酸一酰基氯化物(252.5克,1.70摩尔)和氟化铯(284克,1.87摩尔)转化成二次蒸馏的本标题产品,沸点48~50℃/35毫米;124~126℃(大气压)。
1H-核磁共振谱(CDCl3)250MHz,δ:4.76(d,2H,J=6Hz),5.28(dd,1H,J=1,7Hz),5.37(dd,1H,J=1,17Hz),5.90(ddt,1H,J=6,11,17Hz)。
13C-核磁共振(CDCl3)63MHz,δ:68.5(t),120.4(t),129.7(d),146.3(d,JC-F=375Hz),153.0(d,JC-C-F=87Hz)。
红外线(纯)1860(C=0),1770(C=0),1120厘米-1。
制备方法3
2-氯烯丙基乙二酸一酰基氯化物
〔(2-氯烯丙基氧基)草酰氯〕
在氮气气氛下将草酰氯(130毫升,1.49摩尔)放入干燥的三颈瓶中,并冷却到0℃,边搅拌边逐滴加进2-氯烯丙基醇(138克,1.49摩尔)把温度保持在0~2℃,以此方法控制HCl的剧烈逸出。然后才可温热至室温且保持16小时,并蒸馏,得到214克本标题产品,沸点82~84℃/23毫米。
制备方法4
苄基乙二酸一酰基氯化物
〔(苄基氧基)草酰氯〕
在氮气气氛中,将草酰氯(262毫升)溶于1升无水醚,并加热至回流,在该温度下,通过70分钟时间添加207毫升苄醇,待回流16小时后将醚除去,残余物经减压蒸馏,得到372克(94%)本标题产品,沸点85℃/0.7毫米。
制备方法5
草酸,半苄基酯
将上例制备的标题产品480克,0.91摩尔)的乙醚(800毫升)溶液,置于丙酮干冰浴中冷却。当该混合物温热至0℃时,将氢氧化铵水溶液(2M,906毫升,0.91摩尔)分批加入,然后该混合物温热至室温,搅拌1小时,同时用95毫升2M氢氧化铵调节pH值至8.5。分离水相,用400毫升(每次)乙醚萃取两次,用500毫升新鲜的乙醚使其分层,冷却至10℃,并且用2M HCl把pH值调节到1.5。有机相和水相被分离,水相用400毫升(每次)乙醚萃取两次,把三个酸性有机相加以合并,用500毫升盐水洗涤,再用硫酸钠干燥,移去硫酸钠,得到163克白色固体的标题产品。
1H-核磁共振谱(CDCl3)δ(ppm):5.2(s,1H),6.95(s,2H),7.3(s,5H)。
制备方法6
草酸苄基新戊酰氧甲酯
将上例制备的产品(163克,0.91摩尔)溶解于1升氯仿,用碳酸氢钠(76.2克,0.91摩尔)小心地中和(起泡沫)。另外,将1.5升硫酸氢四丁铵(308克,0.91摩尔)的水(1.5升)溶液与相同量的碳酸氢钠小心地中和。将前一个浆液缓慢地加到后一个溶液中,将混合物剧烈搅拌20分钟,水相被分离,用500毫升新鲜的氯仿洗涤。将有机相合并,用硫酸钠干燥,除去硫酸钠,得到478克草酸四丁铵苄基酯。将草酸四丁铵苄基酯溶解在400毫升丙酮中。加进新戊酸氯甲基酯(118毫升,0.82摩尔),混合物在氮气气氛中,于室温下搅拌混合物16小时。蒸出丙酮,将剩余物溶解在1升乙酸乙酯中,用500毫升(每次)水洗涤四次,用500毫升盐水洗涤一次,用硫酸钠干燥,除去硫酸钠,得到201克油状的本标题产品。薄层层析,比移值为0.60(乙酸乙酯与正己烷之比为2∶3)。
1H-核磁共振谱(CDCl3,90MHz)δ(ppm):1.21(s,9H),5.2(s,2H),5.8(s,2H),7.3(s,5H)。
制备方法7
草酸半新戊酰氧甲基酯
将上例制备的标题产品(27.3克,0.093摩尔)和2.8克10%Pd/C混合在150毫升乙酸乙酯中,并于4个大气压及室温下,置于帕尔(Paar)氢化装置中氢化1.5小时。通过硅藻土的过滤,回收催化剂。除去滤液,得到19.3克油状的标题产品。
1H-核磁共振谱(CDCl3,90MHz)δ(ppm):1.21(s,9H),5.96(s,2H),10.31(s,1H)。
制备方法8
新戊酰氧甲基乙二酸一酰基氯化物
将上例制备的标题产品(19.2克,0.094摩尔)溶解于20毫升苯,并通过20分钟时间。分批加入到草酰氯(47.7克,33毫升,0.376摩尔)的苯(100毫升)溶液中。30分钟后,除去苯并蒸馏残余物(19.2克),得到16.4克本标题产品。沸点83℃/0.4毫米。
制备方法9
新戊酰氧甲基乙二酸一酰基氟化物
〔(新戊酰氧甲基草酰氟化物〕
(CH3)3C(CO)OCH2O(CO)COF
将氟亚磺酸钾(80%KSO2F,2.40克,含KSO2F为1.92克,0.016摩尔)加到草酰氯(3.50克,0.016摩尔),该混合物在油浴中逐渐加热到60℃,在此温度时,大量的气体开始逸出,移去油浴。一旦反应变弱,油浴就复位,使混合物加热至80℃,保持15分钟后冷却到60℃,在60℃时从油浴中蒸馏出1.19克本标题产品,沸点为52~54℃/0.4毫米。在-50℃时凝固,室温时熔化。
13C-核磁共振谱:在89Hz和252.6Hz草酸羰基系统,测得其值为176.6,152.6和151.5,148.1和140.2,81.7,38.8和26.6。
Claims (21)
1、一种制备式(Ⅰ)或式(Ⅱb)化合物及其衍生物的方法,
---(Ⅱb) 〔其中,R3是-CH2-C =CH2或-CH2-O-C-C(CH3)3,X是氢或氯〕, <math><msup><mi></mi><msub><mi>|</mi></msup><mi>X</mi></msub></math> <math><msup><mi></mi><msub><mi>‖</mi></msup><mi>O</mi></msub></math> 该方法包括以下步骤:
a)在叔胺存在下,于0~-80℃之间,在反应惰性溶剂中,以化学式为F-C-C-O-R3的酰基氟〔其中R3的定义与上述相同〕酰化式( <math><msup><mi></mi><msub><mi>‖</mi></msup><mi>O</mi></msub></math> <math><msup><mi></mi><msub><mi>‖</mi></msup><mi>O</mi></msub></math> Ⅲa)化合物而产生式(Ⅲb)化合物,
---(Ⅲb)
〔式(Ⅲa)和式(Ⅲb)中,R1是一个常用的甲硅烷基羟基保护基,R3和X的定义与上述相同〕。
(b)环化式(Ⅲb)化合物,产生式(Ⅱa)化合物
---(Ⅱa)
〔其中,R1和R3的定义与上述相同〕
(c)水解式(Ⅱa)化合物中甲硅烷基醚基团,产生式(Ⅱb)化合物,
(d)当R3是CH2-C=CH时,解封式(Ⅱb)化合物中酯官能团,产 <math><msup><mi></mi><msub><mi>|</mi></msup><mi>X</mi></msub></math> 生式(Ⅰ)化合物,或其在医学上可接受的阳离子盐。
2、根据权利要求1的方法,其中连接在硫羟烷环上的官能团具有顺式关系的立体化学结构。
3、根据权利要求2的方法,其中R1是
4、根据权利要求3的方法,其中R3是
-CH2-CH=CH2 <math><msup><mi></mi><msub><mi>|</mi></msup><mi>Cl</mi></msub></math>
5、根据权利要求3的方法,其中R3是
-CH2-CH=CH2
6、根据权利要求3的方法,其中R3是
-CH2-O-C-C(CH3)3 <math><msup><mi></mi><msub><mi>‖</mi></msup><mi>O</mi></msub></math>
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US78827385A | 1985-10-17 | 1985-10-17 | |
US788,273 | 1985-10-17 | ||
US87795786A | 1986-06-24 | 1986-06-24 | |
US877,831 | 1986-06-24 | ||
US06/877,831 US4739047A (en) | 1985-10-17 | 1986-06-24 | Intermediates for 2-(1-oxo-3-thiolanyl)-2-penem antibiotics |
US877,957 | 1986-06-24 |
Publications (2)
Publication Number | Publication Date |
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CN86106583A CN86106583A (zh) | 1987-04-22 |
CN86106583B true CN86106583B (zh) | 1988-07-06 |
Family
ID=27419851
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN86106583A Expired CN86106583B (zh) | 1985-10-17 | 1986-10-16 | 抗菌素的制备方法 |
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EP (1) | EP0223397B1 (zh) |
KR (1) | KR890004559B1 (zh) |
CN (1) | CN86106583B (zh) |
AT (1) | ATE66923T1 (zh) |
DE (1) | DE3681255D1 (zh) |
DK (1) | DK495286A (zh) |
EG (1) | EG18143A (zh) |
ES (1) | ES2029794T3 (zh) |
FI (1) | FI83654C (zh) |
GR (1) | GR3002766T3 (zh) |
HU (1) | HU198066B (zh) |
IE (1) | IE59260B1 (zh) |
IL (1) | IL80295A0 (zh) |
NO (1) | NO165839C (zh) |
NZ (1) | NZ217944A (zh) |
PL (1) | PL149240B1 (zh) |
PT (1) | PT83560B (zh) |
YU (1) | YU43956B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5013729A (en) * | 1987-05-11 | 1991-05-07 | Pfizer Inc. | Diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acids |
HUT63167A (en) * | 1989-03-28 | 1993-07-28 | Pfizer | Process for producing antibacterial 2-carbapenem derivatives and pharmaceutical compositions comprising same as active ingredient |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US4347183A (en) * | 1981-02-02 | 1982-08-31 | Schering Corporation | Process for the synthesis of penems and carbapenems |
DE3464610D1 (de) * | 1983-06-21 | 1987-08-13 | Pfizer | 2-alkylthiopenem derivatives |
-
1986
- 1986-10-10 EP EP86307840A patent/EP0223397B1/en not_active Expired - Lifetime
- 1986-10-10 AT AT86307840T patent/ATE66923T1/de not_active IP Right Cessation
- 1986-10-10 DE DE8686307840T patent/DE3681255D1/de not_active Expired - Fee Related
- 1986-10-10 ES ES198686307840T patent/ES2029794T3/es not_active Expired - Lifetime
- 1986-10-14 IL IL80295A patent/IL80295A0/xx not_active IP Right Cessation
- 1986-10-15 NZ NZ217944A patent/NZ217944A/xx unknown
- 1986-10-16 EG EG653/86A patent/EG18143A/xx active
- 1986-10-16 PL PL1986261891A patent/PL149240B1/pl unknown
- 1986-10-16 HU HU864320D patent/HU198066B/hu not_active IP Right Cessation
- 1986-10-16 FI FI864182A patent/FI83654C/fi not_active IP Right Cessation
- 1986-10-16 KR KR1019860008669A patent/KR890004559B1/ko not_active IP Right Cessation
- 1986-10-16 DK DK495286A patent/DK495286A/da not_active Application Discontinuation
- 1986-10-16 YU YU1762/86A patent/YU43956B/xx unknown
- 1986-10-16 IE IE273986A patent/IE59260B1/en not_active IP Right Cessation
- 1986-10-16 CN CN86106583A patent/CN86106583B/zh not_active Expired
- 1986-10-16 PT PT83560A patent/PT83560B/pt not_active IP Right Cessation
- 1986-10-16 NO NO864125A patent/NO165839C/no unknown
-
1991
- 1991-09-20 GR GR91401378T patent/GR3002766T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
FI83654B (fi) | 1991-04-30 |
YU43956B (en) | 1989-12-31 |
DE3681255D1 (de) | 1991-10-10 |
KR870004039A (ko) | 1987-05-07 |
FI864182A (fi) | 1987-04-18 |
NZ217944A (en) | 1989-06-28 |
NO864125L (no) | 1987-04-21 |
EP0223397A2 (en) | 1987-05-27 |
IL80295A0 (en) | 1987-01-30 |
FI864182A0 (fi) | 1986-10-16 |
PT83560B (pt) | 1989-05-31 |
EP0223397B1 (en) | 1991-09-04 |
EG18143A (en) | 1992-08-30 |
KR890004559B1 (ko) | 1989-11-15 |
ES2029794T3 (es) | 1992-10-01 |
PL261891A1 (en) | 1988-08-04 |
PL149240B1 (en) | 1990-01-31 |
CN86106583A (zh) | 1987-04-22 |
NO165839B (no) | 1991-01-07 |
HUT45065A (en) | 1988-05-30 |
YU176286A (en) | 1988-02-29 |
IE862739L (en) | 1987-04-17 |
PT83560A (en) | 1986-11-01 |
DK495286D0 (da) | 1986-10-16 |
HU198066B (en) | 1989-07-28 |
EP0223397A3 (en) | 1988-12-14 |
DK495286A (da) | 1987-04-18 |
FI83654C (fi) | 1991-08-12 |
IE59260B1 (en) | 1994-01-26 |
NO165839C (no) | 1991-04-17 |
ATE66923T1 (de) | 1991-09-15 |
NO864125D0 (no) | 1986-10-16 |
GR3002766T3 (en) | 1993-01-25 |
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