CN86102077A - 碳化青霉烯中间体的制备方法 - Google Patents
碳化青霉烯中间体的制备方法 Download PDFInfo
- Publication number
- CN86102077A CN86102077A CN198686102077A CN86102077A CN86102077A CN 86102077 A CN86102077 A CN 86102077A CN 198686102077 A CN198686102077 A CN 198686102077A CN 86102077 A CN86102077 A CN 86102077A CN 86102077 A CN86102077 A CN 86102077A
- Authority
- CN
- China
- Prior art keywords
- nitrobenzyl
- ester
- alkyl
- methyl
- hydrogen
- 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.)
- Pending
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000000543 intermediate Substances 0.000 title description 26
- 238000003763 carbonization Methods 0.000 title description 2
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 58
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 12
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 11
- 101150065749 Churc1 gene Proteins 0.000 claims description 11
- 102100038239 Protein Churchill Human genes 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 7
- 125000004185 ester group Chemical group 0.000 claims description 5
- BABPEPRNSRIYFA-UHFFFAOYSA-N silyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)O[SiH3] BABPEPRNSRIYFA-UHFFFAOYSA-N 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 51
- -1 allyl ester Chemical group 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 38
- 150000002148 esters Chemical class 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 29
- 239000012954 diazonium Substances 0.000 description 26
- 239000000243 solution Substances 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 150000002085 enols Chemical group 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 15
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 13
- 229920002554 vinyl polymer Polymers 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 9
- 229930188189 sulfomycin Natural products 0.000 description 8
- 108010051634 sulfomycin Proteins 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 7
- 229910001873 dinitrogen Inorganic materials 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 6
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000007429 general method Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 4
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- AXLMPTNTPOWPLT-UHFFFAOYSA-N prop-2-enyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OCC=C AXLMPTNTPOWPLT-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 4
- 235000005074 zinc chloride Nutrition 0.000 description 4
- 239000011592 zinc chloride Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 3
- HOPKHJSQWOIIQO-UHFFFAOYSA-N C[SiH2]C.[O] Chemical compound C[SiH2]C.[O] HOPKHJSQWOIIQO-UHFFFAOYSA-N 0.000 description 3
- 229910004298 SiO 2 Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000007171 acid catalysis Methods 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical class OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 238000006884 silylation reaction Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 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 2
- 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 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- RWRIWBAIICGTTQ-UHFFFAOYSA-N difluoromethane Chemical compound FCF RWRIWBAIICGTTQ-UHFFFAOYSA-N 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000011968 lewis acid catalyst Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 229940070710 valerate Drugs 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 2
- KQPGVCMZXFBYMM-UHFFFAOYSA-N (4-nitrophenyl)methyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 KQPGVCMZXFBYMM-UHFFFAOYSA-N 0.000 description 1
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 1
- ZLTWIJREHQCJJL-UHFFFAOYSA-N 1-trimethylsilylethanol Chemical compound CC(O)[Si](C)(C)C ZLTWIJREHQCJJL-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 240000002319 Citrus sinensis Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000190932 Rhodopseudomonas Species 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 241001147855 Streptomyces cattleya Species 0.000 description 1
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- LGDAGYXJBDILKZ-UHFFFAOYSA-N [2-methyl-1,1-dioxo-3-(pyridin-2-ylcarbamoyl)-1$l^{6},2-benzothiazin-4-yl] 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 LGDAGYXJBDILKZ-UHFFFAOYSA-N 0.000 description 1
- RAUONEIRZDXULB-UHFFFAOYSA-N [3-(1-hydroxyethyl)-4-oxoazetidin-2-yl] acetate Chemical compound CC(O)C1C(OC(C)=O)NC1=O RAUONEIRZDXULB-UHFFFAOYSA-N 0.000 description 1
- GARJITDFQFOYKD-UHFFFAOYSA-N [N-]=[N+]=[N-].[Li+].[Si+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] Chemical class [N-]=[N+]=[N-].[Li+].[Si+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] GARJITDFQFOYKD-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- DPFCZRAGEMLFTN-UHFFFAOYSA-N dimethylsilyl trifluoromethanesulfonate Chemical compound C[SiH](C)OS(=O)(=O)C(F)(F)F DPFCZRAGEMLFTN-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- DLLJVQNYBYOKGS-UHFFFAOYSA-N ethoxyethane;pentane Chemical compound CCCCC.CCOCC DLLJVQNYBYOKGS-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- RBBOWEDMXHTEPA-UHFFFAOYSA-N hexane;toluene Chemical compound CCCCCC.CC1=CC=CC=C1 RBBOWEDMXHTEPA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
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Abstract
本文叙述了制备具有下式的碳代青霉烯类关键中间体的新方法,
式中R5和R6分别独立地表示氢或甲基,R1表示普通的羧基保护基。
Description
相关申请:本申请是我们于1983年3月7日提交的共同未决申请第472,443号的继续部分申请。
本发明是关于制备用于合成硫霉素(thienamycin)和其它碳代青霉烯类(carbapenen)抗菌素关键中间体的新方法。
具有抗菌作用的下式硫霉素原来是通过链霉菌属(streptomyces cattleya)发酵而制得,如美国专利3,950,357所述。
硫霉素是极有效的广谱抗菌素,它对于各种假单胞菌属,对于具有众所周知的抗β-内酰胺抗菌素的有机体呈现出显著的活性。
因为硫霉素具有优异的生物活性,所以人们制备了大量硫霉素衍生物,尽管人们在合成这类衍生物时,一直努力合成在碳代青霉烯环系统的6位上带有除羟乙基以外的各种取代基,但是羟乙基仍被认为是对最佳活性来说最可取的6位取代基。
已经制备的其它衍生物中,碳代青霉烯核在1位上进行了单或双取代,较好是用甲基取代(例如参见欧洲专利申请54,917)。
由于通过发酵制备硫霉素和其衍生物的方法不能令人满意,因此已有文献报道了几种全合成的方法,(例如参见美国专利4,287,123;4,269,772;4,282,148;4,273,709;4,290,947;和欧洲专利申请7973和54,917)。尽管各种合成方法采用不同的原料,但都经过具有下式共同的重氮中间体:
其中R5和R6分别独立地代表氢或甲基,R1表示普通的羧基保护基。中间体Ⅰ最好的羧基保护基之一是对一硝基苄基,该对一硝基苄基在最终生成碳代青霉烯之后通过催化加氢可以容易地去除。另一最好的保护基是烯丙基酯,该烯丙基酯用含有钯化合物和氧化三苯膦混合物的催化剂,在对质子有惰性的溶剂(如四氢呋喃,乙醚或二氯甲烷)中可以容易地被除去。
最近进行的尝试是由容易获得的6-APA合成中间体Ⅰ(然后再合成硫霉素和其它碳代青霉烯衍生物)。例如Karady等人在《美国化学学会杂志》(J.Am.Chem.Soc.)103(22)第6765-6767页(1981年)公开了下述方法:
通过用2-重氮基乙酰乙酸苄酯的烯醇式甲硅烷基醚
与具有下式的邻位被保护的氮杂环丁酮进行取代反应,
其中P是叔丁基二甲基甲硅烷基。
《四面体简讯》(Tetrahedron lett.)23(22)第2293-2296页(1982年)上揭示由4-乙酰氧基-3-(1-羟乙基)-2-氮杂环丁酮和具有下式相应的甲硅烷基烯醇式醚,
通过路易斯酸催化烷基化,可以制备下式的重氮中间体:
Yoshida等在《化学药品公报》(Chem.Pharm.Bull)29(10)第2899-2909页(1981年)中报道了将6-APA转变成下式邻位被保护的氮杂环丁酮的另一合成方法:
由上述《四面体简讯》参考资料揭示的方法可将该酮转变成具有式Ⅰ的重氮中间体。
式Ⅰ的重氮中间体是较好的碳代青霉烯中间体,这就需要有一种方法将容易得到的具有通式Ⅱ的氮杂环丁酮化合物转变成相应的具有式Ⅰ的酯中间体,
其中L是普通的离去基团,如卤素或乙酰氧基,P是普通的羟基保护基,如三有机甲硅烷基。
文献〔例如参见,《四面体简讯》23(22):第2293-2296(1982年)以及《四面体简讯》23(4)第379-382,(1982年)〕中已经揭示,如同它们的甲硅烷基烯醇式醚一样,酮也可用路易斯酸催化烷基化,因此可以设想通过式Ⅱ合适的氮杂环丁酮化合物和具有式Ⅲ的重氮乙酰乙酸酯的烯醇式甲硅烷基醚,用路易斯酸催化烷基化。可以制备所需的酯中间体Ⅰ或其羟基被保护的衍生物。
其中R5和R6是分别独立的氢和甲基,R1是普通的羧基保护基,R1,R2和R3是分别独立的C1~C4烷基或者
不幸的是,本发明人发现当需要对-硝基苄基保护基时,或使用叔-丁基二甲基甲硅烷基羟基保护基时,已知的制备式Ⅲ化合物的方法不能实现。因此先有技术中制备重氮基乙酰乙酸酯的烯醇式甲硅烷基醚采用了将下式的重氮乙酰乙酸酯进行甲硅烷基化,
其中R1是具有下式的烯醇式甲硅烷基醚酯的羧基保护基,
该甲硅烷基化是在强碱存在下(例如三甲基氯硅烷和锂碱,如六甲基二硅叠氮化锂)应用三甲基甲硅烷基卤化物,即甲硅烷基化试剂进行的。当这种先有技术方法采用对-硝基苄基酯时,
由于具有高度活性的亚甲基的存在,所以形成烯醇式酯(enolate)而需要的强碱与对-硝基苄酯是不能共存的。但是应用较弱的有机碱,如三烷基胺和三有机甲硅烷基卤化物的甲硅烷基化试剂却不能得到所需要的烯醇式甲硅烷基醚。此外,先有技术中的方法一般能够制备出以下类型的三甲基四硅烷基烯醇式醚:
其中R1是普通的酯保护基,但不是高活性的酯(如对-硝基苄酯),可是这种方法制备相应的叔-丁基二甲基甲硅烷基烯醇式醚却是不成功的。按以下所述该醚是特别好的碳代青霉烯中间体。
本发明的目的是提供一种通用的甲硅烷基化新方法,该方法可用来制备具有下式的甲硅烷基烯醇式醚:
其中R5和R6是分别独立的氢或甲基,R1是普通的羧基保护基,R1、R2和R3分别独立的C1-C4烷基,或者
或者表示
式ⅢA由下式中间体制备
其中R5,R6和R1的定义同上。
制备出中间体Ⅲ之后,将中间体ⅢA与合适的邻位被保护的氮杂环丁酮反应,
(其中R和L的定义同上),如果需要的话再除去羟基保护基,则可得到关键的碳代青霉烯中间体Ⅰ或其羟基被保护的衍生物。
本发明基于下述意外的发现,即其有下式的重氮基乙酰乙酸对-硝基苄基酯。
(其中R5和R6是分别独立的氢或甲基)能够成功地转变成相应的具有下式的烯醇式甲硅烷基醚中间体
其中R5和R6的定义同上,R1,R2和R3表示分别独立的C1-C4烷基,或者
该转变是在惰性有机溶剂中,在有机碱的存在下将式Ⅳ′化合物与下式的三有机甲硅烷基三氟甲基磺酸酯甲硅烷基化试剂反应而实现。
其中R1,R2和R3的定义同上。使用甲硅烷基三氟甲基磺酸酯甲硅烷基化试剂代替先有技术中的甲硅烷基氯化物,将允许采用有机碱(如三烷基胺,例如三〔C1-C4〕烷基胺)代替先有技术中的强碱,因此能够成功地以高产率制得所需的甲硅烷基烯醇式醚中间体Ⅲ′,而无需顾虑对-硝基苄基中高活性亚甲基的存在。
中间体Ⅳ′和三有机甲硅烷基三氟甲基磺酸酯硅烷基化试剂的反应是在惰性有机溶剂(如二氟甲烷,四氢呋喃,四氟化碳,二噁烷,二甲氧基乙烷,乙醚或氯仿)中进行,温度约为-40℃至30℃。最适宜的反应温度是在0~5℃之间。
三有机甲硅烷基三氟甲基磺酸酯可以是任何三烷基(C1-C4烷基)甲硅烷基三氟甲基磺酸酯,例如三甲基甲硅烷基三氟甲基磺酸酯,三异丙基甲硅烷基三氟甲基磺酸酯,三乙基甲硅烷基三氟甲基磺酸酯,或叔-丁基二甲基甲硅烷基三氟甲基磺酸酯;也可以是叔-丁基二苯基甲硅烷基三氟甲基磺酸酯或2,4,6-三-(叔丁基苯氧基)二甲基-甲硅烷基三氟甲基磺酸酯。最好的甲硅烷基化试剂是叔-丁基二甲基甲硅烷基三氟甲基磺酸酯。
适宜与三有机甲硅烷基三氟甲基磺酸酯甲硅烷基化试剂一起使用的有机胺碱是二异丙基乙胺,DBU(1,8-二氮杂二环〔5、4、0〕十一碳-7-烯),DBN(1,5-二氮杂二环〔4、3、0〕壬-5-烯),尤其是三(C1-C4)烷基胺(如三乙胺、三甲胺、三丁胺、三丙胺)。
有机碱,三有机甲硅烷基三氟甲基磺酸酯和中间体Ⅳ′一般约以等克分子反应,但应用的碱稍微过量,最好的摩尔比约是,中间体Ⅳ′:三有机甲硅烷基三氟甲基磺酸酯:碱约为1∶1.2∶1.4。
最先制备的式Ⅲ′化合物是三甲基甲硅烷基烯醇式醚,尽管由上述方法很容易制备,且产率高,但是这些中间体不太稳定,与水接触或仅在大气压下就会水解成α-重氮基乙酰乙酸对-硝基苄酯,以而造成处理上的困难。为了解决这个问题,采用了叔-丁基二甲基甲硅烷基三氟甲基磺酸酯代替三甲基甲硅烷基三氟甲基磺酸酯制得相应的叔-丁基二甲基甲硅烷基烯醇式醚。与三甲基甲硅烷基烯醇式醚相比,该叔-丁基二甲基用硅烷基烯醇式醚对中性水稳定的多,因此可带水处理。例如已经将对-硝基苄基2-重氮基-3-(叔-丁基二甲基甲硅烷氧基)-3-丁烯酸酯化合物放在带盖的瓶中,于冰箱(0~5℃)里贮存达一年多,没有重氮基乙酰乙酸酯的水解发生。
经发现,上述制备对-硝基苄基α-重氮基乙酰乙酸酯的甲硅烷烯醇式醚的方法,对多种α-重氮基乙酰乙酸酯的制备都是通用的。因此本发明在最广泛的范围内提出了具有下列的烯醇式甲硅烷基醚中间体:
其中R5和R6是分别独立的氢或甲基,R1,R2和R3是分别独立的C1-C4烷基,或者
R1表示羧酸普通的酯保护基,该中间体是由ⅣA化合物与式Ⅴ的三有机甲硅烷基三氟甲基磺酸酯甲硅烷基化试剂在惰性有机溶剂和有机碱的存在下制备。
其中R5,R6,R1,R1,R2和R3的定义同上。反应条件如以上制备式Ⅲ′化合物所述。
本发明一个较好的实施方案包括下式的新化合物以及它们的制备方法,
其中R5和R6是分别独立的氢或甲基,R7是选自下列基团的酯基:C1-C4烷基,对-硝基苄基,
-CH2CH=CH2,-CH2CH=CHC6H5,-CH2CH=CHCO2CH3,
R1,R2和R3是分别独立的C1-C4烷基,或者
R7不可以是烯丙基或C1-C4烷基。
本发明另一个较好的实施方案包括下式的化合物:
其中R5和R6分别独立地表示氢或甲基,R1,R2和R3分别独立地表示C1-C4烷基,或者
另一个较好的实施方案包括下式的化合物
其中R5和R6分别独立地表示氢或甲基,R7是选自下列基团的酯类:C1-C4烷基,对-硝基苄基,
在上述较好的方案中,R5和R6最好都是氢,或者其中之一是氢,另一个是甲基。
制备出式Ⅲ的中间体之后,进一步根据本发明,可以将其用来制备已知的重氮中间体:
其中R4是氢或普通的羟基保护基,R5,R6和R7的定义同上。
式Ⅲ中间体是在惰性有机溶剂和路易斯酸催化剂的存在下与合适的下式邻位被保护的氮杂环丁酮反应。
其中L是普通的离去基团,R4′是普通的羟基保护基,如果需要的话,则除去羟基保护基可得到相应的羟乙基中间体。合适的惰性有机溶剂的例子有:二氯甲烷,氯仿,四氯化碳,二噁烷,乙醚,四氢呋喃或二甲氧基乙烷。合适的路易斯酸催化剂包括氯化锌,碘化锌,溴化锌,四氯化钛,溴化镁,三氟化硼,氯化铝,氯化锡,三甲基三氟甲基磺酸酯(TMF.OTf),和氯化铁,较好的溶剂是二氯甲烷,较好的催化剂是氯化锌。
式ⅡA的氮杂环丁酮化合物是已知的,可由已知方法制备。该化合物的羟烷基由普通的羟基保护基保护。所采用的具体保护基不是关键的,可以从先有技术中许多这类基团中选择,但是最好使用三有机甲硅烷基保护基,例如三甲基甲硅烷基或叔-丁基二甲基甲硅烷基,因为这些基团用HCl甲醇溶液或氟化合物离子(例如四-正丁基氟化铵/四氯呋喃)处理很容易除去。其它合适的羟基保护基的例子包括可通过催化加氢除去的对硝基-苄氧基羰基,可通过Pd(Pφ(Pφ3)4催化反应除去的烯丙氧基羰基,以及可用Zn-醋酸甲醇溶液处理除去的2-三卤乙氧基羰基(-CO2CH2CX3,其中X=Cl或Br)。离去基团L可以是任何普通的离去基团,如卤素(如氯)或酰氧基(例如乙酰氧基,丙酰氧基或叔-丁酰氧基,最好是乙酰氧基,一般情况下,最好加过量的式Ⅲ甲硅烷基烯醇式醚到式Ⅱ的氮杂环丁酮中。
然后进行烷基化反应,生成羟基被保护的重氮中间体,再由已知方法除去保护基,得到所需的中间体ⅠA。如上述,三有机甲硅烷基保护基是特别好的,因为它们容易被除去而又不破坏分子的其余部分。
重氮中间体ⅠA可由已知方法转变成具有有效抗菌活性的硫霉素和各种其它碳代青霉烯衍生物。
以下实施例是详细叙述本发明,并不限定本发明的范围。熔点由Gallenkamp熔点仪测定,未经校正,红外光谱是根据Perkin-Elmer267光栅红外光谱仪记录的。′H核磁共振波谱由Varian EM-360(60兆赫)或由Varian CFT-20(80兆赫)核磁共振波谱仪测定,除非另有说明。内标采用四甲基硅烷,报告的化学位移是相对于内标的百万分之几(δ)。紫外光谱由Unicam SP8-100UV光谱仪记录。旋光度由Perkin-Elmer 141型旋光仪测定。四氢呋喃刚从氢化铝中蒸馏出来。使用的无水乙醚(来自Fisher)未经进一步处理,其它所有溶剂均为试剂级,使用前在分子筛中保存,三乙胺和四甲基亚乙基二胺从CaH2蒸馏出,并在NaOH中保存。无水氯化锌在使用前于减压下熔融。根据Regits*的一般方法制备重氮乙酰乙酸烯丙基酯和重氮乙酰乙酸乙酯。分析薄层色谱(tlc)是在预涂布板上进行(硅胶60F-254,E.默克公司)。通过紫外光,碘或钼酸铵(Ⅵ)进行显色。制备性层析色谱(plc)是在硅胶60GF-254(E.默克公司)制备的硅胶板上进行的。对于柱层析,采用70~230筛孔的硅胶60(E.默克)。
*(a).M.Regitz和A.Liedhegener,化学学报(Chem.Ber(德)99:3128(1966);
(b).M.Regitz,应用化学(Angew,Chem.)(西德79:786(1967)〕;
(c).M.Regits,合成(synthesis);351(1972)。
原料的制备
制备例1
对硝基苄基乙酰乙酸酯
缓慢蒸馏乙酰乙酸乙酯(140克,1.08摩尔)和对-硝基苄醇(153克,1.00摩尔),使用前用乙醚洗涤过)在1升甲苯中的混合物,在15小时内收集900毫升溶剂。冷却之后,在硅藻土上过滤出所有不溶物,再用甲苯洗涤,并在真空中蒸发得到280克粗油,该油在5℃从乙醚(280毫升)中结晶,得到181.55克(0.766摩尔,产率76.6%)灰白色结晶的标题化合物:熔点40°~42℃;ir(薄膜)v最大:1740(酯),1715(C=0),1515和1345(NO2)cm-1;′Hmy(CDCl3)δ:1.98(S,杂质),2.32(3H,S,CH3),3.62(2H,S,-COCH2CO2R),5.08(S,杂质),5.28(2H,S,-CO2CH2Ar),7.53(2H,“d”,J=9Hz,ArH),和8.23ppm(2H,“d”,J=9Hz,ArH);Rf0.45(乙醚)。从甲苯-己烷中重结晶得到分析样品,熔点47~49℃。元素分析C11H11NO5的计算值:
C,55.70;H,4.67;N,5.91
测定值:C,55.59;H,4.62;N,5.85。
制备例2
三甲基甲硅烷基乙酰乙酸酯
加热乙酰乙酸乙酯(2.60克,20毫摩尔;Aldrich)和三甲基甲硅烷基乙醇(2.51克,21.1毫摩尔,Fluka)在100毫升甲苯中的溶液,用维格罗分馏柱(1.7厘米×7厘米)在80°~100℃缓慢蒸馏,在10小时内除去大部分溶剂。残余物在减压下用维格罗分馏柱(1.7厘米×7厘米)蒸馏,得到3.34克(16.5摩尔,产率82.7%)无色油状的标题化合物:Rf0.32(20%乙酸乙酯/己烷);沸点85℃~88℃(0.3乇);ir(纯的)最大:1740(酮)和1720(酯)cm-1;
′Hmr(CDCl3):0.07(9H,S,SiMe3),1.00(2H,“t”,J=8Hz,SiCH2),1.93(0.45H,S,MeC(OH)=),2.28(2.55H,S,MeCo),3.12(0.15H,S,烯醇式的OH),3.43(1.7H,S,COCH2),4.2(2H,“t”,J=8Hz,CO2CH2),和4.95(0.15H,S,烯醇式的乙烯基质子)ppm;
元素分析C9H18O3Si的计算值:C 53.43,H 8.97
实测值:C 53.19,H 8.82
制备例3
对硝基苄基2-重氮基-3-氧代丁酸酯
在0~5℃及氮气流下,于15分钟内向对-硝基苄基乙酰乙酸酯(134.6克,0.568摩尔)和三乙胺(79.01毫升,0.568摩尔)在340毫升CH3CN的溶液中加入对-甲苯磺酰基叠氮化物(130克,0.639摩尔,纯度97%)。在上述期间标题化合物开始沉淀。移走冷却浴,并在室温下搅拌混合物3小时。再在冰浴中冷却混合物30分钟,滤出沉淀,依次用75毫升冷CH3CN和200毫升冷乙醚洗涤,并干燥,得到135.06克(0.514摩尔,产率90.4%)淡黄色粉末状的标题化合物:′Hmr(CDCl3)δ:2.50(3H,S,-CH3),5.38(2H,S,-CO2CH2Ar),7.53(2H,“d”,J=9Hz,芳香族Hs)和8.27ppm(2H,“d”,J=9Hz,芳香族Hs);ir(CH2Cl2)V最大:2130(N2),1720(酯),1655(C=O),1520和1350cm-1(NO2);Rf0.65(乙酸乙酯)。
制备例4
2-三甲基甲硅烷基乙基α-重氮乙酰乙酸酯
在冰浴冷却下向三甲基甲硅烷基乙基乙酰乙酸酯(10.6克,50.0毫摩尔)和三乙胺(7.10毫升,51.5毫摩尔在85毫升乙腈的溶液中加入对-甲苯磺酰叠氮化物(10.0克,50.7毫摩尔),反应混合物在室温下搅拌20小时,真空蒸出溶剂之后,用乙醚(90毫升)萃取残余物,萃取液依次用KOH(3.0克)在83毫升水中的溶液,KOH(0.9克)在30毫升水中的溶液和盐水洗涤,并用Na2SO4干燥。真空蒸出溶剂后得到11.6克粗油,该粗油通过柱层析(SiO2,150克)纯化,用20%乙酸乙酯/己烷洗脱,得到9.65克(42.3毫摩尔,产率84.5%)微黄色油状的标题化合物;Rf0.44(20%乙酸乙酯/己烷);ir(纯的)V最大:2130(C=N2),1715(酯),和1660(酮)cm-1;UV(CH2Cl2λ最大:257nm(ε7200);′Hmr(CDCl3)δ:0.07(9H),S,SiMes),1.03(2H,“t”,J=8Hz,CH2Si),2.47(3H,S,COCH3),和4.30(2H,“t”,J=8Hz,CO2CH2)ppm。
制备例5
对-硝基苄基-2-重氮基-3-氧代-正-戊酸酯
将50克(0.35摩尔)3-氧代-正-戊酸乙酯和54克(0.35摩尔)对-硝基苄醇在400毫升甲苯中的溶液在130~140℃不用回流冷凝器加热18小时。溶剂蒸发后得到黄色结晶状物,该结晶状物从乙醚-戊烷中重结晶,得到75克(产率86%)对硝基苄基3-氧代-正-戊酸酯(3)。熔点33-34℃。IR(KBr)v1740和1705cm-1。NMR(CDCl3)δ1.20(3H,t,J=7.0Hz),2.65(2H,q,J=7.0Hz),3.60(2H,S),5.28(2H,S),7.45(2H,d),J=9.5Hz),和8.18(2H,d,J=9.5Hz)。在0℃下,向55.5克(0.22摩尔化合物3在500毫升CH3CN的溶液中加入45克(0.44摩尔)TEA,再加入50克(10.22摩尔)对-羧基苯磺酰叠氮化合物。移走冰浴后,将混合物搅拌90分钟。过滤沉淀物,用CH3CN洗涤,滤液被浓缩至约100毫升体积,随后用800毫升乙酸乙酯稀释,得到的有机溶液用NaHCO3水溶液,盐水洗涤,并用MgSO4干燥,蒸发干燥后的溶剂,得到55克(产率90%)淡黄色晶体的化合物4。熔点96~97℃,IR(KBr)v2120和1710cm-1。NMR(CDCl3)δ1.20(3H,t,J=7.0Hz),2.85(2H,q,J=7.0Hz),5.40(2H,S),7.50(2H,d,J=8.0Hz),和8.15(2H,d,J=8.0Hz)。
制备例6
重氮乙酰乙酸烯丙酯
A.乙酰乙酸烯丙酯
向装有磁力搅拌器、用于蒸馏的维格罗分馏柱以及加热套和带有氮气通入管的2升烧瓶中加入4.0摩尔(432毫升)乙酰乙酸甲酯和8.0摩尔(464.6克)烯丙醇,反应混合物在92℃蒸馏12小时,再加入136毫升(2.0摩尔)烯丙醇,并将混合物蒸馏23小时,然后再加入136毫升(2.0摩尔)烯丙醇,并将混合物蒸馏16小时。再在真空下蒸馏反应混合物,收集105-110℃/35mmHg产品,得到414克乙酰乙酸烯丙酯(产率73%)。
B.重氮乙酰乙酸烯丙酯
向乙酰乙酸烯丙酯(226.5克,1.594摩尔)在3升乙腈的溶液和三乙胺(243.4毫升,1.753摩尔)中,在1小时内于冷却下加入对-甲苯磺酰叠氮化物(345.3毫升,1.753摩尔),保持温度在约20℃。该反应混合物变黄,然后在室温下,于氮气流中搅拌该混合物18小时。并在旋转蒸发器中浓缩。残余物溶于乙醚(2.6升)和1M KOH水溶液(800毫升)中。有机相用1M KOH(500毫升)洗涤5次,并用盐水(400毫升)洗涤1次。用MgSO4干燥后在旋转蒸发器上浓缩(温度≤30℃),得到260.2克(97%)标题化合物
根据上述的一般方法,可以制备下列起始原料
R=
-CH2CH=CH2
-CH2CH3
-CH2CH=CHC6H5
-CH2CH=CHCO2CH3
-CH2CH=CHCH3
-CH2CH2Si(CH3)3
实施例1
制备对-硝基苄基2-重氮基-3-三甲基甲硅烷氧基-3-丁烯酸酯
在0~5℃于氮气流中,向对-硝基苄基α-重氮乙酰乙酸酯(236毫克,1毫摩尔)和三乙胺(0.15毫升,1.08毫摩尔)在2毫升CH2Cl2的悬浮液中加入三甲基甲硅烷基三氟甲基磺酸酯0.22毫升,搅拌混合物30分钟。向得到的黄色澄清溶液中加入干燥的己烷(30毫升),反应混合物再搅拌10分钟。分出似油的沉淀物后,真空下蒸发己烷溶液,得到的黄色固体再用干燥的己烷(50毫升)溶解。用硅藻土滤除不溶物,真空下蒸发滤液,得到277毫克(0.90毫摩尔,产率90%)黄色结晶的标题化合物:ir(薄膜)v最大:2100(N2),1705(酯),1520和1345cm-1(NO2);′Hmr(CDCl3)δ:0.27(9H,S,-SiMe3),4.23(1H,d,J=2Hz,乙烯基质子),4.93(1H,d,J=2Hz,乙烯基质子),5.32(2H,S,-CO2CH2Ar),7.48(2H,“d”,J=9Hz,芳香族质子),和8.23ppm(2H,“d”,J=9Hz,芳香族质子)。
实施例2
制备对-硝基苄基2-重氮基-3-叔-丁基二甲基甲硅烷氧基-3-丁烯酸酯
在2℃及氮气流下,于30分钟内向对-硝基苄基α-重氮乙酰乙酸酯(26.30克,0.10摩尔)和三乙胺(14.57克;20.00毫升,0.14摩尔)在200毫升水二氯甲烷的悬浮液中加入叔-丁基二甲基甲硅烷基三氟甲基磺酸酯(31.72克,27.50毫升,0.12摩尔)。混合物在2℃搅拌1小时。橙色清液用二氯甲烷(50毫升)稀释,并依次用水(3×200毫升)和盐水(100毫升)洗涤,用Na2SO4干燥,蒸发,得到37.40克(0.099摩尔,产率99%)黄色固体的标题化合物:′Hmr(CDCl3,EM-360A,60MHz)δ:0.26(6H,S,Si(CH3)2),0.96(9H,S,SiC(CH3)3),4.25(1H,d,J=2.5Hz,4-H),4.97(1H,d,J=2.5Hz,4-H),5.32(2H,S,-CO2CH2Ar),7.48(2H,“d”,J=9.0Hz,ArH′)和8.22ppm(2H,“d”,J=9.0Hz,ArH),ir(薄膜)v最大:2090(N2),1694(酯),1600(C=C)和1344cm-1(NO2)
实施例3
制备2-重氮基-3-三甲基甲硅烷氧基-3-丁烯酸酯的一般方法
R=
3a -CH2CH=CH2
3b -CH2CH2Si(CH3)3
3c -CH2CH3
在0~5℃及干燥氮气流下向1毫摩尔α-重氮乙酰乙酸酯(烯丙基酯,三甲基甲硅烷基乙酯和乙基酯)以及三乙胺(0.20毫升,1.4毫摩尔)在2毫升无水CH2Cl2或CCl4的搅拌溶液中,加入三甲基甲硅烷基三氟甲磺酸酯(0.22毫升,1.1毫摩尔Aldrich),混合物在0~5℃和N2气流下搅拌30分钟。然后向得到的黄色澄清溶液中加入无水己烷(5毫升),随后在氮气流下搅拌10分钟。通过重力过滤法去除油样的沉淀物后,真空下蒸发己烷溶液,残余物再溶解于10毫升无水己烷中。不溶物再次用重力过滤法除去,真空下蒸发滤液得到3a,3b和3c,为黄色结晶或者浅橙色油状物,产率77~97%。由于产物对水分敏感,所以整个操作应在无水条件下进行。
3a:(烯丙基酯):产率77%:ir(纯的)v最大:2100(C=N2),1710(酯),和1605(C=C)cm-1,′Hmr(CCl4)δ:0.20(9H,S,SiMe3),4.15(1H,d,J=2Hz,乙烯基质子),4.63(2H,d,J=5Hz,CO2CH2),4.95(1H,d,J=2Hz,乙烯基质子),和5-6.2(3H,m,乙烯基质子)ppm。
3b:(三甲基甲硅烷基-乙酯):产率97%;ir(纯的)v最大:2090(C=N2),1705(酯),和1605(C=C)cm-1;′Hmr(CCl4)δ:0.07(9H,S,SiMe3),0.25(9H,S,OSiMe3),1.00(2H,“t”,J=8Hz,CH2Si),4.15(1H,d,J=2Hz,乙烯基质子),4.23(2H,“t”,J=8Hz,CO2CH2),4.98(1H,d,J=2Hz,乙烯基质子)ppm。
3c(乙酯):产率78%;ir(纯的)v最大:2090(C=N2),1710(酯),和1605(C=C)cm-1;′Hmr(CCl4)δ:0.25(9H,S,SiMe3),1.32(3H,t,J=7Hz,CH3),4.17(1H,d,J=2Hz,乙烯基质子),4.23(2H,q,J=7Hz,CH3,4.17(1H,d,J=2Hz,乙烯基质子)ppm
实施例4
制备2-重氮基-3-(叔-丁基二甲基甲硅烷氧基)-3丁烯酸酯的一般方法
R=
4a -CH2CH=CH2
4b -CH2CH2Si(CH3)3
4c -CH2CH3
在0~5℃和氮气流下,向1毫摩尔α-重氮乙酰乙酸酯(烯丙基酯,三甲基甲硅烷乙酯和乙基酯)和三乙胺(0.20毫升,1.4毫摩尔)在2毫升无水CH2Cl2的搅拌溶液中加入叔-丁基二甲基甲硅烷基三氟甲磺酸酯(0.28毫升,1.2毫摩尔,Fluka)。在0~5℃将黄色混合物搅拌15分钟,并用己烷(20毫升)稀释,依次用稀的NaHCO3水溶液和盐水洗涤,经Na2SO4干燥,蒸发,得到R=4a~4c的浅橙色油状物,产率93~99%。
4a(烯丙基酯):产率96%;Rf0.6(20%乙酸乙酯/己烷;部分在薄板层析上分解为α-重氮乙酸酯);ir(薄膜)v最大:2100(C=N2),1715(酯),和1610(C=C)cm-1;UV(CH2Cl2)v最大:280nm(ε6000);′Hmr(CDCl3)δ:0.23(6H,S,SiMe2),0.93(9H,S,Si-叔-丁基),4.20(1H,d,J=5Hz,CO2CH2),4.95(1H,d,J=2Hz,乙烯基质子),和5-6.3(3H,m,乙烯基质子)ppm。
4b(三甲基甲硅烷基乙酯):产率94%,Rf0.7(20%乙酸乙酯/己烷;部分在薄板层析上分解为α-重氮乙酸酯;ir(薄板)v最大:2100(C=N2),1710(酯),和1610(C=C)cm-1;UV(CH2Cl2)λ最大:280nm(ε7600);′Hmr(丙酮d6;CFT-20)δ:0.06(9H,S,SiMe3),0.25(6H,S,SiMe2),0.94(9H,S,Si-叔丁基),1.05(2H,t,J=8.3Hz,CO2CH2CH2SiMe3),4.31(1H,d,J=1.8Hz,乙烯基质子)ppm。4c(乙基酯):产率99%,Rf0.66(20%乙酸乙酯/己烷;部分在薄板层析上分解成α-重氮乙酸酯);
ir(薄膜)v最大:2090(C=N2),1710(酯)和1610(C=C)cm-1;
UV(CH2Cl2)-λmax:282nm(ε7950);′Hmr(丙酮-d6;CFT-20)δ:0.25(6H,S,SiMe2),0.94(9H,S,Si-叔丁基),1.26(3H,t,J=7.1Hz,CO2CH2CH3);4.25(2H,q,J=7.1Hz,CO2CH2CH3);4.28(1H,d,J=1.9Hz,乙烯基质子)ppm。
实施例5
制备1-对-硝基苄氧基羰基-1-重氮基-2-叔-丁基二甲基-甲硅烷氧基-2-丁烯
40分钟内向54克(0.2摩尔)化合物4在400毫升CH2Cl2并冷却至0℃的溶液中加入41.4克(0.4摩尔)TEA,继而加入溶于30毫升CH2Cl2中的56克(0.21摩尔)叔-丁基二甲基甲硅烷基氯化物。溶液搅拌120分钟,然后用冰水洗涤。CH2Cl2溶液经MgSO4干燥,随之过滤,真空下蒸发,得到68克(产率89%)化合物5为黄色固体,熔点54-55℃,IR(KBr)v2080和1695cm-1。化合物5的核磁共振光谱表明,所得到的化合物5在烯键位置上是反式/顺式混合物,比值为9∶1。核磁共振(CDCl3,要主异构件)δ0.15(6H,S),0.90(9H,S),1.58(3H,d,J=7.0Hz),5.15(2H,S),7.30(2H,d,J=9.0Hz)和8.0(2H,d,J=9.0Hz)。
实施例6
按照实施例1-5的一般方法,改换合适的起始原料,可以制得下列化合物:
R5R6R1R2R3R7
H H 异丙基 异丙基 异丙基 对-硝基苄基
H H ″ ″ ″ -CH2CH=CH2
H H ″ ″ ″ -CH2CH=CHC6H5
H H ″ ″ ″ -CH2CH=CHCO2CH3
H H ″ ″ ″ -CH2CH=CHCH3
H H ″ ″ ″ -CH2CH2Si(CH3)3
H H ″ ″ ″
CH3H ″ ″ ″ 对-硝基苄基
H H ″ ″ ″ -CH2CH=CH2
H H ″ ″ ″ -CH2CH=CHC6H5
H H ″ ″ ″ -CH2CH=CHCO2CH3
H H ″ ″ ″ -CH2CH=CHCH3
H H ″ ″ ″
H H ″ ″ ″ -CH2CH2Si(CH3)3
H H C6H5叔-丁基 C6H5对-硝基苄基
H H ″ ″ ″ -CH2CH=CH2
H H ″ ″ ″ -CH2CH=CHC6H5
H H ″ ″ ″ -CH2CH=CHCO2CH3
H H ″ ″ ″ -CH2CH=CHCH3
H H ″ ″ ″ -CH2CH2Si(CH3)3
CH3H C6H5叔-丁基 C6H5对-硝基苄基
H H ″ ″ ″ -CH2CH=CH2
H H ″ ″ ″ -CH2CH=CHC6H5
H H ″ ″ ″ -CH2CH=CHCO2CH3
H H ″ ″ ″ -CH2CH=CHCH3
H H ″ ″ ″
H H ″ ″ ″ -CH2CH2Si(CH3)3
H H ″ ″ ″ -CH2CH=CH2
H H ″ ″ ″ -CH2CH=CHC6H5
H H ″ ″ ″ -CH2CH=CHCO2CH3
H H ″ ″ ″ -CH2CH=CHCH3
H H ″ ″ ″ -CH2CH2Si(CH3)3
CH3CH3CH3叔-丁基 CH3对-硝基苄基
H H ″ ″ ″ -CH2CH=CH2
H H ″ ″ ″ -CH2CH=CHC6H5
H H ″ ″ ″ -CH2CH=CHCO2CH3
H H ″ ″ ″ -CH2CH=CHCH3
H H ″ ″ ″ -CH2CH2Si(CH3)3
H H ″ ″ ″
H H ″ ″ ″ -CH2CH=CH2
H H ″ ″ ″ -CH2CH=CHC6H5
H H ″ ″ ″ -CH2CH=CHCO2CH3
H H ″ ″ ″ -CH2CH=CHCH3
H H ″ ″ ″
H H ″ ″ ″ -CH2CH2Si(CH3)3
CH3CH3CH3CH3CH3对-硝基苄基
H H ″ ″ ″ -CH2CH=CH2
H H ″ ″ ″ -CH2CH=CHC6H5
H H ″ ″ ″ -CH2CH=CHCO2CH3
H H ″ ″ ″
H H ″ ″ ″ -CH2CH=CHCH3
H H ″ ″ ″ -CH2CH2Si(CH3)3
实施例7
制备(3S,4R)-3〔(1R)-羟乙基〕-4-〔3-(4-硝基苄氧基)羰基-2-氧代-3-重氮丙基〕氮杂环丁-2-酮
在氮气流下向无水氯化锌(34毫克,0.25毫摩尔)在2毫升二氯甲烷的悬浮液中,加入溶于4毫升二氯甲烷中的(1′R,3R,4R)-3-(1′-叔-丁基二甲基甲硅烷氧基乙基)-4-乙酰氧基-氮杂环丁-2-酮(144毫克,0.5毫摩尔)溶液,继之加入固体4-硝基苄基-2-重氮基-3-叔丁基二甲基-甲硅烷氧基-3-丁烯酸酯(350毫克,0.95毫摩尔)。得到的混合物在室温和氮气下搅拌4.5小时,用乙酸乙酯(50毫升)稀释,然后依次用饱和的碳酸氢钠溶液(2×25毫升)和盐水(30毫升)洗涤。用Na2SO4干燥后蒸发,得到油样的黄色固体粗品,通过柱层析〔(SiO2,30克),用二氯甲烷/乙酸乙酯(4∶1)洗脱〕纯化,得到198毫克(0.405毫摩尔,产率为81%)油状的标题化合物,用薄板层析和′Hmr鉴定,与已知方法制备的可信样品相同。
实施例8
制备(3S,4R)-3-〔(1R)-羟乙基〕-4-〔3-(4-硝基苄氧基)羰基-2-氧代-3-重氮丙基〕氮杂环丁-2-酮。
向(3S,4R)-3-〔(1R)-(叔-丁基二甲基甲硅烷氧基)乙基〕-4-〔3-(4-硝基苄氧基)羰基-2-氧代-3-重氮丙基〕氮杂环丁-2-酮(72毫克,0.15毫摩尔)在1.0毫升甲醇的溶液中加入1N HCl水溶液(0.2毫升),混合物在室温下搅拌2小时,这时薄板层析(乙酸乙酯为展开剂)表明反应完成了。在这一期间内标题化合物沉淀出来,过滤后,依次用冷CH3OH-H2O(9∶1)和冷乙醚漂洗,得到43毫克(0.11毫摩尔,产率73%)标题化合物为白色固体。标题化合物同样也可由(3S,4R)-3-{(1R)-〔(2,4,6-三-叔-丁基苯氧基)二甲基甲硅烷氧基〕乙基}-4-〔3-(4-硝基苄氧基)羰基-2-氧代-3-重氮丙基〕氮杂环丁-2-酮得到。
实施例9
制备(3S,4R)-3-{(1R-〔2,4,6-三-叔-丁基苯氧基)二甲基甲硅烷氧基〕乙基}-4-〔3-(4-硝基苄基)氧羰基-2-氧代-3-重氮丙基〕氮杂环丁-2-酮
按上述制备相应的叔-丁基二甲基甲硅烷基衍生物的方法由(3R,4R和4S)-4-乙酰氧基-3-{(1R-〔(2,4,6-三-叔-丁基苯氧基)-二甲基甲硅烷氧基〕乙基}-2-氮杂环丁酮制备标题化合物,产率84%。
′Hmr(CDCl3,80MHz)δ:0.26(3H,S,SiMe),0.40(3H,S,SiMe),1.27(9H,S,叔-丁基),1.41(18H,S,(叔-丁基)2),2.92(1H,dd,J3-1,=4.7Hz,J3-4=2.5Hz,3-H),2.97(1H,dd,J偕=17.6Hz,J1″b-4=9.6Hz,1″-Hb),3.40(1H,dd,J偕=17.6Hz,J1″a-4=3.5Hz,1″-Ha),3.98-4.24(1H,m,4-H),4.32-4.57(1H,m,1′-H),5.35(2H,S,-CO2CH2Ar),5.95(1H,brs,NH),7.22(2H,S,醚的ArH),7.52(2H,“d”,J=8.7Hz,酯的ArH)和8.25ppm(2H,“d”,J=8.7Hz,酯的ArH):ir(纯的)v最大:3300(br,NH),2137(-N2),1755(β-内酰胺),1720(酯),1651(C=O),1523和1345cm-1(NO2)。
实施例10
4β-1-甲基-3-重氮基-3-对-硝基苄氧基羰基-2-氧代-丙基)-3α-〔1-(R)-叔-丁基二甲基甲硅烷氧基乙基〕-氮杂环丁-2-酮
向12.5克(0.1摩尔)无水ZnCl2在700毫升CH2Cl2的悬浮液中加入60.4克(0.21摩尔)化合物6,在23℃搅拌15分钟后冷却到0℃。将106克(0.27摩尔)化合物5在200毫升CH2Cl2中的溶液在90分钟内滴加到上述反应溶液中,并不用冷却浴再搅拌120分钟。得到的反应混合物用NaHCO3水溶液(4×150毫升),水和盐水洗涤,并用MgSO4干燥,干燥过的溶剂经蒸发后得深色油状物,该油状物通过SiO2柱纯化,用乙酸乙酯-CH2Cl2(1∶9)为洗脱剂,得到51.5克(54%)化合物7为白色结晶,熔点112~114℃,IR(KBr)v2130,1760和1720cm-1。化合物7的360兆赫核磁共振光谱表明,得到的化合物7是混合物,在1-甲基位置的比值是2∶1,NMR(CDCl3)δ0.3-0.6(6H,2S),0.8(9H,2S),1.05-1.15(6H,m),2.68(0.66H,q,J=6.6和2.0Hz),2.88(0.34,q,J=6.6和2.0Hz),3.57(1H,m),3.84(1H,m),4.09(1H,m),5.17(2H,双S,5.84(0.66H,S),5.95(0.34H,S),7.52(2H,d,J=8.5Hz)和8.23(2H,d,J=8.5Hz)。
Claims (38)
4、根据权利要求1的方法,在所制备的化合物中,R7为对硝基苄基,R5和R6均为氢,其结构式如下:
6、根据权利要求4的方法,其中
8、根据权利要求7的方法,其中R1,R2和R3分别是甲基。
9、根据权利要求7的方法,其中R1和R3分别是甲基,并且R2是叔-丁基。
10、根据权利要求7的方法,其中
12、根据权利要求7的方法,其中R1,R2和R3分别是异丙基。
13、根据权利要求1的方法,在所制备的化合物中,
其中R5和R6分别是独立的氢或甲基,R7选自下述基团的酯基:C1-C4烷基,对-硝基苄基,
当R5和R6是氢时,R7不是对硝基苄基。
15、根据权利要求14的方法,其中R7是-CH2CH=CH2。
16、根据权利要求14的方法,其中R7是-CH2CH=CHC6H5。
17、根据权利要求14的方法,其中R7是-CH2CH=CHCO2CH3。
20、根据权利要求14的方法,其中R7是-CH2CH=CHCH3。
23、根据权利要求14的方法,其中R7是-CH2CH2Si(CH3)3。
26、根据权利要求25的方法,其中R7是C1-C4烷基。
27、根据权利要求25的方法,其中R7是-CH2CH=CH2。
28、根据权利要求25的方法,其中R7是-CH2CH=CHC6H5。
29、根据权利要求25的方法,其中R7是-CH2CH=CHCO2CH3。
32、根据权利要求25的方法,其中R7是-CH2CH=CHCH3。
35、根据权利要求25的方法,其中R7是
-CH2CH2Si(CH3)3
37、根据权利要求1的方法,其中该反应在温度约为-40℃至+30℃之间进行。
38、根据权利要求1或2的方法,其中有机碱是C1-C4三烷基胺,溶剂是二氯甲烷。
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CN102690282A (zh) * | 2011-07-07 | 2012-09-26 | 深圳市海滨制药有限公司 | 晶体形式的1β甲基碳青霉烯类抗生素中间体及其制备方法 |
CN106565535A (zh) * | 2016-11-15 | 2017-04-19 | 山西师范大学 | 2‑重氮‑1‑芳基酮类化合物的制备方法 |
CN107556212A (zh) * | 2017-09-14 | 2018-01-09 | 台州昌霖化工科技有限公司 | 一种制备2‑重氮乙酰乙酸对硝基苄酯的方法 |
CN114516820A (zh) * | 2022-02-25 | 2022-05-20 | 山东艾孚特科技有限公司 | 一种制备2-重氮乙酰乙酸对硝基苄酯的方法 |
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US4772683A (en) * | 1986-02-24 | 1988-09-20 | Bristol-Myers Company | High percentage beta-yield synthesis of carbapenem intermediates |
JP2675625B2 (ja) * | 1989-01-12 | 1997-11-12 | 鐘淵化学工業株式会社 | エノールシリルエーテル化合物の製造方法 |
US5340927A (en) * | 1989-07-18 | 1994-08-23 | Merck & Co., Inc. | Process for the preparation of 2-diazo-3-trisubstituted silyloxy 3-butenoates |
NZ234411A (en) * | 1989-07-18 | 1991-05-28 | Merck & Co Inc | Preparation of 2-diazo-3-silyloxy-3-butenoate esters |
DE4014649A1 (de) * | 1990-05-08 | 1991-11-14 | Hoechst Ag | Neue mehrfunktionelle verbindungen mit (alpha)-diazo-ss-ketoester- und sulfonsaeureester-einheiten, verfahren zu ihrer herstellung und deren verwendung |
JP2000166962A (ja) * | 1998-12-08 | 2000-06-20 | Tatsu Ifukube | 触覚刺激装置及び方法 |
DE602004025016D1 (de) | 2003-08-28 | 2010-02-25 | Ranbaxy Lab Ltd | Verfahren zur herstellung von estern von 2-diazo-3-trimethylsilyloxy-3-butensäure |
US20070037971A1 (en) * | 2005-07-29 | 2007-02-15 | Meeran Hashim Nizar P N | Process for desilylation of carbapenem intermediates |
ES2391713T3 (es) * | 2008-07-30 | 2012-11-29 | Ranbaxy Laboratories Limited | Proceso para la preparación de compuestos de carbapenem |
WO2011048583A1 (en) | 2009-10-23 | 2011-04-28 | Ranbaxy Laboratories Limited | Process for the preparation of carbapenem compounds |
CN102643211A (zh) * | 2012-04-10 | 2012-08-22 | 平顶山佳瑞高科实业有限公司 | 一种2-重氮乙酰乙酸对硝基苄酯的制备方法 |
WO2017132321A1 (en) | 2016-01-29 | 2017-08-03 | The Johns Hopkins University | Novel inhibitors of bacterial growth |
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WO1982003445A1 (en) * | 1981-04-03 | 1982-10-14 | Nagamoto Shunichi | Display unit of a cooking apparatus for selectively displaying image signals from several image signal sources |
US4444685A (en) * | 1981-04-27 | 1984-04-24 | Merck & Co., Inc. | Stereospecific synthesis of thienamycin from penicillin |
CA1190236A (en) * | 1981-10-23 | 1985-07-09 | Edward J.J. Grabowski | Antibiotic synthesis |
US4525582A (en) * | 1982-06-22 | 1985-06-25 | Merck & Co., Inc. | Silyl, benzyl, p-nitrobenyl, or methyl esters of diazoacetate, a synthon used in the conversion of penicillin to thienamycin |
NZ205626A (en) * | 1982-09-28 | 1986-12-05 | Bristol Myers Co | Carbapenem antibiotics |
CA1220215A (en) * | 1983-03-07 | 1987-04-07 | Yasutsugu Ueda | Carbapenem intermediates |
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CN106565535A (zh) * | 2016-11-15 | 2017-04-19 | 山西师范大学 | 2‑重氮‑1‑芳基酮类化合物的制备方法 |
CN106565535B (zh) * | 2016-11-15 | 2018-07-17 | 山西师范大学 | 2-重氮-1-芳基酮类化合物的制备方法 |
CN107556212A (zh) * | 2017-09-14 | 2018-01-09 | 台州昌霖化工科技有限公司 | 一种制备2‑重氮乙酰乙酸对硝基苄酯的方法 |
CN107556212B (zh) * | 2017-09-14 | 2020-03-24 | 台州昌霖化工科技有限公司 | 一种制备2-重氮乙酰乙酸对硝基苄酯的方法 |
CN114516820A (zh) * | 2022-02-25 | 2022-05-20 | 山东艾孚特科技有限公司 | 一种制备2-重氮乙酰乙酸对硝基苄酯的方法 |
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