CN1193322A - 合成卡巴青(Carbapenem)中间体的改进方法 - Google Patents
合成卡巴青(Carbapenem)中间体的改进方法 Download PDFInfo
- Publication number
- CN1193322A CN1193322A CN96196325A CN96196325A CN1193322A CN 1193322 A CN1193322 A CN 1193322A CN 96196325 A CN96196325 A CN 96196325A CN 96196325 A CN96196325 A CN 96196325A CN 1193322 A CN1193322 A CN 1193322A
- Authority
- CN
- China
- Prior art keywords
- compound
- structural formula
- following structural
- alkali
- methyl
- 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
Links
- 238000000034 method Methods 0.000 title claims abstract description 31
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 239000000543 intermediate Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 16
- -1 triethylsilyl Chemical group 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 13
- 150000002460 imidazoles Chemical class 0.000 claims description 10
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 9
- 229940011051 isopropyl acetate Drugs 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 244000025254 Cannabis sativa Species 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 229910052703 rhodium Inorganic materials 0.000 description 5
- 239000010948 rhodium Substances 0.000 description 5
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 4
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KIGXMYYGQYMICF-UHFFFAOYSA-N Diphenylphosphine Acid Chemical group C=1C=CC=CC=1P(=O)(CCCCC(=O)O)C1=CC=CC=C1 KIGXMYYGQYMICF-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
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 229940102001 zinc bromide Drugs 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
-
- 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
-
- 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
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
公开一种合成结构式(1)或(2)化合物的方法,其中R代表H或甲基,而P代表三乙基甲硅烷基或三甲基甲硅烷基。结构式(3)或(4)的化合物在有碱和基本上不反应的溶剂存在下与P-Cl反应(其中P如上所定义的)产生结构式(1)或(2)的化合物。
Description
本发明涉及一种卡巴青(Carbapenem)中间体,特别是如下结构式化合物的改进合成方法:和
其中R代表氢或甲基,而P代表三乙基甲硅烷基或三甲基甲硅烷基。过去,已将类似的这类中间体用于合成卡巴青(Carbapenem)抗菌素。然而,迄今为止合成这些抗菌素的手段必需使用的中间体极不稳定。此外,过去所公开的合成方法产率很低,并需要多次分离和提纯步骤。
本文所述及的卡巴青(Carbapenem)抗菌素中间体,例如是1982年9月21日授予Christensen等人的美国专利No.4,350,631和1991年2月19日授予Christensen的美国专利No.4,994,568中所提及的。在上述专利各自所公开的方法中,使用催化剂或照射使下列结构式的重氮基化合物环化:这样产生1-α和1-β甲基异构体的混合物,这些异构体在进一步化学变性以前依次需要分离。
最近,很多现有的合成卡巴青(Carbapenem)抗菌素的方法利用了一种如下结构式的中间体:该中间体在2位具有一个活性离去基团,即三氟甲磺酸根。这一化合物极不稳定,并且不能以可容许的利用率水平大规模使用。从而,本发明的一个目的是避免这一中间体。
本发明提供了避免不稳定中间体的方案,并且在许多场合下制得了在进一步使用前很少需要或不需要提纯的,结晶形式的中间体,从而克服了上述这些缺点。
本发明公开了一种合成如下结构式化合物的方法:或
其中R代表H或甲基,而P代表三乙基甲硅烷基或三甲基甲硅烷基。该方法包括在有碱和基本上不反应的溶剂存在下,使如下结构式的化合物与P-Cl反应:或
其中P为如上所定义的,产生如下结构式的化合物:或
上面所示的重氮化合物1和二环酮酯2(R=甲基)的1-β甲基异构物高度合适用作卡巴青(Carbapenem)中间体,因为当给哺乳类动物患者施药以治疗细菌感染时,1-β甲基卡巴青(Carbapenem)抗菌素具有降低脱氢酞酶生物失活的趋势。通常,最终产物的1-β甲基异构体比1H或1-α甲基异构体更具抗失活性。
二环酮酯2可在2位进一步反应,形成一个离去基团,例如以L表示,该L代表二苯磷酸根、三氟甲磺酸根、甲苯磺酸根、甲磺酸根、氟磺酸根、氯化物等,以形成合适的活化卡巴青(Carbapenem)中间体。该活化的卡巴青(Carbapenem)中间体,例如通过使用一种钯催化剂,如在合适溶剂中的Pd2(dba)3·CHCl3和三(2,4,6-三甲氧苯基)膦,容易在2位与取代基偶合。有关偶合反应的进一步细节可由美国专利No.5034384得知。
在另一较佳实施方案中,结构式4的化合物(其中R代表H或甲基)在有碱和基本上不反应的溶剂存在下与P-Cl反应,产生如下结构式2的化合物:
此处所用的PNB是指保护基团对硝基苄基。
缩写THF是指四氢呋喃。
缩写OAc是指乙酸根,即CH3C(O)O-。从而溶剂乙酸乙酯缩写为EtOAc,而乙酸异丙酯缩写为iPrOAc。
TES是指基团三乙基甲硅烷基。
TMS是指基团三甲基甲硅烷基。
Et3N是指三乙胺。
dba是指二亚苄基丙酮。
一般地说,本发明的目的是利用晶状中间体,并避免采用不稳定的中间体。此外,立体专一性和区域专一性反应更受青睐。如下的方案是这些反应的代表。
方案1
方案2
方案1和方案2的起始物料可按照美国专利No.4454332(1984年6月12日授权)和No.4312871(1982年1月26日授权)得到。对以上所指出的每种方案,通过在有碱存在下将化合物3或4与P-Cl反应,可获得稳定的,均匀的晶状中间体。这是优于其他合成卡巴青(Carbapenem)方法的未预期到的和令人惊异的优点。
有很多使上述重氮基中间体环化以生成二环酮酯2或4的方法。较佳的环化方法包括在有铑催化剂,如乙酸铑或辛酸铑存在下的反应。
同样地,当使二环酮酯2的2位活化时,酐L2O或卤化物L-Cl可在有含氮碱存在下并在基本上不反应的溶剂中,与二环酮酯结合,生成活化的卡巴青5。然后,在2位具有合适基团L的该活化的卡巴青可按照美国专利No.5034384所介绍的方法与适当的取代基偶合。可按本文所描述的方法合成的Carbapenem是公开的,而适于这样连接的基团可在例如美国专利No.5034384中找到。
本文优选所用基本上不反应的溶剂是二甲基甲酰胺、四氢呋喃(THF)、乙酸异丙酯、乙酸乙酯和二氯甲烷。最优选使用它们的混合物。
本文所述方法中较佳的碱是咪唑。
用于与L2O或L-Cl活化反应的含氮碱包括三乙胺、二异丙基乙胺和二异丙胺。
优选的有价值的L包括磺酸根离去基团,如三氟甲磺酸根(triflate)、甲磺酸根(mesylate)、甲苯磺酸根(tosylate)和氟磺酸根,膦酸残基,如二苯基膦酸根以及卤化物离去基团,如氯化物、溴化物或碘化物。最佳为三氟甲磺酸根(OTf)、氟磺酸根(OSO2F)、甲磺酸根(OMs)、二苯基磷酸根和甲苯磺酸根(OTs)。
实施例1
将化合物3a(7.8g)和咪唑(3.4g)溶于乙酸乙酯(70ml,筛选无水的)中,并将该溶液在室温下搅拌10分钟。将该溶液冷却,并在保持温度-10至-1℃条件下添加三甲基甲硅烷氯(3.57ml)。形成白-黄色悬浮液。
使该悬浮液加温至室温并在室温下搅拌1.5小时。倾入磷酸盐缓冲液(0.01M,80ml,pH6.8)中。分离各相并用NaHCO3水溶液(饱和,40ml)洗涤有机相。用Na2SO4干燥。过滤并蒸发滤液至干。将滤液载在快速硅胶柱(40cm直径×180cm高)上。装填进30%EtOAc和己烷(+0.025%Et3N)。馏分18-55含有化合物1c。实施例2
将装备有N2入口、热电偶探测器,和滴液漏斗的250ml3颈烧瓶,装入THF(20ml;KF≤80μg/ml)、乙酸异丙酯(IPAC;90ml;KF≤80μg/ml)、化合物3a(15g;38.4mmol)和咪唑(4.7g;69.0mmol)。在室温下将该浆料搅拌10分钟直至溶解完全(KF≤140μg/ml)。当在100分钟内缓慢地添加TESCl(9.0ml;53.6mmol)时,将该溶液保持在18-22℃。添加结束后,将该批料在20℃老化2小时。通过HPLC测定该反应混合物。在245nm波长处起始物料应小于0.15%面积。
该反应混合物在室温下于庚烷(30ml)和0.01M磷酸盐缓冲液(100ml;pH6.8)的混合物中骤停反应。在室温下搅拌30分钟后,分离有机层。用0.01M磷酸盐缓冲液(pH6.8;每次100ml)洗涤有机层两次。
在18-20℃/110-80mmHg下将有机层浓缩至约35ml(GC显示6.3V/V%庚烷)。在18-20℃/110-80mmHg下进一步浓缩时缓慢添加庚烷(30ml),保持体积在40ml左右。
在发生结晶后,于室温缓慢添加补充的庚烷(90ml),并将该悬浮液在20℃老化1小时,然后在0℃老化1小时。
将晶体过滤并用IPAC和庚烷混合液(3∶97V/V;100ml)洗涤(然后浆料沉降),而后在氮气流下干燥。得到白色晶状固体产物(18g;93%产率;99.6面积%)。实施例3
在室温下将咪唑(80mg)和TESCl(0.15ml)添加入在THF(1ml)和EtOAc(2ml)混合物中的3b(245mg)溶液中。在搅拌2小时后,用己烷(3ml)稀释该反应混合物,并用磷酸盐缓冲液(pH7.0;6ml)洗涤两次。将有机层通过MgSO4干燥并浓缩得到粗产物1f,通过硅胶柱色谱使用己烷和EtOAc混合物(3∶2-1∶1)洗脱将该粗产物进一步提纯,得到纯1f(310mg)。实施例5
将化合物1d(16.0kg)、辛酸铑(0.123kg)、无水溴化锌(71g)和无水二氯甲烷(63.42L;KF<100μg/ml)装入干燥反应器中。以三次真空/氮填充循环使该溶液脱氧,然后在氮气中加热至回流90分钟,得到化合物2d溶液。实施例6
由化合物1c开始,使用实施例5中所规定的工艺步骤,得到化合物2c。实施例7
将化合物3a(1.1g)的二氯甲烷(4ml)溶液与溴化锌(10mg)和辛酸铑(10mg)于回流下加热4小时。将含有化合物4a的溶液冷却至-78℃。在-78℃下将三乙基甲硅烷基氯(0.65ml)和咪唑(285mg)混合物添加入该溶液中。在-78℃下老化1小时后,将该反应混合物缓慢地加温升至0℃。根据NMR和HPLC分析,该溶液主要含有化合物2d。实施例8
由化合物1e开始,使用实施例8所规定的工艺步骤,得到TMS保护的中间体2e。实施例10
在室温下将TESCl(0.66ml)缓慢地添加入4a(0.97g)和咪唑(343mg)在THF(5ml)和EtOAc(5ml)混合物里的溶液中。在搅拌2小时后,用10mlEtOAc稀释该反应混合物并用磷酸盐缓冲液(pH7.0;15ml)洗涤两次。通过MgSO4干燥有机层,减压下浓缩,得到粗产物2f(1.235g)。
Claims (13)
3.根据权利要求1所述的方法,其中基本上不反应的溶剂是二甲基甲酰胺、四氢呋喃、乙酸异丙酯、乙酸乙酯或二氯甲烷。
4.根据权利要求3所述的方法,其中碱为咪唑。
6.根据权利要求5所述的方法,其中基本上不反应的溶剂为二甲基甲酰胺、四氢呋喃、乙酸异丙酯、乙酸乙酯或二氯甲烷。
7.根据权利要求6所述的方法,其中碱为咪唑。
8.一种合成下式化合物的方法,其中R代表H或甲基,所述方法包括在有碱和基本上不反应溶剂存在下用三甲基甲硅烷基氯处理如下结构式的化合物:产生如下结构式的化合物:
9.根据权利要求8所述的方法,其中基本上不反应的溶剂为二甲基甲酰胺、四氢呋喃、乙酸异丙酯、乙酸乙酯或二氯甲烷。
10.根据权利要求9所述的方法,其中碱为咪唑。
12.根据权利要求11所述的方法,其中基本上不反应的溶剂为二甲基甲酰胺、四氢呋喃、乙酸异丙酯、乙酸乙酯或二氯甲烷。
13.根据权利要求12所述的方法,其中碱为咪唑。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US58595P | 1995-06-28 | 1995-06-28 | |
US60/000,585 | 1995-06-28 | ||
GB9602921.0 | 1996-02-13 | ||
GBGB9602921.0A GB9602921D0 (en) | 1996-02-13 | 1996-02-13 | Improved process for synthesizing carbapenem intermediates |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1193322A true CN1193322A (zh) | 1998-09-16 |
Family
ID=26308678
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96196325A Pending CN1193322A (zh) | 1995-06-28 | 1996-06-24 | 合成卡巴青(Carbapenem)中间体的改进方法 |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0836607A1 (zh) |
JP (1) | JPH11513979A (zh) |
KR (1) | KR19990028406A (zh) |
CN (1) | CN1193322A (zh) |
AR (1) | AR002507A1 (zh) |
AU (1) | AU696543B2 (zh) |
BR (1) | BR9609338A (zh) |
CA (1) | CA2224439A1 (zh) |
CZ (1) | CZ419097A3 (zh) |
EA (1) | EA199800096A1 (zh) |
HU (1) | HUP9903016A3 (zh) |
SK (1) | SK176597A3 (zh) |
WO (1) | WO1997001564A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT2326648E (pt) | 2008-07-30 | 2012-10-31 | Ranbaxy Lab Ltd | Processo de preparação de compostos de carbapenem |
WO2011048583A1 (en) | 2009-10-23 | 2011-04-28 | Ranbaxy Laboratories Limited | Process for the preparation of carbapenem compounds |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4683301A (en) * | 1982-04-08 | 1987-07-28 | Bristol-Myers Company | Carbapenem antibiotics |
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 |
NZ234411A (en) * | 1989-07-18 | 1991-05-28 | Merck & Co Inc | Preparation of 2-diazo-3-silyloxy-3-butenoate esters |
DE3934100A1 (de) * | 1989-10-12 | 1991-04-18 | Bayer Ag | Verfahren zur herstellung von 0-silylierten hydroxylverbindungen und ihre verwendung zur herstellung von estergruppen aufweisenden isocyanaten |
-
1996
- 1996-06-18 AR ARP960103190A patent/AR002507A1/es unknown
- 1996-06-24 BR BR9609338A patent/BR9609338A/pt unknown
- 1996-06-24 AU AU63921/96A patent/AU696543B2/en not_active Ceased
- 1996-06-24 EA EA199800096A patent/EA199800096A1/ru unknown
- 1996-06-24 CZ CZ974190A patent/CZ419097A3/cs unknown
- 1996-06-24 SK SK1765-97A patent/SK176597A3/sk unknown
- 1996-06-24 EP EP96923404A patent/EP0836607A1/en not_active Withdrawn
- 1996-06-24 CA CA002224439A patent/CA2224439A1/en not_active Abandoned
- 1996-06-24 WO PCT/US1996/010783 patent/WO1997001564A1/en not_active Application Discontinuation
- 1996-06-24 CN CN96196325A patent/CN1193322A/zh active Pending
- 1996-06-24 HU HU9903016A patent/HUP9903016A3/hu unknown
- 1996-06-24 JP JP9504502A patent/JPH11513979A/ja active Pending
- 1996-06-24 KR KR1019970709722A patent/KR19990028406A/ko not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
BR9609338A (pt) | 1999-05-11 |
EP0836607A1 (en) | 1998-04-22 |
MX9800041A (es) | 1998-08-30 |
JPH11513979A (ja) | 1999-11-30 |
SK176597A3 (en) | 1998-07-08 |
HUP9903016A3 (en) | 2000-04-28 |
AU696543B2 (en) | 1998-09-10 |
AR002507A1 (es) | 1998-03-25 |
KR19990028406A (ko) | 1999-04-15 |
EA199800096A1 (ru) | 1998-08-27 |
WO1997001564A1 (en) | 1997-01-16 |
CA2224439A1 (en) | 1997-01-16 |
AU6392196A (en) | 1997-01-30 |
CZ419097A3 (cs) | 1998-07-15 |
HUP9903016A2 (hu) | 2000-03-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0126709B1 (de) | Verfahren zur Herstellung von optisch aktiven Azetidinonen | |
Denmark et al. | Stereoselective alkylations of chiral, phosphorus-stabilized benzylic carbanions | |
CN1028428C (zh) | 23-(c1-c6烷基肟)-ll-f28249化合物的制备方法 | |
Arrieta et al. | Reagents and synthetic methods. Part 67. Preparation of 4-unsubstituted. beta.-lactams from 4-acetoxyazetidin-2-ones. A formal approach to monobactams and nocardicins | |
DE3637243A1 (de) | Neue phosphorsulfidderivate von deoxynucleosiden oder deoxynucleotiden und deren verwendung | |
IE861047L (en) | Carbapenem intermediates | |
EP0650973B1 (de) | Racemische Metallocenkomplexe und Verfahren zu ihrer Herstellung | |
O'Neal et al. | Oxidation and methylation reactions of PH-substituted (silylamino) phosphines | |
CN1193322A (zh) | 合成卡巴青(Carbapenem)中间体的改进方法 | |
KR100371893B1 (ko) | 2-메틸스피로(1,3-옥사티올란-5,3')퀴누클리딘의 제조 방법 | |
US4278792A (en) | Method of producing derivatives of 6-β-amidinopenicillanic acid | |
EP0665234B1 (de) | Verfahren zur Herstellung von Biscyclopentadienyl-Verbindungen | |
CN1100753C (zh) | 制备晶体o-甲基异脲醋酸盐的方法 | |
CN116410192B (zh) | 具有多个手性中心的2,3-多取代吲哚嗪、其衍生物及其制备方法和应用 | |
CN1015716B (zh) | 阻聚剂用的亚磷酸(2,2,6,6-四甲基哌啶氮氧自由基)混合酯及其工业生产方法 | |
CN115353437B (zh) | 一种顺-2-甲基-7-十八烯以及顺式-7,8-环氧-2-甲基十八烷的合成方法 | |
KR0183184B1 (ko) | 3-엑소메틸렌 세팜설폭사이드의 제조방법 | |
SU1129210A1 (ru) | Способ получени 3-хлор-1-метилпропен-1-илдихлорфосфата | |
CN87102774A (zh) | N-(磺酰甲基)甲酰胺制备方法 | |
MXPA98000041A (en) | Improved procedure to synthetic carbape intermediaries | |
AT393839B (de) | Stereogesteuertes verfahren zur herstellung von neuen penem-verbindungen | |
US4552975A (en) | Manufacturing process for N-carbobenzyloxy-L-glutamic acid-α-cholinester salt | |
US3775468A (en) | Optically active beta-halogenoalkyl isocyanates | |
US4663451A (en) | Process for the synthesis of penems and penams | |
US5001239A (en) | Formation of reissert compound of benzoyl benzimidazole |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C01 | Deemed withdrawal of patent application (patent law 1993) | ||
WD01 | Invention patent application deemed withdrawn after publication |