CN1211988A - 制备2－卤甲基－青霉烯的方法及其在制备抗菌青霉烯中的应用 - Google Patents
制备2－卤甲基－青霉烯的方法及其在制备抗菌青霉烯中的应用 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims abstract description 14
- 150000002961 penems Chemical class 0.000 title description 3
- 230000000844 anti-bacterial effect Effects 0.000 title 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 15
- KCGJHOZUYJMGLQ-ZCFIWIBFSA-N (5r)-3-(chloromethyl)-4-thia-1-azabicyclo[3.2.0]hept-2-en-7-one Chemical compound S1C(CCl)=CN2C(=O)C[C@H]21 KCGJHOZUYJMGLQ-ZCFIWIBFSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- -1 acetyl sulphur-azetidinone Chemical compound 0.000 claims description 10
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012675 alcoholic extract Substances 0.000 claims description 3
- 230000000903 blocking effect Effects 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- ZXMSTCRBSAVFDO-UHFFFAOYSA-N dimethoxy(methyl)phosphane Chemical compound COP(C)OC ZXMSTCRBSAVFDO-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 229940102001 zinc bromide Drugs 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 claims 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- 125000006502 nitrobenzyl group Chemical group 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 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 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- HNOLIWBAJVIBOU-UHFFFAOYSA-N prop-2-enyl 2-chloro-2-oxoacetate Chemical compound ClC(=O)C(=O)OCC=C HNOLIWBAJVIBOU-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- XLSKKGUFOUYWOC-ZCFIWIBFSA-N (5r)-3-(hydroxymethyl)-4-thia-1-azabicyclo[3.2.0]hept-2-en-7-one Chemical compound S1C(CO)=CN2C(=O)C[C@H]21 XLSKKGUFOUYWOC-ZCFIWIBFSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YHQCVABIRHBYMX-UHFFFAOYSA-N CN(C)C.CN(C)C.CN(C)C.OP(O)O Chemical compound CN(C)C.CN(C)C.CN(C)C.OP(O)O YHQCVABIRHBYMX-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WOIVNLSVAKYSKX-UHFFFAOYSA-N benzyl nitrate Chemical compound [O-][N+](=O)OCC1=CC=CC=C1 WOIVNLSVAKYSKX-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
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- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
公开了一种制备2－卤甲基－青霉烯(特别是2－氯甲基－青霉烯)的方法,其包括作为中间步骤的形成相应的2－卤乙酰硫－氮杂环丁酮。
Description
本发明涉及2-卤甲基-青霉烯(penem)(特别是2-氯甲基-青霉烯)的制备方法，它可用于制备抗菌青霉烯。
已知青霉烯衍生物是一种具有广谱抗菌活性的化合物(见Wise R.“TheCarbapenem and Penem 抗菌素-简述-Antimicrob,Newsl.7,73-80(1990))。
还知道分子式(Ⅰ)的2-卤甲基-青霉烯，特别是2-氯甲基-青霉烯是制备抗菌性青霉烯有用的中间体[G.Pentassuglia等人“抗菌素杂志”Vol.48,399～407(1995)]。已知的制备2-卤甲基-青霉烯(Ⅰ)的方法包括相应2-羟甲基-青霉烯(Ⅱ)的制备：
其中R1和R2如其后所定义。
化合物(Ⅱ)的制备要求一系列多且复杂的反应步骤，产率低且需使用保护性基团和昂贵的反应试剂，这些对于工业生产来说是不适用的。
此外，化合物(Ⅱ)的合成还要求进行多次色谱分离用于对已得到的化合物进行纯化，因为，做为粗产物使用的化合物，在下面所述酸或碱的反应条件下所具有的低稳定性而不适用。
本发明涉及式(Ⅰ)的2-卤甲基-青霉烯(特别是2-氯甲基-青霉烯)的制备方法
其中R1代表醇羟基的保护基团，R2代表羧基的保护基团，X代表卤素，特别是氯，制备方法包括中间步骤，即相应2-卤乙酰硫-氮杂环丁酮的制备。
已发现，并且正是本发明的目的所在：即：使用市场上易买到的产品为反应起始物质仅通过三个反应步骤即可得到2-卤甲基-青霉烯(Ⅰ)特别是2-氯甲基-青霉烯)的方法。该合成途径，如所附反应流程所述，不需中间步骤如保护和去保护及在合成过程中为得到最终产物而利用所有的碳原子，即可得到如式(Ⅰ)的化合物。另外，本发明的目的方法不涉及对中间产物进行复杂的分离和纯化，因而化合物(Ⅰ)具有高产率。另外，反应条件允许得到具有高立体选择性的化合物，因为，按照本发明，在反应过程中，只形成所希望的旋光异构体。除去保护性基团后，分子式(Ⅰ)所示的化合物2-卤甲基-青霉烯可直接转变为所要的最终产物。
如流程所述，根据本发明，制备方法包括式(Ⅲ)化合物(3R,4R)-4-乙酸基-3-[R1O-乙基]-2-氮杂环丁酮和2-卤硫乙酸(见分子式Ⅳ)的反应，其中R1如上所定义，X代表卤素，制备的例子可参见：Arndt,Bekir,Berichte,63 B,2390(1930)。此反应在有机碱和路易斯酸的存在条件下在一种非质子有机溶剂中进行，优选的非质子有机溶剂有二噁烷、四氢呋喃、氯仿，反应温度为-10℃～+40℃，有机碱为三乙胺或二异丙基乙胺，路易斯酸为碘化锌、溴化锌、氯化锌、氯化铝。2-卤乙酰硫氮杂环丁酮(Ⅴ)不需进一步纯化即可与草酰氯酯(Ⅵ)反应。
这一反应在有机碱如三乙胺或二异丙基乙胺的存在条件下，反应温度-20℃～+10℃，在非质子有机溶剂如二噁烷、四氢呋喃、甲苯、氯仿中完成。
在有机亚磷酸盐，如三乙基亚磷酸盐或三甲基亚磷酸盐；或膦酸盐，如二甲氧基甲基膦的作用下，在有机溶剂如甲苯、二甲苯、氯仿、二氯甲烷中当反应温度为20°～140℃，反应1～120h，所得β-内酰胺中的氮元素经酰化得到中间体(Ⅶ)可环化成相应物质2-卤甲基-青霉烯(Ⅰ)。
含有粗2-卤甲基青霉烯(Ⅰ)的反应混合物，不需要进一步纯化，可直接使用，得到所需要的青霉烯衍生物(例子可参见US-4,794,109所述)。
具体地，本发明涉及了2-氯甲基青霉烯[分子式(Ⅰ)的化合物，其中X=C1,R1和R2如上所定义]的制备方法。
根据本发明，保护醇羟基的R1优选为三-C1-6烷基甲硅烷基(如叔丁基-二甲基-甲硅烷基和三甲基甲硅烷基)、烯丙氧基羰酰基，对硝基苄基氧基羰酰基；而保护羧基的基团R2优选为烯丙基、苄基(也可能用甲氧基或硝基所取代)、CH2OCO(O)mR4，其中R4代表C1-6烷基，m代表0或1。
本发明中，卤素是：氯、溴、碘，特别是氯。
下面的例子可进一步说明本发明。
实施例1
(3S,4R)-3[(R)-叔丁基二甲基甲硅氧乙基]-4-(2-氯乙酰硫基)-2-氮杂环丁酮
在20℃，氮气保护条件下，将83.3克(0.261mols)的碘化锌加入50克(0.174mol)的(3R,4R)-4-乙酸基-3-[(R)-叔丁基二甲基甲硅烷氧乙基]-2-氮杂环丁酮的溶液中；15分钟后，加入38.3克(0.346mol)的2-氯乙酸。将混合物冷却至12℃，1小时后，再将26.5ml(0.910mol)三乙胺与50ml的二噁烷的混合溶液加入其中。将混合物于同样温度下，搅拌2小时。再加入5.0ml(0.036mol)的三乙胺且搅拌30分钟。
将此溶液倒入3％的NaHSO4冷溶液中，并用乙酸乙酯萃取。有机相用溶液NaHSO33％、NaHCO35％、水、NaCl10％冲洗，并用无水Na2SO4干燥。通过真空干燥，蒸发溶剂，可得到黄棕色产物。加入乙醚，并蒸发溶剂，可得乳白色固体。产率：57克(97％)。
1H NMR(200MHz)(CDCl3):d 0.07(3H,S),0.08(3H,S),0.88(9H,S)；1.21(3H,d,J=6.3Hz),3.23(1H,dd,J=2.3,4.0Hz),4.22(2H,S),4.27(1H,qd,J=3.7,6.3Hz),5.32(1H,d,J=2.3Hz),6.4(1H,br s)。13CNMR(50MHz)(CDCl3):d-4.3,-5.1,17.9,22.3,25.7,48.0,52.4,64.6,65.4,166.1,194.8。MS TS(m/z):(M+H)+338,(M+NH4)+355。
实施例2
(3S,4R)-1-(烯丙氧基乙二酰基)-3-[(R)-叔丁基二甲基-甲硅氧乙基]-4-(2-氯乙酰硫)-2-氮杂环丁酮
将42.3ml(0.338mol)的烯丙氧基乙二酰氯于0℃～3℃，氮气保护的条件下加入到含有57克(0.169mol)(3S,4R)-3-[(R)-叔丁基二甲基甲硅氧烷乙基]-4-(2-氯乙酰硫)-2-氮杂环丁酮的四氢呋喃(500ml)的溶液中。搅拌混合物数分钟并且在45分钟内，将含有43.4ml(0.254mol)二异丙基乙胺的四氢呋喃(40ml)的混合溶液一滴一滴的加入。将此混合物在相同的温度下搅拌30分钟。再加入15ml(0.087mol)二异丙基乙胺，搅拌溶液30分钟，过滤。
将滤液倒入NaHCO35％的冷溶液中，用n-esane萃取，并用相同的溶剂冲洗过滤器上残留的固体，将有机相集中在一起，用水和NaCl10％冲洗，并用无水Na2SO4干燥。蒸发掉溶剂，即可得到棕色油状物，它可用于进行下列反应步骤，而不需进一步纯化。
产率：73.0克(96％)。
1H NMR(200MHz)(CDCl3):d-0.04(3H,S),-0.09(3H,S),0.85(9H,S),1.24(3H,d,J=6.3Hz),3.52(1H,t,J=3Hz),4.26(2H,S),4.38(1H,qd,J=3,6.3Hz),4.70-4.82(2H,m),5.22-5.46(2H,m),5.80～6.06(1H,m),5.97(1H,d,J=3Hz)。13C NMR(50 MHz)(CDCl3):d-5.2,-4.3,17.8,21.7,25.6,47.9,53,8,64.7,66.3,67.4,120.1,130.5,154.5,159.0,162.9,190.7 msTS(m/z):(m+NH4)+467。
实施例3
烯丙基(5R,6S)-2-氯甲基-6[(R)-1-叔丁基二甲基甲硅氧乙基)-青霉烯-3-羧酸酯
向含有73克(0.162 mol)(3S,4R)-1-(烯丙氧基乙二酰基)-3-[(R)-叔丁基二甲基甲硅氧乙基]-4-(2-氯乙酰硫)-2-氮杂环丁酮的甲苯(730ml)溶液中加入59克(0.356mol)的三乙基亚磷酸酯。并将此溶液回流3小时。再将溶液冷却并在真空条件下浓缩，经柱色谱后，(硅胶；环己烷/乙酸乙酯3:1V/V)，可得所需要的烯丙基(5R,6S)-2-氯甲基-6[(R)-1-叔丁基二甲基甲硅氧乙基]-青霉烯-3-羧酸酯的黄色油状物。
产率：82％。
高效液体色谱
HPLC:1)柱：Hgpersil 5 ODS 5mm C18,4.6×250mm；流动相：水/乙腈20∶80V/V；流速=1ml/分，1=220,320nm；tR=8.4分。2)柱：BondClone 10,10mm,C18,3.9×300mm；流动相：水/乙腈20∶80V/V，流速=1ml/min,1=205,245nm；tR=9.6分。
1H NMR(200MHz)(CDCl3):d 0.07(6H,S),0.87(9H,S),1.23(3H,d,J=6.2Hz),3.73(1H,dd,J=1.6,4.3Hz),4.60～4.81(2H,m),4.62和4.94(2H,ABq,J=14Hz),5.20～5.47(2H,m),5.63(1H,d,J=1.6Hz),5.81-6.03(1H,m)。13CMR(50Hz)(CDCl3):d-5.3,-4.7,17.9,22.3,25.6,37.6(CH2-Cl),62.4,64.9.65.9,72.0,118.6,121.8,131.2,150.9,158.9,172.3。mS EI:(m/z)417(M+)。
实施例4：
将14.1ml(0.113mol)的烯丙氧基乙二酰氯在0℃～3℃,氮气条件下加入含有19克(0.056mol)(3S,4R)-1-(烯丙氧基乙二酰)-3-[(R)-叔丁基二甲基-甲硅烷氧乙基]-4-(2-氯乙酰硫)-2-氮杂环丁酮的无水甲苯(150ml)的溶液中。将此溶液搅拌数分钟，再将含有11.7ml(0.084mol)三乙基胺的甲胺(10ml的混合溶液)一滴一滴的加入。在不变的温度条件下，将此溶液搅拌90分钟。再加入3.9ml(0.028moles)三乙胺。并将该溶液搅拌90分钟并过滤。用冷NaHCO35％水溶液，水和NaCl10％溶液冲洗滤液；再用无水Na2SO4干燥并过滤。再加入20.4克(0.123mol)三乙基亚磷酸盐，并将该混合物回流3小时。
溶液在真空条件下经冷却、浓缩，并通过柱色谱纯化(硅胶；环己烷/乙酸乙酯3∶1V/V)，得到所需要的黄色油状物烯丙基(5R,6s)-2-氯甲基-6-((R)-1-叔丁基二甲基甲硅烷氧乙基)-青霉烯-3-羧酸酯。
产率：71％。
Claims (8)
1．制备式(Ⅰ)所示的2-卤甲基-青霉烯的方法，
其中R1代表醇羟基的保护基团，R2代表羧基的保护基，X代表一个卤素，其制法包括中间步骤，即制备相应的2-卤乙酰硫-氮杂环丁酮(Ⅴ)，
其中X代表卤素。
2．权利要求1的方法，其中：a)在有机碱和路易酸的存在条件下，反应温度为-10℃～+40℃，式(Ⅲ)所示化合物与2-卤硫代乙酸在有机溶剂中反应，得到权利要求1中所定义的式(Ⅴ)所示化合物；
其中R1如上所定义
b)在有机碱存在条件下，反应温度为-60℃～+20℃，优选是-20℃～+10℃时，上述式(V)所示化合物与草酰氯在有机溶剂中反应，得到式(Ⅶ)所示化合物其中R1,R2,X如上所定义；
c)在有机亚磷酸盐或膦酸盐的作用下，在合适的溶剂中，于20℃～140℃反应1～120h，式(Ⅶ)所示化合物最后发生环化反应。
3．权利要求1的方法，用于制备通式(Ⅰ)的衍生物，其中所述保护基R1可以是下列基团：叔丁基二甲基甲硅烷基，三甲基甲硅烷基、烯丙氧基羰酰基、对硝基苄基氧化羰基；基团R2可以是下列基团：烯丙基，苯基(也可能用甲氧基或硝基所取代)，CH2OCO(O)mR4，其中R4是C1～6烷基，m代表0或1；优选的有机械有三乙胺或二异丙乙胺，该路易斯酸选自：碘化锌、溴化锌、氯化锌，氯化铝以及有机亚磷酸盐或膦酸盐是三甲基-、三乙基亚磷酸盐或二甲氧基甲基膦。
4．权利要求1或2的方法，其中所述2-卤硫代乙酸是2-氯硫代乙酸。
5．权利要求3的方法，其中所得化合物(Ⅰ)是权利要求1中式(Ⅰ)所示化合物，其中R1=叔丁基二甲基甲硅烷基，R2=烯丙基，X=氯。
6．式(Ⅴ)所示化合物
其中R1和X如上所定义。
7．式(Ⅶ)所示化合物
其中R1,R2和X如上所定义。
8．权利要求5或6的化合物，其中所述X=氯。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT96FI000033A IT1286558B1 (it) | 1996-02-27 | 1996-02-27 | Processo per la preparazione di 2-alogenometil-penems e loro uso per la preparazione di penems antibatterici |
| ITFI96A000033 | 1996-02-27 |
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| Publication Number | Publication Date |
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| CN1211988A true CN1211988A (zh) | 1999-03-24 |
| CN1116298C CN1116298C (zh) | 2003-07-30 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN97192589A Expired - Fee Related CN1116298C (zh) | 1996-02-27 | 1997-02-19 | 制备2－卤甲基－青霉烯的方法及其在制备抗菌青霉烯中的应用 |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US6153747A (zh) |
| EP (1) | EP0883620B1 (zh) |
| CN (1) | CN1116298C (zh) |
| AU (1) | AU1792397A (zh) |
| CA (1) | CA2247269A1 (zh) |
| DE (1) | DE69715158T2 (zh) |
| ES (1) | ES2180926T3 (zh) |
| IT (1) | IT1286558B1 (zh) |
| PL (1) | PL328435A1 (zh) |
| RU (1) | RU2175971C2 (zh) |
| WO (1) | WO1997031922A1 (zh) |
| ZA (1) | ZA971471B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT368506B (de) * | 1979-02-24 | 1982-10-25 | Erba Farmitalia | Verfahren zur herstellung von neuen penemcarbonsaeuren und deren salzen |
| GB2118181B (en) * | 1982-04-08 | 1986-07-30 | Erba Farmitalia | Substituted penem derivatives and new process for their preparation |
| US4794109A (en) * | 1982-11-16 | 1988-12-27 | Ciba-Geigy Corporation | 6-hydroxy-lower alkylpenem compounds, pharmaceutical preparations that contain these compounds, and the use of the latter |
| JPS59152387A (ja) * | 1983-02-10 | 1984-08-31 | Shionogi & Co Ltd | 新規ペネム化合物 |
| GB8321677D0 (en) * | 1983-08-11 | 1983-09-14 | Erba Farmitalia | Preparation of penems |
| GB9110507D0 (en) * | 1991-05-15 | 1991-07-03 | Smithkline Beecham Plc | Chemical compounds |
-
1996
- 1996-02-27 IT IT96FI000033A patent/IT1286558B1/it active IP Right Grant
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1997
- 1997-02-19 EP EP97903325A patent/EP0883620B1/en not_active Expired - Lifetime
- 1997-02-19 CA CA002247269A patent/CA2247269A1/en not_active Abandoned
- 1997-02-19 WO PCT/EP1997/000783 patent/WO1997031922A1/en active IP Right Grant
- 1997-02-19 PL PL97328435A patent/PL328435A1/xx unknown
- 1997-02-19 AU AU17923/97A patent/AU1792397A/en not_active Abandoned
- 1997-02-19 CN CN97192589A patent/CN1116298C/zh not_active Expired - Fee Related
- 1997-02-19 RU RU98117732/04A patent/RU2175971C2/ru not_active IP Right Cessation
- 1997-02-19 ES ES97903325T patent/ES2180926T3/es not_active Expired - Lifetime
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- 1997-02-20 ZA ZA9701471A patent/ZA971471B/xx unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| PL328435A1 (en) | 1999-02-01 |
| ITFI960033A1 (it) | 1997-08-27 |
| CA2247269A1 (en) | 1997-09-04 |
| CN1116298C (zh) | 2003-07-30 |
| ES2180926T3 (es) | 2003-02-16 |
| ITFI960033A0 (it) | 1996-02-27 |
| ZA971471B (en) | 1997-09-04 |
| DE69715158D1 (de) | 2002-10-10 |
| RU2175971C2 (ru) | 2001-11-20 |
| EP0883620B1 (en) | 2002-09-04 |
| WO1997031922A1 (en) | 1997-09-04 |
| US6153747A (en) | 2000-11-28 |
| EP0883620A1 (en) | 1998-12-16 |
| IT1286558B1 (it) | 1998-07-15 |
| DE69715158T2 (de) | 2003-05-15 |
| AU1792397A (en) | 1997-09-16 |
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