DE3921830A1 - METHOD FOR PRODUCING PENEMAS - Google Patents
METHOD FOR PRODUCING PENEMASInfo
- Publication number
- DE3921830A1 DE3921830A1 DE3921830A DE3921830A DE3921830A1 DE 3921830 A1 DE3921830 A1 DE 3921830A1 DE 3921830 A DE3921830 A DE 3921830A DE 3921830 A DE3921830 A DE 3921830A DE 3921830 A1 DE3921830 A1 DE 3921830A1
- Authority
- DE
- Germany
- Prior art keywords
- group
- formula
- compound
- unsubstituted
- substituted
- 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.)
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- 238000004519 manufacturing process Methods 0.000 title claims description 6
- -1 benzoyloxymethyl Chemical group 0.000 claims abstract description 49
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 125000006239 protecting group Chemical group 0.000 claims abstract description 7
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-O Piperidinium(1+) Chemical compound C1CC[NH2+]CC1 NQRYJNQNLNOLGT-UHFFFAOYSA-O 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 125000005846 1-(alkanoyloxy)ethyl group Chemical group 0.000 claims abstract description 3
- 125000005848 1-(alkoxycarbonyloxy)ethyl group Chemical group 0.000 claims abstract description 3
- 125000005042 acyloxymethyl group Chemical group 0.000 claims abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000005206 alkoxycarbonyloxymethyl group Chemical group 0.000 claims abstract description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 3
- 125000003944 tolyl group Chemical group 0.000 claims abstract description 3
- 125000001589 carboacyl group Chemical group 0.000 claims abstract 4
- 238000000034 method Methods 0.000 claims description 21
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 229910052725 zinc Inorganic materials 0.000 claims description 10
- 239000011701 zinc Substances 0.000 claims description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052709 silver Inorganic materials 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 239000004332 silver Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 238000005949 ozonolysis reaction Methods 0.000 claims description 3
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 239000000956 alloy Substances 0.000 claims description 2
- 229910045601 alloy Inorganic materials 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 150000002961 penems Chemical class 0.000 abstract description 5
- 230000000844 anti-bacterial effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- FZKGLCPKPZBGLX-ROXVQFJHSA-N acetyloxymethyl (5r,6s)-3-(carbamoyloxymethyl)-6-[(1r)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound S1C(COC(N)=O)=C(C(=O)OCOC(C)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 FZKGLCPKPZBGLX-ROXVQFJHSA-N 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical class NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- NMZCDTDPTLTPSC-PUQNFTFYSA-N acetyloxymethyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(methoxymethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound O[C@H](C)[C@@H]1[C@@H]2N(C(=C(S2)COC)C(=O)OCOC(C)=O)C1=O NMZCDTDPTLTPSC-PUQNFTFYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 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
- 244000309464 bull Species 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000004246 zinc acetate Substances 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
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von 6-[(1R)-Hydroxyethyl]penemen, die in der Synthese antibakterieller Mittel nützlich sind, sie betrifft auch Zwischenprodukte, die im Verfahren verwendet werden, sowie die Herstellung der Zwischenprodukte.The present invention relates to a method for Preparation of 6 - [(1R) -Hydroxyethyl] penemen, which in the Synthesis of antibacterial agents are useful, it concerns also intermediate products that are used in the process, as well as the production of the intermediate products.
Insbesondere betrifft die Erfindung ein Verfahren zur Herstellung von Verbindungen der Formel (I)In particular, the invention relates to a method for Preparation of compounds of formula (I)
worin Rwhere R
- (a) Alkanoyloxymethyl oder 1-(Alkanoyloxy)ethyl, worin der Alkanoylrest ein geradkettiges oder verzweigtes C2-10-Alkanoyl oder eine C4-8-Cycloalkanoylgruppe ist;(a) alkanoyloxymethyl or 1- (alkanoyloxy) ethyl, wherein the alkanoyl group is a straight or branched C 2-10 alkanoyl or a C 4-8 cycloalkanoyl group;
- (b) Benzoyloxymethyl oder 1-(Benzoyloxy)ethyl;(b) benzoyloxymethyl or 1- (benzoyloxy) ethyl;
- (c) Alkoxycarbonyloxymethyl oder 1-(Alkoxycarbonyloxy)ethyl;(c) alkoxycarbonyloxymethyl or 1- (alkoxycarbonyloxy) ethyl;
- (d) 3-Phthalidyl;(d) 3-phthalidyl;
- (e) 2-Oxo-1,3-dioxolan-4-yl, und zwar unsubstituiert oder substituiert durch eine C1-4-Alkylgruppe in der 5-Position;(e) 2-oxo-1,3-dioxolan-4-yl, unsubstituted or substituted by a C 1-4 alkyl group in the 5-position;
- (f) -CH₂COOR′, worin R′ ein geradkettiges oder verzweigtes C1-4-Alkyl oder Benzyl ist; oder(f) -CH₂COOR ', wherein R' is a straight or branched C 1-4 alkyl or benzyl; or
- (g) 2-Oxotetrahydrofuran-5-yl, und zwar unsubstituiert oder substituiert durch eine C1-4-Alkylgruppe in der 4-Position, darstellt;(g) 2-Oxotetrahydrofuran-5-yl, unsubstituted or substituted by a C 1-4 alkyl group in the 4-position;
R₁ Tetrahydrofuranyl oder eine unsubstituierte oder substituierte C1-4-Alkyl-, Methylphenyl- oder Methylphenoxymethylgruppe ist, wobei die Substituenten aus den Gruppen ausgewählt sind:R₁ is tetrahydrofuranyl or an unsubstituted or substituted C 1-4 alkyl, methylphenyl or methylphenoxymethyl group, the substituents being selected from the groups:
- (i) Carbamoyloxy, C1-18-Alkoxy, Carboxy oder freies oder geschütztes Hydroxy und(i) carbamoyloxy, C 1-18 alkoxy, carboxy or free or protected hydroxy and
- (ii) unsubstituiertes oder substituiertes und/oder kondensiertes Pyridinium, N-Methylpyrrolidinium oder Piperidinium, wobei die Substituenten eine genannte Gruppe (i) oder eine unsubstituierte oder durch eine Sulfonyloxy- oder Carboxygruppe substituierte C1-4-Alkylgruppe sind; und(ii) unsubstituted or substituted and / or fused pyridinium, N-methylpyrrolidinium or piperidinium, the substituents being a said group (i) or an unsubstituted or substituted by a sulfonyloxy or carboxy group C 1-4 alkyl group; and
R₂ ein Wasserstoffatom oder eine Schutzgruppe für die
Hydroxygruppe bedeutet,
wobei man eine Verbindung der Formel (II)R₂ represents a hydrogen atom or a protective group for the hydroxy group,
where a compound of formula (II)
reduziert, worin R, R₁ und R₂ wie vorstehend definiert sind.reduced, wherein R, R₁ and R₂ are as defined above.
Die Alkoxyreste enthalten vorzugsweise 1 bis 6 Kohlenstoffatome, und noch bevorzugter 1 bis 4 Kohlenstoffatome. R₂ oder die Schutzgruppe für die Hydroxygruppe in R₁ kann beispielsweise eine p-Nitrobenzyloxycarbonyl-, Trimethylsilyl-, t-Butyldimethylsilyl-, t-Butyldiphenylsilyl-, Methoxymethyl-, Benzyl-, p-Bromphenacyl, Triphenylmethyl- oder Tetrahydropyranylgruppe sein.The alkoxy radicals preferably contain 1 to 6 Carbon atoms, and more preferably 1 to 4 carbon atoms. R₂ or the protective group for the hydroxy group in R₁ can for example a p-nitrobenzyloxycarbonyl, trimethylsilyl, t-butyldimethylsilyl-, t-butyldiphenylsilyl-, methoxymethyl-, Benzyl, p-bromophenacyl, triphenylmethyl or Be tetrahydropyranyl group.
Beispiele der Gruppen, die an die Pyridinium-, N-Methylpyrrolidinium- und Piperidiniumgruppen kondensiert sein können, sind eine Phenylgruppe und eine gesättigte oder ungesättigte cycloaliphatische oder heterozyklische C5-7-Gruppe. Die heterozyklische Gruppe kann beispielsweise 1 bis 4 Heteroatome enthalten, ausgewählt aus Sauerstoff-, Stickstoff- und Schwefelatomen. Bevorzugte Gruppen, die an die Pyridinium-, N-Methylpyrrolidinium- und Piperidiniumgruppen kondensiert sind, sind: Examples of the groups which may be fused to the pyridinium, N-methylpyrrolidinium and piperidinium groups are a phenyl group and a saturated or unsaturated cycloaliphatic or heterocyclic C 5-7 group. The heterocyclic group can contain, for example, 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms. Preferred groups fused to the pyridinium, N-methylpyrrolidinium and piperidinium groups are:
Beispiele von Verbindungen der Formel (I) sind beschrieben in der europäischen Patentanmeldung 8 83 05 277.1, GB-A-21 33 010 und GB-A-20 97 786.Examples of compounds of formula (I) are described in European patent application 8 83 05 277.1, GB-A-21 33 010 and GB-A-20 97 786.
Die vorliegende Erfindung stellt auch eine Verbindung der Formel (II) und ferner ein Verfahren zur Herstellung einer Verbindung der Formel (II) zur Verfügung, wobei man eine Verbindung der Formel (V)The present invention also provides a combination of Formula (II) and further a method for producing a Compound of formula (II) available, wherein one Compound of formula (V)
zyklisiert, worin R, R₁ und R₂ wie vorstehend definiert sind.cyclized, wherein R, R₁ and R₂ are as defined above.
Die Verbindung der Formel (V) kann durch Ozonolyse einer Verbindung der Formel (III) hergestellt werden: The compound of formula (V) can be obtained by ozonolysis Compound of formula (III) can be prepared:
worin R, R₁ und R₂ wie vorstehend definiert sind.wherein R, R₁ and R₂ are as defined above.
Das Verfahren der vorliegenden Erfindung liefert Peneme der Formel (I) in guter Ausbeute und hoher optischer Reinheit. Es unterscheidet sich vom Stand der Technik dadurch, daß das Bromatom am β-Lactamring bis zur letzten Stufe beibehalten wird. Der Ersatz des Bromatoms durch ein Wasserstoffatom erfolgt mit höherer Stereoselektivität an der Verbindung der Formel (II) als an anderen im Verfahren in früheren Stufen vorliegenden Zwischenprodukten. Darüber hinaus sind die im Verfahren enthaltenen Zwischenprodukte stabiler und leichter zu handhaben als andere, über die früher berichtet wurde, und können deshalb ohne Zersetzung aufbewahrt werden.The process of the present invention provides penems of formula (I) in good yield and high optical purity. It differs from the prior art in that the bromine atom on the β- lactam ring is retained up to the last stage. The bromine atom is replaced by a hydrogen atom with higher stereoselectivity on the compound of the formula (II) than on other intermediates present in the process in earlier stages. In addition, the intermediates contained in the process are more stable and easier to handle than others previously reported and can therefore be stored without decomposition.
Die Konfiguration der Verbindungen der Formel (II) ist [5R,6S,(1R)], um die bevorzugte endgültige [5R,6S,(1R)]-Stereochemie des Penemkernes zu erhalten. Das Ausgangsmaterial für die Verbindung von Formel (III) kann bequem aus 6-Aminopenicillansäure hergestellt werden, wie in EP-A-01 88 247 beschrieben. Die vorliegende Erfindung erlaubt daher die Synthese von Verbindungen der Formel (I), und zwar direkt aus 6-Aminopenicillansäure, wie dies im folgenden Reaktionsschema zusammengefaßt dargestellt ist. The configuration of the compounds of formula (II) is [5R, 6S, (1R)] to the preferred final [5R, 6S, (1R)] - stereochemistry of the penile nucleus. The Starting material for the compound of formula (III) can can be conveniently made from 6-aminopenicillanic acid, such as in EP-A-01 88 247. The present invention therefore allows the synthesis of compounds of formula (I), and directly from 6-aminopenicillanic acid, as in following reaction scheme is summarized.
In dem Schema werden Verbindungen der Formel (V) im allgemeinen bei einer niedrigen Temperatur durch Ozonolyse von Verbindungen (III) hergestellt und im allgemeinen durch Behandlung mit Triethylphosphit oder Trimethylphosphit in einem inerten organischen Lösungsmittel, wie Chloroform, Benzol, Toluol oder Xylol, zu Verbindungen (II) zyklisiert. Beispiele von Reaktionsbedingungen für die Zyklisierung sind im Detail beschrieben in C. Battistini et al., Tetrahedron Lett. 25, 2595 (1984); A. Yoshida et al., Chem. Pharm. Bull., 31, 768 (1983) und der darin enthaltenen Referenzliteratur, sowie in US-A-46 31 150.In the scheme, compounds of formula (V) in generally at a low temperature by ozonolysis of compounds (III) prepared and in general by Treatment with triethyl phosphite or trimethyl phosphite in an inert organic solvent such as chloroform, Benzene, toluene or xylene, cyclized to compounds (II). Examples of reaction conditions for the cyclization are described in detail in C. Battistini et al., Tetrahedron Lett. 25: 2595 (1984); A. Yoshida et al., Chem. Pharm. Bull., 31, 768 (1983) and the contained therein Reference literature, as well as in US-A-46 31 150.
Die Verbindungen der Formel (II) werden in jeder geeigneten Weise, wie einer katalytischen Hydrierung oder einer Behandlung mit reduzierenden Metallen, zu den Verbindungen (I) reduziert. Vorzugsweise werden Peneme (I) aus (II) durch Behandlung mit Zink oder einer Legierung davon mit einem anderen Metall, wie Kupfer oder Silber, erhalten. Die Reaktion wird vorzugsweise in einem organischen Lösungsmittel, wie Acetonitril, Ethylether, t-Butylmethylether, Ethylacetat, Tetrahydrofuran, Aceton, Chloroform oder Methylenchlorid, in Gegenwart einer wäßrigen Lösung von Ammonium- oder Zinkcarboxylat oder -halogenid durchgeführt. Die Reaktionstemperatur reicht im allgemeinen von -20 bis +80°C. Am Ende der Reaktion werden die Peneme der Formel (I) durch herkömmliche Aufarbeitungsverfahren gewonnen. Die Rohprodukte der Reaktion werden, falls notwendig, von ihren Schutzgruppen befreit und durch Säulenchromatografie gereinigt.The compounds of formula (II) are in any suitable Way, like a catalytic hydrogenation or one Treatment with reducing metals, to the compounds (I) reduced. Penems (I) from (II) are preferably by treatment with zinc or an alloy thereof another metal, such as copper or silver. The Reaction is preferably in an organic solvent, such as acetonitrile, ethyl ether, t-butyl methyl ether, Ethyl acetate, tetrahydrofuran, acetone, chloroform or Methylene chloride, in the presence of an aqueous solution of Ammonium or zinc carboxylate or halide performed. The reaction temperature generally ranges from -20 to + 80 ° C. At the end of the reaction, the penems of the formula (I) obtained by conventional processing methods. The Crude products of the reaction are, if necessary, of theirs Protective groups freed and by column chromatography cleaned.
Die Peneme der Formel (I) sind antibakterielle Mittel. Sie können deshalb als Arzneimittel formuliert werden, wobei sie auch einen pharmazeutisch verträglichen Träger oder ein Verdünnungsmittel enthalten. The penems of formula (I) are antibacterial agents. they can therefore be formulated as a drug, where it is also a pharmaceutically acceptable carrier or contain a diluent.
Die folgenden Beispiele verdeutlichen die vorliegende Erfindung.The following examples illustrate the present one Invention.
(3S,4R)-1-(1-Acetoxymethyloxycarbonyl-2-methyl-1-propenyl)- 4-acylthio-3-brom-3-[1-(R)-hydroxyethyl]-azetidin-2-on (III, R=CH₂OCOCH₃, R₂=H) wurde aus Acetoxymethyl (3S,5R,6S)-6-brom-6-[1-(R)-hydroxyethyl]-penicillanat (IV, R=CH₂OCOCH₃) hergestellt, wie von Alpegiani et al., J. Am. Chem. Soc. 107, 6398 (1985), beschrieben.(3S, 4R) -1- (1-acetoxymethyloxycarbonyl-2-methyl-1-propenyl) - 4-acylthio-3-bromo-3- [1- (R) -hydroxyethyl] -azetidin-2-one (III, R = CH₂OCOCH₃, R₂ = H) was from acetoxymethyl (3S, 5R, 6S) -6-bromo-6- [1- (R) -hydroxyethyl] penicillanate (IV, R = CH₂OCOCH₃) made as described by Alpegiani et al., J. Am. Chem. Soc. 107, 6398 (1985).
Rohes (III) wurde in sein Trimethylsilyl-(TMS)-Derivat gemäß herkömmlicher Verfahren überführt.Crude (III) was converted into its trimethylsilyl (TMS) derivative according to transferred to conventional methods.
Das geschützte Azetidinon (III) (20 mMol) wurde in trockenem Methylenchlorid (300 ml) bei -78°C gelöst. Ozon wurde bei derselben Temperatur 4 bis 6 Stunden lang durch die Lösung geblubbert. Am Ende der Reaktion wurde Stickstoff durchgeleitet, um überschüssiges Ozon zu entfernen, und man ließ die Mischung 0°C erreichen. Die Lösung wurde mit Natriumbisulfit (0,2 M, 2 × 100 ml) gewaschen und über Natriumsulfat getrocknet. Eindampfen der Lösung ergab das Oxamid (V), das einige Tage lang ohne jede Zersetzung aufbewahrt werden konnte.The protected azetidinone (III) (20 mmol) was dried Methylene chloride (300 ml) dissolved at -78 ° C. Ozone was added the same temperature for 4 to 6 hours through the solution bubbled. At the end of the reaction became nitrogen passed through to remove excess ozone, and one allowed the mixture to reach 0 ° C. The solution was with Sodium bisulfite (0.2 M, 2 x 100 ml) washed and over Dried sodium sulfate. Evaporation of the solution gave this Oxamide (V), which for a few days without any decomposition could be kept.
- (Va) (R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=TMS): weißer Schaum; 80% Ausbeute; 1H-NMR delta (CDCl₃): 0,2 (9H, s, OTMS), 1,55 (3H, d, CH₃-CH), 2,15 (3H, s, OCOCH₃), 4,18 (1H, m, H-8), 4,82 (2H, AB-System, SCOCH₂), 5,1 (2H, br, NH₂), 5,9 (2H, AB-System, CH₂OCOCH₃), 6,23 (1H, s, H-5).(Va) (R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = TMS): white foam; 80% yield; 1H-NMR delta (CDCl₃): 0.2 (9H, s, OTMS), 1.55 (3H, d, CH ₃-CH), 2.15 (3H, s, OCOCH₃), 4.18 (1H, m, H-8), 4.82 (2H, AB system, SCOCH₂), 5.1 (2H, br, NH₂), 5.9 (2H, AB system, CH ₂OCOCH₃), 6.23 (1H , s, H-5).
- (Vb) (R=CH₂OCOCH₃, R₁=CH₂OCH₃, R₂=TMS): Öl; 82% Ausbeute; 1H-NMR delta (CDCl₃): 0,2 (9H, s, OTMS), 1,55 (3H, d, CH₃CH), 2,15 (3H, s, OCOCH₃), 3,5 (3H, s, OCH₃), 4,13-4,22 (3H: SCOCH₂ und H-8), 5,9 (2H, AB-System, CH₂OCOCH₃), 6,22 (1H, s, H-5).(Vb) (R = CH₂OCOCH₃, R₁ = CH₂OCH₃, R₂ = TMS): oil; 82% yield; 1H-NMR delta (CDCl₃): 0.2 (9H, s, OTMS), 1.55 (3H, d, CH ₃CH), 2.15 (3H, s, OCOCH₃), 3.5 (3H, s, OCH₃), 4.13-4.22 (3H: SCOCH₂ and H-8), 5.9 (2H, AB system, CH ₂OCOCH₃), 6.22 (1H, s, H-5).
- (Vc) (R=CH₂OCOCH₃, R₁=CH₃, R₂=TMS): Öl; 75% Ausbeute; 1H-NMR delta (CDCl₃): 0,2 (9H, s, OTMS), 1,55 (3H, d, CH₃-CH), 2,15 (3H, s, OCOCH₃), 2,35 (3H, s, SCOCH₃), 4,12 (1H, m, H-8), 5,85 (2H, AB-System, CH₂OCOCH₃), 6,02 (1H, s, H-5).(Vc) (R = CH₂OCOCH₃, R₁ = CH₃, R₂ = TMS): oil; 75% yield; 1H-NMR delta (CDCl₃): 0.2 (9H, s, OTMS), 1.55 (3H, d, CH₃-CH), 2.15 (3H, s, OCOCH₃), 2.35 (3H, s , SCOCH₃), 4.12 (1H, m, H-8), 5.85 (2H, AB system, CH ₂OCOCH₃), 6.02 (1H, s, H-5).
Rohes (V) wurde in trockenem Toluol oder Xylol (70 ml) gelöst; Triethylphosphit (8,7 ml, 50 mMol) wurde zugegeben und die Lösung 1 bis 6 Stunden lang am Rückfluß gekocht. Am Ende der Reaktion wurde die Mischung auf 20°C abgekühlt, mit Phosphatpuffer gewaschen (pH=7,3 × 20 ml) und über Natriumsulfat getrocknet. Eindampfen des Lösungsmittels ergab ein Öl, welches durch Säulenchromatografie gereinigt wurde, um das 8-O-geschützte Brompenem (II) zu ergeben.Crude (V) was in dry toluene or xylene (70 ml) solved; Triethyl phosphite (8.7 ml, 50 mmol) was added and the solution was refluxed for 1 to 6 hours. At the end of the reaction the mixture was cooled to 20 ° C, washed with phosphate buffer (pH = 7.3 × 20 ml) and over Dried sodium sulfate. Evaporation of the solvent resulted in Oil purified by column chromatography to to give the 8-O-protected bromene compound (II).
- (IIa) (R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=TMS): gelbes Öl; 50% Ausbeute; 1H-NMR delta (CDCl₃): 0,13 (9H, s, OTMS), 1,28 (3H, d, CH₃CH), 2,1 (3H, s, OCOCH₃), 4,33 (1H, m, H-8), 5,0-5,5 (2H, AB-System, CH₂OCONH₂), 4,95 (2H, br, OCONH₂), 5,75 (1H, s, H-5), 5,85 (2H, AB-System, CH₂OCOCH₃).(IIa) (R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = TMS): yellow oil; 50% yield; 1H-NMR delta (CDCl₃): 0.13 (9H, s, OTMS), 1.28 (3H, d, CH ₃CH), 2.1 (3H, s, OCOCH₃), 4.33 (1H, m, H-8), 5.0-5.5 (2H, AB system, CH ₂OCONH₂), 4.95 (2H, br, OCONH₂), 5.75 (1H, s, H-5), 5.85 (2H, AB system, CH ₂OCOCH₃).
- (IIb) (R=CH₂OCOCH₃, R₁=CH₂OCH₃, R₂=TMS): gelbes Öl; 57% Ausbeute; 1H-NMR delta (CDCl₃): 0,13 (9H, s, OTMS), 1,3 (3H, d, CH₃CH), 2,13 (3H, s, OCOCH₃), 3,4 (3H, s, OCH₃), 4,37 (1H, m, H-8), 4,64 (2H, AB-System, CH₂OCH₃), 5,24 (1H, s, H-5), 5,85 (2H, AB-System, CH₂OCOCH₃).(IIb) (R = CH₂OCOCH₃, R₁ = CH₂OCH₃, R₂ = TMS): yellow oil; 57% yield; 1H-NMR delta (CDCl₃): 0.13 (9H, s, OTMS), 1.3 (3H, d, CH ₃CH), 2.13 (3H, s, OCOCH₃), 3.4 (3H, s, OCH₃), 4.37 (1H, m, H-8), 4.64 (2H, AB system, CH ₂OCH₃), 5.24 (1H, s, H-5), 5.85 (2H, AB System, CH ₂OCOCH₃).
- (IIc) (R=CH₂OCOCH₃, R₁=CH₃, R₂=TMS): gelbes Öl; 42% Ausbeute; 1H-NMR delta (CDCl₃): 0,13 (9H, s, OTMS), 1,3 (3H, d, CH₃CH), 2,12 (3H, s, OCOCH₃), 2,4 (3H, s, 2-CH₃), 4,35 (1H, m, H-8), 5,71 (1H, s, H-5), 5,85 (2H, AB-System, CH₂OCOCH₃).(IIc) (R = CH₂OCOCH₃, R₁ = CH₃, R₂ = TMS): yellow oil; 42% yield; 1H-NMR delta (CDCl₃): 0.13 (9H, s, OTMS), 1.3 (3H, d, CH ₃CH), 2.12 (3H, s, OCOCH₃), 2.4 (3H, s, 2-CH₃), 4.35 (1H, m, H-8), 5.71 (1H, s, H-5), 5.85 (2H, AB system, CH ₂OCOCH₃).
Das geschützte (II), erhalten wie vorstehend beschrieben, wurde gemäß herkömmlicher Verfahren von der Schutzgruppe befreit, um das entsprechende 8-OH-Brompenem (II) zu ergeben.The protected (II) obtained as described above was established by the protecting group according to conventional procedures freed to the corresponding 8-OH bromophenem (II) surrender.
- (IIe) (R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=H): gelbes Öl; 1H-NMR delta (CDCl₃): 1,3 (3H, d, CH₃CH), 2,13 (3H, s, OCOCH₃), 2,7 (1H, br, OH), 4,38 (1H, m, H-8), 5,05-5,47 (2H, AB-System, CH₂OCONH₂), 4,98 (2H, br, OCONH₂), 5,81 (1H, s, H-5), 5,87 (2H, AB-System, CH₂OCOCH₃).(IIe) (R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = H): yellow oil; 1H-NMR delta (CDCl₃): 1.3 (3H, d, CH ₃CH), 2.13 (3H, s, OCOCH₃), 2.7 (1H, br, OH), 4.38 (1H, m, H-8), 5.05-5.47 (2H, AB system, CH ₂OCONH₂), 4.98 (2H, br, OCONH₂), 5.81 (1H, s, H-5), 5.87 (2H, AB system, CH ₂OCOCH₃).
- (IIf) (R=CH₂OCOCH₃, R₁=CH₂OCH₃, R₂=H): gelbes Öl; 1H-NMR delta (CDCl₃): 1,3 (3H, d, CH₃CH), 2,13 (3H, s, OCOCH₃), 2,6 (1H, br, OH), 3,4 (3H, s, OCH₃), 4,40 (1H, m, H-8), 4,64 (2H, AB-System, CH₂OCH₃), 5,76 (1H, s, H-5), 5,85 (2H, AB-System, CH₂OCOCH₃).(IIf) (R = CH₂OCOCH₃, R₁ = CH₂OCH₃, R₂ = H): yellow oil; 1H-NMR delta (CDCl₃): 1.3 (3H, d, CH ₃CH), 2.13 (3H, s, OCOCH₃), 2.6 (1H, br, OH), 3.4 (3H, s, OCH₃), 4.40 (1H, m, H-8), 4.64 (2H, AB system, CH ₂OCH₃), 5.76 (1H, s, H-5), 5.85 (2H, AB System, CH ₂OCOCH₃).
- (IIg) (R=CH₂OCOCH₃, R₁=CH₃, R₂=H), gelbes Öl; 1H-NMR delta (CDCl₃): 1,3 (3H, d, CH₃CH), 2,12 (3H, s, OCOCH₃), 2,4 (3H, s, 2-CH₃), 2,9 (1H, br, OH), 4,35 (1H, m, H-8), 5,75 (1H, s, H-5), 5,9 (2H, AB-System, CH₂OCOCH₃).(IIg) (R = CH₂OCOCH₃, R₁ = CH₃, R₂ = H), yellow oil; 1H-NMR delta (CDCl₃): 1.3 (3H, d, CH ₃CH), 2.12 (3H, s, OCOCH₃), 2.4 (3H, s, 2-CH₃), 2.9 (1H, br, OH), 4.35 (1H, m, H-8), 5.75 (1H, s, H-5), 5.9 (2H, AB system, CH ₂OCOCH₃).
Acetoxymethyl (5R,6S)-2-carbamoyloxymethyl-6-brom-6-[1-(R)-hydroxyethyl]-penem-3-c-arboxylat [(IIe): R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=H] (880 mg, 2 mMol) wurden in Acetonitril (40 ml) gelöst. 1 M Ammoniumacetat (10 ml, 10 mMol) und ein Silber/Zink-Paar (520 mg, 0,4% Ag) wurde zugefügt und die Mischung bei 20°C 75 Minuten lang gerührt. Am Ende der Reaktion wurde die Mischung filtriert, mit Ethylacetat verdünnt und mit Salzlösung gewaschen. Eindampfen des Lösungsmittels und Reinigung durch Säulenchromatografie (Kieselgel, Ethylether/Ethylacetat 60 : 40 V/V) ergaben Acetoxymethyl (5R,6S)-2-carbamoyloxymethyl-6-[1-(R)-hydroxyethyl]-penem-3-carboxyl-at [(Ie): R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=H] als einen weißen Feststoff. Ausbeute: 252 mg (35%); 1H-NMR (CDCl₃): delta 1,35 (3H, d, CH₃CH), 1,5-1,8 (1H, br, OH), 2,13 (3H, s, OCOCH₃), 3,77 (1H, dd, H-6), 4,22 (1H, m, H-8), 4,82 (2H, br, NH₂), 5,27 (2H, AB-System, CH₂OCONH₂), 5,65 (1H, d, H-5), 5,85 (2H, AB-System, CH₂OCOCH₃).Acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-3-c-arboxylate [(IIe): R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = H ] (880 mg, 2 mmol) were dissolved in acetonitrile (40 ml). 1 M ammonium acetate (10 ml, 10 mmol) and a silver / zinc pair (520 mg, 0.4% Ag) were added and the mixture was stirred at 20 ° C for 75 minutes. At the end of the reaction the mixture was filtered, diluted with ethyl acetate and washed with brine. Evaporation of the solvent and purification by column chromatography (silica gel, ethyl ether / ethyl acetate 60:40 V / V) gave acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6- [1- (R) -hydroxyethyl] -penem-3-carboxyl- at [(Ie): R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = H] as a white solid. Yield: 252 mg (35%); 1H-NMR (CDCl₃): delta 1.35 (3H, d, CH ₃CH), 1.5-1.8 (1H, br, OH), 2.13 (3H, s, OCOCH₃), 3.77 ( 1H, dd, H-6), 4.22 (1H, m, H-8), 4.82 (2H, br, NH₂), 5.27 (2H, AB system, CH ₂OCONH₂), 5.65 (1H, d, H-5), 5.85 (2H, AB system, CH ₂OCOCH₃).
Acetoxymethyl (5R,6S)-2-carbamoyloxymethyl-6-brom-6-[1-(R)-hydroxyethyl]-penem-3-c-arboxylat [(IIe): R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=H] (924 mg, 2,1 mMol) wurden in 95%igem Ethanol (18 ml) gelöst. Kalziumcarbonat (420 mg, 4,2 mMol) und 10% Palladium-auf-Kalziumcarbonat (40 mg, 0,228 mMol Pd) wurden zugefügt und die Mischung unter Wasserstoffatmosphäre 1 Stunde lang bei Raumtemperatur gerührt. Der Katalysator wurde abfiltriert und die alkoholische Lösung mit Ethylacetat verdünnt, mit Salzlösung gewaschen und über Natriumsulfat getrocknet. Eindampfen der Lösung und Reinigung durch Säulenchromatografie (Kieselgel, Ethylether/Ethylacetat 60 : 40, V/V) ergaben Acetoxymethyl (5R,6S)-2-carbamoyloxymethyl-6-[1-(R)-hydroxyethyl]-penem-3-carboxyl-at [(Ie): R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=H] als einen weißen Feststoff. Ausbeute: 258 mg (34%).Acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-3-c-arboxylate [(IIe): R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = H] (924 mg, 2.1 mmol) were in 95% Dissolved ethanol (18 ml). Calcium carbonate (420 mg, 4.2 mmol) and 10% palladium on calcium carbonate (40 mg, 0.228 mmol Pd) were added and the mixture under a hydrogen atmosphere Stirred for 1 hour at room temperature. The catalyst was filtered off and the alcoholic solution with Diluted ethyl acetate, washed with brine and over Dried sodium sulfate. Evaporation of the solution and cleaning by column chromatography (silica gel, ethyl ether / ethyl acetate 60:40, v / v) gave acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6- [1- (R) -hydroxyethyl] -penem-3-carboxylate [(Ie): R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = H] as a white solid. Yield: 258 mg (34%).
Acetoxymethyl (5R,6S)-2-carbamoyloxymethyl-6-brom-6-[1-(R)- trimethylsilyloxyethyl]-penem-3-carboxylat [(IIa): R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=TMS] (1,02 g, 2 mMol) wurden in Acetonitril (40 ml) gelöst. 1 M Ammoniumformiat (10 ml, 10 mMol) und aktiviertes Zink (260 mg, 4 mMol) wurden zugefügt und die Mischung bei 20°C 30 Minuten lang gerührt. Am Ende der Reaktion wurde die Mischung filtriert, mit Ethylacetat verdünnt und mit Salzlösung gewaschen. Eindampfen der Lösung und Reinigung durch Säulenchromatografie (Kieselgel, Ethylether/Ethylacetat 2 : 1 V/V) ergaben Acetoxymethyl (5R,6S)-2-carbamoyloxymethyl-6-[1-(R)-trimethylsilyloxyethyl]-penem--3-carboxylat [(Ia) R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=TMS]; gelbes Öl; Ausbeute: 260 mg (30%); 1H-NMR (CDCl₃): delta 0,13 (9H, s, TMS), 1,24 (3H, d, CH₃CH), 2,12 (3H, s, OCOCH₃), 3,70 (1H, dd, H-6), 4,18 (1H, m, H-8), 4,95 (2H, br, NH₂), 5,27 (2H, AB-System, CH₂OCONH₂), 5,53 (1H, d, H-5), 5,83 (2H, AB-System, CH₂OCOCH₃). Acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) - trimethylsilyloxyethyl] -penem-3-carboxylate [(IIa): R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = TMS] ( 1.02 g, 2 mmol) was dissolved in acetonitrile (40 ml). 1 M ammonium formate (10 ml, 10 mmol) and activated zinc (260 mg, 4 mmol) were added and the mixture was stirred at 20 ° C for 30 minutes. At the end of the reaction the mixture was filtered, diluted with ethyl acetate and washed with brine. Evaporation of the solution and purification by column chromatography (silica gel, ethyl ether / ethyl acetate 2: 1 v / v) gave acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6- [1- (R) -trimethylsilyloxyethyl] -penem - 3-carboxylate [(Ia) R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = TMS]; yellow oil; Yield: 260 mg (30%); 1H-NMR (CDCl₃): delta 0.13 (9H, s, TMS), 1.24 (3H, d, CH ₃CH), 2.12 (3H, s, OCOCH₃), 3.70 (1H, dd, H-6), 4.18 (1H, m, H-8), 4.95 (2H, br, NH₂), 5.27 (2H, AB system, CH ₂OCONH₂), 5.53 (1H, d , H-5), 5.83 (2H, AB system, CH ₂OCOCH₃).
Acetoxymethyl (5R,6S)-2-methoxymethyl-6-brom-6-[1-(R)-hydroxyethyl]-penem-3-carbox-ylat [(IIf): R=CH₂OCOCH₃, R₁=CH₂OCH₃, R₂=H] (820 mg, 2 mMol) wurden in Ethylether (40 ml) gelöst. 1 M Ammoniumacetat (10 ml, 10 mMol) und 85%iges Zink (615 mg, 8 mMol) wurden zugegeben und die Mischung bei Raumtemperatur 2 Stunden lang gerührt. Am Ende der Reaktion wurde die Mischung filtriert, mit Salzlösung gewaschen und über Natriumsulfat getrocknet. Eindampfen der Lösung und Reinigung durch Säulenchromatografie (Kieselgel, Ethylether) ergaben Acetoxymethyl (5R,6S)-2-methoxymethyl-6-[1-(R)-hydroxyethyl]-penem-3-carboxylat [(If): R=CH₂OCOCH₃, R₁=CH₂OCH₃, R₂=H]; Öl; Ausbeute: 250 mg (38%); 1H-NMR (CDCl₃): delta 1,33 (3H, d, CH₃CH), 2,13 (3H, s, OCOCH₃), 3,42 (3H, s, OCH₃), 3,72 (1H, dd, H-6), 4,22 (1H, m, H-8), 4,61 (2H, AB-System, CH₂OCH₃), 5,62 (1H, d, H-5), 5,83 (2H, AB-System, CH₂OCOCH₃).Acetoxymethyl (5R, 6S) -2-methoxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-3-carbox-ylate [(IIf): R = CH₂OCOCH₃, R₁ = CH₂OCH₃, R₂ = H ] (820 mg, 2 mmol) were dissolved in ethyl ether (40 ml). 1 M ammonium acetate (10 ml, 10 mmol) and 85% zinc (615 mg, 8 mmol) were added and the mixture was stirred at room temperature for 2 hours. At the end of the reaction the mixture was filtered, washed with brine and dried over sodium sulfate. Evaporation of the solution and purification by column chromatography (silica gel, ethyl ether) gave acetoxymethyl (5R, 6S) -2-methoxymethyl-6- [1- (R) -hydroxyethyl] -penem-3-carboxylate [(If): R = CH₂OCOCH₃, R₁ = CH₂OCH₃, R₂ = H]; Oil; Yield: 250 mg (38%); 1H-NMR (CDCl₃): delta 1.33 (3H, d, CH ₃CH), 2.13 (3H, s, OCOCH₃), 3.42 (3H, s, OCH₃), 3.72 (1H, dd, H-6), 4.22 (1H, m, H-8), 4.61 (2H, AB system, CH ₂OCH₃), 5.62 (1H, d, H-5), 5.83 (2H , AB system, CH ₂OCOCH₃).
Acetoxymethyl (5R,6S)-2-carbamoyloxymethyl-6-brom-6-[1-(R)-hydroxyethyl]-penem-3-c-arboxylat [(IIe): R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=H] (880 mg, 2 mMol) wurden in Acetonitril (40 ml) gelöst. 1 M Zinkacetat (10 ml, 10 mMol) und ein Silber/Zink-Paar (520 mg, 0,4% Ag) wurden zugegeben und die Mischung bei 20°C 40 Minuten lang gerührt. Am Ende der Reaktion wurde die Mischung filtriert, mit Ethylacetat verdünnt und mit Salzlösung gewaschen. Eindampfen des Lösungsmittels und Reinigung durch Säulenchromatografie (Kieselgel), Ethylether/Ethylacetat 60/40 V/V) ergaben Acetoxymethyl (5R,6S)-2-carbamoyloxymethyl-6-[1-(R)-hydroxyethyl]-penem-3-carboxyl-at [(Ie): R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=H] als einen weißen Feststoff; Ausbeute 215 mg (30%).Acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-3-c-arboxylate [(IIe): R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = H] (880 mg, 2 mmol) were in acetonitrile (40 ml) dissolved. 1 M zinc acetate (10 ml, 10 mmol) and a Silver / zinc pair (520 mg, 0.4% Ag) were added and the Mixture stirred at 20 ° C for 40 minutes. At the end of The mixture was filtered, with ethyl acetate diluted and washed with brine. Evaporation of the solvent and purification by column chromatography (silica gel), Ethyl ether / ethyl acetate 60/40 V / V) gave acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6- [1- (R) -hydroxyethyl] -penem-3-carboxylate [(Ie): R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = H] as a white solid; Yield 215 mg (30%).
Acetoxymethyl (5R,6S)-2-carbamoyloxymethyl-6-brom-6-[1-(R)-hydroxyethyl]-penem-3-c-arboxylat [(IIe): R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=H] (880 mg, 2 mMol) wurden in Acetonitril (40 ml) gelöst. 1 M Ammoniumchlorid (10 ml, 10 mMol) und ein Silber/Zink-Paar (520 mg, 0,4% Ag) wurden zugefügt und die Mischung bei 20°C 20 Minuten lang gerührt. Am Ende der Reaktion wurde die Mischung filtriert, mit Ethylacetat verdünnt und mit Salzlösung gewaschen. Eindampfen des Lösungsmittels und Reinigung durch Säulenchromatografie (Kieselgel, Ethylether/Ethylacetat 60 : 40 V/V) ergaben Acetoxymethyl (5R,6S)-2-carbamoyloxymethyl-6-[1-(R)-hydroxyethyl]-penem-3-carboxyl-at [(Ie): R=CH₂OCOCH₃, R₁=CH₂OCONH₂, R₂=H] als einen weißen Feststoff. Ausbeute 180 mg (28%).Acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-3-c-arboxylate [(IIe): R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = H] (880 mg, 2 mmol) were in acetonitrile (40 ml) dissolved. 1 M ammonium chloride (10 ml, 10 mmol) and a silver / zinc pair (520 mg, 0.4% Ag) was added and the mixture was stirred at 20 ° C for 20 minutes. At the end of The mixture was filtered, with ethyl acetate diluted and washed with brine. Evaporation of the solvent and purification by column chromatography (silica gel, Ethyl ether / ethyl acetate 60: 40 v / v) gave acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6- [1- (R) -hydroxyethyl] -penem-3-carboxylate [(Ie): R = CH₂OCOCH₃, R₁ = CH₂OCONH₂, R₂ = H] as one white solid. Yield 180 mg (28%).
Acetoxymethyl (5R,6S)-2-methyl-6-brom-[1-(R)-hydroxyethyl]-penem-3-carboxylat [(IIg): R=CH₂OCOCH₃, R₁=CH₃, R₂=H] (760 mg, 2 mMol) wurde in Ethylacetat (40 ml) gelöst. 1 M Ammoniumacetat (10 ml, 10 mMol) und 85%iges Zink (615 mg, 8 mMol) wurden zugefügt und die Mischung bei 20°C 2 Stunden lang gerührt. Am Ende der Reaktion wurde die Mischung filtriert, mit Salzlösung gewaschen und über Natriumsulfat getrocknet. Eindampfen des Lösungsmittels und Reinigung durch Säulenchromatografie (Kieselgel, Ethylether) ergaben Acetoxymethyl (5R,6S)-2-methyl-6-[1-(R)-hydroxyethyl]-penem-3-carboxylat [(Ig): R=CH₂OCOCH₃, R₁=CH₃, R₂=H]; gelbes Öl; Ausbeute: 110 mg (18%); 1H-NMR (CDCl₃): delta 1,3 (3H, d, CH₃CH), 2,13 (3H, s, OCOCH₃), 2,38 (3H, s, 2-CH₃), 2,80 (1H, br, OH), 3,80 (1H, dd, H-6), 4,20 (1H, m, H-8), 5,65 (1H, d, H-5), 5,85 (2H, AB-System, CH₂OCOCH₃).Acetoxymethyl (5R, 6S) -2-methyl-6-bromo- [1- (R) -hydroxyethyl] -penem-3-carboxylate [(IIg): R = CH₂OCOCH₃, R₁ = CH₃, R₂ = H] (760 mg , 2 mmol) was dissolved in ethyl acetate (40 ml). 1 M ammonium acetate (10 ml, 10 mmol) and 85% zinc (615 mg, 8 mmol) were added and the mixture was stirred at 20 ° C for 2 hours. At the end of the reaction the mixture was filtered, washed with brine and dried over sodium sulfate. Evaporation of the solvent and purification by column chromatography (silica gel, ethyl ether) gave acetoxymethyl (5R, 6S) -2-methyl-6- [1- (R) -hydroxyethyl] -penem-3-carboxylate [(Ig): R = CH₂OCOCH₃, R₁ = CH₃, R₂ = H]; yellow oil; Yield: 110 mg (18%); 1H-NMR (CDCl₃): delta 1.3 (3H, d, CH ₃CH), 2.13 (3H, s, OCOCH₃), 2.38 (3H, s, 2-CH₃), 2.80 (1H, br, OH), 3.80 (1H, dd, H-6), 4.20 (1H, m, H-8), 5.65 (1H, d, H-5), 5.85 (2H, AB system, CH ₂OCOCH₃).
Claims (18)
- (a) Alkanoyloxymethyl oder 1-(Alkanoyloxy)ethyl, worin der Alkanoylrest ein geradkettiges oder verzweigtes C1-10-Alkanoyl oder eine C4-8-Cycloalkanoylgruppe ist;
- (b) Benzoyloxymethyl oder 1-(Benzoyloxy)ethyl;
- (c) Alkoxycarbonyloxymethyl oder 1-(Alkoxycarbonyloxy)ethyl;
- (d) 3-Phthalidyl;
- (e) 2-Oxo-1,3-dioxolan-4-yl, und zwar unsubstituiert oder substituiert durch eine C1-4-Alkylgruppe in der 5-Position;
- (f) -CH₂COOR′, worin R′ ein geradkettiges oder verzweigtes C1-4-Alkyl oder Benzyl ist; oder
- (g) 2-Oxotetrahydrofuran-5-yl, und zwar unsubstituiert oder substituiert durch eine C1-4-Alkylgruppe in der 4-Position, darstellt;
- (a) alkanoyloxymethyl or 1- (alkanoyloxy) ethyl, wherein the alkanoyl residue is a straight or branched C 1-10 alkanoyl or a C 4-8 cycloalkanoyl group;
- (b) benzoyloxymethyl or 1- (benzoyloxy) ethyl;
- (c) alkoxycarbonyloxymethyl or 1- (alkoxycarbonyloxy) ethyl;
- (d) 3-phthalidyl;
- (e) 2-oxo-1,3-dioxolan-4-yl, unsubstituted or substituted by a C 1-4 alkyl group in the 5-position;
- (f) -CH₂COOR ', wherein R' is a straight or branched C 1-4 alkyl or benzyl; or
- (g) 2-Oxotetrahydrofuran-5-yl, unsubstituted or substituted by a C 1-4 alkyl group in the 4-position;
- (i) Carbamoyloxy, C1-18-Alkoxy, Carboxy oder freies oder geschütztes Hydroxy und
- (ii) unsubstituiertes oder substituiertes und/oder kondensiertes Pyridinium, N-Methylpyrrolidinium oder Piperidinium, wobei die Substituenten eine genannte Gruppe (i) oder eine unsubstituierte oder durch eine Sulfonyloxy- oder Carboxygruppe substituierte C1-4-Alkylgruppe sind; und
- (i) carbamoyloxy, C 1-18 alkoxy, carboxy or free or protected hydroxy and
- (ii) unsubstituted or substituted and / or fused pyridinium, N-methylpyrrolidinium or piperidinium, the substituents being a said group (i) or an unsubstituted or substituted by a sulfonyloxy or carboxy group C 1-4 alkyl group; and
wobei man eine Verbindung der Formel (II) reduziert, worin R, R₁ und R₂ wie vorstehend definiert sind.R₂ represents a hydrogen atom or a protective group for the hydroxy group,
where a compound of formula (II) reduced, wherein R, R₁ and R₂ are as defined above.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8815821A GB2220203B (en) | 1988-07-04 | 1988-07-04 | Process for penems |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3921830A1 true DE3921830A1 (en) | 1990-02-22 |
Family
ID=10639813
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE3921830A Withdrawn DE3921830A1 (en) | 1988-07-04 | 1989-07-03 | METHOD FOR PRODUCING PENEMAS |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP2922220B2 (en) |
| DE (1) | DE3921830A1 (en) |
| GB (1) | GB2220203B (en) |
| IT (1) | IT1230959B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69133273T2 (en) * | 1990-08-20 | 2004-05-13 | Daiichi Suntory Pharma Co., Ltd. | Antibacterial penem ester derivatives |
| US5506225A (en) * | 1990-08-20 | 1996-04-09 | Suntory Limited | Antibacterial penem compounds |
| US5703068A (en) * | 1990-08-20 | 1997-12-30 | Suntory Limited | Penem compounds |
-
1988
- 1988-07-04 GB GB8815821A patent/GB2220203B/en not_active Expired - Fee Related
-
1989
- 1989-06-30 IT IT8921055A patent/IT1230959B/en active
- 1989-07-03 JP JP1171736A patent/JP2922220B2/en not_active Expired - Lifetime
- 1989-07-03 DE DE3921830A patent/DE3921830A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| GB2220203A (en) | 1990-01-04 |
| IT1230959B (en) | 1991-11-08 |
| GB2220203B (en) | 1991-09-11 |
| IT8921055A0 (en) | 1989-06-30 |
| GB8815821D0 (en) | 1988-08-10 |
| JPH0267287A (en) | 1990-03-07 |
| JP2922220B2 (en) | 1999-07-19 |
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