GB2220203A - Process for penems; 6-bromopenems - Google Patents
Process for penems; 6-bromopenems Download PDFInfo
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- GB2220203A GB2220203A GB8815821A GB8815821A GB2220203A GB 2220203 A GB2220203 A GB 2220203A GB 8815821 A GB8815821 A GB 8815821A GB 8815821 A GB8815821 A GB 8815821A GB 2220203 A GB2220203 A GB 2220203A
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- 238000000034 method Methods 0.000 title claims description 31
- 150000002961 penems Chemical class 0.000 title description 8
- -1 benzoyloxymethyl Chemical group 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 27
- 229910052725 zinc Inorganic materials 0.000 claims description 9
- 239000011701 zinc Substances 0.000 claims description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 229910052709 silver Inorganic materials 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 5
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000004332 silver Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-O Piperidinium(1+) Chemical compound C1CC[NH2+]CC1 NQRYJNQNLNOLGT-UHFFFAOYSA-O 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000005949 ozonolysis reaction Methods 0.000 claims description 3
- 125000005846 1-(alkanoyloxy)ethyl group Chemical group 0.000 claims description 2
- 125000005848 1-(alkoxycarbonyloxy)ethyl group Chemical group 0.000 claims description 2
- 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
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 2
- 125000005206 alkoxycarbonyloxymethyl group Chemical group 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
- 229910052794 bromium Inorganic materials 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
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 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
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 101150041968 CDC13 gene Proteins 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000004440 column chromatography Methods 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
- 238000000746 purification Methods 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
- 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
- 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
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 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
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical group C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- BJDTWVQNEWIULP-RXMQYKEDSA-N (5R)-3-bromo-4-thia-1-azabicyclo[3.2.0]hept-2-en-7-one Chemical compound BrC=1S[C@H]2N(C=1)C(C2)=O BJDTWVQNEWIULP-RXMQYKEDSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-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
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-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
- 239000003242 anti bacterial agent Substances 0.000 description 2
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 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
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- IYPZTSDEYRDCBO-AJAOVWJASA-N (5R)-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound O[C@H](C)C1[C@@H]2N(C(=CS2)C(=O)O)C1=O IYPZTSDEYRDCBO-AJAOVWJASA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 1
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- WOOSCPWOYYLIHS-UHFFFAOYSA-N Oxoamide Chemical compound CNC(=O)CCC(=O)C1=CC=CN=C1 WOOSCPWOYYLIHS-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- UCTLHLZWKJIXJI-LXIBVNSESA-N [(3s,8r,9s,10r,13s,14s)-17-chloro-16-formyl-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C([C@@H]12)C[C@]3(C)C(Cl)=C(C=O)C[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 UCTLHLZWKJIXJI-LXIBVNSESA-N 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
- 239000002253 acid Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000007775 late Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- BSWGGJHLVUUXTL-UHFFFAOYSA-N silver zinc Chemical compound [Zn].[Ag] BSWGGJHLVUUXTL-UHFFFAOYSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 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)
Description
PROCESS FOR PENEMS 2220203 The present invention relates -to a process for
preparing 6-((1R)- hydroxyethyll penems useful in the synthesis of antibacterial agents. to intermediates used in the process and to the preparation of the intermediates, more particularly the invention re lates to a process for the preparation of compounds of formula (I):
ORt H S R, wherein:
COOR ( 1) R reprsents a) alkanoyloxymethyl or 1-(alkanoyloxy)ethyl wherein the alkanoyl moiety is a straight or branched C 2_ C 10 alkanoyl or C4-C. 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 I-C 4 alkyl group in the 5 position; f) -CH 2 COORI wherein R' is a Cl-C4 straight or branched alkyl or benzyl; or g) 2-oxotetrahydrofuran-5-yl unsubstitted or substituted by a cl-c 4 alkyl group at the 4 position; R, is tetrahydrofuranyl or an unsubstituted or substituted C JL-C4 alkyl, methylphenyl or methylphenoxymethyl group, the substituents being chosen from the groups:
(i) carbamoyloxy, CJL-C1$ 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 a C1-C 4 alkyl group unsubstituted or substituted by a sulfonyloxy or carboxy group; and R 2 represents a hydrogen atom or a hydroxy protecting group; which process comprises reducing a compound of formula (II) 0 R., p r 1 S R, 0 d;; (11) COOR wherein R, R, and R 2 are as defined above.
The alkoxy moieties preferably contain 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. R 2 or the hydroxy protecting moiety in R. may be, for example, a p-nitrobenzyloxycarbonyl, trimethylsilyl, - 3 t-butyldimethylsilyl, t-butyldiphenylsilyl, methoxymethyl, benzyl, pbromophenacyl, triphenylmethyl or tetrahydropyranyl group.
Examples of groups which may be fused to the pyridinium, Nmethylpyrrolidinium, and piperidinium groups are a phenyl group and a C.C. saturated or unsaturated I cycloaliphatic or heterocyclic group. The heterocyclic group may, for example, contain from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur atoms. Prefered groups which may be fused to the pyridinium, N-methylpyrrolidinium and piperidinium groups are:
0 5 [D 1 0.1 0 - 0 MC 0; CS and 0 P 0 Examples of compounds of formula (I) are described in European Patent Application No. 88305277.1, GB-A-2,133,010 and GB-A-2,097,786.
The present invention also provides a compound of formula (II) and further provides a process for preparing a compound of formula (II), which process comprises cyclizing a compound of formula (V) OR2 Cr 1= S.,.RI N 0 ≥0 COOR v 11 0 wherein R, R, and R 2 are as defined above.
The compound of formula (V) may be prepared by ozonolysis of a compound of formula (III):
0% Br 5 1. K1 R, 0 N ≥< COOR III wherein R, R, and R 2 are as defined above.
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 is maintained on the C-lactam nucleus until the last step. The substitution of the bromine atom with a hydrogen atom proceeds with higher stereoselectivity on the compound of formula (I1) than on other intermediates earlier in the process. Moreover the intermediates involved in the process are more stable, easier to handle than those previously - 5 reported and can therefore be stored without decomposition.
The configuration of the compounds of formula (II) is 15R,6S,(lR)], in order to obtain the preferred final 15R,6S,(lR)] stereochemistry of the penem nucleus. The starting material of formula (III) can be conveniently prepared from 6-aminopenicillanic acid as described in EP-A-0188247. The present invention therefore allows the synthesis of compounds of formula (1) directly from 6-4minopenicillanic acid, as summarized in the following Reaction Scheme.
Compounds of formula (V) in the scheme are prepared by ozonolysis, generally at a low temperature, of compounds (III) and are cyclized into compounds (II), generally by treatment with triethylphosphite or trimethylphosphite in an inert organic solvent, such as chloroform, benzene, toluene or xylene. Examples of conditions for said cyclization are detailed in C. Battistini et al., Tetrahedron Lett. 25, 2595, (1984); A. Yoshida et al. Chem.Pharm.Bull. 31, 768, (1983), and references therein, and in US-A-4,631,150.
Compounds of formula (II) are reduced to the compounds (1) in any appropriate fashion such as catalytic hydrogenation or treatment with reducing metals. Preferably penems M are obtained from (II) by treatment with zinc or an alloy thereof with another metal such as copper or' silver. The reaction is preferably carried out in an organic solvent such as acetonitrile, ethyl ether, H2N ', r S 0 COOH 6-AP.A h R2 gr "0' S,,.oR, 11 0 (f -N ≥0 COOR (v) a-- OH Br 00 ir S ei N 0 (IV) OR..
1,11,11,11,111 yr S Rt N 1 COOR COOR (11) REACTION SCHEME OR.t er S% R4 '000 r 0 e)e N 1 OOR (m) 0% H S R4 0,j: c o m- 1 0, N ( 1) 1 0 1 COOR 7 t-butylmethyl ether, ethyl acetate, tetrahydrofuran, acetone, chloroform or methylene chloride, in the presence of an aqueous solution of ammonium or zinc carboxylate-or halide. The reaction temperature is generally from -200C to +800C. At the end of the reaction, penems of formula (I) are recovered by conventional work-up. The reaction crudes, when necessary, are deprotected and purified by column chromatography.
The penems of formula (1) are antibacterial agents. They may therefore be formulated as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier or diluent.
The following Examples illustrate the present invention:
0 Example 1
Preparation of bromopenems (I1) (general procedure) (3S,4R)-1-(1-acctoxymethyloxycarbonyl-2-methYl-l-propenyl)4-acylthio-3-bromo-3-[1-(R)-hydroxyathyl]-azetidin-2-one (1111 R=CH20COCH3,R2=H) was prepared from acctoxymethyl (3S,5R,W6-brorno-b-tl(R)-hydroxyethyl3-penicillanate (IV, R= CH20COC3) as described in Alpegiani et al. J.Am.Chem. Soc., J_Q_7, 6398, Crude Ull) was converted into its trimethylsilyl (TMS) derivative according to conventional procedures.
The protected azetidinone (Ill) (20 mmol) was dissolved in dry methylene chloride (300 mL) at -780C. Ozone was bubbled through the solution at the same temperature for 4-6 h. At the end of the reaction nitrogen was passed through to remove the excess ozone, and the mixture allowed to reach OC. The solution was washed with sodium bisulfite (0.2 M, 2 x 100 mL) and dried over sodium sulfate. Evaporation of the solvent gave oxoamide (V), which could be stored for a few days without any decomposition.
Va (R = CH20COCH3, R1 = CH20CONH2, R2 = THS): white foam; 80% yield; 1HWR 8 (CDC13): 0.2 (9H,s,OTMS), 1.55 (3H,d,CH3-CH), 2.15 (3H,5,0COCH3), 4. 18 0H,m,H-8), 4.82 (2H,AB aystem,SCOCH2), 5.1 (2H,br,NH2), 5.9 (2H,A8 system,CH20COCH3), 6.23 0H,a,H-5).
Vb (R = CH20COCH3, R1 = CH20CH39 R2 = TMS): oil; 82% yield; 1H-MR 8 (CDC]3): 0.2 (9H,rw,OTMS), 1.55 (3H,d,QUCH). 2.15 (3H,s,0COCH3), 3.5 (3H, &,0CH3), 4.13-4.22 (3H: SCOCH2 and H-8), 5.9 (2H,AE system,CH20COCH3), 6. 22 (1H,a,H-5).
VC (R = CH20COCH3, RI = CH3, R2=TMS): oil; 75% yield; IH-NMR 6 (CDC13) 0.2 (SH,s,OTMS), 1.55 (3H,d,CH3-CH), 2.15 (3H,5,0COCH3), 2.35 (3H,5,SCOCH3), 4.12 (IH^H-8), 5.85 (2H, AB system,Q_HZOCOCH3)g 6.02 (1H,a,H-5).
Crude (V) was dissolved in dry toluene or xylene (70 L); triathyl phosphite (8.7 mL, 50 mmol) was added and the solution refluxed for 1-6 h. At the end of the reaction, the mixture was cooled to WC, washed with phosphate buffer (pH=7, 3 x 20 mO and dried over sodium sulfate. Evaporation of the solvent gave an oil, which was purified by column chromatography to afford the 8-0-protected bromopenem (11).
IIa (R = CH20COCH3, R1 = CH20CONH2, R2 = TMS): yellow oil; 50% yield; 1HMR 8 (CDC13): 0.13 (9H,s,017MS), 1.28 (3H,d,CH3CH), 2.1 (3H,s,OCOCH3), 4. 33 (1H^H-8), 5.0-5.5 (2H, AB system, CH20CONH2), 4.95 (2H,br,OCONH2), 5. 75 (1H,s,H-5), 5.85 (2H,AS system, CH20COCH3).
1Ib (R = CH20COCH3, R1 = CH20CH3, R2 = THS): yellow oil; 57% yield; 1H-MR 8 (CDC13): 0.13 (9H9s,OTMS), 1.3 (3H,d,CH3CH), 2.13 (3H,s,OCOCH3), 3.4 (3H,&,0CH3),.4.37 (1H^H-8), 4.64 (2H, AE system,gffiZOCH3), 5.24 (1Hgs,H-5), 5.85 (2H, AB system, QUOCOCH3).
Ilc (R CH20COCH3, R1 CH3, R2=TMS): yellow oil;42% yield; IH-NMR 8 (CDC13) 0.13 (9H,6,0TMS), 1.3 (3H,d,CH3CH), 2.12 OH,s,0COCH3), 2.4 (3H,s,2-CH3), 4.35 (IH^H-8), 5.71 OH,a,H-5), 5.85 (2H, AE system, CH20COCH3).
The protected (11), obtained as described above, was deprotected according to =nventional methods to give the corresponding 8-OH bromopenem (II).
(R = CH20COCH3, R1 = CH20CONH2, R2 = H): yellow 011; 1H-MR 8 (CDC13): 1.3 (3H,dICH3CH)v 2.13 (3H,s,0COCH3), 2.7 (1H,br,OH), 4.38 (1H,m,H-8), 5.05-5. 47 (2H, AS system. "H OCONH2), 4.98 (2H,hr,0CONH2), 5.81 5.87 (2H,AS system, CH20COCH3).
1If (R = CH20COCH3, R1 = CH20CH3, R2 = H): yellow oil; 1H-MR 8 (CDC13) 1. 3 (3H,d,CH3CH), 2.13 (3H,s,OCOCH3), 2.6 (1H,br,OH), 3.4 (3H,s,OCH3), 4.40 (1H^H-8), 4.64 (2H, AS system,QHOOCH3), 5.76 (1H,s,H-5), 5.85 (241, AS system, QH20COCH3).
119 (R = CH20COCH3, RI = CH3, R2=H): yellow oil;1H-WR 8 (CDC13):1.3 (3H,d,CH3CH), 2.12 (3H,s,OCOCH3), 2.4 (3H,s,2-CH3), 2.5 OH,br,OH), 4.35 5.75 (1H,s,H-5), 5.9 (2H, AS system, CH20COCH3).
k - 1 1 - - Example 2
1 Acetoxymethyl (SR,6S)-2-carbamoyloxymethyl-6-bromo-6-[1-(R)hydroxyethyll-pancm-3-carboxylate [(IIe) R=CH20COCH3; R1=CH20COM2; R2=H] (880 mg 2 Mmol) was dissolved in acwtonitrile 40 mL). 1 M ammonium acetate ( 10 mLg 10 mml and silver/zinc couple 520 mg, 0.4% Aq) were added and the mixture ati.rred at 20C for 75 min. 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 etherlethyl acetate 60:40 v/v) gave acetoxymethyl (SR,6S)-2-carbamoyloxymethyl 6-[1-(R)-hydroxyethyl]-penem-3-carboxylate [(Ie): R=CH20COCH3; RI=CH20CONH2; R2=H] as a white solid. Yield: 252 mg (35%).
1H-MR (CDC13) 6 1.35 (3H,d,CH3CH), 1.5-1.8 (1H,br,,OH), 2.13 (3H,5,0COCH3), 3.77 OH,dd,H-6), 4.22 (1H,m,H-8), 4.82 (2H,br,NH2), 5.27 (2H, AS system, CH20CONH2), 5.65 (1H,d,H-5), 5.85 (2H, AS system, CH20COCH3).
Example 3
Acetoxymethyl (SR,6S)-2-carbamoyloxymethyl-6-bromo-6-[I-(R) hydroxyethyll-penem-3-carboxylate I(IIe) R=CH20COCH3 RI=CH20CONH2; R2=Hl (924 mg, 2.1 mmol) was dissolved in 95 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 stirred under ihydrogen atmosphere for 1 h at room temperature. The catalyst was filtored lDff and the alcoholic solution diluted with ethyl acetate, wastsed with brine and dried over sodium sulfate. Evaporation ofthe solvent and purification by column chromatography silica gel,ethyl other/othyl acetate 60:40 v/v gave acetoxymethyl (SR,SS)-.2-carbamoyloxymethyl 6-11-(R)-hydroxyethyll-penem-3-carboxylate I(Ie) R=CH20COCH3; RI=CH20CONH2; R2=Hl as a white solid. Yiolsf: 258 mg (34%).
Example 4
Acetoxymethyl (SR,65)-2-carbainoyloxyfnethyl-6-bromo-6-[1-(R)trimethylsilyloxyethyl)-pencm-3-carboxylate 1(11a): R=CH20COCH3 RI=CH2MMM2; R2-c7TMS] (1.02 9 2 =ol) was dissolved in acetonitrile 40 mL). 1 M ammonijLm foe ( 10 mL, 10 mmol) and activated zinc (260 mg, 4 v=l) were added and the mixture stirred at 20C for 30 min. At ttm end of the reaction, the mixture was filtered, diluted with yl acetate and washed with brine. Evaporation of the solvent and:purification by column chromatography ( silica gel, ethyl,tlothyl acetate 2:1 v/v) gave acetoxymethyl (SR,65)-2-zarbwnoyloxymothyl-6-fl-(R)trimethylellyloxyathyl]-pensm-3 -carboxylate ú(1a):R= CH20COCH3; RI=CH20COM2; R2t-M453. Yellow oil. Yield: 260 mg (30x).
IH-NMR (CDC13) 8 0.13 (9H,s,TMS), 1.24 (3H,d,CH3CH), 2.12 0H,s,0COCH3), 3. 70 0H,dd,H-6)l 4.18 (1H.m,H-8), 4.95 (2H,br,NH2), 5.27 (2H, AS system CH20CONH2), 5.53 (1H,d,H-5), 5.83 (2H, AS system, QBa0COCH3).
Example 5
Acetoxymethyl (SR,6S)-2-methoxymethyl-6-bromo-6-[l-(R)hydroxyethyl]-penem-3-carboxylate U11f) R=CH20COCH3, RI=CH20CH3, R2=H] (820 mg, 2 mmol) was dissolved in ethyl ether (40 mL). 1M ammonium acetate (10 mL, 10 mmol) and 85% zinc (615 mg, 8 mmol) were added and the mixture stirred at room temperature for 2 h. 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 colum chromatography silica gel, ethyl ether gave acetoxymethyl (5R,6S)-2-methoxymethyl-6-[l(R)-hydroxyethyl]-penem-3-carboxylate [(If): R=CH20COCH3, Rl=CH20CH3, R2=H].
Oil. Yield: 250 mg (38%).
1H-NMR (CDC13): 8 1.33 (3H,d,CH3CH), 2.13 (3H,s,OCOCH3), 3.42 (3H,,OCH3)9 3.72 (lHtdd,H-6)9 4.22 (1H^H-S),4.61 (2H, AS systems M OCH3), 6.62 (lH,d,H-5), 5.83 (2H, AS system, Q.HZOCOCH3).
i Example 6.
Acetoxymethyl (SR,6S)-2-carbamoyloxymethyl-6-bromo-6-[I-(R)hydroxythyl3-ponem-3-carboxylate UIle) R=CH20COCH3; RI=CH20CONHZ; R2=Hl (880 mg 2 mmol) was dissolved in acetonitrile 40 mL I M zinc acetate (10 mL, 10 mmol) and silver-zinc couple (520 mg,- 0.4% Ag) were added and the mixture stirred at 20'C for 40 min. 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-[l-(R)-hydroxyethyll-penem-3-carboxylate [(Ie): R=CH20COCH3; RI=CH20CONH2; R2=Hl as a white solid. Yield: 215 mg (30%).
Example 7
Acetoxymethyl (SR,6S)-2-carbamoyloxymethyl-6-bromo-6-[I-(R)hydroxyethyl3-penem-3-carboxylate UIle) R=CH20COCH3; RI=CH20CONH2; R2=Hl (880 mg 2 mmol) was dissolved in acetonitrile ( 40 ML). 1 M ammonium chloride ( 10 mL, 10 mmol and silver/zinc couple 520 mg, 0.4% Ag) were added and the mixture stirred at 2OgC for 20 min. 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 t 60:40 vIv) gave acetoxymethyl (5R,65)-2-carbamoyloxymethyl-; 6-[1-(R)hydroxyethyl]-pencm-3-carboxylate [(Ie): R=CH20COCH3; R1=CH20COM2; R2=H] as a white solid. Yield: 130 mg (28%).
Example 8
Acetoxymethyl (5R,6S)-2-methyl-6-bromo-6-El-(R)-hydroxyethyllpenem-3-carboxylate E(119) R=CH20COCH3, RI=C+43, R2=Hl (760 mg, 2 mmol) was dissolved in ethyl acetate (40 mL). IM ammonium acetate (10 mL, 10 mmol) and 85% zinc ( 615 mg, 8 mmol) were added and the mixture stirred at 20'C for 3 h. 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-[I-(R)-hydroxyethyll-penem- 3-carboxylate [(Ig): R=CH20COCH3, RI=CH3, R2=H].
Yellow oil. Yield: 110 mg (18%).
IH-NMR (CDC13): 8 1.3 (3H,d,CH3CH), 2.13 (3H,s,OOOCH3), 2.38 (3H,s,2-CH3), 2.80 (IH,br,OH), 3.80 (IH,dd,H-6), 4.20 (1H^H-8), 5.65 (1H, d,H-5), 5.85 (2H, AS system, = OCOCH3).
Claims (16)
1. A process for the preparation of a compound of formula M:
0% H 5 R, 0 N 1 wherein COOR R reprsents a) alkanoyloxymethyl or 1-(alkanoyloxy)ethyl wherein the alkanoyl moiety is a straight or branched C 2- C,. alkanoyl or C4-CS 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 I-C 4 alkyl group in the 5 position; f) -CH 2 COORI wherein R, is a CI-C 4 straight or branched alkyl or benzyl; or g) 2-oxotetrahydrofuran-S-yl unsubstituted or substituted by a C,-C4 alkyl group at the 4 position; R, is tetrahydrofuranyl or an unsubstituted or substituted c I-C4 alkyl, methylphenyl or methylphenoxymethyl group, the 1 1 - 17 substituents being chosen from the groups: M carbamoyloxy, Ci-Ci. 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 a C,-C 4 alkyl group unsubstituted or substituted by a sulfonyloxy or carboxy group; and R 2 represents a hydrogen atom or a hydroxy protecting group; which process comprises reducing a compound of formula (II) OR., Pr S R,,:1 COOR (%1) wherein R, R, and R 2 are as defined above.
2. A process atcording to claim 1 wherein reduction is effected by catalytic hydrogenation.
3. A process according to claim 1 wherein reduction is effected by treatment with a reducing metal.
4. A process according to claim 3 in which the reducing metal is zinc or an alloy thereof with another metal.
5. A process according to claim 4 wherein the reducing metal is zinc alloyed with copper or silver.
6. A process according to any one of the preceding claims wherein R2 or the hydroxy protecting moiety in R, is a p-nitrobenzyloxy carbonyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, methoxymethyl, benzyl, p-bromophenacyl, triphenylmethyl or tetrahydropyranyl group.
7.' A process according to any one of the preceding claims wherein R1 is unsubstituted or substituted 41 pyridinium, N-methylpyrrolidinium or piperidinium fused with a phenyl, C,-C, saturated or unsaturated cycloaliphatic or heterocyclic group.
8. A process according to any one of the preceding claims in which the reduction is carried out in an organic solvent in the presence of an aqueous solution of an ammonium or zinc carboxylate or halide at a temperature of from -20C to +80'C.
9. A compound of the formula (II) as defined in any one of claims 1, 6 and 7.
10. A process for preparing a compound of formula (II) as defined in claim 9 which process comprises cyclizing a compound of formula (V).
OR2 pr S N ≥=0 0 COOR V wherein R, R, and R 2 are as defined in claim 6 or 7.
1
11. A process according to claim 10 wherein the cyclization is carried out using triethylphosphite or trimethylphosphite in an inert organic solvent.
12. A process according to claim 10 or 11 wherein compound of formula (V) is prepared by ozonolysis of a compound of formula (III) 0% Br S %,t,,ooor R4 1 N ≥< OOR the III wherein R, R, and R 2 are as defined in claim 10.
13. A process for the preparation of a compound of formula (I) as defined in claim 1, said process being substantially as hereinbefore described in any one of Examples 2 to 8.
14. A compound of formula (II) as defined in claim 1 which is specifically identified herein.
15. A process for the preparation of a compound of formula (11) as defined in claim 1, said process being substantially as hereinbefore described in Example 1.
16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a compound of formula (1) prepared by a process as claimed in any one of claims 1 to 8.
Published 1989 atThe Patent Office. State House,66171 High Holborn, LondonWCIR 4TP. Further copies maybe obtalnedfrom ThePatentOfnee. Sales Branch, St Mary Cray, Orpington, Kent BR5 3RD. Printed by Multiplex techniques ltd, St Mary Cray, Kent, Con. 1/87
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8815821A GB2220203B (en) | 1988-07-04 | 1988-07-04 | Process for penems |
| IT8921055A IT1230959B (en) | 1988-07-04 | 1989-06-30 | PROCESS FOR PENEM. |
| DE3921830A DE3921830A1 (en) | 1988-07-04 | 1989-07-03 | METHOD FOR PRODUCING PENEMAS |
| JP1171736A JP2922220B2 (en) | 1988-07-04 | 1989-07-03 | Penem recipe |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8815821A GB2220203B (en) | 1988-07-04 | 1988-07-04 | Process for penems |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8815821D0 GB8815821D0 (en) | 1988-08-10 |
| GB2220203A true GB2220203A (en) | 1990-01-04 |
| GB2220203B GB2220203B (en) | 1991-09-11 |
Family
ID=10639813
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8815821A Expired - Fee Related GB2220203B (en) | 1988-07-04 | 1988-07-04 | Process for penems |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP2922220B2 (en) |
| DE (1) | DE3921830A1 (en) |
| GB (1) | GB2220203B (en) |
| IT (1) | IT1230959B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US5830889A (en) * | 1990-08-20 | 1998-11-03 | Suntory Limited | Antibacterial penem esters derivatives |
-
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
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| EP0544905B1 (en) * | 1990-08-20 | 1998-10-14 | Suntory Limited | Antibacterial penem compounds |
| US5830889A (en) * | 1990-08-20 | 1998-11-03 | Suntory Limited | Antibacterial penem esters derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8815821D0 (en) | 1988-08-10 |
| JPH0267287A (en) | 1990-03-07 |
| JP2922220B2 (en) | 1999-07-19 |
| IT8921055A0 (en) | 1989-06-30 |
| IT1230959B (en) | 1991-11-08 |
| GB2220203B (en) | 1991-09-11 |
| DE3921830A1 (en) | 1990-02-22 |
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| Date | Code | Title | Description |
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| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19940704 |