AU620982B2 - A process for the preparation of penem compounds - Google Patents
A process for the preparation of penem compounds Download PDFInfo
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- AU620982B2 AU620982B2 AU53906/90A AU5390690A AU620982B2 AU 620982 B2 AU620982 B2 AU 620982B2 AU 53906/90 A AU53906/90 A AU 53906/90A AU 5390690 A AU5390690 A AU 5390690A AU 620982 B2 AU620982 B2 AU 620982B2
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- Australia
- Prior art keywords
- alkoxy
- alkyl
- phenyl
- amino
- unsubstituted
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 6
- 150000002961 penems Chemical class 0.000 title description 6
- -1 phenoxy, phenyl Chemical group 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004468 heterocyclylthio group Chemical group 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 150000002903 organophosphorus compounds Chemical class 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000006303 photolysis reaction Methods 0.000 claims description 2
- 230000015843 photosynthesis, light reaction Effects 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 125000004144 cyclobuten-1-yl group Chemical group [H]C1=C(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 210000002837 heart atrium Anatomy 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 239000002023 wood Substances 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 2
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102100022653 Histone H1.5 Human genes 0.000 description 1
- 101000899879 Homo sapiens Histone H1.5 Proteins 0.000 description 1
- 101000913968 Ipomoea purpurea Chalcone synthase C Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241001307210 Pene Species 0.000 description 1
- 101000907988 Petunia hybrida Chalcone-flavanone isomerase C Proteins 0.000 description 1
- 101100202463 Schizophyllum commune SC14 gene Proteins 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000005600 alkyl phosphonate group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004467 aryl imino group Chemical group 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- ZXMSTCRBSAVFDO-UHFFFAOYSA-N dimethoxy(methyl)phosphane Chemical compound COP(C)OC ZXMSTCRBSAVFDO-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000005030 pyridylthio group Chemical group N1=C(C=CC=C1)S* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene 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
- C07D499/04—Preparation
- C07D499/06—Preparation by forming the ring or condensed ring systems
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pens And Brushes (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
pp.Tergau i.I. Lapice To the Commissioner of Patents j w Form COMMONWEALTH OF AUSTRALIA PAT ENTS ACT 1952.69 COMPLETE SPECIFICATION
(ORIGINAL)
Class mnt. Class Application Number: Lodged: Cornplew Specificati on Lodged: Accepted: Published! Priority Rela;ted Art Name of Applicant H-OECHST ATIENGESELLSCKAFr 'Address of Applicant Actual Inventor Bruningstra~se, D-6230 of Germany Frankfurt/Main 80, Federal Republic KARL-HEINZ BUDT, WALTER DURCKHEIMER, GERD FISCHER, ROLF HORLEIN, REINER KIRRSTEITER, and~ RUDOLF LAITRELL WATERMARK PATENT TRADEMARK ATTORNEYS.
LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Address for Service Complete Specification for the Invention entitled: A PROCESS FOR THE PREPARATION OF PENEM CCt4POUNDS The following statement Is a full description of this Invention, Including the best method of performing It known to us 1.
-A
1 I- r I .T HOECHST AKTIENGESELLSCHAFT HOE 89/F 135K Dr. v.F./PP Description A process for the preparation of penem compounds The invention relates to a process for the preparation of penem compounds.
4ti I 4r t0r 0444 lIC 0D 00( 0 0 ohIO 0 0000 0 00a a0, 4 0 0 00 o15 o Penem derivatives of the formula I are valuable compounds with antibiotic properties. A synthetic process disclosed in the literature for penem derivatives I entails intramolecular cyclization of azetidinone derivatives of the formula II with trialkyl phosphites. However, this process often provides only poor yields. Moreover, the reaction is slow and requires elevated reaction temperatures, for example reflux in toluene. Under these reaction conditions there is frequently partial inversion of configuration at C-5, which results in undesired (5S,6S)-penems.
It has now been found that the described disadvantages of the known process can be avoided if dialkyl alkylphosphonites are used in place of trialkyl phosphites for the 20 cyclization reaction. These novel reagents permit the reaction temperatures to be lower, for example room temperature, and result in shorter reaction times. Higher yields and purer products are achieved thereby. In addition, the undesired isomerigation to (5S,6S)-penems is avoided. The dialkyl alkylphosphonates and dialkyl alkylthiophosphonates formed as by-products can be removed in a straightforward manner.
Hence the invention relates to a process for the preparation of penem derivatives of the formula I, in which the preferred configuration is (5R,6S) p ,-0 F i f.4 7, -2- 31 j and in which R' denotes hydrogen,, (C-C 4 -alkyl, (C-C2) -alkoxy, (C-C)-alkylthio, phenoxy, phenyl (the phenyl rings being unsubstituted or substituted once or twice by carboxyl, (C, 1
-C
4 -alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl (C-C)-alkylaminocarbonyl, cyano, F, [1 Cl or Br), (C 3
-C
8 -cycloalkyl, (C 3 -Cr,)-cycloalkyloxy,
(C
5 -C)-oxacycloalkyl (saturated or singly or doubly unsaturated), (C 3 -Cr,)-oxocycloalkyl, (C 3 -C-1,-bis-
(CI-C
3 )-lyoy -ylakl (C 3
-C
5 -I (Cl-C 3 -alkylino]-cycloalkyl, (C-C 8 -[arylimino 3cycloalkyl,
(C
3
-C
6 -hydroxyiminocyc loalkyl, (C 3
-C
6
-(C-C
3 -alkyloxyimino) -cycloalkyl, in which the cycloalkyl radical is unsubstituted or substituted once or twice by Cl-C 3 -alkyl, preferably methyl, by (Cl-C 3 -4 alkoxy, preferably methoxy, by halogen, preferably chlorine, or by methylene and is saturated or can contain one or two double bonds, V 0t 4 R 2 denotes hydrogen or a customary carboxyl protective group which can be eliminated by hydrolysis, photolysis, oxidation, reduction or enzymatically, R 3 denotes hydrogen, -alkyl, -alkenyl, (Cl-C)-alkoxy, (C-C 7 -cycloalkyl, phenyl, 2-oxo-1,3dioxolyl, triazolyl, thiazolyl, amino, acylaxnino or alkoxy.
Suitable and particularly preferred substituents are the following: Ri hydrogen, (C 1
-C
4 )-alkyl (for example methyl, ethyl, hydroxymethyl and axinomethyl) (Cl-C4) -alkoxy (for example methoxy and ethoxy), (C.-CO)-alkylthiot (for example methylthio, ethylthio, and propylthio),F phenoxy (for example 4-c arboxamidophenoxy or 4cyanophenoxy), phenyl (for example 4is~ I. III S-C-R j -3carboxamidophenyl or 4-cyanophenyl), saturated or unsaturated (C 5 -oxacycloalkyl (for example tetrahydrofuryl or furyl), (C4-C 6 )-oxocycloalkyl (for example 1-oxo-3-cyclobutyl), 3hy4droxyiminocyclobutyl, 3-methoxyiminocyclobutyl and 3 ,3-dimethoxycyclobutyl.
R
3 l-hydroxyethyl (in which the OH group is free or protected by trimethylsilyl, diphenyl-tert butylsilyl, allyloxycarbonyl, trichioroethyloxycarbonyl or 4-nitrobenzyloxycarbonyl), (C 1
-C
3 )-alkoxy (for example methoxy or ethoxy), (C 1
-C
3 -alkenyl, for example triazolylethylene or thiazolylethylene.
The (Cl-CA) -alkylI and (C,-C 4 -alkoxy groups in the substitutent R' are either unsubstituted or substituted once or twice by hydroxyl, (Cl-C) -alkoxy, (Cl-C 4 -acyloxy, am1inio, (Cl-C4) -alkylamino, -acylamino, mercapto,F (C-C)-alkvylthio or heterocytcLylthio, for example thiazolyl-, thiadiazolyl-, pyridylthio.
tt 4 4 Phenyl. nuclei are liks,%wise unsubstituted or substituted once or twice by carbo.Nyl, (CI-C 4 ,)-alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl, (C 1
-C
4 -alkylaminocarbonyl, cyano or halogen, preferably F, Cl, Br.
The (C- 4 -alkyl and -alkoxy groups in R 3 are 'j either unsubstituted or substituted by hydroxyl, (Cl-CA) alkoxy, (C-CO-acyloxy, amino, (Cl-C 4 )-alkylamino, (C 1
-C
4 acyl amino, mercaptoo (Cl-CO)-alkylthio or heterocyclylthio, it being possible for an OH group to be free or protected by trimethylsilyl, diphenyl-tert.-butylsilyl, allyloxycarbonyl, trichioroethoxycarbonyl. or 4nitrobenzyl.oxyca.-bonyl.
Xn the procopss 6ccording to the invention, the compounds of the formula I are prepared by reacting a compound ofF the formula II rU -4-
X
S R in which X denotes uxygen or sulfur, and R1, R 2 and R 3 have the above meaning, with a trivalent organic phosphorus compound of the formula III 5 F F.
F F F F F F
R
6 P 4
NOR
F 4 15 in which R6 denotes (C 1
-C
4 -alkyl, for example mtthy1, ethyl or trifluoromethyl, phenyl which can be substituted by.
(Cl-C 3 )-alkyl or (C-C 3 -alkoxy, and R 4 and R 5 are identical or different and denote (Cl-C4)alkyl, allyl, benzyl, or phenyl which can be substituted by (C-C 3 )-alkyl or (Cl-C)-alkoxy.
The reaction between a compound II and a compound III can be carried out in a suitable organic solvent, for example in tetrahydrofuran, ethyl acetate, an aromatic hydrocarbon such as benzene, toluene or xylene, or a halogenated hydrocarbon such as dichloromethane, trichioromethane or 1,1, 2-trichloroethane.
The reaction temperature can vary between +10 0 C and 160 0
C,
preferably between +20*C and +70 0
C.
The concentration of the compound II, to be cyclized is between 1 mol/1 and 100 mmol/l, preferably between 2 mmol/l and 20 mmol/l.
equivalents, relative to II.
The compounds of the formulae II and III are known or can be prepared by processes disclosed in the literature.
The examples which follow serve to illustrate the invention further.
Example 1 fi i 1 4-Nitrobenzyl (5R,6S)-6-[(1R)-tert.-butyldimethylsilyl- 0 oxyethyl (4-aminocarbonylphenoxy)penem-3-carboxylate 130 mg (0.2 mmol) of (3S,4R)-4-[(aminocarbonyl)-phenoxythiocarbonylthio3-3-[(lR)-tert.-butyldimethylsilyloxyethyl) 4-nitrobenzyloxycarbonyl)-azetidin-2-one were dissolved in 90 ml of CHC13 under an argon atmosphee at 55°C. To this was added within 30 minutes a solution of mg (0.8 mmol) of dimethyl methylphosphonite CH 3 P(OCh3) 2 in 10 ml of CHCI 3 and, after addition was complete, the mixture was then stirred for 2 hours and, after cooling, worked up. Extraction with 1 N aHCO 3 solution, 1 N KHSO 4 solution and water was carried out, and the organic phase was dried with magnesium sulfate and concentrated in S« vacuo. The crude product provided, after flash chromatot graphy (SiO 2 70-200 pm 10 H.O; first toluene ethyl acetate 20 1, then 1 1 for elution), the title compound in 83 yield.
The compounds I listed in Table 1 were obtained analogously from the starting substances II listed in Table 2 under the reaction conditions listed in Table 3.
pW_ data on the pene. I according to the invention Exampl e RIR 2 1 H-NMR (COC1 3 8 (p"pm) -OAt QLCONH2 PNB -CH(OTBOMS)CH 3 2 D.O CONH2 3 0O44Q'CNH 2 -C11 2 CH=C11 2
CH
2
CH
2 S iMe 3 8.17, 7.55 (4H1, AA-88', J=8.7 Hz, aromat. H -of P118); 7.83, 7.21 (411 AA'BB', J=8.8 aromat. H of benzamide); 5,65 (1H, d, J=1.4, H1-5); 5.38, 5.21 (2H, AR, J=13.8, Benzyl-11); 4.41-4,42 (lIN, m, -CH(OTBDMS)-); 3.76 (1IN, dd J=1.4. 4.8, 11-6); 1.25 (3H1, d, J=6.2, CH 3 0.82 (9H, s. tert.-Butyl-H); 0.09, 0.05 (6H1, 2 x s, Si(C11 3 2 7 J3. 7.21, (411, M'BB'1, J=8.8, aromat. HI ofbenzamlde; 5.78-5.94 (111, m, 5.62 (1H, d. J1I.i, 5.40-5.17 (2H1, m, =C1 2 4.66 !211, m, COZ-C11 2 4.25 (1IN, -CII(OTBDMS)-); 3.71 (111, dd, J=1.4, 4.8, 11-6); 1.25 (3H1, d, J=6.2, CH 3 0.88 (91, S, tert.-Butyl-1); 0.09, 0.05 (611, 2 x s, Si(C11 3 2 7.BZ, 7.20 AAMBB', J=8.8. aromat. H Of benzamlde); 5.61 (IN1, d. J=1.4, 11-5); 4-20-4.30 (311, m, -CH(OTBDMS)- and 'C1 2
CH
3.72 (1IN, dd, J=1.4, 4.8, 11-6); 1.25 (3H11d, J=6.2, C11 3 0.96 (2H1, m, CH 2 Si); 0.87 (911, s, tert.-utyl-1); 0.1-0.01 (total 1511, 3 x s, Si(C11 3 3 TBDMS t-butyldimethylsilyl Me Methyl PNB para-Nitrobenzy! IRON -buyldmetylslyl Me Metyl 118= pra-itrbeny'! TE 1,1,2-Trlchloroethane fl77
U'
*E 4 a 4 4 *i o Table I Continuation a a a 4 a a a *OQ 0 a 0 rro orr o rr a -a a fi n P a -a n r r i r^ Example R1 R 2 R3 1 1-NMR (COCI) 8 (ppm) 4 0C1 3
-CH
2 CH=C1 2 -CH(OTBDMS)CH3
OCH
3 6
OCH
3
PNB
-CHCH
2 SiMe 3 5,.85-6.02 (1M, m, 5.55 (1H, d, J=1.4, 5.43-5.17 (total2f, m, C14 2 4.65 (2H, m, C0 2 -C1 2 4.25 (1H, m, -CH(GTBDMS)-);.4.00 (3H, s, OCH 3 3.65 (1H, dd, J=1.4, 4.8, 1,25 (3H, d, J=6.2,
CH
3 0.90 (9H, s, tert-Butyl-H); 0.10 (6H.
2 x s, Si(C1 3 2 8.20, 7.60 (4H,AA'88, J=8.7 Hz, aromat. H of PNB); 5.61 (11, d, J=1.4, 5.39 and 5.19 (2H, ABq, 14Hz, Benzyl-H); 4.25 (1N, m, -CH(OTBDMS)-); 4.04 (3H, s, OCH 3 3.71 (11, dd, J=1.4, 4.8, 046); 1.27 (3H, d, J=6.2), C1 3 0.82 tert.-Butyl-H); 0.09, 0.05 (6H, 2 x s, Si(CH 3 2 5.52 (1H, d. J=1.4, 4.25 (total3H, m, -CH(OTDBMS)-, CH 2 -OCO); 4.00 s, 0C1 3 3.65 (1H, dd, J=1.4, 4.8, 1.25 (3H, d, J=6.2, CH 3 1.05 m, CH 2 Si); 0.90 (9, s, tert.-Butyl-H); 0.5-0.1 (15, 3 x s, Si(C1 3 3 8.29, 7.59 AA'BB', J=8.7 Hz, aromat H of PNB); 5.55 (1H, d, J=1.4, 5.39and 5.19 (2H, ABq, 414z, Benzyl-H); 4.72 (11, m, 4.25 (11, m, -CH(OTBOS)-); 3.66 (1H, dd, J=1.4, 4.8, 2.0-1.5 (total8H, Cyclopentyl-CHZ); 1.27 (3H, d, J=6.2, CH3-); 0.82 (9H, s, tert.-Butyl-H); 0.08, 0.05 k6H, 2 x s, Si(CH 3 2 7 0[J -PHN so i -i L- -I Table I Continuation Exapl eR R2 R 1H NMR NEW (POm) -M -013 8 0Q 9
SCH
3 PNB -CH(OTBDMS)CH3 -C4 2 C1--CH2 8.19, 7.61 (4H, AA'BB', J=8.7Hz, aromat. H of PNB); 5.55 (1H, d, J=1.4, 5.29 and 5.19 (2H, ABq, 14Hz, Benzyl-H); 4.21-4-12 (total.',NI m, 1'-CH and -CH(OTBDMS)-); 3.66 (14, dd, J=1.4, 4.8, 2.05-1.3 (total 1014, m, Cyclohexyl-C1 2 1.27 (3H, d, J=6.2,
CH
3 0.82 (9H, s, tert.-Btuyl-H); 0.08, 0.05 (6H, 2 x s, Si(C1 3 2 5-85-6.02 (1H, m, 5.61 (1H, d, J=1.4, 5.43, 5.37, 5.22, 5.19 (tt12H, 4 x d, CH 2 4.70 m, C0 2
-CH
2 4.22 (11, m, -CH(OTBDS)-); 3.68 (1H, dd, J=1.4, 4.8, 2.51 s, SCH 3 -123 (3H, d, J=6.2, CH3); 0.88 (94, s, tert.-Outyl-H); 0.10 (6H, 2 x s, Si(C1 3 2 8.21, 7.51 (4H, AA'BB', J=8.7 Hz, aromat. H of PNB); 5.66 d, J=1.4, 5.41and 5,21 (2H, ABq, 14Hz, Benzyl-H); 4.25 (1H, m, -CH(OTBOS)-); 3.71, 1H, dd, j1.4, 4.8, 2.52 (3H, s, SC1 3 1.25 (3H, d, J=6.2,
CH
3 0.82 (9H, s, tert.-Butyl-H); 0.09, 0.05 2 x s, Si(CH3) 2 5.59 (lI, d, J=1.4, 4.0-4.31 (zus.
3H, m, -CH(OTBDMS)-, C14f-0C0); 3.66 (114 dd, J=1.4, 4.8, 2.50 (3 s, SCH 3 1.21 (3H, d, J=6.2, CU 3 1.08 (2H, m, C 2 Si); 0.89 (9H, s, tert.-Butyl-H); 0.01-0.11 3 x s, Si(U1 3 2 SC4 3
PHD
11 SC14 3 -CH2CH2SiIe3
-L
rr ,nn ~rr rr .4 Table I Continuation Example RI R 2
R
3 1 H-NMR (CODC1 3 8 (29
IOQ
-CH
2
CH
2 S IMe3 -CH(OTBDMS)CH3
-CH
2
CH
2 SiMe 3 5.52 and 5.45 (totallH, d, J=1.4, 5.42-5.35 (1H, m, 4.31-4.15 (totl1H, M, -CH(OTBOMS)- andZH2-OCa); 4.03-3.77 (2H, m, 5'-CH 2 3.64 (1H, m, 2.51-2.34 (1H, 2 2.05-1.71 (3H, m, 3',4'-CH 2 1-25 (total3H, m, CH 3 1.08 (2H, m, 0.87 (9H, m, CH 2 Siand tert.-Butyl-H); 0.09-0.11 (15H, m, Si(CH 3 3 7.68, 7.52, 6.5. (total3H, 3 x m, Furyl-H); 5.56 (1H, d, J=1.4; 4.34-4.21 (total3H, m, -CH(OTBDMS)-fnd. C1 2 -OCO); 3.69 (1H. dd, J=1.4, 4.8, 1.28 (314, d, J=6.2, C143-); 1.10 (2H, m, CH 2 Si); 0.91 (9H, m, tert.-Butyl-H); 0.01-0.11 (15, 3 x s, Si(C1 3 3 7.50, 7.39 (totaiSH, 2 x m, Phenyl-H); 5.69 (1H, d, J1.4. 4.31 (1H, m, -CH(OTBD45)-); 4.19 (2H, m, C1 2 -OCO); 3.78 (1H, dd, J-1.4, 4.8, 1.32 d, J=6.2, 0.93 (totalllH m, CH 2 Siand tert.-PAyl-H); 0.01-0.11 (15, 3 x s, Si(C11 3 3 -0-
-CI
2 C1 2 SiMe3 Compound 0140 is prepared fram 2 dIfferent precursors in Example 14 and 1, 6-.Mw I It a 4 I Table I Continuation a -1 a -r I OCb rr F- 4 r r r 4 LI nri ni-~C
LI-
S: Example R 2 3 16 O CO 2
CH
2 CH=CH -C 2 CHZSiie 3
-CH(OTBDMS)C"
3 1 H-NIR (CODC 3 8 (ppm) 17 is 19 KXH H 3:
-CH
2
CH
2 Site 3
SCH
2
CH=CH
2
-CH
2
CH
2 SiMe 3 8.06, 7.53 (4H, AA'BB, J=8.8 Hz, aromat. H); 6.1-5.94 (1H4, m, 5.71 (1H, d, J=.4, 5.44-5.20 (2H, m, =CH 2 4.84 (2H, m, C0 2
-CH
2 /Allyl); 4.27 (1H, m, -CH(OTBDMS)-); 4.16 (2H, m, CO 2
CH
2 /T4SE); 3.78 (19, dd, J=1.4, 4.8, 1.28 d, J=6.2, CH 3 0.91 (9H, s, tert.-Butyl-H); 0.11-0.01 4 x s, Si(CH 3 2 5.58 J=1,4 Hz, 4.52 1H, Cyclobutyl); 4.25 (in, 3H, C02CH 2 and CHCH 3 3.70 (dd, J=5 andlHz, 3.15-3.5S-(m, 4 Cyclobutyl-H); 1.28 (3H, d, J=6Hz, CHCH 3 1.08 (Mn, 2H, CH 2 0.88 9H, tert.-Outy1-H); 0.18 6H, Si(CH 3 2 0.06 9H4, Si(CH 3 3 5.86-6.03 1P=CH); 5.61 fd, 7=14z, 5.22-5.45 2=C" 2 4.72 2H, C02CH 2 4.51 19, Cyvclobutyl); 4.25 CHCH 3 3.72 (dd, J=5 and 1 Hz, 3.15-T55 (m, 4-Cyc'lobutyl-H); 1.28 (3H, d, J=6Hz, CHCH 3 0.88 9H, tert.-Butyl-H); 0.10 6fflSi(CH 3 2 5.52 JlHz, 4.2-4.32 3H, CO 2
CH
2 und CHCH 3 4.0-4.14 19, Cyclobutyl); 3-67 (dd, J=5 and 1Hz, 3.15 and 3.16 (je s, 2 x 3H, OCH 3 2.5-2.7 2H, Cyclobutyl); 2.1-2.22 2H, Cyclobutyl), 1.28 (3H, d, .!-f6Hz, CHCH 3 1.08 2H, CH Si); 0.88 s, 9H, tert.-Butyl-H), 0.10 6H, Sif CH3)2); 0.06 9H, Si(C9 3 3 1~ rr rr P~ i L L-L) LL -C Table 2 Starting compounds R S1 0 2t tC R Example R2 R3X 1 0 ~CO4H 2 *PNB -CH(OTBDMS) S 2 -0 ~CONH 2
-CH
2
CH=CH
2
S
CtO~'CNH -CH 2
CH
2 Si Me3 S t t t4 OCH 3
-CH
2 CHi=CH 2
S
1 5 OCH 3
-N
6 OCH 3
-CH
2
CH
2 SiI~e3
S
7O1j 0PNB
S
8-PNB gg s 9 SH 3
-CH
2
CH=CH
2
S
-12- Example RI R2 R3X
SCH
3 -PNB of s 11 SCH 3
-CH
2
CH
2 SiMe3 s 12 -CHZCH 2 Si~e3 0 13 1A -CH 2
CH
2 SiP~e 3 0 I 14 -CHZCH 2 SiMe 3 0
-CH
2
CH
2 SiMe 3 s 16 .C0CH 2 CH=CH2~ -CH 2
CH
2 SiMe 3 0 17 -0-CH 2
CH
2 SiMe 3 0 18 -CI 2 CH=CHZ 0 19 H3-CH 2
CH
2 Si~e 3 0 a a p a a a 0 0 a a aa-0 en a a a a a.
a oa a 4
SCR
Conc. ~~Temp.Recintm(hYel% Examle Reagant III Equivalents of III Cffo.) Solvent Oq)Ratintm(h il
CH
3 P(OCH3)2
K
CH
3
P(OC
2 H5:,Z CHC1 3 1.1-2-TCE CHC1 3 if It It 'i to 2 1 2 0,5 0,5 2 3 3 6 1 1 2,5 0 0
P.
rt 0 Ms 0 rt 0 Ft 0
I.&
0 CI43P(OCII3)2- CHPN2')
Claims (4)
1. A process for the preparation of a penemn compound i in which R 5 S 0 CO 2 R 2 R1 denotes hydrogen, (Ci -C 4 )-alkyl, (CI-Cl 2 )-alkoxy, (Ci -C 1 2 )-alkylthio, phenoxy, phenyl (the phenyl rings being, unsubstituted or substituted once or twice by carboxyl, (Cl-C 4 )-alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl, V (Cl-C 4 )-aikylaminocarbonyl, cyano, F, CI or Br), (C 3 -Cs)-cycloalkyl, (C 3 -C 6 cycloalkyloxy, (C 5 -C 6 )-oxacycloalkyl (saturated or singly or doubly #1 t cycloalkyl, (C 3 1 -C 3 )-alkyllmino]-cycloalkyl, (Cs-C6)-[aryliminO]- cycloalkyl, (C 3 -Cre)-hydroxyinocycloalkyl, (C 3 -C6)-(C 1 -C 3 -alkyloxyimino)- cycloalkyl, in which the cy',Ioalkyl radical Is unsubstituted or substituted once or twice by Cl-C 3 -alkyl, by (C 1 -C 3 )-alkoxy, by halogen, or by methylene and Is saturated or can contain one or two double bonds, the (CI-C 4 )-alkyl and (Ci-C 4 alkoxy groups in the substituent RI 1 are either unsubstituted or substituted once or twice by hydroxyl, (C 1 -C 4 )-alkoxy, (Cl-C 4 )-acyloxy, amino, (Cl-C 4 )-alkyl- amino, (C 1 -C 4 )-acylamlno, mercapto, (C 1 -C 4 )-alkylthlo or heterocyclylthio, 44: 4 2 denotes hydrogen or a customary carboxyl protection group which can be eliminated by hydrolysis, photolysis, oxidation, reduction or enzymatically, R3 denotes hydrogen, (CJ-C 4 )-alkyl, (CI-C 4 )-alkenyl, (Cl-C 4 )-alkoxy, (C 4 -C 7 cycloalkyl, phenyl, 2-oxo-1 ,3-dioxolyl, triazolyl, thlazolyl, amino, acylamino 31 or alkoxy, the (Cl-C 4 )-alkyl and (Cl-C 4 )-alkoxy groups in R 3 are either unsubstituted or substituted by hydroxyl, (C C 4 )-alkoxy, (C 1 -C 4 -acy loxy,0 amino, (C 1 -C 4 )-alkylamino, (Cj-C 4 )-acylamlno, mercapto, (C 1 -C 4 )-alkylthlo or heterocyclylihio, It being possible for an OH group to be free or protected by trimethylsilyl, diphenylbtert.-butylsilyl, allyloxycarbonyl, trichioroethoxy- carbonyl or 4-nitrobenzyloxycarbonyl which comprises reactino a compound of the formula ii 0A _t TO T x 002 R in which X denotes oxygen or sulfur, and Ri, R2 and R3 have the above meaning, with a trivalent organic phosphorus compound of the formula iii CR4 R 6 -P in which R6 denotes (C-C 4 )-alkyl, phenyl which can be substituted by (Cl-C 3 )-alkyl or (Ci C 3 )-alkoxy, and R4 and R5S are Ideontical or different and denote (C 4 )-alkyl, allyl, benzyl, or phenyl which can be substituted by (01-03)-alkyl or (01-03)-alkoxy.
2. The process as claimed in claim 1, wherein the reaction of compound ii with 113: is carried out in an organic solvent.
3. The process as claimed In claim 1, wherein the reaction is carried out. -It between 100C and +1 60c00.
4. The process as claimed In claim 1, wherein R1 denotes hydrogen, (Cij1C 4 )-alkyl, (Ci-04 )-alkoxy, (Ci -C 3 )-alkylthio,j phenoxy, phenyl (the phenyl nuclei being substituted by (Ci -C 4 )-alkoxy- carbonyl, aminocarbonyl or cyano), (C 5 -0 6 )-oxacycloalkyl, (04-06) oxocycloalkyl, 3-hydroxyiminocyclobutyl, 3-methoxyimlnocyclobutyl, 3,3- dimethoxycyclobutyl, 3- methoxy-2-cyclobu ton-1 -yI, 2-msihoxy-1 cyclobuten-1 -yl and 4-methoxy-3-cyclohexen-1 -yl, the (CI -C 4 )-alkyl and (CI-C34)-alkoxy groups In the substituent Ri are either unsubstituted or Atubstituted once or twice by hydroxyl, (C 1 -0 4 )-alkoxy, (CI-C 4 )-acyloxy, .Jo 16 amino, (C 1 -C 4 )-alkyl-amino, (Ci -C 4 )-acylamino, mercapto, (Ci -C 4 alkylthio or heterocyclylthio, R 3 denotes 1-hydroxyethyl (in which the OH group s free or protected by trimethylsilyl, diphenyl-tert.-butylsilyl, allyloxycarbonyl, trichloroethoxy- carbonyl or 4-nitrobenzyloxycarbonyl), -C 3 )-alkoxy, (Ci -C 3 )-alkenyl, C, C3)-alkoxy groups in R3 are either unsubstituted or substitued by hydroxyl, (Ci- C 4 )-alkoxy, (Cl-C 4 )-acyloxy, amino, (Ci -C 4 )-alkylamino, (01-04) acylamino, mercapto, (Cl-C 4 )-alkylthio or heterocyclylthio, it being possible for an OH group to be free or proteoted by trimethylsilyl, diphenyl-tert.-butyl- silyl, allyloxycarbonyl, trichloroethoxycarbonyl or 4-nitrobenzyloxycarbonyl. c C C C 4 C I $1 4i #1 S C C C IC I S C S S S III C CISSSI I C 1141 C S C S C C CC C C I I C *t C 4 TI,, DATED this 17th day of December, 1991. HOECHST AKTIENGESELLJSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BUR WOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA AU005390690.WPC
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3914389 | 1989-04-29 | ||
| DE19893914389 DE3914389A1 (en) | 1989-04-29 | 1989-04-29 | Prodn. of penem antibiotics - by reacting 4-acyl:thio-1- oxalyl-2-azetidinone cpds. with phosphonite di:ester |
| DE19893917287 DE3917287A1 (en) | 1989-05-27 | 1989-05-27 | Prodn. of penem antibiotics |
| DE3917287 | 1989-05-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU5390690A AU5390690A (en) | 1990-11-01 |
| AU620982B2 true AU620982B2 (en) | 1992-02-27 |
Family
ID=25880482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU53906/90A Ceased AU620982B2 (en) | 1989-04-29 | 1990-04-27 | A process for the preparation of penem compounds |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0399228A1 (en) |
| JP (1) | JPH02306978A (en) |
| KR (1) | KR900016224A (en) |
| AU (1) | AU620982B2 (en) |
| CA (1) | CA2015580A1 (en) |
| FI (1) | FI902110A7 (en) |
| NO (1) | NO173871C (en) |
| PT (1) | PT93893A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU652954B2 (en) * | 1990-08-20 | 1994-09-15 | Asubio Pharma Co., Ltd. | Antibacterial penem esters derivatives |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3839987A1 (en) * | 1988-11-26 | 1990-05-31 | Hoechst Ag | PENEM DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
| JP3148235B2 (en) * | 1990-08-20 | 2001-03-19 | サントリー株式会社 | Antibacterial penem compounds |
| GB9216102D0 (en) * | 1992-07-29 | 1992-09-09 | Smithkline Beecham Plc | Pharmaceutical substances |
| IT1286558B1 (en) * | 1996-02-27 | 1998-07-15 | Menarini Farma Ind | PROCESS FOR THE PREPARATION OF 2-HALOGENOMETHYL-PENEMS AND THEIR USE FOR THE PREPARATION OF ANTIBACTERIAL PENEMS |
| EP1489061B1 (en) * | 2002-03-26 | 2011-08-31 | Nippon Soda Co., Ltd. | Process for producing cyclic compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2144743A (en) * | 1983-08-11 | 1985-03-13 | Erba Farmitalia | Process for the preparation of penems |
| AU7004287A (en) * | 1986-03-17 | 1987-09-24 | Schering Corporation | 2-heterocyclylthio penems |
| AU7676687A (en) * | 1986-08-12 | 1988-02-18 | Hoechst Uk Ltd. | Preparation of antibacterial 7-oxo-4-thia-1-azabicyclo(3,2,0)hept-2-ene derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0275002A1 (en) * | 1987-01-09 | 1988-07-20 | Hoechst Aktiengesellschaft | Process for the production of 7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene derivatives |
-
1990
- 1990-04-25 EP EP90107815A patent/EP0399228A1/en not_active Withdrawn
- 1990-04-26 FI FI902110A patent/FI902110A7/en not_active Application Discontinuation
- 1990-04-27 PT PT93893A patent/PT93893A/en not_active Application Discontinuation
- 1990-04-27 AU AU53906/90A patent/AU620982B2/en not_active Ceased
- 1990-04-27 NO NO901893A patent/NO173871C/en unknown
- 1990-04-27 KR KR1019900005962A patent/KR900016224A/en not_active Withdrawn
- 1990-04-27 JP JP2115038A patent/JPH02306978A/en active Pending
- 1990-04-27 CA CA002015580A patent/CA2015580A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2144743A (en) * | 1983-08-11 | 1985-03-13 | Erba Farmitalia | Process for the preparation of penems |
| AU7004287A (en) * | 1986-03-17 | 1987-09-24 | Schering Corporation | 2-heterocyclylthio penems |
| AU7676687A (en) * | 1986-08-12 | 1988-02-18 | Hoechst Uk Ltd. | Preparation of antibacterial 7-oxo-4-thia-1-azabicyclo(3,2,0)hept-2-ene derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU652954B2 (en) * | 1990-08-20 | 1994-09-15 | Asubio Pharma Co., Ltd. | Antibacterial penem esters derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02306978A (en) | 1990-12-20 |
| AU5390690A (en) | 1990-11-01 |
| FI902110A0 (en) | 1990-04-26 |
| NO901893L (en) | 1990-10-30 |
| PT93893A (en) | 1990-11-20 |
| FI902110A7 (en) | 1990-10-30 |
| EP0399228A1 (en) | 1990-11-28 |
| NO173871C (en) | 1994-02-16 |
| CA2015580A1 (en) | 1990-10-29 |
| NO901893D0 (en) | 1990-04-27 |
| KR900016224A (en) | 1990-11-13 |
| NO173871B (en) | 1993-11-08 |
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