WO1999052908A1 - Titanium catalyzed preparation of carbapenem intermediates - Google Patents
Titanium catalyzed preparation of carbapenem intermediates Download PDFInfo
- Publication number
- WO1999052908A1 WO1999052908A1 PCT/US1999/007956 US9907956W WO9952908A1 WO 1999052908 A1 WO1999052908 A1 WO 1999052908A1 US 9907956 W US9907956 W US 9907956W WO 9952908 A1 WO9952908 A1 WO 9952908A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- alkyl
- produce
- hoc
- Prior art date
Links
- 0 C[C@@](*)[C@](C1)C([C@@](C)C(COC([*+])=O)=*2)N2C1=O Chemical compound C[C@@](*)[C@](C1)C([C@@](C)C(COC([*+])=O)=*2)N2C1=O 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/04—Preparation by forming the ring or condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
Definitions
- the present invention relates to a process for synthesizing l- ⁇ -methyl-2- hydroxymethyl carbapenem intermediates. Generally the carbapenems are substituted at the 2-position. The intermediate compounds are included as well. European applications 0330108, 0102239, 0212404, 0695753 and 0476649 disclose methods for synthesizing various antibiotic derivatives.
- carbapenems are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). These antibacterials thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens. There is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time relatively free from undesirable side effects.
- MRSA methicillin resistant Staphylococcus aureus
- MRSE methicillin resistant Staphylococcus epidermidis
- MRCNS methicillin resistant coagulase negative Staphylococci
- the invention describes a short and high yielding synthesis of protected l- ⁇ -methyl-2-hydroxymethyl substituted carbapenems as key intermediates for the synthesis of anti-MRSA carbapenem antibiotics.
- the synthesis involves a highly diastereoselective addition of a titanium, zirconium or hafnium enolate of a suitably protected l-hydroxy-2- butanone derivative with 4-acyl-2-azetidinone.
- the resulting derivatized 2-azetidinone product is obtained largely as a single diastereomer rather than a mixture.
- the two chiral centers which are produced are of the correct absolute stereochemical
- R 1 represents H or a suitable protecting group for an alcohol
- R 2 represents a benzyl, C ⁇ alkyl or aryl
- Y represents C ⁇ g alkyl, O, NH or S
- X represents O, NH, or S comprising reacting a compound of formula 1:
- R 1 is described above and R 4 represents C 1 . 15 alkyl, aryl or C 1 ar alkyl; with a compound of formula 3:
- R 2 , X and Y are as previously defined in the presence of WZ 4 and an amine to produce a compound of formula 2, wherein W is a titanium, zirconium or hafnium metal and Z represents halo, sulfonate, alkoxy, aryloxy or combination thereof.
- the present invention relates to a process for making protected l- ⁇ -methyl-2-hydroxymethyl substituted carbapenems which are key intermediates in the synthesis of anti-MRSA carbapenem antibiotics (such as those disclosed in USSN 08/825,786 filed on April 08, 1997, the teachings of which are hereby incorporated by reference).
- the intermediates can be readily coupled to a wide range of functional groups (see USSN 08/825,786).
- the invention is described herein in detail using the terms defined below unless otherwise specified.
- alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t- butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, selected from R ⁇ and R 1 , as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group”.
- Cycloalkyl is a species of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
- alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
- alkynyl refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond.
- Preferred alkynyl groups include ethynyl, propynyl and butynyl.
- Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like.
- An aryl group thus contains at least one ring having at least 5 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms.
- the preferred aryl groups are phenyl, naphthyl and phenanthrenyl.
- Aryl groups may likewise be substituted as defined.
- Preferred substituted aryls include phenyl and naphthyl.
- Aryl also refer to heteroaryl, which is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a poly cyclic aromatic group having 8 to 16 atoms, containing at least one heteroatom, O, S, S(O), S ⁇ 2 or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein.
- Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole and the like.
- aralkyl is intended to mean an aryl or heteroaralkyl moiety, as defined above, attached through a C ⁇ g alkyl linker, where alkyl is defined above.
- alkyl is defined above.
- aralkyls include, but are not limited to, benzyl, naphtylmethyl, phenylpropyl, 2-pyridylmethyl, 2-imidazolylethyl, 2-quinolinylmethy, 2-imidazolylmethyl and the like.
- polycyclic heteroaromatics examples include benzopyrans, benzofurans, benzopyrroles, benzimidazoles, benzothiazoles, quinolines, purines, isoquinolines, benzopyrimidines, dibenzofurans, dibenzothiophenes, 1,8-naphthosultams,
- heterocycle refers to a 5-16 membered cycloalkyl group (nonaromatic) with 1-4 rings, in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by heteroatoms.
- heteroatom means O, S, S(O), S(0) 2 or N, selected on an independent basis.
- Halogen and "halo" refer to bromine, chlorine, fluorine and iodine.
- protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.
- R 1 and R 5 represent alcohol and carboxyl protecting groups, respectively.
- Y may represent a protecting group for X, which in turn represents O or N.
- These groups are generally removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule.
- Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.
- carboxyl protecting groups R 5 include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl groups such as t-butyldimethylsilyl (TBDMS), trimethylsilyl, (TMS), triethylsilyl (TES), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p- nitrobenzyl (pNB), 4-pyridylm ethyl and t-butyl, preferably pNB and benzyl.
- TDMS t-butyldimethylsilyl
- TMS trimethylsilyl
- TES triethylsilyl
- phenacyl p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p- nitrobenzyl (pNB), 4-pyridylm ethyl and t-but
- suitable alcohol protecting groups R 1 include hydrogen, trialkylsilyl, diarylalkylsilyl, aryldialkylsilyl or trityl such as TMS, TES, TBDMS, alkyl carbonates such as benzyl carbonate, allyl carbonate, benzyl ether, diarylalkylsilyl, aryldialkylsilyl & trityl and the like.
- Preferred R 1 groups are trialkylsilyl or hydrogen.
- R 1 represents H or a suitable protecting group for an alcohol
- R 2 represents a benzyl, C ⁇ alkyl or aryl
- Y represents C ⁇ 3 alkyl, O, NH or S
- X represents O, NH, or S
- R 5 represents a carboxy protecting group, comprising reacting a compound of formula 2:
- R 1 represents H or a suitable protecting group for an alcohol
- R 2 represents a benzyl, C ⁇ .6 alkyl or aryl
- Y represents C l 3 alkyl, O, NH or S
- X represents O, NH, or S
- R 5 represents a carboxy protecting group, comprising reacting a compound of formula 5:
- R 1 , R 2 , R 5 , X and Y are as previously described with a phosphite or phosphonite reagent to produce a compound of formula 6.
- R 1 represents H or a suitable protecting group for an alcohol
- R 2 represents a benzyl, C ⁇ alkyl or aryl
- Y represents C ⁇ g alkyl, O, NH or S
- X represents O, NH, or S
- R 5 represents a carboxy protecting group, comprising reacting a compound of formula 2:
- R 1 represents H or a suitable protecting group for an alcohol
- R 2 represents a benzyl, C ⁇ alkyl or aryl
- Y represents C ⁇ g alkyl, O, NH or S
- X represents O, NH, or S
- R 5 represents a carboxy protecting group, comprising reacting a compound of formula 1:
- R 1 is described above and R 4 represents C ⁇ alkyl, aryl or C ⁇ _ 6 aralkyl; with a compound of formula 3:
- R 2 , X and Y are as previously defined in the presence of WZ 4 and an amine to produce a compound of formula 2:
- W is a titanium, zirconium or hafnium metal and Z represents halo, sulfonate, alkoxy, aryloxy or combination thereof, and Rl, R2, X and Y are as previously described, reacting a compound of formula 2 with an activated oxalic acid agent in the presence of a base to produce a compound of formula 5 HoC
- R 1 represents H or a suitable protecting group for an alcohol
- R 2 represents a benzyl, C ⁇ g alkyl or aryl
- Y represents C ⁇ g alkyl, O, NH or S
- X represents O, NH, or S
- R 5 represents a carboxy protecting group, comprising reacting a compound of formula 1:
- R 1 is described above and R 4 represents C 1 . 15 alkyl, aryl or C 1 6 ar alkyl; with a compound of formula 3:
- R 2 , X and Y are as previously defined in the presence of WZ 4 and an amine to produce a compound of formula 2:
- W is a titanium, zirconium or hafnium metal and Z represents halo, sulfonate, alkoxy, aryloxy or combination thereof, and Rl, R2, X and Y are as previously described, and reacting a compound of formula 2 with an oxalimide forming agent in the presence of a base to produce a compound of formula 5.
- Suitable amines includes trialkylamines such as triethylamine, tributylamine, trimethylamine, ethyl dimethylamine, tri- n-propylamine, di-isopropylethylamine, aniline, N j N-di-C ⁇ g - alkylanilines such as N,N-diethylaniline and the like.
- Suitable bases include trialkylamines such as triethylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine and the like, l,8-diazabicyclo[5.4.0.]undec-7-ene (DBU), pyridine, imidazole, lutidine, collidine, 4-dimethylaminomethylpyridine, inorganic carbonates and bicarbonates such as sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, and the like and tartrates such as potassium sodium tartrate, potassium tartrate, potassium bitartrate, sodium tartrate, sodium bitartrate and the like, preferably pyridine, lutidine or collidine.
- DBU diazabicyclo[5.4.0.]undec-7-ene
- Suitable phosphites include P(OR a )(OR b )(OR c ); P(OR a )(OR b )(NR c R d ); P(R a )(R b )(R c ); catechol phosphites or catechol dimer phosphites, wherein R a , R b , R c and R d may be the same or different and represent a straight or branched chain C ⁇ g alkyl or a phenyl, both of which may be optionally substituted with, for example, a C ⁇ alkyl.
- Preferable phosphites are trialkylphosphites such as triethyl phosphite, tributyl phosphite, triisopropyl phosphite, trimethyl phosphite and the like, most preferably triethylphosphite.
- Suitable phosphonites include P(OR e )(OR f )(R ), wherein R e and R f independently represent C 1 4 alkyl, allyl, benzyl or phenyl, optionally substituted with C ⁇ alkyl or C ⁇ alkoxy and R g presents C ⁇ alkyl, trifluoromethyl or phenyl, which is optionally substituted with C 1.3 alkyl or C 1.3 alkoxy.
- Suitable activated oxylic acid agents include acid and carbodiimide moieties such as oxalyl chloride and benzyl oxalyl chloride.
- R 1 represents an alcohol protecting group selected from the group consisting of: H, TES, TMS, TBDMS, pNB, p- nitrobenzyloxycarbonyl, allyl and allyloxycarbonyl.
- R 5 represents an carboxylic acid protecting group selected from the group consisting of: p-nitrobenzyl (pNB), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), allyl, p-methoxybenzyl, benzyl, trichloroethyl, 2- trimethylsilyl ethyl, and the like.
- pNB p-nitrobenzyl
- TMS trimethylsilyl
- TES triethylsilyl
- TDMS tert-butyldimethylsilyl
- allyl p-methoxybenzyl, benzyl, trichloroethyl, 2- trimethylsilyl ethyl, and the like.
- Still other processes that are of particular interest are those described above wherein Y represents O or CH 2 . Still other processes that are of particular interest are those described above wherein Y represents O.
- Typical conditions for the reaction involve generation of the titanium, zirconium or hafnium enolate of a suitably protected derivative of 1-hydroxybutanone such as an alkyl or aryl carbonate, preferably ethyl carbonate or isobutylcarbonate. This can be achieved by the addition of the corresponding metal tetrahalide to the derivative of 1- hydroxybutanone followed by addition of a trialkylamine.
- the stoichiometry of the enolate formation requires at about 0.5 to 3.0 equivalents, preferably 1 to 2.0 equivalents of metal tetrahalide. About 0.5 to about 5 equivalents, preferably about 1 to about 3 equivalents and most preferably about 1 to about 2.0 equivalents of trialkyl amine is used.
- the enolate generation is generally carried out at a temperature of about -80°C to about 60°C, preferably about -40°C to about 30°C.
- the azetidinone is added to the enolate and the reaction temperature warmed to about 0°C - 30°C.
- the stoichiometry of the reaction requires about 1.0 to about 5 equivalents, preferably about 1 to about 2.0 equivalents of the enolate of the alkyl or aryl carbonate of 1- hydroxybutanone or its synthetic equivalent.
- Suitable solvents for the reaction include aromatic solvents such as benzene, toluene, xylene and the like, ethereal solvents such as tetrahydrofuran (THF), diethyl ether, dioxane and the like and haloalkyl solvents such as 1,2 dichloroethane, dichloromethane, chloroform, and the like, preferably the aromatic solvents.
- aromatic solvents such as benzene, toluene, xylene and the like
- ethereal solvents such as tetrahydrofuran (THF), diethyl ether, dioxane and the like
- haloalkyl solvents such as 1,2 dichloroethane, dichloromethane, chloroform, and the like, preferably the aromatic solvents.
- the azetidinone is reacted with, for example, a titanium enolate of the ethyl or isobutyl carbonate of 1- hydroxy-2-butanone, preferably the isobutyl carbonate moiety.
- the protecting group e.g. TBDMS
- HF hydrofluoric acid
- HC1 HC1
- fluorosilicic acid H 2 SiF 6
- another alcohol protecting group e.g. TES derivative, typically using TESC1, benzyl ethers or allyl ethers
- a base such as imidazole or pyridine.
- the cyclization step typically involves reacting the oxalimide in the presence of a phosphite or phosphonite reagent, preferably a trialkylphosphite agent.
- cyclization requires from about 2 to about 6 equivalents, preferably about 2.5 to about 5 equivalents of the phosphite or phosphonite.
- the cyclization is generally carried out at a temperature of about 25°C to about 200°C, depending on the nature of the phosphorus reagent used. When using a trialkylphosphite reagent the temperature is generally about 90°C to about 160°C.
- the carbapenem produced in the cyclization is a key intermediate in the synthesis of anti-MRSA carbapenem antibiotics and can be readily coupled to a wide range of functional groups in via methods taught in USSN 08/825,786.
- the final product may be characterized structurally by techniques such as NMR, IR, MS, and UV.
- the final product if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.
- the compounds of the present invention are valuable intermediates for antibacterial agents that are active against various Gram-positive and to a lesser extent Gram-negative bacteria, and accordingly find utility in human and veterinary medicine.
- MRSA/MRCNS In vitro antibacterial activity is predictive of in vivo activity when the compounds are administered to a mammal infected with a susceptible bacterial organism.
- Titanium tetrachloride solution was added to a solution of the isobutyl carbonate in toluene at -40°C. Tributylamine was added. The acetoxy azetidinone was then added and the reaction stirred at room temperature. After 3 hours the reaction was quenched with dilute hydrochloric acid. The toluene layer was washed with dilute HCl. The toluene layer was used in the subsequent step. Isolated prod, 13C NMR (CDC13) ⁇ -5.0, -4.3, 11.7, 17.9, 18.8, 22.5, 25.8, 27.8, 44.6, 51.0, 61.7, 65.4, 69.8, 74.8, 154.8, 168.3, 205.65
- Example 2 To the toluene solution from Example 1 was added acetonitrile and the HF solution. After 6 hours the reaction was quenched with aq. Rochelles salt. The toluene layer was dried and the solvent was removed. The crystalline product was swished with hexanes and filtered to yield 4-[3- ((l-oxy-2-oxobutane)isobutyl carbonate)] -2-azetidinone (23.3g) as a white solid.
- Triethyl phosphite was added to a solution of TES oxalimide isobutyl carbonate in xylene. The reaction was heated to 135°C for 3 hours. The reaction was given several aqueous washes, dried and the solvent removed in vacuo to afford the desired compound (12.2g).
- lH NMR (399.87 MHz, CDCI3) d 8.22 (m, 2 H), 7.66 (m, 2 H), 5.57 (d,
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99916629A EP1071685A4 (en) | 1998-04-16 | 1999-04-12 | Titanium catalyzed preparation of carbapenem intermediates |
CA002328219A CA2328219A1 (en) | 1998-04-16 | 1999-04-12 | Titanium catalyzed preparation of carbapenem intermediates |
JP2000543465A JP2002511470A (en) | 1998-04-16 | 1999-04-12 | Preparation of Carbapenem Intermediates with Titanium Catalyst |
AU34908/99A AU745980B2 (en) | 1998-04-16 | 1999-04-12 | Titanium catalyzed preparation of carbapenem intermediates |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8200398P | 1998-04-16 | 1998-04-16 | |
US60/082,003 | 1998-04-16 | ||
GBGB9811297.2A GB9811297D0 (en) | 1998-05-26 | 1998-05-26 | Process for the synthesis of carbapenem intermediates, and compounds produced |
GB9811297.2 | 1998-05-26 | ||
US9142298P | 1998-07-01 | 1998-07-01 | |
US60/091,422 | 1998-07-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999052908A1 true WO1999052908A1 (en) | 1999-10-21 |
Family
ID=27269329
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/007956 WO1999052908A1 (en) | 1998-04-16 | 1999-04-12 | Titanium catalyzed preparation of carbapenem intermediates |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1071685A4 (en) |
JP (1) | JP2002511470A (en) |
AU (1) | AU745980B2 (en) |
CA (1) | CA2328219A1 (en) |
WO (1) | WO1999052908A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6489471B1 (en) | 1998-06-17 | 2002-12-03 | Merck & Co., Inc. | Process for the synthesis of carbapenem intermediates, and compounds produced |
WO2003080571A1 (en) * | 2002-03-25 | 2003-10-02 | Takasago International Corporation | Process for producing azetidinone compounds |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5756725A (en) * | 1996-04-24 | 1998-05-26 | Merck & Co., Inc. | Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8804058D0 (en) * | 1988-02-22 | 1988-03-23 | Fujisawa Pharmaceutical Co | 3-alkenyl-1-azabicyclo(3 2 0)hept-2-ene-2-carboxylic acid compounds |
IL99513A0 (en) * | 1990-09-20 | 1992-08-18 | Hoechst Ag | Process for the preparation of carbapenem compounds |
JP3220985B2 (en) * | 1991-12-26 | 2001-10-22 | 日本曹達株式会社 | Method for producing 4-substituted azetidinone derivatives |
-
1999
- 1999-04-12 CA CA002328219A patent/CA2328219A1/en not_active Abandoned
- 1999-04-12 JP JP2000543465A patent/JP2002511470A/en not_active Withdrawn
- 1999-04-12 AU AU34908/99A patent/AU745980B2/en not_active Ceased
- 1999-04-12 WO PCT/US1999/007956 patent/WO1999052908A1/en not_active Application Discontinuation
- 1999-04-12 EP EP99916629A patent/EP1071685A4/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5756725A (en) * | 1996-04-24 | 1998-05-26 | Merck & Co., Inc. | Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment |
Non-Patent Citations (1)
Title |
---|
See also references of EP1071685A4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6489471B1 (en) | 1998-06-17 | 2002-12-03 | Merck & Co., Inc. | Process for the synthesis of carbapenem intermediates, and compounds produced |
WO2003080571A1 (en) * | 2002-03-25 | 2003-10-02 | Takasago International Corporation | Process for producing azetidinone compounds |
Also Published As
Publication number | Publication date |
---|---|
AU745980B2 (en) | 2002-04-11 |
EP1071685A1 (en) | 2001-01-31 |
AU3490899A (en) | 1999-11-01 |
JP2002511470A (en) | 2002-04-16 |
CA2328219A1 (en) | 1999-10-21 |
EP1071685A4 (en) | 2001-07-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0176064A1 (en) | Intermediates for the production of 7-oxo-4-thia-1-aza[3,2,0]heptane and 7-oxo-4-thia-1-aza[3,2,0]hept-2-ene derivatives | |
US5459260A (en) | Tricyclic or tetracyclic carbapenem compounds, their production and use | |
Shibata et al. | Synthetic studies of 1-β-methylcarbapenem antibiotics | |
US6395894B2 (en) | Process for the synthesis of carbapenem intermidiates, and compounds produced | |
IL97275A (en) | 2-Substituted alkyl-3-carboxy carbapenems as antibiotics and a method of producing them | |
AU745980B2 (en) | Titanium catalyzed preparation of carbapenem intermediates | |
JPH0516433B2 (en) | ||
JPH0532668A (en) | Preparation of substituted 2-thioxopenam and 2-substituted thiopenem | |
JP2000344774A (en) | Production of carbapenem compound | |
US6194568B1 (en) | Process for synthesizing carbapenem intermediates | |
PL172378B1 (en) | Method of obtaining novel 4-substituted azetidinones | |
HU204269B (en) | Process for producing antibiotica of 1-carba-cepheme sceleton | |
KR100246950B1 (en) | Novel carbapenem compounds and the process for the preparation thereof | |
KR100262240B1 (en) | 3-substituted-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate compounds | |
NO873353L (en) | PROCEDURE FOR THE PREPARATION OF ANTIBACTERIAL 7-OXO-4-TIA-1-AZABICYCLO (3.2.0) HEPT-2-EN DERIVATIVES. | |
KR100523986B1 (en) | Carbapenem derivatives with an antibacterial activity against resistant strains and preparation thereof | |
KR100246951B1 (en) | Novel carbapenem compounds | |
JP3003002B2 (en) | Tricyclic carbapenem compounds | |
JPH0586062A (en) | Polycyclic carbapenem compound | |
KR100246952B1 (en) | Novel carbapenem compounds | |
KR970011389B1 (en) | Novel carbapenam antibiotics and the preparation thereof | |
KR100246953B1 (en) | Novel carbapenem compounds | |
KR970011388B1 (en) | Novel carbapenem antibiotics and the preparation thereof | |
CA1197841A (en) | 7-oxo-4-thia-1-aza[3,2,0]heptane and 7-oxo-4-thia- 1-aza[3,2,0]-hept-2-ene derivatives | |
Kuroboshi et al. | Diastereoselective synthesis of 6-bromo-6-(1-hydroxyethyl) penicillanate by cross-coupling of 6, 6-dibromopenicillanate and acetaldehyde pronmoted with grgnard reagents: Role of amine ligands |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK SL TJ TM TR TT UA US UZ VN YU ZA |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
ENP | Entry into the national phase |
Ref document number: 2328219 Country of ref document: CA Ref country code: CA Ref document number: 2328219 Kind code of ref document: A Format of ref document f/p: F Ref country code: JP Ref document number: 2000 543465 Kind code of ref document: A Format of ref document f/p: F |
|
NENP | Non-entry into the national phase |
Ref country code: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 34908/99 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1999916629 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1999916629 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 34908/99 Country of ref document: AU |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1999916629 Country of ref document: EP |