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EP0906312A1 - Procede pour la preparation des derives de carbapenem et leurs intermediaires - Google Patents

Procede pour la preparation des derives de carbapenem et leurs intermediaires

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Publication number
EP0906312A1
EP0906312A1 EP97926097A EP97926097A EP0906312A1 EP 0906312 A1 EP0906312 A1 EP 0906312A1 EP 97926097 A EP97926097 A EP 97926097A EP 97926097 A EP97926097 A EP 97926097A EP 0906312 A1 EP0906312 A1 EP 0906312A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
formula
compound
optionally substituted
enyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97926097A
Other languages
German (de)
English (en)
Inventor
Timothy Charles University of Bristol GALLAGHER
Neil James Hales
Robert Hugh Bradbury
Richard Process Development Dept. WISEDALE
Sarah Ruth Martel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca UK Ltd
Original Assignee
Zeneca Ltd
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Filing date
Publication date
Application filed by Zeneca Ltd filed Critical Zeneca Ltd
Publication of EP0906312A1 publication Critical patent/EP0906312A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D205/10—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • 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
    • 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

Definitions

  • the invention relates to a process for the manufacture of carbapenem and carbapenam derivatives which are intermediates for antibiotic compounds, some of which are ⁇ -lactamase inhibitors and some of which are antibiotics in their own right.
  • the invention provides a process for the preparation of compounds of the formula
  • R' is hydrogen or optionally substituted: C,. 6 alkyl, C,. 6 alkylthio or C,. 6 alkoxy;
  • R 2 is hydrogen, halogen or optionally substituted: C,. 6 alkyl, C 3 _ 6 alkenyl, arylC,. 3 alkyl, aryl, heteroarylC,. 3 alkyl, heteroaryl, heterocyclyl, heterocyclylC 1 . 3 alkyl, C V7 cycloalkyl, C 3 . 7 cycloalkylC,. 3 alkyl, C 5 . 7 cycloalkyenyl, C 5 . 7 cycloalkenylC, 3 alkyl.
  • R 2 is of the formula R 6 CONH- wherein R 6 is an organic group; or
  • R 1 and R 2 together form an optionally substituted C 3 . 6 alkylene chain wherein one methylene group is optionally replaced by -N(R n )-, -O- or -S-, (C 3 . 6 alkylene chains wherein one methylene group is optionally replaced by -N(R")-, -O- or -S- are hereafter referred to as C 3 . 6 heteroalkylene), wherein R" is hydrogen, C,. 6 alkanoyl, phenylC M alkyl or C,. 6 alkyl; or R' and R 2 together form a group of the formula: R a
  • R a and R b are independently hydrogen or optionally substituted C. ⁇ alkyl, aryl or heteroaryl; or R a and R b , together with the carbon atom to which they are attached, form an optionally substituted C 4 . 7 cycloalkyl, C 4 . 7 cycloalkenyl or heterocyclyl ring, each optionally fused to a benzene or heteroaryl ring;
  • R 3 is hydrogen, cyano or halo or optionally substituted: C,. 6 alkyl or of the formula -S(O) n R 7 (n is 0, 1 or 2) wherein R 7 is C,. 6 alkyl, arylC,. 3 alkyl, aryl, C 3 . 6 alkenyl, arylprop-2-enyl, heteroarylC,. 3 alkyl, heteroaryl or heteroarylprop-2-enyl or, when n is 2, R 7 is NR 8 R 9 wherein R 8 and R 9 are independently hydrogen, or optionally substituted: C,. 6 alkyl, C 3.6 alkenyl, arylC ⁇ alkyl, arylprop-2-enyl, heteroarylC,.
  • R 3 alkyl, heteroarylprop-2-enyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form an optionally substituted heteroaryl ring or R 3 is optionally substituted: C,. 6 alkoxy, C 3 . 6 alkenyloxy, arylC,. 3 alkoxy, heteroarylC,_ 3 alkoxy, arylprop-2-enyloxy, heteroarylprop-2-enyloxy, aryloxy or heteroaryloxy or R 3 is of the formula -COR 10 wherein R'° is hydrogen or optionally substituted: C, .6 alkyl, C 3.6 alkenyl, arylC,.
  • R 10 is of the formula NR 8 R 9 wherein R 8 and R 9 are as hereinabove defined, or R 3 is of the formula -CO 2 R" wherein R" is hydrogen or optionally substituted: C, .6 alkyl, C 3 . 6 alkenyl, arylC,.
  • R 4 is hydrogen, halo, cyano or optionally substituted: C, ⁇ alkyl, C 3 . 6 alkenyl, arylC,. 3 alkyl, heteroarylC
  • R 4 is of the formula -CONR l3 R 14 wherein R 13 or R 14 are independently hydrogen or optionally substituted: arylC, .3 alkyl, C, .6 alkyl, C 3.6 alkenyl, heteroarylC, .3 alkyl, heteroarylprop-2-enyl, arylprop-2-enyl, aryl or heteroaryl or R 13 and R 14 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or R 4 is of the formula -S(O) n R 17 wherein n is 0, 1 or 2 and R 17 is optionally substituted: C, .6 alkyl, arylC, .3 alkyl, C 3.6 alkenyl, heteroarylC,.
  • R 17 is of the formula -NR I5 R 16 wherein R 15 and R 16 are independently hydrogen or optionally substituted: C alkyl, C 3 . 6 alkenyl, heteroarylC
  • R 4 is of the formula -COR 18 wherein R 18 is as hereinabove defined or R 4 is of the formula -Se(O) q R 7 (q is 0, I or 2) wherein, when q is 0, R 7 is as hereinabove defined and when q is 1 or 2, R 7 is optionally substituted: aryl or heteroaryl;
  • R 5 is cyano or of the formula -CO ;
  • R 19 wherein R' 9 is hydrogen or optionally substituted: C, .6 alkyl. arylC M alkyl, heteroaryl, heteroarylC,. 3 alkyl, C 3 . 6 alkenyl, arylprop-2-enyl or heteroarylprop-2enyl or R 5 is of the formula -COR 20 wherein R 20 is hydrogen or optionally substituted C,. 6 alkyl. arylC,. 3 alkyl, heteroarylC,. 3 alkyl, aryl or heteroaryl; and wherein any functional groups are optionally protected; and salts thereof; which process includes the step of reacting the intermediate formed by heating a compound of the formula (II):
  • the compounds of the formula (I) are useful as intermediates in the preparation of ⁇ 2 carbapenems and may possess antibacterial properties and/or inhibit ⁇ -lactamase.
  • the invention provides a process for the preparation of compounds of the formula (III):
  • R 1 , R 2 and R 5 are as hereinabove defined and
  • R 21 is nitro or R 2 ' is of the formula -Se(O) q R 7 (q is 0) wherein R 7 is as hereinabove defined, or R 2 ' is as hereinabove defined for R 3 ;
  • R 22 is nitro or R 22 is of the formula -Se(0) q R 7 wherein q and R 7 are as hereinabove defined, or R 22 is as hereinabove defined for R 3 ;
  • R 23 and R 24 are independently nitro, of the formula -OR 43 wherein R 43 is C,. 6 alkyl. arylC,. 3 alkyl or C 2.6 alkenyl, or as hereinabove defined for R 4 ; or R 2 ' and R 22 , or R 22 and R 24 . or R 23 and R 24 together form an optionally substituted C 3 . 7 alkylene chain wherein 1 or 2 methylene groups are optionally replaced by -N(R n )-, -O- or -S-, (C 3 .
  • R 2, -R 24 are as hereinabove defined; and thereinafter, if necessary, removing any protecting groups.
  • the compounds of the formula (III) are useful as intermediates in the preparation of ⁇ 2 carbapenems and may possess antibacterial properties and/or inhibit ⁇ -lactamase.
  • the stabilised 1 ,3-dipole (IVa) is believed to be the important reaction intermediate.
  • the intermediate is formed by reacting the compound of the formula (II) in an inert solvent in a temperature range of 50°C to 180°C.
  • the intermediate is formed by reacting the compound of the formula (II) in an inert solvent in a temperature range of 80°C to 1 10°C.
  • the inert solvent is acetonitrile, propionitrile. toluene, chloroform or o-dichlorobenzene. Most preferably the inert solvent is acetonitrile.
  • (V) may be prepared from a compound of the formula (III) in situ.
  • Suitable eliminatable groups include benzene selenyl; the oxide of which readily eliminates.
  • the compounds of the formula (V) may be of value in the treatement of bacterial infections and/or inhibit ⁇ -lactamase in their own right.
  • Carbapenem compounds of the formula (V) can be converted into carbapenem compounds of the formula (VI):
  • Suitable pharmaceutically-acceptable salts include acid addition salts such as hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid.
  • suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N- ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine.
  • Preferred pharmaceutically-acceptable salts are sodium and potassium salts. However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
  • the process of the invention may also be used in the preparation of chemical compound libraries. It may be used to provide a common synthetic step at any convenient stage of library synthesis, such as at the penultimate or last stage.
  • the libraries so prepared may comprise any convenient number of individual, and diverse, chemical compounds, such as from tens to hundreds, hundreds to thousands, thousands to tens ot thousands, tens of thousands to hundreds of thousands, hundreds of thousands to a million or more individual compounds. Suitable and preferred chemical moieties for inclusion in the library will be apparent to the chemist of ordinary skill.
  • alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R' and R 2 include halo, trifluoromethyl, nitro. hydroxy, amino, C M alkylamino. diC M alkylamino, cyano, C,. 6 alkoxy, carboxy, C,. 6 alkylS(O) p ( p is 0, 1 or 2), C,. 6 alkyl (optionally substituted by hydroxy, amino, halo, nitro, cyano, hydroxyimino or C M alkoxyimino), carbamoyl, C M alkylcarbamoyl, di(C M alkyl)carbamoyl, C,.
  • alkylsulphonyl hydroxyiminoC,. 6 alkyl, C l.4 alkoxyiminoC U6 alkyl and C,. 6 alkylcarbamoylamino.
  • Particular optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R 4 , R 23 and R 24 include halo, trifluoromethyl, nitro, hydroxy, amino, C M alkylamino, diC M alkylamino, cyano, C ⁇ alkoxy, carboxy, C,.
  • Optional substituents for ring nitrogen atoms in heteroaryl groups include C M alkyl and C M alkanoyl.
  • R 23 and R 24 may be optionally substituted by halo, C M alkyl, trifluoromethyl, nitro, hydroxy, amino, C M alkylamino, di-(C M alkyl)amino, cyano, C M alkoxy, carboxy, C M alkanoyl or carbamoyl.
  • a heteroaryl ring system is a monocyclic aryl ring system having 5 or 6 ring atoms wherein 1 , 2 or 3 ring atoms are selected from nitrogen, oxygen and sulphur or a bicyclic aryl ring system having 8 to 10 ring atoms wherein 1 , 2, 3 or 4 ring atoms are selected from nitrogen, oxygen and sulphur.
  • heteroaryl rings include pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, 1,2,4-, 1,2,5- and 1 ,3,4-thiadiazolyl, thienyl, furyl and oxazolyl and 1 ,2,3- and 1 ,2,4-triazolyl.
  • An aryl ring system is phenyl. naphthyl or a tricyclic aryl ring system.
  • an aryl ring system is phenyl.
  • a heterocyclylium ring is a positively charged saturated or partially saturated monocyclic ring system, having 5 or 6 ring atoms, or a positively charged bicyclic ring system, having 8 to 10 ring atoms, containing one ring nitrogen atom and 0-2 further hetero ring atoms selected from nitrogen, oxygen and sulphur.
  • a heteroarylium ring is a positively charged monocyclic aryl ring system, having 5 or 6 ring atoms, or a positively charged bicyclic aryl ring system, having 8 to 10 ring atoms, containing one ring nitrogen atom and 0 - 2 further hetero ring atoms selected from nitrogen, oxygen and sulphur.
  • a heterocyclyl ring system is a saturated or partially saturated monocyclic ring system having 5 or 6 ring atoms or a saturated or partially saturated bicyclic ring system having 8 to 10 ring atoms, each containing 1 - 3 hetero ring atoms selected from nitrogen, oxygen and sulphur and wherein any ring sulphur and nitrogen atoms are optionally oxidized.
  • tricyclic ring systems include optionally substituted bicyclic heteroaryl ring systems to which is fused a benzene ring.
  • tricyclic rings include, dibenzofuran and dibenzothiophene.
  • a C 3 . 7 cycloalkyl group is a saturated monocyclic ring system having from 3 to 7 ring atoms.
  • a C 5.7 cycloalkenyl group is a monocyclic ring system having from 5 to 7 ring atoms and containing one double bond.
  • alkyl when used herein includes straight chain and branched chain substituents for example C M alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
  • An organic group also includes C,. 6 alkyl ( phenyl, heteroaryl, arylC M alkyl and heteroarylC,. 3 alkyl.
  • Optional substituents for carbon atoms in C,. 6 and C 3 . 7 alkylene and heteroalkylene chains include halo, trifluoromethyl, nitro, oxo, hydroxy, amino, C,. 4 alkylamino, di(C M alkyl)amino, cyano, C, ⁇ alkoxy, C M alkyl-S(O) p -(p is 0, 1 or 2), C M alkanoyl and C M alkyl optionally substituted by hydroxy, halo, nitro, cyano or amino;
  • Examples of C ⁇ alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl; examples of carboxy C,. 3 alkyl are carboxymethyl, 2-carboxyethyl, 1 -carboxyethyl and 3-carboxypropyl; examples of C
  • alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl; examples of tetrazolyC, .3 alkyl are tetrazolylmethyl and 2-tetrazolylethyl; examples of C M alkoxy are methoxy, ethoxy, propoxy and isopropoxy; an example of C 3 . 6 alkenyl is allyl; an example of C 2 .
  • 6 alkynyl is propynyl; examples of C M alkanoyl are formyl, acetyl, propionyl and butyroyl; examples of halo are fluoro, chloro, bromo and iodo; examples of C M alkylamino are methylamino, ethylamino, propylamino and isopropylamino; examples of di(C M alkyl)amino are dimethylamino, diethylamino and ethylmethylamino; examples of C M alkylS(O) p - are methylthio, methanesulphinyl and methanesulphonyl; examples of C M alkylcarbamoyl are methylcarbamoyl and ethylcarbamoyl; examples of di(C U4 alkyl)carbamoyl are dimethylcarbamoyi, diethylcarbamoyl and
  • C M alkyl are methyl, ethyl, propyl and isopropyl;
  • examples of C M alkoxycarbonylamino are methoxycarbonylamino and ethoxycarbonylamino;
  • examples of C M alkanoylamino are acetamido and propionamido;
  • Examples of 4 alkyl)amino are N-methylacetamido and N-methylpropionamido; examples of C M alkanesulphonamido are methanesulphonamido and ethanesulphonamido; examples of C ⁇ .alkylaminosulphonyl are methylaminosulphonyl and ethylaminosulphonyl: examples of di(C M alkyl)aminosulphonyl are dimethylaminosulphonyl, diethylaminosulphonyl and ethylmethylaminosulphonyl; examples of C M alkanoyioxy are acetoxy and propionyloxy; examples of formylC,. 4 alkyl are formylmethyl and 2-formylethyl; and examples of C M alkoxyimino are methoxyimino and ethoxyimino.
  • alkylene chains examples include trimethylene, but-1 ,4-diyI, pent-1 ,5-diyl and hex-l ,6-diyl.
  • Examples of C 3.6 heteroalkylene chains include -CH 2 NHCH 2 -, -CH 2 OCH 2 -, -CH 2 SCH 2 -, -CH 2 CH 2 NHCH 2 - and -O-CH 2 CH 2 CH 2 -,
  • Examples of C 3.7 alkylene and heteroaikylene chains optionally containing a double bond and optionally fused to a benzene or heteroaryl ring include:
  • X and Y are independently NH, oxygen, sulphur, methylene, -CO- or -CH(R m )- wherein R m is hydrogen, halo, nitro. amino, hydroxy, cyano or C M alkyl
  • -CH 2 CH 2 CH CH-
  • -CH 2 CH CHCH 2 CH 2 -
  • -OCH 2 CH CHCH 2 - and -SCH 2 CH 2 CH 2 -.
  • the present invention relates to all tautomeric forms of the compounds disclosed.
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods. For example see 'Protective Groups in Organic Synthesis " , by T.W. Greene et. al., second edition, 1991.
  • Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • protecting groups are given below for the sake of convenience, in which "lower” signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. For example, it will be appreciated that polymer-supported protecting groups are included such as those employed in solid phase synthesis (see 'Polymer-supported Reactions in organic synthesis', by P. Hodge and D.C. Sherrington, 1980). Where specific examples of methods for the removal of protecting groups are given below, these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
  • a carboxyl protecting group may be the residue of an ester- forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • Examples of carboxy protecting groups include straight or branched chain
  • (l-12C)alkyl groups eg. isopropyl. t-butyl
  • lower alkoxy lower alkyl groups eg methoxymethyl, ethoxymethyl, isobutoxymethyl
  • lower aliphatic acyloxy lower alkyl groups eg.
  • lower alkoxycarbonyloxy lower alkyl groups eg 1 -methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl
  • Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis or hydro genation.
  • hydroxyl protecting groups include lower alkenyl groups (eg allyl); lower alkanoyl groups (eg acetyl); lower alkoxycarbonyl groups (eg t-butoxycarbonyl); lower alkenyloxycarbonyl groups (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl. p-nitrobenzyloxycarbonyl); tri lower alkylsilyl (eg trimethylsilyl, t-butyldimethylsilyl) and aryl lower alkyl (eg benzyl) groups.
  • lower alkenyl groups eg allyl
  • lower alkanoyl groups eg acetyl
  • lower alkoxycarbonyl groups eg t-butoxycarbonyl
  • lower alkenyloxycarbonyl groups eg ally
  • amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg p_-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl): lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, g-nitrobenzyloxycarbonyl; trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups.
  • lower alkoxycarbonyl eg
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as E-nitrobenzyloxycarbonyl, hydrogenation and for groups such as o-nitrobenzyloxycarbonyl, photo lyrically.
  • the invention relates to all enantiomeric and diasteromeric forms unless explicitly indicated otherwise.
  • R 2 is significantly larger than R 1 , the enantiomer with the
  • 5-position stereochemistry as depicted in formulae (I) and (III) is obtained in significantly larger quantities relative to the other enantiomer.
  • the position of the substituents in the product is determined by the regiochemistry of the reaction.
  • the reaction of the intermediate with a co-reagent olefm or acetylene generally gives both of the possible regioisomers.
  • the substituents on the olefm or acetylene are electronically similar the major product will be the one that minimises steric interactions of the substituents at points where these substituents clash.
  • electronic effects dominate the regiochemistry of the ring- forming process may be predicted by considering the magnitude of the interactions between the interacting orbitals as described by Houk (K.N. Houk, Ace. Chem.
  • alkylthio-, alkylseleno-, and carbonyl- and similar conjugating and electron withdrawing substituents preferentially form the 2-substituent of the product (R 23 or R 24 ), whereas hydrogen and alkyl substituents show little discrimination between either position.
  • the relative orientation of the substituents in the product is determined by the stereochemistry of the reaction.
  • the indicated hydrogen (the ring junction C5) will be preferably cis to the sterically larger of the substituents R 1 and R 2 .
  • the substituent R 5 will be preferably cis to the indicated hydrogen at C5.
  • the relative orientation of the substituents on an olefinic co-reagent will be preferably retained in the product of cycloaddition so that R 21 and R 23 will preferably be mutually cis in that product and R 22 and R 24 will preferably be mutually cis in that product.
  • Olefm substituents such as alkyl that show little electronic effect on the relative position (regiochemistry) of the substituents will preferably be cis to the indicated hydrogen at C5; alkylthio-, alkylseleno-, and carbonyl- and similar conjugating and electron withdrawing substituents will be preferably trans to the indicated hydrogen at C5.
  • R 1 and R 2 are different and enantiomerically enriched lactone (II) is used, the products of the reaction are similarly enantiomerically enriched and when enantiomerically pure lactone (II) is used, the products of the reaction are similarly enantiomerically pure.
  • R' and R 2 are the same or when racemic lactone (II) is used, the products are also racemic.
  • a particular enantiomer may be isolated from a mixture of the enantiomers by resolution.
  • a suitable organic base for example, N,N,N-trimethyl(l-phenylethyl)ammonium hydroxide
  • reaction with an optically active form of a suitable organic base for example, N,N,N-trimethyl(l-phenylethyl)ammonium hydroxide
  • suitable solvent for example a (l-4C)alkanol
  • the optically active form of said compound of formula (I), (III), (V) or (VI) may be liberated by treatment with acid using a conventional procedure.
  • R 1 is no bigger than R 2 More preferably R 2 is bigger than R 1 .
  • R' is hydrogen.
  • R 2 is hydrogen, halo or optionally substituted: C,. 6 alkyl, aryl, heteroaryl, arylC,. 3 alkyl, heteroary!C,. 3 alkyl, C,. 6 alkoxy, C,. 6 alkylthio or of the formula R 6 CONH-.
  • R 2 is hydrogen or optionally substituted: C,. 6 alkyl, phenylC, .3 alkyl or phenyl, wherein the optional substituents are selected from hydroxy, halo, nitro. amino, C M alkoxy or C,. 4 alkylthio and the hydroxy and amino groups are optionally protected.
  • R 2 is hydrogen or C,. 6 alkyl optionally substituted by protected hydroxy, or fluoro.
  • R 3 is hydrogen, cyano or optionally substituted C,. 6 alkyl or R 3 is of the formula -CO 2 R 32 wherein R 32 is optionally substituted: C,. ⁇ alkyl, aryl or arylC,. 3 alkyl or R 3 is of the formula -CONR 33 (R 34 ) wherein R 33 and R 34 are independently hydrogen or optionally substituted: C, .6 alkyl. arylC,. 3 alkyl, or R 33 and R 34 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or R 3 is of the formula -COR 35 wherein R 35 is optionally substituted: hydrogen, C,. 6 alkyl, arylC M alkyl or aryl. More preferably R 3 is hydrogen or optionally substitued: C,. 6 alkyl or C M alkoxycarbonyl.
  • R 3 is hydrogen or C,. 4 alkoxycarbonyl.
  • R 4 is cyano, C,. 6 alkyl, arylC,. 3 alkyl, heteroarylC,. 3 alkyl, aryl, heteroaryl or of the formula -CO 2 R 18 wherein R 18 is as hereinabove defined or R 4 is of the formula
  • R 13 and R' 4 are as hereinabove defined or R 4 is of the formula -COR 35 wherein R 35 is as hereinabove defined or R 4 is of the formula -SR 36 wherein R 36 is optionally substituted:C
  • R 4 is cyano, C, .6 alkyl, aryl or of the formula -CO 2 R 39 wherein R 39 is hydrogen or optionally substituted: C h alky 1, C 3 ⁇ alkenyl, arylC ⁇ alkyl, arylprop-2-enyl or aryl or R 4 is of the formula -CONR 40 (R 41 ) wherein R 40 and R 41 are independently hydrogen or optionally substituted: C ⁇ alkyl, arylC,.
  • R 4 is of the formula -COR 35 wherein R 35 is as hereinabove defined or R 4 is of the formula -SR 36 wherein R 36 is as hereinabove defined or R 4 is of the formula -Se(O) q R 7 wherein q is 0 and R 7 is as hereinabove defined.
  • R 4 is C,. 6 aikyl, phenyl or of the formula -CO 2 R 39 wherein R 39 is hydrogen or optionally substituted: C,. 6 alkyl or arylC,. 3 alkyl or R 4 is of the formula -COR 35 wherein R 35 is as hereinabove defined or R 4 is of the formula -SR 36 wherein R 36 is optionally substituted: C, .6 alkyl, aryl or heteroaryl.
  • R 4 is C,. 6 alkyl, phenyl or of the formula -C0 2 R 39 wherein R 39 is C,. 6 alkyl or of the formula -SR 36 wherein R 36 is optionally substituted: C,. 6 alkyl or phenyl or R 4 is of the formula -SR 36 wherein R 36 is aryl or heteroaryl.
  • R 4 is methyl, ethyl, phenyl or of the formula -CO 2 R 39 wherein R 39 is methyl or ethyl or R 4 is of the formula -SR 36 wherein R 36 is pentyl, 2-(acetamido)ethyl or phenyl or R 4 is of the formula -SR 36 wherein R 36 is phenyl.
  • R 5 is cyano or of the formula -C0 2 R 39 wherein R 39 is as hereinabove defined, or R" is of the formula -COR 35 wherein R 35 is as hereinabove defined.
  • R 5 is of the formula -C0 2 R 39 wherein R 39 is as hereinabove defined.
  • R 21 is hydrogen, cyano or optionally substituted C,. 6 alkyl, aryl or a group of the formula -SO 2 R 31 wherein R 3 ' is as hereinabove defined or R 21 is of the formula -CO 2 R 32 (wherein R 32 is as hereinabove defined) or R 2 ' is of the formula -CONR 13 R 14 (wherein R 13 and R 14 are as hereinabove defined) or of the formula -COR 35 (wherein R 35 is as hereinabove defined) or R 21 , together with R 22 , forms an optionally substituted C 4 .
  • R 21 is hydrogen or optionally substituted C,. 6 alkyl. Most preferably R 21 is hydrogen.
  • R 22 is hydrogen, cyano, halo or optionally substituted: C,. 6 alkyl, C, .6 alkoxy, ary!C, .3 alkoxy, heteroaryl C,. 3 alkoxy, aryloxy, heteroaryloxy or of the formula -S(O) n R 7 , -COR 10 or -CO 2 R 32 (wherein n, R 7 , R !0 and R 32 are as hereinabove defined) or R 22 , together with R 21 or R 24 , forms an optionally substituted C 4 _ 6 alkylene chain wherein one methylene group is optionally replaced by -N(R r )-, -O- or -S-, wherein R n is as hereinabove defined, and the chain optionally contains one double bond and is optionally fused to an aryl or heteroaryl ring.
  • R 22 is hydrogen, cyano or optionally substituted C,. 6 alkyl or aryl or a group of the formula -SO 2 R 31 , -CO 2 R 32 , -CONR 13 (R 14 ) or of the formula -COR 35 (wherein R 13 , R 14 , R 3 ', R 32 and R 35 are as hereinabove defined) or R 22 and R 24 together form a chain as hereinabove defined.
  • R 22 is hydrogen or optionally substituted: C,. 6 alkyl or aryl or arylsulphonyl or R 22 is of the formula -CO 2 R 39 or -COR 39 wherein R 39 is as hereinabove defined or R 22 and R 24 together form a chain as hereinabove defined.
  • R 22 is hydrogen, methyl, phenylsulphonyl of the formula -CO 2 R 39 , wherein R 39 is methyl or ethyl or R 22 and R 24 together form a chain as hereinabove defined.
  • R 23 is hydrogen, nitro, halo, cyano, C,. 6 alkoxy, arylC,. 3 alkoxy, aryloxy, heteroarylC, .3 alkoxy, arylC, .3 alkoxy or R 23 is of the formula -C0 2 R 18 wherein R 18 is as hereinabove defined or R 23 is of the formula -S(O) n R 36 wherein n is 0, 1 or 2 and R 36 is as hereinabove defined or R 23 is of the formula -COR 37 wherein R 37 is as hereinabove defined for R 18 or R 37 is of the formula -NR ,3 R 14 wherein R 13 and R 14 are as hereinabove defined or R 37 is C,.
  • R 23 forms a chain together with R 21 or R 24 as hereinabove defined, or R 23 is optionally substituted C, .6 alkylseleno or arylseleno.
  • R 23 is hydrogen, halo or C,. 6 alkylthio, arylthio, C,. 6 alkylseleno or arylseleno.
  • R 24 is nitro, cyano or optionally substituted: C,. 6 alkyl. arylC,. 3 alkyl, heteroarylC, .3 alkyl, aryl or heteroaryl or R 24 is of the formula -CO 2 R 18 wherein R 18 is as hereinabove defined, or R 24 is of the formula -CONR 13 R 4 wherein R 13 and R 14 are as hereinabove defined or R 24 is of the formula -S(O) n R 36 wherein n and R 36 are as hereinabove defined, or R 24 , together with R 22 , forms an optionally substituted C 3 cognitive 6 alkylene chain wherein one methylene group is optionally replaced by -N(R n )-, -O- or -S-. wherein R n is as hereinabove defined and wherein the chain optionally contains one double bond and is optionally fused to a benzene or heteroaryl ring or R 23 and R 24 together form a C 3 .
  • R 24 is nitro, cyano, aryl or of the formula -CO 2 R 39 wherein R 39 is as hereinabove defined or R 24 is of the formula -CONR 40 (R 41 ) wherein R 40 and R 41 are as hereinabove defined or R 24 is of the formula -COR 35 wherein R 35 is as hereinabove defined or R 24 is of the formula -S(O) ⁇ R 36 is as hereinabove defined, or R 24 , together with R 22 , forms a C,. 5 alkylene chain and is optionally substituted by hydroxy, C,. 6 alkoxy or oxo and optionally fused to a benzene or heteroaryl ring.
  • R 24 is optionally substituted aryllsulphonyl, arylthio, C,. 6 alkylsulphonyl, C, .6 alkylsulphinyl, C,. 6 alkylthio, C,. 6 alkylseleno or arylseleno or of the formula -CO 2 R 42 .
  • R 42 is hydrogen, C,. 6 alkyl or arylC,. 3 alkyl or R 24 , together with R 22 , forms a C, .5 alkylene chain and is optionally substituted by hydroxy, C,. 6 alkoxy or oxo and optionally fused to a benzene ring.
  • R 24 is optionally substituted phenylsulphonyl, phenylthio, methanesulphonyl, methanesulphinyl, methanethio or phenylseleno or of the formula
  • R 42 is methyl or ethyl, or R 24 , together with R 22 . forms a C,. s alkylene chain and is optionally substituted by hydroxy, C,. 6 alkoxy or oxo and optionally fused to a benzene ring.
  • R 43 is methyl, ethyl, benzyl or allyl.
  • Preferred optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R 1 and R 2 include halo, trifluoromethyl, nitro, hydroxy, amino, cyano, C,. 6 alkoxy, carboxy, C, .6 alkyIS(O) p ( p is 0, 1 or 2), C,. 6 alkyl. carbamoyl,
  • Preferred optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R 3 , R 21 and R 22 include halo, trifluoromethyl, nitro, hydroxy, amino, cyano, C ⁇ alkoxy, carboxy, C,. 6 alkyl S(O) p (p is 0, 1 or 2), C,. 6 alkyl, carbamoyl,
  • Preferred optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R 4 , R 23 and R 24 include halo, trifluoromethyl, nitro. hydroxy. amino, C,. 4 alkylamino. diC,. 4 alkylamino, cyano, C, ⁇ alkoxy, carboxy, C,. 6 alkylS(O) p - (p is 0, 1 or 2), C,.
  • Preferred optional substituents for the alkylene chain formed by R 22 and R 24 include oxo, hydroxy and C,. 6 alkoxy.
  • a compound of the formula (II) can be prepared by methods known in the carbapenem art. For example by the general methods of scheme 1.
  • a compound of the formula (XI) may be reacted to form a compound of the formula
  • a compound of the formula (XI) may be prepared by reacting a compound of the formula (X) in a diazo exchange reaction with, for example. N-ethyl 2-azidobenzthiazolium fluoroborate using the method disclosed in Heterocycles Vol. 16, No. 9, 1981 or methods analogous thereto.
  • a compound of the formula (IX) wherein L is chloro may be prepared from a compound of the formula (IX) wherein L is acetoxy, by methods known in the art.
  • a compound of the formula (X) may be prepared from a compound of the formula (IX) by reacting the latter compound with a compound of the formula R 5 -CH 2 CO 2 H using the method described in Heterocycles Vol. 16, No. 9, 1981 or methods analogous thereto.
  • a compound of the formula (II) may be prepared by ozonolysis of a compound of the formula (XVI) (A.G. Brown, D. F. Corbett, J. Goodacre, J. B. Harbridge, T.T. Howarth, R.J. Ponsford, I. Stirling and T. J. King. J. Chem. Soc, Perkin Trans. I. 1984, 635).
  • a compound of the formula (XVI) may be prepared from a compound of the formula (XV), which in turn may be prepared from a compound of the formula (XIV), using methods described in (E. Hunt, GB Patent No 15299.3) or by methods analogous thereto.
  • a compound of the formula (XIV) may be prepared from a compound of the formula (XIII), which in turn may be prepared from a compound of the formula (XII), by methods described in German patent application DE 4,142,423 or by methods analogous thereto.
  • a compound of the formula (XII) may be prepared from a compound of the formula
  • a compound of the formula (II), wherein R' and R 2 are hydrogen, may be prepared by ozonolysis of a compound of the formula (VII):
  • a compound of the formula (I) may be prepared by reacting the intermediate, formed from the compounds of the formula (II), with a compound of the formula R 3 - ⁇ -R 4 in situ.
  • a compound of the formula (III) may be prepared by reacting the intermediate, formed from a compound of the formula (II), with a compound of the formula
  • a compound of the formula (II) may be converted to the intermediate, believed to be of formula (IVa) or (IVb) , by heating it in acetonitrile or in another inert solvent such as other lower alkylnitriles, for example propionitrile, an aromatic hydrocarbon, for example toluene, an ether for example di-isopropyl ether, a halogenated solvent, for example 1 ,1 ,2-trichloroethane or an aliphatic hydrocarbon such as decalin. in a temperature range of 70-160°C, until the lactone is converted, which is usually between 30 minutes and 24 hours, most usually between 1 and 6 hours.
  • a compound of the formula (I) may be converted into a compound of the formula (V) by base catalysed isomerisation.
  • base catalysed isomerisation For example see 'S.M. Schmitt. D.B.R. Johnston, and B.G. Christensen, J. Org. Chem. 1980, 45, 1 135 and 1 142', and in a similar vein, ⁇ M. W. Foxton, R.C. Mearman, C. E. Newall, and P. Ward, Tetrahedron Letts., 1981 , 22, 2497'.
  • a compound of the formula (I) may be converted into a compound of the formula (III), wherein one of R 21 and R 22 is hydrogen and the other is as defined for R 3 and one of R 22 and R 23 is hydrogen and the other is as defined for R ⁇ by catalytic hydrogenation. with palladium on carbon as the catalyst, for example.
  • a compound of the formula (III), wherein at least one of R 23 and R 24 is an eliminatable group, may be converted into a compound of the formula (V) by base-catalysed or thermal elimination.
  • An eliminatable group is a group which can be eliminated together with a hydrogen in the 3-position of the penam ring.
  • Examples of base-catalysed eliminatable groups include arylsulphonyloxy, methanesulphonyloxy (for example see M. Miyashita, N. Chida, and A. Yoshikoshi, J. Chem. Soc, Chem. Commun., 1984, 195 and M. Shibuya, M. Kuretani, and S.
  • thermally eliminatable groups include the oxides of phenylselenyl (phenylselenyl is conveniently oxidised in situ), nitro and arylsulphinyl.
  • a compound of the formula (VIII) may then be converted to a compound of the formula (V) by base-catalysed or thermal elimination.
  • the antibacterial properties of the carbapenems prepared using the process of the present invention may be demonstrated in vivo in conventional tests.
  • Example 1 ( ⁇ ) p-Nitrobenzyl (2R. 3R. 7S, 8 ⁇ -5-nhenyl-4.6,10-trioxo-1.5- diazatricvclo[6.2.0.0 3 ' 7 ]-decane-2-carboxylate.
  • Example 7 ( ⁇ ) Sodium (IR. 2R. 3R. 55)-3-methoxycarbonyl-4-rnethyl-7-oxo-l- azabicyclof3.2.01heptane-2--carboxylate.
  • the benzyl (25, 5R, 6 ⁇ -6-[l(R)-/.?rt-buryIdimethylsilyloxyethyl]-3,7-dioxo-4-oxa-l- azabicyclo[3.2.0]heptane-2-carboxylate used in this example was prepared as follows: To a solution of benzyl (35, 4R)-3-[l(R)-/er/-butyldimethylsiIyloxyethyl]-2-azetidinone-4-yl diazomalonate (894 mg, 2.0 mmol) in CH 2 C1 2 (20.0 cm 3 ) was added Rh 2 (OAc) 4 (2.5 mol%) and the reaction mixture heated at reflux for 24 h.
  • Example 18 Benzyl (25. 5R. 6 ⁇ -H(R)-fgr/-butyldimethylsilyloxyethyll-3-methylthio-7- oxo-l-azabicvclo[3.2.Q
  • Phenyl vinyl selenide H.J. Reich, W.W. Willis Jr., and P.D. Clark, 7 Org. Chem., 1981, 46, 2775
  • p-nitrobenzyl 25, 5 ⁇
  • p-nitrobenzyl 25, 5 ⁇ -3,7-dioxo-4-oxa-l- azabicyclo[3.2.0]heptane-2-carboxylate
  • o- dichlorobenzene 2mL
  • reaction mixture was partitioned between ethyl acetate (5 mL) and water (5 mL) and the aqueous phase was extracted with ethyl acetate (5 mL).
  • the organic phases were combined, washed with brine , dried (sodium sulfate) and evaporated in vacuo to give a pale yelow oil.
  • Example 21 ( ⁇ ) p-Nitrobenzyl-(25. 3R.75.85)-4,10-dioxo-3-phenylselenenyl-l- azatricvclo[6.2.0.0 37 ldecane-2-carboxylate and ( ⁇ ) p-nitrohenzyl-(25. 35.7R.85.-4.10- dioxo-3-phenvIselenenyl-l-azatricvclol6.2.0.0 3,7 ldecane-2-carboxylate.
  • the components of the mixture had characteristic 'H-nmr spectra: ( ⁇ )/?-Nitrobenzyl (25, 3R, 75, 8 ⁇ )-4-oxo-10-oxa-2-phenylselenenyl-l- azatricyclo[6.2.0.03,7]decane-2-carboxylate, ⁇ H (270 MHz:CDCl 3 ) 1.95 - 2.65 (5 H, m), 2.84 (1 H.
  • Example 22 ( ⁇ ) p-Nitrobenzyl-(25. 3R .85, 9.y)-4.1 l-dioxo-3-nhenylselenenyl-l- azatricvc ⁇ or7.2.0.0 38 lundecane-2-carboxylate and ( ⁇ ) p-nitrobenzyl-(25. 35. 8R. 95V4.11 dioxo-3-phenylseIenenyl-l-azatricvclo[7.2.0.0 38 lundecane-2-carboxyIate.
  • Example 23 ( ⁇ ) p-NitrobenzvI (25. 3R. 9S. 105V4.12-dioxo-3-phenylselenenyl-l- azatricvclof8.2.0.0 39 ldodecane-2-carboxylate.

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Abstract

L'invention a pour objet un procédé pour la préparation des composés de la formule (I) où R?1, R2, R3, R4 et R5¿ sont tels que définis et où tous les groupes fonctionnels sont éventuellement protégés. L'invention concerne aussi des sels de ces composés. Ce procédé consiste à faire réagir l'intermédiaire formé en chauffant un composé de la formule (II) dans un solvent inerte avec un composé de la formule R3- -R?4 où R1, R2, R3, R4 et R5¿ sont tels que définis et les groupes fonctionnels sont éventuellement protégés. En outre, le procédé consiste, si nécessaire, à extraire les groupes de protection. Les composés de la formule (I) sont des intermédiaires utiles dans la préparation de Δ2 carbapenems et peuvent présenter des propriétés antibactériennes et/ou inhiber la β-lactamase.
EP97926097A 1996-06-12 1997-06-10 Procede pour la preparation des derives de carbapenem et leurs intermediaires Withdrawn EP0906312A1 (fr)

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GBGB9612275.9A GB9612275D0 (en) 1996-06-12 1996-06-12 Process
GB9612275 1996-06-12
PCT/GB1997/001560 WO1997047621A1 (fr) 1996-06-12 1997-06-10 Procede pour la preparation des derives de carbapenem et leurs intermediaires

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US3487090A (en) * 1968-12-23 1969-12-30 Bristol Myers Co Disulfides of 3-blocked amino-2-azetidinones
GB1273243A (en) * 1969-08-21 1972-05-03 Bristol Myers Co 2-azetidinones
CA1024518A (fr) * 1972-04-10 1978-01-17 Queen's University Acetidinones - preparation et utilisation

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