CA1251454A - PROCESS FOR THE MANUFACTURE OF .beta.-LACTAMES - Google Patents
PROCESS FOR THE MANUFACTURE OF .beta.-LACTAMESInfo
- Publication number
- CA1251454A CA1251454A CA000444812A CA444812A CA1251454A CA 1251454 A CA1251454 A CA 1251454A CA 000444812 A CA000444812 A CA 000444812A CA 444812 A CA444812 A CA 444812A CA 1251454 A CA1251454 A CA 1251454A
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- Prior art keywords
- signifies
- dimethyl
- process according
- dioxolan
- amino
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Abstract Optically uniform .beta.-lactams of the formula I
wherein R1 signifies lower alkanoyl, lower alkoxycarbonyl or benzoyl, R2 signifies hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or cyano, R3 signi-fies hydrogen or lower alkyl, B signifies lower alkylidene, lower cycloalkylidene or carbonyl and Z signifies lower 2-alkenyl or 2,4-di(lower alkoxy)benzyl, and their optical antipodes can be manufactured by reacting a salt of a carboxylic acid of the formula II
wherein R1, R2 and R3 have the above significance, in the presence of a reactive derivative of an organic sulphonic acid and a base with an optically uniform compound of the formula III
wherein B and Z have the above signifi-cance, or the optical antipode thereof and can be converted into antimicrobially active, optically uniform substances which contain a .beta.-lactam ring.
wherein R1 signifies lower alkanoyl, lower alkoxycarbonyl or benzoyl, R2 signifies hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or cyano, R3 signi-fies hydrogen or lower alkyl, B signifies lower alkylidene, lower cycloalkylidene or carbonyl and Z signifies lower 2-alkenyl or 2,4-di(lower alkoxy)benzyl, and their optical antipodes can be manufactured by reacting a salt of a carboxylic acid of the formula II
wherein R1, R2 and R3 have the above significance, in the presence of a reactive derivative of an organic sulphonic acid and a base with an optically uniform compound of the formula III
wherein B and Z have the above signifi-cance, or the optical antipode thereof and can be converted into antimicrobially active, optically uniform substances which contain a .beta.-lactam ring.
Description
~;~S~L~54 The present invention is concerned with a process for the manufacture of novel, op~ically uniform ~-lactams of the general formula 15Rl H H i ~ H W
O
wherein Rl signifies Lower alkanoyl, lower alkoxycarbonyl or benzoyl, R2 sig-nifies hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or cyano, R3 signifies hydrogen or lower alkyl, B signifies lower alkylidene, lower cycloalkylidene or carbonyl and æ sig-nifies lower 2-alkenyl or 2,4-di(lower alkoxy)benzyl, and their corresponding optical antipodes, which process comprises reacting a salt of a carboxylic acid of the general formula Nt/14.12.83 ~ ~5~
Rl H
R2/~ ~, R COOH II
wherein Rl, R2 and R3 have the above significa~ce, in the presence o a reactive derivative of an organlc sulphonic acid and a base with an optically uniform com-pound of the general formula N
Z
wherein B and Z have the above sig-nificance, or the optical antipode thereof.
The term "lower" denotes groups and compounds con-taining at most 7, preferably at most 4, carbon atoms. The term "alkyl" denotes straight-chain or branched-chain saturated hydrocarbon groups such as methyl, ethyl and iso-propyl. The term "alkoxy" denotes alkyl ether groups such as methoxy and ethoxy. The term "alkanoyl" denotes straight-chain or branch~d-chain saturated fatty acid groups such as formyl and acetylO The term "2-alkenyl'~ denotes straight-chain or branched-chain hydrocarbon groups containing at least 3 carbon atoms which have a double bond in the 2,3-. ~
~J,,~i~
~5~
position such as allyl. The term "alkylidene" denotes groupssuch as methylene and isopropylidene. The term "cyclo-alkylidene" denotes cyclic hydrocarbon groups containing at least 3 carbon atoms such as cyclohexylidene.
The term 'aryl" used below sign:Lfies phenyl optionally substituted by halogen or lower alkyl. The term "haloalkyl" used below denotes alkyl groups substituted by halogen such as trifluoromethyl. The term "halogen" sig-nifies fluorine, chlorine, bromine or iodine.
In a particular embodiment the present invention embraces the manufacture of compounds of formula I in which Rl signifies lower alkoxycarbcnyl, R2 signifies hydrogen, B signifies lower alkylidene and Z signl~ies lower 2-alkenyl.
The compounds listed hereinafter are representative compounds falling within formula I above:
~0 Methyl (Z)-3-~[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]-2-butenoate, (3S,4S)-l-allyl-3-[[(Z)-2-benzoyl-1-methylvinyl]-amino]-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidi-none, diethyl ~[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]methylene]malonate, methyl (Z)-3-~[(2S,3S)-1-(2,4-dimethoxybenzyl)-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]-amino]-2-butenoate and (3S,4S)-3-[[(Z)-2-benzoyl-1-methylvinyl]amino}-1-(2,4-dimethoxybenzyl)-4-[(R) 2,2-dimethyl-1,3 dioxolan-4 yl~-2-azetidinone.
The reaction in accordance with the invention is a cycloadaition which is familiar to the person skilled in the art. There is obtained a compound of formula I above a,.
or the optical antipode thereof in which the substituents in the 3- and 4-position of the azetidinone ring stand in cis-rel tionship to one another as expec:ted. Howe~er, it has surprisingly been found that the use of an optically active compound of formula III (or the optical antipode thereof) in ~he abo~e cycloaddition induces two new optical centres in high optical yield. In the products obtained the second possible cis-cycloaddition product, which would be diastereoisomeric to the product actually obtained, could not be detected.
As reactive organic sulphonic acid derivatives there come into consideration for the present purpose primarily compounds of the general formula R4-So2-X IV
wherein X signifies halogen or the group -OS02-R and R4 signifies aryl, lower alkyl or lower haloalkyl.
The preferred sulphonic acid derivatives are the compounds of formula IV in which X signifies halogen, especially chlorine,and R4 signifies phenyl optionally substituted by halogen or lower alkyl, such as p-toluenesulphonyl chlo-ride, p chlorobenzenesulphonyl chloride and ben~enesulphonyl chloride.
As bases there are preferably used tertiary amines, with tertiary aliphatic amines such as diisopropylethylamine and triethylamine being especially suitable.
The carboxylic acid of formula II is introduced into the reaction in the form of a carboxylic acid salt. Salts which come into consideration are primarily alkali metal ~5~
salts and ammonium salts derived from tertiary amines. In an especially preferred embodiment an alkali metal salt, especially the potassium salt, of carboxylic acids of formula II are used.
Suitable inert organic solvents for the process in accordance with the invention are, for example, ethers such as tetrahydrofuran, diethyl ether, tobutyl methyl ether, dioxan, ethylene glycol dimeth~l ether or the like, halo-genated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane or the like, acetonitrile, dimethyl-formamide or the like. Halogenated hydrocarbons such as methylene chloride are especially suitable solvents. The above cycloaddition is carried out in a temperature xange of about -30C to about 50C. The reaction temperature preferably lies in a range of about 0C to room temperature.
The compounds of formula III or their optical anti-podes used as starting materials can be prepared by reacting an aldehyde of the general formula r /~\
~ V
OHC
wherein B has the above significance, or its opti~al antipode with an amine of the general formula S~ 5~
wherein Z has the above significance.
The reaction is preferably carried out in an inert organic solvent, for ex~mple in a halogenated hydrocarbon such as methylene chloride, chlorororm, 1,2-dichloroethane and the like or in a hydrocarbon such as benzene, toluene and the like. The water formed during the react:ion is preferably removed continuously during the reaction, for example by azeotropic distillation or by working in the presence of a water entraining agent, for example in the presence of a suitable molecular sieve, or of other customary drying agents such as potassium carbonate, magnesium sulphate and the like. When the water formed during the reaction is removed azeotropically the reaction is carried out at the boiling point of the chosen solvent; when a water-entraining agent is used the reactlon is preferably carried out at room temperature.
The compounds of formula III and their corresponding ~o optical antipodes, which surprisingly yield optically uni~orm products in the cycloaddition described above, need not necessarily be isolated, but can be subjected directly to the cycloaddition in accordance with the invention.
The compounds of formula I obtainable in accordance with the invention are novel and can be used for the manufacture of antimicrobially active, optically uniform substances which contain a ~-lactam ring. Such antimicro-bially active substances can be manufactured from the compounds of formula I obtainable in accordance with the invention according to methods known per se, whereby the choice of reagents and reaction conditions, depending on the desired target compound, present no difficulties to the person skilled in the art.
The compounds of formula I can be used, in par-ticular, for the manufacture o antimicrobially active compo~nds of the general formula s O H
~ - C ~ C - N ~ ~6 VII
10H2N OR ~ N~
wherein R5 signifies hydrogen, lower 15alkyl or carboxy-lower alkyl and R6 signifies carbamoyl or carbamoyloxy-methyl, and their pharmaceutically acceptable salts. The use o~
the cycloaddition in accordance with the lnvention for the manufacture o antlmicrobially active, optically uniform substances containing a ~-lactam ring such as the afore-mentioned compounds of formula VII is likewise an object of the prPsent invention.
The compounds of formula VII can be manufactured, for example, in accordance with the following Reaction Scheme and ~he following description relating thereto. The symbols Rl, R2, R3, R5, R6, B and Z used in the Reaction Scheme have the above significance and Z' signifies a readily cleavable N-protecting group, preferably a readily cleavable acyl group such as t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl and the like.
~.~5~
REACTION SCHEME
H 2N_~ z ~ ~N
O Z O ~Z O ~zO ~Z
I VIII XI
o -- 1 H2H~/ ~ N~CH20CONN2 N~OH Z--No~CHO
IX XIV Z XIII XII
N~ /R COOCN3 ~N~OOCR3 ,N
O ~R ~ -- ~
O~SO H ~ ~ H~NOH
XXI II XXII XXI
H H
O
wherein Rl signifies Lower alkanoyl, lower alkoxycarbonyl or benzoyl, R2 sig-nifies hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or cyano, R3 signifies hydrogen or lower alkyl, B signifies lower alkylidene, lower cycloalkylidene or carbonyl and æ sig-nifies lower 2-alkenyl or 2,4-di(lower alkoxy)benzyl, and their corresponding optical antipodes, which process comprises reacting a salt of a carboxylic acid of the general formula Nt/14.12.83 ~ ~5~
Rl H
R2/~ ~, R COOH II
wherein Rl, R2 and R3 have the above significa~ce, in the presence o a reactive derivative of an organlc sulphonic acid and a base with an optically uniform com-pound of the general formula N
Z
wherein B and Z have the above sig-nificance, or the optical antipode thereof.
The term "lower" denotes groups and compounds con-taining at most 7, preferably at most 4, carbon atoms. The term "alkyl" denotes straight-chain or branched-chain saturated hydrocarbon groups such as methyl, ethyl and iso-propyl. The term "alkoxy" denotes alkyl ether groups such as methoxy and ethoxy. The term "alkanoyl" denotes straight-chain or branch~d-chain saturated fatty acid groups such as formyl and acetylO The term "2-alkenyl'~ denotes straight-chain or branched-chain hydrocarbon groups containing at least 3 carbon atoms which have a double bond in the 2,3-. ~
~J,,~i~
~5~
position such as allyl. The term "alkylidene" denotes groupssuch as methylene and isopropylidene. The term "cyclo-alkylidene" denotes cyclic hydrocarbon groups containing at least 3 carbon atoms such as cyclohexylidene.
The term 'aryl" used below sign:Lfies phenyl optionally substituted by halogen or lower alkyl. The term "haloalkyl" used below denotes alkyl groups substituted by halogen such as trifluoromethyl. The term "halogen" sig-nifies fluorine, chlorine, bromine or iodine.
In a particular embodiment the present invention embraces the manufacture of compounds of formula I in which Rl signifies lower alkoxycarbcnyl, R2 signifies hydrogen, B signifies lower alkylidene and Z signl~ies lower 2-alkenyl.
The compounds listed hereinafter are representative compounds falling within formula I above:
~0 Methyl (Z)-3-~[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]-2-butenoate, (3S,4S)-l-allyl-3-[[(Z)-2-benzoyl-1-methylvinyl]-amino]-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidi-none, diethyl ~[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]methylene]malonate, methyl (Z)-3-~[(2S,3S)-1-(2,4-dimethoxybenzyl)-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]-amino]-2-butenoate and (3S,4S)-3-[[(Z)-2-benzoyl-1-methylvinyl]amino}-1-(2,4-dimethoxybenzyl)-4-[(R) 2,2-dimethyl-1,3 dioxolan-4 yl~-2-azetidinone.
The reaction in accordance with the invention is a cycloadaition which is familiar to the person skilled in the art. There is obtained a compound of formula I above a,.
or the optical antipode thereof in which the substituents in the 3- and 4-position of the azetidinone ring stand in cis-rel tionship to one another as expec:ted. Howe~er, it has surprisingly been found that the use of an optically active compound of formula III (or the optical antipode thereof) in ~he abo~e cycloaddition induces two new optical centres in high optical yield. In the products obtained the second possible cis-cycloaddition product, which would be diastereoisomeric to the product actually obtained, could not be detected.
As reactive organic sulphonic acid derivatives there come into consideration for the present purpose primarily compounds of the general formula R4-So2-X IV
wherein X signifies halogen or the group -OS02-R and R4 signifies aryl, lower alkyl or lower haloalkyl.
The preferred sulphonic acid derivatives are the compounds of formula IV in which X signifies halogen, especially chlorine,and R4 signifies phenyl optionally substituted by halogen or lower alkyl, such as p-toluenesulphonyl chlo-ride, p chlorobenzenesulphonyl chloride and ben~enesulphonyl chloride.
As bases there are preferably used tertiary amines, with tertiary aliphatic amines such as diisopropylethylamine and triethylamine being especially suitable.
The carboxylic acid of formula II is introduced into the reaction in the form of a carboxylic acid salt. Salts which come into consideration are primarily alkali metal ~5~
salts and ammonium salts derived from tertiary amines. In an especially preferred embodiment an alkali metal salt, especially the potassium salt, of carboxylic acids of formula II are used.
Suitable inert organic solvents for the process in accordance with the invention are, for example, ethers such as tetrahydrofuran, diethyl ether, tobutyl methyl ether, dioxan, ethylene glycol dimeth~l ether or the like, halo-genated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane or the like, acetonitrile, dimethyl-formamide or the like. Halogenated hydrocarbons such as methylene chloride are especially suitable solvents. The above cycloaddition is carried out in a temperature xange of about -30C to about 50C. The reaction temperature preferably lies in a range of about 0C to room temperature.
The compounds of formula III or their optical anti-podes used as starting materials can be prepared by reacting an aldehyde of the general formula r /~\
~ V
OHC
wherein B has the above significance, or its opti~al antipode with an amine of the general formula S~ 5~
wherein Z has the above significance.
The reaction is preferably carried out in an inert organic solvent, for ex~mple in a halogenated hydrocarbon such as methylene chloride, chlorororm, 1,2-dichloroethane and the like or in a hydrocarbon such as benzene, toluene and the like. The water formed during the react:ion is preferably removed continuously during the reaction, for example by azeotropic distillation or by working in the presence of a water entraining agent, for example in the presence of a suitable molecular sieve, or of other customary drying agents such as potassium carbonate, magnesium sulphate and the like. When the water formed during the reaction is removed azeotropically the reaction is carried out at the boiling point of the chosen solvent; when a water-entraining agent is used the reactlon is preferably carried out at room temperature.
The compounds of formula III and their corresponding ~o optical antipodes, which surprisingly yield optically uni~orm products in the cycloaddition described above, need not necessarily be isolated, but can be subjected directly to the cycloaddition in accordance with the invention.
The compounds of formula I obtainable in accordance with the invention are novel and can be used for the manufacture of antimicrobially active, optically uniform substances which contain a ~-lactam ring. Such antimicro-bially active substances can be manufactured from the compounds of formula I obtainable in accordance with the invention according to methods known per se, whereby the choice of reagents and reaction conditions, depending on the desired target compound, present no difficulties to the person skilled in the art.
The compounds of formula I can be used, in par-ticular, for the manufacture o antimicrobially active compo~nds of the general formula s O H
~ - C ~ C - N ~ ~6 VII
10H2N OR ~ N~
wherein R5 signifies hydrogen, lower 15alkyl or carboxy-lower alkyl and R6 signifies carbamoyl or carbamoyloxy-methyl, and their pharmaceutically acceptable salts. The use o~
the cycloaddition in accordance with the lnvention for the manufacture o antlmicrobially active, optically uniform substances containing a ~-lactam ring such as the afore-mentioned compounds of formula VII is likewise an object of the prPsent invention.
The compounds of formula VII can be manufactured, for example, in accordance with the following Reaction Scheme and ~he following description relating thereto. The symbols Rl, R2, R3, R5, R6, B and Z used in the Reaction Scheme have the above significance and Z' signifies a readily cleavable N-protecting group, preferably a readily cleavable acyl group such as t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl and the like.
~.~5~
REACTION SCHEME
H 2N_~ z ~ ~N
O Z O ~Z O ~zO ~Z
I VIII XI
o -- 1 H2H~/ ~ N~CH20CONN2 N~OH Z--No~CHO
IX XIV Z XIII XII
N~ /R COOCN3 ~N~OOCR3 ,N
O ~R ~ -- ~
O~SO H ~ ~ H~NOH
XXI II XXII XXI
H H
2 ~R6 J_N
O ~SO H
XVI I ~ O E~
N ~R~;
H2N`OR '~ SO3H
VII
~ ~ - 9 A compound of formula VIII is obtained by the mild acidic hydrolysis of a compound of formula I. The hydro-lysis of a compound of formula I can be carried out, for example, by treating the compound of formula I with an acid in the presence of water and optionally a water-miscible solvent such a~ acetone, tetrahydrofuran, dioxan, dimethyl sulphoxide, dimethylformamida or the like. As acids ~here come into consideration, for example, mineral acids such as hydrochloric acid and sulphuric acid, or organic acids such as p-toluenesulphonic acid, pyridinium p-toluenesulphonate or the like, or sulphuric acidic ion exchangers. Depending on the conditions used the dioxolan ring is also cleaved during this reaction, there being obtained a compound of formula IX.
By treating a compound o~ formula VIII or IX with an agent yielding the group Z' there is obtained a compound of formula X or XI. Suitable agents yielding the group Z' are, for example, chlorformic acid esters sucn as benzyl chloroformate, t-butyl chloroformate, 2,2,2-trichloxoethyl chloroformate and the like. This reaction is conveniently carried out in an inert organic solvent, for example in a halogenated hydrocarbon such as methylene chloride, chloro-form and the like, and conveniently in the presence of anacid-binding agent such as butylene oxide, triethylamine, quinuclidine etc. The reaction is conveniently carried out at room temperature.
The hydrolysis of a compound of formula X to give a compound of formula XI is preferably carried out under mild acidic conditions. In a preferred embodiment the desired reaction is carried out by trans-acetalization in a lower alcohol such as methanol or ethanol and in the presence of a suitable acidic catalyst. Suitable catalysts are, for example, sulphuric acidic ion exchangers, pyridinium $~
p-toluenesulphonate, p~toluenesulphonic acid and the like.
In this case the hydrolysis is preferably carried out at room temperature. The hydrolysis can, however, also be s carried out readily in the presence of water and a water-miscible solvent such as tetrahydrofuran, dioxan, dimethyl sulphoxide,dimethylformamide or the like.
The cleavage of the diol grouping in a compound of formula XI is carried out according to methods which are known per se and which are familiar to any person skilled in the art, and can be accomplished, for example, using sodium periodate in water. If desired, this reaction can be carried out in the presence of a solubilizer such as tetrahydrofuran, dioxan, methanol, ethanol or the like.
This reaction yields an aldehyde of formula XII.
The reduction of an aldehyde of formula XII to give a primary alcohol of formula XIII is alsv carried out according to methods which are known per se and which are familiar to any person skilled in the art, for example by treatment with sodium borohydride in a lower alcohol such as ethanol, isopropanol or the like.
By reacting a compound of formula XIII with chloro-sulphonyl isocyanate in an inert organic solvent there is obtained a compound of formula XIV. Suitable solvents are, for example, ethers such as diethyl ether r t-butyl methyl ether and ethylene glycol dimethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, acetonitrile, dimethylformamide, dimethyl sulphoxide, acetone and the like. The reaction is preferably carried out in a temperature range of about 0C to about room temperature.
By cleaving the protecting group denoted by Z from a compound of formula XIV there is obtained a corresponding 5~
compound of formula XV. The cleavage of a 2,4~di(lower alkoxy)benzyl group is conveniently carried out by mild OXl-dation. Suitable oxidation agents are, for example, potas-sium peroxyd.isulphate or ammonium peroxydisulphate, theoxidation being carried out in water at a pH of 6-8. A
suitable buffer is, for example, disodium hydrogen phos-phate.
A lower 2-alkenyl group is cleaved by isomerization thereof to a l-alkenyl group and subsequent oxidative cleavage of the latter. The isomeriæation of the double bond is preferably carried out with the aid of an isomeri-zation catalyst, for example with a palladium dihalicle such as palladium dichlorlde or with a tris(triphenylphosphine)-rhodium (I) hallde (e.g. with the corresponding chloride) or also with palladlum-on-carbon in the presence of a protonic acid such as hydrochloric acid or phosphoric acid. As the solvent there is conveniently used ethanol, methylene chloride or a mixture thereof with water. The reaction temperature conveniently lies in a range of about 50C to the boiling point of the reaction mixture.
The oxidative cleavag~ of the lower l-alkenyl group can be carried out, for example, by treatment with an alkali metal permanganate, Eor example potassium permanganate, there being preferably used an aqueous potassium perman-ganate solution. If desired, the oxidation can be carried out with the aid of an alkali metal periodate (e.g. potas-sium periodate) in the presence of a catalytic amount ofthe mentioned alkali metal permanganate. The reaction is preferably carried out in an aqueous, bufered medium, especially an aqueous medium buffered to pH 7-8, but it can also be carried out in a water-miscible organic solvent, for example in acetone, dimethoxyethane, dioxan or tetra-hydrofuran, with the addition of a weak organic base such as - 12 ~ S ~
pyridine or in a mixture of one of these solvents with the mentioned aqueous buffer. The reaction can, however, also be carried out in a two-phase system using a phase transfer catalyst. Methylene ~hloride or benzene, for example, can be used as th~ organic phase which is not miscible with water. Conventional phase transfer catalysts can be used, especially organic quaternary ammonium halides such a~
benzyltriethylammonium chloride, tetra-n-butylammonium bromide and cetyltrimethylammonium bromide. The oxidative cleavage is preferably carried out at a temperature between about 0C and 25C.
The compounds of formula XV in which R6 signifies carbamoyl can be obtained by oxldizing an aldehyde of formula XII according to methods known per se to give a carboxyllc acid of formula XVIII, esterifying the carboxylic acid o ormula XVIII, or example with methyl iodide in the presence o potassium carbonate, cleaving off the protecting group denoted by Z in the manner described above from the resulting compound of formula XIX and treating the compound of formula XX obtained with hydroxylamine.
The compounds of ormula XV in which R6 signifies carbamoyl can, however, also be obtained by treating a compound of formula XII with hydroxylamine, converting the resulting oxime o formula XXI in a manner known per se into the nitrile of ormula XXII, cleaving off thererom the protecting group denoted by Z as described above and saponifying the nitrile group in the resulting compound of formula XXIII in a manner known per se to the carbamoyl group.
By treating a compound of formula XV with sulphur trioxide or a suitable complex of sulphur trioxide there is obtained a compound of formula XYI. Suitable sulphur tri-- 13 ~.~ S~6~
oxide complexes are, for example, complexes with pyridine, trimethylamine, picoline, dimethylform~mide and the like.
An ether such as dioxan, pyridine, acet:onitrile, dimethyl-formamide or the like is conveniently used as the solvent.
The preferred solvent is acetonitrile. The reaction is preferably carried out at a temperature between about 0C
and 80C.
By cleaving off the protecting group denoted by Z' from a compound of formula XVI there is obtained a compound of formula XVII. A benzyloxycarbonyl group can be cleaved off, for example, hydrogenolytically, for example by treatment wlth elemental hydrogen in the presence of palladium-on-carbon. A t-butoxycarbonyl group aan be cleaved off, for example, by treatment with trifluoroacetic acid or ormic acid. A trichloroethoxycarbonyl group can be cleaved off, for example, by treatment with zinc in the presence of an acid such as acetic acid or hydrochloric acid.
By acylating a compound of formula XVII with a reactive functional derivative of a carboxylic acid of the general formula ~C_ COOH XXIV
~ ~R
wherein R5 has the above significance, there is finally obtained the desired target compound of formula VII. It will be appreciated that the compound of formula XXIV must be suitably protected when R5 signifies hydrogen or carboxy-lower alkyl, the protecting group is removed after the acylation has been carried out. As reactive functional derivatives of compounds of formula XXIV
there can be used, for example, corresponding acid an~
hydrides, mixed anhydrides, benzthiazolyl thioesters and the like.
- 15 - ~ ~ 5~
The following Examples illustrate the present inven-tion in more detail; they are, however, not intended to be limiting in any manner. All temperatures are given in degrees Celsius.
a) 12 g (92.16 mmol) of isopropylidene-~ glyceralde-hyde are dissolved in 200 ml of methylene chloride, treated firstly with 60 g of magnesium ulphate and then dropwise over a period of 10 minutes with 5.26 g (92.16 mmol) of
O ~SO H
XVI I ~ O E~
N ~R~;
H2N`OR '~ SO3H
VII
~ ~ - 9 A compound of formula VIII is obtained by the mild acidic hydrolysis of a compound of formula I. The hydro-lysis of a compound of formula I can be carried out, for example, by treating the compound of formula I with an acid in the presence of water and optionally a water-miscible solvent such a~ acetone, tetrahydrofuran, dioxan, dimethyl sulphoxide, dimethylformamida or the like. As acids ~here come into consideration, for example, mineral acids such as hydrochloric acid and sulphuric acid, or organic acids such as p-toluenesulphonic acid, pyridinium p-toluenesulphonate or the like, or sulphuric acidic ion exchangers. Depending on the conditions used the dioxolan ring is also cleaved during this reaction, there being obtained a compound of formula IX.
By treating a compound o~ formula VIII or IX with an agent yielding the group Z' there is obtained a compound of formula X or XI. Suitable agents yielding the group Z' are, for example, chlorformic acid esters sucn as benzyl chloroformate, t-butyl chloroformate, 2,2,2-trichloxoethyl chloroformate and the like. This reaction is conveniently carried out in an inert organic solvent, for example in a halogenated hydrocarbon such as methylene chloride, chloro-form and the like, and conveniently in the presence of anacid-binding agent such as butylene oxide, triethylamine, quinuclidine etc. The reaction is conveniently carried out at room temperature.
The hydrolysis of a compound of formula X to give a compound of formula XI is preferably carried out under mild acidic conditions. In a preferred embodiment the desired reaction is carried out by trans-acetalization in a lower alcohol such as methanol or ethanol and in the presence of a suitable acidic catalyst. Suitable catalysts are, for example, sulphuric acidic ion exchangers, pyridinium $~
p-toluenesulphonate, p~toluenesulphonic acid and the like.
In this case the hydrolysis is preferably carried out at room temperature. The hydrolysis can, however, also be s carried out readily in the presence of water and a water-miscible solvent such as tetrahydrofuran, dioxan, dimethyl sulphoxide,dimethylformamide or the like.
The cleavage of the diol grouping in a compound of formula XI is carried out according to methods which are known per se and which are familiar to any person skilled in the art, and can be accomplished, for example, using sodium periodate in water. If desired, this reaction can be carried out in the presence of a solubilizer such as tetrahydrofuran, dioxan, methanol, ethanol or the like.
This reaction yields an aldehyde of formula XII.
The reduction of an aldehyde of formula XII to give a primary alcohol of formula XIII is alsv carried out according to methods which are known per se and which are familiar to any person skilled in the art, for example by treatment with sodium borohydride in a lower alcohol such as ethanol, isopropanol or the like.
By reacting a compound of formula XIII with chloro-sulphonyl isocyanate in an inert organic solvent there is obtained a compound of formula XIV. Suitable solvents are, for example, ethers such as diethyl ether r t-butyl methyl ether and ethylene glycol dimethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, acetonitrile, dimethylformamide, dimethyl sulphoxide, acetone and the like. The reaction is preferably carried out in a temperature range of about 0C to about room temperature.
By cleaving the protecting group denoted by Z from a compound of formula XIV there is obtained a corresponding 5~
compound of formula XV. The cleavage of a 2,4~di(lower alkoxy)benzyl group is conveniently carried out by mild OXl-dation. Suitable oxidation agents are, for example, potas-sium peroxyd.isulphate or ammonium peroxydisulphate, theoxidation being carried out in water at a pH of 6-8. A
suitable buffer is, for example, disodium hydrogen phos-phate.
A lower 2-alkenyl group is cleaved by isomerization thereof to a l-alkenyl group and subsequent oxidative cleavage of the latter. The isomeriæation of the double bond is preferably carried out with the aid of an isomeri-zation catalyst, for example with a palladium dihalicle such as palladium dichlorlde or with a tris(triphenylphosphine)-rhodium (I) hallde (e.g. with the corresponding chloride) or also with palladlum-on-carbon in the presence of a protonic acid such as hydrochloric acid or phosphoric acid. As the solvent there is conveniently used ethanol, methylene chloride or a mixture thereof with water. The reaction temperature conveniently lies in a range of about 50C to the boiling point of the reaction mixture.
The oxidative cleavag~ of the lower l-alkenyl group can be carried out, for example, by treatment with an alkali metal permanganate, Eor example potassium permanganate, there being preferably used an aqueous potassium perman-ganate solution. If desired, the oxidation can be carried out with the aid of an alkali metal periodate (e.g. potas-sium periodate) in the presence of a catalytic amount ofthe mentioned alkali metal permanganate. The reaction is preferably carried out in an aqueous, bufered medium, especially an aqueous medium buffered to pH 7-8, but it can also be carried out in a water-miscible organic solvent, for example in acetone, dimethoxyethane, dioxan or tetra-hydrofuran, with the addition of a weak organic base such as - 12 ~ S ~
pyridine or in a mixture of one of these solvents with the mentioned aqueous buffer. The reaction can, however, also be carried out in a two-phase system using a phase transfer catalyst. Methylene ~hloride or benzene, for example, can be used as th~ organic phase which is not miscible with water. Conventional phase transfer catalysts can be used, especially organic quaternary ammonium halides such a~
benzyltriethylammonium chloride, tetra-n-butylammonium bromide and cetyltrimethylammonium bromide. The oxidative cleavage is preferably carried out at a temperature between about 0C and 25C.
The compounds of formula XV in which R6 signifies carbamoyl can be obtained by oxldizing an aldehyde of formula XII according to methods known per se to give a carboxyllc acid of formula XVIII, esterifying the carboxylic acid o ormula XVIII, or example with methyl iodide in the presence o potassium carbonate, cleaving off the protecting group denoted by Z in the manner described above from the resulting compound of formula XIX and treating the compound of formula XX obtained with hydroxylamine.
The compounds of ormula XV in which R6 signifies carbamoyl can, however, also be obtained by treating a compound of formula XII with hydroxylamine, converting the resulting oxime o formula XXI in a manner known per se into the nitrile of ormula XXII, cleaving off thererom the protecting group denoted by Z as described above and saponifying the nitrile group in the resulting compound of formula XXIII in a manner known per se to the carbamoyl group.
By treating a compound of formula XV with sulphur trioxide or a suitable complex of sulphur trioxide there is obtained a compound of formula XYI. Suitable sulphur tri-- 13 ~.~ S~6~
oxide complexes are, for example, complexes with pyridine, trimethylamine, picoline, dimethylform~mide and the like.
An ether such as dioxan, pyridine, acet:onitrile, dimethyl-formamide or the like is conveniently used as the solvent.
The preferred solvent is acetonitrile. The reaction is preferably carried out at a temperature between about 0C
and 80C.
By cleaving off the protecting group denoted by Z' from a compound of formula XVI there is obtained a compound of formula XVII. A benzyloxycarbonyl group can be cleaved off, for example, hydrogenolytically, for example by treatment wlth elemental hydrogen in the presence of palladium-on-carbon. A t-butoxycarbonyl group aan be cleaved off, for example, by treatment with trifluoroacetic acid or ormic acid. A trichloroethoxycarbonyl group can be cleaved off, for example, by treatment with zinc in the presence of an acid such as acetic acid or hydrochloric acid.
By acylating a compound of formula XVII with a reactive functional derivative of a carboxylic acid of the general formula ~C_ COOH XXIV
~ ~R
wherein R5 has the above significance, there is finally obtained the desired target compound of formula VII. It will be appreciated that the compound of formula XXIV must be suitably protected when R5 signifies hydrogen or carboxy-lower alkyl, the protecting group is removed after the acylation has been carried out. As reactive functional derivatives of compounds of formula XXIV
there can be used, for example, corresponding acid an~
hydrides, mixed anhydrides, benzthiazolyl thioesters and the like.
- 15 - ~ ~ 5~
The following Examples illustrate the present inven-tion in more detail; they are, however, not intended to be limiting in any manner. All temperatures are given in degrees Celsius.
a) 12 g (92.16 mmol) of isopropylidene-~ glyceralde-hyde are dissolved in 200 ml of methylene chloride, treated firstly with 60 g of magnesium ulphate and then dropwise over a period of 10 minutes with 5.26 g (92.16 mmol) of
3-amino-1-propene in 50 ml of methylene chloride and the suspension is stirred at room temperature ~or 5 hours.
The magnesium sulphate is filtered off and the cleax colour-less solution ls evaporated on a rotary evaporator. 14.6 g (86.3 mmol; 93.6~) of pure isopxopylidene-L-glyceraldehyde allylimine are obtalned.
b) 8.64 g (51.1 mmol) of isopropylidene-L-glyceralde-hyde allylimine are dissolved in 400 ml of methylene chlo-ride, treated firstly with 10.32 g (102.2 mmol) of tri-ethylamine and then with 10.79 g (51.1 mmol) of potassium N-(l-methyl-2-methoxycarbonyl~inyl)aminoacetate, the sus-pension is cooled to 0 and treated dropwise within 5 min-utes with 9.74 g (51.1 mmol) of p-toluenesulphonyl chlo-ride in 50 ml of methylene chloride. The cooling bath is removed, the mixture is stirred at room temperature for 8 hours, treated with 200 ml of water, the organic phase is separated and evaporated. The crude product is chromato-graphed on silica gel while eluting with hexane/ethyl acetate (8:2). There are obtained 13.0 g (40.0 mmol; 78~) of methyl (Z)-3-[~(2S,3S)-l-allyl~2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-g-oxo 3-azetidinyl]amino]-2-butenoate as an oil which solidifies slowly upon standing. A product of melting point 98~ is obtained by crystallization from ether/hexane.
Example 2 1.7 g (10 mmol) of isopropylidene-L-glyceralde-hyde allylimine are dissolved in 80 ml of methylene chlo-ride, treated firstly with 3~03 g (30 mmol) of triethyl-amine and then with 2.6 g (10 mmol) of potassium N~
methyl-2-benzoylvinyl)aminoacetate and the suspensio~ is cooled to 0. 2.85 g (15 mmol) of p-toluenesulphonyl chloride in 10 ml of methylene chloride are added dropwise thereto, the mixture ls stirred at room temperature Eor 5 hours, washed with 100 ml of water and evaporated. The.
crude product is purifled on silica gel using hexane/ethyl acetate (7:3) ~or the elution. There are obtained 1.5 g (4.04 mmol; 40%) o~ ~3S,4S)-l-allyl-3~[~(Z)-2-benzoyl-1-methylvinyl]amino]-4-[(R)-2,2-dlmethyl-1,3-dioxolan-4-yl]-2-azetidlnone as a pure oil which crystallizes out from a mixture of ether and hexane and then has a melting point of 154-156.
Ex~mp e 3 ;
1.7 g (10 mmol) of isopropylidene-L-glyceraldehyde allylimine are dlssolved in 80 ml of methylene chloride and treated firstly with 3.03 g (30 mmol) of triethylamine and then with 2.8 g (10 mmol) of potassium N-(2,2-diethoxy-carbonylvinyl)aminoacetate. 2.85 g (15 mmol) of p-toluene-sulphonyl chloride in 20 ml of methylene chloride are then added dropwise to the solution which is cooled in ice and the mixture is stirred at room temperature for 5 hours. The mixture is subsequently washed with 100 ml of water, the organic phase is evaporated and the crude product obtained is chromatographed on silica gel while eluting with hexane/
ethyl acetate (7:3). There are obtained 1.15 g (2.9 mmol;
29%) of pure diethyl [[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-~.2.S~
1,3-dioxolan-4-yl]-4 oxo-3-azetidinyl]amino]methylene]-malonate as an oil.
IR spectrum (film): bands, inter alia, at 1755, 1740, 1700, 1660 and 1600 cm 1.
3~75 g (13.44 mmol~ of isopropylidene-L-glyceralde-hyde (2,4-dimethoxybenzyl)imine [obtained from isopropyl-idene-L-glyceraldehyde and 2,4-dimethoxybenzylamine in a manner analogous to that described in Example la)] are dissolved in 150 ml of methylene chloride and treated with 3.25 g (32.25 mmol) of triethylamine. 3.40 g (16.12 mmol) of potassium N~ methyl-2-methoxycarbonylvinyl)aminoacetate are added and the suspension is cooled ko 0. 3.40 g ~16.12 mmol) of p-toluenesulphonyl chloride in 50 ml o~
methylene chloride are added dropwise thereto withln 5 minutes and the mixture is stirred at room temperature for 15 hours. After washing with 100 ml of water and evapo-rating the organic phase, the residue is purified by chroma-tography on silica gel using hexane/ethyl acetate (7:3) as the eluting agent. There are obtained 3.45 g (7.94 mmol;
59%) of pure methyl ~Z)-3-[[(2S,3S)-1-(2,4-dimethoxybenzyl)-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-a~etidinyl]-amino]-2-butenoate as an oil which solidifies slowly.
After crystallization from ether/hexane, the product has a melting point of 121.
Examp~e_5 2.8 g (10 mmol) of isopropylidene-L-glyceraldehyde (2,4-dimethoxybenzyl)imine are dissolved in 125 ml of methylene chloride and treated with 3.03 g (30 mmol~ of triethylamine. 2.6 g (10 mmol) of potassium N-(l-methyl-1 benzoyl-vinyl)aminoacetate are then added and the sus-pension is stirred strongly at 0. 2.85 g (15 mmol) of p-- 18 - ~ ~ S~
toluenesulphonyl chloride in 50 ml of methylene chloride are slowly added dropwis~ thereto and the mixture is stirred at room temperatuxe for 5 hours. The mixture is then treated with 100 ml of water, the orgallic phase is separated and evaporated. The residue is chromatographed on silica gel using hexane/ethyl acetate (7:3) as the eluting agent.
There are o~tained 1.4 g (2.91 mmol; .29%) of pure ~3S,4S)-3-[[(Z)-2-benzoyl-1-methylvinyl]amino]--1-(2,4-dimethoxy-benzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidi-none which crystallizes out from ether/hexane and then has a meltlng point of 177-179.
Example 6 6.48 g (20 mmol) of methyl (Z)-3-[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]~
amino]-2-butenoate are dissolved in 40 ml of acetone and treated with 3.80 g (20 mmol) of p-toluenesulphonic acid monohydrate in 20 ml of acetone. The clear solution is stirred at room temperature for 15 minutes and then treated slowly with 120 ml of ether. The precipitated product is filtered off and dried. There are obtained 6.4 g (15.3 mmol;
77%) of pure (3S,4S)-cis-3-amino-1-allyl-4-[~R~-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone p-toluenesulphonate of melting point 165.
Identical products are obtained when (3S,4S)-l-allyl-3~[[(Z)-2-benzoyl-1-methylvinyl]amino]-4 [(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone and diethyl [[[(2S, 3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan~4-yl]-4-oxo-3-azetidinyl]amino]methylene]malonate are subjected to the same reaction conditions. The yields lie between 75% and 80%.
The magnesium sulphate is filtered off and the cleax colour-less solution ls evaporated on a rotary evaporator. 14.6 g (86.3 mmol; 93.6~) of pure isopxopylidene-L-glyceraldehyde allylimine are obtalned.
b) 8.64 g (51.1 mmol) of isopropylidene-L-glyceralde-hyde allylimine are dissolved in 400 ml of methylene chlo-ride, treated firstly with 10.32 g (102.2 mmol) of tri-ethylamine and then with 10.79 g (51.1 mmol) of potassium N-(l-methyl-2-methoxycarbonyl~inyl)aminoacetate, the sus-pension is cooled to 0 and treated dropwise within 5 min-utes with 9.74 g (51.1 mmol) of p-toluenesulphonyl chlo-ride in 50 ml of methylene chloride. The cooling bath is removed, the mixture is stirred at room temperature for 8 hours, treated with 200 ml of water, the organic phase is separated and evaporated. The crude product is chromato-graphed on silica gel while eluting with hexane/ethyl acetate (8:2). There are obtained 13.0 g (40.0 mmol; 78~) of methyl (Z)-3-[~(2S,3S)-l-allyl~2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-g-oxo 3-azetidinyl]amino]-2-butenoate as an oil which solidifies slowly upon standing. A product of melting point 98~ is obtained by crystallization from ether/hexane.
Example 2 1.7 g (10 mmol) of isopropylidene-L-glyceralde-hyde allylimine are dissolved in 80 ml of methylene chlo-ride, treated firstly with 3~03 g (30 mmol) of triethyl-amine and then with 2.6 g (10 mmol) of potassium N~
methyl-2-benzoylvinyl)aminoacetate and the suspensio~ is cooled to 0. 2.85 g (15 mmol) of p-toluenesulphonyl chloride in 10 ml of methylene chloride are added dropwise thereto, the mixture ls stirred at room temperature Eor 5 hours, washed with 100 ml of water and evaporated. The.
crude product is purifled on silica gel using hexane/ethyl acetate (7:3) ~or the elution. There are obtained 1.5 g (4.04 mmol; 40%) o~ ~3S,4S)-l-allyl-3~[~(Z)-2-benzoyl-1-methylvinyl]amino]-4-[(R)-2,2-dlmethyl-1,3-dioxolan-4-yl]-2-azetidlnone as a pure oil which crystallizes out from a mixture of ether and hexane and then has a melting point of 154-156.
Ex~mp e 3 ;
1.7 g (10 mmol) of isopropylidene-L-glyceraldehyde allylimine are dlssolved in 80 ml of methylene chloride and treated firstly with 3.03 g (30 mmol) of triethylamine and then with 2.8 g (10 mmol) of potassium N-(2,2-diethoxy-carbonylvinyl)aminoacetate. 2.85 g (15 mmol) of p-toluene-sulphonyl chloride in 20 ml of methylene chloride are then added dropwise to the solution which is cooled in ice and the mixture is stirred at room temperature for 5 hours. The mixture is subsequently washed with 100 ml of water, the organic phase is evaporated and the crude product obtained is chromatographed on silica gel while eluting with hexane/
ethyl acetate (7:3). There are obtained 1.15 g (2.9 mmol;
29%) of pure diethyl [[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-~.2.S~
1,3-dioxolan-4-yl]-4 oxo-3-azetidinyl]amino]methylene]-malonate as an oil.
IR spectrum (film): bands, inter alia, at 1755, 1740, 1700, 1660 and 1600 cm 1.
3~75 g (13.44 mmol~ of isopropylidene-L-glyceralde-hyde (2,4-dimethoxybenzyl)imine [obtained from isopropyl-idene-L-glyceraldehyde and 2,4-dimethoxybenzylamine in a manner analogous to that described in Example la)] are dissolved in 150 ml of methylene chloride and treated with 3.25 g (32.25 mmol) of triethylamine. 3.40 g (16.12 mmol) of potassium N~ methyl-2-methoxycarbonylvinyl)aminoacetate are added and the suspension is cooled ko 0. 3.40 g ~16.12 mmol) of p-toluenesulphonyl chloride in 50 ml o~
methylene chloride are added dropwise thereto withln 5 minutes and the mixture is stirred at room temperature for 15 hours. After washing with 100 ml of water and evapo-rating the organic phase, the residue is purified by chroma-tography on silica gel using hexane/ethyl acetate (7:3) as the eluting agent. There are obtained 3.45 g (7.94 mmol;
59%) of pure methyl ~Z)-3-[[(2S,3S)-1-(2,4-dimethoxybenzyl)-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-a~etidinyl]-amino]-2-butenoate as an oil which solidifies slowly.
After crystallization from ether/hexane, the product has a melting point of 121.
Examp~e_5 2.8 g (10 mmol) of isopropylidene-L-glyceraldehyde (2,4-dimethoxybenzyl)imine are dissolved in 125 ml of methylene chloride and treated with 3.03 g (30 mmol~ of triethylamine. 2.6 g (10 mmol) of potassium N-(l-methyl-1 benzoyl-vinyl)aminoacetate are then added and the sus-pension is stirred strongly at 0. 2.85 g (15 mmol) of p-- 18 - ~ ~ S~
toluenesulphonyl chloride in 50 ml of methylene chloride are slowly added dropwis~ thereto and the mixture is stirred at room temperatuxe for 5 hours. The mixture is then treated with 100 ml of water, the orgallic phase is separated and evaporated. The residue is chromatographed on silica gel using hexane/ethyl acetate (7:3) as the eluting agent.
There are o~tained 1.4 g (2.91 mmol; .29%) of pure ~3S,4S)-3-[[(Z)-2-benzoyl-1-methylvinyl]amino]--1-(2,4-dimethoxy-benzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidi-none which crystallizes out from ether/hexane and then has a meltlng point of 177-179.
Example 6 6.48 g (20 mmol) of methyl (Z)-3-[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]~
amino]-2-butenoate are dissolved in 40 ml of acetone and treated with 3.80 g (20 mmol) of p-toluenesulphonic acid monohydrate in 20 ml of acetone. The clear solution is stirred at room temperature for 15 minutes and then treated slowly with 120 ml of ether. The precipitated product is filtered off and dried. There are obtained 6.4 g (15.3 mmol;
77%) of pure (3S,4S)-cis-3-amino-1-allyl-4-[~R~-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone p-toluenesulphonate of melting point 165.
Identical products are obtained when (3S,4S)-l-allyl-3~[[(Z)-2-benzoyl-1-methylvinyl]amino]-4 [(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone and diethyl [[[(2S, 3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan~4-yl]-4-oxo-3-azetidinyl]amino]methylene]malonate are subjected to the same reaction conditions. The yields lie between 75% and 80%.
Claims (24)
1. A process for the manufacture of optically uniform .beta.-lactams of the general formula I
wherein R1 signifies lower alkanoyl, lower alkoxycarbonyl or benzoyl, R2 signifies hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or cyano, R3 signifies hydrogen or lower alkyl, B signifies lower alkylidene, lower cycloalkylidene or carbonyl and Z signifies lower 2-alkenyl or 2,4-di(lower alkoxy)benzyl, and their corresponding optical antipodes, which process comprises reacting a salt of a carboxylic acid of the general formula II
wherein R1, R2 and R3 have the above significance, in the presence of a reactive derivative of an organic sulphonic acid and a base with an optically uniform compound of the general formula III
wherein B and Z have the above sig-nificance, or the optical antipode thereof.
wherein R1 signifies lower alkanoyl, lower alkoxycarbonyl or benzoyl, R2 signifies hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or cyano, R3 signifies hydrogen or lower alkyl, B signifies lower alkylidene, lower cycloalkylidene or carbonyl and Z signifies lower 2-alkenyl or 2,4-di(lower alkoxy)benzyl, and their corresponding optical antipodes, which process comprises reacting a salt of a carboxylic acid of the general formula II
wherein R1, R2 and R3 have the above significance, in the presence of a reactive derivative of an organic sulphonic acid and a base with an optically uniform compound of the general formula III
wherein B and Z have the above sig-nificance, or the optical antipode thereof.
2. A process according to claim 1, wherein R1 signifies lower alkoxycarbonyl and R2 signifies hydrogen.
3. A process according to claim 2, wherein B
signifies lower alkylidene.
signifies lower alkylidene.
4. A process according to claim 1, 2 or 3, wherein Z signifies 2-alkenyl.
5. A process according to claim 1, wherein methyl (Z)-3-[[(2S,3S)-1-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]-2-butenoate is manufactured, by reacting isopropylidene-L-glyceraldehydeallylimine in the presence of p-toluenesulphonylchloride with potassium N-(1-methyl-2-methoxycarbonylvinyl)aminoacetate;
6. A process according to claim 1, wherein (3S,4S)-1-allyl-3-[[(Z)-2-benzoyl-1-methylvinyl]amino]-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone is manufactured, by reacting isopropylidene-L-glyceraldehydeallylimine in the presence of p-toluenesulphonylchloride with potassium N-(1-methyl-2-benzoylvinyl)aminoacetate.
7. A process according to claim 1, wherein diethyl [[[(2S,3S)-1-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]methylene]malonate is manufactured, by reacting isopropylidene-L-glyceraldehydeallylimine in the presence of p-toluenesulphonylchloride with potassium N-(2,2-diethoxycarbonylvinyl)aminoacetate.
8. A process according to claim 1, wherein methyl (Z)-3-[[(2S,3S)-1-(2,4-dimethoxybenzyl)-2 [(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]-2-butenoate is manufactured, by reacting isopropylidene-L-glyceraldehyde(2,4-dimethoxybenzyl)imine in the presence of p-toluenesulphonylchloride with potassium N-(1-methyl-2-methoxycarbonylvinyl)aminoacetate.
9. A process according to claim 1, wherein (3S,4S)-3 [[(Z)-2-benzoyl-1-methylvinyl]amino]-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone is manufactured, by reacting isopropylidene-L-glyceraldehyde-(2,4-dimethoxybenzyl)imine in the presence of p-toluene-sulphonylchloride with potassium N-(1-methyl-1-benzoyl-vinyl)aminoacetate.
10. A process according to claim 1, wherein the reactive derivative of an organic sulphonic acid is a compound of the general formula wherein X signifies halogen or the group -OSO2-R4 and R4 signifies aryl, lower alkyl or lower haloalkyl.
11. A process according to claim 10, wherein X signifies halogen, and R4 signifies phenyl, optionally substituted by halogen or lower alkyl.
12. A process as in claim 10 or 11 wherein x is chlorine.
13. A process according to any one of claims 1, 2 or 3, wherein the base is a tertiary amine.
14. A process according to any one of claims 1, 2 or 3, wherein an alkali metal salt, of a carboxylic acid of formula II is used.
15. A process according to claim 1, 2 or 3, wherein the potassium salt of a carboxylic acid of formula II is used.
16. Optically uniform .beta.-lactams of the general formula wherein R1 signifies lower alkanoyl, lower alkoxycarbonyl or benzoyl, R2 signifies hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or cyano, R3 signifies hydrogen or lower alkyl, B signifies lower alkylidene, lower cycloalkylidene or carbonyl and Z signifies lower 2-alkenyl or 2,4-di(lower alkoxy)benzyl, and their corresponding optical antipodes.
17. Compounds according to claim 16, wherein signifies lower alkoxycarbonyl and R signifies hydrogen.
18. Compounds according to claim 17, wherein B
signifies lower alkylidene.
signifies lower alkylidene.
19. Compounds according to claim 16, 17 or 18, wherein Z signifies 2-alkenyl.
20. Methyl (Z)-3-[[(2S,3S)-1-allyl-2-[(R)-2, 2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]
amino]-2-butenoate.
amino]-2-butenoate.
21. (3S,4S)-1-Allyl-3-[[(Z)-2-benzoyl-1-methylvinyl]
amino]-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone.
amino]-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone.
22. Diethyl [[[(2S,3S)-1-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]methylene]
malonate.
malonate.
23. Methyl (Z)-3-[[(2S,3S)-1-(2,4-dimethoxybenzyl)-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]-2-butenoate.
24. (3S,4S)-3-[[(Z)-2-Benzoyl-1-methylvinyl]
amino]-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone.
amino]-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH32083 | 1983-01-20 | ||
| CH320/83 | 1983-01-20 |
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| Publication Number | Publication Date |
|---|---|
| CA1251454A true CA1251454A (en) | 1989-03-21 |
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ID=4184333
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000444812A Expired CA1251454A (en) | 1983-01-20 | 1984-01-06 | PROCESS FOR THE MANUFACTURE OF .beta.-LACTAMES |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0116854B1 (en) |
| JP (1) | JPS59137479A (en) |
| KR (1) | KR840007230A (en) |
| AT (1) | ATE37879T1 (en) |
| AU (1) | AU566914B2 (en) |
| CA (1) | CA1251454A (en) |
| DE (1) | DE3474549D1 (en) |
| DK (1) | DK24084A (en) |
| IE (1) | IE56572B1 (en) |
| IL (1) | IL70685A (en) |
| NZ (1) | NZ206831A (en) |
| PH (1) | PH19214A (en) |
| ZA (1) | ZA84292B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK36784A (en) * | 1983-02-25 | 1984-08-26 | Hoffmann La Roche | PROCEDURE FOR PREPARING CHIRAL ALDEHYDES |
| DK411384A (en) * | 1983-10-03 | 1985-04-04 | Hoffmann La Roche | PROCEDURE FOR THE PREPARATION OF AZETIDINE UNDIVERIVES |
| US5138050A (en) * | 1988-06-30 | 1992-08-11 | Merck & Co., Inc. | 6-amido-1-methyl carbapenems |
| US5395931A (en) * | 1988-06-30 | 1995-03-07 | Merck & Co., Inc. | 6-amido-1-methyl-2-(substituted-thio)carbapenems |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1262128A (en) * | 1981-08-27 | 1989-10-03 | Christian N. Hubschwerlen | .beta.-lactams |
| EP0096296B1 (en) * | 1982-06-03 | 1987-07-29 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | 1-sulfo-2-oxoazetidine derivatives |
| CA1204746A (en) * | 1982-08-19 | 1986-05-20 | Hoffmann-La Roche Limited | .beta. LACTAMS |
| DK36784A (en) * | 1983-02-25 | 1984-08-26 | Hoffmann La Roche | PROCEDURE FOR PREPARING CHIRAL ALDEHYDES |
-
1984
- 1984-01-06 CA CA000444812A patent/CA1251454A/en not_active Expired
- 1984-01-13 IL IL70685A patent/IL70685A/en not_active IP Right Cessation
- 1984-01-13 ZA ZA84292A patent/ZA84292B/en unknown
- 1984-01-13 NZ NZ206831A patent/NZ206831A/en unknown
- 1984-01-16 AU AU23288/84A patent/AU566914B2/en not_active Ceased
- 1984-01-17 AT AT84100452T patent/ATE37879T1/en active
- 1984-01-17 DE DE8484100452T patent/DE3474549D1/en not_active Expired
- 1984-01-17 EP EP84100452A patent/EP0116854B1/en not_active Expired
- 1984-01-18 JP JP59005852A patent/JPS59137479A/en active Pending
- 1984-01-19 KR KR1019840000230A patent/KR840007230A/en not_active Ceased
- 1984-01-19 PH PH30129A patent/PH19214A/en unknown
- 1984-01-19 DK DK24084A patent/DK24084A/en not_active Application Discontinuation
- 1984-01-19 IE IE114/84A patent/IE56572B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE3474549D1 (en) | 1988-11-17 |
| DK24084D0 (en) | 1984-01-19 |
| NZ206831A (en) | 1987-04-30 |
| IE56572B1 (en) | 1991-09-11 |
| ZA84292B (en) | 1984-09-26 |
| PH19214A (en) | 1986-02-04 |
| DK24084A (en) | 1984-07-21 |
| IL70685A (en) | 1988-09-30 |
| EP0116854A3 (en) | 1984-12-05 |
| IL70685A0 (en) | 1984-04-30 |
| EP0116854B1 (en) | 1988-10-12 |
| EP0116854A2 (en) | 1984-08-29 |
| IE840114L (en) | 1984-07-20 |
| ATE37879T1 (en) | 1988-10-15 |
| AU2328884A (en) | 1984-07-26 |
| KR840007230A (en) | 1984-12-06 |
| AU566914B2 (en) | 1987-11-05 |
| JPS59137479A (en) | 1984-08-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |