CA1048016A - Antibiotics - Google Patents
AntibioticsInfo
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- CA1048016A CA1048016A CA293,802A CA293802A CA1048016A CA 1048016 A CA1048016 A CA 1048016A CA 293802 A CA293802 A CA 293802A CA 1048016 A CA1048016 A CA 1048016A
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Abstract
ABSTRACT OF THE DISCLOSURE
Cephalosporin antibiotics in which the 7.beta.-acylamido group has the structure where R1 is a furyl, thienyl or phenyl group and R2 is a C1-C4 alkyl, C3 -C7 cycloalkyl or phenylgroup except that R2 may not represent a methyl group when R1 represents a furyl group, and in which the 3-position substituent is a carbamoyloxymethyl group possess a particularly valuable combination of properties, exhibiting high anti-bacterial activity against a broad range of gram positive and gram negative organisms, particularly high stability to .beta.-lactamases produced by various organisms, and stability in vivo. Such compounds include the non-toxic salts, biologically acceptable esters, 1-oxides and solvates of the parent 4-carboxylic acids.
The compounds are syn isomers or exist as mixtures of syn and anti isomers containing at least 90% of the syn isomer. The above compounds may be prepared by (a) acylation of the corresponding 7-amino compound or (b) carbamoylation of the corresponding 3-hydroxymethyl compound.
Cephalosporin antibiotics in which the 7.beta.-acylamido group has the structure where R1 is a furyl, thienyl or phenyl group and R2 is a C1-C4 alkyl, C3 -C7 cycloalkyl or phenylgroup except that R2 may not represent a methyl group when R1 represents a furyl group, and in which the 3-position substituent is a carbamoyloxymethyl group possess a particularly valuable combination of properties, exhibiting high anti-bacterial activity against a broad range of gram positive and gram negative organisms, particularly high stability to .beta.-lactamases produced by various organisms, and stability in vivo. Such compounds include the non-toxic salts, biologically acceptable esters, 1-oxides and solvates of the parent 4-carboxylic acids.
The compounds are syn isomers or exist as mixtures of syn and anti isomers containing at least 90% of the syn isomer. The above compounds may be prepared by (a) acylation of the corresponding 7-amino compound or (b) carbamoylation of the corresponding 3-hydroxymethyl compound.
Description
~ hl'5 application is a divisional of our copending Canadian Patent Application Serial No. 207,441 filed August 20, 1974.
This invention is concerned with improvements in or relating to antibiotics of the cephalosporin series.
The cephalosporin compounds in this specification are named with reference to "cepham" after J.Amer. Chem.
Soc., 1962, 84, 3400, the term "cephem" referring to the basic cepham structure with one double bond.
Man~ cephalosporin compounds possessing a degree of antibacterial activity are known in the art, these compounds possessing ~ unsaturation and ordinarily being substituted at the 3-position by a methyl or substituted methyl group and at the 7~-position by an acylamido group. It is now well recognised that the antibiotic properties of a particular ceph-3-em~4-carboxy-lic acid are predominantly controlled by the nature of both the 7~-acylamido group thereof and the 3-position substituent which the compound carries; considerable research has been undertaken to find combinations of such groups which will yield antibiotics with particular pro-perties.
Cephalosporin antibiotics are widely used in $he treatment of diseases caused by pathogenic bacteria in human beings and animals, for example in the treatment of diseases caused by bacteria which are resistant to 0~
This invention is concerned with improvements in or relating to antibiotics of the cephalosporin series.
The cephalosporin compounds in this specification are named with reference to "cepham" after J.Amer. Chem.
Soc., 1962, 84, 3400, the term "cephem" referring to the basic cepham structure with one double bond.
Man~ cephalosporin compounds possessing a degree of antibacterial activity are known in the art, these compounds possessing ~ unsaturation and ordinarily being substituted at the 3-position by a methyl or substituted methyl group and at the 7~-position by an acylamido group. It is now well recognised that the antibiotic properties of a particular ceph-3-em~4-carboxy-lic acid are predominantly controlled by the nature of both the 7~-acylamido group thereof and the 3-position substituent which the compound carries; considerable research has been undertaken to find combinations of such groups which will yield antibiotics with particular pro-perties.
Cephalosporin antibiotics are widely used in $he treatment of diseases caused by pathogenic bacteria in human beings and animals, for example in the treatment of diseases caused by bacteria which are resistant to 0~
- 2 ~
~ 6 other antibiotics such as penicillin compounds and in the treatment of penicillin-sensitive patients. In many applications it is desirable to employ a cephalosporin antibiotic which exhibits activity against both gram positive and gram negative microorganisms, and a significant amount of research has been directed to the development of improved broad spectrum cephalosporin antibiotics.
The practical utility of a significant number of known commercial and experimental cephalosporin antibiotics is limited by their relatively high susceptibility to the ~-lactamases which are produced by many bacteria. A desirable property of a broad spectrum cephalosporin antibiotic is therefore that it should exhibit substantial resistance to ~lactamases, including those produced by gram negative microorganisms.
A further difficulty with many cephalosporin antibiotics intended for therapeutic applications is that they are subject to degradation in vivo. Thus a significant number of known cephalosporin antibiotics have been found to suffer the disadvantage that following .administration they are deactivated, often rapidly, ~048(~6 by enzymes (e,g, esterases) present in the body.
As a result of prolonged ~tudies of numerous cephalosporin compou~ds we have now found a class of cephalosporln antibiotics having a particular combination of 7~-acylamido group and 3-position substituent which endows the compounds with good broad spectrum activity coupled with the above-described desiderata of high ~-lactamase stability and good stability in vivo.
These compounds are characterised in that the 7~-acylamido group is a 2-aryl-2-(etherified oxyimino)acetamido group which is substantially in the s~n configuration (as hereinafter defined) and that the 3-substituent is a carbamoyloxymethyl group.
The present invention, therefore provides anti-biotic compounds of the general formula H H
, R c.CONH l I ~ S ~ (I) OR N~ ~ - CH20.CO.NH2 COOH
(where R represe~ts a furyl, thienyl or phenyl group and R2 represents a Cl-C4 alkyl group, a C3-C7 cycloaIkyl _ 4 _ ~4~16 group or a phenyl group except that R2 may not represent a methyl group when Rl represents a furyl group) and non-toxic salts, biologically acceptable esters,l-oxides and solvates thereof,the compounds being ~y~ isomers or existing as mixtures of syn and anti isomers containing at least 90% of the syn isomer. Most preferably the compounds are the syn isomers essentially free from the corresponding anti isomers, The compounds of the invention are def-lned as having the sYn (cis) isomeric form as regards the con-figuration of the group oR2 with respect to thecarboxamido group In this specification the ~y~ configuration is structurally denoted thus:-R .C.CONH-oR2 The syn configuration is assigned on the basis of the work of Ahmad and Spenser as reported in Can, J. Chem.
1961, 39, 1340.
The term "non-toxic"as applied to salts, esters, 1-oxides and solvates (especially hydrates) of the compounds of the invention means such derivatives which are physiol-ogically acceptable in the dosage at which they are . . 1048~6 admlnlstered.
Salts which may be formed from the compounds of general formula I include inorganic base salts such as alkali metal (e.g. sodium and potassium),alkaline earth metal (e.g. calcium) and organic base (e.g.
procaine, phenylethylbenzylamine, dibenzylethylene-diamine, ethanolamine, diethanolamine, triethanolamine and N-methylglucosamine) salts. The salts may also comprise resinates, formed with, for example a polystyrene resin or cross-linked polystyrene divinylbenzene copolymer resin containing amino or quaternary amino groups.
Where R in general formula I is a furyl group it may be fur-2-yl or fur-3-yl and when it is a thienyl group it may be thien-2-yl or thien-3-yl.
As indicated above, the group R2 in formula I
represents an alkyl group containing 1-4 carbon atoms, e.g, a methyl, ethyl or t-butyl group; a cycloalkyl group containing 3-7 carbon atoms, e.g. a cyclopentyl group;
or a phenyl group.
. .
~ 6 The compounds of formula (I), as indicated above, possess a particularly valuable combination of properties, exhibiting high antibacterial activity against a broad range of gram-positive and gram-negative organisms The breadth of the activity spectrum is enhanced by the particularly high stability of the compounds to .~-lactamases produced by various gram-negative organisms The compounds show the advantageous property of good stability in ViVQ, parti~ularly to esterases The properties possessed by the compounds of formula (I) render them useful in the treatment of a variety of diseases caused by pathogenic bacteria in human beings and animals.
~0480~6 Where insoluble salts of the compound (I) are desired in a particular application, for example for use in depot preparations, such salts may be formed in conventional manner, for example wi-th appropriate organic amines.
The invention further provides a process for the preparation of an antibiotic compound of formula I
(as hereinbefore defined~ or a non-toxic salt, biologic-ally acceptable ester, l-oxide or solvate thereof which comprises either (A~ condensing a compound of general formula E~
H2N , '~ ~
O ~ CH20.CO NHR12 ~II) COORl 1 (wherein B is = S or = S~ O; R is hydrogen or a carboxyl blockinggroup, e.g. the residue of an ester-forming aliphatic or araliphatic alcohol or an ester-forming phenol, silanol or stannanol, or a symmetrical or mixed anhydride group derived from an appropriate acid; R 2 is hydrogen or an N~protecting group, e.g 1C1148~1~
an acyl group, especially a lower alkanoyl group such as acetyl, a hal~-substituted lower alkanoyl group such as mono~, di- or tri-chloroacetyl, or a chlorosulphonyl - group) or an acid addition salt thereof(e,g, an acid addition salt formed with, for example, a mineral : acid such as hydrochloric, hydrobromic,sulphuric, nitric or phosphoric acid or an organic acid such as methane sulpho~ic or toluene p-sulphonic acid) or an N-silyl derivative thereof, with:an acylating agent corresponding 10 to the acid Rl,C.COOH
ll (III) N oR2 (wherein R and R2 have the above-defined meanings), or (B) reacting a compound of the formula H H
R ,C.CO,NH ~ I - r B ~
N ~ oR2 O ~ N ~ CH2H (IV) COOR
g ~V~80~6 (wherein Rl, R2, B and Rll have the above defined meanings) with a carbamoylating agent serving to form a carbamoyloxy-methyl group or an N-protected carbamoyloxy-methyl group at the 3-position; whereafter, if necessary and/or desired in each instance, any of the following reactions (C), in any appropriate sequence are carried out:-(i) removal of any carboxyl blocking or N-protecting groups, and (ii)ireduction of a cephalosporin sulphoxide product to yield the corresponding sulphide; and finally (D) recovering the desired compound of formula I if desired after conversion of the compound to a non-toxic salt,biologically acceptable ester, l-oxide or solvate .
thereof, Non-toxic derivatives of the compounds of formula I
may be formed in any convenient way, for example accord-ing to methods well known in the art, Thus, for example, base salts may be formed by reaction of the cephalosporin acid with sodium or potassium 2-ethylhexanoate. Bio-logically acceptable esterderivatives may be formed using conventional esterifying agents. l-Oxides may be formed by treatment of the corresponding cephalosporin sulphide with an appropriate oxidising agent, for example with a peracid such as metaperiodic acid,perac~tic 1~48~L6 acid, monoperphthalic acid or m-chloroperbenzoic acid, or with t-butyl hypochlorite conveniently in the presence of a weak base such as pyridine, Compounds of formula I may conveniently be prepared by condensing a compound of formula (II) with an acylating "
~48g;)~;6 agent comprising an acid halide, particularly an acid chloride or bromide, corresponding to the acid (III).
Such acylation may be effected at temperatures of from -50 to +50C, preferably -20 to ~30C. The acylation may be effected in aqueous or non aqueous media.
Acylation with an acid halide may be effected in the pres~nce of an acid binding agent (e.g. a tertiary amine such as triethylamine or dimethylaniline, an inorganic base such as calcium carbonate or sodium bi-carbonate, or an oxirane, preferably a lower-1,2-alkylene oxide such as ethylene oxide or propylene oxide) which serves to bind hydrogen halide liberated in the acylation reaction.
The free acid form of a compound of formula (III) may itself be used as the acylating agent. Such acylations are desirably conducted in the presence of, for example, a carbodiimide such as N,N'-diethyl-, dipropyl- or diisopropylcarbodiimide, N,N'~dicyclohexyl-carbodiimide, or N-ethyl-N'-~-dimethylamLnopropylcar-bodiimide; a carbonyl compound such as carbonyldiimidazole;
8~6 or an isoxazolinium salt such as N-ethyl-5-ph~ylisoxa-zolinium-3'-sulphonate or N-t-butyl-5-methyliso~azolinium perchlorate. The condensation reaction is desirably effected in an anhydrous reaction medium, e.g. methylene chloride, dimethylformamide or acetonitrile.
Acylation may also be effected with other amide-forming derivatives of the free acid (III) such as, for example, a symmetrical anhydride or a mixed anhydride, e,g. with pivalic acid or formedwith a haloformate such as a lower alkyl haloformate. The ~ixed or symmetrical anhydrides may be generated in situ.
Thus, for example, a mixed anhydride may be generated using N ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.
Mixed anhydrides may also be formed with phosphorus acids (for example phosphoric or phosphorous acids), sulphuric acid or aliphatic or aromatic sulphonic acids (for example p-toluenesulphonic acidj.
Where a starting material of formula (IV) is employed, suitable carbamoylating agents include isocyanates of general formula R13 NC0 (V) ~ 8~16 where R13 is a labile substituent group; such carbamoylating agents serve to form at the 3-position an N-protected carbamoyloxymethyl group of formula --CH20, CO . NHR13 (where R13 has the above~defined m~aning) which may be converted to the desirèd unsubstituted 3-carbamoyloxymethyl group by subsequent cleavage of the group R13, for example by hydrolysis,Labile groups R13 which are readily cleavable upon such subsequent treatment include chlorosulphonyl and bromosulphonyl; aralkyl.groups such as benæyl, ~-methoxybenzyl and diphenylmethyl; t-butyl; halogenated lower alkanoyl groups such as dichloroacetyl and trichloroacetyl; and halo-genated lower alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl, R 3 groups of this type, with the exception of aralkyl groups such as diphenylmethyl, may -generally be cleaved by acid or base catalysed hydrolysis (e.g, by base catalysed hydrolysis using sodlum bicarbonate) Halogenated groups suc~.as chlorosulphonyl, trichloroacetyl and 2,2,2~trichloroethoxycarbonyl may also be cleaved re-ductively, while groups such as chloroacetyl may also becleaved by treatment with ~hioamides such as thioure~. Aralkyl ~(~48~6 groups such as diphenylmethyl are conveniently cleaved by treatment with acid, e.g. a strong organic acid such as trifluoroacetic acidO
The carbamoylating agent of formula (V) is desirably used in excess(for example at least 1.1 moles relative to the compound of formula (-IV) The carbamoylation may be assisted by the presence of base, e.g. a tertiary organic base such as a tri-(lower alkyl)amine (e.g. triethylamine) or by employing the acid(IV)in the form of an alkali metal (e.g. sodium) salt, although such assistance may not be necessary in the case of more active isocyanates, e.g.
compounds ~V) when R is a strongly electron-withdrawing group such as chlorosulphonyl or trichloroacetyl.
Carbamoylations involving reaction of a free acid (1~
with excess isocyanate (V~ wherein R13 is a group such as chlorosuIphonyl or trichloroacetyl are thus of particular practical advantage by virtue of the simplicity of the reaction conditions, since there is no need for temporary blocking and subsequent deblocking of the 4-position carboxy group of the cephalosporin and since the electron withdrawing R group in the resulting N-protected 3 1~4~ 6 -carbamoyloxymethyl cephalosporin product is readily removed by, for example, hydrolysis with aqueous sodium bicarbonate .
It should be noted that it may be convenient to retain or even to introduce an N-substituting group R
during trans~ormations of;intermediate 3-carbamoyloxymethyl compounds in order to minimise unwanted side reactions involving the carbamoyloxymethyl ~roup. .
Another useful carbamoylating agent is cyanic acid, which is conveniently generated in situ from, for example, an alkali metal cyanate such as sodium cyanate, the reaction being facilitated by the presence of an acid, e.g. a strong organic acid such as trifluoroacetic acid.
Cyanic acid effectively corresponds to the compound of formula (V) wherein R is hydrogen and therefore converts compo~nds of formula V directly to their 3-carbamoyloxymethyl analogues.
~ 6 other antibiotics such as penicillin compounds and in the treatment of penicillin-sensitive patients. In many applications it is desirable to employ a cephalosporin antibiotic which exhibits activity against both gram positive and gram negative microorganisms, and a significant amount of research has been directed to the development of improved broad spectrum cephalosporin antibiotics.
The practical utility of a significant number of known commercial and experimental cephalosporin antibiotics is limited by their relatively high susceptibility to the ~-lactamases which are produced by many bacteria. A desirable property of a broad spectrum cephalosporin antibiotic is therefore that it should exhibit substantial resistance to ~lactamases, including those produced by gram negative microorganisms.
A further difficulty with many cephalosporin antibiotics intended for therapeutic applications is that they are subject to degradation in vivo. Thus a significant number of known cephalosporin antibiotics have been found to suffer the disadvantage that following .administration they are deactivated, often rapidly, ~048(~6 by enzymes (e,g, esterases) present in the body.
As a result of prolonged ~tudies of numerous cephalosporin compou~ds we have now found a class of cephalosporln antibiotics having a particular combination of 7~-acylamido group and 3-position substituent which endows the compounds with good broad spectrum activity coupled with the above-described desiderata of high ~-lactamase stability and good stability in vivo.
These compounds are characterised in that the 7~-acylamido group is a 2-aryl-2-(etherified oxyimino)acetamido group which is substantially in the s~n configuration (as hereinafter defined) and that the 3-substituent is a carbamoyloxymethyl group.
The present invention, therefore provides anti-biotic compounds of the general formula H H
, R c.CONH l I ~ S ~ (I) OR N~ ~ - CH20.CO.NH2 COOH
(where R represe~ts a furyl, thienyl or phenyl group and R2 represents a Cl-C4 alkyl group, a C3-C7 cycloaIkyl _ 4 _ ~4~16 group or a phenyl group except that R2 may not represent a methyl group when Rl represents a furyl group) and non-toxic salts, biologically acceptable esters,l-oxides and solvates thereof,the compounds being ~y~ isomers or existing as mixtures of syn and anti isomers containing at least 90% of the syn isomer. Most preferably the compounds are the syn isomers essentially free from the corresponding anti isomers, The compounds of the invention are def-lned as having the sYn (cis) isomeric form as regards the con-figuration of the group oR2 with respect to thecarboxamido group In this specification the ~y~ configuration is structurally denoted thus:-R .C.CONH-oR2 The syn configuration is assigned on the basis of the work of Ahmad and Spenser as reported in Can, J. Chem.
1961, 39, 1340.
The term "non-toxic"as applied to salts, esters, 1-oxides and solvates (especially hydrates) of the compounds of the invention means such derivatives which are physiol-ogically acceptable in the dosage at which they are . . 1048~6 admlnlstered.
Salts which may be formed from the compounds of general formula I include inorganic base salts such as alkali metal (e.g. sodium and potassium),alkaline earth metal (e.g. calcium) and organic base (e.g.
procaine, phenylethylbenzylamine, dibenzylethylene-diamine, ethanolamine, diethanolamine, triethanolamine and N-methylglucosamine) salts. The salts may also comprise resinates, formed with, for example a polystyrene resin or cross-linked polystyrene divinylbenzene copolymer resin containing amino or quaternary amino groups.
Where R in general formula I is a furyl group it may be fur-2-yl or fur-3-yl and when it is a thienyl group it may be thien-2-yl or thien-3-yl.
As indicated above, the group R2 in formula I
represents an alkyl group containing 1-4 carbon atoms, e.g, a methyl, ethyl or t-butyl group; a cycloalkyl group containing 3-7 carbon atoms, e.g. a cyclopentyl group;
or a phenyl group.
. .
~ 6 The compounds of formula (I), as indicated above, possess a particularly valuable combination of properties, exhibiting high antibacterial activity against a broad range of gram-positive and gram-negative organisms The breadth of the activity spectrum is enhanced by the particularly high stability of the compounds to .~-lactamases produced by various gram-negative organisms The compounds show the advantageous property of good stability in ViVQ, parti~ularly to esterases The properties possessed by the compounds of formula (I) render them useful in the treatment of a variety of diseases caused by pathogenic bacteria in human beings and animals.
~0480~6 Where insoluble salts of the compound (I) are desired in a particular application, for example for use in depot preparations, such salts may be formed in conventional manner, for example wi-th appropriate organic amines.
The invention further provides a process for the preparation of an antibiotic compound of formula I
(as hereinbefore defined~ or a non-toxic salt, biologic-ally acceptable ester, l-oxide or solvate thereof which comprises either (A~ condensing a compound of general formula E~
H2N , '~ ~
O ~ CH20.CO NHR12 ~II) COORl 1 (wherein B is = S or = S~ O; R is hydrogen or a carboxyl blockinggroup, e.g. the residue of an ester-forming aliphatic or araliphatic alcohol or an ester-forming phenol, silanol or stannanol, or a symmetrical or mixed anhydride group derived from an appropriate acid; R 2 is hydrogen or an N~protecting group, e.g 1C1148~1~
an acyl group, especially a lower alkanoyl group such as acetyl, a hal~-substituted lower alkanoyl group such as mono~, di- or tri-chloroacetyl, or a chlorosulphonyl - group) or an acid addition salt thereof(e,g, an acid addition salt formed with, for example, a mineral : acid such as hydrochloric, hydrobromic,sulphuric, nitric or phosphoric acid or an organic acid such as methane sulpho~ic or toluene p-sulphonic acid) or an N-silyl derivative thereof, with:an acylating agent corresponding 10 to the acid Rl,C.COOH
ll (III) N oR2 (wherein R and R2 have the above-defined meanings), or (B) reacting a compound of the formula H H
R ,C.CO,NH ~ I - r B ~
N ~ oR2 O ~ N ~ CH2H (IV) COOR
g ~V~80~6 (wherein Rl, R2, B and Rll have the above defined meanings) with a carbamoylating agent serving to form a carbamoyloxy-methyl group or an N-protected carbamoyloxy-methyl group at the 3-position; whereafter, if necessary and/or desired in each instance, any of the following reactions (C), in any appropriate sequence are carried out:-(i) removal of any carboxyl blocking or N-protecting groups, and (ii)ireduction of a cephalosporin sulphoxide product to yield the corresponding sulphide; and finally (D) recovering the desired compound of formula I if desired after conversion of the compound to a non-toxic salt,biologically acceptable ester, l-oxide or solvate .
thereof, Non-toxic derivatives of the compounds of formula I
may be formed in any convenient way, for example accord-ing to methods well known in the art, Thus, for example, base salts may be formed by reaction of the cephalosporin acid with sodium or potassium 2-ethylhexanoate. Bio-logically acceptable esterderivatives may be formed using conventional esterifying agents. l-Oxides may be formed by treatment of the corresponding cephalosporin sulphide with an appropriate oxidising agent, for example with a peracid such as metaperiodic acid,perac~tic 1~48~L6 acid, monoperphthalic acid or m-chloroperbenzoic acid, or with t-butyl hypochlorite conveniently in the presence of a weak base such as pyridine, Compounds of formula I may conveniently be prepared by condensing a compound of formula (II) with an acylating "
~48g;)~;6 agent comprising an acid halide, particularly an acid chloride or bromide, corresponding to the acid (III).
Such acylation may be effected at temperatures of from -50 to +50C, preferably -20 to ~30C. The acylation may be effected in aqueous or non aqueous media.
Acylation with an acid halide may be effected in the pres~nce of an acid binding agent (e.g. a tertiary amine such as triethylamine or dimethylaniline, an inorganic base such as calcium carbonate or sodium bi-carbonate, or an oxirane, preferably a lower-1,2-alkylene oxide such as ethylene oxide or propylene oxide) which serves to bind hydrogen halide liberated in the acylation reaction.
The free acid form of a compound of formula (III) may itself be used as the acylating agent. Such acylations are desirably conducted in the presence of, for example, a carbodiimide such as N,N'-diethyl-, dipropyl- or diisopropylcarbodiimide, N,N'~dicyclohexyl-carbodiimide, or N-ethyl-N'-~-dimethylamLnopropylcar-bodiimide; a carbonyl compound such as carbonyldiimidazole;
8~6 or an isoxazolinium salt such as N-ethyl-5-ph~ylisoxa-zolinium-3'-sulphonate or N-t-butyl-5-methyliso~azolinium perchlorate. The condensation reaction is desirably effected in an anhydrous reaction medium, e.g. methylene chloride, dimethylformamide or acetonitrile.
Acylation may also be effected with other amide-forming derivatives of the free acid (III) such as, for example, a symmetrical anhydride or a mixed anhydride, e,g. with pivalic acid or formedwith a haloformate such as a lower alkyl haloformate. The ~ixed or symmetrical anhydrides may be generated in situ.
Thus, for example, a mixed anhydride may be generated using N ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.
Mixed anhydrides may also be formed with phosphorus acids (for example phosphoric or phosphorous acids), sulphuric acid or aliphatic or aromatic sulphonic acids (for example p-toluenesulphonic acidj.
Where a starting material of formula (IV) is employed, suitable carbamoylating agents include isocyanates of general formula R13 NC0 (V) ~ 8~16 where R13 is a labile substituent group; such carbamoylating agents serve to form at the 3-position an N-protected carbamoyloxymethyl group of formula --CH20, CO . NHR13 (where R13 has the above~defined m~aning) which may be converted to the desirèd unsubstituted 3-carbamoyloxymethyl group by subsequent cleavage of the group R13, for example by hydrolysis,Labile groups R13 which are readily cleavable upon such subsequent treatment include chlorosulphonyl and bromosulphonyl; aralkyl.groups such as benæyl, ~-methoxybenzyl and diphenylmethyl; t-butyl; halogenated lower alkanoyl groups such as dichloroacetyl and trichloroacetyl; and halo-genated lower alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl, R 3 groups of this type, with the exception of aralkyl groups such as diphenylmethyl, may -generally be cleaved by acid or base catalysed hydrolysis (e.g, by base catalysed hydrolysis using sodlum bicarbonate) Halogenated groups suc~.as chlorosulphonyl, trichloroacetyl and 2,2,2~trichloroethoxycarbonyl may also be cleaved re-ductively, while groups such as chloroacetyl may also becleaved by treatment with ~hioamides such as thioure~. Aralkyl ~(~48~6 groups such as diphenylmethyl are conveniently cleaved by treatment with acid, e.g. a strong organic acid such as trifluoroacetic acidO
The carbamoylating agent of formula (V) is desirably used in excess(for example at least 1.1 moles relative to the compound of formula (-IV) The carbamoylation may be assisted by the presence of base, e.g. a tertiary organic base such as a tri-(lower alkyl)amine (e.g. triethylamine) or by employing the acid(IV)in the form of an alkali metal (e.g. sodium) salt, although such assistance may not be necessary in the case of more active isocyanates, e.g.
compounds ~V) when R is a strongly electron-withdrawing group such as chlorosulphonyl or trichloroacetyl.
Carbamoylations involving reaction of a free acid (1~
with excess isocyanate (V~ wherein R13 is a group such as chlorosuIphonyl or trichloroacetyl are thus of particular practical advantage by virtue of the simplicity of the reaction conditions, since there is no need for temporary blocking and subsequent deblocking of the 4-position carboxy group of the cephalosporin and since the electron withdrawing R group in the resulting N-protected 3 1~4~ 6 -carbamoyloxymethyl cephalosporin product is readily removed by, for example, hydrolysis with aqueous sodium bicarbonate .
It should be noted that it may be convenient to retain or even to introduce an N-substituting group R
during trans~ormations of;intermediate 3-carbamoyloxymethyl compounds in order to minimise unwanted side reactions involving the carbamoyloxymethyl ~roup. .
Another useful carbamoylating agent is cyanic acid, which is conveniently generated in situ from, for example, an alkali metal cyanate such as sodium cyanate, the reaction being facilitated by the presence of an acid, e.g. a strong organic acid such as trifluoroacetic acid.
Cyanic acid effectively corresponds to the compound of formula (V) wherein R is hydrogen and therefore converts compo~nds of formula V directly to their 3-carbamoyloxymethyl analogues.
3-Hydroxymethyl starting material for use in the . process of this embodiment of the invention may be prepared by, for example, the methods described in British Patent No.
1,121,308 and Belgian Patent No. 783~449.
- 16 ~
~CJ 4~L6 Any blocking group substituting the 4-carboxy group of compounds of formula tlI) or (IV) is desirably a group which may readily be split off at a later stage of a reaction sequence and advantageously is a group containing 1-20 carbon atoms. Suitable blocked carboxyl groups are well known in the art, a list of-representative groups being included in our a:Eorementioned Belgian Patent No 783,449 ,~referred blocked carboxyl groups lnclude aryl lower alkoxycarbonyl groups such as ~-methoxybenzyloxycarbonyl, p-nitrobenzyloxy carbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups such as t-butoxycarbonyl; and lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. The carboxyl blocking group may subsequently be removed by any of the appropriate methods disclosed in the literature; thus7 for example, acid or base catalysed hydrolysis is applicable in many cases, as are enzymically-catalysed hydrolyses.
Where at the end of a given preparative sequence a s.ulphoxide analogue of a compound of formula I is obtained,conversion to the corresponding sulphide may, for example, be effected by reduction of the corresponding acyloxysulphonium or alkyloxysulphonium salt prepared in situ by, for example, _ 17 -~4~ L6 reaction with acetyl chloride in the case of an acetoxysulphonium salt, reduction being effected by, for example sodium dithionite or by iodide ion (as in a solution of potassium iodide in a water miscible solvent such as acetic acid, tetrahydrofuran, dioxan, dimethylformamide or dimethylacetamide). The reaction may be effected at a temperature of -20 to +50C.
The antibiotic compounds of formula (I) may be - formulated for administration in any convenient way, by analogy with other antibiotics, for example in the form of pharmaceutical compositions comprising a compound of formula I or a non-toxic salt, biologically acceptable ester, l-oxide or sol~ate thereo~ adapted for use in human or veterinary medicine Such compositions may be presented for use in c~ ventional manner with the aid of any necessary pharmaceutical carriers or excipients.
L80~6 The antibiotic compounds according to the invention may be formulated for injection and may be presented in unit dose form in ampoules, or in multi-dose containers with added preservative. The compositions may take such forms as suspensions, solutions and emulsions in-oily or ~queous vehicles, and may contain formulatorv agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile, pyrogen~free water, before use.
For veterinary medicine the compositions may, for example, be formulated as intramammary preparations in either long acting or quick-release bases.
In gen~ral the compositions may contain from 0.1%
upwards, e.g. 0;1-99%, preferably from 10-60% of the active material, depending on the method of administration.
Where the compositions comprise dosage units, each unit will preferably contain 501500 mg of the active ingredient.
; 20 The dosage as employed for adult human treatment will ~C3 48(~L6 preferably range from 500 - 4000 mg per day, depending on the route and frequency of administration The compounds according to the invention may be administered in combination with other compatible therapeutic agents such as antibiotics, for example penicillins, other cephalosporins or tetracyclines.
8~6 The following examples illustrate the invention.
All temperatures are in C. Meltlng polnts were determined on a Kofler block.
~L~48~6 A) PREPARATION OF STARTING MATERIALS
Preparation 1 a) Diphenylmethyl (6R,7R)-7-(Thien-2-ylacetamido~-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylate.
Trichloroacetyl isocyanate (13.2 g, 70 mmole) was added to a stirred suspension of diphenylmethyl (6R,7R)-3-hydroxymethyl-7-Cthien~2-ylacetamido)ceph-3-em-4 carboxylate (26.0 g, 50 mmole) in anhydrous acetone (600 ml) at 20. The solid soon dissolved and after the mixture had been stirred at 20 for 1 hour it was chilled for 1 hour and the resulting solid was filtered off and washed with ether to give the title compound (33.1 g, 93%), 183 to 184; [~21 + 24 (c 0. 95 in DMS0); Ainf 235 nm (~ 14,500) and ~in~ 256 nm (E 8,820).
IR, NMR and microanalytical data confirmed the structure as that of the title compound.
b~ Diphenylmethyl (6R,7R)-?-Amino-3-trichloroacetyl-carbamoy_oxymethylceph-3-em-4-carboxylate _ ue~
sulphonic Acid Sal_.
Anhydrous pyridine (31ml9 0.384 mole) was added to a solution of phosphorus pentachloride (20 g, 96 mmole) in dry dichloromethane (300 ml) - 22 ~
~48~16 at 3. The suspension was stirred for 10 minutes at 3 and diphenylmethyl (6R,7R)-7-(thien-2-ylacetamido)-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carbox~rlate (22.5 g, 32 mmole) was added; the reaction was stirred at c 2 for 1 hour. The dark solution was poured slowly into à cold (0) anhydrous mixture of methanol (80 ml) and dichloromethane (200 ml~ with the temperature kept below 5. The temperature of the solution was then allowed to rise to 23 and, after stirring the solution at this temperature for 1 hour, water (200 ml) was added. The organic layer was separated and washed with 2N-sulphuric acid, water, sodium bicarbonate solution and water, dried over magnesium sulphate, and evaporated in vacuoO The resulting oil was dissolved in ethyl acetate and a solution of toluene-~-sulphonic acid monohydrate (6.0 g, 31.5 mmole) in ethyl acetate was- added.
The combined solutions (ca. 350 ml) were poured into diethyl ether (ca. 1 litre) and the resulting solid was filtered off and dried in vacuo to give the title compound (17.2 g, 72~/~), m.p. 150 to 153; [a~D + 7 5 (c 0.82 in DMS0); AmaX 263 nm ( 7,600) and ~'inf 267 nm (E 7,350).
~ ~ 80 ~
IR, NMR and microanalytical data confirmed the structure as that of the title compound.
Evaporation of the filtrate and trituration of the residue with ethanol afforded unchanged starting material (3.2 g, 14.2~
c) Diphenylmeth~ R~7R 7-~mino-3-carbamoyloxymethyl-The toluene-~-sulphonic acid salt of diphenylmethyl (6R,7R)-7-amino-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylate (17.2g9 22.7 mmole)was dissolved in a mixture of anhydrous methanol (900 ml) and acetyl chloride (45 ml) and left to stand at 20 for 5 hours. Removal of the solvent under reduced pressure gave an oil, which was dissolved in dichloromethane. This solution was shaken with aqueous sodium bicarbonate solution and then washed with water. Toluene-~-sulphonic acid monohydrate (~.3 g, 22.7'mmole) was added and the solvent was evaporated in-vacuo. The residue was dissolved in hot isopropanol (ca, 150 ml) and the solution was poured into diisopropyl ether (ca 600 ml), The precipitated solid was filtered ~ 24 ~IL0~8~
off and dried in vacu~ to give the title compound (8.9 g, 64%), m.p. 110 to 112; [a]21 -14 (c 1 0 i CHC13); ~maX 259 nm (E 6,120) and ~lnf 227 nm (e 15,800).
IR, NMR and microanalytical data confirmed the structure as that of the title compound.
Preparation 2 Di ~ bamoyloxymethylceph-3-em-4-carboxylate_Toluene-p ~ lphonic Acid Salt A stirred suspension of phosphorus pentachloride (156 g, 0.75 mole) in dry dichloromethane (1.5 litres) was cooled in an ice-bath and treated with pyridine (60.5 ml, 0.75 mole) at such a rate that the temperature of the mixture remained at ca. 20 to 25. The mixture was stirred and cooled to 8 ~nd diphenylmethyl (6R,7R)-7-(thien-2-yl)acetamido-3-trichloroacetyl-carbamoyloxymethylceph 3-em-4-carboxylate (354.5 g,0.5 mole) was added in portions over 10 minutes. The mixture was stirred at ca. 8 or 1.75 hours and then added over 10 minutes to a stirred mixture of butane-1,3-diol (225 ml, 2.5 mole) and dichloromethane (500 ml) precooled to -20 so that the tem-perature of the mixture was kept in the range -15 to -20.
.
_ 25 The cooling b~th was removed and the mixture was stirred at ca.
-10 for 20 minutes. Water (1 litre) was added and the two-phase mixture was stirred for 30 minutes. The aqueous phase was extracted with dichloromethane (2x500 ml), and the organic phases were washed sequentiaIly with 2N hydrochloric acid (1 litre) combined and evaporated to a brown gum. The gum was dissolved in methanoL (3.6 litres) and this solution was stirred and treated with saturated aqueous sodium hydrogen carbonate solution (1.2 litre~ over a period of 10 minutes. The mixture was stirred at ca. 20 for 1.5 hours and a small quantity of brown solid was removed by filtration. The yellow filtrate was concentrated in vacuo (bath temp. not greater than 40) to ca 1.5 litres and water (1.5 litres) was added. The resulting suspension was refrigerated for 1 hour, and the yellow solid was filtered off, washed well wlth water, sucked as dry as possible and dried in vacuo at 40 for 24 hours. The greasy solid th~s obtained, fo~lowed by toluene-p-sulphonic acid monohydrate (81 g, 0 425 mole), were added to stirred chloroform (2 litres).
After several minutes the toluene-p-sulphonic acid salt 20 - began to crystallise~ Stirring was continued for a further 30 minutes, after which the water was removed azeotropically 10480~6 in vacuo with continuous replacement of the chloroform so as .. . .
to maintain a volume of 2 litres. The suspension was re-rigerated overnight and the product was filtered off, slurry washed with chloroform (2x250 ml), refiltered, washed by displacement wi~h chloroform (250 ml) and dried in vacuo at 40 to give the title oompou~d as an off-white crystalline ~ solid (237.. 8 g, 74 1%); ~m (EtOH) 262 nm ( 7,250); the NMR spectrum (Me2SO-d6) indicated the presence of O.25 mole of chloroform.
o J Preparation 3 (6R,7R2-7-Amino-3-carbamoyloxvmethylceph-3-em-4-carbox~].ic Acid Diphenylmethyl (6R,7R)-7~amino-3-carbamoyloxymethylceph-3 em-4-carboxylate toluene-p-sulphonic acid salt (300.0 g, 0.44 mole), solvated with ca. 0.6 mole of chloroform, was added in portions over 30 minutes to a stirred mixture ~
trifluoroacetic acid (300 ml) and anisole (300 ml) immersed in a water-bath at 20. The temperature of the mixture rose from 23 to 28.over the first 20 minutes but fell back to 26 by the end of the addition. The golden yellow solution was stirred for 1 hour, the temperature falling to 21, and ~0~81D~6 was then added to a stirred mixture of ethyl acetate (1.5 litres) and water (l.S litres) immersed in an ice-bath. The pH of the stirred mixture was adjusted to 3~8 over 10 minutes with ammonia solution (S G. 0.880), the temperature rising to 38.
The suspension was stirred and cooled to 10 over 1.25 hours and filtered. The cream soiid was washed with water (750 ml) and ethyl acetate (4 x 200 ml) and dried in vacuo to give the (115.6 g, 96.2%); ~ (pH6 phosphate) 265nm max (7,750); purity by HPL (high pressure liquid chromatography) 99.7%.
Microanalytical data confirmed the structure as that of the title compound.
Example 1 (6R,7R~-3-Carbamoyloxymet~ 7-C2-methoxyimillo-2-(thien-2-yl)acetamido~ceph-3-em-4-carboxylic Acld ~n isomer`j A mixture of N,N-dimethylacetamide (10 ml); acetonitrile (10 ml), triethylamine (2.8 ml, 20 mmole), (6R,7R)-7-amino-3 carbamoyloxymethyl-ceph-3-em-4-carboxylic acid (1.09 g, 4 mmole) q~7d ~a~4r ~/o ,~, was stirred at oo for 90 minutes 5 the solid slowly dissolving~
Meanwhile a solution of phosphorus pentachloride (1.0 g, 4.8 ^ - 28 -1~ ~ 8~ ~ 6
1,121,308 and Belgian Patent No. 783~449.
- 16 ~
~CJ 4~L6 Any blocking group substituting the 4-carboxy group of compounds of formula tlI) or (IV) is desirably a group which may readily be split off at a later stage of a reaction sequence and advantageously is a group containing 1-20 carbon atoms. Suitable blocked carboxyl groups are well known in the art, a list of-representative groups being included in our a:Eorementioned Belgian Patent No 783,449 ,~referred blocked carboxyl groups lnclude aryl lower alkoxycarbonyl groups such as ~-methoxybenzyloxycarbonyl, p-nitrobenzyloxy carbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups such as t-butoxycarbonyl; and lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. The carboxyl blocking group may subsequently be removed by any of the appropriate methods disclosed in the literature; thus7 for example, acid or base catalysed hydrolysis is applicable in many cases, as are enzymically-catalysed hydrolyses.
Where at the end of a given preparative sequence a s.ulphoxide analogue of a compound of formula I is obtained,conversion to the corresponding sulphide may, for example, be effected by reduction of the corresponding acyloxysulphonium or alkyloxysulphonium salt prepared in situ by, for example, _ 17 -~4~ L6 reaction with acetyl chloride in the case of an acetoxysulphonium salt, reduction being effected by, for example sodium dithionite or by iodide ion (as in a solution of potassium iodide in a water miscible solvent such as acetic acid, tetrahydrofuran, dioxan, dimethylformamide or dimethylacetamide). The reaction may be effected at a temperature of -20 to +50C.
The antibiotic compounds of formula (I) may be - formulated for administration in any convenient way, by analogy with other antibiotics, for example in the form of pharmaceutical compositions comprising a compound of formula I or a non-toxic salt, biologically acceptable ester, l-oxide or sol~ate thereo~ adapted for use in human or veterinary medicine Such compositions may be presented for use in c~ ventional manner with the aid of any necessary pharmaceutical carriers or excipients.
L80~6 The antibiotic compounds according to the invention may be formulated for injection and may be presented in unit dose form in ampoules, or in multi-dose containers with added preservative. The compositions may take such forms as suspensions, solutions and emulsions in-oily or ~queous vehicles, and may contain formulatorv agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile, pyrogen~free water, before use.
For veterinary medicine the compositions may, for example, be formulated as intramammary preparations in either long acting or quick-release bases.
In gen~ral the compositions may contain from 0.1%
upwards, e.g. 0;1-99%, preferably from 10-60% of the active material, depending on the method of administration.
Where the compositions comprise dosage units, each unit will preferably contain 501500 mg of the active ingredient.
; 20 The dosage as employed for adult human treatment will ~C3 48(~L6 preferably range from 500 - 4000 mg per day, depending on the route and frequency of administration The compounds according to the invention may be administered in combination with other compatible therapeutic agents such as antibiotics, for example penicillins, other cephalosporins or tetracyclines.
8~6 The following examples illustrate the invention.
All temperatures are in C. Meltlng polnts were determined on a Kofler block.
~L~48~6 A) PREPARATION OF STARTING MATERIALS
Preparation 1 a) Diphenylmethyl (6R,7R)-7-(Thien-2-ylacetamido~-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylate.
Trichloroacetyl isocyanate (13.2 g, 70 mmole) was added to a stirred suspension of diphenylmethyl (6R,7R)-3-hydroxymethyl-7-Cthien~2-ylacetamido)ceph-3-em-4 carboxylate (26.0 g, 50 mmole) in anhydrous acetone (600 ml) at 20. The solid soon dissolved and after the mixture had been stirred at 20 for 1 hour it was chilled for 1 hour and the resulting solid was filtered off and washed with ether to give the title compound (33.1 g, 93%), 183 to 184; [~21 + 24 (c 0. 95 in DMS0); Ainf 235 nm (~ 14,500) and ~in~ 256 nm (E 8,820).
IR, NMR and microanalytical data confirmed the structure as that of the title compound.
b~ Diphenylmethyl (6R,7R)-?-Amino-3-trichloroacetyl-carbamoy_oxymethylceph-3-em-4-carboxylate _ ue~
sulphonic Acid Sal_.
Anhydrous pyridine (31ml9 0.384 mole) was added to a solution of phosphorus pentachloride (20 g, 96 mmole) in dry dichloromethane (300 ml) - 22 ~
~48~16 at 3. The suspension was stirred for 10 minutes at 3 and diphenylmethyl (6R,7R)-7-(thien-2-ylacetamido)-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carbox~rlate (22.5 g, 32 mmole) was added; the reaction was stirred at c 2 for 1 hour. The dark solution was poured slowly into à cold (0) anhydrous mixture of methanol (80 ml) and dichloromethane (200 ml~ with the temperature kept below 5. The temperature of the solution was then allowed to rise to 23 and, after stirring the solution at this temperature for 1 hour, water (200 ml) was added. The organic layer was separated and washed with 2N-sulphuric acid, water, sodium bicarbonate solution and water, dried over magnesium sulphate, and evaporated in vacuoO The resulting oil was dissolved in ethyl acetate and a solution of toluene-~-sulphonic acid monohydrate (6.0 g, 31.5 mmole) in ethyl acetate was- added.
The combined solutions (ca. 350 ml) were poured into diethyl ether (ca. 1 litre) and the resulting solid was filtered off and dried in vacuo to give the title compound (17.2 g, 72~/~), m.p. 150 to 153; [a~D + 7 5 (c 0.82 in DMS0); AmaX 263 nm ( 7,600) and ~'inf 267 nm (E 7,350).
~ ~ 80 ~
IR, NMR and microanalytical data confirmed the structure as that of the title compound.
Evaporation of the filtrate and trituration of the residue with ethanol afforded unchanged starting material (3.2 g, 14.2~
c) Diphenylmeth~ R~7R 7-~mino-3-carbamoyloxymethyl-The toluene-~-sulphonic acid salt of diphenylmethyl (6R,7R)-7-amino-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylate (17.2g9 22.7 mmole)was dissolved in a mixture of anhydrous methanol (900 ml) and acetyl chloride (45 ml) and left to stand at 20 for 5 hours. Removal of the solvent under reduced pressure gave an oil, which was dissolved in dichloromethane. This solution was shaken with aqueous sodium bicarbonate solution and then washed with water. Toluene-~-sulphonic acid monohydrate (~.3 g, 22.7'mmole) was added and the solvent was evaporated in-vacuo. The residue was dissolved in hot isopropanol (ca, 150 ml) and the solution was poured into diisopropyl ether (ca 600 ml), The precipitated solid was filtered ~ 24 ~IL0~8~
off and dried in vacu~ to give the title compound (8.9 g, 64%), m.p. 110 to 112; [a]21 -14 (c 1 0 i CHC13); ~maX 259 nm (E 6,120) and ~lnf 227 nm (e 15,800).
IR, NMR and microanalytical data confirmed the structure as that of the title compound.
Preparation 2 Di ~ bamoyloxymethylceph-3-em-4-carboxylate_Toluene-p ~ lphonic Acid Salt A stirred suspension of phosphorus pentachloride (156 g, 0.75 mole) in dry dichloromethane (1.5 litres) was cooled in an ice-bath and treated with pyridine (60.5 ml, 0.75 mole) at such a rate that the temperature of the mixture remained at ca. 20 to 25. The mixture was stirred and cooled to 8 ~nd diphenylmethyl (6R,7R)-7-(thien-2-yl)acetamido-3-trichloroacetyl-carbamoyloxymethylceph 3-em-4-carboxylate (354.5 g,0.5 mole) was added in portions over 10 minutes. The mixture was stirred at ca. 8 or 1.75 hours and then added over 10 minutes to a stirred mixture of butane-1,3-diol (225 ml, 2.5 mole) and dichloromethane (500 ml) precooled to -20 so that the tem-perature of the mixture was kept in the range -15 to -20.
.
_ 25 The cooling b~th was removed and the mixture was stirred at ca.
-10 for 20 minutes. Water (1 litre) was added and the two-phase mixture was stirred for 30 minutes. The aqueous phase was extracted with dichloromethane (2x500 ml), and the organic phases were washed sequentiaIly with 2N hydrochloric acid (1 litre) combined and evaporated to a brown gum. The gum was dissolved in methanoL (3.6 litres) and this solution was stirred and treated with saturated aqueous sodium hydrogen carbonate solution (1.2 litre~ over a period of 10 minutes. The mixture was stirred at ca. 20 for 1.5 hours and a small quantity of brown solid was removed by filtration. The yellow filtrate was concentrated in vacuo (bath temp. not greater than 40) to ca 1.5 litres and water (1.5 litres) was added. The resulting suspension was refrigerated for 1 hour, and the yellow solid was filtered off, washed well wlth water, sucked as dry as possible and dried in vacuo at 40 for 24 hours. The greasy solid th~s obtained, fo~lowed by toluene-p-sulphonic acid monohydrate (81 g, 0 425 mole), were added to stirred chloroform (2 litres).
After several minutes the toluene-p-sulphonic acid salt 20 - began to crystallise~ Stirring was continued for a further 30 minutes, after which the water was removed azeotropically 10480~6 in vacuo with continuous replacement of the chloroform so as .. . .
to maintain a volume of 2 litres. The suspension was re-rigerated overnight and the product was filtered off, slurry washed with chloroform (2x250 ml), refiltered, washed by displacement wi~h chloroform (250 ml) and dried in vacuo at 40 to give the title oompou~d as an off-white crystalline ~ solid (237.. 8 g, 74 1%); ~m (EtOH) 262 nm ( 7,250); the NMR spectrum (Me2SO-d6) indicated the presence of O.25 mole of chloroform.
o J Preparation 3 (6R,7R2-7-Amino-3-carbamoyloxvmethylceph-3-em-4-carbox~].ic Acid Diphenylmethyl (6R,7R)-7~amino-3-carbamoyloxymethylceph-3 em-4-carboxylate toluene-p-sulphonic acid salt (300.0 g, 0.44 mole), solvated with ca. 0.6 mole of chloroform, was added in portions over 30 minutes to a stirred mixture ~
trifluoroacetic acid (300 ml) and anisole (300 ml) immersed in a water-bath at 20. The temperature of the mixture rose from 23 to 28.over the first 20 minutes but fell back to 26 by the end of the addition. The golden yellow solution was stirred for 1 hour, the temperature falling to 21, and ~0~81D~6 was then added to a stirred mixture of ethyl acetate (1.5 litres) and water (l.S litres) immersed in an ice-bath. The pH of the stirred mixture was adjusted to 3~8 over 10 minutes with ammonia solution (S G. 0.880), the temperature rising to 38.
The suspension was stirred and cooled to 10 over 1.25 hours and filtered. The cream soiid was washed with water (750 ml) and ethyl acetate (4 x 200 ml) and dried in vacuo to give the (115.6 g, 96.2%); ~ (pH6 phosphate) 265nm max (7,750); purity by HPL (high pressure liquid chromatography) 99.7%.
Microanalytical data confirmed the structure as that of the title compound.
Example 1 (6R,7R~-3-Carbamoyloxymet~ 7-C2-methoxyimillo-2-(thien-2-yl)acetamido~ceph-3-em-4-carboxylic Acld ~n isomer`j A mixture of N,N-dimethylacetamide (10 ml); acetonitrile (10 ml), triethylamine (2.8 ml, 20 mmole), (6R,7R)-7-amino-3 carbamoyloxymethyl-ceph-3-em-4-carboxylic acid (1.09 g, 4 mmole) q~7d ~a~4r ~/o ,~, was stirred at oo for 90 minutes 5 the solid slowly dissolving~
Meanwhile a solution of phosphorus pentachloride (1.0 g, 4.8 ^ - 28 -1~ ~ 8~ ~ 6
4,8 mmole) in dry dichloromethane (12 ml~ was cooled to oo, and N, N~dimethylacetamide (2 ml) was added, The resulting solution was recooled to -10 and sodium 2-methoxyimino-2-(thien-2-yl)acetate (syn isomer) (923 mg, 4.8 mmole) was added The mixture was stirred at -10 for 15 minutes and crushed ice (3 g) was added The mixture ~was stirred at oo for 10 minutes, whereafter the lower dichloromethane phase was added over 10 minutes to the cephalosporin solution prepared above, cooled to -10 so that the reaction temperature rose steadily to 0 The mixture was stirred at 0 to 2 for 1 hour 2N-Hydrochloric acid (50 ml) was then added and after shaking the mixture a solid separated. The solid was filtered, washed and dried in vacuo to give the title compound (888 mg, 50%) Its properties are: m p 157 to 163, ~~20 +57 3O
(c 1.0 in dioxan), RpAC 0 8* Solvent system A*, ~max (pH6 buffer) 262 5 nm (~ 15,550), and inflexion at 235 nm (s10,350~ (DMS0-d6) 0 20 (d.J 8 Hz, NH), 2 29 (dd J 2 and 5 Hz, thienyl C5-H), 2.7 to 2.9 (m, thienyl C3-H and C4-H), 3 40 (s CONH2),4 13 (dd, J 5 and 8 Hz.
C7-H), 4 75 (d J 5Hz, C6-H), 5 01 and 5.34 (AB-q. J 13 Hz, C3-CH~),6.08 (s.NOCH3),and 6 42 (collapsed ~L04~
Ab-q, C2~H2) Ymax (Nujol) 3700 to 2100 ~CO2H), 3480, 3440, 3365, and 3255 ~NH and NH2), 1760 (azetidin-2-one), 1722 (CO2H), 1709 ~OCONH2) and 1652 and 1530 cm 1 (amide). *See "Notes" after Table 1.
The title compound may also be prepared by treating acetone (750 ml) at 0 with trichloroacetyl isocyanate (240 mmole), recooling the solution to 0, and adding (6R,7R)-7-[2-methoxyimino-2-(thien-2-yl)acet-amido]-3-hydroxymethylceph-3-em-4-carboxylic acid (syn isomer) (120 mmole) in portions over 5 minutes with stirring so that the reaction temperature does not exceed 6. The solution is then stirred for a further 15 minutes and methanol (4.5 ml) added. The solution is concentrated to 60 ml and the concentrate dissolved in methanol (750 ml). Sodium bicarbonate (540 mmole) in water (600 ml) is then added, followed by activated charcoal (4.5 g), and the resulting suspension is stirred at room temperature for 2 hours.
The charcoal is removed by filtration through Keiselguhr and the light yellow filtrate is adjusted to pH 4.5 by the addition of dilute hydrochloric acid.
The solution is concentrated to half volume under reduced pressure and an equal volume of water is added. The pH is adjusted to 2.0 with dilute hydro-chloric acid and the product is isolated by filtration, washed with water (3 x 150 ml) and dried at 40 for 16 hours in vacuo to give the title compound.
In an al~ernative procedure, a slurry of (6R,7R)-7-[2-methoxy-imino-2-(thien-2-yl)acetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (syn isomer) (120 mmole) in dichloromethane (70 ml)/tetrahydrofuran (25 ml) -at 5 is trea~ed with dichloroacetyl isocyanate (25 mmole). The reaction mixture is then treated as above to give the title compound.
In yet another procedure, a slurry of (6R,7R)-7-[2-methoxyimino-2-(thien-2-yl)acetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (syn isomer) (50 mmole) in dry acetonitrile (250 ml) is treated at between 5 and 10 with chlorosulfonyl isocyanate (75 mmole) in acetonitrile (80 ml). The reaction mixture is stirred at between 0 and 5 for 10 minutes and water (50 ml) is added. The mixture is stirred at ca 20, and after 20 minutes a white __ crystalline solid is separated. Evaporation and filtration gives the title compound.
-~ t - 30 -10481DgL6 Examele 2 a) iphenylmeth~ (6R,7R)-3-Carbamoyloxymethyl-7- ~
(fur-2- ~ iminoacetamido~ceph-3-em-4-carboxylate_ (syn isomer~
A solution of DL-dicyclohexylcarbodiimide (7.75 g, 0.382 mole) in dry dichloromethane (50 ml) was added over 10 minutes to a solution o~ diphenylmethyl (6R,7R)-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate (13.7 g, 0.312 mole) and 2-(fur-2-ylj-2-phenoxyiminoacetic acid (syn isomer) (8.8 g, 0,382 mole) in dry dichloromethane (200 ml) at 0.
Ater 45 minute-s, a solid (presumably N,N'-dicyclohexyl urea) was filtered o~f, and the filtrate was washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulphate, and evaporated on a rotary evaporator The residue was chromatographed on a Silica gel (lkg) column. Less polar impurities than the reqired product were eluted w1th dichloromethane (1 litre), acetone:
dichloromethane=2:98 (1 litr~, acetone:dichloromethane-
(c 1.0 in dioxan), RpAC 0 8* Solvent system A*, ~max (pH6 buffer) 262 5 nm (~ 15,550), and inflexion at 235 nm (s10,350~ (DMS0-d6) 0 20 (d.J 8 Hz, NH), 2 29 (dd J 2 and 5 Hz, thienyl C5-H), 2.7 to 2.9 (m, thienyl C3-H and C4-H), 3 40 (s CONH2),4 13 (dd, J 5 and 8 Hz.
C7-H), 4 75 (d J 5Hz, C6-H), 5 01 and 5.34 (AB-q. J 13 Hz, C3-CH~),6.08 (s.NOCH3),and 6 42 (collapsed ~L04~
Ab-q, C2~H2) Ymax (Nujol) 3700 to 2100 ~CO2H), 3480, 3440, 3365, and 3255 ~NH and NH2), 1760 (azetidin-2-one), 1722 (CO2H), 1709 ~OCONH2) and 1652 and 1530 cm 1 (amide). *See "Notes" after Table 1.
The title compound may also be prepared by treating acetone (750 ml) at 0 with trichloroacetyl isocyanate (240 mmole), recooling the solution to 0, and adding (6R,7R)-7-[2-methoxyimino-2-(thien-2-yl)acet-amido]-3-hydroxymethylceph-3-em-4-carboxylic acid (syn isomer) (120 mmole) in portions over 5 minutes with stirring so that the reaction temperature does not exceed 6. The solution is then stirred for a further 15 minutes and methanol (4.5 ml) added. The solution is concentrated to 60 ml and the concentrate dissolved in methanol (750 ml). Sodium bicarbonate (540 mmole) in water (600 ml) is then added, followed by activated charcoal (4.5 g), and the resulting suspension is stirred at room temperature for 2 hours.
The charcoal is removed by filtration through Keiselguhr and the light yellow filtrate is adjusted to pH 4.5 by the addition of dilute hydrochloric acid.
The solution is concentrated to half volume under reduced pressure and an equal volume of water is added. The pH is adjusted to 2.0 with dilute hydro-chloric acid and the product is isolated by filtration, washed with water (3 x 150 ml) and dried at 40 for 16 hours in vacuo to give the title compound.
In an al~ernative procedure, a slurry of (6R,7R)-7-[2-methoxy-imino-2-(thien-2-yl)acetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (syn isomer) (120 mmole) in dichloromethane (70 ml)/tetrahydrofuran (25 ml) -at 5 is trea~ed with dichloroacetyl isocyanate (25 mmole). The reaction mixture is then treated as above to give the title compound.
In yet another procedure, a slurry of (6R,7R)-7-[2-methoxyimino-2-(thien-2-yl)acetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (syn isomer) (50 mmole) in dry acetonitrile (250 ml) is treated at between 5 and 10 with chlorosulfonyl isocyanate (75 mmole) in acetonitrile (80 ml). The reaction mixture is stirred at between 0 and 5 for 10 minutes and water (50 ml) is added. The mixture is stirred at ca 20, and after 20 minutes a white __ crystalline solid is separated. Evaporation and filtration gives the title compound.
-~ t - 30 -10481DgL6 Examele 2 a) iphenylmeth~ (6R,7R)-3-Carbamoyloxymethyl-7- ~
(fur-2- ~ iminoacetamido~ceph-3-em-4-carboxylate_ (syn isomer~
A solution of DL-dicyclohexylcarbodiimide (7.75 g, 0.382 mole) in dry dichloromethane (50 ml) was added over 10 minutes to a solution o~ diphenylmethyl (6R,7R)-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate (13.7 g, 0.312 mole) and 2-(fur-2-ylj-2-phenoxyiminoacetic acid (syn isomer) (8.8 g, 0,382 mole) in dry dichloromethane (200 ml) at 0.
Ater 45 minute-s, a solid (presumably N,N'-dicyclohexyl urea) was filtered o~f, and the filtrate was washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulphate, and evaporated on a rotary evaporator The residue was chromatographed on a Silica gel (lkg) column. Less polar impurities than the reqired product were eluted w1th dichloromethane (1 litre), acetone:
dichloromethane=2:98 (1 litr~, acetone:dichloromethane-
5 95 (L litres). gractions eluted with acetone: dichloro-methane=10:90 and acetone:dichloromethane = 15:85 were ~048~ 6 evaporated to a gum (llg) which was triturated with diethyl ether to give a solid (8.35 g, 41%). This was filt-ered off and purified further by crystallisation from aqueous ethanol to give the title com~und (7.6 g), m.p.
143 to 146, [a]22 ~ 48 (c l.0,.~Ie2S) ; ~max 273nm ( 18,700), ~i f 271 nm (17,600) and ~max 254 nm (E16,5000).
.
IR, NMR and microanalytical data confirmed tha structure as that of the title compound.
b) Sod um (6R,7R)-3-Carbamoyloxymethy~ -[2-(fur-2-yl)-2-phenoxyiminoacetamidolceph-3-em-4-carboxYlate (syn isomer~
Trifluoroacetic acid (30 ml) was added over 10 minutes to an ice-cooled mixture of anisole (8 ml) and diphenylmethyl (6R,7R)-3-carbamoyloxymethyl-7-[2-(fur-2-yl) 2-phenoxyiminoacetamido]ceph-3-em-4- carboxylate (syn isomer) (7.4 g, 11.4 mmole). After a further 5 minutes at - 32 - .
1~48~6 0, the dark solution was carefully poured into a mixture of a saturated aqueous solution of sodium bicarbonate and ether acetate. The aqueous solution was separated and treated with activated charcoal. The ethyl acetate layer was washed with water and the aqueous wash was combined with the sodium bicarbonate extract and acidified with concentrated hydrochloric acid. This acidic solution was extracted with a mixture of ethyl acetate and diethyl ether which was then;washed 5 times with water, dried over magnesium sulphate, and evaporated in vacuo. The residue was washed with diethyl ether and diisopropyl ether to give the cephalosporin acid (4.5 g, 82%) as a solid.
This acid was dissolvedin ethyl acetate (150 ml) and a solution of sodium 2-ethylhexanoate in ethyl acetate (10 ml,containing lO mmole) was added. The solution was -cooled in an ice-bath and stirred for 1.5 hours during which time the product (2.84 g) crystallised out, lea~ing unchanged acid (1.1 g was recovered by precipitation with petrol b.p. 60 to 80) in solution. The solid was filtered off to give the title compound Physical constants for the title compound are given in Table 1 hereinafter.
1~8~3~6 Example a) Diphen~lmethyl(6R,7R)-3 C~rb~ ~ thyl-7~ y imino-2-phe~y~acetamido)ce~-3-em-4-carboxylate (syn isomer) Diphenylmethyl (6R,7R)-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate ~toluenesulphonic acid saLt (1.83g, 3mmole) was added to a mixture of saturated aqueous sodium bicarbonate solution (50ml) and dichloromethane (lOOml). The mixture was shaken to dissolve the solid and the organic layer was separated, washed with water (twice), dried ~er sodium sulphate, and concentrated under reduced pressure to about 15ml. Thls solution was cooled to 0 and solutions of D,L-dicyclohexyl~
carbodlimid2 (824mg,-4~nole) in dry dichloromethane (lOml) and 2-methoxyimino-2-phenylac2tic acid (~ isomer) (716mg, 4mmole) in dry dichloromethane (lOml) were added. The~reaction mixture was stirred at 0 for 70 minutes; it was then iltered, washed with 2N-sulphuric acid, water, saturated aqueous sodium bicarbonate solution, water and brine, dried over sodium sulphate and evaporated to give a yellow solid (2.05g). ~nis was dissolved in hot ethyl acetate (25ml), which was cooled and dicyclohexyl urea was filtered off. Addition of diisopropyl ether to the filtrate precipi ated a solid which was filtered 1~ ~8 ~ ~ 6 off, stirred and washed with diisopropyl ether, filtered, and finally washed with diethyl ether to give the title compound (1.10 g, 61.5%), m.p. 178-182; Ca]D +22.5 (c 1, CHC13)~ ~ 258.5 nm ( 18,500); ~ f 295 nm ( E 3,120).
IR, NMR and microanalytical data confirmed the structure as that of the title compound.
b) (6R,7R~-3-Carbamoyloxymethyl-7-(2=methoxyimino-2-E_en~lacetamido)ceph-3-em-4-carboxy~ic Acid (syn isomer) Trifluoroacetic acid (4 ml) was added slowly to a mixture of anisole (1 ml) and diphenylmethyl (6R,7R)-3-carbamoyloxymethyl-7(2-methoxyimino-2-phenylacetamido) ceph-3-em-4-carboxylate (syn isomer) (1.00 g, 1.66 mmole) which had been cooled in an ice-bath. The reaction mixture was stirred for the next 10 minutes The flask wa~ then removed from the ice-bath and excess trifluoroacetic acid was removed on a rotary evaporator.
Trituration of the residue withethyl acetate (10 ml), filtration and washing with diethyl ether (25 ml and 10 ml) gave the title com~ nd (75%).
Physical constants for the title compound are given in Table 1 hereinafter.
Example 4 a) DI;phenylmethyl (6R,7R)-3-Carbamoyloxymethyl-7-(2-phenoxyimino-2-phenylacetamido)ceph-3-em-4-carbox-ylate ~09L8~6 (syn isomer~
The process of Example 3 (a) was repeated, except that 2 phenoxyimino-2-phenylacetic acid (syn isomer) was used in place of the 2-methoxyimino-2-phenylacetic acid (syn isomer), to give a red sticky foam. This crude product was crystallised from aqueous acetone to give a red solld (1.3 g) which was washed t~lice (with stirring) with diethyl ether to give the title come~nd (675 mg, 34%) m.p. 138-140; [a]D ~ 44-5 (c 1, CHC13); ~EtOH
264 nm (~ 1~7,400); ~inOH 268 and 281 nm (E ]6,850 and 14,000) as a white solid. The residu~ obtained after evaporating the mother liquors and washings was crystallised from ethanol to give further title compound ~; (431 mg, 17%~ in two crops, which were washed with diethyl ether with stirring.
~R, NMR and microanalytical data confirmed the structure as that of the title compound.
b) Sodium.(6R,7R)-3-Carbamo~loxymethvl-7-(2-phenoxyimino -2-phenylacetamido)ceph-3-em-4-carboxylate (s~n isomer) Treatment of the product of (a) above in accordance - - with ~he method of Example 3 (b) gave the crude cephalosporin 1~4~
acid, which was stirred with ethyl acetate and saturated aqueous sodi~ bicarbonate solutlon. The resulting precipitate was filtered off and washed with acetone and ether to give ' ~ , Tl the title compound (66%), having the physical constants shown in Table 1 hereinafter.
Example 5 a) Di~henylmethy~ (6R,7R~-3-Carbamo~loxymethyl-7-[2-cyclopentyloxyimino-2-(fur-2-yl)-acetamido~_eph-3-em-4-carboxylate (s~n isomer) The process of Example 3 (a) was repeated, except that 2-cyclopentyloxyimino-2-(fur-2-yl)acetic acid (syn isomer) was used in place of the 2-methoxyimino-2-phenylacetic acid (syn isomer) to give a foam (1.77 g), which was triturated with ethyl acetate to give the title compound (1.30 g, 67%), m.p. 102-108; [a]D + 12.5 (c 1, CHC13);
AmaXH 278 nm ( E 16,650~, as a pale~yellow solid.
b) ~R,7R)-3-Carbamoyloxy__thyl-7-L2-cyclopentyloxi-mino-2 (fur-2-yl)acetam _ Jceph-3-em-4-carboxylic Acid (syn isomer) Treatment of the product of (a) above in accordance with the method of Example 3 (b) gave the crude cephalosporin acid, which was precipitated from ethyl acetate with diisopropyl ~ . .
~48~16 ether to give the title compound (55%), having the physical constants shown in Table l hereinafter.
Example 6 a) Diphenylmethyl (6R,7R)-3-Carbamoyloxymethyl-7-(2-ethoxyimino-2-phenylac_tamido)ceph-3-em-4-carboxylate (syn isomer) The process of Example 3 (a) was repeated D except that 2-ethoxyimino-2-phenylacetic acid (syn isomer) was used in place of the 2 methoxyimino-2-phenylacetic acid (syn isomer). Crystallisation of the crude product from methanol gave the title compound (l.30 g, 53%) in three crops, m.p. 199-202; [a]D ~ 9 7 (c 1, dioxan);
~EtOH 259 nm (~ 20,000); AEinfH 295 nm (f 3,700 ).
b) (6R~ 3-Carbamoyloxymeth ~
phenylacetamido)ceph-3-em-4-carboxylic Acid (syn isomer) . .
~reatment of the product of (a) above in accordance with the method of Example 3(b) gave the crude cephalosporin acid, which was triturated with ethyl acetate (3 ml), filtered off~ and washed (with stirring) with ethyl acetate (5 ml) and then diethyl ether (2x10 ml) to give the title com~_und as a white solid (413 mg, 64%). A further quantity (180 mg, 27%) crystallised from the filtrates and was filtered off, and washed with diethyl ether.
Physical constants for the title compound are shown in Table 1 hereinafter.
Example _ 7 .
a) Diphenylmethyl (6R,7R)-3-Carbamoyloxymethyl-7-[2-t-butoxyimino-2-(thien-2-yl)-acetamido]ceph-3-em-4-carboxylate ~ .
The process of Example 3 ~a) was repeated, except that 2-t butoxyimino-2-(thien-2-yl)acetic acid (syn isomer) was used in place of the 2-methoxyimino-2-phenylacetic acid (syn isomer). The crude product was purified by stirring a suspension in diisopropyl ether (2x25 ml) to give the title compound as a pale-pink solid ~1.90 g9 73%), m.p.
148-152; [~]D + 8.5 (c 1, CHC13); AEtOH 262 and 282 nm (f 14,500 and 13,200).
b) Sodium (6R,7R)-3-Carbamoyloxymeth~l1-?-[2-t-butoxyimino-2-(thien-2-yl)acetamidolceE~-3-em-4-carbox~ate (syn_isomer) Treatment of the product of (a) above in accordance with the method of Example 3(b) gave the cephalosporin acid as a gum which solidified when triturated with diisopropyl -ether to give a crude product (1.20 g, 94%~. A portion of this acid (811 mg, 1.68 mmole) and sodium 2-ethylhexanoate (282 mg, 1.68 mmole) were stirred in n-butanol (5 ml) at 20 for 10 minutes and at 0 for 20 minutes. The resulting yellow solid was filtered off and washed with cold n-butanol (3 ml) and-diisopropyl ether (7 ml) to give the title compound (495 mg, 58%), having the physical constants shown in Table 1 bereinafter.
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(1) RpaC = (Rf of compound) (Rf of (6R,7R)-3-acetoxymethyl-7-phenylacetamidoceph-3-em-4-carboxylic acid) Solvent system (A) is n-butanol: ethanol: water :: (4:1:5) . , Solvent system (B) is n-propanol: water (7:3) ~ ~ .
(2) inf, denotes sn inflection (3) Trifluoracetic acid spectrum - -.
.~: , ^ '
143 to 146, [a]22 ~ 48 (c l.0,.~Ie2S) ; ~max 273nm ( 18,700), ~i f 271 nm (17,600) and ~max 254 nm (E16,5000).
.
IR, NMR and microanalytical data confirmed tha structure as that of the title compound.
b) Sod um (6R,7R)-3-Carbamoyloxymethy~ -[2-(fur-2-yl)-2-phenoxyiminoacetamidolceph-3-em-4-carboxYlate (syn isomer~
Trifluoroacetic acid (30 ml) was added over 10 minutes to an ice-cooled mixture of anisole (8 ml) and diphenylmethyl (6R,7R)-3-carbamoyloxymethyl-7-[2-(fur-2-yl) 2-phenoxyiminoacetamido]ceph-3-em-4- carboxylate (syn isomer) (7.4 g, 11.4 mmole). After a further 5 minutes at - 32 - .
1~48~6 0, the dark solution was carefully poured into a mixture of a saturated aqueous solution of sodium bicarbonate and ether acetate. The aqueous solution was separated and treated with activated charcoal. The ethyl acetate layer was washed with water and the aqueous wash was combined with the sodium bicarbonate extract and acidified with concentrated hydrochloric acid. This acidic solution was extracted with a mixture of ethyl acetate and diethyl ether which was then;washed 5 times with water, dried over magnesium sulphate, and evaporated in vacuo. The residue was washed with diethyl ether and diisopropyl ether to give the cephalosporin acid (4.5 g, 82%) as a solid.
This acid was dissolvedin ethyl acetate (150 ml) and a solution of sodium 2-ethylhexanoate in ethyl acetate (10 ml,containing lO mmole) was added. The solution was -cooled in an ice-bath and stirred for 1.5 hours during which time the product (2.84 g) crystallised out, lea~ing unchanged acid (1.1 g was recovered by precipitation with petrol b.p. 60 to 80) in solution. The solid was filtered off to give the title compound Physical constants for the title compound are given in Table 1 hereinafter.
1~8~3~6 Example a) Diphen~lmethyl(6R,7R)-3 C~rb~ ~ thyl-7~ y imino-2-phe~y~acetamido)ce~-3-em-4-carboxylate (syn isomer) Diphenylmethyl (6R,7R)-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate ~toluenesulphonic acid saLt (1.83g, 3mmole) was added to a mixture of saturated aqueous sodium bicarbonate solution (50ml) and dichloromethane (lOOml). The mixture was shaken to dissolve the solid and the organic layer was separated, washed with water (twice), dried ~er sodium sulphate, and concentrated under reduced pressure to about 15ml. Thls solution was cooled to 0 and solutions of D,L-dicyclohexyl~
carbodlimid2 (824mg,-4~nole) in dry dichloromethane (lOml) and 2-methoxyimino-2-phenylac2tic acid (~ isomer) (716mg, 4mmole) in dry dichloromethane (lOml) were added. The~reaction mixture was stirred at 0 for 70 minutes; it was then iltered, washed with 2N-sulphuric acid, water, saturated aqueous sodium bicarbonate solution, water and brine, dried over sodium sulphate and evaporated to give a yellow solid (2.05g). ~nis was dissolved in hot ethyl acetate (25ml), which was cooled and dicyclohexyl urea was filtered off. Addition of diisopropyl ether to the filtrate precipi ated a solid which was filtered 1~ ~8 ~ ~ 6 off, stirred and washed with diisopropyl ether, filtered, and finally washed with diethyl ether to give the title compound (1.10 g, 61.5%), m.p. 178-182; Ca]D +22.5 (c 1, CHC13)~ ~ 258.5 nm ( 18,500); ~ f 295 nm ( E 3,120).
IR, NMR and microanalytical data confirmed the structure as that of the title compound.
b) (6R,7R~-3-Carbamoyloxymethyl-7-(2=methoxyimino-2-E_en~lacetamido)ceph-3-em-4-carboxy~ic Acid (syn isomer) Trifluoroacetic acid (4 ml) was added slowly to a mixture of anisole (1 ml) and diphenylmethyl (6R,7R)-3-carbamoyloxymethyl-7(2-methoxyimino-2-phenylacetamido) ceph-3-em-4-carboxylate (syn isomer) (1.00 g, 1.66 mmole) which had been cooled in an ice-bath. The reaction mixture was stirred for the next 10 minutes The flask wa~ then removed from the ice-bath and excess trifluoroacetic acid was removed on a rotary evaporator.
Trituration of the residue withethyl acetate (10 ml), filtration and washing with diethyl ether (25 ml and 10 ml) gave the title com~ nd (75%).
Physical constants for the title compound are given in Table 1 hereinafter.
Example 4 a) DI;phenylmethyl (6R,7R)-3-Carbamoyloxymethyl-7-(2-phenoxyimino-2-phenylacetamido)ceph-3-em-4-carbox-ylate ~09L8~6 (syn isomer~
The process of Example 3 (a) was repeated, except that 2 phenoxyimino-2-phenylacetic acid (syn isomer) was used in place of the 2-methoxyimino-2-phenylacetic acid (syn isomer), to give a red sticky foam. This crude product was crystallised from aqueous acetone to give a red solld (1.3 g) which was washed t~lice (with stirring) with diethyl ether to give the title come~nd (675 mg, 34%) m.p. 138-140; [a]D ~ 44-5 (c 1, CHC13); ~EtOH
264 nm (~ 1~7,400); ~inOH 268 and 281 nm (E ]6,850 and 14,000) as a white solid. The residu~ obtained after evaporating the mother liquors and washings was crystallised from ethanol to give further title compound ~; (431 mg, 17%~ in two crops, which were washed with diethyl ether with stirring.
~R, NMR and microanalytical data confirmed the structure as that of the title compound.
b) Sodium.(6R,7R)-3-Carbamo~loxymethvl-7-(2-phenoxyimino -2-phenylacetamido)ceph-3-em-4-carboxylate (s~n isomer) Treatment of the product of (a) above in accordance - - with ~he method of Example 3 (b) gave the crude cephalosporin 1~4~
acid, which was stirred with ethyl acetate and saturated aqueous sodi~ bicarbonate solutlon. The resulting precipitate was filtered off and washed with acetone and ether to give ' ~ , Tl the title compound (66%), having the physical constants shown in Table 1 hereinafter.
Example 5 a) Di~henylmethy~ (6R,7R~-3-Carbamo~loxymethyl-7-[2-cyclopentyloxyimino-2-(fur-2-yl)-acetamido~_eph-3-em-4-carboxylate (s~n isomer) The process of Example 3 (a) was repeated, except that 2-cyclopentyloxyimino-2-(fur-2-yl)acetic acid (syn isomer) was used in place of the 2-methoxyimino-2-phenylacetic acid (syn isomer) to give a foam (1.77 g), which was triturated with ethyl acetate to give the title compound (1.30 g, 67%), m.p. 102-108; [a]D + 12.5 (c 1, CHC13);
AmaXH 278 nm ( E 16,650~, as a pale~yellow solid.
b) ~R,7R)-3-Carbamoyloxy__thyl-7-L2-cyclopentyloxi-mino-2 (fur-2-yl)acetam _ Jceph-3-em-4-carboxylic Acid (syn isomer) Treatment of the product of (a) above in accordance with the method of Example 3 (b) gave the crude cephalosporin acid, which was precipitated from ethyl acetate with diisopropyl ~ . .
~48~16 ether to give the title compound (55%), having the physical constants shown in Table l hereinafter.
Example 6 a) Diphenylmethyl (6R,7R)-3-Carbamoyloxymethyl-7-(2-ethoxyimino-2-phenylac_tamido)ceph-3-em-4-carboxylate (syn isomer) The process of Example 3 (a) was repeated D except that 2-ethoxyimino-2-phenylacetic acid (syn isomer) was used in place of the 2 methoxyimino-2-phenylacetic acid (syn isomer). Crystallisation of the crude product from methanol gave the title compound (l.30 g, 53%) in three crops, m.p. 199-202; [a]D ~ 9 7 (c 1, dioxan);
~EtOH 259 nm (~ 20,000); AEinfH 295 nm (f 3,700 ).
b) (6R~ 3-Carbamoyloxymeth ~
phenylacetamido)ceph-3-em-4-carboxylic Acid (syn isomer) . .
~reatment of the product of (a) above in accordance with the method of Example 3(b) gave the crude cephalosporin acid, which was triturated with ethyl acetate (3 ml), filtered off~ and washed (with stirring) with ethyl acetate (5 ml) and then diethyl ether (2x10 ml) to give the title com~_und as a white solid (413 mg, 64%). A further quantity (180 mg, 27%) crystallised from the filtrates and was filtered off, and washed with diethyl ether.
Physical constants for the title compound are shown in Table 1 hereinafter.
Example _ 7 .
a) Diphenylmethyl (6R,7R)-3-Carbamoyloxymethyl-7-[2-t-butoxyimino-2-(thien-2-yl)-acetamido]ceph-3-em-4-carboxylate ~ .
The process of Example 3 ~a) was repeated, except that 2-t butoxyimino-2-(thien-2-yl)acetic acid (syn isomer) was used in place of the 2-methoxyimino-2-phenylacetic acid (syn isomer). The crude product was purified by stirring a suspension in diisopropyl ether (2x25 ml) to give the title compound as a pale-pink solid ~1.90 g9 73%), m.p.
148-152; [~]D + 8.5 (c 1, CHC13); AEtOH 262 and 282 nm (f 14,500 and 13,200).
b) Sodium (6R,7R)-3-Carbamoyloxymeth~l1-?-[2-t-butoxyimino-2-(thien-2-yl)acetamidolceE~-3-em-4-carbox~ate (syn_isomer) Treatment of the product of (a) above in accordance with the method of Example 3(b) gave the cephalosporin acid as a gum which solidified when triturated with diisopropyl -ether to give a crude product (1.20 g, 94%~. A portion of this acid (811 mg, 1.68 mmole) and sodium 2-ethylhexanoate (282 mg, 1.68 mmole) were stirred in n-butanol (5 ml) at 20 for 10 minutes and at 0 for 20 minutes. The resulting yellow solid was filtered off and washed with cold n-butanol (3 ml) and-diisopropyl ether (7 ml) to give the title compound (495 mg, 58%), having the physical constants shown in Table 1 bereinafter.
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(1) RpaC = (Rf of compound) (Rf of (6R,7R)-3-acetoxymethyl-7-phenylacetamidoceph-3-em-4-carboxylic acid) Solvent system (A) is n-butanol: ethanol: water :: (4:1:5) . , Solvent system (B) is n-propanol: water (7:3) ~ ~ .
(2) inf, denotes sn inflection (3) Trifluoracetic acid spectrum - -.
.~: , ^ '
Claims (30)
1. A process for the preparation of an antibiotic compound of the general formula (I) (wherein R1 represents a furyl, thienyl or phenyl group and R2 represents a C1-C4 alkyl group, a C3-C7 cycloalkyl group or a phenyl group except that R2 may not represent a methyl group when R1 represents a furyl group) said com-pound being a syn isomer or existing as a mixture of syn and anti isomers containing at least 90% of the syn isomer, and the non-toxic salts, biologically acceptable esters, 1-oxides and solvates thereof, which comprises (A) con-densing a compound of general formula (II) (wherein B is > S or > S ? O; R11 is hydrogen or a carboxyl blocking group; and R12 is hydrogen or an N-protecting group) or an acid addition salt or N-silyl derivative thereof with an acylating agent corresponding to the acid.
(III) (where R1 and R2 are as defined above); or (B) reacting a compound of the formula (IV) (wherein R1, R1, B and R11 have the above-defined meanings) with a carbamoylating agent serving to form a carbamoyloxy-methyl group or an N-protected carbamoyloxymethyl group at the 3-position; whereafter if necessary and/or desired in each instance, any of the following reactions: (C), in any appropriate sequence are carried out:-(i) removal of any carboxyl blocking or N-protecting groups and (ii) reduction of a cephalosporin sulphoxide product to yield the corresponding sulphide; and finally (D) recovering the desired compound of formula I if desired after conversion of the compound to a non-toxic salt, biologically acceptable ester, 1-oxide or solvate thereof.
(III) (where R1 and R2 are as defined above); or (B) reacting a compound of the formula (IV) (wherein R1, R1, B and R11 have the above-defined meanings) with a carbamoylating agent serving to form a carbamoyloxy-methyl group or an N-protected carbamoyloxymethyl group at the 3-position; whereafter if necessary and/or desired in each instance, any of the following reactions: (C), in any appropriate sequence are carried out:-(i) removal of any carboxyl blocking or N-protecting groups and (ii) reduction of a cephalosporin sulphoxide product to yield the corresponding sulphide; and finally (D) recovering the desired compound of formula I if desired after conversion of the compound to a non-toxic salt, biologically acceptable ester, 1-oxide or solvate thereof.
2. A process as claimed in claim 1 wherein the compound of formula I or the said non-toxic salt; biologically acceptable ester, 1-oxide or solvate thereof is recovered as the syn isomer essentially free from the anti isomer.
3. A process as claimed in claim 1 wherein a compound (II) is condensed with an acid halide corresponding to the acid (III).
4. A process as claimed in claim 3, wherein the condensation is effected in the presence of an acid binding agent comprising a tertiary amine, an inorganic base or an oxirane.
5. A process as claimed in claim 1 wherein a compound (II) is condensed with a free acid (III) in the presence of a conden-sation agent comprising a carbodiimide, carbonyl diimidazole or an isoxazolinium salt.
6. A process as claimed in claim 1 wherein a compound (IV) is reacted with a carbamoylating agent comprising an isocyanate of formula R13 .NCO (V) where R13 is a labile substituent group.
7. A process as claimed in claim 6 wherein a compound (IV) wherein R11 is a hydrogen is reacted with an excess of a compound (V) wherein R13 is a strongly electron withdrawing group.
8. A process as claimed in claim 1 wherein a compound (IV) is carbamoylated by reaction with trichloroacetyl isocyanate, dichloroacetyl isocyanate or chlorosulfonyl isocyanate.
9. Compounds of formula I (as defined in claim 1) and non-toxic salts, biologically acceptable esters, 1-oxides and solvates thereof whenever prepared by a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
10. A process as claimed in claim 1 wherein R1 in the said compound of formula III or IV represents a fur-2-yl group.
11. Compounds of formula I (wherein R2 represents a fur-2-yl group and R2 is as defined in claim 1) and non-toxic salts, biologically acceptable esters, 1-oxides and solvates thereof whenever prepared by a process as claimed in claim 10 or by an obvious chemical equivalent thereof.
12. A process as claimed in claim 1 wherein R2 in the said compound of formula III or IV represents a methyl, ethyl, t-butyl, cyclopentyl or phenyl group.
13. Compounds of formula I (wherein R2 represents a methyl, ethyl, t-butyl, cyclopentyl or phenyl group and R1 is as defined in claim 1) and non-toxic salts, biologically acceptable esters, 1-oxides and solvates thereof whenever prepared by a process as claimed in claim 12 or by an obvious chemicalequivalent thereof.
14 A process as claimed in claim 1 wherein R1 in the said compound of formula III or IV represents a fur-2-yl group and R2 represents a phenyl group.
15. (6R, 7R)-3-Carbamoyloxymethyl-7-[2-(fur-2-yl)-2-phenoxyiminoacetamide] ceph-3 -em-4-carboxylic acid (syn isomer) and non-toxic salts, biologically accep-table esters, 1-oxides and solvates thereof whenever prepared by a process as claimed in claim 14 or by an obvious chemical equivalent thereof.
16, A process as claimed in claim 1 wherein R1 in the said compound of formula III or IV represents a fur-2-yl group and R2 represents a cyclopentyl group.
17. (6R, 7R)-3-Carbamoyloxymethyl-7-[2-cyclopentyloxy-imino-2-(fur-2-yl) acetamide]ceph-3-em-4-carboxylic acid (syn isomer) and non-toxic salts, biologically acceptable esters, 1-oxides and solvates thereof whenever prepared by a process as claimed in claim 16 or by an obvious chemical equivalent thereof,
18. A process as claimed in claim 1 wherein R1 in the said compound of formula III or IV represents a phenyl group and R2 represents a methyl group.
19. (6R,7R)-3-Carbamoyloxymethyl-7-[2-methoxyimino-2-phenylacetamido]ceph-3-em-4-carboxylic acid (syn isomer) and non-toxic salts, biologically acceptable esters, 1-oxides and solvates thereof whenever prepared by a process as claimed in claim 18 or by an obvious chemical equivalent thereof.
20. A process as claimed in claim 1 wherein R1 in the said compound of formula III or IV represents a phenyl group and R2 represents an ethyl group.
21. (6R,7R)-3-Carbamoyloxymethyl-7-[2-ethoxyimino-2-phenylacetamido]ceph-3-em-4-carboxylic acid (syn isomer) and non-toxic salts, biologically acceptable esters, 1-oxides and solvates thereof whenever prepared by a process as claimed in claim 20 or by an obvious chemical equivalent thereof.
22. A process as claimed in claim 1 wherein R1 and R2 in the said compound of formula III or IV each represent a phenyl group.
23. (6R,7R)-3-Carbamoyloxymethyl-7-[2-phenoxyimino-2-phenylacetamido]ceph-3-em-4-carboxylic acid (syn isomer) and non-toxic salts,biologically acceptable esters, 1-oxides and solvates thereof whenever prepared by a process as claimed in claim 22 or by an obvious chemical equivalent thereo.
24. A process as claimed in claim 1 wherein R1 in the said compound of formula III or IV represents a thien-2-yl group and R2 represents a t-butyl group.
25. (6R,7R) 3-Carbamoyloxymethyl-7-[2-t-butoxyimino-2-(thien-2-yl)acetamido]ceph-3-em-4-carboxylic acid (syn isomer) and non-toxic salts, biologically acceptable esters, 1-oxides and solvates thereof whenever prepared by a process as claimed in claim 24 or by an obvious chemical equivalent thereof,
26. A process as claimed in claim 1 wherein R2 in the said compound of formula III or IV represents a thien-2-yl group and R2 represents a methyl group.
27. (6R,7R)-3-Carbamoyloxymethyl-7-C2-methoxyimino-2-(thien-2-yl)acetamido] ceph-3-em-4-carboxylic acid (syn isomer) and non-toxic salts, biologically acceptable esters, 1-oxides and solvates thereof whenever prepared by a process as claimed in claim 26 or by an obvious chemicai.
equivalent thereof.
equivalent thereof.
28. A process as claimed in claim 1 wherein the said compound of formula I is converted into the sodium salt thereof.
29. A process as claimed in claim 28 in which the said compound of formula I is converted into the sodium salt thereof by reaction with sodium 2-ethylhexanoate.
30. The sodium salt of a compound of formula I (as defined in claim 1) whenever prepared by a process as claimed in claim 28 or claim 29 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3964573A GB1453049A (en) | 1973-08-21 | 1973-08-21 | Cephalosporing antibiotics |
| CA207,441A CA1057283A (en) | 1973-08-21 | 1974-08-20 | 3-carbamoyloxymethyl-7-(2-(fur-2-yl)-2-methoxyiminoacetamido) ceph-3-em-4-carboxylic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1048016A true CA1048016A (en) | 1979-02-06 |
Family
ID=25667666
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA293,802A Expired CA1048016A (en) | 1973-08-21 | 1977-12-23 | Antibiotics |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1048016A (en) |
-
1977
- 1977-12-23 CA CA293,802A patent/CA1048016A/en not_active Expired
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