CA1238911A - Substituted amino thiazole derivatives - Google Patents
Substituted amino thiazole derivativesInfo
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- CA1238911A CA1238911A CA000505254A CA505254A CA1238911A CA 1238911 A CA1238911 A CA 1238911A CA 000505254 A CA000505254 A CA 000505254A CA 505254 A CA505254 A CA 505254A CA 1238911 A CA1238911 A CA 1238911A
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Abstract
Abstract INTERMEDIATE PRODUCTS FOR THE
PREPARATION OF Z-CEPHALOSPORINS
High7y active substantially pure Z-isomers of cephalosporins are produced by the following synthesis:
(IX) (X) (XI) (XII) + (XIII) (XIV) (XV ) ( XVI) (XVII ) (XVIII ) in which R1, R4 and R5 are various organic radicals, R2 is alkoxycarbonyl, Y is Cl, Br or -o-SO2-R5, and X is a conventional cephalosporin substituent.
Many of the intermediates are new, especially in pure Z-form.
PREPARATION OF Z-CEPHALOSPORINS
High7y active substantially pure Z-isomers of cephalosporins are produced by the following synthesis:
(IX) (X) (XI) (XII) + (XIII) (XIV) (XV ) ( XVI) (XVII ) (XVIII ) in which R1, R4 and R5 are various organic radicals, R2 is alkoxycarbonyl, Y is Cl, Br or -o-SO2-R5, and X is a conventional cephalosporin substituent.
Many of the intermediates are new, especially in pure Z-form.
Description
This is a divisional application of Serial Number 415,708 filed November 17, 1982.
The invention relates -to certain intermediate compounds, to processes or their production and to their use for the prep-aration oE certian cephalosporins.
Cephalosporins of the general formula S H H
H N 3-~¢ CO-NH / Sl (I) R Ox N ~5~ X
in which Rl denotes an alkyl or aryl radical, are mentioned in German Patent Of~enlegungschrift 30 37 997, published on May 5, o 1982. These compounds have a broad antibacterial activity both against Gxam-negative and also against Gram-positive bacteria.
According to the process mentioned in this publication, the compounds o:E the :Eormula (I) are prepared according to the Eollowing reaction scheme:
vial Rl CHO Hal . H2N C NH S
1 C2Et .~ C2Et H2N ;C02Et (II) (III) (IV) 1 Alkali (I) Coupling R
l (V) ~;~3~
The invention relates -to certain intermediate compounds, to processes or their production and to their use for the prep-aration oE certian cephalosporins.
Cephalosporins of the general formula S H H
H N 3-~¢ CO-NH / Sl (I) R Ox N ~5~ X
in which Rl denotes an alkyl or aryl radical, are mentioned in German Patent Of~enlegungschrift 30 37 997, published on May 5, o 1982. These compounds have a broad antibacterial activity both against Gxam-negative and also against Gram-positive bacteria.
According to the process mentioned in this publication, the compounds o:E the :Eormula (I) are prepared according to the Eollowing reaction scheme:
vial Rl CHO Hal . H2N C NH S
1 C2Et .~ C2Et H2N ;C02Et (II) (III) (IV) 1 Alkali (I) Coupling R
l (V) ~;~3~
-2- 23189-5448D
However, this process leads only to unsatisfactory yields of compounds of the Eormula (I) in which Rl denotes an alkyl radical.
Thus, for example, for -the case in which Rl denotes an isopropyl radical, on reaction of the compound of formula (III) with thiourea, in addition to the desired compound of formula (IV), the products o the following formulae 2N ~\N 3 C2Et 2 ~\N3`~ C02Et N 3 C2Et (VI) (VII) /
are obtained as by far the largest fraction, due to deconjugation of the double bond and to Michael addition.
Further, when Rl denotes an alkyl radical, when the processes described in the application mentioned (with for example, hydroxybenzotriazole/DCC) are used for the coupling of the acids of formula (V) to the 7-amino-cephalosporanic acids to give the products of the formula (I), isomerisation of the double bond -to give the products of the formula:
2 ~N-3 X (VII~
occurs to a large extent. However, the compounds of the fomula (VIII) generally show only about 1/10 of the biological activity of the compounds of the formula (I).
A process for the preparation of the compounds of the formula (I) has now been found, which proceeds via new intermediate products, and which does not have the abovemen-tioned disadvan-tages.
According to the present invention, there is pro-vided a compound of the general formula R -NH-R3-o~cO l (XI) in which R2 denotes Co2R3, R and R4 can be the same or differen-t and can denote an alkyl, cycloalkyl, alkenyl or cycloalkenyl radical, each of which may have 1 to 5 substituents selected :Erom the group consisting of (Cl-C4) alkyl, (Cl-C4) O-alkyl, halogen, C--N, tr.i[(Cl-C5) alkyl]- silyl and optionally substituted phenyl; or denote an aryl or heterocyclyl radical, each of which may have 1 to 5 substituents, wherein the substituents of the aryl and heterocyclic radicals and the above mentioned phenyl are (Cl-C4) alkyl, (Cl-C4) O-alkyl, (Cl-C4) S-alkyl, alkyloxycarbonyl, halogen, phenyl, nitro or C_N, there being at least one carbon atom separating hetero-atoms as substit-uents of the radicals and double bonds in the alkenyl andcycloalkenyl radicals from the oxycarbonyl group, Rl represents an alkyl or cycloalkyl radical, each _4_ ox which may have 1 to 5 substituents selected from the group consisting oE (Cl-C6) alkyl, (Cl-C6) O-alkyl, (Cl-C6) S-alkyl, (Cl-C6) N-al~yl, (Cl-C6) alkyloxycarbonyl or option-ally substituted phenyl; or Rl represents an aryl or hetero-cyclic radical, each of which may have 1 to 5 substituents, wherein the substituents of the aryl and heterocyclic radicals and the above mentioned phenyl are selected from -the group consisting of (Cl-C6) alkyl, (Cl-C6) O~alkyl, (Cl-C6) S-alkyl, alkyloxycarbonyl, halogen or phenyl.
The present invention also provides a process for producing a compound of the above formula, which process comp.rises reacting a compound of formula (X) R2-~=< 3~
CO
o R3 (X) in which R , R3 and R~ are as defined above, in a solvent for the reactants, at a low temperature, with a base and then with an aldehyde of the general formula Rl-CHO, in which Rl is as defined above.
The compound of the present invention is useful as an intermediate for the production of a compound of -the ~3~91~
general formula ~3~Rl on in which C02H
l represents an alkyl or cycloalkyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (Cl-C6) alkyl, (Cl-C6) O-alkyl, (Cl-C6) S-alkyl, (Cl-C6) N-alkyl, (Cl-C6) alkyloxycarbonyl or optionally sub-stituted phenyl; or Rl represents an aryl or heterocyclic radical, each of which may have 1 to 5 substituents wherein the substituents of the aryl and heterocyclic radicals and the above mentioned phenyl are selected from the group consisting of (Cl-C6~ alkyl, (Cl-C6) O-alkyl, (Cl-C6) S-alkyl, alkyloxy-carbonyl, halogen or phenyl, and X represents a hydrogen, (Cl-C4) alkyl, halogen, (Cl-C4) alkoxy,hydroxymethyl,formyl-oxymethyl, ~(Cl-C4) alkyl]- carbonyloxymethyl, aminocarbonyl-oxymethyl, pyridiniummethyl, 4-carbamoylpridiniummethyl or heterocyclythiomethyl radical wherein heterocycly represents a radical of the formula No ' ON R7 or in which R6 denotes hydrogen, methyl, 2-dimethylaminoethyl, carboxymethyl or sulphomethyl and, R denotes hydrogen or methyl The overall process for producing the compound of formula (I) may be described as follows a) a compound of the general formula ~<\N~3\/ C02R
(IX) in which R3 and R4 can be the same or different and can denote an alkyl, cycloa:lkyl, alkenyl, or cycloa].kenyl radical., each of which may have 1 to 5 substituents selected from the group consisting of ~Cl-C4) alkyl, (Cl-C4) O-alkyl, halogen, C-N, -tri~(Cl-C5) alkyl]- silyl and optionally substi-tuted phenyl;
or denote an aryl or heterocyclyl radical, each of which may have 1 to 5 substituents, wherein the subs-tituents of the aryl and heterocyclic radicals and the above mentioned phenyl are (Cl-C4) alkyl, (Cl-C4) O alkyl, (Cl-C4) S-alkyl, alkyloxycarbonyl, halogen, phenyl, nitro or C-N, there being at least one carbon atom separating hetero-atoms as substituents ox the radicals and double bonds in the alkenyl and cycloalkenyl radicals from the oxycarbonyl group, is reacted with a pyrocarbonic acid ester of the general formula ~23~
R3-o-Co-o-Co-o-R (IXa) in whlch R3 has the meaning given above, ~3~
b) the product of the general formula R2-N=< C02R4 (X) Co R
in which R2 denotes C02R3, and R3 and R4 have the meanings given above, thus obtained is initially reacted with a suitable base and then with an aldehyde of the general formula Rl-CHO, in which Rl has the meaning given above, to give a compound of the general formula R -NH N 02R4 (XI) R3-o co oJ~ Rl in which Rl, R2, R3 and R4 have the meanings given above, which c) is then treated with a base to give a compound of the general formula R -NH I\ Co2R4 (XII) in which Rl, R2 and R4 have the meanings given above, d) the Z-acid of the general formula Rl (XIII) in which Rl and R2 have the meanings given above, or R2 may be hydrogen, is then obtained from the compound of formula (XII~
by separation of the Z and E isomers and subsequent saponifi-cation or by selective saponification, and e) the Z-acid of formula (XIII) is -then reacted with a compound of the general formula in which Z denotes a chlorine or bromine atom or -o-So2-R5, and R denotes an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or hete-tocyclyl radical, to give a compound of the general formula R -NH- Co_o_s02-R
l ~X~I) R5 and Z have the meanings given above, which : f) is then coupled with a cephalosporanic acid of the general formula ox - No 02H (XVII) in which X has the meaning given above, and g) the protective group R2 is then split off unless, R2 is hydrogen.
The process according to the present invention for the production of compounds of formula (I) may be summarised in the following reac-tion scheme:
~2~
2(R -O-CO)2o S
Co2R4 No Co2R4 2 R1 CHO
(IX) R3 R2HN 3 X co2R4 R2NHi selective l2 saponification (XI) (XII) (XIII) (XIV) l. Si.lylation Separation (XIV)~ (XIII) -I (XIV) --I (XIII) 2. Base l. Base S
(XIII) - - R -NH 5 2. XSo2R5 N CO-O S02 (XV) (XVI) (XVI) + H2N R2-NH CO-NH
: (XVII) (XVIII) (I) Further details of the reaction steps for the prod-uction of compounds of formula (I) are given later in the specification.
Particularly preferred compounds of formula (X) according to the invention are those in which, R denotes o-CO-C (CH3)3 R denotes C(CEI3)3 and R4 denotes opti.onally substituted alkyl radical with 1 to 15 carbon atoms, an optionally substituted alkenyl radical with 3 to 15 carbon atoms, an optionally sub-stituted cycloalkyl radical with 3 to 10 carbon atoms, an optionally substituted cycloalkenyl radical with 5 to 10 carbon atoms, an optionally substituted aryl radical with 1 to 3 rings or an optionally substituted heterocyclyl radical with 1 to 3 rings, which can contain up to 5 hetero atoms selected from nitrogen, sulphur and oxygen.
Especially preferred compo~mds of formula (X) according to:the invention are those in which : R2 denotes a tert.-butoxycarbonyl radical, R denotes a tert.-butyl radical, and $~
R4 denotes a methyl, ethyl, tert. butyl or trimethyl-silyl ethyl radical.
The alkyl, alkenyl, cycloalkyl and cylcoalkenyl, radicals mentioned can be substituted by alkyl radicals with 1 to 4 carbon atoms, O-alkyl radicals with 1 to 4 carbon atoms, halogen (preferably chlorine), optionally substituted phenyl radicals, C-N and tri-(C~ to C5 alkyl)-silyl.
All the aryl and hererocyclyl radicals, including the phenyl radicals mentioned, can be substituted by alkyl~ O-alkyl, S-alkyl, alkyloxycarbonyl, halogen and phenyl radicals, it being possible for all alkyl radicals to have 1 to 4 carbon atoms, and by nitro and C-N.
When the radicals R3 and/or R4 are substituted, preferably by the abovementioned substituents, they can carry 1 to 5, preferably 1 or 2, substituents.
It is particularly advantageous for the process when R2 denotes a protective group which is stable to base and removable in acid, such as tert.-butoxy-carbonyl, and when R4 denotes a radical which is saponifiable by base, such as methyl or ethyl.
The compounds of the formula (IX) used in the process according to the invention for the production of compounds of formula (X) are known in themselves (see, for example, E. Campaine and T.P. Selby, J. Heterocycl. Chem. 17 (1980)).
Particularly suitable solvents for the production of compounds ox formula (X) are aprotic polar solvents such as 'I
~3~
acetonitrile, dimethylformamide, hexamethylphosphoric acid triamide or dimethyl sulphoxide, particularly the latter two.
The reaction takes place particularly advantageously at room temperature or a lower temperatures, for example, between 10 and -50C, the components generally being allowed to react with one another for 1 to 7 days. The pyrocarbonic acid ester of formula (IXa) is generally employed in 2 to 2.5 mol-equivalents.
Other solvents, higher temperatures or acylation catalysts, such as 4-dimethylaminopyridine, strongly favor the formation of the undesired products of the formula N CO R4 (XIX) o In the process according to the invention for the preparation of the novel compounds of the formula (XI) generally the compound of the Eormula (X) is treated with 1 to 1.1 equivalents oE a base in a solvent Eor the reactants at a low temperature, and then 1 to 1.2 equivalents oE an aldehyde of the formula Rl-CHO is added.
Solvents which may be used for this reaction are, for example, dimethylformamide, diethyl ether, tetrahydrofuran or toluene- preferably tetrahydrofuran - and bases which may be used are alcoholates, hydrides, amides or organometallics - preferably potassium tert.-butylate, lithium diisopropylamide and butyllithium. To carry out the reaction, the base is generally .
9~.
added, at -50 to -80~C, to a solution of the compound of formula (X), and then the aldehyde is added at -50 to -60C, and the mixture is stirred at -50 to -60C for about 12 hours. To isolate the product of the formula (XI), the mixture may be neutralised and worked up.
Preferred compounds of the formula (XI) are those in which R2 to R4 have the meanings given above and Rl denotes an optionally substituted alkyl radical with 1 to 15 carbon atoms, an optionally substituted cycloalkyl .radical with 3 to 10 carbon atoms, an optionally substituted carbocyclic or heterocyclic aryl radical with 1 or 2 rings or an optionally substituted hetero-cyclic radical with 1 to 3 rings, which can contain up to 5 heteroatoms selected from nitrogen, sulphur and oxygen atoms.
Suitable substituents for alkyl and cycloalkyl are alkyl radicals with 1 to 6 carbon atoms, O-alkyl radicals with 1 to 6 carbon atoms, S-alkyl radicals with 1 to 6 carbon atoms, N-alkyl radicals with 1 to 6 carbon atoms, alkyloxycarbonyl radicals with 1 to 6 carbon atoms and optionally substituted phenyl radicals.
All the aryl and heterocyclyl radicals, including the phenyl radicals mentioned, can be substituted by alkyl, O-alkyl, S-alkyl, alkyloxycarbonyl, halogen, preferably chlorine, and phenyl radicals, it being possible for all the alkyl radicals to carry 1 to 6 carbon atoms.
8~
If Rl represents a substituted (preferably by the abovementioned substituents) radical, 1 to 5, preferably 1 or 2, substituents are preferred.
It is particularly preferred that Rl denotes an alkyl radical with 1 to 10 carbon atoms or a cycloalkyl radical with
However, this process leads only to unsatisfactory yields of compounds of the Eormula (I) in which Rl denotes an alkyl radical.
Thus, for example, for -the case in which Rl denotes an isopropyl radical, on reaction of the compound of formula (III) with thiourea, in addition to the desired compound of formula (IV), the products o the following formulae 2N ~\N 3 C2Et 2 ~\N3`~ C02Et N 3 C2Et (VI) (VII) /
are obtained as by far the largest fraction, due to deconjugation of the double bond and to Michael addition.
Further, when Rl denotes an alkyl radical, when the processes described in the application mentioned (with for example, hydroxybenzotriazole/DCC) are used for the coupling of the acids of formula (V) to the 7-amino-cephalosporanic acids to give the products of the formula (I), isomerisation of the double bond -to give the products of the formula:
2 ~N-3 X (VII~
occurs to a large extent. However, the compounds of the fomula (VIII) generally show only about 1/10 of the biological activity of the compounds of the formula (I).
A process for the preparation of the compounds of the formula (I) has now been found, which proceeds via new intermediate products, and which does not have the abovemen-tioned disadvan-tages.
According to the present invention, there is pro-vided a compound of the general formula R -NH-R3-o~cO l (XI) in which R2 denotes Co2R3, R and R4 can be the same or differen-t and can denote an alkyl, cycloalkyl, alkenyl or cycloalkenyl radical, each of which may have 1 to 5 substituents selected :Erom the group consisting of (Cl-C4) alkyl, (Cl-C4) O-alkyl, halogen, C--N, tr.i[(Cl-C5) alkyl]- silyl and optionally substituted phenyl; or denote an aryl or heterocyclyl radical, each of which may have 1 to 5 substituents, wherein the substituents of the aryl and heterocyclic radicals and the above mentioned phenyl are (Cl-C4) alkyl, (Cl-C4) O-alkyl, (Cl-C4) S-alkyl, alkyloxycarbonyl, halogen, phenyl, nitro or C_N, there being at least one carbon atom separating hetero-atoms as substit-uents of the radicals and double bonds in the alkenyl andcycloalkenyl radicals from the oxycarbonyl group, Rl represents an alkyl or cycloalkyl radical, each _4_ ox which may have 1 to 5 substituents selected from the group consisting oE (Cl-C6) alkyl, (Cl-C6) O-alkyl, (Cl-C6) S-alkyl, (Cl-C6) N-al~yl, (Cl-C6) alkyloxycarbonyl or option-ally substituted phenyl; or Rl represents an aryl or hetero-cyclic radical, each of which may have 1 to 5 substituents, wherein the substituents of the aryl and heterocyclic radicals and the above mentioned phenyl are selected from -the group consisting of (Cl-C6) alkyl, (Cl-C6) O~alkyl, (Cl-C6) S-alkyl, alkyloxycarbonyl, halogen or phenyl.
The present invention also provides a process for producing a compound of the above formula, which process comp.rises reacting a compound of formula (X) R2-~=< 3~
CO
o R3 (X) in which R , R3 and R~ are as defined above, in a solvent for the reactants, at a low temperature, with a base and then with an aldehyde of the general formula Rl-CHO, in which Rl is as defined above.
The compound of the present invention is useful as an intermediate for the production of a compound of -the ~3~91~
general formula ~3~Rl on in which C02H
l represents an alkyl or cycloalkyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (Cl-C6) alkyl, (Cl-C6) O-alkyl, (Cl-C6) S-alkyl, (Cl-C6) N-alkyl, (Cl-C6) alkyloxycarbonyl or optionally sub-stituted phenyl; or Rl represents an aryl or heterocyclic radical, each of which may have 1 to 5 substituents wherein the substituents of the aryl and heterocyclic radicals and the above mentioned phenyl are selected from the group consisting of (Cl-C6~ alkyl, (Cl-C6) O-alkyl, (Cl-C6) S-alkyl, alkyloxy-carbonyl, halogen or phenyl, and X represents a hydrogen, (Cl-C4) alkyl, halogen, (Cl-C4) alkoxy,hydroxymethyl,formyl-oxymethyl, ~(Cl-C4) alkyl]- carbonyloxymethyl, aminocarbonyl-oxymethyl, pyridiniummethyl, 4-carbamoylpridiniummethyl or heterocyclythiomethyl radical wherein heterocycly represents a radical of the formula No ' ON R7 or in which R6 denotes hydrogen, methyl, 2-dimethylaminoethyl, carboxymethyl or sulphomethyl and, R denotes hydrogen or methyl The overall process for producing the compound of formula (I) may be described as follows a) a compound of the general formula ~<\N~3\/ C02R
(IX) in which R3 and R4 can be the same or different and can denote an alkyl, cycloa:lkyl, alkenyl, or cycloa].kenyl radical., each of which may have 1 to 5 substituents selected from the group consisting of ~Cl-C4) alkyl, (Cl-C4) O-alkyl, halogen, C-N, -tri~(Cl-C5) alkyl]- silyl and optionally substi-tuted phenyl;
or denote an aryl or heterocyclyl radical, each of which may have 1 to 5 substituents, wherein the subs-tituents of the aryl and heterocyclic radicals and the above mentioned phenyl are (Cl-C4) alkyl, (Cl-C4) O alkyl, (Cl-C4) S-alkyl, alkyloxycarbonyl, halogen, phenyl, nitro or C-N, there being at least one carbon atom separating hetero-atoms as substituents ox the radicals and double bonds in the alkenyl and cycloalkenyl radicals from the oxycarbonyl group, is reacted with a pyrocarbonic acid ester of the general formula ~23~
R3-o-Co-o-Co-o-R (IXa) in whlch R3 has the meaning given above, ~3~
b) the product of the general formula R2-N=< C02R4 (X) Co R
in which R2 denotes C02R3, and R3 and R4 have the meanings given above, thus obtained is initially reacted with a suitable base and then with an aldehyde of the general formula Rl-CHO, in which Rl has the meaning given above, to give a compound of the general formula R -NH N 02R4 (XI) R3-o co oJ~ Rl in which Rl, R2, R3 and R4 have the meanings given above, which c) is then treated with a base to give a compound of the general formula R -NH I\ Co2R4 (XII) in which Rl, R2 and R4 have the meanings given above, d) the Z-acid of the general formula Rl (XIII) in which Rl and R2 have the meanings given above, or R2 may be hydrogen, is then obtained from the compound of formula (XII~
by separation of the Z and E isomers and subsequent saponifi-cation or by selective saponification, and e) the Z-acid of formula (XIII) is -then reacted with a compound of the general formula in which Z denotes a chlorine or bromine atom or -o-So2-R5, and R denotes an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or hete-tocyclyl radical, to give a compound of the general formula R -NH- Co_o_s02-R
l ~X~I) R5 and Z have the meanings given above, which : f) is then coupled with a cephalosporanic acid of the general formula ox - No 02H (XVII) in which X has the meaning given above, and g) the protective group R2 is then split off unless, R2 is hydrogen.
The process according to the present invention for the production of compounds of formula (I) may be summarised in the following reac-tion scheme:
~2~
2(R -O-CO)2o S
Co2R4 No Co2R4 2 R1 CHO
(IX) R3 R2HN 3 X co2R4 R2NHi selective l2 saponification (XI) (XII) (XIII) (XIV) l. Si.lylation Separation (XIV)~ (XIII) -I (XIV) --I (XIII) 2. Base l. Base S
(XIII) - - R -NH 5 2. XSo2R5 N CO-O S02 (XV) (XVI) (XVI) + H2N R2-NH CO-NH
: (XVII) (XVIII) (I) Further details of the reaction steps for the prod-uction of compounds of formula (I) are given later in the specification.
Particularly preferred compounds of formula (X) according to the invention are those in which, R denotes o-CO-C (CH3)3 R denotes C(CEI3)3 and R4 denotes opti.onally substituted alkyl radical with 1 to 15 carbon atoms, an optionally substituted alkenyl radical with 3 to 15 carbon atoms, an optionally sub-stituted cycloalkyl radical with 3 to 10 carbon atoms, an optionally substituted cycloalkenyl radical with 5 to 10 carbon atoms, an optionally substituted aryl radical with 1 to 3 rings or an optionally substituted heterocyclyl radical with 1 to 3 rings, which can contain up to 5 hetero atoms selected from nitrogen, sulphur and oxygen.
Especially preferred compo~mds of formula (X) according to:the invention are those in which : R2 denotes a tert.-butoxycarbonyl radical, R denotes a tert.-butyl radical, and $~
R4 denotes a methyl, ethyl, tert. butyl or trimethyl-silyl ethyl radical.
The alkyl, alkenyl, cycloalkyl and cylcoalkenyl, radicals mentioned can be substituted by alkyl radicals with 1 to 4 carbon atoms, O-alkyl radicals with 1 to 4 carbon atoms, halogen (preferably chlorine), optionally substituted phenyl radicals, C-N and tri-(C~ to C5 alkyl)-silyl.
All the aryl and hererocyclyl radicals, including the phenyl radicals mentioned, can be substituted by alkyl~ O-alkyl, S-alkyl, alkyloxycarbonyl, halogen and phenyl radicals, it being possible for all alkyl radicals to have 1 to 4 carbon atoms, and by nitro and C-N.
When the radicals R3 and/or R4 are substituted, preferably by the abovementioned substituents, they can carry 1 to 5, preferably 1 or 2, substituents.
It is particularly advantageous for the process when R2 denotes a protective group which is stable to base and removable in acid, such as tert.-butoxy-carbonyl, and when R4 denotes a radical which is saponifiable by base, such as methyl or ethyl.
The compounds of the formula (IX) used in the process according to the invention for the production of compounds of formula (X) are known in themselves (see, for example, E. Campaine and T.P. Selby, J. Heterocycl. Chem. 17 (1980)).
Particularly suitable solvents for the production of compounds ox formula (X) are aprotic polar solvents such as 'I
~3~
acetonitrile, dimethylformamide, hexamethylphosphoric acid triamide or dimethyl sulphoxide, particularly the latter two.
The reaction takes place particularly advantageously at room temperature or a lower temperatures, for example, between 10 and -50C, the components generally being allowed to react with one another for 1 to 7 days. The pyrocarbonic acid ester of formula (IXa) is generally employed in 2 to 2.5 mol-equivalents.
Other solvents, higher temperatures or acylation catalysts, such as 4-dimethylaminopyridine, strongly favor the formation of the undesired products of the formula N CO R4 (XIX) o In the process according to the invention for the preparation of the novel compounds of the formula (XI) generally the compound of the Eormula (X) is treated with 1 to 1.1 equivalents oE a base in a solvent Eor the reactants at a low temperature, and then 1 to 1.2 equivalents oE an aldehyde of the formula Rl-CHO is added.
Solvents which may be used for this reaction are, for example, dimethylformamide, diethyl ether, tetrahydrofuran or toluene- preferably tetrahydrofuran - and bases which may be used are alcoholates, hydrides, amides or organometallics - preferably potassium tert.-butylate, lithium diisopropylamide and butyllithium. To carry out the reaction, the base is generally .
9~.
added, at -50 to -80~C, to a solution of the compound of formula (X), and then the aldehyde is added at -50 to -60C, and the mixture is stirred at -50 to -60C for about 12 hours. To isolate the product of the formula (XI), the mixture may be neutralised and worked up.
Preferred compounds of the formula (XI) are those in which R2 to R4 have the meanings given above and Rl denotes an optionally substituted alkyl radical with 1 to 15 carbon atoms, an optionally substituted cycloalkyl .radical with 3 to 10 carbon atoms, an optionally substituted carbocyclic or heterocyclic aryl radical with 1 or 2 rings or an optionally substituted hetero-cyclic radical with 1 to 3 rings, which can contain up to 5 heteroatoms selected from nitrogen, sulphur and oxygen atoms.
Suitable substituents for alkyl and cycloalkyl are alkyl radicals with 1 to 6 carbon atoms, O-alkyl radicals with 1 to 6 carbon atoms, S-alkyl radicals with 1 to 6 carbon atoms, N-alkyl radicals with 1 to 6 carbon atoms, alkyloxycarbonyl radicals with 1 to 6 carbon atoms and optionally substituted phenyl radicals.
All the aryl and heterocyclyl radicals, including the phenyl radicals mentioned, can be substituted by alkyl, O-alkyl, S-alkyl, alkyloxycarbonyl, halogen, preferably chlorine, and phenyl radicals, it being possible for all the alkyl radicals to carry 1 to 6 carbon atoms.
8~
If Rl represents a substituted (preferably by the abovementioned substituents) radical, 1 to 5, preferably 1 or 2, substituents are preferred.
It is particularly preferred that Rl denotes an alkyl radical with 1 to 10 carbon atoms or a cycloalkyl radical with
3 to 10 carbon atoms, which, in each case, can be substituted ; by 1 or 2 alkyl radicals with 1 to 6 carbon atoms and~or 1 or 2 phenyl radicals.
It is unnecessary to isolate the compounds of the formula (XI) on carrying out the process according to the invention for the preparation of the compounds of the formula (I). On the contrary, it is advantageous to convert the former directly into the compounds of the formula (XII) in situ. For this purpose, it is generally sufficient to allow the mixture after addition of the aldehyde Rl-C~IO to warm to room temperature and to stir it over-night at room temperature. If the elimination reaction of the compound of formula (XI) to give the compound of formula (XII) is not then complete, 1 to 1.2 equivalents of a base (such as a hydride, an alcoholate or an amide - particularly potassium tert.-butylate) is added and the mixture stirred at room temperature forabout 10 hours.
If, on the other hand, the compounds of the formula (XI) had been previously isolated, for the preparation of the compounds of the formula (XII~, 1.1 to 2.2 equivalents of a base are added to a solution of the compounds of the formula (XI) in a suitable solvent.
~238~
The solvent and the base used can be those mentioned for the reaction of the compound of formula (X) to give the compound of ormula (XI), preferably tetrahydrofuran and potassium tert.-butylate.
The compounds of the formula (XII) are obtained as mixtures of E/Z isomers, which, for example, may be separated by recrystallisation or by column chromatography on silica gel.
Rl, R2 and R4 in the compounds of the formula (XII) have the same meaning as in the compounds of the formula (XI).
For the preparation of the Z-carboxylic acids of the formula (XIII), the Z-esters, which can be obtained by separation of the mixture of the E/Z isomers of the esters of the formula (XII), can be saponifiedO However, it is more favourable for carrying out the process for the preparation of the compounds of ; the formula (I) to saponify selectively the mixture of E/Z isomers of the esters of the formula (XII) in such a manner that the E-esters are first converted, under mild conditions, into the E-carboxylic acids of the formula (XIV), and separated out and then the remaining Z-esters, in which the ester group is more sterically shielded, are saponified under more drastic conditions to give the Z-carboxylic acids of the formula (XIII).
The mild conditions for saponification, which lead to the E-carboxylic acids (XIV), are, for example, ethanol/2 N sodium hydroxide solution/room temperature/24 hours. It is advantageous to carry out the saponification in such a manner that, after conversion of the compounds of the formula (XI) into the compounds ., of the formula (XII), 2 N sodium hydroxide solution is directly added to the reaction mixture and this is stirred at room temperature or with sliyht heating until the E-esters are saponified. Thereafter the Z-esters are removed from the mixture by extraction under alkaline conditions and they are saponified under more drastic conditions.
More drastic conditions for saponification are, for example, ethanol/2 N sodium hydroxide solution/24 hours reflux-possibly even more concentrated sodium hydroxide solution or higher-boiling solvents, for example dioxane.
The desired Z-carboxylic acids of the formula (XIII)and the E-carboxylic acids of the formula (XIV) are obtained in this manner. The latter may be converted back, after conversion into the silyl esters, for example, with bistrimethylsilylacetamide, in a suitable solvent, for example, diethyl ether or tetrahydrofuran, with a base, such as potassium tert.-butylate and subsequent hydrolysis with dilute acid into mixture of the E-carboxylic acids of the formula (XIV) and the Z-carboxylic acids of the formula (XIII).
The z-carboxylic acids of the formula (XIII) may be isolated in pure form from this mixture of E/Z isomers, for example by crystallisation or by separation on an ion exchanger.
Separation with the aid of ion exchangers is simple, since the Z-carboxylic acids of the formula (XIII) have a much higher acidity than the E-carboxylic acids of the formula (XIV). Thus, the E-carboxylic acids of the formula (XIV) are eluted just with ~23~
methanol from weakly basic ion exchanters, whilst, in contrast, the Z-carboxylic acids of the formula (XIII) are only eluted after addition of electrolytes, fox example, 2 N sodium hydroxide solution. Weakly basic ion exchangers are to be understood as including those ion exchangers in solid or liquid form which contain tertiary amino groups, for example Lewatit MP 62.
Rl and R2 in the compounds of the formula (XIII) and (XIV) have the same meaning as in the compounds of the formula (XII). In addition, R2 can be a hydrogen atom, if, before saponification, R2 in thecompounds of the formula (XII) was a protective group saponifiable by alkali (such as a methyloxycar-bonyl group). However, it is more advantageous for carrying out the process for the process for the preparation of the compounds of -the formula I) if R2 is a protective group which is stable under the conditions of saponification, preferably tert.-butyloxycarbonyl.
A large number of methods, which in the last analysis are derived from peptide chemistry, are known in cephalosporin chemistry for coupling carboxylic acids to 7-aminocephalosporanic acids. However, these methods fail on attempting to form the amide bond between the Z-carboxylic acids of the formula (XIII~ and the cephalosporanic acids of the formula (XVII~, or they only lead to very poor yields, particularly when Rl is an alkyl radical.
The reasons for this are to be found in the large steric hindrance of the carboxyl group in the carboxylic acids of the formula (XIII) by the radical Rl and in the pronounced tendency of the radical Rl , I, ;~ :;
to isomeri.se into the E-form after activation of the carboxyl function, for example, conversion lnto the acid chloride. Then, after reaction with the 7-aminocephalosporanic acids of the formula (XVII), the desired compounds of the formula (XVIII) are not obtained, but rather the compounds of the formula 2 S (XXI) or mixtures of the two.
It has now been found that the Z-carboxylic acids of the formula (XIII) can be activated in a simple, mild and inexpensive manner without the abovementioned disadvantages by converting them into the mixed anhydrides of the formula (XVI) at low temperatures.
As indicated previously, these compounds of the formula (XVI) are new and form a further subject of the present invention.
In these compounds R5, when optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl radical, can be substituted by a substituent selected from halogen, alkyl, aryl, O-alkyl, S-alkyl, CN, alkoxycarbonyl and nitro. Expecially preferred compounds of formula (XVI) are those, in which R5 denotes an alkyl radical with 1 to 10 carbon atoms, which is optionally substituted by fluorine, chlorine, CN, phenyl, alkyl-oxycarbonyi, alkyloxy or alkyl (it being preferred for ~2;3lS ~.~.
-21- 23189-5~48D
the al~yl groups of these substituents to carry 1 to 4 carbon atoms); or denotes a phenyl radical, which is optionally substituted by fluorine, chlorine, bromine, CN, alkyl, alkyloxy, alkylthio and alkyloxycarbonyl (it being preferred for the alkyl groups of these sub-stituents to carry 1 to 4 carbon atoms), and nitro, trifluoromethyl and phenyl.
When R5 is substituted, there are preferably 1 to 3 substituents, preferably those mentioned, present.
In very particularly preferred compounds of formula (XVI) R5 represents a methyl or p-tolyl radical.
This type of mixed anhydrides of the formula (XVI) is preferably prepared by dissolving the carboxylic acid of formula (XIII) and a suitable amine in equimolar amounts in a suitable solvent and allowing them to react with 1 to 1.05 equivalents of a sulphonic acid derivative oE the formula (XV).
Suitable solvents here are any of the solvents which are stable under the reaction conditions (such as diethyl ether, tetrahydrofuran, acetonitrile, acetone, methylene chloride, chloro-0 form or dimethylformamide).
Suitable amines are tertiary amines (such as triethylamine or tributylamine) and also sterically hindered secondary amines (such as diisopropylamine).
The reactions can be carried out at a temperature between -80C and room temperature, low temperatures preventing isomer-isation of the substituents on the double bond. The reactions are advantageously carried out at -20 to -50C with a duration of reaction of 10 minutes to 6 hours.
The compounds of the formula (XVI) can be isolated by using, for example, tetrahydrofuran as the solvent and triethyl-amine as the base, Eiltering off under suction the triethylamine hydrochloride formed anddistilling off the solvent in vacuo.
However, it is more advantageous to react the solutions of the compounds of the formula (XVI) obtained directly with the cephalosporanic acids of the formula (XVII). For this purpose, the cephalosporanic acids of the formula (XVII) are dissolved in a suitable solvent with 2 to 4 equivalents of an amine, the solution is pre-cooled to the desired subsequent reaction temperature and this solution at this temperatue is added to the solution of the compound of the formula (XVI) described above. In order to prevent isomerisation of the radical Rl in the reaction products of the formula (XVIII), the reaction is advantageously carried out at -60 to -30C and the mixture is allowed to reach room temperature overnight.
The amines and solvents mentioned for the preparation of the compounds of the formula (XVI) can be used to dissolve the cephalosporanic acids of the formula (XVII). If solutions with satisfactory concentrations of the cephalosporanic acids of formula (XVII) cannot be obtained in this manner, it is obviously also possible to employ the readily soluble esters of the compounds of the formula (XVII), which are sufficiently well-known from cephalosporin chemistry such assilyl~ tert.-butyl or diphenyl-.
~23~39~
-22a- 23189-5448D
methyl esters).
After work-up, the compounds of the formula (XVIII) are obtained, in which R1 and R2 exhibit the meanings mentioned for the compounds of the formula (XVI) and X represents a group suitable as a cephalospori.n substituent for example denotes hydrogen, Cl to C4 alkyl, halogen, Cl to C4 alkoxy, hydroxymethyl, formyloxymethyl, (Cl to C4 alkyl)-carbonyloxymethyl, aminocarbonyloxymethyl, pyridiniummethyl, 4-carbamoylpyridiniummethyl or heterocyclylthio-methyl ("heterocyclyl" preferably representing a radical of the formula CH3 N -N r-N N -N N--~
ON ' So R , S
in which R6 denotes hydrogen, methyl, 2-dimethylaminoethyl, carboxymethyl or sulphomethyl and R7 denotes hydrogen or methyl).
Preferred compounds of formula (XVIII) are those, in which X denotes hydrogen, chlorine, methoxy, hydroxy-methyl, acetyloxymethyl, aminocarbonyloxymethyl, pyridiniurnmethyl \\ or CH2-S US
l l ~CH3 CH3 CH2 CH2 No CH
~3~
-22b- 23189-5448D
The compound of the formula (I), in which Al and X
exhibit the meaning mentioned for the compounds of the formula (XVIII), is obtained from the compounds of the formula (XVIII) after splitting off the protective group R . As already mentioned for the compounds of the formula (X), it is extremely advantageous for the complete reaction sequence for the preparation of the compounds of the formula (I) to be carried out directly from the compounds of the formula (X) if R2 is a protective group stable in base which may be selectively split off, such as tert.-butyloxycarbo_yl (split off with trifluoroacetic acid).
The process according to the present invention and the production of compounds according to the invention are illustrated by the following Examples.
Example 1 Ethyl2-tert.-butoxycarbonylimino-3-tert,-butoxycarbonyll-4-thiazolin-4-yiacetate 186 g (l mol) of e-thyl 2-aminothiazol-4-ylacetate, 300 ml of dimethyl sulphoxide and 500 g (2.3 mol) of 98% di-tert.-butyl pyrocarbonate are stirred at room temperature for 7 days.
Then 3.5 1 of ice-water are added with ice cooling at max. 20C, the mixture is stirred for 30 minutes, the precipitate is filtered off under suction, is washed with 2 l of water and is taken up in 2 l of methylene chloride. The water is separated off, the methyl-ene chloride phase is dried over Na2SO4 and concentrated on a rotary evaporator. The oil obtained is taken up immediately (before crystallisation starts) for crystallisation in 2 l of petroleum ether. Yield 302 g (78~), melting point 90C.
Example 2 Methyl2--tert.-butoxycarbonylimino-3-tert.-buto-~ycarbonnyl-
It is unnecessary to isolate the compounds of the formula (XI) on carrying out the process according to the invention for the preparation of the compounds of the formula (I). On the contrary, it is advantageous to convert the former directly into the compounds of the formula (XII) in situ. For this purpose, it is generally sufficient to allow the mixture after addition of the aldehyde Rl-C~IO to warm to room temperature and to stir it over-night at room temperature. If the elimination reaction of the compound of formula (XI) to give the compound of formula (XII) is not then complete, 1 to 1.2 equivalents of a base (such as a hydride, an alcoholate or an amide - particularly potassium tert.-butylate) is added and the mixture stirred at room temperature forabout 10 hours.
If, on the other hand, the compounds of the formula (XI) had been previously isolated, for the preparation of the compounds of the formula (XII~, 1.1 to 2.2 equivalents of a base are added to a solution of the compounds of the formula (XI) in a suitable solvent.
~238~
The solvent and the base used can be those mentioned for the reaction of the compound of formula (X) to give the compound of ormula (XI), preferably tetrahydrofuran and potassium tert.-butylate.
The compounds of the formula (XII) are obtained as mixtures of E/Z isomers, which, for example, may be separated by recrystallisation or by column chromatography on silica gel.
Rl, R2 and R4 in the compounds of the formula (XII) have the same meaning as in the compounds of the formula (XI).
For the preparation of the Z-carboxylic acids of the formula (XIII), the Z-esters, which can be obtained by separation of the mixture of the E/Z isomers of the esters of the formula (XII), can be saponifiedO However, it is more favourable for carrying out the process for the preparation of the compounds of ; the formula (I) to saponify selectively the mixture of E/Z isomers of the esters of the formula (XII) in such a manner that the E-esters are first converted, under mild conditions, into the E-carboxylic acids of the formula (XIV), and separated out and then the remaining Z-esters, in which the ester group is more sterically shielded, are saponified under more drastic conditions to give the Z-carboxylic acids of the formula (XIII).
The mild conditions for saponification, which lead to the E-carboxylic acids (XIV), are, for example, ethanol/2 N sodium hydroxide solution/room temperature/24 hours. It is advantageous to carry out the saponification in such a manner that, after conversion of the compounds of the formula (XI) into the compounds ., of the formula (XII), 2 N sodium hydroxide solution is directly added to the reaction mixture and this is stirred at room temperature or with sliyht heating until the E-esters are saponified. Thereafter the Z-esters are removed from the mixture by extraction under alkaline conditions and they are saponified under more drastic conditions.
More drastic conditions for saponification are, for example, ethanol/2 N sodium hydroxide solution/24 hours reflux-possibly even more concentrated sodium hydroxide solution or higher-boiling solvents, for example dioxane.
The desired Z-carboxylic acids of the formula (XIII)and the E-carboxylic acids of the formula (XIV) are obtained in this manner. The latter may be converted back, after conversion into the silyl esters, for example, with bistrimethylsilylacetamide, in a suitable solvent, for example, diethyl ether or tetrahydrofuran, with a base, such as potassium tert.-butylate and subsequent hydrolysis with dilute acid into mixture of the E-carboxylic acids of the formula (XIV) and the Z-carboxylic acids of the formula (XIII).
The z-carboxylic acids of the formula (XIII) may be isolated in pure form from this mixture of E/Z isomers, for example by crystallisation or by separation on an ion exchanger.
Separation with the aid of ion exchangers is simple, since the Z-carboxylic acids of the formula (XIII) have a much higher acidity than the E-carboxylic acids of the formula (XIV). Thus, the E-carboxylic acids of the formula (XIV) are eluted just with ~23~
methanol from weakly basic ion exchanters, whilst, in contrast, the Z-carboxylic acids of the formula (XIII) are only eluted after addition of electrolytes, fox example, 2 N sodium hydroxide solution. Weakly basic ion exchangers are to be understood as including those ion exchangers in solid or liquid form which contain tertiary amino groups, for example Lewatit MP 62.
Rl and R2 in the compounds of the formula (XIII) and (XIV) have the same meaning as in the compounds of the formula (XII). In addition, R2 can be a hydrogen atom, if, before saponification, R2 in thecompounds of the formula (XII) was a protective group saponifiable by alkali (such as a methyloxycar-bonyl group). However, it is more advantageous for carrying out the process for the process for the preparation of the compounds of -the formula I) if R2 is a protective group which is stable under the conditions of saponification, preferably tert.-butyloxycarbonyl.
A large number of methods, which in the last analysis are derived from peptide chemistry, are known in cephalosporin chemistry for coupling carboxylic acids to 7-aminocephalosporanic acids. However, these methods fail on attempting to form the amide bond between the Z-carboxylic acids of the formula (XIII~ and the cephalosporanic acids of the formula (XVII~, or they only lead to very poor yields, particularly when Rl is an alkyl radical.
The reasons for this are to be found in the large steric hindrance of the carboxyl group in the carboxylic acids of the formula (XIII) by the radical Rl and in the pronounced tendency of the radical Rl , I, ;~ :;
to isomeri.se into the E-form after activation of the carboxyl function, for example, conversion lnto the acid chloride. Then, after reaction with the 7-aminocephalosporanic acids of the formula (XVII), the desired compounds of the formula (XVIII) are not obtained, but rather the compounds of the formula 2 S (XXI) or mixtures of the two.
It has now been found that the Z-carboxylic acids of the formula (XIII) can be activated in a simple, mild and inexpensive manner without the abovementioned disadvantages by converting them into the mixed anhydrides of the formula (XVI) at low temperatures.
As indicated previously, these compounds of the formula (XVI) are new and form a further subject of the present invention.
In these compounds R5, when optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl radical, can be substituted by a substituent selected from halogen, alkyl, aryl, O-alkyl, S-alkyl, CN, alkoxycarbonyl and nitro. Expecially preferred compounds of formula (XVI) are those, in which R5 denotes an alkyl radical with 1 to 10 carbon atoms, which is optionally substituted by fluorine, chlorine, CN, phenyl, alkyl-oxycarbonyi, alkyloxy or alkyl (it being preferred for ~2;3lS ~.~.
-21- 23189-5~48D
the al~yl groups of these substituents to carry 1 to 4 carbon atoms); or denotes a phenyl radical, which is optionally substituted by fluorine, chlorine, bromine, CN, alkyl, alkyloxy, alkylthio and alkyloxycarbonyl (it being preferred for the alkyl groups of these sub-stituents to carry 1 to 4 carbon atoms), and nitro, trifluoromethyl and phenyl.
When R5 is substituted, there are preferably 1 to 3 substituents, preferably those mentioned, present.
In very particularly preferred compounds of formula (XVI) R5 represents a methyl or p-tolyl radical.
This type of mixed anhydrides of the formula (XVI) is preferably prepared by dissolving the carboxylic acid of formula (XIII) and a suitable amine in equimolar amounts in a suitable solvent and allowing them to react with 1 to 1.05 equivalents of a sulphonic acid derivative oE the formula (XV).
Suitable solvents here are any of the solvents which are stable under the reaction conditions (such as diethyl ether, tetrahydrofuran, acetonitrile, acetone, methylene chloride, chloro-0 form or dimethylformamide).
Suitable amines are tertiary amines (such as triethylamine or tributylamine) and also sterically hindered secondary amines (such as diisopropylamine).
The reactions can be carried out at a temperature between -80C and room temperature, low temperatures preventing isomer-isation of the substituents on the double bond. The reactions are advantageously carried out at -20 to -50C with a duration of reaction of 10 minutes to 6 hours.
The compounds of the formula (XVI) can be isolated by using, for example, tetrahydrofuran as the solvent and triethyl-amine as the base, Eiltering off under suction the triethylamine hydrochloride formed anddistilling off the solvent in vacuo.
However, it is more advantageous to react the solutions of the compounds of the formula (XVI) obtained directly with the cephalosporanic acids of the formula (XVII). For this purpose, the cephalosporanic acids of the formula (XVII) are dissolved in a suitable solvent with 2 to 4 equivalents of an amine, the solution is pre-cooled to the desired subsequent reaction temperature and this solution at this temperatue is added to the solution of the compound of the formula (XVI) described above. In order to prevent isomerisation of the radical Rl in the reaction products of the formula (XVIII), the reaction is advantageously carried out at -60 to -30C and the mixture is allowed to reach room temperature overnight.
The amines and solvents mentioned for the preparation of the compounds of the formula (XVI) can be used to dissolve the cephalosporanic acids of the formula (XVII). If solutions with satisfactory concentrations of the cephalosporanic acids of formula (XVII) cannot be obtained in this manner, it is obviously also possible to employ the readily soluble esters of the compounds of the formula (XVII), which are sufficiently well-known from cephalosporin chemistry such assilyl~ tert.-butyl or diphenyl-.
~23~39~
-22a- 23189-5448D
methyl esters).
After work-up, the compounds of the formula (XVIII) are obtained, in which R1 and R2 exhibit the meanings mentioned for the compounds of the formula (XVI) and X represents a group suitable as a cephalospori.n substituent for example denotes hydrogen, Cl to C4 alkyl, halogen, Cl to C4 alkoxy, hydroxymethyl, formyloxymethyl, (Cl to C4 alkyl)-carbonyloxymethyl, aminocarbonyloxymethyl, pyridiniummethyl, 4-carbamoylpyridiniummethyl or heterocyclylthio-methyl ("heterocyclyl" preferably representing a radical of the formula CH3 N -N r-N N -N N--~
ON ' So R , S
in which R6 denotes hydrogen, methyl, 2-dimethylaminoethyl, carboxymethyl or sulphomethyl and R7 denotes hydrogen or methyl).
Preferred compounds of formula (XVIII) are those, in which X denotes hydrogen, chlorine, methoxy, hydroxy-methyl, acetyloxymethyl, aminocarbonyloxymethyl, pyridiniurnmethyl \\ or CH2-S US
l l ~CH3 CH3 CH2 CH2 No CH
~3~
-22b- 23189-5448D
The compound of the formula (I), in which Al and X
exhibit the meaning mentioned for the compounds of the formula (XVIII), is obtained from the compounds of the formula (XVIII) after splitting off the protective group R . As already mentioned for the compounds of the formula (X), it is extremely advantageous for the complete reaction sequence for the preparation of the compounds of the formula (I) to be carried out directly from the compounds of the formula (X) if R2 is a protective group stable in base which may be selectively split off, such as tert.-butyloxycarbo_yl (split off with trifluoroacetic acid).
The process according to the present invention and the production of compounds according to the invention are illustrated by the following Examples.
Example 1 Ethyl2-tert.-butoxycarbonylimino-3-tert,-butoxycarbonyll-4-thiazolin-4-yiacetate 186 g (l mol) of e-thyl 2-aminothiazol-4-ylacetate, 300 ml of dimethyl sulphoxide and 500 g (2.3 mol) of 98% di-tert.-butyl pyrocarbonate are stirred at room temperature for 7 days.
Then 3.5 1 of ice-water are added with ice cooling at max. 20C, the mixture is stirred for 30 minutes, the precipitate is filtered off under suction, is washed with 2 l of water and is taken up in 2 l of methylene chloride. The water is separated off, the methyl-ene chloride phase is dried over Na2SO4 and concentrated on a rotary evaporator. The oil obtained is taken up immediately (before crystallisation starts) for crystallisation in 2 l of petroleum ether. Yield 302 g (78~), melting point 90C.
Example 2 Methyl2--tert.-butoxycarbonylimino-3-tert.-buto-~ycarbonnyl-
4-thiazolin-4-ylacetate _ is prepared from methyl 2-aminothiazol-4-yl acetate in analogy to Example 1.
Yield 670/o, melting point 67-69C.
Example 3 Ethyl2-ethoxycarbonylimino-3-etho~jcarbonyl-4-thiazolinn-4-~lacetate .... .. .. _ .
is prepared from ethyl 2-aminothiazol-4-ylace~ate and diethyl pyrocarbonate in analogy to Example 1.
Yield 71%, melting point 102C.
Example 4 Tert.-butyl 2-tert.-buto~Jcarbonylimino-3-tert -outo.Yycar-bonyl-4-thiazolin-L~_ylacetate 157 g (0.5 mol) of tert.-~utyl 2-aminothiazol-4-ylacetate, 150 ml of dimeth~l sulpho~ide and 260 g (1.2 mols) of 98% di-tert.-butyl pyrocarbonate fore reacted in analogy to Example 1.
Yield 62%.
Example 5 Trimethylsilylethyl 2-aminothiazol-4-ylacetate . _ , .
11.2 g (15.8 ml, 0.1 mol) of trimethylsilyl-ethanol, 100 mg of 4-dimethylaminopyridine and 11.4 g OI
dicyclohe~lcarbodiimide are added at room temperature to 7.9 g (0.05 mol) of 2-aminothiazol-4-ylacetic acid in 50 ml of acetoni-trile and the mixture is stirred for 2 days. The precipitated urea is then filtered off under suction, washed with ether, the washings are con-centrated on a rotary evaporator and the residue is takenup in ether and the ethereal solution is washed with 0.5 N hydrochloric acid and with NaHC03 solution, dried over MgS04 and concentrated on a rotary evaporator. After concentration of the solution and addition of petroleum Le A 21 370 ~23~
ether, the desired ester crystallises out.
Yield 2.8 g.
Example Trimethylsilylethyl 2 tert.-butylo~Jcarbonylimino-3-tert.-butoxycarbonyl-4-thiazolin ~-ylacela~e is prepared from trimethylsilyl 2-aminothiazol-4-ylacetate in analog to Example 1.
Yield 50~.
Example 7 Ethyl 1-(2-tert.-outoxycarbonylaminothiazol-4-yl)-2-tert.-butoxycarbonyloxypropanecarboxylate . _ .
11.2 g (0.03 mol)-of ethyl 2-tert.-butoxycarb-onylimino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylaace-tate weredissolved in 80 ml of anhydrous tetrahydrofuran, and, under nitrogen at -50 to -60C, 20 ml (0.032 mol) of a 15% strength solution of n-butyllithium in n-hexane was aided, hollowed by 1.91 ml (0.034 mol) of acetalde-hyde. The mixture is stirred at -50 to -60C for 2 hours, then 30 ml of a 10% strength solution of citric acid in water is added and the mixture is allowed to warm to root temperature. To work up, the tetrahydro-furan is distilled off at room temperature in vacuo, the residue is extracted with methylene chloride, the organic extract is dried over Na2S04 and the solvent is distilled off. 10.~ g of an oil is obtained which, according to NMR, is a mixture of diastereo~ers (TLC: cyclohexane/
ether 1:1).
Example 8 Ethyl1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(E,Z))-propenecarboxylate .. . . . . .................... .
The mixture is prepared as indicated in Example 7.Howe~er, after addition of the acetaldehyde, it is allowed to warm to room temperature, is then stirred overnight and is only then worked up as indicated in Le A 21 370 ~3~
Example 7. 9.2 g of an oil is obtained which, accord-ing to NMR and TLC (cyclohexane/ether 1:1, Z isomer runs higher) is an approximately 1:1 mixture of E/Z isomers.
The two compounds can be separated on silica gel 60 (mobile phase cyclohexane/ether 1:1).
Z isomer:
H-NMR (250 MHz, CDC13): = 10.5 (bs; lH, NH), 6~95 (s; lH, S-CH), 6.88 (q; J=
7 Hz, lH, CH-CH3), 4.35 (q;
J=7 Hz, 2H, CH-CH~), 2.04 (d, J=7 Hz, 3H, CH-CH3), 1.50 (s;
9H, C(CH3)3), 1.36 (t; J=7 Hz, 3H, CH2-CX3).
E isomer:
lH-NMR (250 MHz,CDC13): = 10.5 (bs; lH, I), 7.22 (q; J=7 Hz, lH, CH-CH3), 6.94 (s; lH, S-CH), 4.19 (q; J=7 Hz, 2H, CH2 -CH3), 1.95 (d;
J=7 Hz, 3H, CH-CH3), 1.52 (s;
9H~ C(CH3)3), 1.22 (t; J=7 Hz, 3H, CH2-C_3).
Exam~le_9 Ethyl 2-(2-tert.-butoxycarbonylaminothiazol-4-yl)-2(E,Z)-benzylideneace-tate . _ _ 3.86 g (0.01 mol) ox ethyl 2-tert.-butoxycarbonyl-imino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetaate in 40 ml of anhydrous tetrahydrofuran are cooled down to -50, 2.8 g (0.024 mol) of potassium tert.-butylate are added, the mixture is stirred until solution is complete and 1.11 ml (0.012 mol) of benzaldehyde is added. The mixture is allowed to warm to room temperature and is stirred overnight.
- To work up, about 12 ml of 2 N HCl areadded with cooling in ice and monitoring the pH, until a pH of 4-5 is reached, the tetrahydrofuran and then the tert.-Le A 21 370 ~3~
_ 2~ _ butanol are removed in vacuo and the residue is extractedwith methylene chlorideO After drying over Na2S0~, the methylene chloride is removed in vacuo. 3.1 g o an oil is obtained, which, according to NMR and TLC
(cyclohexane/ether 1:1), is an approximately 1:1 mixture of E/Z isomers.
Example 10 1-(2-tert.-~utoxycarbonylaminothiazol-4-~1)-1-(Z)--pro-penecarboxylic acid ... _ , . ...
0.145 mol (56 g) of ethyl 2-tert.-butoxycarbonyl-imino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetaate and 400 ml of anhydrous tetrahydrofuran are initially intro-duced under nitrogen and, at -60 to -50C, 0 16 mol of n-butyllithium in hexane (15% strength, 100 ml) is added dropwise. Then 9.55 ml (0.17 mol) of acetaldehyde is immediately added, the mixture is stirred for 10 minutes at ~60C and then overnight at room temperature Then 250 ml of 2 N sodium hydroxide solution is added and the two-phase mixture is vigorously stirred at room temperature for 24 hours. The tetrahydrofuran i6 then distilled off at room temperature in vacuo and the alkaline phase is extracted twice with 100 ml of methylene chloride each time. After acidification of the aqueous phase to pH 2-3 and extraction, the 1-(2-tert.-25 but5xycarbonylaminothiazol-4-yl)-l(E)-propenecarbooxylic acid is obtained (21.0 g, 51%, melting point = 195C
(~`rom aceto~itrile)).
me methylene chloride phase is concentrated in vacuo, the residue is taken up in 250 ml of ethanol, this is treated with 250 ml of 2 N sodium hydroxide solu-tion and heated at 60C for 24 hours.
After removal of the ethanol by distillation, the alkaline phase is extracted once with 100 ml of methylene chloride) the extract is discarded, the alkaline phase is acidified to pH 2-3 and the desired 1-(2-tèrt.-Le A 21 370 ~2~
buto~ycarbonylaminothiazol-4-~-l(Z)-propenecarboxyylic acid is extracted with methylene chloride (8.3 g, 20%, melting point = 18~C (from acetonitrile)).
Example 11 . .
Yield 670/o, melting point 67-69C.
Example 3 Ethyl2-ethoxycarbonylimino-3-etho~jcarbonyl-4-thiazolinn-4-~lacetate .... .. .. _ .
is prepared from ethyl 2-aminothiazol-4-ylace~ate and diethyl pyrocarbonate in analogy to Example 1.
Yield 71%, melting point 102C.
Example 4 Tert.-butyl 2-tert.-buto~Jcarbonylimino-3-tert -outo.Yycar-bonyl-4-thiazolin-L~_ylacetate 157 g (0.5 mol) of tert.-~utyl 2-aminothiazol-4-ylacetate, 150 ml of dimeth~l sulpho~ide and 260 g (1.2 mols) of 98% di-tert.-butyl pyrocarbonate fore reacted in analogy to Example 1.
Yield 62%.
Example 5 Trimethylsilylethyl 2-aminothiazol-4-ylacetate . _ , .
11.2 g (15.8 ml, 0.1 mol) of trimethylsilyl-ethanol, 100 mg of 4-dimethylaminopyridine and 11.4 g OI
dicyclohe~lcarbodiimide are added at room temperature to 7.9 g (0.05 mol) of 2-aminothiazol-4-ylacetic acid in 50 ml of acetoni-trile and the mixture is stirred for 2 days. The precipitated urea is then filtered off under suction, washed with ether, the washings are con-centrated on a rotary evaporator and the residue is takenup in ether and the ethereal solution is washed with 0.5 N hydrochloric acid and with NaHC03 solution, dried over MgS04 and concentrated on a rotary evaporator. After concentration of the solution and addition of petroleum Le A 21 370 ~23~
ether, the desired ester crystallises out.
Yield 2.8 g.
Example Trimethylsilylethyl 2 tert.-butylo~Jcarbonylimino-3-tert.-butoxycarbonyl-4-thiazolin ~-ylacela~e is prepared from trimethylsilyl 2-aminothiazol-4-ylacetate in analog to Example 1.
Yield 50~.
Example 7 Ethyl 1-(2-tert.-outoxycarbonylaminothiazol-4-yl)-2-tert.-butoxycarbonyloxypropanecarboxylate . _ .
11.2 g (0.03 mol)-of ethyl 2-tert.-butoxycarb-onylimino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylaace-tate weredissolved in 80 ml of anhydrous tetrahydrofuran, and, under nitrogen at -50 to -60C, 20 ml (0.032 mol) of a 15% strength solution of n-butyllithium in n-hexane was aided, hollowed by 1.91 ml (0.034 mol) of acetalde-hyde. The mixture is stirred at -50 to -60C for 2 hours, then 30 ml of a 10% strength solution of citric acid in water is added and the mixture is allowed to warm to root temperature. To work up, the tetrahydro-furan is distilled off at room temperature in vacuo, the residue is extracted with methylene chloride, the organic extract is dried over Na2S04 and the solvent is distilled off. 10.~ g of an oil is obtained which, according to NMR, is a mixture of diastereo~ers (TLC: cyclohexane/
ether 1:1).
Example 8 Ethyl1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(E,Z))-propenecarboxylate .. . . . . .................... .
The mixture is prepared as indicated in Example 7.Howe~er, after addition of the acetaldehyde, it is allowed to warm to room temperature, is then stirred overnight and is only then worked up as indicated in Le A 21 370 ~3~
Example 7. 9.2 g of an oil is obtained which, accord-ing to NMR and TLC (cyclohexane/ether 1:1, Z isomer runs higher) is an approximately 1:1 mixture of E/Z isomers.
The two compounds can be separated on silica gel 60 (mobile phase cyclohexane/ether 1:1).
Z isomer:
H-NMR (250 MHz, CDC13): = 10.5 (bs; lH, NH), 6~95 (s; lH, S-CH), 6.88 (q; J=
7 Hz, lH, CH-CH3), 4.35 (q;
J=7 Hz, 2H, CH-CH~), 2.04 (d, J=7 Hz, 3H, CH-CH3), 1.50 (s;
9H, C(CH3)3), 1.36 (t; J=7 Hz, 3H, CH2-CX3).
E isomer:
lH-NMR (250 MHz,CDC13): = 10.5 (bs; lH, I), 7.22 (q; J=7 Hz, lH, CH-CH3), 6.94 (s; lH, S-CH), 4.19 (q; J=7 Hz, 2H, CH2 -CH3), 1.95 (d;
J=7 Hz, 3H, CH-CH3), 1.52 (s;
9H~ C(CH3)3), 1.22 (t; J=7 Hz, 3H, CH2-C_3).
Exam~le_9 Ethyl 2-(2-tert.-butoxycarbonylaminothiazol-4-yl)-2(E,Z)-benzylideneace-tate . _ _ 3.86 g (0.01 mol) ox ethyl 2-tert.-butoxycarbonyl-imino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetaate in 40 ml of anhydrous tetrahydrofuran are cooled down to -50, 2.8 g (0.024 mol) of potassium tert.-butylate are added, the mixture is stirred until solution is complete and 1.11 ml (0.012 mol) of benzaldehyde is added. The mixture is allowed to warm to room temperature and is stirred overnight.
- To work up, about 12 ml of 2 N HCl areadded with cooling in ice and monitoring the pH, until a pH of 4-5 is reached, the tetrahydrofuran and then the tert.-Le A 21 370 ~3~
_ 2~ _ butanol are removed in vacuo and the residue is extractedwith methylene chlorideO After drying over Na2S0~, the methylene chloride is removed in vacuo. 3.1 g o an oil is obtained, which, according to NMR and TLC
(cyclohexane/ether 1:1), is an approximately 1:1 mixture of E/Z isomers.
Example 10 1-(2-tert.-~utoxycarbonylaminothiazol-4-~1)-1-(Z)--pro-penecarboxylic acid ... _ , . ...
0.145 mol (56 g) of ethyl 2-tert.-butoxycarbonyl-imino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetaate and 400 ml of anhydrous tetrahydrofuran are initially intro-duced under nitrogen and, at -60 to -50C, 0 16 mol of n-butyllithium in hexane (15% strength, 100 ml) is added dropwise. Then 9.55 ml (0.17 mol) of acetaldehyde is immediately added, the mixture is stirred for 10 minutes at ~60C and then overnight at room temperature Then 250 ml of 2 N sodium hydroxide solution is added and the two-phase mixture is vigorously stirred at room temperature for 24 hours. The tetrahydrofuran i6 then distilled off at room temperature in vacuo and the alkaline phase is extracted twice with 100 ml of methylene chloride each time. After acidification of the aqueous phase to pH 2-3 and extraction, the 1-(2-tert.-25 but5xycarbonylaminothiazol-4-yl)-l(E)-propenecarbooxylic acid is obtained (21.0 g, 51%, melting point = 195C
(~`rom aceto~itrile)).
me methylene chloride phase is concentrated in vacuo, the residue is taken up in 250 ml of ethanol, this is treated with 250 ml of 2 N sodium hydroxide solu-tion and heated at 60C for 24 hours.
After removal of the ethanol by distillation, the alkaline phase is extracted once with 100 ml of methylene chloride) the extract is discarded, the alkaline phase is acidified to pH 2-3 and the desired 1-(2-tèrt.-Le A 21 370 ~2~
buto~ycarbonylaminothiazol-4-~-l(Z)-propenecarboxyylic acid is extracted with methylene chloride (8.3 g, 20%, melting point = 18~C (from acetonitrile)).
Example 11 . .
5 1-(2-tert.-3utoxycarbonylaminothiazol-L~--yl)-l(Z))-'ou4ene-carboxylic acid Preparation ln analogy to Example 10 with pro-panal instead of acetaldehyde (yield 17%, melting point 172C from acetonitrile).
Example 12 1-(2-tert.~butoxycarbonylaminothiazol-4-yl)-l(Z)-ppentene-carboxyllc acid , Preparation in analogy to Example 10 with buta-nal instead ox acetaldehyde (melting point 162-3C~
from acetonitrile).
Example 13 .
1-(2-tert.--Butoxycarbonylaminothiazol-4-yl)-l(Z)--hexene-carboxylic acid Preparation in analogy to Example 10 with penta-nal instead of acetaldeh~de (melting point 158C, from acetonitrile).
Example 14 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-hheptene-carboxylic acid . .
Preparation in analogy to Example 10 with hexa-nal instead of acetaldehyde (melting point 130-1C, from acetonitrile).
Example 15 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-ooctene-carboxylic acid . _ _ Preparation in analogy to Example 10 with hepta-nal instead of acetaldehyde (melting point 154C~ from acetonitrile).
Le A 21 370 _ - 2~ -Example 16 1-(2-tert.-B~ltoxycarbonylaminothlazol-4-yl)-3-~etthyl-l(Z)-butenecarboxylic acid ... . _ . .. . _ .
Preparation in analogy to Example 10 with iso-butyraldehyde instead of acetaldehyde (melting point 169-71C, prom acetonitrile)~
Example 17 1-(2-tert.-~utoxycarbonylaminothiazol-4-yl)-4-methhyl-1(Z)-pentenecarboxylic acid , Preparation in analogy to Example 10 ilk iso-valeraldehyde instead of acetaldehyde (melting joint 173C, from acetonitrile).
Example 18 2-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-3-cycllohexyl-(Z)-acrylic acid .. ..
Preparation in analogy to Example 10 with cyclo-hexylaldehyde instead of acetaldehyde (melting point 210C, from acetonitrile).
Example 19 20 1-(2-tert.-Butoxycarbonylaminothiazo1-4-yl)-4-phennyl-l(Z)-butenecarboxylic acid Preparation in analogy to Example 10 with dihydro-ci~mamaldehydeinsteadof acetaldehyde (melting point 174C, from acetonitrile).
Example 20 1-(2-tert,-Butoxycarbonylaminothiazol~4 yl)-l(Z)-propene-carboxylic acid 0~43 mol (122 g) of 1-(2 tert.-butoxycarbonyl-aminothiazol 4-yl)-l(E)-propenecarboxylic acid in 800 ml 3o of anhydrous tetrahydrofuran is treated with 0.52 mol (129 ml) of bistrimethylsilylacetamide and the mixture is stirred at room temperature for 1 hour. It is then cooled down to -60C, 1.74 mols (200 g) of po-tassium Le A 21_370 tert.-butylate (98%) is added, the mixture is allo~red to warm to room temperature and is stirred at room tempera-ture overnight To work up, 100 ml of water is added Chile cool-ing in ice, the pH is adjusted to 6-8 wi th about 900 ml of 2 N HCl, the tetrahydrofuran is removed in vacuo, the pH is adjusted to 2-3 and the mixture is extracted 3 times with 300 ml of methylene chloride. The extract is dried, cancentrated on a rotary evaporator and the residue is dissolved in 700 ml of methanol. T'ne methanolic solutlon is run through a column (2.5 x 80 cm;
400 ml) containing weakly basic ion exchanger Lel~atit MP 62, at a rate of about 10 ml/minu~e, the column is washed with 2 1 of methanol and eluted with ' 1 of methanol/2 N sodium hydroxide solution 10:1. The elu-ate is concen-trated, acidified to pH 2-3 with 2 N HCl and extracted with methylene chloride. After drying over Na2S04 and distilling off the methylene ohloride, 50 g (41%) of the desired Z-propenecarboxylic acid is obtained. The E~propenecarboxylic acid which did not isomerise is recovered from the column by evaporating the methanolic washings.
ample 21 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-ppentene-carboxylic acid By isomerisa-tion of the corresponding E-pentene-carboxylic acid in analogy to Example 20 Yield 45%.
Example 22 30 1-(2-ter-t.-Butoxycarbonylaminothia701-4-yl)-l(Z)--propene-carboxylic methanesulphonic anhydride 0.005 mol (1.42 g-) of 1-(2-tert.-butoxycarbonyl-aminothiazol-4-yl)-l(Z)-propenecarboxylic acid and 0.0055 mol (o.76 ml) of triethylamine are dissolved in 10 ml of anhydrous tetrahydrofuran and cooled down to -50C.
Le A 21 370 -.
~a,iSd3~
Then 0.0051 mol (0 40 ml) of methanesulphonyl chloride are added and the mixture is stirred at -40 to -50C for 5 hours. Then the triethylamine hydrochloride is filtered off under suction with exclusion of H20 and the tetrahydrofuran is distilled off in vacuo at -10C.
The mixed anhydride is obtained as an oil which readily isomerises into the E form on warming (l~MR).
Example 2~
1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-bbutene-carbo~ylic ~-toluenesulphonic anhydride Preparation i.n analogy to Example 22 from the appropriate Z-butenecarboxylic acid and p-toluenesul-phonyl chloride at -20 to -~0C.
Example 24 15 7-cl-(2-tert~-Butoxycarbonylaminothiazol-4-yl)-l(zz)-pr penecarboxamido]-3-acetoxymethyl-3-cephem-4-carboxxylic acid .. .. . . . . . .
0.005 mol (1.42 g) ox 1-(2 ter-t.-butoxycarbonyl-aminothiazol-4 yl)-l(Z)-propenecarbo~ylic acid and 0.0055 mol (0.76 ml) of triethylamine are dissolved in 20 ml of anhydrous methylene chloride, the mixture is cooled down to -50C, 0.0051 mol (0.40 ml) of me-thanesulphonyl chlor-ide is added and the mixture is stirred at -50 to -40C
for 5 hours.
Then a solution of 0~006 mol (1.63 g) of 3-acet-oxymethyl-7-amino-3-cephem-4-carboxylic acid and 0 013 mol (1.80 ml) of triethylamine in 20 ml of anhydrous methyl-ene chloride, which has been previously cooled to -50C, is added and the mixture is allowed to warm to room temperature over 12 hours.
To work up, the mixture is washed twice with 10 ml of H20 each time, the methylene chloride phase is covered with 40 ml of H20 and acidified, with stirring and cooling in ice, to pH 2-3 with 1 N HCl. The organic phase is separated of, the H20 phase is extracted 2 times with Le A 21 ~70 ~3~39~L
- 31 _ 20 ml of methylene chloride each time, the combined methylene chloride phases are washed with saturated NaCl solutlon, dried over Na2S04 and concentrated in vacuo on a rotary evapora-tor. The desired cepha'o-sporin is obtained almost aua~ti-tatively, Example 25 7-cl-(2~tert~-Butoxycarbcnylaminothiazol-4-yl)-l(zz)-propenecarboxamido~-3~ methyl-1 H-tetrazol-~-~l)thio-methyl-3-cephem-4-carbo~Jlic acid .. . .. . _ Preparation is carried out in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxylic acid and 7-amino-3-(1-methyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Yield 92%.
Exam le 26 7-Cl-(2-tert~-Buto~yycarbonylaminothiazol-4-yl)-l((z)-butenecarboxyamido]-3-aceto~methyl-3-cephem-4-carbboxylic acid Preparation in analogy to Example 24 prom 1-(2tert.-butoxycarbonylaminothiazol-4-yl)-1-(Z)-butenne-carboxylic acid and 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid.
Example 27 7-cl-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(zz)-butenecarboxamido]-3-(1 methyl-l H-te~trazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid _ _ . _ . .
Preparation in analogy to Example 24 from 1-(2-tert.~
butoxycarbonylaminothiazol-4-yl)-l(Z)-butenecarboxxylic acid and 7-amino-3-(1-methyl-1 H-tetrazol-5-yl)-thio-methyl--3-cephem-4-carboxylic acid.
yield 88%.
~xam~le 28 7-Cl-(2-tert.-Butoxycarbonylaminothlazol-4-yl)-l(Z)-heptenecarboxamido]-3-acetoxymethyl-3-cephem--4-car-boxylic acid ~;~3~
Preparation in analogy to Example 24 from 1-(2--tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)--heptene-carboxylic acid and 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid.
Yield 90%.
Example 29 7-C1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(ZZ)-hep-tenecarboxamido~-3-(1-methyl-1 ~-tetrazol-5-yl)-thio-methyl-3-cephem-4-carboxylic acid Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-heptenne-carboxylic acid and 7-amino-3-(1-me~hyl~ elf thiomethyl-3-cephem-4-carboxylic acid.
Yield 85%.
Example 30 7-C1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-3-mmethyl-1(Z)-butenecarboxamido~-3-acetoxymethyl-3-cephem-44-car-boxylic acid , . _ .
Preparation in analogy -to Example 24 from 20 1-(z-tert~-butoxycarbonylaminothiazol-4-yl)-3-methhyl-l(z) butenecarboxylic acid and 3 aceto~Jmethyl-7-amino-3-ceph-em-4-carboxylic acid.
Yield 93%.
Example 31 25 7-C1-(2--tert.-Butoxycarbonylaminothiazol-4-yl)-4--phenyl-1(Z)-butenecarboxamido]-3-acetoxymethyl-3-cephem-44-car-boxylic acid - Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-4-~henny'-1~
butenecarboxylic acid æ~d ~-acetoxymethyl-7-amino-3-cephem-4~carboxy1ic acid. Yield 95%.
ExamPle 32 7-Cl-(2-tert~-Butoxycarbonylaminothiazol-4-yl)-l(zz) propenecarboxamido]-3-methyl-3-cephem-4-carboxylicc acid Le A 21 370 ~L23~
Preparation in analogy to Example 24 Irom 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(z)-propenne-carboxylic acid and 7-amino-3-methyl-3-cephem-4-carbo~Jlic acid. Unlike Example 24, the 7-amino-3-methyl-3-ceph-em-4-carboxylic acid is dissolved in methylene chloride with the equimolar amount of diisopropylamine instead of with triethylamine.
Yield 88%.
Example 3 107-cl-(2-tert.-Butoxycar~onylaminothiazol-4-yl)-l(zz)-propenecarboxamldo]~3-aminocarbonyloxymethyl-3-cepphem-4-Garbo,Yylic acid Preparation in analogy to Example 24 Irom 1-(2-tert,-butoxycarbonylaminothiazol-4-yl)-l(Z)-ppropene-carboxylic acid and 7-amino-3-aminocarbonylo~ymethyl-3-cephem-4-carboxylic acid. Unlike Example 24, the 7-amino-3-aminocarbonyloxymethyl-3-cephem-4-carboxxylic acid is no-t dissollled in methylene chloride l~ith tri-ethylamine, but in anhydrous dimethyl~ormamide with the equimolar amount of diiso~ropylamine, and the solution obtained is added to the mi,ced carbo~cylic sulphonic anhydride in methylene chloride, Towork up, themixtureis evaporated at 0C in vacuo, the residue is taken up in water, extracted with methylene chloride, the aqueous phase is co~jered l~ith ethyl acetate and acidified to pH 2-3. The product separates out as an oil between the phases.
Example_34 Diphenylmethyl 7-Cl-(2-tert.-butoxycarbonylaminothiazol-30 4-yl)-l(Z)-propenecarboxamido]-3-CePhem-4-Carboxyllate Preparation in analogy to Example 24 prom 1-(2-tert,-butoxycarbonylaminothiazol-4-yl)-l(Z)-ppropene-carboxylic acid and diphenylmethyl 7-amino-3-cephem-4-carboxylate.
Yield 93%.
Le A 21 370 ~;~3~
_ ~4 _ Example 35 7-C1-(2-Aminothiazol~4-yl)-l(Z)-propenecarboxamidool-3-acetoxymethyl-3-cephem-4-carboxylic acid 10 ml of trifluoroacetic acid is added to the BOC-protected cephalosporin from Example 24, and the mix-ture is stirred at room temperature for 30 minutes.
m e trifluoroacetic acid is then removed at room tempera-ture in vacuo, the residue is trea-ted with 20 ml of methanol/H20 10:1 and then with 10% strength NaHC03 solution, until a clear solution at pH 6-7 is obtained.
The pH is then slowly adjusted to 3 ;~ 'r or Of the methanol is slowly removed in vacuo and, if neces-sary, the pH is adjusted again to 3. The precipitated product is filtered off under suction. Yield 70,S.
Examples 36-44 The cephalosporins from the Examples 25 to 34 are unblocked in analogy to example 35. Yields are between 50 and 90%.
Le A 21 370 . _ .
Example 12 1-(2-tert.~butoxycarbonylaminothiazol-4-yl)-l(Z)-ppentene-carboxyllc acid , Preparation in analogy to Example 10 with buta-nal instead ox acetaldehyde (melting point 162-3C~
from acetonitrile).
Example 13 .
1-(2-tert.--Butoxycarbonylaminothiazol-4-yl)-l(Z)--hexene-carboxylic acid Preparation in analogy to Example 10 with penta-nal instead of acetaldeh~de (melting point 158C, from acetonitrile).
Example 14 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-hheptene-carboxylic acid . .
Preparation in analogy to Example 10 with hexa-nal instead of acetaldehyde (melting point 130-1C, from acetonitrile).
Example 15 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-ooctene-carboxylic acid . _ _ Preparation in analogy to Example 10 with hepta-nal instead of acetaldehyde (melting point 154C~ from acetonitrile).
Le A 21 370 _ - 2~ -Example 16 1-(2-tert.-B~ltoxycarbonylaminothlazol-4-yl)-3-~etthyl-l(Z)-butenecarboxylic acid ... . _ . .. . _ .
Preparation in analogy to Example 10 with iso-butyraldehyde instead of acetaldehyde (melting point 169-71C, prom acetonitrile)~
Example 17 1-(2-tert.-~utoxycarbonylaminothiazol-4-yl)-4-methhyl-1(Z)-pentenecarboxylic acid , Preparation in analogy to Example 10 ilk iso-valeraldehyde instead of acetaldehyde (melting joint 173C, from acetonitrile).
Example 18 2-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-3-cycllohexyl-(Z)-acrylic acid .. ..
Preparation in analogy to Example 10 with cyclo-hexylaldehyde instead of acetaldehyde (melting point 210C, from acetonitrile).
Example 19 20 1-(2-tert.-Butoxycarbonylaminothiazo1-4-yl)-4-phennyl-l(Z)-butenecarboxylic acid Preparation in analogy to Example 10 with dihydro-ci~mamaldehydeinsteadof acetaldehyde (melting point 174C, from acetonitrile).
Example 20 1-(2-tert,-Butoxycarbonylaminothiazol~4 yl)-l(Z)-propene-carboxylic acid 0~43 mol (122 g) of 1-(2 tert.-butoxycarbonyl-aminothiazol 4-yl)-l(E)-propenecarboxylic acid in 800 ml 3o of anhydrous tetrahydrofuran is treated with 0.52 mol (129 ml) of bistrimethylsilylacetamide and the mixture is stirred at room temperature for 1 hour. It is then cooled down to -60C, 1.74 mols (200 g) of po-tassium Le A 21_370 tert.-butylate (98%) is added, the mixture is allo~red to warm to room temperature and is stirred at room tempera-ture overnight To work up, 100 ml of water is added Chile cool-ing in ice, the pH is adjusted to 6-8 wi th about 900 ml of 2 N HCl, the tetrahydrofuran is removed in vacuo, the pH is adjusted to 2-3 and the mixture is extracted 3 times with 300 ml of methylene chloride. The extract is dried, cancentrated on a rotary evaporator and the residue is dissolved in 700 ml of methanol. T'ne methanolic solutlon is run through a column (2.5 x 80 cm;
400 ml) containing weakly basic ion exchanger Lel~atit MP 62, at a rate of about 10 ml/minu~e, the column is washed with 2 1 of methanol and eluted with ' 1 of methanol/2 N sodium hydroxide solution 10:1. The elu-ate is concen-trated, acidified to pH 2-3 with 2 N HCl and extracted with methylene chloride. After drying over Na2S04 and distilling off the methylene ohloride, 50 g (41%) of the desired Z-propenecarboxylic acid is obtained. The E~propenecarboxylic acid which did not isomerise is recovered from the column by evaporating the methanolic washings.
ample 21 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-ppentene-carboxylic acid By isomerisa-tion of the corresponding E-pentene-carboxylic acid in analogy to Example 20 Yield 45%.
Example 22 30 1-(2-ter-t.-Butoxycarbonylaminothia701-4-yl)-l(Z)--propene-carboxylic methanesulphonic anhydride 0.005 mol (1.42 g-) of 1-(2-tert.-butoxycarbonyl-aminothiazol-4-yl)-l(Z)-propenecarboxylic acid and 0.0055 mol (o.76 ml) of triethylamine are dissolved in 10 ml of anhydrous tetrahydrofuran and cooled down to -50C.
Le A 21 370 -.
~a,iSd3~
Then 0.0051 mol (0 40 ml) of methanesulphonyl chloride are added and the mixture is stirred at -40 to -50C for 5 hours. Then the triethylamine hydrochloride is filtered off under suction with exclusion of H20 and the tetrahydrofuran is distilled off in vacuo at -10C.
The mixed anhydride is obtained as an oil which readily isomerises into the E form on warming (l~MR).
Example 2~
1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-bbutene-carbo~ylic ~-toluenesulphonic anhydride Preparation i.n analogy to Example 22 from the appropriate Z-butenecarboxylic acid and p-toluenesul-phonyl chloride at -20 to -~0C.
Example 24 15 7-cl-(2-tert~-Butoxycarbonylaminothiazol-4-yl)-l(zz)-pr penecarboxamido]-3-acetoxymethyl-3-cephem-4-carboxxylic acid .. .. . . . . . .
0.005 mol (1.42 g) ox 1-(2 ter-t.-butoxycarbonyl-aminothiazol-4 yl)-l(Z)-propenecarbo~ylic acid and 0.0055 mol (0.76 ml) of triethylamine are dissolved in 20 ml of anhydrous methylene chloride, the mixture is cooled down to -50C, 0.0051 mol (0.40 ml) of me-thanesulphonyl chlor-ide is added and the mixture is stirred at -50 to -40C
for 5 hours.
Then a solution of 0~006 mol (1.63 g) of 3-acet-oxymethyl-7-amino-3-cephem-4-carboxylic acid and 0 013 mol (1.80 ml) of triethylamine in 20 ml of anhydrous methyl-ene chloride, which has been previously cooled to -50C, is added and the mixture is allowed to warm to room temperature over 12 hours.
To work up, the mixture is washed twice with 10 ml of H20 each time, the methylene chloride phase is covered with 40 ml of H20 and acidified, with stirring and cooling in ice, to pH 2-3 with 1 N HCl. The organic phase is separated of, the H20 phase is extracted 2 times with Le A 21 ~70 ~3~39~L
- 31 _ 20 ml of methylene chloride each time, the combined methylene chloride phases are washed with saturated NaCl solutlon, dried over Na2S04 and concentrated in vacuo on a rotary evapora-tor. The desired cepha'o-sporin is obtained almost aua~ti-tatively, Example 25 7-cl-(2~tert~-Butoxycarbcnylaminothiazol-4-yl)-l(zz)-propenecarboxamido~-3~ methyl-1 H-tetrazol-~-~l)thio-methyl-3-cephem-4-carbo~Jlic acid .. . .. . _ Preparation is carried out in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxylic acid and 7-amino-3-(1-methyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Yield 92%.
Exam le 26 7-Cl-(2-tert~-Buto~yycarbonylaminothiazol-4-yl)-l((z)-butenecarboxyamido]-3-aceto~methyl-3-cephem-4-carbboxylic acid Preparation in analogy to Example 24 prom 1-(2tert.-butoxycarbonylaminothiazol-4-yl)-1-(Z)-butenne-carboxylic acid and 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid.
Example 27 7-cl-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(zz)-butenecarboxamido]-3-(1 methyl-l H-te~trazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid _ _ . _ . .
Preparation in analogy to Example 24 from 1-(2-tert.~
butoxycarbonylaminothiazol-4-yl)-l(Z)-butenecarboxxylic acid and 7-amino-3-(1-methyl-1 H-tetrazol-5-yl)-thio-methyl--3-cephem-4-carboxylic acid.
yield 88%.
~xam~le 28 7-Cl-(2-tert.-Butoxycarbonylaminothlazol-4-yl)-l(Z)-heptenecarboxamido]-3-acetoxymethyl-3-cephem--4-car-boxylic acid ~;~3~
Preparation in analogy to Example 24 from 1-(2--tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)--heptene-carboxylic acid and 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid.
Yield 90%.
Example 29 7-C1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(ZZ)-hep-tenecarboxamido~-3-(1-methyl-1 ~-tetrazol-5-yl)-thio-methyl-3-cephem-4-carboxylic acid Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-heptenne-carboxylic acid and 7-amino-3-(1-me~hyl~ elf thiomethyl-3-cephem-4-carboxylic acid.
Yield 85%.
Example 30 7-C1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-3-mmethyl-1(Z)-butenecarboxamido~-3-acetoxymethyl-3-cephem-44-car-boxylic acid , . _ .
Preparation in analogy -to Example 24 from 20 1-(z-tert~-butoxycarbonylaminothiazol-4-yl)-3-methhyl-l(z) butenecarboxylic acid and 3 aceto~Jmethyl-7-amino-3-ceph-em-4-carboxylic acid.
Yield 93%.
Example 31 25 7-C1-(2--tert.-Butoxycarbonylaminothiazol-4-yl)-4--phenyl-1(Z)-butenecarboxamido]-3-acetoxymethyl-3-cephem-44-car-boxylic acid - Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-4-~henny'-1~
butenecarboxylic acid æ~d ~-acetoxymethyl-7-amino-3-cephem-4~carboxy1ic acid. Yield 95%.
ExamPle 32 7-Cl-(2-tert~-Butoxycarbonylaminothiazol-4-yl)-l(zz) propenecarboxamido]-3-methyl-3-cephem-4-carboxylicc acid Le A 21 370 ~L23~
Preparation in analogy to Example 24 Irom 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(z)-propenne-carboxylic acid and 7-amino-3-methyl-3-cephem-4-carbo~Jlic acid. Unlike Example 24, the 7-amino-3-methyl-3-ceph-em-4-carboxylic acid is dissolved in methylene chloride with the equimolar amount of diisopropylamine instead of with triethylamine.
Yield 88%.
Example 3 107-cl-(2-tert.-Butoxycar~onylaminothiazol-4-yl)-l(zz)-propenecarboxamldo]~3-aminocarbonyloxymethyl-3-cepphem-4-Garbo,Yylic acid Preparation in analogy to Example 24 Irom 1-(2-tert,-butoxycarbonylaminothiazol-4-yl)-l(Z)-ppropene-carboxylic acid and 7-amino-3-aminocarbonylo~ymethyl-3-cephem-4-carboxylic acid. Unlike Example 24, the 7-amino-3-aminocarbonyloxymethyl-3-cephem-4-carboxxylic acid is no-t dissollled in methylene chloride l~ith tri-ethylamine, but in anhydrous dimethyl~ormamide with the equimolar amount of diiso~ropylamine, and the solution obtained is added to the mi,ced carbo~cylic sulphonic anhydride in methylene chloride, Towork up, themixtureis evaporated at 0C in vacuo, the residue is taken up in water, extracted with methylene chloride, the aqueous phase is co~jered l~ith ethyl acetate and acidified to pH 2-3. The product separates out as an oil between the phases.
Example_34 Diphenylmethyl 7-Cl-(2-tert.-butoxycarbonylaminothiazol-30 4-yl)-l(Z)-propenecarboxamido]-3-CePhem-4-Carboxyllate Preparation in analogy to Example 24 prom 1-(2-tert,-butoxycarbonylaminothiazol-4-yl)-l(Z)-ppropene-carboxylic acid and diphenylmethyl 7-amino-3-cephem-4-carboxylate.
Yield 93%.
Le A 21 370 ~;~3~
_ ~4 _ Example 35 7-C1-(2-Aminothiazol~4-yl)-l(Z)-propenecarboxamidool-3-acetoxymethyl-3-cephem-4-carboxylic acid 10 ml of trifluoroacetic acid is added to the BOC-protected cephalosporin from Example 24, and the mix-ture is stirred at room temperature for 30 minutes.
m e trifluoroacetic acid is then removed at room tempera-ture in vacuo, the residue is trea-ted with 20 ml of methanol/H20 10:1 and then with 10% strength NaHC03 solution, until a clear solution at pH 6-7 is obtained.
The pH is then slowly adjusted to 3 ;~ 'r or Of the methanol is slowly removed in vacuo and, if neces-sary, the pH is adjusted again to 3. The precipitated product is filtered off under suction. Yield 70,S.
Examples 36-44 The cephalosporins from the Examples 25 to 34 are unblocked in analogy to example 35. Yields are between 50 and 90%.
Le A 21 370 . _ .
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the general formula (in which R2 denotes CO2R3, R3 and R4 can be the same or differnt and denote (i) an alkyl radical with 1 to 15 carbon atoms, (ii) an alkenyl radical with 3 to 15 carbon atoms, (iii) a cycloalkyl radical with 3 to 10 carbon atoms, (iv) a cycloalkenyl radical with 5 to 10 carbon atoms, (v) a carbocyclic aryl radical with 1 to 3 rings, or (vi) a heterocyclic radical of the formula:
or (wherein R6 is hydrogen, methyl, 2-dimethylamino-ethyl, carboxymethyl or sulphomethyl, and R7 is hydrogen or methyl), each of the alkyl (i), the alkenyl (ii), the cycloalkyl (iii), and the cycloalkenyl (iv) radicals optionally having 1 to 5 substituents selected from the group consisting of (C1-C4)-alkyl, (C1-C4)alkoxy, halogen, CN, tri[(C1-C5)alkyl]silyl or phenyl, each of the carbocyclic aryl (v) and the phenyl substituent optionally having 1 to 5 substituents selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkoxycarbonyl, halogen, phenyl, nitro and CN, R1represents an alkyl with 1 to 10 carbon atoms or cycloalkyl with 3 to 10 carbon atoms radical, each of which may have 1 to 5 substituents selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio,(C1-C6)alkyl-amino, (C1-C6)alkyloxycarbonyl and phenyl; or R1 represents a carbocyclic aryl radical with 1 to 3 rings or a heterocyclic radical of the formula:
or (wherein R6 is hydrogen, methyl, 2-dimethylaminoethyl, carboxymethyl or sulphomethyl, and R7 is hydrogen or methyl, the carbocyclic aryl and the above mentioned phenyl substituent optionally having 1 to 5 substituents selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkyloxycarbonyl, halogen and phenyl)), which process - 36a -comprises reacting a compound of formula (X) (X) (in which R2, R3 and R4 are as defined above), in a solvent for the reactants, at a low temperature, with a base and then with an aldehyde of the general formula R1-CHO, (in which R1 is as defined above).
or (wherein R6 is hydrogen, methyl, 2-dimethylamino-ethyl, carboxymethyl or sulphomethyl, and R7 is hydrogen or methyl), each of the alkyl (i), the alkenyl (ii), the cycloalkyl (iii), and the cycloalkenyl (iv) radicals optionally having 1 to 5 substituents selected from the group consisting of (C1-C4)-alkyl, (C1-C4)alkoxy, halogen, CN, tri[(C1-C5)alkyl]silyl or phenyl, each of the carbocyclic aryl (v) and the phenyl substituent optionally having 1 to 5 substituents selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkoxycarbonyl, halogen, phenyl, nitro and CN, R1represents an alkyl with 1 to 10 carbon atoms or cycloalkyl with 3 to 10 carbon atoms radical, each of which may have 1 to 5 substituents selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio,(C1-C6)alkyl-amino, (C1-C6)alkyloxycarbonyl and phenyl; or R1 represents a carbocyclic aryl radical with 1 to 3 rings or a heterocyclic radical of the formula:
or (wherein R6 is hydrogen, methyl, 2-dimethylaminoethyl, carboxymethyl or sulphomethyl, and R7 is hydrogen or methyl, the carbocyclic aryl and the above mentioned phenyl substituent optionally having 1 to 5 substituents selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkyloxycarbonyl, halogen and phenyl)), which process - 36a -comprises reacting a compound of formula (X) (X) (in which R2, R3 and R4 are as defined above), in a solvent for the reactants, at a low temperature, with a base and then with an aldehyde of the general formula R1-CHO, (in which R1 is as defined above).
2. The process according to claim 1, in which in the starting materials R1 represents an alkyl radical with 1 to 15 carbon atoms or, a cycloalkyl radical with 3 to 10 carbon atoms, each of which may have 1 or 2 of the substituents defined in claim 1, or R1 represents a carbocyclic aryl radical with 1 or 2 rings which may have 1 or 2 of the substituents as defined in claim 1.
3. A process according to claim 2, wherein R3 is C(CH3)3, and R4 is an alkyl radical with 1 to 15 carbon atoms, an alkenyl radical with 3 to 15 carbon atoms, a cycloalkyl radical with 3 to 10 carbon atoms, a cycloalkenyl radical with 5 to 10 carbon atoms, or phenyl, wherein the alkyl radical may be substituted by tri[(C1-C5)alkyl]silyl.
4. The process according to claim 1, 2 or 3, in which 1 to 1.1 equivalents of base, then 1 to 1.2 equivalents of the aldehyde are employed.
5. The process according to claim 1, 2 or 3, in which the base is added, at -50° to -80°C, to a solution of the compound of formula (X), and then the aldehyde is added at -50° to -60°C, and the mixture is stirred at -50° to -60°C for about 12 hours.
6. The process according to claim 1, 2 or 3, in which the solvent is tetrahydrofuran.
7. The process according to claim 1, 2 or 3, in which the base is potassium tert.-butylate, lithium diisopropylamide or butyllithium.
8. A compound of the formula (XI) as defined in claim 1, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000541321A CA1247109A (en) | 1981-11-19 | 1987-07-06 | Intermediates for the preparation of cephalosporins and their preparation |
| CA000541405A CA1240985A (en) | 1981-11-19 | 1987-07-06 | Preparation of cephalosporins |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3145727.4 | 1981-11-19 | ||
| DE19813145727 DE3145727A1 (en) | 1981-11-19 | 1981-11-19 | INTERMEDIATE PRODUCTS, METHOD FOR THE PRODUCTION THEREOF AND METHOD FOR THE PRODUCTION OF CEPHALOSPORINES |
| CA000415708A CA1212949A (en) | 1981-11-19 | 1982-11-17 | Intermediate products, process for their preparation and process for the preparation of cephalosporins |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000415708A Division CA1212949A (en) | 1981-11-19 | 1982-11-17 | Intermediate products, process for their preparation and process for the preparation of cephalosporins |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000541405A Division CA1240985A (en) | 1981-11-19 | 1987-07-06 | Preparation of cephalosporins |
| CA000541321A Division CA1247109A (en) | 1981-11-19 | 1987-07-06 | Intermediates for the preparation of cephalosporins and their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1238911A true CA1238911A (en) | 1988-07-05 |
Family
ID=25669864
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000505254A Expired CA1238911A (en) | 1981-11-19 | 1986-03-26 | Substituted amino thiazole derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1238911A (en) |
-
1986
- 1986-03-26 CA CA000505254A patent/CA1238911A/en not_active Expired
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