CA1240985A - Preparation of cephalosporins - Google Patents
Preparation of cephalosporinsInfo
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- CA1240985A CA1240985A CA000541405A CA541405A CA1240985A CA 1240985 A CA1240985 A CA 1240985A CA 000541405 A CA000541405 A CA 000541405A CA 541405 A CA541405 A CA 541405A CA 1240985 A CA1240985 A CA 1240985A
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Abstract
Abstract of the Disclosure Highly active substantially pure z-isomers of cephalo-sporins of the formula:
(I) (in which R1 denotes alkyl, cycloalkyl, aryl or heterocyclic radical, and X denotes hydrogen, alkyl, halogen, alkoxy, hydroxy-methyl, formyloxymethyl, alkylcarbonyloxymethyl, aminocarbonyloxymethyl, pyridinium methyl, 4-carbamoylpyridinium methyl or heterocyclylthio-methyl) are produced by reacting corresponding Z-isomers of the formula:
(XVI) (in which R2 denotes -CO2R3 or hydrogen, R3 denotes alkyl, cycloalkyl, alkenyl, cycloalkenyl aryl or heterocyclic radical, and R5 denotes alkyl, alkenyl, cycloalkyl, cycloalkenyl, carbocyclic or heterocyclic aryl or heterocyclic radical) with a cephalosporanic acid of the formula:
(XVII) and splitting of the group -CO2R3 of present. The intermediate Z-isomers (XVI) may be produced by reacting Z-isomer acids of the formula:
(XIII) with a compound of the formula:
(in which Z denotes Cl, Br or O-SO2-R5).
(I) (in which R1 denotes alkyl, cycloalkyl, aryl or heterocyclic radical, and X denotes hydrogen, alkyl, halogen, alkoxy, hydroxy-methyl, formyloxymethyl, alkylcarbonyloxymethyl, aminocarbonyloxymethyl, pyridinium methyl, 4-carbamoylpyridinium methyl or heterocyclylthio-methyl) are produced by reacting corresponding Z-isomers of the formula:
(XVI) (in which R2 denotes -CO2R3 or hydrogen, R3 denotes alkyl, cycloalkyl, alkenyl, cycloalkenyl aryl or heterocyclic radical, and R5 denotes alkyl, alkenyl, cycloalkyl, cycloalkenyl, carbocyclic or heterocyclic aryl or heterocyclic radical) with a cephalosporanic acid of the formula:
(XVII) and splitting of the group -CO2R3 of present. The intermediate Z-isomers (XVI) may be produced by reacting Z-isomer acids of the formula:
(XIII) with a compound of the formula:
(in which Z denotes Cl, Br or O-SO2-R5).
Description
12~098~
This is a divisional application of Serial Number 505,254 filed March 26, 1986 which in turn is a divisional application of Serial Number 415,708 filed November 17, 1982.
The invention relates to the preparation of certain cephalosporins.
Cephalosporins of the general formula CO-NH ~ ( I
in which Rl denotes an alkyl or aryl radical, are mentioned in German Offenlegungschrift 30 37 997, published on May 5, 1982.
These compounds have a broad antibacterial activity both against Gram-negative and also against Gram-positive bacteria.
According to the process mentioned in this publication, the compounds of the formula (I) are prepared according to the following reaction scheme:
~1 R -CHO Hal H2~ C NH
~C02Et ~ C2Et 2 ~ H2N~ 3~, C02Et (II) ( III ) ~1 (IV) LLL~Rl Alkali I) ~ coupling (V) '~
1240~8~
This is a divisional application of Serial Number 505,254 filed March 26, 1986 which in turn is a divisional application of Serial Number 415,708 filed November 17, 1982.
The invention relates to the preparation of certain cephalosporins.
Cephalosporins of the general formula CO-NH ~ ( I
in which Rl denotes an alkyl or aryl radical, are mentioned in German Offenlegungschrift 30 37 997, published on May 5, 1982.
These compounds have a broad antibacterial activity both against Gram-negative and also against Gram-positive bacteria.
According to the process mentioned in this publication, the compounds of the formula (I) are prepared according to the following reaction scheme:
~1 R -CHO Hal H2~ C NH
~C02Et ~ C2Et 2 ~ H2N~ 3~, C02Et (II) ( III ) ~1 (IV) LLL~Rl Alkali I) ~ coupling (V) '~
1240~8~
- 2 - 23189-544BF
However, this process leads only to unsatisfactory yields of compounds of the formula (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 of the following formulae N ~\~ 2 t --~\N~I~ C02Et (VI) (VII) are obtained a~ by far the largest fraction, due to deconjugation of the double bond and to Michael addition.
Furthermore, 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-aminocephalosporanic acids to give the products of the formula (I), isomerisation of the double bond to give the products of the formula:
i 2N ~ ~ CO-NH ~ ~ (VIII) 1~40385
However, this process leads only to unsatisfactory yields of compounds of the formula (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 of the following formulae N ~\~ 2 t --~\N~I~ C02Et (VI) (VII) are obtained a~ by far the largest fraction, due to deconjugation of the double bond and to Michael addition.
Furthermore, 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-aminocephalosporanic acids to give the products of the formula (I), isomerisation of the double bond to give the products of the formula:
i 2N ~ ~ CO-NH ~ ~ (VIII) 1~40385
- 3 - 23189-5448F
occurs to a large extent. However, the compounds of the formula (VIII) generally show only aout 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 inter-mediate products, and which does not have the abovementioned dis-advantages.
According to the present invention, there is provided a process for the production of a compound of the general formula:
/~
2 ~ ~_ ~ C0-~H ~ S
l o ~ ~ X (I) co2 (in which Rl 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 substituted 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-C~) O-alkyl, (Cl-C6) S-alkyl, alkyloxycarbonyl, halogen or phenyl, and ~24Q98~
_ 4 - 23189-5448F
X represents hydrogen, (Cl-C4) alkyl, halogen (Cl-c4) alkoxy, hydroxymethyl, formyloxymethyl, [(Cl-C4) alkyl]-carbonyloxymethyl, aminocarbonyloxymethyl, pyridiniummethyl, 4-carbamoylpyridinium~
methyl or heterocyclythiomethyl radical wherein heterocyclyl represents a radical of the formula:
~N ' -~S ~ R or ~ S
(in which R6 denotes hydrogen, methyl, 2-dimethylaminoethyl, carboxy-methyl or sulphomethyl and, R7 denotes hydrogen or methyl), which process comprises:
coupling a compound of the general formula R -NH ~\ ~ Co-o-So2-R5 ll (XVI) ~Rl (in which Rl is as defined above, ~2~0~
R2 denotes Co2R3 or hydrogen, R3 denotes an alkyl, cycloalkyl, alkenyl or cycloalkenyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (Cl-C4) alkyl, (Cl-C4) 0-alkyl, halogen, C--N, tri-[(Cl-Cs) alkyl]-silyl and optionally substituted phenyl, or denote an aryl or heterocyclyl radical, each of which may have 1 to 5 sub-stituents, 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, alkyloxy-carbonyl, halogen, phenyl, nitro or C--N, there being at least one carbon atom separating heteroatoms as sub-stituents of the radicals and double bonds in the alkenyl and cycloalkenyl radicals from the oxycarbonyl group, and R5 denotes an alkyl, alkenyl, cycloalkyl, cycloalkenyl, carbocyclic or heterocyclic aryl or heterocyclyl radical each of which may have 1 to 3 substituents selected from the group consisting of halogen, alkyl, aryl, O-alkyl, S-alkyl, CN, alkoxycarbonyl or nitro), with a cephalo-sporanic acid of the general formula:
`r~ 1 ~ N ~ (XVII) O I X
(in which X is as defined above), and then splitting off the protectivegroup R2 except when R2 is hydrogen.
lZ40~15 A preferred overall process for producing the compound of formula (I) starting from an easily available material may be described as follows:
a) a compound of the general fo~mula 2 ~ ~ ~ Co2R4 (IX) tin which R4 denotes an alkyl, cycloalkyl, alkenyl, or cycloalkenyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (C1-C4) alkyl, (Cl-C4) O-alkyl, halogen, C-N, tri[(Cl-Cs) 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-~, there being at least one carbon atom separating hetero-atoms as substituents of 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 R3-o-Co-o-Co-o-R3 (IXa) (in which R3 can be the same or different from R4 and has the meaning given to R4), b) the product of the general formula 12409~
~ 7 ~ 23189-5448F
2 S ~
N ~ N ~ C02R (X) oo in which R3 R2 denotes Co~R3, 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 ~ \ ~ C02R (XI) R -O-CO-O R
(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 R2-NH ~ Co2R4 R (XII) ~09~35 (in which R1, R2 and R4 have the meanings given above~, d) the Z-acid of the general formula R -NH --~\N ~ CO H
2 (XIII) R
(in which Rl and R2 have t~e meanings given above, or R2 may be hydrogen) is then obtained from the compound o~ formula (XII) by separation of the Z and E isomers and subsequent saponification or by selective saponification, and e) the Z-acid of formula (XIII) is then reacted with a compound of the general formula Z-So2-R5 (in which Z denotes a chlorine or bromine atom or -o-So2-R5 , and R5 denotes an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl radical), to give a compound of the general formula I
R -NH ~ ~ 5 \~ / CO-O-S02-R
I ~ Rl (XVI) ~24Q9~3~
(in which Rl, R2 and R5 have the meanings given above), which f) is then coupled with a cephalosporanic acid of the general formula 2 ~ S
/J J7~\x C02H (XVII) (in which X has the meaning given above), and g) the protective group R2 is then split off unless, R2 is hydrogen.
The preferred overall process including the reaction according to the present invention forthe production of compounds of formula (I) may be summarized in the following reaction scheme:
R2HN ~ ~ 4 (R -O-CO)20 2 S ~ 1 Base C=O
( IX ) (X) 124~
2 ~ ~ 4 Base_ ~ R NH ~ ~ o R4 'flcation >
R O~C-O R
(XI) (XII) 3~ 1 + ~ ~ ~ Co2H
(XIII) (XIV) 1. Silylation Separation (XIV) > (XIII) + (XIV) (XIII) 2. Base _ .
~LZ40~8~:;
~ 23189-5448F
1. Base (XIII) R2 NH ~ ~ 5 2. XSo2R5 N~ ~ CO-O-S02-R
(XV) (XVI) base (XVI ) + H2N ~ ~ R2_NH~ 1 ~O~X
(XVII) (XVIII) (I) Further details of the reaction steps for the production of compounds of formula (I) are given later in -the specification.
Particularly preferred compounds of formula (X) are those in which, R2 denotes 0-CO-C(CH3)3, R3 denotes C(CH3)3 and R4 denotes optionally substituted alkyl radical with 1 to 15 I 10 carbon atoms, an optionally substituted alkenyl radical with 3 to 15 carbon atoms, an optionally substituted cyclo-alkyl 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 compounds of formula (X) are those in which R2 denotes a tert.-butoxycarbonyl radical, R3 denotes a tert.-butyl radical, and R4 denotes a methyl, ethyl, tert. butyl ~r trimethylsilyl ethyl radical.
The alkyl, alkenyl, cycloalkyl and cycloalkenyl, radicals mentioned can be substituted by alkyl radicals . ~
~2~
with 1 to 4 carbon atoms, O~alkyl radicals with 1 to 4 carbon atoms, halogen (preferably chlorine3, optionally substituted phenyl radicals, C-N and tri-(Cl to C5 alkyl)-silyl, All the aryl and heterocyclyl 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, prefer-ably 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 of formula (X) are aprotic polar solvents such as aceto-nitrile, dimethylformamide, hexamethylphosphoric acid triamide or dimethyl sulphoxide, particularly the latter two. The reaction takes place particularly advantageously at room temperature or at lower temperatures, for example, between 10 and -50C, the compon-ents generally being allowed to react with oneanother for 1 to 7 days. The pyrocarbonic acid ester of formula (IXa) is generally employed in 2 to 2.5 mol-equivalents.
- 14 - 12~0985 23189-5448F
Other solvents~ higher temperatures or acylation catalysts, such as 4-dimethylaminopyridine, strongly fa~our the formation of the undesired products of the formula.
~ ~ ~ CO2R (XIX) o In the process according to the invention for the prep-aration of the novel compounds of the formula (XI), generally the compound of the fGrmula (X) is treated with 1 to 1.1 equivalents of a base in a solvent for the reactants at a low temperature, and then 1 to 1.2 equivalents of 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 added, at -50 to -80C, 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 12~0~85 atoms, an optionally substituted carbocyclic or heterocyclic arvl radical with 1 or 2 rings or an optionally substituted hetero-cyclic radical with 1 to 3 rings, which can contain up to 5 hetero-atoms selected from nitrogen, sulphur and oxygen atoms.
Suitable substituentsfor 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.
If Rl represents a substituted (preferably by the above-mentioned 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 con-trary, 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 ~; ~2~(~9~
aldehyde Rl-CHO to warm to xoom 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 tempera-ture for about 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. The solvent and the base used can be those mentioned for the reaction of the compound of formula (X3 to give the compound of formula (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 chromatograph-y on silica gel.
Rl, R 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 sapo~fied. 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 X
~24098~
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 con-version 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 tempera-ture or with slight 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 tetrahydro-furan, with a base, such as potassium tert.-butylate and subsequent hydrolysis with dilute acid into a mixture of the E-carboxylic acids of the formula (XIV) and the Z-carboxylic acids of the formula (XIII).
~1 ~24~985 The Z-carboxylic acids of the formula (XIII) may be isolated in pure form from this mixture o~ 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 methanol from weakly basic ion exchangers, whilst, in contrast, the Z-carboxylic acids of the formula (XIII) are only eluted after addition of electrolytes, for example, 2 N sodium hydroxide solution. Weakly basic ion exchangers are to be understood as including those ion exchangers in solid or liquid 40rm 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 the compounds of the formula (XII) was a protective group saponifiable by alkali (such as a methyloxycarbonyl group). How-ever, it is more advantageous for carrying out the process for the preparation of the compounds of the formula (I) if R2 is a pro-tective group which is stable under the conditions of saponifica-tion, preferably tert.-butyloxycarbonyl.
A large number of methods, which in the last analysis are derived from peptide chemistry, are known in cephalosporin chemis-try 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 ceph-* Trade Mark 124098~
= 19 -- 23189-5448F
alosporanic acids of the formula (XVII), ox they only lead to very poor yields, particularly when R 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 to isomerise into the E-form after activation of the carboxyl function, for example, conversion into the acid chloride. Then, after re-action 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 R -NH ~ ~ CO-NH ~ ~ (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 and without the abovementioned disadvantages by converting them into the mixed anhydrides of the formula (XVI) at low temper-atures.
As indicated previously, these compounds of the formula I (XVI) are new and form a further subject of the present invention.
In these compounds R5, when an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or hetero-cyclyl radical, can be substituted by a substituent selected from halogen, alkyl, aryl, O-alkyl, S-alkyl, CN, alkoxycarbonyl and nitro.
',~i 09~5 Especially preferred compounds of formula (X~I) are those, in which R5 denotes an alkyl radical with 1 to 10 carbon atoms, which is optionally substituted by fluorine, chlorine, CN, phenyl, alkyloxycarbonyl, alkyloxy or alkyl (it being preferred for the alkyl 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 substituents to carry 1 to 4 carbon atoms), and nitro, trifluoromethyl and phenyl.
When R5 is substituted, there are preferably 1 to 3 sub-stituents, preferably those mentioned, present.
In very particularly preferred compounds of formula (XVI) R represents a methyl or p-tolyl radical.
This type of mixed anhydrides of the formula (XVI) is preferably prepared by dissolving the caroxylic 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 of 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-form or dimethylformamide).
Suitable amines are tertiary amines (such as triethyl-amine or tributylamine) and also sterically hindered secondary amines (such as diisopropylamine).
~.,"i, ~409~35 - 21 - 23189~5448F
The reactions can be carried out at ~ temperature between -80C and room temperature. low temperatures preventin~ isomerisa-tion of the su~stituents 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, filtering off under suction the triethylamine hydrochloride formed and distillina 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 cephalo-sporanic acids of the formula (XVII). For this purpose, the ce~halos~oranic 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 temperature 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.
I 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 the 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 , ~l~24()98~
cephalosporin chemistry (such as silyl, tert.-butyl or diphenyl-methyl esters).
After work-up, the compounds of the formula (XVIII) are obtained, in which Rl and R2 exhibit the meanings mentioned for the compounds of the formula (XVI) and X represents a group suitable as a cephalosporin substituent for example denotes hydrogen, Cl to C4 alkyl, halogen, Cl to C4 alkoxy, hydroxymethyl, formyloxymethyl, (Cl to C4 alkyl)-carbonyloxymethyl, aminocarbonyloxymethyl, pyri-diniummethyl, 4-carbamoylpyridiniummethyl or heterocyclylthiomethyl ("heterocyclyl" preferably representing a radical of the formula \\N ~ R7 ~ ~N
N N S 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, hydroxymethyl, acetyloxymethyl, aminocarbonyloxymethyl, pyridiniummethyl N--N N N
N--N
CH2 S--~N/N , CH2S ~N,N or CH -S ~ ~
¦ I ~ CH3 Me .
~LZ~og8~
- 22a - 23189-5448F
The compound of the formula (Il~ in which Rl 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 R2. As already mentioned for the com-pounds 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 R is a protective group stable in base which may be selectively split off, such as tert.-butyloxycarbonyl (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 Ethyl 2-tert.-butoxycarbonylimino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetate -186 g (1 mol) of ethyl 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 1 of water and is taken up in 2 1 of methylene chloride. The water is separated off, the methylene chloride phase is dried over Na2SO4 and concentrated on a rotary evaporator. The oil obtained is taken up immediately (before crystallisation starts) for crystallisationin 21 ofpetroleum ether.
Yield 302 g (78~), melting point 90C.
~J
~LZ~09~3S
_ 23 _ 23189-5448F
Exam~le 2 Methyl 2-tert.-butoxycarbonylimlno-3-tert.-butoxycarbonyl-
occurs to a large extent. However, the compounds of the formula (VIII) generally show only aout 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 inter-mediate products, and which does not have the abovementioned dis-advantages.
According to the present invention, there is provided a process for the production of a compound of the general formula:
/~
2 ~ ~_ ~ C0-~H ~ S
l o ~ ~ X (I) co2 (in which Rl 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 substituted 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-C~) O-alkyl, (Cl-C6) S-alkyl, alkyloxycarbonyl, halogen or phenyl, and ~24Q98~
_ 4 - 23189-5448F
X represents hydrogen, (Cl-C4) alkyl, halogen (Cl-c4) alkoxy, hydroxymethyl, formyloxymethyl, [(Cl-C4) alkyl]-carbonyloxymethyl, aminocarbonyloxymethyl, pyridiniummethyl, 4-carbamoylpyridinium~
methyl or heterocyclythiomethyl radical wherein heterocyclyl represents a radical of the formula:
~N ' -~S ~ R or ~ S
(in which R6 denotes hydrogen, methyl, 2-dimethylaminoethyl, carboxy-methyl or sulphomethyl and, R7 denotes hydrogen or methyl), which process comprises:
coupling a compound of the general formula R -NH ~\ ~ Co-o-So2-R5 ll (XVI) ~Rl (in which Rl is as defined above, ~2~0~
R2 denotes Co2R3 or hydrogen, R3 denotes an alkyl, cycloalkyl, alkenyl or cycloalkenyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (Cl-C4) alkyl, (Cl-C4) 0-alkyl, halogen, C--N, tri-[(Cl-Cs) alkyl]-silyl and optionally substituted phenyl, or denote an aryl or heterocyclyl radical, each of which may have 1 to 5 sub-stituents, 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, alkyloxy-carbonyl, halogen, phenyl, nitro or C--N, there being at least one carbon atom separating heteroatoms as sub-stituents of the radicals and double bonds in the alkenyl and cycloalkenyl radicals from the oxycarbonyl group, and R5 denotes an alkyl, alkenyl, cycloalkyl, cycloalkenyl, carbocyclic or heterocyclic aryl or heterocyclyl radical each of which may have 1 to 3 substituents selected from the group consisting of halogen, alkyl, aryl, O-alkyl, S-alkyl, CN, alkoxycarbonyl or nitro), with a cephalo-sporanic acid of the general formula:
`r~ 1 ~ N ~ (XVII) O I X
(in which X is as defined above), and then splitting off the protectivegroup R2 except when R2 is hydrogen.
lZ40~15 A preferred overall process for producing the compound of formula (I) starting from an easily available material may be described as follows:
a) a compound of the general fo~mula 2 ~ ~ ~ Co2R4 (IX) tin which R4 denotes an alkyl, cycloalkyl, alkenyl, or cycloalkenyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (C1-C4) alkyl, (Cl-C4) O-alkyl, halogen, C-N, tri[(Cl-Cs) 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-~, there being at least one carbon atom separating hetero-atoms as substituents of 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 R3-o-Co-o-Co-o-R3 (IXa) (in which R3 can be the same or different from R4 and has the meaning given to R4), b) the product of the general formula 12409~
~ 7 ~ 23189-5448F
2 S ~
N ~ N ~ C02R (X) oo in which R3 R2 denotes Co~R3, 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 ~ \ ~ C02R (XI) R -O-CO-O R
(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 R2-NH ~ Co2R4 R (XII) ~09~35 (in which R1, R2 and R4 have the meanings given above~, d) the Z-acid of the general formula R -NH --~\N ~ CO H
2 (XIII) R
(in which Rl and R2 have t~e meanings given above, or R2 may be hydrogen) is then obtained from the compound o~ formula (XII) by separation of the Z and E isomers and subsequent saponification or by selective saponification, and e) the Z-acid of formula (XIII) is then reacted with a compound of the general formula Z-So2-R5 (in which Z denotes a chlorine or bromine atom or -o-So2-R5 , and R5 denotes an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl radical), to give a compound of the general formula I
R -NH ~ ~ 5 \~ / CO-O-S02-R
I ~ Rl (XVI) ~24Q9~3~
(in which Rl, R2 and R5 have the meanings given above), which f) is then coupled with a cephalosporanic acid of the general formula 2 ~ S
/J J7~\x C02H (XVII) (in which X has the meaning given above), and g) the protective group R2 is then split off unless, R2 is hydrogen.
The preferred overall process including the reaction according to the present invention forthe production of compounds of formula (I) may be summarized in the following reaction scheme:
R2HN ~ ~ 4 (R -O-CO)20 2 S ~ 1 Base C=O
( IX ) (X) 124~
2 ~ ~ 4 Base_ ~ R NH ~ ~ o R4 'flcation >
R O~C-O R
(XI) (XII) 3~ 1 + ~ ~ ~ Co2H
(XIII) (XIV) 1. Silylation Separation (XIV) > (XIII) + (XIV) (XIII) 2. Base _ .
~LZ40~8~:;
~ 23189-5448F
1. Base (XIII) R2 NH ~ ~ 5 2. XSo2R5 N~ ~ CO-O-S02-R
(XV) (XVI) base (XVI ) + H2N ~ ~ R2_NH~ 1 ~O~X
(XVII) (XVIII) (I) Further details of the reaction steps for the production of compounds of formula (I) are given later in -the specification.
Particularly preferred compounds of formula (X) are those in which, R2 denotes 0-CO-C(CH3)3, R3 denotes C(CH3)3 and R4 denotes optionally substituted alkyl radical with 1 to 15 I 10 carbon atoms, an optionally substituted alkenyl radical with 3 to 15 carbon atoms, an optionally substituted cyclo-alkyl 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 compounds of formula (X) are those in which R2 denotes a tert.-butoxycarbonyl radical, R3 denotes a tert.-butyl radical, and R4 denotes a methyl, ethyl, tert. butyl ~r trimethylsilyl ethyl radical.
The alkyl, alkenyl, cycloalkyl and cycloalkenyl, radicals mentioned can be substituted by alkyl radicals . ~
~2~
with 1 to 4 carbon atoms, O~alkyl radicals with 1 to 4 carbon atoms, halogen (preferably chlorine3, optionally substituted phenyl radicals, C-N and tri-(Cl to C5 alkyl)-silyl, All the aryl and heterocyclyl 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, prefer-ably 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 of formula (X) are aprotic polar solvents such as aceto-nitrile, dimethylformamide, hexamethylphosphoric acid triamide or dimethyl sulphoxide, particularly the latter two. The reaction takes place particularly advantageously at room temperature or at lower temperatures, for example, between 10 and -50C, the compon-ents generally being allowed to react with oneanother for 1 to 7 days. The pyrocarbonic acid ester of formula (IXa) is generally employed in 2 to 2.5 mol-equivalents.
- 14 - 12~0985 23189-5448F
Other solvents~ higher temperatures or acylation catalysts, such as 4-dimethylaminopyridine, strongly fa~our the formation of the undesired products of the formula.
~ ~ ~ CO2R (XIX) o In the process according to the invention for the prep-aration of the novel compounds of the formula (XI), generally the compound of the fGrmula (X) is treated with 1 to 1.1 equivalents of a base in a solvent for the reactants at a low temperature, and then 1 to 1.2 equivalents of 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 added, at -50 to -80C, 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 12~0~85 atoms, an optionally substituted carbocyclic or heterocyclic arvl radical with 1 or 2 rings or an optionally substituted hetero-cyclic radical with 1 to 3 rings, which can contain up to 5 hetero-atoms selected from nitrogen, sulphur and oxygen atoms.
Suitable substituentsfor 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.
If Rl represents a substituted (preferably by the above-mentioned 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 con-trary, 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 ~; ~2~(~9~
aldehyde Rl-CHO to warm to xoom 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 tempera-ture for about 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. The solvent and the base used can be those mentioned for the reaction of the compound of formula (X3 to give the compound of formula (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 chromatograph-y on silica gel.
Rl, R 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 sapo~fied. 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 X
~24098~
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 con-version 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 tempera-ture or with slight 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 tetrahydro-furan, with a base, such as potassium tert.-butylate and subsequent hydrolysis with dilute acid into a mixture of the E-carboxylic acids of the formula (XIV) and the Z-carboxylic acids of the formula (XIII).
~1 ~24~985 The Z-carboxylic acids of the formula (XIII) may be isolated in pure form from this mixture o~ 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 methanol from weakly basic ion exchangers, whilst, in contrast, the Z-carboxylic acids of the formula (XIII) are only eluted after addition of electrolytes, for example, 2 N sodium hydroxide solution. Weakly basic ion exchangers are to be understood as including those ion exchangers in solid or liquid 40rm 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 the compounds of the formula (XII) was a protective group saponifiable by alkali (such as a methyloxycarbonyl group). How-ever, it is more advantageous for carrying out the process for the preparation of the compounds of the formula (I) if R2 is a pro-tective group which is stable under the conditions of saponifica-tion, preferably tert.-butyloxycarbonyl.
A large number of methods, which in the last analysis are derived from peptide chemistry, are known in cephalosporin chemis-try 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 ceph-* Trade Mark 124098~
= 19 -- 23189-5448F
alosporanic acids of the formula (XVII), ox they only lead to very poor yields, particularly when R 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 to isomerise into the E-form after activation of the carboxyl function, for example, conversion into the acid chloride. Then, after re-action 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 R -NH ~ ~ CO-NH ~ ~ (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 and without the abovementioned disadvantages by converting them into the mixed anhydrides of the formula (XVI) at low temper-atures.
As indicated previously, these compounds of the formula I (XVI) are new and form a further subject of the present invention.
In these compounds R5, when an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or hetero-cyclyl radical, can be substituted by a substituent selected from halogen, alkyl, aryl, O-alkyl, S-alkyl, CN, alkoxycarbonyl and nitro.
',~i 09~5 Especially preferred compounds of formula (X~I) are those, in which R5 denotes an alkyl radical with 1 to 10 carbon atoms, which is optionally substituted by fluorine, chlorine, CN, phenyl, alkyloxycarbonyl, alkyloxy or alkyl (it being preferred for the alkyl 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 substituents to carry 1 to 4 carbon atoms), and nitro, trifluoromethyl and phenyl.
When R5 is substituted, there are preferably 1 to 3 sub-stituents, preferably those mentioned, present.
In very particularly preferred compounds of formula (XVI) R represents a methyl or p-tolyl radical.
This type of mixed anhydrides of the formula (XVI) is preferably prepared by dissolving the caroxylic 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 of 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-form or dimethylformamide).
Suitable amines are tertiary amines (such as triethyl-amine or tributylamine) and also sterically hindered secondary amines (such as diisopropylamine).
~.,"i, ~409~35 - 21 - 23189~5448F
The reactions can be carried out at ~ temperature between -80C and room temperature. low temperatures preventin~ isomerisa-tion of the su~stituents 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, filtering off under suction the triethylamine hydrochloride formed and distillina 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 cephalo-sporanic acids of the formula (XVII). For this purpose, the ce~halos~oranic 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 temperature 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.
I 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 the 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 , ~l~24()98~
cephalosporin chemistry (such as silyl, tert.-butyl or diphenyl-methyl esters).
After work-up, the compounds of the formula (XVIII) are obtained, in which Rl and R2 exhibit the meanings mentioned for the compounds of the formula (XVI) and X represents a group suitable as a cephalosporin substituent for example denotes hydrogen, Cl to C4 alkyl, halogen, Cl to C4 alkoxy, hydroxymethyl, formyloxymethyl, (Cl to C4 alkyl)-carbonyloxymethyl, aminocarbonyloxymethyl, pyri-diniummethyl, 4-carbamoylpyridiniummethyl or heterocyclylthiomethyl ("heterocyclyl" preferably representing a radical of the formula \\N ~ R7 ~ ~N
N N S 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, hydroxymethyl, acetyloxymethyl, aminocarbonyloxymethyl, pyridiniummethyl N--N N N
N--N
CH2 S--~N/N , CH2S ~N,N or CH -S ~ ~
¦ I ~ CH3 Me .
~LZ~og8~
- 22a - 23189-5448F
The compound of the formula (Il~ in which Rl 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 R2. As already mentioned for the com-pounds 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 R is a protective group stable in base which may be selectively split off, such as tert.-butyloxycarbonyl (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 Ethyl 2-tert.-butoxycarbonylimino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetate -186 g (1 mol) of ethyl 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 1 of water and is taken up in 2 1 of methylene chloride. The water is separated off, the methylene chloride phase is dried over Na2SO4 and concentrated on a rotary evaporator. The oil obtained is taken up immediately (before crystallisation starts) for crystallisationin 21 ofpetroleum ether.
Yield 302 g (78~), melting point 90C.
~J
~LZ~09~3S
_ 23 _ 23189-5448F
Exam~le 2 Methyl 2-tert.-butoxycarbonylimlno-3-tert.-butoxycarbonyl-
4-thiazo~in-4-ylacetate is prepared from methyl 2-aminothiazol-4-yl acetate in analogy to Example 1.
Yield 67%, melting point 67-69C.
Exam~le 3 Ethyl 2-ethoxycarbonylimino-3-ethoxycarbonyl-4-thiazolin-4-ylacetate is prepared from ethyl 2-aminothiazol-4-ylacetate and diethyl pyrocarbonate in analogy to Example 1.
Yield 71%, melting point 102C.
Exam~le 4 Tert.-butyl 2-ter-t -buto~Jcarbonylimino-3-tert.-butoxycar-bonyl-4-thiazolin-4-ylaceta~e _ ~ .
157 g (0.5 mol) of tert.-butyl 2-aminothiazol-4-ylacetate, 150 ml of dimethyl sulphoxide and 260 g (1.2 mols) of g8% di-tert.-butyl pyrocarbonate were reacted in analogy to Example 1.
Yield 620~.
Exam~le ~
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 of dicyclohexylcarbodiimide are added at room temperature to 7.9 g (0.05 mol) of 2-aminothiazol-4-ylacetic acid in 50 ml o~ acetonitrile 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 ~ , , . - .
' - ~
~24C~98~
ether, the desired ester crystallises out.
Yield 2.8 g.
Exam~le o Trimethylsilylethyl 2-tert.-butyloxycarbonylimino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetate is prepared frorn trimethylsilyl 2-aminothiazol-4-ylacetate in analogy to Example 1.
Yield 50%.
Exam~le 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-ylace-tate weredissolved in 80 ml of anhydrous tetrahydrofuran, and, under nitrogen at -50 to -60C, 20 ml (0.032 mol) of a 15% strength solutlon of n-butyllithium in n-hexane wasadded, followed 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 room 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. 10.8 g of an oil is obtained which, according to NMR, is a mixture of diastereorers (TLC: cyclohexane/
ether 1:1).
Exam~le 8 Ethyl 1-(2-tert.-butoxycarbOnylaminothiazol-4-yl)-l(E,Z)-propenecarboxylate me mixture is prepared as indicated in Example 7.However, 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 ~Z~098~
_ 2 ~ _ 23189-5448F
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
Yield 67%, melting point 67-69C.
Exam~le 3 Ethyl 2-ethoxycarbonylimino-3-ethoxycarbonyl-4-thiazolin-4-ylacetate is prepared from ethyl 2-aminothiazol-4-ylacetate and diethyl pyrocarbonate in analogy to Example 1.
Yield 71%, melting point 102C.
Exam~le 4 Tert.-butyl 2-ter-t -buto~Jcarbonylimino-3-tert.-butoxycar-bonyl-4-thiazolin-4-ylaceta~e _ ~ .
157 g (0.5 mol) of tert.-butyl 2-aminothiazol-4-ylacetate, 150 ml of dimethyl sulphoxide and 260 g (1.2 mols) of g8% di-tert.-butyl pyrocarbonate were reacted in analogy to Example 1.
Yield 620~.
Exam~le ~
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 of dicyclohexylcarbodiimide are added at room temperature to 7.9 g (0.05 mol) of 2-aminothiazol-4-ylacetic acid in 50 ml o~ acetonitrile 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 ~ , , . - .
' - ~
~24C~98~
ether, the desired ester crystallises out.
Yield 2.8 g.
Exam~le o Trimethylsilylethyl 2-tert.-butyloxycarbonylimino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetate is prepared frorn trimethylsilyl 2-aminothiazol-4-ylacetate in analogy to Example 1.
Yield 50%.
Exam~le 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-ylace-tate weredissolved in 80 ml of anhydrous tetrahydrofuran, and, under nitrogen at -50 to -60C, 20 ml (0.032 mol) of a 15% strength solutlon of n-butyllithium in n-hexane wasadded, followed 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 room 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. 10.8 g of an oil is obtained which, according to NMR, is a mixture of diastereorers (TLC: cyclohexane/
ether 1:1).
Exam~le 8 Ethyl 1-(2-tert.-butoxycarbOnylaminothiazol-4-yl)-l(E,Z)-propenecarboxylate me mixture is prepared as indicated in Example 7.However, 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 ~Z~098~
_ 2 ~ _ 23189-5448F
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
5 (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-CH3), 2.04 (d, J=7 Hz, 3H, CH-CH3), 1.50 (s;
9H, C(CH3)3), 1.36 (t; J=7 Hz, 3H, CH2-CH3).
E isomer:
1H-N~R (250 MHz, CDC13): o = 10.5 (bs; lH, NH), 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-CH3).
Exam~le_9 Ethyl 2-(2-tert.-butoxycarbonylaminothiazol-4-yl)-2(E,Z)-benzylideneacetate 3.86 G (0.Ol mol) of ethyl 2-tert.-butoxycarbonyl-imino-3-tert~-butoxycarbonyl-4-thiazolin-4-ylacetate 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 3o 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 worl~ 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 , lZ40985 ~ 23189-5448F
"
butanol are removed in vacuo and the residue is extrac~ed with methylene chloride. After drying over Na2S04, the methylene chloride is removed in vacuo. 3.1 g of an oil is obtained, which, according to Nl~R and TLC
(cyclohe~ane/ether 1:1), is an approximately 1:1 mixture of E/Z isomers.
Exam~le 10 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-1-(Z)-pro-penecarbo~ylic acid .
0.145 mol (5~ g) of ethyl 2-tert.-butoxycarbonyl-imino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetate and 40C ml of anhydrous tetrahydrofuran are initially intro-duced under nitrogen and, at -~0 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 is 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.-butoxycarbonylaminothiazol-4-yl)-l(E)-propenecarboxylic acid is obtained (21.0 g, 51%, melting point = 195C
(from acetonitrile)).
The 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 60 C for 24 hours.
After removal of the ethanol by distillation, the alkaline phase is extracted o~ce with 100 ml of methylene chloride, the extract is discarded, the alkaline phase is acidified to pH 2-3 and the desired 1-(2-tert.-Le A 21 370 ...... . . .. .
lZ~0985 butoxycarbonylaminothiazol-4-y~-l(z)-propenecarboxylic acid is extracted with methylene chloride (8.3 g, 20%, melting point = 183C (from acetonitrile)).
Exam~le 11 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-butene-carboxylic acid _ _ _ _ . _ Preparation in analogy to ~Yample 10 with pro-panal instead of acetaldehyde (yield 17/o~ mel~ing point 172C from acetonitrile).
Exam~le 12 1-(2-tert.-butoxycarbonylaminothiazol-4-yl~-l(Z)-pentene-carboxylic acid _ _ . _ _ Preparation in analogy to Example 10 with buta-nal instead of acetaldehyde (melting point l62-3C, from acetonitrile).
Exam~le 13 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-hexene-carboxylic acid Preparation in analogy to Example 10 with penta-nal instead of acetaldehyde (melting point 158C, from acetonitrile).
Exam~le 14 1-(2-ter~.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-~eptene-carboxylic acid Preparation iIl analogy to Example 10 with hexa-nal instead of acetaldehyde (melting point 130-1C, from acetonitrile).
Exam~le 15 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl~-l(Z)-octene-carboxylic acid . _ - Preparation in analogy to Example 10 with hepta-nal instead of acetaldehyde (melting point 164C, from acetonitrile).
~e A 21 370 12~985i - 2$ - 23189-5448F
Ex_mPle 16 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-3-methyl-l(Z)-butenecarboxylic acid Preparation in analogy to Example 10 with iso-butyraldehyde instead of acetaldehyde (melting point 169-71C, from acetonitrile)~
- Example 17 . _ .
1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-4-methyl-l(Z)-pentenecarboxylic acid Preparation in analogy to Example 10 ~ h iso-valeraldehyde instead of acetaldehyde (melting point 173C, from acetonitrile).
Exam~le 18 2-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-3-cyclohexyl-(Z)-acrylic acid Preparation in analogy to Example 10 with cyclo-hexylaldehyde instead of acetaldehyde (melting point ~ 210C, from acetonitrile).
Example 19 1-(2-tert.-Butoxycarbonylaminothiazo1-4-yl)-4-phenyl-l(Z)-butenecarboxylic acid Preparation in analogy to Example 10 with dihydro-cinnamaldehydeinsteadof acetaldehyde (melting point 174C, from acetonitrile).
Example 20 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-carboxylic acid ., ~
0.4~ mol (122 g) of 1-(2-tert.-butoxycarbonyl-aminothiazol-4-yl)-l(E)-propenecarboxylic acid in 800 ml 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 potassium Le A 21 370 ~2~85 tert.-butylate (98%) is added, the m~c~ure is allowed to warm to room temperature and is stirred at room tempera-ture overnighi.
To wor~ up, 100 ml of water is added ~hile cool-ing in ice, the pH is adjusted to 6-8 wi~h 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 chloriàe. The extract is dried, concentrated on a rotary evaporator and the residue is dissolved in 700 ml of methanol. The methanolic solution is run ~hrough a column (2.5 x 80 cm;
400 ml) containing ~eakl~ basic ion exchan~er Lewatit MP 62, at a rate of about 10 ml/.~inute, the column is washed ~ith 2 1 of methanol and eluted ~ith 1 1 of me-thanol/2 N sodium hydroxide solution 10:1. m e elu-ate is concentrated, acidified io pH 2-3 with 2 N HCl and extracted with methylene chloride. After drying over Na2S04 and distilling off the methylene chloride, 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.
Exam~le_21 1-(2-tert.-Butoxycarbonylaminothiazol-4-Yl)-l(Z)-pentene-carboxylic acid -By isomerisation of the corresponding E-pentene-carboxylic acid in analogy to Example 20 Yield 45%.
Example 22 1-(2-tert~-Butoxycarbonylaminothia7ol-4-yl)-l(z)-propene carbo~ylic methanesulphonic anhydride . _ 0.005 mol (1.42 g) of 1-(2-tert.-outoxycarbonyl-aminot~iazol-4-yl)-l(Z)-propenecarbo~Jlic acid and 0.0055 mol (0.76 ml) of triethylamine are dissolved in 10 ml of anhydrous tetrahydrofuran and cooled down to -50C.
Le A 21 ~70 ~24Q98~:i 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.
m e mixed anhydride is obtained as an oil which readily isomerises into the E form on warming (NMR).
Exam~le 23 l-(Z-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-butene-carboxylic p-toluenesulphonic anhydride Preparation in analo~y to Example 22 from the appropriate Z-butenecarbo~flic acid and p-toluenesul-phonyl chloride at -20 to -~0C.
Exam~le 24 _ _ _ 7-[1-(2-tert.-~utoxycarbonylaminothiazol-4-yl)-l(Z)-pr penecarboxamido]-3-aceto~ymethyl-3-cephem-4-carboxylic acid .... . . .
0.005 mol (1.42 g) of 1-(2-tert.-butoxycarbonyl-aminothiazol-4-yl)-l(Z)-propenecarboxylic acid and 0.0055 mol (0.76 ml) of triethylamine are dissolved ln 20 ml of anhydrous methylene chloride, the mixture is cooled down to -50C, 0.0051 mol (0.40 ml) of methanesulphonyl chlor-ide is added and the mixture is stirred at -50 to -40C
for 5 hours.
Then a solution of 0.00~ 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 off, the H20 phase is extracted 2 times with Le A 21 370 . . .
1240~t~5 ..
- 31 _ 23189-5448F
20 ml of methylene chloride each time the combined methylene chloride phases are washed l~ith saturated NaCl solution dried over Na2S04 and concentrated in vacuo on a rotary evaporator. The desired cep~a o-sporin is obtained a~mos~ auant tatively.
Exam~le 25 7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxamido]-3-(1-methyl-1 H-tetrazol-5~yl)thio-methyl-3-cephem-4-carboxylic acid Preparation is carried out in analogy to Example 24 from 1-(2-tert.-butox-ycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxyllc acid and 7-amino-3-(1-methyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Yield 92%.
Exam~le 26 7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-butenecarboxyamido]-3-aceto~ymethyl-3-cephem-4-carboxylic acid Preparation in analogy to Example 24 ~rom 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-1-(Z)-butene-carboxylic acid and 3-acetox~methyl-7-amino-3-cephem-4-carboxylic acid.
Exam~le 27 7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-butenecarboxamido]-3-(1-methyl-1 H-tetrazol-5-yl)thio-methyl-3-cephem-4-carbox-ylic acid . _ _ . . .
Preparation in analogy to Example 24 ~om 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-butenecarboxylic acid and 7-amino~3-(1-methyl-1 H-tetrazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid.
Yield 88%, Exam~le 28 - 7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-heptenecarboxamido]-3-aCetoxymethyl-3-cephem-4-car-boxylic acid Le A 21 370 , . ~ ., .
~ 3.2~0985 Prepara~ion in analogy to Example 2k from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-heptene-carboxylic acid and 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid.
Yield 90%.
Exam~le 29 7-[1~(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-hep-tenecarboxamido~-3-(1-methyl-1 ~-tetrazol-5-yl)-thio-methyl-3-cephem-4-carbox-ylic acid Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-heptene-carboxylic acid and 7-amino-3-(1-meth~Jl~ e~a~ol-~-yl) thiomethyl-3-cephem-4-carboxylic acid.
Yield 85%.
Exam~le 30 7-[1-(2-tert,-Butoxycarbonylaminothiazol-4-yl)-3-methyl-l(Z)-butenecarboxamido]-3-acetoxymethyl-3-cephem-4-car-boxylic acid Preparation in analo~y to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-3-methyl_l(z)_ butenecarboxylic acid and 3-acetoxymethyl-7-amino-3-ceph-em-4-carboxylic acid.
Yield 93%, Example 31 7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-4-phenyl-l(Z)-butenecarboxamido]-3-acetoxymethyl-3-cephem-4-car-boxylic acid -Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-Yl)-4-~henyl-l(Z)-butenecarboxylic acid ~d ~-acetoxymethyl-7-amino-3-cephem 4-carboxylic acid. Yield 95%.
ExamPle 32 7-C1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxamido]-3-methyl-3-cephem-4-carboxylic acid Le A 21 370 .
~240985 Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-carboxylic acid and 7-amino-3-methyl-3-cephem-k-carboxylic 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 ins~ead of with triethylamine.
Yield 88%.
Exam~le 33 7-~1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxamido]-3-aminocarbonyloxymethyl-3-cephem-4-carboxylic acid Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-carboxylic acid and 7-amino-3-aminocarbonyloxymethyl-3-cephem-4-carbox~Jlic acid. Unlike Example 24, the 7-amino-3-aminocarbonylo~methyl-3-cephem-4-carboxylic acid is not dissolved in methylene chloride with tri-ethylamine, but in anhydrous dimethylformamide with the equimolar amount of diisopropylamine, and the solution obtained is added to the mixed carboxylic 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 aaueous phase is covered with ethyl acetate and acidified to pH 2-3. The product separates out as an oil bet~een the phases.
I Exam~le 34 Diphenylmethyl 7-~1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxamido]-3-cephem-4-carboxylate ... . _ . _ Preparation in analogy to Example 24 from 1-(2-tert -butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-carboxylic acid and diphenylmethyl 7-amino~3-cephem-4-carboxylate.
Yield 93%.
Le A 21 370 .
12~)985 3~ 23189-5448F
Examle 35 7-[1-(2-Aminothiazol-4-yl)-l(Z)-propenecarboxamido~-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 tem~era-ture in vacuo, the residue is treated 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 ~ vr ' ~ 51, 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 700,6.
Exam~les 36-44 The cephalosporins from the Examples 25 to 34 are unblocked in analogy to Example ~5. Yields are between 50 and 90%.
Le A 21 370
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-CH3), 2.04 (d, J=7 Hz, 3H, CH-CH3), 1.50 (s;
9H, C(CH3)3), 1.36 (t; J=7 Hz, 3H, CH2-CH3).
E isomer:
1H-N~R (250 MHz, CDC13): o = 10.5 (bs; lH, NH), 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-CH3).
Exam~le_9 Ethyl 2-(2-tert.-butoxycarbonylaminothiazol-4-yl)-2(E,Z)-benzylideneacetate 3.86 G (0.Ol mol) of ethyl 2-tert.-butoxycarbonyl-imino-3-tert~-butoxycarbonyl-4-thiazolin-4-ylacetate 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 3o 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 worl~ 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 , lZ40985 ~ 23189-5448F
"
butanol are removed in vacuo and the residue is extrac~ed with methylene chloride. After drying over Na2S04, the methylene chloride is removed in vacuo. 3.1 g of an oil is obtained, which, according to Nl~R and TLC
(cyclohe~ane/ether 1:1), is an approximately 1:1 mixture of E/Z isomers.
Exam~le 10 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-1-(Z)-pro-penecarbo~ylic acid .
0.145 mol (5~ g) of ethyl 2-tert.-butoxycarbonyl-imino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetate and 40C ml of anhydrous tetrahydrofuran are initially intro-duced under nitrogen and, at -~0 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 is 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.-butoxycarbonylaminothiazol-4-yl)-l(E)-propenecarboxylic acid is obtained (21.0 g, 51%, melting point = 195C
(from acetonitrile)).
The 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 60 C for 24 hours.
After removal of the ethanol by distillation, the alkaline phase is extracted o~ce with 100 ml of methylene chloride, the extract is discarded, the alkaline phase is acidified to pH 2-3 and the desired 1-(2-tert.-Le A 21 370 ...... . . .. .
lZ~0985 butoxycarbonylaminothiazol-4-y~-l(z)-propenecarboxylic acid is extracted with methylene chloride (8.3 g, 20%, melting point = 183C (from acetonitrile)).
Exam~le 11 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-butene-carboxylic acid _ _ _ _ . _ Preparation in analogy to ~Yample 10 with pro-panal instead of acetaldehyde (yield 17/o~ mel~ing point 172C from acetonitrile).
Exam~le 12 1-(2-tert.-butoxycarbonylaminothiazol-4-yl~-l(Z)-pentene-carboxylic acid _ _ . _ _ Preparation in analogy to Example 10 with buta-nal instead of acetaldehyde (melting point l62-3C, from acetonitrile).
Exam~le 13 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-hexene-carboxylic acid Preparation in analogy to Example 10 with penta-nal instead of acetaldehyde (melting point 158C, from acetonitrile).
Exam~le 14 1-(2-ter~.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-~eptene-carboxylic acid Preparation iIl analogy to Example 10 with hexa-nal instead of acetaldehyde (melting point 130-1C, from acetonitrile).
Exam~le 15 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl~-l(Z)-octene-carboxylic acid . _ - Preparation in analogy to Example 10 with hepta-nal instead of acetaldehyde (melting point 164C, from acetonitrile).
~e A 21 370 12~985i - 2$ - 23189-5448F
Ex_mPle 16 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-3-methyl-l(Z)-butenecarboxylic acid Preparation in analogy to Example 10 with iso-butyraldehyde instead of acetaldehyde (melting point 169-71C, from acetonitrile)~
- Example 17 . _ .
1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-4-methyl-l(Z)-pentenecarboxylic acid Preparation in analogy to Example 10 ~ h iso-valeraldehyde instead of acetaldehyde (melting point 173C, from acetonitrile).
Exam~le 18 2-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-3-cyclohexyl-(Z)-acrylic acid Preparation in analogy to Example 10 with cyclo-hexylaldehyde instead of acetaldehyde (melting point ~ 210C, from acetonitrile).
Example 19 1-(2-tert.-Butoxycarbonylaminothiazo1-4-yl)-4-phenyl-l(Z)-butenecarboxylic acid Preparation in analogy to Example 10 with dihydro-cinnamaldehydeinsteadof acetaldehyde (melting point 174C, from acetonitrile).
Example 20 1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-carboxylic acid ., ~
0.4~ mol (122 g) of 1-(2-tert.-butoxycarbonyl-aminothiazol-4-yl)-l(E)-propenecarboxylic acid in 800 ml 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 potassium Le A 21 370 ~2~85 tert.-butylate (98%) is added, the m~c~ure is allowed to warm to room temperature and is stirred at room tempera-ture overnighi.
To wor~ up, 100 ml of water is added ~hile cool-ing in ice, the pH is adjusted to 6-8 wi~h 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 chloriàe. The extract is dried, concentrated on a rotary evaporator and the residue is dissolved in 700 ml of methanol. The methanolic solution is run ~hrough a column (2.5 x 80 cm;
400 ml) containing ~eakl~ basic ion exchan~er Lewatit MP 62, at a rate of about 10 ml/.~inute, the column is washed ~ith 2 1 of methanol and eluted ~ith 1 1 of me-thanol/2 N sodium hydroxide solution 10:1. m e elu-ate is concentrated, acidified io pH 2-3 with 2 N HCl and extracted with methylene chloride. After drying over Na2S04 and distilling off the methylene chloride, 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.
Exam~le_21 1-(2-tert.-Butoxycarbonylaminothiazol-4-Yl)-l(Z)-pentene-carboxylic acid -By isomerisation of the corresponding E-pentene-carboxylic acid in analogy to Example 20 Yield 45%.
Example 22 1-(2-tert~-Butoxycarbonylaminothia7ol-4-yl)-l(z)-propene carbo~ylic methanesulphonic anhydride . _ 0.005 mol (1.42 g) of 1-(2-tert.-outoxycarbonyl-aminot~iazol-4-yl)-l(Z)-propenecarbo~Jlic acid and 0.0055 mol (0.76 ml) of triethylamine are dissolved in 10 ml of anhydrous tetrahydrofuran and cooled down to -50C.
Le A 21 ~70 ~24Q98~:i 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.
m e mixed anhydride is obtained as an oil which readily isomerises into the E form on warming (NMR).
Exam~le 23 l-(Z-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-butene-carboxylic p-toluenesulphonic anhydride Preparation in analo~y to Example 22 from the appropriate Z-butenecarbo~flic acid and p-toluenesul-phonyl chloride at -20 to -~0C.
Exam~le 24 _ _ _ 7-[1-(2-tert.-~utoxycarbonylaminothiazol-4-yl)-l(Z)-pr penecarboxamido]-3-aceto~ymethyl-3-cephem-4-carboxylic acid .... . . .
0.005 mol (1.42 g) of 1-(2-tert.-butoxycarbonyl-aminothiazol-4-yl)-l(Z)-propenecarboxylic acid and 0.0055 mol (0.76 ml) of triethylamine are dissolved ln 20 ml of anhydrous methylene chloride, the mixture is cooled down to -50C, 0.0051 mol (0.40 ml) of methanesulphonyl chlor-ide is added and the mixture is stirred at -50 to -40C
for 5 hours.
Then a solution of 0.00~ 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 off, the H20 phase is extracted 2 times with Le A 21 370 . . .
1240~t~5 ..
- 31 _ 23189-5448F
20 ml of methylene chloride each time the combined methylene chloride phases are washed l~ith saturated NaCl solution dried over Na2S04 and concentrated in vacuo on a rotary evaporator. The desired cep~a o-sporin is obtained a~mos~ auant tatively.
Exam~le 25 7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxamido]-3-(1-methyl-1 H-tetrazol-5~yl)thio-methyl-3-cephem-4-carboxylic acid Preparation is carried out in analogy to Example 24 from 1-(2-tert.-butox-ycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxyllc acid and 7-amino-3-(1-methyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Yield 92%.
Exam~le 26 7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-butenecarboxyamido]-3-aceto~ymethyl-3-cephem-4-carboxylic acid Preparation in analogy to Example 24 ~rom 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-1-(Z)-butene-carboxylic acid and 3-acetox~methyl-7-amino-3-cephem-4-carboxylic acid.
Exam~le 27 7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-butenecarboxamido]-3-(1-methyl-1 H-tetrazol-5-yl)thio-methyl-3-cephem-4-carbox-ylic acid . _ _ . . .
Preparation in analogy to Example 24 ~om 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-butenecarboxylic acid and 7-amino~3-(1-methyl-1 H-tetrazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid.
Yield 88%, Exam~le 28 - 7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-heptenecarboxamido]-3-aCetoxymethyl-3-cephem-4-car-boxylic acid Le A 21 370 , . ~ ., .
~ 3.2~0985 Prepara~ion in analogy to Example 2k from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-heptene-carboxylic acid and 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid.
Yield 90%.
Exam~le 29 7-[1~(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-hep-tenecarboxamido~-3-(1-methyl-1 ~-tetrazol-5-yl)-thio-methyl-3-cephem-4-carbox-ylic acid Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-heptene-carboxylic acid and 7-amino-3-(1-meth~Jl~ e~a~ol-~-yl) thiomethyl-3-cephem-4-carboxylic acid.
Yield 85%.
Exam~le 30 7-[1-(2-tert,-Butoxycarbonylaminothiazol-4-yl)-3-methyl-l(Z)-butenecarboxamido]-3-acetoxymethyl-3-cephem-4-car-boxylic acid Preparation in analo~y to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-3-methyl_l(z)_ butenecarboxylic acid and 3-acetoxymethyl-7-amino-3-ceph-em-4-carboxylic acid.
Yield 93%, Example 31 7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-4-phenyl-l(Z)-butenecarboxamido]-3-acetoxymethyl-3-cephem-4-car-boxylic acid -Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-Yl)-4-~henyl-l(Z)-butenecarboxylic acid ~d ~-acetoxymethyl-7-amino-3-cephem 4-carboxylic acid. Yield 95%.
ExamPle 32 7-C1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxamido]-3-methyl-3-cephem-4-carboxylic acid Le A 21 370 .
~240985 Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-carboxylic acid and 7-amino-3-methyl-3-cephem-k-carboxylic 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 ins~ead of with triethylamine.
Yield 88%.
Exam~le 33 7-~1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxamido]-3-aminocarbonyloxymethyl-3-cephem-4-carboxylic acid Preparation in analogy to Example 24 from 1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-carboxylic acid and 7-amino-3-aminocarbonyloxymethyl-3-cephem-4-carbox~Jlic acid. Unlike Example 24, the 7-amino-3-aminocarbonylo~methyl-3-cephem-4-carboxylic acid is not dissolved in methylene chloride with tri-ethylamine, but in anhydrous dimethylformamide with the equimolar amount of diisopropylamine, and the solution obtained is added to the mixed carboxylic 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 aaueous phase is covered with ethyl acetate and acidified to pH 2-3. The product separates out as an oil bet~een the phases.
I Exam~le 34 Diphenylmethyl 7-~1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-propenecarboxamido]-3-cephem-4-carboxylate ... . _ . _ Preparation in analogy to Example 24 from 1-(2-tert -butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-carboxylic acid and diphenylmethyl 7-amino~3-cephem-4-carboxylate.
Yield 93%.
Le A 21 370 .
12~)985 3~ 23189-5448F
Examle 35 7-[1-(2-Aminothiazol-4-yl)-l(Z)-propenecarboxamido~-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 tem~era-ture in vacuo, the residue is treated 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 ~ vr ' ~ 51, 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 700,6.
Exam~les 36-44 The cephalosporins from the Examples 25 to 34 are unblocked in analogy to Example ~5. Yields are between 50 and 90%.
Le A 21 370
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of a compound of the general formula:
(I) (in which R1 represents an alkyl or cycloalkyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) O-alkyl, (C1-C6) S-alkyl, (C1-C6) N-alkyl, (C1-C6) alkyloxycarbonyl or optionally substituted phenyl; or R1 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 (C1-C6) alkyl, (C1-C6) O-alkyl, (C1-C6) S-alkyl, alkyloxycarbonyl, halogen or phenyl, and X represents hydrogen, (C1-C4) alkyl, halogen (C1-C4) alkoxy, hydroxymethyl, formyloxymethyl, [(C1-C4) alkyl]-carbonyloxymethyl, aminocarbonyloxymethyl, pyridinium-methyl, 4-carbamoylpyridiniummethyl or heterocyclythio-methyl radical wherein heterocyclyl represents a radical of the formula:
or (in which R6 denotes hydrogen, methyl, 2-dimethylaminoethyl, carboxy-methyl or sulphomethyl and, R7 denotes hydrogen or methyl), which process comprises:
coupling a compound of the general formula (XVI) (in which R1 is as defined above, R2 denotes CO2R3 or hydrogen, R3 denotes an alkyl, cycloalkyl, alkenyl or cycloalkenyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (C1-C4) alkyl, (C1-C4) O-alkyl, halogen, C?N, tri-[(C1-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 (C1-C4) alkyl, (C1-C4) O-alkyl, (C1-C4) S-alkyl, alkyloxy-carbonyl, halogen, phenyl, nitro or C?N, there being at least one carbon atom separating heteroatoms as sub-stituents of the radicals and double bonds in the alkenyl and cycloalkenyl radicals from the oxycarbonyl group, and R5 denotes an alkyl, alkenyl, cycloalkyl, cycloalkenyl, carbocyclic or heterocyclic aryl or heterocyclyl radical each of which may have 1 to 3 substituents selected from the group consisting of halogen, alkyl, aryl, O-alkyl, S-alkyl, CN, alkoxycarbonyl or nitro), with a cephalo-sporanic acid of the general formula:
(XVII) (in which X is as defined above), and then splitting off the protec-tive group R2 except when R2 is hydrogen.
(I) (in which R1 represents an alkyl or cycloalkyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) O-alkyl, (C1-C6) S-alkyl, (C1-C6) N-alkyl, (C1-C6) alkyloxycarbonyl or optionally substituted phenyl; or R1 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 (C1-C6) alkyl, (C1-C6) O-alkyl, (C1-C6) S-alkyl, alkyloxycarbonyl, halogen or phenyl, and X represents hydrogen, (C1-C4) alkyl, halogen (C1-C4) alkoxy, hydroxymethyl, formyloxymethyl, [(C1-C4) alkyl]-carbonyloxymethyl, aminocarbonyloxymethyl, pyridinium-methyl, 4-carbamoylpyridiniummethyl or heterocyclythio-methyl radical wherein heterocyclyl represents a radical of the formula:
or (in which R6 denotes hydrogen, methyl, 2-dimethylaminoethyl, carboxy-methyl or sulphomethyl and, R7 denotes hydrogen or methyl), which process comprises:
coupling a compound of the general formula (XVI) (in which R1 is as defined above, R2 denotes CO2R3 or hydrogen, R3 denotes an alkyl, cycloalkyl, alkenyl or cycloalkenyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (C1-C4) alkyl, (C1-C4) O-alkyl, halogen, C?N, tri-[(C1-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 (C1-C4) alkyl, (C1-C4) O-alkyl, (C1-C4) S-alkyl, alkyloxy-carbonyl, halogen, phenyl, nitro or C?N, there being at least one carbon atom separating heteroatoms as sub-stituents of the radicals and double bonds in the alkenyl and cycloalkenyl radicals from the oxycarbonyl group, and R5 denotes an alkyl, alkenyl, cycloalkyl, cycloalkenyl, carbocyclic or heterocyclic aryl or heterocyclyl radical each of which may have 1 to 3 substituents selected from the group consisting of halogen, alkyl, aryl, O-alkyl, S-alkyl, CN, alkoxycarbonyl or nitro), with a cephalo-sporanic acid of the general formula:
(XVII) (in which X is as defined above), and then splitting off the protec-tive group R2 except when R2 is hydrogen.
2. The process according to claim 1, in which the compound of formula (XVI) is prepared by reacting a Z-acid of the general formula:
(XIII) (in which the symbols have the meanings given before), with a compound of the general formula Z-SO2-R5 (in which Z denotes chlorine or bromine atom or -O-SO2-R5, and R5 is as defined before).
(XIII) (in which the symbols have the meanings given before), with a compound of the general formula Z-SO2-R5 (in which Z denotes chlorine or bromine atom or -O-SO2-R5, and R5 is as defined before).
3. The process according to claim 2, in which the Z-acid of formula (XIII) is obtained by separating the Z and E isomers of the ester of the formula:
(XII) (in which R1 is as defined before, R2 represents CO2R3, and R4 represents an alkyl, cycloalkyl, alkenyl, or cycloalkenyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (C1-C4) alkyl, (C1-C4) O-alkyl, halogen, C?N, tri-[(C1-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 (C1-C4) alkyl, (C1-C4) O-alkyl, (C1-C4) S-alkyl, alkyloxy-carbonyl, halogen, phenyl, nitro or C?N, there being at least one carbon atom separating heteroatoms as substituents of the radicals and double bonds in the alkenyl and cycloalkenyl radicals from the oxycarbonyl group), followed by a subsequent saponification or by selectively saponifying the ester of formula (XII).
(XII) (in which R1 is as defined before, R2 represents CO2R3, and R4 represents an alkyl, cycloalkyl, alkenyl, or cycloalkenyl radical, each of which may have 1 to 5 substituents selected from the group consisting of (C1-C4) alkyl, (C1-C4) O-alkyl, halogen, C?N, tri-[(C1-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 (C1-C4) alkyl, (C1-C4) O-alkyl, (C1-C4) S-alkyl, alkyloxy-carbonyl, halogen, phenyl, nitro or C?N, there being at least one carbon atom separating heteroatoms as substituents of the radicals and double bonds in the alkenyl and cycloalkenyl radicals from the oxycarbonyl group), followed by a subsequent saponification or by selectively saponifying the ester of formula (XII).
4. The process according to claim 3, in which the Z and E
isomer mixture of the ester of formula (XII) is obtained by reacting a compound of the general formula:
(XI) (in which the symbols have the meanings given before), with a base.
isomer mixture of the ester of formula (XII) is obtained by reacting a compound of the general formula:
(XI) (in which the symbols have the meanings given before), with a base.
5. The process according to claim 4, in which the compound of the general formula (XI) is prepared by reacting a compound of the general formula:
(X) (in which the symbols have the meanings given before), with a suitable base, and then with an aldehyde of the general formula R1-CHO (in which R1 is as defined before).
(X) (in which the symbols have the meanings given before), with a suitable base, and then with an aldehyde of the general formula R1-CHO (in which R1 is as defined before).
6. A process according to claim 1, 2 or 3, wherein:
R2 denotes CO2C(CH3)3;
R5 denotes alkyl with 1 to 10 carbon atoms, which may be substituted by fluorine, chlorine, CN, phenyl, lower alkyloxycarbonyl or lower alkoxy, or denotes phenyl which may be substituted by fluorine, chlorine, bromine, CN, lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy, nitro, trifluoromethyl or phenyl; and R1 denotes alkyl with 1 to 10 carbon atoms which may be substituted by 1 or 2 phenyl radicals, denotes cycloalkyl with 3 to 10 carbon atoms which may be substituted by 1 or 2 lower alkyl radicals or by 1 or 2 phenyl radicals or denotes phenyl which may be substituted by lower alkyl, lower alkoxy, lower alkylthio, lower alkoxycarbonyl or halogen.
R2 denotes CO2C(CH3)3;
R5 denotes alkyl with 1 to 10 carbon atoms, which may be substituted by fluorine, chlorine, CN, phenyl, lower alkyloxycarbonyl or lower alkoxy, or denotes phenyl which may be substituted by fluorine, chlorine, bromine, CN, lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy, nitro, trifluoromethyl or phenyl; and R1 denotes alkyl with 1 to 10 carbon atoms which may be substituted by 1 or 2 phenyl radicals, denotes cycloalkyl with 3 to 10 carbon atoms which may be substituted by 1 or 2 lower alkyl radicals or by 1 or 2 phenyl radicals or denotes phenyl which may be substituted by lower alkyl, lower alkoxy, lower alkylthio, lower alkoxycarbonyl or halogen.
7. A process according to claim 1, 2 or 3, wherein:
R2 denotes CO2C(CH3)3;
R5 denotes alkyl with 1 to 10 carbon atoms;
R1 denotes cycloalkyl with 3 to 10 carbon atoms, phenyl, or alkyl with 1 to 10 carbon atoms which may be substituted by a phenyl radical; and X denotes hydrogen, acetoxymethyl, (1-methyl-1H-tetrazol-5-yl)thiomethyl, methyl, or aminocarbonyloxymethyl.
R2 denotes CO2C(CH3)3;
R5 denotes alkyl with 1 to 10 carbon atoms;
R1 denotes cycloalkyl with 3 to 10 carbon atoms, phenyl, or alkyl with 1 to 10 carbon atoms which may be substituted by a phenyl radical; and X denotes hydrogen, acetoxymethyl, (1-methyl-1H-tetrazol-5-yl)thiomethyl, methyl, or aminocarbonyloxymethyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000541405A CA1240985A (en) | 1981-11-19 | 1987-07-06 | Preparation of cephalosporins |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813145727 DE3145727A1 (en) | 1981-11-19 | 1981-11-19 | INTERMEDIATE PRODUCTS, METHOD FOR THE PRODUCTION THEREOF AND METHOD FOR THE PRODUCTION OF CEPHALOSPORINES |
| DEP3145727.4 | 1981-11-19 | ||
| CA000415708A CA1212949A (en) | 1981-11-19 | 1982-11-17 | Intermediate products, process for their preparation and process for the preparation of cephalosporins |
| CA000505254A CA1238911A (en) | 1981-11-19 | 1986-03-26 | Substituted amino thiazole derivatives |
| CA000541405A CA1240985A (en) | 1981-11-19 | 1987-07-06 | Preparation of cephalosporins |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000505254A Division CA1238911A (en) | 1981-11-19 | 1986-03-26 | Substituted amino thiazole derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1240985A true CA1240985A (en) | 1988-08-23 |
Family
ID=27167303
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000541321A Expired CA1247109A (en) | 1981-11-19 | 1987-07-06 | Intermediates for the preparation of cephalosporins and their preparation |
| CA000541405A Expired CA1240985A (en) | 1981-11-19 | 1987-07-06 | Preparation of cephalosporins |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000541321A Expired CA1247109A (en) | 1981-11-19 | 1987-07-06 | Intermediates for the preparation of cephalosporins and their preparation |
Country Status (1)
| Country | Link |
|---|---|
| CA (2) | CA1247109A (en) |
-
1987
- 1987-07-06 CA CA000541321A patent/CA1247109A/en not_active Expired
- 1987-07-06 CA CA000541405A patent/CA1240985A/en not_active Expired
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| Publication number | Publication date |
|---|---|
| CA1247109A (en) | 1988-12-20 |
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