Separation of cephalosporin isomers

Details Separation of cephalosporin isomers Separation of cephalosporin isomers

1997-03-25

2001-05-22

Ford, John M. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06235897

ABSTRACT:

The invention relates to a process of depleting the E- (trans) isomer amount in Z/E (cis/trans) 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid of formula
It is known that the Z-configuration represents the characteristic which determines the advantageous properties of cephalosporin end products in the Gram negative range. Consequently, an active compound with the smallest possible content of E-isomer is desired for optimum efficiency.
Synthetic processes for the production of these antibiotics or intermediates thereof yield Z-isomers in admixture with E-isomers.
In example 37 of EP 0 420 608 the production of 7-&bgr;-phenylacetamido-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid-4-methoxybenzylester is described. According to the
1
H-NMR data given therein, a mixture of the Z/E-isomers is obtained. During production of the desired active compound the isomeric mixture is retained. According to Journal of Antibiotics Vol. XLIII, No. 8, pages 1047-1050, (1990), 7-&bgr;-phenylacetamido-3-[2-(4methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid-4-methoxybenzylester is obtained with a Z/E ratio of 4.7/1. It is pointed out that the isomers at this stage are difficult to separate. Separation is therefore carried out at a later stage, after removing the phenylacetyl group, reacylating with the protected side chain of the active substance, and removing the protecting groups.
In Chem. Pharm. Bull. 39(9), 2433-2436, (1991) the production of the pure Z-isomer of 7-&bgr;-phenylacetyl-3-[2-(4-methyl-5-thiazol)vinyl]-3-cephem-4-carboxylic acid-4-methoxybenzylester from the resultant Z/E-isomeric mixture by partially separating the E-isomer by crystallization and subsequently effecting chromatography on silica gel with benzene and ethyl acetate is described. The solvent mixture used for chromatography and the chromatography material may only be regenerated with difficulty and benzene is a solvent, which should no longer be used due to its carcinogenity.
According to reference example 1 of EP 0 236 231 the analogous benzhydrylester is obtained in pure Z-form, but also only by use of benzene/ethyl acetate as the eluant in the chromatography step. In reference example I of EP 0 175 610, the separation of the pure Z-isomer of 7-phenoxyacetamido-3-[2-(4methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid benzhydrylester is described in the same manner.
A further process for the production of the compounds of formula I, described in EP 597 429, takes place in accordance with the following reaction scheme:
In this formula scheme, R is a silyl protecting group, X is —P
+
(R
4
)
3
I
−
or —P(O)(OR
4
)2 and X
+
is —P
+
(R
4
)
3
or —P(O)(OR
4
)
2
Y. R
4
denotes a lower alkyl group or an aryl group and Y denotes a cation from the alkali series or the protonated form of an organic base. Z/E mixtures of compounds of formula I with an E content of about 20% and more and their preparation are described.
According to the invention in one aspect we have surprisingly found that the Z- (cis) isomer of 7-amino-3-[2-(4methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid of formula
in which the hydrogen atoms at the C═C bond have cis configuration or a Z/E mixture e.g. with a high content of Z isomer may be used as a central intermediate compound in the production of highly effective broad-spectrum antibiotics, for example cefditoren pivoxil of formula
In another aspect we have surprisingly found that Z/E mixtures of, in position 4 and 7 unprotected, 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid having a certain E content may be converted into 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid having a lower E content via an amine salt or via chromatography.
In one aspect the invention provides therefore simple and efficient methods of depleting 7-amino-3-[(E)2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid in Z/E mixtures of 7-amino-3-[2-4-methyl-5-thiazolyl)vinyl]-3-cephem-4carboxylic acid
a) by subjecting an amine salt of a Z/E mixture of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid to crystallization and converting this amine salt into 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid, or
b) by subjecting the Z/E mixture to chromatography.
The process may be a separation process, e.g. for at least partial separation of the E- and Z-isomer and/or to lower, i.e. to deplete the content of the E-isomer in Z/E mixtures, e.g. to enhance the Z content or to provide the pure Z-isomer.
Process a) may be effected as follows:
The amine salt may be formed in a protic or in an aprotic solvent. A compound of formula I may be admixed with an amine, an organic solvent or solvent mixture and optionally water, resulting in a solution or a suspension. Suitable organic solvents are for example alcohols, e.g. methanol, ethanol, one of the isomeric propanols or butanols; ketones, e.g. acetone or methyl ethyl ketone; amides, e.g. dimethylformamide; esters, e.g. ethyl acetate, isopropyl acetate, butyl acetate; nitriles, for example acetonitrile;
optionally in the presence of water; or mixtures of the above solvents; particularly, for example acetone; acetone and water; methanol; methanol and acetone. The mixture may optionally be diluted with a further solvent or solvent mixture, i.e. a solvent or solvent mixture which has poorer solubility for the Z-isomer of the compound of formula II, hereinafter called “counter solvent”. Counter solvents are for example the solvents given above with the exception of amides but with the addition of ethers, e.g. tert. butyl methyl ether, diethylether, tetrahydrofuran and mixtures of such solvents. Conveniently a solvent which may also be used as counter solvent may be used.
Alternatively process a) may be effected as follows:
A Z/E mixture of an amine salt of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid may be dissolved or suspended in a solvent or solvent mixture, and the solubilizing power of the mixture (solubility product) may be optionally readjusted by adding a counter solvent as described above. Solvents and counter solvents which may be used are given above.
Conveniently a solvent which may also be used as counter solvent may be used.
The solvent may be chosen so that the amine salt of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4carboxylic acid having a lower content of E-isomer than the Z/E mixtures of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid used as starting material crystallizes out.
Examples of amines useful in the process of the invention are amines of formula
NR
1
R
2
R
3
wherein R
1
, R
2
and R
3
are the same or different and independently of one another denote hydrogen, (C
1-8
)alkyl, unsubstituted or substituted benzyl or (C
4-8
)cycloalkyl, or R
1
and R
2
together with the nitrogen atom signify a 5- or 6-membered heterocycle, which may contain one or two further hetero atoms, and R
3
is as defined above, for example tert. butylamine, benzylamine, dibenzylamine, dicyclohexylamine, tert.-octylamine (=2,4,4-trimethylpentyl-2-amine), particularly tert. butylamine, dicyclohexylamine, tert.-octylamine.
If a benzyl or dibenzylamine is used the benzyl group may be unsubstituted or substituted by groups which are inert under the reaction conditions. Such groups are for examples (C
1-8
)alkyl, (C
1-8
)alkoxy or alkylthio, halogen, nitro, sulfoxy groups.
If R
1
together with R
2
and the nitrogen atom signify a 5- or 6-membered heterocycle, containing optionally 1 or additional heteroatoms, these are for example nitrogen, oxygen or sulphur atoms. Examples of such heterocycles are morpholine, N-methyl-morpholine, oxazolidine or thiazolidine.
The amine of formula III is for example employed in stoichiometric quantities or in an excess of the compound to be purified.
The amine salt according to the present inventio

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