Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-04
2001-12-25
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S222000
Reexamination Certificate
active
06333409
ABSTRACT:
Process for the purification of a 3-cephem-4-carboxylic acid derivative
The invention relates to methods of reducing the E-(trans) isomer amount in the Z/E (cis/trans) 7-amino-3-(1-propen-cephem-4-carboxylic acid of formula I
The Z-isomer, 7-amino-3-[(Z)-1-propen-1-yl]-3-cephem-4-carboxylic acid of formula Ia
is a central intermediate for the production of highly effective broad-band antibiotics, for example cefprozil and BAY v 3522 of formulae
It is known that the Z-(or cis-)configuration represents the characteristic which determines the advantageous antibacterial properties of cephalosporin end products in the Gram negative range. Consequently, an active substance with the smallest possible proportion of E-(or trans-) isomer is desired for optimum efficiency. For example the undesired E-isomer in cefprozil should not exceed 11% according to the US Pharmocopeia.
Synthetic processes for the production of these antibiotics generally yield Z-isomers in admixture with E-isomers.
During the synthesis of the double bond from the corresponding cephalosporin nucleus by means of a Wittig reaction with acetaldehyde, the ratio of Z- to E-isomers may only be guided in the desired direction to an unsatisfactory extent : UK Patent Application 2 135 305 describes the production of cefprozil, starting with 7&bgr;-[D-2-(t-butoxycarbonylamino)-2-(p-hydroxyphenyl)acetamido]-3-cephem-4-carboxylic acid benzhydrylester. In Procedure-8 of this UK Application, the trans-isomer is separated by high performance liquid chromatography.
In U.S. Pat. No. 4,727 070, a Z/E mixture of 7-[D-2-amino-2-(Z-and E)-1-propen-1-yl)ceph-3-em-4-carboxylic acid (cefprozil) is freed from undesired E isomer by means of a reaction with acetone and subsequent re-cleavage to the active substance. Purification of a most advanced intermediate by chromatography is expensive, and purification by chemical derivation of the end product is of course the most expensive variant.
Less expensive is the production of the relatively isomer-free intermediate product, namely 7-amino-3-[(Z)-1-propen-1-yl]-3-cephem-4-carboxylic acid. However, the necessary olefinization reaction may not progress sufficiently selectively to the desired Z-compound. For example, in UK Patent Application 2 173 798, 7-amino-3-(1-propen-1-yl)-3-cephem-4-carboxylic acid benzhydryl ester.hydrochloride is obtained for example as a maximum 90/10 Z/E mixture in a Wittig reaction as an intermediate stage to the antibiotic cefprozil. From this, ester cleavage takes place to produce 7-amino-3-[(Z)-1-propen-1-yl)-3-cephem-4-carboxylic acid with a proportion of Z-isomer of 9.7%. In Example 4, the ratio of Z/E is 83/17. In EP-A-O 292 806, 7-amino-3-(1-propen-1-yl)-3-cephem-4-carboxylic acid is produced with a maximum Z/E ratio of 91/9. Further purification at the stage of this central intermediate product is not described.
It has been surprisingly found that Z/E 7-amino-3-(1-propen-1-yl]-3-cephem-4-carboxylic acid of formula I with a too high E proportion may be converted into compound of formula I with low E content via the hydrochloride or a metal or amine salt of the compound of formula I or by adsorption chromatography of the compound of formula I.
In particular the invention comprises simple and efficient methods of depleting 7-amino-3-[(E)-1-propen-1-yl]-3-cephem-4-carboxylic acid in Z/E mixtures of 7-amino-3-[1-propen-1-yl]-3-cephem-4-carboxylic acid by
a) forming the hydrochloride of the compound of formula I′
wherein the propenyl group has Z- and E-configuration, from compound of formula I and hydrochloric acid in a solvent or solvent mixture, in which the Z- and E-isomers of formula I′ have different solubilities or
solubilising at least part of 7-amino-3-[(E)-1-propen-1-yl]-3-cephem-4-carboxylic acid hydrochloride in Z/E mixtures of the compound of formula I′ in a solvent or solvent mixture, in which the Z- and E-isomers have different solubilities, and recovering the enriched Z-isomer of formula I′,
and optionally converting the obtained compound of formula I′ into the free compound of formula I with a reduced E-amount by adjusting the pH or
b) forming a salt of formula II
wherein the propenyl group has Z- and E-configuration and X
+
is Li
+
, Na
+
, K
+
, ammonium or a cation of formula III
wherein R
1
, R
2
and R
3
are independently hydrogen, (C
1-8
)alkyl, an optionally substituted benzyl, (C
4-8
)cycloalkyl or R
1
with R
2
and the nitrogen atom signify a 5- or 6-membered heterocycle which optionally contains one or two additional heteroatoms and R
3
is as defined above, whereby one of R
1
, R
2
or R
3
is not hydrogen, by reacting a compound of formula I with a lithium, sodium or potassium base or ammonia or an amine of formula IV
wherein R
1
, R
2
and R
3
are as defined above, in a solvent or solvent mixture, in which the Z- and E-isomers of formula II have different solubilities and precipitating the obtained compound of formula II optionally by adding a counter solvent, or
dissolving a compound of formula I in a solvent or solvent mixture with a lithium, sodium or potassium base or ammonia and precipitating a compound of formula II by adding a lithium, sodium or potassium source or an amine of formula IV and optionally a counter solvent,
and converting the compound of formula II into compound of formula I with a reduced E-amount or the hydrochloride thereof of formula I′ by adding an acid, or
c) subjecting a solution of the compound of formula I to adsorption chromatography.
Process a) may be carried out as follows:
The formation of the hydrochloride is carried out in a solvent or solvent mixture, in which the Z- and E-isomers of formula I′ have different solubilities.
The hydrochloride of formula I′ may be formed both in protic and in aprotic medium. If operating in an aqueous system, the Z/E mixture of the compound of formula I is dissolved in water or an aqueous organic solvent such as aqueous alcohol, e.g. isopropanol, aqueous acetone or acetonitrile, by adding hydrochloric acid, and precipitating the hydrochloride by addition of an organic counter solvent. Suitable organic counter solvents are in particular organic nitriles such as acetonitrile; ketones, e.g. acetone; alcohols, e.g. methanol, ethanol, one of the isomeric propanols or butanols; ethers, e.g. tert.butyl methyl ether, diethylether or tetrahydrofuran or esters, e.g. ethyl or isopropyl acetate or mixtures thereof. If operating in a practically water-free system, the Z/E mixture of formula I is dissolved in concentrated form in an alcohol, e.g. methanol or isopropanol, with water-free hydrochloric acid, and is then diluted with one of the above mentioned counter solvents, whereby the crystalline Z-enriched product is crystallized out.
According to another variant, the hydrochloride of formula I′ may be suspended or dissolved in a solvent or solvent mixture in which the E-isomer of 7-amino-3-(1-propen-1-yl)-3-cephem-4-carboxylic acid hydrochloride is better soluble than the corresponding Z-isomer. Suitable solvents are alcohols, e.g. methanol, ethanol or isopropanol or a sulfone, e.g. sulfolane. Precipitation is then induced by e.g. adjustment of the solubility product of the Z- or E-isomer optionally by addition of one of the above mentioned counter solvent, whereby the hydrochloride of compound of formula I, with a reduced E-amount is obtained.
The hydrochloride which is thereby much improved in its Z/E ratio may subsequently be converted again into the compound of formula I in conventional manner, e.g. by means of pH adjustment in water to the approximate isoelectric point.
If a mixture of Z and E 7-amino-3-(1-propen-1-yl)-3-cephem-4-carboxylic acid of formula I is dissolved in water in an alkali or an acid and is then reprecipitated by setting the pH at the isoelectric point, there is no improvement, but rather a worsening of the Z/E ratio (see comparison tests in Examples 11
a
and 11
b
). On the oth
Ludescher Johannes
Prager Bernhard
Wolf Siegfried
Berch Mark L.
Biochemie Gesellschaft m.b.H.
McNally Lydia T.
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