Process for purification of a cephalosporin derivative

Details Process for purification of a cephalosporin derivative Process for purification of a cephalosporin derivative

2002-09-30

2004-11-30

Berch, Mark L. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06825345

ABSTRACT:

The present invention relates to a process for the purification of 7-[2-[aminothiazol-4-yl)-2-[(carboxymethoxyimino)acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid, e.g. cefixime of formula
Cefixime, e.g. in the form of a trihydrate, is a cephalosporin antibiotic with excellent antibacterial properties and high &bgr;-lactamase stability (see for example H. Yamanaka et al., J.Antibiotics (1985), 38(12), p 1738-1751).
Cefixim may be prepared via a 7-{2-[(2-aminothiazol)-4-yl]-2-[((aryl-or alk)-oxy-carbonyl)-methoxyimino]acetamido}-3-vinyl-ceph-3-em-4-carboxylic acid, which may be prepared according to a novel process.
In one aspect the present invention provides a process for the production of a compound of formula
wherein R denotes alkyl or aryl and wherein the amine group attached to the thiazolyl ring is free or protected, comprising reacting a compound of formula
in free form, protected form or in the form of a salt, with a compound of formula
wherein R denotes alkyl or aryl and wherein the amine group attached to the thiazolyl ring is free or protected, and isolating a compound of formula V from the reaction mixture, e.g. optionally after splitting off protecting groups and/or converting a compound of formula V in the form of a salt into a compound of formula V in free form.
In formula IV and V R denotes alkyl, e.g. (C
1-8
)alkyl, such as (C
1-4
)alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, or isobutyl; e.g. methyl; or aryl, e.g. phenyl, preferably alkyl. Alkyl and aryl may be unsubstituted or substituted, e.g. by groups which are inert under appropriate reaction conditions for the acylation of an amine group.
A compound of formula IV wherein R is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl and wherein the amine group is free or protected is novel.
In another aspect the present invention provides a compound of formula IV wherein R is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl and wherein the amine group attached to the thiazolyl ring is free or protected.
A process according to the present invention may be carried out as follows:
A compound of formula IV may e.g. be prepared by reaction of 2-(2-amino-4-thiazolyl)-(Z)-2-((aryl-or alk)-oxycarbonylmethoxyimino))acetic acid with 2,2′-benzothiazolyl disulphide in an organic solvent, e.g. dichloromethane in the presence of a phosphine, e.g. triphenylphosphine or a phosphite, e.g. triethyl phosphite, e.g. at room temperature. Protection groups of the amine group attached to the thiazolyl ring include protection groups which are conventional in &bgr;-lactam chemistry, e.g. protection groups as described below for the amine group attached in position 7 of the ring structure of a compound of formula III. Protection of the amine group may e.g. be carried out as conventional.
A compound of formula IV, e.g. produced as described above, e.g. without isolation from the reaction mixture, may be reacted with a compound of formula III. A compound of formula III may be in free form, in the form of a salt, e.g. in alkali salt form or in the form of a salt with ammonia, amines, such as a tertiary amines, e.g. trialkylamines, e.g. wherein the alkyl groups independently of each other each denote e.g. (C
1-8
)alkyl, such as (C
1-4
)alkyl e.g. triethylamine or tributylamine; amidines, e.g. DBN or DBU, or guanidines, e.g. tetramethyl guanidine, preferably triethylamine; or a compound of formula III may be in protected form, e.g. wherein functional groups such as the amine group in position 7 and/or the carboxyl group in position 4 of the ring structure are N- and/or O-protected with protecting groups, e.g. as conventional in &bgr;-lactam chemistry, such as silyl groups, e.g. trialkylsilyl-, aryldialkylsilyl-, diarylalkylsilyl groups, e.g. in N,O-bissilylated form. The alkyl and aryl groups may be the same or different. Alkyl includes (C
1-4
)alkyl, aryl includes (C
5-18
)aryl, e.g. (C
6-12
)aryl, such as phenyl groups. Preferred protecting groups are trialkylsilyl groups, e.g. trimethylsilyl groups.
A compound of formula III may preferably be in protected from or in the form of a salt, e.g. in the form of a salt.
A compound of formula III in the form of a salt may be prepared e.g. as convenional in &bgr;-lactam chemistry, e.g. by addition to a salt forming agent to a mixture of a compound of formula III in organic solvent, or, in situ in a mixture of a compound of formula IV and a compound of formula III, e.g. by addition of a salt forming agent, e.g. an amine or ammonia, to a mixture of a compound of formula III, a compound of formula IV and organic solvent. A compound of formula III in protected form, e.g. N,O-bissilylated, may be prepared e.g. as conventional, e.g. analogously to a method as conventional in &bgr;-lactam chemistry. The reaction of a compound of formula III with a compound of formula IV may be carried out in inert organic solvent. Inert organic solvent includes halogenated hydrocarbons, e.g. dichloromethane, carboxylic acid esters, e.g. ethyl acetate, butyl acetate or ketones, e.g. methyl isobutyl ketone, preferably halogentad hydrocarbons; and mixtures of individual inert organic solvent, e.g. as cited above; optionally in the presence of cosolvent, such as an alcohol, e.g. ethanol or methanol, water, or an amide, e.g. dimethylformamide, or a mixture of individual cosolvents, e.g. as cited above. Appropriate reaction temperatures include −40° to 60° C., such as −15° C. to room temperature, e.g. room temperature. Per equivalent of a compound of formula III, 1 to 1.5 equivalents of a compound of formula IV may conveniently be used. A compound of formula V obtained may be isolated and protecting groups optionally present may be splitt off, e.g. analogously to a method as conventional in &bgr;-lactam chemistry and/or a compound of formula V in the form of a salt may be converted into a compound of formula V in free form, e.g. according to a method as conventional. A compound of formula V may be obtained in impure form.
A compound of formula V, e.g. in free form or in the form of a hydrate, e.g. in the form of a sesquihydrate, may e.g. also be produced according to a method as conventional, e.g. by acylating a compound of formula III, e.g. in free form, protected form or in the form of a salt, e.g. as described above, with a 4-halo-3-oxo-2-(aryl-or alk)-oxycarbonyl-methoxyimino butyric acid, wherein aryl and alkyl may have the meaning as described above for R in a compound of formula IV or V, and wherein halo denotes halogenide, preferably bromo, chloro, e.g. chloro; e.g. in an activated form, e.g. activated via Vilsmeier formation, or activated in the form of a halogenide, e.g. bromide, chloride, such as chloride, e.g. prepared by reacting 4-halo-3-oxo-2-((aryl-or alk)-oxycarbonyl-methoxyimino butyric acid, with a carboxylic acid halogenide forming agent, e.g. phosphorous oxychloride, e.g. without isolation of 4-halo-3-oxo-2-(aryl-or alk)-oxycarbonyl-methoxyimino butyric acid halogenide from the reaction mixture, to obtain 7-(2-(chloromethylcarbonyl)-2-(Z)((aryl-or alk)-oxycarbonyl)-methoxyimino)-acetamido)-3-vinyl-ceph-3-em-4-carboxylic acid, wherein the carboxylic group in position 4 of the ring system is free, or protected, or in the form of a salt; which is reacted, e.g. without isolation from the reaction mixture obtained, with thiourea to obtain a compound of formula V wherein the carboxylic acid group in position 4 of the ring system is free, or protected, or in the form of a salt and optionally splitting off protecting groups to obtain a compound of formula V and/or converting a salt of a compound of formula V into a free form of a compound of formula V, e.g. according or analogously to a method as conventional. A compound of formula V may be obtained in impure form.
Purification of a compound of formula V is difficult, e.g. because of its poor solubility in common organic solvents, e.g. halogenated hydrocarbons, ketones or esters.
We have now surprisingly found a simple and effective process for the purification of a compound

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