Vinyl-ACA purification process

Details Vinyl-ACA purification process Vinyl-ACA purification process

2000-05-09

2001-09-04

Berch, Mark L. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C540S215000

Reexamination Certificate

active

06284888

ABSTRACT:

The present invention relates to a process for the purification of vinyl-ACA in a mixture of vinyl-ACA and 7-ADCA, by depletion of 7-ADCA in a mixture of vinyl-ACA and 7-ADCA.
Vinyl-ACA of formula
may be used as intermediate in the production of highly active, oral antibiotics, e.g. cefixime and cefdinir of formulae
Vinyl-ACA may be produced, for example, by Wittig reaction of a corresponding cephalosporin-3-ylide, which may have the amine group and the carboxylic acid attached to the ring system protected, with formaldehyde (see e.g. Journal of Antibiotics, Vol. 38, No. 12, 1739 ff; or EP-0 503 453; or EP-0 597 429). We have found that such vinyl-ACA may be contaminated, e.g. by 7-ADCA. This is consistent with the fact that phosphine alkylenes (ylides) or quaternary phosphonium compounds can hydrolyze to form the corresponding alkane and phosphine oxide (see e.g. Houben Weyl, Methoden der organischen Chemic, Phosphorverbindungen I, volume 12/1, especially pages 108 and 119). We found accordingly, when producing a compound of formula I via a Wittig reaction, as a by-product 7-ADCA of formula
or a protected derivative thereof may be formed. Furthermore, if 7-ACA is produced via fermentative production of cephalosporin C and subsequent conversion to 7-ACA, the thus formed 7-ACA may contain 7-ADCA, because the 7-ADCA-analogous cephalosporin is formed in the course of fermentation, or is not wholly metabolised to cephalosporin C. Thus, 7-ACA, used for example as a starting material for 7-ACA, may often have an undesired 7-ADCA content, for example of more than 1%.
In the production of active cephalosporins, e.g. cefixime and cefdinir, wherein an intermediate of formula I may be used, the 7-ADCA content in vinyl-ACA of formula I should be as low as possible, because upon appropriate further substitution of a compound of formula I, 7-ADCA could react in the same way as vinyl-ACA which would result in contamination of the desired active vinyl-ACA compounds, e.g. cefixime or cefdinir, by analoguously substituted 7-ADCA-compounds, which are difficult to separate.
According to the present invention, vinyl-ACA in a mixture of vinyl-ACA and 7-ADCA can be purified in an economical manner by depletion of 7-ADCA to, e.g. less than 0.1% to 0.8%, such as less than 0.1% to 0.6%, for example 0.3% to 0.8%. This is remarkable, because 7-ADCA and vinyl-ACA are chemically very similar compounds.
In one aspect the present invention provides a process for the depletion of 7-ADCA of formula II in a mixture of 7-ADCA and vinyl-ACA of formula I, preferably by a process,
wherein
a) a mixture of a salt of a compound of formula I and a compound of formula II is subjected to crystallization, the crystallized salt is isolated and converted into a compound of formula I, containing less compound of formula II than the mixture of a compound of formula I and formula II, or
b) a mixture of a compound of formula I and a compound of formula II is subjected to chromatography.
The salt includes for example a cationic salt of the carboxylic acid group and an amine salt of the carboxylic acid group in a compound of formulae I and II.
In a further aspect the present invention provides a process as described above, wherein a mixture of a salt of a compound of formula I and a compound of formula II is a mixture of compounds of formulae
wherein X
+
denotes a cation, or a compound of formula
wherein R
1
, R
2
and R
3
are the same or different and independently of one another denote hydrogen, alkyl, aryl, aralkyl, or cycloalkyl; or
R
1
and R
2
together with the nitrogen atom form a heterocycle and R
3
is as defined above.
The cation includes a cation of the alkali series, for example Li
+
, K
+
, Na
+
.
Preferably R
1
denotes hydrogen and R
2
and R
3
independently from one another denote alkyl or aralkyl. R
1
and R
2
together with the nitrogen atom may denote a heterocycle, preferably a 5- or 6 membered heterocycle, having for example 1 to 3 heteroatoms.
If not otherwise defined herein, any carbon containing radical contains up to 10 carbon atoms. Alkyl includes straight chain or branched C
1-22
alkyl, preferably C
1-12
alkyl, such as C
1-8
alkyl. Aryl includes unsubstituted aryl or substituted aryl, preferably phenyl or, mono- or polysubstituted phenyl. Aralkyl includes unsubstituted aralkyl, or substituted aralkyl, for example benzyl. Cycloalkyl includes C
3-8
cycloalkyl, such as C
3-6
cycloalkyl. A heterocycle includes unsubstituted heterocycle or substituted heterocycle, for example 5- or 6-membered heterocycle. A heterocycle may contain one or several heteroatoms, for example N, S, O. Substituents of any aryl group, aralkyl group and of any heterocycle include substitutents which are inert under the corresponding reaction conditions, for example alkyl, aryl, alkoxy, aryloxy, halogen, nitro, optionally protected amine groups, optionally protected hydroxy.
Process variant a) may be carried out as follows:
A salt of a mixture of a compound of formula I and of formula II may be produced, for example, by adding a salt forming agent to a mixture of a 7-ADCA and vinyl-ACA in a solvent. A salt forming agent includes, for example, a base. A base includes, e.g. an inorganic base, e.g. a hydroxide, for example an alkali hydroxide; and a salt having a cation source; such as an inorganic salt, for example an alkali salt, such as a carbonate, hydrogencarbonate; and an organic salt, for example the salt of a carboxylic acid, for example an alkali salt, of, for example acetic acid or 2-ethylhexanoic acid; and an organic base, for example a nitrogen base, for example ammonia or an amine, for example an amine of formula
wherein R
1
, R
2
and R
3
are as defined above.
In a further aspect the present invention provides a process as described above, wherein a mixture of a salt of a compound of formula I and a compound of formula II is produced by addition of a salt forming agent to a mixture of a compound of formula I as defined in claim
1
and a compound of formula II as defined in claim
1
in a solvent, preferably a process, wherein the salt forming agent is an inorganic base, an inorganic salt, an organic salt or a nitrogen base; preferably, the inorganic base is a hydroxide; the inorganic salt is an inorganic alkali salt; the organic salt is an alkali salt of a carboxylic acid; and the nitrogen base is a compound of formula
wherein R
1
, R
2
and R
3
are as defined above.
A solvent includes an aprotic solvent and a protic solvent, for example an amide, such as N,N-dimethylform-amide, a ketone, such as acetone; an alcohol, such as methanol, ethanol or one of the isomeric propanols or butanols, for example isopropanol; a nitrile such as acetonitrile; ethers or chlorinated hydrocarbons; water; and mixtures of solvents.
In one aspect a mixture of vinyl-ACA and 7-ADCA may be dissolved in water or in an aqueous organic solvent, for example a mixture of water and a ketone; and a mixture of water and an alcohol, such as ethanol or isopropanol; in the presence of a salt forming agent. The pH may be appropriately adjusted, for example by addition of a base, having, for example, a Li, Na or K-source, such as an acetate; particularly in case that an organic base, such as a nitrogen base is used as salt forming agent. An anti-solvent, for example a nitrile, such as acetonitrile; an alcohol such as methanol, ethanol or one of the isomeric propanols or butanols; an ether, such as diethyl ether, tetrahydrofuran or tertbutylmethyl ether; a ketone, such as acetone; or an ester, such as ethyl acetate or acetic acid isopropyl ester; or mixtures of anti-solvent; may be added. The salt of vinyl-ACA, or a mixture of a salt of vinyl-ACA and 7-ADCA, wherein the 7-ADCA content is less than in the mixture used for salt production, may crystallize.
In another aspect a mixture of vinyl-ACA and 7-ADCA may be suspended in a practically water-free organic solvent, such as an amide, a ketone; an alcohol; a nitrile; an ether; a chlorinated hydrocarbon; and mixtures of water-free organic solvent. Preferred solvent include a mixt

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