Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-04
2001-11-06
Berch, Mark L. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S170000
Reexamination Certificate
active
06313289
ABSTRACT:
The present invention relates to a process for the purification of cefixime.
Cefixime of formula
e.g. in form of a trihydrate, is a modern, orally available cephalosporin antibiotic having excellent antibacterial properties and high &bgr;-lactamase stability (see for example H. Yamanaka et al., J. Antibiotics (1985), 38(12), pp. 1738-1751).
According to prior art cefixime may e.g. be produced by reacting a 7-amino-3-vinyl-3-cephem-4-carboxylic acid, e.g. of formula
wherein R
5
and R
6
denote hydrogen or a leaving group and R
7
denotes hydrogen, alkyl, cycloalkyl, alkylaryl, aryl or arylalkyl; such as 7-amino-3-vinyl-3-cephem-4-carboxylic acid of formula
with a 2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)acetic acid of formula
wherein R
9
denotes alkyl, cycloalkyl, alkylaryl, aryl or arylalkyl and R
10
and R
11
denote hydrogen, silyl or acyl, e.g. in a reactive form, such as 2-(aminothiazol-4-yl)-2-(tert.butoxycarbonylmethoxyimino)acetic acid-S-mercaptobenzo-thiazolylester of formula
to give a 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid, e.g. of formula
wherein R
7
, R
9
, R
10
and R
11
are as defined above, e.g. 7-[2-(aminothiazol-4-yl)-2-(tert.butoxycarbonyimethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid of formula
and splitting off a group R
9
, such as tert.butyl, and, if present, any R
7
and/or R
11
which is not hydrogen, to obtain cefixime of formula II, e.g. in form of a trihydrate.
Prior Art Processes May Have Disadvantages.
A compound of formula IA, e.g. of formula I, may be obtained in amorphous form. It was found that, due to its high solubility, solvents such as ethers having in general a low solubilizing effect are to be used for its isolation, e.g. according to EP 030 630 (see e.g. example 53) and thus undesired by-products which have to be separated off may be precipitated beside a compound of formula IA, e.g. of formula I. Isolation of a compound of formula IA, e.g. of formula I in free acid form may also be effected from water but removal of water causes difficulties in a subsequent drying process.
Removal of protecting groups of a compound of formula IA, e.g. of formula I under acidic conditions to obtain cefixime may cause difficulties, e.g. purification is to be carried out via chromatography as e.g. described in H. Yamanaka et al., J. Antibiotics (1985), 38(12), pp. 1738-1751) (yield of 34.1%) and in AU 9526702 (WO 95/33753). According to EP 030 630, example 168, cefixime is precipitated after splitting off protecting groups by addition of diisopropylether having in general a low solubilizing effect and thus undesired by-products may additionally be precipitated.
According to the present invention surprisingly a new process for the production of cefixime in highly pure form has been found. The process according to the present invention may avoid disadvantages of prior art, e.g. by provision of intermediates, such as compounds of formulae I, II and optionally IV in crystalline form, which may have a high purification effect on the end product cefixime.
In one aspect the present invention provides a process for the production of cefixime of formula II, comprising
a. reacting a 7-amino-3-vinyl-3-cephem-4-carboxylic acid of formula IIIA, wherein R
5
and R
6
denote hydrogen or a leaving group and R
7
denotes hydrogen, alkyl, cycloalkyl, alkylaryl, aryl, arylalkyl or silyl, e.g. 7-amino-3-vinyl-3-cephem-4-carboxylic acid of formula III; e.g. in free form or in form of a salt,
with a 2-(aminothiazol-4-yl)-2-carboxymethoxy-imino)acetic acid of formula IVA, wherein R
9
denotes alkyl, cycloalkyl, alkylaryl, aryl or arylalkyl, R
10
denotes hydrogen and R
11
denotes hydrogen, silyl or acyl, e.g. 2-(aminothiazol-4-yl)-2-(tert.butoxycarbonyl-methoxyimino)acetic acid-S-mercaptobenzo-thiazolylester of formula IV; e.g. in free form or in form of a salt and/or in form of a solvate, e.g. an N,N-dimethylacetamide solvate;
to give a 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylic acid of formula IA wherein R
7
, R
9
, R
10
and R
11
are as defined above, e.g. in free form or in form of a salt, e.g. 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid of formula I;
b. reacting a 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylic acid of formula IA, wherein R
7
, R
9
, R
10
and R
11
are as defined above, e.g. 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylic acid of formula I, with an amine of formula
wherein R
1
, R
2
and R
3
independently of each other denote hydrogen, alkyl, cycloalkyl, alkylaryl, aryl or aralkyl, to give a crystalline salt of a compound of formula IA, wherein R
7
, R
9
, R
10
and R
11
are as defined above, e.g. of formula I, with an amine of formula VI, wherein R
1
, R
2
and R
3
are as defined above,
c. reacting the crystalline salt of a compound of formula IA, wherein R
7
, R
9
, R
10
and R
11
are as defined above with an amine of formula VI, wherein R
1
, R
2
and R
3
are as defined above, with sulphuric acid to obtain a 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylic acid, e.g. of formula
wherein R
7
, R
10
and R
11
are as defined above, e.g. a 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylic acid of formula II, in form of a crystalline sulphuric acid addition salt, and, if desired,
d. converting a sulphuric acid addition salt of a compound of formula IIA, wherein R
9
, R
10
and R
11
are as defined above, e.g. a sulphuric acid addition salt of a compound of formula II, into cefixime of formula II, e.g. in form of a solvate, such as a hydrate, e.g. trihydrate.
Any starting compound described herein may be produced as described herein, or according to, e.g. analogous, known methods.
Step A. May Be Carried Out As Follows:
A 7-amino-3-vinyl-3-cephem-4-carboxylic acid, e.g. of formula IIIA, wherein R
5
and R
6
denote hydrogen or a leaving group, including e.g. a silyl group, e.g. R
7
denotes hydrogen and R
6
denotes hydrogen or a silyl group, preferably hydrogen; and R
7
denotes a group as e.g. described for a corresponding group in e.g. H. Yamanaka et al., J. Antibiotics (1985), 38(12), pp.1738-1751, AU 9526702 (WO 95/33753) and EP 030 630, the content of which is introduced herein by reference, and e.g. including hydrogen, alkyl, such as lower alkyl, e.g. tert.butyl, cycloalkyl, alkylaryl, e.g. (lower alkyl)aryl, arylalkyl, e.g. benzhydryl, or silyl; such as hydrogen, alkyl or arylalkyl, preferably hydrogen; in free form or in form of a salt, e.g. an acid addition salt or, in case that R
7
denotes hydrogen, in form of a salt of the carboxylic acid group with a base, e.g. an amine salt; preferably in form of an amine salt; including e.g. a compound of formula III; may be reacted with
a 2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)acetic acid, e.g. of formula IVA, wherein R
9
, R
10
and R
11
denote a group as e.g. described for a corresponding group in e.g. H. Yamanaka et al., J. Antibiotics (1985), 38(12), pp.1738-1751, AU 9526702 (WO 95133753) and EP 030 630; the content of which is introduced herein by reference; and including in the meaning of R
9
alkyl, cycloalkyl, alkylaryl, aryl or arylalkyl, preferably alkyl, such as lower alkyl, e.g. butyl such as tert.butyl; and in the meaning of R
10
and R
11
hydrogen, silyl or acyl, e.g. R
10
denotes hydrogen and R
11
denotes hydrogen, silyl or acyl, e.g. formyl, alkanoyl, such as acetyl, or aralkanoyl, such as benzoyl, preferably formyl or hydrogen, e.g. hydrogen;
e.g. in form of an active derivative of a 2-(arninothiazol-4-yl)-2-(carboxymethoxyimino)-acetic acid such as e.g. described in H. Yamanaka et al., J. Antibiotics (1985), 38(12), pp. 1738-1751, AU 9526702 (WO 95133753), EP 030 630 and U.S. Pat. No. 5,003,073, the content of which is introduced herein by reference; in
Decristoforo Martin
Ludescher Johannes
Miller Ludwig
Sturm Hubert
Veit Werner
Berch Mark L.
Biochemie Gesellschaft m.b.H.
McNally Lydia T.
LandOfFree
Purification process does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Purification process, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Purification process will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2606152