Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-17
2003-01-07
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S228000
Reexamination Certificate
active
06504025
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a process for the preparation of a vinyl-pyrrolidinone cephalosporine derivative of formula I:
The compound of formula I is known and described in WO 99/65920. It is useful for the treatment and prophylaxis of infectious diseases, especially infectious diseases caused by bacterial pathogens, in particular, methicillin resistent
Staphylococcus aureus
(MRSA) and
Pseudomonas aeruginosa.
a) oxidation of a 3-hydroxymethyl-cephem derivative to the corresponding 3-formyl-cephem derivative;
b) reaction of said compound with the ylide of 1-substituted 2-oxo-pyrrolidin compounds to 3-vinyl-pyrrolidone cephem derivatives;
c) deprotection and reaction with 5-amino-[1,2,4]thiadiazol-3-yl)-trityloxyimino-thioacetic acid S-benzothiazol-2-yl ester;
d) deprotection reactions; and
e) subsequent acylation reaction with carbonic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester 4-nitro phenyl ester.
SUMMARY OF THE INVENTION
The present invention is a process for the preparation of a vinyl-pyrrolidinone cephalosporine derivative of formula I
which process comprises:
acylating a compound of formula II
with a compound of formula III
wherein R
1
is a hydroxy protecting group and Y is an activating group of formula Y1
or of formula Y2
or of formula Y3,
in the presence of a base, and protecting of the carboxylic acid group to form a compound of formula IV
wherein R
2
is a carboxylic acid protecting group;
oxidizing the compound of formula IV with an inorganic hypohalite in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxyl radical (TEMPO) or with manganese dioxide, to obtain the corresponding aldehyde derivative of formula V
reacting the compound of formula V with the ylide of the phosphonium salt of formula VI
wherein Ph is phenyl and R is an amino protecting group or a group of formula A
to form a cephalosporine derivative of formula Ia
and;
i) when R is an amino protecting group, cleaving off the protecting groups R
1
, R
2
and R, and reacting the resulting unprotected compound with a compound of formula VII
to obtain the vinyl-pyrrolidinone cephalosporine derivative of formula I; or
ii) when R is a group of formula A, cleaving off the hydroxy and the carboxylic acid protecting groups R
1
and R
2
under acidic conditions to obtain the vinyl-pyrrolidinone cephalosporine derivative of formula I.
The present invention also provides a compound of formula IV
wherein R
1
is a hydroxy protecting group and R
2
is a carboxylic acid protecting group.
In addition, the present invention provides a compound of formula V
wherein R
1
is a hydroxy protecting group and R
2
is a carboxylic acid protecting group.
Compounds IV and V are intermediates in the process of preparing the compound of formula I, in accordance with the present invention.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that the compound of formula I can be manufactured in an improved way by the process of the present invention. The process of the present invention for the preparation of a vinyl-pyrrolidinone cephalosporine derivative of formula I
is characterized in that it comprises
step (a) acylating a compound of formula II
with a compound of formula III
wherein R
1
is a hydroxy protecting group and Y is an activating group, as for example a group of formula Y1
or of formula Y2
or of formula Y3,
in the presence of a base, and subsequently protecting the carboxylic acid group to form the product of formula IV
wherein R
1
is as defined above and R
2
is a carboxylic acid protecting group;
step (b) oxidizing the compound of formula IV with an inorganic hypohalite in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxyl radical (TEMPO) or with manganese dioxide, to obtain the corresponding aldehyde derivative of formula V
wherein R
1
and R
2
are as defined above;
step (c) reacting the compound of formula V with the ylide of the phosphonium salt of formula VI
wherein Ph is phenyl and R is an amino protecting group or a group of formula A
to form the cephalosporine derivatives of formula Ia
wherein R
1
, R
2
and R are as defined above; and
step (d) i) when R is an amino protecting group, cleaving off the protecting groups R
1
, R
2
and R, and reacting the unprotected compound subsequently with a compound of formula VII
to obtain the vinyl-pyrrolidinone cephalosporine derivative of formula I; or
ii) when R is a group of formula A, cleaving off the hydroxy and the carboxylic acid protecting groups R
1
and R
2
under acidic conditions to obtain the vinyl-pyrrolidinone cephalosporine derivative of formula I.
It has been surprisingly found, that due to the combination of process steps according to the invention, formula I is prepared by fewer steps and is obtained in higher yield, thereby decreasing production costs.
In the structural formulae presented herein a wedged bond (
) denotes that the substituent is above the plane of the paper.
The term “hydroxy protecting group” as used herein denotes an alkyl group, a cycloalkyl group or an arylalkyl group. A preferred hydroxy protecting group is an arylalkyl group, especially preferred is a triphenylmethyl (trityl) group.
The term “activating group” as used herein denotes, for example, an activated ester such as a group of formula Y1 (mercaptobenzothiazole thioester) as described in EP 0849269 or of formula Y2 (1-hydroxybenzotriazole esters) or mixed anhydrides in analogy to those described in EP 0812846 such as Y3 (diethyl thiophosphoryl) or acid halides, in particular, acid chlorides in analogy to those described in J. Antibiot. (1984), 37(5), 557-71, which increase the reactivity of the carbon atom of the oxo group of the compound of formula III. The acylation of the compound of formula II with an activated compound of formula III results in a higher yield. A preferred activating group is the mercaptobenzothiazole thioester group.
The term “base” as used herein (step (a)) denotes a common base such as a tertiary amine, amidine base or a guanidine base.
The term “tertiary amine” as used herein denotes a group of formula N(alkyl)
3
in which the same or different alkyl groups are attached to the nitrogen atom. Examples are trimethyl amine, triethyl amine, dimethyl ethyl amine, methyl diethyl amine, tripropyl amine or tributyl amine.
The term “amidine base” as used herein denotes amidines or alkyl amidines in which 1, 2 or 3 hydrogen(s) are substituted by the same or different alkyl groups potentially also forming rings. Preferred amidine bases are 1,8-diazabicyclo[5.4.0]undec-7-en (DBU) and 1,8-diazabicyclo[4.3.0]non-5-en (DBN).
The term “guanidine base” as used herein denotes guanidine or alkyl guanidine in which 1, 2, 3, 4 or 5 hydrogen(s) (in the 1, 2 or 3-position) are substituted by the same or different alkyl group, potentially also forming rings. Preferred guanidine bases are alkyl guanidine bases such as 1,1,3,3-tetramethyl guanidine.
The term “alkyl” as used herein denotes a straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl and the like.
The term “alkoxy” signifies an alkyl group as defined above which is bonded via an oxygen atom. Examples are methoxy, ethoxy, propyloxy, butoxy and the like.
By the term “cycloalkyl” as used herein denotes a 3-7 membered saturated carbocyclic moiety, e.g., cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl or cycloheptyl.
The term “aryl” as used herein denotes a phenyl group or a monosubstituted phenyl group which is substituted in the ortho-, meta- or para- position. Such substituents for the phenyl group are C
1-4
-alkyl groups.
The term “aryloxy” signifies an aryl group as defined above which is bonded via an oxygen atom. Examples are phenyloxy and the like.
The term “arylalkyl” as used herein denotes a hydrocarbon group in which one or more alkyl hydrogen atoms are substituted by an aryl group such as trityl or benzhydryl.
The term “carboxylic acid protecting group” includes protecting groups which are usually used to
Hebeisen Paul
Hilpert Hans
Humm Roland
Basilea Pharmaceutica AG
Berch Mark L.
Ebel Eileen M.
Johnston George W.
Rocha-Tramaloni Patricia S.
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