Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-23
2002-07-02
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
06414140
ABSTRACT:
The invention relates to an economical and simple process for the production of 3-vinylcephalosporin compounds of formula I
wherein R
1
and R
2
may be the same or different and denote hydrogen or an organic radical.
The compounds of formula I are known to be useful starting products for the production of valuable 3-substituted vinyl cephalosporins.
In substituents R
1
and R
2
, the organic radical may signify for example an optionally branched alkyl, alkenyl or alkinyl group; a totally or partially saturated cycloalkyl radical; or an optionally substituted aryl radical, aralkyl radical or heterocycle. The cycloalkyl radical, aryl radical, aralkyl radical or heterocycle may be substituted in any position, for example by halogen, nitrogen, sulphur, alkoxy, aryloxy, or a functional group such as a carbalkoxy or carboxamido group. R
1
and R
2
may also form part of an optionally substituted ring system.
In a preferred embodiment of the invention one of R
1
and R
2
is hydrogen and the other is:
i) hydrogen, lower alkyl, lower alkenyl, or lower alkinyl;
ii) lower cycloalkyl, lower cycloalkyl lower alkyl, aryl, (aryl)-lower alkyl, a heterocyclic group or a heterocyclyl-(lower)-alkyl, the ring of each of which may be optionally substituted by 1 to 3 lower alkoxy, lower alkylthio, halogen, lower alkyl, nitro, hydroxy, acyloxy, carboxy, carbalkoxy, lower alkylcarbonyl, lower alkylsulfonyl, lower alkoxysulfonyl, amino-(lower)-alkyl amino or acylamido groups; or
iii) a group of formula —CH
2
Z, in which Z is a) hydroxy, lower alkoxy, formyloxy, acetyloxy, lower alkylsulfonyloxy, halogen, N-mono(lower)alkylcarbamoyloxy, or N,N-di(lower)alkylcarbamoyloxy; b) a heterocyclic group; c) a group of formula —S(O)
m
R
9
in which R
9
is an aliphatic, araliphatic, alicyclic, aromatic or heterocyclic group, and m is 0, 1 or 2; or d) an acyclic or cyclic ammonium group.
Suitable heterocyclic groups include single or fused heterocyclic rings having 4 to 7, preferably 5- or 6-atoms in each ring. Each ring has up to four hetero atoms in it selected from oxygen, nitrogen and sulphur. Also each heterocyclic ring may have 1 to 3 optional substituents selected from (C
1-4
) alkyl, (C
1-4
) alkoxy, halogen, trihalo-(C
1-4
) alkyl, hydroxy, oxo, mercapto, amino, carboxyl, carbamoyl, di-(C
1-4
) alkylamino, carboxymethyl, carbamoylmethyl, sulfomethyl and methoxycarbonylamino.
Examples of suitable heterocycle rings include unsubstituted and substituted imidazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, triazolylpyridyl, purinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl and triazinyl.
Preferably, suitable heterocycle rings include unsubstituted and substituted 5-hydroxy-4-pyridon-2-yl, 1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; oxazolyl; thiazolyl; 1,3,4-oxadiazolyl; 1,3,4-thiadiazolyl or 1,2,3-thiadiazolyl. Preferably the heterocycle is 1,5-dihydroxy-4-pyridon-2-yl, 5-hydroxy-1-methyl-4-pyridon-2-yl, 5-hydroxy-4-pyridon-2-yl, 1-methyl- 1H-tetrazol-5-yl-2-methyl- 1,3,4-thiadiazol-5-yl, 1-carboxymethyl-1H-tetrazol-5-yl, 6-hydroxy-2-methyl-5-oxo-2H-1,2,4-triazin-3-yl, 1,2,3 -triazol-5-yl, and 4-methyl-thiazol-5-yl.
Examples of acyclic ammonium groups include (1-carbamoyl-2—(carbamoylmethyl)(ethyl)-methylammonium or trimethyl ammonium.
Examples of cyclic ammonium groups are pyrrolidinium, which is N-substituted by alkyl, carbamoylalkyl, aminoalkyl or carboxyalkyl; pyridinium or cyclopentenopyridinium, which may be mono- or di-substituted by alkyl, halogen, hydroxy, carboxamido, alkoxycarbonyl, amino, monoalkylamino or dialkylamino.
Except where otherwise indicated, the organic radicals preferably contain up to 10 carbon atoms and “lower” means the group has up to 4 carbon atoms.
Processes for the production of compounds of formula I are known and are discussed in EP 0503453, the disclosure of which is incorporated by reference. However, as discussed in EP 0503453, these known processes require the use of expensive protection groups and require a multiplicity of intermediate stages. The invention disclosed in EP 0503453 addressed the problems of the prior art by making use of silyl protection groups in a Wittig reaction using 7-amino cephalosporanic acid as starting reagent.
The process disclosed in EP 0503453 proceeds according to the following reaction scheme:
i) a compound of the formula II
in which R is a silyl protecting group, is reacted with a compound of the formula P(R
4
)
3
or P(OR
4
)
3
to produce a compound of formula III
in which X is —P(R
4
)
3
.I or —P(O).(OR
4
)
2
, R is as defined above and R
4
is a lower alkyl group or an aryl group;
ii) the compound of the formula III is then reacted with a strong base to produce a compound of the formula IV
in which X
+
is —P
+
(R
4
)
3
or —P(O).(OR
4
)
2
.Y, R
4
and R are as defined above and Y is a cation of the alkali series or the protonated form of a strong organic base; and
iii) the compound of the formula IV is reacted with a compound of the formula V
in which R
1
and R
2
are as defined above, to produce the compound of the formula I. The resulting process is simple, economical and may be carried out in a single reaction vessel. Also, it has the advantage that the silyl protection groups are removable by simple hydrolysis or alcoholysis.
The base used in step ii) is a strong organic base and guanidines (for example tetramethylguanidine), amidines (for example 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicylo[4.3.0]non-5-ene), alkali salts of nitrogen-containing compounds (for example the Li or Na salts of 1,1,1,3,3,3-hexamethyldisilazane and Li-diisopropylamide), butyllithium, hydrides of alkali metals, and iminophosphoranes are given as suitable examples. It is also mentioned that the bases should be free of moisture and should not contain any parts that could be silylated, so as to maintain the degree of silylation of the product.
It has now been surprisingly found that the process described in EP 0503453 may be carried out using weaker bases. This is of particular advantage since the reaction may be carried out under milder conditions.
Therefore this invention provides a process, substantially as defined above, for the production of a compound of formula I which is improved by the use of a weak base in step ii).
That a weaker base could be used in a Wittig reaction is indeed surprising. The use of the weaker base has the advantage that the possibility of opening the &bgr;-lactam ring is reduced and superfluous condensation of the base with the aldehyde or ketone is avoided or restricted.
Preferably the weak base is such that its conjugate acid has a silylatable function and the reaction step ii) is carried out in the presence of a silylating agent to cause silylation of the silylatable function. Surprisingly, the reaction proceeds without the silyl protecting group on the 7-amino group, which is a very potent silylating agent and which is easily removed, being removed by the base or conjugate acid. If the silyl protecting group were to be removed during the reaction, the amino group would be free to react with the aldehyde or ketone of formula V and this would cause the reaction to collapse.
Preferably the weak base is selected from:
i) compounds that have the formula
in which R
5
is hydrogen, alkyl or aryl; R
6
and R
7
, which may be the same or different, are each an activated group of the formula —COOR
8
, —CN, —SO
2
R
8
, —COR
8
or —CON(R
8
)
2
; or R
5
and R
6
, which may be the same or different, are each aryl and R
7
is an activated group of the formula —COOR
8
, —CN, —SO
2
R
8
, —COR
8
or —CON(R
8
)
2
; W
+
is a cation (for example lithium, sodium, or calcium); and R
8
is alkyl, cycloalkyl or aryl; and
ii) salts of carboxylic acids of the formula R
10
—COO
−
W
+
in which R
10
is an optionally branched alkyl group or an optionally substituted aryl group; and W
+
is as defined above.
Particularly preferred weak bases are lithium and sodium salts of ma
Ascher Gerd
Ludescher Johannes
Sturm Herbert
Wieser Josef
Berch Mark L.
Biochemie Gesellschaft m.b.H.
Pfeiffer Hesna J.
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