Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Utility Patent
1997-10-08
2001-01-02
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S222000, C540S223000, C540S226000, C540S227000
Utility Patent
active
06169180
ABSTRACT:
The invention relates to a new economical and simple process, using a new intermediate compound, for the production of 3′-substituted 7-amino-3-propenyl-4-cephem-carboxylic acid derivatives of formula I
wherein R is hydrogen, a negative charge or a silyl protecting group, R
o
is hydrogen or methoxy, R
1
is hydrogen or a silyl protecting group and X is the radical of a nucleophile, and their acid addition salts.
Compounds of formula I are useful starting products for the production of valuable 3-substituted propenyl cephalosporines.
Illustrative examples of X are
a) an unsaturated heterocyclic ammonium group of formula II
wherein Het
1
signifies a 5- or 6-membered heterocycle which optionally contain one or two additional heteroatoms selected from oxygen, nitrogen or sulphur atoms, R
7
is hydrogen, carboxy, carboxamido, a sulphonic acid radical or a substituent which is usual in &bgr;-lactam chemistry, e.g. alkoxy, hydroxy, acyl, amino, alkylthio mercapto, and wherein both the R
7
signify an optionally substituted, saturated or unsaturated alkyl group, or form part of an optionally substituted, saturated or unsaturated carbocyclic ring or part of a further (anellated) hetero-aromatic ring or
b) an aliphatic ammonium group of formula III
wherein R
2
, R
3
and R
4
may be the same or different and respectively signify alkyl, alkenyl, aryl, hydroxy lower alkyl, carbamoyl lower alkyl, amino lower alkyl, acylamino lower alkyl, cyano lower alkyl or carboxy lower alkyl or R
2
with R
3
and the nitrogen atom signify a carbocyclic unsaturated ring which is alkyl-substituted by R
4
, whereby R
4
may additionally represent a 1,3- or 1,4-alkylene or vinylene bridge or R
2
and R
3
and the nitrogen atom signify a carbocyclic saturated ring, wherein R
4
is a vinylene bridge, or
c) a saturated heterocyclic ammonium group or
d) a nitrogen base of formula IV
—NH—R
5
IV
wherein R
5
signifies hydrogen or has the significance of R
2
, or
e) an optionally substituted tetrazole, triazole, imidazole, pyrrolidine or pyrazole, or
f) an optionally substituted heterocyclic thiole radical of formula V
wherein Het
2
signifies a heterocycle or
g) a thiole radical of formula VI
—S—R
8
VI
wherein R
8
signifies an optionally substituted alkyl, alkenyl, aryl, acyl, carbamoyl, thiocarbamoyl or carbalkoxy radical or the thia-analogues thereof, or
h) N
3
.
Examples of group a) are optionally substituted thiazolium, pyrrolinium, thiadiazolium, oxadiazolium, oxazolium, pyridinium, thiazol[4,5-c]pyridinium, thieno [2,3-b]pyridinium, thieno[3,2-b]pyridinium, isoquinolinium or quinolinium.
Examples of group b) are tri(lower)alkylammonium, especially trimethylammonium, (1-carbamoyl-2-hydroxyethyl)dimethylammonium (carbamoylmethyl)(ethyl)-methylammonium, (cyanomethyl)dimethylammonium, (2-oxopropyl)dimethylammonium or dehydroquinuclidinium.
Examples of group c) are 1-methylpyrrolidinium, pyrrolidinium, piperidinium, 1-methylpiperidinium, 1-methylpiperazinium, 1-methylpyrazolidinium, 1,5-diazabicyclo[3.3.0]octan-1-ium, 1,4-diazabicylo[2.2.2]octan-1-ium, quinuclidinium or 1-aza-5-methyl-4,6-dioxabicyclo[3.3.1]nonan-1-ium.
Examples of group e) are 1,2,4-triazolyl, 1-methyl-1H-tetrazol-5-yl, 1-carboxymethyl-1H-tetrazol-5-yl or 1,2,3-triazol-5-yl.
The term heterocycle in the definition of Het
2
in group f) refers to a single ring or fused heterocyclic rings having 4 to 7, preferably 5- or 6- atoms in each ring, there being up to four hetero atoms in each ring selected from oxygen, nitrogen and sulphur in each ring, which heterocyclic ring may carry 1 to 3 optional substituents selected from (C
1-4
)alkyl, (C
2-4
)alkenyl, (C
1-4
)alkoxy, halogen, trihalo-(C
1-4
)alkyl, hydroxy, acyloxy, oxo, mercapto, amino, carboxyl, carbamoyl, di-(C
1-4
)alkylamino, carboxymethyl, carbomoylmethyl, sulfomethyl and methoxycarbonylamino.
Examples of heterocycle include unsubstituted and substituted imidazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, triazolylpyridyl, purinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl and triazinyl.
Suitable heterocycles 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, 4-methyl-thiazol-5-yl.
Except where otherwise indicated organic radicals contain preferably up to 10 carbon atoms and lower refers to up to 4 carbon atoms.
Examples of acid addition salts are salts of inorganic or organic acids, e.g. hydroiodide or hydrochloride.
A particular preferred group of compounds of formula I comprise those of formula I′
wherein R′ is hydrogen or a negative charge, R
o
′ is hydrogen, and X′ is pyridinium, 1,2,3-triazol-5-ylthio or carbamoylmethylethylmethylammonium and their acid addition salts.
The compounds of formula I are known. They are characterized by their excellent spectrum of activity: for example, in EP A 333 154 and EP A 264 091, a number of compounds having a substituted ammonium-propenyl group and substituted pyridinium-propenyl group are described. EP 315 518 claims compounds of the type having isomeric thienopyridinium-propenyl derivatives. DE 3 404 615 and DE 3 512 225 describe pyridinium- and ammonium-propenyl derivatives which are substituted in the same way. U.S. Pat. No. 4,139,618 describes for example cephalosporin derivatives having thia- or oxadiazol-5-yl-thio groups as substituents.
However, according to methods known from literature, the compounds of formula I can only be produced via several intermediate steps, using extensive protecting group technology. For example, in EP 333 154, 7-&bgr;-(2-phenylacetamido)-3-chloromethylcephem-4-carboxylic acid-p-methoxybenzylester is converted into the vinylogous chloromethyl compound via the analogous iodomethyl compound, phosphonium salt and Wittig reaction with chloroacetaldehyde. The resultant compound is then reacted with a N-nucleophile according to choice, the protecting groups in position 7 and 4 are cleaved in any order and subsequently reacylated with the side chain that is applicable for the respective active substance in position 7. In another reaction sequence, for example, in the first stage the phenylacetyl protecting group at the vinylogous chloromethyl compound is cleaved, then the N-nucleophile is introduced, subsequently the ester protecting group is removed and reacylated or synthesis to form the active substance is effected in reverse order. The disadvantages of this synthesis are on the one hand the high number of stages of synthesis due to extensive protecting group technology, and on the other hand to form the vinylogous compound it is necessary to work with poisonous choroacetaldehyde which is only obtainable with extreme difficulty and with high loss in dry, monomeric form.
Another synthesis strategy is described for example in EP 315 518. Here, 7-amino-3-chloromethylcephem-4-carboxylic acid benzhydryl ester is acylated with the protected active substance side chain, subsequently vinylized again with chloracetaldehyde by means of the corresponding phosphonium salt, chloride is exchanged for iodide, reacted with the corresponding N-heterocycle and the protecting group is subsequently cleaved. Again due to extensive protecting group technology, this synthesis requires a large number of stages of synthesis with some expensive chromatography steps.
Another approach is illustrated by the synthesis method claimed in DE 3 404 615. Here, in reverse order, a Wittig reaction is carried out between a protected 7-acylamino-3-formyl-4-carboxylic acid ester with the
Ludescher Johannes
Sturm Hubert
Wieser Josef
Biochemie Gesellschaft
Ford John M.
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