U.S. patent application number 09/792800 was filed with the patent office on 2001-07-05 for process for the production of 3-vinyl cephalosporins.
Invention is credited to Ascher, Gerd, Ludescher, Johannes, Sturm, Herbert, Wieser, Josef.
Application Number | 20010007029 09/792800 |
Document ID | / |
Family ID | 27542352 |
Filed Date | 2001-07-05 |
United States Patent
Application |
20010007029 |
Kind Code |
A1 |
Wieser, Josef ; et
al. |
July 5, 2001 |
Process for the production of 3-vinyl cephalosporins
Abstract
A process for the production of 3-vinylcephalosporin compounds
of formula 1 wherein R.sub.1 and R.sub.2 may be the same or
different and are hydrogen or an organic radical using a Wittig
reaction in which weak bases are used.
Inventors: |
Wieser, Josef; (Kufstein,
AT) ; Ascher, Gerd; (Kundl, AT) ; Ludescher,
Johannes; (Breitenbach, AT) ; Sturm, Herbert;
(Innsbruck, AT) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS CORPORATION
PATENT AND TRADEMARK DEPT
564 MORRIS AVENUE
SUMMIT
NJ
079011027
|
Family ID: |
27542352 |
Appl. No.: |
09/792800 |
Filed: |
February 23, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09792800 |
Feb 23, 2001 |
|
|
|
08829572 |
Mar 31, 1997 |
|
|
|
08829572 |
Mar 31, 1997 |
|
|
|
08149431 |
Nov 9, 1993 |
|
|
|
08149431 |
Nov 9, 1993 |
|
|
|
08069239 |
May 28, 1993 |
|
|
|
5401841 |
|
|
|
|
08069239 |
May 28, 1993 |
|
|
|
07848457 |
Mar 9, 1992 |
|
|
|
Current U.S.
Class: |
540/214 |
Current CPC
Class: |
C07D 501/00
20130101 |
Class at
Publication: |
540/214 |
International
Class: |
C07D 279/00; C07D
513/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 8, 1991 |
AT |
A 504/91 |
May 17, 1991 |
AT |
A 101/91 |
Nov 10, 1992 |
AT |
A 2212/92 |
Claims
What is claimed is:
1. In a process for the production of a 3-vinylcephalosporin
compound of formula I 9wherein R.sub.1 and R.sub.2 may be the same
or different and denote hydrogen or an organic radical, which
comprises the steps of i) reacting a compound of the formula II
10in which R is a silyl protecting group, with a compound of the
formula P(R.sub.4).sub.3 or P(OR.sub.4).sub.3 to produce a compound
of formula III 11in which X is --P(R.sub.4).sub.3.I or
--P(O).(OR.sub.4).sub.2, R is as defined above and R.sub.4 is a
lower alkyl group or an aryl group; ii) reacting the compound of
the formula III with a base to produce a compound of the formula IV
12in which X.sup.+is --P+(R.sub.4).sub.3 or
--P(O).(OR.sub.4).sub.2.Y, R.sub.4 and R are as defined above and Y
is a cation of the alkali series or the protonated form of the
base; and iii) reacting the compound of the formula IV with a
compound of the formula V 13in which R.sub.1 and R.sub.2 are as
defined above, to produce the compound of the formula I; wherein
the improvement comprises reacting a weak base with the compound of
the formula III in step ii).
2. A process according to claim 1 in which the conjugate acid of
the weak base has an easily silylatable function and the reaction
is carried out in the presence of a silylating agent.
3. A process according to claim 2 in which the weak base is
selected from i) compounds that have the formula 14in which R.sub.5
is hydrogen, alkyl or aryl and R.sub.6 and R.sub.7, which may be
the same or different, are each an activated group of the formula
--COOR.sub.8, --CN, --SO.sub.2R.sub.8, --COR.sub.8 or
--CON(R.sub.8).sub.2; or R.sub.5 and R.sub.6, which may be the same
or different, are each aryl and R.sub.7 is an activated group of
the formula --COOR.sub.8, --CN, --SO.sub.2R.sub.8, --COR.sub.8 or
--CON(R.sub.8).sub.2; W.sup.+is a cation; and R.sub.8 is alkyl,
cycloalkyl or aryl; and ii) salts of carboxylic acids of the
formula R.sub.10--COO.sup.-W.sup.+in which R.sub.10 is an
optionally branched alkyl group or an optionally substituted aryl
group; and W.sup.+is as defined above.
4. A process according to claim 3 in which the weak base is a
lithium or sodium salt of malonic acid diethyl ester, acetoacetic
acid ester, acetic acid, pivalic acid, or ethylhexanoic acid, or is
a lithium salt of benzoic acid.
5. A process according to claim 2 in which the silylating agent is
added to the reaction mixture prior to the addition of the weak
base.
6. A process according to claim 2 in which the silylating agent is
added to the reaction mixture at the same time as the weak
base.
7. A process according to claim 2 in which the silylating agent is
N,O-bis(trimethylsilyl)acetamide or bissilylurea.
Description
[0001] The invention relates to an economical and simple process
for the production of 3-vinylcephalosporin compounds of formula I
2
[0002] wherein R.sub.1 and R.sub.2 may be the same or different and
denote hydrogen or an organic radical.
[0003] The compounds of formula I are known to be useful starting
products for the production of valuable 3-substituted vinyl
cephalosporins.
[0004] In substituents R.sub.1 and R.sub.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.sub.1 and R.sub.2 may
also form part of an optionally substituted ring system.
[0005] In a preferred embodiment of the invention one of R.sub.1
and R.sub.2 is hydrogen and the other is:
[0006] i) hydrogen, lower alkyl, lower alkenyl, or lower
alkinyl;
[0007] 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
[0008] iii) a group of formula --CH.sub.2Z, 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).sub.mR.sub.9 in which R.sub.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.
[0009] 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.sub.1-4) alkyl,
(C.sub.1-4) alkoxy, halogen, trihalo-(C.sub.1-4) alkyl, hydroxy,
oxo, mercapto, amino, carboxyl, carbamoyl, di-(C.sub.1-4)
alkylamino, carboxymethyl, carbamoylmethyl, sulfomethyl and
methoxycarbonylamino.
[0010] 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.
[0011] 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-triaz- in-3-yl, 1,2,3
-triazol-5-yl, and 4-methyl-thiazol-5-yl.
[0012] Examples of acyclic ammonium groups include
(1-carbamoyl-2--hydroxy- ethyl)-dimethylammonium,
(carbamoylmethyl)(ethyl)-methylammonium or trimethyl ammonium.
[0013] 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.
[0014] 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.
[0015] 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.
[0016] The process disclosed in EP 0503453 proceeds according to
the following reaction scheme:
[0017] i) a compound of the formula II 3
[0018] in which R is a silyl protecting group, is reacted with a
compound of the formula P(R.sub.4).sub.3 or P(OR.sub.4).sub.3 to
produce a compound of formula III 4
[0019] in which X is --P(R.sub.4).sub.3.I or
--P(O).(OR.sub.4).sub.2, R is as defined above and R.sub.4 is a
lower alkyl group or an aryl group;
[0020] ii) the compound of the formula III is then reacted with a
strong base to produce a compound of the formula IV 5
[0021] in which X.sup.+is --P.sup.+(R.sub.4).sub.3 or
--P(O).(OR.sub.4).sub.2.Y, R.sub.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
[0022] iii) the compound of the formula IV is reacted with a
compound of the formula V 6
[0023] in which R.sub.1 and R.sub.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.
[0024] 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.
[0025] 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.
[0026] 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).
[0027] 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 .beta.-lactam ring is reduced
and superfluous condensation of the base with the aldehyde or
ketone is avoided or restricted.
[0028] 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:
[0029] i) compounds that have the formula 7
[0030] in which R.sub.5 is hydrogen, alkyl or aryl; R.sub.6 and
R.sub.7, which may be the same or different, are each an activated
group of the formula --COOR.sub.8, --CN, --SO.sub.2R.sub.8,
--COR.sub.8, or --CON(R.sub.8).sub.2; or R.sub.5 and R.sub.6, which
may be the same or different, are each aryl and R.sub.7 is an
activated group of the formula --COOR.sub.8, --CN,
--SO.sub.2R.sub.8, --COR.sub.8 or --CON(R.sub.8).sub.2; W.sup.+is a
cation (for example lithium, sodium, or calcium); and R.sub.8 is
alkyl, cycloalkyl or aryl; and
[0031] ii) salts of carboxylic acids of the formula
R.sub.10--COO.sup.-W.sup.+in which R.sub.10 is an optionally
branched alkyl group or an optionally substituted aryl group; and
W.sup.+is as defined above.
[0032] Particularly preferred weak bases are lithium and sodium
salts of malonic acid diethyl esters, acetoacetic acid esters,
acetic acid, pivalic acid, or ethylhexanoic acids, or lithium salts
of benzoic acids.
[0033] The silylating agent may be added to the reaction mixture
prior to the addition of the weak base or simultaneously with the
weak base; in both cases to cause the silylation of silylatable
function of the conjugate acid of the weak base.
N,O-bis(trimethylsilyl)-acetamide and bissilylurea are particularly
suitable as silylating agents and further examples are given in EP
0503453.
[0034] The reaction may be carried in a suitable solvent or solvent
mixture which is inert under the reaction conditions, for example
an inert ether (such as tetra-hydrofuran, diethyl ether, an
ethylene glycol dialkyl ether or a tert.butylmethyl ether), an
inert amide (such as dimethylformamide, dimethylacetamide or
N-methylpyrrolidone), an urea (such as tetra-methylurea,
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimido- ne, or
1,3,2-imidazolidinone) a nitrile (such as acetonitrile), or a
halogenated hydrocarbon (such as dichloromethane).
[0035] Should a substituent of the aldehyde or the ketone of
formula V contain a function which is easily silylated, this should
be blocked temporarily with an appropriate silylation agent prior
to the reaction. The amount of the compound of formula V may be
stoichiometrical or in excess based on the amount of the compound
of formula IV.
[0036] The reaction may be carried out over a wide temperature
range, preferably at a temperature of between -70.degree. C. and
+70.degree. C.
[0037] The compounds of formula I may be isolated in a conventional
manner. The silyl protecting groups may be removed by simple
hydrolysis or alcoholysis. This may be done either by adding the
desilylation agent to the reaction mixture, or by extracting the
product into a separable aqueous phase, adding water (under
alkaline or acidic conditions) and precipitating by adjusting the
pH value to the isoelectric point, optionally adding an organic
solvent.
[0038] The compounds of formula II are known and may be produced as
described in EP 0503453.
[0039] The compounds of formula I are important starting materials
for the production of valuable cephalosporin antibiotics.
Cephalosporins which are vinyl-substituted in 3-position are either
resorbed orally, or when administered parenterally, are
characterized for their very broad, efficient spectrum of activity.
The following compounds may be produced for example: 8
[0040] In the following examples, which illustrate the invention
more fully, but in no way limit its scope, all temperatures are
given in degrees celsius.
EXAMPLE 1
7-Amino-3-(3-acetoxy-1-propenyl)-3-cephem-4-carboxylic acid
[0041] 7.5 ml of N,O-bis(trimethylsilyl)acetamide is added to 25 ml
of a dichloromethane solution containing 6 g of
7-trimethylsilylamino-3-triphe-
nyl-phosphoniummethyl-3-cephem-4-carboxylic acid
trimethylsilylester-iodid- e on ice. 25 ml of a N-Methylpyrrolidone
solution, at 5 to 10.degree., containing 2.35 g sodium aceto-acetic
acid ethyl ester, is added dropwise. The dark red solution is then
cooled to 2.degree. and 5.16 g acetoxyaldehyde is added dropwise.
The reaction mixture is then stirred for 2 hours at 10.degree. and
then added to a mixture of 100 ml acetic acid and 100 ml water. The
pH of the aqueous phase is adjusted to 7 with ammonia and the
organic phase is separated off. The pH is adjusted to 3.5 by adding
1:1 diluted concentrated HCl, whereupon the title compound
precipitates. The suspension is stirred for 30 minutes at
5.degree., the title compound is filtered off, washed in acetone
and dried.
EXAMPLE 2
7-Amino-3-(prop-1-enyl)-3-cephem-4-carboxylic acid
[0042] 5 ml of N,O-bis(trimethylsilyl)acetamide is added to 25 ml
of a dichloromethane solution containing 6 g of
7-trimethylsilylamino-3-triphe-
nyl-phosphoniummethyl-3-cephem-4-carboxylic acid
trimethylsilylester-iodid- e on ice. 25 ml of a N-Methylpyrrolidone
solution, at 5 to 10.degree., containing 2.35 g sodium malonic acid
diethyl ester, is added dropwise. Thereafter the solution is cooled
to -10.degree. and 1.32 g acetaldehyde, dissolved in 10 ml
dichloromethane, is added. After the addition of the acetaldehyde,
the reaction mixture is stirred for 48 hours at 0.degree..
Thereafter the process proceeds as described in example 1.
EXAMPLE 3
7-Amino-3-(prop-1-enyl)-3-cephem-4-carboxylic acid
[0043] 36.5 ml of N,O-bis(trimethylsilyl)acetamide is added to 500
ml of a dichloromethane solution containing 24 g of
7-trimethylsilylamino-3-triph-
enyl-phosphoniummethyl-3-cephem-4-carboxylic acid
trimethylsilylester-iodi- de at a temperature of -10.degree.. A
suspension of 12.8 g lithium benzoate in 75 ml N-Methylpyrrolidone
is added. 9 g of acetaldehyde is added and the reaction mixture is
stirred for 2 days at 0.degree.. Superfluous acetaldehyde and most
of the dichloromethane are removed in a rotary evaporator. The
residue is then stirred in 1500 ml of water and then filtered. The
residue is dissolved in 200 ml aqueous ammonia and the aqueous
phase is extracted twice using 100 ml dichloromethane. After
removal of the organic phase, 1:1 diluted concentrated HCl is added
to the aqueous phase to bring the pH to 3.5 whereupon the title
compound precipitates. The suspension is stirred for 30 minutes at
50.degree., the title compound is filtered off, washed in acetone
and dried.
EXAMPLE 4
7-Amino-3-(3-acetoxy-1-propen-1-yl)-3-cephem-4-carboxylic acid
[0044] 7.5 ml of N,O-bis(trimethylsilyl)acetamide is added to 25 ml
of a dichloromethane solution containing 6 g of
7-trimethylsilylamino-3-triphe-
nyl-phosphoniummethyl-3-cephem-4-carboxylic acid
trimethylsilylester-iodid- e on ice. 15 ml of a N-methylpyrrilidone
solution containing 2.5 g sodium-ethylhexanoate is added dropwise
at 0 to 5.degree.. 5 ml of acetoxy-acetaldehyde is added dropwise.
The reaction mixture is stirred overnight at 0.degree. and then
processed as described in example 1.
EXAMPLE 5
7-Amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic
acid
[0045] 25 g of a dichloromethane solution containing 10.2 g of
7-trimethylsilylamino-3-triphenyl-phosphoniummethyl-3-cephem-4-carboxylic
acid trimethylsilylester-iodide is cooled to a temperature of
-10.degree.. 4.7 ml of N,O-bis(trimethylsilyl)acetamide, 11 ml
dimethylformamide and 1.1 g lithium acetate are added and the
mixture stirred at 0 to 5.degree. for 30 minutes. A solution of 2 g
of 4-methyl-thiazol-5-carboxyaldehyde in 5 ml dichloromethane is
then added dropwise. The mixture is then stirred for 10 hours at
30.degree., cooled to 10.degree. and stirred for a further hour at
10.degree.. The title compound is separated using a suction filter,
washed with methanol and vacuum dried.
EXAMPLE 6
7-Amino-3-(prop-1-enyl)-3-cephem-4-carboxylic acid
[0046] 220.7 g of a dichloromethane solution containing 68.7 g of
7-trimethylsilylamino-3-triphenyl-phosphoniummethyl-3-cephem-4-carboxylic
acid trimethylsilylester-iodide is cooled to a temperature of
-10.degree.. 58.4 ml of N,O-bis(trimethylsilyl)acetamide and 81 ml
N,N-dimethylacetamide is added while stirring. A solution of 14.05
g lithium pivalate is added and the mixture stirred for 30 minutes
at -10.degree.. 17.2 ml of acetaldehyde is added and the reaction
mixture is stirred for 90 minutes at -10.degree. and then overnight
at 0.degree.. Superfluous acetaldehyde and some of the
dichloromethane are removed in a rotary evaporator under vacuum and
at 20.degree.. The residue is then stirred into 500 ml of ice-cold
water and 100 ml dichloromethane. The pH value is adjusted to 8.5
with aqueous ammonia. The phases are then separated and the aqueous
phase is washed with 100 ml dichloromethane and combined with 200
ml acetone. The pH is adjusted to 3.5 with 1:1 diluted concentrated
hydrochloric acid at 30.degree. to precipitate the title compound.
The suspension is held in the ice bath for 2 hours whilst stirring,
and the title compound is isolated using a suction filter. The
title compound is washed with a mixture of 100 ml of water and 50
ml acetone and then again with 50 ml of acetone. The title compound
is then dried in a vacuum drying chamber at 40.degree..
* * * * *