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Description  |
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The present invention relates to a novel process for preparing
alpha-carboxy-benzyl- and alpha-carboxy-3-thienylmethyl-penicillins and
cephalosporins of general formula I and their pharmaceutically acceptable
salts.
##STR1##
wherein R is alpha-carboxy-alpha-phenyl (or 3-thienyl)acetyl-
X is a divalent group of formula (a) or (b)
##STR2##
WHEREIN Y is --OCOCH.sub.3,hydrogen or a S-monoheterocyclic radical, e.g.
##STR3##
The compounds of formula I show antibacterial activity. Examples of
particularly interesting compounds of formula I are
6-(.alpha.-carboxy-phenylacetamido) penicillanic acid or carbenicillin,
6-[.alpha.-carboxy-.alpha.-(3-thienyl)-acetamido]penicillanic acid or
ticarcillin and
7-[.alpha.-carboxy-.alpha.-(3-thienyl)-acetamido]-3-(1-methyl-tetrazol-5-y
lthiomethyl)-3-cephem-4-carboxylic acid or RIT 3838. The antibacterial
activity of carbenicillin and ticarcillin is described by P. Acred et al.
in Nature 215 (5096) : 25-30 (1967) and by V. Rodriguez et al. in
Antimicr. Agents Chemother. 4(1), 31-6 (1973), respectively. According to
Belgian Pat. No. 646 991, carbenicillin and ticarcillin are prepared from
6-aminopenicillanic acid and a reactive acid of the formula
##STR4##
wherein R is phenyl or 3-thienyl and X represents either hydroxyl group or
chlorine atom, or OR' group where R' represents a protective
group--examples of which are alkyl, aryl, benzyl and substituted
benzyl--which may be further eliminated.
According to U.S. Ser. No. 537,987 application filed by one of us, on Jan.
2, 1975, now abandoned RIT 3838 is prepared from activated
.alpha.-carboxy-3-thienyl-acetic acid and
7-amino-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid.
We have now found, and this is the object of the present invention, that it
is possible to obtain the compounds of formula I when using cyclic acylals
of phenyl (or 3-thienyl)malonic acids as key intermediates.
The process of the invention affords substantial advantages over the prior
process by providing an easier and shorter pathway to get the compounds of
formula I.
The cyclic acylals of phenyl (or 3-thienyl) malonic acids used as key
intermediates in the present invention are the compounds of general
formula II
##STR5##
wherein A is phenyl or 3-thienyl
R' and R" are either identical or different and, when n = 0, represent
lower alkyl radicals of from 1 to 4 carbon atoms, preferably identical and
representing methyl, or, when n is an integer comprised between 1 and 7, n
being preferably 2 or 3, R' and R" are methylene radicals.
The products of general formula II wherein A is phenyl are described by P.
J. Scheuer in J.A.C.S. 80 : 4933-4938 (1958) and by Bernd Eistert et al.
Chem. Ber. 94 : 929-47 (1961). The products of formula II wherein A is
3-thienyl are novel and we have found that these 3-thienyl compounds
cannot be obtained when using the sulfuric acid catalyst employed by P. J.
Scheuer and B. Eistert et al. (loc.cit.) but can be obtained when using
boron trifluoride etherate instead of sulfuric acid.
Prior to this invention, it was also known that a cyclic acylal of malonic
acid (i.e. isopropylidene malonate or Meldrum's acid) and a cyclic acylal
of methylphenylmalonic acid (i.e. isopropylidene methylphenylmalonate) do
react with substituted aniline and with benzylamine respectively (C. D.
Hurd et al. in J.A.C.S. 76 : 5563-64 (1954) and P. J. Scheuer, loc.cit. to
yield the corresponding malonamic acid.
The present invention provides a process for preparing a product of formula
I and which comprises (1) reacting in acetic anhydride phenyl-(or
3-thienyl)-malonic acid or a functional equivalent thereof such as an
ester, more particularly a di-lower alkyl ester, wherein each alkyl
contains from 1 to 4 carbon atoms with a ketone selected from the group
consisting of di-lower alkyl ketones (wherein the alkyl are identical or
different and contains from 1 to 4 carbon atoms, each) and 5 to 10
membered cyclic ketones, preferably acetone in the presence of an acid
catalyst selected from the group comprising sulfuric acid, phosphoric
acid, p-toluene sulfonic acid, aluminium bromide, aluminium chloride,
titanium tetrachloride and boron trifluoride etherate, preferably sulfuric
acid or boron trifluoride etherate with the proviso that, when using
3-thienylmalonic acid, the catalyst is boron trifluoride etherate and (2)
reacting at temperature comprised between -15.degree. C and +30.degree. C
in an anhydrous and non-reactive organic solvent selected from the group
comprising acetonitrile, dichloromethane, ethylacetate,
tetrahydrofuran--preferably tetrahydrofuran the obtained product of
formula II with a compound selected from the group consisting of
6-aminopenicillanic acid or 7-amino-3-acetoxymethyl-, 3-methyl- or
3-monoheterocyclicthiomethyl-3-cephem-4-carboxylic acid of formula
III--preferably
7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid-,
said compound being previously dissolved in an excess of a silyl
derivative selected from the group comprising trichlormethylsilane and
bis-trimethylsilylacetamide--preferably bis-trimethylsilylacetamide and
(3) hydrolyzing the obtained silylated compound by adding thereto either
an organic solvent selected from the group comprising of methanol,
ethanol, propanol, isopropanol, butanol alone or mixed with water or
acetone/water, as known to the art.
According to another embodiment of the present invention and when the
intermediate 2.2-dimethyl-5-phenyl-(or 3-thienyl)-1.3-dioxane-4.6-dione is
desired, step (1) of the above described process is preferably performed
by allowing phenyl-(or 3-thienyl)-malonic acid to react with isopropenyl
acetate in an organic solvent selected from the group comprising acetone,
methylene dichloride, nitromethane and dioxane instead of allowing
phenyl-(or 3-thienyl)-malonic acid to react in acetic anhydride with
acetone.
In a process for preparing a product of formula I, the invention thus
relates to the hereinabove defined steps which comprise reacting a product
of formula II with a silylated product of formula III and hydrolyzing the
obtained silylated compound.
The 6-[.alpha.-carboxy-.alpha.-phenyl (or 3-thienyl)acetamido]penicillanic
acid alkali metal salt or
7-[.alpha.-carboxy-.alpha.-(3-thienyl)-acetamido]-3-substituted-3-cephem-4
-carboxylic acid alkali metal salt, preferably the disodium salt, is
obtained from the acid form by extraction with dilute NaHCO.sub.3
solution.
Our procedure is summarized in the following schema wherein A,R,R',R", X
and n are as defined above.
The following examples illustrate the invention but are not to be
understood as limiting the scope thereof.
EXAMPLE 1
To a suspension of 1730mg (8 mmol) of 6-aminopenicillanic acid in 150 ml.
of anhydrous tetrahydrofuran, there is added 6.5 ml. of
bis-trimethylsilylacetamide. The mixture is stirred to give a solution to
which there is added 1.76 g (8 mmol) of
2.2-dimethyl-5-phenyl-1,3-dioxane-4,6-dione (prepared according to P. J.
Scheuer and S. G. Cohen in J. Amer. Chem. Soc. 80 : 4933-38 (1958). The
mixture is stirred at 25.degree. C for 3 hours.
Methanol (50 ml.) is added thereto and the solution is stirred for 15
minutes. The solvents are removed under reduced pressure and the residue
is taken up with 100 ml. of water, brought to pH 2.5 with 0.5ml. 6NHCl and
extracted three times with 50 ml. of ethyl acetate. The organic layer is
dried over anhydrous sodium sulfate, decanted, decolorized with charcoal
and then filtered. Most of the solvent is evaporated under reduced
pressure and 150 ml. of petroleum ether (50.degree.-70.degree.) is added
thereto.
The suspension is stirred for 15 minutes and filtered. The precipitate is
washed and dried over anhydrous P.sub.2 O.sub.5 under reduced pressure to
yield 6-(.alpha.-carboxy-.alpha.-phenylacetamido) penicillanic acid
(carbenicillin).
An aliquot of the obtained compound (1.55 g-4 mmol) is dissolved in 100 ml.
of ethylacetate and the solution is extracted with 10 ml., 30 ml., 50 ml.,
30 ml. and 10 ml. portions of 0.1 N NaHCO.sub.3.
The three first fractions are pooled together and lyophilized to yield the
disodium salt of 6-(.alpha.-carboxy-.alpha.-phenylacetamido)penicillanic
acid.
R.sub.f = 0.51 (.+-. 0.1) in the system
chloroform/acetonitrile/water/formic acid (35/68/5/2).
nmr (D.sub.2 O) : 7.53 s (5H); 5.66 m (1H + 1H); 4.34 m (1H) appears as 2
singlets corresponding to 50 % of D and 50 % of L isomer, respectively;
and 1.58 m (3H + 3H).
EXAMPLE 2
To a suspension of 9 g (50 mmol) of phenylmalonic acid in 23 ml. of acetic
anhydride there is added 0.5 ml. of concentrated H.sub.2 SO.sub.4. The
mixture is stirred to give a solution to which there is added at once 7.5
ml. (83 mmol) of 2-butanone, the mixture being stirred at 25.degree. C for
1 hour and then maintained at -15.degree. C for 60 hours.
Water (250 ml.) is then added thereto and the mixture is stirred for 30
minutes. The obtained precipitate is washed with 250 ml. of water up to pH
6.5, dried under reduced pressure and dissolved in 100 ml. of chloroform.
The organic solution is dried over anhydrous sodium sulfate; most of the
solvent is evaporated under reduced pressure and 100 ml. of petroleum
ether (50.degree.-70.degree. C) is added thereto. The suspension is
stirred for 30 minutes and filtered. The precipitate is washed with 20 ml.
of petroleum ether (50.degree.-70.degree. C) and dried over P.sub.2
O.sub.5 under reduced pressure to yield
2-ethyl-2-methyl-5-phenyl-1.3-dioxane-4.6-dione. m.p. 135-6.degree. C.
R.sub.f = 0.88 (.+-. 0.1) in acetone : detection with bromocresol green and
KMnO.sub.4.
nmr (CDCl.sub.3) 7.38 s (5H), 4.78 s (splitting) (1H), 2.02 q (splitting)
(2H, J = 7.3 cps), 1.71 s (splitting) (3H), 1.08 t (3H, J = 7.3 cps).
EXAMPLE 3
When 2-butanone is substituted by cyclopentanone in the example 2 and the
procedure described therein carried out,
2.2-tetramethylene-5-phenyl-1.3-dioxane-4.6-dione is obtained. m.p.
155-6.degree. C.
R.sub.f = 0.90 (.+-. 0.1) in acetone; detection with bromocresol green and
KMnO.sub.4.
nmr (DMSO-d.sub.6) 7.44 s (5H), 4.75 s (1H), 2.25 m (4H), 1.85 m (4H).
EXAMPLE 4
When an equivalent amount of
2-ethyl-2-methyl-5-phenyl-1.3-dioxane-4.6-dione as prepared in the example
2 is substituted for 2.2-dimethyl-5-phenyl-1.3-dioxane-4.6-dione and the
reaction with 6-aminopenicillanic acid is carried out as disclosed in the
example 1, 6-(.alpha.-carboxy-.alpha.-phenylacetamido)penicillanic acid
(carbenicillin) is obtained.
EXAMPLE 5
When an equivalent amount of
2.2-tetramethylene-5-phenyl-1.3-dioxane-4.6-dione prepared in the example
3 is substituted for 2.2-dimethyl-5-phenyl-1.3-dioxane-4.6-dione and the
reaction with 6-aminopenicillanic acid is carried out as disclosed in the
example 1, 6-(.alpha.-carboxy-.alpha.-phenylacetamido)penicillanic acid
(carbenicillin) is obtained.
EXAMPLE 6
To a suspension of 3 g (16 mmol) of 3-thiophenemalonic acid in 3.5 ml. of
acetic anhydride there is added 0.15 ml. of boron trifluoride etherate
(corresponding to 48 % of BF.sub.3). The mixture is stirred for 30 minutes
to give a solution to which there is added at once and 0.degree. C 3 ml of
acetone. The mixture is stirred at 25.degree. C for 1 hour and maintained
at -15.degree. C for 12 hours.
Ice water (20 ml.) is then added thereto and the mixture is stirred for 15
minutes and filtered.
The obtained precipitate is taken up in chloroform (50 ml.), the organic
layer is dried over anhydrous sodium sulfate and filtered on DARCO G60 (a
product manufactured and sold by Atlas Chem. Ind., New Murphy Road,
Wilmington, DEL 19899)--charcoal. Most of the solvent is evaporated under
reduced pressure and 50 ml. of petroleum ether (50.degree.-70.degree. C)
is added thereto. The suspension is stirred for 15 minutes and filtered.
The precipitate is washed with 20 ml. of petroleum ether
(50.degree.-70.degree. C) and dried over anhydrous P.sub.2 O.sub.5 under
reduced pressure to yield
2.2-dimethyl-5-(3-thienyl)-1.3-dioxane-4.6-dione. m.p. (decomposition)
128.degree.-130.degree. C. 7
R.sub.f = 0.90 (.+-.0.1) in the system acetonitrile/water (8/2) detection
with bromocresol green and KMnO.sub.4 ; U.V. detection.
nmr (CD.sub.3 CN) 7.46 m (2H), 7.10 m (1H), 5.35 m (1H), 1.81 s (6H).
EXAMPLE 7
To 11.8 g (50 mmol) of phenylmalonic acid diethyl ester in 23 ml. of acetic
anhydride there are added 0.5 ml. of concentrated H.sub.2 SO.sub.4 and 20
ml. of acetone. The mixture is stirred at 25.degree. C for 8 hours, water
(250 ml.) is then added thereto and the mixture is stirred for 30 minutes.
The obtained precipitate is washed with 250 ml. of water up to pH 6.5,
dried under reduced pressure and dissolved in 100 ml. of chloroform. The
organic solution is dried over anhydrous sodium sulfate, most of the
solvent is evaporated under reduced pressure and 100 ml. of petroleum
ether (50.degree.-70.degree. C) is added thereto. The suspension is
stirred for 30 minutes and filtered. The precipitate is washed with 20 ml.
of petroleum ether (50.degree.-70.degree. C) and dried over P.sub.2
O.sub.5 under reduced pressure to yield
2.2-dimethyl-5-phenyl-1.3-dioxane-4.6-dione with the same characteristics
as the compound described by P. J. Scheuer in J.A.C.S. 80, 4933-38 (1958).
EXAMPLE 8
When an equivalent amount of phenylmalonic acid is substituted in the
procedure of example 6 for 3-thiophenemalonic acid and the reaction with
6-aminopenicillanic acid is carried out as disclosed in the example 1,
6-(.alpha.-carboxy-.alpha.-phenylacetamido)penicillanic acid
(carbenicillin) is obtained.
EXAMPLE 9
To 13.02 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole prepared according to
the procedure described by Stolle R. et al. in J. Prakt. Chem. [2], 124,
261-79 (1930) and dissolved in 800 ml. of a 0.2 M phosphate buffer
solution (pH 6.5-6.6), there is added 20.4 g of 7-aminocephalosporanic
acid (7-ACA). The mixture is brought to pH 6.3-6.6 by addition of 21.5 ml.
of triethylamine, heated at 70.degree. C for 80 minutes, at once cooled to
20.degree. C, acidified to pH 3.5 by addition of 65 ml. of 2N HCl and then
stirred for 15 minutes.
The obtained precipitate is filtered, washed with 200 ml. of water, 200 ml.
of methanol and 200 ml. of diethylether and dried under reduced pressure
to yield a crude product which is dissolved in 300 ml. of 2N HCl, treated
with DARCO G60 (a product manufactured and sold by Atlas Chem.
Ind.)-charcoal and filtered.
Crystallization occurs from the filtrate brought to pH 3.7 by addition of
45 ml. of concentrated ammonium hydroxide.
The crystallization medium is stirred for 30 minutes at 25.degree. C and
filtered under reduced pressure. The precipitate is washed with 200 ml. of
water, 200 ml. of methanol and 200 ml. of diethylether and dried at
40.degree. C over P.sub.2 O.sub.5 under reduced pressure to yield
7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
R.sub.f = 0.44 (.+-. 0.10) in the system acetonitrile/water (80/20),
detection with U.V. or bromocresol green.
nmr (D.sub.2 O--Na.sub.2 CO.sub.3) 5.48 d (1H) (J 4.7 c./sec.), 5.08 d (1H)
(J 4.7 c./sec.), 4.40 and 4.06 2d (2 .times. 1H) (J 13 c./sec.), 3.95 s
(3H), 3.86 and 3.43 2d (2 .times. 1H) (J 18 c./sec.).
EXAMPLE 10
To a suspension of 656.7 mg (2 mmol) of
7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (as
prepared in example 9) in 25 ml. of anhydrous tetrahydrofuran there is
added 1.6 ml. of bis-trimethylsilylacetamide. The mixture is stirred to
give a solution to which there is added at once 452.5 mg (2 mmol) of
2.2-dimethyl-5-(3-thienyl)-1.3-dioxane-4.6-dione as prepared in example 6,
the mixture being stirred at 25.degree. C for 8 hours. Tetrahydrofuran is
removed under reduced pressure and the residue is taken up with 30 ml. of
water, brought to pH 2.5 with 0.5 ml. 6N HCl, stirred for 15 minutes and
extracted three times with 25 ml. of ethyl acetate. The organic layer is
dried over anhydrous sodium sulfate and filtered over DARCO G60 (a product
manufactured and sold by Atlas Chem. Ind.)-charcoal. Most of the solvent
is evaporated under reduced pressure and 100 ml. of petroleum ether
(50.degree.-70.degree. C) is added thereto. The suspension is stirred for
30 minutes and filtered. The precipitate is washed with 20 ml. of
petroleum ether (50.degree.-70.degree. C) and dried over anhydrous P.sub.2
O.sub.5 under reduced pressure to yield
DL-7-[.alpha.-carboxy-.alpha.-(3-thienyl)-acetamido]-3-(1-methyl-tetrazol-
5-ylthiomethyl)-3-cephem-4-carboxylic acid (RIT 3838).
nmr (CD.sub.3 OD): 7.70-7.25 m (3H), 5.85 d (1H, J = 5.1 cps) 5.19 d (1H, J
= 5.1 cps), 4.42 m (2H), 4.06 s (3H), 3.77 m (2H).
R.sub.f = 0.55 (.+-. 0.10) in the system
chloroform/acetonitrile/water/formic acid) (35/58/5/2), detection with
U.V.
EXAMPLE 11
To a suspension of 432.56 mg (2 mmol) of 6-aminopenicillanic acid in 40 ml.
of anhydrous tetrahydrofuran, there is added 1.5 ml. of
bis-trimethylsilylacetamide, the mixture being stirred at 25.degree. C for
12 hours.
To the solution there is added at once 452.5 mg (2 mmol) of
2.2-dimethyl-5-(3-thienyl)-1.3-dioxane-4.6-dione, as prepared in example
6, the mixture being stirred at 25.degree. C for 4 hours. When reaction is
carried out as disclosed in the example 10,
6-[.alpha.-carboxy-.alpha.-(3-thienyl) acetamido]penicillanic acid
(ticarcillin) is obtained.
R.sub.f = 0.62 (.+-. 0.1) in the system acetonitrile/water (8/2) U.V.
detection, detection with bromocresol green and KMnO.sub.4.
nmr ((CD.sub.3).sub.2 CO): 8.77 m deuterated with D.sub.2 O (2 .times.
COOH), 8.15 m deuterated with D.sub.2 O (--NH--), 7.75-7.25 m (3H), 5.72 m
(2H), 5.00 s deuterated with D.sub.2 O (1H), 4.40 s (1H), 1.57 s (6H).
EXAMPLE 12
When an equivalent amount of 7-amino-3-heterocyclic
thiomethyl-3-cephem-4-carboxylic acid listed below is substituted in the
procedure of example 10 for
7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid,
the appropriate
.alpha.-carboxy-.alpha.-(3-thienyl)-acetamido-3-heterocyclicthiomethyl-3-c
ephem-4-carboxylic acid is obtained.
7-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic
acid
7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid
7-amino-3-(1-methyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic
acid
7-amino-3-(1,3,4-triazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid
7-amino-3-(5-trifluoromethyl-1,3,4-triazol-2-ylthiomethyl)-3-cephem-4-carbo
xylic acid
7-amino-3-(5-n-butyl-1,3,4-triazol-2-ylthiomethyl)-3-cephem-4-carboxylic
acid
7-amino-3-(5-methyl-1,3,4-oxadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic
acid
7-amino-3-(1,2,3,4-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid
EXAMPLE 13
To a solution of 3.72 g (20 mM) 3-thienylmalonic acid in 2.54 ml. (23.3 mM)
isopropenylacetate and 5 ml. acetone there is added with stirring 0.37 ml.
of boron trifluoride etherate. The mixture is stirred at 0.degree. C for 8
hours and maintained at -15.degree. C for 15 hours, diluted with 30 ml. of
carbon tetrachloride and then filtered. The precipitate is washed with 50
ml. of ether and dried under reduced pressure to yield the same compound
as described in the example 6.
EXAMPLE 14
When an equivalent amount of 7-amino cephalosporanic acid is substituted in
the procedure of example 10 for
7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid,
7-[.alpha.-carboxy-.alpha.-(3-thienyl)-acetamido]cephalosporanic acid is
obtained.
EXAMPLE 15
When an equivalent amount of 7-amino-3-desacetoxy cephalosporanic acid is
substituted in the procedure of example 10 for
7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid,
7-[.alpha.-carboxy-.alpha.-(3-thienyl)-acetamido]-3-desacetoxy
cephalosporanic acid is obtained.
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