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Патент USA US3035057

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United States Patent 0 ” ice
3,035,047
Patented May 15, 1962
1
2
3,035,047
elusive and the “lower” alkyl groups are alkyl groups
having from 1 to 6 carbon atoms inclusive. The pre
ferred penicillins of the present invention are those in
Yvon G. Perron, 106 Stoneerest Drive, Dewitt, N.Y., and
Lee C. Cheney, Woodchuck Hill Road, Fayetteville,
which R is an allyl radical or a “lower”alkyl group, par
PHTHALAMIDD PENICILLINS
ticularly, n-propyl, isopropyl, n-arnyl, n-butyl and t-(butyl.
Also included within the scope of the present invention
are easily hydrolyzed esters which are converted to the
free acid form by chemical or enzymatic hydrolysis.
The products of the present invention are prepared by
No l)rawing. Filed Sept. 25, 1961, Set. No. 140,204
1 Claims. (01. zen-239.1)
This invention relates to new synthetic compounds of
value as antibacterial agents, as nutritional supplements 10 reaction of 6-aminopenicillanic acid, preferably in the
form of a neutral salt such as the sodium salt or the tri
in animal feeds, as agents for the treatment of mastitis
ethylamine salt, with an anhydride of an acid having the
in cattle and as therapeutic agents in poultry and ani
formula
mals, including man, in the treatment especially of in
fectious diseases caused by Gram-positive bacteria and,
more particularly, relates to 6 - (N-substituted-phthal
15
amido)penicillanic acids and nontoxic salts thereof.
This application is a continuation-in-part of our pend
ing United States Patent application Serial No. 74,489,
?led December 8, 1960 now abandoned, which is a con
tinuation-in-part of United States application Serial No.
62,526, ?led October 14, 1960 and now abandoned.
Antibacterial agents such as benzylpenicillin have
proved highly effective in the past in the therapy of in
fections due to Gram-positive bacteria but such agents
suffer from ‘the serious drawbacks of ‘being unstable in
aqueous acid, e.g., upon oral administration, and of be
ing ineffective against numerous so-called resistant strains
where R is as de?ned above, or its functional equiv
valents as an acylating agent for a primary amino group.
Such equivalents include the corresponding mixed anhy
drides with other carboxylic acids, including monoesters,
and particularly lower aliphatic esters, of carbonic acid;
such equivalents in certain cases include the acid chlorides
and acid bromides of the above phthalamic acids.
The N-substituted phthalamic acids which are reacted
of bacteria, e.g., penicillin-resistant strains of Staphy
lococcus aureus (Micrococcus pyogenes var. aureus). In
with 6-aminopenicillanic acid in the preparation of the
addition, benzylpenicillin is not an e?ective agent against 30 compounds of the present invention are readily prepared
many bacteria which produce penicillinase. Many of the
according to methods which are described in the tech
compounds of the present invention, in addition to their
nical literature and which are illustrated in Examples
potent antibacterial activity, exhibit resistance to destruc
1, 3 and 5 below. Phthalic anhydride and many of the
tion by acid or by penicillinase or are effective against
benzylpenicillin-resistant strains of bacteria or inhibit
amines used to prepare such phthalamic acids are com
mercially available and, in addition, can also be readily
benzylpenicillinase and thus potentiate the action of
benzylpenieillin when admixed therewith.
There is provided, according to the present invention,
prepared according to known preparative techniques.
Speci?c techniques for the preparation of certain of the
phthalamic acids are described in Ber. 76, page 1144
a member selected from the group consisting of the acids
having the formula
4.0
0
H
I
0-13.
0
l!
S
/
CH3
Games-rt ‘toe
45
where R is a member selected from the group consisting
of alkylamino, dialkylamino, cycloalkylamino containing
(1943) and C. A. 45, page 8556i.
An elegant procedure for preparing a compound of
the present invention by way of a mixed anhydride with
ethoxy- or isobutoxy-carbonic acid comprises mixing 0.01
mole of phthalamic acid of the structure set forth above,
0.01 mole isobutyl chloroforrnate and 0.011 mol ter
tiary hydrocarbonyl or aliphatic amine such as triethyl
amine in an anhydrous, inert and preferably water
miscible solvent such as p-dioxane (e.g., 20 ml.) and, if
desired, 2 ml. pure, dry acetone for about thirty min
from 3 to 7 carbon atoms, inclusive, allylamino, diallyl 50 utes in the cold, e.g., at about 4° C. To this solution
of the mixed anhydride there is added a chilled solution
amino, phenyl(1ower) alkylamino, morpholino, lower
(al-kyDmorpholino, di(lower)alkylmorph0line, morpho
lino(lower) alkylamino, pyrrolidino, (lower)alkylpyrroli
dino, di(lower)alkylpyrrolidino, N-azepinyl, piperidino,
lower(alkyl)piperidino, rdi(lower)alkylpiperidino, 1,2,5,
6-tetrahydropyridino, N-(lower)-alkylpiperazino, N-phen
ylpiperazino, N-(lower) alkyl) (lower) alkylpiperazino, N
(lower) alkyl - di-(lower) -alkylpiperazino, furfurylamino,
tetrahydrofurhrrylamino,
N - (lower) alkyl - N - furfuryl
amino, N - alkyl - N-anilino, and (lower) alkoxyanilino,
and nontoxic salts thereof, including nontoxic metallic
salts such as sodium, potassium, calcium and aluminum,
the ammonium salt and substituted ammonium salts, e.g.,
salts of such nontoxic amines as tri(lower)alkylamines,
including triethylamine, procaine, dibenzylamine, N-benz
yl-beta-phenethylamine, l-ephenamine, N,N’-dibenzy1
ethylenediamine, dehydroabietylamine, N,N'-bis-dehydro
abiethylethylenediamine, N-(lower)alkylpiperidine, and
of 0.01 mole 6-aminopenicillanic acid and 0.01 mole ter
tiary hydrocarbonyl amine, e.g., triethylarnine, in, for ex
55
ample, 20 ml. of a solvent such as water. The reaction
mixture is stirred for a period of an hour or so to form
the substituted ammonium salt of the desired product.
The mixture may then, if desired, be extracted at al
kaline pH (such as pH 8; aqueous sodium bicarbonate
may be used, for example, if necessary to adjust the pH)
with a water-immiscible solvent such as ether to remove
unreacted starting materials. The product in the aque
ous phase is then converted to the free acid, preferably
in the cold under a layer of ether by the addition of di
lute mineral acid, e.g., 5 N H2804 to pHZ. The free
acid is then extracted into a water-immiscible, neutral
organic solvent such as ether and the extract is washed
with water quickly in the cold, if desired, and then dried,
as with anhydrous NazSO4. The product in the ethereal
extract in its free acid form is then converted to any de
other amines which have been used to form salts with
benzylpenicillin. The term “alkyl” as used herein refers 70 sired metal or amine salt by treatment with the appropri
ate base, e.g., a free amine such as procaine base or a so
to straight and branched chain saturated aliphatic hydro
lution of potassium 2-ethylhexanoate in dry n-butanol.
carbon groups having from 1 to 12 carbon atoms in
3,035,047
>
These salts are usually insoluble in solvents such as ether
and can be recovered in pure form by simple ?ltration.
Since some of the antibiotic substances obtained by
the process of this invention are relatively unstable com
pounds which readily undergo chemical changes result
ing in the loss of an antibiotic activity, it is desirable to
choose reaction conditions which are su?iciently mod
erate to avoid their decomposition. The reaction con
4
Hydrocarbonyl alcohols and tertiary hydrocarbonyl
amines are compounds having the formulae
1'12
R—-0EI and R3—N—-R1
wherein the R groups contain only the elements carbon
and hydrogen.
The following examples will serve to illustrate this
invention without limiting it thereto.
ditions chosen will, of course, depend largely upon the
reactivity of the chemical reagent being used. In most 10
EXAMPLE 1
instances, a compromise has to be made between the use
of very mild conditions for a lengthy period ‘and the use
of more vigorous conditions for a shorter time with the
possibility of decomposing some of the antibiotic sub
stance.
Preparation of N-Allylphthalamic Acid
Phthalic anhydride (0.5 mole; 74.0 gm.) and 300 ml.
of benzene is mixed in a 1 liter, three-necked, round bot
The mixture is stirred for 20 minutes and
a mixture of allylamine (0.5 ml.; 28.5 gm.) in 100 ml.
of benzene is added dropwise over a period of 1/2 hour
and the resulting mixture is stirred for 20 minutes at
room temperature. The reaction mixture is then placed
15 tom flask.
The temperature chosen for the process of preparation
of the derivatives of penicillanic acid should, in general,
not exceed 30° C. and in many cases a suitable tempera
ture is ambient temperature. Since the use of strongly
acid or alkaline conditions in the process of this inven 20 on a steam bath and re?uxed for one hour. The mix
tion should be avoided, it has been found preferable to
ture is then allowed to cool to room temperature, is then
perform the process at a pH of from 6 to 9, and this can
placed in an ice bath for about 20 minutes whereupon
conveniently be achieved by using a butter, for example,
the product is precipitated. The product, N-allylphthah
a solution of sodium bicarbonate, or a sodium phosphate
buffer. In addition to the use of aqueous media for the
desiccator and found to Weigh 92.4 gms. and have a
reaction, including ?ltered fermentation broths or aque
ous solutions of crude 6-aminopenicillanic acid, use can
be made of organic solvents which do not contain reac
Examples of such inert solvents
are dimethylformamide, dimethylacetamide, chloroform,
acetone, methyl isobutyl ketone and dioxane. Frequent
. tive hydrogen atoms.
ly it is highly satisfactory to add an aqueous solution of
a salt of 6-aminopenicillanic acid to a solution or" the
acylating agent in an inert solvent and preferably in an
inert solvent which is miscible with water, such as ace
tone or dimethylformamide. Vigorous stirring is, of
course, advisable when more than one phase is present,
amic acid, is removed by ?ltration, dried overnight in a
melting point of 115°—1l7° C. The product is recrys
tallized from acetone and the recrystallized product is
found to weigh 60.2 gms. and have a melting point of
115-117 ° C.
Analysis.—Calculated:
C,
64.38%;
H,
5.40%.
Found: C, 64.40%; H, 5.50%.
EXAMPLE 2
Preparation of Potassium
6-(Allyl-N'-Phthalamid0)
Penicillanate
Ethyl chloroformate (10 ml.) is added dropwise with
stirring to a solution at about —5° C. of N-allylphthal—
amic acid (20.52 gms.; 0.1 mole), 14 ml. triethylamine,
70 ml. of p-dioxane and 30 ml. of dry acetone. After
lated, if desired, by the techniques used with benzylpeni 40 stirring
for 15 minutes at —5° C., a solution of 6-aminoe
cillin and phenoxymethylpenicillin. Thus the product
penicillanic
acid (21.6 gms; 0.1 mole), 50 ml. of water
can be extracted into diethyl ether or n-butanol at acid
previously chilled to 0° C. and 15 ml. of triethylamine
pH and then recovered by lyophilization or by conver
is added in one portion. The reaction mixture is stirred
sion to a solvent-insoluble salt, as by neutralization with
an n-butanol solution of potassium Z-ethylhexanoate, or 45 vigorously at 0° C. for 2 hours. The reaction mixture
is diluted with an equal volume of Water and extracted
the product can be precipitated from aqueous solution
e.g., solid and liquid or two liquid phases.
At the conclusion of the reaction, the products are iso
as a water-insoluble salt of an amine or recovered direct
ly by lyophilization, preferably in the form of a sodium
three times with methyl isobutyl ketone and the ether
extracts are discarded.
The cold aqueous solution is
layered with methyl isobutyl ketone and acidi?ed to pH
or potassium salt. When formed as the triethylamine
salt, the product is converted to the free acid form and 50 2 with 42% phosphoric acid. The acidi?ed solution is
extracted With 700 ml. of methyl isobutyl ketone in three
thence to other salts in the manner used with benzyl
portions.
The methyl isobutyl ketone extracts, which
penicillin and other penicillins. Thus treatment of such
contain
6~(N-a1lyl-N'-phthalamido)penicillanic
acid, are
a triethylamine compound in Water with sodium hydrox
Washed once with water, dried with sodium sulfate, ?ltered
ide converts it to the sodium salt and the triethylamine
and treated with a solution of potassium 2-ethylhexanoate
may be removed by extraction, as with toluene. Treat 55
in
ether. The solvent is decanted from the product which
ment of the sodium salt with strong aqueous acid con
is then covered with 400 ml. of acetone. The solid prod
vents the compound to the acid form, which can be con
uct, potassium 6-(N-allyl-N'-phthalamido)penicillanate,
verted to other amine salts, e.g., procaine, by reaction
is
then collected by filtration, dried in vacuo over P205,
with the amine base. Salts so formed are isolated by
to weigh 20.0 gms., to contain the ,B-lactam struc
lyophilization or, if the product is insoluble, by ?ltration. 60 found
ture as shown by infrared analysis, to inhibit Staph.
A particularly elegant method of isolating the product as
aurezls Smith at a concentration of 0.8 mcg./ml. and to
a crystalline potassium salt comprises extracting the prod
exhibit versus Staph. aureus Smith upon intramuscular in
uct from an acidic, aqueous solution (e.g., pH 2) into di
jection in mice a CD50 of 6.8 meg/kg.
ethyl ether, drying the ether and adding at least one
EXAMPLE 3
equivalent of a solution of potassium 2-ethylhexanoate 65
(e.g., 0.373 gm./ml.) in dry n-butanol. The potassium
Preparation of N-Benzylphthalamic Acid
salt ‘forms precipitates, usually in crystalline form, and
Phthalic
anhydride (0.5 mole; 74.0 gm.) and 200 ml.
is collected by ?ltration or decantation.
of acetone is mixed in a 1 liter, threefnecked, round
6-aminopenicillanic acid is prepared according to
?'a’sk' equipped with ‘a condenser,‘ stirrer and drop
Batchelor et al. (Nature 183, 257-258, January 24, 1959), 70/bottom
ping funnel and a steam bath is used to dissolve the an
Belgian Patent 569,728 or United States Patent No.
hydride. Benzylamine (0.5 mole; 53.0 gm.) in 50 ml.
2,941,995.
It is used in the above reaction as the salt
of a metal or a tertiary hydrocarbonyl amine or as an
ester of a hydrocarbonyl alcohol.
of acetone is added dropwise to the solution over a 1/2
hour period whereupon the product, N-benzylphthalamic
75 acid, precipitates.
An additional 200 ml. of acetone is
3,035,047
5
5
product contained no imide and titration indicated a purity
of approximately 75%. The product had a carbon and
then added to the reaction mixture which is heated to
re?ux for 1A; hour. The reaction mixture is then cooled
to room temperature. The product is recovered by ?ltra
tion, washed with 60 ml. acetone and dried in vacuo. The
hydrogen analysis as follows: Calculated for C11H14NO3:
Calculated: C, 63.75%; H, 6.32%. Found: C, 63.53%;
H, 7.70%.
crude product (which weighs 111.4 gms.) is recrystallized
from acetone, dried, found to weigh 87.2 gms. and to
melt at 155~156° C.
EXAMPLE 6
Preparation of 6-(N-n-Propyl-N'-Phthalamid0)—Penicil
Analysis.—Calculated: C, 70.58%; H, 5.13%. Found:
C, 70.72%; H, 5.41%.
Preparation of 6-(N-Benzyl-N'-Phthalamid0)Penicillanic
lanic Acid and the Potassium Salt Thereof
Triethylamine (13.9 gms; 0.1 mole) is added in one
portion to a suspension of N-n-propylphthalarnic acid
(20.7 gms.; 0.1 mole) in 100 ml. of tetrahydrofuran
Acid and the Sodium Salt Thereof
Triethylamine (13.9 gms; 0.1 mole) is added in one
whereupon a solution is formed. The solution is cooled
in an ice-salt'acetone bath and isobutyl chloroformate
maintained at about —5° C. The resulting reaction mix- -
0.1 mole) in 40 ml. of water and 15 ml. of triethyl
amine. The resulting reaction mixture is removed from
the cooling bath, stirred at room temperature for 21/2
hours and then diluted with an equal volume of water
EXAMPLE 4
10
portion to a suspension of N-benzylphthalamic acid (25.5 15 (13.7 gms; 0.1 mole) is added dropwise While the tem
perature of the solution is maintained at the temperature
gms.; 0.1 mole) in 150 ml. of tetrahydrofuran whereupon
of the cooling bath. The resulting reaction mixture is
a solution is formed. The solution is cooled to about —5 °
stirred for 1/2 hour and there is added in one portion
C. and isobutyl chloroformate (13.7 gms.; 0.1 mole) is
a chilled solution of 6-aminopenicillanic acid (21.6 gms;
added dropwise while the temperature of the solution is
ture is stirred for 1/2 hour and there is added in one por
tion a chilled solution of G-aminopenicillanic acid (21.6
grns.; 0.1 mole) in 40 ml. of Water and 15 m1. of tri
ethylamine. The resulting reaction mixture is stirred for
14 hour at —5° C. in a cooling bath and thereafter at
room temperature for two hours. The reaction mixture
is diluted with an equal volume of water and extracted
and extracted twice with methyl isobutyl ketone, the
extracts being discarded. The aqueous solution is lay
ered with methyl isobutyl ketone, chilled, and acidi?ed
to pH 2 with 42.5% phosphoric acid. The acidi?ed
aqueous soiution, which contains 6-(N-n~propyl-N’
twice with methyl isobutyl ketone, the extracts being dis
carded. The aqueous solution is layered with methyl 30 phthalamido)penicillanic acid, is extracted twice with
methyl isobutyl ketone and the combined extracts are
isobutyl ketone, chilled and acidi?ed to pH 2 with 42.5%
washed with chilled water, ?ltered through sodium sul
phosphoric acid. The acidi?ed aqueous solution which
fate and dried over sodium sulfate. The sodium sulfate
contains 6-(N-benzyl-N'-phthalamido)penicillanic acid is
extracted twice with methyl isobutyl ketone and the com
is then removed from the extracts and 40 ml. of a 50%
bined extracts are washed with chilled Water, ?ltered
through sodium sulfate and dried over sodium sulfate.
The sodium sulfate is then removed from the extracts
and 33.2 ml. of a 50% solution of sodium Z-ethylhex
cipitate, the potassium salt of 6-(PLn-propyl-N?phthal
amido)penicillanic acid, is collected by ?ltration, slur
anoate is added whereupon a precipitate is formed. The
precipitate, the sodium salt of 6-(N-benzyl-N?phthal
amido)penicillanic acid, is collected by ?ltration, slurried
with acetone, re?ltered, air-dried and then dried in vacuo
over P205. The product is found to weight 11.8 gins,
to contain the ,B-lactam structure as shown by infrared
analysis, to inhibit Staph. aureas Smith at a concentra
tion of 0.4 meg/ml, to exhibit versus Staph. aureus
Smith upon intramuscular injection in mice a CD50 of 17
mcg./kg., and to have the following carbon and hydrogen
analysis.
Calculated for C23H22N3O5Sna: C, 58.1%; H, 4.66%.
Found: C, 54.65%; H, 4.75%.
EXAMPLE 5
Preparation of N-n-Propylphthalamic Acid
To a Warm stirred solution of 'phthalic anhydride (74.0
gms; 0.5 mole) in 200 ml. of acetone is added dropwise
over a 10 minute period n-propyl amine (35.5 gms.; 0.6
mole). During the addition of the amine reflux condi
tions are maintained by the rate of addition of the amine.
solution of potassium Z-ethylhexanOate in n-butanol is
added whereupon a precipitate is formed.
The pre
ried with acetone, re?ltered, air-dried and then dried in
vacuo over P205. The product is found to Weigh 22.5
gms, to contain the ?-lactam structure as shown by in
frared analysis, to inhibit Staph. aareus Smith at a con
centration of 1.6 meg/ml. and to have the following
carbon and hydrogen analysis calculated for
C19H22N3O5SK
Calculated: C, 51.5%; H, 5.00%. Found: C, 48.9%;
H, 5.28%.
EXAMPLE 7
Preparation of 6-(N-n-Amyl-N'-Phrhaiamid0) —Penicil
lanic Acid and Its Potassium Salt
Triethylamine (13.9 gms; 0.1 mole) is added in one
portion to a suspension of N-n-amylphthalamic acid (23.5
gms.; 0.1 mole, prepared by the method of Example 5)
in 150 ml. of tetrahydrofuran whereupon a solution is
formed.
The solution is cooled to about —5° C. and
isobutyl chloroforrnate (13.6 gms; 0.1 mole) in 20 ml.
of tetrahydrofuran is added dropwise while the tempera
ture of the solution is maintained at about —5° C.
The
Additional acetone (75 rnls.) is added during the addi 60 resulting reaction mixture is stirred for 1/2 hour at about
tion of the amine to dilute the suspension of precipitated
0° C. and there is added in one portion a chilled solu
solids. The reaction mixture is then refluxed for an addi—
tion of é-arninopenicillanic acid (21.6 gms; 0.1 mole)
in 60 ml. of water and 15 ml. of triethylamine. The
resulting reaction mixture is stirred for 1/2 hour on the
cooling bath and thereafter stirred at room temperature
sion is chilled, ?ltered, and the ?ltrate is concentrated
and a second crop of precipitate collected. The solids
for 2 hours. The reaction mixture is diluted with an
recovered by ?ltration are recrystallized from methyl
equal volume of Water and extracted twice with methyl
isobutyl ketone and dried in vacuo over P205. The prod
isobutyl ketone, the extracts being discarded. The aque
uct, N-n-propylphthalamic acid, is found to weight 35.6
ous solution is layered with methyl isobutyl ketone,
guts. and to melt at 124-128° C. This product is again 70 ch?led, and acidi?ed to pH 2 with 42.5% phosphoric
recrystallized from dimethylt'ormamide and ether and the
acid. The acidi?ed aqueous solution which contains
6-(N-n-amyl-N’-phthalamido)penicillanic acid is ex
recrystallized product is found to weight 29.2 gms. and
tracted twice with methyl isobutyl ketone and the com
to have a melting point of 141.5—142° C. Upon a third
tional three hours and cooled to room temperature. After
standing several hours at room temperature, the suspen
recrystallization the melting point of the product is raised
to 142—142.5° C.
bined extracts are Washed with chilled water, ?ltered
Infrared analysis indicated that the 75 through sodium sulfate and dried over sodium sulfate.
3,035,047
the extracts being discarded. The aqueous solution is
The sodium sulfate is then removed from the extracts
and 40 ml. of a 50% solution of potassium 2-ethyl
hexanoate in n-butanol is added whereupon a precipitate
layered with methyl isobutyl ‘ketone, chilled, and acidi?ed
to pH 2 with 42.5% phosphoric acid. The acidi?ed aque
ous solution which contains 6-(N-1,2,5,6-tetrahydropyrid~
is formed. The precipitate, the potassium salt of 6-(N
yl-N’-phthalamido)penicil1anic acid is extracted twice
with methyl isobutyl ketone and the combined extracts
are washed with chilled water, ?ltered through sodium sul
n—amyl-N’-phthalamido)penicillanic acid, is collected by
?ltration, slurried with acetone, re?ltered, air-dried and
then dried in vacuo over P205. The product is found
to weigh 28.0 gms., to decompose at 140—145° C., to
contain the B-lactam structure as shown by infrared
fate and dried over sodium sulfate. The sodium sulfate
is then removed from the extracts and 40 ml. of a 50%
analysis, to inhibit Staph. aareus Smith at a concentra 10 solution of potassium ethylhexanoate in n-butanol is
added. Concentration of the solution in vacuo and dilu
tion of 0.8 meg/ml. and to have the following carbon
tion with dry ether yielded a solid. The precipitate, the
and hydrogen analysis calculated for C21H26N3O5SK: C,
53.5%; H, 5.52%. Found: C, 49.65%; H, 5.18%.
potassium salt of 6-(N-1,2,5,6-tetrahydropyridyl-N'
phthalamido)penicillanic acid, is collected by ?ltration,
EXAMPLE 8
slurried with acetone, re?ltered, air-dried and then dried
in vacuo over P205. The product is found to weigh 37.5
gms., to decompose over 140° C., to contain the B-lactam
structure as shown by infrared analysis, to inhibit Staph.
aurezts Smith at a concentration of 0.4 meg/m1. and to
Preparation of 6-(N-Furfuryl-N’-Phthalamid0)—
Penicillanic Acid and Its Potassium Salt
Triethylamine (15 ml.) is added in one portion to a
suspension of N-furfurylphthalamic acid (24.5 gms.; 0.1
mole; prepared as in the method of Example 5) in 150 20 have the following carbon and hydrogen analysis: Calcu
lated for C21H22N3O5SK: C, 53.96%; H, 4.71%. Found:
ml. of tetrahydrofuran whereupon a solution is formed.
C, 49.90%; H, 5.56%.
The solution is cooled to about —5° C. and isobutyl
EXAMPLE 10
chloroformate (13.6 gms.; 0.1 mole) in 20 ml. of tetra
hydrofuran is added dropwise while the temperature of
Preparation of Potassium 6-(N,N-Tetramethylene
the solution is maintained at about —5" C.
The re
25
N’-Phthalamid0)Penicillanate
sulting reaction mixture is stirred for 1/2 hour at about
0° C. and there is added in one portion a chilled solution
Ethyl chloroformate (10 ml.) is added dropwise with
of 6-aminopenicillanic acid (21.6 gms.; 0.1 mole) in 60
ml. of water and 15 ml. of triethylamine. The resulting
reaction mixture is stirred for 1/2 hour in the cooling
ylene-N’-phthalamic acid (21.9 gms.; 0.1 mole), 14 ml.
triethylamine, 70 m1. of p-dioxane and 30 m1. of dry
bath and thereafter stirred at room temperature for 2
hours. The reaction mixture is diluted with an equal
volume of water and extracted twice with methyl iso
tion of 6-aminopenicillanic acid (21.6 gms.; 0.1 mole),
is then removed from the extracts and 40 ml. of a 50%
extracts, which contain 6-(N,N-tetramethylene-N’-phthal
solution of potassium ethylhexanoate in n-butanol is
added whereupon a precipitate is formed. The precipi
tate, the potassium salt of 6—(N-furfuryl-N’-phthalamido)
penicillanic acid, is collected by ?ltration, slurried with
amido)penicillanic acid, are dried with sodium sulfate, ?l
tered and treated with a solution of potassium Z-ethylhex
anoate in n-butanol. The solution is concentrated in
vacuo, diluted with dry ether, and the product collected
and washed with acetone. The solid product, potassium
stirring to a solution at about -5° C. of N,N-tetrameth
acetone.
After stirring for 15 minutes at —5° C. a solu
50 m1. of water previously chilled to 0° C. and 14 ml.
of triethylamine is added in one portion. The reaction
butyl ketone, the extracts being discarded. The aqueous
solution is layered with methyl isobutyl ketone, chilled, 35 mixture is stirred vigorously at 0° C. for 2 hours. The
reaction mixture is extracted three times with methyl iso
and acidi?ed to pH 2 with 42.5% phosphoric acid. The
butyl ketone and the extracts discarded. The cold aque
acidi?ed aqueous solution which contains 6-(N-furfuryl~
ous solution is layered with methyl isobutyl ketone and
N'-phthalamido)penicillanic acid is extracted twice with
acidi?ed to pH 2 with 42% phosphoric acid. The acidi
methyl isobutyl ketone and the combined extracts are
washed with chilled water, ?ltered through sodium sul 40 ?ed solution is extracted with 700 ml. of methyl isobutyl
ketone in three portions. The methyl isobutyl ketone
fate and dried over sodium sulfate. The sodium sulfate
acetone, re?ltered, air-dried and then dried in vacuo
over P205. The product is found to weigh 26.5 gms.,
to decompose at 120° C., to contain the B-lactam struc
ture as shown by infrared analysis, to inhibit Staph. (lltrBllS
Smith at a concentration of 0.8 meg/ml. and to have
6~(N,N - tetramethylene - N’ - phthalamido)penicillanate,
after drying in vacuo over P205, is found to weigh 21.0
gms, to melt with decomposition at 150° C., to contain
the ,B-lactam structure as shown by infrared analysis, to
the following carbon and hydrogen analysis: Calculated
for C21H20N3O6SK: C, 52.39%; H, 4.15%. Found: C,
49.5%; H, 5.01%.
inhibit Staph. aureus Smith at a concentration of 1.6
meg/ml. and to exhibit versus Staph. aureus Smith upon
EXAMPLE 9
EXAMPLE 11
Preparation of 6-(N-1 ,2,5,6-Tetrahydropyridyl-N ’-Ph thal
Preparation 0)‘ Potassium 6-[N-(2-Phenylethyl)-N’
amido)Perzicillanic Acid and Its Potassium Salt
Triethylamine (15 ml.) is added in one portion to a sus 60
intramuscular injection in mice in a CD50 of 9 meg/kg.
Phthalamido]Penicillanate
Ethyl chloroformate (10 ml.) is added dropwise with
pension of 'N-1,2,5 ,6-tetrahydropyridyl-N'—phthalamic acid
stirring to a solution at about —-5 ° C. of N-(2-phenyleth
(23.1 gms.; 0.1 mole; prepared as in the method of Exam
ple 5) in 150 ml. of tetrahydrofuran whereupon a solution
is formed. The solution is cooled to about -5° C. and
isobutyl chloroformate (13.6 gms.; 0.1 mole) in 30 ml. 65
yl)phthalamic acid (26.9 gms.; 0.1 mole), 14 ml. trieth
ylamine, 70 ml. of p-dioxane and 30 ml. of dry acetone.
of tetrahydrofuran is added dropwise while the tempera
ture of the solution is maintained at about '—5° C. The
resulting reaction mixture is stirred for ‘1/2 hour at about
0° C. and added in one portion to a chilled solution of
After stirring for 15 minutes at —5° C. a solution of 6
aminopenicillanic acid (21.6 gms.; 0.1 mole), 50 ml. of
water previously chilled to 0° C. and 15 ml. of triethyl
amine is added in one portion. The reaction mixture is
stirred vigorously at 0° C. for 2 hours. The reaction mix
ture is extracted three times with methyl isobutyl ketone
6-aminophenicillanic acid (21.6 gms.; 0.1 mole) in 60 ml. 70 and the extracts are discarded. The cold aqueous solu
tion is layered with methyl isobutyl ketone and acidi?ed
to pH 2 with 42% phosphoric acid. The acidi?ed solu
tion is extracted with 700 ml. of methyl isobutyl ketone in
three portions. The ether extracts, which contain 6-[N
(2-phenylethyl) - N’ - phthalamidoJpenicillauic acid, are
water and extracted twice with methyl isobutyl ketone,
of water and 15 m1. of triethylamine. The resulting re
action mixture is stirred for v1/2 hour in the cooling bath
and thereafter stirred at room temperature for 2 hours.
The reaction mixture is diluted with an equal volume of
3,035,047
Z-ethylhexanoate in n-butanol is added. The mixture
dried with sodium sulfate, ?ltered and treated with a solu
tion of potassium 2-ethylhexanoate in n-butanol. The
solvent is decanted from the product which is then cov
ered with 400 ml. of acetone. The solid product, potas
concentrated in vacuo to dryness and n-pentane is added
to the precipitate. The precipitate, the potassium salt
of 6-(N-isopropyl-N’-phthalamido)penicillanic acid, is
collected by ?ltration, air-dried and then dried in vacuo
over P205. The product, which ‘retains some moisture,
is found to weigh 15.3 grns., to contain the ?-lactam struc
ture as shown by infrared analysis, to inhibit Staph. aureus
Smith at a concentration of 3.12 meg/ml. and to exhibit
infrared analysis, to inhibit Staph. aureus Smith at a con
centration of 0.8 meg/ml. and to exhibit versus Staph. 10 versus Staph. aureaus Smith upon intramuscular injection
in mice a CD50 of 19 meg/kg.
aureus Smith upon intramuscular injection in mice a CD50
of 23 meg/kg.
EXAMPLE 14
EXAMPLE 12
sium 6- [-N-(Z-phenylethyl)-N’-phthalamido]penicillanate,
is then collected by ?ltration, dried in vacuo over P205,
found to weight 21.6 gms., to melt with decomposition at
130° C., to contain the IB-lactam structure as shown by
Preparation of Potassium 6-(N,N-Pentamethylene
N’-Phthalamido)Penicillanate
Preparation of 6-(N-a-Methylbenzyl-N'-Phthalamido)
15
Ethyl chloroformate (10 m1.) is added dropwise with
stirring to a solution at about -—5° C. of N,N-pentameth
Penicillanic Acid and its Sodium Salt
In the general procedure of Example 4, the N-benzyl
phthalamic acid is replaced by 0.1 mole of N-(wmethyl
benZyD-phthalamic acid and there is obtained the sodium
salt of 6-(N-ot-methylbenZyl-N'-phthalarnido)penicillanic
ylenephthalamic acid (23.3 gms.; 0.1 mole), 14 m1. tri
ethylamine, 70 ml. p-dioxane and 30 ml. dry acetone. 20 acid which is found to weight 11.0 gms., to contain the
After stirring for 15 minutes at -5° C. a solution of 6
{i-lactam ring as shown by infrared analysis, to inhibit
aminopenicillanic acid (21.6 gms.; 0.1 mole), 50 ml. of
Staph. anreas Smith at 1.6 mcg./ml., to exhibit versus
water previously chilled to 0° C. and 14 ml. of triethyl
Staph. aureus Smith upon intramuscular injection in mice
amine is added in one portion. The reaction mixture is
a CD50 of 25 meg/kg. and to have the following carbon
stirred vigorously at 0° C. for 2 hours. The reaction mix 25 and hydrogen analysis: Calculated for C24H24N3O5SNa:
ture is extracted three times with ether and the ether ex
C, 58.9%; H, 4.94%. Found: C, 56.5%; H, 5.14%.
tracts are discarded. The cold aqueous solution is layered
EXAMPLE 15
with methyl isobutyl ketone and acidi?ed to pH 2 with
Preparation
of
6-(N-Hexamethylene-N'-Phthalamido)
42% phosphoric acid. The acidi?ed solution is extracted
Penicillanic Acid and its Potassium Salt
with 700 ml. of methyl isobutyl ketone in three portions.
The methyl isobutyl ketone extracts, which contain 6
(N,N-pentamethylene-N'-phthalamido) penicillanic acid,
are dried with sodium sulfate, ?ltered and treated with a
solution of potassium Z-ethylhexanoate in n-butanol. The
solution is concentrated in vacuo and diluted with dry
ether to produce a precipitate. The solid product, potas
sium 6-(N,N-pentamethylene-N'-phthalamido)penicilla
nate, which may also be termed 6-(N-piperidino-N'—
phthalamido)penicillanate, is then collected by ?ltration,
dried in vacuo over P205, found to weigh 40.0 gms., to 40
melt at 150° C. with decomposition, to contain the @
lactam structure as shown by infrared analysis, to inhibit
Staph. aareus Smith at a concentration of 6.25 mcg./ml.
and to exhibit versus Staph. aztreas Smith upon intra
in the general procedure of Example 8, the N-furfuryl'
phthalamic acid is replaced by 0.1 mole of N-hexamethyl
ene-phthalamic acid and there is obtained the potassium
salt of 6-(N-hexamethylene-N'-phthalamido)penicillanic
acid which is found to Weight 40.5 gms., to contain the
B-lactam ring as shown by infrared analysis, to inhibit
Staph. aureus Smith at 1.6 meg/ml. and to exhibit versus
Staph. aareus Smith upon intramuscular injection in mice
a CD50 of 9 meg/kg.
EXAMPLE 16
Preparation of 6-(N-Tetrahydrofurfuryl-N’-Phthalamido)
Penicillanic Acid and its Potassium Salt
In the general procedure of Example 8, the N-furfuryl
muscular injection in mice a CD50 of 28 meg/kg.
45
phthalamic acid is replaced by 0.1 mole of N-tetrahydro
EXAMPLE 13
furfuryl-phthalamic acid and there is obtained the potas
sium salt of 6-(N-tetrahydrofurfuryl-N'-phthalamido)
Preparation of 64(N—Is0pr0pyl-N’-Phthalamido) —
penicillanic acid which is found to weight 33.0 gms., to
Penicillanic Acid and its Potassium Salt
contain the ?-lactam ring as shown by infrared analysis
Triethylamine (13.9 gms.; 0.1 mole) is added in one 50 and to inhibit Staph. aureus Smith at 1.6 mcg./ ml.
portion to a suspension of N-isopropylphthalamic acid
EXAMPLE 17
(20.5 gins; 0.1 mole; prepared as in the method of Ex
ample 5) in 100 ml. of tetrahydrofuran whereupon a
In the general procedure of Example 2, the N-allyl
solution is formed. The solution is cooled to about —12°
phthalamic acid is replaced by 0.1 mole of N-morpholino
C. and isobutyi chloroformate (13.7 gms; 0.1 mole)
phthalamic acid, -N-(2,6-dimethylmorpho1ino)phthalamic
in 20 ml. of tetrahydrofuran is added dropwise over a
20 minute period while the temperature of the solution
is maintained at about —1‘0° C. The resulting reaction
acid and 1N,N-dibutylphthalamic acid, respectively, and
there is thereby obtained the potassium salt of 6-(N-mor
pholino-N’-phthalamido) penicillanic acid (25.0 gm.; M.P.
mixture is stirred for 1/2 hour at about 0° C. and there
165° C. with decomposition), 6-[N-(2,6-dimethylmor
is added in one portion a chilled solution of 6-amino 60 pholino)-N'-phthalamido]penicillanic acid (43.0 gm.;
penicillanic acid (21.6 gms.; 0.1 mole) in 40 ml. of wa
MP. 108—1l3° C. with decomposition), and 6-(N,N-di
ter and 15 ml. of triethylarnine. The resulting reaction
n-butylphthalamido)penicillanic acid (24 gm.; MP. 115
mixture is stirred for 3 hours at from —10° C. and there
120° C. with decomposition), respectively, each of which
after stirred at room temperature for 1 hour. The reac
is isolated as a solid potassium salt which is found to
tion mixture is diluted with an equal weight of water 65 contain the ?-lactam ring as shown by infrared analysis
and extracted twice with methyl isobutyl ketone, the ex
and to inhibit Staph. aureus Smith at concentrations of
tracts being discarded. The aqueous solution is layered
with methyl isobutyl ketone, chilled, and acidi?ed to pH
2 with 42.5% phosphoric acid. The acidi?ed aqueous
3.12 mcg./ml., >6.25 mcg./ml., and 1.6 mcg./ml., re
spectively.
EXAMPLE 18
solution which contains 6-(N-isopropyl-N'-phthalamido) 70
penicillanic acid is extracted twice with methyl isobutyl
ketone and the combined extracts are washed with chilled
water, ?ltered through sodium sulfate and dried over sodi
um sulfate. The sodium sulfate is then removed from
the extracts and 40 ml. of a 50% solution of potassium 75
Preparation of 6-[0-(Z-Methyl-1,2,3,4-Tetra>hydroquinol
yl-Carbonyl) -Benzamid0]PenicilIanic Acid and its P0
tassium Salt
In the general procedure of Example 8, the N-furfuryl
3,035,047
12.
1l
phthalamic acid is replaced by 0.1 mole of N-1,2,3,4-tetra
soluble potassium salt of 6-(dodecyl~N'-phthalamido)
hydroquinaldinephthalamic acid and there is obtained the
penicillanic acid which is found to weigh 10.5 gms., to
contain the B-lactam ring as shown by infrared analysis
and to inhibit Staph. aureus Smith at 0.4 meg/ml.
EXAMPLE 22
potassium salt of 6-[o-(Z-methyl-l,2,3,4-tetrahydroquinol
yl-carbonyl)-benzamido]penicillanic acid which is found
to Weight 43.5 gms., to contain the ?-lactam ring as shown
by infrared analysis, to decompose at 150° C., to inhibit
Preparation of 6-(N-t-Butyl-N’-Phthalamid0)
Staph. aureus Smith at 1.6 mcg./ml., to exhibit versus
Staph. aureus Smith upon intramuscular injection in mice
Penicillanic Acid and Its Potassium Salt
Triethylamine (13.9 gms; 0.1 mole) is added in one
and hydrogen analysis: Calculated for C26H26N3O5SK: 10 portion to a suspension of N-t-butylphthalamic acid (22.1
C, 58.75%; H, 4.89%. Found: C, 58.15%; H, 5.52%.
gms; 0.1 mole; prepared as in the method of Example 5)
in 100 ml. of teirahydrofuran whereupon a solution is
EXAMPLE 19
formed. The solution is cooled to about —5° C. and
Preparation of 6-(N,N-Diallyl-N’-Phthalamido)
ethyl chloroformate (13.7 gms.; 0.1 mole) in 20 ml. of
Penicillanic Acid and Its Potassium Salt
15 tetrahydrofuran is added dropwise over a 20 minute pe
riod while the temperature of the solution is maintained
Triethylamine (0.1 mole; 13.9 gms.) is added in one
at about —10° C. The resulting reaction mixture is
portion to a suspension of N,N-diallylphthalamic acid
stirred for 1/2 hour at about 0° C. and there is added
(24.5 gms.; 0.1 mole; prepared as in the method of
in one portion a chilled solution of 6-aminopenicillam'c
Example 1) in 100 m1. of tetrahydrofuran whereupon a
solution is formed. The solution is cooled in about 20 acid (21.6 gms.; 0.1 mole) in 50 ml. of water and 15
ml. of triethylamine. The resulting reaction mixture is
—5° C. and isobutyl chloroformate (13.6 gms; 0.1
stirred for 11/2 hours at temperatures of from —5° C. to
mole) in 20 ml. of tetrahydrofuran is added dropwise
5° C. and thereafter stirred at room temperature until evo
while the temperature of the solution is maintained at
lution CO2 ceases. The reaction mixture is diluted with
about -—5° C. The resulting reaction mixture is stirred
for 1/2 hour at about 0° C. and there is added in one 25 an equal weight of water and extracted twice with methyl
isobutyl ketone, the extracts being discarded. The
portion a chilled solution of 6-aminopenicillanic acid (21.6
a CD50 of 45 mcg./ kg. and to have the following carbon
aqueous solution is layered with methyl isobutyl ketone,
chilled, and acidi?ed to pH 2 with 42.5% phosphoric
gms.; 0.1 mole) in 60 ml. of water and 15 ml. of tri- _
ethylamine. The resulting reaction mixture is stirred
for 1/2 hour in the cooling bath and thereafter stirred
at room temperature for 2 hours. The reaction mix
ture is diluted with an equal volume of Water and ex
tracted twice with methyl'isobutyl ketone, the extracts
being discarded. The aqueous solution is layered with
methyl isobutyl ketone, chilled, and acidi?ed to pH
2 with 42.5% phosphoric acid.
The acidi?ed aqueous
solution which contains 6-(N,N-diallyl-N’-phthalamido)
penicillanic acid is extracted twice with methyl isobutyl
acid.
ed twice with methyl isobutyl ketone and the combined
extracts are Washed with chilled Water, ?ltered through
sodium sulfate and dried over sodium sulfate. The
sodium sulfate is then removed from the extracts and 45
H ml. of a 40% solution of potassium Z-ethylhexanoate in
n-butanol is added whereupon a precipitate is formed.
The mixture concentrated in vacuo to dryness. The pre
cipitate, the potassium salt of 6-(N-t-butyl-N’-phthal
ketone and the combined extracts are washed with
chilled water, ?ltered through sodium sulfate and dried
over sodium sulfate. The sodium sulfate is then re
moved from the extracts and 40 ml. of a 50% solution
of potassium 2-ethylhexanoate in n-butanol is added
and the solution is concentrated to a low volume and
diluted with ether whereupon a precipitate is formed.
" amido)penicillanic acid, is collected by ?ltration, air
40 dried and then dried in vacuo over P205. The product,
which retains some moisture, is found to weigh 24.0 gms.,
to have a melting point of 136-137" C. (with decom~
position), to contain the B-lactam structure as shown
' by infrared analysis, to inhibit Staph. aareus Smith at a
The precipitate, the potassium salt of 6-(N,N-diallyl-N’
phthalamido penicillin acid, is collected by ?ltration,
' slurried with acetone, re?ltered, air-dried and then dried
in vacuo over P205. The product is found to weigh
40.5 gms., to contain the ?-lactam structure as shown
by infrared analysis, to inhibit Staph. aureus Smith
at a concentration of 0.8 meg/ml. and to exhibit versus
Staph. aareus Smith upon intramuscular injection in mice
a CD50 of 4 meg/kg.
The acidi?ed aqueous solution which contains
30 6-(N-t-bntyl-N’-phthalamido)penicillanic acid is extract
‘
EXAMPLE 20
In the general procedure of Example 19, the N,N
diallylphthalamic acid is replaced by 0.1 mole of N,N
diisopropylphthalamic acid, N,N-diethylphthalamic acid,
concentration of 3.12 meg/m1. and to exhibit versus
Staph. aureus Smith and a penicillin G-resistant strain
of Staph. aureas upon intramuscular injection in mice
a CD50 of 27 meg/kg. and 20 meg/kg, respectively.
EXAMPLE 23
In the general procedure of Example 13, the N- iso
propylphthalamic acid is replaced by 0.1 mole N-methyl
phthalamic acid, 0.2 mole N-ethylphthalamic acid, 0.2
mole N-isobutylphthalamic acid, and 0.1 mole a-methyl~
propylphthalamic acid, respectively, and there is there
by obtained the potassium salt of 6-(N-methyl-N’-phthal
amido)penicillanic acid, 6-(N-ethyl-N’-phthalamido)
penicillanic acid, 6-(N-isobutylphthalamido)penicillanic
acid and 6(N-a-methylpropylphthalamido)pcnicillanic
and N,N-dimethylphthalamic acid, respectively, and
there is obtained the potassium salt of 6-(N,N-diiso 60 acid, respectively, each of which is isolated as a_ solid
potassium salt which is found to contain the ?-lactam
propyl-Ni’aphthalamido)penicillanic acid, 6—(N,N-dieth
ring as shown by infrared analysis and to inhibit Staph.
yl-N’-phthalamido)penicillanic acid, and 6-(N,N~dimeth
yl-N'-phthalamido)penicillanic acid, respectively, each of
aureus Smith at concentrations of 6.25 mcg./rnl., 3.12
which is isolated as a solid potassium salt which is
mcg./ml., 0.8 mcg./ml., and 3.1 mcg./ml., respectively.
found to contain the B-lactam ring as shown by infra 65
red analysis and to inhibit Staph. aureous Smith at con
EXAMPLE 24
In the general procedure of Example 11, the N-(2
phenylethyl)phthalamic acid is replaced by 0.1 mole N
EXAMPLE 21
(a-methylphenethyl)phthalamic acid, 0.1 mole N-meth
oxyphenyl)phtha1amic
acid, and 0.2 mole N-phenyl-N
70
Preparation of 6-(N-D0decyl-N'-Phthalamido)
ethylphthalamic acid (procedure scaled up accordingly),
Penicillanic Acid and Its Potassium Salt
respectively, and there is thereby obtained the potassium
salt of 6-(N-a-methylphenethyl-N'~phthalamido)penicil
In the general procedure of Example 7, the N-amyl
lanic acid, 6-(N-2-methoxyphenyl-N’-phthalamido)-peni
phthalamic acid is replaced by 0.1 mole of N-dcdecyl
cillanic acid, 6-(N-phenyl-N-ethyl-N'-phthalamido)peni~
phthalarnic acid and there is obtained the solid water
centrations of 0.001% by weight.
3,035,047
14
13
While in the foregoing speci?cation various embodi
cillanic acid, respectively, each of which is isolated as a
solid potassium salt which is found to contain the ?-lac
tam ring as shown by infrared analysis and to inhibit
Staph. aureus Smith at concentrations of 3.1 mcg./ml., 4.4
ments of this invention have been set forth and speci?c
details thereof elaborated for the purpose of illustration,
it will be apparent to those skilled in the art that this in
vention is susceptible to other embodiments and that
many of these details may be varied widely without de
parting from the basic concept and spirit of the invention.
We claim:
1. A member selected from the group consisting of the
mcg./ml., and 3.12 mcg./ml., respectively.
EXAMPLE 25
In the general procedure of Example 12, the N,N-pen
tamethylenephthalamic acid is replaced by 0.1 mole
N-(Z-methyl-S-ethylpiperidino)phthalamic acid, N-pyr
rolidinophthalamic acid, N-(Z-methylpyrrolidino)phthal
10 acids having the formula
amic acid, and N~(2,5-dimethylpyrrolidino)phthalamic
0
LR
acid, respectively, and there is thereby obtained the po
tassiurn salt of 6-[N-(Z-methyl-S-ethylpiperidino) -N’
phthalamidoJpenicillanic acid, 6 - ‘(N - pyrrolidino - N'
phthalamido)penicillanic acid, 6-[N-(2-methylpyrroli
dino)-N'-phthalamido]penicillanic acid, and 6-[N-(2,5-di
15
methylpyrrolidino)-N’-phthalamido]penicillanic acid, re
wherein R is a member selected from the group consist
spectively, each of which is isolated as a solid potassium
salt which is found to contain the B-lactam ring as shown
by infrared analysis and to inhibit Staph. aureus Smith at
ing of alkylamino, dialkylamino, cycloalkylarnino, hav
ing from 3 to 7 carbon atoms inclusive, allylamino,
diallylamino, phenyl(lower)alkylamin0, morpholino,
concentrations of 0.001% by weight.
lower(alkyl)morpholino,
EXAMPLE 26
In the general procedure of Example 12, the N,N-pen 25
tamethylenephthalamic acid is replaced by 0.1 mole N,N
hexamethylenephthalamic acid and there is thereby ob
tained the potassium salt of 6-(N,N-hexarnethylene
phthalamido)penicillanic acid which is isolated as a solid
di(lower)alkyl - morpholino,
morpholino(lower)alkylamino, pyrrolidino, (lower)alkyh
pyrrolidino, di(‘lower)alkylpyrrolidino, N,N-hexamethyl
eneimino, piperidino, 1ower(alkyl)piperidino, di(lower)
alkylpiperidino, 1,2,5,6-tetrahydropyridino, N-(lower)
alkylpiperazino, N-phenylpiperazino, N-(lower)alky1
(lower) alkylpiperazino, N- (lower) alkyl-di(lower) alkyl
furfurylamino, tetrahydrofurfurylamino, N
potassium salt, found to contain the ?-lactam ring as 30 piperazino,
(loWer)alkyl-N-furfurylamino, N-alkyl-N-am‘lino, and
shown by infrared analysis and to inhibit Staph. aureus
(lower)alkoxyanilino and their sodium, potassium, cal
Smith at concentrations of 0.001% by weight.
cium, aluminum and ammonium salts and their nontoxic
EXAMPLE 27
substituted ammonium salts with an amine selected from
In the general procedure of Example 13, the N-isopro
pylphthalamic acid is replaced by 0.078 mole N-(1,1,3,3
the group consisting of tri(lower) -alkylamines, procaine,
35
tetramethylbutyl)phthalamic acid, N-cyclohexylphthal
amine, N,N'-bis-dehydroabietylethylenediamine and N
amic acid, N-(3-morpholinopropyl)phthalamic acid, and
(lower)alkylpiperidine.
N-(Z-methylpiperidino)phthalamic acid, respectively, and
there is thereby obtained the potassium salt of 6-[N
(1,l,3,3 - tetramethylbutyl) - N’ - phthalamido]penicil
lanic acid, 6-(N-cyclohexyl-N'-phthalamido)penicillanic
acid, 6- [N-'( 3-morpholinopropyl) -’N'-phthalamido] peni
cillanic acid, and 6-[N-(2-methylpiperidino)phthal
amido]penicillanic acid, respectively, each of which is
dibenzylamine, N-benzyl-beta-phenethylamine, l-ephen
amine, N,N'-dibenzylethylenediamine, dehydroabietyl
45
.
.
.
.
.
.
6—(N-allybN-phthalamido)penicillanic acid.
6-(N-benzylaN?phthalamido)penicillanic acid.
6-(N-amyl-N’-phthalamido)penicillanic acid.
6-(N-n-propyl-N'-phthalamido)penicillanic acid.
6-(N-isopropyl-N’-phthalamido)penicillanic acid.
6-(N-t-butyl-N'-phthalamido)penicillanic acid.
isolated as a solid potassium salt which is found to con
tain the ,B-lactam ring as shown by infrared analysis and
to inhibit Staph. aureus Smith at concentrations of 2.2
mcg./ml., 2.2 mcg./ml., and >625 mcg./ml., respec
tively.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,951,839
Doyle et a1 ____________ __ Sept. 6, 1960
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