PROCEDE POUR LA PRODUCTION DE 6-ACYLAMINO-2,2-DIMETHYL-3-(5-TETRAZOLYL) PENAMS ET DE COMPOSES INTERMEDIAIRES POUR LA SYNTHESE DE CEUX-CI

PROCESS FOR THE PRODUCTION OF 6-ACYLAMINO-2,2-DIMETHYL-3-(5-TETRAZOLYL) PENAMS AND INTERMEDIATES THEREFOR

Abrégé anglais

Abstract of the Disclosure
A process for the production of 6-acylamino-2,2-dimethyl-3-(5-tetra-
zolyl)penams which comprises reacting an imine derivative of a 6-amino-2,2-
dimethyl-3-(5-tetrazolyl)penam with an organic acid acylating agent or a reactive
derivative thereof. The preparation of the imine derivatives and of the start-
ing 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penams is described.

Revendications

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined as
follows:
1. A process for preparing a compound of the formula
<IMG>
wherein R is selected from the group consisting of hydrogen,
alkyl having from one to twelve carbon atoms, cycloalkyl
having from three to seven carbon atoms, phenyl, substituted
phenyl, naphthyl, substituted naphthyl, furyl, thienyl,
pyridyl, alkenyl having from two to twelve carbon atoms,
each substituted moiety being substituted with up to two
members selected from the group consisting of chloro, bromo,
fluoro, iodo, nitro, alkoxy having from one to four carbon
atoms and alkyl having from one to four carbon atoms; and
Y is selected from the group consisting of
<IMG> and <IMG>
wherein R1 is selected from the group consisting of R2 and
a tetrazolylpenam nitrogen protecting group;
R2 is selected from the group consisting of hydro-
gen, trialkylsilyl having from one to four carbon atoms per
alkyl group, alkanoyloxymethyl having from three to eight
carbon atoms, 1-alkanoyloxyethyl having from four to nine
carbon atoms, phthalidyl and
<IMG>
76

wherein R4, R5, R6 are each selected from the group consist-
ing of hydrogen, chloro, bromo, fluoro, alkyl having from
one to four carbon atoms, alkoxy having from one to four
carbon atoms and phenyl, characterized by reacting the
corresponding 6-amino compound of the formula
<IMG>
with an aldehyde of the formula
R-CHO
wherein R and Y are as defined above.
2. A process according to claim 1, wherein there is
employed as said 6-amino compound starting material a com-
pound wherein R2 is hydrogen
3. A process according to claim 1, wherein there is
employed as said aldehyde starting material a compound
wherein R is phenyl or substituted phenyl as defined in
claim 1
4. A process according to claim 3, wherein there is
employed as said aldehyde starting material a compound wherein
R is 4-nitrophenyl or 2-hydroxyphenyl.
5. A compound of the formula
<IMG>
wherein R is selected from the group consisting of hydrogen,
alkyl having from one to twelve carbon atoms, cycloalkyl
having from three to seven carbon atoms, phenyl, substituted
phenyl, naphthyl, substituted naphthyl, furyl, thienyl,
pyridyl, alkenyl having from two to twelve carbon atoms,
each substituted moiety being substituted with up to two
members selected from the group consisting of chloro, bromo,
77

fluoro, iodo, nitro, alkoxy having from one to four carbon atoms
and alkyl having from one to four carbon atoms; and
Y is selected from the group consisting of
<IMG> and <IMG>
wherein R1 is selected from the group consisting of R2 and
a tetrazolylpenam nitrogen protecting group;
R2 is selected from the group consisting of
hydrogen, trialkylsilyl having from one to four carbon atoms
per alkyl group, alkanoyloxymethyl having from three to
eight carbon atoms, 1-alkanoyloxyethyl having from four
to nine carbon atoms, phthalidyl and
<IMG>
wherein R4, R5, R6 are each selected from the group consist-
ing of hydrogen, chloro, bromo, fluoro, alkyl having from
one to four carbon atoms, alkoxy having from one to four
carbon atoms and phenyl, whenever obtained by the process
of claim 1, or an obvious equivalent thereof.
6. A compound according to claim 5, characterized by
the fact that R2 is hydrogen, whenever obtained by the
process of claim 2, or an obvious equivalent thereof.
7. A compound according to claim 5, characterized
by the fact that R is selected from the group consisting
of phenyl and substituted phenyl as defined in claim 5,
78

whenever obtained by the process of claim 3 or an obvious
equivalent thereof.
8. A compound according to claim 5, characterized by
the fact that R is selected from the group consisting of
4-nitrophenyl and 2-hydroxyphenyl, whenever obtained by the
process of claim 4 or an obvious equivalent thereof.
79

Description

~6~8~
This invention relates to a process for the production of 6-
acylamino-2,2-dimethyl-3-(5-tetrazolyllpenams. Nore particularly, it
relates to $1) a process which comprises acylation of îmines ~Schif~
bases~ of 6-amino-2,2-dimethyl 3-~5-tetrazolyl~penams and certain deriva
S tives thereof which carry a blocking group or pseudo ~locking group on
the tetrazolyl ~oiety followed by hydrolysis o the acylation product to
produce a 6-acylamino-2,2-dimethyl~3-¢5-tetrazolyl~penam, ~2~ imines of
6-amino-2,2-dimethyl-3-C5-tetrazolyl~penams; and ~3~ reaction products of
sald imines with acylating agents.
6-Amino-2,2-dimethyl-3-~5-tetrazolyl~penam ~Formula I below)
and certain derivatives thereof wherein a blocking or pseudo blocking
group is attached to t~e l- or 2-position of the tetrazolyl moiety are
valua~le intermediates for th~ synthesis, by acylation thereof Nith an
activated derivative o~ an organic acid acylating agent5 i~e., an acid
halide, anhydride or ester, of a new class of antibacterial agents,
namely, 6-acylamido-2,2-dimethyl-3-~5-tetra~olyl)penams. Such compounds
are described ;n Canadian Application No. 211,05~.

~L06~ 37
The penicillins, a well kno~n group of anti~iotics, have been the
s-ib~ect of many reviews. J. G. C. Nayle~ in ~Advances in Drug Research,~' ~N.J.Ha~per and A.B. Simmonds, eds.~, Academic Press, New York, NY, Vol. 7, pages
1-105 ~1973~, summarizes the recent literature and discusses the various reac-
S ~ions which have ~een carried o~t at the amino group of 6-amino-2,2-dimethyl-
penam-3-carboxylic acid ¢6-APA), the majority of whlch are directed to forma~
tion of a 6-acylamino group. Schiff Bases of 6-APA and their use for the
recovery and purification o~ 6-APA are descri~ed in U.S. Patents 3,219,669
t and 3,2~,800, respectively~
Imine derivatives of 6-APA, salts a~d esters thereof, and their
acylation to an i~termediate reaction product which is hydrolyzed to a 6-acyl-
amino-2,2-dimethylPenam-3-carhoxylic acid9 known trivially as penicillins, are
described in U.S. Patents 3,631,028, 3,647,781, 3,649,625 and 3,657,224, and
by Bohme in J. Org. Chem. 38, 230-236 ~1973).
The compounds described herein are, for the sake of convenience,
identified as derivatives of penam. The term ~'penam~' has been defined by
Sheehan et al. in the ~ournal of the American Chemical Society, 75, 3293 (1953)
- as referring to the structure
~ ~ 3
Using this terminolog~, the well-known anti~iotic penicillin G is designated 2S
6-~2-phenylacetamido~-2~2-dimethyl-penam-3-carboxylic acid.
Many of the reactants of this invention are also 5-substituted tetra-
zoles, and 5-substituted tetrazoles can e~ist in two isomeric form viz:
N - N N - N
\ N -N ~ N
1 2

887
As will be appreciated hy one skilled in tho art~ ~hen -the substitu~nt repre-
sented ~y Rl or R2 is hydrogen, the t~o forms co-exist in a dynamic tautomeric
equili~rium mixture However, in the case wherein Rl or R2 represent a substi-
tuent other than hydrogen3 the two forms represent different chemical entities
which do not spontaneously ;nterconver-t.
The process of this invention comprises reacting a 6-amino-2,2-
dimethyl-3-~5-tetrazolyl)penam (Formula I)
H2N C~ CY ~ ~3
O = C ~ I
and an aldehyde having the formulag R-C~O (II),
to produce sa;d imin9 ~Schiff base~ having the Formula III
~ \ / 3
R-CH=N - CH - CH `I _CH3
OL__C N _ CH~ III
This imire may be acylated to produce an intermediate of Formula IV
O= C-R
R _ICH ~ ~ \ CH3
X O -C . N H~
and the product hydrolyzed to produce a S-acylamino-2,2-dimethyl-3~5
tetrazolyl~penam of Formula V.
R3 - CO NH_~H fH ~ \ ~ 3
O= _ N
.",~,
~ ~,~

6~88~
In the above formulae, Y is selected from the group consisting of
N - N N - N
¦ and C
Rl \ R2
where;n R1 is selected from the group consisting of R~ and a tetrazolpenam
nitrogen ~rotecting group;
R2 is~selected from the group consisting of hydrogen, trialky].silyl
having from one to four carbon atoms per alkyl group a alkanoyloxymethyl having
from three to eight carbon atoms, l-alkanoyloxyethyl having from four to nine
car~on atoms, phtbalidyl and
~ ~ R4
R~ ~
~,
~herein R43 R5, and R6 are each selected from the group consisting of hydrogen~
chloro~ ~romo, fluoro, alkyl having from one to four car~on atoms~ alkoxy havingfrom one to four car~on atoms and phenyl;
R is the residue of an aldehyde and is an aliphatic (including alkyl
and aralkyl~, homocyclic, including alicyclic and aromatic, or heterocyclic
-mo;ety which may be su~stituted with up to two groups selected from the group
consisting of chloro, bromo~ fluoro, iodo, alkyl, alkoxy, nitro, or hydroxya
R3 is the acyl moiety of an acylating agent,
and X is the residual moiety of the acylating agent~

~)6~38~
The imine ~Schiff base) reactants of Formula III are readily pre-
pared by condensation of an appropriate aldehyde with the appropriate 6-amino-
2,2-dimethyl-3- ~-tetra701yl~penam of Formula I. The condensation is conducted
by mixing the reactants together in a reaction inert solvent in equimolar or
approximately equimolar proportions at ambient temperature. The molar ratio of
aldehyde to amine reactant is not critical. A large excess of either reactant
can be used ~ut, for the sake of economy and ease of recovery of the desired
imines, the molar ratio is generally held to about 1:1.
The reactant is generally carried out at ambient temperature as noted.
However, the temperature is not a critical reaction parameter and higher or
lower temperatures can be used. ~igher temperatures, as expected, require
shorter reaction periods than do lower temperatures. Temperatures outside the
range of 10C. to 70C. are generally avoided because of unnecessarily long
reaction per;ods or to minimize possible side-reactions, e.g., polymerization,
of the imine or the aldehyde component. The preferred temperature is from 20C.
to 30C.
The condensation is conducted in a react;on-inert solvent, that is 9
a solvent which, under the conditions of the condensation, enters into little
or no reaction with the reactants or products. Suitable solvents are ethers
such a~ diethyl ether~ dioxane, tetrahydrofuran and ethyleneglycol dimethyl
ether, N,N~dimethylformamide, chlorinated solvents such as methylene chloride,
chloroformg methyl isobutyl ketone, methylcyclohexanone, alkanols such as those
having from one to four carbon atoms and nitriles such as acetonitrile and
prop;onitr;le.
Methylene chloride is a favored solvent since it also serves as a
highly useful solvent for the subsequent acylation reaction.
Suitable aldehydes are those of Formula II wherein R is selected
from the group consisting of hydrogen 3 alkyl hav;ng from one to twelve carbon
--5--

~06~)8~37
atoms, cycloalkyl having from thres to seven carbon atoms, phenyl, substituted
phenyl, naphthyl, substituted naphthyl, furyl, thienyl, pyridyl, alkenyl having
from two to twel~e carbon atoms~ each substituted moiety being substituted
with up to two memhers selected from the group consisting of chloro, bromo,
S fluoro, iodo, nitro, alkQxy having from one to four carbon atoms and alkyl
having from one to four car~on atoms.
Preferred aldehydes are benzaldehyde and 4-nitrobenzaldehyde which
permit each step of the overall process to proceed smoothly and in good yield.
Non-aqueous solventsg e.g., methylene chloride, are favored when using these
aldehydes s;nce the reaction mixture containing the imine product can be used
directly in the subsequent acylation reaction without the necessity of isolating
the imine.
~ hen either of Rl or R2 is triaklyæilyl, an anhydrous non-hydroxylic
solvent system is used to avoid hydrolysis of the silyl group. The by-product
water generated in the condensation is removed by conducting the condensation in
the presence of a strong water absorhent, e.g., magnesium sulfate, or in the
presence of an excess of the silylated 6-amino-2~2-dimethyl-3-(5-tetrazolyl~-
penam, or in the presence of an excess of the s;lylating agent, e.g., trimethyl-
chloros;lane~ Further, a b;s-silylated-derivative of Formula I can be used as
reactant in the aldehyde condensation. Since s;lylation of 6-amino~2,2-dimethyl-
3_~s~tetrazolyl~penam readily produces a bis-silyl derivative, the bis silyl
derivatives are favored reactants for this condensation when e;ther of Rl or
R2 ;s trialkyl5il~1.
Compounds of Formula III above wherein Y represents the unsubstituted
5-tetrazolyl moiety Rl=R2=~) form salts with inorganic and organic basesO
Such salts are ;ncluded w;thin the scope of this invention. Representative
of such salts as the sodium and potassium salts, and salts with primary,
secondary and tertiary alkylamines wherein the alkyl ~oieties have up to
eight carbon atoms. Illustrative of such amines are methylamine, n-butyl-
0 am;ne, n-octylamine, d;ethylamine~ di-n-hexylamine~ ethyl-n-
--6--

~l~16~887
hexylamine, triethylamineg methyl-di-n-butylamine. Also included are salts with
other organic bases which have been used to form salts with benzylpenicillin,
such as, d~enzylam;ne, ethylenediamine, N)N~-dibenzylethylenediamine, N-ethyl-
piperidine and N benzyl~ -phenethylamine. The salts of Formula III compounds
are frequently u8eful for altering the solubility characteristics of the parent
compounds thus aiding in the recovery from a reaction mixture~ in enhancing
their solubility in a given solvent or for preparation of easily handled forms
of the imines.
The water generated as by-product can be removed from non-aqueous
solvent systems if desired by appropriate means as by addition of a solid desic-
cant such as anhydrous sodium sulfate or magne5ium sulfatea or a molecular sieve.
Representative of the latter are the natural and synthetic crystalline alumino-
silicates~ The syrlthetics are favored because of th~eir greater water-loading
capacity relative to the natural crystalline aluminosilicates. Included among
such adsorbents are chabazite, gemlinite and analcitea naturally occuring
materials9 the synthetic 1~Linde Molecular Sieves produced and distributed by the
Llnde Company, such as Types 4A, 5A9 and 13X, and the IlMicrotraps~ produced by
the Davidson Chemical Company. Such materials sorb and thus effectively remove
water from the reaction medium. The molecular sieve can be added directly to
the reaction mixture or, preferably, the water containing condensate from the
reaction mixture contacted with such material to remove the water. A further
useful adsorbent is neutral activated alumina.
Further, a liquid which forms an azeotrope with water can be used as
svlvent to permit removal of by-product water from non-aqueous systemsO ~inary
or ternary azeotropes can be used. Representative of such liquids are benzene,
carbon tetrachloride, chloroform, diethylether, methylpropylether3 2-methyl-
furan and ethyl acetate, each of which form a binary azeotrope with water.
Representative of solvent pairs which form a ternary system with water are sec-
butyl alcohol-benzene~ sec-butylalcohol-cyclohe~ane, t butyl alcohol-benzene,
0 t-butylalcohol-cyclohexane and carbon tetrachloride-propyl alcohol. A
--7--

1(~6~1t !31~7
ccllection of azeotropic systems is presented in Ind. ~ng. Chem. 19, 508 (1947).
~ ater can also be used as solvent either alone or in combination with
any of the solvents enumerated above. The use of an aqueous solvent system
is generally avoided ;n the case of the more reactive imines such as those
der;ved from aliphat;c aldehydes, benzaldehyde, aryl substituted aliphatic
aldehydes9 e.g. phenylacetaldehyde, alicyclic aldehydes, m-halobenzaldehydes
and m-alkylbenealdehydes. Aqueous solvent systems are often favored with the
less reactive ;m;nes 6uch as those derived from hydroxy substituted benzalde-
hydes and nap~thaldehydes~
When an aqueous solvent system, and particularly when water alone,
;s used as solvent9 the p~ of the reaction mixture is adjusted to about 8, e.g.from about 7.5 to 8.5.
The acylation of the im;nes is accomplished by adding the appropriate
acylating agent to the imine reactant in an aqueous or organic solvent medium.
suitable solvents are those Nhich do not react with the reactants or products
to any appreciable extent under the conditions of the reaction. Representative
of such solvents are water, acetone, dioxane9 tetrahydrofuran, methylene chlo-
ride, chloroform, methyl isobutylketone and mixtures of such solventsO
It ;s generally conducted at a temperature of from about -20C. to
a~out 5QC. Th~ favored temperature range is from about 0C. to about 30C.
The pH of the reaction can vary from about 3 to about 9. In general, the pH
of the acylation reaction is dependent upon the relative stability of the imine.
Imines der;ved from benzaldehyde, m-halobenzaldehydes, aliphatic, alicyclic
or aralkyl ~e.g., phenylacetaldehyde) aldehydes are acylated at ahout pH 6-8
when an aqueous solvent system is used.
The acylation process is applicable to a wide variety of acylating
agents such as reactive derivatives of organic acids of the formula R3COOH.
Typical of reactive derivatiYes ~R3COX) which can ~e used are mixed anhydrides.
--8--

~)6~i387
acid hal;des, acti~e esters~ e.g., thiol, phenolic, cyanomethyl, N-hydroxysuc-
cinimide, N-hydroxyphthalide esters, acid azides, N-carboxy anhydrides and com-
binationS of organic acid with carbodiimides, carbonyldiimidazole, alkoxy
:~ acetylenes.
While any acylating agent can be used, particular interest exists
in those wherein the acyl ~oiety is of Formula VI because of the broad antibac-
terial spectrum of the acylated products.
_~_

6~:)887
R'--~l C
L~J n
wherein n is 0 or 1;
R~ i6 selected from the group consisting of hydrogen, alkyl having
from one to twelve carbon atoms, alkenyl having from two to twelve carbon atoms,
cycloalkyl having from three to seven carbon atoms, cyclohexenyl, 1,4-cyclo-
hexadienyl, l-amlno-cycloalkyl having from four to seven carbon atoms, cyano-
met~yl, S-methyl-3-phenyl-4-isoxazolyl, 5-methyl 3-(o-chlorophenyl)-4_isoxazol-
yl- 5 - methyl-3-~2,6-dichlorophenyl)-4-isoxazolyl, 5-methyl-3-(2-chloro-6-
fluorophenyl~-4-isoxazolyl~ 2-alkoxy-1-naphthyl having from one to four carbon
atoms in said alkoxy group, phenyl, phenoxy, phenylthio, pyridylthio, benzyl,
sydnonyl thienyl, furyl, pyridyl~ thiazolyl, isothiazolyl, pyrmidinyl,
tetrazolylg triazolyl, imidazolyl, pyrazolyl, substituted phenyl, suhstituted
phenoxy, substituted phenylthio, substituted pyridylthio, substituted benzyl,
su~stituted thienyl, substituted furyl, substituted pyridyl, substituted
thiazolyl~ substituted isothiazolyl~ substituted pyrimidinyl, substituted
triazolyl~ substituted tetrazolyl, substituted imidazolyl and substituted
pyrazolyl, each substituted moiety being substituted by up to two members
selected from the grou~ consisting of fluoro, chloro, bromo, hydroxy, amino, N-
alkylamino having from one to four carbon atoms, N,N-dialkylamino having from
one to four carbon atoms in each of said alkyl groups, alkyl having from one
to four carbon atoms, aminomethyl, alkoxy having from one to four carbon atoms,
alkylthio having from one to four carbon atoms and 2-aminoethoxyj
--10--

~06~)8!37
and Q is selected from the group consisting of hydrogen, alkyl having
from one to six carbon atoms; hydroxy, azido, carboxy, sulfo, carbamoyl,
phenoxycarbonyl~ indanyloxycar~onyl, sulfoamino, aminomethyl, amino and
NH~C9-C~2-N~m-cO-A;
wherein A is selected from the group consisting of alkyl having from
one to six car~on atoms, phenyl, substituted phenyl, furyl, thienyl, pyridyl,
pyrrolyl, am;no, N-alkylamino h3ving from one to six carbon atoms, anilino,
su~stituted anilino, guanidino, acylamino having from two to seven car~on
atoms, benzamido, s~bstituted benzamido, thiophenecarboxamido, furancarboxamido,pyridinecarboxamido~ aminomethyl, guanidinomethyl~ alkanecarboxamidinomethyl
having from,three to eight carbon atoms, benzamidinomethyl, ~substituted
benzamidino~methyl~ thiophenecar~oxamidinomethyl, furancarboxamidinomethyl,
pyridinecar~oxamidinomethyl~ pyrrolecarboxamidinomethyl and 2-benæimidazole-
car~oxamidinomethyl~ each substituted moiety being substituted by up to two
mem~ers selected from the group consisting of fluo~o, chloro, bromo~ iodo~
alkyl having from one to four car~on atoms, alkoxy having from one to four
carbon atoms) sulfamyl a carbamoyl and cyano;
and m.is 0 or 1,
provided that when R' is l-aminocycloalkyl, n is 0;
and provided that when R1 is selected from the group consisting of
phenoxy, phenylthio, pyridylthio, suhstituted phenoxy, substituted phenylthio
a~d su~stituted pyridylthio and n is 1, Q is selected from the group consist-
ing of hydrogen, alkyl having from one to six carbon atoms, carboxy, sulfo~
carbamoyl~ phenoxycarbonyl, ~ubstituted phenoxycarbonyl, indanyloxycarbonyl
2S and aminomethylG
--11--

88~
Rl is defined as a tetrazolylpenam nitrogen protecting group. It is
intended ~y this term to connote all groups known, or obvious~ to one skilled
in the art) ~hich can be used ~al to permit the synthesis of compounds of
Formula I ~y the processes described hcreinafter, and (b) can be removed under
conditions whic~ leave the ~-lactam ring system suhstantially intact.
The nature of the tetrazolylpenam nitragen protecting group is not
critical to this invention. It is its ability to perform a specific function
rather than its structure which is important. The selection and identification
of appropriate protecting groups can readily and easily be made by one skilled

1~6~887
in the art. The suitability and effectiveness of a group as a tetrazolylpenam
nitrogen protecting group in this invention are determined by employing a com
pound of Formula I wherein Yl is the ¢Rl-substituted3-5-tetrazolyl-moiety in
question as reactant in the herein-described process for n~aking Formula V
compounds,
As one skilled in the art will recognize, the variables Rl and R2
when defined as alkanoyloxy methyl, l-alkanoyloxyethyl and phthalidyl are, in
a sense~ tetrazolylpenam nitrogen-protecting groups. However, such groups can-
not be removed without substantial degradation of the ~-lactam ring and, thus,
lQ fail to meet the criteria set forth above for a "tetrazolylpenam nitrogen pro-
tecting group" They are, however, referred to herein as "pseudo blocking groups'.'
Exemplary of tetrazolylpenam nitrogen protecting groups are:
~ 7
2 CH
\R8
wherein R~ is an electron-withdrawing group, and R8 is either hydrogen or a
further electron-withdrawing group, which can be the same as or different
from R7.
The funct;on of the electron-withdrawing groups is to render the
hydrogen atom on the adjacent carhon atom sufficiently acidic that the protectlng
group is remova~le in a r`etrograde Michael reaction. Such a reaction is well-
known in the art. ~e.g. ~ouse, "Modern Synthetic Reactions,ll W.A. Benjamin,Inc.a New York/Amsterdam, 1965, page 207). Typical electron-withdrawing groups
are cyano, alkoxycarbonyl having from two to seven carbon atoms, phenoxycarbonyl,
alkylsulfonyl having from one to six carbon atoms, phenylsulfonyl and S02NZlZ2
wherein Zl and Z2 are each selected from the group consisting of hydrogen, alkyl
having from one to four carbon atoms, phenyl and benzyl. A particularly con-
-13-

~0601~87
venient configuration for this protecting group is that wherein R8 is hydrogen;
and preferred values for R7 are alkoxycarbonyl having from two to seven carbon
atoms and phenylsulfonyl.
A further tetrazolylpenam nitrogen protecting group which can be
used is a group of Folmula C~=O)-OR~. Such a group`can be removed by mild
hydrolySis~ such as mild alkaline hydrolysis, or by treatment with a nucleophile,
such as an amine, a thiol or thiolate anion. Although a wide variety of such
groups known in the art can be used, particularly convenient are those wherein
R~ is alkyl having from one to six carbon atoms, benzyl, phenyl or substituted
1~ phenyl, for exa~ple, phenyl substituted by up to two moieties each selected
from one to four carbon atoms and alkoxy having from one to four carbon atoms.
A still further tetrazolylpenam nitrogen protecting group which can
he used ;s a grouping of formula -SO2R9. Such a group is also removed by hydro-
lysiS, or ~y treatment with a nucleophilic agent, as indicated for the group
lS C~=O~-O-R~, and convenient values for R~ are also alkyl hav;ng from one to
six carbon atoms~ benzyl, phenyl, and substituted phenyl, for example3 phenyl
subst;tuted ~y up to two moieties each selected from the group consisting of
nitro, fluoro~ chloro, bromo, alkyl having from one to four carbon atoms and
alkoxy hav;ng from one to four carbon atoms.
Another tetrazolylpenam nitrogen protecting group which can be used
is
~W
- CH
W2
-14-

106~88~
where;n-~l is p~enyl, substituted phenyl, furyl, substituted furylg thienyl or
substituted thienyl, and W2 is hydrogen, alkyl, phenyl, substituted phenyl,
furyl, su~stituted furyl, thienyl or su~stituted t~ienyl, when Nl is phenyl
or substituted phenyl, and W2 is hydrogen, alkyl, phenyl or substituted phenyl,
5 this group can be removed by hydrogenolysis. This group can also be removed
by solvolysis in trifluoroacetic acid, ~hen;the combined effect of Wl and ~2
is sufficient to offer the requisite degree of stahility t~ the incipient car-
~onium ion.
~C~
W2
Part~cularly preferred configurations for this~protecting group which afford
satisfactory yields of compounds of Formula V and are readily re-
moved, are ¢a~ those wherein W2 is hydrogen or alkyl having from one to six
carbon atoms, and Wl is phenyl or phenyl substituted with up to two groups
seleCt~d from the group consisting of hydrogen, hydroxy, nitro, fluoro, chloro,
bromo, iodo, alkyl having from one to six carbon atoms, alkoxy having from one
to six carbon atoms, alkanoyloxy having from two to seven carbon atoms, formyloxy
alkoxymetboxy having from two to seven carbon atoms, phenyl, and benzyl-
oxy; and ~b~ those wherein ~2 is hydrogen or methyl and ~1 is furyl, 5-methyl-
furylg thienyl, or 5-methylthienylO

~608!37
Yet still another tetrazol~lpenam nîtrogen protecting group which can
be used is phenacyl or s~bstituted phenacyl. Such a group is removed by reaction
with a nucleoph~lic reagent, such as -thiophenoxide Typical ph~nacyl groups
which can be used are those of formula
--CH2_ C --~Rlo C
~herein Rl~ is selected from the group consisting of hydrogen, nitro, fluoro,
c~loro9 ~romo, and phenyl.
~ igh~ly useful substituent groups for the 5-tetrazolyl moiety Yl
when Rl or R2 is ~ydrogen are si`lyl groups~ particularly those derived from
silylating agents selected from the group con$isting of
R R
\ / W3
~Si ~
R ~ ) N6 - I ~4
VII VIII
-16-

106~138~
wherein-~3 is selected from the group consisting of halogen and N4 and each of
and N5 is selected from the group consisting of hydrogen, alkyl of from one to
four carbon atoms, phenyl, benzyl, tolyl and dimethylaminophenyl, at least one
of the said N~s ~eing other than halogen and hydrogen; R is alkyl of 1 to 7
carbon atoms, p is an integer from 1 to 2; and '~5 is selected from the group
consisting of halogen and
_ N~W7
~ 8
and ~7 is selected from the group consisting of hydrogen and alkyl of 1 to 7
car~on atoms, and W8 is selected from the group consisting of hydrogen, alkyl
of 1 to 7 carbon atoms and
~3
~ 4
~5
The silyl groups are introduced into the tetrazolyl moiety by
methods ~no~n to those skilled in the art. The silylation reaction is conducted
ln an anhydrous reaction-inert, that is, an anhydrous, non-hydroxylic solvent
O~ t~e type mentioned above, and preferably in methylene chloride, at a tempera-
ture of from about -lC~C. to about -80C., and preferably at from ~20C. to
-60C. The reaction i6 often conducted in the presence of an acid-binding
agent, that is, a base such as an alkali metal carbonate or tertiary amine,
e.g., diet~ylaniline, pyridine, quinoline, and lutidine. The base may be
a part of the silylating agent as is the case when the silylating agent is of
-17-

387
Formula VIII N~erein ~ is -N~7WB, or f ~ormula VII, and said agent is used in
co~ination with a compound of Formula VIII wherein W6 is halogen. Representative
of SUitable silylating agents are those disclosed in U.S. 3,499,909 such as
trimethylchlorosilane, hexamethyldisilazane, triethylchlorsilane, methyltri-
chloros;lane, dimethyldichLorosilane, triethyl~romosilane, tri-n-pro wlchloro-
silane, bromomethyldimethylchlorosilane, tri-n-butylchlorosilane, methyldiethyl-
chLorosilane~ dimethylethylchlorosilane, phenyldimethylbromosilane, benzylmethyl-
8t~ylc~lorosilane~ phenylethylmethylchLorosila~e, trip~enylchlorosilane, tri-
p~enylfluorosilane~ tri-o-tolylchlorosilane, tri-p-d;methylaminophenylchloro-
silane~ N-et~yltriethylsilylamine, hexaethyldisilazane, triphenylsilylamine,
tri-n-propylsilylamine~ tetraethyldimethyldisilazane, tetramethyldiethyldisi-
lazane, tetramethyldiphenyldisilazane, hexaphenyldisilazane, h~exa p-tolyldisila-
zane~ etc., and mixtures of these. The same effect is produced by hexa-alkyl-
cyclo~trisilazanes or octaalkylcyclotetrasilazanes. Other suitable silylating
agentS are silylamides and silylureides, such as a trialkylsilylacetamide and a
~is-trialkylsilylacetamide as is disclosed in U.S Patent 3,~gg,90g.
The preferred silylating agents are dimethyldichlorosilane, trimethyl-
chlorosilane and hexamethyldisilazane, and especially mixtures of these because of
their overall reactivity, availa~ility, ease of handling, satisfactory yields
produced and, as regards t~e mixtures, the generation of ammonia by the disiLa-
zane which serves as acid-~inder. The procedures illustrated herein are those
descri~ed by Pierce in "Silylation of Organic Compounds,l~ Pierce Chemical Com-
pany, Rockford, Illinois.
The favored tetrazolylpenam nitrogen protecting groups are those
uhich can be removed by other than acid conditions. Acid conditions are gener-
ally avoided in order to prevent or minimize degradation of the ~-lactam upon
re val of the protecting group from a compound of Formula V. Illustrative
of such protecting groups are those removable by such means as hydro-
-18-

)887
genolysis ~Rl is ~enzyl or substituted benzyl~, treatment with a base ~Rl is p-
drox~henzyl~ or a substituted silyl group (Rl or R2 is trialkylsilyl)O
The term "tetrazolylpenam nitrogen protecting group~ is intended, in
the most general sense, to CoYer those groups which protect the tetrazole ring
during or after formation thereof and during reaction of the so-protected
tetrazolylpena~ compounds. A group can, therefore, be regarded as a tetrazolyl-
penam nitrogen protecting group when it ~a) can be at-tached to the tetrazolyl
group during or after formation thereof; ~b~ will permit reaction of the 6-
amino group of the tetrazolylpenam, and ~c~ can be removed from the tetrazolyl
moiety of compounds of Formula V without substantial degradation of the tetra-
- zOlylpenam rin$ system~ Illust;rative of such groups, in addition to those
specifically enumerated herein as tetrazolylpenam nitrogen protecting groups
are trialkylsilyl, triphenylmethyl~ and suhstituted triphenylmethyl groups.
--19--

The starting materials ~Formula I~ for this process are prepared by the
reaction sequence described heloN.
In the first step, 6-¢triphenylmethylamino~penicillanic acid (Sheehan
et al., J. Am. Chem. Soc. 81, 5838, 1959) is converted into an amide of formula
S CH3
~C ~ ~ -C-N~ ~ I Y c~3 IX
o ~ ~ C-N~-G
~1
wherein G is selected from the group consisting of -C¢=0~-0-Rg9 -S02-Rg, CH2C~2R7
wherein R3 and R7 are as previously defined, and -CHWlW2, particularly the pre-
ferred conf;gurations thereof definèd above.
In the case wherein G is C~2CH2R7 or -CH~lW2 the amide is prepared
by activation of the 3-carboxy group of 6-~triphenylmethylamino~penicillanic
acidg eOg. ~y mixed anhydride formation, followed by reaction with an equimolar
proport;on of amine of formula N~2CH2C~2R7 or H2N-C~WlW2. Thus, formation of the
mixed anhydride involves reacting an appropriate carboxylate salt of 6-tri-
phenylmethylaminopenic;llanic a~id in a reactlon-inert organic solvent, with
approx;mately equimolar proportions of pivaloyl chloride or lower-alkyl chloro-
formateS. Appropriate salts are, for example, alkali metal salts, such as sodium
or potass;um salts, and amine salts, such as triethylammon;um, pyridinium, N-
ethylpiperidinium or N,N-d;methylanilinium salts. Suitable solvents are chlor,i-
nated hydrocar~ons, such as chloroform, methylene chloride, aromatic hydrocar-
~ons, such as benzene, toluene and xylene, and ethers, such as diethyl ether,~etrahydrofuran and 1,2-dimethoxyethane. The reaction is usually carried out at
a temperature of fron about -50C. to about 30C~, and preferably at about 0C.
and is complete in about one hour. The product is isolated simply by filtering
-20-

387
off the ;nsoluble ma~erial~, and then evapora-ting the solvent in vacuo to give
the crude anhydrid~. The mixed anhydride product need not be isola-ted. It can
be used in situ for reaction with the amine simply by contacting the reactants
in an inert solvent, for about 0.5 to about 2.0 hours, at a temperature in the
range from about -30QC. to about 30C. and preferably at around 0C. The same
solvents identified above for mixed anhydride formation are useful for the instant
reaction.
~hen this reaction is conducted in a water-immiscible solvent, the
product is usually isolated by washing the reaction mixture with ~ater and then
concentrating the organic solvent to dryness in vacuo, to give the crude pro-
duct. The latter product can be used immediately for Step 2, or, if desired,
it can he purified further by well-known methods. It is sometimes convenient
simply to wash the reaction mixture witb water, and then use the so-produced
solut;on of amide directly in Step 2.
In the case wherein G is -C(=0~-0-Rg or S02Rg~ the amide of Formula
V is prepared by reaction of 6-~triphenylmethylamino)penicillanic acid with the
appropriate isocyanate of formula R -0-C~=0~-N=C=0 or Rg~S02~N~C=0. The
react on is usually carried out by contacting substantially equimolar ~uanti-
ties of the reactants, in a reaction inert organic solvent, at a temperature
in the range from about 0C. to about 30C. 3 for a period of from about one hour
to about twenty hours. The product can be isolated simply by removal of thc
solvent in vacuo or the solution of the amide can be used in situ for Step 2.
The isocyanates of formula Rg-O-~C=O)-N=C=O are prepared by reaction of a carb_
amate of formula R9W0-C~=O)-NH2 ~ith oxalyl chloride.
In Step 29 the product from Step 1, or a simple transformation pro-
duct thereof in which any phenolic hydroxy groups are protected by conversion
to formyloxyl alkanoyloxy, or alkoxymethyl groups~ is converted into an imidoyl
chloride by reacting the said amide in a reaction-inert organic solvent with
-21-

~ 106~88~ . ~
¦phosgene and a tertiary amine. About one molar equivalent of phosg~ne is
usually used, but amounts up to about two or three molar equivalents arc
sometimes employed. The tertiary amine is preferably present in an amount
equal to or greater than the amount of phosgene. The reaction is carried out
- 5 1 at a temperature in the range from about -20~C. to about 30C., and pre~efably
lat about 25C. It usually requires a few hours to reach completion. A variety
lof tertiary amines can be u~ed in this process, for example trimethylamine,
¦triethylamine, NjN~dimethylaniline, N-methyimorpholine and pyridine. Typical
¦solvents which can be used are chlorinated hydrocarbons, such as chloroform,
methylene chloride and 1,2-dichloroethane, and ethers such as tetrahydroftlran
and 1,2-dimethoxyethane. If desired, the imidoyl chloride can be isolated by
_ levaporation of the filtered reaction mixture, but in many instances it is con-
Ivenient to use the imino chloride in situ.
¦ Several other reagents, for example, thionyl chloride or a phosphorous
halide such as phosphorous pentachloride are operative in the imidoyl chloride
forming reaction. Moreover, if desired, use can be made of the corresponding
imidoyl bro~ide.
In Step 3 cf the process, the above imidoyl chloride is converted into
- a tetrazolylpenam compound of formula X ; .
~ (C6U ~-C-hH~_CH3 ~X
- 1~ f~
~ G,

1~Z~O~87
Iwherein G i9 as previously defined. This transformation eomprises treating
- the said imidoyl chloride in a~ reaction-inert solvent with about one molar
equiva]ent, or sometimes a small excess, of azide ion. The reaetion mixture
is then stored at or about ambient temperatures for several hours, for example,
overnight, until conversion into tetrazole is substantially complete. A wide
variety of azide ion sources such as trimethylsilyl azide, triethylsilyl azide,
potassium and sodium azide, tributylammonium azide, N,N-dimethylanillnium azide,
N-methylmorpholinium azide and pyridinium aæide; tetramethylguanidinium azide
aTe operative in this proeess. Appropriate solvents in cases wherein the azidej
ion source is a trialkylsilyl azide or a trisubstituted ammonium azide are
¦ - ehloroform, methylene chloride, 1,2-dichloroethane and dipolar aprotic solventsl
¦ such as N-methylpyrrolidone. In reactions where a metal salt of hydrazoic acid¦
/ ~ eonstitutes the azide ion source, dipolar aprotic sol~ents become tlle solvent-
( type of ehoice. Product isolation is achieved using standard methods... When a
low boiling ehlorinated hydrocarbon is the solvent, the reaetion mixture is
¦washed with d;lute alkali and then the organie solvent is evaporated off. When¦;
a dipolar aprotie solvent is the solvent, the reaetion mixture is diluted with
a large exeess of dilute alkali, and then after appropriate adjustment of the
pH, the product is isolated by solvent extraction. .
The N-triphenylmetllyl derivatives tllus obtained are eonverted to
eompounds of formula I by treatment with an aeid such as methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, hydrogen chloride, llydrogen bro-
mide, acetic, propionic, chloroacetic or trifluoroacetic acid. The reaction
is normally carried out by dissolving the starting material in an appropriate
solvent and adding about two molar equivalents of the acid reagent at or about
ambient temperature. Reaction is complete witllin about one hour, and the pro-
duet is present in the reaction medium in the form of the aeid-addition salt
corresponding to the aeid reagent used. Appropriate solvents are diethyl etller,
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, ehloroform, methylene chloride,
l,Z-dichloroet e~ aceton~, mcLhyl e.llyl ketoee, e hyl
1~ ' IZ

~06~8~7
acetate, butyl acetate, hexane, cyclohexane, benzene, methanol, ethanol and
butanol. A favored procedure comprises the use of p-toluenesulfonic acid in
acetone since the p-toluenesulfonate salt of the product often precipitates.
Compounds of formula V wherein Rl and R2 of the 5-tetrazolyl moieties
are hydrogen, alkanoyloxymethyl, l-alkanoyloxyethyl or phthalidyl are useful
antibacterial agents. Compounds of formula V whérein Rl and R2 are triphenyl-
methyl, and those wherein Rl is a tetrazolylpenam nitrogen protecting group as
defined herein are intermediates for the production of 6-acylamido-2,2-dimethyl-
3-(5-tetrazolyl)penams wherein Rl and R2 are hydrogen, alkanoyloxymethyl, 1-
alkanoyloxyethyl or phthalidyl. Removal of the triphenylmethyl, substitutedtriphenylmethyl and tetrazolylpenam nitrogen protecting groups by known methods
affords the corresponding compounds wherein Rl and R2 are hydrogen. Alkylation
of tetrazolyl moieties (Rl=R=H) by the reaction with alkanoyloxymethyl, 1-
alkanoyloxyethyl or phthalidyl chlorides (or bromides) affords bactericidally
active compounds.
The 6-acylamido-2,2-dimethyl-3-(5-tetrazolyl)penams of formula V
wherein Rl or R2 are hydrogen, alkanoyloxymethyl, l-alkanoyloxyethyl or
phthalidyl are valuable antibacterial agents in vitro and in vivo against a
wide variety of gram-positive and gram-negative bacteria. Their useful
activity can readily be demonstrated by in vitro tests against various organisms
in a brainheart infusion medium by the usual two-fold serial dilution technique.
Their in vitro activity renders them useful for topical application in the form
of ointments, creams and the like, or for sterilization purposes, e.g. sick-
room utensils. They are also effective antibacterial agents in vivo in
animals, including man, not only via the parenteral route of administration but
also by the oral route of administration. The oral and parenteral dosage
levels for the herein described compounds are, in general, on the order oE up
to 200 mg./kg. and 100 mg./kg. of the body weight per day, respectively.
For such purposes, the pure materials or mixtures thereof with other
antibiotics can be employed. They may be administered along or in combination
with a pharmaceutical carrier on the basis of the chosen route of administration
and standard pharmaceutical practice. For example, they be administered
- 24 -

)6(~87
orally in the form of tablets containing such excipients as starch, milksugar, certain types of clay, etc. or in capsules alone or in admixture
with the same or equivalent excipients. They may also be administered
orally in the form of elixirs or oral suspensions which may contain flavor-
ing or coloring agents, or be injected parenterally, that is, intramuscularly
or subcutaneously. For parenteral administration, they are best useed in
the form of a sterile aqueous solution which may be either aqueous such
as water, isotonic saline, isotonic dextrose, Ringer's solution, or non-
aqueous such as fatty oils of vegetable origin (cotton seed, peanut oil,
corn, sesame) and other non-aqueous vehicles which will not interfere with
the therapeutic efficiency of the preparation and are non-toxic in the
volume or proportion used (glycerol, propylene glycol, sorbitol).
Additionally, compositions suitable for extemporaneous preparation of
solutions prior to administration may advantageously be made. Such composi-
tions may include liquid diluents, for example propylene glycol, diethyl
carbonate, glycerol, sorbitol, etc.; buffering agents9 as well as local
anesthetics and inorganic salts to afford desirable pharmacological
properties.
Illustrative examples of the process of this invention and
~0 representative preparations for making the necessary starting materials
are provided below.

D6~88~7
~ 1
Benzaldehyde ~2c122 g., 0.02 mol) is added to a solution of 6-amino-
292-dimethyl-3-~5-tetrazolyl~penam ~4.826g., 0.02 mol) in methylene chloride
~50 ml.~ containing anhydrous magnes;um sulfate C5 g.) at room temperature. The
reaction mixture is stirred for 18 hours and is then filtered to remove the
magnes;um sulfateO The product is recovered by evapGration of the solvent under
reduced pressure.
It is converted to the triethylamine, t octyla~ine, di-n-hexylamine,
n-butylamine, dibenzylamine, N,N-dibenzylethylenediaminea phenethylamine, and
N-ethylpiperidine salts by reaction with equimolar quantities of the appropriate
amine in methylene chloride solution. The salts are recovered by evaporation
of the solvent.
-26

~06~7
EXAMPLE 2
The procedure of Example 1 is repeated but using tha appropria-te alde-
hyde and the appropropriate 6-amino-2~2-dimethyl-3-C5-tetrazolyl)penam co~pound
(Formula Il to produce the following compounds and their amine salts:
R-CH=N-CH_ _ CH - S ~ H3
O= ~ CH
~ N
R Rl R R
C6H5 4 3 6 4 2 CH3 H
C6H5 4-C6H5CH20c6HL~cH2 C3H7 L~_C6H5CH20C6H4CH2
C6 5 C ~ - ~ ~ C7H15 ~CH3)C-CH-C ~C-
C6H5 ~CH3)C=CH-CH= -CH2- CllH23 3-CH3-4-C~30c6H4cH2
C6H5 2~4-CCH30)2C6H3CH2- 10 7 H
C6H5 4-~C6 4 2 C10 7 H
C6H5 4-C2H50C6H4CH2- CH=CH-~ =C- H
2-HOC6H4 `4-C6H5C6~4CH2- CH=CH- ~=C- H
4-HOC6H4 3 Cl 4 CH30C6H3CH2 r---CHHCHHC~ H
4-clc6E4 ~ 6H5~2CH ` C6H11 4-n-C3H70c6~l4cH2
3-BrC6H4 3 BrC6H4CH¢C6H~ 2-Cl-5HOC6H3 CH-CH-CH=C-
294-Cl2C6H3 C6HsCHCCH3)~ L~ 9 6 3 (CH3)C-C~-CH=C-
4-N02C6H4 H 2-N02-3-ClC6H3 4-C2H50C6H4CH2-
2-H0C6H4 . H 2-i-C3H 0-R-ClC6H3 H
2-CH30C6H4 ~ 296 (CH3)2c6H3 3-C6H5-4-CH30C6H3CH2-
C6H5CH2 ~ 1 ~ 3 10 6) 3 6 4 (C 3)
C6H5CH2CH2 4-CH30C6H4CH2 1-¢2-H0-3-NO2cloH5) 4-CH30C6H4 2
C6H5CH=CH 4-CH3COOC6H4CH2 1_~2,6-(CH3)2CloH5 C~ 6 5 3
4-N02C6H4 C~ CH-C ~ - 2 (4~ ~ 3)2 10 5)
2-C~OC6H4 ~CH3)C=CH-CH-C- 2-(3-FCloH6) H
c5Hq Hydrogen C4H~CH=CH 2 5
C6H5 2H50 C0 ~ ( 2 5 )2 6 3 ~ ~ 2 6 3)0C0
4-N2C6H4 C6H5CH20-C0 4 N02C6H4 CH2CH CN
-27-

I' . ' I, .
;
;~ ~0~;~887
!!
_ . R__ __ _ RL _ __ R ~
2-HOC611~, - C6?15~C 3 11OC61i4 CH2C112S2N(CH3)2
- 2-Cloll7 (4-N02C6~14)0-CO ~ ( 3 )2 6 3C112C112COOC6}15
?-lh:iel~y1. C215 C C6~15 2C}2 2 61~5
1~ 3 C61~5CH20-C0 C61~5 CH2C1l2s02N(c6~l5)2
6 13 6 5 6 5 2 Cll CH S0 l~;li(il ~1 11 !
~3-ClC6114 C113S02 C6115 C1120C0C(~113)3*
C6H5 3 2 .C6115 CH20COCI-13
Ij4-N02C6H4 C6HsCH2so2 4-~02C6114 CH20COC(CH3)3*
,C6Hll (3-CIi30C6H4)S02 2 6 4 CH20COC5H
3,5-I2C6H hydrogen 2-HOC6H4 CH(CH3)0COC(C113)3 1
t c4ll9 12~4-(N02)2C6H3]S02 2-HOC6114 CH(CH3)0COCH3 1.
~2-Quinoly]. hydrogen C6H5 phthalidyl*
3-indo]yl hydrogen C~13 phthalidyl*
j4-quinolyl 4-methoxybenzyl C6U13 -phthalidyl*
¦~CH2=CH furfuryl C6~111 CH20COC2H5*
! 6 5 C(C6H5)3* C2H5 ( 6 5)3
~4-N02C6H4 C(C6H5)3* 3-Cl-4-n-C4H C6HCtc6H5)3* ,
1~ 6 5 C(4-CH3C6H~)3* 6 4 . .C(C6H5)2(3-ClC6H4)
C10117 C(c6H5)2(4-n-c3H7c6 4)~9--0 C(4-C6HsC6H4)2(c6H5
- i C6H5C112 6 4 2( 6 5 . ( 6 5 3
~C6H5 Si(CH3)3* . 2-HOC6H4 Si(CH3)*
~,3,4-F2C6113 ( C4 9)3 2 6 4 Si(CH3~3*
; C6H5 ( 4 9)3 CH3 Si(CH3)3*
',3,s-Br2C6~13 hydrogen t-C4H9C6H4 C(C6115)3
2j4-(CH3)2C6113 llydl-ogen 2-Cl-6-N02C6113 C(C6H5)3
*Corresponding isomeric 2-tetrazolyl derivative al80 produced.
Il ' ' ,
'.
~! .
-- 28 --
?
1'l .
"

10601387
~XAMFLF, 3
Sallcylidene-6--Amino-2,2-Dlmethyl-3-(5-Tetrazolyl)penam
¦ Salicylaldehyde (2.44 g., 0.02 mol) is added to a solution of 6-amino-
2,2-dimethyl-3-(5-tetrazolyl)penam (4.826g., 0.02 mol) in water (500 ml.) at
pll 8.0 and the mixture stir~ed at room temperature for two hours. Ethylacetate
(500 ml.) is added to the reaction mixture, followed by slow addition of suffi-
cient 6~ hydrochloric acid to bring the pH to 7. The mixture is stirred for a
half hour and the ethylacetate phase separated. The aqueous phase is again
extracted with ethyl acetate and the combined ethyl acetate solutions dried
(~gS0~). Evaporation of the solvent in vacuo affords the title compound.

~ 1060887
. _XAMPLE 4
.- Repetition of the procedure of Example 3 but using the appropriate
aldehyde affords the following compounds
R-~H- -
H C113
. . C~13 C5~{11
3 7 C12H25
. 8 i7 C~12=C
'12 25 (C~13)2C=C~l-
. C6H5 ' C3H7CH=CHC112CH2
3-n-C4HgOC6H4 CH=CH(CH2)8
. l 2~ ~ 3)2 6 3 2-CH30C6114
3,5-(N02)2C6~3 4-IC6H4
Br-4-~loc6H3 . 4 ~ 6 4
3-oll-4-C2llsc6ll3
10 7
. 2-(1-ClCloHG)
2-(6-C~i3Clo~l6)
4,8-~ o)2clo~l5)
G3H5 .
C7~113
H-CH=C-
_ 30 _
., , , . ' ,.

` EXAMPLE 5
N-4-Nitrobenzylidene-6-Amino-2~2-Dimethyl-3-~4-Methoxyhenzyltetrazol-s-yl)penam
A mixture of 4-nitrobenzaldehyde, ~0.726g., 6mmol), 6-amino-2,2-dimethyl
3-¢4-methoxybenzyltetrazol-5-yl)penam ¢1.807g~, 5mmol) and benzene ~250 mlO) is
st;rred and heated to reflux until ~ater is no longer evolved~ Evaporation of
the reaction mixture under reduced pressure affords the title product.

!387
~=~=
The triethylamine salt o~ N-benzylidene-6-amino-2,2-dimethyl-3-(5-
tetrazolyl~penam ~l.Q77g., 2.5 mmol~ is dissolved in methylene chloride ¢100 ml.)
and the solutlon cooled to OQ-5C. Phenylacetyl chloride (~' 0.39~ g., 2.75,mmol)
is added dropwise over a 30 minute period while maintaining the temperature at
0-5C. The reaction mixture ;s stirred for one hour following completion of
addition. Cold water ~10~ ml.~ is then added and the pH adjusted to 2.0 with
concentrated hydr~chloric acid. The mixture is stirred for twenty-minutes,0 the aqueous phase discarded and the organic phase ~ashed with water (50 ml.).
The organic phase is dried ¢Na2S04) and then evaporated to dryness.
- Repitition of this procedure but using the appropriate acyl chloride~
~R3COCl~ in place of phenylacetyl chloride produces 6-acylamido-2,2-d;methyl-
3-~5-tetrazolyl~penam wherein the acyl moiety (R3CO) is:
H
CH3Co
n C3H7CO
n--C3H17C
_ C12 25
CH2=CH-CO
CH2=cHccH2 ) 8CO
C3H5C
C~ llC
6 gCO
6~al'4-C6H7)Co
l-NH2-C6HloCO
1-~2-CH30CloH6)CO
C6~l5 2
~ -32-

` 1061:~887 ~
C6H5CH ~NH2) CO
I_ s~ ''-I _
. ¦ CH=CH-CEl=C-CO
. I . ~
. I CH=CH-CH=C-CO
! 2-NH2CH2-C 6H4 CH2 co
C6H5CH(NHCOCH2NHC(NII)~ pyridyl)CO
2,6 (CH30)2-C6H3CO
3,4-(HO)2C6H3-CH(NH2)Co .
. ¦ . 3-Cl-4-HOC6H3CH(NH2)CO
~ ~0~ , '
¦ CH=CH~GH=C-CH(NH2)CO
10 ¦ 4-H2NSo2C6H4CH(NH2)co
j (2-~5H4N)CH(NH2)CO
~¦ 2 2C
H2NCOCH=CH-CO
. I CNCH2~
15 1 (3-indolyl)cH2cH(NH2)co ,
I - s - - -- I
i CH=CH-C(CHNH2CO)=CH .
(CH3)2CH-CH(NH2)CO
4-CH3 C6H4-so2-NHco
l C6H5CH(CH)
20 ~1 CH3CONHCO
C6H5CH(S03H)CO
(C0-5-indanyl)co
(=~H)NHcoNHcH2co
i~ C6H5NHC ' ' .
25 1 C6H5cH(NHcocH2cl)co
i C6H5CH (NHS02C2H5) CO
! 4-HOC6H4CH2Co
. 6 4 2
~ C6H5CH(NHCOCH3)CO
~ , 4-xoc6H4cH(N~lcoNHc6H4-4-ocH3)co
'. ~ . . ..
I .
~ 3~
~ .
l . ,
.. l ..........
.

~ 1060887
, C6H5CH (N~lso2-2-naplltllyl) CO
6 5c~l(N~lcocH2cH2Nl-32)co
C 6H5 cH (N ~cocH 2NHc ( NH ) NH2 ) co
C6H5cH (N}lcoNHc (NH) Nl32) co
5 ~I C6H5CI3(NHCOCOOCzH5)CO
!l I
' In like manner, the following compounds are prepared using the
;,-appropriate acyl chloride (R3COCl) and the appropriate 6-amino-2,2-dimethyl-3- t
, (substituted tetra~ol-5-yl)penam Schiff bases of Example 2:
" R3CONH-fH - fH ~ S f, CH3
~ O=C - N ---- - CH
!i Rl-N_N ' I
7~ ~
I'' R3
__ _ _ I
~C61~5CH(Nll2)-3 6 4 2
1! 4-Hoc6~l4cH(N~l2)- 6 5 2C6H4cH2
¦ C6H50CH2- 6 4 2
, 2~6-(cH3o)2c6H4cH2- , ' C6H5CH(CH3)
1, .' CH3CH2- , 4-C2H50C6H4CH2 ~ .
15 ; 3-Cl-4-HOC6H3CH2 .C(c6H5)3
2-H2NcH2c6H4cH2- 4-CH30C6H4CH2
,~ , 2-C4H3SCH2- CH20COC(CH3)3
-' sydnonyl- CH(CH3)0COCH3
;j 4-Hoc6~34cH(NH2)- phthalidyl ¦
- 20 .l c6H5cH(NHco-2-pyrrolyl) CH2CH2S02C6H5
. 1! 2-C5H4N-S-CH - Cll20COC5Hll
.' 1-132N--l-C6Hll- C6H5C
, nYC4Hg- C(C6l35)3
C6Hll C(4-C~33C6H4)3
1,1 . I S~
25 I, . Cll3CH2SCI32- CH=CII-CH=C-
!
.; .
~ _ 32b -
., . ', . ' ' .
,.1 , . 1

` 1060887 ' ~ 1,
. ~ .
_ ,
¦ CH3CU20COCH2- (CH3)C~CH-CH-C-
I CGH5CH2CH2- 2 5 '
! CH3C(NH)NHCH2- CH2CH2CN
5 j C6H5CH (OH~ CH2- C61150CO
3-CH3C6H4CH2- . (4-~102C~j,H4)0CO
. I C6H5cH(NHco-2-fu~yl)-- . CH3S02
, C6H5cH(NHco-n-c4~l9)- C6H5C112S2
. j 6 4 ( ( 3)2) 2 2 2 (C 3)2
10 ~ 1-H2N-l-C5Hg-- CH2CH2S2NHCH2C6H5
~ 2-isothia~olyl ~3-CH30C6H4)SO2
¦ A .
I ' .
i . ~ 32c- .

EXAMPLE 7
6-C5-Methyl-3-phenylisoxazole-4-Carboxamido)-2,2-Dimethyl-3-~5-Tetrazolyl)-
penam
The trimethylsilyl derivative of N-4-nitrobenzylidene-6-amino_
2~2-dimethyl-3-~5-tetrazolyl~penam ¢4~45gO~ 0,01 mol) in methylenechloride
~100 ml,) is treated with triethylamine ~l.Olg., 0 01 mole) and the solution
cooled to 0-5C. in an ice bath. A solution o~ 5-methyl-3-phenyliso~azolecar-
bonyl chloride ~2,2g., 0.01 mole) in methylene chloride ~35 ml.) is added over a10-15 minute period and the resulting solution is stirred for 45 minutes at
0-5C. Water ~50 mlOI is-then added and the mixture stirred at 0-5C. as the
pH is adjusted to 2.0 with 6N ~Cl. After addition and 20 minutes of stirring
the organic layer is separated, cooled with water, dried over anhydrous MgS04
and concentrated to dryness. The residue is redissolved in ethyl acetate
~100 ml.) and treated with N-ethylpiperidine ~1.13 g., 0.01 mole). The crystal-
line salt which separates is granulated for 30 minutes, filtered, washed with
ethyl acetate and is dried to give 3~1go ~56%) of the N-ethylpiperidine salt
of ~he title compound.

387
EXAMPLE 8
D-(6-~o-amino-4-hydroxyphenylacetamido)-2,2-dimethyl-3-(5-tetra-
~olvl)Denam
The triethylamine salt of N-4-nitrobenzylidene-6-amino-2,2-dimethyl-3-
~S-tetrazolyl~penam ~2.14 g., S mmole) is dissolved in methylene chloride
¢75 ml.~ and the resulting solution cooled to 0-5C. in an ice bath. The solu-
tion is treated uith 1.6g. ¢5 mmole~ of the ethylchloroformate mixed anhydride
of the methylacetoacetate enamine o~ D-d-phenylglycine ¢prepared from the
enamine in cold acetone ~SO ml.~ and ethylchloroformate ~SlS mg.) containing
a droP of N-methylmorpholine) in acetone. The mi~ed anhydride is added all
at once. After 30 minutes at 0-5CO the reaction is treated with water ~100 ml.)
and the pH th~n adjusted to 2.5 with 6N HCl. After 20 minutes at 0-5C. the
ayers are separated and the aqueous solution adjusted to pH S.l with lN NaOH.
The product cr~$tallizes from solu~ion and is collected by suction filtration
and washed first ~ith water and then ~ith acetone. Air drying afforded ~50 mg.
~5~%~ of the title compound.
-34-

1~6~11~7
EXA~PLE 9
d ~
~-4-n;tro~enzylidene-5-amino-2,2-dimethyl-3-(5-tetra7olyl)penam (3.73g.
a.Ol mole~ is added to water ~lOa ml~ and the pH adjusted to 8.0 with lN NaOH.
A solution of phenoxyacetal chloride ~1.70 g., 0.01 mole) in isopropylether
¢50 ml.) is added dropwise and the pH of the reaction mixture maintained
between 705 and 8.~ ~y the concomitant addition of lN NaOH. After the pH has
levéled off the isopnopyl ether layer is drawn off and discarded. The aqueous
phase is layared w;th methylisobutylketone ¢150 ml.) and the pH adjusted, with
cooling ¢0-5C.,), to 2.5 with 6N HCl. After stirring for 20 minutes, the pH is
readjuSted to 8.0 with 4N NaOH. The organic layer is drawn off and discarded.
The aqueous solution is Layered with fresh methylisobutylketone and the pH
readiusted to p~ 2.0 with 6N HCl. The organic layer is drawn off and treated
with sodium 2-ethylhexanoate ~2.4 g~ in methylisobutylketone (35 ml.) dropwise
over a 10 minute period. The precipitated product, the sodium salt, is granu-
lated~ collected by filtration9 washed with acetone-and air dried to give
2~98 g~ ~79%) of product~
-35-

~ ~
lC3160B87
PREPARATION A
6-(Triphenylmethylamino)-2,2-dimethyl-3-[4-methoxybenzyl]-
tetrazol-5-vl~T~enam
A). 6-¢Triphenylmethylamino~ 2,2-dimethyl-3-(N-[4-methoxy})enzyl]carb-
amoyl~penam.
To a stirred slurry of 86.4 g. ~0.8 mole) ~f 6-aminopenicillanic acid
in 600 ml. of anhydrous chloroform is added 11.2 ml. ~0.4 mole) of triethyl-
amine, and the mixture is stirred at ambient temperature until a clear solu-
tion is obtained ~_. 15 minutes). TG this solution is then added, portion-
lO wise over about 25 minutes, 134.9 g. ~0.44 mole) af 90% pure triphenylmethyl
chloride~ at arnbient temperatureO Stirring is continued for a further 64
hours~ and then 5.6 ml. of triethylamine is added. The solution is cooled to
0-5Co~ and then an ice-cold solution of 38 ml. (0.4 mole) of ethyl chloro-
formate in 80 ml. of chloroform is added dropwise during 30 minutes with the
15 reaction temperature being maintained between 4 and 9C. After a further 15
minutes of stirring, 52.4 ml. ~0.4 mole) of 4-methoxybenzylamine is injec-ted
into the reaction medium, below the surface of the solvent, at 4 to 9C., and
over a period of 30 minutes. Stirring is continued for a further 30 minutes
at 3 to 6C~, for 20 minutes while the reaction medium warms to 20C. The
20 reaction mixture ;s then washed with water9 followed by brine. Finally, it isdried using magnesium sulfate to give a chloroform solution of 6-(triphenyl-
methylamino)-2~2-dimethyl-3-(N-[4-methylbenzyl]carbamoyl)penam.
~B~ 6-~TriphenylmethYlamino~-2~2-dimethyl-3-~1-4-methoxy}::enzyl]-tetrazol-
5-yl~penam.
To a chloroform solution containing 69.4 g. ~0.120 mole) of 6-(tri-
phenylmethylamino~-2~2~dimethyl-3-~ 4-methoxybenzyl]carbamoyl)penam~
--36--

6~;)887
and having a volume of 133,3 ml., prepared hy the ~ethod descrihed in ~A~
above, ;s added a further 132~7 ml. of chloroform, ~ollowed by 29 1 ml. C0.360
molel of pyridine. This solution is cooled to 10C., and then 26.22 g,
~0.126 mole~ of phosphorous pentachlor:ide is added during 15 minutes, uith stir-
ring. Stirring is continued at ca 10C. for 10 minutes~ and then at ambienttemperature for a furthar l.S hours, giving a solution of the imino chloride.
To a one-sixt~ aliquot of this imino chloride solution is added 4.85 ml.
¢0.060 mole) of pyridine, follo~ed by 2.42 ml. (0.060 mole) o~ methanol at ca
25C., uith stirring. After a further 15 minutes o~ stirring 2.03 g. ~0.038
molel of ammonium chloride, followed hy 2,5g g. ~0.03~ molel of gS% pure
sodium azide, is added, The reaction mixture is t~en stirred at ambient
temperature or a further 4 hours. At this point, 4~ ml. of uater and 2~ ml.
of chloroform are added, and then the layers are separated. The organic
phase is washed with water, dried using magnesium sulfa-te, and then concentra-
ted to a small volume m vacuo. This final chloroform solution is added
drop~ise with stirring to a large volume o~ diisopropylether, and, after 30
minute~, the precipitate which has formed is filtered off, This aff~rds 6.1 g.
Of 6_~Triphenylmethylaminol - 2,2-dimethyl-3-¢1-~4-methoxyhenzyl~tetrazol-5-
yl~penam~ The infrared spectrum of the product CKBr disc~ shous an absorption
~and at 17~a cm 1 ¢~ lactam~; and the NMR spectrum ~in CDC13~ sho~s a~sorptions
at 7.25 ppm ¢multiplet~ aromatic hydrogenQ~, 5.40 ppm Cbroad singlet, benzylhydrogens~ 5.05 ppm ~singlet, C-3 hydrogen~, 4.5~-4.30 ppm ~Dultiplet, C-5
and C-6 ~ydrogens~, 3.70 ppm ¢singlet, methoxy hydrogens~, 3.50-3.10 ppm
~broad peak, N~, 1.5~ ppm ~singlet, C-2 methyl hydr4gensl and Q~7S ppm
~singlet. C-2 methyl hydrogens~

~6~
PREPARATION E
6-~Triphenylme-thy~amino2-2,2~dimethyl~3~
~1-[4-benzyloxybenzyl~tetrazol~5-vl)~enam
6-~Triphqnylmethylamino) 2,2-d;methyl-3-~N-4-benzyloxybenzyl]carbam-
oyl~penam To a stirred solution of 20.0 g. of 6-triphenylmethylamino-
penicillanic acid ~Sheehan and Henery-Logan, Journal of the American CheMical
societY~ 81 5836 ~195q]) in 140 ml. of acetone, at 0-5C., is added 6008 ml.
of triethylamine followed by 5.78 ml of isobutyl chloroformate. After a fur-
ther 10 minutes, the mixture is filtered directly into a stirred solution oF
g.28 g. of 4~~enzyloxybenzylamine in 1,000 ml. of water and 300 ml. of acetone
at ambient temperature. The mixture so obtained is stirred for 4 minutes, and
then an additional 50Q mlO of water is added. Stirring is continued for a fur-
ther 7 minutes, and then the reaction mixture is extracted with ether. The
ether is dried using anhydrous magnesium sulfate, and then evaporated to dry-
ness in vacuo. The crude product so obtained is re-dissolved in 200 ml. of
ether9 which is then added dropwise over 10 minutes to 2g500 ml. of hexane.
The solid whic~ precipitates is filtered off, giving 21.5 g. of 6-(triphenyl-
methylamino)-2,2-dimethyl-3-~T-[4-benzyloxybenzyl]carbamoyl)penam
6_~Triphenylmethylamino~-2,2 dimethyl-3-(,chloro-CN-~4-ben~.yloxy-
benzyl~;mino~methyl)penam~ To a stirred solution of 2.0 g. of the above-
descr;bed amide in 10 ml. of dry chloroform, at 0-5C., is added 0.99 mlc of
pyr;dine, followed by 5.42 ml. of a 2.26 M solution of phosgene in chloroform.
The reaction mixture is then stirred at ambient temperature overnight. At
this point, it is evaporated to dryness in vacuo, yielding a viscous gum, which
is extracted with 100 ml. of ether. The ether is filteredg and evaporation of
the ~ ltrate affords the imino chloride as a yellow foam.
-38-

^ -
~6088'7
6-~Triphenylmethylamîno)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]-
tetrazol-5 yl)penam. The above~described imino chloride is re-dissolved in
8 mlO of dry N,N-dimethylformamide. To this solution is added 249 mg. of
potassium azide, and the tur~id solution i~ stirred at ambient temperature for
2.25 hoursO The solvent is evaporated at ambient temperature, under high
vacuum, leaving a brown gumO This residue is partitioned between 60 ml. of
water and 150 ml. o~ ether. The ether phase is separated off, washed with
saturated brine, dried usin~ anhydrous sodium sulfate, and finally evaporated
to drynPss in vacuot The residue is ~80 mgO o~ 6-{triphenylmethylamino)-2,2-
dimethyl-3-C1-~4-benzyloxybenzyl~tetrazol-5-yl~penamO Its NMR spectrum ~in
CDC13~ shoh~s absorption bands at 7.30 ppm ¢multiplet, aromatic hydrogensl~
5045 ppm ¢~uar~et, benzyl hydrogens), 5005 ppm ~singlet, C-3 hydrogen), 5000
ppm ~singlet, benzyl hydrogens~, 4.40 ppm ~multiplet, C 5 and C-6 hydrogens),
1040 ppm ~singlet, C-2 hydrogen) and 0.70 ppm Csinglet, C-2 hydrogen).
-39-

106~38~7
PR~PARATION C
6-~Triphenylmethylamino~-2,2~dimsthyl--3~ furfuryltetrazol-
5-vl)~enam
~A~ 6-¢Triphenylmethylamino)-2,2-dimethyl-3-~N-furI'urylcarbamoyl)penam
To a stirred slurry of 216 g. ¢1 mole) of 6--aminopenicillanic acid in
1500 ml. of chloroform~ is added, at 25-30C., 278 ml. ~2 mole) of triethylamine.
To t~e solution thus ohtained is added~ portion~ise during 25 minutes, 306 g~
Cl.l mole~ of triphenylmethyl chloride, at 25-30C. Stirring is then con-
tinued for 44 hours at am~ient temperature.
A 522-~1. portion ~0.25 mole) of the above 6-~triphenylmethylamino)-
penic;llanic acid solution is cooled to 4C., and then 3.5 ml. of triethylamine
is added. With vigorous sti~ring is then added 23.75 ml. of ethyl chlorofDrmate
at 5-10C. Stirring is continued for a further 30 minutes at ca. 6C. at the
end of the addition, and then 8.43 ml. of furfurylamine is injected into the
reaction m~d;um below the surface of the solvent. At 10 minute intervals, threefurther portions of furfurylamine ~5.90 ml., 4.22 ml. and 3.54 ml.) are then
in~ected into the reaction medium in similar fashion. The total volume of fur-
furylamine added is 22.09 ml. ~0.25 mole), and the temperature is maintained at
ca. 6C. throug`hout the addition of the amine. WheD the addition of the amine is
complete9 the cooling bath is removed and the reaction medium is stirred at
ca.25C. for 45 minutes. It is then washed successively with three portions
of water9 and one portion of brine. Finally, it is dried using anhydrous
magnesium sulfate. This affords 610 ml. of a chloroform solution of 6-triphenyl-methylamino~-2~2-dimethyl-3-¢N-furfurylcarbamoyl)penam. The NMR sp~ctrum of thissolution s~owed absorptions at 7.3 ppm ~17H, m), 6.2 ppm~lH~ m), 4.35 ppm~3H,
m~, 4.~5 ppm ~2H, s), 1.6 ppm~3E, s) and 1.35~3H, s~.
-40-

~6~387
~B~ 6-~Triphenylmethylamino3-2,2-dimethyl-3~ furfuryltetrazol-5 yl)penam.
To a stirred solution of 3.05 g. ¢5.7 mmole) of 6-(triphenylmethyl-
amino3-2~2-dimethyl-3-~N-furfurylcarbamoyl)penam~ in 8 mlO of chloroform, at
OoCO, is added 1.35 ml. ¢17 mmole) of pyridine, followed by 2.64 ml. of a 4.33
M solution of phosgçne in chloroforlll. 5tirring is then continued for 1 hour at
25C. The chloroform, and exeess pilosgene and pyridine, are then removed by
evaporation in vacuo, and the residue is redissolved in 5 ml. of chloroform. The
solution is cooled to 0C., and then 2.25 g. ~14.4 mmole) of tetramethylguani-
dinium azide is added in several small portions. Stirring is continued for 15
minuteS at ambient temperature, and then 20 ml. of chloroform, followed by 30
ml. of water, are added and the pH is adjusted to 6t5. The chloroform layer is
separated offs Nashed with water, follo~ed by brine, and then dr;ed ~MgS04).
Removal of the solvent by evaporation in vacuo leaves 3.37 g. of a dark-red foa~.
The foam is re-dissolved in a small volume of chloroform and absorbed onto a
column of chromatographic silica ge`l. Elution o~ the column with chloroform,
f^llowed ~y evaporation of the appropriate fractions in acuo, affords 6-~tri-
phenylmethylamino)-2~2-dimethyl-3~ furfuryltetrazol-s-yl)penam. The NMR
spectrum of the product ¢CDC133 shows abso~ptions at 7.40 ppm (m, 16H), 6.40
ppm ~m, 2~ 5050 ppm ~s, 2H3, 5.20 ppm ~s, lH3, 4.90 ppm ~m, 2H3, 1.60 ppm
~s, 3H~, and 0.80 ppm ~s, 3H).
-41-
: .

106~
PREPM ATIOU D
6-~Trip~enylm~thylamino~-2,2-dimethyl-3~ 5~methyl-
furfurvl~tetrazol-5-vl)~enam
____
The title compound is prepared according to the procedure of
S Prepara~ion C9 but using 5-methylfurfurylamine in place of furfurylamine. The
NMR spectrum ¢CDC13~ of the product show~ absorptions at 7.36 ppm ~m, 15H),
.33 ppm ~m, lH~, 6.93 ppm ¢m, lH), 5.S0 ppm ¢s, 2H), 5.20 ppm ¢s, lH), 4.50 ppm
~m, 2H), 3.23 ppm ¢d, lH), 2.26 ppm ~s, 3H), 1.63 ppm ~s, 3H) and 0.90 ppm ~m, 3H).
pREPARATI0~ E
6-~Trip~enylmethylamino~-2,2-dimethyl-3-(1-[2,4-dimethoxybenzyl~-
The title compound is prepared in 46% overall yield ~rom 6-~triphenyl-
methylamino~penicillanic acid, by replacin the furfurylamine of Preparat;on C w;th
2~4-dimethoxybenzylamine~ The crude product i~ purified by recrystallization from
a mixture of methylene chloride and methanol, The NMR spectrum of the product
~CDC13~ shows absorpt;on at 7.40 ppm ~m, 16H), 6.45 ppm ~m, 2H)~ 5.40 ppm
~s, 2H~, 4.S0 ppm ~m, 2H~, 3.75 ppm ~s~ 3H), 3.70 ppm (s, 3H), 1~55 ppm ¢s, 3H)
and 0.~0 ~s, 3H~.
-42-

~6(~ 8~7
PREPAPATION F
The procedur~e of Preparat.ion E is repeated, except that the furfuryl-
amine is replaced by an equimolar amount of the appropriate amine, to produce
the following congeners:
6~5)3-N~ CH3
~ N ~ C~J~N ~N
\ //
~ CH ~
,~
12 R13
R12 R13 11
4 CH3 2 H H
3-C1 4~CH30 H
3-C~3 4-CH30 H
3 C6 S 4-CH3Q H
4-CH30 ~ CH3
El H C6 5
3-Br H C6H5
- 4-F H C6 5
H H H
4-C6H5 H H
H ~ CH3
4-CH3 H C6H5
4-n-C3H70 4 H
~ 4-i-c3H7o H
2-CE130 4-CH30 H
--43--

8~7
PREPARATION G
__
6-~Triphenylmethy~amino)-2~2-dimethyl-3~ c4-hydroxybenzyl]
tetrazol-5-vl~Penam
(A~. 6-¢Triphenylmethylamino) 2,2-dimethyl-3-(N-[4-hydroxybenzyl]carbamoyl-
penam.
To a stirred slurry o$ 43.2 g. ~0.20 mole~ of 6-aminopenicillanic
acid in 300 ml. of chloroform is added 55.6 ml. ~0.40 mole~ of triethylamine,
followed by 61.2 g. ¢0.22 mole) of triphenylmethyl chloride, at ambient
temperature- Stirring is then continued for a further 48 hours at ambient
temperature.
A 1207ml. portion ~containing 0.060 mole of trie-thylammonium 6-
[triphenylmethylamino~pen;cillanate~ of thc above çhloroform solution is with-
drawn. It is diluted with a further 40 ml of chloroform~ and then 1.67 ml
~a.012 mole~ of triethylamine is added. The mixture is cooled to ca. 4C.,
in an ice-batn, and then 6.84 ml. of ethyl chloro~ormate is added all at once,
with stirring~- Stirring is çontinued for 30 minutes with ice-bath cooling, andthen 7.5 g. ~0.060 mole~ of 4-hydroxybenzylamine is added. Stirring is con-
tinued for 10 minutes with ice-bath cooling, and then for a further 1 hour
Without cooling. At this point, the chloroform solution is washed wi-th water,
followed by brine, and then dried using anhydrous sodium sulfate~ Removal of
the solvent by evaporation in vacuo affords the crude amide. The crude amide
is ~e~dissolved in 50 ml. af chloroform and absorbed on a column of chromato-
graphic grade silica gel. The column is eluted with chloroform, taking 400 ml.
fractions. Fractions 9 to 15 are combined and concentrated to an oil, ~hich
solidifies on trituration with methylene chloride. After further trituration
-44-

with ether; there is obtained 12.63 g. of 6-~triphenylmethylamino)~2,2-dimethyl-
3_ ~ ~4-hydroxybenzyl~car~amoyl~penam, mOp. 166-168C. ~dec.). The infrared
spectrum o~ the product ¢CHC13 solution) shows absorptions at 1785 cm ~
lactam~ and 1675 cm ~amide I~. The NMR spectrum of the produc-t ~CDC13) shows
absorptiOnS at 7.60-6.40 ppm ~multiplet, 20H, aromatic hydrogens and amide
hydrogen~, 4.70-4,10 ppm ~multiplet, S~, C-5 and C-6 hydrogens~ benæyl methyl-
ene hydrogens and C-3 hydrogen), 2.~8 ppm ~douhlet~ lH, amine nitrogen), 1.64
ppm ~singlet, 3}1, C-2 methyl hydrogens~ and 1.31 ppm (singlet, 3H, C-2 methyl
hydrogeas~.
~B) 6-~Triphenylmethylamino)-2~2-dimethyl-3-¢l-~4-hydroxybqnzyl]tetra
5-yl-penam.
To a stirred solution of 1.69 g. ~3 mmole) of 6-(triphenylmethyl-
amino)-2~2-dimethyl-3-¢N-c4-hydroxybenzyl~carbamoyl)penam ~prepared as des-
cribed in A~ in g ml. of chloroform is added 1 ml. (12 mmole) of pyridine.
The solution is cooled to ca. 4C. in an ice-bath and 0.80 ml. of chlorotra-
methylsilane is addedO The solution is stirred for 40 minutes at ambient
temperature~ and then it is again cooled to ca 4C. Phosgene ~1.5 mlO of a
403M solution in chloroform ~6.45 mmole) is added and the cooling bath is
removed Stirring is continued for a further 105 hou-rs, and then all the
vOlatile components are removed ~y evaporation in vacuo.
The o;ly residue is redissolved in 6 ml. of chloroform and the solu-
~ion is cooled tQ ca. 4C. in an ice-bath. To the stirred solution is added
0.35 g. ~5 mmole~ of tetramethylguanidinium azide, and then stirring is co~-
tinued for a further 1 hour at ambient temperature. At this point, 25 ml~ of
water is added, followed by sufficient 1 N sodium hydroxide to ~ring the p~ of
-45-

~L06~ 37
the aqueous phase to lOo The chloroform layer is separated off, washed with
water, dried using sodium sulfate, and evaporated to dryness in vacuo. The
oily residue ¢2.3 g.) is dissolved in a small volume of chloroform and absorbed
on a column of 30 g. of chromatographic silica gelO The column is eluted with
chloroform, taking 50-ml. fractions. Fractions 13 to lQ are combined and con-
centrated in vacuo to give 0.71 gO of 6-(triphenylmethylamino)-2,2-dimethyl-3-
(1-~4-hydroxybenzyl]tetrazol-S-yl)penamO The infrared spectrum of the product
Cin CHC13) shows an absorption at 1780 cm 1 ~lactam). The NMR spectrum
(CDC13) shows absorption at 7.80-6.67 ppm (multiplet, 20H, aromatic hydrogens
and phenolic hydrogen), 5066-5.10 ppm (quartet, 2H, benzyl methylene hydrogens),
5~02 ppm ~singlet, lH, C-3 hydrogen), 4060-4020 ppm (multiplet, 2Hg C-5 and C-6
hydrogen), 3.10 ppm ~doublet, lH, amine hydrogen), 1.44 ppm (singlet, 3H, C-2
methyl hydrogens)and 0071 ppm ~singlet, 3H, C-2 methyl hydrogens)~
-46-

~06~887
PREPARATIOM
6-~Triphenylmethylamino~-2~2-dimethyl~3-¢l-L4-acetoxybenzyl]~
i tetra~ol~5-vl)~enam
To a stirred solution of 1.69 g. ~3 mmole~ of 6-~triphenylmethyl-
amino~-2,2-d;methyl-3-~N-~4-hydroxy~enzyl~carbamoyl)penam in 9 ml. of chloro-
form is added 1 ml. ~12 mm~le) of pyr.idine. The solution is cooled to ca.
4C. in an ice-bath and 235 mg. of acetyl chloride is added slowly. The
solution is stirred for 2 hours at ambient temparature, and then it is again
cooled to ca. 4C. Phosgene ¢l.S ml. of a 4,3M solution in chloroform
~6.45 mmole~ is added and the cooling bath is removed. Stirring is continued
for a further 105 hours, and then all the volatile components are removed by
evaporation ln vacuo. The residue is redissolved in 6 ml. of chloroform and
the solution is cooled to ca. 4C. in an ice-bath. To the stirred solution
is added 0~5 g. ~6 mmole~ of tetramethylguanidinium azide, and th~n stirring
is continued for a further 1 hour at am~ient temperature. At this point, 25
ml. of water is added, followed ~y su~ficient lN sodium hydroxide to bring the
pH of ~h~ aqueous phase to 10. The chloroform layer is separated off, washed
with water, dried using sodium sulfate, and evaporated to dryness in vacuo,
This aEfords crude 6-~triphenylmethylamino)-2,2-dimethyl-3-~ 4-acetoxybenzyl]-
tetrazol-5-Yl~penam~ which is pur;fied further by chromatography.
When the above procedure is repeated, except that the acetyl chloride
is replaced by an equimolar amount of formic-acetic anhydride and chloromethyl
methyl etherg respectively, the product is 6-CtriphenylmQthylamino)-2,2-dimethyl-
~ -formyloxybenzyl]tetrazol-5-yl)penam and 6-~triphenylmethylamino)-2,2-
dimethyl-3-~ 4-~methoxymeth;oxy~enzyl]tetrazol-5-yl)penam~ respectively,
~47-

~l06V8~37
PREPARATION I
6-Amino-2,2-dimethyl-3-¢1-~4-methoxybenzyl]tetrazol-s-
To a st;rred slurry of 143 g. of 6-Ctriphenylmethylamino~-2,2-di_
S methyl-3~ 4-methoxybenzyl~tetrazol-5-yl)penam in 1,000 ml. of dry acetone
is added 45.~ g. of ~-toluenesulfonic acid mcnohydrate, at ambient tempera-
ture. The solids slowly dissolve, giving a clear solution. After about 15
minutes, the product starts to precipitate. Stirring is continued for a
furt~er 45 minutes after the product starts to appear, and then a first crop
of product is filtered off and washed with chloroform. The acetone i6 evapo-
rated to dryness, and the solid residue is slurried for 45 minutes in 300 ml.
of chloroform. This affords a second crop of product. The t~o crops are com-
bined, slurried for 1 hour in 1~000 ml. of chloroform, filtered off, and dried
in vacuo giving 123 g~ of 6-amino-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-
5-yl~penam ~-toluenesulfonate, m,p. 174-175.5C. The infrared spectrum ~KBr
disc) of the product shows an a~sorption band at 1795 cm 1 The NMR spectrum
~in DMS0-d6~ shoNs absorption bands at 7~20 ppm (multiplet, aromatic hydrogens),
5.8~ ppm ~multiplet, benzyl hydrogens, C-5 hydrogen and C-3 hydrogens)~ 5.20
ppm ~doublet, C-6 hydrogen~ 3.75 ppm ¢s;nglet, methoxy hydrogens, 2.35 ppm
2Q ~singlet, sulfonate methyl hydrogens), 1 70 ppm (singlet, C-2 methyl hydrogens)
and 0.85 ppm ~singlet, C-2 methyl hydrogens).
-48-

~LC3t60887
PREPARATION J
Reaction of the appropriate 6-¢~riphenylmethylamino)-2,2-dimethyl-3-
(l-substituted tetrazol-5-yl~penam with p-toluenesulfonic acid monohydrate, sub-
stantially according to the procedure of Preparation I provides the following com-
S p~unds as their p-toluenesulfonate salts:
Yield
~-amino-2,2-dimethyl-3~ 4- 79
henzyloxyhenzyl3tetrazol~5-yl)-
penam
6-amino-2~2-dimethyl-3-~l-fur- 62
furyltetraæol-5-yl)penam
6-amino-2,2-dimethyl-3-(1_[5_ 54
- met~ylfurfuryl~tetrazol-5-yl)-
penam
6-amino-2~2-dimethyl-3-cl-~2p4- ~9
dimethoxy~enzyl~tetrazol-5-yl~penam
To a stirred solution of 304 mgO of 6-amino_~,2-dimethyl-3~ [4-
benzyloxybenzyl~tetrazol-5-yl~penam ~-toluenesulfonate in 10 ml. of methylene
chloride is added 6g.7 ~1 of triethylamine. After 3 minutes, 5 ml. of water
are added and the mixture is stirred vigorously~ The organic phase is then
removed~ diluted with ether, dried using anhydrous magnesium sulfate, and eva-
porated to dryness ln vacuo. The residue is 18g mg. ~86% yield) of 6 amino-2,-
2-d;methyl-3~ 4-benzyloxYbenzyl]tetrazol-5-yl)penam free base.
In like manner the products of Preparations F-H and S-U are detrityl-
ated to the corresponding 6-amino derivatives.
-4g-

-
1~6~387
PREPARATION ~
6-Amino-2g2-dimethyl-3~5-tetrazolyl)penam
___
A stirred solution of 32.0 g. of 6-amino-2,2-dimethyl-3-~1-[4-
methoxy~enzyl~tetrazol-5-yl~penam p-toluenesulfonate, and 24 mlO of anisole,
in 96 ml. of trifluoroacetic acid is maintained at 40 ~ 1C~ for 35 minutes.
The trif1uoroacetic acid is then removed rapidly by vacuum distillation. A
120-ml. portion of ether is added to the residue, which produces a white floc-
culent suspension. The suspension and solvent is cooled to about 0C., and
to it is then added~ portionwise, 80 ml. of 2N sodium hydroxide, giving two
clear phases. The p~ of the aqueous phase at .this point is about 2.7. The
layers are separated, and the ether phase is discarded~ The pH o~ the aqueous
phase is raised to 4.1 with 2N sodium hydrGxide. This aqueous phase is
then washed uith 100 ml~ of ether and flltered~ It is combined with the cor-
reSponding aqu~ous phasesfrom four other identical experiments, and the total
15 aqueous solution is lyophilized to give crude 6-amino-2,2-dimethyl-3-¢5-
tetraz~lyl~penam. This crude product is slurried in a small amount of water
and filtered off. It is ther re-suspended in water and brcught into solution
by raising the p~ to 7.4 by the addition of sodium hydroxide solution. The
clear solution is extracted with ether and the extracts are discarded. ~he
pH of the aqueous phase ;s adjusted to 4.1 using dilute hydrochloric acid,
and the product which precipitates is filtered off. The infrared spectrum of
the product shows an absorption at 1795 cm . Its NMR spectrum ~in DMSO-d6)
shows absorptions at 5.65 ppm ¢doublet C-5 hydrogen), 5.20 ppm (singlet, C-3
hydrogen~ 4.7Q ppm ~doublet, C-6 hydrogen~, 1.65 ppm ~singlet, C-2 methyl
hydrogens~ and 1.10 ppm ¢singlet, C-2 methyl hydrogens).
~ hen each of the 6-amino~2,2-dimethyl~3-~1-substituted tetrazol-5-yl)
penam p-toluenesulfonate salts of Preparation J is treated with trifluoro-
-
acetic acid/anisole, according to the above procedure, the product in each case
is 6-amino-2~2-diulethyl-3-¢5-tetrazolyl)penam.
-50-

~6C)~137
PREPARATION L
To a stirred solution of 1.69 g. (3 mmole) of 6-~triphenylmethyl-
amino)-2,2-dimet~yl-3-~N-~4-hydroxybenzyl~penam prepared as described in CPre-
S paration G~ in 9 ml. of chloroform is added 1 ml. ~12 mmole) of pyridine.
The solution is cocled to caO 4C. in an ice-bath and 0.80 ml. of chlorotri-
methylsilane is added. The solution is stirred for 40 minutes at ambient
temperature~ and then it is again cooled to ca. 4Co Phosgene (loS ml. of a
4.3 M solution in chloroform 6.45 mmole~ is added and the cooling bath is
removed. Stirring is continued for a further l~S hours, and then all the
volatile c~mponents are rëmoved by evaporation ln vacuo. The oily residue
is redissolued in 6 ml. of chloroform and the solution is cooled to ca. 4C.
in an ice-hath~ To the stirred solution is added 0.95 gO (6 mmole) of tetra-
methylguanidinium azide, and then stirring is continued for a further 1 hour at
ambient temperature. At this point, 25 ml. of water is added, followed by suffi-
cient LN sodium hydroxide to bring the pH of the aqueous phase to 10. The
hloroform layer is removed~ washed with water, dried using sodium sulfate,
and evaporated to dryness in vacuoO This affords crude 6-~triphenylmethylamino)^
2,2- dimethyl-3~ trimethylsilyloxybenzyl]tetrazol-5-yl)penam~ which is
purified by chromatography on silica gel using chloroform as eluant.
To a stirred solution of 200 mg. of the purified trimethylsilyloxy-
benZYl derivative, in 4 ml. of tetrahydrofuran, is added 0.3 ml. of loO N sodium
hydroxide- The solution is stirred at ambient temperature for 50 minutes, and
then the pH is adjusted to 5.7 using 5% hydrochloric acid. The solvent is
removed by evaporation in vacuo to yield crude 6-(triphenylmethylamino)~2,2-
dimethyl-3-~$-tetrazolyl~penam

08~37
PREPARATION ~
6-~Triphenylmethylamino~-2,2-dimethyl-3~ ethoxycarbonyl]-
te-trazol-5-vl~enam
~~~ ~
~A~ 6-~Triphenylmethylamino~--2,2-dimethyl-3-(N ethoxycarbonyl-
S car~amoyl)penam
To a stirred solution of 4D58 gO (10 mmole) 6-~triphenylmethyl-
amino~penicillanic acid and 1.45 ml. (la mmole~ of triethylamine, in 75 ml. of
acetonitrile~ is added l.lS g. ¢10 mmole) of ethoxycarbonyl isocyanate c}i~-
solved in 5 ml. of acetonitrileO The resulting solution is stirred at ca. 25C.
for 16 hours, and then the solvent is removed by evaporation in vacuo. The
residue is re-dissolved in chloroform~ and the chloroform solution is washed
successively with water, sodium bicarbonate solution and sodium chloride sol
ution. The chloroform solution is then dried using anhydrous magnesium sulfate
and evaporated in vacuo. The residue is again re-dissolved in chloroform, and
the chloroform solution is washed with dilute hydrochloric acid, dried using
magnesium sulfate, and again evaporated in vacuo. This affords the crude
product, which is purified ~y chromatography using silica gel as the adsorb-
ant and eluting the column with chloroform containing 4% by volume of ethanolO
The final yield of 6-¢triphenylmethylamino)-2,2-dimethyl-3-~N-[ethoxycarbonyl_
carbamoyl~penam is 2~54 g. ~48% yield).
~B~ 6-~Triphenylmethylamino)-2,2-dimethyl-3~ ethoxycarbonyl]-
tetrazol-5-yl)penam
To a stirred solution of 529 mg. ¢1 mmole) of 6-(triphenylmethyl-
amino~-2~2-dimethyl-3-¢N-~ethoxycarbonyl]carbamoyl)penam and 240 mg. (3 mmole)
of pyridine, in 25 ml. of methylene chloride~ is added 208 mgO ~1 mmole) of
phosphorous pentachloride, at ~C. The reaction mix-
-52-

~6~8~7
ture is stirred at 0C. for O.S hour and then at ca. 25C. for 2 hours. The
solvents and the excess pyridine are then removed by evaporation in vacuo, and
the residue is re-dissolved in 1~ ~1. of chloroform, The latter chloroform
solution is cooled to 0C., and 0.47 g. (3 mmole) of tetramethylguanidinium
azide is added in several small portions with stirring. Stirring is continued
for 2 hours at ambient temperature, and then to the reaction mixture is added
a further 15 ml. of chloroform followed by 30 ml. of water. The pH is adjusted
to 6.5, and then the chloroform layer is removed. The chloroform solution is
washed with water followed by brine, and then it is dr;ed using anhydrous
sodium sulfate. Removal of the solvent by evaporation in vacuo affords crude
6-(triphenylmethylaminol-2,2-dimethyl-3~ [ethoxycarbonyl]tetrazol-5-yl)penam.
The crude product is purified further by chromatography using silica gel.
-53-

- \
~L06~887
PREPARATION N
5tarting with 6-~tr;phenylmethylamino)penicillanic acid and the appro-
pria~e isocyanate, and follo~ing the procedure of Preparation M, the following
compounds are prepared:
~C6~5~3-C~ C~3
O C "' ~N
N _
R ~
R2
C6~5CH20-C-
C6H50-CO-
¢4 N2 C6H4)
~3,4-C12-C6~3)0-Co_
C~3-S02-
C6H5CH2-S02-
C H -S02-
~3-CH30 C6 4) 2
~2~4-[N02]2-C6H3) S02
-54~

~L06~ 37
PREPARATION O
6-~Triphenylmethylamino)-2~2-dimeth
~ enam
To a stirred mixture of 2 ml, o tetrahydrofuran and ~ ml. of water
is added lSO mg9 of 6-~triphenylmethylamino)-292-dimethyl-3-(l-[ethoxycarbonyl]
tetrazol-5-yl~Penam~ The pH of the mixture is adjusted to 9~5, and stirring is
continued at *hat p~ for a further 30 minutes, at ambient temperature. The
~ulk of the tetrahydrofuran is removed by evaporation in vacuo, and the residue
is partitioned between water and ethyl acetate at p~ 9. The ethyl acetate is
removed and discarded. Fresh ethyl acetate is added and the p~ is adjusted to
2Ø The ethyl acetate layer is removed, washed with water, d~ied USiDg
anhydrous sodium sulfate, and evaporated ln vacuo to give the crude title
compound
'~hen each of 6-~triphenylmethylamino)-2,2-dimethyl-3~ substituted
tetrazol-5-yl~penan compounds o Preparation N is hydrolyzed using the above pro-
cedure, the product in sach case is also 6-~triphenylmethylamino)-2,2-dimethyl-
3_~5-tetrazolylipenam.
-55-

~60~}87
.
PR~PARATION P
To a slurry of dry acetone ~S ml.) and 6-triphenylm@thylamino-2,2_
dimethyl-3-~5-tetrazolyllpenam ~483 mg., 1 0 mmole) at room temperature is
S added ~-toluenesulfonic acid monohydrate (209 mg., 1.1 mmole) The resulting
solution is stirred for 10 minutes and then ether ¢30 ml.) is added over a five
minute period. The m;xture is stirred for ten minutes after which the solvent
is decanted from the solid which separates. The solid is dissolved in tetra-
hydrofuran ~30 ml.) and placed on a column ~300 x 6 mm.) packed with 10 g. of
Florisil ~synthetic magnesium silicate~. The column is washed with tetrahydro-
furan until a total of 125 mlO is collected. The eluate is concentrated to dry-
ness under reduced pressure at 40C. to give 210 mg. of solid. The solid is
slurried in ether ~30 ml.), filtered, washed with ether and air-driedO ~ield
= 121 mg. ~50%). The NMR spectrum ~in DMSO-d61 shows absorption bands at 1.08
ppm, ~2s, 3H each, C-2 methyls], 4.60 ~ 5.52 (2d, J=4.0 Hz, 2H, H5 ~ H6), 5.10
¢s, lH, H3~ and 5.88 ~s, 3~, NH3)ppm. ¢s, 3H), 105~ppm ¢s, 3H)~ 4.60 ppm (d, lH),
5.52 ppm ~d,lH~ 5.10ppm ~s,lH), and 5.88 ppm (s,3~).
-56-

1~;08
~,
~D ~ l]tet
To a stirred solution of 554 mg. of 6-~triphenylmethylamino)-2,2-
dimethyl-3-~ ethoxycarbonyl~tetrazol-5-yl~penam in 2 ml. of acetone i6 added
a solution of 190 mg. of ~toluenesulfonic acid monohydrate in 1 ml. of acetone.
Stirring is continued for a further 3 hours, and then the acetone is removed by
evaporation in vacuo. The residue is slurried in ether, filtered and dried, to
give tne title compound as its p-toluenesulfon~te salt.
The a~ove ~toluenesulfonate salt is added to a mixture of lS ml. of
Nater and 15 ml. of chloroform. The p~ of the aqueous phase is adjusted to 7.0
and the chloroform layer is removed. The chloroform is dried using sodium sul-
fate, and then it is evaporated in vacuo to give the tîtle compound as its free
base,
-57-

61)88~7
PREPARA~ION R
Reactlon of the appropriate 6-ctrlphenylmethylamino)-2~2-dimethyl-3
~l-su~stituted tetrazol-5-yl~penam chosen from those in Preparation N with p-
toluenesulfonic acid, according to the procedure of Preparation Q provides the
following compounds as their ~-toluenesulfonate sal-ts.
. ~ 3
~N
11
2 ~
C6 5 2 CO
C6~50-CO-
~4 N2 6 4~ CO
~3,4-Cl2-c6~3~Q-Co
C113-S02-
C6~5C~2-S02
c6~5_so2_
~3 CH3-C6H4)-S2 ~
~2~4-~N02]2~C6~3)-S02
-58-

1C~6()887
\
PREPARATION S
6-~Triphenylmethylamino)-2~2-d;methyl-3~ 2-meth
carbon~lethvl]tetrazole-5-vl~enam
A. 6-~Triphenylmethylamino~-2~2-dimethyl-3-¢N-[2-methoxycarbonylethyl]
carbamoyl~penam
To a stirred solution of 35 g. of 6-~triphenylmethylamino)penicill-
anic acid in 250 ml. of dry~ ethanol-free chloroform, is added 11.7 ml. of
triet~ylamine at 0-3C. The solution t~us obtained is then added dropwise,
with stirring, at 0-6C., to a second solution, prepared from 7.3 mlO of cthyl
chloroformate in 155 ml. of dry? ethanol-free chloroformO Stirring is con-
tinued for a further 10 minutes. This affords a chloroform solution of the
mixed anhydride of 6-~triphenylmethylamino)penicillanic acidO
In a separate flask, a solution of ~ aniline methyl ester is prepared
~y adding 11.7 ml. of triethylamine to a slurry of 10073 g. of ~-aniline methyl
ester hydrochloride and 2 g. of anhydrous sodium sulfate in 115 ml. of dry
ethanol-free chloroform, at ca. 10C, Stirring is continued for a further 10
minutes.
The latter amino-ester solution is then added dropwise, with stirring
at 3-6C., to the above-described mixed anhydride solution. After the end of
the addition, stirring is continued for a further 2 hours.
At this point, ths roaction solution is washed successively with
three portions of water and one portion of brine. The solution is then dried
using anhydrous sodium sulfate, and evaporated in vacuo to give 40.1 g. of
crude 6-ctriphenylmethylamino~-2~2-dimethyl-3-~N-[2-methoxycarbonylethyl]car
25 ~amoyl2penam as a glassy solid, m.p. 60-70C. Thq crude product is purified
by extraoting it into refluxing ether, treating the filtered solution with
-59-

- - -
37
activated car~on, and then re-precipitating the product by t~e addition of
petroleum ether.
B. 6-¢Triphenylmethylamino)-2,2-dimethyl-3-(1-C2-methoxycarbonylethyl]-
tetra~ol-5-yl)penam
To a stirred solution of 2 g. of the amide described under A above,
in 5 ml. of dry, ethanol-free chloroform, is added, at ca. 0C., 1.36 ml. of
pyridine, followed ~y a solution of 620 mg. of phosgene in 4 ml. of dry, ethanol-
free-chloroform. The solution is stirred for 2 5 hours~ at ambient temperature,
and then th9 solvent is removed by evaporation in vacuo. Tha resid~e is re-dis-
1~ solved in ~ ml. of dry, ethanol-free chloroform, and 580 mg. of tetramethylguani
dinium azide is added. The reaction mixture is stirred for 45 minutes, at which
point a further 200 mg~ of tetramethylguanidinium azide i~ added, The reaction
mixture is then stirred 18 hours to complete the conversion to tetrazole. To
the reaction solution is then added saturated sodium bicarbonate so~ution, in
sufficient quantity that the pH of the aqueous phase is 7.6. The chloroform
layer is removed, washed with uater at pH 5, washed with water at pH 7, dried
using anhydrous sodium sulfate, and finally evaporated in vacuo. This affords
2.19 g. of crude product, which is recrystallized from methanol giving 1.11 g
~48% yield~ of product with m.p. 100-105~C. The NMR spectr~m (CDC13) shows
20 absorptions at 7.40 ppm ~m, 15H), 5.15 ppm ~s, 1~)~ 3,80 (m, 4H~, 3.70 ppm
(s, 3H~, 3.1~ ppm ¢t, 2H~, 1.7~ ppm ~s, 3H) and 1.17 ppm (s, 3H), and further
indicates that the product contains methanol of solvation.
-6a_

~136~8~
~RPARATION T
Tha procedure of Preparat;on S is repeated except that the ~-alanin
methyl ester is replaced by the appropriate amine to produce the following
compounds
(C6H5)3 C NH ~ ~ 3CH3
~ N ~ ~ N
O C\
N N
R6-CH2CH2
CN
CC=O)-O-CH~CH3~3
C ¢=O) -O-C6H5
So2_CH3
So2-C6H5
So2-NccH3)2
SO2-N~c6H5?2
S2 -NH-CH2 -C6H5

~L~60~3~37
PREPARATION U
-~Tri henYlmethvlamino)- ~
To a stirred solution of 600 mg. of 6-¢triphenylmethylamino)-2,2-
dimethyl-3-~1-[2-methoxycarhonylethyl]tetrazol ~-5~yl)penam ~containing ca 4.5% of
methanol) in 1 ml. of chloroform, i5 added a solution o 375.2 mg. of diazabi-
cyclo~4.3.0]non-5-ene in O.S ml. of chloroform. Stirring is continued for a
further 3 hours, and then the solution is diluted with a further 2 ml. o$
chloroform. The latter solution is washed quickly with 5 ml. of 2N hydrochloric
acid, and then 8 further 5 ml. of 2N hydrochloric are added. The resulting mix-
ture is cooled to ca 0C., and the solid which precipitates is filtered off,
giving 323 mg. ~71% yield) of the title compound. The NMR spectrum (DMSO-d6) of
the product shows absorptions at 7.40 ppm~m, lSH), 5030 ppm (s, lH), 4.60 ppm
~m, 2H), 1.58 ppm ~s, 3H) and 0.78 ppm ¢s, 3H).
Reaction of each of the 6-~triphenylmethylamino)-2,2-dimethyl-3-(1-
lS substituted te~razol-5-yl~penam compounds of Preparation S with diazobicyclo(4f3.0-
non-S-ene, according to the above procedure, produces in each case, 6-(triphenyl-
methyl amino~-2~2-dimethyl-3-(tetrazol-5-yl)penam.
-62-

PREPARATION V
6-Amino-2,2-d;methyl-3-~2~Cpivaloylo~ymethyl]tetrazol-5-yl)-
~enam
___
To a stirred solution of 0.932 g. C7.21 mmole~ of quinoline in 8.0
ml. of chloroform is added 0.840 g. (r4 ~ 05 mmole~ of phosphorous pentachloride,
The suspension is cooled to 15C., and then 1~81 g. ¢3.84 mmole) of 6-¢2-
phenylacetamido)-2~2-dimethyl-3-¢2-cpivaloyloxymethyl~tetrazol-5-yl)penam is
added. Stirring is continued for a further 30 minutes, at ca -5C., and then
2.15 g. ~35.7 mmole) of n-propanol is added. Stirring is continued for a
further 30 minutes, again at ca -5C., and then 25 ml~ of 9O:10 isopropyl
ether-acetone is added~ followed immediately by a solution of 1.35 g. of sodi-
um chloride in 6.02 ml. of water. The temperature rises to 15C. and then it
;s lowered again to -15C. The precipitate which has formed is filtered off
and dried, giving 1.33 g. ¢88% yield~ of 6-amino-2~2-dimethyl-3-c2-[pivaL
oxymethyl~tetra7ol-~-yi)penam hydrochloride. The infrared spectrum ¢KBr
disc) shows absorptions at 1785 cm C~-lactam) and 1750 cm ~ester). The
NMR spectrum ~DMSO-d6) shows absorptions at 6r70 ppm ¢singlet, 2H, p;valoyloxy
methylene hydrogens), 5.75 ppm ¢douhlet, lH, C-5 hydrogen~ 5.50 ppm ~singlet,
lH3 C-3 hydrogen), 5.70 ppm ~doubletg lHa C-6 hydrogen~g 1.75 ppm ~singlet,
3H, C-2 methyl hydrogens)9 1.20 ppm ¢s;nglet, 9H, t-butyl hydrogens) and
l.lO ppm ~singlet, 3H, C-2 methyl hydrogens).

~(36~87
P~EPARATION ~
The title compound is prepared as its hydrochloride in 90%
yield, from 6-~2-phenylacetamido2-2,2-dimethyl-3-¢1-[pivaloyloxymethyl]-
tetrazol~5-yl)penam, using the method of Preparation V. The infrared
spectrum ¢KBr disc) sbows absorptions at 1780 cm 1 Cp-lactam) and 1740 cm 1
~ester). The NMR spectrum ¢DNSO-d6) shows absorptions at 6.71 ppm ~singlet,
2H, pivaloyloxy methylene hydrogens2, 5.88 ppm ~singlet, lH, C-3 hydrogen),
5 83 ppm ~doublet, lH, C-5 hydrogen), 5.20 ppm ~doublet, lH, C 6 hydrogen)~
1.80 ppm ¢singlet, 3H, C-2 methyl hydrogens), 1.20 ppm ~singlet , 9H, t-butyl
hydrogens~ and 1.16 ppm ~singlet, 3H, C-2 methyl hydrogens).
-64-

PREPARATION X
~!~1~
and
S To a stirred suspension of 2.40 g. of 6-amino-2,2-dimethyl-3-¢5-
tetrazolyl~penam in 15 ml~ of N,N_dim~3thylformamide, is added 2.8 mlO of
triethylamine. Stirring is continued for a further 15 minutes, and then 2068
g. of chloromethyl pivalate is added. The mixture is stirred at ambient
temperature for S hours~ and then it is diluted wi~h 100 ml. of water. It is
then extracted with ethyl acetate. The extract is washed with water, dried
using anhydrous sodium sulfate, and then it is evaporated in vacuo to give a
mixture of the title compounds. The individual isomers are oktained hy chro-
matographic separation of the crude product~
Repitition of this procedure but substituting 3-bromophthalide or the
lS appropriate alkanoyloxyalkyl chloride for pivaloyloxymethyl chloride affords an
isomeric mixture of the corresponding monoalkylated products in which tha
alkanoyloxyalkyl or phthalidyl substituent is located at the 1- or the 2-posi-
tion of the tetra201e ring. The following compounds are thus prepared. ~For
convenience only the alkyl substituent is tabulated):
acetoxymethyl
isobutyryloxymethyl
hexanoyloxymethyl
l-acetoxyethyl
l-pivaloyloxyethyl
l-hexanoyloxyethyl
phthalidyl
propionyloxymethyl

87
P~EPA~ATION Y
To a stirred slurry of 240 mg. of 6-amino-2,2-dimethyl-3-(5-tetra-
z~lyl)penam in 1.5 ml of dry, ethanol-free chloroform, is added 0 36 ml. of
S triethylamine. The mixture is stirred unitl a cloudy solution is obtained,
and then ca. 200 mg. of anhydrous sodium sulfate is addedO Stirring is con-
tinued for a further 15 minutes and than the mixture is filtered. To thefiltrate i8 added 278.5 mg. of triphenylmethyl chloride, and the reaction mix-
ture is stored at am~ient temperature for 4.S hours. At this point, the solventis removed by evaporation in vacuo, leaving the crude title product as a
mixture of isGmers as indicated. The ~rude product is re-dissolved in a small
volume of chloroform and then adsorbed on a small column of silica gel. The
column is eluted with chloroform and the first 20 ml. of eluate are collected
and evaporated to dryness in vacuo. A~small volume of ether is added to the
residue, and the mixture is again evaporated to dryness in vacuo. The latter
residue is washed with ether, to give 357.4 mg. ~77% yield) of a white solid.
The NNR spectrum ~CDC13) shows absorptions at 7.15 ppm ~broad singlet), 5.70
ppm (doublet~, 5.35 ~singlet), 4.55 ~doublet), 1.60 ~singlet) and 1.10 (sin~let).
_66-

~6~8~7
P~EPAR~TION Z
Reaction o~ 6-amino-2p2-dimQthyl-3-~5-tetrazolyl)penam with a substi-
tuted triphenylmethyl chloride as alkylating agent according to the procedure o~
preparation Y affords in each case a mixture of the corresponding 6-amino-2,2-
dimethyl-3-(l-~substituted triphenylmethyl~tetrazol-s-yl)penam and 6-amino 2,2-
dimethyl-3-(2-~SUbstituted triphenylmethyl~tetrazol-5-yl)penam compounds. In
this way, the mixtures of the follo~ing compound and its isomer are produced:
~ R4
N~2 ~ 5 ~ ~3 / C~ ~
O ~ ~ ~N ~ \ R5
N _ ~
R6
R4 _ _ 5 R6
2-F ~ H
3-Cl H H
4-Br . H H
2-C2H5 H H
4-n-C3H7 ~ ~
3-sec-C4Hg H H
4-OC2H5 H H
H 4-C6H5 H
-CH3 3-CH3
H 3-CI 3-Cl
4-Cl H 4-OCH3
4-C6H5 H 4-C6H5
~-CH3 4-CH3 4-CH3
4-i-C3H7 3-OCH3 3-OCH3
The mixtures are separated into the two isomers by chromatography.

387
PREP N A
Nono-Trimethylsilyl Derivative of 6-Amino-2,2-Dimethyl-
To a stirred suspehsion of 2.4 g. of 6-amino-2,2-dimethyl-3-~5-
tetrazolyl~penam in S0 ml~ of chloroform is added 2.8 ml. of triethylamine.
stirring is continued for a further 15 minutes, and then the solution thus
o~tained~ is cooled to 0C. To this solution is then added 1.08 g. of tri-
methylsilYl chloride. Th~ cooling bath is rsmoved, and the reaction mixture
is stirred for a further one hour at ambient temperature, to give a chloroform
sOlution of the mono-trimethylsilyl derivative of 6-amino-2,2-dimethyl-3-~5-
tetrazolyl)penam.
~ an the a~ove procedure is repeated, except that the trimethyl-
silyl chloride used therein is replaced ~y an equimolar a~ount of triethylæilyl
chloride and tri-n-butylsilyl chIoride, respectively, the products are the
mono-triethylsilyl and the mono-tri-n-~utylsilyl derivative of 6-amino-2,2
dimethyl-3-(5-tetrazolyl~penam, respectively,
-68-

~06~ 7
PRE~hRATION EE
Bis-Trialkylsilyl Derivatives of 6-Amino-2~2-dime-thyl-3-~5-
Tetrazolvl~Denam
To a stirred suspension of 2.4 g. of 6-amino-2,2-dimethyl-3-~5-
tetrazolYllpenam in 50 ml. of chloroform is added ~.2 ml. of triethylamine~
stirring is/continued for a further 15 minutes, and the solution thus obtained
is cooled to 0C. To this solution is then added 2.16g. of trimethylsilyl
chloride~ The cooling bath is removed, and the reaction mixture stirred at
- ambient temperature for one hour and then is refluxed for one hour. It is
then cooled to ambient temperature giving a chloroform solution of the bis-
trimethylsilyl derivative of 6-amino-2~2-dimethyl-3-~5-tetrazolyl)penam.
~ hen the above procedure is repeateda except that the.trimethyl-
~ilvl chloride used therein is replaced by an equimolar am3unt of trie~hyl-
silyl chloride and triisopropylsilyl chloride, respectively, thc products are- - 15 the bis-triethyls~lyl and the bis-triisopropyl derivative of 6-amino-2,2-
dimethyl-~-~5-tetrazQlyl)penam, respectively.
-69-

~06~3887
\
PREPARATION CC
a~
A flask containing ~65 mg. of 6-amino-2,2-dimethyl-3-(1-~4-methoxy-
~enzyl~tetrazol-5-yl)penam ~-toluenesulfonate, 40 drops of anisole, and 5 ml.
o trifluoroacetic acid is immersed in a water-~ath maintained at 35-40Co
The progress of the reaction is followed by removing samples at intervals, and
recording their nuclear magnetic resonance spectra. After about 25 minutes3
the removal of the 4 methoxybenzyl group is found to be approximately 90%
completeO At this point the reaction solution is added to a rapidly-stirred,
ice-cold solution o~ lQ ml. of pyridine in 50 ml. of chloroform. 5tirring is
continued for 5 minutes, and then 0.24 ml. of phenylacetyl chlor;de is added.
The cooling bath is removed and the reaction mixture is stirred for a further
2~ minutes. A 100-ml. portion of water is added, and the pH of the a~u~eous
phase is then adjusted to 2.5 by the dropwise addition of 0.5 N hydrochloric
acid. The chloroform layer is separated off, washed with saturated brine,
dried usiDg anhydrous sodiu~ sulfate and then it is evaporated to dryness in
vacu. The crude product thus obtained is re_dissolved in chloroform~ and the
solution is divided into t~o equal portions. To one of these portions is added
an equal volume of water. The layers are stirred vigorously and the p~ of t~e
aqueous phase is raised to 6.9 by the dropwise addition of O.lN sodium hydrox-
ide solution. The chloroform is separated off and discarded, and then an
equal quantity of fresh chloroform is added to the aqueous phaseO The layers
are stirred vigorously and the pH is a~justed to 2.5 using dilute hydrochloric
acid. The chloroform is separated off~ washed with saturated hrineg dried
using anhydrous magnesium sulfate and then evaporated to dryness in vacuo
_70-

~l~6~ 38'7
This affords 197 mg. of an oily resid~e. The residue is re-dissolved in 3 ml.
of chloroform which is then added dropwise to 30 ml. of hexane. The fluffy whitesolid which precipitates is filtered off, giving 80 mg. of 6-(2-phenyl-
acetamido~-2,2-dimethyl-3-~S-tetrazolyl)penam. IRCKBr disc): 17R5, 1660 and
1510 cm . N~R ~DCD13): 7.20 ppm ~s,SH), 5.55 ppm (m, 2H), 5.15 ppm (s, lH),
3,60 ppm ~s, 2Hl, 1.40 ppm ~s, 3H) and l.OS ppm (SJ 3H~,
The MIC of the title compound again~t a strain of ~ ~yo-
y~ is ~0.1 ~g/ml.
-71-

10~0887
PREPARATION DD
6-¢2-Phenox~ tamido~-2,2-dimethyl-3--C5-tetrazolyl)~enam
A stirred slurry of 480 mg. of 6-amino 2,2-dimethyl 3-(5-tetrazolyl)-
penam in 10 ml. of water is cooled to OC., and then the pH is adjusted to 8.0
using lN sodium hydroxide. To this solution is then added 0.25 mlO of phenoxy-
acetyl chloride, in portions, with t4e pH of the solution being maintained
~et~een 7 and 8 duri~g the addition, using 0.1N sodium hydroxide~ The solu-
tion is stirred for a furth~r 30 minutes at 0C. at pH 8. It is then extracted
with chloroform, and the extracts are discarded. The aqueous phase is acid-
ified to p~ 2 with dilute hydrochloric acid, and then it is further extractedwith chloroform. The latter extracts are dried using calcium sulfate and then
evaporated ln vacuo to g;ve the crude product as a gummy solid. This is puri-
fied by dissolving it in 20 ml. of chloroform, and adding the resultant solu-
tion dropwise to 250 ml. of hexane. The precipitate which forms is filtered
Qff, giving 385 mg. of 6-~2-phenoxyacetamido)-2,2-dimethyl-3-~5-tetrazolyl)-
penam as a white amorphous solid. IR spectrum (KBr disc). 1785, 1670 and
1540 cm NMR spectrum ~DMSO-d6~- 7.50-6.70 ppm Cm,5H), 5.70 ppm (m,2H),
5.35 ppm Cs,3H), 4.60 ppm ¢s,2H), 1.60 ppm (s,3H) and 1.05 ppm (s,3H).
The MIC of the title compound against a stra;n of
pyogenes is ~9.1 ~g/ml.
In like manner the 6-amino-2,2-dimethyl-3-~substituted tetrazol-5-yl)
penams of Prqparations I~ J Q, R~ V-Z, AA and BB are acylated with phenoxy-
acetal chloride and phenylacetyl chloride to produce the corresponding acyl
derivatiYes .
-72-

~o60~87
PREPARATION EE
6-~2-Phenylacetamido~-2,2-dim~thyl-3-(1-pivaloyloxymethyl]-
tetrazol-5-yl~penam and 6-~2-Phenylacetamido)-2,2-dimethyl-
~ penam
To a stirred s~spension of 10.0 g. ~0.0264 mole) of 6-~2-phenyl-
acetamido)-2,2-dimethyl-3-~5-tetrazolyl)penam sodium salt, in 105 ml. of
acetone9 is added 2.6 ml. of 25% aq~leous sodium iodide, followed by 4.35 g.
(0.0290 mole~ of chloromethyl pivalate. The mixture is refluxed for 4.5 hours,
and then it is cooled to amhien* temperature. To the mixture is then added
100 ml. of water, and thg resulti~g suspension is extracted with ethyl acetate.
The extracts are dried and evaporated to give 6.3 g. of white foam. The
MIC of this mixture of the title compounds a~ainst Strep. py~ in 0.2
~g/ml.
The whita foam is re-dissolved in a small volyme of 80:20 chloroform-
ethyl acetate and a~sorbed on a column o~ 18Q g. of chromatographic grade
silica gel. The column is then eluted with 80:20 chloroform-ethyl acetate
taking fractions. Each fraction consists o~ 700 drops of solvent. Fractions
55-95 are combined and evaporated in vacuo to give 2~03 g. of 6-C2-phenylacet-
amido~-2,2-dimethyl-3-~2-~pivaloylcxymet~yl]tetrazol-5-yl)penam. IR ~KBr disc)-
1785, 1760, 1670 and 1515 cm . NMR ~DMSO-d6/320): 7.50 (s, 5H), 6.70 ~s, 2H),
6.00-5.60 ~m, 2H~, 3 85 ~s, 2~)~ 1.65 (s, 3H), 1.36 Cs, 9H) and 1.20 ~s? 3H)
ppm. Fractions 100-164 are co~bined and evaporated in vacuo to give 0.80 g. of
6-(2-phenylacetamido)-2,2-dimethyl-3-~ pivaloylo~ymethyl]tetrazol-5-yl)penam.
IR~KBr disc): 1780, 1760, 1670 and 1515 cm . NMR ~DMSO-d6)~D20): 7.50 ~s, 5~)
6.80 ¢s, 2H), 6.50 Cs, 2H), 5~60 ~s, lH), 3.85 ~s, 2H), 1.75 Cs, 3H), 1.36 ~s,
gH~ and 1.34 ~s, 3~) ppm.
73-

1al6~
PREPARATION FF
-
6-c2-phenylacetam~do~-2~2-dimethyl-3~ [2]-[l-acetoxyethyl]
tetra7.ol-S-vl. ~enam
Reaction of 6~ phenylacetamido)-2~2-dimethyl-3-(5-tetrazolyl3penam
S sodium salt with l-aceto~yethyl chlori.de, according to the procedure of Preparation
FF produces the title compound as a mixture of isomers, m.p. 55-70C., yield
28%. IR(KBr disc~: 1780, 1770, 1670 and 1515 cm . NMR (CDC13): 7.20
ts, 6H~, 6.25 ~m, lH3, 5.75-5.40 ¢m, 2H), 5~20 ts, lH), 3060 (s, 2H), 2.00
(m, 6H), 1.45 (s, 3H~ and 0.95 t~s, 3H) ppm.
-74-

-~`
887
~ PREPARATION GG
6-~2-phenylacetamido~-2~2-dimethyl-3-~l-[2]-[3-phthalidyl]
tetrazol-5-vl)~enam
Reaction of 6-~2-phenylacqtamido)-2,2-dimethyl-3-~5-tetrazolyl)penam
sodium salt with 3-bromophthalide, according to the procedure of Preparation GG
produces the title compound as a mixture Q~ isomers~ m~pO 70-85Co, yield
gl%. IR ~KBr disc~: 1785, 1675 and 1500 cm . NMR ¢CDC13): 8.05 - 7.10
~m? ~H~, 6055-6~20 ¢m, 2H), 5.80 ~m, 2H), 5.20 (m, lH), 3060 ¢s, 2H), 1060
~s, 3H) and l~OO ~s, 3H) ppmO
_75-