CA1064019A - Cepham derivatives and preparation thereof - Google Patents

Abstract

Abstract of the Disclosure Certain novel antibacterial 7-acylamin-3-substituted-4-(tetrazol-5-yl)-.DELTA.3-cephem derivatives, and salts thereof, and inter-mediates useful in their preparation.

Description

This invention relates to cepham derivatives.
The co~pounds are antibacterial agents which are of value as animal ~eed supplements~ as therapeutic agents ~or the oontrol of infecti.ous diseases caused by gram-positive and gram-negati~ bacteria, and ~or the sterilization of hosp;tal surfaces and the llke; and to novel intermediates for their pro-duction. More specifically, the antibacterial compounds of the instant inven-tion are acylated~er~at~v~sof 7-amino-3-substituted-a3-cepham compounds which bear a 5-tetrazolyl group at the 4-positionO
In spite of the large number of cepham de~ivatives which ha~e been proposed for use as antibacterial agents, there still exists a need for n~w agsnts.
The antibacterial compounds o~ this in~ention, and the in~ermediates from which they are prapared by acylation, are all novel, and they are com-pletely unantic~pated ;n the pr;or art UOS~ PatO 3,427,302 and 3,468,874 discloae penam deriva~ve= wh~ch incorporats a tetrazolyl ro~p as part of the -~, .

6-acylamino substltuent, and Japanese Pate~t Publication 71-38503 disclose~
cepham der;vatives which incorporate a tetrazoytyl group as part of'-the 7-acyl-amino substituent. Cep'ham deri~atlves ~ith a tetrazolylthiomethyl group at the 3-position are also known r~.s. Pat. NoO 3,641,021~. However, the compounds of the present invention are unique in ha~ing a tetraz;olyl group bonded dlrectly to the cepham nuclcusO
The biological and non-biological uses of tetrazoles has recently been reviewed by ~enson, "Heterocycllc Compounds," Elder~eld, Ed., Vol. 8, ''John Wiley ~ Sons, IncO, New York, N.Yo,'1967, Chapter 19 while a compilation of cepham reference is noted in U.S. Pat. 3,766,176.
It has how been found that certain 7-acylamino-3-substltuted-4-~tetrazolyl-5-yl)-~ -cephams and their salts are useful as antibacterial agents9 while certa m 7-substituted amino-3-substituted-4-carbamoyl- and 4-(tetrazol-5-yl)-~ - and -~2-cephams are valuable mtermediates lead mg to the preparation of these antibiotics.
According to the present invention there is provided a process for the preparation of a cepham derivative of formula:
RNH

~/ ~ CH2A

and the salts thereof; wherein T is a tetra~olyl group which is either ~ ~11 or ~f ~
__~__N ~1 whera m'R'is-s'elected'~rom the group~conslst~ng o~ )'hydrogen,'~2) a nitrogen protecting group which is 2,2,2 ~richloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, benzyloxycarbonyl, or ~ O~

t~ R4 3 ~ ~ ~
i~ ~5

-2-~;4~

wherein R3, R~ and R5 are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, methyl, methoxy and phenyl; and (3) an acyl group of formula:
~ ]n A is selected from the group consis-ting of hydrogen, acetoxy, 1-methyl-5-tetrazolylthio, 2-methyl-1,3,~-t~iad;azolyl-5-.thio and bromo; and R1 ;s selected from -the group consisting of hydrogen,.alkanoyloxymethyl having from three to six carbon a-toms, l-(alkanoyloxy)e-thyl having from~four to seven carbon atoms, methoxymethyl and phthalidyl, and Rll is selected from the group consisting of Rl and is a tetrazolyl cepham nitrogen protecting group or precursor thereof and iY selec-ted from the group consisting of wherein R6 is selected from the group consisti~g of alkyl having from one to:
three carbon atoms and phenyl and R7 is selected from the group consisting of hydroxy, methoxy, alkanoyloxy having two to four carbon atoms and benzyloxy and Ra is selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy~ alkanoyloxy having from two to four carbon atoms, phenyl and benzyloxy and kg ~ ~
wherein Rg and R1o are each selected from the group consisting of hydrogen : and methyl and X ~s selected from the group consisting-of oxygen and sulfur, and Ar is selected from the group consisting of.cyano, bromo~ phenyl, mono- or disubstituted phenyl where each substitu-ent is hydroxy, fluoro, chloro, bromo, amino, methoxy or methyl, phenoxy, phenyl-thio~ pyridylthio, thienyl, 25: 2-methyl-1,3,4-thiadiazol-5 ylthio, 1-tetrazolyl, alkyl having from one to ; ~ twelve carbon atoms~ alkenyl having from two to twelve carbon atoms, cyc~oalkyl ~ .

., .

~6~
having from ~hree -to se.ven carbon a-toms, cyc1oalkerlyl having fro~^~ive to .eight carbon atoms, cycloheptatrienyl, l,~-cyclohexadienyl, l-ami.nocycloalky~ having from four to seven carbon atoms, 5 ;cmethyl-3-pheny.1-4-isoxazolyl, 5-methyl-3-~o-chlorophenyl)-4-isoxaz.olyl, 5-methyl-3-(2,6-dichlorophenyl)-4-isoxazolyl, 5-methyl-3-(2-chloro-6-fluorophenyl)-~-isoxazolyl, 2-alkoxy-1-naphthyl having from one to four carbon atoms in said alkoxy, syndonyl, furyl, pyridyl, thia-zolyl, isothiazol.yl, pyrimidinyl, triazolyl, imidazolyl~ pyrazolyl, substituted phenoxy, substituted phenylthio, substituted pyridylthio, substituted thienyl, substituted furyl, substituted pyridyl, substituted tetrazolyl, substituted thiazolyl, substitu-ted isothiazolyl, substituted pyrimidinyl, subs-tituted tria-zolyl, substituted imidazolyl, and substituted pyrazolyl, each substituted moiety being substituted by up to two members selected from -the group consisting of fluoro, chloro, bromo, hydroxy, hydroxymethyl, ~mino, N,N-dialkylamino having from one to four carbon atoms in each of said alkyl.groups, alkyl hàving frnm ..
one to four carbon atoms, aminomethyl, aminoethyl, alkoxy having from one to four carbon atoms, alkylthio having from one to-four carbon atoms, 2-aminoethoxy and N-alkylamino having from one to four carbon atomsj ~ :
Q ;s selected from the group consisting of hydrogen~ hydroxy, azido amino and carboxy;
n is an integer of Oor) l; provided that when Ar is selected from the group consisting of pyridylthio, phenoxy, phenylthio, 2-methyl-1,3,4-thia-diazol-5-ylthio, bromo and cyano and n is 1, Q is selected from the group con-sisting of hydrogen and carboxy; providing T is N~ R
N~ N N-Rl : 25 when A is bromo, R is not Ar~CH]n~- which process includes in the reac-tion .. .
sequence for the preparation thereof at least one of the following steps.

(1) acylating w;~h an organic acylating agent a compound of the : ~above formula wherein R is hydrogen and T is a tetrazolyl group to give R as ~: !
.~ ...~
~ ~.

;4~
Ar[CH]n~- ;
Q

(2) reactlng a penam of the formula:
RNH ,~S~
~ `~
0 g ~ ~ CH A

o NHR2 wherein R and A are as previously defined and R2 is a tetrazolyl cepham nitro-gen protecting group or precursor~ thereof and is selected from -the group con-sisting of _CH _ ~ R7 wherein R6 is selected from the group consisting of alkyl having from one to three carbon atoms and phenyl and R7 is selected from the group consisting of hydroxy, methoxy, alkanoyloxy having two to four carbon atoms and benzyloxy and R8 is selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy, alkanoyloxy having from t~o to four carbon atoms, phenyl and benzyloxy and wherein R9 and Rlo are each select~d from tho grQup consisting of hydrogen and methyl and X is selected from the group consisting of oxygen and sulfur~ -with a halogenating agent and subsequently with an az;de to form a tetrazolyl group as T,

(3) alkylating a compound of the formula:
RNH S
~f~
G~ ~~CH2A
N ~ ~ H
. -N = N

-5- ..

~69t~

wherein A ;s an hereinbefore defined and whcrein R is hydrogen or amino pro-tecting group, with a halide compound to form Rl other then hydrog~n; or (~ brominating a compound of th~ formula:
RNH ~ S ~

o~r~3\CH3 T' wherein T' is Nl~ N-Rll ' ~
N~ - ~ or N _ ~ Rl and wherein R is hydrogen or an amino protecting group, Rl or Rll -CH2-0-CH3, and to form a compound of Formula I in which A is bromo and, of desired, subsequently removing the methoxymethyl group.
As one skilled in the art can readiay appreciate, the ~-carbon atom of the antibac*erial cepham side chain to which the amino or hydroxy, (Q) moi-ety is attached is an asymmetric carbon atom allowing for the existence of two optically active isomers, the D- and L-diastereoisomers, as well as the race-lS mate, DL, form. In accord with previous findings concerning -the activity of such cephems possessing asymmetric ~-carbom atoms, the compounds of the presen-t invention possessing the D-configuration are more active than those ~f the L--configuration and are the preferred compounds, although the L and DL forms of the instant compounds are also considered within the purview of the present invent;on.
~ urther, it is noteworthy to mention wh;le considering asymmetric centers~ that there are several in the ~3-cephem nucleus, the basic building block from which the compounds of -the present invention are derived. These potent;al additional isomers are not significant ;n this instance since the 7-amino-~ -cepham-4-carboxylic acid employed leading to the products of this invention is that which is produced by fermentation and is consistently of one configurationl ~ -6-. -- , .

.

: . ~ . . .. . ; . - .

In like manner, the term "tetrazole protecting group" or "tetrazolyl cephem nitrogen pro~ecting group" is intended -to connote all groups known, or obvious, to one skilled in ths art, which can be used (a) to permit the synthe-sis of the compounds wherein R is an amino protecting group and R2 is the said tetrazolylcephem nitrogen protecting group, by the process starting with 7- -tprotected amino)cephem-~-carboxylic acid described hereinafterj and (b) can be removed from said compound wherein R is the said tetrazolyl~ephem nitrogen protecting group, wherein R is selected from the group consisting of hydrogen and an amino protecting group, and R is the said tetrazolylcephem nitrogen protecting group, using a method wherein the cephem-ring system rema~ins sub-stantially intact.. It ~s likewise the ability of ths tetrazolylcephem nitrogen protecting group to perform a specific function, to be discussed in more detail hereinafter, rather than its prec;se chemical strùcture, which is important~
and the novelty of the antibacterial agents of the inventi.on does not depend upon the structure of the protecting group. Selection and identification of appropriate protecting groups can be made readily and easily by one skilled in the art, and examples of several applicable groups are given ~ere~nafter . .

-6a-, . . . . . - . - - . ~ . . . . . . . .

This inven~ion rel.ates to certain new and novel compositionæ of matter which are valuaple as antibacterial agen-ts, and as intermediates for preparing said agents. For -the sake of convenience ? these compounds are identified as deriva-tives of ~3-cephem. The -term "~3 cephem" has been defined by Morin et alO in the Journal of the American Chemical Socie-ty, 84, 3400 (1962) as meaning the s~ructure ~ . .

7~- y ~ .

O ~ 3 ~ ~
Using this termdnology, the well-known antibiotic cephalosporin C, is desig-nated as 7-~5-amino-5-càrboxyvaler~ido)-3-ecetoxyme~hyl-~3-cephem-~-carbox~ic lG acid.
Many of the compounds of this invention are also 5-substituted tetra-zoles which can exist in two isomeric formsg viz:

~N w,~ and / ~N

As will be appreciated by one skilled in the~art, when the substi-tuent represented by L is hydrogen, the two forms co-exist in a dynamic tautomeric, equilibrium mixture. However, in the case where L represents a substituent other than hydrogen, the two forms rep~esent different chemical etruc ures which do not spontaneously interoonvert .

~ -7-~ .

`

~6~

In accordance wlth the process employed for synthesizing the cephem intermediates and antibacterial agents of the presen-t invention, two preparative routes are amenable. The firs-~ is illustra-ted as follows:

RN~ ~ ~ RN ~ ~ ~ l O ~ ~ 2 0~ CH2A
02H ~I-NHR2 2 ?~NH ~ ~ ~

l~-R2 , ::

H2N ~ ~

-' ' ' ` -8-t .'', '`' ~

ltglL9 H~N.~

a,~L \~H2A

~ ~ -R

5 ~ Ar [IH lQ~H ~ j .

~CH2A

: 6 wherein R, A, R2, Ar, n and Q are as previously defined by and Rl and R11 are each hydrogen.

~: ' .. , ~: :

- :

. ' ~

~a~

Experimentally, 7-carboxamido-3-substituted-~ cepl~em-L~-carboxylic acids (1), prepared by acylation of the corresponding 7-amino-cephem, are con-ver-ted to the 4-carbamoyl compounds (2) by reacting the 4-carboxy moiety, acti-vated as the 2,4-dinitrophenol ester, with an appropriate amine, R2NH2.
Preparation of compounds 2, wherein R is derived from triphenylmethyl, is achieved ei-ther by alkylation of the 7-amino compound; followed by formation of the 4-carbamoyl group as mentioned above, or by selectively removing the R
acyl group of compounds of s-tructure ~ such as removing the 2~2,2-trihalo-ethoxycarbonyl group using acetic acid and zinc dust, and subsequently alkylat-ing the 7-amino-4-carbamoylcephem compound with the requisite triphenylmethyl chloride.
The reaction o 2 to 3 requires conversion of the 4-carbamoyl moiety of 2 to -the appropriate imino chloride followed~by reaction of this substrate with azide, Formation of the imino chloride is most conveniently carried out lS using phosgene, or phosphorous pentachloride i~ a reaction inert solventlsuch as chloroform, while reac~;onl of the imino chloride wi~h the salt of hydrazoic acid and tetramethylguanidine leads to the formation of the tetrazole ring. As one skilled in the art can readily appreciate, there are many sources of azide which could also ~e employed in this reaction including salts of hydrazoic acid with inorganic bases, such as sodium azide, li}hium azide, potassium azide and ammonium azide. Because of the explosive nature of many metal azides it is advantageous, and in this case preferred, that azides formed from organic bases be employed, tetramethylguan;dine hydrogen azide is particularly suited for this purp~se.
The sequen~ial step for conversion of 3 to 4 requires the removal of the "amino protecting group~" R. The reaction conditions employed to affect this removal are dictated by the nature of the group to be removed. As pre-viously mentioned, the 2,2,2-trihaloethoxycarbonyl moiety is conveniently removed using zinc dust and acetic acid; the triphenylmethyl group is removed `:, - : . . - ~ :, . .

using formic acid; and the benzoxycarbonyl moiety is removed by treating 3 with a mixture of trifluoroacetic acid/anisole (4:1; v/~) and trifluoromethylsulfonic acid. I~ is preferred, in this last mentioned procedure that the reac-tion be conducted at ice-bath temperatures ~0C.) and for a limited period of -time, usually for 4-6 minutes. If higher tempera-tures are employed, such as 25-40C.
temperature, or longer reacti~n times, such as 1-3 hrs. i-t is possible to remove the "tetrazole blocking" group simul-taneously.
Following removal of the "amino protecting" moiety, the R2 variable is removed by treatment of 4 or the p-toluene sulfonic acid salt thereof with the afor~mentioned mixture o trifluoroacetic acid/anisole.
Acylation of 5 with the appropriate carboxylic acid activated either as an acid halide, activated ester, mixed anhydride or the acid with a carbo-diimide provides for the preparation of the antibacterial compounds of the present invent;on.
lS As one skilled in the art can readily appreciate, the presence of other functional groups in the acylating acid may require that said groups be masked to prevent them from undergoing competing reactions. When the acylation is complete the groups can he unmasked.
For example, in preparing compounds of structure 6 wherein Q is amino, it is required that said amino group be blocked, preferably with a tr butoxy carbonyl group, the blocking group being removed by acid treatment after the acylation is complete. A similar practice i5 required wherein Q is hydroxy, in which case a formyl group is employed to mask ths hydroxy group.
Compounds of structure 6 wherein Ar is bromo, n is 1 and Q is.hydro-~5 gen, in addition to having antibacterial activity can be reacted with mercap-tans leading to still additional antibacterial,compounds.
The starting materials for the sequence of reactions are aithér readily available as commercial reagents or can be prepared by literature pro-ce~ures. For example~ tpe 7-amino-3-substituted-~ -cephem-~-carboxylic acids ~:

,- ., ~
. .
.~ , ~ . - . . . . .

~L~6i4~

.are reported in U.S. Patent 3,641,021; -the amines R2NH2 are conveniently pre-pared by one or more procedures as taugh-t by Wagner arld Zook, "Synthetic Organic Chemistry," John Wiley and Sons, Inc., New York, ~;.Y. 1956, Chapt~r 21~, p. 653-727; while the triphenylme-thyl chlorides ernployed are prepared by the procedure as taught by Bachmann, Org. Systhesis, '~ 100 (1943).

.

.

- ~ "

The second procedure suitable for the synthesis o:F the antibactericll compounds of the present invention and th~ intermediates in the preparation there of is illustra-ted as follows:
RNH ~ H3 ~ ~ - CH3 O ~ ~ CH3 0~ NHR2 . 8 N~ /-R2 N=~

_ _,~S

~ CH3 N H

. ~N
:

:: :

; -~.3-. ` ~

RNH ,S
~ .. ~ ~H3 =N N_N~R
1, N_ -R

2 ~ S\

r ~ ...

N N_N~

~ , .

: -14 -Ar[CH] -~CONH S~

N
N~ R~ NR
'

4, Ar[CH]nCONH~\

` 0~ ~CH2A

A` [ IH~ CON~`~H2A

,~ Al~[e~l] NH f~ ~ 1 H

6 , ~ ~ -15-., , ;~
~ ~ ' ` ' .

~ , . . ~ : . ., . ~, .

4~9 wherein R, A, R2, ~r, n ancl Q are as previo-lsly indicated and Rl is methoxy-methyl.
In practice, the 7-acylamino-3-methyl-~ -cephem-~-carboxylic acid 1 is isomerized to the corresponding 7-acylamino-3-methyl-~2-cephem~ carboxyLic acid 7, allowing for -the activation of the 3-methyl in subsequen-t reactions.
Preparation of the 4-carbamoyl group in compounds of structure 8 is carried out by procedures slmilar to those in the first synthetic sequence previously discussed.
Further, in a manner analogous to the firs-t sequence, compoun,ds ~ are transformed into tetrazoles of structure ~ by the same procedures inuolving formation of the imino chloride and its' subsequent in-teraction with azide.
Removal of the "tetrazole protecting" group of compounds 9 leading to lO is affected in the manner previously discussed in the first synthetic route and comprises contacting 9 with trifluoroacetic acid/anisole at 30-50C. for several hours.
Prior.to bromination of the activatad 3-methyl substituent the tetrazole of lO ls blocked by alkylation with chloromethyl methy,l ether. As one skilled in the art will appreciate, alky}ation can, and does, take place a-t both the N
and N2 position3 with alkylat;on predominatir,lg at N2. Since the blocking group is removed in a later s-tep of the sequence it is practical that the two isomers not be separated subsequent to the alkylation. Further, both isomers serve the same purpose and are equally useful in this regard. ' -~
The 3-methyl substituent of ll is brorninated with N-bromosuccinimide in the presence of a peroxide3 a well known type of bromination procedure.
Following the completion of the bromination, the 3~bromomethyl compound is not isolated but allowed to react with a particular nucleoph~lic reagent such as a mercaptan or an ace-tate sal-t giving 12.
Removal of the "amino protecting" group of 12 is carried out by methods previousIy discussed in the first synthetic sequence.

: ~ .

~ -16-~ `'' : ' .

~;4~

Similarly, acylation of 13 is a:Ffected using the aEorementioned procedures, with the same consideration being given to -the protec-tion or "masking" of any flmctional group on the acyla-ting acid which may compete in the acylation reaction with the 7-amino group of the ~2-cephem (13).
Reisomerization of the ~ bond of 1~ to the ~ position is achieved by oxidation of -the sulfur atom of the cephem molec:ule wi-th a per acid such as m-chloroperbenzoic acid giving ~ . Treatmen-t of 15 with stannous chloride and acety1 chloride results in the formation of the desired ~ -cephem of structure 16.
The N~ and N2 blocking groups are removed from 16 using trifluoro-acetic acid/anisole as previously discussed and "masking" groups are removed from the acyl moiety of the 7-acylamino group if they are present.
A modification of the second reaction sequence allows for the prepar-ation of compounds wherein Rl is derived from phthalidyl, or an alkanoyloxy-methyl or l-(alkanoyloxy)ethyl moiety. The procedure leading to the prepar-ation of these compounds utilizes the alkylation of the tetrazole moiety of 10 with an appropriate alkanoyloxymethyl halide or l~alkanoyloxy)ethyl halide (Ulich, et al, J. Am. Chem. Soc., ~3,660 (1921) and Euranto, et al, Acta. Chem., Scand., 20, 1273 (1966) or phthalidyl halide in place of chloromethyl methyl ether. The phthalidyl, alkanoyloxymethyl and l-(alkanoyloxy)ethyl substituted tetrazoles of the final products are pro-drug forms of the final products, and although inactive or of relatively low activity against micro-organisms per se are metabolized to the free tetrazole (Rl=H) when injected parenterally into the animal~ including man. The rate of metabolic conversion of these compounds to the free tetrazole occurs at ~uch a rate as to provide an effective and pro-longed concentration of the free tetrazole in the animal body. In effect, such compounds act as depot sources for the free tetrazole antibac~erial agent.

.

~6~

Regarding the antibacterial activity o~ these pro-dr~lg :Forms, both the N1 and the N2 substitu~ed isomers possess activi-ty and usefulness.
If phthalidyl, alkanoyloxymethy~ or l-(alkanoyloxy)ethyl, Nl/N2 substituted tetra~oles are to be synthesized by the second synthetic route, the reaction step tl6~6) is omit-ted, and only -the masking groups are removed from the acyl po~tio~ of the side chain.
Alternate me-thods exists for the synthesis of those antibacterial products bearing a phthalidyl, alkanoyloxyme-thyl or l-(alkanoyloxy)ethyl group at the Nl/N2 position o the tetrazole moiety. One me-thod embraces alkylation of the base salt of an appropriate 7-amino-3-substituted-'~-(te-trazol-5-yl)-~3-cephem followed by acylation of the 7-amino group as previously discussed. The second method ut;lizes alkylation of the base salt of an appropriate 7-acyl-amino-3-substituted-4-(tetrazol-5-yl)-~3-cephem, both methods`inc1u~irlg the removal of "masking" groups from the side chain, if necessary.
Regarding this second series of reactions leading to the intermediates and inal projduct of the present invention, the preferred "aminoblocking" groups are the 2,2~2-trihaloethoxycarbonyl moieties.
As has been previously noted, a characteristic feature of the acidic compounds of the instant invention, those wherein Rl or Rll are H or Q is carboxy, is their ability to form basic salts. Acid congeners of the present invention are converted to basic salts by the interaction of said acid with an appropriate base in an aqueous or nonaqueous medium. Such basic reagents suit-ably employed in the preparation of said salts can vary in nature, and are meant to contemplate such bases as organic amines, ammonia, alkali metal hydroxides, carbonates, bicar~onates, hydrides and alkoxides, as well as al}cali earth metal hydroxides, hydrides, alkoxides and carbonates. Representative of such bases are ammon;a, primary amines such as n-propylamine, n-buty~amine, aniline~ cyclohexy}amine, benzylamine, _-toluidine, ethylamine, octylamine, secondary amines such as dicyclohexylamine and -tertiary amines such as diethyl-.
~ -18-~'"

~6~ ~9 aniline~ N-methylpyrrolidine, N-methylmorpholine and 1,5-diazabicyclo-[L~,3,0~-L~-nonene; sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide, magnesium hydroxide, calcium hydride and barium hydroxide.
S As one skilled in the art can readily appreciate, some compounds o~
the instant invention are sufficiently basic, by virtue of those final products wherein Q is amino, to form acid addition salts; said salts, especially the pharmaceutically acceptable acid addition salts, are also considered within the scope of this invention.
In addition, those useful intermediates of the present invention which contain a free 7-amino moiety or a free tetrazole (Rl, Rll=H) are also capable of forming acid addition salts and base salts, respectively. These saLts are useful either in the characterization of these!-in-*ePmediates, such as the acidaddition salts, or are utilized in reactions, such as alkylation of the base salt of the tetrazoles.
In utilization of the chemotherapeutic activity o~ those compounds of the present invention which form basic salts, it is preferred, of course, to use pharmaceutically acceptable salts. Although water insolubility, high toxi-city, or lack of crystalline nature may make some sa]t species unsuitable or less desirable for use as such in a given pharmaceutical application, the water insoluble or tox;c salts can be converted to the corresponding acids by decompo-sition of the salts, or alternately they can be converted to any desired pharmaceutically acceptable basic salt. The said pharmaceutically acceptable salts preferred mclude the sodium, aluminum, potassium, calcium, magnesium, ammonium~ and substituted ammonium salts, e.g., procaine, dibenzylamine, N,N-bis(dehydroabietyl)ethylenediamine, l-ephenamine, N-ethylpiperidine, N-benzyl-~-phenethylamine, N,N~-dibenzylethylenediamine, triethylamine, as well as salts with other amines which have been used to form salts wi-th cephems.
: : .
.

.

- - , . , -,: : , . , .: : :

The novel cephems described herein exhibit in vitro activity against a variety of micro-organisms, including both gram-posi-tive and gram-negative bacteria. Their useful activ;ty can readily be demonstrated by in vi-tro -tests against various organisms in a brain-heart in~usion medium by the usual;two-fold serial dilu-tion teclmique. The n vitro ac-tivity of the herein described compounds renders -them useful for -topical applica-tion in -~he form of oin-tments, creams, and the like, or for sterili~ation purposes, e.g., sick:-room utensils.
These novels cephems are also effective antibacterial agents in viuo in animals,including man, not only via the parenteral route of adm;nistration L
but also by the oral route of administration.
Obviously, the physician will ultimately determine the dosage which wilI be ~lost suitable for a particular individual person, and it will vary with the age, weight, and response of the partlcular patient as well as with the nature and extent of the symptoms, the nature of the bacterial in~ection being treated and the pharmacodynamic characteristics of the particular agent tobe administered. It will often be found that when the composition is adminis-tered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a amaller quantity administered parenterally.
- Having full regard for the foregoing factors it is considered that an effective daily oral dose of the compounds of the present invention in humansof approximately 50-1000 mg./kg. per day, with a preferred range of about 250-, ~
750 mg./kg. per day in single or divided doses, and a parenteral dose of 25-500 mg./kg. per day, with a preferred range of about 125-400 mg./kg. per day will effectively alleviate the symptoms of the infect;on. These values are illus-trative, and there may, of course, be individual cases where higher or lower dose ranges are merited.

, , ' ' .
. . .

~ .

9 ,`

The preferred compounds oE the presen-t invention which are useEul as intermediates are 7-(2,2,2-trichloroethoxycarboxamido)-3-methy:l-4-[N-(~-methoxy-benzyl)carbamoyl]-Q3-cephem, 7-tbenzyloxYcarboxami(lo)-3-methy~-4-[N-(~-methoxY-benzyl)carbamoyl]-Q -cephem, 7-(N-triphenylmethylamino)-3-methyl-4-[N-(~-methoxy-benzyl)carbamoyl~-Q -cephem, 7-(2,2,2-trichloroethoxycarboxamido)-3-ace-toxy-methyl-4-~N-(p-methoxybenzyl)carbamoyl~-Q3-cephem, 7-(~enzyloxycarboxamido)-3-acetoxymethyl-4-[N-(p-me-thoxybenzyl)carbamoyl]-Q3-cephem, 7-(N-triphenylmethyl-amino)-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl]-Q3-cephem, 7-(2,2,2-trichloroethoxycarboxamido)-3-methyl-4-[N-(_-methoxybenzyl)carbamoyl]-~2-cephem, ~, ~
10 7-(2,2,2-trichloroethoxycarboxamido)-3-methyl-4-[1-(_-methoxybenzyl)tetrazol-5-yl]-Q -cephem, 7-(N-triphenylamino)-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Q -cephem, 7-amino-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Q3-cephem, 7-(benzyloxycarboxamido)-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl~-3 , , , Q -cephem, 7-(2,2,2-trichloroethoxycarboxamido)-3-acetoxymethyl-4-[1-(--methoxy-15 benzyl)tetrazol-5-yl]-Q -cephem~ 7-amino-3-acetoxymethyl-4-[1-(p-methoxybenzyl)-tetrazol-5-yl]-Q -cephem, 7-(benzyloxycarboxamido)-3-(1-methyltetrazol-S-ylthio-methyl)-4-[1-(p~methoxybenzyl)tetrazol-5-yl]-Q -cephem, 7-(2,2,2-tr.~chloroethoxy-carboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl-4-[1-(_-methoxybenzyl)-tetrazol-5-yl]-Q3-cephem, 7-amino-3-(2-methyl-1,3,4-thiadiazo~-5-yl-thiome-thyl)-2Q 4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Q -cephem, 7-(2~2,2-trichloroethoxycarbox-amido)-3-methyl-4-[1-(p-methoxybenzyl)-te-trazol-5-yl] -a -cephem, 7-(benzyloxy-carboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(~-methoxybenzyl)-tetrazol-5-yl~-a -cephem, 7-amino-3-methyl-4-(tetrazol-5-yl)-~ -cephem, 7-amino-3-acetoxymethyl-4-(tetrazol-5-yl)-Q -cephem, 7-amino-3-(2-methyl-1,3,4-thiadia-25 zol-5-ylthiomethyl)-4-(tetrazol-5-yl)-Q3-cephem, 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-Q3-cephem, 7-(2,2,2-trichloroethoxycarboxamido)-3-methyl-4-ttetrazol-5-yl)-Q2-cephem, 7-(2,2,2-trichloroethoxycarboxamido)-3-me~hyl-4-[1 _ ~methoxymethyl)tetrazol-5-yl]-a2-cephem, 7-(2,2,2--trichloroethoxy-carboxamido)-3-methyl-4-[2-tmethoxymethyl)tetrazol-5-yl]-Q2-cephem, ''' ., .

4~

7-Amino-3-methyl-4-[1-tmethoxymethyl)tetrazol-S-yl]-Q2-cephem, 7-amino 3-methyl-4-[2-(methoxymethyl)tetrazol-5-yl]-~2-cephem, 7-amino-3-acetoxymethyl-~-[l-~methoxyme-thyL)tetrazol-5-yl~-~2-cephem, 7--ami~o-3-acetoxymethyl-4-~1-(methoxymethyl)tetrazol-5-yl]-~2-cephem, 7-amino-3-(1-methyltetrazol-5-ylthio-S methyl)-~-Cl-(methoxymethyl)-tetrazol-5-yl~-Q -cephem, 7-amino-3-(1-methyltet-razol-5-ylthiomethyl)-~-~2-(me-thoxymethyl)tetrazol-5-yl]-~2-cephem, 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthlomethyl)-4-[1-methoxymethy:L)tetrazol-5-yl~-a -cephem, 7-amino-3-~2-methyl-1,3,4-thiadiazol-5--ylthiomethyl)-4-C2-(methoxy-" , . l methyl)tetrazol-5-yl]-~-cephem, 7-(2,2,2--trichloroethoxycarboxamido)-3-bromo-! 2 , , , 10 methyl-4-~1-methoxymethyl)tetrazol-5-yl]-~ -cephem and 7-(2,2,2-trichloroeth~xy-carboxamido)-3-bromomethyl-4-C2-(methoxymethyl)tetrazol-5-yl~-~2-cephem.
The preferred antibacterial agents of the present invention are 7-phenylacetamido-3-methyl-~-(tetrazoi-5-yl)-~3-cephem, 7-phenoxyacetamido-3-msthyl-4-(tetrazol-S-yl)-~3-cephem, 7-(2-thienylacetamido)-3-methyl-4-(tetra-15 zol-5-yl)-~ -cephe~, 7-phenylacetamido-3-methyl-4-[2-(~ivaloyloxymethyl)tetra-zol-5-yl~-~3-cephem~ ~-phenoxyacetamido-3-methyl-4-t2-(pivaloyloxymethyl~tet-razol-5-yl]-~3-cephem and 7-(2-thienyLacetamido)-3-methyl-4-[2-(pivaloyloxy-methyl)tetrazol-5-yl]-~3-cephem.
The antimicrob;al data of a number of compounds of th~ instant ; 20 invention against ~SEY$~m~Ç~ 12Y89I~_ are provided in the following table.
The tests were run under standardized conditions in which nutrisnt broth containing variou~ COnCeDtratiOnS of the test material was seedqd with the particular organism specified, and the min;mum concentration (MIC) at which growth o~ each organism failed to occur was observed and recorded.

~ ~ .
?

.. . .

: ' 'rABL~ I

R'CONH... I._.. ._I'' N~ H

NH
~ ~ .
N . vN
Il~ vitr~o Rl A _ _ _ MIC-Tmc /!nlO) C6H5CH2- H 0.78 6 5 2 H 3.1 ~S~ CH2 H 0,4 i H 6.2 ~N~/
D-C6H5CH- H 1.. 5 OH
D-4-HOC6H4CH- H 1.5 : N 2 C6 5~ H 1.5 : 10 N --~N H 0.78 C~H ~ S f S 2 N- - N 3.12 D~C6H5~.H- S <~
OH
: : CH

CH OCOOH3 1.6 N~ N 0.1

5- CH3 ~ ~ , -22a-~ !~

` . :

The no~eL an~lbdc~ær-lal agents of the present invention ar-e remarkably effeCtlVe ln treat.irlg d number of lnfec-tlons caused by suscept;ble gram-negative and gram-posltive ba~teLla in poul~ry and anlmals ;ncluding man. For such pur-poses, the pure material3 or mixtures thereof with other antibiotics can be employed. They may ~e adminis~ered alone or in combinat;on w;th a pharmaceutical carrier Oll the basis of thH chosen route of adminietration and standard pharmaceutical practice~ For example, they may be adrninistered orally in the form of ~ablets conta;ning such excipients as starch, milk sugar~ certain types of clay, etc., or in capsules alone or ;n admix~ure with the same or equlvalent exc;pients. They may also be administered orally in the form of elixirs or oral suspensions which may contain flavoring or coloring agents, or be injected parenterally, that is, ;ntramuscularly or subcutaneously. For parenteral adm;nistration, they are best used in the form of a sterile aqueous soLution wh;ch may be either aqueous such as water, isotonic saline, isotonic dextrose, Ritlger~s solut;on, or non-aqueous such as fatty oils of vegetable origin (cotton seed, peanut o;l, corn, sesame) and other non-aqueous vehicles which will not interfere with the therapeutic efficiency of -the preparation and are nontoxic in the volume or proportlon used tglycerol, propylene glycol, sorbitol~O Addition-ally, compositions suitable for e~temporaneous preparation of solut;ons prior to adminlstration inay advantageously be made Such compositions may include liquid diluents, for example, propylene glycol, die~hyl carbonate, glycerol, sorbltol, etc.; bufferlng agents, as well as local anesthetics and inor~anic salts to afford desirable pharmacological proper-ties.
The following examples are provided solely for the purpose of fur-ther illustra~lon. Infrared tIR) apec~ra are measured as potassium bromide discs tKBr discs) or as Nujol mulls, and diagnostlc absorption bands are reported in wave numbers tcm 1), Nuclear magnetic resonance spectra tNMR) are measured at 60 ~Hz for solu~ion in deuterochloroform ~C~CL3~, perdeutro d;methyl sulfoxide ~,~ ' ' .

(DMSO~d6) or deuterium o~ide (D20), and pe.-lk posi-tions are expresqed in partsper m~llion ~ppM) downfield frorll tetramethylsilane or sodiurn 2,2--dime-thyl-2-silapentane-5-sulfonate. The folLowing abbreviations for peak shapes are used: s, singlet; d, doublet, t, triplet; q, quartet; m, multiplet.

_~L~_ :

E~AMPLE 1 7-(2',2',2'-Trichloroethoxycarbo~am~do)-3-methyl-4-[N-_ _ p-methoxyben~yl)carbamoylJ-Q -cephem A. 7-(2',2',2'-Trichloroethoxycarboxamido)-3-me-thyl-~3-cephem-4-carboxylic acld To a suspension of 555 g. of 7-amino-3-methyl-~ -cephem-4-carboxylic ac1d in 16.65 1. of 1:2 ace~one/water solution is added 600 g. of sodium bicar-bonate and the mixture allowed to stir at room temperature for 30 min. To the resulting solution is added, over a 45 min. period, 600 g. of 2,2,2-trichloro-ethoxycarbonyl chl.or;de~ and the reaction mixture allowed to stir for an addi-tional 18 hrs. The m;xture is extracted with methylene chloride and the aqueous layer separated and acidified to pH 2 with 5N hydrochloric acid. The acidified aqueous is extracted w;th fresh methylene chloride (3 x 1.5 1. and 2 x 500 ml.) and the comb med organic layers washed successively with 5N hydro-chloric acid (2 x 500 ml,i) and water (3 ~ 500 ml.), and dried over magnesium -~ulfate. The thlck o;l, which remains after the solvent is removed in vacuo, i6 d;ssolved.in 2 1. of diethyl ether and added dropwise to 1.5 1. of petroleum ether. The ;ntermediat~ product slowly crystalli~e~ from solution t70% yie~a~.
NMR ~DMSOd6): ~ - 5.4 (q) lH; Sol (d) lH; 4.85 (s) lH; 3.42 (s) 2H;
2~0 (s) 3H.
IR (KBr disc) y max: 1770 cm 1 (~-lactam carbonyl).
The product i6 stored i.n a dloxane solution for use iD subseque~t rea~ i rs without f~rther purification.

; ' :
:.

B. 7-(2',2',2'-Trichloroethoxycarboxamido~-3-methyl-4-[N-(~-methoxybenzyl)-carbamoyl]-~3-cephem~
A solution containlng 1.84 g. of 2,~-dinitrophenol in 35 ml. of methylene chloride ;s treated with 4 g. of 7-(2~,2~,2'-trichloroethoxycarbox-amido)-3-methyl-A -cephem-4-carboxylic acid in a minimum a~ount of dioxane followed by a solution of 2.1 g. of dicyclohexyl c~rbodiimide in 20 ml. of methylene chloride. After allowing ~he reac~;on mixture to stir for 30 min. at room temperature, the dicyclohexyl urea is filtered, washed with methylene chloride, and the filtrate and washings combined and trea-ted with 1.4 g. of _-methoxybenzylamine in 14 ml. of merhylene chloride.
After 30 min. at room temperature~ the reaction mixture is washed with a saturated sod;um carbonate solution and the organic phase dried over magnesium sulfate. The thick oil, which remains after the solvent is removed under reduced pressure, is triturated wlth petroleum ether. The crystallized product is f;ltered and dried to give 4.0 g, of a pale yellow solid.
NMR (DMSOd6): ~- 8.5 (t) lH; 7.0 (q) 4H; 5.3 (q) and 4.9S (d) 2H;
4.8 (s) 2H; 4.3 (d) 2H; 3.7 (s) 3H; 3.45 (broad) 2H and 2 (s) 3H.
IR tKBr dis~ ~ :1770 crn (~-lactam carbonyl).
EXAMPLE_2`
Start;ng with the appropriate amine and requisite 7-amino-3-methyl-~ -cephem-4-carboxyl1c acid, and utilizing the procedure of Example 1, the follow;ng 7-acylam;no-3-methyl-4-(N-substituted carbamoyl)-~ -cephems are synthes;zed:

~ . ~. .. .. . ... . .. . . . . . . . .

RNH ~

_ N ~ 3 ~CNH-R2 C13CCH20CO- 4-C5H5cH20c6H4cH2 3 (2 4-C6H5CH20-3-FC6H3CH2 SC13CCH20C0- 2 Cl 4 CH30C6H3CH2 C13CCH20CO- 3-Cl-4-HOC6H3CH2-. C13CCH20C0- 3.,4-(CH30)2C6H3CH2-C13CCH20C0- 4-HOC6H4cH(cH3)-C13CCH20CO- 2-Br-4-CH30C6H3cH2~ :.
10C13CCH20C0- 4-CH30C6HI~CH(~)-C13CCH20C0- 2,4-(CH30)2C6H3CH(CH3)-C13CCH20CO- 4-CH30C6H4CH(n-c3H7 ) .. C13CCH20CO_ 4-C2H5C02C6H4CH2 15C13CCH20CO- 3~F-4-CH3C02C6H3CH2-C13CCH20C0- 4 HOC6H4CH(0)- ..

: C13CCH20C0_ 3 I 4 CH30C6H3CH2 C13CCH20C0- 4_(l-c3H7cQ2)c6H4cH2-C13CCH20C0- 3,4 (C6HscH2o)2 6 3 2 20C13CCH2QCQ- 4-CH30C6H4CH(CH3~
C13CCH20CP- 4-CH30C6H4CH(C2H5) C13CCH20Co 3 F 4 CH30C6H3CH2 3CCH20C0_ 3-C1-4-CH30C6H3CH(CH3)-C13CCH20CO- 4-HOC6H4~H2-25:C13CCH20C0- 4-CH3C02C6H4cH2 3CCH20Co 3-F-4-HOC6H3CH2-C13CCH20C0- 3-CH30-4-cH3co2c6H4cH2 .

__ _ C13CCH20CO~ cGH5cH2oc6H3cH(cH3 C13CCH20CO- 3-Cl-4-c6~l5cH20c6H3cH2 C13CCH20CO- 3,4-(C2H5c2 )2C6H3CH2 S C13CCH20CO- 4-(n-C3H7C02 )C6H4CH2-C13CCH20C~- 4_(1_C3H7C02)C6HI~CH(C2H5)-C13CCH20C0- 2-furylmethyl-C13CCH20C0- S-methyl-2-furylmathyl-C13CCH20C0- 2-thlenylmethyl-C13CCH20C0~ 5-me-thyl-2-thienylmethyl-C13CCH20C0- 1-(2-furyl)ethyl-C13CCH20C0- 1-(S-methyl-2-furyl)ethyl-Br3CcH20CO- 4-C6H5CH20C6H4CH2 Br3CCH 20C0 4-C6H5CH20-3-FC6H3CH2 Br3CCH20C0- 2 Cl 4 C 3 C6 3 2 Br3CCH20CO- 3-C1-4-HOC6H3CH2-Br3CCH20C0- 2 Br 4 3 6 3 2 Br3CCH20CO- 2,4-~CH30)2C6H3CH(CH3) Br3CCH20CO- 4-C2H5C02C6H4CH2 Br3CCH20C0- 3-CH3-4 CH3C6H3CH2 Br3CCH20CO- 3-F-4-CH~C02C6H3CH2-Br3CCH2oco_ 3-I-4-CH3-()~ 6H3CH2-Br3CcH2oco- . 4-(1-C3H7C02)C6H4CH2-Br3CCH20CO- . 3'4-(C6H5CH20)2C6H3CH2 Br3CCH20C0- 4-CH30C6H4CH(CH3) Br3CCH20CO_ L~-CH30C6HL~CH(C2H5 ) Br3ccH2oco- 3~4-(CH30)2C6H3cH2- .
Br3CCH20CO- 3-F-4-CH30c6H3cH2-Br3CCH20C0- 3-C1-4-CH30C6H3CH(CH3)-~ ..... _ . _ Br3CCH20CO- L~-HOC6H4CH2-Br3CCH20CO- 4-HOC6H4cH~cH3~-Br3CCH20CO- 3 2 6 4 2 Br3CCH20CO- 3-C1~4-HOC6H3CH2-Br3CCH20CO- 3-C1-4-CH3C02C6H3CH2-Br3CCH20CO- 4-C6H5CH20C6H3CH(CH3) Br3CCH20CO- 3-Cl-4-C6H5CH20C6H3CH2-Br3CCH20CO- 2-F-4~HOC6H3CH2-Br3CCH20CO- 3,4-~C2H$C02 )2C6H3CH2 Br3CCH20CO- 4-~n-C3H7c02 ~C6H4CH2-Br3CCH20CO- 2-furylmethyl-Br3CCH20CO- 5-methyl-2-furylmethyl-Br3CCH20CO- 2-~hlenylmethyl-Br3CCH20CO- 1-~2-furyl)e-thyl-Br3CCH20CO- 1-(5-methyl-2 furyl~ethyl--' ~"' : :: :

::~ :

,~

~, ~:XA~PLE 3 7-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-[1 p-methoxybenzyltetrazol-5-y.r',~3-cephem _ To a suspension of 100 g. of 7-t2',2'!,2'-trichloroethoxycarboxamido)-S 3-me~hyl-l~-CN-t~-methoxybenzyl)carbamoyl]-~3-cephem in 2 1. of chloroform is added dropwise 250 ml. of -toluene con-taining 30 g. of phosgene over a 15 min.
period. AEter a further lS m;n. a solution of 24 g. of dry pyridine in 100 ml.
of chloroform ~s added drop~ise over 45 min., during which a solution is effected and carbon dioxide is slowly evolved. The solution is stirred ~or 90 min., and is subsequently concentrated to half volume in vacuo to remove the excess phosgene. Chloroform (2 1.) is added, and to this stirred solution is then added 45 g. of tetramethyl guanidinium azide in 250 ml. of chloroform.
After 2 hrsO, the chloroform solution is washed successively with water (2 x 500 ml.), saturated sodium carbonate solution t2 x 300 ml.), 2.5N hydrochloric acid and water (1 x 250 ml.). The organic phase is dried over magnesium sul ~ate and concentrated in vacuo to a gummy solid, lG2 g~ The product is further purified by chromatographing on a column of alumina t306 g.) using chloro~orm as the solvent (408 ml.) and eluate tl.5 1.). The eluate is added with stirring to 6 1. o~ petroleum ether, resulting in the precipitation of tho product as a light brown solid, 79 g.
NMR tCDC13): ~ = 6.9 tq) 4H, 5.4 tm) 3H; 4.~ tdj lH; ~7 ts) 2H;

3.7 ts) 3H, 3.3 tq) 3H and 1.4 ts) 3H.
IR tKBr disc)y: 1770 cm 1 (~-lactam carbo~yl).

:
.:

~: :
~ -30-,.: , . :

, -: . . ..

, .... ~. . . .. ... . . .. . .

In a slmilar manner, 250 mg. of 7-~2~,2',2~-trichloroethoxycarbox amido)-3-methyl-[N-(~-methoxybenzyl)carbamoyl]-~ -cephem, 0.007 ml. o pyridine and 2.6 mg. of phosphorous pentachloride in 6 ml. of chloroform yield the cor-responding imino chloride, which on treatmen-t with tetramethyl guanidinium azide tl g.) in 2 ml. of chloroform gave 220 mg. of the desired tetrazole, identical in all respects with that obtained above.

Utilizing the intermediate amides of Example 2, and employing the procedure of Example 3, the following tetrazole derivatives are synthesized:

R-NH S
~ .

Rll C13CCH20C0- 2 Cl C 3 6 3 2 C13CCH20CO- 3-Cl-4-HOC6H3CH2-15C13CCH20C0- 3,4-(CH30)2C6H3CH2-C13CCH20CO- 4-HOC6H4cH(cH3)-C13CCH20CO- 2-Br-4-CH30C6H3CH2-C13CCH20C0_ 4 CH30C6H4CH(0) C13CCH20Co_ 2,4-~CH30)2C6H3CH(CH3) 20C13CCH20C0- 4-CH30C6H4CH(_-c3H7) C13CCH20CO_ , ~-c2H5co2c6H4cH2 C13CCH20CO- 3--F-4-cH3co2c6H3cH2 :

- R Rll C13CCH20CO- 4-HOC6H,~CH(0 )-C13CCH20C0- 4 ti C3H7CO2)C6H4CH2 C13CCH2OCO- 3,4-~C6H5CH2O)2C6H3C 2 C13CCH20CO- 4-CH30c6H4cH(cH3)-C13CCH20CO- 4-CH30C6H4CH(C2H5 C13CCH20C0- 3-C1-4-CH3OC6H3CH(CH3)-C13CCH20CO- 3-CH30-4-CH3C02c6H4cH2 C13CCH20CO- 4-C6H5CH20C6H3CH(CH3) C13CCH2OCO- 3-Cl-4-C6H5CH2OC6H3CH2-C13CCH20CO- 3,4-(C2H5C02)2C6H3CH2 C1.3CCH20CO- 4-(n-C3H7CO2)C6H4C 2 C13CCH2OCO- 4-(i-C3H7c02)c6H4cH(c2 5 C13CCH20CO- 2-furylmethyl-C13CCH20CO- 5-methyl-2-furylmethyl-C13CCH20CO- 2-thienylmethyl- . .
C13CCH2OC0- 5-methyl-2-thienylmethyl-C13CCH20CO- 1-(2-f~yl~ethyl-C13CCH20CO- 1-(5-methyl-2-furyl~)ethyl-B~3CCH2~CO- 4-C6H5cH2Oc6H4cH2 Br3CCH20CQ- ~-c6H5cH2o-3-Fc6H3cH2 : Br3CCH2OCO- 2 Cl 4 3 6 3 2 :
...

:
~ ' ' . . , :
, ' ' ' .
~ 32-. .

; / ! . : ! . : . : ' . '~; ,'.

_ R

, Br3CCl120co- 4-cl-4-Hoc6ll3cH2-Br3cc~l2oco- 2-Br~ c~l3oc6H3cH2 Br3ccl~2oco- 2,4-(C~13O)2C6li3C~I(CH3 Br CCM20C0- 4-C2H5G02c6ll~,~t2-,Br3Ct~H20Co- 3-C}~3-4-CE13(~C6~3CH2-. Br3CCH20C0- 3-F-4-c~3co2c6}l3cH2 . , Br3ccl~2oco- 3-I-4-cH3oc6}~3~H
: . Br3ccH2oco- 4-(i-c~l7co2)c6ll4cH2-Br3cc~l2oco- 3,4-(C6~l5cll2)2c6 3 2 Br3cc~l2oco- 4-cH3oc6H4cll tcH3) .. Br3ccH2oco- 4-cH3oc6ll4cll(c2 5 Br3ccH2oco- 3,4-(CH3)2C6 3 2 Br3cc~2oco- 3-~-4-cH3oc6H3cH
Br3ccil2oco- 3-cl-4-cH3oc6H3cH(cH3) . Br3CCH20CO- 3-Cl-4-CH30C6H3CH ~CH3)-Br3cc~2oco- 4-HOC6H4CH2- . ;
Br3ccH2oco- 4-HOC6H4cH(cH3)-Br CCH20C0- 4-CH3~02c~4cH2 Br CCH OC0- 3-cl~4-Hoc6H3cH
. Br CCH OC0- 3-Cl-4-c~3c02c6H3~H2-: 3 20CO 4-C6H5C~20C6H3cH(cH3)-Br3ccH2oco- 3-cl-4-C6H5CH20C6H3CH2- .
. 'Br3CCH2OC0- 2-F-4-C~15CH20C.6H3C~l2 .
; 25 3 20C0 3,4-(C2}15C02)2c6H3cH2-Prr3ccH2oco- 4 (n-C3~17C2)C6H4C 2 :: . Br3CCH20C0- 2-furylmethyl-. . Br3CCH20Co- S-methyl-2-furylmethyl-Br3ccH2oco 2-th~enylmethyl-~: 30 : ~r3CCH20C0- 1-(2-furyl)ethyl-¦ Ar3CCH20CO- 1-(5-rechyl-2-f-lryl)ethyl-. , " " '.

, . ' " .
~33-.

. .' :, :, - -' - ~ " . .: . - , ~

4~ 9 EXAMPJ,E 5 7-Amino-3-methyl-4 [l-(p-methoxybenzyl)tetra~ol-5-y~ cephem To 73 g. of 7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-Cl-(~-methoxybenzyl~tetrazol-5-yl~-Q3-cephem in 500 ml. of 95% acetic acid is added 25 g. of zinc dust, and the mixture stirred vlgorously for 3 hrs. a-t room tempera-ture. The mixture is filtered, and the filtrate added to a large ~olume of water and extracted with chloroform. The organic layer is washed with water and the product extrac-ted from the organic phase with lN hydrochloric acid.
The aqueous is washed with chloroform, basified with 2N sodium hydroxide solu-tion to pH 7 and ex-tracted with chloroform. The chloroform layer is dried over magnesium sulfate and concentrated under reduced pressure to a small ~olume.
On addition of the concentrate to petroleum ether, the product is precipitated.
The solids are filtered and dried, 30 g.
NMR (DMSOd6): ~ = 7(2 q) 8H; 5.5(s) 2H~ 5.4(d) lH; 5.05(d~ lH; 3.7(s) 3H; 3.6(s) 2H; 2.2(s) 3H and l.~(s) 3H.

Start;ng with the intermediate tetra~oles of Example 4~ and repeating - the procedure of Example 5, the following congeners are synthesized:
,S
H2 T--N~ ~ .

N~ ~ -R
\, 1 11 N = N
.

' ~ ~ .

~ - :

~11 -4 -C6H5 CH20C6H,~CH2 -I~-C6H5CH20-3-FC6H3CH2-3-Cl-4-HOC6H3CH2-3,4-(CH30)2C6H3CH2-

6 4 ( 3) 2-Br-4-CH30C6H3CH2-4-CH30C6H4CH(0)-2,4-~CH30)2C6H3CH(cH3)~
4-CH30c6H4cH(n-c3H7 ) C 3 H3 6 3 2`
4-C2H5c02c6H4cH2-4-HOC6H4CH(0)-3-I-4-CH30c6H3cH2-: 4_(i_C3H7c02Jc6H4cH2-3,4-(C6H5cH20)2c6H3cH2 4-CH30C6H4CH( CH3 ) -4-CH30C6H4CH(c2H5) : F 3 6 3 2 3-C1-4-CH30C6H3CH(CH3)-4-C6H5CH20C6H3CH(CH3) 3 -Cl -4 -C6H4CH20C6H3CH2 -3,4-(C2H5CG2)2C6H3CH2 4~(n~C3H7c2)c6H4cH2 4-(i-C3H7c02)c6H4cH(c2 5 2-furylmethyl-,, : 5-methyl-2-~ylmethyl-2-thienylmethyl-5-methyl-2-thienylmethyl-2-uryl)ethyl-1-(5-methyl-2-furyl)ethyl-:

~:
_ ~ ', ' .

.. . . ..

7-Am:no-3-methyl-4~(tetrazol-5-yl)-Q -cephem A mixture o~ 7.0 g. of 7-amino-3-methyl-4~ p-methoxyben3yl]-tetra~ol-5-yl)-~3-cephem in 50 ml. of trifluoroacetic acid/anisole (4:1) is allowed to stand at 50C. for 5 hrs. The solution i5 subs~quently poured into a large volume of stirred die-thyl ether, and -the precipitate which forms is ~iltered. The solids are dissolved in water, which is extracted several times with ethyl aceta-te, adjusted to pH 7.0 with 2N aqueous sodium hydroxide and extracted again. The aqueous solution containing the product is freeze dried to give 3.2 g. of the desired compound (containing some sodium trifluoro-acetate).
NMR (DMSOd6): ~ = 5.0(d) lH; 4.6~d) lHj 3.4(qj 2H; 1.9(s) 3H and 1.3(s) 3H.
EXAMPLE B
In an analogous manner, when the procedure oE Example 7 is repeated, starting with the compounds oE Example 6, 7-amino-3-methyl-4-(tètrazol-5-yl)-~3-cephem is produced.
EXA~PLE 9 Sodium bicarbonate (500 ) is added portionwise over 45 min. to a stirred ælurry o;f 7-amino-3-methyl-~3-cephem-4-carboxylic acid (S60 g.) in cold water (5.6 liters) and acetone t5.6 liters). When effervescence has ~ ~ .

i.:: :
. ~ , .
~ ~ -36-'r~ f ceased, ben~yl chloroformate (~i90 g.) is added and the solution stirred at room temparature o~ernightO The r~act~on mixture ;5 then extracted with ethyl acetate ~2 x 1 llter), and the pH of the separatad aqueous layer adjusted to 2 'by -th~ addit~ion of 2N hydrochloric acid. This mixture is then extracted with ethyl acetate ~2 x 1 l;ter), and the solven-t from the separated organic layer removed _ vacuo. Tha resultant solid is dissolved in hot ethanol (2 liters), and diluted with wa~m water ~5 liters), to furnish 7-tbenzyloxycarboxamido),-3-methyl-~3-cephem-4-carboxyli,c acid as a white solid (750 g.), which is dried _ ~acuo at 60C.
NMR (DMSOd6): ~ = 8.3(d) lH, 7.3(m) 5H, 5.~(q) lH; 5.1~d) lH, 5(s) 2H; 3.4(q) 2H and 2.1(s) 3H.
EXAMPLE 1~
Utiliælng th~ procedure of Example 9, but starting w~th a suitably ring substituted benzyl chloroformate wherein the substituent is selected from the group consisting of halo, methyl and methoxy~ the corresponding 7-(substi-tuted ben~yloxycarboxamido)-3-methyl-a3-cephem-4-carboxylic acids are ~prepared.
` " ' ~ !
~ ~'' : .
. : . ' ~i4~
.

7-(Benzyloxycarboxamido)33-me~hyl-4-[N-(p-methoxybenzyl)-carbamoyl]-Q -cephem , ~,,, . . . ~ . . ~ .
A mixture of 7-(benzyloxycarboxamido)--3-methyl-~3-cephem-~-carboxylic acid (34.8 g.) and 2,~-dini-trophenol (18.4 g.) are dissolved in dry dioxane (700 ml.). Dicyclohexylcarbodiimide (20.6 g.) is then added and the solu-tion stirred Eor 20 min. at room -tempera-ture. Af-ter this time, the precipitated dicyclohexylurea is filtered off, and the filtrate treated with ~-methoxy-benzylamine (13.7 g.~ which is added over 10 min. After a further 15 min., the reaction mixture is diluted with dry ether (1.4 liters). The precipitate is filtered off, washed w;th dry ether (500 ml.), and dried _ vacuo at 50C.
to yield 40 g. of the desired product as a white solid.
NMR (DMSOd6): S = 8.4(m~ 2H; 7(q) 4H; 5.3(q~ lH; 5.1(s) 2H~ 5(d) lH, 4.3(d) 2H~ 3.7(s) 3H, 3.3(s) 2H and 2(s) 3H.

Starting with the appropriate amine and requisite 7-(benzyloxy-carboxamido)-3-methyl-Q3-cephem-4-carboxylic acid and employing the procedure of Example 11, the following ~3-cephems are prepared:

0CH20CONH~

,.,:

, :

~ . ~

:

64~g 4-C6H5cH20c6H4cH2 2-Cl-4-CH30C6H3CH2-3-Cl-4-HOC6H3CH2-3,4-(CH30)2C6H3CH2-4 HOC6H.~CH(CH3) 2 Br 4 C 30C6 3 2 4-CH30C6H4CH(0)-2'4-(CH30)2C6H3CH(CH3) 4-CH30c6H4cH(n-c3H7 ) 4-HoC6H4CHt0)-3-I-4-CH30c6H3cH2-4-(1-C3H7C02)C6HL~CH2-3'4-(C6H5CH20)2C6H3CH2 4-CH30C6H4CH(CH3 ) 4-CH30C6H4cH(c2H5) 3 F 4 CH30C6H3 H~
3-C1-4-CH30C6H3CH(CH3)-4-H~)C6H4CH2 -3-CH30-4-CH3C02C6H4cH2 -4-C6HSCH20C6H3CH(CH3)_ 3 Cl 4 C6HL~cH20 6 3 2 3,4-(C2H5C02 )2C6H3CH2 ~_(n-C3H7C02 )C6HI~CH2 4~ C3H7C02~C6H4CH(C2H5)-2-furylmethyl-5-methyL-2 furylmethyl-~ 2-thienylmethyl-: 35 ~: S-methyl-2-thienylme~hyl-l-t2-furyl)ethyl-1-(5-methyl-2-furyl)ethyl-~, -:
EXAMPLE_13 7-Amino-3-methyl-4- LN -(p-me-thoxybenzyl)~arbamoyl~-~3-ceRhem ~
7-~Benzyloxycarboxamido)-3-mcthyl-4-[N-~-methoxybenzyl)carbamoyl]-~ -cephem (20 g.) is d;ssolved in hydrobromic acid/acetic acid ~200 ml.) and the solution stlrred at room temperature until gas evolution c.eases. The mix-ture is poured into a`largc volume (ca. 2 liters) of stirred ether and the resulting precipitate collected. The solid is dissolved in water and the aque-ous solution washed wi~h ethyl acetate t2x). The aqueous solution is adjusted to pH 7.5 with sodium bicarbonate and the suspension extracted with chloroform.
The chloroform extract is dried ~MgS04) and evaporated under reduced pressure to leave the product as a pale yellow solid (7.7 g.).
NMR (DMSOd6): ~ = 8.0(t) lH; 7.0(q) 4H; 4.8(d) ~H; 4.6(d) lH; 4.4(d) 2H; 3.7(s) 3H; 3.2(q) 2H; 2.1(s) 2H and 2.0(s) 3H.

Starting wi~h the intermediates of Example 12, and following the deacylatioD procedure of Example 13, the following 7-amino-~ -cephem deriva-tives are synthesized:
H2N ~S ~
`nN I
0 ~ ~ ~ H3 ~-NH-R2 ' .
.
-~6~9 4-C6H5CH20C6HL~cH2 3-C1-4-HOC6H3CH2- .
3,4-(CH30)2C6H3CH2-4 6 4 ( 3) 2 Br 4 CH3 6 3C 2 4 3 6 4 (0) 2'4-(CH30)2C6H3CH(CH3) 4-CH30C6H4CH(n-C3H7) 3-CH3-4-cH30c6H3cH2-~ 15 . 4-HOC6H4CH(0)-4-(i_C3H7CO2)C6H4CH2-3,4-(C6H5CH2O)2C6H3cH2-` ~;
4-CH30C6H4CH(CH3) 4-CH3OC6H4CH~c2H5) :
3-F-4-CH3Oc6H3cH2-3-Cl-4-CH3OC6H3CH(CH3)-~ 4-CH3c02c6H4cH2-~: 25 ~ 3-F-4-HOC6H3CH2-3-CH30 -4-CH3C02C6H4CH2- -:
:: 4-C6H5CH20C6H3CH(CH3)_ 3-Cl-4-C6H4cH2c6H3cH2-3,4-(C2H5C02 )2C6H3CH2 : 30 4-(n-C3H7cO2)c6H4cH2-4 (1 3 7 2~ 6 4 ( 2 5) ;~ ~ 2-furylmethyl-5-methyl-2-furylmethyl-2~thienylme~hyl-5-methyl-2-'tthienylmethyl-:1-(2-furyl)ethyl-: 1-(5-methyl-2-fu~yl)ethyl-' ."
... .
:: :

XA~PL~ 15 7-(N 'F~iphenylme-thylamino)-33methyl-4-CN~ methoxybenzyl)-To 24 ~; of 7-amino~3-methyl-4-[N-(p~methoxybenzyl)~arbamoyl]-~3~
S ceph~ in chLoro~orm (ethanol free; 300 ml.) is cldded triphenylmethyl chlori~e (~1.0 ~.) and trietbylamine (7.64 g.). The mix~ure i6 alLow~d to stand at room temperature in the abs~nce o~ light for 15 hrs. The solution is then ailuted several-fold ~;th chloroform and washed twice with water. The organic solu-~tion is dried (Mg504) and evaporated to dryness to leave the re~uired product as a foam. Trituration wi-~h light petr~leum ether gives a pals yellow solid (40 g.).
NM~ (CDC13): 6 7.29 9H; 4.6(q) lH, 4.4(d~ 2H; ~,1(d) lH; 3,7(s) 3H~ 3.0, 3H and 2.0~s) 3H.
E~AMPLE 16 The procedure of Example 15 is repeated, subst~tu-tin~ ths 7-amino-~3-cephem~ o~ E~ample 14 for 7-amino-3-methyl-4-[N-(p-methoxybenzyl~carbamoyl]-~3 ccphem9 to provide the followin~ compounds:

03CNH ~ S ~

-NH-R

. , ' : :
~ .

¦ 1 G~;4 Lil9 . . 2 ~
4--C6~15C~120C684cH2 _ , .
4-C6}15c~l20-3-Fc6H3cH2 ' 2-~1''4~CH30C6H3CH~2-. 3-Cl-4-HOC6H~CH2-3,4-(CH30~2c6H3cH2~
4~0C6~1~CIi(C~13)- .
2-Br-4-CH30C ~ 3C~12-~ 4-CH30C6~14( ll (0) - , .
2~4~ 30)2c6H3cH(cH3~-. . 4-CH30C6~14CH~n C3H7) , , . ' 3-CH3-4-CH30C6H3CH2 , 4-C2~5C02C6H4cH2 .
3 F~4-cH3co2c6H3c~l2-. . 15. ~ 4-HOC6H4c~l(0)- .
. . . ' 3-I-4~CH30C6H3C~2 . .
. 4-(l-C3~17C02)C~4C~2-. ' . ' 3, 4- (C6l~scH2o) 256H3CH2 , 4-CH30C6H~,CH (CH3) - , ' ' . .
.4-~H30C6~i4cR(c2H5)- ' ., . . 3-F-4-CH30C6~3CH2_ , . ~ 3-Cl-4-CH3Q~,H3CH(C~13)~
. 4 HOC61~4CH2 :
4-CH3c02c6H4cH2~ , . , .

- . . 3-CH30-4-C~13C02~6H4cH2 ' ' . 4~c6H5cH2oc6~l3cH~CH3)-. 3-cl-4-c6H4c~I2oc~H3cH2 .
3,4-~21~5Co2)2c6H3cH2 , .
30 ~ ~ 4-(n-c3H7co2)c6~4cH2 ~ - .
: ~ C3~17CO~)c6~4cH(c2H5) 2~furylmethyl- ~
5~methyl-2~furylmethyl- . .
. ~ 2-thienylmethyl- ... .

: ~ : 5~ethyl-2-th$enylmethyl-: : ~-(2-fu~yl)e~h~l-5-methyl--2-fury1)ethyl-:, :! . .
:~ : -43- ~
~, . , , . .
.... ," . .. . . . . ... , .. .. _.
: ' The procedure of Example 15 is again repeated, starting with -the appropriate triphenylmethyl chloride and 7-amino-A -cephem from Example 14 to give the following compounds:

R~

~ - NH ~ S

R5 t ~ ~ CH3 . ~ -NH-R2 H- H- 2-CH3- 4-C H'CH 0-3-FC H3CH2-H- H 3-CH30- 2-Cl-4-CH30C6H3CH2-10 H- H 4-CH30- 3-C1-4~HOC6H3CH2-H- H- 2-F- 3,4 (CH3 )2 6 3 2 H- H- 4-F-~ 4 H0 6 4 ( 3) H- H- 3-C1- 2-Br-4`CH30C6H3CH2-H- H- 4-C1- 4-CH30C6H4CH(0)-15 H- H- 4-Br- 2~4-(CH3Q)2C6H3CH(CH3) H- 4-CH3- 4-CH3- 4-CH30c6H4cH(n-c3H7) .l . H- 4-CH3- U-CH3- 3-CH -4-CH -OC H3CH2-H- 4-CH3- 4-CH30- 4-C2H5C02C6H4cH2 :~:H- 4-CH30- 4-CH30- 3-F-4-cH3co2c6H3cH
20 H- 3-CH30- 3-F- 4-H0C6H4CH(0)-H- 3-CH30- 4-F- 3-I-4-CH30c6H3cH2-H- ~ 3-CH30- 4-F- 4-(i-c3H7c02)c6HL~cH2 H- 4-~1- 3-C1- 3,4 (C6 5 2 )~ 6 3 2 H- 4-Cl- 4-F- 4-CH30C6H4CH(CH3) ~ 25 H- 4 C1- 4-Br- 4-CH30c~H4cH(c2H5)-: H- ~-Br~ 4-Br- 3-F-4-CH30c6H3cH2 4~ :

H- 3-Br- ~ 4-CH30- 3-c~ c~l3oc6H3cH(c~l3) H- 4-Br- 4-CH3- ~ HOC6 4 2 H- H- C6H5- 4-CH3c02c6H4cH2 H- C6H5- C6H5- 3-F-4-Hoc6H3cH2-2-CH3- 2-CH3- 4-CH3- 3-CH30-4-CH3C02c6H4cH2 4-CH30- 4-CH3- 4-CH3- 4-C6H5cH20c6H3cH~cH3) 4-CH3- 2-Cl- 4-CH3- 3-cl-4-c6H5cH2oc6H
4-CH3- 4-Br- 4-OCH3- 3~4-(C2H5c02)2c6H3cH2-4-CH3- 4-CH3- 4-CH3- 4-~n--c3H7co2)c6H4cH2 4-CH3- 4~CH3- 4-CH3- 4-(i-C3H7C02)C6H,~CH(C2H5)-4-CH3- 4 6 5 4-Cl- 2-furylmethyl-4-Cl- 2-Cl- 4-Cl- 5-methyl-2-furylmethyl-3-Cl- 4-CH3- 4-CH3- 2--thienylmethyl-4-CH30- 4-CH30- 4-CH30- 5-methyl-2-thienylmethyl-4-F- 4-Br- 4-F- 1-(2-furyl)ethyl-2-Cl- 2-F- 4-Br- 1-(5-methyl-2-furyl)e-thyl-~., `

: . .

: -45-:

.

1a~6~

7-(N-Triphenylmethylamino)-3-methyl-~-~1-(p-methoxybenzyl)-tetrazol-5-yl]-L3-cephem 7-(N-Triphenylmethylam;no)-3-methyl-4-[N-tp-me-thaxybenzyl)carbamoyl~-~ -cephem (2.8 g.) in ethanol-free chloro~orm ~7.'i ml.) containing pyridine (0.6 g.) is treated with phosgene in chloroform (3.7 ml.) 1.7M). The,reacti~n is allowed to st;r for 30 min. at room temperature. The excess phosgene is removed under reduced pressure and addit;onal chloroform added until the vol-ume of solution is 10 ml. Tetramethyguanidine hydrogen azide (2.4 g.) in chloroform (5 ml.) is added to the above prepared solution and the, reaction allowed to stir at room temperature for 20 min. The solution is washed with water, dried (MgS0l~) and evaporated under reduced pressure to give an oil.
Trituration with light petroleum ether gives 2.2 g. of the desired product.-NMR (CDC13): ~ = 7.2, l9H; 5.3(s) 2H; 4.4(q) lH; 4.2(d) lH; 3~6(s) 3H; 3.0, 3H and 1.2(s~ 3H.

The following Q -cephems are prepared by repeating the procedure of Example 18, starting w;th the appropr;ate intermediates of Examples 16 and 17: -4 ~ ' R5 ~ ~ 3 ., ` !l lOG~ l 9 .
. I ,, ,.` ,., ` .
R3 ~4 R5 R:2 .

~_ H- H- 4~~6~1SC~ Oc6~ c1~2 ¦ H~ ~_ H- 4- C6H5C~l2o-3 -Fc~l13c~l2 . ¦ H- H- H.- 2-Cl-4-CH30C6~l3c~12 ~ _ H- 3-Cl-4~~l0C6~l3cll2 . ¦ }l_ H- H- 3,4~(C~l30)2c6~3c~l2 ¦ H- H~ ~_ 4~HOC6H4CH(CH3)-H- B- H- 2-B~-4-C~l3oc6~l3cll2 l ' ?I H- : Fl- ~ 4~CH30c6H4cH (~)~
- 1~ ~ il- H- H- 2,4-(C~130)2C6H3C~(CI~3) .
H- H- H~ 4-C~30C6H4CH(n-c3H7) . H- H- 3-C113-4-CH30C6H3CH2 . . , . H- H- H- 4-C2}15c02c6H4c~2 I H~ 1- 3-F-4-CH3C02C6H3CH2- .
H- ~_ H- 4-HOC6H4cH (0) -. . H- H- H- 3-I-4 CH30C6H3CH2-H-. H- H- 4-(i-C3H7C02)C6H4CH2 .: ` ~_ B~ ~- 3,4-(C6E15CH20)2C6H3CH2 11- H- H- 4-C~13oc6~ c~ 13) 2n . H- H- H 4-C~i OC H,C~i(C '~ic)-Il- H- ~_ 3-F-4 CH30C6H3CH2- .
N- H- ~_ . . 3_C~ -Cll3oc6H3cH (CH3~-. ~ . H- H - H- 4-F10 C5H4CH 2-. H- H- ~_ 4-Cl13C02c6H4cH2 . .
. ~_ H- ~- 3-F-4-HOC6H3CH2-- : ~ H- H- 3-CH30-4-cH3co2c6H4cH2 ; ~ ~ . . , ~_ H- ~~ 4-C6H5CH20C6H3CH(CH3) : H- .H-- H- . 3-Cl-4-c6~lsc~l20c6H3cH2 . H- H- H- 3"4-(C2H5C02)~C6~13CH2 .: ~_ H- H- 4-tn-C3H7c02)c6F~4cH2- q H- H~ H- 4--(i-C3H7C02) C6H4CH t~2 S) ~: . H- H- ~- 2-furyl~ethyl- .

: : H- ~- H- S-~e~hyl-2-furylme~hyl- .
: ~ H- H- H~ hienylmethyl-: ~ 35 H- ~ H- ~ Fl- S-~ethyl-2-thienyl~etnyl-. : . . .
. :: ' ` ' .
.
. . .. , .

~" ' ,, ;, ', '`' '.'.'' ' . _ ........ . `~ '' , ' - . . , , ~ . .. . ~ , , R3 Rb ~5 n~ H- l-t2-furyl)ethyl-~- H ' ~- l-C5-~ethyl-2-furyl~ethyl-. ~ H- . H~ 4-~13- 4-C6,tl5C1120C6H4c~l2 S H- ~_ 2-CH3- 4-C6H5cH20-3-Fc6~l3cH2 H-- ~1_ 3-CH30- 2-Cl-4-C~-l30c6~l3c 2 H- H- 4-CH30- 4-Cl-4-HOC6H3C1 2 ~_ H- 2-F- 2-Br-4-CH30C6~13C 12 ~
. H- H- 4- F- 2~4 (CU30)2C6H3C (C ~3) ~_ H- 3-Cl- 4-C2H5c02c6'l4cH2 -H- H- 4-Cl- 3~G13-4-C~30C6H3CH2 H- H- 4~Br- 3-F-4-CH3c02c6~3c~2 H- 4-CH3- 4-C113- 3-I-4-(;M30C6H3C~i2 . ~1- 4-CH3- 4-CU3- 4-(i-c3H7co2)c6-l4cY2 .
i5 . H- 4-CH3- 3 ' ( 6 5 2 ~ 2 6 3 2 . . H- 4-CH30- 4-CH30~ 4-CE130C6H4cll (C1~3)-.... . . H- 3-CH 0- 3-F- 4- CH30C6H4Ctl (C,,}ls) H- 3-C~I~0- 4-F- 3,4-(C~130)2C6H3CH ~-. ~ . H-- 3-C1~30- 4-F- 3-F-4-c~l30c6~3c~2 . .
2~ li- 4-Cl- 3-Cl- 3-Cl~4-CH30C6~13CH (C!13)-. ~ . H 4-Cl- 4-F 4-HoC6H4CH2 ~ . -; . . H- 4-Cl- 4-Br- 4-}~OG6~14CH (C}13) , . . . H- 4-Br- 4-Br- 4-CH3C02c6H4cH2 - ~ H- 3~Br 4-CH30- 3-Cl-4-HOC6113CH2-~ . H- 4-Br- 4~~3~ 3-Cl-4-CH3C02C6H3CH2 H- H- C6H5- 6 5 ;~ 6 3 ( 3) : : B- C6H5 C6H5- 3-Cl-4-C6H5c~20c6H3c~l2 : . 2-CH3- 2-CH3- 4-l;H3 6 3 2 ~ 4-~H30- 4-CH3- 4-CH3~ 3,4-(C2}'.5c02)2c6H3cH2 4-CH3- 2-Cl- 4-GH3- 4- (n-G3H7C02) C6H4CH2 ; : 4-~H~- 4-Br- 4-OCH3- 2~furylmethyl-4-(~13- 4~-CH - 4~CR3- 5-~.ethyl-2-furyl~nethyl-: ~ ~ 4-~13- 4-CH3- 4-CH3- 2~thienyl~ethyl-4-~13 4-C6Rs~ 4-Cl- 1-~2-furyl)ethyl-4-Cl- 2-C1~ 4-Cl- 1-(5-methyl-2-furyl~ethyl-~ ~ .
' : `
- . -4~
'", ' . , 4~::1L9 , EXAMPLE 20 7-Amino-3-methy~-4-~1-(p-methoxybenzyl)tetrazol-5- ~ Q3-ceE~em 7-(N-Triphenylmethylamino)-3-methyl-4-[1-(p-methoxybenzyl)tetraaol-5-yl]-Q3-cephem ~1.5 g.) is -treated with formic ac.id (30 ml.) and the'soLution allowed to stand at room tempe~ature for 30 min. The solution is poured into water ~100 ml.) and the aqueous suspension washed with ethyl acetate. The aqueous solution is adjusted to pH 7.5 with 2N aqueous sodiu~ hydroxide and the mixture extracted with chloroform. The organic solution is dried ~MgS04) and evaporated under reduced pressure to leave a foam. Trituration with light petroleum ether gives 400 mg. of the desired product as a solid.
NMR (CDC13): ~ ~ 7~0(q) 4H; 5.4~s) 2H; 4.9(d) lH; 4.6td) lH, 3.7(s) 3H; 3~3(q) 2H; 2.0(s) 2H and 1~4(s) 3H~ ` -In a similar manner, when the compounds of Example 19 are subjectedto the above hydrolysis conditions, the following 7-amino-~3-cephems are produced, said produGts'being identical'with''those of Example'6: ' - ` ' H2 ~ S~
: N ....
:: ~ 0~ ~:
1 ' ' ' .' ' \N-R

Rll N~

'~ 20 ~ ~ 2-Cl-~-CH3OC6H3CH2--Cl-4-HOC6H3CH2-3, 4 - ( CH30 ) 2C6H3CH2 -4-HOC5H4CH(CH3)-; 2-Br-4-CH30C6H3CH2-~ ~ 4-CH30C6HL~CH~0)-:::
~ -49-: :

:: :
:

. ~ . . .. .. . . ~ . . . . .. .. . . .

;4~"3 2,4-(CH30)2C6H3CH(CH3)-4-CH30c6H4cH(n-c3H7 ) 3 CH3 4 CH30C6H,3CH2 4-C2H5C02C6HL~cH2 6 4 ~ 0 ) 3-I-4-CH30c6H3cH2~
4_(i_C3H7C02)C6H4CH2_ : .
3,4-(C6H5CH20)2C6H3CH2 H3 6 L~CH(CH3) 4-CH30C6H4CH(c2H5 ) 3-F-4-CH30c6H3cH2-3-Cl-4-CH OC H CH(CH )-L~-C6H5CH20C6H3CH(CH3) 3-Cl-4-C6H5CH20C6H3CH2-3,4-(C2H6C02)2C6H3CH2 4-(n-C3H7C02)C6H4cH2 4-(i-C3H7c02)c6H4cH(c2 5 2-furylmethyl-: 25 5-methyl-2rfuryl~e-thyl-: 2-thienylmethyl-5-methyl-2-thieTiylmethyl-(2-furyl)ethyl-1-(5-methyl-2-furyl)ethyl : .
s 7-[D-tc~amino-c~phenyl)acetamido]-3-methyl-L~-(tetrazol-5-yl)-~ -cephem A. 7-~D-( ~t-Butoxycarbaxamido- ~phenyl)acetamido]-3-methyl--4-(te-trazol-5-S vl)-~3-cephem .~_ D-( ~t-Butoxycarboxamido-orphenyl)acetic acid (0.251 g.) in tetra-hydro~uran (2 ml.) is treated with trie-thylamine ~0.101 g.) and ethyl chloro-formate (0.108 g.) at -lO~C. After 15 min. at this temperature, th~ sodium salt of 7-amino-3-methyl-4-(tetrazol-5-yl)-Q3-cephem (0.400 g.) in wate~i (3 ml.) is added wi~h stirring in one portion. ~he mixture is dilu-ted with tetra-hydrofuran (2 ml.) and allowed to warm up to room temperature, After one hr.
the solution is adjusted to pH 2 with 2N hydrochloric acid and the suspension extracted with ethyl acetate. The ethyl acetate solution is waahed w~h water dried tMgSo~), concentrated under reduced pressure, and pou~ed into a large v~lume of light petroleum ether to give a white solid. The compound is recrystallized from chloroform (316 ml.). ~ -NMR (DMSOd6): ~ = 7.6(d) lH; 7.2, 5H; 6.0(d) lH; 5.6~q) lH; 5.2(d) lH; 4.9(d) lH; 3.3(q) 2H, 2.0(s) 3H and 1.2(s) 9H.

B. 7-CD-(GrAmino- ~phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-~ -cephem trifluoroacetate .
7-CD~ t-Butoxycarboxamido-~-phenyl)acetamido]-3-methyl-~-{t~t~a zoL-5-yl)-~ -cephem (26 mg.) is dissolved in tri1uoroacetic acid (0.5 ml.) and allowed to stand at room temperature for 20 min. To the solution is added ether and the precipitate collected (24 mg.).
.
NMR (DMSOd6-D20): ~ - 7.4(s) 5H; 5.6(d) lH; 5.1(d) lH; 5.0(s) lH;

3.4, 2H and 2.0(s~ 3H.

, ' 7-[D- ~Amino-~-(p-hydroxyphenyl)ace-tamido]-3-me-thyl-4-(tetrazol-5-vl)-~3-ce~hem ~ , . . .
The procedures of Example 21A and B are repea-ted, starting with the requisite D-~ ~t-bu-toxycarboxamido-~ -hydroxyphenyl)]acetic acid in place of D-( ~t-bu-toxycarboxamido-~-phenyl)ace-tic acid, to provide the desired product.IR (CH2C12): YmaX; 1780 cm ~-lactam carbonyl); 1660 cm 1 (-CONH-).

, ~ ' .

.

' :. .

- - . . . . - ~. . -- - ., ~ , , -, - . - ~ .,: - , - - . . -~ ;4~1L9 The procedures of Example 21A and ~ are again repeated, starting with the appropriate o~amino acid derivative, said compounds being prepared by known procedures such as those taught by Greens~:ein and ~intz in "Chemistry S o~ Amino Acids~, John Wiley and Sons, Inc., New YorX~London, 1961, p. 698-700 and the reference ci-ted therein; and resolved into their op-tical isomers by the me~hods taught by Greenstein and Wintz, loc. ci-t., p. 715-755, Nishimura et al., ~ippon Kagaku 2asshi, 82, 1688 (1961), Belg, Pat. 795,874 and British Pat. 1,221,227, to provide the following cephem analogs:
*

Ar-ClHCONH~ S

~ ~ CH3 l~C~ ~ , Ar '~(Configuration) 3,4-(H0)2C6H3- DL
4-(CH30)C6H4- D
lS 4-HOC6H4- L~
2-thienyl- D
3-Cl-4-HOC6H3- D
4-ClC6H4- DL
~3-ClC6H4- DL

2-Br-5-HOC6H3- DL
3-~C6HI~- D

2-ClC6H4- D
2-ClC6H4-3-BrC6H4-. .
. . b'~

... .. . . .. . .. . .

, ' ' . . ' . ' . . ' , .~ :, , ' . :, , ' 1~:96'~9 Ar *(configuration .-- '-- .~_-._A .___.. __ -3-BrC6H4- L
3-ClC6H4- D
4-ClQ6H4- D
2,4-C12C6H3- DL

6 4 D .

4-BrC6H4- D

2~CH30C6H4- DL
3~4-tCH30)2C6H3- DL
~ ( 3 )~ 6 3 D
3-thienyl- D
3-thienyl- DL

3~H2NC6H4- D

3-Cl-5-(CH30)C6H3- D
2-Cl-4-CH3C6H3- DL
~ 25 2-F-3-CH3C6H3- D
:: 2-CH3-4-CH OC H3- DL

.... .

~;

A. 7-(D-~-Formyloxy~henylacetamido)-3-methyl-4-(tetrazol-5-yl) ~3-c~phem __ D-0-Formylmandelic acid (1.8 g.) in e-ther (15 ml.) is treated with oxalyl chloride (2.5 ml.~ and one drop of dimethylformamide. After the vigorous reaction has subsided (30 min.) the e-ther is removed under reduced pressure and the residue in THF (10 ml.) is added to a stirred solution of 7-amino=3-methyl-4-(tetrazol-5-yl)-~3-cephem (1 g.) in water/THF mixture (1:1;
~0 ml.) coDtaining excess sodium bicarbonate. After stirrin~ for a further hour at room temperature the mixture is adiusted to p~ 2 with 2N hydrochloric acid and the mixture extracted with ethyl a~etate. The organic solution is -washed with water, dried (MgS0~), and eva~orated under reduced pressure to leave the reguired product as a solid (350 mg.).
NMR (~MSOd6): ~ ~ 8.2(s) lH, 7.2(s) 5H, 6.0(s) lH~ 5.5(q) lH, 5.1(d) 15 lN; 3.5(s) 2H and 2.0, 3H.
B. 7-(D-o~ drox henyl~cetamido)-3-meth 1-4-(tetrazol-5- 1)-~3-ce hem 7-(~-o-Formylo~yphenylacetamido)-3-methyl-4-(tetrazol-5-yl)-~3-cephem (0.34 g.) ~s dissolved in excess a~ueous sodium bicar~onate and allowed to stand at 30C. for 3 hrs. The solution is adjusted to pH 2 with 2N
2Q hydrochloric acid and the suspension ex~racted with ethyl ac~tate. The or-ganic solution is dricd (MgS04) and evaporated under reduced pressure ~9. leave the required p~oduct as a solid (0.26 g.).
NMR ~SOd6): ~ = 9.0, lH; 7.3(s) 5H, 5.6~q) 1~; 5.2td~ lH; 5.1(s) . lM, 3.6ts) 2H and 2.0(s) 3H.

.: :

,... ........ ,.. "

10~;4~19 EXAMPL~ ?5 Starting with the req-lisite mandelic acid derivative, prepared by the method as taught in "Organic Syn-thesis," John Wi~ey and Sons, Inc., New York/London, 1956, Coll. Vol. I, p. 336, and employing the procedure of E~ample 24, the following congeners are synthesi~ed:
Ar-CHCON ~ ~

~\ ' N ~H
N _ N
~ *tconfiguration) 2-ClC6H4- D
3-ClC6H4- D
4-ClC6H4- DL
2-~C6H4- L

3-BrC6H4- , DL

~ 4-CH30C6H4- D
; 4-CH OC6H4- DL

~-HOC6H4- D

` 25 2,4-C12C6H3- D
: 2,3-Cl C H - DL

- 3,5-C12C6H3- D
:
.

~ .
.
~ -56-11:11~;4~19 ~ ~ ( conf i~ura t ion ) 2-Cl-4-FC6H3- D
3-Cl 4-FC6H3- DL
3-Cl-4-BrC6H3- 1, 3,4uBr2C6H3- E~
~1-$'-4-CH3C6H3- 1~1~.,.

,4 ~H() )2C6H3 lil 3-Cl-4-ROC6H3- L
2-F-4-~OC6H3- DL
2 ~ 4 CH30C6H3 D~
3 ~ 5 ~ C~3~0 ~2C6H3 1) 3-CR30-4-HoC6H3-~r~6~ C~ `3-. L
~ 2~4-$~C~ D
~-H N 4~C1;3~C~H - DL
3-~H3-4-~N~6 3 D

i; . .

~ ' :

:: ' , :; :
.
, :

.

: ~ ~ 5 7- .
, ,, 7-(2-C~anoacetamido)-3-methyl-4-(tetra~ol-5-yl)-~3-cephem To a stirred suspension of 7-amino-3-methyl-4-(te-trazol-5-yl)-~ -cephem tosylate sal-t t576 mg.) in methylene chloride (20 ml.) ~mder nitrogen, is added triethylamine (450 mg.). Af-ter stirring for 20 min. at room tempera-ture, this solu-tion is then trea-ted with the N-hydroxysuccinimide ester of cyanoacetic acid (470 mg.) all in one portion. Af-ter stirring overnight, under nitrogen, the reaction mixture is poured into water (30 ml.) and the pH of the aqueous phase is adjusted to 8Ø The methylene chloride layer is separated off. The aqueous phase is acidifice to pH 2, and then extracted with ethyl acetate. The ethyl acetate is washed with water, dried (sodium sulfate) and the solvent removed under vacuum. Tri-turation of the residue with dry ether gives -the product as a pale yellow solid (55 mg.).
NMR (DMSOd6): v = 5.7(q) lHj 5.2(d) lH; 3.8(s) 2H; 3.6(s) 2H and 2.0 (d) 6H.
EXAUPLE 27 .
.
7-(2-Carboxyphenylacetamido)-3-methyl-4-(tetrazol-5-yl)-~3-cephem sodiu~ salt -Ph tyl malonic acid (0.79 g.) is dissolved in distilled water (25 ml.) and the pH of the solution adjus-ted to 6.0 by adding 2N sodium hydroxide solutlon. A solution of 7-amino-3-methyl-4-(tetra7ol-5-yl)-~V-cephem (0.65 g.) in lv~ ml. distilled water (pH adjusted to 6 by addition of 2N sodium~
hydroxide solution) is then added, and the reaction mixture cooled to 0C.
l-Ethyl-3-(3-dimethylaminoprop-1-yl)carbodiimide (1.6 g.) is added and the solution stirred to 3.5 hrs., during which time the pH is maintained in the :: :

~ .

-range 6.1 to 6.3 by the dropwise addi-tion of dilu-te hydrochloric acid. At this point, the pH is raised to 7.3 by -the addition of saturated sodium bicar-bonate solution, and the reac-tion mixture is extracted with ethyl acetate.
The extract is discarded. The aqueous phase is then acidified to pH 3 using 0.4M phosphoric acid, and again extracted with ethyl acetate (-two 50 ml. por-tions). The latter extract is dried, and concentrated to a volume of about 25 ml. To this solution is then added a solution of sodium 2-ethylhexanoate (1 g.) in 20 ml. of ethyl acetate. The precipitate which forms is filtered to give 0.75 g. of the disodium salt Of7-(2-ca~o~y-2-phenylacetamido-3-methyl-4-(tetrazol-S-yl)- ~3 cephem. The infrared spectrum of the product (KBr disc) shows absorptions at 1760 cm 1 (~-lactam carbonyl), 1660 cm 1 ~ami-de I band) and 1660 cm 1 (carboxylate carbonyl).
NMR (D2O): ~ = 7.4(m) 5H; 5.7(d) lH; 5.2(d) lH; 3.4(m) 2H and 1.9 (s) 3H.
EXAMP~E 28 Substituting 2-thienyl malonic acid for phenyl malonic acid in the proced~lre of Example 27, leads to the synthesis of 7-[o,~2-thienyl)-~-carboxy-acetamido]-3,methy~1-4-(tetra7ol-5-yl)-~3-cephem.
NMR (DMSOd6): ~ = 2.1ts) 3H; 3.3(m) 2H; 5~s) lH; 5.6(m) lH; 6.8-7.5 (m) 3H.
IR (KBr disc) ~ ~ 1770 cm (~-lactam carbonyl); 1670 cm (-CONH-).
Similarly, by employing the appropriate malonic acid derivative and repeating the procedure of Example 27, the following compounds are prepared:

' .
: ' , .

:: :
"

.. :

.. . . .. . . ::

Ar-CHCONH\ /S
~02H ~
~CH3 N~ \NH
N =:~/

?-ClC6H.~- ' 4-ClC6H4-3-BrC6H4-2 -FC6H4 ~
. 4-FC H4-4-CH30C6H,~ -2 ,4-C12C6H3-3 '4 F2C6 3 . 3-F-4-BrC6H3-3-C~ HOC6H3-3'4-(CH30)2C6H3 2û 3-thienyl -: '' , , ~ .

.

: .

, :' ,., ~

4~

7-Phenylacetamlc1O-3-methyl-4-(tetrazol 5-yl)-~3-cephem Phenacetyl chloride (2.3 g.) in acetone (5 ml.) is added clropwise to a stirred solution of 7-amino-3-methyl-4-(te-trazol-5-yl)-~3-cephem sodium salt (1.31 g.) in aqueous acetone (20 ml.) over 20 min. at room temperature.
Sodium hydroxide (2~ is added simultaneously to keep pH at 8tO.5. The solu-tion, a:Fter the addition, is stirred for a further l5 min. The acetone is remo~ed under reduced pressure and -the pH of the aqueaus solution adjusted to 2 with 2N hydrochloric acid. The suspension is extracted with ethyl acetate, the organic solu~ion dried ~MgS04) and evaporated under reduced pressure to leave an oil which solidifies after trituration with ether (440 mg.).
NMR (DMSOd6): ~ = 9.0td) lH; 7.2(s) 5.6(q) lH; 5.2(d) lH; 3.5~s) 4H and 2.0(s) 3H.

7-Phenoxyacetamido~3-methyl-4-(tetrazol-5-yl)-~3-cephem ~.
Phenoxyacetyl chloride (2.56 g.) in acetone (5 ml.) is added drop-wise to a stirred solution of 7-amino-3-methyl-4~(tetrazol-5-yl)-~3-cephem sodium salt (1.31 g.) in aqueous acetone (30 ml.) over 20 min. a-t room tempera-ture. Sodium hydroxide (2N) is added simultaneously to keep the pH at 8tO.5.
The solution is ~hen allowed to stir for a further 15 min. The aceto~e is removed under reduced pressure and the pH of the aqueous solution adjusted to -2 with hydrochloric acid (2N). The suspension is extracted with e-thyl acetate and the organic solution dried (MgS04). Evaporation and trituration;of the residue gives the desired product as a solid (370 mg.).
NMR (DMSOd6): ~ = 9.0(d) lH; 7.0~m) 5H, 5.6(q) lH; 5.2(d) lM, 4.6(s~
2H; 3.8(s) 2H and 2.0(s~ 2H.

; ' ' ' : . .
.
, ~ .
~' .

...... ... . .. .... .
...... . . ~, .. . . . . . . - .. : . . . . . - .

1~i4~

Employing -the procedure of Example 29 and 3Q, and starting with the requisite reagents, the following ~ -cephems are synthesized:
7-Bromoacetamido-3-methyl-4-(tetrazol~5-yl)-A3-cephem~
S NMR (DMSOd6): ~ = 2.15(s) 3H; 3.7(m) 2H; 4.1(s) 2H; 5.4(d) lH and 5.2 (m) lH;
7-~ ~azido-a-phenylacetamido)-3-msthy~-4-(tetrazol-5-yl)-a -cephem, NMR (DMSOd6): ~= 9.2(s) lH; 7.35(s) SH; 5.6(s) lH; 5.15(q'~ 2H; 3.58 (s) 2H and 1.98~s) 3H;
7~ ttetrazol-5-yl)acetamido]-3-m~thyl-4-~tetrazol-5-yl)-~ -cephem, NMR ~DMSOd6): ~= 2.0~s) 3H; 3.6~s) 2Hj 5.05-5.15~d) lH; 5.15(s) 2H;
5.5-5.8~q) lH and 9.5(s) lH;
7-(0-phenyl*hioacetamido)-3-methyl-4-(tetrazol-5-yl)-~3-cephem, NMR ~DMSOd6): ~= 9.18(d) lH, 7.23(m) 5H; 5.63(q) lH; 5.35(d) lH;
3.77(s) 2H; 3.6(m) 2H and 2.03(s) 3H;
7-[a-t2,6-dimethoxyphenyl)carboxamido]-3-me-tnyl-4-(tetrazol-S-yl)-Q -cephem, NMR (DMSOd6): ~= 2.0(s) 3H; 3.6(s) 2H; 3.7(s) 6H, 5.05-5.15(d) lH, 5.5-5.8~q) lH; 6.5-6.7~d) 2H and 7.0-7.3(m) lH, 7-~2-thienylglyoxylamido)-3-methyl-4-~tetrazol~5-yl)-~ -cephem NMR ~DMSOd6): ~= 2.0(s) 3H; 3.6(s) 2H; 5.1-5.15~d) lH; 5.4-5.7(q~
lH; 7.05-7.15(m) lH and 7.8-8.1(m) 2H; and 7-~o,~2-thienyl)acetamido]-3-methyl-4-~tetrazol-5-yl)-~3-cephem, NMR (DMSOd6): ~-= 2.0(s) 3H; 3.6(s) 2H; 3.8(s) 2H; 5.1-5.15(d) lH;
5.5-5.8(q) lH; 6.95-7.0(d) 2H and 7.1-7.2(m) lH.

`' .

.

1~6~
EXA~PLE 32 Starting wi-th the appropriate acid chloride and 7-am.;no-3-methyl-4-~te^trazol-S-yl)-~3-cephem and employing the procedure ~.Examples 29 and 30, the following congeners are prepared:
30 ~f~

. ~

N _ Ar _Q_ n C6H5- _ o 2-ClC6H4- - O
4-C1~6H4- -2'3-Cl2C6H3- - O
3,4-C12C6H3- -3,5-F2C6H3- - O
4-BrC6H4- _ O
3'4-B~2C6H3- - O
3-HOC6H4- - ' O
4-HOC~H4_ - O
:: 4-H2NC6H4- ~_ o ~; : 20 3 Cl 4 HOC6H3 3-F-4-HOC6H3- _ O

3-Br-4-CH30C6H3- - O
:~ 3-CH3-4-HOC6~l3- - O
~ 3-CH3-4-ClC6H3- 0 2-thienyl- - O

.

~: ~ : : :
::
~ . .:
~' .

Ar Q n 3-thienyl- - 0 2-ClC6H4- N3 4-ClC6H4- N3 2,4-C12C6H3- N3 ' 2 6 3 N3 4-~rC6H4- N3 3-C1-4-HOC H ~ N3 3-Cl-4-H2NC6H3- N3 1 ,.

3-CH_-4-CH30C6H3- N3 2-thienyl- N3 3-tbieny1- ~33 `

::

~ ~ .

: :

, ,, ~ , - - : - :
- . . ,. , . ., . . , . ., - , : . - . . ..

36~

7-[~-Hydroxy-~-(2-thienyl)acetamido]-3-methyl-4-ttetrazol-5-yl)-~3-cephem 7-(2-Thienylglyoxyl~mi-do)-3-methyl-4-(tetra~1-5-~ -cephem (1.50 g.) in water (30 ml.) is converted to -the sodium salt with 2N sodium hydroxide, This solution is cooled ;n ice and anhydrous sodiu~ acetate (1.53 g.~ is added.
Sodium borohydride (276 mg.) is t~en added in small portions over a 45 min.
~eriod. The ~H is kept at 8, hy adding glacial acetic acid alternately with sodium borohydride. After the addi~io~s, the pH is kept at 8 for 45 min. with the ice bath removed. The solution is layered with ethyl acetate and the pH
adjust~d to 2 with 40% phosphoric acid. The organic layer is separated, washed with ~ater, dried (Na2S04), fil-tered and concentrated in vacuo until solids crystallize. The product ls filtersd, washed wi~h dry et~e~ ~nd driea ~nder v~cuum, 360 mg.
~MR (DMSOd6): ~ = 7.2~m? lH; 7.0, 2H, 5.4~m) 1H; 5.0(s) 2Hj 3.5j 2H-dnd 2.0(s) 3H.

~-[2-(2-methyl-1,3,4-thi~diazol-5-yl-thio-acetamido~]-3-methyl-4-(tetrazol-5-yl)-~3~ hem Triethylamine (0.2 ml.) is added to a cold 0C. suspensio~ of 7-(2-kromoacetamido)-3-methyl-4-~tetrazol-5-yl)-Q -cephem (0.5 g.) in methylene chloride (15 ml.). To the resultant pale yellow solution is added a slurry of ~-methyl-~,3,4-thiadiazole-5-thiol (~.19 ~.) and t~e solution stirrei at 0C.
Aft~r ~ hrs. the product which has precipitated is collested ~y filtration 25 ~0.3 ~.). -NMR (DMSOd6): ~ = 9.3(d) lH; 5.6(m) lHj 5.2(d) lHj 4.15(s) 2H~ 306 ~s) 2H; 2.7(s) 3~ and 2.05(s) 3H.

. . . .
''~ ' '' ' '-~ ~- -65-_ ~l~6~

.
The prdcedure of Example 3l~ is repeated, starting with 7-(2-bromo-acetamido)-3-methyl-4-(tetrazol-5-yl)-Q3-cephem and 1-methyl-5-mercapto~
tetrazole (Lieber, et al., Can. J. Chem., 37, 101 ~1959) to provide S 7~ 1-methyltetrazol-5-ylthio)acetamido~-3-methyl-4-(tetrazol-5-yl)-~3-cephem.
NMR ~DMSOd6): ~ = 9.28(d) lH; 5.6(q) lH; 5.24(d) lH; 4.13(s) 2H;
3.95(s) 3H; 3.59(m) 2H and 2.01(s) 3H.

.

: ~ , ~ ~ .

~: :

~ ~ ~ -66-.~ .. :w~

. . , . . . ,. ,.~ ., . . , . . ~ . . . .. - : .

Again, the procedure o~ Example 34 is repeated, employing 4 mercapto-pyridine and 7-(2-bromoacetamido)-3-methyl-4-(tetrazol-5-yl)-~3-cephem to give 7-C2-(4-pyridylthiol)acetamido]-3-methyl-4-(tetrazo]-5-yl)-~3-cephem.
NMR (DMSOd6): ~ = 9.32(d) lH; B.41(m) 2H; 7.33(m) 2H; 5.7-5~6(q) lH; 5.~5(d) lH, 3.95(d) 2H; 3.6(m) 2H and 2.03(g) '3H.

~ -67-4~33L~

7-(2',2',2'-Trichloroethoxycarboxamido)-3-acetoxymethyl-4-[N-(~-methoxvbenzvl)carbamovl]-~3-cel~hbm A. 7-(2',2',2'-Trichloroethoxycarboxamido)-3-acetoxymethyl-~ -cephem-4~carboxvlic acid Sodium b;carbonate (300 g.) is added portionwise to a s-tirred slurry of` 7-amino-cephalosporanic acid t408 g.) in aqueous acetone (2:1; 5 liters:2 S
liters). 2~2',2'-Trichloroethyl chloroformate (350 g.) is then added drop-wise over 45 min. and the mixture stirred for a further 5 hrs. at room 10 temperature.
The acetone is removed in vacuo, and the aqueous solution is then diluted to 10 liters with dis-tilled wa-ter. The pH o the solutior is adjusted ~o 2 with 50% hydrochloric acid, and the mixture extracted with ethyl acetate (5 x l.S liters). The combined organic layers are washed wi~h water (2 x 2 15 liters), dried (2~gSO4~) and the solution concentrated to a volume of 1.5 liters.
The conc~Eltrate is slowly added to petroleum ether (b.p. 60-80C., 15 liters) and the precipltated solid washed with petroleum ether (b.p. 30-40C.
- 2 x 2 liters). The precipitate is dried in vacuo at 45C. to furnish 7-(2',2~,2~-tricl~loroethoxycarbony1)-amino-3-acetoxymeth 1-~ -ce hem-4-carbox lic~ Y P
20 acid as a white solid (490 g.).

NMR (DMSOd6): ~ = lO(d) lHI 5.5(q) lH; S.l(d) lH; 4.8(q) 2H; 4.8(s) 2~I, 3.5(s) 2H and 2.0(s) 3H.

B. 7-(2',2',2'-Trich~oroethoxycarboxamidol-3-acetoxy-4-tN-( -methoxybenzyl)-carbamo~l]-~3-cephem ,:
Starting with the acid of Example 37A and following the procedure of Example lB, the desired product is prepared in moderate yield.
:: .
NMR (CD~13): ~ = 2.0(s) 3H; 3.4(s) 2H, 3.8(s) 3H; 4.45(dl 2H; 4.75 ~s~ 2H~ 4.9tmj ~H; 5.5(q? lH; 6.2(b) lH and ~.l(q) 4H.
,' ' , ~ ~ -68-:: :

7-(2',2',2'-Trichloroethoxycarboxamido)~3-(2-methyl-carbamo l-Q3-ce hem A. 7-(2',2',2'-Trich.30roethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-cepham-4-carboxylic ac:id _ _ Following the procedure o:F Example 37A, but employing as the cephem 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-Q3-cephem 4-carboxylic acid ~U.S. 3,641,021), the desired product is prepared.
NMR (CDC13): ~ = 5.4(m) 2H; 5.1(d) lH; 4.85ts) 2H; 4.4(q) 2H; 3.7(s) 2H and 2.7(s) 3H.
B. 7-(2',2',2'-Trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4=~N-(p-methoxybenzyl)carba-oyl~-~3-cephem Employing the product of Example 38A and using the procedure of 15 Example 37B and lB, the desired intermediate product is synthesized.
NMR (CDC13): ~l = 7.0(q) 2H; 6.1(m) lH; 5.4(q) lH; 4.9(d) lH; 4.7(s) 2H, 4.4(m) 4H, 3.75(s) 3H and 3.6(s) 2H.

The procedure of Example 37 is repea-ted, starting with the appropri-20 ata 2',2',2'-trihaloethyl chloro:Formate, Q -cephem-4-carboxylic acid and amine, to give the following analogs:
RNH
`r~ I' ''' , ' O ~I\~CH20COCH3 ~NH-R2 .
~ .

: ~ :
:

.~

~64V~
R R
C13CCH20CO- 4-C6H5cH20c6HL~c~l2 C13CCH20CO- 4-C6H5CH20-3-FC6H3C~i2 C13CCH20CO- 2-Cl-4-CH30C6H3CH2-C13CCH20C0- 3~Cl-4-HOC6H3CH2-C13CCH20CO- 3, 4- ( CH30)~C6H3CH2-C13CCH20C0- 4-HOC6H4cH(cH3)-C13CCH20CO- 2-Br-4-CH30C6H3CH2-C13CCH20CO- 4-CH30C6HL~CH(0)-C13CCH20CO- 2,4-(CH30)2C6H3CH~CH3)-C13CCH20CO- 4-CH30C6H4CH(n-c3H7) C13CCH20CO- 3-CH3-4-cH30c6H3cH2 C13CCH20C0- 4-C2H6c02c6H4c 2 C13CCH20C0- 6 4 ( ) C13CCH20C0- 4~ C3H7C02)C6H4CH2 C13CCH20CO- 3,4-(C6H5CH2d)2C6H3CH2 C13CCH20CO- 4-CH30C6H4CH(CH3)-C13CCH20C0- 4-CH30C6H4CH(C2H5 C13¢CH20CO- 3-F-4-CH30c6H3cH2-C13CCH20CO- 3-Cl-4-CH30C6H3CH(CH3)-C13CCH20CO- 4-HOC6Hl~cH~-C13CCH20CO- 3-CH30-4-CH3C02C6H4cH2-C13CCH20C- ' 4-C6H5CH20C6H3CH(CH3) C13CCH20CO- 3~4-(C2H5C02)2C6H3CH2 C13CCH20C0- 4 (n-c3H7co2)c6H4cH2-C13CCH20C0- 4-(i-C3H7C02)C6H4cH(c2 5 : Cl~CCH20C0- 2-furylmethyl-C13CCH20C0- 5-methyl-2-furylmethyl-C13CCH20C0- 2-thienyImethyl-; 35 C13CCH20C0- 5-metpyl-2-thienylmethyl-: C13CCH20C0 1-(2-~uryl)ethyl-C13CCH20C0- 1-(5-me-thyl-2-furyl)ethyl-~: -70-.

.
..... . . . .

R R
Br3CCH20CO- ~-C6H5CH20C6~ C~l2 Br3CCH20CO- I~_C6H5cH2o-3-Fc6H3cH2 Br3CCH20C0- 2 Cl 4 CH30C6H3CH2 Br3CCH20C0- 4-Cl-4-HOC6H3CH2-Br3CCH20C0- 2 CH3 6 3 2 Br3CCH20C0- 2,4 ( H30)2 6 3 ( 3) Br3CCH20CO- ~-C2H5C02C6H4CH2 Br3CCH20C0- 3 CH3 4 CH30C6H3CH2 Br3CCH20CO- 3-F-4-CH3C02C6H3CH2-Br3CCH20CO- 3-I-4-CH3~C6H3CH2-Br3CCH20C0- 4_(i_C3H7C02)C6H4CH2~
Br3CCH20CO- 3~4-(C6H5CH20~2C6H3CH2 Br3CCH20CO- 4-CH30C6H,~CH(CH3)-Br3CCH2OC0- 4-CH3Oc6~4cH(c2H5)-Br3CCH20CO- 3,4-(CH30)2C6H3CH2 : Br3CCH20C0- 3 F 4 C~30C6 3 H2 Br3CCH20CO- 3-Cl-4-CH30C6H3CHtCH3)-Br3CCH20CO- 4-HOC6H4cH2-Br3CCH20CO- 4 HOC6 4CH(CH3) Br3CCH20C0- 4~H3C02C6H4CH2 - Br3CCH20CO- 3-Cl-4-HOC6H3CH2-Br3CCH20CO- 3-Cl-4-CH3C02C6H3CH2-Br3CCH20co_ L~_C6H5CH20C6H3CH(`CH3~
Br3CCH20C0- 3-Cl-4-C6H5CH2OC6H3CH2-Br3CCH20CO- 2-F-4-HOC6H3CH2-Br3CCH20CO- 3,4-(C2H5c02)2c6H3cH2 Br3CCH20CO- 4-(n~C3H7C02 )C6H4CH2-Br3CCH2oco_ 2-furylmethyl-Br3CCH20C0- 5-methyl-2-furylmethyl-: Br3CCH20C0- 2-thienylmethyl-Br3CCH20C0- 1-(2-furyl)ethyl-: 3r3CcH2oco 1-(5-methyl 2-furyl)ethyl-~ .
'~

_ ~' . ~

: , : .

i4`~3~9 EXAMPLE 1~ 0 The procedure of Example 38 is repea-ted, starting with the requisi-te reagents, to give -the following analogs:
S
RNH`~ N N
N ~ ~ ~ ~

~ -NH-R2 3 : ~:
~: ' ~ ~ -72-.

. . R R2 C13CCH20CO- 4-C6H5CH20C6H,~CH2-C13CCH20CO- 3-Cl-4-HOC6H3CH2-Cl CCH ~rcO r ~ ~ ( 3 )2 6 3 2 ' C13CCH20CO- 4-HOC6H4CH(cH3)-C13CCH20CO- 2-~r-4-CH30C6H3CH2-C13CCH20CO- 4-CH30C6H,~CH(0 )-C13CCH20C0- ~ ( 3 ?2 6 3 ( 3) C13CCH20CO- 4-CH30C6H4CH(n-C3H7?
C13CCH20C0- 3 CH3 4 CH3bC6H3CH2 C13CCH20CO- 4-C2H6c02c6H4cH2-C13CCH20C0- 4-HOC6H4CH(0)-' ~ C13CCH20CO_ , 3-I-4-cH30c6H3cH2-Cl3ccH2oco- 4-(i-C~,H7C02)c6H4cH2 ' C13CCH20CO- ' 3,4-(C6H5CH20)2C6H3cH2-'C13CCH20CO- 4-CH30C6H4CH(CH3).
. G13CCH20C0- . 4-CH30C6H~CH(C2H5) C13CCH20Co_ 3-F-4-CH30C6H3CH2-, - C13CCH20Co 3-Cl-4-CH30C6H3CH(CH3)-C13CCH20Co_ 4-HOC6H4CH2-C13CcH20cO- . 3 F C6 3 2 ' . 013CCH20CC- 3-CH30-4-CH3C02C6H4 (ÇH2 C13CCH20C0- 4-C6H5C~20C6H3cH(cH3) - C13CCH20C0- 3 Cl 4 C6H5CH~OC6H3CH2 '` ~ ,C13CCH20Co_ 3,4-tC2H5C02)2C6H3CH2 C13CCH20C0 4-(n-C3H7Ç~)C6H4CH2~
C13CCH20C0- 4-(i-C3H7C02)C6H4CH(C2H5) . ~13ccH2oco- .2-furylmethyl-C13CCH20C0- . . 5-methyl-2-furylmethyl-: C13CCH20C0- ~-thienylmethyl-C13CCH20C0- 5-methyl-2-thienylmethyl : C13CCH20Co~ (2-furyl)ethyl- .
C13CCH20C0- 1-~5-methyl-2-~uryl)ethyl--' ' ' , " ' , ; L~

Br3CCH20CQ- L~_c6H5cH20c6HL~cH2 Br3CCH20C0- 4-C ~I C~l20-3-FC6H3CH2-Br3CCH20C0- 2 Cl 4 C 3 6 3 2 Br3CCH20C0- 4-C1-4-HOC6H3CH2-Br3CCH20C0- 2-Br-4-CH30C6H3CH2-Br3CCH20CO- 2,4-(CH30)2C6H3CH(CH3) Br3CCH20CO- L~-C2H5C02C6H4CH2 3r3CCH20C0- 3 CH3 4 CH30C6 3 2 Br3CCH20CO- 3-F-4-c~l3co2c6H3cH2 Br3CCH20CO- 3-I-4-cH3oc6H3cH
'Br3CCH20CO- 4-(~-c3H7co2)c6H4cH2-Br3CCH20C0- . 3~4-(c6H5cH2o)2c6H3c 2 Br3CCH20CO- 4-CH30C6H4CH(CH3) ~r3CCH20C0- 4-cH3oc6H4cH(c2 5 Br3CCH20CO- 3,4-(CH30)2C6H3CH2 Br3CCH20C0- 3 F 4 CH3C6 3 2 Br3CCH20C0- 3 C1 4 CH30C6 3 ~ 3) Br3CCH20C0- 4 HOC6 4 2 Br3CCH20C0- 4-HOC6H4CH(CH3)-Br3CCH20CO- 4-CH3C02C6H4CH2 Br3CCH20co- . 3-Cl-4-HOC6H3CH2-B 3 2 3-cl-4-cH3co2c6H3cH
Br3CCH20CO- ' 4-c6H5cH2oc6H3cH(cH3) Br3CCH20C0- 3-cl-4-c6H5cH2oc6H3cH
Br.3CCH20CO- 2-F-4-Hoc6H3cH2-Br3CCH20C0- 3~4-(c2H5co2)2c6H3cH2 Br3CCH20CO- ' 4-(n-C3E17C02 )C6HI~CH2-Br3CCH20C0- 2-furylmethyl-Br3CCH20C0- 5-methyl-2-furylmethyl-Br3CCH20C0- 2-thienylmethyl- `
Br3CCH20C0- 1-(2-furyl)ethyl-Br3 2 1-(5-me~hyl-2-furyl)ethyl-, .

: -74-. .

, - .. : : ,: : ; : : - : ~ ..
.. , . . , . . . ~ . - . ,, -19~9 7 _ ( 2',2~,2~-Trichloroethoxycarboxamido)-3-acetoxymethyl-4-[1-(p methoxybe~zyl)tetra~ol-5-yl]-~3-cephem Phosphorous pentachloride (1.68 g., 8 mmole) is added to a stirred soltuion of 7-(2',2',2'-trichloroethoxycarboxamido)-3-acetaxymethyl-4-[N-(~-methoxybenzyl)carbamoyl~-~3-cephem (2.26 g., 4 mmole) and pyridine (0.64 g.,

8 mmole) in dry, ethanol-free chloroform (30 ml.) at 0-5C. After 30 min.
NMR indicated that the amide had completely reacted (disappearance of the 2 proton doublet at 84.45). A solution of tetramethylguanidinium azide (6.3 g., 40 mmole) in dry ethanol-free chloroform (20 ml.) is added dropwise over a period of 10 min. to the cooled solution. After a further 10 min. the ice-bath is removed and the reaction mixture is stirred at ambient temperature for 30 min. The reaction mixture is washed with wate~, a~ueous sodium bicarbonate solution (3 x), 6N hydrochloric acid (3 x), water, and dried over magnesium sul~hate. Evaporation of the solvent affords the crude product as a pale brown solid (1.5 g.). Column chromatography o~ silica gel commencing with hexane as eluent and adding gradually increasing proportions of ether, finally eluting with 100% ether affords the pure (by tIc) product. ! " :-i,l NMR (DMSOd6): ~ = 1.8(s~ 3H, 3.6(q) 2Hj`3.~(s) 3H, 4.2(q) 2H~ 4.8(s) 2H; 5.1(d) lH~ 5.6(m) 3H, 6.3(d) lH and 7.4(q) 4H.
; EXAMPLE 42 7-(2',2',2~-Trichloroethoxycarboxamido)-3-t2-methyl-1,~,4 thiadiaæol-s-~lthiomethyl)-4-El-(p-methoxybenzyl)tetrazol-5-yl~ cephem Starting wi~h the cepXem of Example 38B and following -the procedure of Example 41, -the desired product is synthesized.
NMR (C~C13): 8 = 7.0~q) 4H, 5.5(s) 2H; 5.4~m) 2H; 4.7(s) 2H; 4.1(m) 2H, 5.75(s) 3H and 5.65~m) 2H.

.

.

,, , ~ ... . ,. . . . . . . . . . . : .

l~S,4~1L9 Star-t;ng ~ith -t:he intermedia-t:es o:F Example 39, and employing the procedure of Example ~1, the following ~3-cephems arè synthesized:

R-NH S

0'~ ~CH20COCH3 ~1,~ 11 i ~, ~: , ,.

;; : ~

: . .
: -~ ' ' ;4~

C1 3C~'112()CO~ 't~ll5C~ '' -3 2 L~ C6ll5CH20-3~FC6H3('~l2 C13CCH20C.0 2 Cl 4 CH30C6H3CH2 5013CCH2QC0- 3-Cl-L~~H0~,6H3 2 C13CCH20CO- 3,4-~CH30~2C6H3CH2 C13CCH20CO- 4-HC6~L~cHtc~l3 ) C13CCH20CO- 2- Br-4-CH30C6H3CH2-C13CCH20CO- 4-CH30C6HL~CH(0) 10C13CCH20C0- 2,4 (CH30)2C6H3CH(CH3) C13CCH20CO- 4-CH30C6H4CH(n-c3Pl7) 3CCH20Co- 3 CH3 4 CH30C6H3CH2 C~3CCH20CO- 4 C2H6C02C6HL~CH2 15C13CCH20C0- 4-HOC6H4CH~0)-C13CCH20CO- 3-I-4-CH30C6H3C~2-C13CCH20C0- 4-(i-C3H7c02)~6~hcH2 C13CCH20C0- 3,4 ( ~ 5 2)2 6 3 2 C13CCH20C0- 3 6 4 ( 3) C13CCH20C0- 4-CH30C6~ CH(C2H5)- :
C13CCH20CO- 3-F-4-CH30c6H3cH2-. C13CCH20Co_ 3 6 3 ( 3) C13CCH20CO- 4-HOC6HL~CH2- _ C13CCH20CO- 4-CH3C02C6HI~CH2-C13CCH20CO- 3-CH30-4-CH3C02C6H4CH3- `.
C13CCH20Co- 4-C6H5CH20C6H3CH(CH3) C13CCH20CO- 3-cl-4-c6H5cH2oc6H3cH2 Ci3CCH2oCo- 3,4-(C2H5C02 )2C6H3CH2 C13CCH20C0- 4-(n-C3H7C2)C6H4cH2 . ; C13CCH20co- 4-(i C3H7C02)C6H4CH(C2H
: : : C13CCH20Co 2-furylmethyl- :
C13CCH20C0- ~-rnethyl-2~furylmethyl-C13CCH20C0- 2-thienylmethyl : ; 35 C13CCH20C0- ~-rnethyl-2-thienylmethyl-: ~C13CCH20C0- 1-(2-furyl)ethyl-3CCH20co_ 1-(5-methyl-2-furyl)ethyl-:i ~: : :

:: :

.~ ~
.

~L~6~ g 6 5 2 6 ~C~12 Br3CCH20C~- 4-C6H5cH20-3-F¢6H3c~2 Br3CCH20C0- 2 Cl 4 CH30C6H3CH2 Br3CCH~OC0- 4~Cl-4-HOC6H3CH2-Br3CCH20C0- 2 Br 4 CH30C6H3CH2 Br3CCH20C0- ,4 (CH30~2C6H3CHtCH3) Br3CCH20CO- I~-C2H5C02C6HL~CH2 13r3CCH20CO- 3-CH3-4-CH30C6H3cH2-Br3CCH20CO- 3-F-4-CH3C02C6H3CH2-Br3CCH20CO- 3-:L-4-CH30c6H3cH2-Br3CCH20C0- 4_(1_C3H7C02)C6H4CH2-Br3CCH20CO- 3,4-(c6H5cH2o)2c6H3cH2 4-CH30C6H,~CHtCH3 )-Br3CCH20C0- 4-CH30C6H4cH~c2H5) Br3CCH20C0- 3,4-(CH30)2C6H3CH2-Br3CCH20CO- 3-F-4-CH30C6H3cH2-Br3CCH20CO- , 3-Cl-4-CH30C6H3CH(CH3~- ' .
Br3CCH20C0- 6 4 2 Br3CCH20C0- 4-HOC6H4CH~CH3)-Br3CCH20CO- 4-CH3C02C6H4CH2- ' ':
Br3CCH20CO- 3-Cl-4-HOC6H3CH2-3 2 3-Cl-4-CH3C02C6H3CH2-Br3CCH20C0- 4 C6H5CH20C6H3cH(cH3) 25Br3CCH20C0- 3-C1 ~4-C6H5CH2c6H3cH2~
Br3CCH20CO- 2-F-4-HOC6H3CH2 Br3CCH20CO- 3 ,4 -~ C2H5C02 )2C6H3CH2 Br3CCH20CO- 4-tn-C3H7C02 )C6H4CH2-Br3CCH20C0- 2-furylmethyl-30Br3CCH20C0~- S-methyl-2-furylmethyl-Br3CCH20C0- 2-thienylmethyl-3 H2 1-~2-furyl)ethyl-Br3CCH20C0 1-~5-methyl-2-furyl~ethyl- .

.
.

: : :
-78- .

~ . ... . . .... .

~4~

EXAMPLE '~'~
In a manner similar to the procedure of Example 41, and starting with the intermediates of Example 40, the following congeners are synthesized:

RNH / S
~ ~ ~ N~ ~ N
O ~ ~ CH2S ~ ~ H3 N~ N-Rll ~ : .

: ;
:
~, :

. ~

R R
C13CCH20CO~
C13CCH20CO- 4-C6H5CH20-3-E`C6H3CH2-C13CCH2QCO- 3-Cl-4-HOC6H3CH2-C13CCH20CO- 3,4-(CH30)2C6H3CH2 C13CCH20CO- 4 HC6 4 ( 3) C13CCH20CO- 2-~r-4-CH30C6H3CH2-C13CCH20CO- 4-CH30C6H4CH(0)-C13CCH20CO- 2,4-(CH30)2C6H3CH(CH3)-C13CCH20CO- 4-CH30c6H4cH(n C3H7) C13CCH20CO- 4-HOC6H4CH(~)- .

C13CCH20CO- 4-~1-C3H7CO2)C6H4CH2-C13CCH20CO- 3,4-(C6H5CH20)2C6H3CH2 C13CCH20CO- 4-CH30C6H4CH(CH3) C13CCH20CO- 4-CH30C6H4cH(c2H5) C13CCH20CO- 3-cl-4-cH3oc6H3cH(cH3) : C13CCH20CO- 3 CH30 4 C 3 2 6 4 2 ,~ C13CCH20CO- 4-C6H5CH20C6H3CH(CH3) C13CCH20CO- 3-Cl-4-C6H5CH20C6H3CH2 , C13CCH20CO- 3,4-(C2H5C02)2C6H3CH2 C13CCH20CO- 4-(n-C3H7C2)c6H4cH2 C13CCH20CO- 4-(i-C3H7C02)C6H,~CH(C2Hs)-: C13ccH2oco- 2-furylmethyl-:: C13CCH20C- 5-methyl-2-furylmethyl- `
: : C1 CCH OCO- 2rthîenylmethyl-: . 3 2 C13CCH20CO- 5-methyl-2-thienylmethyl-C13CCH20CO- 1-(2-furyl)ethyl-~ ~ C13CCH20CO- 1-~5-methyl-2-furyl)ethyl-: . . , . -80-. ~ .

.. . . . .
~ ~ .
' ' ' ' .
:~:. .. ,. .. .... . .: ., . . . . :. - . :-. - -~i4~

CC~ OCO i~_C311sc~l2oc3~ c~l2-Br3CCH20C0~ C6H5cH2o 3~FC6~l3c 2 Br3CCH20CO- 2-C~ -CH30C6H3CH2-Br3CCH20C0- 4-Cl-4-HOC6H3CH2-Br3CCH20C0- 2 H3 6 3 2 Br3CCH20C0- 3 2 6 3 3 Br3CCH20CO- 4-C2H5c02c6H4cH2 Br3CCH20CO- 3-CH3-4-CH30C6H3CH2 Br3CCH20CO- 3-F-4-CH3C02C6H3CH2-Br3CCH20CO- 3-I-4-CH30c6H3cH2-Br3CCH20C0- 4-(i-C3H7C02)C6H4cH2 9r3CCH20C0- 3,4-(C6H5CH20)2C6H3C 2 Br3CCH20C0- 4-CH30C6H4CH(CH3) Br3CCH20C0- 4-CH30C6H4cH(c2H5) Br3CCH20C0- 3,4-(CH30)2C6H3CH2 Br3CCH20CO- 3-F-4-CH30C6H3CH2-Br3CCH20C0- 3-Cl-4-CH30C6H3CH(CH3)-~r3CCH20CO- 4-HOC6H4cH2-Br3CCH20C0- 6 4 ( 3) Br3CCH20CO- 4-CH3C02C6H4CH2-Br3CCH20CO- 3-Cl-4-HOC6H3CH2-Br3CCH20CO- 3-Cl-4-CH3C02C6H3CH2-Br3CCH20C0- 4-C6H5CH20C6H3CH(CH3) : 25 Br3CCH20C0- 3_Cl_4-c6H5cH2oc6H3cH2 Br3CCH20CO- 2-F-4-HOC6H3CH2-:, Br3CCH20CO- 3,4-(C2H5C02)2C6H3CH2 Br3CCH20CO- 4-~n-C3H7C2)C6H4CH2 Br3CCH20C0- 2-furylmethyl-Br3CCH20C0- 5-methyl-2-furylmethyl-Br3CCH20C0- 2-thienylmsthyl-~r3CCH20C0- 1-(2-furyl)ethyl-Br3CCH20C0- 1-(5-methyl-l-furyl)e-thyl~

' .
: ..

~, \

.: ~ .. - : - . , : , . .

7-Amino-3-acetoxymethyl-4-rl-(p-~ thoxybcnzyl)t~trclzol-s-y~ 3-cepllern Ac-tivatecl zinc dus-t (300 mg.) is added -to a stirred solution of 7-~2~,2~,2~-trichloroethoxycarboxamido-3-acetoxymethyl-4-[1-(p-methoxybenzyl-tetrazol-5-yl]-~3-cephem ~300 mg. 0.5 mmole) in 90% acetlc acid (3 ml.) and the suspension is stirred a-t ambient -tempera~ure for 30 min. The reaction mixture is filtercd, and evaporated -to dryness. The resultant yellow foam is dissolved in chloroform, and the solution extrac-ted -twice with dilute hydro-chloric acid. The aqueous e~tracts are mixed with chloroform, and dilute sodium hydroxide is added to the stirred mixture to pH 7Ø The mixture is filtered to remove precipitated inorganic salts, the layers separated, and the , aque~us solution extracted twice w;~h chloroform. The combi~ed organic ex-tracts are washed with water and dried over magnesium sulphate. Evaporation of the solvent affords the product as a pale yellow solid (110 mg.), pure by -t.l.c.
NMR (CDC13): ~ = l.9(s) lH; 2.0(s) 3H; 3.45-(q) 2H, 3.8(s) 3H; 4 3~q) 2H; 3.8(s) 3H; 4.3(q~ 2H; 4.65(d) lH; 4.95(d) lH; 5.5(s) 2H and 7.1tq) I~H.
Similarly, starting with 7-(2',2',2'-trichloroetho~ycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiGmethyl)-4-[1-(p-methoxybenzyi)tetrazol-5-yl]-~3-cephem and following -the procedure of Example 45, 7-amino-3-t~-me-thyl-1,3 ? 4-thiadiazol-5-ylthiomethyl)-4-~l-tp-methoxybenzyl~tetrazol-5-yl]-~ -cephem is prepared. . :;

NMR (CDC13): ~ = 7.0tq) 4H, 5.55(s) 2Hj 409~:d) lH; 4.6tm) lH, 3.8 ~s) 3H; 3.65tm) 2H` and 2.7(s) 3H.
. ' : ' :

: : , : ~ .

, .

... , . . , . . ~ . ~ .. .. ... , . . . , .~ . .

9L~

The procedure oF ~xample 45 is repeated, startln~ with -the interme-diate ~3-cephems oE Examples 43 and 44, to give the following analogs:

H2N~ ~ ~

o~L `15 CH20COCHa -Rll : ' ~ -83-' :
~'' , - ..

Rll ~-c6~5cH2-3-FC6~13c}'2 2 Cl 4 C 3 6 3 2 3-C~-L~ IOC ~I C~
3,4-(CH30)2C6H3CH2-4-HOC6H,~CH(CH3)-2 ~r 4 CH3 C6 3 2 L~ CH OC H CH(P) 2'4-(CH30)2C6H3CH(CH3) 4-CH30C6H4CH(n-C3H7 ) 4-C2H5c02c6H4cH2 3 F 4 CH3Co2 6 3 2 4-HOC6H4CH(0)-4-(i-C3H7Co2)c6H4cH -3~4-tC6H5CH2O)2C6H3CH2 4-cH3oc6H4cH(cH3)-4-CH30C6H4CH(c2 5) . 4-CH3C02C6H4CH2 4-C6H5CH20C6H3CHtCH3)-3-Cl-4-C6H4CH2oc6H3cH2-` 3 4 (C H C0 ) C H CH -(_ 3 7 2) 6 4 2 4-(i-c3H7co2)c6H4cH(c2 5 : 2-furylmathyl-:~ : 5-methyl-2-furylmethyl-~: :
: 2-thienylmethyl-5-methyl 2-thienylm~thyl-1-(2-furyl)ethyl-1-(5-methyl-2-furyl)ethyl-~ .
~, ~
~ 4-.
:~ :

and H2N ~ / ~ N ~ U
~ c~2s~ CH3 ~d~
~-Rll ~11 . _ 4-C6H5CH20C6H4cH2 4-C6H5cH20-3-Fc6H3cH2 2 Cl 4 CH30C6H3CH2 3-Cl-4-HOC6H3CH2-3,4-~CH30)2C6H3CH2-4-HOC6H4CHtCH3)-2 Br 4 3 6 3 2 lQ 4-CH30C6H4CH(0)-2'4-(CH30)2C6H3CH(CH3) 4-CH30C6H4CH(n-C3H7 ) 4-C2H5c02c6H4cH2 4-HOC6H4CH(0)-4-(i_C3H7CO2)C6H4CH2-3~4-(c6H5cH2o)2c6H3cH2 4-CH30c6H4cH(cH3)-4-CH30C6H4CH(C2H5) 3_P-4-CH30C6H3CH2- .
3-Cl-4-CH30C6H3CH(CH3)-3-CH30 -4-CH3c02c6H4cH2 : 4~C6H5cH2oc6H3cH(cH3)-3-Cl-L~ -C6H4CH20C6H3CH2 3,4 (C2H5 2)2 6 3 2 4-(n-C3H7c02 )C6H4CH2 4-(i-C3H7C2)c6H4cH(c2H5) 2-furylmethyl-; 5 methyl-2-furylmethyl-2-thienylmethyl-5-methyl-2-thlenylmethyl-1-(2-furyl)ethyl-1-(5-methyl-5-furyl)ethyl- -85-4~:~9 7-Amino-3-(2-m~-thyl-1,3,4-thladiazol-5-ylthiomethyl)-4-(tetrazol-5-Yl)-~3-c:ephem . . _. . _ _ . ._ ._ 7-Amino-3-(2-me-thyl-1,3,~-thiadiazol-5--ylthiomethyl)-L~-[l-~p-methoxybenzyl)tetrazol-5-yl~-~3-c~phem ~125 mg.) is dissolved in acetone (2 ml.) and p-toluenesulphonic acid (60 mg.) in acetone (1 ml.) added. The salt precipitates out as a brown oil after addi-tion of ether -to this mixture. The solvent is decanted and ths residue washed (3 x) with ether t30 ml.). The residual oil is dissolved in trifluoroacetic acid/anisole (4:1 v/v; 2 ml.) and heated on a water bath, in a stoppered flask (25 ml.) for 3 hr. at 38C.
At the end of this time the reaction mixture is poured into dry ether, the organic solvents decanted from the instantly formed precipitate, and the residual solids washed with further portions of ether (3 x 30 ml.).
The crude deprotected material was taken up in acetone~water (pH 2.5), ex-lS tracted wlth ethyl acetate, the pH of ~he aqueous phase adjusted to 7.6 with aqueous sodium hydroxide (2N) and re-extracted with ethyl ace~ate. Concentra-tion of the a~ueous phase in vacuo, to dryness, affords a solid. This com-pound is characterized by acylation of the above sodium salt with 2',2',2'-trichloroethoxycarbonyl chloride using the procedure of Example lA to give 7-(2',2',2'-trichloroethoxycar~o~amido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio-methyl-4-(tetrazol-S-yl?-~3-ce~hem.
NMR (CDC13): ~ = 4.7(d) lH, 4.2(m) lH; 5.1(s) 2H; 5.35Ss) 2H, 6.0(m) 2H and 7.2(s) 3H.
.
':

~ ~ .

~ ~ .
~:
.

Similar to the proced~lre oE Example 47, and star-t.ing with the com-pounds of Example 46, 7-amino-3-acetoxymethyl-4-(tetrazol-5-yl)-~ -cephem and 7-amino-3-~2-methyl-1,3,4-thiadiazol-5-yl-thiome-thyl-L~-(te-trazol-5-yl)-~3-cephem are prepared.

.

Sodium bicarbonate (~2 g , 0.5 mole) ls added gradually to a vigorously stirred suspension of 7-amino-3-acetoxymethyl Q3-cephem-4-carboxylic acid (50 g., 0.18 mmole) ln ace-tone/wa-ter (250/500 ml.). A solution of benzyl chloroformate (36 gO~ 0.21 mole) in acetone (70 ml.) is added dropwise -to -the stirred solution over a period of 45 min. Af-ter- stirring for six hr. the ace-tone is removed on the rotary evaporator and -the aqueous residue washed with ethyl acetate to remove ;mpurities. The aqueous solution i9 overlaid with ethyl acetate and acidified to pH 4Ø The combined ethyl acetate solutions from the extractions of the aqueous solution are washed with water and dried over magnesium sulphate. Evaporation of the ethyl acetate affords the product, 7-benzyloxycarboxamido-3-a-cetoxymethyl-Q -cephem-4-carboxylic acid, as an off-white solid (56 g.), pure by t.l.c.
NMR (DMSOd6): ~ = 2~0(s) 3H; 3.5(s) 2H; 4.8-5.2(m) 5H and 7.3(s) 5H.
SimilarlY are prepared ylthiomethyl)- -cephem-4-carboxylic acid, NMR (DMSOd6): ~ = 7.5(s) 5Hj 6.6(d) lH, 6.2(s) 3H; 4.4(b) 2H; 4.04 ~s) 3H and 3.8(s) 2H;
7-Benzyloxycarboxam;do-3-methyl-Q3-cephem-4-carboxylic acid; and 7-Benzyloxycarboxamido-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethy1)--cephem-4-carboxylic acid.

~; . .

7-Benzyloxycarboxamido-3-acetoxyme-thyl-4-[N-(~-methoxybenzyl?carbamoyl]-~3-cephem A solution of 2,4-d;n;trophenol ~22 g., 0.1 mole) in methylene chloride (100 ml.) is added to a solu-tion of 7-benzyloxycarboxamido-3-acetoxy-methyl-~3-cephem-4-carboxylic acid ~41 g., 0.1 mole) in dry dloxane (400 ml.).
To this stirred solution is added a solution of dicyclohexylcarbodiimide (21 g., 0.1 mole) in dloxane (100 ml.). After 1.5 hr. the precipi-tate of dicyclo-hexylurea is removed by filtrationO To the filtrate is added a solution of ~-methoxybenzylamine (13.7 g., 0.1 mole) in dioxane (100 ml.). After stirringfor 6 hrs. the precipitated solid is filtered, washed with ether and ethyl acetate and dried, affording the product as a white solid (30 g.) pure by t.l.c.
NNR (DMSOd6): ~ = 2.0(s) 3H; 3.4(s) 2H; 3.7(s) 3H; 4.3(d) 2H; 4.9 (d) 2H; 5.0(m~ 4H, 5.4(q) lH and 7.0(m) 9H.
In a similar manner is prepared 7-benzyloxycarboxamido-3-¦1-methyl-tetrazol-5-ylthiomethyl)-4-[N-(p methoxybenzyl?carbamoyl]-~ -cephem.
NMR (C~C13): ~ = 7.4(s) 5H, 7.1(q) 4H~ 7.7(m) 2H; 5.25(s) 2H; 5.45 (d) lH; 4.5(m) 4H; 4.0(s) 3H, 5.9(s) 3H and 5.79(s) 2H; and 7-benzyloxycarboxamido-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-0 4-[N-(p-methoxybenzy1)carbamoyl3 b3~cephem.

Starting with the appropriate 3-substituted-7-benzyloxycarboxamido-~3-cephem-4-carboxylic acid from Example 49, and employing the procedures of Example 50, the following am;de intermediates are prepared:

~ .

.

; .. , , . . . . ~ . .. . - . - . . . . .. . - -I~cH2ocoN~ ~ S`~
...
.1 ~ --CH2A

4-C6H5cH20c6H4cH2 CH3C02-3-Cl-4-HOC6H3CH2-CH3C02-3,4-(CH30~2C6H3CH2 CH3C02-4-CH30C6H4CH(0)-CH3C02-4_(1_C3H7C02)C6H4CH2- CH3C02-4-CH30C6H4CH(CH3 ) CH3C02-~_CH30-4-CH3CO2C6H3CH2- CH3C2 2-furylmethyl-CH3C02-1-(2-furyl)ethyl-CH3C02-4-CH30C6H4CH(0)-C3H3N2S2*
4-C2H5C02C6H4C~l2 C3H3N2S2*
4-t1-C3H7C02)C6H4CH2- C3H3 2 2 3 F-4-HOC6H3CH2-C3H3N2S2*
4-HOC6H4CH(CH3~- -C3H3N2 2 4-CH30c6H~cH(c2H5) C3H3N2S2*
; 4-cH3oc6H4cH(n--c3H7)- C3H3N2 2 ;~

.
:

.: ~ , . , . - ~ ..

~4~

L~-cH3oc6H4cH(n-c3H7)- C2 3 ~jSI
2 Br 3 6 3 2 C2H3 4-HOC6H4CH(IZ~)- C2~13N"S l 5-methyl-2-furylrnethyl- C2H3N4SI
4-C6H5CH20C6H4CH2 C2H3N,IS
3'4-(CH3C02 )2C6H3CH2- C2H3N,~S i 4-(i-C3H7C02)C6H4CH2- C2 3 4 2-furylmethyl- C2H3N4 5-methyl-2-thienylmethyl- C2H3N4S~

C3 3N2 2 ~

C2H3N4S = -S-~ ~ C 3 ~ N / :

Phosphorous pen-tachlorlde (4 2 g., 20 Tmnole) is aclded to a suspension of 7-benzyloxycarboxamido-3-acetoxymethyl-~-~N-(p-methoxybenzyl)carbamoyl]-~ -cephem (5.3 g , 10 mmole) m dry, ethan~ ree ehloroform (100 ml.) contain-ing pyridine (1.7 g., 20 mmole). After 30 min., NMR indicates the reaction is complete.
The solution is cooled in an ice-bath ~md a solution of tetramethyl-g-l~nidinium azide (16.0 g., 100 mmole) in dry, ethanol-free chloroform is added dropwise over a period of 20 min. AEter a further lO min. the ice-bath is removed and stirring is eontinued for 30 min. at ambient temperatures. The solution is washed with water, sodium biearbonate solution (3 x~, 6N hydro-chlorie aeid (3 x), water, and dried over magnesium sulphate. Evaporation oE
the solvent affords the erude produet as a brown solid (3.7 g.), whieh is purified by column ehromatography on siliea. Elution with dichloromethane:-hexane (1:1) and then with ether:diehloromethane:hexane (2:1::L) removes im-purities. Elution with ether affords the produet, 7-benzyloxycarboxamido-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-~ -cephem, as a white solid, pure by t.l.c.
NMR (DMSOd~ l.9(s) 3H; 3.65(s) 2H; 3.8(s) 3H, 4.3(s) 2H;
5.15(s) 2H; 5.35(dj lH; 5.6(m) 3H; 7.2(m) 9H and 8.6(d) 1~.
Similarly is prepared 7-benzyloxycarboxamido-3~ met~yltetrazol-5-ylthiomethyl)-4 ~1-(p-methoxybenzy~)tetrazol-5-yl]-~ -eephem.
NMR (DMSOd6): ~ = 7.3~s) 5H, 7.05(q) 4H, 6.5(s) 3H, 6.2(d) lH; 5.05 (s) 23; 3085(s) 3H, 3.7(s) 3H~ 3.5-4(m) 2H and 3.3(s) 2H.
'' ' ~ .

:

L~a Employing the procedure o~ Example 52, and starting with th~ arnides of Example 51, the following tetrazole ;ntermed;ates ara synthesized:
0CH20CONH~,fS~
r-~ 1 ~H2A

N ~-R
N
Rll A
~

4-C6H5cH20c6H4cH2 CH3C02-3-Cl-4-HOC~j,H3CH2- CH3C02-3,4-(CH30)2C6H3CH2- CH3C02-3 6 4 (0) CH3C02-4-(i-C3H7C02)C6H4CH2- CH3C02-4-CH30C6H4CH(CH3) CH3C02-3-CH30-4-cH3co2c6H3cH2- CH3C02-15 ?-furylmethyl- CH3C02-1-(2-furyl)ethyl- CH3C02-3-F-4-CH3C02C6H3CH2 C3H3N2S2*
: 4-CEI30C6H4CH(0)- C3H3N2S2*
4-C2H5C02C6H4CH2 C 3H3N2S2*
4 (- 3 7 2) 6 4 2 C3H3N2S2*

4-HOC6~l4cH(cH3)- C3H3N2 2 : : 4-CH30C6H4CH(C2H5 )- C3H3N2S2*
~ 4-CH30C6H~,~,CH (n-C 3H7 ) _ C3H3N2 S2 ,. ::

~ .

: -93-:
`,. .

i~i4~L9 Rll A
~-cH30C6H,~cH(n-c3H7) C2H3N,~S'I-2 3r 4 CH3C6 3 2 C2H3N~St 4-HOC6H4cH(0 )- C2H3N4S I
5 5-methyl-2-furylme-thyl- 2 3 4 L~C6H5CH20C6HI~CH2 C2H3N4 3,4-(CH3C02 )2C6H3CH2 C2H3N4 4-(i-C3H7CO2)C6H4CH2 C2H3N4 2-furylmethyl- C2H3N~S~
5-methyl-2-~hienylmethyl- C2H3N4 3 3 2 2 ~

2H3N4S~S-CII ~ CH3 N ~ ~

;4~1~

7-Amino-3-acetoxymethyl-4-(tetrazol-5-yl)-~ -cephem 7-Benzyloxycarboxamldo-3-acetoxymethyl-4-[1-(~-methoxybenzyl)tetra-zol-5-yl] ~ ~cephem (100 mg.) is dissolved in -trifluoroacetic acid/anisole (4:1, v/v), (0.5 cc) and to th;s reddish-brown solution trifluoromethanesul-phonic acid is added from a Pasteur pipette (25 drops). Immediate efferves-cence is observed and the solution t~lrns cherry-red.
After 3 min. at room temperature the reaction mixture is quenched by addition of ether (sodium dried). A brown gum is deposited, the supernatant liquids are decanted, and the residue washed again with ether.
The viscous gum is redissolved in the minimum volum~;:of methylene chloride containing 1% triethylamine and the solution chromàto'grapped on silica (2 mm, 20 x 20, Kieselgel G F254) using acetonitrile/water (6:1 v/v) as the elut;ng solvent. ' 'The band at r.f. 0O4 was removed and extracted with 1% triethyl-amine/methylene chloride (3 x 150 ml~). The organic'extracts are evaporated to dryness _ vacuo to afford a white solid, a mixture of 7-amino-3-acetoxy- - -methyl-4-(tetrazol-5-yl)-~3-cephem and triethylamine hydrochloride.
NMR (CDC13~: ~ = 5.25(d) lH; 4.9(m) 2H and 2.05(s) 3H.

7-Amino-3-(1-methyltetrazol-5-ylthiomethyl)-4-(tetrazol-5-~ m In a manner similar -to Example 54, starting with 7-benzyloxycarbox-amido-3-(1-methyltetrazol-5-ylthiomethyl)-4-~ -methoxybenzyl)tetrazol-5-~` 25 yl)-~3-cephem, the crude product is obtained.

: .
'~
:: `

: : _9 5 _ "

' ,. ' . .

... . . . ..

~16~

The Zwitterion is isolated by crystallization of the crude reaction mixture, after precipitatiorI wi-th cIry ether, from a minimum vo].wne of potas-sium hydrogen phosphate pH 7 buffer. Af-ter ini-tial dissolution of the crude react;on mixture the Zwitterion precipitates as a cream-yellow solid and is S pure by thin layer chromatography.
NMR (DMSOd6): o = 5.1(d) lH; 4.8(d) lH, 4.3~q) 2H; 3.9(s) 3H and 3.7(s) 2H.

Employing the experimental conditions of Example 54, and starting with the requ;site products of Example 53, the in-termediates 7-amino-3-acetoxy-4-(tetrazol-S-yl)-~3-cephem, 7-amino-3-(1-methyltetrazol-5-ylthiomethyl?-4-~tetrazol-5-yl)-~ -cephem and 7-amino-3-(2-methyl~1,3,4-thiadiazol-5-ylthio-methyl-4-(tetrazol-5-yl)-~ -cephem are produced.

_9~ _ , .. . , .. . . . , ., , . - - , -~XAMPLE 57 7-(2',~',2'-Trlchloroethoxycarboxamido)-3-methyl-~2-cephern 4-carboxyllc acid _ .
7-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-~ -cephem-4-carboxylic 5 acid t66.6 g.) and N-hydroxysuccinimide (21.6 g.) in dioxane (200 ml.) at room temperature is treated ith dicyclohexylcarbodiimide (35.6 g.) and the m;xture allowed to stir for one hour at room -temperature. The mixture is filtered and the filtrate evaporated under reduced pressure to leave an oil which is dissolved ;n pyridine (400 ml.) at 7C. and is then treated wi-th aqueous sodium hydroxide (7.5 g. in 100 ml.) with vigorous stirring. The mix-ture ;s allowed to warm to 25C. and stirring continued for a further 1.75 hrs. The pyridine is evaporated under reduced pressure and the residue poured onto ice. The pH is ad~usted to 2 with 6N HCl acid and the precipitate ex-tracted into ethyl acetate. The organic solution is washed with ~N HCl acid, water, and then evaporated under reduced pressure. The residue is dissolved in aqueous sodium carbonate solution and the resultant solution is washed with ethyl acetate. The aqueous solut;on is treated with charcoal, filtered and the pH of the filtrate ad~useed to 2 w;th 6N HCl acid. The precipitate is extracted into ethyl acetate and the organ;c solution is treated with charcoal, filtered, and dried (MgSO4). The solution is then evapora-ted under reduced pressure to leave the required product as a foam, which solidifies on tritura-tion with petroleum ether (48.0 g.) and is essentially pure by chromatography.
NMR (CDC13) ~ = 7.5(d) lH, 6.0(q) lH, 5.2(m) 2H; 4.7(s) 2H; 4.6(s) lH and l.9(s) 3Ho ' I

.
,.
. .

, .. ~ .. _~ .
In a similar manner to Example 57, startlng with 7-(2',2',2'-trl-bromoethoxyearboxamido)-3-methyl-~3-cephem-4-earboxylie acid prepared by the general proeedure of Example lA, in place of the corresponding chloro eompound, 7-(2',2',2'-tribromoethoxycarboxa~ido)-3-methyl-~ -cephem-4-carboxylic aeld is produced.

. :

. . .
7-(2',2',2'-Trlchloroe-thoxycarboxamido)-3-methyl-~-LN-(~-methoxybenzyl)carbamoyl]-Q2-cephem 7-(2',2',2'-Trichloroe-thoxycarboxamido)-3-methyl-~ -cephem-~carboxylic acid (46.0 g.) and N-hydroxysuccinimide (14.3 gO) in dioxane (750 ml.) is treated after 1 hr. with dicyclohexylcarbodiimide (24.3 g.) at room temperature with stirring. To this s-tirred solu-tion is added p-methoxybenzylamine (32.8 g.) in dioxane t200 ml.) and the mixture s-tirred for a further hour at room temperature. The mix~ure is filtered and the solu-tion s-tirrad for a further hour at room temperature. The mixture ls filtered and the solution concentrat ed to 300 ml. under reduced pressure. The concentrate is pcured into a saturated aqueous Na2C03 solution (2 liters) and the precipitate collected.
The precipitate is washed with water, lN HCl, and finally water. The solid is dried under reduced pressure at 100C. for 16 hrs. to furnish 7-15 (2~,2~,2~-trichloroethoxycarboxamido)-3-methyl-4-~N-(p-methoxyphenyl)carb-amoyl] ~ ~2-cephem (58.6 g.). A sample ;s recrystallized from acetone (m.p.
219-220C.).
NMR (DMSOd6): ~ =7.0(q) 4H; 6.0(q) lH; 5.2(m~ 2H; 4.7ts) 2H; 4.6(s) lH; 4.2(d) 2H; 3.7(s) 3H and 1.7(s) 3H.

Starting with 7-(2~,2',2~-trichloroethoxycarboxamido~-3-methyl-a2-cephem-4-carboxylic acid, prepared by the procedure of Example 57, and the appropriate amine, and repeating the procedure of Example 59, the following ;ntermed;ate am;des are prepared:
C13CCH20C-NH y S ~

~ ~ CH3 ; 0 NH-R2 _99_ ~i4~t~

. _~
4-C6H5C~l~Oc6~ c 2 ~ -c6H5cH2o-3-E C6H3CH2 2-C1-4-CH30C6H3cH2- .
3-Cl-4-HOC6H3CH2-3,4-(CH30)2C6H3CH2-4-HOC6H4cH(cH3)-2-Br-4-CH30C6H3CH2-4 CH30C6H4CH(0) 2'4-(CH30)2C6H3CII(CH3) 4-CH30C6H4CH(n C3H7 4-C2H5C2CfiH4CH2 4-HOC6H4CH(0)-4~ C3H7c02~c6H4cH2-3'4 tC6H~CH2)2C6H3 H2 4-CH30C6H4CH(CH3) 4-CH30C6H4CH(C2H5) 3-F-4-CH30c6H3cH2-3-Cl-4-CH30C5H3CHtCH3)-: 3-CH30-4-CH3C02C6H3CH2-4-C6HscH2c6H3cH(cH3)-3-Cl-4 -C6H4CH20C6H3CH2 -3,4-(C2H5C02)2C6H3CH2 4 (n c3H7C02)C6 4 H2 4-(1-C3H7C02~C6H4CH(C2H5)-2-furylmethyl-: 5-methyl-2-furylm~thyl-2-thienylmethyl-; : 35 5-methyl-2-thienylmethyl-l-t2-furyl)ethyl-l-t5-methyl-2-furyl)ethyl-~ ~ -100-:- - :
- .. . , . ;~ . - i .. .~ , . . , - , , .. . . . ~ . . -. . .. . .

4~1~

Simllarly, when 7-(2',2',2'-tribromoe-thoxycarboxamido)-3-me-thyl-a2-cephem-4-carboxylic acid is employed as the reagent in place of 7-(2l,2~,2l-trichloroethoxycarboxamido)-3-methyl-~ -cephem-4~carboxylic acid in the proce-dure of Example 59 along with the appropriate amine, the following amides aresynthesi~ed:

3r3ccH20co~
\NH-R

.

::
.
:~

. ~ .

. . ~ . . , . . ~ ; - . . . . . , . , ., . . ~ i . .. :

~9~4~19 .

2 Cl ~ CH30C6H3CH2 I~-Cl-4-HOC6H3CH2-2-~r-~-CM3C6~l3CH~.~
2'L~-(CH30)2C6H3CH~C~I3) 3-F-4~CH;,C02C6H3CH2-3-~-4-CH30C6H3Ctl2 -4-(1-C3H7C02)C6H4CH2-3'4-(C6H5CH20)2C6H3CH2 4-CH3c6H~cH~cH3)-4-CH30C6H4cH(c2HS) 3,4-(CH30)2C6H3CH2 3-Cl-4-CH30C6H3CH(CH3)-3-Cl-4-cH3co2c6H3cH
: 4-c6HscH2oc6~3cH(cH3) 25 ~ 3 Cl 4 C6H5CH20C6H3CH2 3,4-(C2~15C02)2C6~3cH2 4~(n~C3H7c2)c6H4cH2 2 furylmethyl-30 ~ 5-methyl-2-furylmethyl-2-thienylmethyl- ~ ~ -: 1-(2- ~ yl3ethyl-(S-methyl-2-furyl)ethyl-1~4~

EXA~PLE 62 ~ .
7-(2',2',2'-Trichloroethoxyc~r~boxamido)-3-methyl-4-[1-(~-methoxy-benzyl)-tetrazol-5-yl]-~ -cephem _ _ 7-t2',2',2'-Tr;chloroe-thoxycarboxamido)-3-methyl-4-~N-(~-methoxy-benzyl)carbamoyl]-~ -cephem (44.2 g.) and pyridine (14.06 g.) in chloro$or~n ~300 ml., ethanol free) at 40C. is trea-ted with phosphorous pentachloride (27.5 gO) and the mixture stirred at 40C. for 3 hrs. The solution is cooled to room temperature and tetramethylguanidiniu~ azide (87.~ g.) added, and the solution allowed to stir at room temperature for 2 hrs. The solution is then washed w;th water, aqueous sodium b;carbonate, lN HCl acid, water, and dried (MgS0l~). The organic solution is evaporated under reduced pressure to leave a gum which is dissolved in ethyl acetate (200 ml.) and passed down a column of alum;na. The fract;on contain;ng the requ;red product i5 collected and the solution evaporated to dryness under reduced pressure to yield the product as a pale orange solid (4204 g.j.
NMR ~CDC13): ~ : 7.0(q) 4H; 6.1(d) lH; 6.0(s) lH, 5.6(q) 2H; 5.4(s) . lH, 5.2(q) lH; 4.8(d) lH, 4~7(s) 2H; 3.7~s) 3H and 1.5(s) 3H.

.
In a manner sim;lar to the procedure of Example 62, the amides o$

Example 60 are converted to the corresponding tetrazoles of the structure:
: : :
H2ocoNH ~ ~

o ~ CH3 \
-~ N _ N
~ . ..
~: :
, : :: : `

`: :

`: :
: : :

:

:

1~964~3~

L~ -C6~5CE~2oc6HL~cH2 2-Cl-4-CH30C6H3CH2-3-Cl-4-HOC6H3CH2-3,4-~CEI30)2C6H3CH2-4-HOC6H~CH(CH3)-2-Br-4-CH30C6H3CH2-4-CH30C6H4CH(0)-2'4-(CE~30)2C6H3CH~CH3) 4-CH30c6H4cH(n-c3H7 3-CH3-4-cH30c6H3cEl2 4-C2H5C02C6HL~cH2 HC6H4CH ( Q~ ) -,3~ -CH30C6E13CH2-4_(1_C3H7C02)C6H4CH2-3~4-(C6H5CH2)2c6H3cH2-3 6 4 ( 3) 4-CH30C6H4cH(c2 5) 3-F-4-CH30c6H3cH2-3 C1 4 H3 C6 3 ~ 3) , ~ .4-HOC6H4CH2-4-CH3c02c6H4cH2-25: 3-F-4-HOC6H3CH2-3-C~30-4-CH3C~2C6H4CH2 -4-C6H5CH20C6H3CH(CH3) 3-Cl-4-C6H4CH20C6H3CH2 -3,4-(C2H5C02 )2C6H3CH2-4-(n-C3H7C02)C6H4CH2-4 (1-C3H7C02)C6H4CH(C2H5)_ . : : 2-furylmethyl-S-methyl-2-furylmethyl-2-th;enylmethyl-: 5-methyl-2-thienylmethyl-. ~
2-furyl)ethyl-1-(5-methyl-2-furyl)ethyl-: : `

~ -104-:: :
: ~' ' : .

EXAMPLE 6l~
Employing the procedure of Example 62, and starting with the requl-slte reagents and -the appropriate amide from Example 61, the following -tetrazole intermedia~e~ are syn-theslzed:
r3 H2 ~ S

~ ~ CH3 M~N

: .
:~ ' .

:

-105- ' ~

; "' ' . .
, Rll 4-C6H5CH20C6HL~.CH2 -2 Cl 4 CH30C6H3CH2 4-Cl-4-HOC6H3CH2-2 Br 4 CH30C6H3CH2 2,4-(cH30)2c6H3cH(cH3) 4-C2H5C02C6HL~CH2 3-CH3~4-CH30C6~l3CH2-4~ C3H7C02~C6H4CH2-3'4-(C6H5cH2)2c6H3cH2 4-CH30C6H4CH(CH3) 4-CH30C6H4CH(c2H5 ) 3,4-~CH30)2C6H3CH2 3-F-4-CH30c5H3cH2-3-Cl-4-CH30C6H3CH(CH3)-4-CH3C02c6H~cH?
3 Cl 4 HC6H3CH2 3_Cl_4-cH3co2c6H3cH2 4-C6H5cH20c6H3cH(cH3) 3-C1-4-C6H5CH20C6~3CH2 3,4-(C2H5c02)2c6H3 C3H7C02 ~C~jH4CH2 2-furylmethyl-5-methyl-2-furylmethyl-~ ~ . 2-thienylm~thyl-H ~ 2-furyl~ethyl-: 1-~5-methyl-2-f~ryl~ hyl-:: ' `' : : :
' EXAMP~E 65 7-(2',2',2'-Trlchloroethox~clrboxamido)-3-methyl-4-(tetrazol-5-yl~
7-(2',2',2'-Tr;chloroethoxycarboxamido)-3-methyl-4~ methoxybenz-yl)-tetrazol~ 5-y~ 2-cephem (~0.7 g.) in trifluoY~oacetic acid (280 ml.) con-taining anisole (70 ml.) is allowed to s-tand at 50C. for 6 hrs. The solution is poured into water (1 ll-ter) and the suspension extracted w-tih ethyl acetate.
The organlc solutlon is extracted w;th saturated aqueous sodium b;carbonate and the aqueous solution is ad~usted to pH 2 with lN HCl acid, and the precipitate extracted into ethyl ace-tate. The organic solution i5 dried (MgS04) and evaporated under reduced pressure to g;ve 7-(2',2',2'-trichloroethoxycarbox-amido)-3-methyl-~-(tetrazol-5-yl)-~ -cephem as a pale brown solid (23.2 g.).
A sample is recrystall;zed from chloroform (ethanol free) m.p. 165-167C.
NMR (DMSOd6): ~ ~ 6.4(q) lH; 5.8(s) lH; 5.2(m) 2H, 4.8(s) 2H and lS 108(s) 3H.
EXA~PLE 66 The procedure of Example 65 is repeated, starting with the reagents of Example 63, to produce 7-(2',2',2'~trichloroe-thoxycarboxamido)-3-methyl-4-(tetrazol-5-yl)-~2-cephem, identical w;th that formed in Example 65.

Start;ng w;th the ;ntermediates of Example 64~ and following the procedure of Example 65, `7-(2',2',2' tibromoethoxycarboxamido)-3-methyl-4-(tetrasol-5-yl)-~ c-~hem is for~ed.

.

' . ' .

.:

7-(2',2',2'-~richloroe-thoxycarboxamido)-3-methyl-4-(methoxymethyl-tetrazol-5-yl)-Q2-c em _ _ _ To a suspensioll oF 7-(2~,2~,2~-trichluroe-thoxycarboxamido-3-methyl L~(te-trazol-5-yl)~ cephem ~3.27 g.) in methylene chloride (50 ml.) ls added in turn, triethylamine (2.22 g.) and chloromethyl methyl ether (1.76 g.) and the solut~on stirred at room temperature for 30 min. The solution is -then washed with water, aqueous sodium bicarbona-te, and dr;ed (MgS0~). Evaporation under reduced pressure g;ves 7-(2',2~,2'-trichloroethoxycarboxamido)-3-methyl-4-(methoxymethyltetrazol-5-yl)-~2-cephem (7.3 g.) as a cream solid.
NMR CDC13): ~ = 6.4(d) lH, 6.0(q) lH; 5.8(s) 2H, 4.7(s) 2H, 3.L~(m) 3H and 1.7(s) 3Ho Employin~ the appropriate tetrazole of Example 65 or 66 and the requisite alkyl halide, and repeat mg the procedure of Example 68, the follow-ing mixture of co~pounds is formed:
;/ ~ ~ ~ C~

N ~ ~ -Rll ~C
R = N _ N-R

: ' .

-108~

.
, , . .... .~ , . .. . . ... . .. . . : . . . . -~9S~L~

11 1~_, Br3CCE~20CO- CH30CH2-Br3CCH20CO- CH3C02CH2-Br3CCH20CO~ C2H5C02CH2-5Br3CCH20C0- CH3C02CH( CH3 ) -Br3CCH20CO- (CH3)2CHC02CH2-Br3CCH20CO- C2H5C02CH(CH3)-Br3CCH20C0- ( CH3 ) 3CC02CH2 -Br3CCH20CO- CH3(C~2 )2C02CH2 10Br3CCH20CO- (CH3)3cc02cH(cH3) Br3CCH20CO- CH3(CH2 )3C02CH3 Br 3CCH20C0 - ( CH3 ) 2CH~CH2 C02 CH2 Br3CCH20CO- C8H52-15C13CCH2OC0- CH3C02CH(CH3)-C13CCH20CO- C2H5C02CH(CH3)-C13CCH20C0- ( CH3 ) 3CC02CH2-C13CCH20C0- ~CH3)2CHC02CH2-20C13CCH20C0- CH3(cH2)3co2cH2 C13CCH20CO- CH3(CH2)3C02CH(CH,3) C13CCH20CO- (CH3)2CHCH2C02CH2 C 8 5 2 ~ \0 . ~ '.

.

~L~6~
XAMPL~ 70 7-(2',2',2'-TrichLoroethoxycarboxamido)-3 (l-methyltetrazoL-5-ylthiomethyl)-4-(methoxymethyltetrazol~9-yl)-Q -cephem 7-(2~2~2~-Trichloroethoxycarboxamido)-3-methyl-L~-tmetpoxymethyl-tetrazol-5-yl)-~ -cephem (8.0 g~) in carbon t&trachloride (160 m~) and chloro-Eorm (16 ml.) was deoxygenated. M-Bromosuccinimide (3.20 g.) and benzoyl peroxide (200 mg.) is added and the stirred mixture at 10-15C. illuminated ~n (250 watt, tungsteD lamp) for 2 hrs. During -this time additional chloroform is added to maintaln a clear supernatant, and a ~urther amount of benzoyl peroxide ~200 mg.) added 30 min. after the start of illumination.
The succinimide is fil-tered off and the filtra-te treated with the triethylamine salt of 5-mercapto-1-methyltetrazole (3.40 g.) for 2.5 hrs. at 45C. The organic solution is then washed with water, aqueous sodium bicar-bonate, water a~d finally dried (MgS04). The organic solution is evaporated to dryness under reduced pressure, The residue is purif;ed by means of col-umn chromatography (Sil;ca gelj ethyl acetate; l;ght petroleum ether, 1:1) to give -the desired product (3.0 g.).
NMR (CDC13): ~ = 6.6(s) lH, 6.2(d) lH; 6.0(s) lH, 5.9(s) 2H; 5.4(m) 2H; 4.8(s) 2Hj 4.2(q) 2H, 4.0(s) 3H and 3.5(s) 3H.

7-(2',2',2t-TrichloroethoxycarboxELmido?-3-(2-methyl-1,3,4-7-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-(methoxymethyl-tetrazol-5-ylthiome-thyl)-a2-cephem (4.0 g.) ;n carbon tetrachloride (60 ml.) ~ d chloroform (3 ml.) is treated with N-bromo succinimide and benzoyl ~:

peroxide as in Example 70. The produc~ is similarly treated w:i.th the trï-ethylamine salt of 5-mercapto-2-me-thyl-thiadiazol (2 g.) to g;ve, after column chromatography (sllica, ethyl acetate/light pe-troleum ether 1:l.), 7-(2~,2',2~-trichloroethoxycarboxamido)-3-(2-methyl-1,3~-thiadiaæol-5-ylthiomethyl)-4-~methoxymethyl-tetrazol-5-yl)-a -cephem (1.1 g.).
NMR tCDC13): ~ = 6.6(s) lH; 6.3(d) lH; 6.1(s) lH; 5.9(s) 2H; 5.3-5.7 (m) 2H; 4.8(s) 2H; 401tq) 2H; 3.5(s) 3H and 2.7(s) 3H.

-Following the procedure of Example 70 or 71, and starting with the requisite a -cephems from Example 68 and Example 69~ and the appropriate mercapten, the following compounds are formed:
RNH S
~ ~ and RNH~ .

~ H2A o~ y~ CH2A

N ~ N N ~N-R
N_ R R /R
C13CCH20CO- CH3C02CH3- C3~13N2S2-i' C13CCH20CO- CH3C02CH(CH3)- 3 3 2 2 C13CCH20C0- ~CH3)3CC02CH2- C3H3N2S2 C13CCH20CO- CH3(CH2)3C02cH(cH3)- C3H3N2 2 C13CCH20CO- C2H5C02CH2- C3H3N2S2-*
C13CCH20CO- (CH3)3CC02CH2- C2H3N,~S 1-C13CCH20CO- CH3C02CH2- C2H3N4S ~
C13CCH20CO- # C8H502- C2H3~4S-t C13CCH20CO- C2H5C02CH2- C2H3N~S-C13CCH20CQ- CH3C02CH(CH3)- C2H3NL~S-t Br3ccH2oco- CH3OCH2- C3 3 2 2 Br3CCH20CO- CH3C02CH2- C3H3N2S2-*
Br3CCH2OCO_ CH3CO2CH(CH3) C3H3N2S2 *
Br3CCH2OCO- CH3(CH2)C2CH2 C3H3N2 2 Br3CCH2OC- (CH3)3CCO2CH2 C3H3N2 2 Br3CCH2OCO- tCH3)2CHCH2CO2CH2- C3H3N2 2 Br3CCH20CO- CH30CH2- C2H3N,~S
Br3ccH2oco- 3(CH2 )3Co2cH(cH3)- C2H3N4S
Br3CCH20CO- CH3co2cH(cH3)- C2H3N4S-t Br3CCH2OCO_ (CH3)3CCO2CH2 C2 3 4 Br3CCH20CO- CM3C02CH2- C2H3NL~S-Br3CCH20CO- C2H5C02CH2- C2H3NL~S-~
Br3CCH2OCO- # C8HSO2 C2H3N4 - ~)~S/I\CH3 C2H3N4S = -S~ CH3 8 5 2 l~

O

7-(2',2',2'-Trichloroethoxycarbo~amido~-3-(1-me-thyl-tetrazol-5-yl-thiomethyl)-4-(methoxymethyltetrazol-5-yl)-~2-cephem (2.0 g~) in acetic acid-water mixture (7:3, 20 ml.) a-t O~C is treated wi-th activa-ted ~inc dust (2.0 g.) w;th stirr;ng. Af-ter one hour the mixture is filter~d and the filtrate diluted with water (100 ml.). The pH of the mixture was adjusted to 2 with lN
HCl acid and then washed tw;ce w;-th ethyl acetate. The pH of the clear aqueous solut;on ;s adjusted to 6 with sodium bicarbonate and the mixture ex-tracted with chloroform. The organic solution is washed with pH 7 buffer, dried (MgS0~), and, finally, evaporated under reduced pressure to leave 7-am;no-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)_~2-cephem (0.9 g.) as a foam, pure by chromatography.
NMR (CDC13): ~ = 6.6(s) lH; 5.95(s) lH5 5.85(s) 2H; 5.25(d) lH; 4.70 (d) lH; 4.1(q) 2H, 3.95(s) 3H and 3.5(s) 3H.
In a similar manner is prepared 7-amino-3-(2-methyl-1,3,4-thiadiazol-NMR (CDC13): ~ = 6.8(s) lH; 6.4(s) lH, 6.0(s) 2H; 5.4(d) lH; 408(d~
lH; 4.2(q) 2H, 3.7(s) 3H and 3a2(s) 2H.

3y subs-tituting the appropriate compound of Example 69 for the Q2_ cephem of Example 79, and following the experimental procedure of Example 73, the following 7-am;no-Q -cephems are formed:

Ff~ ~CH3 N-R
::

~ -113-CH3C02C~12 -CH3C02CH(CH3)-C2H5C02CH(CH3 )-(CH3)2CHC02CH2-(CH3)3C02CH2-CH3tCH2 )2C02CH2-CH3(CH2)3C02CH(C~3)-(CH3)2CHCEI2C02CH2 (CH3)3CC02CH(CH3)-2 ~ ~ ~ O

~ -114-,' :

EX~MPL,E 75 The prooedure of Exa~ple 73 is again repeated, starting with the appropriate ~2-cephems of Example 72, -to give -the following congeners:

N - - N
C H2S ~ ~ ~ CH3 and N ~ ` N-R
--N

S H2~ ~ CH2 ~ ~ ~ CH3 N~ ~N
\\ I .
N _ N-R

CH3C02CH(CH3 )-(CH3)3CC02CH2 CH3(cH2)3co2cH(cH3) ~CH3)2CHCH2c02cH2 Again, the procedure of Example 73, applied to -the requisite com-pounds o~ Example 72, provides -the following intermediates:

~12N S

O / ~ CH2S-C - N-CH3 ~J
N
and ~ ~ CH2S-C ____~ N-CH3 1~ J
N~ ~N ~ N ~
\\ l N N-Rl (CH3)3CC02CH2-CH3C02CH(CH3)-CH3(CH2)3C02cH(cH3~

3 5 2 ~

7-(Tetrclzo~ yldceLdmido)-3-(2-lTlethsr~ 3~4-thicldiaæol-5-vlthiomethvl~-4-(tel:r~Lzol-5-y~ l!3-cephem A. 7-(Tetrazol-l-ylace-tamido)-3-(2-me-thyl-1,3,~ thiadiazol-5-ylthiomethyl)-4-(methoxymethxl-tetra~ol-5-yl)-~2-cephem _ _ _ 7-Amino-3-(2-methyl-1,3,4-thiadia~ol-S-yl-thiomethyl)-4-(methoxymethyl-tetrazol-5-yl)-A -cephem (430 mg.) and -tetra~ol-l-yl acetic acid (133 mg.) in -tetrahydro~uran (10 rnl.) and ace-tonitrile (10 ml.) ;s treated with dicyclo-hexylcarbodiimide (215 mg.) and the mixture allowed to stand at room tempera-ture for 1 hr. The mixture is filtered and evaporated under reduced pressureto leave 7-(tetrazol-1-ylacetamldo)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio-methyl)-4-(methoxymethyltetrazol-5-yl)-~2-cephem (520 mg.) as a cream solid, pure by thin layer chroma-tography.
NMR (CDC13): ~ - 9.1(s) lH; 6.6(s) lH; 6.Q(s) lH; 5.g(s) 2H; 5.4(s) 2H; 5.4(s) lH; 5.2(d) lH; 4.0(q) 2Hj 3.4(s) 3H and 2.6(s) 3H.

B. 7-(Tetrazol-l-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-S-yl)-~3-cephem l-oxide_ 7-(Tetrazol-l-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio-methyl)-4-(methoxymethyltetrazol-5-yl)-~2-cephem (500 mg.) in chloroform (20 ml.) is treated with m-chloroperbenzoic acid (219 mg.) at 0C. with stirring.
After 1 hr. at 0C. pyridine is added (40 mg.) and the mixture allowed to warm to room temperature. After a further hour the mixture is concentrated under reduced pressure and diethyl ether added to the concentrate. The cream solid which precipitates is collected, dried under reduced pressure and the required product (410 mg.~ is obtained as a cream solid, pure by chromatography.
NMR (DMSOd6/acetone d6): ~ = 8.9(s) lH; 6.0(s) 2H; 6.0~ lH; 5.6~s) 2H; 5.2(d) lH 4.5(q) 2H, 4.0~s) 2H, 3.5(s) 3H and 2.7(s) 3H.

.

-117~

1~4~

C. 7-tTetrazol~ ylaceta~n;do)-3-('2-methyl-1,3,4-th.iadiazol-5-ylthiomethYl)-4-(methoxvmethvlte-trazol-5-yl)-l~3-cephem 7-~TetrdzoL-1 -ylace-tamiclo~-3-(2-methyl.-1,3,4--thiad;azol-5-ylthio-methyl)-~-(methoxyme-thyltetrazol-5-yl)-~3-cephem 1-oxide (400 mg.) ln dimethyl-formamide (10 ml.) is treated wi-th anhydrous stannous chloride (400 mg.) and acetyl chloride (200 mg.) a-t 0C. wi-th s-tirring. The mixture is allowed -to stir for one hour and is then poured into ar, excess of water. The aqueous mix-ture is extracted several times with chloroform, and the organic solution washed several times with water. The chloroform solution is dried (MgS04) and evaporated under reduced pressure to give the required compound as a foam (250 mg.), pure by thin layer chromatography.
NMR (CDC13): ~ = 9.0(s) lH; 8.7(d) lH; 6.0(s) 2H; 6.0, lH; 5.4(s) 2H; 5.2(d) lH; 4.4(q) 2H, 3.7(s) 2H; 3.4(s) 3H and 2.7(s) 2H.

D. 7-(Tetrazol-l-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol~5-ylthiomethyl~-4-(tetrazol-5-yl)-~3-cephem _ _ 7-(Tetrazol-l-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio-methyl)-4-(methoxyme-thyltetra~ol-5-yl)-~3-cephem (70 mg.) in trifluoroacetic acid (2 ml.) and anisole (0~5 ml.) is allowed to stand at 20C. for 6 hrs.
After this time the trifluoroacetic acid is removed under reduced pressure to leave an oil. Th;s res;due ;s diluted with ethyl acetate and the result;ng organ;c solution extracted w;th saturated aqueous sodium bicarbonate solution.
The aqueous solution ;s ac;dified to pH 2 with 2N HCl acid and the solut;on extracted with ethyl acetate. The organic solu-tion is dried (MgSO4) and eva-porated under reduced pressure to leave an oil which crystallizes on addit;on of diethyl ether, to give the required product as coiorless needles (35 mg.), pure by chromatography.
NMR (tri~luoroacet;c acid-d): ~ = 9.5(s) lH; 5.8(d) lH; 5.5(s) 2H;
5.2(d) lH; ~.5~s) 2H; 3.6(s) 2H and 2.8(s) 3H.

, S-tarting wi~h the appropriate methoxym~thyl substi~uted ~ -cephems of Examples 73 and 74 and ac;ds, and employing the procedure of Example 77A-D, the following compounds are synthesized:
Ar ~ 9} CON9 ~ ~

~NH
N~N
________I_C______ Q
C6H5- - ~ H-10 , C 2C6 3 0 C2H3N4S-3'4-C12C6H3- - 0 C2H3N4S *

4-FC6H4~ - O C2H3N4S-3,5-F2C6H3- - 0 2H3 4 *
6 4 C2H3N4s-3'4-Br2C6H3- - 0 C2H3NI~S-6 4 C2H3N4S *
6 4 C2H3N4S ~
4-CH3C6}!4- _ O C2H3N4S-203-Cl-4-HOC6H3- - 0 C3H3N2S2 .

3-Br-4-CH30C6H3- - O C3H3N2S~-3-CH3-4-HOC6H3- - 0 C3 3N2S2 .
253-CH3-4-ClC6H3~ - 0 C3H3N2S
2-th;enyl - C3H3N2S2 :

~.

Ar Q n A
3-th.;~nyl- - 0 3 3 2 2 2-ClC6H4- N3 1 H-4-ClC6H4- N3 1 H-2,4-C12C6H3- N3 1 H-4-FC6~4~ N3 1 H-' 2 6 3 N3 1 C2H3N4S-*
4-BrC6H4- N3 1 C2H3N4S-*
4-HOC6H4- N3 1 C2H3N4S-*
3-HOC6H4- N3 1 C2H3N4S-*
4-CH30C6H4- N3 1 C2H3NL~S-3-F-4-HOC6H3- N3 1 C2H3N4S-*
3-Cl-4 HOC6H3- N3 1 C2H3N4S-*
3-Br-4-CH30C6H3- N3 1 C3H3N2S~-t 4-CH3C6H4- N3 1 C3H3N2S2-~
3-Cl-4-CH3C6H3- N3 3 3 2 2 4-CH3C6H4- N3 1 C3H3N2S2-~
3-CH3-4-CH30c6H3- N3 1 C3H3N2S
2-thienyl- N3 3 3 2 2 3-thienyl- N3 1 C3H3N2S2-~
*C2H3N4S = CH3N _ Cl-S-N~N~

S ~ ~ H

~ .
, .

EXAMPLE 7~

7-D~ Iydl~o~y-~ E)hellyldce-tamido)-3-~-mettlyl-tetraæoL-S-___y~ o~nethyl~-4 (tet--razoL-5-yl)-~ -ce~e__m _ _ Ao 7-D-(~-Formyloxy-~-phenylace-tan~i~o)-3~ methy:L-tetrazol-5-ylthiomethyl)-4-(methoxvmethvltetrazol-5~vl)-~ -cephem _ _ __ .
Start;ng with the appropriate reagents and following the procedure of Example 77A, the desired intermedia-te is prepared.
NMR (CDC13): ~= a.2(s) lH; 7.3(s) 5H; 6.4(s) lH; 6.2(s) lH; 5.9(s) lH; 5.7(s) 2H; S.S(q) lH; 5.2(d) lH; 4.0(q) 2H; 3.9(s) 3H and 3.4(s) 3H.

B. 7-D-(~-Forrnyloxy-~-phenylacetamid3)-3-(1-methy:Ltetrazol-S-ylthiomethyl)-4-(methoxymethyltetrazol-5 Yl? - ~ cephem l-oxide _ _ Employing the above intermediate from Example 79A and following the procedure of Example 77B, the desired compound is isolated and used in subse-quent reaction without further purification.

C. 7-D-( ~Formyloxy-o~phenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxvmethvltetrazol-5-vl)- ~3-ce~hem The procedure of Example 77C is employed, starting with the appro-priate compound from Example 79B, -to give the desired product.
NMR (CDC13): ~ = 8.3(s) lH; 7.4(s) 5Hj 603(s) lH; 6.0(s) 2H; 6.0, lH, 5.2(d) lH; 4.5(q) ~H, 4~0(S) 3H; 3.8(s) 2H and 3.5~s) 3H.
D. 7-D-(o~Formyloxy-~-phenylacetamido)-3-(1-methylte-trazol-5-ylthiomethyl)-4-(tetrazol-5-yl) ~3-cePhem _. . _ _ The trifluoroacetic acid-an;sole treatment of Example 77D is repeated, start;ng with the produc-t of Example 79C, to provide the desired product.
~MR (acetone-d6/D2O)o ~ - 8.3(s) lH; 7.5(m) 5H; 6.2(s) lH; 5.9(d) lH; 5.3(d) lH; 4.4(s) 2H and 4.0(HOD).
(acetone d6JD2OJtrifluoroacetic acid-d): ~ = 4.4(s) 2H; 4.0(s) 3H and 3.9(s~ 2H.

. . .

E. 7~D-(o~hydroxy-~-phenylacetamido)-3-(]-methyltetraæol-5-y:Lthiomethyl)-4-(tetra~ol-5-yl)-~3-cephem 7-D-(c-E`ormyloxy-o-p}lellylace-tamldo)-3-~l-me-thyltetrazol-5-ylthio-methyl)-~l-(tetrazol-5-yl)-~ -cephem (lOO mg.) in aqueous sodium bicarbonate solution (5 ml.) is allowed to stand a-t room temperatllre for 3 hrs. The p~ of the reaction mix-ture is adjusted to 2 with 2N HCl acid and extracted with ethyl acetate. The organic solution ls dried (MgSOL~) and evaporated under reduced pressure to leave the required product as a cream solid (35 mg.), essentially pure by thin layer chroma-tography.

Again, start;ng w;th the requ;site methoxymethyl substituted ~2_ cephems of Examples 73 and 74 and the zppropriately substituted ~-formyloxy-~~
phenylacetic acld, and employ;ng the procedure of Example 77A-D, the following ~ -cephems are prepared:

Ar-CHCONH~ CH2~A

N = N

Ar ~:(c~c~n ~ uratioll) A
2-ClC6H4- D H-3-ClC6H4- D H-4-ClC6114- DL H-2-FC6H4- 1~ H-4-F'C6H~- D C2H3N4S-*
4-FC6H,~ C2H3N4'~-~
3-BrC6H4- DL 2 3N4S
3-CH3C6H4- D C2H3N4S-*
4-CH3C6H~- DL C2H3NL~S-*
L'-CH30C6H~- D C2H3N4S-*

3-CH30C6H4- D C2H3N4S-*
2-HOC6HL~- D C2H3N4S-*

2-C1-4-FC H _ D C2H3N4S-*
3-C1-4-FC H - DL C2H3N4S-*
3-Cl-4-BrC H _ L 2 3N4S
' 2C6H3 D C2H3N~S-*
3-F-4-CH3C6H3- DL C2H3N4S-*
3-CH3-4-CH30C H _ D C2H3N4S-3,4-(HO)2C6H3- D 2 3N4S
3-Cl-4~HOC6H _ L 3 3 2 2 3,5-(CH30)2C6H3- D C3H3N2S2-~

3-Br-S-HOC H _ L C3H3N2S2-~
3-CH3-4-HOC H _ D 3 3 2 2 3-CH3-4-CH3C H _ D 3 3N2S2 3 CH3C ~4 D 3 3 2 2 1 2,4-C12C6H3- D C3H3N2S2-~
2,3-C12C6H3- DL 3 3 2 2 2C6H3 D 3 3N2 2 t , .

~;4~

C2H3N4S = CH3N_C-S~

~N ~;
C3H3N2S2 = N _ N
~s ~L 3 ~ ~ .

, .. -- . ~ ~

. .
7-D~ mino-N-phenylacetamido)-3-(1-methylte-trazol-5-yl~ m~- _ trazol-5-yl)-~3-cephem trifluoroacetate_ A. 7-[D-C-(t-butoxycarbonylamino)-phenylacetamido~-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methox~methy~-te~:razol-5-yl)-~ -ceEhem 7-~mino-3-(1-me-thyl-tetrazol-5-ylthiomethyl)-4-(methoxymethyl-tetrazol-5-yl)-~2-cephem (100 mg.) and N-t-bu-toxycarbonylphenylglycine (63.4 mg.) in ethyl acetate-acetoni-trile (1:1, 2 ml.) is -treated wi-th dicyclohe~ylcarbodi-imide (52 mg.) at 15C. After one hour the mixture is filtered and the fil-trate diluted with ethyl acetate (10 ml.) and the resulting solution washed wtih lN HCl acid, a~ueous sod;um bicarbonate, and finally water. Drying (MgS04) and evaporation under reduced pressure gave -the product (152 mg.) as a pale yellow solid.
NMR (CDC13): ~ = 7.25(s) 5H; 6.5(s) lH, 6.0(s) lH; 5.8(s) 2H~ 5.6(m) 2H; 5.3(m) 2H; 4.1(q) 2H; 3.9(s) 3H; 3.5(s) 3H and 1.4(s) 9H.

B~ 7-[D-~`~-(t-butoxycarbonylamino)phenylacetamido]-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxvmethyltetrazol-5-yl)-~3-ce~hem l-oxide - . m ~
7-~D-~-(t-butoxycarbonylamino)phenylacetamido]-3-(1--methyltetrazol-5-ylthiGmethyl)-4-(methoxymethyltetrazol-5-yl)-~ -cephem (140 mg., 0.22 mmole) in chloroform (2 ml.) is treated with m-chloroperbenzoic acid (51 mg., 85%) at 0C. with stirring. The solution is kept at 0C. for one hour and then pyridine ~20 mg.) is added and the solution allowed to warm to room tempera-ture and is kept at this temperature for a further 2 hrs.
The reaction mlxture is diluted with chloroform and washed with lN
HCl acid, aqueous sodium bicarbonate and dried (MgS04~. Evapora-tion under reduced pressure gives the required product as a cream solid (120 mg.).
This material was used directly in -the next reaction without further purification.

C. 7-~D-c~(t-bu~o.xycarbonylam.ino)phenylacetamido-3-(1-methyltetrazol-5-yl-thiome-th~)-4~ _t ol 5 ~ ephem _ _ -7 CD ~ -blItOXYCar~)OX ~1an1LnO)PherlY1a~e-tam:idO~-3-(1-methY1t~traZO1 5-ylthiomethyl)-~-(methoxymethyltetra~ol-5-yl)-~3-cephem l-oxide (120 mg.) is suspended in dimethylformamide (0.3 ml.) and acetoni-trile (0.75 ml.), and the mixture is treated w.ith acetyl chloride (60 mg.) and anhydrous stannous chlo-ride (38 mg.) with stirring at 0C. for one hour. The mix-ture ;s then allowed to warm up to room temperature and allowed to stir for a further one hour. The mixture is concentrated under reduced pressure and then diluted with ethyl acetate. The organic solution is washed with water and aqueous sodium bicar-bonate and finally dried (MgS04). Evaporation under reduced pressure gives an o;l which was purified by preparative thin layer chromatography (silica, ethyl acetate-light petroleum ether, 3:2) to give the required product as a pale yellow foam (60 mg.).
NMR (CDC13): ~ = 7.4~s) 5H; 7.2(d) lH; 5.8(m) 4H; 5.3(d) lH; 5.2(d) lH; 4.5(q) 2H; 4.0(s~ 3H; 3.8(s) 2H; 3.6(s) 3H and 1.5(s) 9H.

D. 7-D-(~-am;no~-phenylacetamido) 3-(1-methyltetrazol-5-ylthiomethyl-4-(tetrazol-5-vl)-~3-ceDhem trifluoroacetate 7-[D-~-t-~utoxycar~onylamino~-phenyl)acetamido] 3-(1-methyltetra-zol-5-ylthiomethyl)-4-(methoxymethyltetra~ol-5-yl)-~3-cephem (55 mg.) in tri-fluoroacetic ac;d (2 ml.) and anisole ~0.5 mlO) is allowed to s-tand at 20C.
for 6 hrs. The trifluoroacetic acid is evaporated under reduced pressure and the residue trea-ted with ether. The solid which results is collected and washed with portions of dry ether. The solid is dried under high vacuum to give the desired product as the trifluoroacetic acid salt.
NMR (D20/DMSOd6~trifluoroacetic acid-d): ~ = 7.4(s) 5H; 5.8(d) lH;
5.2(d~ lH; 5.1(s) lH; 4.2(s) 2H; 400(s~ 3H and 3.6(s) 2H.

.

EXAMPLE a2 The procedLIre of Example 81A-D is repea-ted, starting with the appropriately subst;-tuted N-_-butoxycarbonylphenylglycine and requisi-te methoxy-methyl substitu-ted ~2-cephems of ~xamples 73 and 74, to provide the followi~g products:
Ar-~HCONI~ S~

(~ ~CH2-A

N,~C '~ NH
N _ N

.

: ~ ' .

~:

~;4~1~

Ar ~co~ ~ura tion ) A
3-HOC6H~- D H-3.4-tHo)2C6H3- DL H-4-(cH3O)c6HL~- D H-2--th;enyl- D H-3-Cl-4-HOC6HL~- D H-ClC6H4 ~C2H3N4S-'~
3-ClC6H4- DLC2H3N4S-*
4 FC6H4 . DC2H3N4S-*
2 -Br-5-HOC6H3- DL C2H3N4S-*
3-FC6H4- DC2H3N4S-*
6 L~ LC2H3N4S-*
2-ClC6H4- DC2H3N4S-*
2-ClC6H4- LC2H3N4S-*
3-BrC6H4- D 2 3 4 3-BrC6H4- LC2H3N4S-*
3-ClC6H4- DC2H3NL~S-4-ClC6H4- DC2H3N4S-*
2,4-C12C6H3- DLC2H3N4S-*

4-BrC6H4- DC3 3 2S2 3-HOC6H4- LC3H3N2S2-~
6 4 DLC3H3N2S2-~
CH3C6H4 DC3H3N2S2-t 2-CH30C6HL~- ~hC3H3N2S2-~
3,4-(CH3O)2C6H3- DL 3 3 2 2 3,5L(CH30)2C6H3- 11 C3H3N2S2-~' 3-thienyl- DC3 3N2 2 ` 3--thienyl- DLC3H3N2S2-~
4~CH3C6H4- D 3 3 2 2 3-Cl-4-CH3C6H3- D C3HaN2S2-t . ,.. : ... . ... ... .. ......... . . .

Ar ~ L _--!Y~ iL A
3-Cl-5-(cH30)c6H3- . D 3 3 2 2 .
2-Cl-4-CH3C6H5- DL 3 3 2 2 1 2-F-3~CH3C6H3- D 3 3 2 2 C2H3N4S = CH3N - f-S-N ~N
~N
t C3H3N2S2 = N _ N
-S ~ ~ CH3 Starting with the ~ -cephem products of Examples 54 through 56 and lQ the appropriately substituted phenylmalonic acid, and employing the procedureof Example 27, the sodium salts of the following compounds are prepared:

Ar-CHCONi~ C}/-A

N~Y ~jH
N ~ N

: -129-1~64~1~

~r A
2-ClC6H4- C~13C02-4-ClC6H4- CH3C02-3-BrC6H4- CH3C02-2-FC6HI~- CH3C02-6 4 C2H3N4S-*
4-CH30C6HI~- 2 3 4 4-CH3C6H4- C2H3N,~S-*
4-HOC6H4- C2H3N4S-*
4-H2NC6H4- C2H3N4S-*
2,4-C12C6H3- CH3C02-3-F-4-BrC6H3- CH3 2 3-Cl-4-HOC6H3- CH3C02-3,4-(CH30)2C6H3-C3H3N2S2- 1 3 Cl 4 H2 6 3 `C3 3 2 2 3-thienyl- 3 3 2 2 3-thienyl- , 3 2 4-CH30C6H4- CH3C2 ' . ' *
C2H3N4S = CH31 C-S- ,' ~N ~
C3 3 2 2 ~ ~ CH

:

~ -130 . .. .
.. ' -.. ~ . , ~ i4~

Employlng the procedure of Example 77A-C, and s-tarting with the appropriate alkanoyloxymethyl and l-(alkanoyloxy)ethyl substituted ~-cephems of Example 74 through 76, and the appropriate acids the fo}lowing products are prepared:
A~ ~ CH ~ CONH ~ S

~H2 N ~ N-Rl ~ N
\~ /
N _ N N _ N-R
.

.

.
~' ....
.: - . - . : , ,; - ~ . : . .:, , . , : . , * * ~
I 'I I I I I . N N C~ C`J N -N
Z ~ Z~ ~ ~ ~ ~ Z~ Z~ Z~ Z~ Z
:r: 3~ C X :E~ X X X ~
:~ ~ X ~ :~ X ~ C) O O C~ C~ O O C~ O O c~ o :r X
~N 5N xN C~ l N
C~ ~ ~ ~ X X N C~ N N C~ N
I I I I C~C~ N N C`l N ~3 8 o ~ o ~ N C`l l I
~ x ~: x tc " 8 " ~ ~ ~ 5 X
Q ~ C~ VN V ~ C.) V C)~ V C ) V ~1 ~N N ~C~ ~N ~C`I oC`l N V c) OOOOOOO^^~ V~VVVVC.)C~OO
X ~ ~ ~ ~ ~ V V C3 V ~ ~ N C`l X ~C
C~ C~ V C~ V V V V ~ O C.> V V V V V ~) V C~

.CIOOOOOOOOOOOO-1 l ~ l l l~ l x~
l l l ~ ~ v ~ ~
D X I O V V
~: ~ II ~D X X~ I ~ 1~ Vo V~
V V I I ~ ~ V ~ ~ ~C ~ O
1' C) X N ~C ~ I X V I i J
~9 3 ~ r~l X ~ N ID ~ ~0 ~ V .~ I Q .~ I I 19 11 IC) C~ V ~) ~ 4 V m v v ~ I

: . ~'~ ~ I m ~ ~ 5: v 'V~ rL, ~ : ~ 1 1 ~, ~ I I r ~ ~ N
~ :' , : :

.-1~6~

* ~ C ~ C ~' JC *tn ~n ~n v~ ~n ~n~ tn ~n~ ~ ~n u~
z~ z~ z~ æ~ ~ ~ z~ ~ ~ ~ z~
¢ X ~ X ~
I I .1 1 I C~l N ~ NC~ C~ N C~ N N

:~
. C~
~, 0 I I C~ N C`l C`l ~ C~
~ X ~ X 5 X ~,7 ~1 N C`l O O O O O O O
OOC~ OOOOOOC~O
X ~ X ~ ~ X ~ X :1: ~ X

z æ æ æ æ æ ~ æ æ z ~ æ :z: Z z; :z I X~ X~g o c~
:c ; ~ ~c ~ ~ ~ 3 x ~ c~ ~ ~ ~ c,~ ~ ~,~ ~ ~: R
~ q ~I X

:

.

-. .

~64i~g C2H3N4S = CH3N - I-S-N;~N f N

C3H3N2S2 = N - N
S ~ 3 C H50- = ~
~l .

EXAaPLE 85 Again, employing the alkanoyloxymethyl an~ l-(alkanoyloxy)ethyl cephems of Examples 74-76 and the appropriate acids, apd utilizing the proce-dure of Example 79-A-C, the following compounds are prepared:
*
Ar-CHCONH ,S
OH ~ ~
O ~ 2 ~'~~~~~ ' .
N ~ N-R N ~ N
N _ N N ~ N-R

.
~ .

1~i4~9 ,. *. ~ .
~ ~e # sc * :: * * * * *
¢ tn tn~ tn~ tn~ tn~ tn~ tnJ cn~ tn~ tnJ tn~ ~nN tn~ tnN
Z Z :~; Z Zi Z Zi Z; Z Zi Z Z Z Z
I I I I I I I I I N C`l ~ N C~ N C~
X X ~C U C,> c~> C.) U C~ U C,~ ~ ) C ) C ~ ~) C.

X 3 X ~[ ~ U C ) C,> C,~
I I I I I N C`l N N C`~ `-- ~ ~ ~' I I I
C~l N C~l N N O O O O O ~C ~ ~:: X N ~ C~l C~ U C_) U C.) ~ ~ > ~ c,) o o o o C~l C~l N
C~ O O O O O O O O O O '~ C ,~ C~ U C ) O O O
C ) U ~U~ [ C ~ X ~ ~N ~N N N 1: X ::C

R
:: ~ : :

~ a~ al ~1 ~1 a~ ~1 al ~1 al Ql ~1 al ~1 al al ~1 ~1 al al ~1 t, ._ *

: I "
I ~ C XID
h I I I I ~ ~ X ~ t~ I I I I ~ ID ~ ID co ~I
(S~ X D C~ U o o (g r-l r~ CO $~ 1 ~ X C ~ 5~ 0 0 0 C3 5 1 1 1 ~1 ~I ~~1 ~ ~~q y y y y y ~ X ~ ~ r Y Y Y
N C~ N ~ ~ N ~ :t:t N N N ~ N ~ ~

.

;
:
:
:: ~

-`' ~i4~

¢, C~ N C`~ N
:z~ æ~ :z~ z~ z~ z~ z~ z~ z~
X X 5~ X X ~: X :~

~C~I ~N ~ ~ `_ ~ ~ C"l C~l 5C~I N O O
_ C~ l N C~ l N ~ C'7 ~ 5 ~ ~ X~ ~ ~ ~ C~ ~ ~ ~ '' _ .

1~ " ~ l Q i ~ l 1~ ~ I R l R l 1~
C<D I I . IC~ X~ >~ X
I ~C~ O ~ D O ~9 C.) 3 0 --` X C.) O X
C'~ ~ ô ~ ~ ~ X XC'~ ~ ~ ~ ~ ~
~ 0 :: ~ FL~ y ~ C~ ~ ~ ~ C~ m c~
:: ~' ~ ~ ~ C`~ N ~

. ~

.

* C2H3N4S = CH3N - f-S-N

~ N~
C3H3N2S2 =N _ N
~s~C~l3 C8H50 = ~/~

Utilizing the procedure of Example BlA-C, and starting with the :alkanoyloxymethyl and l-(alkanoyloxy)ethyl ~2-cephems of Examples 7~-76 and theappropriately substituted N-t-butoxycarbonylphenylglycine, the following pro-:ducts are prepared:
Ar-CNCO~H

N~ ~ N-Rl N
- N _ N-R

, .

~ .
:~
.

:

::

~ . : . - , . - -, . . :: - ..

i3~

.,~ ,, .,~ ~ ~ ~ ~
I I I I I I I I I C~ N C`l C~ N
¢Z t Z~ Z~ Z t ~zj t z t _t _t _t C`l C`l N ~ ~ C`l N
I I I I I I ~ N ~ ~ ~ ~ ~ N N C~) ~ ~ ~ Cl~ ~t) C~) I
~ ~ 1 * 1 ~
C~l N C~ C~l N
~ X :Z 5: ~ I I I I I I ' C.). C ) C.~ C ~ C_) ~ N C~l C"l N C`l C~ C`l C`l N N 5: X ~ C X
I I I C~ C,) C ~ C ) C ) C`l C`l N C`l N C~ I I I I
N C`J N I C~ ) ~ O O O O O O C`J N N N
X !T I X ~ ~ ~ C~ C~ C~ C~ C~ C~ X 5: ~ X
~r N N N N X X ~. X 5~i ~ ~) ~ ~) ~ ~) N N C`l C~ I I I I
OOOOC~C~C.)C~C~ `^OOOOOOOO
C~ C_~C~ C~ C~ C~ U) ~ U~

.
:
1~
h '1: I C.. ~ C.) I r~ 9 1 1 0 1 1 1 1 1 1 U~ ~D
i C~C~ t I ~ I I =t =t ~ =t ::1 C~ C~ I I I
~~ C ~ ,C O X ~ C _t I ~ C X X X X C~ =t ~ C O ~rl _t O O ~ D m~C D CU I oCD c~ D ~9 Cl~ U~ ID r~
O ~C~ O S r l ~I r~ C~ ~ C~ C~ r l r l ,C~ C~ r-l r-l I I C~ C) C.) IJ C~ C~ C~ c~ c') Iq a~ c~ c~ _t C~l c10 _t Cl) _t N C~ _t C~l N C~ ~ C~ ~ N C~ N Cl> cr~

-13~-~C~-C~ *~ *~*~*~'.C~
¢ Z~ Z~ Z~ Z~,, Z;~ ~; Z; Zi :Z
X 5C~ ~C~ ~C~ , ~ Xc~l C~
5 5 ~ 5 X X X

C`l C'~ C`l C~ C`l C~l C`l ~ . . . . .
C`l C~ C~ C~ C)C~ C~ C_) X X`J ~C~I ~C~ ~C`I
ooooooo~c~c~c~c~c~x~
C) C~ o o o o o o C~ C>
, C~l C~l ~ C~l C~l C~ C~ X ~ X ~ X ~ X ::C
II ~ ~ ~ X ~ ~ ~ C~l C~ ~ C~l C~ C~ C~ C~
~ o oc~ o Q
, ~1~ ~Irl--~ `--~ `--~--~--~--' --~ ~C`I ~N ~C~ ~C~ XC`I C~ O C.) co a> ~C X 5~ X X ~ C,)' C.> X ~C

I
rl . .
.

: J.C , c ~ D 5 D ô C~ 1: 0 I N C~l O ~ C~ U3 : ~ X
:~ : ~ a(D
: ~ ~ D o 3~ a o o ~ ~ x ~ ~ ~ I ~:
:: m P:: x c > c~ ~ y I y y ~ ~ ~ - :' 139_ : .
~; .

, ~ .
: ' . .

. ~ . . .

C2H NL S = CH3N--C-S-`` N ' 3H3N2S2 N_N
-S J~ ~CH3 C8H5 = ~t) 1~

-lL~O--.~ - , . .. . . . . . .

1~64~

EXA~PLE 87 The procedure of Example 77-A-C is repeated, s-tarting with the requisite acid and alkanoyloxymethyl and l-(alkanoyloxyjethyl a2-cephems of Examples 74-76, to give the following congeners:
S Ar tCH2~Co~H_ f~

..
N ~ -R N
/ 1 ~\ /
N - N N N-R
____~L____ n Rl A

6 5 1 CH3(CH2)3C02CH2- H-C6 5 1 3 2 ( 3) H-10C6H5- 1 (CH3)3CC02CH2- H-4-C5H4S- 1 C2H5C02CH2- C2H3N4 *
4 C5H4S 1 (CH3)2CHC02CH2- C2H3N4S-j 154-C5H4S- 1 CH3C02CH(CH3)- C2H3 4 C6H5S- 1 CH3C02CH(CH3)- C2H3N4S-C6H5S- 1 (CH3)2CHCH2C02CH2- C2 3 4 *
C6H5S- 1 CH3(CH2~2C02CH2- C2 3 4 *
C6H5S-- 1 C2 5 2 (C 3) C2H3N4S-6 5 1 2 5 2 ( 3) C3H3N2S2-~
C6H5S- 1 (CH3)3CC02CH2- C3 3 2 2 6H5- 1 C8H50- # H-25C6H5S- 1 CsH50- # H-CN } CH3C02CH2- H-Br 3 2)2 02CH2 H-3-C~H3S- O CH3C2CH2- H-~ 3-C4H3S- 1 CH3C02CH2- H-:

:"
~, :
, .

N ,.,N
~N~' 3H3N2S2 = N--N

# C8H5 = ~) -1L~2-~, ~

:

~L~6i4~

The Eollowing ingredients are blended together in the indicated proportions by weight.
Sucrose, U.S.P. 80.0 Tapioca Starch 13.5 Magnesium Stearate6.5 7-Phenylacetamido 3-methyl~
ttetrazol-5-yl)-~3-cephem 100.0 After the composition is thoroughly blended, tablets are punched lO from the mixture, each tablet being of suck size as to contain 100 mg. of the cephem compound.
Tablets are also prepared containing respectively 50 and 250 mg. of active ingredient, by selecting the appropriate proportions of cephem compound and excipient blend in each case.

The f~llowing ingredients are blended together in the indicated proportions by weight.
Calcium carbonate 17.6 Dicalcium phosphate 18.8 20 ` Magnesium trisilicate 5.2 Lactose, U.S.P. 5.2 Potato starch 0.8 7-Phenoxyacetamido-3-methyl50.0 4 (tetrazol-5-yl)-~ -cephem The thoroughly-mixed pharmaceutical composition is fiIled into soft gelatin capsules, such that each capsule contains lO0 mg. of active ingredient.
Capsules are also prepared containing respectively 50 and 250 mg. of active ingredient by varying the proportions of cephem compound and excipient blendc :
.
-1~3-.

EX~MPLE 90 ~ = = . .
The sodium salt of 7-(2-thienylace-tamido)-3-methyl-4-(tetrazol-5-yl)-~3-cephem is thoroughly mixed and ground with sodium citrate (4% by weight).
The ground, dry mixture is sterilized and packed into s-terile vials, which are then stoppered wi-th serum caps under sterile conditions. When it is in-tended to use this preparation, suf~icient sterile water is injected into the vials to dissolve the contents, and give a solution containing 25 mg./ml. of active ingredient. For parenteral use, the solutior is wi-thdrawn from the vials using a hypodermic syringe.
In a similar manner, by vaIying the amount of water added, solutions containing respectively 10, 50, 100 and 200 mg./ml. of active ingredient are prepared.

7-[D~ Amino-~-phenyl)acetamido]-3-methyl-4-~tetrazol-5-yl)-~3-cephem Po-tassium Salt To a stirred solution of 1.94 g. 7-[D-(~-amino-~-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-~3-cephem in 100 ml. of methanol, cooled to -30C., is added dropwise sufficient l.ON solution of potassium hydroxide in methanol such that one equivalent of base is added. The mixture is allowed to warm to 20 0C., and then it is added dropwise with stirring to 700 ml. of ether. The solid which precipitates is removed by filtration and dried under high vacuum.
This affords the title potassium salt in good yield.
When the above procedure is repeated, except that the potassium hydro-xide used therein is replaced by an equimolar amount o~ sodium hydroxide the pro-25 duct is the sodium salt of 7-~D-(~-amino- ~phenyl)acetamido~-3-methyl-4-(tetrazol-5-yl)-~3-cephem.

-1~4-7 [D-(o~Amino-~-(p-hydrox~phenyl)acetam;do]-3-methyl-4-(-tetrazol-5-yl)-Q cephem Calcium Salt ~ ~ . _ To a stirred solution of 3.87 g. of 7-CD-(~-amino-a-(p-hydroxyphenyl)-acetamido]-3-methyl-4--(tetrazol-5-yl)-a3-cephem in 40 ml. of dimethylformamide is added a turbid solution of 370 mg. of calcium hydroxide over 5 minutes.
The mixture is heated at 35-40C. for 1 hour, and then an additional 30 ml. of dimethylformamide is added. Heating at 35-40C. is continued for a further 30 minutes, and then the cooled solution is added dropwise to 700 ml. of ether.
An oil precipitates. The solvent is decanted off and to the residue is added 100 ml. of ethanol, followed by 400 ml. of ether. The oil slowly solidifies and then it is recovered by filtration and dried under high vacuum. This affords the title calcium salt.

.
7-[D-(a-Amin~-o-phenyl)acetamido]-3-methyl-4-~tetrazol-5-yl)-a -ce~hem Hvdrochloride Salt A slurry of 50 mg. of 7-[D-(o~amino- ~phenyl)acetamido}-3-methyl-4-(tetrazol-5-yl)-Q3Lcephem in 2 ml. of de-ionized water is stirred for 5 minutes at ambient temperature. The pH is then adjusted to 2.45 using dilute hydrochloric acid, and the solution thus obtained is immediately lyophilized.

This a~fords the hydrochloride salt of the desired compound, a white solid.

~ -145-

Claims (83)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a cephem derivative of formula:

...I

and the salts thereof; wherein T is a tetrazolyl group which is either or wherein R is selected from the group consisting of (1) hydrogen; (2) a nitrogen protecting group which is 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxy-carbonyl, benzyloxycarbonyl, or wherein R3, R4 and R5 are each selected from the group consisting of hydrogen, chloro, bromol fluoro, methyl, methoxy and phenyl; and (3) an acyl group of formula:

;

A is selected from the group consisting of hydrogen, acetoxy, 1-methyl-5-tetrazolylthio, 2-methyl-1,3,4-thiadiazolyl-5-thio and bromo; and R1 is selected from the group consisting of hydrogen, alkanoyloxymethyl having from three to six carbon atoms, 1-(alkanoyloxy)ethyl having from four to seven carbon atoms, methoxymethyl and phthalidyl, and R11 is selected from the group consisting of R1 and is a tetrazolyl cephem nitrogen protecting group or precursor thereof and is selected from the group con-sisting of wherein R6 is selected from the group consisting of alkyl having from one to three carbon atoms and phenyl and R7 is selected from the group consisting of hydroxy, methoxy, alkanoyloxy having two to four carbon atoms and benzyloxy and R8 is selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy, alkanoyloxy having from two to four carbon atoms, phenyl and benzyloxy and wherein R9 and R10 are each selected from the group con-sisting of hydrogen and methyl and X is selected from the group consisting of oxygen and sulfur; and Ar is selected from the group consisting of cyano, bromo, phenyl, mono- or disubstituted phenyl where each substituent is hydroxy, fluoro, chloro, bromo, amino, methoxy or methyl, phenoxy, phenylthio, pyridylthio, thienyl, 2-methyl-1,3,4-thiadiazol-5-ylthio, 1-tetrazolyl, alkyl having from one to twelve carbon atoms, alkenyl having from two to twelve carbon atoms, cycloalkyl having from three to seven carbon atoms, cycloalkenyl having from five to eight carbon atoms, cycloheptatrienyl, 1,4-cyclohexadienyl, 1-aminocycloalkyl having from four to seven carbon atoms, 5-methyl-3 phenyl-4-isoxazolyl, 5-methyl-3-(o-chlorophenyl)-4-isoxazolyl, 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, sydnonyl, furyl, pyridyl, thiazolyl, isothia-zolyl, pyrimidinyl, triazolyl, imidazolyl, pyrazolyl, substituted phenoxy, substituted phenylthio, substituted pyridylthio, substituted thienyl, substituted furyl, substituted pyridyl, substituted tetrazolyl, substituted thiazolyl, substituted isothiazolyl, substituted pyrimidinyl, substituted triazolyl, substituted imidazolyl, and substituted pyrazolyl, each substituted moiety being substituted by up to two members selected from the group consisting of fluoro, chloro, bromo, hydroxy, hydroxy-methyl, amino, 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, aminoethyl, alkoxy having from one to four carbon atoms, alkylthio having from one to four carbon atoms, 2-aminoethoxy and N-alkylamino having from one to four carbon atoms;
Q is selected from the group consisting of hydrogen, hydroxy, azido, amino and carboxy;
n is an integer of 0 or 1; provided that when Ar is selected from the group consisting of pyridylthio, phenoxy, phenylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, bromo and cyano and n is 1, Q is selected from the group consisting of hydrogen and carboxy; providing T is or when A is bromo, R is not which process in-cludes in the reaction sequence for the preparation thereof at least one of the following steps:
(1) acylating with an organic acylating agent a compound of the above formula wherein R is hydrogen and T is a tetrazolyl group to give R as ;

(2) reacting a penam of the formula:

wherein R and A are as previously defined and R2 is a tetrazolyl cephem nitrogen protecting group or precursor thereof and is selected from the group consisting of wherein R6 is selected from the group consisting of alkyl having from one to three carbon atoms and phenyl and R7 is selected from the group consisting of hydroxy, methoxy, alkanoyloxy having two to four carbon atoms and benzyloxy and R8 is selected from the group consist-ing of hydrogen, hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy, alkanoyloxy having from two to four carbon atoms, phenyl and benzyloxy and wherein R9 and R10 are each selected from the group consisting of hydrogen and methyl and X is selected from the group consisting of oxygen and sulfur; with a halogenating agent and subsequently with an azide to form a tetrazolyl group as T;
(3) alkylating a compound of the formula:

wherein A is as hereinbefore defined and wherein R
is hydrogen or amino protecting group, with a halide compound to form R1 other than hydrogen; or (4) brominating a compound of the formula:

wherein T' is or and wherein R is hydrogen or an amino protecting group R1 or R11 -CH2-O-CH3; and to form a compound of Formula I in which A is bromo and, if desired, subsequently removing the methoxymethyl group.

2. A process according to claim 1, for pre-paring a compound of the formula:

wherein Ac is the acyl group ;

T is the tetrazolyl group of the formula:

or wherein R1 is hydrogen, alkanoyloxymethyl having from three to six carbon atoms, 1-(alkanoyloxy)ethyl having from four to seven carbon atoms, methoxymethyl or phthalidyl;
R11 is R1 or a tetrazolylcephem nitrogen pro-tecting group as defined in claim 1;
A is hydrogen, acetoxy, 1-methyl-5-tetrazolyl-thio, or 2-methyl-1,3,4-thiadiazolyl-5-thio which comprises acylating a compound of the formula:

with an organic acid acylating agent of the formula:

wherein Y1 is hydroxy, chloro, bromo, a mixed anhydride moiety or an activated ester moiety and Ar, Q and n are as defined in claim 1.

3. A process according to claim 2, wherein after acylation of the amino group, any tetrazolyl cephem nitrogen protecting group is removed.

4. A process according to claim 2, wherein R1 or R11 is hydrogen.

5. A process according to claim 2, wherein R11 or R1 is alkanoyloxymethyl, 1-(alkanoyloxy)-ethyl, methoxymethyl or phthalidyl.

6. A process according to claim 2, wherein R11 is or wherein R6 is hydrogen, alkyl having from one to three carbon atoms or phenyl;
R7 is hydroxy, methoxy, alkanoyloxy hav-ing two to four carbon atoms, or benzyloxy; and R8 is hydrogen, hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy, alkanoyloxy having two to four carbon atoms, phenyl or benzyloxy;
R9 and R10 are each hydrogen or methyl and X is oxygen or sulfur.

7. A process according to claim 2, wherein A
is hydrogen.

8. A process according to claim 2, wherein A
is acetoxy.

9. A process according to claim 2, wherein said acylating agent is one wherein Ar is phenyl, phenoxy or 2-thienyl, and n is 1 and wherein said compound of the formula is one wherein A is hydrogen and T is the tetrazolyl group as defined in claim 2.

10. A process according to claim 9, for the production of 7-phenylacetamido-3-methyl-4-(tetrazol-5-yl)-.DELTA.3-cephem or 7-phenoxyacetamido-3-methyl-4-(tetrazol-5-yl)-.DELTA.3-cephem or 7-(2-thienylacetamido)-3-methyl-4-(tetrazol-5-yl)-.DELTA.3-cephem by reaction of phenyl acetic acid, phenoxy acetic acid or 2-thienyl acetic acid or the acyl chloride or bromide, mixed anhydride or activated ester thereof with a compound of the formula:

11. A process according to claim 9, for the production of 7-phenylacetamido-3-methyl-4-[2 (pival-oyloxymethyl)-tetrazol-5-yl]-.DELTA.3-cephem, 7-phenoxy-acetamido-3-methyl-4-[2-(pivaloyloxymethyl)-tetrazol-5-yl]-.DELTA.3-cephem or 7-(2-thienylacetamido)-3-methyl-4-[2-(pivaloyloxymethyl)-tetrazol-5-yl]-.DELTA.3-cephem by reaction of phenyl acetic acid, phenoxy acetic acid, thienyl acetic acid, or the acyl chloride or bromide, or mixed anhydride or activated ester thereof with a compound of the formula:

wherein R1 is pivaloyloxy methyl.

12. A process according to claim 1, for pre-paring a compound of the formula:

wherein R is the amino protecting group as defined in claim 1; T is a tetrazol group of the formula:

wherein R2 is the tetrazolylcephem nitrogen protect-ing group;
A' is hydrogen, acetoxy, 1-methyl-5-tetrazol-ylthio, or 2-methyl-1,3,4-thiadiazolyl-5-thio, which includes the step of converting the amide group of a compound of formula:

wherein R2 is a potential tetrazolylcephem nitrogen protecting group to the tetrazolyl group T by reac-tion of said amide with a halogenating agent and sub sequently with an azide.

13. A process according to claim 12, wherein the tetrazolylcephem nitrogen protecting group is p-methoxybenzyl.

14. A process according to claim 13, wherein the tetrazolylcephem nitrogen protecting group is removed following formation of the tetrazolyl ring.

15. A process according to claim 13, wherein the amino protecting group is removed following formation of the tetrazolyl ring.

16. A process according to claim 13, wherein there is employed as said starting compound the formula:

a compound wherein R2 is p-methoxybenzyl and A' is as defined in claim 13.

17. A process according to claim 16, wherein there is employed as said starting material a com-pound wherein R is 2,2,2-trichloroethoxycarbonyl and A' is hydrogen.

18. A process according to claim 16, wherein there is employed as said starting material a com-pound wherein R is triphenylmethyl and A' is hydrogen.

19. A process according to claim 16, wherein there is employed as said starting material a com-pound wherein R is benzyloxycarboxy and A' is acetoxy.

20. A process according to claim 16, wherein there is employed as said starting material a com-pound wherein R is 2,2,2-trichloroethoxycarbonyl and A' is acetoxy.

21. A process according to claim 16, wherein there is employed as said starting material a com-pound wherein R is hydrogen and A' is acetoxy.

22. A process according to claim 16, wherein there is employed as said starting material a com-pound wherein R is benzyloxycarbonyl and A' is 1-methyltetrazolyl-5-yl-thio.

23. A process according to claim 16, wherein in the starting material R is 2,2,2-txichloroethoxy-carbonyl and A' is 2-methyl-1,3,4-thiadiazol-5-yl-thiomethyl.

24. A process according to claim 16, wherein there is employed as said starting material a com-pound wherein R is hydrogen and A' is 2-methyl-1,3,4-thiadiazol-5-ylthiomethyl.

25. A process according to claim 16, wherein in the starting material R is benzyloxycarbonyl and A' is 2-methyl-1,3,4-thiadiazol-5-ylthiomethyl.

26. A process according to claim 14, wherein in the starting material R is hydrogen and A' is hydrogen.

27. A process according to claim 14, wherein in the starting matarial R is hydrogen and A' is acetoxy.

28. A process according to claim 14, wherein in the starting material R is hydrogen and A' is 2-methyl-1,3,4-thiadiazol-5-ylthiomethyl.

29. A process according to claim 14, wherein in the starting material R is hydrogen and A' is 1-methyltetrazol-5-ylthiomethyl.

30. A process according to claim 14, wherein in the starting material R is 2,2,2-trichloroethoxy-carbonyl and A' is hydrogen.

31. A process according to claim 1, for pre-paring a compound of the formula:

wherein R is hydrogen or a nitrogen protecting group as defined in claim 1, A' is hydrogenl acetoxy, 1-methyl-5-tetrazolylthio or 2-methyl-1,3,4-thiadiazol-yl-5-thio: T is a tetrazolyl group of the formula:

or wherein R11' or R1' is alkanoyloxymethyl having from three to six carbon atoms, 1-(alkanoyloxy)-ethyl having from four to seven carbon atoms, meth-oxymethyl or phthalidyl; which comprises alkylating the corresponding tetrazolyl compound wherein R11' or R1' is hydrogen with R1' halide.

32. A process according to claim 31, wherein any amino protecting group is removed following alkylation.

33. A process according to claim 32, wherein R1' or R11' is methoxymethyl.

34. A process according to claim 31, wherein both R1' and R11' are methoxymethyl.

35. A process according to claim 33, wherein in the starting material R is 2,2,2-trichloroethoxy-carbonyl.

36. A process according to claim 33, wherein in the starting material R is hydrogen.

37. A process according to claim 1, for the production of a compound of the formula:

wherein R is selected from the group consisting of 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxy-carbonyl, benzyloxycarbonyl, hydrogen and wherein R3, R4 and R5 are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, methyl, methoxy and phenyl; wherein T is or R1 is selected from the group consisting of hydrogen, alkanoyloxymethyl having from three to six carbon atoms, 1-(alkanoyloxy)ethyl having from four to seven carbon atoms, methoxymethyl and phthalidyl; and R11 is selected from the group consisting of hydrogen, alkanoyloxymethyl having from three to six carbon atoms, 1-(alkanoyloxy)ethyl having from four to seven carbon atoms, methoxymethyl and phthalidyl;

wherein R6 is selected from the group consisting of alkyl having from one to three carbon atoms and phenyl and R7 is selected from the group consisting of hydroxy, methoxy, alkanoyloxy having two to four carbon atoms, and benzyloxy; and R8 is selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy, alkanoloxy having two to four carbon atoms, phenyl and benzyloxy and wherein R9 and R10 are each selected from the group consisting of hydrogen and methyl and X is selected from the group consisting of oxygen and sulfur which comprises brominating a compound of the formula:

38. A process according to claim 37, wherein the brominated product obtained is subsequently re-acted with a mercaptan of the formula A'''SH or acetate salt to give a compound of the formula:

wherein A" is acetoxy, or A"' wherein A"' is 1-methyl-5-tetrazolyl or 2-methyl-1,3,4-thiadiazol-5-yl.

39. A process according to claim 37, wherein there is employed as starting material a compound wherein R is 2,2,2-trichloroethoxycarbonyl.

40. A process according to claim 37, wherein there is employed as starting material 7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[1-(methoxyy-methyl)tetrazol-5-yl]-.DELTA.2-cephem.

41. A process according to claim 37, wherein there is employed as starting material 7-(2',2',2'-trichloroethoxycarboxamido)-4-[2-(methoxymethyl)-tetrazolyl-5-yl]-.DELTA.2cephem.

42. A process according to claim 38, wherein thera is employed as starting material an acetate salt and said brominated product is 7-amino-3-bromo-methyl-4-[1-(methoxymethyl)-tetrazol-5-yl]-.DELTA.2cephem.

43. A process according to claim 38, wherein there is employed as starting material 1-methyl-tetrazol-5-ylthiol and said brominated product is 7-amino-3-bromomethyl-4-[1-(methoxymethyl)-tetrazol-5 yl]-.DELTA.2-cephem.

44. A process according to claim 38, wherein there is employed as starting material 1-methyl-tetrazol-5-ylthiol and said brominated product is 7-amino-3-bromomethyl-4-[2-(methoxymethyl)-tetrazol-5-yl]-.DELTA.2-cephem.

45. A process according to claim 38, wherein there is employed as starting material 2-methyl-1,3,4-thiadiazol-5-ylthiol and said brominated product is 7-amino-3-bromomethyl-4-[1-(methoxymethyl)-tetrazol-5-yl]-.DELTA.2-cephem.

46. A process according to claim 38, wherein there is employed as starting material 2-methyl-1,3,4-thiadiazol-5-ylthiol and said brominated product is 7-amino-3-bromomethyl-4-[2-(methoxymethyl)-tetrazol-5-yl]-.DELTA.2-cephem.

47. A process according to claim 37, wherein in the starting material R is tribromoethoxycarbonyl.

48. A process according to claim 1, for prepar-ing a compound of formula:

wherein R is hydrogen or a nitrogen protecting group as defined in claim 1; T" is a tetrazolyl group of the formula:

or which comprises brominating a compound of the formula:

and, if desired, subsequently removing the methoxy-methyl group.

49. A cephem derivative of formula:

and the salts thereof;

wherein T is a tetrazolyl group which is either or wherein R is selected from the group consisting of (1) hydrogen; (2) a nitrogen protecting group which is 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromo-ethoxycarbonyl, benzyloxycarbonyl, or wherein R3, R4 and R5 are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, methyl, methoxy and phenyl; and (3) an acyl group of formula ;

A is selected from the group consisting of hydrogen, acetoxy, 1-methyl-5-tetrazolylthio, 2-meth-yl-1,3,4-thiadiazolyl-5-thio and bromo; and R2 is a tetrazoyl cephem nitrogen pro-tecting group or precursor thereof and is selected from the group consisting of wherein R6 is selected from the group consisting of alkyl having from one to three carbon atoms and phenyl and R7 is selected from the group consisting of hydroxy, methoxy, alkanoyloxy having two to four carbon atoms and benzyloxy and R8 is selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy, alkanoyloxy having from two to four carbon atoms, phenyl and benzyloxy and wherein R9 and R10 are each selected from the group consisting of hydrogen and methyl and X is selected from the group consisting of oxygen and sulfur;
R1 is selected from the group consisting of hydrogen, alkanoyloxymethyl having from three to six carbon atoms, 1-(alkanoyloxy)ethyl having from four to seven carbon atoms, methoxymethyl and phthalidyl; and R11 is selected from the group consisting of R1 and R2;
Ar is selected from the group consisting of cyano, bromo, phenyl, mono- or disubstituted phenyl where each substituent is hydroxy, fluoro, chloro, bromo, amino, methoxy, or methyl, phenoxy, phenylthio, pyridylthio, thienyl, 2-methyl-1,3,4-thiadiazol-5-ylthio, 1-tetrazolyl, alkyl having from one to twelve carbon atoms, alkenyl having from two to twelve carbon atoms, cycloalkyl having from three to seven carbon atoms, cycloalkenyl having from five to eight carbon atoms, cycloheptatrienyl, 1,4-cyclo-hexadienyl, 1-aminocycloalkyl having from four to seven carbon atoms, 5-methyl-3-phenyl-4-isoxazolyl, 5-methyl-3-(o-chlorophenyl)-4-isoxazolyl, 5-methy1-3-(2,6-dichlorophenyl)-4-isoxazolyl, 5-methyl-3-12-chloro-6-fluarophenyl)-4-isoxazolyl, 2-alkoxy-1-naphthyl having from one to four carbon atoms in said alkoxy, sydnonyl, furyl, pyridyl, thiazolyl, isothiazolyl, pyrimidinyl, triazolyl, imidazolyl, pyrazolyl, substituted phenoxy, substituted phenyl-thio, substituted pyridylthio, substituted thienyl, substituted furyl, substituted pyridyl, substituted tetrazolyl, substituted thiazolyl, substituted iso-thiazolyl, substituted pyrimidinyl, substituted triazolyl, substituted imidazolyl, and substituted pyrazolyl, each substituted moiety being substituted by up to two members selected from the group con-sisting of fluoro, chloro, bromo, hydroxy, hydroxy-methyl, amino, N,N-dialkylamino having from one to four carbon atoms in each of said alkyl groups, alkyl having from one to four carbon atoms, amino-methyl, aminoethyl, alkoxy having from one to four carbon atoms, alkylthio having from one to four carbon atoms, 2-aminoethoxy and N-alkylamino having from one to four carbon atoms;
Q is selected from the group consisting of hydrogen, hydroxy, azido, amino and carboxy;
n is an integer of 0 or 1; provided that when Ar is selected from the group consisting of pyridylthio, phenoxy, phenylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, bromo, and cyano and n is 1, Q
is selected from the group consisting of hydrogen and carboxy;
whenever obtained by the process of claim 1

50. A compound of the formula:

and the salts thereof, wherein R is an amino protecting group selected from the group consisting of 2,2,2-trichloroethoxy-carbonyl, 2,2,2-tribromoethoxycarbonyl, benzyloxy-carbonyl, and wherein R3, R4 and R5 are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, methyl, methoxy and phenyl;
A is selected from the group consisting of hydrogen, acetoxy, 1-methyl-5-tetrazolylthio, and 2-methyl-1,3,4-thiadiazolyl-5-thio; and R2 is a tetrazolyl cephem nitrogen pro-tecting group whenever obtained by the process of claim 12.

51. A compound according to claim 50, wherein A is said hydrogen, acetoxy, 1-methyl-5-tetrazolyl-thio, and 2-methyl-1,3,4-thiadiazolyl-5-thio and R2 is p-methoxybenzyl whenever obtained by the process of claim 13.

52. 7-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-.DELTA.3-cephem whenever prepared by the process of claim 17.

53. 7-(N-Triphenylmethylamino)-3-methyl-4-[1-(p-methoxybenzyl)-tetrazolyl-5-yl]-.DELTA.3-cephem when-ever obtained by the process of claim 18.

54. 7-(Benzyloxycarboxamido)-3-acetoxymethyl-4-[1-(p-methoxybenzyl)-tetrazol-5-yl]-.DELTA.3-cephem whenever obtained by the process of claim 19.

55. 7-(2',2',2'-Trichloroethoxycarboxamido)-3-acetoxymethyl-4-[1-(p-methoxybenzyl)-tetrazol-5-yl]-.DELTA.3-cephem whenever obtained by the process of claim 20.

56. 7-Amino-3-acetoxymethyl-4-[1-(p-methoxy-benzyl)-tetrazol-5-yl]-.DELTA.3-cephem whenever obtained by the process of claim 21.

57. 7-(Benzyloxycarboxamido)-3-(1-methyl-tetrazol-5-ylthiomethyl)-4-[(p-methoxybenzyl)tetrazol-5-yl]-.DELTA.3-cephem whenever obtained by the process of claim 22.

58. 7-(2',2',2'-Trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-.DELTA.3-cephem whenever obtained by the process of claim 23.

53. 7-Amino-3-(2-methyl-1,3,4-thiadiazol-5-yl thiomethyl)-4-11-(p-methoxybenzyl)-tetrazol-5-yl]-.DELTA.3-cephem whenever obtained by the process of claim 24.

60. 7-(Benzyloxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)-tetrazol-5-yl]-.DELTA.3-cephem whenever obtained by the process of claim 25.

61. A compound of the formula:

wherein R and A' are as defined in claim 12 whenever obtained by the process of claim 14.

62. 7-Amino-3-methyl-4-(tetrazol-5-yl)-.DELTA.3-cephem whenever obtained by the process of claim 26.

63. 7-Amino-3-acetoxymethyl-4-(tetrazol-5-yl)-.DELTA.3-cephem whenever obtained by the process of claim 27.

64. 7-Amino-3-(2-methyl-1,3,4-thiadiazol-5-yl -thiomethyl)-4-(tetrazol-5-yl)-.DELTA.3-cephem whenever obtained by the proeess of claim 28.

65. 7-Amino-3-(1-methyltetrazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-.DELTA.3-cephem whenever obtained by the process of claim 29.

66. 7-(2', 2', 2'-Triehloroethoxyearboxamido)-3-methyl-4-(tetrazol-5-yl)-.DELTA.3-cephem whenever obtained by the proeess of claim 30.

67. A compound of the formula:

wherein T' is or and R and A' are as defined in claim 31, whenever obtained by the process of claim 34.

68. A compound of the formula:

wherein R is 2',2",2'-trichloroethoxycarboxamido and T'is or and A' is as defined in claim 31, whenever obtained by the process of claim 35.

69. A compound of the formula:

wherein T' is or A' is as defined in claim 31, whenever obtained by the process of claim 36.

70. 7-Amino-3-acetoxymethyl-4-[1-(methoxymethyl)-tetrazol-5-yl]-.DELTA.2-cephem whenever obtained by the process of claim 42.

71. 7-Amino-3-(1-methylte-trazol-5-ylthiomethyl)-4-[1-(methoxymethyl)-tetrazol-5-yl]-.DELTA.2-cephem whenever obtained by the process of claim 43.

72. 7-Amino-3-(1-methyltetrazol-5-ylthiomethyl)-4-[2-(methoxymethyl)-tetrazol-5-yl]-.DELTA.2 -cephem when-ever obtained by the process of claim 44.

73. 7-Amino-3-(2-methyl-1,3,4-thiadiazol-5-yl-thiomethyl)-4-[1-(methoxymethyl)-tetrazol-5-yl]-.DELTA.2-cephem whenever obtained by the process of claim 45.

74. 7-Amino-3-(2--methyl-1,3,4-thicadiazol-5-ylthiomethyl)-4-[2-(methoxymethyl)-tetrazol-5-yl]-.DELTA.-cephem whenever obtained by the process of claim 46.

75. 7-(2',2',2'-Tribromoethoxycarboxamido)-3-bromomethyl-4-[1-tetrazol-5-yl]-.DELTA.2 cephem whenever obtained by the process of claim 47.

76. A compound selected from the group con-sisting of:

and wherein R is selected from the group consisting of 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxy-carbonyl, benzyloxycarbonyl, hydrogen and wherein R3, R4 and R5 are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, methyl, methoxy and phenyl;
R1 is selected from the group consisting of hydrogen, alkanoyloxy having from three to six carbon atoms, 1-(alkanoyloxy)ethyl having from four to seven carbon atoms, methoxymethyl, and phthalidyl;
and R11 is selected from the group consist-ing of hydrogen, alkanoyloxymethyl having from three to six carbon atoms, 1-(alkanoyloxy)ethyl having from four to seven carbon atoms, methoxymethyl, phthalidyl, wherein R6 is selected from the group consisting of alkyl having from one to three carbon atoms and phenyl and R7 is selected from the group consisting of hydroxy, methoxy, alkanoyloxy having two to four carbon atoms and benzyloxy and R8 is selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy, alkanoyloxy having from two to four carbon atoms, phenyl and benzyloxy and wherein R9 and R10 are each selected from the group consisting of hydrogen and methyl and X is selected from the group consisting of oxygen and sulfur when-ever obtained by the process of claim 37.

77. A compound according to claim 76, wherein R is 2,2,2-trichloroethoxycarbonyl whenever obtained by the process of claim 39.

78. 7-(2',2',2'-Trichloroethoxycarboxamido)-3-bromomethyl-4-[1-(methoxymethyl)-tetrazol-5-yl]-.DELTA.22-cephem whenever obtained by the process of claim 40.

79. 7-(2',2',2'-Trichloroethoxycarboxamido)-3-bromomethyl-4-[2-(methoxymethyl)-tetrazol-5-yl]-.DELTA.2-cephem whenever obtained by the process of claim 41.

80. A cephem derivative when prepared hy a pro-cess according to claim 2, and of the formula:

and the salts thereof; wherein Ac, T and A are as defined in claim 2.

81. A compound of the formula:

wherein Q, T and A are as defined in claim 2 and where-in n is 1; Ar is selected from the group consisting of phenyl, phenoxy, and 2-thienyl; and A is hydrogen whenever prepared by the process of claim 9.

82. 7-Phenylacetamido-3-methyl-4-(tetrazol-5-yl)-.DELTA.3-cephem, or 7-phenoxyacetamido-3-methyl-4-(tetra-zol-5-yl)-.DELTA.3-cephem, or 7-(2-thienylacetamido)-3-methyl-4-(tetrazol-5-yl)-.DELTA.3-cephem, whenever prepared by the process of claim 10.

83. 7-Phenylacetamido-3-methyl-4-[2-(pivaloyl-oxymethyl)-tetrazol-5-yl]-.DELTA.3-cephem, 7-phenoxyacet-amido-3-methyl-4-[2-(pivaloyloxymethyl)-tetrazol-5-yl]-.DELTA.3-cephem, 7-(2-thienylacetamido)-3-methyl-4-[2-(pivaloyloxymethyl)-tetrazol-5-yl]-.DELTA.3-cephem when-ever prepared by the process of claim 11.