CA1042421A - Process for producting 7-acylamido-7-alkoxycephalosporins - Google Patents

Abstract

ABSTRACT OF THE DICLOSURE
The present invention relates to a proce3s for the preparation of 7-acvlamido-7-alkoxycephalosporins which comprises reacting a 7-(5-amino-5-carboxyvaleramido)-7-methoxycephalosporin with amino and acid groups protected, with PCl5 or other agent capable of forming an imino halide;
thereafter reacting the resulting imino halide under essentially non-aqueous conditions with a primary lower-alkanol of C1-C4 or with methan-d3-ol, to yield a nucleus bearing a 7-alkoxv group derived from the primary lower-alkanol or methan-d3-ol. In situ acylation of the nucleus affords 7-acylamido-7-alkoxycephalosporins in good yield. These products can he deesterified to yield the corresponding acids, which exhihit antibacterial activity.

Description

42~ ` :
The present invention relates to a proces~ for the preparation of 7-acylamido-7-alkoxycephalosporins which comprises reactiny a 7-~5-amino-5-carboxyvaleramido)--7-methoxycephalosporin with amino and acid groups protected, with PCl5 or other agent capable of forming an imino halide;
thereafter reacting the resulting imino halide under essentially non aqueous conditions with a primary lower-alkanol o~ Cl-C4 or wlth methan-d3-ol, to yield a nucleus bearing a 7-alkoxy group derived from the primary lower-alkanol or methan-~ -ol. In situ acylation of the nucleus affords 7-acylamido-7-alkoxycephalosporins ~n good yield. The~e products can` be deesterified to yi~ld the corresponding acids, which exhibit antibacterial activity.
An article by Nagàrajan et al. in J. Am. Chem. Soc.
93: 9 ~May 5, 1971~ describes novel antibiotics o~ the follcwing structural formulae:

ûCI13 5 HOOC--ÇH ~CHz) :~CO~H

hH8 ~L 1' ~CHsOCC11:~

and O
COt)~

OCH;~ S

H OO C-~H ( CU 2 ~ ;~ CO~H ~

~CH20C~JHz C()OH

6~3 2 ~ .
~3 ' .
.
~ .

~o~
These antibiotic~ are named 7-~5-a~ino-5-c~rboxyvaleramido~-7-met~oxycephalosporanic acid and 7-~5-amino-5-carboxy-valeramido)-7-methoxy-3-car~amoyloxymethyl-3-cephem~4-carboxylic acid, respectively. Alternatively, they are referred to as antibiotic~ Al6884 and Al68861; c~. Belgian patents 754,424 and 754,693. The latter o~ these antibiotics is also described, as antibiotic "842A", by Belgian Patent 764,160.
In addition, Belgian Patent 764,160 describes an antibiotic "8l0A" w~ich is of the formula HOOC-CH~CH2~3CONH _ ~ ~

NH2 ~ ¦ ~ CH~O~-~2CH - ~ ~ ~ ~ H

COOH

This antibotic i5 named 7~tS-amino-5-carboxyvaleramido)-7-methoxy-3~ methoxy-p-hydroxycinnamoyloxymethyl~-cephem-4-car~oxylic acid.
In common ~ith other cephalosporins, these antibiotics can be treated ~y the PCl5 method to remove the 7-acyl group and yield a nucleus; this nucleus, if desired, can be reacylated to introduce a different 7-acyl group.
H~wever, there has no~ been discovered an improved method for cleaving and reacylating the foregoing antibiotics, as well as other 3-position modifications thereof. In addition, the process can be used as a method of introducing into the foregoing antibiotics, or the same 3-position modifications thereof, a different 7-alkoxy moiety or a 7-methoxy-~3 moiety in lieu of the original 7-methoxy group.

.: . , .. . . . ..
.: : .. ..

4~1 :
Thus, the present invention in one aspect re~ides in a process for preparing compounds of the formula:

H OR
R5 - N~ ~ ~ S ~

O~ ~ CH2-R
COOR
wherei~ R5 is hydrogen, Cl-C~ alkanoyl, azidoacetyl, cyanoacetyl, haloacetyl, Ar-C~-C- where Ar denotes phenyl, thienyl, ~uryl, or phenyl substituted with from -~
one to three substituents selected from the group consisting of fluorine~ chlorine, bromine, iodine, trifluoromethyl, protected amino, protected hydroxy, Cl-C3 alkyl, Cl-C3 alXoxy, cyano, and nitro, ;
Ar'-Y-C~2-C- where Ar' represents phenylj or substituted phenyl as defined above, and is oxygen or sulfur, Ar-C~-C- where Ar is as defined above~ and B is - -8 protected amino, protected hydroxy, . protected carboxy~ or

2-(lH-tetrazol-l-yl)acetyl;
R represents primary loweralkyl of Cl-C4 or methyl-d3 ~-20 Rl represents acetoxy, car~amoyloxy, propionyloxy, ;: .
benzoyloxy, methoxy, methylthio, l-methyl- :
1,2,3,4-tetrazol-5-ylthio, or 5-methyl-1,3,4-thiadiazol-2-ylthio; and R2A represents hydrogen or R2, in which R2 represents ~, .

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

~ -- .
lV~Z~2~
alkyl o$ Cl-C6, 2,2,2-trichloroethyl, ~-iodoethyl, tert-alkenyl of C5-C7, tert-alkynyl of C5-C7, ben~yl, nitrobenzyl, methoxybenzyl, dimethoxybenzyl, cyanomethyl, nitrophenyl, dinitrophenyl, 2,4,6-trinitro-phenyl, bis~-methoxyphenyl~methylr triphenyl-methyl, diphenylmethyl, benzyloxymethyl, loweralkanoyloxymethyl of C3-C6, or phenacyl;
which comprises reacting an imino halide compound of the formula:

300C-C (C~i!)3-C=N~

4~ N~ CH2-OOR;~B
where;n X represents bxomide or chloride;
Rl is as defined abov~;
R2B~represents R~ as defined above, lower alkanoyl of C~-C4 o a radical of the ormula~
R
R3 7 Si -wherein each R independently representslower alkyl of Cl-C4 or halo selected from the group consisting of bromo, chloro, fluoro, and iodo subject to the limitation that at least one R represents lower alkyl as defined; and R4 represents an acylamido group wherein the acyl is alkanoyl of Cl-C4, benzoyl, naphthoyl, alkoxycarbonyl of C2-C5, cycloalkoxycarbonyl of C6-C7, benzyloxycarbonyl, naphthyloxycarbonyl, ~ ~ .
~ 4a-~24Z~
one of the above groups substituted with from one to three groups, each select~d from ; the group consisting of halo, nitro, lower alkoxy of Cl-C4, cyano, and in the instance of benzoyl, naphthoyl, benzyloxy, and naphthyloxy, by loweralkyl of Cl-C4, or phthaloyl;
with an alcohol of the formula R-OH under essentially non-aqueous conditions to form a compound of formula I wherein R5 is hydrogen; and if desired reacting the compound of formula I wherein R5 is hydrogen in situ with a compound of one of the formulae: :

~-R5 and 2 ~'' wherein`X represents halogen, preferably bromine or chlorine,~
and R5 represents Cl-C8 alkanoyl; :~
azidoacetyl; :
cyanoacetyl; ~ :
haloacetyl;
Ar-CH2-~- where Ar denotes phenyl, thienyl, furyl, ~ ~.

or phenyl substituted with from one to three substi-tuents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, protected amino, protected hydroxy, Cl-C3 alkyl, Cl-C3 alkoxy, ~:
cyano, and nitro; ~ :
AR'-Y-CH2-~ where Ar' represents phenyl, or substituteld : :
phenyl as defined above, and Y is oxygen or sulfur;
Ar-8H-~- where Ar is as defined above, and B is protected amino, protected hydroxy, protected carboxy; or 2-(lH-tetrazol-l-yl)acetyl.
..
~ -4b-! ",~

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

4~
In another aspect the present invention resides in compounds of the formula:

3 OCD3 CH2Rl O CooR2A , ...

wherein Rl, R2A and R5 are as previously defined.
The starting imino halide is preferably prepared in situ by the reaction of a compound of the formula: :

R BoOC- f (CH2)3CONH
R ~ N ~ CH2-Rl-COOR2B :' 20.
, ' ,;
.' ' :.
".; ~ .

..... . .. . . . . .. . - . - . . . .

9LZ~L `
with PC15 or other acid hallde.
Preferably, the resulti.ng product, i.Q., a compound of the formul~:

OR
H 2 N tl,~S~
,~I~CH z-R
.' ' o//

. is ~ubsequentlv reacylated in situ wlth a compound of one : lO of the formulae X-Rs and o~R5) z where{n X rep~e~ents halogen, ~referably bromine or .. . .
: ~ chlorine, and :
wherein R5 reprQsents Cl-C8 alkanoYl; :

; azidoacet~l;

: ~yanoace~yl;

-~ haloacetyl;

Ar-CH~-~ where Ar denotes phenyl, thienyl~ furyl, pyrrolyl, ox ~henvl substituted with ~rom one - to three substituents selected from the group . , .
consistina of fluorine, chlorine, bro~ine, iodine, tri~luoromethyl, proteoted amino, protected ; hy~roxy~ Cl-C3 a~ , Cl-C3 alkoxy, cyano, a~d nitro;
Ar'-Y-C~2-~- where Ar' represent~ phenyl, pyridyl, or substi~uted phenyl as defined ~bove, and Y i~
oxygen or sulfur;
'~ ~
Ar~H- - where Ar is as defined above, and B i~

protected amino, protected hydroxy, prote~ted ~-3~73 ~ ~

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

~042421 carhoxy, -C~ or -N3;
2-(3-~ydnone)acetyl; or 2-(lH-tetrazol-l-yl)acetyl. The protected amino is preferably a~ino substituted by such protecting groups as benzyloxycarbonyl, ~-nitrobenzyloxycarbonyl, alkoxycarhonyl of C2-C5, cycloalkoxvcarbonvl of C6-C7, triphenylmethyl, or 2,2,2-trichloroethoxycarbonyl. The protected hydroxy group i5 preferably a group of the formula CH3OC~l2O- or H~O~.
The protected carboxy grou~ i9 preferably a carbsxy grou~
protected as described for the carboxy groups in the starting compounds.
The reacylated compounds wherein R2A represents hydrogen exhibit antibacterial activity. In the instance of compound~ wherein R2A represents any of the specified ester groups, or where other protecting groups are present, the reacylated compounds can be dee~terified and such other protecting groups removed to yield proclucts exhibiting antihacterial activity.
The startin~ materials to he employed in accordance with the present inven~ion R2BOOC-~H(CH 2) 3-CON~--R4 ~ N~CH 2 -R

are prepared in known procedures. More particularly, anti-biotic A16~84, A16886I, or 810A is reacted (1) to protect the amino group t (2) to protect the acid groups, and in the case of antibiotic 810A, (3) to protect the -OH group.

~-3673 7 :- .

2~Zl The pr~tection o the amino ~roup i~ conveniently obtained by reacting antibiotic ~16R84 t A16886I, or 810A
with a suitable acyl halide, anhydrid~, or ketene to form an acylamido yrou~. ~he identity of the acylamldo group thereby formed is not critical. Suita~le acylamido groups are those wherein the acyl is:
- alkanoyl of Cl-C
benzoyl, naphthoyl, '10 alkoxycar}~onyl of C2-C5, cycloalkoxycarbonyl of C6-C7, benzylo.~ycarhonyl, -- naphthyloxycarbonyl, : one of the above groups substituted with from one to three grou~s, each selected from the group consisting of halo, nitro, loweralkoxy of Cl-C4, cyano, and, in the instance of benzoyl, , naphthoyl, benzyloxy, and naphthyloxy, by ; loweralkyl of Cl C~, or phthaloyl.
"Halo" is employed to refer to bromo, chloro, iodo, and ; ~luoro. Representative suitable groups include the following: formyl, acetyl, propion~1, chloroacetyl, dichloroacetyl, benzoyl, ~-nitrobenzoyl, phthaloyl r ~-methoxybenæoyl, cyclohexyloxycarbonyl, tert-butoxycarbonyl, phenoxycarbonvl, or benzyloxycarbonyl. For convenience in separating the protectad amino compound, a salt thereof can be prepared.
In one embodiment, the carboxyl groups are protected by esterification. The identity of ~he ester ~-3673 8 ,. . .
. ~ , ~ ., .

~o~
group 1~ not critlcal; suitable ~roup~ are those which can easily be split off after the protec~ion is no longer required.
Piepre~entative ~nd suitable ~roups, when the esterificat~on is carried out as a separa~e step, includ~ alkyl of Cl~C6, 2,2,2-trichloroethyl, 2-iodoethyl, tert-alkenyl of C5-C7, tert-alkynyl of C5-C7, benzyl, ar-nitrobenzyl, tetrahydropyranyl, succinimidometh~l, phthalimidomethyl, ar-methoxy~enzvl, ar,ar-di~ethoxybenzyl, cyanomethyl, nitroph~nyl, dinitrophenyl, 2,4,6-trinitrophenyl, bis-~-methoxyphenyl)meth~ riphenylmethyl, diphenylmeth~l, benzyloxymethyl, loweralkanoyloxymethyl of C3-C6, and phenacyl.
In a second and often preferred emhodiment, the protection of the carhoxyl groups is carried out as an ~. initial part of the cleavage reactions, hy employing either a ; reactant which will orm a mixed anhydride, or a silane com-pound. The mixed anhvdride is prepared in conventional ~ procedures, as, for example, hy reactin~ the antibiotic ~ with an acyl halide. The identity o.f the latt2r reactant, and its corresponding moiety in the mixed anhydride, is not critical. Suitahle groups include the loweralkanoyl moieties ~` and such moieties bearing substituents. ~owever, owing to their ease of preparation, the simple loweralkanoyl groups, such a~ those conkainin~ from 2 to 4 carbon atoms, are -; pref~rred.
Th~ silane compound to be used ~n protection o th~
; carboxyl groups is suitably a compound of the formula . R~
R3~-S i-R3 R ~

wherein aach ~3 ind~penden tly represent~ loweralkyl of ~-3~73 9 10~L~4Zl ; Cl-C4 or halo selected from the group con~isting of bromo, chloro, fluoro, and iodo--subject to the l~mitation that at least one R3 re~esents halo and at lea~t one R3 repre-sent8 loweralkyl as defined. A pref~rred sil~ne comnound : is trimethylchlorosilane. Other suitAhle co~ounds include dimethyldichlorosilane, methyltrichlorosilane, diethyldifluorosilane, or bromotrimethylsilane.
The R
R3\-Si-R ~
protecting group can al~o be introduced hy reactin~ the antibiotic with a silylamide, urea, or urethane, as describad in Belgian Patent 737,761.
In the case o both the silyl ester and mixed anhydride protecting groups, the reaction of the imino halide with alcohol in accordance with the present invention removes : such groups, yieldlng nucl~us as free acid.
Alternately, the carboxyl and amino groups in the ~-amino-adipoyl side chain can he blocked by ring ~ormation as, for example, by formation of an imidazolidine ring.
In the case of antibiotic 810A, protection of the -OH group is readily achieved by known procedures, e.g., by reaction with chlorome~hyl methyl ~ther or with ~-~romo-phenacyl bromide (see Fiaser ~ Fieser, Reagents ~or Organic Synthesis, John Wil~y & 50ns, New York 1968, Vol~ I, page 133 and Vol~ III, page 34, respectively).
Those compounds to be e~ployed as ~tarting materials wherein R represents propionyloxy, benzoyloxy, methoxy~
methylthio, l-meth~1-1,2,3,4-tetrazol-5-ylthio, or 5-methyl-1,3,4-thi~diazol-2-~lthio are prepared as de~cribed in ~-3673 10 ,. . ~ . . ,, : . .

, ~4Z~z~
Belgian patent 7fi~,52~. The compounds can thfefn be treated, as desf~ribed ahovfe, to protect the amfino and ac i~ d groups.
By whichever procedurec; ohtained, the resulting protected comf~founfc R2BOOC-~If(CH2~3-CONf~ S

~CH:~-R~

is thereafter reacted with an af~ent capahle of forming an imino halide. While phosphorus pentachloride is the pre-ferred agent, other acid halides can be used. Thus, other suitable agents include phosphorus oxyc1l10ride, phosphorus tricffhloride, thionyl chloride, phosf~ene, oxalyl chloride, and the complex compound fofrmef' fro~ o-dihydxox~benzene ~ and phosphorus trichloride.
-i The starting compound and the imino-halide-forming agent are reacted with one another in an~ convenient fashion.
Generally, good results are o~tained when employing the ; reactants in amounts representing one molecular proportion of the starting compound and from two to five molecular propoxtions of the imino-halide-forming agent. The reaction goes forward under temperatures of from -50 to 50 C~, but i~
- preferably conducted at about room temperatures. The reaction ., is preferably conducted in the presence of a tertiaxy amina, for example, triethylamine, p~ridine, or dimethylani-line.
fO Thi~ reaGtion produce~ an imino halide of tha ~ormula:

i-3 6 73 11 4Z:l R2BOOC-~H(CH2)3-~=N f ~s~
N ~ CH2R
C()OR
which is thereafter reacted, without separation, in the critical step o the present invention.
It has been founcl that when the imino halide i~
treated with an alcohol as def.ined in the pr~sent invention, there i5 obtain~d, directly, the desired nucleu~:

"'10 ~ S
,~N~----CH 2 R

,~ COOR2A
, Use of an alcohol in accordance with the present invention i. obviates the need for water, as described by the pxior art, and thereby obviates risk of degradation of the nucleus, which appears to be of lesser ~tability under aqueous - conditions.
In addition to the foregoing advantages, u~e of an alcohol as herein defined provides a method for introducing a different 7-alko~y group or for introducing the methoxy-`' d3 group. Tha precise mechanism is not und~rstood, but treatment with an alcohol in accordance with the present ,~, invention results in a nucleus bearing a 7-alkoxy group derived from the alkanol employed. When it is desired to - ret~in a 7-me hoxy group, methanol is to be used.
The introduction of the 7-alkoxy group from the al-X-3673 1~

1~9LZ4~L
cohol i8 acco~panied by some epimerization at the 7~position.
Antibiotics A16884, A168~6I, and ~BlnA (a~ well a~ the other 3-po~ition derivatives therleof) are believed to exist in the 7-~-methoxy configuration, the 7-(S-amino-5-carboxyvaleramido) group being in ~he ~-configuration.
Reacylated compoun~s prepared in accordance with the present invention exis~ as a mixture of ~- and ~-alkoxy compounds;
the precise ratio varies with the particular acyl moiety.
- The alcohol to be usad in this step of the present process can b~ any primary loweralkanol of Cl-C4, i.e., methanol, ethanol, n-propanol, n-~utanol, or isobutanol; or the alcohol can be methan-d3-ol. In carrying out the reaction, the alcohol is added to a ~olution containing the imino halide intermediate. It i5 essential for good yields that the solution be essentially non-aqueous and tha~ it be maintained e~sentially non-aqueous until the nucleus has been reacylated. The reaction goes forward over a range of temperatures, such as from -70 to +50 C~;
: however, the reaction is preferably con~ucted initially at 0 C., followed by warming to room temperatures for a ~ew minutes, then returnin~ to 0 C~
The pro~ortions of imino haiide and alcohol are not critical and vary with the precise reaction and reactants.
It i~ believed that the reaction of imino halide and alcohol, per se, consumes two molecular pxoportions of the alcohol per molecular proportion of the imino halide. However, additional alcohol is consumed by excess PC15 or other acid halide.
Also, wher~ the acid groups are protected by a mixed anhydride or ~ilyl ~roup (R2- loweralkanoyl or ~-3673 13 ~ . ~ , , . . . ,. .. .. : . . .

`:; ~CI424~2~

~S' R ~ 1 ) alkanol is consumed by reaction with these groups. In practice, it has be~n found that good r~sults ar~ ohtained by emplovin~ th~ alcohol in large excess, such as five to ten molecular proportions of alcohol per molecular propor-tion of imino halide.
The product:OR

H ~ N+~
~-N~ CH2R

- can he separated from the reaction mixture, if desired; how-~, ever, such separation should be carried out under ~lightly basic conditions. Better results are ohtained when the ; product is reacylated in situ. ~he reacylation iq accom-.~ plished by reaction with a compound o one of the formulae X-R5 and o~R5)~ whe~ein X and R5 are as defined herein-above. The acylation reaction is conducted in accordance with conventional procedures. The resulting compounds:

OR

--N H ~
O r CH~Rl : COOR~A
are useful, in that thos~ of ~he compounds wherein R2~=
an estar group can be hydrolyzed to the free acid compounds (R2A- H). The free acids with the OR group in the configuration are useful as antibacterial agen~s; see Belgian patent 768,528. In the ~-OR epimer ~orm, the esters :, ~, : ~ ;

~0~
can be treatecl in accordance with the process of the present invention, to yield a mixture of a- and ~-alkoxy e~ters, the ~ alkoxy epi~ers bein~ useful as described above.
The followinq ~xample~ i]lustrate the practice of the present in~ention and will enable those skilled in the art to practice the inventioll. In numerous of the syntheses reported in these examples, deuterated compounds were utilized as solvents and as re~gents other than the reactant, to enable easy identification of product hy nmr s~ectroscopy.
The use of suc~ deuterated compounds is therefore not criti-- cal to the practice of the invention.

EXAMPLE 1: PREPA~ATIO~ OF 7-AMINO-7-METHOXYCEPHALOSPORANIC
ACID, METHYL ~STER
7 (5-Phthalimido-5-carhoxyvaleramido)-7-methoxy-cephalosporanic acid, dimethyl ester (60.~ milligrams; 0.1 millimole) was mixed at room temperature with methylene chloride-d2 (0.5 millilitex), p~ridine-cl5 ~21 milli~rams; 0.25 ; millimole), and phosphorus pentachloride (42 milli~rams;
0.2 millimole). The reaction mixture was maintained for ~ about one hour, then cooled to 0 C. and maintained thereat :;20 for about another hour. Plethanol-d (5n milli~rams; 1.44 millimoles) was aclded an~ the reaction mixture held for one-half hour, yielding ~he desired 7-amino~7-methoxycepha~
losporanic acid, meth~1 ester ln SltU
In a representative ~uch preparation, th~ reaction mixture was monitored by nmr spectroscopy. The addition of the phosphorus pentachloride resulted in a downfield shift -, of the signal for the a-me~hylene group of the valeramido side chain. Prior to addition of the phosphoru~ pentachlo-ride, there was a broad 4-proton resonance centered about 2.35 ppm; a~ter the addition (but priox to addition of , , .

~042421 methanol~ there was a ~-~roton triple~ at 2.74 ppm (J ~ 7 cps) lndicatin~ formation of the imino chloride. Followin~
; addition of the methanol the triplet disappeared and a

4~proton resonance centered at 2.35 ~m ~as ree~tahlished.

EXAMPL~ 2: P~PARATIO?J o~ 7-PHIJNOXYAC~T~lIDO-7-MET~IOXYC~PIIA-LosponA~Ic ACID M~T~IYL E5Tr~R
To the reaction mixture containin~ 7-amino-7-methox~-cephalosporanic acid meth~l ester (preparecl as described Example 1) chloroform-_ (0.5 milliliter) pyridine-d5 tl27 ~10 milligrams; 1.52 millimoles) an~ ~henoxyacetyl chloride (131 milliqrams: 0.77 millimole) were added at 0 C. The reaction mixture was maintained at 0 C. for lS minutes and then warmed up to r~om temperature for 10 ~inutes. The reaction mixture was then wor~ed up in conventional pro-cedures; these procedures were essentially the same as those reported hereinbelow in Exa~ple 9 beginning with the addition of dry methanol except that methylene chloride was used herein in lieu of the chloroform reported in Example 9.
The resultin~ methylene chloride ~hase was chromato~raphed ~20 on thick layer plates witll benzene/ether 7:3 as developer and acetone as aluent. ~ass spectra showed a parent peak at 450 consistent with the c~lculated molecular formula (450.4) for the ecpected 7-phenox~acetamido-7 methoxy cephalosporanic acid methyl ester.
The co~pound was also suhjected to high resolution mass spectroscopy; it indicated a parent ion with mass 450-1106- ~theory for C20H22~J~8S 450.1097).
In a representative preparation as de~cribed above the product was subjected to nmr spectroscopy in CDC13~ ~ 2.05 (s 3H 3-CH2OCOCH3); 3.41 (two q 2H 2-CH2); 3.51 and 3.54 . ~ . .
:, ~)4~4'~
(two s, 3H, 7-OCil3 two epimers); 3.87 (s, 3H, 4-CooCH3); 4.08 (broad, 2H, 00CH2CONH); 4.96 (two q, 2H~ 3-CH2OCOCH3); 5~12 (s~ 0.15H~ 6-H of 7-~-OCH3 epimer); and 5.23 ppm (s~ ~0.ô5H~
6H of 7-~-OCH3 epime~).

EXAMoeLE 3: PREPARATION OF 7-AMINO-7-METHOXYCEP~LOSPORANIC
ACID
8-(5-Phthalimido-5-carboxyvaleramido)-7-methoxy-cephalosporanic acid (57.6 milligrams; 0.1 millimole) was mixed ith 0.5 milliliter of methylene chloride d2 and the mixture cooled to 0 C. Dimethylaniline (80.5 milligrams;
0.72 millimole) and acetyl chloride-d3 (28.5 milligrams; 0.35 - millimole) were added and the reaction mixture maintained at 0 C. and vibrated. Within fifteen minutes3 all substances had ~one into solution; an hour latex, phosphorus penta-chloride (73 milligrams, 0.35 millimole) was added and the reaction mixture likewise vibrated. Within 25 minutes the phosphorus pentach1Oride had gone into solution,land the reaction mixture was held for several hours. The reaction -~ mixture was then storsd in dry ice for two hours and sub-sequently brought up to 0 C. Methanol-d (96 milligrams;
3.0 millimole) was added and the reaction mixture vibrated and brought up to room temperature five minutes later, yielding in situ the desired 7-amino-7-methoxycephalosporanic acid ~XAMPL~ 4: PREPARATION OF 7-PHENOXYACETAMIDO-7-METHOXYCEP~
LOSPORANIC ACID
''' :
To the final reaction mixture reported i n Example 3, chloroform-d(0.5 milliliter~, pyridine-d5(276 milligrams;
3.5 millimoles), and phenoxyacetyl chloride (273 milligrams;
1.6 millimoles~ were added at 0 C. and the resulting reac~
tion mixture vibrated. Tw~nty minutes later, 0.5 milliliter . , .
,." . ~

z.~
of chloroform and 96 milligram~ of methanol (3.0 millimoles) were added. The reaction mixture was diluted to 10 milliliters with chloroform, extracted with two 15-milli-liter portions of sodium bicarhonate solution, and the sodium bicarbonate solutions washed with 20 milliliters of chloroform. Th~ chloroform and sodium ~icarbonate layers were separated and 50 milliliters of chloroform were added to the sodium bicarbonate layer, and it was then acidified to pH 2.5 with phosphoric acid and the chloroform layer sepaxated. The solution was extracted again with 20 milli-liters of chl~roform. The last two chloroform layers, obtained fro~ the acidified bicarbonate solution were combined and evaporated, yielding a total of 35.2 milligrams of 7-phenoxyacetami~o-7-methoxycephalosporanic acid.

EX~MPLE 5: PRE~A~TION OF 7-PH~OXYPHE~OXYPIIENACET~IDO-7-METHO~Y-C~PHALOSPOR~IC ACID, 7-Phenoxyacekamido-7-methox~cephalosporanic acid was prepared in the same procedures as reported in Examples 3-4, except that 7-~5-chloroacetamido-5-carboxyvaleramido)-7~
methoxycephalosporanic acid ~52.2 milligrams; 0.1 millimole) was employed as the starting material. Other reactants and materials were, initially, m~thylene chloride-d2 (0.5 milliliter); N,N-di~ethylaniline (80.5 milligrams; 0.72 millimole~; and acetyl chloride-d3 (28.5 milligrams; 0.35 millimole); then phosphorus pentachloride (73 milligrams;
0.35 millimole); subse~uent reagents and amounts, ; and the workup procedures, were the same as in Examples 3 and 4. ~orkup yielded 454 milligrams of 7-phenoxyaceta-mido~7-methoxycephalosporanic acid.

X-3673 1~

EXAM~Le 6: PREPARATION OF 7-A~INO-7-ME~10XY-d3-CEP~L~L
SPORANIC ACID, METHYL ESTER
7-(5-Phthalimido-5-carboxyvaleramido)-7-methoxy-cephalosporanic acid, dimethyl ester (60.4 milligrams; 0.1 millimole)~ methylene chloride-d2 (0.5 milliliter), and pyridine-d5 (21 milligrams, 0.31 millimole) were mixed at room temperature and phosphorus pentachloride ~42 milligrams; 0.2 millimole) added. The reaction mixture was held for about five hours. The reaction mixture was then cooled to 0 C. and methan-d3-ol-d (52 milllgrams;
1044 millimoles) added. As a result of these operations, there was obtained in situ the desired 7-amino-7-methoxy- ;
d3_cephalosporanic acid, methyl ester.

EXANPLE 7: PREPARATION OF 7-PHENOXYACETANIDO~7-METHOXY-a3-CEPHALOSPORANIC ACID, METHYL ESTER
To the reaction mixture obtained as reported in Example 6, there was added chloroform-d (0.5 milliliter)~
pyridine-d5 ~127 milligrams; 1.52 millimole)~ and phenoxy-acetyl chloride (131 milligrams; 0.77~millimole). The reaction mixture was thereafter treated as described in Example 9. After conventional workup, there was obtained 18 milligrams of the starting 7-(5-phthalimido-5-carboxy-valeramido)-7-methoxycephalosporanic acid~ dimethyl ester;
16.2 milligrams of 7-(5-phthalimido-5-carbomethoxy-d3-valeramido)-7~methoxycephalosporanic aci~, methy~ ester;
111 milligrams of phenoxyacetic acid, methyl-d-3 ester; and 19 milligrams of the desired 7~phenoxyacetamido-7-methoxy-d3-cephalosporanic acid, methyl ester. High resolution mass spectroscopy of the 7-phenoxyacetamido-7-methoxy~d3-cephalosporanic acid, methyl ester, showed a parent peak with mass 453.1277 (theory for C20D3Hl9N2~8s~ 453.1285).

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

~2~Z~
Nmr spectroscopy (CDC13) showed 82.og (s~3H~-CH20COCH3);
3.45 (m~2H~2-Cll2); 3.91 (t,3H, 4~COOCH3); 4.61 and 4.62 (2 sharp peaks, total 2H, 00CH2CONH); 4.98 (q,2H,3-CH2-OCOCH3); and 5.15 and 5.26 ppm (2 sharp peaks, 0.3H and 0.7H, respectively, 6-H of 7-~-0~13 and 7-~-OCH3 epimers, respectively).

EXAMPLE 8: PREPARATION OF 7-AP~NO-7-METHOXYCEPHALOSPORANIC

7-(5-Phthalimido-5-carboxyvaleramido)-7-methoxy-cephalosporanic acid, dibenzhydryl ester (910 milligrams;
1 millimole) was dissolved in 5 milliters of methylene chloride and the solution stirred at 0 C. Pyridine (0.198 gram; 0.20 milliliter; 2.5 millimoles) was then added, followed by phosphorus pentachloride (0.42 gram; 200 milli-moles). The reaction mixture was stirred at room te~perature for 1.5 hours. Anhydrous methanol (0.46 gram; 0.59 milli-liter; 14.4 millimole) was then added, follgwed by 10 minutes stirring at 0 C. and 5 minutes stirring at room temperature.
The resulting reaction mixture, contalning the desired 7-amino~7-methoxycephalosporanic acid, benzhydryl ester, was again cooled to O C. and divided into two portions.

EXAMPLE 9: PREPARATION OF 7-PHENOXYACETAMIDO-7-METHOXYCEPHA~
LOSPORANIC ACID~ BEN2HYDRYL ESTER
To one of the portions of reaction mixture prepared as described in Example 8 and containing 7-amino-7-methoxy-cephalosporanic acid, benzhydryl ester, there was added chloroform (2.5 milliliters) containing pyridine (0.60;
7.6 millimoles). The reaction mixture was stirred for 5 minutes, then phenoxyacetyl chloride (0.68 ~gram; 3.85 mlllimoles) was added. The reaction mixture was stirred at 0 C. for 15 minutes, then at room temperature for 10 minutes. Dry methanol (0.3 milliliter) was added and the . i ~4Z~
reaction mixture stirred at room ternperature for another 5 minutes. The reaction mlxture was subsequently poured into ice water and the chlorvform phase washed with dilute HCl, then with several ~olumes of water, and then dried sequen-tially over sodium chloride and over magnesium sulfate. The chloroform was removed on a rotary evaporator, yielding an oil, 1~14 gram.
This oil was chromatographed and the fraction contain-ing 7-phenoxyacetamido-7-methoxycephalosporanic acid, benzhydryl ester, separated and subjected to nmr spectroscopy (CDC13):
1.97, 1.98 (two s, 3H, 3-CH20COCH3)3 3.4 (two q, 2Hl 2-CH2); 3.54 (broad, 3H, 7-OCH3); 4.56 (two s, 2H, 0OCH2-CONH); 4.9 (two q, 2H, 3-CH2OCOCH3); 5011 (s~ 0.4H, 6-H
of 7-q~OCH3 epimer); and 5.24 ppm (s, Oa6~ 6~H of 7-~-OCH3 epimer).
The same fraction was chromatographed ;lnto two portions, one containing the 7-~-methoxy stereoisomer (32 milligrams), the other containing both 7-a~methoxy and 7 -~-methoxy epimers (57 milligrams~.

EXA~ LE 10: PREPARATION OF 7-~-PEHNOXY~CETAMIDO-7-~-METHOXY
CEPHALOSP~RANIC ACID
The fraction prepared as described in Example 9 and containing both 7-~-methoxy and 7 ~ methoxy epimers was thereafter treated to remove the benzhydryl ester.~ The fraction was dissolved in a 1:1 mixture of trifluoroacetic acid-formic acid (002 milliliter) and after 5 minutes at room temperature, methylene chloride ~4-milliliters) was added and the mixture rotary evaporated to dryness at room temperature~ Ethyl acetate was added and the mixture extracted with dilute sodium bicarbonate. The sodium bicarbonate extract was washed with ethyl acetate, then :: :
:: . .

~0~2~2~
acidified to pH 1.5 under ethyl acetate. The phases were then separated and the ethyl acetate extract dried over magnesium sulfate, filtered, and evaporated to dryness.
The foregoing procedures yielded the c-epimer, 7-~-phenoxyacetamldo~7-drmethoxycephalosporanic acid: nmr (CDC13),~ 2~06 (s, 3H, 3-CH2OCOCH3); 3.36 (q, 2H, 2-CH2;
3.54 (s, 3H, 7~0CH3); 4.61 ~broad, 2H, 0OCH2CONH); 5.04 (q, 2H, 3-CH2OCOCH3); and 5.12 ppm (s, lHg 6-H).

EXAMPLE 11: PREPARATION OF 7-ACEIAMIDO-7~METHOXYCEPHA-LOSPORANIC ACID, BENZH~DRYL ESTER
The second portion of reaction mixture prepared as described in Example 8 and containing 7-amino~7-methoxy-cephalosporanic acid, benzhydryl ester, was acylated with acetyl chloride. The procedures and reagents other than the acyl halide were the same as those reported in Example 9. As a result, there was obtained 7-acetamido-7-methoxy-cephalosporanic acid~ benzhydryl ester: nmr (CDC13) ~1.96 and 1.97 (two s; 6H, 3-CH2OCoCH3 and 7-CH3CONH); 3.38 (q, 2H~ 2-CH2); 3.50 (broadg 3Hj 7-OCH3); h.81 (two q, 2H~
3-CH2OCOCH3~; 5.10 (s projecting from anothsr signal, 6-H
of 7-q-OCH3 epimer); and 5.20 ~pm (s, 0.6H, 6-H of 7-~-OCH3 epimer).

-~4~
SUPPLEMENT~RY DISCLOSU~E

The following exampl~ describes additional ~pecific compounds prepared in accordance with the present invention:

Example 12: ~
The following compounds also are prepared by the . .
process described in Examples 3 and 4: : :

7-mandelamido-7-methoxy-3-(5--methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4-carboxylic~acid U.V. (EtOH) ~ - 270 m~ ~ 4000.
7-mandelamido-7-methoxy-3-(1-methyl-1,2,3,4-tetrazol-~-yl-thiomethyl)-3-cephem-4-carboxylic acid ~;
U.V. ~EtOH) ~ = 270 m~, ~ = 4000. ~-:
7-[2-(2-thienyl)acetamido]-7-methoxy-3-acetoxymethyl-3~
cephem-4-carboxylic acid .
U.V. (MeOH) ~ = 260 m~ = 8000.
7-C2-(2-thienyl)acetamido~-7-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid U.V. (EtOH) ~ = 265 mll, ~ = 7000.

7-r2~2-thienyl)acetamido]-7-methoxy-3-(5-methyl-1~3~4- `
thiadiazol-2-yl-thiomethyl)-3-cephem-4-carboxylic acid U.V. (EtOH) ~ = 265 m~ ~ 6000.
7-[2-(2-thienyl)acetamido]-7-methoxy-3-(l-methyl-l~2~3~4-tetrazol-5-yl-thiomethyl)-3-cepnem-4-carboxylic acid U.V. (EtOH) ~ = 270 m~ ~ 6000.

~-3673 B

Claims (22)

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

1. A process for preparing compounds of the formula:
I
wherein R5 is hydrogen, C1-C8 alkanoyl, azidoacetyl, cyanoacetyl, haloacetyl, where Ar denotes phenyl, thienyl, furyl, or phenyl substituted with from one to three substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, protected amino, protected hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, and nitro, where Ar' represents phenyl, or substituted phenyl as defined above, and Y is oxygen or sulfur, where Ar is as defined above, and B is protected amino, protected hydroxy, protected carboxy, or 2-(1H-tetrazol-1-yl)acetyl;
R° represents primary loweralkyl of C1-C4 or methyl-d3;

Rl represents acetoxy, carbamoyloxy, propionyloxy, benzoyloxy, methoxy, methylthio, 1-methyl-1,2,3,4-tetrazol-5-ylthio, or 5-methyl-1,3,4-thiadiazol-2-ylthio; and R2A represents hydrogen or R2, in which R2 represents alkyl of C1-C6, 2,2,2-trichloroethyl, 2-iodoethyl, tert-alkenyl of C5-C7, tert-alkynyl of C5-C7, benzyl, nitrobenzyl, methoxybenzyl, dimethoxybenzyl, cyanomethyl, nitrophenyl, dinitrophenyl, 2,4,6-trinitro-phenyl, bis(p-methoxyphenyl)methyl, triphenyl-methyl, diphenylmethyl, benzyloxymethyl, loweralkanoyloxymethyl of C3-C6, or phenacyl;
which comprises reacting an imino halide compound of the formula:
wherein X represents bromide or chloride;
R1 is as defined above;
R2B represents R2 as defined above, lower alkanoyl of C1-C4 or a radical of the formula:
wherein each R3 independently represents lower alkyl of C1-C4 or halo selected from the group consisting of bromo, chloro, fluoro, and iodo subject to the limitation that at least one R3 represents lower alkyl as defined; and R4 represents an acylamido group wherein the acyl is alkanoyl of C1-C4, benzoyl, naphthoyl, alkoxycarbonyl of C2-C5, cycloalkoxycarbonyl of C6-C7, benzyloxycarbonyl, naphthyloxycarbonyl, one of the above groups substituted with from one to three groups, each selected from the group consisting of halo, nitro, lower alkoxy of C1-C4, cyano, and in the instance of benzoyl, naphthoyl, benzyloxy, and naphthyloxy, by loweralkyl of Cl-C4, or phthaloyl;
with an alcohol of the formula R°-OH under essentially non-aqueous conditions to form a compound of formula I wherein R5 is hydrogen; and if desired reacting the compound of formula I wherein R5 is hydrogen in situ with a compound of one of the formulae:
X-R5 and O(R5) wherein X represents halogen, preferably bromine or chlorine, and R5 represents C1-C8 alkanoyl;
azidoacetyl;
cyanoacetyl;
haloacetyl;
where Ar denotes phenyl, thienyl, furyl, or phenyl substituted with from one to three substi-tuents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, protected amino, protected hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, and nitro;
where Ar' represents phenyl, or substituted phenyl as defined above, and Y is oxygen or sulfur;
where Ar is as defined above, and B is protected amino, protected hydroxy, protected carboxy; or 2-(1H-tetrazol-1-yl)acetyl.

2. The process of claim 1 wherein R5 is hydrogen.

3. The process of claim 1 wherein R1 is acetoxy.

4. The process of claim 1 wherein R° is methyl-d3.

5. The process of claim 2 wherein R° is methyl-d3.

6. Compounds of the formula wherein R1, R2A and R5 are as defined in claim 1, when prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

7. Compounds of the formula wherein R1 and R2A are as defined in claim 1, when prepared by the process of claim 5 or by an obvious chemical equlvalent thereof.

8. The process of claim 1 for preparing methyl 7-amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate which comprises reacting methyl 7-(5-methoxycarbonyl-5-phthalimido-1-chloro-pentylidene)amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate with methanol.

9. The process of claim 1 for preparing 7-amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid which comprises reacting 7-(5-carboxy-5-phthalimido-1-chloro pentylidene)amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid with methanol.

10. The process of claim 1 for preparing 7-amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid which comprises reacting 7-(5-chlorcacetamido-5-carboxy-1-chloro-pentylidene)amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid with methanol.

11. The process of claim 1 for preparing methyl 7-amino-7-methoxy-d3-3-acetoxymethyl-3-cephem-4-carboxylate which comprises reacting methyl 7-(5-methoxycarbonyl-5-phthalimido-1-chloro-pentylidene)amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate with methan-d3-ol-d.

12. The process of claim 1 ror preparing benzhydryl 7-amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate which comprises reacting benzhydryl 7-(5-diphenylmethoxycarbonyl-5-phthalimido-1-chloro-pentylidene)amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate with methanol.

13. The process of claim 1 wherein the compound of formula I in which R5 is hydrogen is subsequently reacted in situ with a compound of one of the formulae:
X-R and O?R5)2 wherein X represents halogen, preferably bromine or chlorine, a nd R5 represents C1-C8 alkanoyl;
azidoacetyl;
cyanoacetyl;
haloacetyl;
where Ar denotes phenyl, thienyl, furyl, or phenyl substituted with from one to three substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, protected amino, protected hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, and nitro;
where Ar' represents phenyl, or substituted phenyl as defined above, and Y is oxygen or sulfur;
where Ar is defined above, and B is protected amino, protected hydroxy, protected carboxy; or 2-(1H-tetrazol-1-yl) acetyl.

14. The process of claim 13 wherein R1 represents acetoxy.

15. The process of claim 13 for preparing methyl 7-phenoxyacetamido-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate which comprises reacting methyl 7-(5-methoxycarbonyl-5-phthalimido-1-chloro-pentylidene)amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate with methanol; followed by reaction with phenoxyacetyl chloride.

16. The process of claim 13 for preparing 7-phenoxy-acetamido-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid which comprises reacting 7-(5-carboxy-5-phthalimido-1-chloro-pentylidene)-amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid with methanol; followed by reaction with phenoxyacetyl chloride.

17. The process of claim 13 for preparing 7-phenoxy-acetamido-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid which comprises reacting 7-(5-carboxy-5-chloroacetamido-1-chloro-pentylidene)amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid with methanol; followed by reaction with phenoxyacetyl chloride.

18. The process of claim 13 for preparing methyl 7-phenoxyacetamido-7-methoxy-d3-3-acetoxymethyl-3-cephem-4-carboxylate which comprises reacting methyl 7-(5-methoxycarbonyl-5 phthalimido-1-chloro-pentylidene)amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate with methan-d3-ol-d; followed by reaction with phenoxyacetyl chloride.

19. The process of claim 13 for preparing benzhydryl 7-phenoxyacetamido-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate which comprises reacting benzhydryl 7-(5-diphenylmethoxycarbonyl-5-phtbalimido-1-chloro-pentylidene)amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate with methanol; followed by reaction with phenoxyacetyl chloride.

20. The process of claim 13 for preparing benzhydryl 7-acetamido-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate which comprises reacting benzhydryl 7-(5-diphenylmethoxycarbonyl-5-phthalimido-1-chloro-pentylidene)amino-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate with methanol; followed by reaction with acetyl chloride.

21. The compound methyl 7-amino-7-methoxy-d3--3-acetoxymethyl-3-cephem-4-carboxylate, whenever prepared or produced by the process of claim 11 or by an obvious chemical equivalent thereof.

22. The compound methyl 7-phenoxyacetamido-7--methoxy-d3-3-acetoxymethyl-3-cephem-4-carboxylate, whenever prepared or produced by the process of claim 18 or by an obvious chemical equivalent thereof.