CA1076560A

CA1076560A - 3-heterocyclic thiomethylcephalosporins

Info

Publication number: CA1076560A
Application number: CA163,909A
Authority: CA
Inventors: George L. Dunn; John R. E. Hoover
Original assignee: Smith Kline and French Canada Ltd
Current assignee: GlaxoSmithKline Inc
Priority date: 1972-06-14
Filing date: 1973-02-16
Publication date: 1980-04-29
Also published as: SE416472B; CH589093A5; IE37499B1; CA999293A; HU168689B; FI56843B; PL91074B1; FI56843C; DE2316866B2; FR2187299B1; PH9941A; GB1358027A; ES413501A1; DK142913B; NL7305206A; IE37409B1; JPS4931689A; AU5234573A; IE37499L; SE404190B

Abstract

ABSTRACT OF THE DISCLOSURE

Cephalosporin compounds substituted at the 7-position with .alpha.-aminophenylacetamido and at the 3-position with a triazolyl group are prepared by displacement of a 3-acetoxymethyl compound with the apprepriate mercapto-heterocycle or 7-acylation of an appropriately-substituted cephalosporin nucleus. The products are antibacterial agents.

Description

~ . ~ ~

This invention relates to ant'ibacterial cephalosporin compounds. In particular the invention relates to 7-p-hydroxyphenylacetamido-3-heterocyclic thiomethylcephalosporins of the following formula Ho~ cHcoNH~
\~CH2 S~R
COOH '-wherein R is l,233-triazolyl, unsubstituted or with 1 Or 2 groups 6elected f p ds of iornula I. In parti invention relates to a process for preparing said compounds ng an acetoxymethyl cephalosporin compound o~ the R ~H ~ S ~ -~L ~2ococH3 ~ " ' COOH

~5 in WhiCh Rl is H0 ~ CHCo / , the NH2 group being suitably protected as needed~ or H~ ~ith a heterocy~lic th~ol compound HS-R

~ 2 _ ~ 1-:

B

.

~L~76~ii6~

where R is as defined above; when R is H, acylating the resulting compound with a p-hydroxyphenylacetic acid compound of the formula H ~ CHCOOH

IV
or an acylating or activated derivative thereof, the NH2 group being suitably protected as needed; and then removing any protective group.
Among the preferred compounds of the invention are:
7-(p-hydroxy-~-aminophenylacetamido)-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid, 7-(p-hydroxy-~-aminophenylacetamido)-3-(4-methyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
The antibacterial compounds of this invention unexpec-tedly have advantageous properties compared with related compounds. For example, the compound 7-(a-amino-p-hydroxyphenylacetamido)-3-(1,2,3-triazol--4-ylthiomethyl)-3-cephem-4~carboxylic acid (compound 60771) is advantageous over the compound 7-(~-aminophenylacetamido)-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid (compound 60222) in producing higher peak serum concentra-tions in mice and particularly higher serum half-lives.
As a result, the activity observed upon on both oral and subcutaneous administration to mice is significantly improved as demonstrated by lower ED50's. Data obtained are presented inZTables A ànd B.

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TABLE A

Route of Peak Concen- Half-life Compound Dose Administration tration (~g/ml.) (min.) 60771 20 mg/kg p.o. 52 62 60222 20 mg/kg p.o. 13 48 60771 20 mg/kg s.c. 54 71 60222 20 mg/kg s.c. 35 34 ~ TABLE B
~ .
Mouse Protection Studies Compound Test organism Route of Administration ED (mg/kg-) ~ 50 60771 E. coli 12140 s.c. ~0.8, 0.8 60222 ~. coli 12140 s.c. ~3, 3.6 60771 E. coli 12140 p.o. ~0.8, 1.2 60222 E. coli 12140 p.o. ~12.5, 4 60771 K. pneumoniae s.c. 0.6, 0.6 -60222 K. pneumoniae s.c. 4.8 60771 K. pneumoniae p.o. 0.4, 0.5 60222 K. pneumoniae p.o. 12.5 Compound 60771 also is advantageous over 7~ amino-p-hydroxyphenylacetamido)-3-(5-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid (compound 61529) in having significantly lower ED50's in the mouse protection test. Data obtained are presented in Table C.

:

61;~

TABLE C
Mouse Protection Studies Com~ound Test organism Route of Adminis-tration ED50 (_~/kg.) 60771 E. coli 12140 s.c. ~0.8, 0.8 61529 E. coli 12140 s.c. 10.7 60771 E. coli 12140 p.o. (0.8, 1.2 61529 E. coli 12140 p.o. 7.5 60771 K. pneumoniae s.c. 0.6, 0.6 61529 K. pneumoniae s.c. 8.6 60771 K. pneumoniae p.o. 0.4, 0.5 61529 K. pneumoniae p.o. 16.

In addition9 the compound 7-(~-amino-p-hydroxy-phenylacetamido)-3-(4-methyl-1,2,3 triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (61775) is advantageous over 7-(d-aminophenylacetamido)-3-(4-methyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (61348) in having lower ED50's in mouse protection studies. The data are presented in Table D below.
TABLE D_ Mo_se Protection Studies Compound Test organism Route of Administration ED50(mg/
61775 E. coli 12140 s.c. 1.8 61348 E. coli 12140 s.c. 42, 18.2 61775 E. coli 12140 p.o. 3.6, 3 61348 E. coli 12140 p.o. 50, 19 61775 K. pneumoniae s.c. 2.8 61348 K. pneumoniae s.c. 20 61775 K. pneumoniae p.o. 5.2 61348 K. pneumoniae p.o. 146 6~6~

Also, the compound 7-( a-amino-p~hydroxyphenyl_ acetamido)-3-(1-methyl-1~2~3~triazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid (60876) is advantageous over 8~(a -aminophenylacetamido)-3-(1-methyl-1~2,3-triazol~5-ylthiomethyl)-3-cephem~4-carboxylic acid (60637) in having lower ED50's and higher peak serum levels and half-lives, as shown in Tables E and F, respectively.
TABLE E
Mouse Protection Studies ~ Test or~_nism Route of Administration ED5~ (mg/k~.) 60876 E. coli 12140 s.c. 5.2 60637 E. coli 12140 s~c~ 21.5 60876 E. coli 12140 p.o. 6.2 60637 E. coli 12140 p.o. 50 60876 K. pneumonlae s.c. 3.5 60637 K. pneumoniae s.c. 40 60876 K. pneumoniae p.o~ 6 60637 K. pneumoniae p.o. 200 TABLE F
Serum Concentrations in Mice ~ .
Route Peak Concen- Half-life Comeound Dose Administration tration (ugLml.) (min.
60876 20 mg/kg. p.o. 14 48 60637 20 mg/kg. p.o. 1~8 *
60876 20 mg/kg. s.c. 44 48 60637 20 mg/~g. s.c. 21 12 * Too small to be meoningful.
Generally it can be said that the compounds of this invention are superior in terms of lower protective doses and/or high and prolonged serum levels.

~ 560 1 Th~ compounds of the invention may be prepared by acylating the 7~amino group of the approprlate 7~amino 3-heterQcyclic ~hiomethyl cephalosporin nucleus with a p-hydroxyphenylglyclne. Prior ~c acylation9 it is de~irable to protec~ ~he amino group on the glycine moiety with an easily removable protective group such as t-butoxycarbonyl, benzyl~xycarbonyl, tr~ chloroethoxycarbonyl 9 or simi:Lar protective group co~only used in the synthexis of peptides.
For acyla~ion3 the carboxyl group of the ~cyla~ g agent can io be ac~lva~ed by conver~ion to the acid chloride or to a mixed anhydride with, ~or example~ a lower alk~l chloroformate.
The car~o~cyl group can al60 be aetivated by convar~ion to ~he 2,4; dini~rophenyl or N-hydroxysuccinimidoyl esters. I:E
an e~ter of the cephalo~porin n~cleu~, for example, the 15 benzhydryl~ t-butyl, trichloroethyl, or a benzyl est0r i8 used, ~che prot¢cted phenylglyclne can be coupled directly to the 7-amino group by using a carbodiimide such a6 dicyclohe2ylcarbodiim$de. Alterna~ively9 the protected phenylglycine can be activated :E0F cor~ensat~on with the 20 appropriaes cephalosporin ll~cleus b~ reacting it firs~ h c~rbonyl diimidazole or its equival~nt.
The compound~ of the present invention are alYo prepared by reaction of a compound differing from one of formula I in ~hat the 3~ub~ cuen~ i~ acetoxymethyl ra~her 25 than R-'chiomethyl, with a mercaptoheterocycleO The reac~ion i~ preferably conduct~d at a pH near neutrality~ The solv~nt is preferably w~ter or ~ater-acetone. The reactio~
m~y be carried out at tempera~ures from about room tempera~ure to 1:he boiling point of the solvent, ~he time o reaction 30 varying with ~he particul~r temperature, solven~ and r~ac~ants.

1 Th~ reaction produc~ is isolated by careful acidification of the reaction mixture and extrac~ion wi~h an appropriate organic solvent. The aQamino gr~up on the phenylglycine starting material should be protected with a readily remov~ble group such as t~butoxycarbonyl9 carbobenzyLo~y or trichloroethoxycarbonyl. The displacemen~ ~t the 3-positl.on is then conducted, followed by removal of th~ prote~tive group in the co~ventional manner.
The s~arting materials or use in the 3~displace-ment of a 7-acylated cephalosporanic acid, are described in the litera~ure or obtainable by known me~hods. The starting materials for use în ~he 7-acyla~lon of a 3~he~erocyclic thiomethyl nucleus are prepared by d:Lsplac~ng the 3-acetoxy group of an alkali metal salt of 7-aminocephalosporanic acid (7~-ACA~ with an alkali metal s~lt of lthe heterocyclic thiol in9 for examp~, hot aqueou3 aceton~. . .
It is recognized that due to the asymmetrlc a-carbon ~n the 7-acetamîdo group optical isomers wlll e~ist, The D is~mer is the preferred i~omer~ however, the L isomer and

2~ the racsm~c mixture are also within th~ ~cope of th~s invention.
The compounds are formulated into injectable or oral formulations in the same ma~ner as other cephalosporln antlbiotics. They are administered by injec~ion or orally to prevent and trea~ bacterial ln~ections in doses whlch will vary with the n~ture and severity of the inventlon and the age, welght, ~nd conditlon of the sub~ectc The co~pounds where Y ls NH2 are generally administered either orally or parenterally.
Due to the presence of both ~n amlne group and a ~ 8 ~

~7 ~ 56 ~

1 ca~boxylic acid group in certai~ of the cephalosporLn compounds of this in~entiony it is possible~ by sta~dard methods 9 to prepare ~oth acid and base salts of pharma~
ceutically acceptable nontoxic acids and bases as well as ~he S zwitterionic forms of the compoundsO Salts9 when obtained9 are readily con~erted to the ~witterion~ by known methodsO
Salt~ of compounds that contain ~ly an acidic function are also prepared using pharmaceutically acceptabLe nonto~ic bases. It is to be understood that all ~hese sal~s ar~
included within the ~cop~ of this inven~ion.
The following examples are inte~ded to illu~trat~
the procasses and c~mpound~ of th~ in~ention9 but are not ~o be construed as limiting the scope thereof.
~E
5 7-~a;~mino-p-hydroxyphenylacetamido)-3~(192~3-~riaæol~
c acid To a stirred solution N-t~butoxyedrbonyl~p~
hydroxyphenylglycine (10.75 ~J 0.0375 mol) ln dry ~etrahydro-uran (150 m~) was added triethylamine (5~2 mlg 0~0~75 mol~.
The mi~ture was cooled to -10 and then ~sobutyL chl~ro-2~
formate ~4O92 ml, 000375 mol) was added dropwise over a lO
minute period. The reaction mixture was stirred at -10 for 70 minu~e~ and ~hen a cold solution of 7~ACA (10.1 g~
0.0375 mol) ln 5~O aqueous tetrahydrofi~ran (140 ml~ and triethylamine (6.75 g, 0.0487 mol) wa~ added over a 15 minute period. The reaction wa~ stirred at ~5 ~:o 0~ for one ho~r and at room ~emperature for 2 hours. The organic solvents were evapora~ed and water (150 ml~ wa~ added to the aqueous residueO The solution was extrac~ed wlth ~thyl acetate and the aqueous phase was ~epara~cedg covered wi~h _ g 1~76~

l fresh ethyl acetate9 acldiLied to pH 2.8, and fil~ered The pha~es were separated and the acidic solu~ion reextracted with ethyl acetate. The exLracts of the acidified aqueous solutlon were combined, dried9 and evaporated to giv~ the S N-butoxycarbonyl derivative of 7-(a-am~no~p~hydroxyphenyl~
acetamido)cephalosporanic acid.
A mixture of the above product (3.0 g9 0.00493 ~,ol) in pH 6.4 phosphate buffer (30 ml~ was treated with NaHC03 (l.085 g9 0.0l233 mol~ and then 4-mercaptu-l92~3-triazole (0.748 g, 0.0074 mol). The ~olution was warmed to 70 and stirred at 70 + 3 for 2.75 hours. The solution was covled, filtered, and acidlfied ~o pH 2.5, producing a residue. The solvents were decanted and the residu~ washed with water.
The product was dissolved in ethyl acetate, washed with water, dried, and evaporated to the N-protected product which was reprecipltated from acetone-chloro~orm.
The proteoted product was s~irred at 0 ~o 5 wlth a 9:1 trifluoroacet~c acid:anis~le solu~lon for 70 minutes The solvents were evaporated and the residue was poured with rapid s~irrin~ into ether (350 ml~. Tl-e solid was collected, dissolved ln water9 and stirred with basîc lon-exchange resin (Amberlite IR-45, a polystyrene amine anionlc resin) until the pH rema~ned constant. The resin was ilt~red o~f and the aqueous solution lyophilized to give th~ product~
Hl~N605S2n2 H20: C, 43.379 1-1~ 4~45; N 16 86~
Found. C, 43.67, ~19 4.14, N) 16062.
EX~MF~LE 2 7-(D-~-Amino-p-hydroxyphenylacetam~(1O)-3 (4~methYl~ 9 3-triazo1-~y~thiomethy~ 3-c~phem-4-carbox~lic acld 5-~enzamido-4~methyl-l,2,3-thiadiaæole ~6~60 gmO, 0O03 mole, prepared as descrlbed In Berichte 99, 1629 (1966)]

* Trad~mark - lO

o.i~
, ....... .
- , . ' ,~ ~ .

, . , ' ' 76~i6~

was oombined with 60 mlO oE 2 N NaOH and the ~olution heated under ref~x overnightO After caO 25 h~urs of heatlngg the reaction m~ ture was cooled in ice arld 120 mlO of 2N HCl added with stlrringO Thc ~aixture was then refrlgerated ov~3r 5 ~:he weekend. The prec~p~ta~ed solid ~berl20lc acld~ wa~
then filtered off while the mlxtur~ was still c~ldo The solid was washed with a little water arad t:he pH of the filtrate adjusted to 30û WLt:h llD% NaOHO The aqueous solutlon was extracted with ethyl acetate four timesO The ex~raets were dried and f~teredO Sod~um 2-e~hylhexansate was added until no more preeip~tat~on occ~rred. The so1id sodium salt of 5-mercapto~4~methylw19293~riazole was i1tered of and then dried under vacuum, To a stirring susperlsion of 6.78 gm. ~0.013 mole) of 7~(a-t-butoxycarbonylamino~p-hydroxypheny1acetamido)~
cephalosporanic acLd and 3.82 gmO (0.02 mo1e~ of the sodium saLt of 5-mercapts~4-methyl~ 13293r-tr~azole in 100 ml. of pH
604 phosphate buffer was added 1.09 gmO (0~013 mole) of NaHC03. The mi.xture wa~ heated at 70 ~or 4-1/2 hours9 ~he Z0 reaetion being monitored by TLCo It w~s allowed to cool arld the resulting gum stirred with water and any insoluble~
fil~ered o:Ef. The solutlorl was covered with ethyl acetate and put in the re:Erigera~or overnight.
The layers were Jchen separated arld the aque~us 1ayer acidified to p~ 3.0 with 3N HC1. I~ was ~hen extrac~ed several times W~ttl e~yl aceta~e and ~he extracts dr~ed and evaporated. The resultlng gum was tr>it.urated with ether to give 2.69 gm. of solid~ S~nall amo~nt~ were ~hen reprecipi~at-ed tw~ce from methanol~ther9 and then the desired m~ter~al ~0 wa~ precipitated with petroleurn ether. ~he resulting solid 6~
1 (1.75 gmO) was chromatographed on 1~0 gmO of ~ilica gel using 90:10:3 chloroformomethanol:formic acid. The co~umn yielded 0o80 gmO of the t~bu~oxycarbonyl derivatlve of the title compound.
The above derivative (0.80 gm., 0.00139 mole~ wa~
placed in a mall rou~bot~om flask with a drying tube and immer~ed i~ an ice bath. ~bout 10 ml. of cold trifluoro~
acetic acid was added and the mi~ture stirred in the cold for about 15 minutes~ ~hen evapora~ed over 15 minutes. The residue was poured i~to approximately 100 ml. of e~her and ~he resulting soLid collected and digsolved in ~bou~ 25 ml.
o~ wa~er. t was then st~rred with IR 45 Amberlite res~n, a basic ion-e~change polystyre~e re~ln (washed 3 tlmes), unt~l t~e ~olution reached pH about 5O5~ The resin was filtered off and the ~olution lyophilized over~ight to give the title p~oduct.
Calc'd for ~lgH2oN605S2l2~3/4 H200 G, Found- C, 43~75, H~ 4.80, ~, 15~27 E~AMPLE .3 When ~he t butoxycarbo~yl derivative of 7-(a-am~no-p hydro~yphe~ylacetam~do)cephalospora~ic aci~ is reac~d wi~h the appropriate mercaptoheterocycle according to the procedure o Example 19 the foll~wing compounds are obtal~ed~
7-(a~amino~p~hydroxyphenylacetamido)~3 (l-methyl~l, 293 2S triazol 40ylthio~ethyl)-3~cephem- 4-carbo~i;ylic acid 7~ (a am~ r~o-p-hydro~phenylacetamido) ~3 (l-m~thyl-l, 2, 3-tri~zol 5 ylthiolDethyl)~3~c~phem-4-car~ox~rlic acid .-calc d ~ar Ç1~E~20~605S2-2~I20: C, 44-38; ~ 4-7~ 16-~Q
Found: C, 44.71; H, 4.42; N, 15.74.
7 (a-~mina-p~hydr~yphen~l~c~mido)-3-(2-m~thyl~ 3-triazol-4-ylthloma~yl)-3-cephem-4-carboxyl~c acid The compourlds described in examples 1-3 are also prep~red by reacting ~he appropriate 7-amino-3rhet~rocyclic thiomethyl-3~cephem54-carboxylic acid with the mixed * Trademark ~6176~

anhydride formed from N-t-butoxycarbonyl-p-hydroxyphenyl-glycine and isobutyl chloroformate or trichloroacetyl chloride.
The N-protective group is removed with trifluoroacetic acid or glacial acetic acid-HCI.

For parenteral administration a pharmaceutical composition can be prepared by dissolving S00 mg. of sodium 7-( a-amino-p-hydroxyphenylacetamido)-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem 4-carboxylate in 2 ml. of sterile water or normal saline solutionO Any of the other cephalosporins disclosed herein may be formulated in a similar manner.

__ A capsule for oral administration can be prepared by mixing 500 mg. of a cephalosporin disclosed herein, 250 mg. of lactose, and 75 mg~ of magnesium stearate. The other hereindisclosed products are similarly formulated.

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Claims

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

1. A process for preparing a compound of the formula where R is 1, 2, 3-triazolyl, unsubstituted or substituted with 1 or 2 groups selected from the group consisting of lower alkyl of 1-4 carbon atoms, comprising (1) reacting an acetoxymethyl cephalosporin compound of the formula where R1 is , the NH2 group being suitably protected as needed, or H, with a heterocyclic thiol compound of the formula HS-R, where R is as defined above;
(2) when R1 is H, acylating the resulting compound with a p-hydroxyphenylacetic acid compound of the formula or an acylating or activated derivative thereof, the NH2 group being suitably protected as needed; and (3) then removing any protective group.

2. A process as claimed in claim 1 for preparing 7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid comprising reacting the N-t-butoxycarbonyl derivative of 7-(.alpha.-amino-p-hydroxy-phenylacetamido)cephalosporanic acid with 4-mercapto-1,2,3-triazole and then removing the protective group with tri-fluoroacetic acid.

3. A process as claimed in claim 1 for preparing a 7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(4-lower alkyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid comprising reacting the N-t-butoxycarbonyl derivative of 7-(.alpha.-amino-p-hydroxyphenylacetamido)cephalosporanic acid with a 4-lower alkyl-5-mercapto-1,2,3-triazole and then removing the protective group with trifluoroacetic acid, wherein said lower alkyl is an alkyl of from 1 to 4 carbon atoms.

4. A process as claimed in claim 1, for preparing 7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(4-methyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid comprising reacting the N-t-butoxycarbonyl derivative of 7-(.alpha.-amino-p-hydroxy-phenylacetamido)cephalosporanic acid with 4-methyl-5-mercapto-1,2,3-triazole and then removing the protective group with tri-fluoroacetic acid.

5. A compound of the formula where R is 1,2,3-triazolyl, unsubstituted or substituted with 1 or 2 groups selected from the group consisting of lower alkyl of 1-4 carbon atoms when prepared by the process of claim 1 or its obvious chemical equivalent.

6. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid, when prepared by the process of claim 2 or its obvious chemical equivalent.

7. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-(4-methyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, when prepared by the process of claim 4 or its obvious chemical equivalent.

8. The process according to claim 1 for preparing 7-(.alpha.-amino p-hydroxyphenylacetamido)-3-(1-methyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid comprising reacting the N-t-butoxycarbonyl derivative of 7-(.alpha.-amino-p-hydroxy-phenylacetamido)cephalosporanic acid with 5-mercapto-1-methyl-1,2,3-triazole and then removing the protective group with trifluoroacetic acid.

9. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-(1-methyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, when prepared by the process of claim 8 or its obvious chemical equivalent.

10. The process according to claim 1 for preparing 7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(1,2,3-triazol-4-ylthio-methyl)-3-cephem-4-carboxylic acid comprising acylating a compound of the formula wherein R is 1,2,3-triazol-4-yl, with a p-hydroxy-acetic acid compound of the formula or an acylating or activated derivative thereof, the NH2 group being suitably protected as needed;
and then removing any protective group.

11. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid, when prepared by the process of claim 10 of its obvious chemical equivalent.

12. The process according to claim 1 for preparing 7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid which comprises reacting 7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid or a protected derivative thereof with 5-mercapto-1H-1,2,3-triazole.

13. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid whenever prepared by the process of claim 12.

14. The process according to claim 1 for preparing 7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid which comprises re-acting 7-amino-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid or a protected derivative thereof with an acylating derivative of .alpha.-amino-p-hydroxyphenylacetic acid.

15. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-(1H-1, 2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid whenever prepared by the process of claim 14.