CA1043773A - 2-lower alkyl-2 or 3-cephem-4-carboxylic acid derivatives and processes for preparation thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel 2-lower alkyl 2(or 3)-cephem-4-carboxylic acid derivatives and their process of preparation are provided of formula

Description

2-l.OWER .!~L~'.YL-2 or ~-CEPHI~1~1-4-CAXBGi~YLIC ACI~) DERIVATIV~ D PROCl~SSES F()R PR~PAP~T-LO~i :
T~ERE O~ --~he present invention relates to 2-lower alkyl-2 or 3-cephem-4-carbox-flic acid derivatives. I~iore particularly, it relates to new 2-lo~er alkyl-2 or 3-cephem- 4 carboxylic acid derivatives which have antimicrobial activities and to processes fo~
the preparation thereof, to pharmaceutical composi~
tion comprisin~ the same, and to a method of using the same therapeutically in the treatment of infec-tions.
Accordingly, it is one object of this invention to provide the antimicrobiall~ active 2-lower alkyl-2 or 3-cephem-4-carboxylic acid derivatives, which `~
~-~ are active against a number of microorgarisms.
;
Another object of the present invention is to provide processes for the ~reparation of 2-lo~er ~-alkyl-2 or 3-cephem-4-carboxylic acid derivatives by s~nthesis.
A further object of the invention is to provide ¦~ pharmaceutical composition comprising, as effective -antimicrobial agents, said 2-lo~er alkyl-2 or 3-~¦ cephem-4-carboxylic acid derivatives and the salt thereof.
Still further object of the present invention is to provide a method of treating infections di-sease caused by bacteria in human and animals.

i :.1 ~, . . ' ' ' ~

According to the invention there is provided 2-lower -~
alkyl-2 or 3-cephem-4-carboxylic acid derivatives which are novel compounds and can be represented by the following formula (I) ., .
.

. N ~

, Wherein 1 . Rl is amino or a substituted amino, particularly 2,2-di(lower)-alkyl-4-aryl-5-oxoimidazolidin-1-yl or acylamino `' 2 R is carboxy or a protected carboxy, R3 is lower alkyl, and ~ ~0 ' ':
.1 X is -S- or -S-. ~ :

According to the present invention, the 2-lower alkyl-2 or 3-cephem-4-carboxylic acid derivatives can be prepared by various procedures, and the said processes are illustrated . collectively for convenience's sake by the following scheme, in : : :

~, which the process comprising step, (II) ~ is a fundamental `~

"~ process and the others are alternative processes.
'',, ~:

N _ Rl ~ _ R3 ~:~ 2 (II) ~ ' ', .
:

,~ - 2 -, . .

.. . . .. .. .
'':',: .
`,: : . . ~ : ' ' `~ :
~0~3~77~

o~
Rl '; ~ 3 R~ R3 (Ia) (Ib) ` O
R~ T- R3 Rl _[~ S\ - R3 N ,-~ 0~ "~
. R R2 ~ :
. 10 (Ib) (Ia) R~ r X~l R3 H2~X~--R3 "---- N ,~ R2 j (Ic ) (Id) ~:

R21 ''~ 3 Rlb ~1 ~ 3 .' 20 , ' ~`

O
~', (Ie) (If) :~i 25 ., , ` "~N~ ~ R3 . R2 R2 .
~ 0 (Ig) (Ih) ,.; .
... " ' :, .~
.: -- 3 --.~ .

,. ~

Rl~ L ' ``~ R3 Rlf ~ ~ A~ R3 (Ii) `(Ij)

3 Rl R2a COOH
(Ik) (Il) ~;

~`

R4-CHCo N _ ~ X ~ R3 NH2 " ._ N 2 (Im) (In) :~:, ~! 20 ?j wherein Rl is amino or a substituted amino, -R2 is carboxy or a protected carboxy, . ~-~
R3 is lower alkyl, `~ R4 is aryl, ~ ~ :
.~ , -' ~ 25 R5 and R~ are each lower alkyl, .~
;~ o X is -S- or -S-, :~
Rla is a protected amino, ~; Rlb and Rlb are each acylamino, .~ RlC is acylamino ha~ing a protected amino, Rld is ac~lamino having an amino, _ 4 -.~', , ' ' ' - - - --- : , ~ ~ : :
, ;7~

Rl~ is acylamino havin~ a protected hydroxy, Rlf is acylamino having a hydro~y, and R2a is a protected carboxy.
The starting cornpound (II) is novel and can be prepared by reacting the corresponcling 2-lower alkyl-2-halomethyl-6-substituted penam-3-carboxylic acid or its l-oxide or derivative a-t the carboxy group thereo~ with a base.
In the above and subsequent description, the term "a substltuted amino" in Rl means suitable substituted amino groups ~11hich may include hydrazino, ~ -~
mono(or di)-(lower)alkylamino, mono(or di)-(lower)-alkenylamino, lower alkylideneamino, ar(lower)alkyl-ideneamino, 2,2-di(lower)alkyl-4-aryl-5-oxoimida-' 15 zolidin-l-yl, acylamino and amino group substituted by other amino protecting groups than the acyl ;` ~;~
groups. ~`~
- In the above suitable substituted amino group, ~`~ suitable lower alkyl moiety in the mono(or di)-lower alkylamino may include methyl, ethyl, propyl, iso-` propyl, butyl, etc.; `-`~ suitable lower alkenyl moiety in the mono(or di)-~ lower alkenylamino may include~ allyl, 2-butenyl, - etc.;
suitable lower alkylidene moiety in the lower alkyl-ideneamino may include ethylidene, propylidene, butylidene, etc.;
suitable ar(lo~Ner)alkylidene moiety in the ar(lower)-alkylidene may include benzylidene, phenethylidene, etc.;

, ~ .
` - 5 -`:
:' ~. ~L~L 3 ~ 7 3 sui-table 2,2-di(lower3alkyl-~-aryl-5-oxoimidazolidin- :
l-yl may include 2~2-climethyl-4-phenyl-5-oxoimidazoli-clin-l-yl, 2,2-diethyl-4-phenyl-5-oxoimidazolidin-1-yl, etc.; ~ -sui-table acyl moiety in the acylamino groups may include carbamoyl~ aliphatic acyl groups and acyl groups containing an aromatic or heterocyclic ring, examples of which are illustrated below .
That is, suitable aliphatic acyl groups may include saturated or unsaturated, lo~ler or hi~her alkanoyl groups which may be branched or ~Ihich may `~
contain a cyclic ring; such as 10tl~er or higher aliphatic acyl groups, for example~ lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.), hi~her alkanoyl (e.g., octanoyl, lauroyl, palmitoyl, etcO), lower alkenoyl (e.g. 7 acryloyl, crotonoyl, etc.), lower alkynoyl (e.g., propynoyl, etcO), lower or higher cycloalkane~
carbonyl (e.g., cyclopentanecarbonyl cyclohexane-carbonyl, cycloheptanecarbonyl, etc.), lo~rer or 1 ~ ~ .
higher cycloalkyl(lower)alkanoyl (e.g., cyclopentyl~
acetyl, cyclohexylacetyl, cycloheptylacetyl, cyclo-hexylpropionyl, cycloheptylpropionyl, etc.), lower or higher cycloalkadiene carbonyl (e.g., dihydro-. . .
~, benzoyl, etc.), lower or higher cycloalkadienyl-`
(lower)alkanoyl (e.~., dihydrophenylacetyl, dihydro-- phenylpropionyl, etc.), etc.; and lo~r~er or higher`~

aliphatic acyl groups containing a oxygen or sulfur !~ 30 atom, for example, lower alkoxy(lower)alkanoyl (e.g., ., ,:

.. . . . . . . .

7 ~ ;~

1 m~t'rlO~ypro~ion~yl~ et )~
lk lt~io(lo~er)alk~nY~ ( thylthioacety~ ethY
~,er all~enylthio(lol'?r) lthiOp~opiony~ etC- ) cycloalkylthio(lo~Ner)alkano~yl (C?- ~ cyclo~entYl-Cycloh~x~Jlthiopropiony ~
1 er or higher cycloalk y cyclopentylox~ac etyl ~ y , ., ~, lo~er or higher cy = ' 1 (e ~;., dihydroPhen Y : ; -~ acetyl, dihydrophenoxypropion .~ dien~lthio(lo~er)a~-xanoyl (e-~

`- dihydrophenyl~hioacetyl~ Y
b nyl (~.~,., methox~'~car Y .:
propc~xycarbonyl ~ 1 cy P
rbo-nyl. butoxycarbony ' :~
' a~bonyl, etC ~ ) 1 ]-' 'er g cyclOpen~TloxyCar a b nyl cyclo~leptyloxycar Y
cycloalkanedienyloxy "` dihydropheno~-cycarbony-- . ,~
t ble acyl gruPs cntai ;'.! ~e naphthalen~ and th ` 25 ;nclude, for ex p carbamoyl, etc.), aryloyl (e.~-- benzoyl~ toluoyl~
~ ~thylna.phtho,~rl, phth~ Y .
'`''''' ' lfonyl tetrahydronaph "
ar(lo~ler)alkano~-l (c.~ he~ ac~t~Jl~ phe~yl- t i yl phen~lblltyryl~ to J

- 7 ~ ~ ~;

. . ~ . . , , ,, :

'7 7;~
naphthylacetyl, tetrah~Jdronaphthylacetyl, indanyl-acetyl, etc.), ancl the car~on ~tom in the alkyl moiety of said ar(lo~/er)alkanoyl group may be replaced by an oxygen or sulfur atom or carbonyl group, example of t~hich are aryloxy(lo~ver)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, phenoxy-butyryl, ~ylyloxyacetyl, etc.), arylo.cycarbonyl (e.g., phenoxycarbonyl, xylyloxycarbonyl, naphthyl-oxycarbonyl, indanyloxycarbonyl, etc.), ar(lower)-alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyl-oxycarbonyl, etcO), arylthio(lower)~lkanoyl (e.g., phenylthioacetyl, phenylthiopropionyl, etc.), aryl-¦ glyoxyloyl (e.~0, phenylglyoxyloyl, etc.), etc.
~¦ ~uitable acyl groups containing an heterocyclic ring may include heterocyclic carbonyl or hetero-¦ cyclic lower alkanoyl; and the heterocyclic ring in the heterocyclic carbonyl or heterocyc]ic lower alkanoyl may be saturated or unsaturated, monocyclic or polycyclic and may contain at least one hetero-atom, such as an oxygen, sulfur, nitrogen atom or the like, examples of ~hich are illustrated by un-saturated 3 to 8-membered heteromonocyclic contain-l¦ ing a sulphur atom (e.g., thienyl, etc.), unsatu-~ rated condensed-heterocyclic containing a sulfur `~ 25 àtom (e.g., benzothienyl, etc.), unsaturated 3 to 8-membered heteromonocyclic containing an oxygen atom (e.g., furyl, 2(or 4-pyranyl, 5,6-dihydro-2~-pyran-3-yl, etc.), unsaturated 3 to 8-membered heteromonocyclic containing l to 4 nitrogen atom(s) i 30 (e.g., pyrrolyl, 2(or 3)H-pyrrolyl, 2(or 3)pyrrolinyl, .
..
.''~' ' : ' ' ', :
, 3~7~

imidazo]yl,`pyraYolyl~ pyridyl, pJrimidyl, pyrazinyl, p~ridazinyl, l~ telrlzoli~l, 2H--tetrazoly], etc.), satura-ted 3 to 8-rnembered heteromonocycllc contain-ing 1 to 2 nitrogen atom(s) (e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperadinyl, etc.), unsaturated condensed-heterocyclic containing 1 to 3 nitrogen atom(s) (e.g., indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, l(or 2)H-indazoly], l(or 2)H-benzo-triazolyl, etc.), unsa-turated ~ to 8-membered heteromonocyclic contain~
ing an oxy~en atom(s) and 1 to 3 nitrogen atom(s) (e.g , oxazolyl, isoxazolyl, oxacliazolyl~ e-tc.), `saturated 3 to 8-membered neteromonocyclic con-taining 1 to 2 oxygen atom(s) and 1 to 2 nitrogen atom(s) (e.~., sydnonyl, etc.), unsclturated 3 to 8-membered heteromonocyclic cont~ining a sulEur atom and 1 to 3 nitrogen atom(s) (e~g., thiazolyl, thiadiazolyl, etc.), unsaturated condensed-hetero- ~-cyclic containing an oxy~en atom and 1 to 2 nitrogen ' 20 atom(s) (e.g., benzoxazolyl, benzoxadiazolyl, etc.) ! and unsaturated condensed-heterocyclic containing a sulfur atom and 1 to 2 nitrogen atom(s) (e.g., benzothiazolyl, benzothiadiazolyl, etc.), etc.
And, the carbon atom in the lo~/er alkyl moiety in said heterocyclic lower alkanoyl as mentioned above may be replaced by an oxygen or sulfur atom examples J~ of which are heterocyclic lo~er alkoxycarbonyl~
heterocyclic-oxycarbonyl, heterocyclic-oxy(lower)- -;
~, alkanoyl and heterocyclic-thio(lower)alkanoyl Further, the carbamoyl, the aliphatic acyl ` _ 9 _ :' .~ .

, i ` ` `
~ 377~

- groups and the acyl grollps containing an aro~.atic or heterocyclic rin~ as mentioned above may hflve 1 to 10 appropriate substituent(s) such as lo~!er alkyl (e.g., ~ethyl, ethyl, propyl, isopropyl, etc.), lo~er alkenyl (e.g., l-propenyl, allyl, etc.), lower or higher c-ycloalkyl (e.g., cyclopropyl, cyclopentyl, ~ cyclohexyl, cycloheptyl, etc.), lo~er alkoxy (e.g., -~ methoxy, ethoxy, propox~J, iso~ropoxy, etcO3, lower ~;
alkylthio (e.~., methylthio, ethylthio, etc.), aryl (e.g. 9 phenyl, xylyl, tolyl, indanyl, etc.), ar(lower)-il alkyl (e.g., benzyl, phenethyl, etc.), halogen ~` (eOg., chlorine, bromine, fluorine, etc.)~ halo- ~-`j phenyl (e.i~., chlorophenyl, bromophenyl, etc.), ¦ halophenoxy (e. æ., chlorophenoxy, bromophenoxy, etc.), cyano, lower alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, etc.), lor!er alkaneiulfonyl (e.
methanesulfonyl, ethanesulfonyl, etc.), lo~!er alkoxy-carbonyl(lower)alko~y (e.~., methoxycarbonylmethoxy, `~` ethoxycarbonylethoxy, l-cyclopropylethoxycarbonyl-methoxy, tertiarybutoxycarbonylmethoxy, etc.~, x nitro, sulfo, amino, a3ido, mercapto, carboxy, ~`~ hydroxy, hydroxyamino, !!lono(or di)alkylamino (e.g., t `~ mono(or di)methylamino, mono(or di)ethylamino, `,~ mono(or di)propylamino, mono(or di)iso~ropylamino, ~ 25 etc.), and the like.
`~ ~'hen the acyl group as mentioned above may have a functional group, such as amino, hydroxy, mercapto, carboxy, etc., and the functional ~roup ~! may also be protected ~y an appropriate protective ~tl 30 ~roup.
:.. ,' ~ :

''1 ~ .
'.`~, ' ~ , 377~3 ~uitable protective group for the amino group may include any of the conventional protective group, for example, the acyl groups or other groups than the acyl groups such as trityl, 2-nitrophenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthyl-methylene, 3-hydroxy-4-pyridylmethylene, l-methoxy-carbonyl-2-propylidene, 1-ethoxycarbonyl-2-propyl-idene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-propylidene, 1-rN-(2-methoxyphenyl)carbamoylJ -2-propylidene, 1- ~-(4-methoxyphenyl)carbamoylJ -2-propylidene, 2-ethoxy-carbonylcyclohexylidene, 2-ethoxycarbonylcyclo-pentylidene, 2-acetylc~yclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene(among these, l-rnethoxycarbonyl-2-propylidene and 2-ethoxycarbonylcyclohexylidene groups may be representable as l-methoxycarbonyl-l-pr~pene-2-yl and 2-ethoxycarbonyl-1-cyclohexenyl group , respectively),mono(or di)silyl, etc.;
~ suitable protective groups for hydroxy or mercapto ~ groups may include any of the conventional protective ,¦ groups for hydroxy or mercapto groups, for example, the acyl groups or other groups than the acyl group such as benz~l, trityl, methoxymethyl, 2-nitro-phenylthio, 2,4-dinitrophenylthio, etc.; and ,, ;~ suitable protective groups for the carboxy group may include any of those conventional protective groups used for protecting a carboxy group, for example, ~ lo~er alkyl ester (e.g., methyl ester, ethyl ester, i, 30 propyl ester, butyl ester, l-cyclopropylethyl ester, .. ,1 ~.

-~ - Il -,,~, ' . '.

~(~137~73 tertiarybutyl ester, etc.), mono(or ~li or tri)halo-(lower)alkyl ester (e.g., chloromethyl ester, 2,2,2-trichloroethyl ester, 3,3-dibromopropyl ester, etc.), aryl ester (e.g., phenyl ester, nitrophenyl ester, indanyl ester, etc.), ar(lower)alkyl ester (e.g., benzyl ester, diphenylmethyl ester, triphenylmethyl ester, p-nitrobenzyl ester, p-bromobenzyl ester, etc.), tri(lower)alkylsilyl ester (e.g., trimethylsilyl `` ester, triethylsilyl ester, etc.),etc.
Further, as the amino protective group other j than an acyl group Tr~hich is mentioned in the above paragraph for explanation of the term "a substi-tuted amino", there may be also illustrated the same amino protective groups as those which are examplified as the protective groups for the amino radical in the acyl group as mentioned above.
articularly suitable examples of the acyl ¦ groups may be illustrated as follows:
(1) lo~er alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, l-cyclopropyl-etho~ycarbonyl, butoxycarbonyl, tertiarybutoxy-¦ carbonyl, etc.), ;
(2) phenyl(lower)alkoxycarbonyl .~e.g., benzyloxy-carbonyl, phenethyloxycarbonyl, etc.), ~; 25 (3) nhenylcarbamoyl, ~ (4) phenylglyoxyloyl, :~ (5) lower alkoxyphenylglyoxyloyl (e.g., 2-r2-(or 3- or 4-)met~oxypheny~ glyoxyloyl, 2-'~2-(or 3- or ~ 4-)ethoxypheny~ glyoxyloyl~ etc.), .~ 30 (6) phenylthiocarbonyl, ~o^~37 ~ ~
, (7) cyaro(lo~er)alkanoyl (~.g., ~-cyanoacetyl, 3-cyanopropionyl, 4-cyanobutyryl, ete.), (8) lower alkylthio(lo~s~er)~lkanoyl (e.g., 2-methyl-thioacetyl, 2-methylthiobutyryl, 2-ethylthioaeetyl, 3-methylthiopropionyl, ete.), (9) lower alkenylthio(lo~er)alkanoyl (e.g., 2-.~ allylthioaeetyl, 3-allylthiopropionyl, ete.), (10) phenylthio(lower)alkanoyl (e.g., 2-phenylthio-aeetyl, 3-phenylthiopropionyl, ete.), (11) phenoxy(lower)alkanoyl (e.g., 2-phenoxyacetyl, 3-phenoxypropionyl, 4-phenoxybutyryl, ete.), (12) phenyl(lower)alkanoyl (e.g., 2-phenylaeetyl, l 3-phenylpropionyl, 4-phenylbutyryl, ete.), r' I (13) halophenyl(lo~er)alkanoyl (e.g., 2-~2 (or 3-or 4-)chlorophenyl~ acetyl, 2- C2-(or 3- or 4-)bromo- ~
phenyl~ acetyl, 3-l?-(or 3- or 4-)ehlQrophenyl!- -propionyl, ete.), ~: (14) phenyl and amino substituted lower alkanoyl . (e.g., phenyl~lyeyl, 3-amlno-3-phenylpropionyl, etc.), -1-;~ - . .. : ~
, 20 ~ (15) phenyl and lower alkoxycarbonylamino substi-- tuted lower alkano~J1 (e.g., N-methoxyearbonyl-3~ phenylglyeyl, N-ethoxycarbonylphenylglycyl, N-(l- ;

~¦ eyelopropylethoxy)-earbonyl-phenylglyeyl, N-tertiary- ~

butoxyearbonylphenylglyeyl, 2-(1-cyclopropylethoxy)- ~ ~-carbonylamino-3-phenylpropionyl, etc.), --(16) phenyl and trihalo(lower)alkoxyearbonylamino ~`~ substituted lower alkano~l (e.~ -trichloroethoxy- -~, earbonylphenylglyeyl, 3-triehloroethoxyearbonylamino- i ;

~, 3-phenylpropionyl, ~-tribromoethoxyearbonylphenyl- `~

.', 30 glyeyl, ete.), `~ ;
'i , ,~ .
:, . 1~ ~ .
.~ . ~ ~

~ ~ 13~7~7~
(17) phen~il ar~-l nitror,her.oxy(lo\~er)al~allo~lamino substitute~ lo~:er al'~anoyl (e g.~ ~-L2-C2-(or 3-or 4-~nitropheno~y3ace~yllphQnylglycyl, etc.), (18) phenyl and thiadiazol-~-lthio(lo1A!er)alkanoyl-amino substituted 10~l3er alkanoyl (e.g., N-(1,3,4-; thiadia~ol-2-~l)thioacetylphenylglvcyl, 2-~3-(1,3, ~ ;

4-thiadiazol-2-yl)thiopropionyl3amino-3-phenyl-proplonyl, etc.), i (19) hy~roxyphenyl and amino substituted lower alkanoyl (e.g., 2 an.ino-2-lL2-(or 3- or 4-)hydroxy-phenyl¦acetyl, 2-amino-3-l2-(or 3- or 4 )hydroxy-phenyl~propionyl, etc.), (20) hydroxyphenyl and lo~er alkoxycarbonylamino ~¦ substitutQd lower al!~anoyl (e.g., 2-methoxycarbonyl-amino-2- C2~(or 3- or 4-)hydroxyphenyl¦acetyl, 2-(l-cyclopropylethoxy)carbonylamino-~-[2-(or 3- or 4-)hydroxyphenyllacetyl, 2-tertiarybutoxycarbonyl-amino-2--C2-(or 3- or 4-)hydroxypheny~ acetyl, etc.), (21) lower alkoxyphen~Jl and anino substituted lower alkanoyl (e.g., 2-amino-2-l2-(or 3- or 4-)methoxy--~ pheny~ acetyl~ 2-amino-3- ~2-(or 3- or 4-)methoxy- - ;
phenyl~ acetyl, etc.), (22) lower alkoxyphenyl and lower alkoxycarbonyl- ;
amino substituted lower alkanoyl (e.g., 2-methoxy-carbonylamino-2- ~-(or 3- or 4-)methoxyphenyl~acetyl, 2-(1-cyclopropylethoxy)carbonylamino-2-l2-(or 3- or ,1 4-)methoxyphenyl~acet~l, 2-tertiarybutoxycarbonyl-amino-2-~?-(or 3- or 4-)methoxyphenyl~acetyl, etc.), ` (23) lower alkylthiophenyl and arlino substituted 3 lower alkanoyl (e.~., 2-amino-2-~2 (or 3- or 4-)-' .

..j' ~

methylthiopnenyll-acet;yl, 2-amino-~-L2-(or 3- or 4-)ethylthiophenyll-propionyl, etc.), __!
(24) lower alkylthioph~nyl and lower alkox~sarbonyl-`~ amino substitu~,?d lower alkanoyl (e.g., 2-methoxy-carbonylamino-2-l2-(or 3-- or 4-)methylthiopheny~ -~ .
acetyl, 2-(1-cycloF)~opylethoxy)carbonylamino-2 ~2-` (or 3- or 4-)methylthloph~?nyl¦-aGetyl, 2-tertiary-butoxycarbonylamino-2-L2-(or 3- or ~-)methylthio-pheny~ acet~31, 2-tertiar-ybutoxycarbonylamino-3- L2-~l 10 (or 3- or 4-)ethy]thiopheryll propionyl, etc.), `~- (25) lo~er al~ylsulfinylphenyl and amino sub~tituted ;I lower alkanoyl (e.g., 2-amino~2- C2-(or 3- or 4-)-`- t methy~sulfinylphenyllacetyl, 2-amino-3-r?-(or 3- or ' 4-)ethylsulfinylpheny~ propionyl, etc.), "``' 15 (26) lo~er alkylsulfinylphenyl and lower alkoxy- `
carbonylamino substituted lower alkanoyl (e.g., 2-methoxycarbonylamino-2- L2-(or 3- or 4-)methylsulfinyl-phenyl3acetvl, 2-(1-cyclopropylethoxy)carbonylamino-~ 3-L2-(or 3- or 4-)ethylsulfinyl~henyl'lpropionyl, 2-'~ 20 tertiarybutoxyc~rbonylamino-2- ~-(or 3- or 4-)methyl~
sulfinylphenyl~ ac~tyl, etcc) 7 .~ (27) carboxy(lol~er)alkoxyphenyl and amino substi-tuted lower alkano71 (e.g., 2-amino-2- C-(or 3- -'' or 4-)carboxymethoxyphenyllact?tyl, 2-amino-3- L2- ' '`
(or 3- or 4-)carboxymetho~Yyphenyl]propionyl,-etc;
' (28) lower alkoxycarbonyl(lo~.er)alkoxyphenyl and lo~ier alkoxycarbonylamino substitute~ lower alkanoyl . :~
(e.g., 2-methoxycarbonylam-ino-2- ~2-(or 3- or 4-)-methoxycarbonylmethox~-y,~enyl~ acetyl, 3-(1-cyclo-~3.! 30 propylethoxy)carbonylamino-3- ~-(or 3- or 4-)ethoxy-~3773 carbonylr~lethoxyphenyl,propionyl, 2-tertiarybutoxy-carbonylamlno-2-L'-(or 3- or 4-)tertiarybutoxy-carbonylmethoxypherlyl~ acetyl, etc.), (29) lower alkanesulfonamidophen~l and lower alkoxy-carbon;ylamino substituted lo~Jer alkanoyl (e.g., 2-methoxycarbonylamino-2-r?-~or 3- or 4-)methane-sulfonamidophenyl~ acetyl, 3-(1-cyclopropylethoxy)-carbonylamino-3- C2-(or 3- or 4-)ethanesulfonamido-phenyl~ propionyl, 2-tertiarybutoxycarbonylamino-2-r2-(or 3- or 4-)methanesulfonamidophenyl]acetyl, ~tc.), ' (30) dihydrophenyl and amino substituted lo~!er ;l~ alkanoyl (e.~., 2-amino-2-(2,5-dihydrophenyl)acetyl, i~ 2-amino-3-(2,5-dihydrophenyl)propionyl, etc.), `¦ 15 (31) dihydrophenyl and lo~ler alkoxycarbonylamino substituted lower alkanoyl (e.g., 2-methoxycarbonyl- ~
amino-2-(2,5-dihydrophenyl)acetyl, 2-(1-cyclopropyl- ~ ;
ethoxy)carbonylamino-2-(2,5-dihydrophenyl)acetyl, ~ ~ :
1 2-tertiarybutoxycarbonylamino-2-(2,5-dihydrophenyl) ¦ 20 acetyl, 2-tertiarybutoxycarbonylamino-3-(2,5-di-,I hvdrophenyl)propionyl, e-tc.), (32) phenyl and azido substituted lo~/er alkanoyl ~'~ (e.g., 2-azido-2-phenylacetyl, 3-azido-,-phenyl-propionyl, etc.), -i 25 ~33) phenyl and hydroxy substituted lo~!er alkanoyl ;~ (e.g., 2-hydroxy 2-phenylacetyl, 2-hydroxy-3-. ~ .
phenyln opionyl, etc.), (34) phen~l and lo~ler alkanoyloxy substituted lo~er ~, alkanoyl (e.g., 2-for~yloxy-2-phenylacetyl, 2-, ~ , .
i 30 acetoxy-2-phenylacetyl, 3-prorionyloxy-3-phenyl- ~ ~
' ,1 ' ' :

, ~ .
:
.

37~7;~

propionyl, etc.), (35) pheny- and r,yric~ylcarbonyloxy substituted lower alkanoyl (e.~., 2-nicotinoyloxy-2-phenyl-acetyl, 2-isonicotinoyloxy-2-phenylacetyl, etc.), (36) phenyl and sulfo substituted lower alkanoyl (e.g. 9 2-phenyl-2-sulfoacetyl, 3-phenyl-3-sulfo- ~ ~ -propionyl, etc.), (37) phenyl and indanyloxycarbonyl substituted lower alkanoyl (e.~., 2-(5-indanyloxy)carbonyl- 2-phenylacetyl, 3-(5-indanyloxy)carbonyl-3-phenyl-acetyl, etc.), (38) thienyl(lower)alkanoyl (e.g., 2-(2-thienyl)-acetyl, 3-(2-thienyl)propionyl, etc.), (39) thienyl and amino substituted lower alkanoyl (e.g., 2-amino-2-(2-thienyl)acetyl, 2-amino-3- :~
(2-thienyl)propionyl, etc.), (40) thienyl and lower alkoxycarbonylamino substi-tuted lower alkanoyl (e.g., 2-methoxycarbonylamino- ~ ~
. . .
2-(2-thienyl)acetyl, ~-(l-cyclopropylethoxy)carbonyl- ;
~¦ 20 amino-2-(2-thienyl)acetyl, 2-tertiarybutoxycarbonyl-amino-2-(2-thienyl)acetyl, 3-tertiarybutoxycarbonyl-amino-3-(2-~hienyl)propionyl, etc.), l (41) thienyl and hydroxy substituted lower alkanoyl ~;
;~ ` (e.~., 2-hydroxy-2-(2-thienyl)acetyl, 3-hydroxy-~1 25 3-(2-thienyl)propionyl, etc.), ~; (42) dihydropyranyl and amino substituted lower alXanoyl (e.g., 2-amino-2-(5,6-dihydro-2~-pyran-3- - `
yl)acetyl, 2-amino-3-(5,6-dihyclro-2H-pyran-3-yl)-pxopionyl, etc.), ~;
, 30 (43) dihydropyranyl and lower alkoxycarbonylamino .1 - 17 - . .

. ~
.', . . , . ,' ' ', . ' :
""' '" ' .. ' .~ O ~ ~ 7 7 ~
substituted lower alkanoyl (eOg., 2-methoxycarbonyl-amino-2-(5,6-dihy~ro-2H-pyran-3-yl)acetyl, 2-(1-cyclopropylethoxy)carbonylamino-2-(5 9 6-dihydro-- 2H-pyran-3-yl)acetyl, 2-tertiarybutoxycarbonylamino-2-(5,6-dihydro-2H-pyran-3-yl)acetyl, 2-tertiary~
butoxycarbonylamino-3-(5,6-dihydro-2H-pyran-3-yl)-propionyl, etc.), (44) pyridyl substituted lower alkanoyl (e.g., ~ -2-(3-pyridyl)acetyl, 3-(3-pyridyl)propionyl, etc.), (45) thiadiazolyl(lower)alkanoyl (e.gO, 2-(1,2,5~
; thiadiazol-3-yl)acetyl, 2-(1,3,4-thiadiazol-2-yl)-acetyl, 3-(1,2,5-thiadiazol-3-yl)propionyl, etc.), (46) lo~rer alkylthiadiazolyloxy(lo~1er)alkanoyl (e.g., 2-(5-methyl-113,4-thiadiazol-2-yloxy)acetyl, ; ~ ..
2-(4-methyl-1,2,5-thiadiazol-3-yloxy)acetyl, 2-(5-ethyl-1,3,4-thiadiazol-2-yloxy)propionyl, etc.), J (47) thiadiazolylthio(lower)alkanoyl (e.g., 2-(1, 3,4-thiadiazol-2-ylthio)acetyl, 2-(1,2,5-thiadiazol-'~ 3-ylthio)acetyl, 3-(1,394-thiadiazol-2-ylthio)pro- -~
- 20 pionyl, etc~), -(48) tetrazolyl(lower)alkanoyl (e~g., 2-(lH-tetrazol-l-yl)acetyl~ ~-(lX-tetrazol-l-yl)propionyl, 4-(lH-;~ tetrazol-l-yl)butyryl, etc~
-, (49) 3-halophenyl-5-lower alkylisoxazol-4-ylcarbonyl ;
(e.g., 3- [2-(or 3- or 4-)chlorophenyl¦-5-methyl-, isoxazol-4-ylcarbonyl, 3-~?-(or 3- or 4-)bromo-phenyl~-5-ethylisoxazol-4-ylcarbonyl, etc.), (50) halobenzotriazolyl(lower)alkanoyl (eOg., 2- ~-(or 5- or 6- or 7-)chloro-lH-benzo-triazol-l-yl~ -acetyl, 2-[4-(or 5- or 6- or 7-)bromo-lH-benzo-.; , . . :. .

7~
' ' `
-triazol-l-yllacetyl, 3- ILL~_(Or 5_ or 6- or 7-)fluoro-2EI-benzotriazol-2-yl]propionyl, etc.), (~1) sydnonyl(lower)alkanoyl (e.g., 2-(sydnon-3- ;
yl)acetyl, 3-(sydnon-3-yl)propionyl, etc.), s -(52) phthaloyl, (53) lower alkanoylaminobenzenesulfonyl (eOg., 2-` (or 3- or 4-)acetamidobenzenesulfonyl, 2-(or 3- or 4-)propionamidobenzenesulfonyl1 etc.), (54) phenyl and halophenoxy substituted lower 10 alkanoyl (e.g., 2-phenyl-2-¦2-(or ~- or 4-)chloro-phenoxy~acetyl, 2-phenyl-2-~2-(or 3- or 4-)bromo-phenox~ ace-tyl, etc.), The term "a protected amino" in Rla and in the acylamino having a pro-tected amino for RlC may 15 include acylamino and amino group substituted by other amino protecting groups than the acyl groups ` as illustrated above.
'~ The term "a protected hydroxy" in the acylamino ~avin~ a protected hydroxy may include hydroxy pro-20 tected by the same conventional protective groups ;` for hydroxy as illustrated above.
~ The term "acylamino" in Rlb, Rlb , the acyl-1;~ amino having a protected amino for RlC, the acyl-1 -: .
amino having an amino for Rld, the acylamino having 25 a protected hydroxy for Rle and the acylamino having a hydroxy for Rlf may include the same acylamino as illustrated above:
The term "a protected carboxy group" in R2 and 3~ R2a may include ester, acid amide, acid anhydride, `i 30 etc. ~-, ~-,,.: , . ' , . ' :' ' .,. :: `. ~:

~ uitable esters may include silyl esters, alipha-tic esters and estcrs containing an aromatic or hetero-cyclic ring. ~he suitable silyl esters may be illust-; rated by e~amples tri(lo~er)alkylsilyl (e.g., tri-methylsilyl, triethylsilyl, ctc.) esters, etc.
'~he suitable aliphatic esters may include saturated or unsaturated, lower or higher alkyl esters which may be branched or ~hich may contain a cyclic ring, such as lo~!er or hi~;her aliphatic esters, for example, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, l-cyclopropylethyl, ~utyl, tertiarybutyl, etc.) esters, higher alkyl (eOg.~ octyl, nonyl, undecyl, ' ~ etc.) esters, lower alkenyl (e.~., vinyl, l-propenyl, 'j allyl, 3-butenyl, etc.) esters, lower alkynyl (e.g., 3-butynyl, 4-pentynyl, etc.) esters, lower or higher ¦ cycloalkyl (e.g., cyclopentyl, cyclohexyl, cyclo-¦ heptyl, etc.) esters, etc~, and lo-!er or higher ~`¦ aliphatic esters containing a nitrogen, sulfur or oxygen atom, for e~ample, lower alkoxy(lower)alkyl :. . .
(e.g., methoxymethyl, ethoxyethyl, methoxyethyl, ~¦ etc.) esters. lower alkylthio(lower)alkyl (eOg., methylthiomethyl, ethylthioethyl, methylthiorropyl, ~¦ etc.) esters, di(lo~1er)alkylamino (e.g., dimethyl-~¦ amino, diethylamino, dipropylamino, etc.) esters, .~ 25 lo~er alkylideneamino (e.g., ethylideneamino, pro-~ - pylideneamino, isopropylideneamino, etc.) esters, - lo~er alkylsulfenyl(lo~ier)alkyl (e.g., methyl-3, sulfenyllrlethyl, ethylslllfenylmethyl ~ etc.)-esters, etc.
~ 30 The suitable esters containing an aromatic ring .~.
_ 20 -'1 , 10.~37 ~
may include, for e~cample, aryl (e.g., phenyl, xylyl, tolyl, naphthyl, indanyl, dihydroanthryl, etc.) esters, ar(lower)alkyl (e.g., benzyl, phenethyl, ; etc.) esters, aryloxy(lower)alkvl (ecg., phenoxy-methyl, phenoxyethyl, phenoxypropyl, etc.) esters, arylthio(lower)alkyl (e.g., phenylthiomethyl, phenylthioethyl, phenylthiopropyl, etc.) esters, arylsulfen~l(loil1er)alkyl (e.g., phenvlsulfenyl-methyl, phenylsulfenylethyl, etc.).esters, aryloxy(lower)-alkyl (e.g., benzoylmethyl, toluoylethyl, etc.)esters, ~i aryloylamino (e.g., phthalimido, etc.) esters, etc.;
The suitable esters containin~ an heterocyclic ring .. ~.may include, for example, heterocyclic esters, ~ heterocyclic los}ler alkyl esters, etc.; in u~hich i 15 the suitable heterocyclic esters may include, for example, saturated or unsaturated, condensed or uncondensed 3 to 8-membered heterocyclic containing 1 to 4 hetero-atom(s) such as an oxygell, sulfur and .
nitro~en atom (e.g., pyridyl, piperidino, 2-p~ridon-l-y1, tetrahydropyranyl, quinolyl, pyrazolyl, etc.) esters, etc., and the suitable heterocyclic lower alkyl esters may include, for example, saturated or unsaturated, condensed or uncondensed 3 -to 8-1~ membered heterocyclic containing 1 to 4 hetero- ;
`~! 25 atom(s) such as an oxygen, sulfur and nitrogen atom ~ (e.g., pyridyl~ piperidino, 2-pyridon-1-yl, tetra-.J~ hydropyranyl, quinolyl, pyrazolyl, etc.) substi-,1 tuted losver al~yl (e.g., methyl, ethyl, propyl, etc.) ~, esters, etc.;
, ~ .
The silyl esters, the aliphatic esters and the _ 21 --.~
, ,1 ~Sp ,.... . . ~ , , . ~
. .

37~3 esters contaLning an aroln~tic or heterocyclic ring as mentioned above may have 1 ~o 10 a~,propriate substituent(s) such as lo~ler alkyl (e.g., methyl, ethyl, propy~, isopropyl, butyl, tertiarybutyl, etc.), lower alkoxy (e.~., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiaryo~toxy, etc.), lower alkylthio (2.g., methylthio, ethylthio, propylthio, etc.), lower alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, propylsul~lnyl, etc.), lower alkane~
sulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), phenylazo, halogen (e.g~, chlorine, bromine, fluorine, etc.), cyano, nitro, etc., examples of which are illustrated by mono(or di or tri)halo-(lower)alkyl (e.g., chloromethyl, bromoethyl, di-I 15 chloromethyl, 2,2,2-trichloroethyl, 2,2,2-tribromo-ethyl, etc.) esters, cyano(lo~ler)alkyl (e.g., cyano- ~ ~
methyl, cyanoethyl, etc.) esters, mono(or di or ;
tri or tetra or penta)halophenyl (e.g., 4-chloro-phenyl, 3,5-dibromophenyl, 2,4,5-trichlorophenyl, ¦ 20 2,4,6-trichlorophenyl, pentachlorophenyl, etc.) esters, lol~Jer alkanesulfonylphenyl (e.g., 4-me-thane-~¦ sulfonylpheryl, 2-ethanesulfonylphenyl, etc.) esters, 2-(or 3- or 4-)phenylazophenyl esters, mono(or di or tri)nitrophenyl (e.gO, 4-nitrophenyl, ~! 25 2,4-dinitrophenyl, 3,4,5-trinitrophenyl, etc.) ~¦ esters, mono(or di or tri or tetra or penta)halo-'~ phenyl(lo~ler)alkyl (e.g., 2-chlorobenzyl, 2,4-dibromobenzyl, 3,4~5-trichlorobenzyl, pentachloro-~¦ benzyl, etc.) esters, mono(or di or tri)nitrophenyl-,$ 30 (lower)alkyl (e.g., 2-nitrobenzyl, 2,4-dinitrobenzyl, ~ ` - 22 -. , .

3,4,5 trinitro~)e~zyl, e-tc.) estPrs, mono(or di or tri)(lol~/erjalko~-;phenyl(lo~ler)alkyl (e.~., 2-me-thoxybenz~l, 3,4-dimethoxy~enzyl, 3,4,5-tri-methoxybenz~l, etc.) esters, hydroxy and di(lower)-alkylphenyl(lo~rJer)alkyl (e.g., 3,5-dimethyl-4-hydroxybenzyl, 3,5-ditertiarybutyl-~-hydroxybenzyl, I etc.) esters, etc.
The suitable acid amides may include, for ~ example, N-lo~!er alkyl acid amide (e.g~, N-methyl `¦ 10 acid amide, N-ethyl acid amide, etc.), I~,N-di(lower)- -r,~ alkyl acid amide (e.g., N,N-dimethyl acid amide, N,N-diethyl acid amide, ~-methyl-N-ethyl acid amide, ` etc.), N-phenyl acid amide, or an acid amide ~ith pyrazole, imidazole, 4-lower alkylimidazole (eOg., 4-methylimida701e, 4-ethylimidazole, etc.), etc.
~ he suitable acid anhydrides include, for example, an acid anhydride with a di(lower)alkyl phosphate (eOg., dimethyl phosphate~ diethyl phos- -phate, etc.), dibenzylphosphate, phosphoric acid ., . ~ ~.
halide (e.g., phosphoric acid chloride, phosphoric acid bromide, etc.), di(lower)alkyl phosphite (eOg., ,., ~i dimethyl phosphite, diethyl phosphite, etc.), l sulfurous acid, thiosulfuric acid, sulfuric acid, ~ lower alk~l carbonate (e.g., methyl carbonate; `
,.,~
ethyl carbonate, etc.), hydrazoic acid, hydrohalo-genic acid (e.g., hydrochloric acid, hydrobromic acid, etc.), saturated or unsaturated lower aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-et'lylbutanoic acid, crotonic acid, valeric acid, propionic acid, etc.), saturated ~ ~-:

'' ' ` ' ' ' . ' ' ' ' ~ ' ' " ' ~V~37'73 or unsaturated halo(lo er)~lipha~ic carbox~lic acid (e.g., chloroace-tic acid 3-chloro-2-pentenoic acid, 3-bromo-2-butenoic acid, etc.), substituted lower aliphatic -carboxvlic acid (e.g., phenylacetic acid, phenoxyacetic acid, ~uranacetic acid, thiophene-acetic acid, etc.), aromatic carboxylic acid (e.g., benzoic acid, etc.), or a symmetric acid anhydride, etc. ~
,;'' ' ~' '"
~ 10 ; ~ .
; . "
:
~he term "lower alkyl" in R3, R5 and R6 means 1 15 the one having strai~ht, branched or cyclic to 1 to 6 carbon chain such as methyl, ethyl, propyl, iso-, propyl, butyl, tert-butyl, cyclohexYl, etc.:
~¦ ~he term "aryl" in R4 means, for example~ phenyl, -~ naphthyl, etc.
In the ahove and subseauent description, the term "lower" m~ans one to six carbon chain and the ! term "higher" means seven to slxteen carbon chain, which may be branched or may contain a c~Jclic ring.
~he object compound (I) in the present inven--¦ 25 tion can be prepared by reacting the starting ¦ compound (II) with a ~eu!is acid, ,¦ Suitable Lewis acid used in this reaction includes, for example, boron halide ~e.g., boron ~ ;
¦ trichloride, boron tribromide, boron trifluoride, etc.), titanium halicle (e.g., titanium tetrachloride, . . ,, - 2~ -.. _ _ . ... .. .. _ .. .. . . .. .. . . .
: . , . -.
, 3'7~

titanium tetrabromi(le~ etc.), æirconium halide (e.~., zirconium tetrachloricle, ziroconium tetrabromide, etc.) stannie halide ~e.~., stannic chloride, ` stannie bromide, etc.), antimony halide (e.~., -i 5 antimony trichloride, antimony pentachloride, etc.), bismuth chloride, alurninum halide (e.g., aluminum ehloride, aluminum ~romide, ete.), zine ehloride, ferric chloride, toluenesulfonlc aeid, polyphos-phoric acid ester, sulfurie acid, triehloroaeetic -. 10 acid, trifluoroacetic acid, zinc sulfate, ferric sulfate, ete.
;~ ~his reaetion is usually carried out in the presenee of a solvent.
Suitable solvent ~sed in the present invention Y 15 ineludes any solvent ~vhich doPs not give bad influenee to the reaetion, for example, methyleneehloride, ~¦ chloroform, benzene, tetrahydrofuran, dimethyl-~1- formamide, earbondisulfide, ete.
:
; ~here is no particular limitation to the present reaction temperature, and the reaetion ean be usually earried out under mild co~ditions sueh as under eooling to at ambient temperature.
In the present reaetion, the objeet eompound (I) is sometimes obtained as a mixture of 2-cephem ~" 25 eompound and 3-eephem eompound and/or the 3-eephem -~
`l~, stereomers at two position of the cephem ring, and, `il if neeessary, these mixtures ean be separated by .j eonventional methods sueh as recrystallization.
~he present invention ineludes, within its . 30 ~,', j . ., .
;~ - 25 -' . ~ , " ., , scop~, the C;lSe~ the carboxy group is chani~ed into - the protected carbox~f group and the protected carboxy group is chani~ed into the o~ner protected carboxy groups or into the free carboxy group and the !, 5 protected ~mino i~roup is changed into the free amino group during the reaction or post-treating in the present reaction.
,:hen the ob3ect compound (I) is used ir the next step, it can be used with or without isola-tion and/or purificatior., i.e., it can be used as a mixture of 2-cephem compound and 3-cephem compound and/or the 3-cephem stereomers at two position of ~~ the cephem ring.
,l The object compound (Ib) can be prepared by oxidizing the compound (Ia). ~he present oxidizing I reaction is carried out under conditions so that `i` the -S- group can be chan~ed into the -S- group.
,r Oxidation in the present reaction is conducted by a conventional mathod such as a method of using a oxidizing agent, for example, halogen (e.g., chlorine, bromine, etc.), halo~en compound (e.g., isocyanuroylchloride, phenyliododichloride, etc.), ozone, inorganic per acid (e.g., periodic acid, .;~ ~ .
persul~uric acid, etc.), organic per acid ~e.g., - -~
` 25 perbenzoic acid, m-chloroperbenzoic acid, performic ~
acid, peracetic acid, chloroperacetic acid, tri- -fluoroperacetic acid, etcO), a metal salt of the ¦ inorganic or organic peracid, hydrogen peroxide, -,~ urea-hydrogen peroxide, etc.
., I
-¦ 3 l'he present reaction is preferabIy carried out -'`''`1 . :

in the presence of a compound comprising a Group ; Vb or VIb metcll in the ~erlo~lc Table, for example, tungstic acid, molybdic acid7 vanadic acid, or the like, or an aIkall metal (e.g., sodium, potassium, etc.), alkaline earth metal (e.gO, calcium, magne-sium, etc.), ammonium salt thereof, or vanadium pentoxide.
~he present oxldizing reaction is usually carried out in the presence of a solvent such as ,~ 10 water, acetic acid, chloroform, meth~lene chloride, lower alcohol (e.g~, methanol, ethanol, etc~
tetrahydrofuran, dioxane, dil~ethylformamide or any ~` other solvent which doe~ not give bad influence to i~ the present reaction.
.,.
There is no particular limitation to the ~¦ reaction temperature, and the present reaction is usually carried out at ambient temperature or under cooling.
The present invention includes, ~it~in its ,~ 20 scope, the cases that the carboxy group is changed into the protected carboxy group and the protected carboxy group is changed lnto the other protected ~¦ carboxy group or into the frée carboxy group and ~he protected amino group is changed into the free i 25 amino group during the reaction or post-treating in ~'~ the present reaction. -~
~; The object compound (Ia) can be prepared by ~ reducing the object compound (Ib).
¦ ~he reducing reaction is carried out under ~l 30 conditions 50 that the -S- group can be changed ., ~a . .

3'7i~3 into l,he ~ ;rouli.
¦ R~duction in t~.e present ri~action is conducted ; by a cor!ventional method such as a method of using stannous chloride or metal thiosulfate (~.g., sodium .thiosulfa-te, potassium thiosulfate, etc.), or a combinatior of acid chloride and said stannous chloride or metal thiosulfate; or phosphorus trichlo-ride, phosphrus pentachloride, silicon trichloride, ~ etc. and a method described in Japanese patent il 10 official gazette No. 21111/1972.

he pre~ent reaction is usually carried out in a solvent which does not give bad influence to the ~`~
reaction, lor example, dimethylformamide, aceto-nitrile, acetoacetic acid ester, tetrahydrofuran, chloroform, methylene chloride, dioxane, etc.
~here is no limitation to the present reaction temperature, and it may be suitably selected accord-ing to the compound (Ib) and reduction method to be used in the reaction.
., ~he present invention includes, within its scope, the casesthat the carboxy group is changed into the protected carboxy group and the protected ~ -carboxy group is changed into the other protected j carboxy group or into the free carboxy ~roup and ~ 25 the protected amino ~roup is changed into the free ,.
amino group durin~ the reaction or post-treating in `;i' ...
the ~resent reaction.

The object compound (Id) can be prepared by ~ subjectin;~ the compound (Ic) to elimination reaction ¦ 30 of the protective group of the arnino .-md the object . ~ .
,~ _ 28 --.. I ~ . ~

compound (Ih) can be preparec~ by subjecting ~he compound (Ig) to elimination reaction of the pro-- tective group of the amino, respectively.
The presen-t elimination reaction is carried '' ' 5 out in accordance with a conventional method such ~' as hydrolysis, using an acid, treatment- wi~h hydra-zine, reduction, and the like. lhese methods may be selected depending on kind of the protective , groups to be eliminated. '~'hen the protective "' 10 group is an acyl group, it may also be eliminated i by treating wi-th an iminohalogenating agent and then with an iminoesterifying agent, if necessary, followed by hydrolysis.
The elimination reaction with the aci'd is one of the most commonly applied methods for eliminating the protective groups such as benzyloxycarbonyl ' substituted benzyloxycarbonyl, alkoxycarbonyl, sub-¦ ~ stituted alkoxycarbonyl aralkoxycarbonyl adamantylo-'~ xycarbonyl, trityl, substituted phenylthio, substi-tuted aralkylidene, substituted'alkylidene, substi-7 : tuted cycloalkylidene, etc. Suitable acid may include, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p toluenesulfonic acid, and the like, and the most suitable acid is an acid , 25 tlhich can be easily distilled off under reduced i~ pressure, for example, formic acid, trifluoroacetic ' acid, etc. The acid suitable for the reaction can '~ be selected according to the protected group to be ~1 eliminated and other factors. ~iihen the elimination reaction is conducted with the acid, it can be !~ ~
",1 .. , . ........ . ~ , .

i carried out in the presence or absence of a solvent.
~uitable solvent inc]u(les a hydrophilic organic solvent, water or a mixed solvent thereof. The elimination reaction with hydrazine is commonly applied for eliminating, for example, phthaloyl.
~he reduction is generally applied for eliminating, for example, trichloroethoxycarbonyl,ben%yloxycarbo~
¦ nyl, substituted benzyloxycarbonyl, 2-pyridylmethoxy- -carbonyl, etc. '~he reduction applicable for the 3l 10 elimination reaction of the present invention may include, for example, reduction with a metal (e.g., tin, zinc, iron, e1C. ) or a combination of metalic ~ co~pound (e.g., chromous chloride, chromous acetate, ¦ etc.) and an organic or inorganic acld (e.g., acetic ! 15 acid, pro~ionic acid, hydrochloric acid, etc.), and reduction in the presence of a metalic catalyst for catalytic reduction. The metalic catalyst for cataly-i tic reduction may include, for example, Raney-nickel, ¦ platinum oxide, palladium carbon and other conven-tional catalysts.
~he protective group, -trifluoroacetyl can be ¦ usually eliminated by treating with water in the presence or absence of the base, and halogen substi-tuted-alkoxycarbonyl and 8-~uinolyloxycarbonyl are usually eliminated by treating with a heavy metal such as copper, zinc, etc.
':rhen the protective group is acyl, the acyl can ~ -j be eliminated by reacting with thc iminohalogenating agent and then ~lrith the iminoetherifying agent, if necessary, followed by hydrolysis. Suitable imino- ;~

~1 I, 37~73 halogenating agents may inclucle, for e~ample, phos-phorus trichloride, phosphrus pentachloride, phos-phorus tribromide, phosp~orus pentabromid~, phos-phorus oxychloride, thionyl chloride, phosgene, etc.
Reaction temperature in iminohalogenation is not limitative and the reaction sufficiently proceeds at ambient temperature or cooled one. Suitable iminoetherifying agents, with which the resultant in the imlnohalogenating reaction is reacted, may include an alcohol such as an alkanol (e.g., methanol, ethanol, propanol, isopropanol, butanol, tertiary butanol, etc.) or the corresponding alkanol having alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, buthoxy, e-tc.) as substituent(s) at the alkyl moiety thereof, and a metal alkoxide such as alkali metal alkoxide (e.g., sodium alkoxide, potassium alkoxide, etc.) or alka ine earth metal alkoxide (e.g., calcium alkoxide, barium alkoxide, etc.), ~`
each of which is derived from the said alcohol.
~20 Reaction temperature in imlnoetherification is also ~ not limitative and the reaction sufficiently ¦ proceeds at ambient temperature or cooled one. ;~
~ ~hus obtained reaction product is, if necessary, J hydrolyzed, ~he hydrolysis sufficiently proceeds by pouring the reaction mixture to water or a mixture of water and a hydrophilic solvent such as methanol, ethanol, etc. In this hydrolysis, ~1ater ¦ may contain a base such as alkali metal bicarbonate, ~, trialkylamine, etc. or an acid such as dilute 1 30 hydrochloric acid, acetic acid, etc. l.. rhen the .1 , 0;~3!7~)3 : .
pro-tective group is acyl, the acyl can be also elimina-ted b~J hydrolysis as men-tioned above or by the other conventional hyclrolysis The reaction temperature is not limitative and `-~
may be suitably selected in accordance with the protective group for amino and the elimina-tion method as mentioned above~ and the present reac-tion is preferably carried out under a mild condi-tion such as under cooling or slightly warming.
The present invention includes, within its scope, the cases tha-t the protected carboxy group is changed into the other protected carboxy group or into the free carboxy group durin~ the reaction or post-treating in the present reactionO
rChus obtained compounds (Id) and ~Ih) can be converted to a desirable acid addition sal-t there-, of by a conventional method 9 if necessary.

~he object compound (Ie) can be prepared by reacting the compound (Id) or a salt thereof with 20 an acylating agent. -; ;

~uitable salt of the compound (Id) may include .: .
organic acid salt (e.g., acetate, maleate, tartrate~
benzenesulfonate, toluenesulfonate, etc.) and inorganic acid salt (e.~., hydrochloride, sulfate, phosphate, etc.), and the like.
~ s acylating agents in the present reaction, there may be examplified an aliphatic, aromatic and heterocyclic carboxylic acid; and the corres-ponding sulfonic acid, carbonic acid ester, ;~
carbamic acid and thio acid, and the reactive ` ':, .

- ~2 -!.. , , . . i ~ . .

~37~73 derivati~es of the above aci~s.
AS the reactive derivati~Jes, there may be exemplifi~d and acid anhyclride, an activated a~ide, an activated ester, an isocyanate and an isothio-cyanate, etc., example of which are illustrated byan acid azide, an miYed acid anhydride with an acid such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, dialkylphos-phorous acid, sulfurous acid, thiosulfuric acid,hydrohalo~enic acid (e.g., hvdrochloric acicl, sulfuric acid, Mon~alkyl ce~rbonate, aliphatic ~ ;~
carboxylic acid (e.g., acetic acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid), aromatic carboxylic acid (e.g., benzoic acid), or symmetrical acid anhydride, an acid amide with pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, an ester (e.g., cyanomethyl ester, methoxymethyl ester7 vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, tri-ohlorophenyl ester, pentachlorophenyl ester, ~
methanesulfonylphenyl ester, phenylazophenyl ester, ;~ i phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl ~;
thioester, or ester with N,N-dimethylhydroxylamine, l-hydroxy-2-~lII)-pyridone, N-hydroxysuccinimide or N-hydroxyphthalimicle). -~he above reactive derivatives are selected .:
3_ ~ 3~Ji~ ~
according to -the liind of the acid to be used~ In the acylating reaction, i~!hen free acid is used, there may be preferably added a condensing agent such as N,N'-dicyclohexylcarbodiimide, N~cyclohexyl-N'-morpho-linoethylcarbodiimide, ~T-cyclohexy-~T'-(4-diethylamino-cyc1ohexyl)carbodiimide, I~T,N'-diethylcarbodiimide, N,N'-diiso~ropylcarbodiimide, N-ethyl-~'-(3-dimethyl-aminopropyl)carbodiimide, N,N'-carbonyldi-(2-methyl-imidazole), pentamethyleneketene-N-cyclohexylimide, diphenylketene-N-cyclohexylimine, alXoxyacetylene, l-alkoxyl-l-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionylchloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydro-xybenzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)-isoxazolium hydroxide intramolecular salt, (chloro-I meth~lene)-dimethylammonium chloride, 2,2,4~4,6,6-¦ hexachloro-2,2,4,4~6,6-he~ahydro-193,5,2,4,6-triaza- `~
¦~ triphosphorine, or a mixed condensing agent such as i~ 20 triphenylphosphine and a carbon -tetrahalide (e.g., carbon tetrachloride, carbon tetrabromide, etc.) or a halogen (e g., chlorine, bromine, etc ), and the Iike.
:, ~
The example of an acyl group to be introduced 1 into the amino group in the compound (Id) by the above acylating agent may be a group dehydroxylated ~ ;
~; from each of an aliphatic, aromatic and hetero- -~ cyclic carboxylic acid, an1 the corresponding ~ -~
I sulfonic acid, carbonic acid ester, carbamic acid ~ and thio acid, etc. ? and more ~articular acyl group .
may be the same acyl grou~ as illustrated in the ' :
_ 3~ _ ~' - ~ ,. .

.'377~
explan~tio~. o~ ~he ~c~-l rrouli in the lcylamino ~oup for ~1.
The present acylating reaction is usually ; carried out in a solvent wl~ich doe5 not give ~ad influence to the reaction, for example, ~later, acetone, dioxane, acetonitrile, chioroform, methylene chlori~e, ethane dichloride, tetrahydro-furan, ethyl acet;ate, dimethylformamide, pyridine, -~
j etc., and the hyclrophilic solvent mentioned above can be used as a mixed solvent with water.
~he present acylating reaction can be carried out in the presence of a base such as inorganic base (e.g., alkali metal bicarbonate, etc.) and an organic base such as trial~ylamine (e.g., tri-` 15 methylamine, trieth~Tlamine, tributylamine, etc.), N-methylmorpholin~, N-methylpiperidine, N,N-dialkyl-j aniline (e.~., N~-dimethylaniline, N,N-diethyl-¦ aniline, etc.), N,N-dialkylbenzylamine (e.g., ~,N-¦ dimeth~lbenzvlamine, N,N-diethylbenz~lamine, etc.),pyridine, picoline, lutidine, 175-diazabicyclo L4 3,0~non-5-ene, 1,4-diazabicyclor2,2,2~octane, 1,8 - diazabic~-clo r5,~ O~undecene-7, etc.
¦ In the present reaction, a liquid base or liquid condensing agent can be also used as a solvent.
There is~ no limitation to the present reaction 'l temperature, and the present reaction can be carried ~`out at cooled or at ambient temperature.
¦ The present inYention may include the cases that the free carboxy grcup i5 changed into the ~0 protected c~rbo~y group and the protected carboxy . . " ~.
- ~5 -:
: ~ :

:, . , ' ~

3`~77~

is changed lnto the other ~rotected carboxy ~,roup or into the free carboxy ~roup in the pre~ent reac-tion or post-treating in the present reaction.
~he object compound (If) can be prepared by reactin~ the compound (Ie) with a trialkyloxonium-haloborate or an iminohalo~enating agent and an iminoetherifying a~ent, and then reacting the resulting com~ound ~ith an acylating agent, if necessary, followed by hydrolysisO
Suitable trialkyloxoniumhaloborate includes, I for example, trimethyloxoniumchloroborate, tri-methyloxoniumfluoroborate~ triethyloxoniumfluoro-borate, etc.
Suitable iminohalogenating agents may include, for example, phosphorus trichloride, phosphorus ~ ~
pentachloride, phosphorus tribromide, phosphorus ~ I
pentabromide, phosphorus oxychloride, thionyl ~ ~-chloride, phos$ene, etc.
~uitable iminoetherifying agents, with r~hich ;
20 ~ the resultant in the imlnohalogenating reaction is reacted, may include an alcohol such as an alkanol (e.g., methanol, ethanol, propanol, isopropanol, . : ;: : .
butanol, tertiary butanol, etc.) or the corres~
: . . -ponding alkanol having alkoxy (e.g., methoxy, ~ ;
~ 25 ethoxy, propoxy, isopropoxy, buthoxy, etc.) as sub-¦~ stituent(s) at the alkyl moiety thereof and a metal alkoxide sueh as alkali metal alkoxide (e.g., sodium alkoxide, potassium alkoxide, etc.) or alkaline ¦ earth metal akoxide (e.g., calcium alkoxicle, barium ~-j 30 alkoxide, ?tC. ) derived from the saicl alcohol ~ - 36 -! ~ -., .,,, .. , ~ , ' ' ' ., '.'. 1 ~ ', ' . , .

3~73 Th~ e reactior~s are usually carried out in a solveI~t whi~h cloes not ~ive 'had influence to these reactions, for example, chloroform, methylene chlorile, tetrahydroflzran, dioxane, etc. , ~; ;
, 5 There are no particular limitation to these '~ reaction temperature, and these reactions are often carried out at ambient or cooled teMperature.
The acylating reaction can be carried out under the similar conditions as de~scribed in the acylating reaction of the compound (Id).
I Thus obtained reaction product is, if necessary, hydrolyzed. The hydroiysis sufficiently proceeds ~ by pouring the reaction mixture to ~ater or a mixture -~ , of water and a hydrophilic solvent such as methanol, ethanol, etc. In this hydrolysis, water may contain a base such as alXali metal bicarbonate, trialkyl-amine, etc. or an acid such as dilute hydrochloric acid, acetic acid, etc.
In the above reactions, the acylamino grou~
Rlb in the compound (Ie) is changed to the other - , ac~Jlamino group'for Xlb in the compound (If) which is derived from the acylating agent. `~
The present invention may include the cases that the free carboxy group is changed into the ¦ 25 protected carboxy group and the protected carboxy is changed into the other ~rotected carboxy group ~;
' or into the free carboxy ~roup in these reactions ~ , ~ ,an~ post-treating in these reactions. ` ' 7 The object compound (Ij~ can be prepared by ~ 30 subjecting the compound (Ii) to elimination reaction J 37 _ ` `' .. ' ', ., ,~ ' ' ' ' ~ 3773 of th? r!rot,?~tiv~ ;roup of hydroxy.
The preseI.t elimination reaction is carried out in accordance ~lith a conventional method such as a met~.od of using an acid or a base, reduction, and the like. ~hese methods may be selected depen-ding on kind of the pro-tective groups to be elimi-nated. ~he elimination reaction with the acid is one of the most commonly applied methods for eliminating the protective groups such as benzyloxy~
! 10 carbonyl substituted benzyloxycarbonyl, alkoxy~
carbonyl, substituted alkoxycarbonyl, aralkoxy- ~ ;
carbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, etc. Suitable acid may include, for `
~ ; ;
example, formic acid, trifluoroacetic acid, benzene-15 sulfonic acid, p-toluenesulfonic acid, and the like, -~
! and the most suitable acid is an acid which can be .
easily distilled off under reduced pressure, for ~ example, formic acid, trifluoroacetic acid, etc.
; ~he acid suitable for the reaction can be selected according to the protected group to be eliminated ~ ;
and other factors~ hen the elimination reaction ~ ``
with the acid may be carried out in the presence of a solvent, such as a hydrophillc or~anic solvent, ~ ~.ater or a mixed~ solvent thereof. ~he elimination - 25 reaction with the base is appiled for eliminating acyl group.
~; ~uitable base may include, ~or example, an ;~ inor~anic base such as alkali metal (e.g., sodium, potassium, etc.), alkaline earth metal (e.g., ma~ne~
sium, calcium, etc.), the hydroxide or carbonate 37~3 or bicarbonl-t~ -th(ireoE, an(l t~e like, or an organic base such as trialkylamine (e.g., trir~ethylamine, triethylaminf-, e-tc.), picoline, ~ methylpyrrolidine, ~-methyl morpholine, 1,5-diazabic~clo~4,3,0~non-

5-ene, 1,4-diazabicyclol,~,2,2¦octane, 1,8-diazabi-cyclor5,4,0~undecene-7, and the like. The elimina-tion reaction with the base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.
'~he reduction is generally applied for elimina-ting, for example, trichloroethoxycarbonyl, benzyloxy-carbonyl, subs-tituted benæyloxycarbonyl9 2-pyridyl-me-thoxycarbonyl, etc.
~he reduction applicable for the elimination reaction of the present invention may include9 for example, reduction using a metal (e~g.9 tin, zinc, ~ -iron9 etc.) or a combination of metalic compound (e.g., chromous chloride, chromous acetate9 etc.) and an organic or inorganic acid (eOg.9 acetic acid, ~ -propionic acid, hydrochloric acid9 e-tc~), and reduc-tion in the presence of a metalic catalyst for eatalytie reduction. ~he metalie eatalys-ts for catalytic reduction may include, for example, Raney-niekél9 platinum oxide9 palladium carbon and other conventional catalysts. ~he protective group, trifluoroacetyl can be usually eliminated by treating wlth water in the presence or absence of the base, and halogen substituted-alkoxycarbonyl and 8-quinolyl-oxycarbonyl are usually eliminated by treating with a heavy metal such as copper, zinc, etc.

_ ~9 _ " ' ' ~: ' ' '' ', :~ "` ~ . .

.!hen ~he pro-tective group is trifluoroacet~l, it can be eli1nirlated by bre-Jting ~ith water or ~ater in the presence of a kase, an(l ~1hen the pro-tective group is halo~en substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, those can be eliminated by treatin~ ~ith a heavy metal such as copper, lead, and the like.
`;hen the protective group is acyl, the acyl can be eliminated by hydroiysis as mentioned above or by other conventional hydrolysis.
~he reaction temperature ~s not limitative and may suitably selected in accordance with the -~
protective group for hydroxy and the elimination method, and the present reaction is preferably `~
`carried out under a mild condition such as under cooling or slightly tA~arming. ~ -.
The present invention inclu~le, ~ithln its scope, the case that the protected carboxy ~roup is changed - ~ . . .
J~ ~into t~e other protected carboxy group or into the 1` 20 free carboxy group during the reaction or post-treati treating in the present reaction.
, ~
The present invention also include, within its scope, the case that when the compound (Ii) possesses `
furthermore one or more protected amino, protected ~ -` 25 ~ carboxy and/or, protected mercapto groups in the ~ acylamino grcup at 7 position on cephem ring, said ¦ groups are changed into corresponding free groups ~ during the reaction. 3 , 3 ~he object compound (Il~ can be prepared by subjecting the compound (Ik) to elimination reaction !-- 40 ~
` :
~ .:

.:.;. . ,.:.-: . . . : : , .: : .. : . .
- ~ :, : .
:: :., .: : . . - . , of t~le pro~ectivf- gro~ll) of t~e c~lrboh-~.
In the pr~sent ~limin;ltion reaction, all convelltional mel-hods used in the elimirlation reaction, all con~enticnal method~ used i~ the elimination reac-tion of the protec-ted carboxy, for example, reduction, hydrolysis, etc. can be applicable. liihen the pro-tected group is an ~cti~e ester, active amide or acid anhydride, tho~e can be elimina-ted by hydrolysis, usually elininated undor mild hydrolysis conditions such as by contactln~ with water. The reduction can be applicable for eliminating~ for example, 2~
iodoethyl ester, 2~2,2-trichloroethyl ester, benzyl ester, etc. '~he elimination reaction with an acid can be applicable for eliminating the protected groups such as p-metho~ybenæyl ester, tert-butyl ester, tert-pentyl ester, trityl ester, diphenyl-methyl ester, bis(methoxyphenyl)methyl ester, 3,4-¦ dimethoxybenzyl ester, l-cyclopropylethyl ester, an~ ;
¦ the like. '~he elimination reaction witn an anhydrous ¦~ 20 basic catalyst can be applicable for eliminatlng the protective groups such as ethynyl ester, 4-hydroxy-3,5-di~tert-butyl)benzyl ester, and the like.
The reduction appllcable for the elimination reac~
tion of the present in~ention ~ay include, for exam -,.....
- 25 example, reduction using a combina-tion of a metal (e.g., zinc, zinc amalgam, etc.) or a chrome salt compound (e.g., chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g., acetic acid, propionic acid, hydrochloric acià, etc,), 3 and reduction in the prcsence of a metalic catalytic .

, ; -. - ' ; ~ ' :

~ t reduction. The metalic c~talysts f~r catalytic reduction inc1ude, for exa~.ple, platin~ catalyst (e.g., platin~m wire, spongy platinum, platinum blac~, platinum colloid, etc.), palladium catalyst (e.g., palladium spongy, palladium black, palladium oxide, palladium on barium sulfate, palladium on barium carbon~te, palladium on charcoal,palladium on silica gel, pa]ladium colloid, e-tc.), nickel cata- -lyst (e.g~., reduced nickel, nickel oxide, Raney nickel ! IJrushibara nicl~el, etc.), etc. Suitable acid used f~r the elimlnltion reaction may inc]ude, ~ ~;
for example~ formic acid, trihaloacetic acid (e.g., trichloroacetic acid, trifluoroacetic acid, etc.), hydrochloric acid, hydrofluoric acid, p-toluene~
sulfon~c acid, trifluorometharlesulfonic acid, ~ixed ; acid of h~drocllloric acid and acetic ~cid, etc.), etc.
i Suitable anhydrous basic catalyst for the elimina-~ tlon reaction may include; for example, sodium thlo-¦ ~henolate, (CI~3)2~iCu, etc. l^`hen-the protective ~¦ 20 group ls eliminated by treating with water or a -liquid acid in tne reaction, the present reaction , ~ , , . , -.
can be carried out without solvent~
In the present reaction, can be used any solvent which does not give bad influence to the present reaction ~or example, dimethylformamide, methylene chloride, chloroform, tetr~hydrofuran, acetone, ~ethanol, et~anol and the like.
~` There is no particlllar limitation to the reaction temperatllre, an(l it r!~a-y suitably selected according ~l 30 to the s-tartiIIg compound and an elimination method '~ ~
.,, ~ .
:
.. , , ,,, ~; . .

i`7~2 to be practiccllly appli~d. The present invention includes the case th!~-t a protected c~rboxy, hydroxy, mercapto or amino group contalned in the startin~
compound is chan~ed into each free carboxy, hydroxy, mercapto or amino group~ respectively, during the present re~ction or post-treating in the present reaction. Thus obtained corapound (Il) can be ;
converted to a desirable metal (e.~., sodium, - - -potassium, etc.) sal:t or an organic base salt there-of, if necessary.
~he object compound (In) can be prepared by reacting the compound (Im) or a salt thereof with a lower alkanone of the general formula: R5-Co-H6 in which R5 and R6 are each lower alkyl.
Suitable salt of the compound (Im) may include organic acid salt (e.g., acetate, ma~eate, tartrate, ~ benzenesulfonate, toluenesulfonate, etc.) and in-J organic acid salt (eOg., hydrochloride, sulfate, . .
phosphate,-etc.), and the likeO
Suitable lo~ver alkanone of th~ ~eneral formula~
R5-Co-R6 may include, for example, acetone, 2-buta-¦ none, 2-pentanone, 3-hexanone, etc.
~he present reaction can be preferably carried out in the presence of an base, for example, an inorganic base~such as alkali metal (e.g., lithium, - sodium, potassium, etc.), and alkaline earth metal .~
(e.~., m~gnesium, calcium, etc.), and the corres- -ponding hydroxide, car~on;~te, bicarbonate, and the 1 like; an organic base such as tertiary amine (e.g., i;i 30 trimethylamine, tri~th~Jlamine, tripropylamine, tri-`~ - 43 _ isopropylamine, tI~ibut,yl~lmlne, dimethybenzylalni~e, triphenethylcll~ine, pyrrolidi~e, picoline, ~-picoline, N-methylpiperidine, N-methyln!orpholine, N,M'-di-methylpiperazine, 1,5-diazabicyclo~4,3,0Jnon-5-ene, ;~
1,4-diazabicyclo ~,2,2~ octane, 1,8-diazabicyclo-- -C5~4~ undecene-7, etc.); quarternary a~monium-hydroxide compound, and the like.
The preser.t reaction can be carried out with or withGut solvent.
.~
Suitable solvent include any solvent which does not give bad influence to the reaction, for example, dimethylformamide, dimethylsulfoxide, hexamethyl- ~ I
phosphoramide, tetramethylurea, tetrahydrofuran, methylene ehloride, dioxane, glyme, diglyme, aceto-nitrile, phosphate buffer, ete.
~here is no particular limitation to the present reaetion temperature, and the present reaction I proceed~satisfaetori]y at room temperature or under l~ eooling and may be hastened by heating.
~he present invention may include the cases ;~
that the flee carboxy group is changed into the proteeted earboxy grou~ and the proteeted carboxy -~ ~;
group is ehanged into other protected carboxy group or into the free carboxy group during the present ;~
~ 25 reaetion and post-treatin~ in the present reaetion.
j ~he obtained compound (In) ean be converted to a desirable acid salt, for example, an organic aeid salt (e.g., aceta-te, maleate, tartrate, benæene~
~ sulfonate, toluenesulfonate, ete.) and an inorganie i 30 aeid salt (e.g., hyclrochloride, sulfate, phosphate, 1 ' ' :
~ - 44 -3r~

etc.).
The rresent invertion r;iay lnciude the cases that 2-cephern corlpound, j-cer~llem compound and ~-ce~hem stereome~3 at t~ro position of the 3-ce~hem ring are ~omet~mes changed each other during the above mentioned reactions in alternative 7,processes or post-treating thereof.
~ ihen the object compound (I) has free carboxy group(s), it can be con~Terted to a metal (e.g., sodi~, potaC~sium~ magnesium9 etc.) salt or an organic amine (e.g~ 9 methyla~ine, diethylsamine, trimethylaraine5 triethylamine, aniline, pyridine,-picoline, N,N'-dibenzylethylenediamine9 etc.) salt by a conventiona] method, and when the object com compound (I) has free ar-ino group(s)9 it can be converted to an inorganic acid salt (e.g.9 hydro-chloride, sulfate, etc.) or an organic acid salt (e.~.9 acetate, maleate, tartrate, etc.) by a conventional method.
~ 20 - ;~

`I: ` . . .. .-.`
,.~ . : : : .
l ~

i~ , l ~
~25 ` `

.', ~ ~ .

$ 4~

. '~' ' ' ' , . . .. .
' ~ '., , ;' ; '''~ ' lU~377~

'` ' ;' ~he object compounds (I) of this invention nave antimicrobial activities against various pathogenic microorganisms and may be useful for treatment of diseases infected by such micro~
organisms in human and animals.
~ .
With regard to representative object compounds ;
~ of this invention, antimicrobial activities are ! 15 illustrated for reference in the follo~ing. The IC values (mcg/ml) against ~taphylococcus aureus 209-P JC-l and Bacillus subtilis~ATCC-6633 of the I object compounds (I) are shown below.
¦ ~ Method for estimatlon o~ antimicrobial activit~ ;
:
ir vitro In vitro antimicrobial activity was determined -by the two-fold agar-plate dilution method as des~
cribed below.
One loopful of an~overnight~ culture of each test strain in Trypticase-soy broth (108 viable cells per ml) was ~streaked~on~heart infuslon agar (HI-¦ agar) containlng~graded concentration of antibiotics, ~ and the minimum inhibitor~ concentration (~i~IC) ~as ¦~ expressed in terms of mcg/ml after incubation at 37C for 20 hours.

'. . . . ..
'::

: ' ' ' ~ .

.t ~a~ d'-~

(1) 2~i.1ethyl-7- rl~ r2~ ,4-thiadiazol-2-ylthio)~cetylj-phenylglycylJamino-3-cephem-4-carboxylic acld ~ , S. clureus: 1.56; B. subtilis: ~i.13 -:. -(2) 2-I~;ethyl-7- L2-hydroxy-2-(2-thlenyl)aceta~idol-3-cephem-4-carboxylic acid . -S. ~ureus: 0.78; Bo subtilis: 0.78 : (3) 2-Methyl-7-L?-(5-indanyloxy)carbonyl-2-phenyl-acetamido~-3-cephem-4-carboxylic acid S. aureaus: 1.56; B. subtilis: 6.25 (4) 2-i'~:~ethyl-7-~i2-isonicotinoyloxy-2-pher~ylacetamido)-3-cephem-4-carboxylic acid S. aureaus: 0.39; B. subtilis: 0.78 . (5) 2-rl~ethyl-7-[2-(2-thienyl)acetamid~ -3-cephem-4-carboxylic acid I5 S, aureaus: 0.78; B. subtilis: 0.39 - ~ :
I (6) 2-Methyl-7-[2-(3-chlorophenyl)acetamido~ -3- ~:
cephem-4-carboxylic acid -. aureaus: 0.1; B. subtilis: 0.2 . ~ . (7) 2-~;1ethyl-7-(2-hydroxy-2-phenJlacetamido)-3 ` 20 cephem-4-carboxylic acid ~ : ~
S. aureaus: 0.7~; B. subtilis: G.39 ~ :
(8) 2-~;.ethyl-7-(2-phenylacetamido)-3-cephem-4- ~i-! earboxylic acid S. aureaus: 0.78; B. subtilis: 0.2 ~.
i 25 (9) 2-Eqethyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic ~cid . aureaus: 0.2; B. subtilis: 0.2 (10) 2-'rTetht~1-7-(2-azido-2-phenylacetamido)-3-cepkem- -t~ 4-earboxylic acid 3 ~o s aureaus: 1.56; 3. subtilis: G.39 ~ 7 -I ~
.. ..
: :: . . .
~ ' ~ . ! -'7 7~
(il) ,~ lethyl-'7~ (1,3,L~-thi.a(liazol-2-ylthio)- ~ .
acetamldoI-3-ceI)hem-4-carboxylis aci~
S. ~ureaus: 1.56; B. subtilis: 0.7~
(12) 2-Methyl-7-~2-(1,2,5-tniadiazol-3-yl)acetamido~ -3-cephem-4-carboxylic acid . aureaus: 3.13; B. subtilis: 1.56 ~13) 2-Methyl-7-(2-cya;loacetamido)-3-cephem-4-carboxylic acid S. aureaus: 3.13; B. su~tilis: 3.13 (14) 2-Meth~l-7- r2-(allylthio)acetamido~ -3-cephem-4-carbox~lic acid S. aureaus: 1.55; B. subtilis: 1.56 (15) 2-I.Iethyl-?-l2-,(3-pyridyl)acetamido~ -3-cephem~
4-carboxylic acid S. aureaus: 3.13; B. subt-ilis: 0.78 (16) 2-Methyl 7-r2-amino-2-(methylthiophenyl)-acetamid~ -3-cephem-4-carboxylic acid . aureaus: 3.13; B. subtilis: 6.25 ~he object compound (I) of the present invention ZO may be formulated for administration in any convenient~
ay by analogy wlth other antibiotic substances.
` ~hus, the composition comprising t-he compounds (I) can be used in the~form of pharmaceutical preparations, for example, in solid, semisolid or liquid form, whlch contain the active object ;~
compound (I) in adml~xture with a pharmacelltical or inorganic carrier or excipient sultable for external ¦ ~ or parenteral alplications. The active ingredient may be compounded, ~or example, rlith~the usual carriers for tablets, peletts, capsules, supposi~

:

: i ~ - :. .:, :, '7 ~

tories, solutions, en~ulsions, a~ueous sus~ensions anl o-ther ~orm suitable ~o~ use. The carriers lllhich can be usë~ are glucose, lactose, gum acacia, gelatin, mannitol, starch paste, ma3nesillm trisili-cate9 talc, corn starch, keratin, colloidal silica,potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents can be contained in the composit~ons of this inventlon.
The compositions of -this invention can also contain preservative or bacteriostatic agents thereby ;~
I keeping the active ingredient in the desired pre-parations stable in activity.
~he active object compound (I~ is included in the ;
compositions of this invention in an amount suffi-cient to produce the desired therapeutic effect upon the bacterially infected process or condition.
~ hile the dosage or therapeutically effective -i 20 auantity of the compound varies from and also i depends upon the age and condition of each indivi-dual patient being treated, a daily dose of about 0.5 - 5 g., preferably 1 - 2 g/day of the active ingredient is generally given for treating diseases against which the object compound (I) is useful.

- 49 _ - ;.
~.
. . .
.

7~3 :- :
`,':
Having now generally described the invention, a further understanding can be attained by reference -to certain specific examples which are provided herein for purposes of illustration only and are not intended to be construed as limiting unless otherwise so indicated.
. '' ' Reaction of: :~

~xample 1 A solution of aluminum bromide (3,LT g.) in dried dlchloromethane (20 ml.) was dropwise added at -10C over about 10 minutes to a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylate (4.6 g.) in dried dichloromethane (30 ml.). After addition, the reaction mixture was stirred for 4.5 hours at room temperature, washed in turn with 2% hydro-chloric acid (30 ml.) three times, a saturated .
sodium bicarbonate aqueous solution and a satu-rated sodium chloride aqueous solution. After ;
: ~
25 dr~ing over magnesium sulfate, the solvent was dis-tilled off and the residue was washed with ether and collected by filtration to give 2,2,2-trichloroe-thyl 2-methyl-7-(2-phenylacetamido)-3~
~ cephem-4-carboxylate (3.3 g.); ~his compound ~as ¦~ 3 recrystallized from ethanol to give crystals, :.: ~- ~ -: , -.:
' . ' '.'' ' ` ;

mp 175 to 178C.

Example 2 A solution of aluminum bromide (0.4 g.) in dried dichloromethane (5 ml.) was dropwise added under ice-cooling to a suspension of 2,2,2-tri~
chloroethyl 2-methyl-2,3-methylene-6-~2-(lH-tetrazol-l-yl)acetamidolpenam-3-carboxylate (0.46 g.) in dried dichloromethane (10 ml.). After s-tirring -for 4 hours at room temperature, the reaction ~ ~
mixture was washed in turn with 2% hydrochloric p~ ;
acid three times, a saturated sodium bicarbonate `~-aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After dryin~,the solvent was distilled off and the residue was crystallized from ethanol to give 2,2,2-trichloroethyl 2-methyl-7-{2-(lH- ``
tetrazol-l-yl)acetamido}-3-cephem-4-carboxylate (0.24 g.), mp 168 to 170C. ~-.; ~
Example 3 ~itanium tetrachloride (0.19 g.) was added to a solution of 2,2,2-trichloroethyl 2-methyl- ~;
2,3-methylene-6-(2-phenylacetamido)penam-3 carboxylate (0.46 g.) in dried dichloromethane -~
(5 ml.) and the mixture was stirred for 2.5 hours.
After the reaction, the reaction mixture was ~-washed in turn with 2C/o hydrochloric acid three times, a saturated sodium bicarbonate aqueous ~
solution and a saturated sodium chloride aqueous ~ -- 51 - ~ 2 .. ... .... ,, . ~. . .. .

'773 solution and then dried over magnesium sulfate.
After the solvent was distilled off the residue (0.43 g.) was purified by column chromatography on ;~
silica gel (10 g.) using chloroform as developing solvent to ~ive 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylate (0.1 g.), -~
mp 136 to 137C.

Example 4 Aluminum chloride (2.66 g.) was added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylate (9.2 g.) in dried dichloromethane (100 ml.) and the mixture was stirred for 7 hours at room temperature. After the reaction, the reaction mixture was washed in turn with 2% hydro- -chloric acid three times, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After drying, the solvent was distilled off and -the residue was purified by column chromatography on silica gel (200 g.) using .
chloroform as developing solvent to give 2,2,2- ~ -trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (2.4 g.), mp 175 to 178C.

Example 5 A solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(benzyloxycarboxamido)penam-3- ~-carboxylate (0~58 g.) in dried dichloromethane ,' ,~
. .; . . ~ . :

'7~
(10 ml.) was dropwise added at -15 to -12C to a solution of ~luminum bromide (~.5 g.) in dried dichloromethane (10 ml.), and -the mixture ~/as stirred for 20 minutes at the same temperature and -~
then for 1.5 hours at room temperature. After the reaction, the reaction mixture was washed in turn with 5~0 hydrochloric acid, water, 5% sodium `~
bicarbonate aqueous solution and water, dried and the solvent ~1as distilled off to give oily substance. ~ `-The oily substance was dissolved in e-thanol, ` ~ ~-allowed to standg after which precipitated crystals ~ `
were collected by filtration and dried to give 2,2,2-trichloroethyl 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylate, mp 143 to 144C.
: .
! Example 6 A solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-~2-(3-chlorophenyl)acetamido}penam-3-carboxylate (3.4 g.) in dried dichloromethane (50 ml.) was dropwise added at -15C to a solution of aluminum bromide (2.8 g.) in dried dichloro-methane (20 ml.) and the mixture was stirred for 3 hours at room temperature. After the reaction, the reaction mixture was washed in turn with 5%

hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water and then ~ried. After the solvent was disti]led off, the residue was crystallized from ether to give 2,2,2-trichloro-ethyl 2-methyl-7-~2-(3-chlorophenyl)acetamido~

3 3-cephem-4-carboxylate (2.9 g.), mp 144 to 145.5C

- 53 - E L~
. .

`, - , . ~ .: ~ ~ , ` ` /
:` : :: -` - ` `
,.: . ` ` ` ~ ` :

L3~73 (dec.). -: '-Example 7 A solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-~2-(2-thienyl)acetamidolpenam-3-carboxylate (1.74 g.) in dried dichloromethane (20 ml.) was dropwise added at -15C to a solution of aluminum bromide (2.14 g.) in dried dichloro-methane (10 ml.) and the mixture was stirred for -4 hours at room temperature. After the reaction, the reaction mixture was washed in turn with 5%
hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water and then dried. After the solvent was distilled off, the residue (powder) was recrystallized from ethanol to give 2,2,2-tri~
chloroethyl 2-methyl-7-¦2-(2-thienyl)acetamido}-3-cephem-4-carboxylate (1.46 g.), mp 161 to 162C
(dec.).

~ . ~
Example 8 A solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-~2-(1,2,5-thiadiazol-3-yl)acetamido}_ ;
penam-3-carboxylate (16.5 g.) in dried dichloro-methane (100 ml.) was gradually dropwise added to -a solution of aluminum bromide (17.5 g.) in di- -~
chloromethane (1~ ml.) at below -10C. ~hen, the mixture was stirred for 2 hours at below 0C and stirred for further 2 hours at room temperature.
After the reaction, the reaction mixture was washed in turn with 2~yo hydrochloric acid (100 ml.) twice, _ 54 _ E 5 .. - . , . .. , .; . :: . :
:
... . . .
,. . : :......... -- ~ : ... .

~ 3'773 a saturated sodium blcarbonate aqueous solutlon and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After drying, `~`
the solvent was distilled off to give powdery 2,2, 2-trichloroethyl 2-methyl-7-{2-(1,2,5-thiadiazol-3-yl)acetamidol-3-cephem-4-carboxylate (13.2 g.), ;~
mp ]80 to 185C (dec.).
~ ':
~xample 9 : ~ .
10A solution of methyl 2-methyl-2,3-methylene-

6-(2-phenoxyacetamido)-penam-3-carboxylate (2.1 g.) ~~
in dried dichloromethane (11 ml.) was dropwise added over 8 minutes at -10C to a solution of aluminum bromide (2.32 g.) in dried dichloromethane 15(23 ml.) and the reaction temperature was gradually - -elevated to room temperature, after which the mix-ture was stirred for 4.4 hours at room temperature.
After th`e reaction, the reaction mixture was poured into ice-water (150 ml.) and the dichloromethane layer was separated, after which the aqueous layer was once extracted with chloroform. ~he combined dichloromethane and chloroform extract was washed in turn with water, 2% hydrochloric acid, water, a dilute sodium bicarbonate a~ueous solution and water, and then dried over magnesium sulfate.
After the solvent was distilled off, the obtained yellow oil was purified by column chromatography ~ -on silica gel (15 g.) using chloroform as developing solvent to give orange oil of methyl 2-methyl-7- ` ~
30(2-phenoxyacetamido)-3-cephem-4-carboxylate (0.7 g.). ',',A ~`

- 55 - ~ 6 ., ' ' ~ ~ :
,., . . ,, . ,,, , , : . , . ,~- . ;, ~:' .

:: . : ; , . ~ ~ .
': : '' : . .......... , 3~73 ~. :
Infrared ~bsor~-tion Spectrum (chloroform) 3400, 1785, 1726, 1689 cm~

~xample 10 `-A solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenoxyacetamido)penam-3-carboxylate (lo 39 g~ ) in dried dichloromethane (7 ml.) was dropwise added over 10 minutes at -10~
to a solution of aluminum bromide (1.16 g.) in dried dichloromethane (12 ml.), and the reaction tempe~
rature was gradually elevated to room temperature, after which -the mixture was stirred for 4 hours at room temperature. After the reaction, the reaction mixture was poured into ice-water (70 ml.) and the dichloromethane layer was separated, after which the aqueous layer was once extracted wi-th chloroform.
~he combined dichloromethane and chloroform layer was washed in turn with water, 2% hydrochloric acid, water, a dilute sodium bicarbonate aqueous solution ~
and water, and then dried over magnesium sulfate. ~ ;
After the solvent was distilled off, the obtained pale brown oil (1.2 g.) was crystallized by adding ether and a small amount of isopropyl ether. ~he crystals were collected by filtration, followed by washing wit~ isopropyl ether and recrystallized from a mixture of benzene: isopropyl ether (1:3) to give colorless granules of 2,2,2-trichloroethyl 2-methyl- --~

7-(2-phenoxyacetamido)-3-cephem-4-carboxylate ~ ` i (0.9 g.), mp 118 to 120C.

~, - 56 - E 7 ;;

Example 11 A solution of 292,2--trichloroethyl 2-methyl-2,3-methylene-6-~2-phenylacetamido)penam-3-carbo- -xylate (0.92 g.) in dried dichloromethane (5 ml.) was dropwise added at -10C over about 5 minutes to a solution of aluminum bromide (0.8 g.) in dried dichloromethane (10 ml.) and the mixture was stirred for 2 hours at room temperature. After the reaction was completed, the reaction mixture was washed in turn with 2% hydrochloric acid, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residual ;
crystals were washed with ether and dried to gi~e 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (0.74 g.), mp 175 to 178C.
And the residue obtained by concentrating the ether washing was purified by column chromatography on silica gel to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (0.05 g.), . :.: - , . , mp 118 to 120C, which is a stereoisomer at 2 position of the above obtained 2,2,2-trichloro-ethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate, mp 175 to 178C, and 2,2,2-trichloro-ethyl 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylate (0.05 g.), mp 136 to 137C.
The above obtained 2,2,2--trichloroethyl 2-meth~
7-(2-phenylacetamido)-3-cephem-4-carboxylate, mp -~ ;
118 to 120C, was recrystallized from benzene to ,. .:

` ~ ''; ~ ' ' , ~ive crystals, mp 120 to 123C.

Example 12 `~
A solution of aluminum bromide (1.7 g.) in carbon disulfide (40 ml.) was dropwise added under stirring at room temperature to a suspension of 2- -~
methyl-2,3-rnethylene-6-(2-phenylacetamido)penam-3-carboxylic acid (0.66 g.) in carbon disulfide (70 ml.) and the mixture was stirred for 20 hours at the same temperature. After the reaction was completed, the reaction mixture was poured into 5~/o hydrochloric acid (200 ml.) and the hydrochloric acid layer was separated and -thcn extracted with ethyl acetate.
~he extract was washed with water and dried, after which the solvent was distilled off. The residue was recrystallized from acetonitrile to give 2-methyl-7-(2-phenylace-tamido)-3-cephem-4-carboxylic acid (0.33 g.), mp 109C (dec.).
~he following compounds were obtained by using a similar manner as those of the Examples l to 12. ~-~

1) 2-Methyl-7-~N-(l-cyclopropylethoxy)-carbonyl- ~`
phenylglycyl~amino-3-cephem-4-carboxylic acid, - mp 16~ to 169C.
j 2) 2-Methyl-7-{2-(lH-tetrazol-l-yl)ace-tamido~-3-cephem-4-carboxylic acid, mp 202 to 203C (dec.).
3) 2-Methyl-7-~2-(2-thienyl)acetamido}-3-cephem-4-carboxylic acid, mp 175C (dcc.). ;~
4) 2-lMethyl-7~benzyloxycarboxamido-3-cephem-4 carboxylic acid, mp 167 to 169C (decO).
5) 2-Methyl-7-(2-phenylthioacetamido)-3-cephem-4- "
, ~
, - 58 - E 9 .

~. , .
, , ' .:

~ 3'~i7~ ~ ~

carboxylic acid, mp 168 to 171C (dec.).
6) 2-Methyl-7-12-(3-chlorophenyl)acetamido}-3- ~ -cephem-4-carboxylic acid, mp 173 to 174C (dec.).
7) 2-Methyl-7-~3-(N-tert.-bu-toxycarbonylamino)-3-(2-thienyl)propionamido¦-3-cephem-4-carboxylic acid, mp 167 to 170C (dec.).

8) 2-~ethyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid, mp 162 to 166C.

9) 2-Methyl-7-(3-phenylureido)-3-cephem-4-carbo-xylic acid, mp 148 to 151C. ~ -

10) 2-Methyl-7-~2-(1,3,4-thiadiazol-2-ylthio)-acetamido~-3-cephem-4-carboxylic acid, mp 197 to

11) 2-Methyl-7-¦N-tert.-butoxycarbonyl-2-(2-thienyl)glycyl~amino-3-cephem-4-carboxylic acid, powder.

12) 2-Methyl-7-¦2-(5-methyl-1,3,4-thiadiazol-2- -yloxy)acetamido~-3-cephem-4-carboxylic acid, mp 113 to 116C.

13) 2-Methyl-7-l3-(2-chlorophenyl)-5-methylisoxazol- ;~
4-yl~carboxamido-3-cephem-4-carboxylic acid, mp ;,~
202 to 203C. `~

14) 2-Methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid, mp 181 to 183C (dec.).

15) 2-Methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid, mp 121 to 123C. ~ ~

16) 2-Methyl-?-(2-formyloxy-2-phenylacetamido)- ; -. .
3-cephem-4-carboxylic acid, powder.

17) 2-Methyl-7-(1-cyclopropylethoxy)carboxamido-3-cephem-4-carboxylic acid, mp 158.5 to 160C (dec.).

- 59 - ~ 10 ... . .

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

r~f ~

18) 2~2~2-Trichloroethyl 2-methyl-7-{N~ cyclo-propylethoxy)carbonylphenylglycyl~amino-3-cephem- ~
4-carbox~late, mp 165 to 167.5C. ~ '

19) 2,2,2-Trichloroethyl 2-methyl-7-(2-phenyl-thio-acetamido)-3-cephem-4-carboxylate, mp 140 to 142C.

20) 2,2,2-Trichloroethyl 2-methyl-7-~3-(N-tert.-butoxycarbonylamino)-3-(2-thienyl)propionamido}-~-cephem-4-carboxylate, mp 1~8 to 192C.

21) 2,2,2-~richloroethyl 2-methyl-7-(2-cyano- ~;
acetamido)-3-cephem-4-carboxylate, mp 160 to 165C
(dec.). ''

22) 2,2,2-Trichloroethyl 2-methyl-7-(3-phenyl-ureido)-3-cephem-4-carbox~Jlate, mp 172 to 174C.

23) 2,2,2-Trichloroethyl 2-methyl-7-~2-(193,4- ';
thiadiazol-~2-ylthio)acetamido}-3-cephem-4-carbo-xylate, mp 130 to 140C (dec.).

24) 2,2,2-Trichloroethyl 2-methyl-7-~N-tert.-butoxycarbonyl-2-(2-thienyl)glycyl~amino-3-cephem-4-carboxylate, powder.
,

25) 2,2,2-Trichloroethyl 2-methyl-7-{2-(5-methyl- '~
1,3,4-thiadiazol-2-yloxy)acetamido~-3-cephem-4- -carboxylate, amorphous. -~

26) 2,2,2-Trichloroethyl 2-methyl-7-~3-(2-chloro-phenyl)-5-methylisoxazol-4-yl}carboxamido-3-cephem-4-carboxylate, amorphous. '

27) 2,2,2-Trichloroethyl 2-methyl-7-(2-methyl'thio-acetamido)-3-cephem-4-carboxylate, mp 151 to 153C.

28) 2,2,2-Trichloroethyl 2-methyl-7-(2-allylthio- ~;' - '-acetamido)-3-cephem-4-carboxylate, mp 96C. '

29) 2,2,2-Trichloroethyl 2-methyl-7-(2-formyloxy-,'` ' - 60 - E 11 ;~

., . ,. -.
.. , ; . , .

7t~
-2-phenylac~t~mido)-3-cephem-4-carboxylate~
po~der.

30) 2,2,2-~richloroethyl 2-methyl-7-(1-cyclo-propylethoxy)carboxamido-3-cephem-4-carboxylate, colorless powder.

31) 2,2,2-Trichloroethyl 2-methyl-7-¦N-tert.-butoxycarbonyl--2-(4-hydroxyphenyl)-D-glycyl}amino-3-cephem-4-carboxylate, mp 130 to 135C (dec.)~

32) 2,2,2-Trichloroethyl 2-methyl-7-~N-tert.-butoxycarbonyl-2-(4-methylthiophenyl)glycyllamino-3-cephem-4-carboxylate, mp 115 to 120C.

33) 2,2,2-~richloroethyl 2-methyl-7 (N-tert.-butoxycarbonyl-2-(4-methoxyphenyl)glycyl~amino-3-cephem-4-carboxylate, mp 92 to 95C (dec.).

34) 2,2,2-1'richloroethyl 2-methyl-7-~N-tert.-butoxycarbonyl-2-(2,5-dihydrophenyl)glycyl~amino-3-cephem-4-carboxylate, mp 104 to 111C (dec.).

35) 2,2,2-~richloroethyl 2-methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylate, mp 150C (dec.). `~

36) 2,2,2-~richloroethyl 2-methyl-7-lN-(l-cyclo-propylethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl~amino-3-cephem-4-carboxylate, mp 118 to 120C (dec~

37) 2,2,2-Trichloroethyl 2-methyl-7-{N-tert.- ;~ J
butoxycarbonyl-2-(4-tert.-butoxycarbonylmethoxy-phenyl)glycyl~amino-3-cephem-4-carboxylate, powder. ~

38) 2,2,2-~richloroethyl 2-methyl-7-{N-(1,3,4- .
thiadiazol-2-yl)thiomethylcarbonyl-2-phenyl-glycyl}amino-3-cephem-4-carboxylate, mp 148 to ~ tj'~7 150C (dec.).

39) 2,2,2-Trichloroeth~J1 2-methyl-7-~N-tert.-butoxycarbonyl-2-(4-methylsulfinylphenyl)glycyl}-amino-3-cephem-4-carboxylate, mp 115 to 125C.

40) 2,2,2-Trichloroethyl 2-methyl-7-(2-isonicoti-noyloxy-2 phenylacetamido)-3-cephem-4-carboxylate, mp 100 to 115C (dec.)~

41) 2,2,2-Trichloroethyl 2-methyl-7-{2-(5-indanyl)-oxycarbonyl-2-phenylacetamido}-3-cephem-4-carboxylate, -mp 165 to 170C. `~

42) 2-Methyl-7-~D-2-(4-hydroxyphenyl)glycyl~amino- ~-3-cephem-4-carboxylic acid, powder. ^

43) 2-Methyl-7-~2-(5,6-dihydro-2H-Pyran-3-yl)gly-cyl}-amino-3-cephem-4-carboxylic acid, mp 125 to 128C (dec.)

44) 2-Methyl-7-{2-(3-methanesulfonamidophenyl)glycyl~
amino-3-cephem-4-carboxylic acid, mp 192 to 1~3a (dec.).

45) 2-Methyl-7-~2-(4-carboxymethoxyphenyl)glycyl~-amino-3-cephem-4-carboxylic acid, powder~

46) 2-Methyl-7-~2-(4-methylthiophenyl)glycyl~amino~
3-cephem-4-carboxylic acid, mp 165 to 175C.

47) 2-Methyl-7-{2-(4-methoxyphenyl)glycyl~amino-3- -cephem-4-carboxylic acid, mp 165 -to 168C. "~

48) 2-Methyl-7-~2-(2,5-dihydrophenyl)glycyl~amino- ~
3-cephem-4-carboxylic acid~ mp 168C (dec.) ~ `

49) 2-Methyl-7-~2-(4-methylsulfinylphenyl)glycyl}-amino-3-cephem-4-carboxylic acid, powder.

50) 2,2,2-Trichloroethyl 2-methyl-7-{2-(5,6-dihydro-2H-pyran-3-yl)acetamido3-3-cephem-4~
'~' . ` ' - - 62 - ~ 13 ~

': - ` ` , : . . ` , ~ 3~3 carboxylate, mp 149.5 to 150.5C.

51) 2-Methyl-7-~2-(5,6-dihydro-2H-pyran-3-yl)-acetamido}-3-cephem-4-carboxylic acid, mp 172.5 to 173.5C (dec.).

52) 2,2,2-Trichloroethyl 2-methyl-7-~N-tert.-buto-xycarbonyl-2-(3-methanesulfonamidophenyl)glycyl}-amino-3-cephem-4-carboxylate, amorphous.
J 53) 2-Methyl-7-{N-tert.-butoxycarbonyl-2-(3-methanesulfonamidophenyl)glycyl~amino-3-cephem-4-carboxylic acid, oil.
54) 2-Methyl-7-(4-methoxyphenyl)glyoxylamido-3-cephem-4-carboxylic acid, mp 188 to 189C (dec~
55) 2-Methyl-7-(N-tert.-butoxycarbonylphenyl-D-g amino-3-cephem-4-carboxylic acid, mp 125 to 127C (dec.).
56) 2-Methyl-7-(N-/2-(2-nitrophenoxy)acetyl}phenylglyCyl~
amino-3-cephem 4-carboxylic acid, mp 135 to 137C(decO). ;~
57) 2,2,2-~richloroethyl 2-methyl-7-(N-tert.- `
butoxycarbonylphenyl-D-glycyl)amino-3-cephem-4-carboxylate, mp 115 to 116C (dec.). ` ~;
, .. . ..

, .. ...

. :... .:

~- 30 i - 63 - ~ 14 .,", .. , ., , , , , , .. .. ,, ., , , . ,. ~

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

3~773 Rl ~ o~ R3 X~ ~ 9 I-R3 R- ~ -Example 1 A solution of 3-chloroperbenzoic acid (0.44 g.) ln chloroform (5 ml.) was dropwise added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate -~ :
- (0.92 g.) in chloroform (10 ml.) and the mixture was stirred ~or 1.5 hours at the same temperature.
After the reaction, the precipitating crystals were filtered off and the filtrate was washed in turn t.~ith a sodium bicarbonate aqueous solution - and a saturated sodium chloride aqueous solution, followed by drying over magnesium sulfate, and ;~
then the solvent was distilled off. ~he residue was crystallized using a small amount of ether to ; 20 give 2,2,2-trichloroethyl 2-methyl-7-(2-phenyl~
~ . .
acetamido)-3-cephem-4-carboxylate-1-oxide, mp 173 to 175C.
;'~`';, Example 2 ,, A sollltion of 3-chloroperbenzoic acid (0.40 g.) - `
in dichloromethane (10 ml.) was dropwise added to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylate (0.92 g.) " -in dichlorome-thane (10 ml.) and the mixture was ;
stirred for 1 hour. After the reaction was -, . . ` ... .~ . .
.: . . :

" ~L'1 ~7 ~
completed, the reaction mixture was filtered and the filtrate was washed in turn wi-th a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, after w~ich the solvent was distilled of~
under reduced pressure. The residue wa,s recrystallized from ethanol to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylaceta-mido)-3-cephem-4-carboxylate-1-oxide (0.56 g.), mp 173 to 175C.
And the above recrystallization mother liquid was concentrated and the residue was crystallized using - ether to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenyl-acetamido)-3-cephem-4-carboxylate-1-oxide (0.34 g.), mp 160C, which is a stereoisomer at 2 position of the above obtained 2,2,2-trichloro-ethyl 2-methyl-7-(2-phenyl- `~
acetamido)-3-cephem-4-carboxylate-1-oxide, mp 173 to 175C.

"' ;' ' ~. , ' i~ "

':

-.' , .. ... . .. .. . .

~lO~37~3 :~
o R ~ -i S;~l R3 R~ R3 R2 R2 ;

Example 1 Phosphorus trichloride (0.5 ml.) was dropwise added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate-1-oxide (0.72 g.) in dimethyl-formamide (5 ml~) and the mixture was stirred for 1 hour at the same temperature. After the reaction, the reaction mixture was poured into a mixture of ethyl acetate (40 ml.) and ice-water (40 ml.), and the ethyl acetate layer was separated. ~he aqueous layer was further extracted with ethyl acetate (10 ml.), and the ethyl acetate layer was combined.
The combined solution was washed in turn with 5%
hydrochloric acid? a sodium bicarbonate aqueou~
solution and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. lhe dried solution was treated with activated charcoal ~ -and -the solvent was distilled off. The residue ;~ -was crystallized with a small amount of ether to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenyl~
acetamido)-3-cephem-4-carboxylate (0.43 g.), mp 175 to 178C.
The follovving compounds were obtained by using the similar procedure as that of the Example 1.
3 1) 2,2,2-Trichloroethyl 2-methyl-7-~2-(lH-t~trazol- , - .: ,- ~., , . . - ~,............................ .
: : ... ;, :.,. . : . - . , ~ :

3~73 l-yl)acetamido~-~-cephem-4-carboxylate, mp 168 to ~70C
2) 2,2,2-Trichloroethyl 2-methyl-7-benzyloxy-carboxamido-3-cephem-4-carboxylate, mp 143 to 144C. -3) 2~2,2-Trichloroethyl 2-methyl-7-~2-(3-chloro-phenyl)acetamido¦-3-cephem-4-carboxylate, mp 144 to 145.5C (dec.).
4) 2,2,2-~richloroethyl 2-methyl-7-¦2-(2-thienyl)~
acetamidol-3-cephem-4-carboxylate, mp 161 to 162C (dec.)0 ;"``;
5) 2,2,2-~richloroethyl 2-methyl-7-~2-(1,2,5-thia-diazol-3-yl)acetamido}-3-cephem-4-carboxylate, ;~
mp 180 to 185C (dec.).
6) Methyl 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylate, oil~
7) 2,2,2-~richloroethyl 2-methyl-7-(2-phenoxy-acetamido)-3-cephem-4-carboxylate, mp 118 to 120C.
8) 2-i~ethyl-7-lN-(l-cyclopropylethoxy)carbonyl-phenylglycyl~amino-3-cephem-4-carboxylic acid, mp 168 to 169C.
9) 2-Methyl-7-{2-(lH-tetrazol-l-yl)-acetamido~-3- -cephem-4-carboxylic acid, mp 202 to 203C (dec.).
10) 2-Methyl-7-~2-(2-thienyl)acetamido~-3-cephem-4-carboxylic acid, mp 175C (dec.).
11) 2-Methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylic acid, mp 167 to 169C (dec.).
12) 2-Methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid, mp 168 to 171C (dec.).
13) 2-Methyl-7-{2-(3-chlorophenyl)acetamido~-3-cephem-4-carboxylic acid, mp 173 to 174C (dec.).
:`

: ~

37~73 ~;
14) 2-Methyl-7-~3-(N-tert.-butoxycarbonylamino)-~
(2-thienyl)propionamido~-3-cephem-4-carboxylic acid, mp 167 to 170C (dec.)0 15) 2-Methyl-7-(2~cyanoacetamido)-3-cephem-4-carboxylic acid, mp 162 to 166C.
16) 2-Methyl-7-(3-phenylureido)-3-cephem-4-carbo-xylic acid, mp 148 to 151C. ;;~ ;
17) 2-Methyl-7-(2-(1,3,4-thiadiazol-2-ylthio)- `~
acetamido~-3-cephem-4-carboxylic acid, mp 197 to 199C.
18) 2-Methyl-7-(N-tert.-butoxycarbonyl-2-thienyl-~lycyl)amino-3-cephem-4-carboxylic acid, powder.
19) 2-Methyl-7-~2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido~-3-cephem-4-carboxylic acid, mp -11~ to 116C.
20) 2-Methyl-7-{3-(2-chlorophenyl)-5-methyliso- ~` ;
xazol-4-yl¦carboxamido-3-cephem--4-carboxylic acid, ~ `
mp 202 to 203C.
21) 2-Methyl-7-(2-methylthioace-tamido) 3-cephem- ;-` 20 *-carboxylic acid, mp 181 to 183C (dec.) ~; 22) 2-Methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid, mp 121 to 123C.
23) 2-Methyl-7-(2-formyloxy-2-phenylacetamido)-~ 3-cephem-4-carboxyllc acid, powder.
;~ 25 24) 2-Methyl-7-~1-cyclopropylethoxy)carboxamido-3-cephem-4-carboxylic acid, mp 158.5 to 160C
(dec.).
25) 2,2,2-~richloroethyl 2-methyl-7-lN-(l-cyclo-propylethoxy)carbonylphenyl~lycyl}amino-3-cephem-4-carboxylate, mp 165 to 167.5C.

3~7~3 26) 2,2,2-TrichLoroethy1 2-methyl-7-(2-phenylthio-acetamido)-~-cephem-4-carboxylate, mp 140 to 142Co 27) 2,2,2-Trichloroethyl 2-methyl-'7-~3-(N-tert.-bu-toxycarbonylamino)-3-(2-thienyl)propionamido}-3- ~ -cephem-4-carboxylate, mp 188 to 192C.
28) 2,2,2-Trichloroethyl 2-methyl-7-(2-cyano-acetamido)-3-cephem-4-carboxylate, mp 160 to 165C
(dec.).
29) 2,2,2-Trichloroethyl 2-methyl-7-(3-phenylureido)~
3-cephem-4-carboxylate, mp 172 to 174C.
30) 2,2,2-Trichloroethyl 2-methyl-7-~2-(1,3,4- `~
thiadiazol-2-ylthio)acetamido}-3-cephem-4-carbo-xylate, mp 130 to 140C (dec.). `~; `
31) 2,2,2-Trichloroethyl 2-methyl-7-(N-tert.-butoxycarbonyl-2-thienylglycyl)amino-3-cephem-4-carboxylate, pow~er.
32) 2,2,2-Trichloroethyl 2-methyl-7-f2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido~-3-cephem-~
carboxylate, amorphous.
33) 2,2,2-~richloroethyl 2-methyl-7-f3-(2-chloro-phenyl)~5-methylisoxazol-~-yl~carboxamido-3-cephem-4-carboxylate, amorphous.
34) 2,2,2-Trichloroethyl 2-methyl-7-(2-methylthio~
acetamido)-3-cephem-4-carboxylate, mp 151 to 153C.
35) 2,2,2-Trichloroethyl 2-methyl-7-(2-allylthio-acetamido)-3-cephem-4-carboxylate, mp 96C.
36) 2,2,2-Trichloroethyl 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylate, powder.
37) 2,2,2-Trichloroethyl 2-methyl-7-(1-cyclopropyl- ~
ethoxy)carboxamido-3-cephem-4-carboxylate, mp 181 `

- 69 - ~ 20 : ~ : . . . . . . . .

37~73 to 183~C.
38) 2-Methyl-7-(phenyl~lycyl)amlno-3-cephem-4_ carboxylic acid, mp 168.5 to 171C.
39) 2-Methyl ?-J3-amino-3-(2-thienyl)-propion-amido)-3-cephem-4-carboxylic acid, mp 218 to 221C
(dec.).
40) 2-~J~ethyl-7t2-(2-thienyl)~lycyl}amino-3-cephem-4-earboxylic acid, mp 145 to 149C (dec.). -41) 2-Methyl-7-(2-hydroxy-2-phenylacetamido)-3-cephem-4-carboxylic acid, mp 172 to 173C.
42) 2,2,2-~riehloroethyl 2-methyl-7-amino-3-eephem-4-carboxylate hydrochloride, mp 185 to 187C
(dec.).
43) 2-Methyl-7-amino-3-cephem-4-carboxylie acid, mp 220C (dec.).

~ .

:
; 25 ;
. ' ' : ~

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

3~6'~3 ~ `. -la X R3 ~ X _ R3 R -~~~ ~ J ~ I ~ J

O I R2 . ,: ~:
R2 ~ ~ .

~xam2~ 2 methyl_nf~ c~ClPrPY

carboxamido 3 i e~ or 2 hOurs at roomformlc aClEther (20 mlO) ~!as added under ice~
temPeratUrei ture and the sUpern ..
coolin~ toi whiCh ~,rocedUre waS
tant was remcip 2C 222C (dec~

--~ ) nd phosphorus pentaCh ~ ere added in turn under coollng ride (1.43 g ~ 2 2~2-trichlor Z5 at 5 hyl 7-(Z-pheny hloromethane carboxylate t . red After dissolu-the mixture was stlr ~o rature was ele ~ated to f t room temperature~ an .-;, .. . .. ,.,,,.,,., : ~ -"' ,,' ' ~ ' ' ~ O~L377;3 stirred for 4 hours, To this solution was dropwise added absolute methanol (1.47 g~) under cooling at ' ' -lO to -15C. After stirring for l hour at the same temperature and 1.5 hours at 2 to 3C, the ~ ' precipitated crystals were collected by filtration, washed with a small amount of dichloromethane and --ether, and dried to give colorless crystals of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem- - ~ ' 4-carboxylate hydrochloride (1.26 g.), mp 185 to - ' 187C (dec.). ~imilar results were obtained by '~
using the following compounds as a starting compound instead of 2,2,2 trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxyla~te.

Rla--T -l' 'J~ CH3 ~, 0~ N ~

No. ¦ Rla ¦ Property mp 165 to 167.5C

2 I,N-CH2CONH- mp 168 to 170C ~s;~
_ _ _ , - - ~ S'l CH2CON~- 3 ~ k; t~ 162C

L~ ~ --S-CH2CONH- mp 140 to 142C

~ --CH20CONH- mp 143 to l44~C
:'~' - ..

- 72 - ~ 23 ,' ' 1 , .: . .
;,. .
., , " ' " ' ~, 10;~3773 .!-CHCH2CONH - .
6 ~ NHCOOC. C~3 mp 188 to 192C :
. __ _ 7 NC-CH2CONH- mp 160 to 165C
! (dec.) . _ _ - ~:
8 ~ --N HC ~N H- mp 172 to 174C
'. . , ~
i N.- N mp 130 to 140C
9 ~S~I~ ~CH2coNrI- ~ (dec.) _ _ _ l~Sil- C H C O N HC-H .
NHCOOC '-- CE~33 Amorphous 11 N3cQs~ocH2coNH- Amo~phous ~-- --~'1 - ---- -12 ~ r CH Amorphous ~-:
.
13 CH3-S-CH2CONH_ . mp 151 to 153C
., . ~ . : :
I . 14 `CH2aC~CH2SCH2CONH- mp 96C
. _.

- 15 OCHO mp 142 to 147C
! : Cl ~ . mp 144 to 145.5C
16 -CH2CONH- (d~c.)l 17 ~ CH2CONH- ~ mp 180 to 185C ~ : ' ~ (deG-) i~ , ¦ 18 ~ 0-CH2CONH_ ~ mp 118 to 120C

~ ~ .
Example i 30 ~rimethylchlorosilane (55 ml.) ~as added to ¦ . - 73 E 24 'I :

.. ;....... . . . ~ .... . . ...

a susper]sion of 2-methy1-7-(2-phen~lacetamido)-3-cephem-4-carboxylic acid ~18.15 g.) in dichloro-methane ~4~0 ml.), and the mixture ~as stirred for 10 minutes.
To the mixture was added dimethylaniline ~ (41.5 ml.), and the mixture was refluxed for 1 ; hour. hfter the mixture was cooled at -30 to -40C, to a mixture was added phosphorus pentachloride (16.6 g.), and the mixture was stirred for 2 hours at the same temperature, after which methanol (185 ml.) was added to the s~lution and the mixture was stirred for 1 hour at the same temperature.
Water (250 ml.) was added to the reaction mixture - and this solution was stirred for 30 minutes at i5 -10 to 0C, after which the aqueous layer was ~ ;
separated. ~he aqueous layer was adjusted to ¦ pH 3 to 4 with lN sodium hydroxide aqueous solution at O to 10C, and the precipitated crystals ~1ere collected by filtration, washed in turn with water, acetone and ether, and then dried to give whi~e ~ -I crystals of 2-methyl-7-amino-3-cephem-4-carboxylic 3 acid ~6~9 g.), mp 222C (dec.).
Similar results were obtained by using the ¦ following compounds as a starting compound instead ~ -25 of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid.

R ~ 3 - , N .~
¦ O COOH
~ 30 - - -i ..
I _ 74 _ E 25 .

~, `' ~:::: ' : . : . .. . . .
'. . : :
.. . .. .

3~73 No. I Rla I Property ¦ : .
_ _ __ , ~ cHcoNH- mp 16~ to 169C : .
. _ 2 I `N-CH2CONH- ¦ mp 202 to 203C
. N=CH (dec.) . ___ . ~.
3 r~ CH2CONH- mp 175C (dec.) .
_ _ _ _ _ 4 .~ -S-CH2CONH - mp 158 to 171C
_ (dec.) ::
/~ -CH20CONH- mp 167 to 169C ;-~ ,.
; 6 '`Sll-,CHcH2cONHH- ¦ mp 167 to 170C . :~
, NHCOOC~CH3 1 (dec.) : I -_ ~ _ . ___ ~ 15 7 N C - CH2CONH- mp 162 to 166C
_ I _ ~ 8 . ~ -N H a ONH - I mp 148 to 151C ~ .
. _ 1 N~ NI
! ~ 9 ~S~-S-CH2CONH- mp 197 to 199C
I 2~ .
t ~ ¢S~ C, H C O N H-- I
NHCooc \c~ I Amorphous 11 N-~ . mp 113 to 116C . ~:
. N3C'`S'`OCH2CONH- .
~; . Cl .12 ~ ~ -CONE- mp 202 to 203C
:'Z . . l ' , ' 1~ CH3-S-CH2CONH- mp 181 to 183C
(dec.) ¦ : -. , , ~ __ __ _ : ' ' lL~ CH2=C~C~2SCE2CNH- mp 121 to 123C

.
.' . , i . _ 75 _ ~ ~ 26 , .

., .............. , ' , . . '' ,; . I
. . .
'''' ' ' ' ' '' . ' ~ ' ' , 37~73 _ _ _ __ ______ Q,~ Amorphous I C--1 ~~~--~ // `~C~12CONH- I mp 173 to 1 74C

17 ~ ~ CH2CONH- ¦ mp 147 to 149C

~IO.. ~\ CIHCONH- C-l~ I
18 ¦ NHCOOC ~; CH~ I Powder ~, .:
I .

, , ~
' ~:',' ' '` ~
i, ~,.,"

- , .

~ "'~':

i ~ .

r . , t ' ' ' . ' ' ~0437~73 H2N - ~ ~ R~ Rlb ¦ ~ ~ R~

" N ~ 0 N
R2 R2 :~
.

xample 1 A solution of N-(l-cyclopropylethoxycarbonyl)~
phenylglyclne (1063 g), triethylamine (0.60 g) and ;~
dimethylbenzylamine (2 drops) in dried dichloromethane (10 ml) was dropwise added at -10C to a solution of ethyl chloroformate (0.67 g) in dried dichloromethane (15 ml), and the mixture was stirred for 1 hour.
~he mixture was cooled at -10 -to 15C and to the mixture was dropwise added over 10 minutes a solution of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (2.2 g) and triethylamine (0.55 g) in dried dichloromethane (20 ml), a~ter which the mix~ure was stirred for 2.5 hours at the same temperature.
After the reaction, the reaction mixture was in turn washed with water, 2% hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a saturated sodium -~
chloride aqueous solution and then dried over magnesium ;-sulfate. After the sol~ent was distilled off under ; `
reduced pressure, the residue was pulverized by adding isopropyl ether, after which the powder was collected by ~iltration and dried to give 2,2,2-trichloroethyl 2 methyl-7-cN-(l-cyclopropylethoxy)carbonylphenylglycyl~
amino-3-cephem-4-carboxylate (3.0 g), mp 165 to 167.5C.

77 _ E 28 .. : : .

IL~43'-7~7~

Example 2 A solution of 2-(lH-tetrazol-l-yl)acetic acid (1.08 g)~ triethylamine (0.96 g) and dimethylbenzylamine ~ ~
(2 drops) in dried dichloromethane (10 ml) was dropwise ~ :
added over 10 minutes at -10C to a solution of pivaloyl chloride (1020 g) in dried dichloromethane (20 ml), and ~ :
the mixture was stirred for 1 hour at the same temperatureO
A solution of 2,2,2--trichloroethyl 2-methyl-7-amino-3-chephem-4-carboxylate hydrochloride (3O05 g) and tri-ethylamine (008 g) in dried dichloromethane (20 ml) was dropwise added over 10 minutes to the mixture, and the -~
mixture was stirred for 3 hoursO After the reaction, `
the reaction mixture was in turn washed with water, 5% ` ~
hydrochloric acid, a saturated sodium becarbonate ~ .
aqueous solution and a saturated sodium chloride aqueous solution, and then dried over magnesium solfate.
After the solvent was distilled off~ the obtained residue :
was washed with ether and collected by filtr~tion to give colorless crystals of 2,2,2-trichloroethyl 2-methyl-7-~ 20 ~2-(lH-tetrazol-l-yl)acetamido]-3-cephem-4-carboxylate : (2.34 g), mp 168 to 170C o xample 3 .:
2,2,2-~richloroethyl 2-methyl-7-amino-3-cephem-4- ~:
carboxylate hydrochloride (300 g) was suspended in dried -dichloromethane (50 ml) and then dissolved by adding : triethylamine (0072 g) and dimethylaniline (109 g) under cooling at -15C. ~o a solution was dropwise added a solution of (2-thienyl)acetyl chloride (2.0 g) in dried dichloromethane (10 ml) under stirring and cooling - 78 - ~ 29 . - ~
~lO437~73 at the same -temperature, and the mixture was stirred for 1.5 hours at -the same temperatureO After the reaction, the reaction mixture was in turn washed with 5'~o hydro-chloric acid, water, 55~ sodium bicarbonate aqueous solution and water and then driedO After the solvent was distilled off, the residue was dissolved in ether, allowed to stand, after which the precipitated crystals were collected by filtration and dried to give crystals of 2,2,2-trichloroethyl 2-methyl-7-~2-(2-thienyl)~
acetamido~-3-cephem-4-catboxylate (3~2 g), mp 161 to ~;
162C (decO)~

Example 4 2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.0 g) was suspended in dried dichloromethane (50 ml) and then dissolved by adding triethylamine (0.72 g) and dimethylamiline (1.9 g) under cooling at -15C. ~o a mix-ture was dropwise added a solution of phenylthioacetyl chloride (2.2 g) in dried dichloromethane (10 ml) under s-tirring, and the mixture was stirred for 105 hours at the same temperatureO After the reaction, the reaction mixture was in turn washed ~ith 5% hydrochloric acid, water, 5G/o sodium bicarbonate aqueous solution and water and then dried. After -the solvent was distilled off, ether was added to the residue, after whlch the precipitated crystals were collected by filtra- `
tion and dried to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate (3.4 g), mp 140 to 142Co ~ ;~

- 79 - ~ 3 ; , . .

~ 3~73 Example 5 A solution of 2~2,2-trichloroe~thyl 2-methyl-7-amino~
3-cephe~-4-carboxylate hydrochloride (3.0 g), triethyl-amine (0.72 g) and dimethylaniline (1.9 g) in dried dichloromethane (50 ml) was dropwise added at -15C over 1.5 hours to a solution o~ benzyl chloroformate (202 g) ~-in dried dichloromethane (10 ml) 9 and the mixture was stirred ~or 1 hour at the same -temperature. After the -reaction, the reaction mixture was in turn washed with 5~ hydrochloric acid, water9 5% sodium bicarbonate aqueous solution and water and then dried. After the solvent was distilled off~ the residue was dissolved in ethanol, after which the precipitated crystals were collected by filtration and dried to give crystals of 2,2,2-trichloro-ethyl 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxy-late (3.2 g), mp 143 to 1~4C.

' ",:
E~ample 6 A solution of 3-(N-tert.-butoxycarbonylamino)-3- -(2-thienyl)propionic acid (795 mg) and triethylamine (240 mg) in dichloromethane (10 ml) was dropwise added under cooling at -15 to -10C over about 20 minutes to `
a solution of isobutyl chloroformate (330 mg) in dried dichloromethane (10 ml). The mixture was ~urther stirred for 1 hour at the same temperature to give the solution of the mixed anhydride. A solution which was prepared by adding trie-thylamine (160 mg) and dimethylaniline (50 mg) to a solution of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-~-carboxylate hydrochloride (760 mg) in -~
dichloromethane was added at -15 to -10C to the above .. .. , .............. . , ~ , , , . ~ . .
'': ' " . ~ . , ' .......... .:- ' ,' ' . . ' ', : , : . ' ': . : . ' - ~: ' ' : ` ' mer,tioned mix~d anhydride solution, af~er which the mixture 1.5J~S stirred for ~ hours at the same temlperatllre and further 3 hours at room te~lperature. After the reaction, dichloro-methane was distilled off. The residue was dissolved in ethyl acetate (150 1l1), and the solution was in turn washed vrith 5C,~ hyclrochloric acid (20 ml), 5~o sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate.
The solvent was distilled off under reduced pressure to - .
give 2,2,2~trichloroethyl 2-methyl-7- L3-(~-tert.-butoxycarbonylamino)-3-(2-thiehyl)-propionamido~-3-cephem-4-carboxylate (1.17 g), mp 188 to 192C.

I ~xample A solution of triethylamine (0.9 g) and di~ethyl-aniline (0.15 g) in dichloromethane (20 ml) was added under stirring and ice-cooling to a suspension of 2,2,2 ~ trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate I hydrochloride (3.82 g3 in dried dichloromethane (80 ml). ¦
~ 20 ~o the mixture were added cyanoacetic acid (0.85 g) and ¦ dicyclohexylcarbodiimide (2.25 g), and the ~ixture was ~ stirred-for 1 hour undèr ice-coolingO To the mixture was 3 added 5C' hydrochloric acid (50 ml), and the mixture was ¦ stirred for 30 minutes, after which the organic layer was separated, washed in turn with 5% hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a ¦ saturated sodium chloride aqueous solution and then dried over ~lagnesium sulfate. ~he solvent was distilled off to give colorless powder of 2,2,2-trichloroethyl 2-methyl-7-~2-cyanoacetamido)-3-cephem-~-carboxylate (3.5 g), .. . .
~ - 81 - E 32 ` ~

3~7~
mp 160 to 165C. (dec.).
Example 8 2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.82 g) was suspended in dichloro-methane (30 ml), and then dissolved by adding triethylamine -(0.9 g) and dimethylaniline (0.1 g). To the solution was added phenylisocyanate (1.2 g) under stirring and ice-cooling, and the mixture was stirred for 5 hours. 10% Hydrochloric acid was added to the reaction mixture, and the mixture was stirred for 10 minutes. The reaction mixture was filtered, and the dichloromethane layer was separated from the filtrate, washed in turn with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off to give 2,2,2-trichloroethyl 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylate (4.2 g), mp. 172 to 174C.

Example 9 2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.82 g) was suspended in dried dichloromethane (80 ml) and dissolved by adding under stirring and ice-cooling a solution of triethylamine (0.9 g) and dimethylaniline (0.15 g) in dichloromethane (20 ml). To the solution were added (1,3,4-thiadiazol-2-ylthio)acetic acid (1.8 g) and dicyclohexylcarbodimide -(2.25 g) under stirring and ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. To th_ reaction .

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

~10'~3 ~

~.ixture, was added 5';~ hydrochloric acid (50 ml), and ~he mix-tuIe was stirred for 30 minu-tes, after which the or~anic layer ~as separated~ washed in turn with 5~0 hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and then dried over magnesium sulfate. The solvent was distilled off to give pale brown powder of 2,2,2-trichloro-ethyl 2-methyl-7-~2-(1,3,4-thiadiazol-2-ylthio)acetamido] -3-cephem-4-carboxylate (4.5 g), mp 130 to 140C (dec.).

Example 10 ~-Tert ~butoxycarbonyl-2-(2-thienyl )~3 -~lycine i (930 mg) was added to dried dichloromethane (15 ml) and dissolved, by adding triethylamine (360 mg). ~o ~ solution was dropwise added a solution of pivaloyl chloride i (400 mg) in dichloromethane (1 ml) under stirring and ! cooling at -10 to -15C, and the mixture was stirred for 2 hours at the same temperature to give the solution of mixed anhydride. 2,2,2-~richloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (1.15 g) was suspended , in dichloromethane (10 ml) and dissolved by stirring for .~ several minutes after addition of 2,6-lutidine (0.64 ~
under stirring and ice~cooling. ~his solution cooled at -10C was at once added to the above-mentioned mixed anhydr~ide solution, and the mixture was stirred for 1.5 hours at -15C and for 0.5 hour at room temperature.
After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue ~as extracted by adding ethyl acetate and 2 to 3Co sul~uric acid.
'rhe ethyl acetate layer was in turn washed with water t .. . . .

.

a saturated sodium bicarbonate a~ueous solution and water ~nd dried o~er magnesium sulfa'e. Af-ter the solvent was removed under reduced pressure, the residue was pulverized b-~ adding a mixture of ether and petroleum ether, collected by filtratiorl and dried to give 2,2,2-trichloroeth~J1 2-methy~7-(N-tert~-butoxycarbonyl-2-thienylglycyl)amino-3-cephem-4-carboxylate (1.77 g).
Infrared Absorption Spectrum (Nujol) 3320, 1790, 1740, 1710, 1690, 16~0, 1632 cm~l -:
xample 11 A solution of pivaloyl chloride (2.0 g) in dichloro-methane (5 ml) was dropwise added under stirring and I cooling at -15C to a solution of (5-methyl-1,3,4-thia-diazol-2-yloxy)acetic acid (3.13 g) and triethylamine (1.80 g) in dried dichloromethane (50 ml), and the mixture was stirred for 2 hours at the same temperature to give the mixed anhydride solution. While, 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride -(5.75~g) was suspended in dichloromethane (40 ml) and dissolved by stirring for 10-20 minutes after addition of 2,6-lutidine (2.0 g) under ice-cooling and then cooling ¦ at -15C, and then this solution was at once added to the ¦ above-mentioned mixed anhydride solution. ~he mixture was ~
~ 25 stirred for 1.5 hours at the same temperature and for ;;~;
-~ 30 minutes at room temperature. A~ter the reaction, the ~ reaction mixture was in turn washed with 5% sulfuric 3 acid, w~ter, a saturated sodium bicarbonate aqueous solution and water and dried over magnesium sulfate.
~he solvent was removed under reduced pressure to ~ive - 84 - ~ 35 ~: : ' '' '. ', ' ' ' ' ~ '' : ' .' ~: . . ' ' ~ , .

:~)43773 colorless ~morph~us 2,2,2-trichloroethyl 2-methyl-7-[2-(5-methyl-1~3,4-thiadiazol-2-yloxy)acetamido~-3-cephem-4-carboxylate (7.23 g).
Infrared Absorption Spectrum (Chloroform) ` 5 3420, 17S0, 1740, 1700, 1635 cm~

` ~xample 12 ~hionyl chloride (5 ml) was added to L3-(2-chloro-phenyl)-5-methylisoxazol-4-yl~carboxylic acid (855 mg), and the mixture was refluxed for 2 hours, and then thionyl chloride was removed under reduced pressure.
~hus obtained [3-(2-chlorophenyl)-5-methylisoxazol-4-yl]-carbonyl chloride was dissolved in dried dichloromethane (3 to 4 ml). 2,2,2-~richloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (1.15 ~) was suspended in dichloromethane (10 ml) and disssolved by addlng ~ triethylamine (250 mg) and 2,6-lutidine (0.64 g), after j which the solution was ice-cooled. To this solution was ¦ dropwise added the above-mentioned acid chloride solution, ¦ 20 and the mixture was stirred for 1 hour under ice-cooling.
j After the reaction, the reaction mlxture was concentrated ¦ under reduced pressure, and the residue was extracted by ~ -adding ethylacetate and 2~ sulfuric acid. ~he extract was in turn washed with water, a saturated sodium bicarbo-nate aqueous solution and water, and dried over magnesium ~ sulfate. ~he sol~ent was distilled off under reduced i pressure to give amorphous 2,2,2-trichloroethyl 2-methyl- ~
j 7-~3-(2-chlorophenyl)-5-methylisoxazol-4~yl~carboxamido- ~ `
3-cephem-4-car~ox~late (1.82 g).

~ 85 - E 36 . ~

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

~0~3773 C '" Infr~red Abso~tion ~pectrum (Mujol) 3340 ~ 1790, 171-0, 1675 cm~

Example 13 Methylthioacetic acid (0.42 g) r~as added to thionyl chloride (5 ml), and the mixture was allowed to stand for 40 minutes at room temperature and for 5 minutes at 40 to 50C~ after ~rhich thionyl chloride was removed under reduced pressure. To the residue was added benzene (5 ml), 10 and then removed under reduced pressure to Zgive methyl- ;
thioacetyl chloridc (0.47 g). 292,2-~richloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride I (0.764 g) w-~s suspended in dichloromethane (~ ml), and . .
Z then dissolved by adding a solution of triethylamine (0.18 g) in dichloromethane (2 ml) and a solution of ¦ dimethylaniline (0.266 g) in dichloromathane (2 ml) at ¦ ~30C. ~o this solution was added at -30C the above ¦ obtained methylthioacetyl chloride (0038 g), and the ! mixture was stirred for 30 minutes at -the same temperature, ~ 20 after which the reaction temperature was gradually ¦ elevated to -10C over 1 hour under stirring. After the ;~
reaction, the reaction mixture was in turn washed with 5~o hydrochloric acid, water, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous . : .
! 25 solution, and dried over magnesium sulfate. After the ¦ solvent ~rras distilled off, the crystalline residue (0.81 g) ;
was recrystallized from ethanol to give colorless needless ! of 2,2,2-trichloroetl1yl 2-methyl-7- r ( 2-methylthio)-Z' acetamido]-3-cephem-4-carboxylate (0.62 g) 9 mp 151 to ' 30 153C.
1 1 ~$ t~ya d~ ~?a vk - 86 - ~ 37 ,1 :
.: . ~ , - , --. -- , . .. - . . : . .

~,xa!rlpl ~
To a suspension of 2,2,2-trichloroethyl 2-~ethyl-7-; amino-3-cephe~-4-carbo~;late hydrochloride (0.764 g) in dried dichloromethane (8 ml) ~lere added at -30C a solution of triethylamine (0.18 g) in dichlorometh~ne (2 ml) and then a solution of dimeth~Jlaniline (0.27 g) in dichloro-methane (2 ml). While, allylthioacetic acid (0.528 g) . ~;
was added to thionyl chloride (5 ml) and the mixture was allowed to stand for 20 minutes at room temperature and 5 minutes at 50C, after which thionyl chloride was :.
removed under reduced pressure 9 and the residue ~.vas added : a small amount of benzene, and then removed under reduc~d pressure to give allythioacetyl chloride (0.527 g).
A solution of thus obtained allylthioacet~-l chloride (0.452 g) in dichloromethane (3 ml) was dropwise added at ~30C over 5 minutes to the above-mentioned solution of ~ 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-¦ carboxylate, a~d the mixture was stirrad for 1 hour at -20C. After the reaction, the reaction mixture was in turn ~ -washed twice with 5,o hydrochloric acid, once with water, ! twice with a saturated sodium bicarbonate aqueous solution I and onco with a saturated sodium chloride aqueous solution, ¦ and dried over magnesium sulfate. After the solvent ¦~ was distilled off, the residue (0.82.g) was recrystallized .
from a mixture of ether and isopropy]. ether to give 2,2,2-trichloroethyl 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carbox~ylate (0.71 g), mp 96C.

. - 87 - ~ 3~ :

... . ' ' - ~ - ` . :
.: . ~. ; ..

- ~
.

Ex~
A solution of dicyclohexylcarbocliimide (0.99 g) in tetrnhydrofuran (5 ml) was dropwise added under stirring and cooling at -20C -to a solution of (2-formyloxy)phenyl-acetic acid (0.864 g) in tetrahydroLuran (15 ml), and the mixture was stirred for 30 minutes at the same temperature. -~o the solution was dropwise added at -20C a solution which was prepared by adding 2,2,2-trichloroethyl 2-me~hyl-7-amino-3-cephem-4-carboxylate hydrochloride (1.53 g) and I0 triethylamine (0.4 g) at -20C to dichloromethane (23 ml). ~ -~he reaction temperature of the mixture was Oradually elevated to 0C over 1.5 hours under stirring. ~he reactlon mixture was stirred for additional 1.5 hours at 0C, followed by filtration of the precipitates, and the i 15 filtrate was concentrated to dryness under reduced pressure. A small amount of ethyl acetate was added to the residue, followed by filtration o:E the insoluble material, and the filtrate was in turn washed with 5So hydrochloric acid, water, a saturated sodium bicarbonate aqueous ;~ 20 solution and a saturated sodium chloride aqueous solution, I and dried over magnesium sulfate. After the solution was filtered by passing through silicagel (about 2 g), the solvent was distilled off, after which the residue was pulverized by adding ether, collected by filtration, and dried to give 2,2,2-trichloroethyl 2-methyl-7-(2-formyloxy~
2-phenyl-acetamido)-3-cephem-4-carboxylate (1.72 g), mp 142 to 147C. ~
, :

~ 30 .
.
- 88 - E 39 ~ ~
.. ~ e~ , ',~

~x~ p1~ 16 ~ rie~hylamil~e (l.C~2 g) ~was addcd -to a suspension which was ~repar~d b,~, suspending 2,2,2-trichloro~thyl 2-methyl-7-amino-3-cephQm-4-carboxylate hydrochloride (1.92 g) in tetra~ydrofuran (20 ml) under cooling at -10C. And then the mixture was vigorously stirred.
To the solution, was dropwise added over about 10 minutes a solution of l-cyclopropylethyl chloroformate (5.5m mole) in tetrabydrofuran (20 ml), and the mixture was stirred for 1.5 hours at the same temperature. After the reaction was completed, t'.e reaction mixture was filtered, and the filtrate was concentrated below room temperature. ~he residue was dissolved in ethyl acetate (30 ml), and this solution was in turn washed with 5~,J hydrochloric acid, a sodium bicarbonate aqueous solution and a saturated sodium i chloride aqueous solution, and dried over magnesium ' sulfate, after which the sol~ent ~vas distilled offO The ¦ residue was pulverized by adding a small amount of iso-~ propyl ether.
¦ 20 The powder was coll~cted by filtration and dried to give ¦ 2,2j2-trichloroethyl 2-methyl-7-(1-cyclopropylethoxy)-I carboxarr~ido-3-cephem-4-carboxylate (1.4 g), mp 181 to 183C.

Example 17 A mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid (0 214 g), bis(trimethylsilyl)acetamide (0.40 g) and dichloromethane (4 ml) was homogenized by stirring for ¦ 30 to 40 minute~s at room temperature, ~nd to this solution was dropwise added over about 15 minutes under stirring - 89 - ~ 40 i ~ .
, . .

1377~

and cooling a-t -15 to -20C a solution of triethylamine salt ~-~
of ~ d anhydrid~ of 2-sulfo-2-phenylacetic acid with ethoxycarbonic acid (0.389 g) in dried dichloromethane (4 ml), after which the mixture was stirred for 2 hours at -10 to -15C. After the reaction, dichloromethane was -removed. To the residue was added ethyl acetate, and the mixture was allowed to stand~ after which the precipitate was extracted with water. ~he extract was washed with ethyl acetate and lyophilized. ~he residual powder was dissolved in a small quantity of water, and the solution was adjusted to pH 6 to 7 by adding sodium bicarbonate.
After water was distilled off, the residue was washed with ethanol and pulverized to give disodium salt of 2-methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylic acid (Ool o) mp 265C (dec.). This compound was treated accord-¦ ing to the conventional manner to give 2-methyl-7-(2-sulfo-1 2-phenylacetamido)-3-cephem-4-carboxylic acid, 115C
¦ (vesication), 200 to 220C (dec.).

¦~ 20 Example 18 A suspension of 2,2,2-trichloroethyl-2-methyl-7-amino-3-cephem-4-carboxylate hydrochlorid~ (6.9 g) in dried dichloromethane (70 ml) was homogenized by adding triethylamine (1.48 g) and N,N-di~ethylaniline (0.44 g) ~-under stirrin~ and ice-cooling and by stirring for 30 : :~
minutes at room temperature. A solution of triethylamine salt of-mixed anhydride of 2-sulfo-2-phenylacetic acid with ethcxycàrbonic acid (8.5 g) in dried dichloromethane (~0 ml) was dropwise added over about 30 minutes under stirring and cooling at -20 to -25C to the above-mentioned ,~ ' _ 90 _ :E 41 : ~
~ ~ .

. . . . . . . . .
' . ': ' ` ' . .
. .

~'' 3 7 ~
.solut;ion, and the ~ixture was stirrcd ,or 1.5 hours at -10 to --15C and for 1 hour at rovm tcmpcrature. After the reaction, dichlorom~than~ ~tas rc~lovcd at lo~v temperature, and the rc-sidu~ as dissolved in ethyl acetate, after which the solution was ~qashed with cooled 5,., hydl~ochloric acid and three times ~.vith water, and then dried. Thc solvent was distilled off at lo~,v ter.1perat-lIe to ~ivc 2,2,2-trichloro~tllyl 2-methyl-7-(2-sulfo-2-phenylacetamido)-3--aepher~-4-carboxylate (11.5 g),amorphous.
Example 19 A mixturc of dimethylform~lide (0.805 g) and thionyl chl~ride (1.55 g) was warmed for 30 minutes at 50C with ~nough shaking, and then excess thionyl chloridc was removad under reduced pressure. ~he residual cr~stals were washed twice Wit}l a small amount of absolute ether, and then ether ~ras removed under r~duced pressure. The residual crystals were dissolved in dried dichloromethane (40 ml), and to the SOlUtiOIl ~Jas added at 0C thienylglycolic acid tO-95 g). The mixture was cooled at -50C, and to the mixture ~as dropwise added over 30 minutes a solution of triathylamine (1.11 ~) in dri~d dichloromethane (10 ml), after which the mixtur~ was ~tirred for 30 r;linutes at the same temperature. ~o the solution ~raS dropwise added over 30 r~linutes at -50C a solution which was prepared by -~
stirring a mixture of 2-metllyl-7-amino-3-cepher.~-4-carboxylic acid (1.075 ~), bi.s(tri~thylsilyl)ac~tamide (2.04 g) and ~ -dried dichloro~ethane (25 ml) for 2 hours at room ~emperature. Tlle mixture was stirred for 2 hours at ~he same temperature and for 1 hour at -20 to -30C.

,:

; . .
; ~ . . . .
- ~
- , . . . ~ .
. ?
.
.

~3773 After thc reaction, water (10 ml) lqas addecl at 0C to the reaction mixtu-c, and then dichloromethane was removed under reduccd pres~ure. o the residue was added water (40 ml), after which the solution was extractcd twice Witil ethyl acetate (5~ ml). ~he e~{tract was extracted three times with a sodiw~ bicarbonate aqueous solution (50 ml), and the aquecus extract was washed with ethyl acetate (50 ml), adausted to pH2 with 5,0 sulfuric acid and extrac~ed three times with ethyl acetate ~30 ml), after which the extract was washed with water and dried. After the solvent w~ s distillcd off, the residue was pulverized by adding isopropyl ether to give pale yellow powder of 2-methyl--7-L2-hydroxy-2-(2^thienyl)-acetamido~-3-cephem-4-carboxylic acld (1.32 g), mp 91 to 96C (dec.).
~he following compounds were obatined in the similar maImers as described in the above mentioned :3xamples.

1) 2,2,2-~richloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate~ mp 175 to 178C~
2) 2,2,2-~richloroethyl ~-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylate, mp 136 to 137C. -~.
3) 2,2,2-~richloroethyl 2-methyl-7-L2-(3-chlorophenyl)-acetamido3-3-cephem-4-carboxylate, mp 144 to 144.5C ;~
td~c.).
.

4) 2,2,2-Trichloroath~l 2-methyl-7-L2-(1,2,5-thiadiazol-~yl)acetamido3 -3-caphem-4-carboxylate, mp 180 to 185C (dec.).

- 92 - ~ 43 ~ , .

5) Methyl 2-methyL-7-(2-phenoxyacetamido)-3-cephem-4-cal~boxylate, oil.

6) 2,2,2-Trichloroethyl 2-methyl-7-(2-phenoxyacetamido)-3-cepham-4-carboxylate, mp 118 to 120Co 7) 2,2,2-rrichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate-1-oxide, mp 173 to 175C.

10 8) 2-Methyl-7-~N-(l-cyclopropylethoxy)-carbonylphenyl-glycyl~amino-3-cephem-4-carboxylic acid, mp 168 to 169Co ` 9) 2-Methyl-7-~2-(1~-tetrazol-1-yl)acetamido~-3-cephem- ~;;;
4-carboxylic acid, mp 202 to 203C (dec.).
` ~'.' .
10) 2-Methyl-7-C2-(2-thienyl)acetamido~ -3-cephem-4-carboxylic acid, mp 175C (dec.).

¦ 20 11) 2-Methyl-7-bs~zyloxycarboxamido-3-cephem-4-`carboIic acid, mp 167 to 169C (decO).

12) 2-Methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid, mp 168 to 171C (dec.).
::

¦~ 13) 2-Methyl-7-L2-(3-chlorophenyl)acetoamido~- ~
l 3-cephem-4-carboxylic acid, mp 173 to 174C (dec.).
:1 ~
14) 2-Methyl-7-[3-~N-tert.-butoxycarbonylamino)-3-~2-thienyl)propionamido~-3-cephem-4-carboxylic acid, - 93 - ~ 44 .

10~ 73 mp 167 to 170C (dec.)0 15) 2-Methyl-7-(2-c-yanoacetamido)-3-cephem-4-carboxylic acid7 mp 162 to 166C.
16) 2-Methyl-7 (3-phenylureido)-3-cephem-4-carboxylic ~-acid, mp 148 to 151C

17) 2-Methyl-7-L2-(1,3,4-thiadiazol-2-ylthio)acetamido~
3-cephem-4-carboxylic acid~ mp 197 to 199Co ~ ;~

18) 2-Methyl-7-CN-tert.butoxycarbonyl-2-thienylglycyl~
amino-3-cephem-4-carboxylic acid~ powderO

19) 2-Methyl-7-~2-(5-methyl-1,3,4-thiadiazol-2-yloxy)- ~ ~:
acetamido~-3-cephem-4-carboxylic acid, mp 113 to 116C. `

20) 2-Methyl-7-C3-(2-chlorophenyl)-5-methylisoxazol-4-yl~
carboxamido-3-cephem-4-carboxylic acid, mp 202 to 203aO ;~

21) 2-Methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic -~
acid, mp 181 to 183C (dec.).
22) 2-Methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid, mp 121 to 123C.
:
23) 2-Methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid 7 powder.

:IV43~773 24) 2-Methyl-7-(1-cyclopropylethoxy)carboxamido-3-cephem-4-carboxylic acid, mp 158.5 to 160C
(decO ) O

25) 2-Methyl-7-(2-azido-2-phenylacetamido)-3-cephem-4-carboxylic acid~ mp 65 to 68C.

26) 2,2,2-trichloroethyl 2-methyl-7-LN-tertO-butoxy--carbonyl-2--(4-hydroxyphenyl)-D-glycyl~amino-3-cephem-4-carboxylate, mp 130 to 135C (dec.) 27) 2-Methyl-7-[2-(3-pyridyl)acetamido~-3-cephem-4-carboxylic acid~ mp 147 to 149C (dec.).

28) 2-Methyl 7-CN-tert.-butoxycarbonyl-2-(2~5-dihydro-phenyl)glycyl~amino-3-cephem-4-carboxylic acid, mp 126 to 131C (decO) 29) 2-Methyl-7-LN-tert.-butoxycarbonyl-2-(4-hydroxy-phenyl)-D-glycyl~amino-3-cephem-4-carboxylic acid, powderO ~ `

30) 2-Methyl-7- N-tertO-butoxycarbonyl-2-(4-methylthio-phenyl)glycyl amino-3-cephem-4-carboxylic acid, mp 110 to 120C.

31) 2-Methyl-7-CN-tert.butoxycarbonyl-2-(4-methoxy-phenyl)glycyl~amino-3-cephem-4-carboxylic acid, mp 81 to 86C (decO) :: :: :: .

~x~

32) 2,2,2-~richloroethyl 2-methyl-7-[N-tert.-butoxycarbonyl-2-(4-methylthiophenyl)-glycyl amin ~ ;
3-cephem-4-carboxylate, mp 115 to 120~o 33) 2,2,2-~richloroethyl 2-methyl-7-~N-tertO-butoxy-carbonyl-2-(4-methoxyphenyl)-glycyl~amino-3-cephem-4-carboxylate, mp 92 to 95~ (dec.).

34) 2,2,2-~richloroethyl 2-methyl-7-LN-tertO-butoxy- ~ -~
carbonyl-2-(2,5-dihydrophenyl)-glycyl~amino-3-cephem-4-carboxylate, mp 104 to 110C (dec.).

35) 2,2,2-~richloroethyl 2-methyl-7-CN-(l-cyclopropyl-ethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)-glycyl~amino-3-cephem-4-carboxylate, mp 118 to ~
126~ (dec O)~ ` ' `
. , .
36) 292,2-~richloroethyl 2-methyl-7-CN-tert.-butoxy-carbonyl-2-(4-tert.-butoxycarbonylmethoxyphenyl)-glycyl]amino-3-cephem-4-carboxylate, powder.

37) 2,2,2-~richloroethyl 2-methyl-7-rN-(1l394-thiadiazol- `
2-yl)thiomethylcarbonyl-2-phenylglycyl]amino-3-cephem-4-carboxylate, mp 148 to 150C (dec.). ~-38) 2,292-~richloroethyl 2-methyl-7-LN-tert.-butoxy-carbonyl-2-(4-me-thylsulfinylphenylglycyl3amino-3- ~`
cephem-4-carboxylate, mp 115 to 125C.

- 96 - ~ 47 s ,, , ; : . ~ . .
' ' '~ ' ' ' . . : ' ' : : .-. ' ' ' .; :
' .: ~ `" ; " ' ', ,. ', ~ ' ' .; . , . :
. . ... . , . - ~

-~0~3773 39) 2-Methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid, mp 217 to 219C. ~ -40) 2,2,2-r~richloroethyl 2-methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylate, mp 100 to 115C (dec.) .
41) 2,2,2-~richloroethyl 2-methyl-7-L2-(5-indanyl)-; oxycarbonyl-2-phenylacetamido~-3-cephem-4-carboxylate, mp 165 to 170C.

42) 2-Methyl-7-[N-(1,3,4-thiadiazol-2-yl)thiomethyl-carbonyl-2-phenylglyeyl~amino-3-ce~hem-4-earboxylic acid, mp 143 to 145C (dec.).

43) 2-Methyl-7-CN-tert.-butoxycarbonyl-2-(4-tert~
butoxycarbonylmethoxyphenyl)glycyl~amino-3-cephem-4-carboxylic acid, powder.

44) 2-Methyl-7-CN-(l-cyclopropylethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glyeyl~amino-3-cephem-4-carboxylic aeid, mp 195 to 197Co 45) 2-Methyl-7-[2-(1,2,5-thiadiazol-3-yl)-acetamido~-3-cephem-4-carboxylic acid, mp 188 to 190 (decO).
.;
46) 2-Methyl-7-CN-tertO-butoxycarbonyl-2-(3-methane-sulfonamidophenyl)glycyl~amino-3-eephem-4-earboxylie aeid, oil. ~ -~;

- 97 - E 48 ~
. ;~ . ' .
. . . . . . .. . . .

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

~ 3i77~

47) 2-Methyl-7-[N-~ert.-butoxycarbonyl-2-(4-methyl-sulfinylphenyl)glycyl~amino-3-cephem-4-carboxylic ~
acid, mp 110 to 120C. ~ -48) 2-Methyl-7-L2~(5-indenyl)oxycarbonyl-2-phenylacetamido~-3-cephem-4-carboxylic acid, 90 to 95C (softening), 150 to 160C (decO)O
~ ~ .

49) 292,2-Trichloroethyl 2-methyl-7-~2-(5,6-dihydro-2H-pyran-3-yl)acetamido~-3-cephem-4-carboxylate, mp 149.5 to 150 5C. `~

50) 2-Methyl-7-~2-(5,6-dihydro-2II-pyran-3-yl)-acetamido~-3-cephem-4-carboxylic acid, mp 17?o5 to 173.5C
(decO) 51) 2,2,2-Trichloroe-thyl 2-methyl-7-~N-tert.-butoxy-carbonyl-2-(3-methanesulfonamidophenyl)glycyl~amino-3-cephem-4-carboxylate, amorphous 52) 2-Methyl-7-(4-methoxyphenyl)glyoxylamido-3-cephem-4-carboxylic acid, mp 188 to 189~ (dec, ;'

53) 2-Methyl-7-(N-tertO-butoxycarbonylphenyl-D-glycyl)amino-3-cephem-4-carboxylic acid, mp 125 to 127~ (dec.). ~;

54) 2 Methyl-7-[~-C2-(2~nitrophenoxy)acetyl~phenylglycyl~
amino-3-cephem-4-carboxylic acid, mp 135 to 136~
(dec a ) ''~~ ' '~ ' ..
': . ' '.,'~ ' ' ' , ' '' ' . ' ~317~7~

55) 2,2,2-Trichloroethyl 2-methyl-7 (N-tert.-butoxy-carbonylphenyl-D-glycyl)amino-3-cephem~4-carboxylate, 115 to 116~ (dec.).
' ::

'~

15 .

' ,`: `: ,~

'; ~; ' : . :

~ 99 ~ E 50 ' ' ', : . ', . , .. ,, / . ~ , ' ! ' :. .': ' .

~4~ 7~73 .~ .

R~ t~3 Rlb' ~ -R3 Exam~le 1 Pyridine (0.296 g) and phosphorous pentachloride (0.616 g) were added in turn under stirring and cooling at -15C to a solution of 2,2,2-trichloroethyl 2-methyl ~`
7-(2-phenylacetamido)-3-cephem-4-carboxylate (1.12 g), mp 175 to 178C7 in dried dichloromethane (20 ml), and the mixture was stirred for 20 minutes at the same temperature and further for 2 hours at room temperature. ~o the mixture was added absolute methanol (5 ml) under cooling ;~
at -15C, and then the mixture was stirred for 1 hour at the same temperature. ~o the mixture were dropwise added ;~
in turn dimethylaniline (2.2 g) and a solution of 2-thienylacetyl chloride (0.42 g) in dried dichloromethane (5 ml) at the same temperature, and then the mixture was stirred for 2.5 hours at the same temperature. After the . ~ .
reaction, the reaction mixture was in turn washed with ;~
5% hydrochloric acid~ water, 5% sodlum bicarbonate aqueous solution and water, and then dried. ~fter the ;~
solution was concentrated, the obtained oily substance ~`
was crystallized by adding ether to give 27272-trichloro-ethyl 2-methyl-7-~2-(2-thienyl)acetamido~-3-cephem-4 carboxylate (750 ~g), mp 161 to 162C (dec.)0 ~he followinr, compounds were obtained by usin~ a similar manner as that of the above Example ;. .

- 100 - ~ E 51 ~
. ~ .

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

:
i~O437~3 1) 2~2~2-Trichloroethyl 2-methyl-7-C2-(3-chlorophenyl)~ , acetamido~-3 cephem-4-carboxylate, mp 144 to 144.5C
(dec.) 2) 2,2,2-~richloroethyl 2-me-thyl-7-~2-(1,2~5-thiadiazol-3-yl)acetamido3-3-eephem-4-earboxylate~ mp 180 to 185C (dec.)~

3) Methyl 2-methyl-7-(2-phenoxyaeetamido)-3-eephem-4-earboxylate) oil.

4) 2,2~2-~riehloroethyl 2-methyl-7-(2-phenoxyaeetamido)-3-eephem-4-earboxylate, mp 118 to 120C.

15 5) 2-Methyl-7-[N-(1-eyelopropylethoxy)earbonylphenyl-~lyeyl~amino-3-eephem-4-earboxylie aeid, mp 168 to `
169Co ~.`;

6) 2-Methyl-7-~2-(lH-tetrazol-l-yl)aeetamido~-3-cephem- ~-4-carboxylic acid~ mp 202 to 203C (dec O ) . ' '." `': ' 7) 2-Methyl-7-L2-(2-thienyl)acetamido]-3-eephem-4- `~
earboxylie aeid, mp 175C (deeO).

8) 2-Methyl-7-(2-phenylthioaeetamido)-3-eephem-4 ,~ CarbOXyliC aeid, mp I68 to 171C (deeO). ~ ~
,, .' - .
9) 2-Methyl-7-~2-(3-ehlorophenyl)aeetamido~-3-eephem-4- ;~
earboxylie aeid, mp 173 to 174C (dec.).

.,, ','.'' ` ~ .
- 101 - ~ 52 ``~ ~

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

~37~3 10) 2-M~ethy~ 7-L3-(N-tertO-butoxycarbonylamino)-3-(2-thienyl)propional~ido~-3-cephem-4-carboxylie aeid, ~ :~
~p 167 to 170C (dec~)~
:
11) 2-Me~hyl-7-(2-cyarloacetamido)-3-cephem-4-carboxylic acid~ mp 162 to 166C.

12) 2-Methyl-7-~2-(1,3~4-thiadiazol-2-ylthio)acetamido~
3-eephem-4-earboxylie aeid, mp 197 to 199C.

13) 2-Methyl-7~N-tertO-butoxyearbonyl-2-thienylglycyl~-amino-3-cephem~4-carboxylic acid, powderO :~

14) 2-Methyl-7-C2-(5-methyl-1,3,4-thiadiazol-2-yloxy) aeetamido~-3-eephem-4-earboxylie aeid, mp 113 to 116C - `

15) 2-Methyl-7-C3-(2-ehlorophenyl)-5-methylisoxazol-4-yl~earboxamido-3-eephem-4-earboxylie aeid, mp 202 -to 203C.

16) 2-Methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylie aeid, mp 181 to 183C (dee.). ~ ;`.-17) 2-Methyl-7-(2-allylthioaeetamido)-3-eephem-4-earboxylie .
aeid, mp 121 to 123C. ; :

18) 2-Methyl-7-(2-azido-2-phenylacetamido)-3-cephem-4-earboxylie aeid, mp 65 to 68C. - ~
~ : .

.~lV~.~3~77~

19) 2,2,2 tric~l:Lo:roe-thyl 2-methyl-7-LN-ter-t.-butoxy-carbon~Jl-2-(4--hydroxyphenyl)-D-glycyl.~amino-3-cephem-4-carboxyla-te, mp 130 to 135C (decO)O
.

20) 2-Methyl-7-[2-(3-pyridyl)acetamido~-3-cephem-4-carboxylic p~cid, mp 147 to 149C (decO)O

21) 2-Methyl-7-[N-tertO-butoxycarbonyl-2-(2,5-dihydro-phenyl)glycyl]amino-3-cephem-4-carboxylic acid, mp 126 to 131C (decO)O
~: .
22) 2-Methyl-7-[N-tertO-butoxycarbonyl-2-(4-hydroxy-phenyl)-D-glycyl~amino-3-cephem-4-carboxylic acid, powderO ~'' ~, 23) 2-Methyl-7-CN-tert.-butoxycarbonyl-2-(4-methylthio~
;: phenyl)glycyl~amino-3-cephem-4-carboxylic acid9 ;~
mp 110 to 120Co ., ~
, 24) 2-1~ethyl-7-CN-tertO-butoxycarbonyl-2-(4-methox~henyl)- .
glycyl~amino-3-cephem-4-carboxylic acid, ::: ;, : . .
~ : : mp 81 to 86C (decO) .~
... . .

25) 2,2,2-~richloroethyl 2-methyl-7-~N-ter-tO-butoxy- ;`
carbonyl-2-(4-methylthiophenyl)glycyl~amino-3-cephem- ..
4-carboxylate9 mp 115 to 120C~

. j,. . . .
26) 2,2,2-Trichloroethyl 2-methyl-7-CN-tertO-butoxycarbonyl- `~ :
2-(4-methoxyphenyl)glycyl~amino-3-cephem-4-carboxylate, mp 92 to 95C (decO) `~

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

37'7;~

2?) 2,2,2-Trichloroeth;yl 2-rne-thyl-7- LN -tert.-butoxy~
car~nyl-2-(~,5-dihydrophen~l)glycyl~amino ~-cephem-4-carboxylate, mp 104 to 111C (dec.)~

28) 2,2,2-Trichloroethyl 2-methyl-7-[N-(l-cyclopropyl-ethoxy)carbonyl-2-(5,6-dihydro-2~-pyran-3-yl)glycyl~-amino-3-cephem-4-carboxylate, mp 118 to 126C
(dec.).

29) 2,2,2-Trichloroethyl 2-methyl-7-~N-tert.-butoxy-carbonyl-2-(4-tert.-butoxycarbonylmethoxyphenyl)- ~-glycyl~amino-3-cephem-4-carboxylate, powder.

30) 2,2,2-Trichloroe-thyl 2-methyl-7-~N-(1,3,4-thiadiazol-2-yl)thiomethylcarbonyl-2-phenylglycyl~amino-3-cephem-4-carboxylate, mp 148 to 150C (dec.).

31) 2,2,2-Trichloroethyl 2-methyl-7-~N-tert.-butoxy-carbonyl-2-(4-methylsulfinylphenyl)Olycyl~amino-3-cephem-4-carboxylate, mp 115 to 125C.
;
¦ 32) 2-Methyl-7-(2-isonicotino~Tloxy-2-phenylacetamido)-3-¦ cephem-4-carboxylic acidg mp 217 to 219C.

33) 2,2,2-Trichloroethyl 2-methyl-7-(2-isonicotinoyloxy-~! 2-phenylacetamido)-3-cephem-4-carboxylate, i mp lC0 to 115C (dec.).
':
34) 2,2,2-Trichloroethyl 2-methyl-7-[2-(5-indanyl)oxty-car~onyl-2-phenylacetamido]-3-cephem-4-carboxylate, ?
, ; - 104 - E 55 l ~ .
, .' . . .
"' ~ , ' ' "

~ ~13 7 mp 165 t,o 170~C.

35) 2-Meti1~Jl-?~ (1,3,4-thiadiazol-2-~l)thiom~th~l-carbonyl-2-phenylglycylJamino-3-cephem-4-carboxylic acid, mp 143 to 145C (dec.j.

36) 2-Methyl-7-CN-tert.-butoxycarbonyl-2-(4-tert.-butoxycarbonylmethoxyphenyl)glycyl~amino-3-cephem-; -4-carboxylic acid, powder.
' : ~' 37) 2-~Iethyl-7-[N-(l-cyclopropylethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl~amino-3--cephem-4- ~;
carbonylic acid1 mp 195 to 197C.
- -38) 2-~Iethyl-7-~2-(1,2,5-thiadiazol-3-yl)acetamido~-3-' cephem-4-carboxylic acid, mp 188 to 190C (dec.).

¦ ` 39) 2-Methyl-7-(N-tert~-butoxycarbonyl-2-(3-methanesulfon-~! amidophenyl)glycyl amino-3-cephem-4-carboxylic acid, :: . ... ~ ,. .
oil.

40) 2-Methyl-7-CN-tert.-butoxycarbonyl-2-(4 methyl-sulfinylphenyl)glycyl~amino-3-cephem-4-carboxylic acid, mp 110 to 120C.
~ -~ . . -~ ` 41) 2-~Iethyl-7-L2-(5-indanyl)oxycarbonyl-2-phenyl-3 - acetamido~-3-cephem-4-carboxylic acid, 90 to 95C ;~
, (softening), 150 to 160C (dec.).

, .
- lOS _ E 56 ~;~ - - . :

37rt~3 42) 2~2~2-~'rlchloroe-thyl 2-methyl--7-LN~ cyclopropyl-ethoxy)carbonylphenylgrlycyl~-amino-3-cephem-4-carboxylate~ mp 165 to 167.5C~

43) 2,2,2-Trichloroethyl 2-methyl-7-L2-(lH-tetrazol-1-yl)-acetamido~-3-cephem-4-carboxylate, mp 168 to 170Co 44 ) 2,2,2-Trichloroe-thyl 2-methyl-7-(2-phenylthioace-tamido)-3-cephem-4-carboxylate, mp 140 to 142C.
45) 2,2,2-Trichloroethyl 2-methyl-7-C3-(N-tert.-butoxy-carbonyla~ino)-3-(2-thienyl)-propionamido] 3-cephem- ;
4~carboxylate, mp 188 to 192C.

4~) 2,2,2-~richloroethyl 2-methyl-7-(2-cyanoacetamido)- ~ -.
3-cephem-4-carboxylate, mp 160 to 165C (dec.).

47) 2,2,2-Trichloroethyl 2-methyl-7-~2-(1,3~4-thiadiazol-2-ylthio)acetamido~3-cephem-4-carboxylate, mp 130 to 140C ~dec.).
.
48) 2,2,2-Trichloroethyl 2-methyl-7-(~-tert.butoxycarbonyl- ~
2-thienyl$1ycyl)amlno-3-cephem-4-carboxylate, powd~r. -: - .
49) 2,2,2-Trichloroethyl 2-methyl-7-~2-(5-methyl-1,3,4- -thiadiazol-2-yloxy)acetamido~-3-cephem-4-carboxylate, colorless crystalsO

50) 2,2,2-~rich]oroethyl 2-methyl-7-~3-(2-chlorophenyl)-5-methylisoxazol-4-yl~carboxamido-3-cephem-4--: . . - , ,- ~ . ., . ,;,,:
,......... . . . .

r~

37~73 carboxylate, amorphous.

51) 2,2,2-Trichloroethyl 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylate, mp 151 to 153C.
-~
52) 2,2,2-Trichloroethyl 2-methyl-7 (2-allylthioacetamido)-3-cephem-4-carboxylate, mp 96C.
:
53) 2-Methyl-7--(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylic acid9 115C (vesication), 200 to 220C

(dec.).

54) 2,2,2-Trichloroethyl 2 methyl-7-(2-sulfo-2-phenyl-acetamido)-3-cephem-4-carboxylate, amorphous. ;~
55) 2-Methyl-7-L2-hydroxy-2-(2-thienyl)acetamido~3- `
cephem-4-carboxylic acid, mp 91 to 96C (dec.).
~ .' '

56) 2,2,2-Trichloroethyl 2-methyl-7-C2-(5,6-dihydro-2 pyran-3-yl)acetamido~-3-cephem-4-carboxylate, mp 149.5 to 150.5C. ; ~`~

57) 2-Methyl-7-~2-(5,6-dihydro-2H-pyran-3-yl)acetamido~_ ~
3-cephem-4-carboxylic acid~ mp 172.5 to 173.5C ~-(dec.).

~.;:

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

7~3 Rlc r ~ - R3 ld ~ / X ~-R3 N ~ -~3 N ~
R2 R2 -- . .- . .
Example A solution of 2-methyl-7-~N-(l-cyclopropylethoxy)-carbonyl-2-~henylglycyl]amino-3-cephem-4-carboxylic acid (2~0 g) in formic acid (10 ml) was stirred for 205 hours ~ -at room temperatureO hfter the reaction was completed, ~`
ether (30 ml) was added to the reaction mixture, and the supernatent was removed three times by decantation.
Colorless powder was collec-ted by filtration and washed with ether4 Thus obtained powder was suspended in a mixture of acetonitrile (15 m]) and water (1 ml), and the suspension was stirred ~or 105 hours under ice-cooling.
The precipitate was collected by fil-tration and dried to give 2-methyl -7- ( 2-phenylglycyl)amino-3-cephem-4-carboxylic acid (1.13 g), mp 16805 to 171Co ' Example 2 A solution of 2-methyl-7-L3-(tert.-butoxycarbonyl-amino)-3-(2-thienyl)propionamido~-3-cephem-4-carboxylic ;~
acid (310 mg) in formic acid (1.5 ml) was stirred for 4 hours at room temperature. After the reaction was completed, the solvent was distilled off from the reaction mixture, and the residue was pulverized by treating with ethyl acetate. Thus obtained yellow powder was suspended in a mixture of acetonitrile (10 ml) and water (3 ml), and the ~ ~
, , - 108 - E 59 ~ ~
~' :.'-'.
;: '.

~ V ~7 suspension WclS stirred for 1 hour. The precipitate was collected by filtration, and dried to give 2-methyl-7-L3-amino-3-(2-thienyl)propionamido~-3-cephem-4-carboxylic acid (180 mg), mp 218 to 221C (decO)~ `
Example 3 A solution of 2-methyl-7-~N-(tert.-buto~ycarbonyl)-2-(2-thienyl)glycyl~amino-3-cephem-4-carboxylic acid (2O34 g) in formic acid (10 ml) was stirred for 4 hours at ~-room temperatureD After the reaction was completed~ the solvent was distilled off under reduced pressure from the reaction mixture~ and the residue was pulverized by treating with ethyl acetateO The powder (1.79 g) was dissolved in w~ter (40 ml) and -the solution was stirred for 3 minutes 7 and then filteredO The filtrate was lyophilized to give 2-methyl-7-~2-(2-thienyl)glycyl~amino-3-cephem-4-carboxylic acid (1.5 g), mp 145 to 149Co xample 4 A solution of 2-methyl-7-~D-N-(tert.-butoxycarbonyl)-2-(4-hydroxyphenyl)glycyl~-amino-3-cephem-4-carboxylic acid (2.0 g) in formic acid (40 ml) was stirred for 5 hours at room temperature. After the reaction was completed7 the reaction mixture was concen-trated under reduced pressure, and the residue was dissolved in a mixture of water and ethyl acetate. The aqueous layer was separated and lyophilized to give powdery 2-methyl-7-[D-2-~4-hydroxy- `~
phenyl)glycyl~amino-3-cephem-4-carboxylic acid (1.38 g).

-- 109 - ~ 60 -: . , .. : , , ' ~ 04 3!~'d ~
Nuclear l~lagnetic I~esonance Spectrum (D20+DCl,I ) 8.60 (3H, d, J=7.0Hz) 6.1-6.7 (l~I, m) 4.95 (lH, d~ J=4.5Hz) 5 4.62 (1~, s) 4.11 (lH, d, J=4.5Hz) - 3.40 (lH, d, J-6Hz) 2.93 (2H, d, J=8.5Hz) 2.48 (2H, d, J=8.5Hz) A mixture of 2-methyl-7-CN-(~l-cyclopropylethoxy)-carbonyl-2-(5,6-dihydro-2~i-pyran-3-yl)glycyl~amino-3-cephem-4-carboxylic acid t3.0 g) and formic acid t20 ml) was stirred for 3 hours at room temperature. After the reaction was completed, formic acid was removed from the reaction mixture under reduced pressure at room temperature.
The residue was pulverized with acetonitrile and the powder was collected by filtration. ~he powder was in turn washed with acetonitrile and waterl and dried to ~iv~ 2-methyl-7-~2-t5,6-dihydro-2~-pyran-3-yl)glycyl~ amino-3-cephem-4-carboxylic acid ~2~20 g), mp 125 to 128C ~ ~
(dec.). ~ -Example 6 -~
.
A solution of 2-methyl-7-C~-tert.-buto~ycarbonyl)-2-(3-methanesulfonamidophenyl)glycyl~ amino-3-cephem-4-carboxylic acid (2.5 g) in formic acid (45 ml) was stirred for 4 hours at 8 to 15C. After the reaction was completed, formic acid was removed from the reaction mixture under - 110 - ~ 61 , " ~ ~

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

reduced pressure at 30Co The residue was pulverized by adding cthyl acetate, and the powder was collected by filtration and then dissolved in water (70 ml). ~thyl acetate was addcd to the solution, follovred by shaking the~
rnixture, and the aqueous layer was separated. The aqueous layer was tre~ted with charcoal and then lyophilized.
Methanol (15 ml) and water (3 ml) were added -to the residue and thc mixture was stirred for 30 minute.s at room temperature, filtered and dried to give powdery 2-methyl-7-[2-(3-methanesulfonar~idophenyl)glycyl~amino-3-cephcm-4-carboxylic acid (1.2 g), mp 192 to 193C (decO)~

Exa~lpl~ 7 -A solution of 2-methyl-7-CN-(tert.-butoxycarbonyl)-2-(4-tert.-butoxycarbonylmethyoxyphenyl)glycyl]amino-3- -cephem-4-carboxylic acid (3.0 g) in formic acid (50 ml) was stirred ior 3 hours at 45C. After -the reaction was compl~ted, formic acid was rer,1oved from th~ reac-tion mixture under reduced prcssure, followed by adding acetonitrile (20 rnl) to the residue, and the residue was pulverized by addin~ water (2 ml) under stirring. The powder was collected by filtration, washed with acetonitrile and dried to give powdery 2-methyl-7-C2-(4-carboxymethoxy-phenyl)glycyl~-amino-3-cephem-4-carboxylic acid (1.81 g). -~
Nuclear LIasnetic Resonance Spcctrum (D20+DCl,l j 8.51, 8.60 (3H, 2~, J=7.5~Iz) ~ ~:
6.3 (lH, m) 5.20 (2~, s) Llr~95 (1~1, d, J=4.5~1z) ~ 30 4.69 (lH, s) .

~, - ~,' 1^: ., , - , - . . ~ ~. . .
.. .. . .

~_OL?~3 7 7 ~

5~ ~.32 (lH, 2d, ~T = L~ Z ) .
3.20, 3032 (lH, 2s) 2.90 (2~1, d, J=9Hz) 2.46 (2H, d, J=9Hz) Example A solution of 2-methyl-7-lN-(tert.~butoxycarbonyl)- -2~(4-methyithiophenyl)glycyl~amino-3-cephem-4-carboxylic acid (3.0 g) in formic acid (100 ml) was stirred for 1 lQ hour under anhydrous condition at room temperature.
After the reaction was completed, the solvent was removed from the reaction mixture undcr reduced pressure, and the ' residue was dissolved in a mixture of water and ethyl i acetate, after which the aqueous layer was separated.
~he aqueous layer was washed with ethyl acetate, and the organic solvent was completely removed under reduced pressure~ The insoluble material was collected by filtration and lyo~hilized to give ~,vhite powder of 2-methyl-7-C2-(4-methylthiophenyl)glycyl~amino-3-cephem-4--carboxylic ¦~~ 2Q ~acid (1.2 g), mp 165 to 175C o ' ' ' ' , I ~ ' ' :
~ A solution of 2-methyl-7-LN-(tert.-butoxycarbonyl)-2-¦~ (4-methoxyphenyl)glycyl~amlno-3-cephem-4-carboxylic acid ; ;
~ 25 (3~80 g) in formic acid (20 ml) was stirred for 4.5 hours ! - at room temperature. After the reaction was completed, ¦ formic acid was removed from the reaction mixture below 35~ under reduced pressure, and the residue was pulverized by adding acetonitrile, after which the powder was collected by filtration to give 2.9 g of the powder. The powder ?
, ,' :, `' . . ~ -. . . .

'7'7~

(2.6 g) was suspended in acetonitrile (50 ml). li~ater (1.5 ml) was added to the suspension, after which the mixture was stirred for 1 hour at room temperaturc.
~he precipitate was collected by filtration and dried to give 2-mcthyl-7-~2 (4-methoxyphenyl)glycyl~amino-3-cephem-4-carboxylic acid (2.15 g), mp 165 to 168C (dec.).
' ~
Example 10 A mixture of 2-methyl-7-[N-(tert.-butoxycarbonyl)-2-(1,4-cyclohexadienyl)glycyl~amino-3-cephem-4-carboxylic acid (317 mg) and formic acid (3017 ml) was stirred for 4 hours at room temperature. After the reaction was completed, formic acid was removed under reduced pressure from the reaction mixture alld the residue was pulverized 1 15 by adding ether. The powder was collected by filtration ¦ and dissolved in 95'c acetonitrile aqueous solution (27 ml), I and then th~ solution was stirred for an hour.
¦ Precipitates were collected by filtration and dried to give white crystals of 2-methyl-7-~2-(1,4-~rclohexadienyl)glycyl]-amino-3-cephem-4-carboxylic acid (200 mg), mp 168C
(dec.).
, ' ' : ~:
Exam~le 11 A solution of 2-methyl-7-~N-(tert.-butoxycarbonyl)~
2-(4-methylsulfinylphenyljglycyl~amino-3-cephem-4-carboxylic acid (2.9 g) in formic acid (7.5 ml) was stirrcd for 1 ;-hour at room temperàture under anhydrous condition.
~! After the reaction was completed, the solvent was removed under rcduced pressure from the reaction mixture, and the residue was dissolved in a small amount of water, after ~, .'' ~ - 113 - ~ 64 ,,9 : ' ', " : ~ ' :

3 ~ ~ ~

which acetonitrile was added to the solution, and the precipitated ^rystals were collected by filtration.
~he crystals were dissolved in water and the solution was lyophilized to ~ive powdery 2-methyl-7-L2-(4-methyl- :
sulfinylphenyl)glycyl~amino-3-cephem-4-carboxylic acid (1.5 g), mp 178 to 180C (dec.)O

:

'' ;

':
~ .

. ':

1 . , ~
. ,.
... ..
. ~ ~ ;' ~.'' ' : , '',"`' ~ "
.
~ 25 ,; ~ .

.~ , ~. 30 ,'~
~ - 114 - :E 65 .
'. , . , , ' ,' '' '' , . ' '.. , , .' . .''. '.' ' .'', . .. ': " ' . ', '' ' ' "', ,'' ' ,,' : ' . :
... . .' . . . ' ~
.
~" .'. ' . . : ,. . .

Rle ~ - R3 Rlf ~ ~ ~_ R3 ~ N 0 N ~

..xample A 1% solution of phenolphthalein in 95';~ et~lanol (1 drop) was added to a solution of 2-methyl-7-(D-2-phenyl-2-formyloxyacetamido3-3-cephem-4-carboxylic acid (0.43 g) in a mixture of water (5 ml) and methanol (7 ml).
Every after disappearance of red ~olour of phenolphthalein, lN sodium hydroxide aqueous solution was dropwise added under ice-cooling to the solution. This operation was done to -the time of disappearance of 2-methyl-7-(D-2-phenyl-2-formyloxyacetamido)-3-cephem-4-carboxylic acid in the ; reaction mixture, and the solution was adjusted to pH3 with 10'~ hydrochloric acid. Methanol was removed from the reaction mixture under reduced pressure, and the precipitated gu~ny material was extracted four times with ethyl acetate (10 ml). ~he cxtract was combincd, and the combined solution was dricd o~er magnesium sulfate, after which the sol~ent was removed under reduced pressure.
The residue was treated with isopropyl ether to give ;~
powder of 2-methyl-7-(D-2-phenyl-2-hydroxyacetamido)-3-cephem-4-carboxylic acid (0.29 g), mp 172 to 173C
(d~c.).
The following compound was obtained by using a similar ;~
manncr. 2-Methyl-7-~2-(2-thienyl)-2-hydroxyacetamido~-3-cephern-L~-carboxylic acid, mp 91 to 96C (dec.).

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

~V~3 7~ ~

O R3 Rl - " ~ R3 R2a COOH

Example 1 `
: .
Zinc powder (300 ~) was added under stirring at 5C
to a solution of 2~2,2-trichloroethyl 2-methyl-7-~N~
cyclopropylethyoxy)carbonylphenylglycyl~amino-3-cephem-4-carboxylate (2.95 g) in a mixture of anhydrous dimethyl-formamido(l2.5 ml) and acetic acid (3.75 ml)~ and the mixture was stirred for 1.5 hours. After the reaction, ~ `
zinc powder was filtered off and washed with dime-thyl-i5 formamide (2 ml). ~he filtrate and the washings were combined, and the combined solution was extracted by pouring into a mixture of ethyl acetate (50 ml)~ ice-water (50 ml) and 10/o hydrochloric acid (3 ml)O ~he .
aqueous layer was further extracted with ethyl acetate ~
(20 ml). ~he extract was combined~ and then washed three ~ ;
times with water (20 ml) and once with a saturated sodium chloride aqueous solution and then dried over magnesium sulfateO ~fter drying, the solvent was distilled off and the obtained residue was washed with ether and dried `
to give colorless crystals of 2-methyl-7-LN-(l-cyclo- ;~
propylethoxy)carbonylphenylglycyl~amino-3-cephem-4-carboxylic acid (2~01 g), mp 16~ to 169C.

., ~' 3o .

- 116 - E 67 ~ ~
' ' "

.~ . . . . - .

`

37~7~
Example 2 __ Zinc powder (2.4 g) was added under ice-cooling and stirring to a solution of 2,2,2-trichloroethyl 2-~lethyl-7-~2-(lH-tetra~;ol-l-yl)acetarlido~-~-ccphem-4-carboxylate (2.0 g) in a mixture of anh~Jdrous dimethylformamide (10 ml) and acetic acid ( ~ ml), and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was extracted by pouring into a mixture of ethyl acetate (50 ml), ice-water and 10~' hydrochloric acid (5 ml).
~he aqueous layer was further extracted with ethyl acetate (10 ml) and the ethyl acetate extract was combined, washed twice with water and dried over magnesium sulfate.
I After the solvent was distilled off, the residue was-1 35 crystallized by adding a small amount of ether to give ¦ colorless crystals of 2-methyl-7-C2-(lH-tetrazol-l-yl)-I acetamido~-3-cephem-4-carboxylic acid (0.97 g), I mp 202 to 203C (decOjO
: ~ :
¦ 20 Example 3 ~ Acetic acid (3 ml) and zinc powder (2.4 g) were added i under stirring and ice-cooling to a solution of 2,2,2-! trichloroethyl 2-methyl-7-~2-(2-thienyl)acetamido~-3-cephem-4-carboxylate (1.8 g) in anhydrous dimethyl-formamide (10 ml), and the mixture was stirred for 1 hour at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was extracted by -~
pouring into a mixture of 5% hydrochloric acid (50 ml) t and ethyl acetate (40 ml). ~he ethyl acetate layer was ¦ 3 washed with water and dried. After the solvent was ~ .
~ - 117 - E 68 "
'7 distl~led off, the resi(llle was dissolved in ether and allowed to stand, after ~/hich the precipitating crystals were col]ecued by filtration and dricd to give 2-methyl-7-~2-(2-thienyl)acetamido~-3~cephem-4-carboxylic acid (1.2 g), mp 175~C (dec.).

Example 4 Acetic acid (3 ml) and zinc powder (2.4 g) were added under stirrin~ and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxyla-te (1.9 g) in anhydrous dimethylformamide (10 ml), and the mixture was stirred for 1 hour at the same temperaturç. After the reaction, zinc powder was filtered off, and the filtrate was poured into a mixture of 5~
hydrochloric acid (50 ml) and ethyl acetate (40 ml), and extracted. ~he extract was washed with water and then dried;
~ After the solvent was distilled off, the residue was ¦ crystallized by adding ether to give colorless crystals of ! 2-meth~1-7-benzvloxycarboxamido-3-cephem-4-carboxylic acid ¦ 20 (1.13 g), mp 167 to 169C (dec.). ~ ~
'-~: ` - -3 Example 5 ~: :-:
Acetic acid (4.5 ml) and zinc powder (3.~ g) were added under stirring and ice-cooling to a solution of 2,2,2- , trichloroet~yl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate (2.79 g) in anhydrous dimethylformamide (15 ml), and the mixture was stirred for 2 hours at the same teMperatureO A~ter the re~ction, zinc powder was filtered off, and the filtrate was poured into a mixture of 5~o ~
~¦ 3 hydrochloric acid (75 ml) and ethyl acetate (50 ml), and ~ -- 118 -- ~ 69 .
''l ~ '' ~ ~3~
extracted. The cx-tract was w~shcd with water and dried.
A~ter the sclvent was dist.lled of~`, the residue was crystali~ed by addin~ et~er to ~ive colorless crystals of 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid (2.0 g), mp 168 to 1'71C (dec.).

Example 6 Acetic acid (4.1 ml) and zinc powder (3.4 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(3-chlorophenyl)-aceta~ido~-3-cephem-4-carboxylate (2.6 g) in anhydrous dimethylfor~amide (30 ml), and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, ; zine powder was filtere~d off, and the filtrate was poured into a mixture of 5,o hydrochloric acid (150 ml) and ethyl aeetate (75 ml), and then extraeted. ~he extract was washed with water and dried. A~ter the solvent was distilled off, the residue was erystallized by adding aeetonitrile. The erystals were collected by filtr~tion, ¦ 20 washed with ether and dried to give colorless crystals of ! 2-methyl-7-~2-(3-ehlorophenyl)aeeta~ido]-3-cephem-4-earboxylic acid (Io4 g), mp 173 to 174C ~dec.).

Exam~l~ ?
~inc powder (0.6 g) ~as added under eooling at 0 to 5C to a solution of 2,2,2~trichloroethyl 2-methyl-7 (N-tert.-butoxyearbonylamino)-3-(2-thienylpropionamido~-.i .
3-eephe~-4-earboxylate (0.54 g) in a mixture of anhydrous dimethylformamide (3 ~1) and aeetic aeid (1 ~1), and the ~ixture was stirred for 2 hours. hfter the reaction, ''I .

.
i lOf~37 ~ ~
zinc powder ~,vas filtered off, and the filtrate was poured into a mixture of ethyl ace-tate (50 ml) and 5% hydrochloric acid (30 ml), and then extractedO The extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, after which the solvent was distilled off to give 2-methyl-7-t3-(N-tert~-butoxycarbonyl-ar.lino)-3-(2--thienyl)propionamido~-3-cephem-4-carboxylic acid (0.365 g), mp 167 to 170C (dec.).

Example 8 Acetic acid (4 ml) and zinc powder (3 g) were added under stirrin~ and ice coolin~ to a solution of 2,2,2- ~ ~-trichloroethyl 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylate (3.2 g) in anhydrous dimethylformamide (15 ml), and the mixture was stirred for 1 hour at the same temperature~ After the reaction, ethyl acetate (100 ml) was added to the reaction mixture. The insoluble ma-terial was iltered off, and the filtrate was washed with 5~o hydrochloric acid saturated with sodium chloride, and then extracted with a saturated sodium bicarbonate aqueous solution. The extract was acidified with lOC/o hydrochloric ;; ~;~
acid and extracted with ethyl acetate. The extract was ~ ;
washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After the solvent was distilled off, the crystalline residue was recrystallized ~ - -from a mixture of ethyl acetate and benzene to give 2 methyl-7-(2-cyanoace-tamido)-3-cephem-4-carboxylic acid (2.3 g), mp 162 to 166Co ;
~.`'-" ;' , ,~ . ,~ , ' . .. . ' , ' ; ' . , ' . - . ' ' . ~ ' ~xample 9 Acetic acid (8 ml) and zinc powder (6 g) were added under stirring and ice-cooling to a solu-tion of 2,2,2-trichloroethyl 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylate (4.1 g) in anhydrous dimethylformamide (30 ml), and the mixture was stirred for 1 hour under ice-cooling and then 3.5 hours at room temperatureO Af-ter the reac-tion, 10~ hydrochloric acid and ethyl acetate were added to the reaction mixture. The insoluble material was filtered off and the ethyl aceta-te layer was separated, and then extracted with a sodium bicarbonate aqueous solutionO The extract was acidified wi-th lOC,' hydrochloric acid and extracted with ethyl acetate, after which the extract was dried over magnesium sulfate. After the solvent was dis-tilled off, the residue was crys-tallized by adding ether to give 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid (1.0 g), mp 14~ to 151a.

xample 10 Acetic acid (8 ml) and zinc powder (6 g) were added under stirrin~g and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-C2-(1,3,4-thiadiazol-2-ylthio)-acetamido~-3-cephem-4-carboxylate (4.65 g) in anh~drous dimethylformamide (30 ml), and the mixture was stirred for 1 hour at the same temperature After -the reaction, ethyl acetate (150 ml) was added -to the reaction mixture.
The insoluble material was filtered off, and the filtrate was washed with 5~ hydrochloric acid saturated with sodium chloride, and then ex-tracted with a sodium bicarbonat-e aqueous solution. The extr~ct was acidified with 10%

-hydrochloric acid and extracted with ethyl acetate, after which the ethyl ace-tate layer was washed with a saturated sodium chloride aqueous solution and dried over ~agnesium sulfateO After the solvent was distilled off, the residue was recrystallized from a mix-ture of ethyl acetate and benzene to give 2-methyl-7-L2-(1,3,4-thiadiazol-2-ylthio)-acetamido~-3-cephem-4-carboxylic acid (1.5 g), mp 197 to 199~.

Example 11 -Acetic acid (ln6 ml) and zinc powder (1~2 g) were added under s-tirring and ice-cooling to a solution of ~ ~`
2,2,2--trichloroethyl 2-methyl-7-CN-tert.-butoxycarbonyl-2-(2-thienyl)glycyl~amino-3-cephem-4-carboxylate (1.52 g) in anhydrous dimethylformamide (10 ml), and the mixture was stirred for 1 hour at the same temperature. After the reaction, zinc powder was filtered off, and the filtra-te was poured into an ice-cooled mixture of 2 to 3~v hydro-chlorlc acid and ethyl acetate and then extracted. The extract was washed with water, extracted with a sodium -bicarbonate a~ueous solution, after which the aqueous ~-layer was acidified by adding 5,v sulfuric acid and ethyl acetate and extracted with ethyl ace-tate. The extract was -`~
washed with water, dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure.
The residue was pulverized by adding isopropyl ether9 collected by filtration and dried to give amorphous 2- ~

methyl-7-CN-tert.-butoxycarbonyl-2-(2-thienyl)glycyl~amino- ;
3-cèphem-4-carboxylic acid (0.7 g).
~
'~'. ' ' ' - 122 - E 73 ~

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

.. ,.~ .

3 ~ 7;3 Infrared .~bsor~tion ~pectr~ (~rujol) 3300, 1789~ 1725, 1710, 1690, 1678 cm~

Exz.mple 12 Acetic acid (8 ml) and zinc powder (6 g) vere added under ice-coolin~ to a solution of 2,2,2-trichloroethyl 2-nethyl-7-[2-(5-~ethyl-193,4-thiadia~ol-2-yloxy)acetah~ido~ - ;
~-cephem-4-carboxylate (6.60 g) in anhydrous dimethyl-formamide (40 ml), and the ~ixture was stirred for 1.5 hours. After the reaction, zinc powder was filtered and .
; ~ashed with dimeth~lforr;lamide. The filtrate and the , washings were cor.lbined, and the cor.1bincd solution was I poured into an ice-cooled mixture of ethyl acetate and 2 to 390 hydrochloric acid, and then extracted~ ~he extr~ct i 15 was extracted with a sodium bicarbonate aqueous solution ~-¦ and the aqueous solution was acidifi~d with hydrochloric ¦ acid, and then extracted with ethyl acetate. The aqueous ~ ~:
j layer was saturated with sodium chloride, and then ¦~ extracted, four times with ethylacetate ~80 ml), after ~ 20 which the both ethyl acetate extràct was corlbined. After ¦ the combined extracted was dried over maO~nesium sulfate, th`e soIvent was distilled off under reduced pressure.
3 The residue ~vas crystallized by adding ether to give ~l dimethylformamlde adduct of 2-methyl-7-L2-(5-mcthyl-1,3,4-thiadiazol-2-yloxy)aGetamido~-3-cephem-4-carboxylic acid "~ (2.0 g), mp 113 to 116C.

' E~ample 13 Zinc powder (0.6 g) 1.vas added under stirrin~ and ~:
ice-coollng to a solution of 2,2,2~trichloroethyl 2-methyl-.
'; ,~
, . , ; ': .
" , '' ,, ' :- ....
' ' 7 ~
7- ~-(2-c~loro~)h~llyl)-5-rlet~lJlisoxaz!~1-4-yl~carboxa~ido-3-c~Ejhe~-4-c~ro~ latc (~.~ g) in a L1ixture of anhydrous di~cthylf~ ?~.ide (5 r11) and acetic acid (008 ml), and the mixtur, ~as stirred f3r 40 ~inutes at th~ sarle tempc-ratu~e. After the reaction, zinc powder was filtered and washed with dil~ethylior~a~llidc. ~he filtrat~ and the washings were combined, and the co~bined solution was poured into an ice-cooled mixture of ethyl acetate and 2 to 3So hydrochloric acid, and then extracted with ethyl acetate. The extract was extracted with a sQdiu bicarbonate aqueous solution 9 clnd the aqucous laycr was acidified with lo~k sulfuric acid and then extr~cted with ethyl acetate, after which the extract was washed with j water and dried o~er ~a~nesiu~ sulfate.
After the solvent v~as distilled off under reduced pressure, the oily substance was crystallized by adding ether, and 1 the crystals were collected by filtration, and then washed ¦ with ether to give 2-rlethyl-7-~-(2-chlorophenyl)-5-! methylisoxazol-4-yl~carboxamido-3-cephem-4-carboxylic acid (0.2 ~), ~p 202 to 203C
1 . ..........
hxample 14 2,2,2-~richloroethyl 2-methyl-7-(2-~ethylthio-¦ acetamido)-3-cephem-4-carboxylate (0.48 g), glacial acetic acid (0.48 ml) and zinc po~vder (0.48 ~) were added to ¦ anhydrous dil~ethylfor~aLlide (5 nl), and the ~ixture was stirred f3r 1 hour under ice-cooling. A~ter the reaction, zinc powder was filtered off. rrhe filtrate was poured into a mixture of 3Sb hydrochl3ric acid (10 ml) and cthyl acetate ~0 (10 ~1), and the ethyl acetate layer was separated.
~ ~ ' - 124 - E 75 ~
. ~ , .

~he aqu~U ~lc e~ l ac~t t~ J
et~lyl acet~ (10 ml) aS was e1 ith a saturat~d s The co OUS solutl n and dried O~r g aft , d re~ldue ~-as r~

preSsur~ t~ls were collected Y
d 1th ~ther to gi~e 2 m acetamido)-3-cephe~-4-carboxylic acid (o.29 ~ 7 181 to 1~3C (dec.). ~ ~
~; ;, '. ' Example 15 5 g) was ~dd~d to a solutin 0~
~inc powder (5'52 ~th 1-7-(2-all~Jlthioacetamido)- ~-2 272-trichloroethyl ~ hydrOus dimethYl~
3-~caphem-4-carboxylate 5 (5 5 ml) wa5 formamide (55.5 ml) an i h the mixtur~
dr0pwise added t eactiOn~ zinc pWder was s-t:lrre~ ~or 1 h 1 ac~tate. ~he was filt cO~bined~ a~ter whiCh 20 ~ and th~ WaS of 5So hydrochloric a was poured int a mlx th n extr3cted ~e aqUeous and ethyl acetate (1 d t-qice q~th ethyl acetate- .
layer wàs furth mbined, and the comb ~he eth~l acet~t~ Y h saturated sodiu~
ethyl acetate ay d then dried o~er ~agn~si chlOride aqueUs so u at~d under reduced sulfat~ After th ~ ~o aDOUt I d w~th iSopropyl dthor .. . .; . .. : ~ : . -,.3 7 ~ ~ -crys-t~lls o~ l;h~ r~ 2~ llylthioac~ta!r.ido)-3-cepher~l-4-carboxylic ~cid. (3~6~ g), l1p 121 to 123C. Moleover the i`iltrate was concon-tr~ted. and the obtRined cryst~ls were washGd witn isopropyl eth~r and then dri~d to give 2-m~thyl-7-(2-allylthioacetamido)-3-cG-phel~-4-carbox71ic .
; acid (0.75 g).

Exa~ple 16 . 2,2,2-Tric]lloroethyl 2-methyl-7-(2-formyloxy-2-phenylaceta~ido)-3-c~phe~-4-carboxylate (1.58 g), zinc -~
powder (1.5 g) and glacial acetic c~cid (1.5 ml) were :. -added to anhydrous dimethylfor~ar:lide (15 ml) ~ and the mixture was stirred for 1 hour under ice-cooling. :~
After the reaction, zinc powder was filtered off, and the .
filtrate was poured into ~ mixture of 5,~ hydrochloric acid ~ ~.
(30 ml) and.ethyl acetate (30 ml) and then extracted. The I aqueous layer was further extracted twice with eth~l ¦ acetate (30 ml). ~he ethyl acetate layer was combined, ;~
~¦ and the combined solution was washed with 5G~ hydrochloric acid and~water, and then dried o-~er magnesium sulfate.
~ After the solvent was distilled off under reduced pressure, ¦ the residue was pulverized by adding isopropyl ether9 .
followed by filtration, and dried to give amorphous 2~
~ .
: methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid (1.0 g).
Infrared Absorptlon Spectrum (Nujol) 3280, 1787, 1720, 1678 cm~

3 -~

t ",,, 7~
r ~ r~
_ Zinc pow~r (1.2 rr) was added under ice-coolin~ to a sol~tion of ~ tr:i.c`nloroet~ l 2-rlethyl-7-(1-cyclo-provylethox~)ca~bo~ai:li(lo-,-cephem-~-car~oxylate (0.92 g) in a mixture of dimet~.ylformamide (5 ml) and acetic acid (1.5 ml)~ an~ the ~ixt~re was stirred for 1.5 hours at the sarrle t~lperature. After the rea~tion, zinc powder was filtered oif and ~rashed with dimethylforrlarlide (2 ml).
?,!e dimethyl~ormar~.ide layer uas poured into a mixture of -0 ei;h,yl acetate (30 ml), water (30 rnl) and 10,v hydrochloric .-~
acid (2 ml) an~ extrlc1ied. ~he dimethJ~lforma.~ide layer was further extracted ~Ji-th eth;l acetate (10 r.ll). The : -ethyl acetate extract Wcl5 com~ined, washed in turn with wate~r, a saturated so~i~m chloride aqueous solution, dried over ma~nesium su.lfate, after whi.ch the solvent was ~:
disti.lled ofrO mhe re~iduè ~;as pulverized ll.sin~ a small amount of ether to give 2-methyl-7-(1-cyclopropylethoxy)-ear~ox~mido-3-cephem-4-carbox~lic acid (0.45 ~), .
mp 158.5 to 160C (dec.). ~ .
. ~ .
_xam~)le 18 -~
Acetie acid (1 r.~l) a~.ld æinc powder ~2.0 ~) were added under ice-coolin~ to a solution of 2,2,2-trichloro~thyl 2 methyl-7-amino-3-cephem-4-carboxylate hydrochloride (1.53 g) in dimethylformamide (lG ml) and the mixture was stirred for 1 hour at -5 to 0C, after ~vhich the reaction .
mixture rJas filtered. The filtered zinc powder was washed with dimethylforlllamide and the filtrate ~nd the washîn~s were combined, after which a fel.v mls. of water was adcled to the solution. The preci~itated cr~stals v!ere collected ~f 37 d ~
; bv fil~rc~tion a~lcl dissolved in a small ~mount of a sodiumb~caLbonai-e aqueols solution and then the incoluble material W'-lS .`iliered off. ~`he f`iltrate wes adjus-ted to p~I4 with l~t~o hydrochloric aci~ and the precipitated crystals were collected by filtration 5 washed with 1Nater and acetone an~ dried to ~ive 2-mQthyl-7-amino-3-cephem-4-carboxylic ~ -acid (0.3$ g), mp 222C (decO).
',' Example 19 ; 10 Zinc powder (2.4 g) was added under ice-coolin~ to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacet-amido)-3-cephem-4-carboxylate (1.85 ~) in a mixture of ``
dimethylformamide (10 ml) and acetic acid (3 ml), and the mixture was stirred for 2 hours, after which the reaction mixture was liltered. ~he filtrate l.vas poured into a mixture of ethyl acetate (50 ml), ice-water (50 ml) and ~- -.
10~ hydrochloric acid (2 ml), and then the ethyl acetate .
la~Jer was separated. ~he aqueous layer was further extr~cted with ethyl acetate (10 ml)0 ~he e-thyl-acetate la-~er was combined, and the combined solution was in turn washed with water and a saturated sodium chloride aqueous solution, . .
¦ dried over magnesium sulfate 9 after which the solvent was distilled off. ~he residue t~as crystallized by adding a small quantity of acetonitrile and the precipitated crystals ~.rère collected by filtration and dried to give ¦ colorless crystals of 2-methyl-7-(2-phenylacetamido)-3-cephem-L~-carboxylic acid (1.2 g)~ mp 109C (dec.).

:~
- 128 - ~ 7 'I ~

~,, " r ' ', ' ' ' ~ ' ' , ' l~?.o Zinc powder (0.9 g) was aclded under ice-cooling to a soluti.ol~ of 2;2,2-tric~lloroethyl 2-mcthyl~7-(2-pherlyl-acetamido) 3-cephem-4-ca.rboxy.late (0.69 g), mp 120 to 5 130C, i~ a mixture of dimethylformamide (5 ml) and acetic acid (1 ml), and the mixture was stirred for 1.5 hours, fo].lowed by filtration of the reaction mixture, after which the filtered zinc was washed wIth a small amount of dimethyl-.formamide. ~he filtrate and the washings were combined and the combined solution was poured into a mixture of ethyl acetate (30 ml), water (30 ml) and 10% hydrochloric acid (2 ml), after which the ethyl acetate layer was :~
separated. The aqueous layer was fur-ther extracted with ethyl acetate (10 ml). ~he ethyl acetate layer was . ~
combined, and the combined solution was in turn washed -:
with water,.a saturated sodium chloride aqueous solution, dried over magnesium sulfate, after which the solvent was ,I di.stilled off. ~he residue was crystallized by adding a small quantity of acetonitrile, and the precipitated ¦ 20 crystals were collected by filtration and dried to give ~ 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid .I (0.34 g), mp 121C, which is an isomer at 2 position of 2-methyl-7-(2-phenylacetamido)-~-cephem-4-carboxylic acid, mp 109C (dec.), which was obtained in Exanple 19.
"
`~ ~xample 21 Zinc powder (1~8 g) was added under ice-cooling to a ~I solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenyl-j acetamido)-2-cep~em-4-carboxylate (1.0 g) in a mixture of ~ 30 dimethylformamide (7.5 ml) and acetic acid (2.5 ml), and .l 129 - ,. E 80 ~'~

~(~43 7t73 : ~
-the mixture ~as stirred for 1.5 hours, followed by ~iltra-tion oL the reac-tion mixture 9 and -the filtered zinc was ~-washed with dimethylforrlamide (2 ml)0 ~he filtrate and the washing~ were combined and the combined solution was poured into a mixture o~` ethyl acetate (30 ml), ice-water (30 ml) and 10% hydrochloric acid (2 ml), after which the ethyl acetate layer was separa-tedO ~he a~ueous layer was further extracted with ethyl acetate (10 ml). The ethyl acetate layer was combined~ and the combined solution was in turn washed with water~ a saturated sodium chloride aqueous solutiong dried over magnesium sul~ate, after which -the --solvent was distilled offO ~he residue was crystallized by addin~ a small quantity of ether~ after which the precipitated crystals were collected by filtration and dried to.give colorless crystals of 2-methyl-7-(2-phenyl~
acetamido)-2-cephem-4-carboxylic acid (0.45 g), mp 204C. ~:
~he following compounds were obtained by using -the similar procedures as those o:~ the above Examples.

1) 2-Methyl-7-(phenylglycyl)amino-3-cephem-4-carboxylic acid, mp 168.5 to 171C.

2) 2-Methyl-7-[3-amino-3-(2-thienyl)propionamido~-3-cephem-4-carboxylic acid, mp 21~ to 221C (dec.).

3) 2-Methyl-7-~(2-thienyl)glycyl~-amino-3-cephem-4-carboxylic acid, mp 145 to 149C (dec.) 4) 2-Methyl-7-(2-hydroxy-2-phenylacetamido)-3-cephem-4-carboxylic acid, mp 172 to 173Co ~`~

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

3 6~r~
5) 2-l~.;eth;yl-7-ï~ tert.--buto;Jcal~bonyl-2-(2,5- -dihydrophcnyl)glycyl~amiIlo-3-cep`~em~4-carboxylic acid, mp 126 to 131C (dec.).

..
6) 2-Methyl-7-Ll~i-tert.-butoxycarbonyl-2-(4-hydroxy-pheI~yl)-D-~lycyl~amino-3-cephem-4-carboxylic acid, powder.

," '~, 7) 2 Methyl-7-LN-tert -butoxycarbonyl-2-(4-methylthio-phenyl)gl-ycyl~amino-3-cephem-4-carboxylic acid, mp 110 to 120Co 1 8) 2-Methyl-7-~N-tert.-butoxycarbonyl-2-(4-methoxy-phenyl)glycyl~amino-3--cephem-4-carboxylic acid, mp 81 to 86C (dec.).

! 9) 2-~qethyl-7-(2-sulfo-2-phenyl-acetamido)-3-cephem-¦ 4-earboxylic acid, 115C (vesieation), 200 to 220C
(dec.).

10) 2-llIethyl-7-(2-azido-2-phenylacetamido)-3-c~phem-4-earboxylic acid, mp 65 to 68~C.
.

11) 2~ ethyl-7-[2-(3-pyr1dyl)acetamido~-3-cephem-4- ~ ;
earboxylie acid, mp 147 to 149C (dec.).

1 , ` .
12) 2-~Iethyl-7-~2-hydroxy-2-(2-thienyl)acetamido~-3-eephem-4-carboxylic acid, mp 91 to 96C (dec~
' I ~ ..
:, ~' 30 .. . .. .
. . ., : .

~0~ 37 7 3 :- :
13) 2-~1ethyl-7-lN-(1,3,~-thiadia~ol-2-yl)thiomethyl-carbonyl~2-phenylglycyl~amino-3-cephem-4-carboxylic acid, mp 143 to 145C (dec.).

14) 2-Methyl-7-~N-tert.-butoxycarbonyl-2-(4-tert.-butoxycarbonylmethoxyphenyl)glycyl~-amino-3-cephem- ;, 4-carboxylic acid, powder.
.
15) 2-Methyl-7- ~-(1-cyclopropylethoxy)carbonyl-2-(5,6-, 10 dihydro-2Fi-pyran-3-yl)glycyl~amino-3-cephem-4-! carboxylic acid, mp 195 to 197C.
' 16) 2-IIfethyl-7-c2-(1,2,5-thiadiazol-3-yl)acetamido3-3-cephem-4-carboxylic acid, mp 1~8 to 190C (dec.) ` 17) 2-Methyl-7-CN-tert.-butoxycarbonyl-2-(3-methanesulfon-j amidophenyl)glycyl~amino-3-cephem~4-carboxylic acid, oil.

18) 2-Methyl-7-rN-tert.-butoxycarbonyl-2-(4-methyl~
sulfinylphenyl)glycyl~amino-3-cephem-4-carboxylic , acid, mp 110 to 120C.
-I 193 2-Methyl-7-~2-(5-indanyl)oxycarbonyl-2~phenyl-.i 25 acetamido~-3-cephem-4-carboxylic acid, 90 to 95C
~ (softening), 150 to 160C (dec.).
' 20) 2-Methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid, mp 217 to 219C.

:: `

7'~

21j ~ .eth/1-7-l,D-2-(4~~rdroxypherl~1)gl~Jc-Jl'ari~no-3-cephem-4-c-trboxylic a~ld, po~lder.

22) 2-Methyl-7-r2-(5,G-dihydro-2~l-p~-ran-3-yl)glycyl~
amino-3-cephein-4--carboy~lic aci~, mp 125 to 128C
(dec.).
, 2~) 2~ ethyl-7-r2-(3-methanesulf~namidophenyl)glycyl~- -amino-3-cephem-4-carboxylic acid, mp 192 to 193C
(dec.).

24) 2-2~1ethyl-7-~2-(4-carboxymethoxyphenyl)glycyl~dmino-3~cephem-4-carboxylic acid, powder.

I 15 25) 2-Methyl-7-j2-(4-methylthiophenyl)glycyl~a~ino-3-¦ cephem-4~carboxylic acid, mp 165 to 175C.

! 26) 2-Methyl-7-~2-(4-methoxyphenyl)~lycyl~amino-3-cephem-4-carboxylic acid, mp 165 to 168Co 27) 2-Methyl-7-~2-(2~5-dihydrophenyl)glycylljamino-3-cephem-4-carboxylic acid~ mp 16~C (dec.)0 28) 2-~.Iethyl-7-L2-(4-methylsulfinylphenyl)glycylJamino~
3-cephem-4-carboxylic ~cid, powder.

29) 2-Methyl-7-~2-(5,6-dihydro-2E-pyran-3-yl)acetamido3-1 3-cephem-4-carboxylic acid, mp 172.5 to 173.5C
¦ (dec.).

- 133 - ~ 84 ! ~

' ' ' ': ' . ?

~3'7'~
30) 2-l~let~ J!-7-(4-r~,el;hoxy~ enJl)~31yo~yla~nido-3-cephem-4-car~,ox~;lic acid, mp lc~ o li~(~-i (àec. ) .
~', '.

31 ) 2-~le-t llyl -7- ( N-t ert . -but ox~car bonylphenyl- D-glycyl ) amino -3-c~pheLq-4-caI~box,-llic acid, mp 125 to 127-; (deo. ) ~
"
32 ) 2-Meth~1-7-~N- [2- ( 2-ni "rophenoxy) acetyl~ phenylglycyl~
amino-3-cepheL~1-4-carbox~lic acicl, L~lp 135 tG 137~
, (dec. ).
` 10 , , ,, ...

,- : -, ~

-3 . : . .

, .

,,l 30 ' I . . ~- .
134 - E ~35 '; ' , , , ' ~ ~ ; ~ ' : ' ~0~3~7~
. :

Il -C~IC0~ R4 I ~0 _" X ` -R~

NH2 0~ N R ~ R

Example A suspension of 2-methyl-7-(2-phenylglycyl)amino-3-cephem-4-carboxylic acid (1.0 g) in water (10 ml) was adjusted to pII 8.8 by adding dropwi~e lO~o sodium ~- hydroxide. ~o the suspension was added acetone (10 ml), and the mixture was stirred for 24 hours in an ice bath.
Acetone was remove~ under reduced pressure, and then the aqueous layèr was adjusted to about pH 3.5 with 10~
h~drochloric acid, and then extracted three times with ethyl acetate (20 ml). ~he residue obtained by distilling off ethyI acetate was dissolved in a small amount of -~
aoetone, and then a small quantity of insoluble material was filtrated off A great quantity of ether was added to the filtrate, and then the precipitate was collected by filtration to give 2-methyl-7-(2,2-dimethyl-4-phellyl-5-oxoimidazolidin-l-yl)-3-cephem-4-carboxylic acid (0.30 g), mp 160 to 162C (dec.)~

1 i ~,~, . .
: '' ~ . . ' :, ' . ' :, ~";' ' . ' ' ' ~ - ' ' .P ~ 37 ~ ~3 SUPPLEMENTARY DISCLOSURE

This disclosure and the Principal Disclosure relate to 2-lower alkyl 2 or 3-cephem-~-carboxylic acid derivatives and their process of preparation.
The derivatives have anti-microbial activity as described in detail in the Principal Disclosure.
Thus the invention relates to a novel class of compounds of formula (I) as defined in the PrLncipal Disclosure and their process of preparation.
It will be understood that when R2 in formula (I) is a free carboxylic acid group COOH that pharmaceutically acceptable salts of -the acid are included in the scope of the invention, for example, the salts of a metal, for example, sodium, potassium or magnesium, or of an organic amine, for example, methylamine, diethylamine, trimethylamine, triethyl-amine, aniline, pyridine, picoline and N,N'-dibenzylethylene-diamine.
Further, it will be understood that esters of the free acids of formula (I~, wherein R2 is COOH are included within the scope of the invention; in this case the ester group _ ;:
may be considered a protecting group for the carboxylic acid group.
The compounds of formula(I)wherein R2 is an ester group can be readily obtained by esterifying the corres-ponding compound of formula (I), wherein R2 is carboxy or its salt. The esterification reaction is carried out in accordance with conventional methods. Such conventional esterification is preferably carried out in a solvent which does not adversely influence the reaction, for example, N,N-dimethyl-..
formamide, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate and the like.
' .. : . . . ~
.. ~ ` ` . :
.. . . . . . .

7 7~
The reaction temperature for the esterification reaction is not critical.
It will further be understood that pharmaceutically acceptable acid addition salts of compounds of formula (I) are included within the scope of the invention, the acid addition salts being formed at the site of the amino group Rl in a con-ventional manner.
The invention is further illustrated by reference to the following examples, which are not intended to be construed as limiting the invention.
Example S.D.
Following the procedure of Examples 1 - 12 at pages 50 - 58 of the Principal Disclosure the -following compounds were prepared in a similar manner.

58) 2-Methyl-7-[2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 2-methyl-7- `~
C2-(2-imino~2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, m.p~ 250 to 255C. (dec~), from 2-methyl-2,3-methylene-6- ~`
[2-(2-aminothiazol-4-yl)acetamido]penam-3-carboxylic acid and aluminum bromide.

59) Pivaloyloxymethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)-acetamido~-3-cephem-4-carboxylate hydrochloride, which can be represented as pivaloyloxymethyl 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate hydrochloride, m.p. 185 to 190 C. (dec.), from pivaloyloxymethyl-2-methyl-2,3-methylene-6-[2-(2-aminothiazol-4-yl)-acetamido]penam-3-carboxylate hydrochloride and aluminum bromide.
ExamPle S.D. 2 The followin~ compounds were obtained in a similar manner to the procedure in Example 1 at page 100 of the Principal Disclosure.

.. . ..

. . . .. :

7~
5~) 2~Methyl-7-~2-(2-aminoth:iazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, which can be represented as 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, m.p. 250 to 255 C. (dec.), from 2-methyl-7-~2-phenylacetamido) ~3-cephem-4-carboxylic acid and 2-aminothiazol-4-acetyl chloride.
59) Pivaloyloxymethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate hydrochloride, which can be represented as pivaloyloxymethyl 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate hydrochloride, mOp. 185 to 190C~ (dec.), from pivaloyloxymethyl 2-methyl-7-(phenylacetamido)-3-cephem-4-carboxylate hydrochloride and 2-amino-khiazol-4-acetyl chloride.
Example S.D. 3 The following compou~ds were obtained by a procedure corresponding to that of Example 1 at pa~e 66 of the Principal Disclosure utilizing appropriate starting material.
44) 2-Methyl-7-[2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, m.p. 250 to 255C. (dec.j, from 2-methyl-7-~2- "
(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid-l-oxide by reduction with phosphorus trichloride.
45) Pivaloyloxymethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate hydrochloride, which can be represented as pivaloyloxymethyl 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate hydro-chloride, m.p. 185 to 190 C. (dec.), from pivaloyloxymethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate-l-oxide hydrochloride by reduction with phosphorus trichloride.

B:~
:

~ "` . ...................... ~ . - ~ .

.. . ~ , . , Ex.mple S.D~ ~

The following example further illustrates the conversion of an amino compound of formula (Id) to a substituted amino compound of formula tIe) which has been illustrated in Examplesl to 19 at pages 77 to 99 of the Principal Disclosure.
To a suspension of 2-(2-aminothiazol-4-yl)acetic acid, which can be represented as 2-(2-imino-2,3-dihydrothiazol-4-yl)-acetic acid, (1.64 g.) in dried methylene chloride (50ml.) was introduced dried hydrogen chloride gas for 10 minutes under ~`
ice-cooling and stirring, and to the mixture was gradually added phosphorus pentachloride (5.44 g.) under ice-cooling and stirring.
The mixture was stirred for 1 hour under ice-cooling, and then the reaction mixture was concentrated below at room temperature.
The residue was dissolved in dried acetone (12 ml.), and the solution was dropwise added to a solution of 2-methyl-7-amino-3-cephem-4-carboxylic acid (1.712 g.) ln a mixture of acetone (40 ml.), water (40 ml.) and sodium bicarbonate (1.344 g.) over about 15 minutes under ice-cooling and stirring, and then the mixture was further stirred for 1.5 hours under ice-cooling while the mixture was kept to pH 6 to 7 with 20% sodium carbonate aqueous solution. After the reaction, acetone was distilled off under reduced pressure from the reaction mixture, the residual aqueous solution was adjusted to pH 2.8 with concentrated hydro-chloric acid, and then the mlxture was stirred for 28 hours at room temperature~ The precipitated crystals were collected by filtration, washed with water and dried to give 2-methyl-7-~2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 2-methyl-7-[2-(2-imino-2,3-dihydro-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (1.456 g.), m.p. 250 to 255 C. (dec.).

~ .

B ~ ~
., .~ . ;

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

I.R. spectrum (~ujol)*
1760 cm~
N.M.R. Spectrum (D20 + NiaHC03,~) 1.44 (d, J=7.5 Hz, 2-CH3) 3.57 (s, CH2C0) 3.5-3.9 (m, 2-H) 5.07 (d, J=5Hz, 6-H) 5.75 (d, J=5Hz, 7-H) 6.35 (d, J=6Hz, 3-H) 6.50 (s, 5-H on thiazole ring).
The following compounds were obtained in a similar manner as described in connection with the above Example with appropriate changes in the starting materials to produce the speci~ied compounds.
1) 2,2,2-Trichloroethyl 2-methyl-7-(2-phenylacetamido)- ~ -3-cephem~4-carboxylate, mp 175 to 178C.
2~ 2,2,2-Trichloroethyl 2-methyl-7-~2-phenylacetamldo)- -2-cephem-4-carboxylate, mp 136 to 137C.
3~ 2,2,2-~richloroethyl 2-methyl-7-[2-(3-chlorophenyl)-acetamido]-3-cephem-4-carboxylate, mp 144 to 144.5C. ~
~dec.). ~ ~-4) 2,2,2-Trichloroethyl 2-methyl-7-[2-tl,2,5-thiadia~iol-3-yl)acetamido]-3 cephem-4-carboxylate, mp 180 to 18SC (dec.).

, ~ ' ' _ ~40 -,. , ~, .. ., ~ .

~l0~3~71~3 5) Methyl 2-methyl-7-(2-phenoxyacetamido) 3-cephe~4-carboxylate, oil.
6) 2,2,2-Trichloroethyl 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylate, mp 118 to 120C.
7) 2,2,2-Trichloroethyl 2-methyl-7-(2-phènylacetamido)- -3-cephe~4-carboxylate-1-o~ide, ~p 173 to 175C.
8) 2-Methyl-7-[N-(l-cyclopropylethoxy)-carbonylphenyl-glycyl]amino-3-cephem-4-carboxylic acid, mp 168 to 169C.
9) 2-Methyl-7-[2-(lH-tetraæol-l-yl)acetamido]-3-cephem-4-carboxylic acid, mp 202 to 203C (dèc.).
10) 2-Methyl-7-[2-(2-thienyl)acetamido]-3-cephem~
carboxylic acid, mp 175C (dec.).
11) 2-Methyl-7-benzyloxycarboxamido-3-cephe~4-carboxylic acid, mp 167 to 169C (dec.).
12) 2-Methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid, mp 168 to 171C (dec.).
13) 2-Methyl-7-[2-(3-chlorophenyl)acetoamido]-3-cephem-4-carboxylic acid, mp 173 to 174C (dec.).
14) 2-Methyl-7-[3-(N-tert.-butoxycarbonylamino)-3 (2-thienyl)propionamido~-3-cephem-4-carboxylic acid, !, . ~ . - :
:,: . , , . ` ; . ' .-' , ' ' , ~ .
.. ' ~ : , .

mp 167 to 170C (dec.).
15) 2-Methyl-7-(2-cyanoacetamido)-3-cephemA-carboxylic acid, mp 162 to 166C.
16) 2-Methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid, mp 148 to 151C.
17) 2-Methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]- :
3-cephem A -carboxylic acid, mp 197 to 199C.
18) 2-Methyl-7-~-tert,butoxycarbonyl-2-thienylglycyl]-amino-3-cephem-4-carboxylic acid, powder.
19) 2-Methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)- ~-acetamido]-3-cephem A-carboxylic acid, mp 113 to 116C.
20) 2-Methyl-7 [3-(2-chlorophenyl)-5-methylisoxazol-4-ylj-carboxamido-3-cephem~4-carboxylic acid, mp 202 to 203C.
21) 2-Methyl-7-(2-methylthioacetamido)-3-cephemA-carboxylic .
acid, mp 181,to 183C (dec.).
22) 2-Methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid, mp 121 to 123C.
23) 2-Methyl-7-(2-formy;oxy-2-phenylacetàmido)-3-cephem~
4-carboxylic acid, powder.

.. . . . . :
~ , . ' ' ' 3LO~ 7~7~, 24) 2-Methyl-7-(1-cyclopropylethoxy)carboxamido-3- ~-cephe~4-carboxylic acid, n~p 158.5 to 160C
(dec.).
25) 2-Methyl-7-(2-azido-2-phenylacetamido)-3-cephe~
4-carboxylic acid, mp 65 to 68C.
26) 2,2,2-trichloroethyl 2-methyl-7-[N-tert.-butoxy-carbonyl-2-(4-hydroxyphenyl)-D-glycyl]amin~ 3-cephe~4-carboxylate, mp 130 to 135C (dec.).
27) 2-Methyl-7-[2-(3-pyridyl)acetamido]-3-cephe~4-carboxylic acid, mp 147 to 149C (dec.).
28) 2-Methyl 7-[N-t~rt.-butoxycarbonyl-2-(2,5-dihydro-phenyl)glycyl]amino-3-cephe~4-carboxylic acid, mp 126 to 131C tdec.).
29) 2-Methyl-7-[Nrtert.-butoxycarbonyl-2-(4-hydroxy-phenyl)-D-glycyl]amino-3-cephem-4-carboacylic acid, powder.
30) 2-Methyl-7-N-tert.-buto~ycarbonyl-2-(4-methylthio-phenyl)glycyl arnino-3-cephem-4-carboxylic acid, ~p 110 to 120C.
31) 2-Methyl-7-~N-tert.butoxycarbonyl-2-(4-metho~y-phenyl)glycyl]amino-3-cephem-4-carboocylic acid, ~p 81 to 86C (dec.).
~::

. ' ., . ~ . ~
;' `"' ' .-32) ~,2,2-Trichloroethyl 2-methyl-7-[N-tert.-butoxycarbonyl-2-(4-methylthiophenyl)-glycyl amino]-3-cephem~4-carboxylate, mp 115 to 1~0C.
33) 2,2,2-Trichloroethyl 2-me~hyl-7-[N-tert.-butoxy-carbonyl-2-(4-methoxyphenyl~-glycyl]amino-3-cephem-4-carboxylate, mp 92 to 95C (dec.).
34) 2,2,2-Trichloroethyl 2-methyl-7-[N-tert.-butoxy-carbonyl-2-(2,5-dihydrophenyl)-glycyl]amino-3-cephem~4-carboxylate, mp 104 to 110C (dec.).
35) 2,2,2-Trichloroethyl 2-methyl-7-[N-(l-cyclopropyl-ethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)-glycyl]amino-3-cephem-4-carboxylate, mp 118 to 126C (dec.).
36) 2,2,2-Trichloroethyl 2-methyl-7-[N-tert.-butoxy-carbonyl-2-(4-tert.-butoxycarbonylmethoxyphenyl)-glycyl]amino-3-cephem-4-carboxylate, powder.
37) 2,2,2-Trichloroethyl 2-methyl-7-[N-(1,3,4-thiadiazol-2-yl)thiomethylcarbonyl-2-phenyl~lycyl]amino-3-cephem~4-carboxylate, mp 148 to 150C (dec.)O
38) 2,2,2~Trichloroethy,l 2-methyl-7-[N-tert.-butoxy-carbonyl-2-(4-methylsulfinylphenylglycyl]amino-3-cephem-4-carbo~ylate, mp llS to 12SC.

.

39) 2-Methyl-7-~2-i~onicotinoyloxy-2-phenylacetam~do )-3-cephe~4-carboxylic acid, ~p 217 to 219C.
40) 2,2,2-Trichloroethyl 2-methyl-7 (2-isonicotinoyloxy-2-phenylacetamido)-3-cephe}n 4-carbc~xylate, mp 100 to 115C (dec.).
41) 2,2,2-Trichloroethyl 2-methyl-7-~2-(5-indanyl)-oxycarbonyl-2-phenylacetamido]-3-cephe~4-carboxylate, mp 165 to 170C.
42) 2-Methyl-7-[N-(1,3,4-thiadiazol-2-yl)thiomethyl-carbonyl-2-phenylglycyl]amino-3-cephe~4-carboxylic acid, mp 143 to 145 (dec.).
43~ 2-Methyl-7-[~-tert.-butoxycarbonyl-2-(4-tert.-butoxycarbonylmethoxyphenyl)glycyl]amino-3-cephe~
4-carboxylic acid, powder.
44) 2-Methyl-7-[N-(l-cyclopropyletho~y)carbonyl-2-(5,6-di-hydro-2H-pyran-3-yl)glycyl]amino--3-cepheD~4-carboxylic acid, ~p 195 to 197C, 45) 2-Methyl-7-[2-(1,2,5-thiadiazol-3-yl)-acetamido]-3-cephe~4-carboxylic acid, mp 188 to 190 (dec.).
46) 2-Methyl-7-[N-tert.-butoxycarbonyl-2-(3-methane~
~ul~onamidophenyl)glycyl]amino-3-cephe~4-carboxylic acid, oil.
~ , ' ' ' ~
' ~
~; ~.',, ~ , . .. .

.

,,, ",, , . . . . . . . , . ~ . .

~ J~
47) 2-Methyl-7-[N-tert.-butoxycarbonyl-2-(4-methyl-sulfinylphenyl~glyeyl]amino-3-eephem-4-earboxylic acid, mp 110 to 120C.
48) 2-Methyl-7-[2-(5-indenyl)oxyearbonyl-2-phenylaeetamido]-3-eephem-4-carbQxylic acid, 90 to 95C (softening), 150 to 160C (dec.).
49) 2,2,2-Trichloroethyl 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cephem-4-earboxylate, mp 149.5 ~o 150.5C.
50) 2-Methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)-acetamido]-3-eephem-4-carboxylie acid, mp 172,5 to 173.5C
(dec.)~
51) 2,2,2-Triehloroethyl 2-methyl-7-[N-tert.-butoxy-earbonyl-2-(3-methane~ulfonamidophenyl)glyeyl]amino-3-eephem A-earboxylate, amorphous.
52) 2-Methyl-7-(4-methoxyphenyl)glyoxylamido-3-eephemr 4-carboxylie aeid, mp 188 to 189C (dee.).
53) 2-Methyl-7~ tert.-butoxyearbonylphenyl-D-glyeyl)amino-3-cephem}4-carboxylie aeid, mp 125 to 127C (dee.).
54) 2-Methyl-7-[~-[2-(2-nitrophenoxy)aeetyl]phenylglyeyl]-amino-3-eephem-4-earboxylie acid, mp 135 to 136C
(dee a ) ' ' ~ ' ;

` ~' .

~(~4~'7~

55) 2,2,2-Trichloroethyl 2-methyl-7-(N-tert.-butoxy-carbonylphenyl-D-glycyl)amino-3-cephem-4-carboxylate, 115 to 116C (dec.).

56) Pivaloyloxymethyl 2-methyl 7-[2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate hydrochloride, which can be represented as pivaloyloxymethyl 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate hydrochloride, m. p~ 185 to 190C. (dec.), from pivaloyloxymethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride and 2-(2- ~-~
aminothiazol-4-yl)acetic acld. ~ ~-Example S.D. 5 The following compounds were obtained in a manner similar to that of Examples 1 to 11 at pages 108 - 114 of the Principal Disclosure.
1) 2-Methyl-7-C2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 2-methyl-7-C2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3 cephem-4-carboxylic acid, m.p. 250 to 255 C. (dec~ rom 2-methyl-7-~2-(2-tert.-butoxycarbonylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid and formic acid, 2) Pivaloyloxymethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate hydrochloride, which can be represented as pivaloyloxymethyl 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate hydrochloride, m.p. 185 to 190C. (dec.), ~rom pivaloyloxymethyl 2-methyl-7-C2-(2-tert -butoxycarbonylaminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate hydrochloride and formic acid. ~;

'`'' ' `
t;, .. ~ ' '' '` "
~ ~ . . ; .. . . . . . ' , . ! `
~:' ., ' :` . ' : ' "
'`'`'~ "' '' ' '"' " ' ' ' '' i' . . ' . . . . , ' 1 (;)f~ ~ -? ~
Example S.D. 6 .
The following compound was prepared using similar procedures as in Examples 1 to 21 at pages 116 to 130 of the Principal Disclosure.
33) 2-Methyl-7-[2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, m.p. 250 to 255 C. (decO), from 2,2,2-trichloro-ethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate by reduction with zinc powder and acetic acid.

Example S.D. 7 - This example illustrates the preparation of a compound of ~ormula I in which R2 is an ester group from the corresponding free acid or a salt thereof.
To a solution of sodium 2-methyl-7-[2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate, which can be represented as sodium 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4~yl) acetamido]-3-cephem-4-carboxylate, (1 g.) in N,N-dimethylformamide (10 ml.) was added iodomethyl pivalate (0O76 g~) under ice-cooling, and the mixture was stirred for 20 minutes at the same temperature.
After the reaction, to the reaction mixture was added ethyl acetate (60 ml.). The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water in turn and then concentrated under reduced pressure~ To the con-centrated small amount of residue were added 10% hydrochloric acid (2.5 ml.) and ether (20 ml.) under ice-cooling and then the mixture was stirred for 5 minutes at the same temperature. The precipitated crystals were collected by filtration, washed with ether and then dried under reduced pressure to give pivaloyloxy-methyl 2-methyl-7-[2-(2-aminothiazol-4-yl)-acetamido]-3-cephem- -4-carboxylate hydrochloride, which can be represented as pivaloyl- ;
oxymethyl 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4-yl) .
':

7r73 acetamido]-3-ceph~m-4-carboxylate hydrochloride, (0.873 g.), m.p. 185 to 190C. (dec.).
I.R. Spectrum (Nujo ~
1757, 1740, 1698 cm 1 N. M. R. Spectrum ((CD3)2S0, ~) ;
1.16 (s, (CH3)2C-1.43 (d, J=7.5 Hz, 2-CH3) ~ -- 3064 (s, CH2C0) -- j . .
3~85-4.10 (m, 2-H) 5.13 (d, J=5 Hz, 6-H) 5.70-6.05 (m, 7-H and COOCH200C) 6.67 (s, 5H on thiazole ring) ~;
6.72 (d, J=6 Hz, 3-H).

rQ~Qrn~k :

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

~,... ..

.' '.; ~ .

~: -- lg9 - :

. . . .,. .. ~. ~ .. . . ..
;,.. ., . . ... , ,. ,. , - .
.. , - ; ... , .. .. " . . . . , .-.
....... , . .. .... . . ... ., .. . . .. .. ;. . .

Claims (438)

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 compound of the general formula:

wherein R1 is amino, 2,2-di(lower)alkyl-4-aryl-5-oxoimidazolidin-1-yl or acylamino, R2 is carboxy or a protected carboxy, R3 is lower alkyl and X is -S- or -?-, and pharmaceutically acceptable salt thereof, which comprises a) reacting a compound of the general formula:

wherein R1, R2, R3 and X are each as defined above, with a Lewis acid to produce a compound of the general formula:

wherein R1, R2, R3 and X are each as defined above, or b) oxidizing a compound of the general formula:

wherein R1, R2 and R3 are each as defined above, to produce a compound of the general formula:

Wherein R1, R2 and R3 are each as defined above, or c) reducing a compound of the general formula:

wherein R1, R2 and R3 are each as defined above, to produce a compound of the general formula:

wherein R1, R2 and R3 are each as defined above, or d) subjecting a compound of the general formula:

Wherein R2, R3 and X are each as defined above, and R1a is a protected amino, to elimination reaction of the protective group of the amino to produce a compound of the general formula:

Wherein R2, R3 and X are each as defined above, or a salt thereof, or e) reacting a compound of the general formula:

wherein R2, R3 and X are each as defined above, or a salt thereof with an acylating agent to produce a compound of the general formula:
wherein R2, R3 and X are each as defined above, and R1b is acylamino, or f) reacting a compound of the general formula:

wherein R1b, R2, R3 and X are each as defined above, with a trialkyloxoniumhaloborate or an iminohalogenating agent and an iminoetherifying agent, and then reacting the resulting compound with an acylating agent, if necessary, followed by hydrolysis to produce a compound of the general formula:

wherein R2, R3 and X are each as defined above, and R1b is acylamino, or g) subjecting a compound of the general formula:

wherein R2, R3 and X are each as defined above, and R1c is acylamino having a protected amino, to elimination reaction of the protective group of the amino, to produce a compound of the general formula:

wherein R2, R3 and X are each as defined above, and R1d is acylamino having an amino, or a salt thereof, or h) subjecting a compound of the general formula:

wherein R2, R3 and X are each as defined above, and R1e is acylamino having a protected hydroxy, to elimination reaction of the protective group of the hydroxy, to produce a compound of the general formula:

Wherein R2, R3 and X are each as defined above, and R1f is acylamino having a hydroxy, or i) subjecting a compound of the general formula:

wherein R1, R3 and X are each as defined above, and R2a is a protected carboxy, to elimination reaction of the protective group of the carboxy, to produce a compound of the general formula:

Wherein R1, R3 and X are each as defined above, or a salt thereof, or j) reacting a compound of the general formula:

wherein R2, R3 and X are each as defined above, and R4 is aryl, or a salt thereof with a lower alkanone of the general formula: R5-CO-R6 wherein R5 and R6 are each lower alkyl, to produce a compound of the general formula:

wherein R2, R3, R4, R5, R6 and X are each as defined above, or a salt thereof, k) esterifying a compound of the general formula:

wherein R1 is amino, 2,2-di(lower)alkyl-4-aryl-5-oxoimidazolidin-1-yl or acylamino, R3 is lower alkyl and X is -S- or -?-, to produce a compound of formula:

wherein R1, R3 and X are as defined above and R2 is esterified carboxy.

2. A process for the preparation of a compound of the general formula:

wherein R1 is amino, 2,2-di(lower)alkyl-4-aryl-5-oxoimidazolidin-1-yl or acylamino, R2 is carboxy or a protected carboxy, R3 is lower alkyl and X is -S- or -?-, and pharmaceutically acceptable salt thereof, which comprises reacting a compound of the general formula:

wherein R1, R2, R3 and X are each as defined above, with a Lewis acid.

3. A process according to claim 2, wherein R1 is amino, 2,2-di(lower)alkyl-4-phenyl-5-oxoimidazolidin-1-yl, lower alkoxycarbonylamino, phenyl(lower)alkoxycarbonylamino, 3-phenylureido, lower alkoxyphenylglyoxylamido, cyano(lower)alkanoylamino, lower alkylthio(lower)alkanoylamino, lower alkenylthio(lower)alkanoylamino, phenylthio(lower)alkanoylamino, phenoxy(lower)alkanoylamino, phenyl(lower)alkanoylamino, halophenyl(lower)alkanoylamino, phenyl and amino substituted lower alkanoylamino, phenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, phenyl and nitrophenoxy(lower)alkanoylamino substituted lower alkanoylamino, phenyl and thiadiazolylthio(lower)alkanoylamino sub-stituted lower alkanoylamino, hydroxyphenyl and amino substituted lower alkanoylamino, hydroxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkoxyphenyl and amino substituted lower alkanoylamino, lower alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylthiophenyl and amino substituted lower alkanoylamino, lower alkylthiophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylsulfinylphenyl and amino substituted lower alkanoylamino, lower alkylsulfinylphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, carboxy(lower)alkoxyphenyl and amino substituted lower alkanoylamino, lower alkoxycarbonyl(lower)alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and amino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, dihydrophenyl and amino substituted lower alkanoylamino, dihydrophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, phenyl and azido substituted lower alkanoylamino, phenyl and hydroxy substituted lower alkanoylamino, phenyl and lower alkanoyloxy substituted lower alkanoylamino, phenyl and pyridylcarbonyloxy substituted lower alkanoylamino, phenyl and sulfo substituted lower alkanoylamino, phenyl and indanyloxycarbonyl substituted lower alkanoylamino, thienyl(lower)alkanoylamino, thienyl and amino substituted lower alkanoylamino, thienyl and lower alkoxycarbonylamino substituted lower alkanoylamino, thienyl and hydroxy substituted lower alkanoylamino, dihydropyranyl(lower)alkanoylamino, dihydropyranyl and amino substituted lower alkanoylamino, dihydropyranyl and lower alkoxycarbonylamino substituted lower alkanoylamino, pyridyl(lower)alkanoylamino, thiadiazolyl(lower)alkanoylamino, lower alkylthiadiazolyloxy(lower)alkanoylamino, thiadiazolylthio(lower)alkanoylamino, tetrazolyl(lower)alkanoylamino, halophenyl and lower alkyl substituted isoxazolylcarboxamido, R2 is carboxy, lower alkoxycarbonyl or trihalo(lower)alkoxycarbonyl, R3 is lower alkyl and X is -S- or -?-,

4. A process according to claim 3, for preparing a 3-cephem derivative with the double bond in the 3-position, wherein R1 is amino, 2,2-dimethyl-4-phenyl-5-oxoimidazolidin-1-yl, (1-cyclopropylethyoxy)carboxamido, benzyloxycarboxamido, 3-phenylureido, 2-(4-methoxyphenyl)glyoxylamido, 2-cyanoacetamido, 2-methylthioacetamido, 2-(allylthio)acetamido, 2-(phenylthio)acetamido, 2-phenoxyacetamido, 2-phenylacetamido, 2-(3-chlorophenyl)acetamido, phenylglycylamino, N-(1-cyclopropylethoxy)carbonylphenylglycylamino, N-tertiarybutoxycarbonylphenylglycylamino, N-[2-(2-nitrophenoxy)acetyl]phenylglycylamino, N-(1,3,4-thiadiazol-2-ylthio)acetyl-phenylglycylamino, 2-amino-2-(4-hydroxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-hydroxyphenyl)acetamido, 2-amino-2-(4-methoxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methoxyphenyl)acetamido, 2-amino-2-(4-methylthiophenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methylthiophenyl) acetamido, 2-amino-2-(4-methylsulfinylphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methylsulfinylphenyl)-acetamido, 2-amino-2-(4-carboxymethoxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-tertiarybutoxycarbonyl-methoxyphenyl)acetamido, 2-amino-2-(3-methanesulfonamidophenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(3-methanesulfonamido-phenyl)-acetamido, 2-amino-2-(2,5-dihydrophenyl)acetamido, 2-tertiarybutoxycarbonylamino-2 (2,5-dihydrophenyl)acetamido, 2-azido-2-phenylacetamido, 2-hydroxy-2-phenylacetamido, 2-formyloxy-2-phenylacetamido, 2-isonicotinoyloxy-2-phenylacetamido, 2-sulfo-2-phenylacetamido, 2-(5-indanyloxy)carbonyl-2-phenylacetamido, 2-(2-thienyl)acetamido, 2-amino-2-(2-thienyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(2-thienyl)acetamido, 3-amino-3-(2-thienyl)propionamido, 3-tertiarybutoxycarbonylamino-3-(2-thienyl)propionamido, 2-hydroxy-2-(2-thienyl)acetamidc, 2-(5,6-dihydro-2H-pyran-3-yl)acetamido, 2-amino-2-(5,6-dihydro-2H-pyran-3-yl)acetamido, 2-(1-cyclopropylethoxy)carbonylamino-2-(5,6-dihydro-2H-pyran-3-yl)acetamido, 2-tertiarybutoxycarbonylamino-2-(5,6-dihydro-2H-pyran-3-yl)-acetamido, 2-(3-pyridyl)acetamido, 2-(1,2,5-thiadiazol-3-yl)acetamido, 2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido, 2-(1,3,4-thiadiazol-2-ylthio)acetamido, 2-(1H-tetrazol-1-yl)acetamido, 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido, R2 is carboxy, methoxycarbonyl or 2,2,2-trichloroethoxy-carbonyl, R3 is methyl and X is -S-.

5. A process according to claim 4, wherein R1 is (1-cyclopropylethoxy)carboxamido and R2 is carboxy.

6. A process according to claim 4, wherein R1 is (1-cyclopropylethoxy)carboxamido and R2 is 2,2,2-trichloroethoxycarbonyl.

7. A process according to claim 4, wherein R1 is benzyloxycarboxamido and R2 is carboxy.

8. A process according to claim 4, wherein R1 is benzyloxycarboxamido and R2 is 2,2,2-trichloroethoxycarbonyl.

9. A process according to claim 4, wherein R1 is 3-phenylureido and R2 is carboxy.

.

10. A process according to claim 4, wherein R1 is 3-phenylureido and R2 is 2,2,2-trichloroethoxycarbonyl.

11. A process according to claim 4, wherein R1 is 2-(4-methoxyphenyl)glyoxylamido and R2 is carboxy.

12. A process according to claim 4, wherein R1 is 2-cyanoacetamido and R2 is carboxy.

13. A process according to claim 4, wherein R1 is 2-cyanoacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

14. A process according to claim 4, wherein R1 is 2-methylthioacetamido and R2 is carboxy.

15. A process according to claim 4, wherein R1 is 2-methylthioacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

16. A process according to claim 4, wherein R1 is 2-(allylthio)acetamido and R2 is carboxy.

17. A process according to claim 4, wherein R1 is 2-(allylthio)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

18. A process according to claim 4, wherein R1 is 2-(phenylthio)acetamido and R2 is carboxy.

19. A process according to claim 4, wherein R1 is 2-(phenylthio)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

20. A process according to claim 4, wherein R1 is 2-phenoxyacetamido and R2 is methoxycarbonyl.

21. A process according to claim 4, wherein R1 is 2-phenoxyacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

22. A process according to claim 4, wherein R1 is 2-phenylacetamido and R2 is carboxy.

23. A process according to claim 4, wherein R1 is 2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

24. A process according to claim 4, wherein R1 is 2-(3-chlorophenyl)acetamido and R2 is carboxy.

25. A process according to claim 4, wherein R1 is 2-(3-chlorophenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

26. A process according to claim 4, wherein R1 is N-(1-cyclopropylethoxy)carbonylphenylglycylamino and R2 is carboxy.

27. A process according to claim 4, wherein R1 is N-(1-cyclopropylethoxy)carbonylphenylglycylamino and R2 is 2,2,2-trichloroethoxycarbonyl.

28. A process according to claim 4, wherein R1 is N-tertiarybutoxycarbonylphenylglycylamino and R2 is carboxy.

29. A process according to claim 4, wherein R1 is N-tertiarybutoxycarbonylphenylglycylamino and R2 is 2,2,2-trichloroethoxycarbonyl.

30. A process according to claim 4, wherein R1 is N-[2-(2-nitrophenoxy)acetyl]phenylglycylamino and R2 is carboxy.

31. A process according to claim 4, wherein R1 is N-(1,3,4-thiadiazol-2-ylthio)acetylphenylglycylamino and R2 is 2,2,2-trichloroethoxycarbonyl.

32. A process according to claim 4, wherein R1 is 2-amino-2-(4-hydroxyphenyl)acetamido and R2 is carboxy.

33. A process according to claim 4, wherein R1 is 2-tertiarybutoxycarbonylamino-2-(4-hydroxyphenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

34. A process according to claim 4, wherein R1 is 2-amino-2-(4-methoxyphenyl)acetamido and R2 is carboxy.

35. A process according to claim 4, wherein R1 is 2-tertiarybutoxycarbonylamino-2-(4-rnethoxyphenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

36. A process according to claim 4, wherein R1 is 2-amino-2-(4-methylthiophenyl)acetamido and R2 is carboxy.

37. A process according to claim 4, wherein R1 is 2-tertiarybutoxycarbonylamino-2-(4-methylthiophenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

38. A process according to claim 4, wherein R1 is 2-amino-2-(4-methylsulfinylphenyl)acetamido and R2 is carboxy.

39. A process according to claim 4, wherein Rl is 2-tertiarybutoxycarbonylamino-2-(4-methylsulfinylphenyl)-acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

40. A process according to claim 4, wherein R1 is 2-amino-2-(4-carboxymethoxyphenyl)acetamido and R2 is carboxy.

41. A process according to claim 4, wherein Rl is 2-tertiarybutoxycarbonylamino-2-(4-tertiarybutoxycarbonyl-methoxyphenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

42. A process according to claim 4, wherein R1 is 2-amino-2-(3-methanesulfonamidophenyl)acetamido and R2 is carboxy.

43. A process according to claim 4, wherein R1 is 2-tertiarybutoxycarbonylamino-2-(3-methanesulfonamidophenyl)-acetamido and R2 is carboxy.

44. A process according to claim 4, wherein R1 is 2-tertiarybutoxycarbonylamino-2-(3-methanesulfonamidophenyl)-acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

45. A process according to claim 4, wherein R1 is 2-amino-2-(2,5-dihydrophenyl)acetamido and R2 is carboxy.

46. A process according to claim 4, wherein R1 is 2-tertiarybutoxycarbonylamino-2-(2,5-dihydrophenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

47. A process according to claim 4, wherein R1 is 2-formyloxy-2-phenylacetamido and R2 is carboxy.

48. A process according to claim 4, wherein R1 is 2-formyloxy-2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

49. A process according to claim 4, wherein R1 is 2-isonicotinoyloxy-2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

50. A process according to claim 4, wherein R1 is 2-sulfo-2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

51. A process according to claim 4, wherein R1 is 2-(5-indanyloxy)carbonyl-2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

52. A process according to claim 4, wherein R1 is 2-(2-thienyl)acetamido and R2 is carboxy.

53. A process according to claim 4, wherein R1 is 2-(2-thienyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

54. A process according to claim 4, wherein R1 is 2-tertiarybutoxycarbonylamino-2-(2-thienyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

55. A process according to claim 4, wherein R1 is 3-tertiarybutoxycarbonylamino-3-(2-thienyl)propionamido and R2 is carboxy.

56. A process according to claim 4, wherein R1 is 3-tertiarybutoxycarbonylamino-3-(2-thienyl)propionamido and R2 is 2,2,2-trichloroethoxycarbonyl.

57. A process according to claim 4, wherein R1 is 2-(5,6-dihydro-2H-pyran-3-yl)acetamido and R2 is carboxy.

58. A process according to claim 4, wherein R1 is 2-(5,6-dihydro-2H-pyran-3-yl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

59. A process according to claim 4, wherein R1 is 2-amino-2-(5,6-dihydro-2H-pyran-3-yl)acetamido and R2 is carboxy.

60. A process according to claim 4, wherein R1 is 2-(1-cyclopropylethoxy)carbonylamino-2-(5,6-dihydro-2H-pyran-3-yl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

61. A process according to claim 4, wherein R1 is 2-(1,2,5-thiadiazol-3-yl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

62. A process according to claim 4, wherein R1 is 2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido and R2 is carboxy.

63. A process according to claim 4, wherein R1 is 2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

64. A process according to claim 4, wherein R1 is 2-(1,3,4-thiadiazol-2-ylthio)acetamido and R2 is carboxy.

65. A process according to claim 4, wherein R1 is 2-(1,3,4-thiadiazol-2-ylthio)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

66. A process according to claim 4, wherein R1 is 2-(1H-tetrazol-1-yl)acetamido and R2 is carboxy.

67. A process according to claim 4, wherein R1 is 2-(1H-tetrazol-1-yl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

68. A process according to claim 4, wherein R1 is 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido and R2 is carboxy.

69. A process according to claim 4, wherein R1 is 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido and R2 is 2,2,2-trichloroethoxycarbonyl.

70. A process according to claim 1(b) for the preparation of a compound of the general formula:

wherein R1 is amino, 2,2-di(lower)alkyl-4-aryl-5-oxoimidazolidin-1-yl or acylamino, R2 is carboxy or a protected carboxy and R3 is lower alkyl, and pharmaceutically acceptable salt thereof, which comprises oxidizing a compound of the general formula:

wherein R1, R2 and R3 are each as defined above.

71. A process according to claim 70, for preparing a 3-cephem derivative with the double bond in the 3-position, wherein R1 is 2-phenylacetamido, R2 is 2,2,2-trichloroethoxycarbonyl, and R3 is methyl.

72. A process according to claim 1(c) for the preparation of a 3-cephem compound of the general formula:

wherein R1 is amino, 2,2-di(lower)alkyl-4-aryl-5-oxoimidazolidin-1-yl or acylamino, R2 is carboxy or a protected carboxy and R3 is lower alkyl, and pharmaceutically acceptable salt thereof, which comprises reducing a compound of the general formula:

wherein R1, R2 and R3 are each as defined above.

73. A process according to claim 72, wherein R3 is methyl.

74. A process according to claim 73, wherein R1 is amino and R2 is carboxy.

75. A process according to claim 73, wherein R1 is amino and R2 is 2,2,2-trichloroethoxycarbonyl.

76. A process according to claim 73, wherein R1 is (1-cyclopropylethoxy)carboxamido and R2 is carboxy.

77. A process according to claim 73, wherein R1 is (1-cyclopropylethoxy)carboxamido and R2 is 2,2,2-trichloroethoxycarbonyl.

78. A process according to claim 73, wherein R1 is benzyloxycarboxamido and R2 is carboxy.

79. A process according to claim 73, wherein R1 is benzyloxycarboxamido and R2 is 2,2,2-trichloroethoxycarbonyl.

80. A process according to claim 73, wherein R1 is 3-phenylureido and R2 is carboxy.

81. A process according to claim 73, wherein R1 is 3-phenylureido and R2 is 2,2,2-trichloroethoxycarbonyl.

82. A process according to claim 73, wherein R1 is 2-cyanoacetamido and R2 is carboxy.

83. A process according to claim 73, wherein R1 is 2-cyanoacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

84. A process according to claim 73, wherein R1 is 2-methylthioacetamido and R2 is carboxy.

85. A process according to claim 73, wherein R1 is 2-methylthioacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

86. A process according to claim 73, wherein R1 is 2-(allylthio)acetamido and R2 is carboxy.

87. A process according to claim 73, wherein R1 is 2-(allylthio)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

88. A process according to claim 73, wherein R1 is 2-(phenylthio)acetamido and R2 is carboxy.

89. A process according to claim 73, wherein R1 is 2-(phenylthio)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

90. A process according to claim 73, wherein R1 is 2-phenoxyacetamido and R2 is methoxycarbonyl.

91. A process according to claim 73, wherein R1 is 2-phenoxyacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

92. A process according to claim 73, wherein R1 is 2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

93. A process according to claim 73, wherein R1 is 2-(3-chlorophenyl)acetamido and R2 is carboxy.

94. A process according to claim 73, wherein R1 is 2-(3-chlorophenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

95. A process according to claim 73, wherein R1 is phenylglycylamino and R2 is carboxy.

96. A process according to olaim 73, wherein R1 is N-(1-cyclopropylethoxy)carbonylphenylglycylamino and R2 is carboxy.

97. A process according to claim 73, wherein R1 is N-(1-cyclopropylethoxy)carbonylphenylglycylamino and R2 is 2,2,2-trichloroethoxycarbonyl.

98. A process according to claim 73, wherein R1 is 2-hydroxy-2-phenylacetamido and R2 is carboxy.

99. A process according to claim 73, wherein R1 is 2-formyloxy-2-phenylacetamido and R2 is carboxy.

100. A process according to claim 73, wherein R1 is 2-formyloxy-2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

101. A process according to claim 73, wherein R1 is 2-(2-thienyl)acetamido and R2 is carboxy.

102. A process according to claim 73, wherein R1 is 2-(2-thienyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

103. A process according to claim 73, wherein R1 is 2-amino-2-(2-thienyl)acetamido and R2 is carboxy.

104. A process according to claim 73, wherein R1 is 2-tertiarybutoxycarbonylamino-2-(2-thienyl)acetamido and R2 is carboxy.

105. A process according to claim 73, wherein R1 is 2-tertiarybutoxycarbonylamino-2-(2-thienyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

106. A process according to claim 73, wherein R1 is 3-amino-3-(2-thienyl)propionamido and R2 is carboxy.

107. A process according to claim 73, wherein R1 is 3-tertiarybutoxycarbonylamino-3-(2-thienyl)propionamido and R2 is carboxy.

108. A process according to claim 73, wherein R1 is 3-tertiarybutoxycarbonylamino-3-(2-thienyl)propionamido and R2 is 2,2,2-trichloroethoxycarbonyl.

109. A process according to claim 73, wherein R1 is 2-(1,2,5-thiadiazol-3-yl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

110. A process according to claim 73, wherein R1 is 2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido and R2 is carboxy.

111. A process according to claim 73, wherein R1 is 2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

112. A process according to claim 73, wherein R1 is 2-(1,3,4-thiadiazol-2-ylthio)acetamido and R2 is carboxy.

113. A process according to claim 73, wherein R1 is 2-(1,3,4-thiadiazol-2-ylthio)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

114. A process according to claim 73, wherein R1 is 2-(1H-tetrazol-1-yl)acetamido and R2 is carboxy.

115. A process according to claim 73, wherein R1 is 2-(1H-tetrazol-1-yl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

116. A process according to claim 73, wherein R1 is 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido and R2 is carboxy.

117. A process according to claim 73, wherein R1 is 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido and R2 is 2,2,2-trichloroethoxycarbonyl.

118. A process according to claim 1(d) for the prepar-ation of a compound of the general formula:

wherein R2 is carboxy or a protected carboxy, R3 is lower alkyl and X is -S- or -?-, and pharmaceutically acceptable salt thereof, which comprises subjecting a compound of the general formula:
wherein R2, R3 and X are each as defined above, and R1a is a protected amino, to elimination reaction of the protective group of the amino.

119. A process according to claim 118, wherein R1a is lower alkoxycarbonylamino, phenyl(lower)alkoxycarbonylamino, 3-phenylureido, lower alkoxyphenylglyoxylamido, cyano(lower)alkanoylamino, lower alkylthio(lower)alkanoylamino, lower alkenylthio(lower)alkanoylamino, phenylthio(lower)alkanoylamino, phenoxy(lower)alkanoylamino, phenyl(lower)alkanoylamino, halophenyl(lower)alkanoylamino, phenyl and amino substituted lower alkanoylamino, phenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, phenyl and nitrophenoxy(lower)alkanoylamino substituted lower alkanoylamino, phenyl and thiadiazolylthio(lower)alkanoylamino substituted lower alkanoylamino, hydroxyphenyl and amino substituted lower alkanoylamino, hydroxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkoxyphenyl and amino substituted lower alkanoylamino, lower alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylthiophenyl and amino substituted lower alkanoylamino, lower alkylthiophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylsulfinylphenyl and amino substituted lower alkanoylamino, lower alkylsulfinylphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, carboxy(lower)alkoxyphenyl and amino substituted lower alkanoylamino, lower alkoxycarbonyl(lower)alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and amino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and lower alkoxycarbonyl-amino substituted lower alkanoylamino, dihydrophenyl and amino substituted lower alkanoylamino, dihydrophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, phenyl and azido substituted lower alkanoylamino, phenyl and hydroxy substituted lower alkanoylamino, phenyl and lower alkanoyloxy substituted lower alkanoylamino, phenyl and pyridylcarbonyloxy substituted lower alkanoylamino, phenyl and sulfo substituted lower alkanoylamino, phenyl and indanyloxycarbonyl substituted lower alkanoylamino, thienyl(lower)alkanoylamino, thienyl and amino substituted lower alkanoylamino, thienyl and lower alkoxycarbonylamino substituted lower alkanoylamino, thianyl and hydroxy substituted lower alkanoylamino, dihydropyranyl(lower)alkanoylamino, dihydropyranyl and amino substituted lower alkanoylamino, dihydropyranyl and lower alkoxycarbonylamino substituted lower alkanoylamino, pyridyl(lower)alkanoylamino, thiadiazolyl(lower)alkanoylamino, lower alkylthiadiazolyloxy(lower)alkanoylamino, thiadiazolylthio(lower)alkanoylamino, tetrazolyl(lower)alkanoylamino, halophenyl and lower alkyl substituted isoxazolylcarboxamido, R2 is carboxy, lower alkoxycarbonyl or trihalo(lower)alkoxycarbonyl, R3 is lower alkyl and X is -S- or -?-.

120. A process according to claim 119, wherain R1a is (1-cyclopropylethoxy)carboxamido, benzyloxycarboxamido, 3-phenylureido, 2-cyanoacetamido, 2-methylthioacetamido, 2-(allylthio)acetamido, 2-(phenylthio)acetamido, 2-phenoxyacetamido, 2-phenylacetamido, 2-(3-chlorophenyl)acetamido, N-(1-cyclopropylethoxy)carbonylphenylglycylamino, 2-tertiarybutoxycarbonylamino-2-(4-hydroxyphenyl)-acetamido, 2-formyloxy-2-phenylacetamido, 2-(2-thienyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(2-thienyl)acetamido, 3-tertiarybutoxycarbonylamino-3-(2-thienyl)propionamido, 2-(3-pyridyl)acetamido, 2-(1,2,5-thiadiazol-3-yl)acetamido, 2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido, 2-(1,3,4-thiadiazol-2-ylthio)acetamido, 2-(1H-tetrazol-1-yl)acetamido or 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido, R2 is carboxy or 2,2,2-trichloroethoxycarbonyl, R3 is methyl and X is -S-.

121. A process according to claim 1(e) for the preparation of a compound of the general formula:

wherein R1b is acylamino, R2 is carboxy or a protected carboxy, R3 is lower alkyl and X is -S- or -?-, and pharmaceutically acceptable salt thereof, which comprises reacting a compound of the general formula:

wherein R2, R3 and X are each as defined above, or a salt thereof with an acylating agent.

122. A process according to claim 121, for preparing a 3-cephem derivative with the double bond in the 3-position, wherein R1b is lower alkoxycarbonylamino, phenyl(lower)alkoxycarbonylamino, 3-phenylureido, lower alkoxyphenylglyoxylamido, cyano(lower)alkanoylamino, lower alkylthio(lower)alkanoylamino, lower alkenylthio(lower)alkanoylamino, phenylthio(lower)alkanoylamino, phenoxy(lower)alkanoylamino, phenyl(lower)alkanoylamino, halophenyl(lower)alkanoylamino, phenyl and amino substituted lower alkanoylamino, phenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, phenyl and nitrophenoxy(lower)alkanoylamino substituted lower alkanoylamino, phenyl and thiadiazolylthio(lower)alkanoylamino substituted lower alkanoylamino, hydroxyphenyl and amino substituted lower alkanoylamino, hydroxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkoxyphenyl and amino substituted lower alkanoyl-amino, lower alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylthiophenyl and amino substituted lower alkanoylamino, lower alkylthiophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylsulfinylphenyl and amino substituted lower alkanoylamino, lower alkylsulfinylphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, carboxy(lower)alkoxyphenyl and amino substituted lower alkanoylamino, lower alkoxycarbonyl(lower)alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and amino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and lower alkoxycarbonyl-amino substituted lower alkanoylamino, dihydrophenyl and amino substituted lower alkanoylamino, dihydrophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, phenyl and azido substituted lower alkanoylamino, phenyl and hydroxy substituted lower alkanoylamino, phenyl and lower alkanoyloxy substituted lower alkanoylamino, phenyl and pyridylcarbonyloxy substituted lower alkanoylamino, phenyl and sulfo substituted lower alkanoylamino, phenyl and indanyloxycarbonyl substituted lower alkanoylamino, thienyl(lower)alkanoylamino, thienyl and amino substituted lower alkanoylamino, thienyl and lower alkoxycarbonylamino substituted lower alkanoylamino, thienyl and hydroxy substituted lower alkanoylamino, dihydropyranyl(lower)alkanoylamino, dihydropyranyl and amino substituted lower alkanoylamino, dihydropyranyl and lower alkoxycarbonylamino substituted lower alkanoylamino, pyridyl(lower)alkanoylamino, thiadiazolyl(lower)alkanoylamino, lower alkylthiadiazolyloxy(lower)alkanoylamino, thiadiazolylthio(lower)alkanoylamino, tetrazolyl(lower)alkanoylamino, halophenyl and lower alkyl substituted isoxazolylcarbox-amido, R2 is carboxy, lower alkoxycarbonyl or trihalo(lower)alkoxycarbonyl, R3 is lower alkyl and X is -S- or -?-.

123. A process according to claim 122, wherein R3 is methyl and X is -S-.

124. A process according to claim 123, wherein R1b is (1-cyclopropylethoxy)carboxamido and R2 is carboxy.

125. A process according to claim 123, wherein X1b is (1-cyclopropylethoxy)carboxamido and R2 is 2,2,2-trichloroethoxycarbonyl.

126. A process according to claim 123, wherein R1b is benzyloxycarboxamido and R2 is carboxy.

127. A process according to claim 123, wherein R1b is benzyloxycarboxamido and R2 is 2,2,2-trichloroethoxycarbonyl.

128. A process according to claim 123, wherein R1b is 3-phenylureido and R2 is carboxy.

129. A process according to claim 123, wherein R1b is 3-phenylureido and R2 is 2,2,2-trichloroethoxycarbonyl.

130. A process according to claim 123, wherein R1b is 2-(4-methoxyphenyl)glyoxylamido and R2 is carboxy.

131. A process according to claim 123, wherein R1b is 2-cyanoacetamido and R2 is carboxy.

132. A process according to claim 123, wherein R1b is 2-cyanoacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

133. A process according to claim 123, wherein R1b is 2-methylthioacetamido and R2 is carboxy.

134. A process according to claim 123, wherein R1b is 2-methylthioacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

135. A process according to claim 123, wherein R1b is 2-(allylthio)acetamido and R2 is carboxy.

136. A process according to elaim 123, wherein R1b is 2-(allylthio)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

137. A process according to claim 123, wherein R1b is 2-(phenylthio)acetamido and R2 is carboxy.

138. A process according to claim 123, wherein R1b is 2-(phenylthio)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

139. A process according to claim 123, wherein R1b is 2-phenoxyacetamido and R2 is methoxycarbonyl.

140. A process according to claim 123, wherein R1b is 2-phenoxyacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

141. A process according to claim 123, wherein R1b is 2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

142. A process according to claim 123, wherein R1b is 2-(3-chlorophenyl)acetamido and R2 is carboxy.

143. A process according to claim 123, wherein R1b is 2-(3-chlorophenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

144. A process according to claim 123, wherein R1b is N-(1-cyclopropylethoxy)carbonylphenylglycylamino and R2 is carboxy.

145. A process according to claim 123, wherein R1b is N-(1-cyclopropylethoxy)carbonylphenylglycylamino and R2 is 2,2,2-trichloroethoxycarbonyl.

146. A process according to claim 123, wherein R1b is N-tertiarybutoxycarbonylphenylglycylamino and R2 is carboxy.

147. A process according to claim 123, wherein R1b is N-tertiarybutoxycarbonylphenylglycylamino and R2 is 2,2,2-trichloroethoxycarbonyl.

148. A process according to claim 123, wherein R1b is N-[2-(2-nitrophenoxy)acetyl]phenylglycylamino and R2 is carboxy.

149. A process according to claim 123, wherein R1b is N-(1,3,4-thiadiazol-2-ylthio)acetylphenylglycylamino and R2 is carboxy.

150. A process according to claim 123, wherein R1b is N-(1,3,4-thiadiazol-2-ylthio)acetylphenylglycylamino and R2 is 2,2,2-trichloroethoxycarbonyl.

151. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(4-hydroxyphenyl)acetamido and R2 is carboxy.

152. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(4-hydroxyphenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

153. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(4-methoxyphenyl)acetamido and R2 is carboxy.

154. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(4-methoxyphenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

155. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(4-methylthiophenyl)acetamido and R2 is carboxy.

156. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(4-methylthiophenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

157. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(4-methylsulfinylphenyl)-acetamido and R2 is carboxy.

158. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(4-methylsulfinylphenyl)-acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

159. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(4-tertiarybutoxycarbonyl-methoxyphenyl)acetamido and R2 is carboxy.

160. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(4-tertiarybutoxycarbonyl-methoxyphenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

161. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(3-methanesulfonamidophenyl)-acetamido and R2 is carboxy.

162. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(3-methanesulfonamidophenyl)-acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

163. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(2,5-dihydrophenyl)acetamido and R2 is carboxy.

164. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(2,5-dihydrophenyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

165. A process according to claim 123, wherein R1b is 2-azido-2-phenylacetamido and R2 is carboxy.

166. A process according to claim 123, wherein R1b is 2-formyloxy-2-phenylacetamido and R2 is carboxy.

167. A process according to claim 123, wherein R1b is 2-formyloxy-2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

168. A process according to claim 123, wherein R1b is 2-isonicotinoyloxy-2-phenylacetamido and R2 is carboxy.

169. A process according to claim 123, wherein R1b is 2-isonicotinoyloxy-2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

170. A process according to claim 123, wherein R1b is 2-sulfo-2-phenylacetamido and R2 is carboxy.

171. A process according to claim 123, wherein R1b is 2-sulfo-2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

172. A process according to claim 123, wherein R1b is 2-(5-indanyloxy)carbonyl-2-phenylacetamido and R2 is carboxy.

173. A process according to claim 123, wherein R1b is 2-(5-indanyloxy)carbonyl-2-phenylacetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

174. A process according to claim 123, wherein R1b is 2-(2-thienyl)acetamido and R2 is carboxy.

175. A process according to claim 123, wherein R1b is 2-(2-thienyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

176. A process according to claim 123, wherein R1b is 2 tertiarybutoxycarbonylamino-2-(2-thienyl)acetamido and R2 is carboxy.

177. A process according to claim 123, wherein R1b is 2-tertiarybutoxycarbonylamino-2-(2-thienyl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

178. A process according to claim 123, wherein R1b is 3-tertiarybutoxycarbonylamino-3-(2-thienyl)propionamido and R2 is carboxy.

179. A process according to claim 123, wherein R1b is 3-tertiarybutoxycarbonylamino-3-(2-thienyl)propionamido and R2 is 2,2,2-trichloroethoxycarbonyl.

180. A process according to claim 123, wherein R1b is 2-hydroxy-2-(2-thienyl)acetamido and R2 is carboxy.

181. A process according to claim 123, wherein R1b is 2-(5,6-dihydro-2H-pyran-3-yl)acetamido and R2 is carboxy.

182. A process according to claim 123, wherein R1b is 2-(5,6-dihydro-2H-pyran-3-yl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

183. A process according to claim 123, wherein R1b is 2-(1-cyclopropylethoxy)carbonylamino-2.(5,6-dihydro-2H-pyran-3-yl)acetamido and R2 is carboxy.

184. A process according to claim 123, wherein R1b is 2-(1-cyclopropylethoxy)carbonylamino-2-(5,6-dihydro-2H-pyran-3-yl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

185. A process according to claim 123, wherein R1b is 2-(3-pyridyl)acetamido and R2 is carboxy.

186. A process according to claim 123, wherein R1b is 2-(1,2,5-thiadiazol-3-yl)acetamido and R2 is carboxy.

187. A process according to claim 123, wherein R1b is 2-(1,2,5-thiadiazol-3-yl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

188. A process according to claim 123, wherein R1b is 2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido and R2 is carboxy.

189. A process according to claim 123, wherein R1b is 2-(5-methyl-1,3,4-thiadiazol-2-yloxy acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

190. A process according to claim 123, wherein R1b is 2-(1,3,4-thiadiazol-2-ylthio)acetamido and R2 is carboxy.

191. A process according to claim 123, wherein R1b is 2-(1,3,4-thiadiazol-2-ylthio)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

192. A process according to claim 123, wherein R1b is 2-(1H-tetrazol-1-yl)acetamido and R2 is carboxy.

193. A process according to claim 123, wherein R1b is 2-(1H-tetrazol-1-yl)acetamido and R2 is 2,2,2-trichloroethoxycarbonyl.

194. A process according to claim 123, wherein R1b is 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido and R2 is carboxy.

195. A process according to claim 123, wherein R1b is 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido and R2 is 2,2,2-trichloroethoxycarbonyl.

196. A process according to claim 122, wherein R1b is 2-phenylacetamido, R2 is 2,2,2-trichloroethoxycarbonyl, R3 is methyl and X is -?-.

197. A process according to claim 1(f) for the preparation of a compound of the general formula:

wherein R1b' is acylamino, R2 is carboxy or a protected carboxy, R3 is lower alkyl and X is -S- or -?-, and pharmaceutically acceptable salt thereof, which comprises reacting a compound of the general formula:

wherein R2, R3 and X are each as defined above, and R1b is acylamino, with a trialkyloxoniumhaloborate or an iminohalogenating agent and an iminoetherifying agent, and then reacting the resulting compound with an acylating agent, if necessary, followed by hydrolysis.

198. A process according to claim 197, wherein R1b is phenoxy(lower)alkanoylamino or phenyl(lower)alkanoylamino, R1b' is lower alkoxycarbonylamino, phenyl(lower)alkoxycarbonylamino, 3-phenylureido, lower alkoxyphenylglyoxylamido, cyano(lower)alkanoylamino, lower alkylthio(lower)alkanoylamino, lower alkenylthio(lower)alkanoylamino, phenylthio(lower)alkanoylamino, halophenyl(lower)alkanoylamino, phenyl and amino substituted lower alkanoylamino, phenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, phenyl and nitrophenoxy(lower)alkanoylamino substituted lower alkanoylamino, phenyl and thiadiazolylthio(lower)alkanoylamino substituted lower alkanoylamino, hydroxyphenyl and amino substituted lower alkanoylamino, hydroxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkoxyphenyl and amino substituted lower alkanoyl-amino, lower alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylthiophenyl and amino substituted lower alkanoylamino, lower alkylthiophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylsulfinylphenyl and amino substituted lower alkanoylamino, lower alkylsulfinylphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, carboxy(lower)alkoxyphenyl and amino substituted lower alkanoylamino, lower alkoxycarbonyl(lower)alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and amino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, dihydrophenyl and amino substituted lower alkanoylamino, dihydrophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, phenyl and azido substituted lower alkanoylamino, phenyl and hydroxy substituted lower alkanoylamino, phenyl and lower alkanoyloxy substituted lower alkanoylamino, phenyl and pyridylcarbonyloxy substituted lower alkanoylamino, phenyl and sulfo substituted lower alkanoylamino, phenyl and indanyloxycarbonyl substituted lower alkanoylamino, thienyl(lower)alkanoylamino, thienyl and amino substituted lower alkanoylamino, thienyl and lower alkoxycarbonylamino substituted lower alkanoylamino, thienyl and hydroxy substituted lower alkanoylamino, dihydropyranyl(lower)alkanoylamino, dihydropyranyl and amino substituted lower alkanoylamino, dihydropyranyl and lower alkoxycarbonylamino substituted lower alkanoylamino, pyridyl(lower)alkanoylamino, thiadiazolyl(lower)alkanoylamino, lower alkylthiadiazolyloxy(lower)alkanoylamino, thiadiazolylthio(lower)alkanoylamino, tetrazolyl(lower)alkanoylamino, halophenyl and lower alkyl substituted isoxazolyl-carboxamido, R2 is carboxy, lower alkoxycarbonyl or trihalo(lower)alkoxycarbonyl, R3 is lower alkyl and X is -S-.

199. A process according to claim 198, wherein R1b is 2-phenoxyacetamido or 2-phenylacetamido, R1b is 2-cyanoacetamido, 2-methylthioacetamido, 2-(allylthio)acetamido, 2-(phenylthio)acetamido, 2-(3-chlorophenyl)acetamido, N-(1-cyclopropylethoxy)carbonylphenylglycylamino, N-(1,3,4-thiadiazol-2-ylthio)acetylphenylglycylamino, 2-tertiarybutoxycarbonylamino-2-(4-hydroxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methoxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methylthiophenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methylsulfinylphenyl)-acetamido, 2-tertiarybutoxycarbonylamino-2-(4-tertiarybutoxycarbonyl-methoxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(3-methanesulfonamidophenyl)-acetamido, 2-tertiarybutoxycarbonylamino-2-(2,5-dihydrophenyl)acetamido, 2-azido-2-phenylacetamido, 2-isonicotinoyloxy-2-phenylacetamido, 2-sulfo-2-phenylacetamido, 2-(5-indanyloxy)carbonyl-2-phenylacetamido, 2-(2-thienyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(2-thienyl)acetamido, 3-tertiarybutoxycarbonylamino-3-(2-thienyl)propionamido, 2-hydroxy-2-(2-thienyl)acetamido, 2-(5,6-dihydro-2H-pyran-3-yl)acetamido, 2-(1-cyclopropylethoxy)carbonylamino-2-(5,6-dihydro-2H-pyran-3-yl)acetamido, 2-(3-pyridyl)acetamido, 2-(1,2,5-thiadiazol-3-yl)acetamido, 2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido, 2-(1,3,4-thiadiazol-2-ylthio)acetamido, 2-(1H-tetrazol-1-yl)acetamido, or 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido, R2 is carboxy, methoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, and R3 is methyl.

200. A process according to claim 1(g) for the preparation of a compound of general formula:

wherein R1d is acylamino having an amino, R2 is carboxy or a protected carboxy, R3 is lower alkyl and X is -S- or -?-, and pharmaceutically acceptable salt thereof, which comprises subjecting a compound of the general formula:

wherein R2, R3 and X are each as defined above, and R1c is acylamino having a protected amino, to elimination reaction of the protective group of the amino.

201. A process according to claim 200, wherein R1c is phenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, hydroxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylthiophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylsulfinylphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkoxycarbonyl(lower)alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and lower alkoxycarboxylamino substituted lower alkanoylamino, dihydrophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, thienyl and lower alkoxycarbonylamino substituted lower alkanoy1amino or dihydropyranyl and lower alkoxycarbonylamino substituted lower alkanoylamino, R1d is phenyl and amino substituted lower alkanoylamino, hydroxyphenyl and amino substituted lower alkanoylamino, lower alkoxyphenyl and amino substituted lower alkanoylamino, lower alkylthiophenyl and amino substituted lower alkanoylamino, lower alkylsulfinylphenyl and amino substituted lower alkanoylamino, carboxy(lower)alkoxyphenyl and amino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and amino substituted lower alkanoylamino, dihydrophenyl and amino substituted lower alkanoylamino, thienyl and amino substituted lower alkanoylamino or dihydropyranyl and amino substituted lower alkanoylamino, R2 is carboxy, R3 is methyl and X is -S-.

202. A process according to claim 201, wherein R1c is N-(1-cyclopropylethoxy)carbonylphenylglycylamino, 2-tertiarybutoxycarbonylamino-2-(4-hydroxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methoxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methylthiophenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methylsulfinylphenyl)-acetamido, 2-tertiarybutoxycarbonylamino-2-(4-tertiarybutoxycarbonyl-methoxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(3-methanesulfonamidophenyl)-acetamido, 2-tertiarybutoxycarbonylamino-2-(2,5-dihydrophenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(2-thienyl)acetamido, 3-tertiarybutoxycarbonylamino-3-(2-thienyl)propionamido or 2-(1-cyclopropylethoxy)carbonylamino-2-(5,6-dihydro-2H-pyran-3-yl)acetamido and R1d is phenylglycylamino, 2-amino-2-(4-hydroxyphenyl)acetamido, 2-amino-2-(4-methoxyphenyl)acetamido, 2-amino-2-(4-methylthiophenyl)acetamido, 2-amino-2-(4-methylsulfinylphenyl)acetamido, 2-amino-2-(4-carboxymethoxyphenyl)acetamido, 2-amino-2-(3-methanesulfonamidophenyl)acetamido, 2-amino-2-(2,5-dihydrophenyl)acetamido, 2-amino-2-(2-thienyl)acetamido, 3-amino-3-(2-thienyl)propionamido or 2-amino-2-(5,6-dihydro-2H-pyran-3-yl)acetamido.

203. A process according to claim 1(h) for the pre-paration of a compound of the general formula:

wherein R1f is acylamino having a hydroxy, R2 is carboxy or a protected carboxy, R3 is lower alkyl and X is -S- or -?-, and pharmaceutically acceptable salt thereof, which comprises subjecting a compound of the general formula:

wherein R2, R3 and X are each as defined above, and R1e is acylamino having a protected hydroxy, to elimination reaction of the protective group of the hydroxy.

204. A process according to claim 1(i) for the preparation of a compound of the general formula:

wherein R1 is amino, 2,2-di(lower)alkyl-4-aryl-5-oxoimidazolidin-1-yl or acylamino, R3 is lower alkyl and X is -S- or -?-, and pharmaceutically acceptable salt thereof, which comprises subjecting a compound of the general formula:

wherein R1, R3 and X are each as defined above, and R2a is a protected carboxy, to elimination reaction of the protective group of the carboxy.

205. A process according to claim 204, wherein R1 is amino 2,2-di(lower)alkyl-4-phenyl-5-oxoimidazolidin-1-yl, lower alkoxycarbonylamino, phenyl(lower)alkoxycarbonylamino, 3-phenylureido, lower alkoxyphenylglyoxylamido, cyano(lower)alkanoylamino, lower alkylthio(lower)alkanoylamino, lower alkenylthio(lower)alkanoylamino, phenylthio(lower)alkanoylamino, phenoxy(lower)alkanoylamino, phenyl(lower)alkanoylamino, halophenyl(lower)alkanoylamino, phenyl and amino substituted lower alkanoylamino, phenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, phenyl and nitrophenoxy(lower)alkanoylamino substituted lower alkanoylamino, phenyl and thiadiazolylthio(lower)alkanoylamino substituted lower alkanoylamino, hydroxyphenyl and amino substituted lower alkanoylamino, hydroxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkoxyphenyl and amino substituted lower alkanoylamino, lower alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylthiophenyl and amino substituted lower alkanoylamino, lower alkylthiophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkylsulfinylphenyl and amino substituted lower alkanoylamino, lower alkylsulfinylphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, carboxy(lower)alkoxyphenyl and amino substituted lower alkanoylamino, lower alkoxycarbonyl(lower)alkoxyphenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and amino substituted lower alkanoylamino, lower alkanesulfonamidophenyl and lower alkoxycarbonyl-amino substituted lower alkanoylamino, dihydrophenyl and amino substituted lower alkanoylamino, dihydrophenyl and lower alkoxycarbonylamino substituted lower alkanoylamino, phenyl and azido substituted lower alkanoylamino, phenyl and hydroxy substituted lower alkanoylamino, phenyl and lower alkanoyloxy substituted lower alkanoylamino, phenyl and pyridylcarbonyloxy substituted lower alkanoylamino, phenyl and sulfo substituted lower alkanoylamino, phenyl and indanyloxycarbonyl substituted lower alkanoylamino, thienyl(lower)alkanoylamino, thienyl and amino substituted lower alkanoylamino, thienyl and lower alkoxycarbonylamino substituted lower alkanoylamino, thienyl and hydroxy substituted lower alkanoylamino, dihydropyranyl(lower)alkanoylamino, dihydropyranyl and amino substituted lower alkanoylamino, dihydropyranyl and lower alkoxycarbonylamino substituted lower alkanoylamino, pyridyl(lower)alkanoylamino, thiadiazolyl(lower)alkanoylamino, lower alkylthiadiazolyloxy(lower)alkanoylamino, thiadiazolylthio(lower)alkanoylamino, tetrazolyl(lower)alkanoylamino, halophenyl and lower alkyl substituted isoxazolylcarboxamido, R2a is lower alkoxycarbonyl or trihalo(lower)alkoxycarbonyl, R3 is lower alkyl and X is -S-.

206. A process according to claim 205, wherein R2a is 2,2,2-trichloroethoxycarbonyl and R3 is methyl.

207. A process according to claim 204, wherein R2a is 2,2,2-trichloroethoxycarbonyl, R3 is methyl, X is -S- and R1 is selected from the group consisting of amino, (1-cyclopropylethoxy)carboxamido, benzyloxycarboxamido, 3-phenylureido, 2-(4-methoxyphenyl)glyoxylamido, 2-cyanoacetamido, 2-methylthioacetamido, 2-(allylthio)acetamido, 2-(phenylthio)acetamido, 2-phenoxyacetamido, 2-phenylacetamido, 2-(3-chlorophenyl)acetamido, phenylglycylamino, N-(1-cyclopropylethoxy)carbonylphenylglycylamino, N-tertiarybutoxycarbonylphenylglycylamino, N-[2-(2-nitrophenoxy)acetyl]phenylglycylamino, N-(1,3,4-thiadiazol-2-ylthio)acetylphenylglycylamino, 2-amino-2-(4-hydroxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-hydroxyphenyl)acetamido, 2-amino-2-(4-methoxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methoxyphenyl)acetamido, 2-amino-2-(4-methylthiophenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methylthiophenyl)acetamido, 2-amino-2-(4-methylsulfinylphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-methylsulfinylphenyl)acetamido, 2-amino-2-(4-carboxymethoxyphenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(4-tertiarybutoxycarbonyl-methoxyphenyl)acetamido, 2-amino-2-(3-methanesulfonamidophenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(3-methanesulfonamidophenyl)-acetamido, 2-amino-2-(2,5-dihydrophenyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(2,5-dihydrophenyl)acetamido, 2-azido-2-phenylacetamido, 2-hydroxy-2-phenylacetamido, 2-formyloxy-2-phenylacetamido, 2-isonicotinoyloxy-2-phenylacetamido, 2-sulfo-2-phenylacetamido, 2-(5-indanyloxy)carbonyl-2-phenylacetamido, 2-(2-thienyl)acetamido, 2-amino-2-(2-thienyl)acetamido, 2-tertiarybutoxycarbonylamino-2-(2-thienyl)acetamido, 3-amino-3-(2-thienyl)propionamido, 3-tertiarybutoxycarbonylamino-3-(2-thienyl)propionamido, 2-hydroxy-2-(2-thienyl)acetamido, 2-(5,6-dihydro-2H-pyran-3-yl)acetamido, 2-amino-2-(5,6-dihydro-2H-pyran-3-yl)acetamido, 2-(1-cyclopropylethoxy)carbonylamino-2-(5,6-dihydro-2H-pyran-3-yl)acetamido, 2-(3-pyridyl)acetamido, 2-(1,2,5-thiadiazol-3-yl)acetamido, 2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido, 2-(1,3,4-thiadiazol-2-ylthio)acetamido, 2-(1H-tetrazol-1-yl)acetamido, 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido.

208. A process according to claim 1(j) for the preparation of a compound of the general formula:

wherein R2 is carboxy or a protected carboxy, R3 is lower alkyl, R4 is aryl, R5 and R6 are each lower alkyl and X is -S- or -?-, and pharmaceutically acceptable salt thereof, which comprises reacting a compound of the general formula:

wherein R2, R3, R4 and X are each as defined above, or a salt thereof with a lower alkanone of the general formula:

wherein R5 and R6 are each as defined above.

209. A compound of the general formula:

wherein R1, R2, R3 and X are each as defined in claim 1 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

210. A compound of the general formula:

wherein R1, R2, R3 and X are each as defined in claim 2 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

211, A compound of the general formula:

wherein R1, R2, R3 and X are each as defined in claim 3 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

212, A compound of the general formula:

wherein R1, R2, R3 and X are each as defined in claim 4 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

213. 2-Methyl-7-(1-cyclopropylethoxy)carboxamido-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

214. 2,2,2-Trichloroethyl 2-methyl-7-(1-cyclopropylethoxy)-carboxamido-3-cephem-4-carboxylate whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

215. 2-Methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

216. 2,2,2-Trichloroethyl 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylate whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.

217. 2-Methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

218. 2,2,2-Trichloroethyl 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylate whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.

219, 2-methyl-7-(4-methoxyphenyl)glyoxyamido-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.

220. 2-Methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.

221. 2,2,2-Trichloroethyl 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

222. 2-Methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.

223. 2,2,2-Trichloroethyl 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

224. 2-Methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.

225. 2,2,2-Trichloroethyl 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

226. 2-Methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 18 or by an obvious chemical equivalent thereof.

227. 2,2,2-Trichloroethyl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.

228. Methyl 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 20 or by an obvious chemical equivalent thereof.

229. 2,2,2-Trichloroethyl 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 21 or by an obvious chemical equivalent thereof.

230. 2-Methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.

231. 2,2,2-Trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 23 or by an obvious chemical equivalent thereof.

232. 2-Methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 24 or by an obvious chemical equivalent thereof.

233. 2,2,2-Trichloroethyl 2-methyl-7-[2-(3-chlorophenyl)-acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 25 or by an obvious chemical equivalent thereof.

234. 2-Methyl-7-[N-(1-cyclopropylethoxy)carbonylphenyl-glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 26 or by an obvious chemical equivalent thereof.

235. 2,2,2-Trichloroethyl 2-methyl-7-[N-(1-cyclopropyl-ethoxy)carbonylphenylglycyl-amino-3-cephem-4-carboxylate whenever prepared by the process of claim 27 or by an obvious chemical equivalent thereof.

236. 2-Methyl-7-(N-tertiarybutoxycarbonylphenyl-D-glycyl)-amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 28 or by an obvious chemical equivalent thereof.

237. 2,2,2-Trichloroethyl 2-methyl-7-(N-tertiarybutoxy-carbonylphenyl-D-glycyl)amino-3-cephem-4-carboxylate whenever prepared by the process of claim 29 or by an obvious chemical equivalent thereof.

238. 2-Methyl-7-[N-[2-(2-nitrophenoxy)acetyl]phenylglycyl]-amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 30 or by an obvious chemical equivalent thereof.

239. 2,2,2-Trichloroethyl 2-methyl-7-[N-(1,3,4-thiadiazol-2-ylthio)acetyl-2-phenylglycyl]amino-3-cephem,4-carboxylate whenever prepared by the process of claim 31 or by an obvious chemical equivalent thereof.

240. 2-Methyl-7-[D-2-(4-hydroxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 32 or by an obvious chemical equivalent thereof.

241. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(4-hydroxyphenyl)-D-glycyl]amino-3-cephem-4-carboxy-late whenever prepared by the process of claim 33 or by an obvious chemical equivalent thereof.

242. 2-Methyl-7-[2-(4-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 34 or by an obvious chemical equivalent thereof.

243. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(4-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 35 or by an obvious chemical equivalent thereof.

244. 2-Methyl-7-[2-(4-methylthiophenyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 36 or by an obvious chemical equivalent thereof.

245. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(4-methylthiophenyl)glycyl]amino-3-cephem-4-carboxy-late whenever prepared by the process of claim 37 or by an obvious chemical equivalent thereof.

246. 2-Methyl-7-[2-(4-methylsulfinylphenyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 38 or by an obvious chemical equivalent thereof.

247. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(4-methylsulfinylphenyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 39 or by an obvious chemical equivalent thereof.

248. 2-Methyl-7-[2-(4-carboxymethoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 40 or by an obvious chemical equivalent thereof.

249. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(4-tertiarybutoxycarbonylmethoxyphenyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 41 or by an obvious chemical equivalent thereof.

250. 2-Methyl-7-[2-(3-methanesulfonamidophenyl)glycyl]-amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 42 or by an obvious chemical equivalent thereof.

251. 2-Methyl-7-[N-tertiarybutoxycarbonyl-2-(3-methane-sulfonamidophenyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 43 or by an obvious chemical equivalent thereof.

252. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(3-methanesulfonamidophenyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 44 or by an obvious chemical equivalent thereof.

253. 2-Methyl-7-[2-(2,5-dihydrophenyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 45 or by an obvious chemical equivalent thereof.

254. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(2,5-dihydrophenyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 46 or by an obvious chemical equivalent thereof.

255. 2-Methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 47 or by an obvious chemical equivalent thereof.

256. 2,2,2-Trichloroethyl 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 48 or by an obvious chemical equivalent thereof.

257. 2,2,2-Trichloroethyl 2-methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 49 or by an obvious chemical equivalent thereof.

258. 2,2,2-Trichloroethyl 2-methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 50 or by an obvious chemical equivalent thereof.

259. 2,2,2-Trichloroethyl 2-methyl-7-[2-(5-indanyl)-oxycarbonyl-2-phenylacetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 51 or by an obvious chemical equivalent thereof.

260. 2-Methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 52 or by an obvious chemical equivalent thereof.

261. 2,2,2-Trichloroethyl 2-methyl-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 53 or by an obvious chemical equivalent thereof.

262. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 54 or by an obvious chemical equivalent thereof.

263. 2-Methyl-7-[3-(N-tertiarybutoxycarbonylamino)-3-(2-thienyl)propionamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 55 or by an obvious chemical equivalent thereof.

264. 2,2,2-Trichloroethyl 2-methyl-7-[3-N-tertiary-butoxycarbonylamino)-3-(2-thienyl)propionamido]-3-cepham-4-carboxylate whenever prepared by the process of claim 56 or by an obvious chemical equivalent thereof.

265. 2-Methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 57 or by an obvious chemical equivalent thereof.

266. 2,2,2-Trichloroethyl 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 58 or by an obvious chemical equivalent thereof.

267. 2-Methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 59 or by an obvious chemical equivalent thereof.

268. 2,2,2-Trichloroethyl 2-methyl-7-[N-(1-cyclopropyl-ethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 60 or by an obvious chemical equivalent thereof.

269. 2,2,2-Trichloroethyl 2-methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 61 or by an obvious chemical equivalent thereof.

270. 2-Methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 62 or by an obvious chemical equivalent thereof.

271. 2,2,2-Trichloroethyl 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 63 or by an obvious chemical equivalent thereof.

272. 2-Methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 64 or by an obvious chemical equivalent thereof.

273. 2,2,2-Trichloroethyl 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 65 or by an obvious chemical equivalent thereof.

274. 2-Methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 66 or by an obvious chemical equivalent thereof.

275. 2,2,2-Trichloroethyl 2-methyl-7-[2(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 67 or by an obvious chemical equivalent thereof.

276. 2-Methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 68 or by an obvious chemical equivalent thereof.

277. 2,2,2-Trichloroethyl 2-methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylate whenever prepared by the process of claim 69 or by an obvious chemical equivalent thereof.

278. A compound of the general formula:

wherein R1, R2 and R3 are each as defined in claim 70 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 70 or by an obvious chemical equivalent thereof.

279. 2,2,2-Trichloroethyl 2-methyl-7-(2-phenylacetamido)-1-oxide-3-cephem-4-carboxylate whenever prepared by the process of claim 71 or by an obvious chemical equivalent thereof.

280. A 3-cephem compound of the general formula:

wherein R1, R2 and R3 are each as defined in claim 72 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 72 or by an obvious chemical equivalent thereof.

281. 2-Methyl-7-amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 74 or by an obvious chemical equivalent thereof.

282. 2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate whenever prepared by the process of claim 75 or by an obvious chemical equivalent thereof.

283. 2-Methyl-7-(1-cyclopropylethoxy)carboxamido-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 76 or by an obvious chemical equivalent thereof.

284. 2,2,2-Trichloroethyl 2-methyl-7-(1-cyclopropyl-ethoxy)carboxamido-3-cephem-4-carboxylate whenever prepared by the process of claim 77 or by an obvious chemical equivalent thereof.

285. 2-Methyl-7-benzyloxycarboxamide-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 78 or by an obvious chemical equivalent thereof.

286. 2,2,2-Trichloroethyl 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylate whenever prepared by the process of claim 79 or by an obvious chemical equivalent thereof.

287. 2-Methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 80 or by an obvious chemical equivalent thereof.

288. 2,2,2-Trichloroethyl 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylate whenever prepared by the process of claim 81 or by an obvious chemical equivalent thereof.

289. 2-Methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 82 or by an obvious chemical equivalent thereof.

290. 2,2,2-Trichloroethyl 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 83 or by an obvious chemical equivalent thereof.

291. 2-Methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 84 or by an obvious chemical equivalent thereof.

292. 2,2,2-Trichloroethyl 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 85 or by an obvious chemical equivalent thereof.

293. 2 Methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 86 or by an obvious chemical equivalent thereof.

294. 2,2,2-Trichloroethyl 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 87 or by an obvious chemical equivalent thereof.

295. 2-Methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 88 or by an obvious chemical equivalent thereof.

296. 2,2,2-Trichloroethyl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 89 or by an obvious chemical equivalent thereof.

297. Methyl 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylate whenevbr prepared by the process of claim 90 or by an obvious chemical equivalent thereof.

298. 2,2,2-Trichloroethyl 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 91 or by an obvious chemical equivalent thereof.

299. 2,2,2-Trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 92 or by an obvious chemical equivalent thereof.

300. 2-Methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 93 or by an obvious chemical equivalent thereof.

301. 2,2,2-Trichloroethyl 2-methyl-7-[2-(3-chlorophenyl)-acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 94 or by an obvious chemical equivalent thereof.

302. 2-Methyl-7-phenylglycylamino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 95 or by an obvious chemical equivalent thereof.

303. 2-Methyl-7-[N-(1-cyclopropylethoxy)carbonylphenyl-glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 96 or by an obvious chemical equivalent thereof.

304. 2,2,2-Trichloroethyl 2-methyl-7-[N-(1-cyclopropyl-ethoxy)carbonylphenylglycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 97 or by an obvious chemical equivalent thereof.

305. A 3-cephem compound as defined in claim 72, wherein R3 is methyl whenever prepared by the process of claim 73 or by an obvious chemical equivalent thereof.

306. 2-Methyl-7-(2-hydroxy-2-phenylacetamido)-3-cephem, 4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 98 or by an obvious chemical equivalent thereof.

307. 2-Methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 99 or by an obvious chemical equivalent thereof.

308. 2,2,2-Trichloroethyl 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 100 or by an obvious chemical equivalent thereof.

309. 2 Methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 101 or by an obvious chemical equivalent thereof.

310. 2,2,2-Trichloroethyl 2-methyl-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 102 or by an obvious chemical equivalent thereof.

311. 2-Methyl-7-[2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 103 or by an obvious chemical equivalent thereof.

312. 2-Methyl-7-[N-tertiarybutoxycarbonyl-2-(2-thienyl)-glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 104 or by an obvious chemical equivalent thereof.

313. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 105 or by an obvious chemical equivalent thereof.

314. 2-Methyl-7-[3-amino-3-(2-thienyl)propionamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 106 or by an obvious chemical equivalent thereof.

315. 2-Methyl-7-[3-(N-tertiarybutoxycarbonylamino)-3-(2-thienyl)propionamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 107 or by an obvious chemical equivalent thereof.

316. 2,2,2-Trichloroethyl 2-methyl-7-[3-(N-tertiarybutoxy-carbonylamino)-3-(2-thienyl)propionamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 108 or by an obvious chemical equivalent thereof.

317. 2,2,2-Trichloroethyl 2-methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 109 or by an obvious chemical equivalent thereof.

318. 2-Methyl-7-[2 (5-methyl-1,3,4-thiadiazol-2-yloxy)-acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 110 or by an obvious chemical equivalent thereof.

319. 2,2,2-Trichloroethyl 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 111 or by an obvious chemical equivalent thereof.

320. 2-Methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 112 or by an obvious chemical equivalent thereof.

321. 2,2,2-Trichloroethyl 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 113 or by an obvious chemical equivalent thereof.

322. 2-Methyl-7-[2-(1H-tetrazol-1-yl)acetamido]3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 114 or by an obvious chemical equivalent thereof.

323. 2,2,2-Trichloroethyl 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 115 or by an obvious chemical equivalent thereof.

324. 2-Methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 116 or by an obvious chemical equivalent thereof.

325. 2,2,2-Trichloroethyl-2-methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylate whenever prepared by the process of claim 117 or by an obvious chemical equivalent thereof.

326. A compound of the general formula:
wherein R2, R3 and X are each as defined in claim 118 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 118 or by an obvious chemical equivalent thereof.

327. A compound of the general formula:
wherein R2, R3 and X are each as defined in claim 119 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 119 or by an obvious chemical equivalent thereof.

328. A compound of the general formula:

wherein R2, R3 and X are each as defined in claim 120 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 120 or by an obvious chemical equivalent thereof.

329. A compound of the general formula:

wherein R1b, R2, R3 and X are each as defined in claim 121 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 121 or by an obvious chemical equivalent thereof.

330. A compound of the general formula:

wherein R1b, R2, R3 and X are each as defined in claim 122 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 122 or by an obvious chemical equivalent thereof.

331. A compound of the general formula:

wherein R1b, R2, R3 and X are each as defined by claim 123 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 123 or by an obvious chemical equivalent thereof.

332. 2-Methyl-7-(1-cyclopropylethyy)carboxamido-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 124 or by an obvious chemical equivalent thereof.

333. 2,2,2-Trichloroethyl 2-methyl-7-(1-cyclopropyl-ethoxy)caxboxamido-3-cephem-4-carboxylate whenever prepared by the process of claim 125 or by an obvious chemical equivalent thereof.

334. 2-Methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 126 or by an obvious chemical equivalent thereof.

335. 2,2,2-Trichloroethyl 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylate whenever prepared by the process of claim 127 or by an obvious chemical equivalent thereof.

336. 2-Methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 128 or by an obvious chemical equivalent thereof.

337. 2,2,2-Trichloroethyl 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylate whenever prepared by the process of claim 129 or by an obvious chemical equivalent thereof.

338. 2-Methyl-7-(4-methoxyphenyl)glyoxylamido-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 130 or by an obvious chemical equivalent thereof.

339. 2-Methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 131 or by an obvious chemical equivalent thereof.

340. 2,2,2-Trichloroethyl 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 132 or by an obvious chernical equivalent thereof.

341. 2-Methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 133 or by an obvious chemical equivalent thereof.

342. 2,2,2-Trichloroethyl 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 134 or by an obvious chemical equivalent thereof.

343. 2-Methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid and pharmacetically acceptable salt thereof whenever prepared by the process of claim 135 or by an obvious chemical equivalent thereof.

344. 2,2,2-Trichloroethyl 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 136 or by an obvious chemical equivalent thereof.

345. 2-Methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 137 or by an obvious chemical equivalent thereof.

346. 2,2,2-Trichloroethyl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 138 or by an obvious chemical equivalent thereof.

347. Methyl 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 139 or by an obvious chemical equivalent thereof.

348. 2,2,2-Trichloroethyl 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 140 or by an obvious chemical equivalent thereof.

349. 2,2,2-Trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 141 or by an obvious chemical equivalent thereof.

350. 2-Methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 142 or by an obvious chemical equivalent thereof.

351. 2,2,2-Trichloroethyl 2-methyl-7-[2-(3-chlorophenyl)-acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 143 or by an obvious chemical equivalent thereof.

352. 2-Methyl-7-[N-(1-cyclopropylethoxy)carbonylphenyl-glycyl]amino-3-cephem-4-carboxylic acid and pharmacetically acceptable salt thereof whenever prepared by the process of claim 144 or by an obvious chemical equivalent thereof.

353. 2,2,2-Trichloroethyl 2-methyl-7-[N-(1-cyclopropyl-ethoxy)carbonylphenylglycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 145 or by an obvious chemical equivalent thereof.

354. 2-Methyl-7-(N-tertiarybutoxycarbonylphenyl-D-glycyl)-amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 146 or by an obvious chemical equivalent thereof.

355. 2,2,2-Trichloroethyl 2-methyl-7-(N-tertiarybutoxy-carbonylphenyl-D-glycyl)amino-3-cephem-4-carboxylate whenever prepared by the process of claim 147 or by an obvious chemical equivalent thereof.

356. 2-Methyl-7-[N-[2-(2-nitrophenoxy)acetyl]phenylglycyl]-amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 148 or by an obvious chemical equivalent thereof.

357. 2-Methyl-7-[N-(1,3,4-thiadiazol-2-ylthio)acetyl-2-phenylglycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 149 or by an obvious chemical equivalent thereof.

358. 2,2,2-Trichloroethyl 2-methyl-7-[N-(1,3,4-thiadiazol-2-ylthio)acetyl-2-phenylglycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 150 or by an obvious chemical equivalent thereof.

359. 2-Methyl-7-[N-tertiarybutoxycarbonyl-2-(4-hydroxyphenyl)-D-glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 151 or by an obvious chemical equivalent thereof.

360. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(4-hydroxyphenyl)-D-glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 152 or by an obvious chemical equivalent thereof.

361. 2-Methyl-7-[N-tertiarybutoxycarbonyl-2-(4-methoxyphenyl)-glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 153 or by an obvious chemical equivalent thereof.

362. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(4-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 154 or by an obvious chemical equivalent thereof.

363. 2-Methyl-7-[N-tertiarybutoxycarbonyl-2-(4-methylthio-phenyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 155 or by an obvious chemical equivalent thereof.

364. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(4-methylthiophenyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 156 or by an obvious chemical equivalent thereof.

365. 2-Methyl-7-[N-tertiarybutoxycarbonyl-2-(4-methyl-sulfinylphenyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 157 or by an obvious chemical equivalent thereof.

366. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(4-methylsulfinylphenyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 158 or by an obvious chemical equivalent thereof.

367. 2-Methy]-7-[N-tertiarybutoxycarbonyl-2-(4-tertiary-butoxycarbonylmethoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 159 or by an obvious chemical equivalent thereof.

368. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(4-tertiarybutoxycarbonylmethoxyphenyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 160 or by an obvious chemical equivalent thereof.

369. 2-Methyl-7-[N-tertiarybutoxycarbonyl-2-(3-methane-sulfonamidophenyl(glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 161 or by an obvious chemical equivalent thereof.

370. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(3-methenesulfonamidophenyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 162 or by an obvious chemical equivalent thereof.

371. 2-Methyl-7-[N-tertiarybutoxycarbonyl-2-(2,5-dihydrophenyl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 163 or by an obvious chemical equivalent thereof.

372. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(2,5-dihydrophenyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 164 or by an obvious chemical equivalent thereof.

373. 2-Methyl-7-(2-azido-2-phenylacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 165 or by an obvious chemical equivalent thereof.

374. 2-Methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 166 or by an obvious chemical equivalent thereof.

375. 2,2,2-Trichloroethyl 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 167 or by an obvious chemical equivalent thereof.

376. 2-Methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 168 or by an obvious chemical equivalent thereof.

377. 2,2,2-Trichloroethyl 2-methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 169 or by an obvious chemical equivalent thereof.

378. 2-Methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the proceas of claim 170 or by an obvious chemical equivalent thereof,

379. 2,2,2-Trichloroethyl 2-methyl-7-(2-sulfo-2-phenyl-acetamido)-3-cephem-4-carboxylate whenever prepared by the process of claim 171 or by an obvious chemical equivalent thereof.

380. 2-Methyl-7-[2-(5-indanyl)oxycarbonyl-2-phenylacetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 172 or by an obvious chemical equivalent thereof.

381. 2,2,2-Trichloroethyl 2-methyl-7-[2-(5-indanyl)oxy-carbonyl-2-phenylacetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 173 or by an obvious chemical equivalent thereof.

382. 2-Methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 174 or by an obvious chemical equivalent thereof.

383. 2,2,2-Trichloroethyl 2 methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 175 or by an obvious chemical equivalent thereof.

384. 2-Methyl-7-[N-tertiarybutoxycarbonyl-2-(2-thienyl)-glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 176 or by an obvious chemical equivalent thereof.

385. 2,2,2-Trichloroethyl 2-methyl-7-[N-tertiarybutoxy-carbonyl-2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 177 or by an obvious chemical equivalent thereof.

386. 2-Methyl-7-[3-(N-tertiarybutoxycarbonylamino)-3-(2-thienyl)propionamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 178 or by an obvious chemical equivalent thereof.

387. 2,2,2-Trichloroethyl 2-methyl-7-[3-(N-tertiarybutoxy-carbonylamino)-3-(2-thienyl)propionamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 179 or by an obvious chemical equivalent thereof.

388. 2-Methyl-7-[2-hydroxy-2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 180 or by an obvious chemical equivalent thereof.

389. 2-Methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 181 or by an obvious chemical equivalent thereof.

390. 2,2,2-Trichloroethyl 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 182 or by an obvious chemical equivalent thereof.

391. 2-Methyl-7-[N-(1-cyclopropylethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 183 or by an obvious chemical equivalent thereof.

392. 2,2,2-Trichloroethyl 2-methyl-7-[N-(1-cyclopropyl-ethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylate whenever prepared by the process of claim 184 or by an obvious chemical equivalent thereof.

393. 2-Methyl-7-[2-(3-pyridyl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 185 or by an obvious chemical equivalent thereof.

394. 2-Methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof thenever prepared by the process of claim 186 or by an obvious chemical equivalent thereof.

395. 2,2,2-Trichloroethyl 2-methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 187 or by an obvious chemical equivalent thereof.

396. 2-Methyl-7-[2-(5-methyl-1,3,4-thiadiezol-2-yloxy)-acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 188 or by an obvious chemical equivalent thereof.

397. 2,2,2-Trichloroethyl 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 189 or by an obvious chemical equivalent thereof.

398. 2-Methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by themprocess of claim 190 or by an obvious chemical equivalent thereof.

399. 2,2,2-Trichloroethyl 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 191 or by an obvious chemical equivalent thereof.

400. 2-Methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 192 or by an obvious chemical equivalent thereof.

401. 2,2,2-Trichloroethyl 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylate whenever prepared by the process of claim 193 or by an obvious chemical equivalent thereof.

402. 2-Methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 194 or by an obvious chemical equivalent thereof.

403. 2,2,2-Trichloroethyl 2-methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylate whenever prepared by the process of claim 195 or by an obvious chemical equivalent thereof.

404. 2,2,2-Trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate-1-oxide whenever prepared by the process of claim 196 or by an obvious chemical equivalent thereof.

405. A compound of the general formula:
wherein R1b', R2, R3 and X are each as defined in claim 197 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 197 or by an obvious chemical equivalent thereof.

406. A compound of the general formula:
wherein R1b', R2, R3 and X are each as defined in claim 198 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 198 or by an obvious chemical equivalent thereof.

407. A compound of the general formula:
wherein R1b', R2, R3 and X are each as defined in claim 199 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 199 or by an obvious chemical equivalent thereof.

408. A compound of the general formula:

wherein R1d, R2, R3 and X are each as defined in claim 200 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 200 or by an obvious chemical equivalent thereof.

409. A compound of the general formula:

wherein R1d, R2, R3 and X are each as defined in claim 201 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 201 or by an obvious chemical equivalent thereof.

410. A compound of the general formula:
wherein R1d, R2, R3 and X are each as defined in claim 202 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 202 or by an obvious chemical equivalent thereof,

411. A compound of the general formula:

wherein R1f, R2, R3 and X are each as defined in claim 203 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 203 or by an obvious chemical equivalent thereof.

412. A compound of the general formula:

wherein R1, R3 and X are each as defined in claim 204 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 204 or by an obvious chemical equivalent thereof.

413. A compound of the general formula:
wherein R1, R3 and A are each as defined in claim 205 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 205 or by an obvious chemical equivalent thereof.

414. A compound of the general formula:

wherein R1, R3 and X are each as defined in claim 206 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 206 or by an obvious chemical equivalent thereof.

415. A compound of the general formula:
wherein R1, R3 and X are as defined in claim 207, whenever prepared by the process of claim 207 or by an obvious chemical equivalent.

416. A compound of the general formula:
wherein R2, R3, R4, R5, R6 and X are each as defined in claim 208 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 208 or by an obvious chemical equivalent thereof.

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE

417. A process according to claim 2, wherein R1 is 2-(2-aminothiazol-4-yl)acetamido, R is carboxy, R3 is methyl and X is -S-, and the double bond is in the 3-position.

418. A process according to claim 2, wherein R1 is 2-(2-aminothiazol-4-yl)acetamido, R2 is pivaloyloxymethoxycarbonyl, R is methyl and X is -S-, and the double bond is in the 3-position.

419. A process according to claim 72, wherein R1 is 2-(2-aminothiazol-4-yl)acetamido, R2 is carboxy and R3 is methyl.

420. A process according to claim 72, wherein R1 is 2-(2-aminothiazol-4-yl)acetamido, R2 is pivaloyloxymethoxycarbonyl and R3 is methyl.

421. A process according to claim 121, wherein R1bis 2-(2-aminothiazo1-4-yl)acetamido, R2 is carboxy, R3 is methyl and X is -S-, and the double bond is in the 3-position.

422. A process according to claim 121, wherein R1b is 2-(2-aminothiazol-4-yl)acetamido, R2 is pivaloyloxymethoxycarbonyl, R3 is methyl and X is -S-, and the double bond is in the 3-position.

423. A process according to claim 197, wherein R1b'is 2-(2-aminothiazol-4-yl)acetamido, R1b is 2-phenylacetamido, R2 is carboxy, R3 is methyl and X is -S-, and the double bond is in the 3-position.

424. A process according to claim 197, wherein R1b'is 2-(2-aminothiazol-4-yl)acetamido, R1b is 2-phenylacetamido, R2 is pivaloyloxymethoxycarbonyl, R3 is methyl and X is -S-, and the double bond is in the 3-position.

425. A process according to claim 200, wherein R1d is 2-(2-aminothiazol-4-yl)acetamido, R2 is carboxy, R3 is methyl and X is -S-, and the double bond is in the 3-position.

426. A process according to claim 200, wherein R1d is 2-(2-aminothiazol-4-yl)acetamido, R2 is pivaloyloxymethoxycarbonyl, R3 is methyl, and X is -S-, and the double bond is in the 3-position.

427. A process according to claim 1(k), wherein a carboxylic acid of said formula wherein R1 is 2-(2-amino-thiazol-4-yl)acetamido, R3 is methyl, X is -S-, and the double bond is in the 3-position is esterified with a pivaloyloxymethyl esterifying agent.

428. 2-Methyl-7-[2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 417 or by an obvious chemical equivalent thereof.

429. Pivaloyloxymethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 418 or by an obvious chemical equivalent thereof.

430. 2-Methyl-7-[2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 419 or by an obvious chemical equivalent thereof.

431. Pivaloyloxymethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 420 or by an obvious chemical equivalent thereof.

432. 2-Methyl-7-[2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 421 or by an obvious chemical equivalent thereof.

433. Pivaloyloxymethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 422 or by an obvious chemical equivalent thereof.

434. 2-Methyl-7-[2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 423 or by an obvious chemical equivalent thereof.

435. Pivaloyloxymethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 424 or by an obvious chemical equivalent thereof.

436. 2-Methyl-7-[2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 425 or by an obvious chemical equivalent thereof.

437. Pivaloyloxymethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 426 or by an obvious chemical equivalent thereof.

438. Pivaloyloxymethyl 2-methyl-7-[2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate and pharmaceutically acceptable salt thereof whenever prepared by the process of claim 427 or by an obvious chemical equivalent thereof.