Antibacterial compounds of the formula ##STR1## (where COB is carboxy or protected carboxy; PA1 Hal is halogen; PA1 R is amino or protected amino; PA1 R' is mercapto-protecting group; and PA1 X is nucleophilic group) Are prepared from penicillin 1-oxides having X on its 2-methyl group, and found to be used as starting materials for preparing cephalosporins.

This invention relates to antibacterial azetidinone compounds (I) and (II) 
represented by the following formula: 
##STR2## 
(where COB is carboxy or protected carboxy; 
Hal is halogen; 
R is amino or protected amino; 
R' is mercapto-protecting group; and 
X is nucleophilic group), 
Their synthesis, and uses. The compounds are also useful intermediates for 
synthesizing cephalosporins from penicillins. 
In compounds (I) and (II), the protected amino represented by R includes 
those which constitute side chains of natural or synthetic penicillins or 
cephalosporins [e.g. acylamino (including diacylamino), hydrocarbylamino 
(including hydrocarbylideneamino), silylamino, sulfenylamino, etc.]. 
The acyl of acylamino represented by R can contain up to 25 carbon atoms 
and includes conventional acyls used in chemistry of penicillins and 
cephalosporins, and is exemplified by an inorganic acyl including carbonic 
acyl (e.g. 2-8C alkoxycarbonyl, 8-15C aralkoxycarbonyl, 6-11C 
aryloxycarbonyl), and organic acyl including 1-5C alkanoyl, 3-8C 
cycloalkanoyl, 7-20C aralkanoyl, 7-11C aroyl, 1-5C arkylsulfonyl, 6-10C 
arylsulfonyl, and 1-5C alkylphosphonyl. 
These acyls, where possible, may have a hetero atom in the main nucleus, 
unsaturation, or substituent e.g. a halogen, (e.g. fluorine, chlorine, 
bromine), nitrogen function (e.g. amino, hydrazo, azido, 1-5C alkylamino, 
6-10C arylamino, 1-8C acylamino, 1-5C alkylideneamino, 1-8C acylimino, 
nitro), oxygen function (e.g. hydroxy, 1-5C alkoxy, 7-20C aralkoxy, 6-10C 
aryloxy, 1-8C acyloxy, oxo), sufur function (e.g. mercapto, 1-5C 
alkylthio, 7-9C aralkylthio, 6-10C arylthio, 1-8C acylthio, thioxo, sulfo, 
sulfonyl, sulfinyl, 1-5C alkoxysulfonyl, 6-10C aryloxysulfonyl, carbon 
function (e.g. 1-5C alkyl, 1-5C alkenyl, 7-10C aralkyl, 6-10C aryl, 
carboxy, 2-6C carbalkoxy, carbamoyl, 1-8C alkanoyl, 7-11C aroyl, 1-5C 
aminoalkyl, 7-10C aralkanoyl, cyano), phosphorus function (e.g. phospho, 
phosphoroyl) or like substituents. 
Representative acyls include following groups: 
1. 1-5C alkanoyl; 
2. 2-5C haloalkanoyl; 
3. azidoacetyl; 
4. cyanoacetyl; 
5. acyls of the formula: 
EQU Ar--CQQ'--CO-- 
(where 
Q and Q' each is hydrogen or methyl; and 
Ar is phenyl, dihydrophenyl, or a monocyclic heterocyclic aromatic group 
containing 1 to 4 hetero atoms selected from nitrogen, oxygen, and/or 
sulfur atoms, each optionally substituted by e.g. 1-5C alkyl, 1-5C alkoxy, 
halogen, trifluoromethyl, hydroxy, cyano, aminomethyl, nitroso, and 
nitro). 
6. acyls of the formula: 
EQU Ar--G--CQQ'--CO-- 
(where 
G is oxygen or sulfur; and 
Ar, Q, and Q' are defined above); 
7. acyls of the formula: 
EQU Ar--CHT--CO-- 
(where 
Ar is defined above; and 
T is 
i. amino, ammonio, amino protected by an aminoprotecting group (including 
acyls e.g. benzyloxycarbonyl, 2-8C alkoxycarbonyl, cyclopentyloxycarbonyl, 
cyclohexyloxycarbonyl, benzyhydryloxycarbonyl, cyclopropylmethoxycarbonyl, 
methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 
guanidylcarbonyl, substituted ureidocarbonyl, b 1-5C alkanoyl, 
pyronecarbonyl, thiopyronecarbonyl, pyridonecarbonyl, and aromatic 
carbocyclic or heterocyclic acyl optionally substituted by e.g. halogen, 
trifluoromethyl, 1-5C alkyl, 1-5C aminoalkyl, 1-5C hydroxyalkyl; trityl, 
and other amino-protecting groups) or protected amino in the form of 
phthalimino or enamino derived from acetoacetates, acetylacetone, 
acetoacetonitrile, and like protecting groups; 
ii. hydroxy, 1-3C alkoxy, or 1-5C acyloxy; 
iii. carboxy, 2-10C alkoxycarbonyl, indanyloxycarbonyl, phenoxycarbonyl, 
dimethylphenoxycarbonyl, or like groups; or 
iv. azido, cyano, carbamoyl, sulfo, 1-3C alkoxysulfonyl, 1-3C 
alkoxyphosphonyl, or like groups); 
8. 3-5C 2-syndon-3-alkanoyl; 
9. 6-8C (2- or 4-pyridon-1-yl) alkanoyl; 
10. 5-aminoadipoyl, 5-aminoadipoyl protected at the amino or carboxy; 
11. acyls of the formula: 
EQU L--O--CO-- 
(where L is an easily removable 1-10C hydrocarbyl e.g. 
2,2,2-trichloroethyl, isobornyl, t-butyl, 1-methylcyclohexy, 
2-alkoxy-t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzyhydryl), 
and the like acyls. 
Typical examples of Ar in the said definition include furyl, thienyl, 
pyrryl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, 
isothiazolyl, thiadiazolyl, thiatriazolyl, pyrazolyl, imidazolyl, 
triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 
triazinyl, and dihydrophenyl, each optionally may be substituted by e.g. 
halogen, 1-5C alkyl, hydroxy, aminomethyl, or 1-3C alkoxy. 
Silyl e.g. tri-1-5C-alkylsilyl, and sulfenyl e.g. phenylsulfenyl, 
o-nitrophenylsulfenyl are conventional aminoprotecting groups. 
The hydrocarbyls of said hydrocarbylamino represented by R include easily 
removable 1-20C aliphatic hydrocarbyls (e.g. 1-5C alkyl, 1-5C alkenyl, 
7-20C aralkyl) and monocyclic aryls optionally substituted by halogen, 
nitrogen-, oxygen-, sulfur-, carbon-, and phosphorus-functions referred to 
above. These hydrocarbyls can be divalent hydrocarbyls e.g. 1-5C alkylene, 
7-15C aralkylene, 1-5C alkylidene, 7-15C aralkylidene, .alpha.-halo-or 
.alpha.-1-5C alkoxy-7-15C-aralkylidene, 13-20C diarylmethylidene, 3-10C 
cycloalkylidene, or other divalent hydrocarbyls. Further, two amino 
substituents being acyl and hydrocarbyl can be combined to form a ring 
structure (4-oxo-3-imidazolidinyl ring, etc. ). These groups can also have 
substituents or unsaturations as cited above. 
COB in Compounds (I) and (II) is carboxy or protected carboxy. 
Representatives of them include those constituting esters [1-5C alkyl 
(e.g. methyl, ethyl, trichloroethyl, t-butyl esters), 7-20C aralkyl (e.g. 
benzyl, methoxybenzyl, nitrobenzyl, diphenylmethyl, trityl esters), 6-12C 
aryl (e.g. phenyl and naphthyl esters), metal (e.g. trimethylthylsilyl, 
methoxydimethylsilyl, trimethylstannyl esters), and other esters], acid 
anhydrides, salts (e.g. sodium, potassium, magnesium, aluminum salts), 
thiol esters, amides, hydrazides, azides, and other derivatives of carboxy 
groups. COB can, where possible, have substituents referred to above e.g. 
halogen, sulfur-, oxygen-, nitrogen-, carbon-, or other functions or can 
be unsaturated. 
Among these protected carboxy, important groups for COB are those inert to 
the reaction and removable after the reaction without adverse effect on 
the other part of the molecule (e.g. 1-3C haloalkyl, 2-10C acylalkyl, 2-7C 
alkoxyalkyl, 2-7C acyloxyalkyl, 7-20C aralkyl esters, 2-6C 
dialkylhydrazides, alkali metal salts, and 1-12C alkylamine salts). 
The protecting group in COB has no meaning other than protection and 
deprotection, and wide variation can be possible without changing the gist 
of this invention. 
X in Compounds (I) and (II) is nucleophilic group. The nucleophilic group 
can be halogen, acyloxy, hydroxy, mercapto, 1-3C alkylthio, 1-12C arylthio 
including heteroaromatic thio represented by partial formula: 
EQU Ar--S-- 
(where Ar is defined above) and other nucleophilic groups bound to methyl 
at position 3 of cephem ring in known cephalosporins. It can be 
exemplified by halogen (e.g. chlorine, bromine, fluorine), acyloxy (e.g. 
formyloxy, acetyloxy, propionyloxy, benzoyloxy, sulfonyloxy, carbonic or 
sulfuric acyloxy), 1-3C alkoxy (e.g. methoxy, ethoxy, butoxy), arylthio 
(e.g. phenylthio, nitrophenylthio, tolylthio, 1,3,4-thiadiazolylthio, 
2-methyl-1,3,4-thiadiazol-5-ylthio, 
2-hydroxymethyl-1,3,4-thiadiazol-5-ylthio, 1-methyltetrazol-5-ylthio, 
1,2,3-triazol-5-ylthio, pyridazin-3-ylthio, 1-oxidopyridin-2-yl-thio) or 
like nucleophiles. 
When a group COB, R, R', or X is unstable under the reaction condition, it 
can be protected prior to and deprotected after the reaction to avoid 
unfavorable side reactions. 
Representative R' in Compounds (I) includes those which are eliminated to 
form penam- or cephem-ring under the reaction conditions, e.g. aliphatic 
or aromatic thio (1-5C alkylthio, 7-15C aralkylthio, 6-10C arylthio, 
etc.), and eliminating group (thiocyanato, arylamino, sulfonyl, sulfo, 
etc.). These mercapto protecting groups can, where possible, possess a 
substituent e.g. oxygen-, nitrogen-, sulfur-, carbon-, etc. functions or 
halogen, or can be unsaturated. Further, they may have a hetero atom in 
the main nucleus. Examples of R' include alkylthio, arylthio (aryl e.g. 
said Ar), acyl, cyano, thiocyano, sulfo, anilino, and other 
mercaptoprotecting groups. 
Suitable Hal is chlorine or bromine, but iodine and pseudohalogens are also 
available. 
Preferable R is phenylacetamido, phenoxyacetamido, tetrazol-1-ylacetamido, 
N-acetyl-N-phenylacetylamino, and 2-thienylacetamido. Preferable COB is 
carboxy, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, 
p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, and 
benzhydryloxycarbonyl. Preferable X is chlorine, acetoxy, 
5-methyl-1,3,4-thiadiazol-2-ylthio, or 1-methyltetrazol-5-ylthio. Most 
preferable R' is benzothiazol-2-ylthio and thiazol-2-ylthio. 
Some of specific and preferable examples of Compounds (I) include those 
having the following groups 
1. COB = benzhydryloxycarbonyl, R = phenoxyacetamido, R' = 
2-benzothiazolylthio, and X = acetoxy; 
2. COB = 2,2,2-trichloroethoxycarbonyl, R = phenylacetamido, R' = 
2-benzothiazolylthio, and X = acetoxy; 
3. COB = benzyloxycarbonyl, R = phenoxyacetamido, R' = 
2-benzothiazolylthio, and X = acetoxy; 
4. COB = benzyhydryloxycarbonyl, R = phenoxyacetamido, R' = 
2-benzothiazolylthio, and X = chloro; 
5. COB = p-methoxybenzyloxycarbonyl, R = 1-tetrazolylacetamido, R' = 
2-benzothiazolylthio, and X = chloro; 
6. COB = benzhydryloxycarbonyl, R = N-phenylacetyl-N-acetylamino, R' = 
2-benzothiazolylthio, and X = acetoxy; or 
7. COB = carboxy, R = 2-thienylacetamido, R' = 2-benzothiazolylthio, and X 
= 5-methyl-1,3,4-thiadiazol-2-ylthio. 
Some of specific and preferable examples of Compounds (II) include those 
having the following groups: 
1. COB = benzhydryloxycarbonyl, Hal = bromo, R = phenoxyacetamido, and X = 
acetoxy; 
2. COB = 2,2,2-trichloroethoxycarbonyl, Hal = bromo, R = phenylacetamido, 
and X = acetoxy; 
3. COB = benzyloxycarbonyl, Hal = bromo, R = phenoxyacetamido, and X = 
acetoxy; 
4. COB = benzhydryloxycarbonyl, Hal = bromo, R = phenoxyacetamido, and X = 
chloro; 
5. COB = p-methoxybenzyloxycarbonyl, Hal = bromo, R = 1-tetrazolacetamido, 
and X = chloro; 
6. COB = diphenylmethoxycarbonyl, Hal = bromo, R = N-phenylacetyl 
N-acetylamino, and X = acetoxy; or 
7. COB = diphenylmethoxycarbonyl, Hal = bromo, R = N-phenylacetyl 
N-acetylamino, and X= chloro, R = 2-thienylacetamide, and X = 5-methyl-b 
1,2,4-thiadiazol-2-ylthio. 
The starting materials of this invention, Compounds (III) and (IV), are 
described in e.g. British Pat. No. 1,445,845 and Japanese patent 
application No. 8994/1976. 
##STR3## 
(where COB, R, and X are defined above). 
Compounds (I) can be prepared by treatment of Compounds (III) or (IV) with 
a compound of the formula: 
EQU HR' 
(where R' is defined above) according to following scheme where COB, R, R', 
and X are defined above: 
##STR4## 
Heating of the starting materials (III) and (IV) at 70.degree. C to 
150.degree. C gives the corresponding compounds where S-oxide and 
2-CH.sub.2 X groups are simultaneously reversed, namely by an inversion of 
the following scheme: 
##STR5## 
(where COB, R, and X are defined above). 
Since both of Compounds (III) and (IV) produce same objective compounds (I) 
under the same reaction condition, they are equally available as starting 
materials of this process. 
The reaction is carried out by merely heating Compounds (III) or (IV) with 
a compound of formula HR' (so-called mercapto or sulfenic acid trapping 
reagent) preferably in nitrogen or argon atmosphere. There is no specific 
limitation of solvents for the reaction, but more preferable ones are 
those having no reactive hydrogen (e.g. hydrocarbon-, halohydrocarbon-, 
ether-, ketone-, amide-, or sulfoxide solvents) when used at 70.degree. to 
150.degree. C. 
Compounds (II) can be prepared by treating Compounds (I) with a 
halogenating reagent (particularly halogen e.g. chlorine, bromine, etc.; 
halide e.g. cupric halides, silver halides), to induce a cyclization 
according to following reaction scheme: 
##STR6## 
(where COB, Hal, R, R', and X are defined above) 
According to an example of suitable methods, halogen is dissolved in an 
inert organic solvent (e.g. hydrocarbon, halohydrocarbon-, alcohol-, 
ether-solvents) and is added to a solution of Compound (I), and is let 
react for 0.5 to 5 hours at -10.degree. C to 50.degree. C to obtain 
Compounds (II). Amides (e.g. acetamide) can be added for smoother reaction 
and for surpressing side reactions. 
Compounds (II) are useful for preparing cephem compounds (V) by a ring 
enlargement reaction according to following scheme: 
##STR7## 
(where COB, Hal, R, and X are defined above). 
The reaction is carried out e.g. by heating in a polar (e.g. 
dimethylsulfoxide) or nonpolar (e.g. toluene) solvent at 40.degree. to 
150.degree. C. Some bases also promote the reaction. 
Compounds (V) can also be prepared by treating Compounds (I) with a 
HR'-eliminating reagent (e.g. halogen; organic acid including carboxylic 
acid, sulfonic acid; inorganic acid including mineral acid; salts of 
organic bases; alkali metal hydroxide; alkali metal alkoxides; organic 
bases; boron trifluoride; metal salts of acids; mercuric oxides; cuprous 
oxide; especially silver fluoride) according to following reaction scheme: 
##STR8## 
(where COB, R, R', and X are defined above). 
The reaction is preferably carried out at 0.degree. to 50.degree. C. 
Compounds (I), (II), and (V) can be obtained from above reaction mixtures 
in conventional manner as extraction, precipitation, recrystallization, 
chromatography, etc. after removing by-products, excess reagents, 
solvents, etc. from the reaction mixture. 
Compounds (I) and (II) are novel substances showing antibacterial activity 
and are useful drugs for preventing or treating bacterial infections e.g. 
caused by Bacillus sp. or Diplococcus sp. in cases of human or animals at 
a daily dose of e.g. 1 to 5 g per man when administered enterally or 
parenterally. In forms of carboxy derivatives, they also can be used as 
intermediates for synthesis of cephalosporins as stated above.