Mercaptotetrazolylalkanohydroxamic acids, salts and ester thereof

5-Mercapto-1H-tetrazole-1-alkanohydroxamic acid, its salts and its esters having the following formula: ##STR1## wherein A is an alkylene group; PA1 M is a hydrogen or light metal atom; and PA1 R is a hydrogen atom, an alkyl group or a hydroxy-protecting group, and its preparation are disclosed. The compounds are useful as medicines and intermediates.

This invention relates to a tetrazolealkanohydroxamic acid derivative 
represented by the following formula: 
##STR2## 
wherein A is an alkylene group; 
M is a hydrogen or light metal atom; and 
R is a hydrogen atom, an alkyl group or a hydroxy-protecting group. 
In the above formula, A is a straight or branched alkylene group, e.g., 1 
to 3C alkylene group; M is a hydrogen atom or light metal atom, e.g., 
lithium, sodium, potassium, calcium, aluminum, etc.; R is a hydrogen atom, 
lower alkyl group, e.g. 1 to 5C alkyl, or hydroxy-protecting group, e.g., 
1 to 6C alkanoyl, 4 to 7C tertiary alkyl, monocyclic aralkyl or aryl 
optionally substituted by e.g., 1 to 3C alkyl or alkoxy, nitro, halogen, 
phenyl or the like. 
The tetrazolealkanohydroxamic acid derivatives are useful as additives to 
synthetic resins and as starting materials for highly effective medicines, 
e.g., cephalosporins. 
The compounds of this invention can be synthesized according to the 
reactions of the following scheme using a conventional method in the art. 
##STR3## 
1. According to one of the synthetic methods, 
5-mercapto-1H-tetrazole-1-alkanoic acid is dissolved in a solvent and 
mixed with an oxyamine compound H.sub.2 NOR in the presence of a 
condensing reagent, e.g., N,N'-dicyclohexylcarbodiimide, 
2-ethoxy-1-ethyl-1,2-dihydroquinoline, N,N'-carbonyldimidazole, etc., in 
the presence of an aromatic base at a temperature between -50.degree. C. 
and 100.degree. C. for a time between 10 minutes and 10 hours. 
Similarly, a reactive ester can be used instead of the free acid, for 
example, an enol ester, e.g., vinyl ester, isopropenyl ester, etc., aryl 
ester, e.g., phenyl ester, halophenyl ester, nitrophenyl ester, 
heterocyclic ester, e.g., pyridyl ester, benzotriazolyl ester, an ester 
with an N-hydroxy compound, e.g., N-hydroxysuccinimide, 
N-hydroxy-phthalimide, or a thiol ester, e.g., methyl thiol ester, 
tetrazolylthiol ester, or the like of the tetrazole-1-alkanoic acid. 
Further, a halide, symmetric anhydride or mixed anhydride with a carbonic 
acid, sulfuric acid, phosphoric acid, carboxylic acid, sulfonic acid or 
the like, can also be used (if required the mercapto group may be 
protected in a conventional manner), in the presence of an acid scavenger, 
e.g., an inorganic base, tertiary amine, aromatic base, oxirane, adsorbent 
or the like as the condensing reagent in a solvent at a temperature 
preferably between -50.degree. C. and 30.degree. C. for, e.g., 10 minutes 
and 10 hours. 
Equivalent methods include the following: 
2. When R is hydrogen, the mercapto-1H-tetrazole-1-alkanohydroxamic acid is 
acylated or alkylated in a conventional manner to form the corresponding 
O-acylated or O-alkylated material. In the alkylation, the mercapto group 
is preferably protected and later deprotected. 
3. An aminoalkanohydroxamic acid derivative may be treated with carbon 
disulfide and methyl iodide in a basic medium and then with hydrogen azide 
at, e.g., a temperature between room temperature and 100.degree. C. 
according to a conventional manner. 
4. 5-Mercapto-1H-tetrazole protected at its mercapto group in a form of a 
thiol ester or thio ether is treated with a haloalkanooxamate or 
diazoalkanooxamate in the presence of a condensing reagent, e.g., alkali 
metal hydride or alkoxide, trialkylamine, aromatic base, at a temperature 
between, e.g., -20.degree. C. and 50.degree. C. The mercapto protecting 
group is then removed in a conventional way. 
The reactions referred to above are generally done at a temperature between 
-30.degree. C. and 100.degree. C., especially -20.degree. C. and 
50.degree. C. for a time between 10 minutes and 10 hours in a solvent, if 
required under anhydrous condition, according to a conventional method, 
e.g., anhydrous or inert gas protection of the reaction medium, stirring, 
etc. The solvent for the reaction may be an industrial solvent belonging 
to the hydrocarbon (e.g., pentane, hexane, octane, benzene, toluene, 
xylene), halohydrocarbon (dichloromethane, chloroform, carbon 
tetrachloride, dichloroethane, trichloroethane, chlorobenzene), ether 
(e.g., diethyl ether, methyl isobutyl ether, dioxane, tetrahydrofuran), 
ketone (e.g., acetone, methyl ethyl ketone, cyclohexanone), ester (e.g., 
ethyl acetate, isobutyl acetate, methyl benzoate), nitrohydrocarbon (e.g., 
nitromethane, nitrobenzene), nitrile (e.g., acetonitrile, benzonitrile), 
amide (e.g., formamide, acetamide, dimethylformamide, dimethylacetamide, 
hexamethylphosphorotriamide), sulfoxide (e.g., dimethyl sulfoxide, 
thiane-1,1-dioxide), carboxylic acid (e.g., formic acid, acetic acid, 
propionic acid), organic base (e.g., diethylamine, triethylamine, 
pyridine, picoline, collidine, quinoline), alcohol (e.g., methanol, 
ethanol, propanol, hexanol, octanol, benzyl alcohol), water or the like or 
a mixture of more than two of the above industrial solvents, when 
appropriate for the reaction to be used. 
The product of the above reactions can be isolated by removing unreacted 
starting materials, by-products, solvents or the like by extraction, 
evaporation, washing, concentration, precipitation, filtration, drying or 
the like conventional method and then purified by e.g., adsorption, 
elution, distillation, precipitation, separating out, chromatography or 
the like conventional work up procedure. 
Specific compounds according to this invention, include the compound (I) 
wherein 
M=H, A=CH.sub.2, R=H; 
M=Na, A=CH.sub.2, R=H; 
M=K, A=CH.sub.2, R=H; 
M=H, A=CH.sub.2, R=CH.sub.3 ; 
M=Na, A=CH.sub.2, R=CH.sub.3 ; 
M=K, A=CH.sub.2, R=CH.sub.3 ; 
M=H, A=CH.sub.2, R=C.sub.2 H.sub.5 ; 
M=Na, A=CH.sub.2, R=C.sub.2 H.sub.5 ; 
M=H, A=CH.sub.2, R=CH(CH.sub.3).sub.2 ; 
M=Na, A=CH.sub.2, R=CH(CH.sub.3).sub.2 ; 
M=H, A=CH.sub.2, R=CH.sub.2 C.sub.6 H.sub.4 OCH.sub.3 -p; 
M=Na, A=CH.sub.2, R=CH.sub.2 C.sub.6 H.sub.4 OCH.sub.3 -p; 
M=H, A=CH(CH.sub.3), R=H; 
M=H, A=CH.sub.2 CH.sub.2, R=CH.sub.3 ; 
M=Na, A=CH.sub.2 CH.sub.2, R=CH.sub.3 ; 
M=K, A=CH.sub.2 CH.sub.2, R=CH.sub.3 ; or 
M=H, A=C(CH.sub.3).sub.2, R=CH.sub.3 ;

The following examples are given to illustrate the embodiments of this 
invention. The abbreviations used are those conventional in the art. 
EXAMPLE 1 
.alpha.-(5-Mercapto-1H-tetrazol-1-yl)acetohydroxamic acid methyl ester 
##STR4## 
(Free acid and N,N'-carbonyldiimidazole) 
To an ice cold and stirred solution of 5-mercapto-1H-tetrazole-1-acetic 
acid (9.6 g) in N,N-dimethylformamide (60 ml) is added 
N,N'-carbonyldiimidazole (11.6 g), and the mixture is stirred at 0.degree. 
C. for 1 hour. To this mixture is added a solution of methoxyamine 
hydrochloride (11.6 g) in a mixture of N,N-dimethylformamide (45 ml) and 
4.6 N-sodium methoxide methanol solution (28.5 ml) and the whole mixture 
is stirred under ice cooling for 1 hour. The reaction mixture is poured 
onto ice water and extracted with a mixture of ethyl acetate and methyl 
ethyl ketone (2:1). The extract solution is washed with water, dried and 
concentrated in vacuum. The residue is crystallized from a mixture of 
acetone and ether to give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid 
methyl ester (7.73 g). mp. 175.degree.-176.degree. C. (decomp.). 
IR (Nujol) .nu.: 3120, 1670 cm.sup.-1. 
NMR (CD.sub.3 COCD.sub.3) .delta.: 3.77 (s, 3H), 5.08 (brs, 2H). 
In a manner similar to above, but substituting methoxyamine hydrochloride 
with the equivalent molar equivalent of ethoxyamine acetate or 
isopropoxyamine sulfate, the corresponding ethyl ester or isopropyl ester 
of the hydroxamic acid can be prepared. 
Ethyl ester NMR (CDCl.sub.3 +CD.sub.3 OD) .delta.: 1.13 (t, J=6 Hz, 3H), 
3.88 (q, J=6 Hz, 2H), 5.08 (s, 2H). 
Isopropyl ester NMR (CDCl.sub.3 +CD.sub.3 OD) .delta.: 1.20 (d, J=7 Hz, 
6H), 4.02 (septet, J=7 Hz, 1H), 5.10 (s, 2H). 
(Free acid and N,N'-dicyclohexylcarbodiimide) 
To an ice cold and stirred solution of 5-mercapto-1H-tetrazole-1-acetic 
acid (320 mg) in methanol (3 ml) are added triethylamine (0.33 ml) and 
N,N'-dicyclohexylcarbodiimide (495 mg), and th mixture is stirred for 7 
hours. To this solution is added a solution of methoxyamine hydrochloride 
(33.4 mg) and triethylamine (56 .mu.l) in methanol (0.3 ml). After the 
addition of a further amount of N,N'-dicyclohexylcarbodiimide (124 mg), 
the mixture is left stand at room temperature overnight. The reaction 
mixture is concentrated under reduced pressure to about 1 ml and then 
diluted with ethyl acetate (8 ml) and 5% sodium hydrogen carbonate (7 ml). 
After the separated solid (461 mg) is removed by filtration, the filtrate 
is saturated with sodium chloride and diluted with ethyl acetate-methyl 
ethyl ketone mixture (1:1). The mixture is acidified to pH 1 with 
hydrochloric acid and extracted with ethyl acetate. The extract is dried 
over magnesium sulfate and concentrated under reduced pressure to give 
5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester (375 mg), 
identical with the product prepared with N,N'-carbonyldiimidazole. 
(Acid chloride) 
To an ice cold solution of 5-mercapto-1H-tetrazole-1-acetic acid (160 mg) 
in acetonitrile (3.2 ml) are added tri-n-butylamine (476 .mu.l) and 
phosphorus oxychloride (183 .mu.l). After 80 minutes' stirring, a solution 
of methoxyamine hydrochloride (167 mg) and tri-n-butylamine (476 .mu.l) in 
hexamethylphosphorotriamide is added to the above solution. After another 
1 hour's stirring at 0.degree. C., the mixture is extracted with 5% 
aqueous sodium hydrogen carbonate (40 ml). The extract solution is washed 
with ethyl acetate, acidified with concentrated hydrochloric acid to pH 
2.5, saturated with sodium chloride and extracted with methyl ethyl 
ketone. The extract is dried over magnesium sulfate and concentrated to 
give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester (134 mg). 
mp. 165.degree.-167.degree. C. (decomp.). 
In a manner similar to above, but substituting phosphorus oxychloride with 
triphenylphosphine (1.2 molar equivalents) and carbon tetrachloride (320 
mg) and the acid chloride is formed in the presence of free methoxyamine 
in N,N-dimethylformamide (2.5 ml), the same product can be obtained in 
high yield. 
(Mixed anhydride) 
To a solution cooled at -28.degree. C. to -35.degree. C. of 
5-mercapto-1H-tetrazole-1-acetic acid (0.8 g) in tetrahydrofuran (40 ml) 
are added N-methylmorpholine (1.26 ml) and ethyl chloroformate (0.62 ml). 
After stirring for 1 hour, a solution of methoxyamine hydrochloride (0.34 
g) and N-methylmorpholine (0.71 ml) in tetrahydrofuran (11 ml) is added to 
the mixture at -50.degree. C. After 2 hours' stirring at about -30.degree. 
C., the mixture is concentrated under reduced pressure, and the resultant 
mixture is diluted with water (50 ml) and ethyl acetate (50 ml). The 
mixture is acidified to pH 2 with hydrochloric acid and extracted with 
ethyl acetate. The extract solution is dried over magnesium sulfate and 
concentrated to give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl 
ester. mp. 165.degree.-167.degree. C. (decomp.). 
In a manner similar to above, but substituting ethyl chloroformate with 
diphenyl chlorophosphonate, N-methylmorpholine with tri-n-butylamine (2 
molar equivalents) and tetrahydrofuran with acetonitrile, the same product 
can be prepared. 
EXAMPLE 2 
(1) .alpha.-(5-mercapto-1H-tetrazol-1-yl)acetohydroxamic acid 
p-methoxybenzyl ester 
##STR5## 
To an ice cold solution of 5-mercapto-1H-tetrazole-1-acetic acid (4.4 g) in 
N,N-dimethylformamide (40 ml) is added N,N'-carbonyldiimidazole (4.86 g), 
and the mixture is stirred under nitrogen for 1 hour. To this solution is 
added a solution of p-methoxybenzyloxyamine (7.9 g) in 
N,N-dimethylformamide (10 ml), and the mixture is stirred under ice 
cooling for 45 minutes. The reaction mixture is poured onto ice water 
containing hydrochloric acid and extracted with ethyl acetate. The extract 
solution is washed with water, dried and concentrated under reduced 
pressure. The residue is crystallized from a mixture of acetone and ether 
to give the title compound (7.3 g). mp. 167.degree.-168.degree. C. 
IR (Nujol) .nu.: 3060, 1630, 1605 cm.sup.-1. 
NMR (CD.sub.3 COCD.sub.3) .delta.: 3.80 (s, 3H), 4.90 (s, 2H), 5.06 (brs, 
2H), 6.97d+7.46d (ABq, J=9 Hz, 4H). 
(p-methoxybenzyloxyamine, one of the starting materials) 
To a solution of N-hydroxyphthalimide (11.1 g) and p-methoxybenzyl bromide 
(13.7 ml) in N,N-dimethylformamide (100 ml) is added triethylamine (6.8 
g), and the mixture is stirred at room temperature for 1 hour and at 
60.degree. to 70.degree. C. for 1 hour. The reaction mixture is poured 
into ice water and extracted with ethyl acetate. The extract solution is 
washed with diluted hydrochloric acid and water, dried and concentrated 
under reduced pressure. The residue is crystallized from methanol to give 
N-p-methoxybenzyloxyphthalimide (17 g). mp. 139.degree.-141.degree. C. 
IR (Nujol) .nu.: 1720 cm.sup.-1. 
NMR (CDCl.sub.3) .delta.: 3.80 (s, 3H), 5.16 (s, 2H), 6.96d+7.55d (ABq, J=9 
Hz, 4H), 7.83 (s, 4H). 
To a solution of N-p-methoxybenzyloxyphthalimide (10.55 g) prepared as 
above in a mixture of N,N-dimethylformamide (70 ml) and methanol (20 ml) 
is added hydrazine hydrate (3.7 ml) with stirring at room temperature, and 
the mixture is stirred for 1 hour at the same temperature. Then, the 
mixture is mixed with 2N-hydrochloric acid (61.5 ml) and stirred for 20 
minutes at the same temperature. The reaction mixture is diluted with 
water (30 ml) and separated crystals are removed by filtration. The 
filtrate is washed with ethyl acetate, made alkaline with potassium 
carbonate and extracted with ethyl acetate. The extract solution is washed 
with water, dried and concentrated under reduced pressure. The residue is 
the objective p-methoxybenzyloxyamine (6.09 g). 
IR (film) .nu.: 3400, 3280, 1660, 1600, 1580 cm.sup.-1. 
NMR (CDCl.sub.3) .delta.: 3.78 (s, 3H), 4.63 (s, 2H), 5.33 (brs, 2H), 
6.91d+7.33d (ABq, J=9 Hz, 4H). 
(2) .alpha.-(5-Mercapto-1H-tetrazol-1-yl)acetohydroxamic acid 
##STR6## 
To a mixed solvent of trifluoroacetic acid (15 ml) and anisole (15 ml) is 
added 5-mercapto-1H-tetrazole-1-acetohydroxamic acid p-methoxybenzyl ester 
(3 g), and the mixture is stirred at room temperature for 2 hours under 
nitrogen gas. The reaction mixture is concentrated under reduced pressure, 
and the resultant material is dissolved in water and passed through a 
column of synthetic resin adsorbent (Diaion HP-20 distributed by 
Mitsubishi Chemical K.K.) (95 ml). The resin is washed with water. The 
fractions containing the main product are combined and concentrated under 
reduced pressure. The resultant solid is crystallized from a mixture of 
ether and hexane to give the title compound (1.83 g). mp. 
105.degree.-107.degree. C. 
IR (Nujol) v: 3100, 1655 cm.sup.-1. 
NMR (CD.sub.3 COCD.sub.3) .delta.: 5.08 (brs, 2H). 
EXAMPLE 3 
Sodium 1-N-methoxycarbamoylmethyl-1H-tetrazol-5-ylmercaptide 
##STR7## 
A solution of 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester 
(945 mg) and sodium hydrogen carbonate (420 mg) in water (30 ml) is frozen 
and lyophilized overnight to give a hygroscopic sodium salt of 
5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester as a solid. 
IR (Nujol) .nu.: 3300br, 1670br cm.sup.-1. 
NMR (D.sub.2 O) .delta.: 4.19 (s, 3H), 5.47 (s, 2H). 
EXAMPLE 4 
.beta.-(5-Mercapto-1H-tetrazol-1-yl)propiohydroxamic acid methyl ester 
##STR8## 
To an ice cold and stirred solution of 5-mercapto-1H-tetrazole-1-propionic 
acid (1.04 g) in N,N-dimethylformamide (60 ml) is added 
N,N'-carbonyldiimidazole (1.16 g). After stirring for 15 minutes at 
0.degree. C., the mixture is mixed with a solution of methoxyamine 
hydrochloride (600 mg) and triethylamine (720 mg) in N,N-dimethylformamide 
(6 ml) and stirred for 1 hour at 0.degree. C. The reaction mixture is 
poured into diluted hydrochloric acid and extracted with a mixture of 
ethyl acetate and methyl ethyl ketone (2:1). The solvent is evaporated 
from the extract to leave crystalline 
5-mercapto-1H-tetrazole-1-propionohydroxamic acid methyl ester (1.2 g). 
mp. 170.degree.-171.degree. C. (decomp.). 
NMR (CD.sub.3 COCD.sub.3) .delta.: 2.77 (brs, 2H), 3.66 (s, 3H), 4.52 (t, 
J=7 Hz, 2H). 
IR (Nujol) .nu.: 3110, 1645 cm.sup.-1.