Method for production of 2-oxyimino-3-oxobutyric acids

An advantageous method of producing in large amounts on a commercial scale 2-substituted oxyimino-3-oxobutyric acids, which are useful as intermediates in the synthesis of e.g. aminothiazole cephalosporins, is characterized by reacting a tert-butyl 2-substituted oxyimino-3-oxobutyrate with a hydrogen halide in an anhydrous organic solvent.

This invention relates to an advantageous method of producing, in large 
amounts on a commercial scale, 2-substituted oxyimino-3-oxobutyric acids, 
which are useful as intermediates in the synthesis of cephalosporin 
compounds, among others. 
2-Substituted oxyimino-3-oxobutyric acids are important intermediates in 
the synthesis of aminothiazole cephalosporins, typically cefmenoxime, for 
instance. Several aminothiazole cephalosporins are already on the market 
and in wide clinical use as antibiotics having a very broad antibacterial 
spectrum. Their structures, pharmacological activities and methods of 
production are described, for example, in Angewandte Chemie, International 
Edition in English, 24, 180-202 (1985) and Journal of Antibiotics, 38, 
1738-1751 (1985). It is the 2-substituted oxyimino-3-oxobutyric acids that 
are used as intermediates in the synthesis of the aminothiazole moieties 
of the above-mentioned aminothiazole cephalosporins. 
In the prior art, the 2-substituted oxyimino-3-oxobutyric acids are 
synthesized by hydrolyzing corresponding 2-substituted 
oxyimino-3-oxobutyric acid esters with an alkali such as sodium hydroxide 
[GB2012276] or hydrolyzing corresponding tert-butyl 2-substituted 
oxyimino-3-oxobutyrates with trifluoroacetic acid [U.S. Pat. No. 4107380, 
U.S. Pat. No. 4191673]. 
However, both the methods are not especially advantageous for 
large-quantity commercial production of 2-substituted 
oxyimino-3-oxobutyric acids. Thus, the method comprising hydrolyzing the 
starting 2-substituted oxyimino-3-oxobutyric acid esters with an alkali is 
disadvantageous in that it gives low yields, whereas the method which 
involves hydrolysis with trifluoroacetic acid is disadvantageous in that 
trifluoroacetic acid, which is an expensive reagent, must be used in 
excess. 
As a result of their intensive investigations to elaborate a method of 
producing 2-substituted oxyimino-3-oxobutyric acids which is advantageous 
in large-quantity commercial production of the same, the present inventors 
found that the reaction of tert-butyl 2-substituted 
oxyimino-3-oxobutyrates with a hydrogen halide in an anhydrous organic 
solvent can give the desired 2-substituted oxyimino-3-oxybutyric acids in 
high purity and in high yield without using any expensive raw material and 
that, accordingly, the method involving said reaction is more advantageous 
as a method of producing 2-substituted oxyimino-3-oxobutyric acids at low 
costs than the known methods. Based on such findings, the present 
invention has now been completed. 
The invention thus provides a method of producing 2-substituted 
oxyimino-3-oxobutyric acids which comprises reacting a tert-butyl 
2-substituted oxyimino-3-oxobutyrate with a hydrogen halide in an 
anhydrous organic solvent. 
Preferred examples of the tert-butyl 2-substituted oxyimino-3-oxobutyrate, 
which are the starting materials in carrying out the method according to 
the invention, are compounds of the formula 
##STR1## 
wherein R is a hydrogen atom or an alkyl group which may optionally be 
substituted. In compounds (I), the alkyl group represented by R is, for 
example, a straight or branched alkyl group having 1 to 4 carbon atoms, 
such as methyl, ethyl, propyl, isopropyl or butyl. The alkyl group 
represented by R may be substituted. Thus, said group may have one or two 
substituents each independently selected from the class consisting of a 
carboxyl group, C.sub.1-4 alkoxycarbonyl group (e.g. methoxycarbonyl, 
ethoxycarbonyl), cycloalkyl groups of 3 to 6 carbon atoms (e.g. 
cyclopropyl), heterocyclic groups (e.g. five-membered heterocyclic groups 
such as imidazol-5-yl) and the like. The "alkyl group which may optionally 
be substituted" as represented by R thus includes, among others, methyl, 
ethyl, cyclopropylmethyl, imidazol-5-ylmethyl, methoxycarbonylmethyl, 
ethoxycarbonylmethyl, 1-methoxycarbonyl-1-methylethyl and 
1-ethoxycarbonyl-1-methylethyl. Typical examples of compounds (I) are 
tert-butyl 2-methoxyimino-3-oxobutyrate and the like. 
Preferred examples of the desired product, namely 2-substituted 
oxyimino-3-oxobutyric acid, are compounds of the formula 
##STR2## 
wherein R is as defined above. In formula (II), R represents a hydrogen 
atom or an alkyl group which may optionally be substituted, as mentioned 
above for formula (I). Typical examples of compounds (II) are 
2-methoxyimino-3-oxobutyric acid and the like. 
Usable as the hydrogen halide are hydrogen chloride, hydrogen bromide, and 
so on. Among them, hydrogen chloride is preferred, however. 
The compounds (I) and (II) mentioned above each may be in the syn 
configuration 
##STR3## 
or in the anti configuration 
##STR4## 
or in the form of a mixture of these. It is to be noted that any of the 
forms or configurations falls within the scope of the present invention. 
The reaction is carried out in an anhydrous organic solvent. The organic 
solvent may be any one which will not adversely affect the reaction. Thus, 
usable as the organic solvent are, for example, nitriles such as 
acetonitrile, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane 
and diethyl ether, halogenated hydrocarbons such as methylene chloride, 
chloroform, dichloroethane and carbon tetrachloride, esters such as ethyl 
acetate and butyl acetate, amides such as N,N-dimethylformamide and 
N,N-dimethylacetamide, hydrocarbons such as benzene, toluene, xylene, 
hexane and pentane, and mixtures of these. Among them, halogenated 
hydrocarbons (in particular, chlorinated hydrocarbons such as methylene 
chloride) are preferred in most cases. Such organic solvent is used 
generally in an amount of 0.1 to 10 liters, preferably 0.5 to 2 liters, 
per mole of tert-butyl 2-substituted oxyimino-3-oxobutyrate. Since the 
presence of water in the reaction mixture promotes byproduct formation, 
the quantity of water contained in the reaction mixture should advisably 
be as small as possible. For that reason, the organic solvent mentioned 
above should desirably be substantially anhydrous with the moisture 
content reduced as far as possible. 
The reaction can be effected by bringing the tert-butyl 2-substituted 
oxyimino-3-oxobutyrate into contact with the hydrogen halide in the 
anhydrous organic solvent. Thus, the reaction is generally carried out by 
bringing the tert-butyl 2-substituted oxyimino-3-oxobutyrate into contact 
with the hydrogen halide, which is in the gaseous form, in the anhydrous 
organic solvent, for example by blowing the hydrogen halide gas into the 
mixture of the starting material and the solvent, if desired under 
pressure or with stirring. The reaction may also be effected by dissolving 
the hydrogen halide in advance in the anhydrous organic solvent employed, 
if desired under pressure or with stirring, and then adding the tert-butyl 
2-substituted oxyimino-3-oxobutyrate to the thus-prepared solution. The 
hydrogen halide is used generally in an amount of 1 to 10 moles, 
preferably 1 to 6 moles, per mole of tert-butyl 2-substituted 
oxyimino-3-oxobutyrate, although said amount may vary depending on the 
organic solvent employed. When, in particular, an alkylene chloride, such 
as methylene chloride, which is preferred as the organic solvent, is used, 
the hydrogen halide is used generally in an amount of 1 to 3 moles, 
preferably 1.2 to 2 moles, per mole of tert-butyl 2-substituted 
oxyimino-3-oxobutyrate. 
The reaction temperature is not critical. The only requirement is that the 
reaction can proceed at the temperature employed. Generally, however, the 
reaction is carried out at -50.degree. C. to 80.degree. C., preferably 
0.degree. C. to 30.degree. C. The hydrogen halide is blown into the 
starting material-solvent mixture generally over a period of 0.5 to 20 
hours, preferably 2 to 10 hours, although the period of hydrogen halide 
feeding should be varied depending on the reaction temperature, the 
solvent and the hydrogen halide quantity. Then, the reaction mixture is 
preferably stirred or allowed to stand generally for 1 to 24 hours, 
preferably 2 to 15 hours. In cases where the hydrogen halide is dissolved 
in advance in the solvent, for example by blowing into the solvent, the 
mixture obtained after addition of tert-butyl 2-substituted 
oxyimino-3-oxobutyrate should advantageously be stirred generally for 1 to 
40 hours, preferably 2 to 20 hours. 
The 2-substituted oxyimino-3-oxobutyric acid formed as a result of the 
reaction can be used as an intermediate for syntheses either in the form 
of the reaction mixture as it is or after isolation from the reaction 
mixture and purification by known means such as concentration, pH 
adjustment, solvent extraction, crystallization, recrystallization, 
chromatography, etc. 
In an example of the use as intermediate for syntheses, the 2-substituted 
oxyimino-3-oxobutyric acid obtained by the method according to the 
invention is reacted, for example, with a halogenating agent in the 
presence of an anhydrous acid catalyst to give a 4-halo-2-substituted 
oxyimino-3-oxobutyric acid, which is useful as an intermediate for 
syntheses, preferably a compound of the formula 
##STR5## 
wherein X is a halogen atom, such as Cl, Br or I, and R is as defined 
above, the notation 
##STR6## 
representing, as mentioned above, that compound (III) is in the syn or 
anti configuration or in the form of a mixture of the syn and anti forms. 
Usable as the halogenating agent in the above reaction are, for example, 
halogens (chlorine, bromine, iodine), sulfuryl halides (sulfuryl chloride, 
etc.), N-halosuccinimides (N-bromosuccinimide, N-chlorosuccinimide, etc.) 
and 1,3-dibromo-5,5-dimethylhydantoin. Among them, bromine, sulfuryl 
chloride, N-bromosuccinimide and the like are preferred in most cases. 
Such halogenating agent is used generally in an amount of 0.5 to 1.5 moles 
per mole of 2-substituted oxyimino-3-oxobutyric acid. The halogenation 
reaction is generally carried out in a solvent. The solvent may be any one 
which will not adversely affect the reaction. Usable as the solvent are, 
for example, hydrocarbons, such as hexane, benzene, toluene and xylene, 
ethers, such as tetrahydrofuran, isopropyl ether, dioxane and diethyl 
ether, halogenated hydrocarbons, such as methylene chloride, chloroform 
and carbon tetrachloride, esters, such as ethyl acetate, ketones, such as 
acetone, amides, such as N,N-dimethylformamide and N,N-dimethylacetamide, 
and mixtures of these. Preferred as the solvent are halogenated 
hydrocarbons, such as methylene chloride, and ethers, such as 
tetrahydrofuran, among others. The reaction temperature is not critical. 
The only requirement is that the halogenation reaction can proceed at the 
temperature employed. Generally, a temperature of -50.degree. C. to 
80.degree. C., preferably -20.degree. C. to 30.degree. C., is employed. 
The anhydrous acid catalyst is, for example, an inorganic acid, such as 
hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid or 
dichlorophosphoric acid, an organic acid, such as formic acid, acetic 
acid, p-toluenesulfonic acid, methanesulfonic acid or trifluoroacetic 
acid, or a Lewis acid, such as boron fluoride, aluminum chloride or 
titanium tetrachloride. That hydrogen bromide solution in acetic acid 
which is commercially available is a preferred example of the anhydrous 
acid catalyst. The 2-substituted oxyimino-3-oxobutyric acid formed by the 
method according to the invention can be subjected to said halogenation 
reaction in the form of the reaction mixture as it is and, in this case, 
the excess of the hydrogen halide used in carrying out the method 
according to the invention can serve as the anhydrous acid catalyst for 
the halogenation reaction. Therefore, when this halogenation reaction is 
conducted after carrying out the method according to the invention, 
4-halo-2-substituted oxyimino-3-oxobutyric acids can be produced 
advantageously in large quantities on a commercial scale. The reaction 
time, which should be varied depending on the solvent used, the 
halogenating agent, the anhydrous acid catalyst, the reaction temperature 
and other factors, generally amounts to 0.5 to 20 hours, preferably 1 to 
6 hours. 
The thus-obtained 4-halo-2-substituted oxyimino-3-oxobutyric acid may be 
used as an intermediate for syntheses either in the form of the reaction 
mixture as obtained or after isolation and purification by known means, 
such as concentration, pH adjustment, solvent extraction, crystallization, 
recrystallization, chromatography, etc. 
Typical examples of the 4-halo-2-substituted oxyimino-3-oxobutyric acid 
obtainable in the above manner are as follows: 
(i) 4-Chloro-2-methoxyimino-3-oxobutyric acid, 
(ii) 4-Bromo-2-methoxyimino-3-oxobutyric acid, and 
(iii) 4-Iodo-2-methoxyimino-3-oxobutyric acid. 
The method according to the invention is very useful as an industrial 
method of producing 2-substituted oxyimino-3-oxobutyric acids since it is 
superior to the prior art methods in the following respects, among others: 
(1) That inexpensive starting materials can be used; 
(2) That the desired products can be obtained in high purity and in high 
yield; and 
(3) That the next step halogenation reaction can be performed 
advantageously. 
As a result, the method according to the invention can serve as an 
advantageous method of producing synthetic intermediates for the 
commercial production of the desired end products in which the 
2-substituted oxyimino-3-oxobutyric acids are used as intermediates. For 
instance, 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-substituted 
oxyiminoacetamido]-3-unsubstituted or substituted-3-cephem-4-carboxylic 
acids or salts or esters thereof, which have excellent antimicrobial 
activity, can be derived from the 2-substituted oxyimino-3-oxobutyric 
acids obtained by the method according to the invention, for example, by 
halogenating the same in the above manner, reacting the thus-obtained 
4-halo-2-substituted oxyimino-3-oxobutyric acids with thiourea, 
converting, if necessary, the resulting (Z)-2-substituted 
oxyimino-2-(aminothiazol-4-yl)acetic acids to reactive derivatives thereof 
having an activated carboxyl group and reacting such acids or reactive 
derivatives with a 7-amino-3-unsubstituted or 
substituted-3-cephem-4-carboxylic acid or a salt or ester thereof, or by 
converting, if necessary, the 4-halo-2-substituted oxyimino-3-oxobutyric 
acids to reactive derivatives thereof having an activated carboxyl group, 
reacting said acids or reactive derivatives with a 7-amino-3-unsubstituted 
or substituted-3-cephem-4-carboxylic acid or a salt or ester thereof and 
reacting the resulting reaction products with thiourea (U.S. Pat. No. 
4098888, GB 1580621, U.S. Pat. No. 4166115, U.S. Pat. No. 4294960, U.S. 
Pat. No. 4278793, U.S. Pat. No. 4152433, GB 2012276, U.S. Pat. No. 4614819 
and U.S. Pat. No. 4656287) 
The following examples illustrate the invention in further detail but are 
by no means limitative of the scope of the invention. 
The symbols used in the examples and reference example respectively have 
the following meanings: 
s: singlet; CDCl.sub.3 : deuteriochloroform; %:% by weight; NMR (nuclear 
magnetic resonance) spectra were measured at 90 MHz with tetramethylsilane 
as an internal standard and the chemical shift values were given in terms 
of .delta. values (ppm).

EXAMPLE 1 
Tertiary-butyl 2-methoxyimino-3-oxobutyrate (805 g) was dissolved in 2.8 
liters of methylene chloride. Hydrogen chloride (210 g) was blown into the 
solution at 3.degree. to 6.degree. C. over 8 hours. Then, the resultant 
mixture was allowed to stand at 5.degree. C. for 15 hours. The supernatant 
was concentrated to dryness to give 556 g of 2-methoxyimino-3-oxobutyric 
acid as a crystalline solid. 
Yield 95.8%. 
NMR (CDCl.sub.3): .delta. 4.17 (3H, s), 2.44 (3H, s) ppm. 
EXAMPLE 2 
Hydrogen chloride was blown into 150 ml of 1,4-dioxane at 15.degree. C. 
until a state of substantial saturation was attained. The hydrogen 
chloride solution thus obtained was diluted with 172 ml of 1,4-dioxane to 
give 363 ml of 4N hydrogen chloride solution in 1,4-dioxane. 
A 200 ml portion of the above 4N hydrogen chloride solution in 1,4-dioxane 
was added to 35.0 g of tert-butyl 2-methoxyimino-3-oxobutyrate and the 
thus-obtained solution was stirred at 23.degree. to 25.degree. C. for 13 
hours. The supernatant was concentrated, 200 ml of methylene chloride was 
added to the residue for dissolution of the latter, 30 ml of 20% aqueous 
sodium chloride was added to the thus-obtained supernatant, the mixture 
was shaken, and the organic layer was separated, dried over 12 g of 
anhydrous magnesium sulfate and concentrated to dryness under reduced 
pressure to give 21.8 g of 2-methoxyimino-3-oxobutyric acid. 
Yield 86.4%. 
The NMR spectrum of this product was in agreement with that obtained in 
Example 1. 
REFERENCE EXAMPLE 
In 3 liters of methylene chloride was dissolved 460 g of the 
2-methoxyimino-3-oxobutyric acid obtained by the procedure of Example 1. 
To the solution was added 46 ml of a 25% hydrogen bromide solution in 
acetic acid. To the resultant solution was added dropwise over 2 hours at 
7.degree. to 15.degree. C. a solution of 372 g of bromine in 372 ml of 
methylene chloride. Nitrogen was then blown into the mixture violently at 
7.degree. to 8.degree. C. for 30 minutes so as to eliminate the byproduct 
hydrogen bromide. Silica gel (Kieselgel 60, 70 to 230 mesh, manufactured 
by Merck; 80 g) and activated carbon (Shirasagi of larger grain A grade, 
manufactured by Takeda Chemical Industries; 30 g) were added to the 
supernatant obtained. The mixture was stirred at 10.degree. to 15.degree. 
C. for 30 minutes and the insoluble matter was removed by filtration. The 
filtrate was concentrated under reduced pressure, the oily residue was 
dissolved in 685 ml of xylene, and the solution was allowed to stand at 
5.degree. C. for 15 hours. The resultant crystalline precipitate was 
collected by filtration, washed with 100 ml of a 1:1 (v/v) mixture of 
xylene and n-hexane and then with 200 ml of n-hexane, and dried under 
reduced pressure to give 434 g of 4-bromo-2-methoxyimino-3-oxobutyric 
acid. The filtrate (mother liquor) was concentrated under reduced pressure 
and the oily residue was crystallized by addition of 238 ml of a 100:15 
(v/v) mixture of xylene and n-hexane to give 82.3 g of 
4-bromo-2-methoxyimino-3-oxobutyric acid as a second crop. 
Yield 72.7%. 
NMR (CDCl.sub.3): .delta. 4.36 (2H, s), 4.20 (3H, s) ppm.