JPH0948772A - Production of aminothiazolylacetic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain, in high purity and yield under mild conditions, a compound useful as a side chain intermediate for cephem-based antibiotics by acylating a 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate with an actid anhydride in the presence of a base. SOLUTION: The objective compound of formula III is obtained by reaction of (A) a compound of formula I [R<1> is a (substituted) 1-8C alkyl, (substituted) 3-8C alkenyl, (substituted) 7-20C aralkyl, benzoylalkyl or (substituted) aryl] with (B) a compound of formula II [R<2> and R<3> are each a (substituted) 1-6C alkyl, (substituted) 7-15C aralkyl or (substituted) aryl] in the presence of (C) a basic catalyst such as potassium (bi)carbonate or sodium (bi)carbonate.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a side chain intermediate of a cephem antibiotic, more specifically, the present invention is an intermediate for producing a cephalosporin derivative having antibacterial properties. -(2-aminothiazole-4-
Ill) -2-acyloxyiminoacetic acid derivative.

[0002]

2. Description of the Related Art 2- (2-Aminothiazol-4-yl) -2-hydroxyiminoacetic acid ester has two reactive groups, an amino group and an oxime group, in its structure. On the other hand, in order to produce various cephem antibiotics, it is necessary to protect only the oxime group, protect only the amino group, or introduce a different protecting group into the amino group after protecting the oxime group. Need to be various derivatives. From such a viewpoint, it is extremely important to selectively acylate only the amino group or the oxime group. Conventionally, 2- (2-aminothiazole-4-
Examples of a method for selectively acylating an oxime group without acylating an amino group when acylating an (yl) -2-hydroxyiminoacetic acid ester include 2-
A method of reacting ethyl (2-aminothiazol-4-yl) -2-hydroxyiminoacetate with an acid halide in the presence of a strong base such as phenyllithium or sodium ethoxide (JP-A-7-97368), 2- ( After ethyl 2-aminothiazol-4-yl) -2-hydroxyiminoacetate and potassium arylate are reacted to prepare a potassium salt of allyl 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetate, A method of reacting with an acid halide (Japanese Patent Laid-Open No. 61-145170) is known. However, the former is performed under severe conditions using strong bases, acid halides, etc., and the strong base must be used in an equivalent amount or more to the substrate, and the latter requires a complicated operation of transesterification and then acylation. Met.

[0003]

Under such circumstances, 2
It has been desired to develop a method for industrially more advantageously acylating the oxime group of-(2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ester.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above problems, and as a result, found a method for selectively acylating only an oxime group under a very mild condition, and conducted various studies. Invented.

That is, the present invention relates to a compound represented by the general formula [I]: (In the formula, R ¹ has a carbon number of 1 to 1 which may have a substituent.
8 alkyl group, 3 to 3 carbon atoms which may have a substituent
8 alkenyl groups, 7 carbon atoms which may have a substituent
To 20 aralkyl groups, benzoylalkyl groups, or aryl groups which may have a substituent. ) And 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ester represented by the general formula [II] (In formula, R < ² > and R < ³ > are the same or different and are a C1-C6 alkyl group which may have a substituent, C7-C15 aralkyl which may have a substituent. Base,
Or a phenyl group which may have a substituent. )
With an acid anhydride represented by the general formula [III] characterized by reacting in the presence of a base catalyst. (In the formula, R ¹ and R ² have the same meanings as described above.) A method for producing 2- (2-aminothiazol-4-yl) -2-acyloxyiminoacetic acid ester is provided. is there.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
R ¹ of 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ester represented by the general formula [I] used in the present invention is methyl, ethyl, propyl,
Substitution of alkyl groups such as isopropyl, butyl and t-butyl, alkoxyalkyl groups such as methoxymethyl and ethoxymethyl, haloalkyl groups such as trichloroethyl, alkylthioalkyl groups such as methylthioethyl, and alkylsulfonylalkyl groups such as methanesulfonylethyl. An alkyl group having 1 to 8 carbon atoms which may have a group; an alkenyl group such as propenyl, allyl and hexenyl, a phenyl substituted alkenyl group such as phenylpropenyl, and an alkyl substituted alkenyl group such as dimethylhexenyl and the like having 3 carbon atoms ~ 8
C7 which may have a substituent such as alkenyl group, benzyl, methylbenzyl, dimethylbenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylbenzyl, di-t-butylhydroxybenzyl, phenylethyl, trityl and the like. To aralkyl group of 20 to 20; benzoylalkyl group such as phenacyl; and aryl group having 6 to 12 carbon atoms which may have a substituent such as phenyl, toluyl, diisopropylphenyl, xylyl, trichlorophenyl and indanyl.

[0007] R ^{2 of the} acid anhydride represented by the general formula [II]
Alternatively, R ³ is an alkyl group having 1 to 6 carbon atoms which may have a substituent such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, amyl, hexyl, chloromethyl, trichloromethyl, and benzyl. An aralkyl group having 7 to 15 carbon atoms which may have a substituent, such as methylbenzyl, dimethylbenzyl, ethoxybenzyl, nitrobenzyl, phenylbenzyl and phenylethyl,
Examples thereof include aryl groups having 6 to 12 carbon atoms such as phenyl, toluyl, xylyl, methoxyphenyl, chlorophenyl and nitrophenyl. Examples of such acid anhydrides include acid anhydrides of acetic acid, propionic acid, valeric acid, benzoic acid, toluic acid, mixed acid anhydrides and the like.

The amount of the acid anhydride [II] used is 2- (2-
Aminothiazol-4-yl) -2-hydroxyiminoacetic acid ester [I] is preferably used in an amount of 0.9 equivalents or more, and in some cases, it may be used as a solvent in a large excess amount, but is more preferably 0. It is about 9 to 2 equivalent times. In the present invention, acylation of the oxime group selectively proceeds even if an acid anhydride is used in an excessive amount.

In the reaction of the present invention, usually, 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ester [I] and acid anhydride [II] are used as a solvent in the presence of a base catalyst. Is carried out.

Examples of the base catalyst used in the present invention include inorganic bases such as alkali metal or alkaline earth metal carbonates, bicarbonates, hydroxides and oxides, preferably sodium carbonate and bicarbonate. Sodium, potassium carbonate, potassium bicarbonate and the like can be mentioned. The amount of the base catalyst used is usually 2 to 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ester [I].
It is about 0.001 to 10 equivalent times, but preferably 0.
It is about 1 to 1 equivalent times.

When a solvent is used in the present invention, examples of such a solvent include hexane, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether, methyl isobutyl ether, dioxane, tetrahydrofuran and acetone. , Methyl isobutyl ketone, cyclohexanone, ethyl acetate, nitromethane, nitrobenzene,
A solvent inert to the reaction such as acetonitrile, benzonitrile, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, dimethylsulfoxide, and other aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, aprotic polar solvents, etc. A single or a mixture is used. The amount used is not particularly limited, but generally the amount used is about 1 to 6 times the weight of 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ester [I]. . Also, an acid anhydride [II] may be used in excess instead of the solvent, and in that case, the reaction proceeds selectively.

The reaction temperature is usually about -50 ° C to about 100 ° C.
The purpose can be achieved in the range of 0 ° C, but preferably about 10 ° C to about 50 ° C. The reaction time is not particularly limited,
The time when the raw materials disappear can be used as the end point of the reaction.
After completion of the reaction, 2- (2-aminothiazol-4-yl) -2-acyl iminoacetic acid ester [III] can be obtained in good yield by an ordinary separation means such as filtration, extraction, concentration and the like. It can also be purified by column chromatography, recrystallization and the like depending on the case.

[0013]

INDUSTRIAL APPLICABILITY The present invention provides 2- (2-aminothiazol-4-yl) -2-acyloxyiminoacetic acid ester, which is useful as a side chain intermediate of a cephem antibiotic, under extremely mild conditions. It is an industrially advantageous production method because it can be obtained with excellent purity and yield.

[0014]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 (Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ethyl ester (10.8 g), potassium carbonate (0.7)
g) and 50 ml of toluene in a mixed solution of acetic anhydride (5.2
g) is added dropwise at 40 ° C., and the mixture is stirred for 7 hours at the same temperature. After completion of the reaction, the reaction solution was sampled and analyzed by an internal standard method of liquid chromatography, and as a result, the reaction yield was 99%. After concentrating the reaction solution, the precipitate is collected by filtration, washed with toluene and dried to obtain (Z) -2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetic acid ethyl ester. ¹ H-NMR δ ppm (DMSO-d ₆ ): 1.40
(3H, t, J = 7.1Hz), 2.24 (3H,
s), 4.48 (2H, d, J = 7.1 Hz),
7.38 (1H, s), 7.50 (2H, s)

Example 2 (Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ethyl ester (10.8 g), sodium hydrogencarbonate (0.
To a mixed solution of 4 g) and 50 ml of ethyl acetate, acetic anhydride (5.2 g) was added dropwise at 40 ° C., and the mixture was stirred at the same temperature for 20 hours. After the reaction was completed, the reaction solution was sampled and analyzed by the internal standard method of liquid chromatography, and as a result, the reaction yield was 96%. After concentrating the reaction solution, the precipitate is collected by filtration, washed with ethyl acetate and dried to obtain (Z) -2- (2
-Aminothiazol-4-yl) -2-acetoxyiminoacetic acid ethyl ester is obtained.

Example 3 (Z) -2- (2-Aminothiazol-4-yl) -2-hydroxyiminoacetic acid ethyl ester (10.8 g), potassium carbonate (0.7)
Propionic anhydride (6.5 g) was added dropwise to a mixed solution of g) and 50 ml of toluene at 40 ° C., and the mixture was stirred at the same temperature for 7 hours. After the reaction was completed, the reaction solution was sampled and analyzed by the internal standard method of liquid chromatography, and as a result, the reaction yield was 97%. After concentrating the reaction solution, the precipitate is collected by filtration, washed with toluene and dried to obtain (Z) -2- (2-aminothiazol-4-yl) -2-propanoyloxyiminoacetic acid ethyl ester.

(Example 4) (Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ethyl ester (10.8 g), potassium carbonate (0.7)
g) and 50 ml of toluene in a mixed solution of benzoic anhydride (1
1.3 g) is added dropwise at 40 ° C., and the mixture is stirred at the same temperature for 7 hours. After completion of the reaction, the reaction solution was sampled and analyzed by the internal standard method of liquid chromatography, and as a result, the reaction yield was 95%. After concentrating the reaction solution, the precipitate is collected by filtration, washed with toluene and dried to obtain (Z) -2- (2-aminothiazol-4-yl) -2-benzoyloxyiminoacetic acid ethyl ester.

Claims (2)

[Claims] 1. A general formula [I] (In the formula, R ¹ has a carbon number of 1 to 1 which may have a substituent.
8 alkyl group, 3 to 3 carbon atoms which may have a substituent
8 alkenyl groups, 7 carbon atoms which may have a substituent
To 20 aralkyl groups, benzoylalkyl groups, or aryl groups which may have a substituent. ) And 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ester represented by the general formula [II] (In formula, R < ² > and R < ³ > are the same or different and are a C1-C6 alkyl group which may have a substituent, C7-C15 aralkyl which may have a substituent. Base,
Or, it represents an aryl group which may have a substituent. )
With an acid anhydride represented by the general formula [III] characterized by reacting in the presence of a base catalyst. (In the formula, R ¹ and R ² have the same meanings as described above.) A method for producing 2- (2-aminothiazol-4-yl) -2-acyloxyiminoacetic acid ester. 2. The method according to claim 1, wherein the base catalyst is potassium or sodium carbonate or bicarbonate.