JPS5919945B2 - Method for producing 2-aminothiazol-4-yl-α-oximinoacetic acid derivative - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula ,,゛゛゛゛□,.

. 0, 0, 30 [In the formula, -COORI represents an optionally protected carboxyl group, and R2NH- represents an optionally protected amino group.

] 2-aminothiazole-4-yl α-
The present invention relates to a method for producing oximinoacetic acid derivatives. 3
5 As a result of various studies, the present inventors found that the general formula [wherein,
represents a halogen atom, and -COORl has the same meaning as above.

[In the formula, R2NH- has the same meaning as above.

2-aminothiazol-4yl-α-oximinoacetic acid derivative [1] can be obtained by reacting with a thiourea compound represented by It was discovered that the compound is a useful synthetic intermediate for penicillins or cephalosporins that have excellent antibacterial activity, and the present invention was completed based on this finding. That is, the present invention provides a 2-aminothiazole, which is characterized by reacting an α-oximino-β-ketoγ-halogenobutyric acid ester [ ] with a thiourea compound [ ] and removing the protecting group as necessary. This invention relates to a method for producing -4-yl-α-oximinoacetic acid derivative [1].

In the above formula, -COORl represents an optionally protected carboxyl group, and therefore R1 represents a hydrogen atom or a protecting group for the carboxyl group.

Any type of protecting group may be used as long as it can be removed under mild conditions such as acidic conditions, alkaline conditions, reducing conditions, etc. without affecting the thiazole nucleus; for example, it is generally used as a protecting group for carboxyl groups in peptide synthesis. For example, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, substituted alkyl groups such as β-methylsulfonylethyl, trichloroethyl, diphenylmethyl, phenyl, tolyl. Aryl groups such as p-tert-butylphenyl, substituted aryl groups such as p-nitrophenyl, aralkyl groups such as benzyl, phenethyl, tolbenzyl, p-methoxybenzyl, p-
Substituted aralkyl groups such as nitrobenzyl are used. R2NH- represents an optionally protected amino group, and therefore R2 represents a hydrogen atom or a protecting group for the amino group. As such a protecting group, a protecting group for an amino group that is easily removed and is commonly used in peptide chemistry is used.
For example, alkylcarbonyl groups such as formyl, acetyl, and propionyl; alkoxycarbonyl groups such as t-butoxycarbonyl; alkoxyalkylcarbonyl groups such as methoxyacetyl and methoxypropionyl; substituted alkoxycarbonyl groups such as trichloroethoxycarbonyl; and alkoxycarbonyl groups such as methoxycarbonylacetyl. Carbonylacetyl groups, aralkyloxycarbonyl groups such as benzyloxycarbonyl, and substituted aralkyloxycarbonyl groups such as p-nitrobenzyloxycarbonyl are frequently used. X represents a halogen atom such as chlorine, bromine, iodine, or fluorine. Target compound of the present invention [
1] can be produced by reacting α-oximino β-keto-γ-halogenobutyric acid esters [] and a thiourea compound []. This reaction is carried out in an organic solvent such as ethanol or tetrahydrofuran. A base is preferably added to the solvent, such as pyridine, triethylamine,
A tertiary base such as N-N-dimethylaniline is used. When R2 is a hydrogen atom, [] itself acts as a base, so there is no need to further add a base. The reaction is
．． The process advantageously proceeds at room temperature to reflux conditions. After the reaction is complete,
The protecting group can be removed as necessary, with or without separating the target product [1]. Removal of the protecting group is
Means commonly used for the removal of each protecting group are used;
For example, alkyl groups such as ethyl and propyl can be treated with acids or alkalis, diarylalkyl groups such as diphenylmethyl, alkoxyaralkyl groups such as p-methoxybenzyl can be treated with acids, and methylsulfonylalkyl groups such as β-methylsulfonylethyl can be treated with alkalis. According to
Halogenoalkyl groups such as β, β, and β-trichloroethyl can be converted to p-nitrobenzyl by zinc and acid.
Catalytic reduction of nitroaralkyl groups. This can be easily done by The protective group R2 of an amino group can be removed by using zinc and acid for halogenoalkoxycarbonyl groups such as β, β, and β-trichloroethoxycarbonyl, and for tertiary alkoxycarbonyl groups such as formyl and t-butoxycarbonyl. With acids, substituted aralkyloxycarbonyl groups such as p-nitrobenzyloxycarbonyl can be easily achieved by catalytic reduction. When both the carboxyl group and the amino group are protected, these protecting groups may be applied at the same time, or one of them may be removed first, taking into account the type of protecting group. The obtained target product [1] can be isolated and purified by known means such as solvent extraction, dissolution, liquid conversion, crystallization, recrystallization, distillation, chromatography, ion exchange, etc. The reaction solution can also be used as a raw material for the next step without further treatment. The object compound of the present application [ ] obtained in this way has a 2-2-
It is a novel intermediate useful for the production of penicillins or cephalosporins having an aminothiazol-4-ylglycylamide group.

Example 1 Ethyl α-oximino-β-oxo-γ-chlorobutyrate 1
9.3f7, thiourea 8.07 in ethanol 200ml
and heated under reflux for 2 hours.

Ethanol was distilled off under reduced pressure, and the residue was dissolved in 10% hydrochloric acid. To remove unreacted ethyl α-oximino-β-oxo-γ-chlorobutyrate from this solution,
After washing twice with 00ml, sodium hydrogen carbonate was added to the solution to adjust the pH to 7. Adjust the temperature to 0 to 7.5 and extract twice with 100 ml each of chloroform. After washing the chloroform layer with water and drying, chloroform was distilled off to obtain 2-aminothiazole-4.
Ethyl -yl-alpha-oximinoacetate is obtained. Yield 6
．． 4370 This product has a melting point of 137-138°C (decomposition point). Is the infrared absorption spectrum (NujOl) 3430?
oxime 1710 (1771-1 shows the absorption of ester)
Add 251η of thiourea and heat to reflux for 6 hours.

After cooling, 50 ml of chloroform is added to the reaction mixture, washed with water, and dried over magnesium sulfate. After chloroform is distilled off under reduced pressure, the residue is purified by silica gel column chromatography to obtain 2(β·β·β-trichloroethoxycarbonylamino)thiazol-4-yl-α-oximinoacetic acid ethyl ester. Yield 160m9. The nuclear magnetic resonance spectrum (100 MHz, in deuterated chloroform) of this product shows triplet and quartet lines of ethyl group at 1.35 and 4.36 ppm, single line of trichloroethoxy group at 4.87 ppm, 7.

A single resonance line of hydrogen at the 5-position of thiazole is shown at 94 ppm.

Reference Example (1) 2.15y of ethyl 2-aminothiazol-4yl-α-oximinoacetate obtained in Example 1 was mixed with 20% of 50% formic acid.
Dissolve in a mixture of ml and 10ml of methanol.

While stirring under ice-cooling, 1.5V of zinc powder was added little by little to the mixture, stirring was continued for 3 hours, and then insoluble materials were removed. The solution is concentrated under reduced pressure to obtain a solution containing crude 2-aminothiazol-4-ylglycineethyl. Add this as is to strong acidic ion exchange resin (H type) Amberlite IR-12.
The formic acid is removed by passing through a column consisting of 0.060 ml and repeated washing with water. Thereafter, the eluate was eluted with 10% aqueous ammonia, and the eluate was concentrated under reduced pressure to obtain 2-aminothiazole-4-ylglycine. Yield: 1.497 (yield: 86.4%). This product is purified by recrystallization from aqueous ethanol and has a melting point of 186.
~190°C (decomposition point). Nuclear magnetic resonance spectrum (
60Mc in trifluoroacetic acid), a single line of side chain methine hydrogen at 5.25 ppm and a single line resonance line of hydrogen on the thiazole ring at 6.75 ppm are shown.

Gives a purple color with ninhydrin reagent. (2) Suspend 3.46V of 2-aminothiazol-4-ylglycine in 100ml of N-N-dimethylacetamide.

While stirring at room temperature, 12.66f7 of β·β·β monotrichloroethoxycarbonyl chloride is added dropwise over 30 minutes. After stirring for a further 30 minutes, 250 ml of ethyl acetate are added to the reaction mixture. After washing with 70 ml of 1N hydrochloric acid, the ethyl acetate layer was separated.

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, X represents a halogen atom, and -COOR^1 represents an optionally protected carboxyl group. ] α-oximino-β-keto-γ-halogenobutyric acid esters and the general formula ▲ Numerical formulas, chemical formulas, tables, etc. . A general formula ▲ which is characterized by reacting with a thiourea compound represented by ] and removing the protecting group as necessary,
There are chemical formulas, tables, etc. ▼ [In the formula, -COOR^1 and R^2NH- have the same meanings as above. ] 2-aminothiazol-4-yl-α-
Method for producing oximinoacetic acid derivatives.