JPH0755941B2 - Method for producing thiadiazolylacetic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] The present invention relates to a method for producing an intermediate of an antibacterial agent.

JP-A-57-158769 discloses a method for producing a thiadiazolylacetic acid derivative useful as an acylating agent for producing a 7-acylaminocephalosporin compound. This method is a method of hydrolyzing the corresponding acetonitrile compound in the presence of a base, but the yield is very low at 30% or less due to the formation of side reaction products, and it cannot be said to be an industrially satisfactory method. .

Therefore, the present inventors have studied the industrial production method of the thiadiazolylacetic acid derivative, and as a result, found that the desired product can be obtained in good yield by hydrolyzing the corresponding novel thiadiazolylacetamide derivative, and completed.

Therefore, an object of the present invention is to provide a novel method for producing a thiadiazolylacetic acid derivative useful as an intermediate for an antibacterial agent.

[Structure of Invention]

The present invention has the general formula: [Wherein R ₁ represents a lower alkyl group, R ₂ represents an amino group which may be protected by a protecting group] or a salt thereof is hydrolyzed in the presence of a base, and a protecting group may be added if necessary. General formula characterized by desorption: [Wherein R ₁ and R ₂ are the same as defined above], and a process for producing thiadiazolylacetic acid or a salt thereof.

The above reaction is carried out in an aqueous solvent in the presence of a base at a reaction temperature of 0 ° C.
It can be carried out at -80 ° C, preferably 45 ° C-55 ° C. Removal of the protecting group can be carried out by a conventional method such as hydrolysis or reduction depending on the kind of the protecting group.

As the base, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate or the like can be used.

As the aqueous solvent, water, a buffer solution, or a mixed solvent thereof with a lower alcohol such as methanol or ethanol can be used.

Examples of the lower alkyl group for R _{1 in} the compounds of the general formulas (I) and (II) include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, sec-butyl and the like. Further, as the type of the protecting group in the “amino group which may be protected by a protecting group” of R ₂ , those generally known as a protecting group for an amino group can be used.
For example, a substituted or unsubstituted lower alkanoyl group such as formyl, acetyl, chloroacetyl, dichloroacetyl, propionyl, and phenoxyacetyl; a substituted or unsubstituted lower alkanoyl group such as benzyloxycarbonyl, t-butoxycarbonyl, p-nitrobenzyloxycarbonyl and the like. Lower alkoxycarbonyl group; trityl, p-methoxybenzyl,
Substituted lower alkyl group such as diphenylmethyl; Substituted silyl group such as trimethylsilyl, t-butyldimethylsilyl; Substituted or unsubstituted benzylidene group such as benzylidene, salicylidene, 3,5-di (t-butyl) -4-hydroxybenzylidene Etc.

As the salt of the compound of the general formula (I), any salt can be used as long as it does not interfere with the above reaction. For example, inorganic acid salts such as hydrochloride, sulfate, carbonate, bicarbonate, hydrobromide, hydroiodide; acetate, maleate, lactate, tartrate, trifluoroacetate, etc. Organic carboxylic acid salts; methanesulfonic acid salts, benzenesulfonic acid salts, organic sulfonic acid salts such as toluenesulfonic acid salts; amino acid salts such as aspartic acid salts and glutamic acid salts.

Examples of the salt of the compound of the general formula (II) include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; hydrochloride salt, sulfate salt and carbonate salt. , Inorganic salts such as bicarbonate, hydrobromide, hydroiodide; organic carboxylates such as acetate, maleate, lactate, tartrate, trifluoroacetate; methanesulfonate, Organic sulfonates such as benzene sulfonate and toluene sulfonate; trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, N-methylglucamine Amine salts such as salts, diethanolamine salts, triethanolamine salts, tris (hydroxymethylamino) methane salts; Arginine salt, aspartate,
Examples thereof include amino acid salts such as lysine salt, glutamate and serine salt.

The compound of the general formula (I) which is the starting compound of the present invention can be obtained by hydrolyzing the corresponding thiadiazolylacetonitrile derivative in the presence of an oxidizing agent such as hydrogen peroxide and a base. Therefore, starting from a thiadiazolylacetonitrile derivative is a two-step reaction in which a thiadiazolylacetamide derivative is obtained from a thiadiazolylacetonitrile derivative and then hydrolyzed to obtain a thiadiazolylacetic acid derivative. This is an industrially superior method with a higher yield than the conventional method in which a thiadiazolylacetic acid derivative is directly obtained from a rilacetonitrile derivative.

Next, the present invention will be described in more detail by showing Examples and Experimental Examples.

Experimental Example 1 (Production of raw material compound) 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamide Water 400 ml, sodium hydroxide 10 g, 35% hydrogen peroxide water 160 ml
80 g of 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetonitrile was added to the mixed solution of, and the mixture was stirred under water cooling for 5 hours. The precipitate is collected, washed with water and acetone, and then dried to obtain the desired product 77.7.
g (yield 88.4%) was obtained.

Experimental Example 2 (Production of raw material compound) 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-ethoxyiminoacetamide 150 ml water, 6.0 g sodium hydroxide and 35% hydrogen peroxide
75 ml of methanol was added to the 30 ml mixed solution, and the mixture was cooled to room temperature. Then, 15.0 g of 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-ethoxyiminoacetonitrile was added to this solution, and the mixture was stirred at room temperature for about 6 hours. After cooling the reaction solution to 10 ° C, the precipitate was removed, water,
It was washed with isopropyl alcohol and ethyl ether.
This was dried to obtain 13.2 g of the desired product (yield 80.6%).

Experimental Example 3 (Production of raw material compound) 2- (5-chloroacetamide-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamide 100 ml of water, 2.0 g of sodium hydroxide and 35% hydrogen peroxide
2- (5-chloroacetamide-1, 10, to a mixed solution of 10.0 ml
5.0 g of 2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetonitrile was added and stirred for 30 minutes. The reaction solution was cooled to −2 ° C. and the precipitate was collected. This is washed with ice water and ethyl ether and then dried to obtain the desired product 2.
I got 0g.

Furthermore, the above liquid was extracted with ethyl acetate. Anhydrous magnesium sulfate was added to this and dried, and then ethyl acetate was distilled off. Isopropyl ether was added to the residue for crystallization to obtain 2.2 g of the desired product.

A total of 4.2 g (yield 78.6%) was obtained as the target product.

Example 1 2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetic acid 80 ml of 2N aqueous sodium hydroxide solution and 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-
A mixture of 4.02 g of methoxyiminoacetamide was added at 50 ° C. to 5
Stir for hours. The reaction solution was cooled to 10 ° C, and the pH of the solution was adjusted to 1 with concentrated hydrochloric acid. This was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and dried. Then, this was concentrated under reduced pressure, and 100 ml of isopropyl ether was added dropwise to the concentrated solution. The insoluble material was removed, washed with isopropyl ether, and dried to obtain 3.2 g (yield 79.2%) of the desired product as a white powder. The purity was 98.2% by HPLC analysis.

Experimental Example 4 (conventional method) 2- (5-amino-1,2,4-thiazizol-3-yl)
-(Z) -2-Methoxyiminoacetic acid 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetonitrile 7.50
To 40 g of water and 40 ml of water, 95 ml of 4N aqueous sodium hydroxide solution was added dropwise at 40 ° C, and the mixture was stirred at 50 ° C to 55 ° C for 5 hours. After cooling the reaction solution to 10 ℃, add 6N hydrochloric acid dropwise to adjust the pH of the solution to 2.4.
Adjusted to. 50 ml of ethyl acetate was added to this to extract and remove impurities. After adjusting the pH to 0.8 by adding 6N hydrochloric acid to the aqueous layer, 0.5 g of activated carbon was added and passed. The solution was extracted with ethyl acetate, and anhydrous magnesium sulfate was added to the extract to dry it. Ethyl acetate was evaporated under reduced pressure, 100 ml of isopropyl ether was added to the residue, and the precipitate was collected. This was dried to obtain 3.5 g of a crude product (purity 79.5% by HPLC analysis) as a pale yellow powder.

Then, 70 ml of ethyl acetate-methyl ethyl ketone (1: 1) was added to 3.5 g of this crude product, and the mixture was heated at 45 ° C to 50 ° C for 15 minutes.
The mixture was passed at the same temperature, washed with 7 ml of ethyl acetate, and dried to obtain 1.6 g of the desired product (yield 19.7%) as a white powder. The purity by HPLC analysis was 97.5%.

Example 2 2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-ethoxyiminoacetic acid 80 ml of 2N sodium hydroxide and 2- (5-amino-1,2,
A mixture of 4-thiadiazol-3-yl)-(Z) -2-ethoxyiminoacetamide (4.0 g) was stirred at 50 ° C for 8 hours. The reaction solution was cooled to 10 ° C, and the pH of the solution was adjusted to 1 with concentrated hydrochloric acid. This was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and dried. Then, after concentration under reduced pressure,
100 ml of isopropyl ether was added dropwise to the concentrated solution. The insoluble material was removed, washed with isopropyl ether, and dried to obtain 3.2 g (yield 80.2%) of the desired product as a white powder.

 ─────────────────────────────────────────────────── --- Continuation of the front page (72) Inventor Isao Sugiyama 29-4 Higashiarai, Yatabe-cho, Tsukuba-gun, Ibaraki Examiner Masato Ikeda

Claims (1)

[Claims] 1. A general formula: [Wherein R ₁ represents a lower alkyl group, R ₂ represents an amino group which may be protected by a protecting group] or a salt thereof is hydrolyzed in the presence of a base, and a protecting group may be added if necessary. General formula characterized by desorption: [Wherein R ₁ and R ₂ are the same as defined above], and a process for producing thiadiazolylacetic acid or a salt thereof.