JPH10195064A - Production of 5-amino-1,2,4-thiadiazoleacetic acid derivative (syn-isomer) - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound advantageous for the production of an intermediate useful as an acylation agent for producing a 7- acylaminocephalosporin compound having excellent antibacterial activity by treating the anti-isomer of the compound with a strong acid. SOLUTION: The objective 2-substituted-hydroxyimino-2-(5-amino-1,2,4- thiadiazol-3-yl)acetic acid derivative (syn-isomer) of the formula I (R<1> is a lower alkyl, etc.; R<2> is a lower alkyloxy, etc.) can be produced by treating the compound of the formula II which is anti-isomer of the objective compound with a strong acid. The treatment is carried out in a solvent capable of dissolving the compound of the formula II such as water or methanol using hydrochloric acid, etc., as the strong acid. The amount of the acid is 0.01-10mol based on 1mol of the anti-isomer and the isomerization reaction temperature is 0-80 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to 5-amino-1,2,
The present invention relates to a method for producing a 4-thiadiazole derivative. An object of the present invention is to provide a compound represented by the following formula (III), which is an intermediate useful as an acylating agent for producing a 7-acylaminocephalosporin compound having excellent antibacterial activity.
-Substituted hydroxyimino-2- (5-amino-1,2,4
-Thiadiazol-3-yl) acetic acid (syn isomer) (II
I) 2- which is advantageous for the production of (R ¹ has the same meaning as described above)
Substituted hydroxyimino-2- (5-amino-1,2,4-
An object of the present invention is to provide a method for producing a thiadiazol-3-yl) acetic acid derivative (I) (syn isomer).

Embedded image

[0002]

BACKGROUND OF THE INVENTION It is generally known that oximes (hydroxyimino forms) are isomerized to a stable form with hydrochloric acid. For example, it is known that a syn-form of p-bromobenzaldehyde oxime isomerized to an anti-form by hydrochloric acid gas.

Embedded image J. Org. Chem., 35 , 3546 (1970).

However, a direct isomerization reaction of a substituted hydroxyimino form having a 1,2,4-thiadiazole ring as shown by the general formulas (I) and (II) from an anti form to a syn form has been reported. It has not been. 1,2,4-
As a method of converting a substituted hydroxyimino form having a thiadiazole ring from an anti isomer to a syn isomer,
The present inventors have already found a method of reacting an anti-isomer represented by the general formula (II) with formic acid to isomerize to a syn-isomer via a formyl derivative (Japanese Patent Application No. 8-3).
No. 00121).

[0004] In the present specification, all compounds having the following partial structure are referred to as compounds having a geometric structure represented by the formula (Sn) as "syn isomers", and are represented by the structure represented by the formula (An) Are referred to as “anti-isomers”.

Embedded image

The present inventors have conducted intensive studies on a method of directly converting a substituted hydroxyimino compound (anti-isomer) represented by the general formula (II) into a syn isomer represented by the general formula (I), and as a result, It has been found that by using an appropriate amount of, isomerization proceeds efficiently while utilizing the difference in solubility between the anti isomer and the syn isomer. The present invention has been completed based on the above findings.

[0006]

The process of the present invention comprises a compound of the general formula (I):

Embedded image (Wherein R ¹ is lower alkyl or fluoromethyl, R ²
Is a lower alkyloxy, an amino group or a hydroxyl group).
(5-amino-1,2,4-thiadiazol-3-yl)
A method for producing an acetic acid derivative (syn isomer) (I),
General formula (II):

Embedded image (Wherein R ¹ and R ² have the same meanings as described above).
2,4-thiadiazol-3-yl) acetic acid derivative (anti isomer) (II) is treated with a strong acid to produce a syn isomer represented by the general formula (I).

That is, the isomerization reaction of the present invention can be represented by the following reaction formula.

Embedded image Here, R ¹ and R ² have the same meaning as described above.

The above reaction is an equilibrium reaction, and the isomerization rate to a syn isomer differs depending on R ² . For example, when R ² is an amino group, an anti-isomer precipitates when an excess acid is used, but when heated with a small amount of acid, the anti-isomer dissolves in methanol, and the syn isomer is insoluble in methanol. The equilibrium shifts to the syn isomer and precipitates as crystals. The isomerization rate is about 90%.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In this specification, "lower alkyl" refers to a C ₁ -C ₅ saturated alkyl group, preferably C ₁ -C ₃ alkyl, more preferably C ₁ -C ₃ alkyl.
₁ is an alkyl of ~C _2. Specifically, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl,
t-butyl, n-pentyl and isopentyl.

When R ² is lower alkyloxy, the isomerization ratio is 85-90%. Since the solubility in methanol differs between the syn isomer and the anti isomer (the syn isomer is hardly soluble), a high purity syn isomer can be separated by washing with methanol.

[0011] If R ² is a hydroxyl group, a little bad and isomerization rate from 60 to 65%. Therefore, industrially, an amide or ester (where R ² is an amino group,
A 2-substituted hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) of the general formula (III) after isomerization to a syn-isomer with a lower alkyloxy group) followed by hydrolysis. It is advantageous to synthesize acetic acid (syn isomer).

The 2-substituted hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid derivative (anti-isomer) represented by the general formula (II) is disclosed in Japanese Patent Application No. 8-284,878.
As reported in US-300121, the general formula (I
V):

Embedded image (In the formula, R ¹ and R ² are the same meaning as above, R ³
Is an alkylsulfonyl or an arylsulfonyl) obtained by reacting a 2-substituted hydroxyimino-2-substituted carbonylacetamido-o-substituted oxime with potassium rhodan.

The solvent used for the isomerization reaction is water, methanol, ethanol or the like, or a mixture thereof, represented by the general formula (II):
Any compound can be used as long as it dissolves the compound represented by the formula: water, methanol or a mixture thereof is economically and industrially favorable.

The acid used may be a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid, an organic acid such as p-toluenesulfonic acid or oxalic acid (excluding formic acid), or a mixture thereof. Hydrochloric acid having a high isomerization efficiency and a high reaction rate is preferable, and more preferably hydrochloric acid gas or concentrated hydrochloric acid is advantageous.

The number of moles of the acid used per mole of the anti-isomer in the isomerization reaction is 1: 0.01 to 10, preferably 1: 0.02 to 5, and more preferably 1: 0.02 to 4. . More specifically, the amount of the acid used varies depending on R ^2. When R ² is a lower alkyloxy group,
The ratio is 1: 0.25 to 5, preferably 1: 0.5 to 2.5, and more preferably 1: 0.75 to 2.0. When R ² is an amino group, it is 1: 0.01 to 0.2, preferably 1: 0.0.
02 to 0.2, more preferably 1: 0.02 to 0.1. However, when R ¹ is CH ₂ F, it is preferable to use a larger amount. 1: 2 when R ² is a hydroxyl group
-10, preferably 1: 2-5, more preferably 1: 2
~ 3.

[0016] The reaction temperature of the isomerization reaction is from 0 to 80 ° C, preferably from 10 to 70 ° C, more preferably from 20 to 60 ° C. More specifically, when R ² is a lower alkyl group, 0 to 50 ° C., preferably from 10 to 40 ° C., more preferably 20 to 35 ° C.. When R ² is an amino group or a hydroxyl group, the temperature is 20 to 80 ° C., preferably 30 to 70 ° C.
° C, more preferably 40 to 60 ° C. R ¹ is CH ₂ F
In this case, the temperature is preferably lower.

Next, the present invention will be described more specifically with reference to Production Examples and Examples. Production Example 1 Methyl 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetate (anti-isomer)
Production of [General Formula (II) (wherein, R ¹ = Me, R ² = OMe)] (1) Production of 2-carboxy-2-methoxyimino-acetamidooxime 2-cyano-2-methoxyimino-acetamido 24 .
4 g (0.19 mol), 32.2 g of sodium bicarbonate (0.19 mol)
38 mol) was suspended in water and hydroxylamine hydrochloride 1
A solution of 3.3 g (0.19 mol) and 18.4 g of water was added to 80-8.
It was added dropwise at 5 ° C. After stirring at the same temperature for 3 hours, the reaction solution was concentrated. After adjusting the pH to 2.0 with 20 g of concentrated hydrochloric acid, the mixture was cooled and the formed crystals were collected by filtration. The obtained crystals were washed with 20 g of methanol, collected by filtration, and dried to obtain 27.1 g of 2-
Carboxy-2-methoxyimino-acetamidooxime was obtained. The crystals contain 14.8% salt. Actual yield 23.1 g, yield 74.8%.

(2) Preparation of o-tosyl-2-methoxycarbonyl-2-methoxyimino-acetamidooxime 18.9 g of 2-carboxy-2-methoxyimino-acetamidooxime obtained above (16.1 g (0.1%)). 1mo
l)), a suspension of methanol (31.5 g) was heated under reflux (63
(〜67 ° C.), 12.5 g (0.11 mol) of thionyl chloride was added dropwise. After completion of the dropwise addition, the mixture was heated under reflux for 2 hours and concentrated under reduced pressure. 80 g of ethyl acetate, sodium bicarbonate 2
5 g (0.3 mol), p-toluenesulfonyl chloride 2
1 g (0.11 mol) was added. At an internal temperature of 5 ° C., 45 g of water was added dropwise, and the mixture was stirred and reacted at the same temperature overnight. 6.7 g of 90% acetic acid
(1.0 mol) was added dropwise, and the mixture was neutralized. 45 g of water was added to the remaining liquid, and the precipitated crystals were collected by cooling and collected by filtration. The obtained crystals were washed with 70 g of toluene, collected by filtration, and dried to obtain 26.3 g (yield: 79.9%) of o.
-Tosyl-2-methoxycarbonyl-2-methoxyimino-acetamidooxime was obtained.

(3) Preparation of methyl 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetate (anti-isomer) 16.2 g (0.167 mol) of potassium rhodan O-Tosyl-2-methoxycarbonyl-2-methoxyimino-acetamidooxime 18.3 obtained above in 53 g of methanol
g (0.056 mol) was added and reacted at 25-30 ° C for 24 hours. The insoluble material was filtered off, and the insoluble material was removed by 46 g of methanol.
And washed. The washing filtrate was combined with the previous reaction filtrate, and methanol was distilled off under reduced pressure. 28 g of water was added to the concentrated residue, and after cooling, the precipitated crystals were collected by filtration, dried and 9.9 g (yield 82).
%) Of 2-methoxyimino-2- (5-amino-1,2,2,
Methyl 4-thiadiazol-3-yl) acetate (anti isomer) was obtained.

Production Example 2 2-Fluoromethoxyimino-2- (5-amino-1,
Methyl 2,4-thiadiazol-3-yl) acetate (anti-isomer) [wherein R ¹ = CH ₂ F, R ²
(OMe))] (1) Production of 2-carboxy-2-fluoromethoxyimino-acetamidooxime Sodium hydroxide 12.2 was added to 46.6 g (267.6 mmol) of ethyl 2-fluoromethoxyimino-cyanoacetate under ice-cooling. A solution of 9 g (321.1 mmol) dissolved in 268 ml of water was added, and the mixture was stirred at room temperature for 3 hours. Under ice cooling, 20.5 g (294.4 mmol) of hydroxylamine hydrochloride and 16.7 g (120.4 mmol) of potassium carbonate were added, and the mixture was stirred overnight at room temperature. 22.3 ml (267.6 mmol) of concentrated hydrochloric acid were added (pH = 2), and the mixture was concentrated at an internal temperature of 30 ° C., and when crystals precipitated, cooled, collected by filtration and dried, and dried to obtain 21.3 g of 2-carboxy-2.
-Fluoromethoxyimino-acetamidooxime was obtained. Yield 44.6%.

(2) Preparation of o-tosyl-2-methoxycarbonyl-2-fluoromethoxyimino-acetamidooxime 17.9 g (100 mmol) of 2-carboxy-2-fluoromethoxyimino-acetamidooxime obtained above
Are suspended in 5 ml of methanol, and 13.1 g of thionyl chloride is suspended.
(110 mmol) and refluxed for 4 hours. The methanol was concentrated and the residue was concentrated by adding 50 ml of ethyl acetate. To a suspension obtained by adding 90 ml of ethyl acetate to the residue, 25.2 g (300 mmol) of sodium bicarbonate and 19.1 g (100 mmol) of p-toluenesulfonyl chloride were added, and 45 ml of water was added, followed by stirring at 5 ° C or lower for 17 hours. Reacted. Post-treatment was carried out in the same manner as in Production Example 1 to obtain 24.0 g (yield: 69.1%) of o-tosyl-2-methoxycarbonyl-2-fluoromethoxyimino-acetamidooxime.

(3) 2-fluoromethoxyimino-2- (5
Preparation of methyl-amino-1,2,4-thiadiazol-3-yl) acetate (anti-isomer) o-Tosyl-2-methoxycarbonyl-2 obtained above
-Fluoromethoxyimino-acetamidooxime 2
Using 2.6 g (65 mmol) and 9.0 g (yield 59.2%) of 2-fluoromethoxyimino-2- (5-amino-1,2,4-thiadiazole- 3- (yl) methyl acetate (anti isomer) was obtained.

Production Example 3 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide (anti-isomer) [General formula (II) wherein R ¹ = Me , R ² = N
H ₂₎ production of] (1) o-tosyl-2-carbamoyl-2-methoxyiminomethyl manufacture of acetamide oxime 2-cyano-2-methoxyiminoacetamide 12.7
g (0.1 mol), 7.3 g of hydroxylamine hydrochloride
(0.105 mol) and 5.56 g (0.0525 mol) of sodium carbonate were added to a suspension of 80 ml of methanol.
Stirred at room temperature for hours. Cool on ice and add 6.89 g of sodium carbonate
(0.065 mol) and methanol (20 ml), p-toluenesulfonyl chloride (21.0 g, 0.11 mol) was added little by little under ice-cooling, and the mixture was stirred at the same temperature for 4 hours. The crystals were dispersed and cooled in 100 ml of water, and the precipitated crystals were collected by filtration, washed with water, and washed with 80 ml of ethyl acetate. The crystals are collected by filtration and dried.
2 g (yield 64.3%) of o-tosyl-2-carbamoyl-2-methoxyiminoacetamidooxime were obtained.

(2) Preparation of 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide (anti isomer) 16.32 g (168 mmol) of potassium rhodane and 67 ml of methanol O-Tosyl-2-carbamoyl- obtained above
17.6 g of 2-methoxyiminoacetamidooxime
(56 mmol) and stirred at room temperature for 24 hours. The insoluble material was separated by filtration, the insoluble material was washed with 70 ml of methanol, the washed filtrate was combined with the reaction filtrate, and methanol was distilled off under reduced pressure. The concentrated residue was purified by silica gel chromatography (chloroform 7: methanol 1) to give 7.6 g (yield 6).
7.5%) of 2-methoxyimino-2- (5-amino-
(1,2,4-thiadiazol-3-yl) acetamide (anti isomer) was obtained.

Production Example 4 2-Fluoromethoxyimino-2- (5-amino-1,
2,4-thiadiazol-3-yl) acetamide (anti-isomer) [general formula (II) (wherein R ¹ ＝ CH ₂ F, R
² = NH ₂ )] 4.9 g (yield 73.8%) of o-tosyl- using 2.9 g (20 mmol) of 2-cyano 2-fluoromethoxyiminoacetamide in the same manner as in Preparation Example 3. 2-carbamoyl-2-fluoromethoxyiminoacetamido oxime was obtained. 2.92 g (30 mmol) of rhodane potassium,
To 12 ml of methanol was added 3.32 g (10 mmol) of o-tosyl-2-carbamoyl-2-fluoromethoxyiminoacetamidooxime obtained above, and the mixture was stirred at room temperature for 24 hours. Post-treated in the same manner as in Production Example 1 to give 1.64 g
(74.9% yield) of 2-fluoromethoxyimino-2
There was obtained-(5-amino-1,2,4-thiadiazol-3-yl) acetamide (anti-isomer).

[0026]

EXAMPLES In the following examples, the ratio between the anti-form and the syn-form was measured by HPLC. Example 1 Methyl 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetate (syn isomer)
Production of [General Formula (I) (wherein, R ¹ = Me, R ² = OMe)] Methyl 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetate ( Anti isomer)
61.4 g (0.287 mol) is suspended in 430 g of methanol and dissolved by adding 10.5 g (0.287 mol) of hydrochloric acid gas. This reaction solution was left at room temperature for 24 hours. At this time, the ratio of syn isomer: anti isomer was about 85:15. After neutralization with a 25% aqueous solution of potassium carbonate to pH 7 to 7.5, methanol was distilled off under reduced pressure (distilled amount: 280).
g), 300 g of water was added, the mixture was cooled to 10 ° C, collected by filtration, and dried to give 2-methoxyimino-2- (5-amino-1,
42 g (yield 68.4%) of methyl 2,4-thiadiazol-3-yl) acetate (syn isomer) was obtained. Its syn isomer purity was 99% or more. mp; 195 to 197 ° C IR (KBr) cm ^-1 ; 3437, 3130, 1722, ¹
618, 1531, 1441, 1406, 1294, 1
_{144,947 NMR (DMSO-d 6)} δ; 3.72 (3H, s), 3.92
(3H, s), 7.96 (2H, bs)

From the filtrate, methanol was distilled off under reduced pressure, and 10
C., filtered and dried to give 2-methoxyimino-2-
(5-amino-1,2,4-thiadiazol-3-yl)
10.5 g of methyl acetate (anti isomer) were obtained. Its purity was 90%.

Example 2 Methyl 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetate (syn isomer)
Production of [General Formula (I) (wherein, R ¹ = Me, R ² = OMe)] Methyl 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetate ( Anti isomer)
47.5 g (0.22 mol) of methanol are suspended in 285 g of methanol, and 45.2 g (0.44 mol) of concentrated hydrochloric acid is added (dissolved). The reaction was left at room temperature for 48 hours. At this time, the ratio of syn isomer: anti isomer was about 80:20. After neutralization with a 20% aqueous potassium carbonate solution to a pH of 7 to 7.5, methanol is distilled off under reduced pressure (distillation amount: 14
5g). 145 g of water was added, cooled (10 ° C.), collected by filtration and dried to obtain 31.8 g (yield 66.9%) of 2-methoxyimino-2- (5-amino-1,2,4-thiadiazole-3). −
Yl) Methyl acetate (syn isomer) was obtained. The purity of this syn isomer was 99% or more.

The filtrate was post-treated in the same manner as in Example 1,
2.4 g of 2-methoxyimino-2- (5-amino-1,
Methyl 2,4-thiadiazol-3-yl) acetate (a mixture of syn and anti isomers) was obtained.

Example 3 2-Fluoromethoxyimino-2- (5-amino-1,
Methyl 2,4-thiadiazol-3-yl) acetate (syn isomer) [wherein R ¹ = CH ₂ F, R ² =
OMe)] Production of 2-fluoromethoxyimino-2- (5-amino-1,
To 10 g (42.7 mmol) of methyl 2,4-thiadiazol-3-yl) acetate (42.7 mmol) was added 57 g of a 4% hydrochloric acid-methanol solution (62.9 mmol of hydrochloric acid), and the mixture was stirred for 6 hours and left at room temperature overnight. . After the reaction, the ratio of syn isomer: anti isomer was 90:10. The pH was adjusted to 7 with a 30% aqueous potassium carbonate solution, methanol was distilled off under reduced pressure (distillation amount: 52 g), water (50 g) was added, cooling, filtration, and drying were performed, and 7.58 g (75.8% yield) was obtained. Of 2-fluoromethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetate (syn isomer). The purity of the syn isomer was 99% or more. mp; 168 to 170 ° C IR (KBr) cm ^-1 ; 3472, 1732, 1618, ¹
535,1441,1408,1288,1138,1
082, 1055, 997, 980, 930, 849,
_{737,600 NMR (DMSO-d 6)} δ; 3.83 (3H, s), 5.72
(2H, d, J = 54Hz), 8.10 (2H, bs)

Example 4 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide (syn isomer)
Preparation of [general formula (I) (wherein, R ¹ = Me, R ² = NH ₂ )] o-tosyl obtained in the same manner as in Preparation Example 3 in 14.58 g (150 mmol) of potassium rhodanate and 60 ml of methanol −
15.72 g (50 mmol) of 2-carbamoyl-2-methoxyiminoacetamidooxime was added and the mixture was added at room temperature for 24 hours.
Stirred for hours. Concentrate the methanol, add 40 ml of water,
After dissolution, 0.5 g of activated carbon was added, the mixture was filtered, the filtrate was cooled, and 8.3 ml (100 mmol) of concentrated hydrochloric acid was added to precipitate crystals. The crystals were collected by filtration to give 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide (anti-isomer) (HPLC content: 81.4%,
Syn isomer 7.9%). Without drying the crystals, 50 ml of methanol and 100 μl (1.2 mmol) of concentrated hydrochloric acid are added, and the mixture is heated and stirred at an internal temperature of about 55 ° C. for 30 minutes. After cooling, filtration, washing (methanol) and drying, 6.87 g (yield 68.3%) of 2-methoxyimino-2- (5-amino-1,2,4-thiadiazole-3-) was obtained.
Yl) acetamide (syn isomer) was obtained. HPLC content 98.6% (anti-isomer 1.2%) mp; 245-250 ° C (dec) IR (KBr) cm ^-1 ; 3429,3252,3173,1
697,1605,1533,1458,1416,1
_{153,1043,874,820 NMR (DMSO-d 6)} δ; 3.83 (3H, s), 7.44
(1H, bs), 7.72 (1H, bs), 7.94 (2H, bs)

Example 5 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide (syn isomer)
Production of [General Formula (I) (wherein, R ¹ = Me, R ² = NH ₂ )] 2-methoxyimino-2- (5-amino-1,2,4-thiadiazole) obtained in Production Example 3 3-yl) acetamide (anti-isomer) 1.0 g (5.0 mmol) in methanol 6
ml, 1N hydrochloric acid (500 μl, 0.5 mmol), and a bath temperature of 50 mL.
Stirred at C for 7 hours. On the way, after heating for 1 hour, 20 mg of a seed crystal of a syn isomer was added. Cool, filter, dry and dry
5 mg (74.5% yield) of 2-methoxyimino-2- (5
-Amino-1,2,4-thiadiazol-3-yl) acetamide (syn isomer) was obtained. HPLC content 99.4%
(0.28% anti-isomer)

Example 6 2-fluoromethoxyimino-2- (5-amino-1,
2,4-thiadiazol-3-yl) acetamide (syn isomer) [wherein R ¹ ＣＨCH ₂ F, R ²
= NH ₂ )] 2-fluoromethoxyimino-2- (5) obtained in Production Example 4
Dissolve 2.19 g (10 mmol) of -amino-1,2,4-thiadiazol-3-yl) acetamide (anti isomer) in 40 ml of methanol, add 13.7 g (15 mmol) of a 4% methanol solution of hydrogen chloride, and add room temperature. For 48 hours (87% syn isomer, 13% anti isomer). After cooling, the pH was adjusted to about 7 with a 30% aqueous potassium carbonate solution, the methanol was concentrated, dispersed with 10 ml of water, cooled and filtered.
Further, it was washed with 8 ml of methanol, collected by filtration, dried and dried to give 2-fluoromethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide (syn isomer).
1.46 g (67.0%) were obtained. IR (KBr) cm ^-1 ; 3412,3186,1701,1
622, 1535, 1420, 1150, 1076, 1
053, 1003, 955, 872, 819 NMR (DMSO-d ₆ ) δ; 5.72 (2H, d, J = 55H)
z), 7.63 (1H, bs), 7.93 (1H, bs), 8.04 (2
H, bs)

Example 7 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) [General formula (I) wherein R ¹ = CH _3, R ² = OH)] Using 2- methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (anti-isomer) 10.
1 g (0.05 mol) was added to 54 g of water and 20 g of methanol. After heating and dissolving, 16 g (0.15 mol) of concentrated hydrochloric acid was added, and the mixture was heated at 45 ° C. for 12 hours. At this time, the ratio of syn isomer: anti isomer was about 65:45. Cooling, filtration,
After drying, 5.0 g (49.5% yield) of 2-methoxyimino-2- (5-amino-1,2,4-thiadiazole-3).
-Yl) acetic acid (syn isomer) was obtained. HPLC content 85.0% (anti-isomer 10.0%)

Claims (1)

[Claims] 1. A compound of the general formula (I): (Wherein R ¹ is lower alkyl or fluoromethyl, R ²
Is a lower alkyloxy, an amino group or a hydroxyl group).
(5-amino-1,2,4-thiadiazol-3-yl)
A method for producing an acetic acid derivative (syn isomer) (I),
General formula (II): (Wherein R ¹ and R ² have the same meanings as described above).
A method characterized in that 2,4-thiadiazol-3-yl) acetic acid derivative (anti isomer) (II) is treated with a strong acid.