JPH0629272B2 - Method for producing acetic acid derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

The compound represented by the following general formula (I) of the present invention is useful as a raw material for producing a 7-acylaminocephalosporin compound having excellent antibacterial activity.

[0002]

The present invention was made with the intention of providing an excellent method for producing the following compound (I).

[0003]

The present invention relates to a novel method for producing 2-substituted hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid or a salt thereof,
And their intermediates. More specifically, the present invention relates to 2-substituted hydroxyimino-2- (5-amino-1,
The present invention relates to a novel method for producing 2,4-thiadiazol-3-yl) acetic acid or a salt thereof, a novel intermediate useful in these methods, and a method for producing the intermediate. Therefore, an object of the present invention is to provide 2-substituted hydroxyimino-2- (5-amino-1,2,2,2) useful as an acylating agent for producing a 7-acylaminocephalosporin compound having excellent antibacterial activity. It is to provide a novel method for producing 4-thiadiazol-3-yl) acetic acid or a salt thereof.

Another object of the present invention is to provide a novel intermediate useful in the method for producing the above-mentioned 2-substituted hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid or a salt thereof. To provide the body. A further object of the present invention is to provide a method for producing the above novel intermediate. 2-Substituted hydroxyimino-2- (5-amino-1,2,4-thiadiazole- which is the object compound of the present invention
3-yl) acetic acid can be represented by the following general formula: [Wherein R ₁ is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cyclo (lower) alkenyl optionally substituted with an appropriate substituent, aryl optionally substituted with an appropriate substituent, or Means a S-containing 5-membered heterocyclic group substituted with an oxo group]

According to the present invention, the target compound, 2-substituted hydroxyimino-2- (5-amino-1,2,4-).
Thiadiazol-3-yl) acetic acid (I) or a salt thereof can be produced by the following method.

【Method】

Objective compound (I) and intermediate (II
In I), (IV), (VI) and (VIII) It is to be understood to include both geometric structures represented by the formula: wherein R ₁ is as defined above. In the present specification, for all the compounds having the above-mentioned partial structure, the compound having the geometric structure represented by the formula (A) is referred to as “syn isomer”, and the compound having the structure represented by the formula (A ′) is Called the "anti-isomer".

Suitable salts of the object compound (I) include salts with inorganic bases such as alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth metal salts (eg calcium salt, magnesium salt etc.). ), Ammonium salts, salts with organic bases such as organic amine salts (eg triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt,
Etc.); Inorganic acid addition salts (eg hydrochloride, hydrobromide, sulfate, phosphate, etc.); Organic acid addition salts, eg organic carboxylic acid or sulfonic acid addition salts (eg formate, trifluoroacetic acid) Salts, methane sulfonates, benzene sulfonates, acetates, P-toluene sulfonates, etc.); salts with basic amino acids (eg, arginine, etc.); included.

In the above description, as well as those set forth below, suitable examples of various definitions within the scope of the present invention are described in detail below. The term "lower" unless otherwise indicated means a group having 1 to 6 carbon atoms. Suitable lower alkyl includes straight chain or branched chain alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, t-pentyl, hexyl and the like. included.

Suitable substituents in the term "lower alkyl optionally substituted with suitable substituents" include halogen (eg chlorine, bromine, fluorine or iodine); carboxy; lower alkylthio (eg methylthio, ethylthio, propylthio). , Butylthio, etc.); aryl (eg phenyl, tolyl, xylyl, mesityl, cumenyl,
Etc.); Aryloxy (eg phenoxy, tolyloxy, mesityloxy, etc.); Lower alkoxy (lower) alkoxy (eg methoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, pentyloxymethoxy, hexyloxymethoxy, hexyloxyethoxy) , Etc); hydroxy;
Lower ankanesulfonyl (eg mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl,
Butanesulfonyl, etc.); aryl substituted with halogen (eg chlorophenyl, fluorophenyl, etc.);
Cyano; includes a protected carboxy group shown below and the like.

Suitable "protected carboxy" includes esterified carboxy and the like, and suitable examples of the ester moiety in the esterified carboxy include lower alkyl ester (eg methyl ester, ethyl ester, propyl). Ester, isopropyl ester, butyl ester, isobutyl ester, t-
Butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) which may have at least one suitable substituent, such as lower alkanoyloxy (lower) alkyl ester ( For example, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc. ), A lower alkanesulfonyl (lower) alkyl ester (for example, 2
-Mesylethyl ester, etc.), or mono (or di- or tri) halo (lower) alkyl ester (eg 2
-Iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkenyl ester (eg vinyl ester, allyl ester, etc.); lower alkynyl ester (eg ethynyl ester, propynyl ester, etc.); at least one suitable An optionally substituted ar (lower) alkyl ester (for example, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); Aryl ester optionally having at least one suitable substituent (eg, phenyl ester, 4-chloro) Eniruesuteru, tolyl ester,
t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.) and the like.

Suitable lower alkenyls include vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl,
3-pentenyl and the like are included, and preferably those having 2 to 4 carbon atoms. Suitable lower alkynyl has 2 to 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl,
3-hexynyl and the like are included, and preferably those having 2 to 4 carbon atoms. Suitable cycloalkyls include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, preferably those having 4 to 7 carbon atoms. Suitable cyclo (lower) alkenyls include those having 3 to 6 carbon atoms, such as cyclopentenyl, cyclohexenyl and the like, preferably those having 5 or 6 carbon atoms. Suitable aryls include phenyl, tolyl,
Xylyl, mesityl, cumenyl and the like, wherein the aryl group is halogen (eg chlorine, bromine, fluorine or iodine), nitro, lower alkoxy (eg methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.), preferably Those having 1 to 4 carbon atoms, halo (lower) alkyl (eg, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, trichloroethyl, etc.), preferably 1 to 3
It may be substituted with 1 to 3 suitable substituents such as those having 4 carbon atoms, carboxy and the like. Suitable S-containing 5-membered heterocyclic groups include groups such as thioranyl, which are substituted with 1 or 2 oxo groups.

The method for producing the object compound (I) or a salt thereof will be described in detail below. Method 1 Compound (III) or a salt thereof can be produced by subjecting compound (II) to a nitrosation reaction. Suitable salts of compound (III) include alkali metal salts (eg sodium salt, potassium salt) and the like. The nitrosating agent used in this reaction is a conventional one capable of reacting with an active methylene compound to form a C-nitroso compound, such as nitrite or an alkali metal nitrite (eg sodium nitrite, etc.). , Or lower alkyl nitrite (eg, t-butyl nitrite, isopentyl nitrite,
Etc.) such as nitrite. When the salt of nitrous acid is used as the nitrosating agent, this reaction is usually carried out in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, acetic acid and the like. On the other hand, when an ester of nitrous acid is used as the nitrosating agent, this reaction is preferably carried out in the presence of a slightly strong base such as an alkali metal alkoxide (eg sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.). To be done. This reaction is usually carried out in a solvent such as water, acetic acid, alcohol (eg ethanol, methanol, etc.), ether, tetrahydrofuran, or another solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Method 2 Compound (IV) or a salt thereof can be prepared by subjecting compound (III) or a salt thereof to a reaction for introducing a substituent on the hydroxyimino group. Suitable salts of the compound (IV) include salts with the same bases as exemplified for the compound (I). The reagent used in the reaction for introducing a substituent onto the hydroxyimino group is represented by the general formula R ₁ -Y (IX) (wherein R ₁ is the same as defined above, and Y is an acid residue). ) Or a compound of the general formula R _1a ═N ₂ (X) (wherein R _1a is a group obtained by removing hydrogen from R ₁ ). When the substituent to be introduced is an aryl which may be substituted with a suitable substituent, in addition to the above-mentioned reagents, the general formula R _1b −X ⁺ —R _1b Y ⁻ (XI) (wherein, Y is as defined above, R _1b is aryl optionally substituted with a suitable substituent, and X 1
Are halogens) can be used in the reaction to introduce a substituent on the hydroxyimino group. Suitable acid residues include hydrohalic acid (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, alkyl sulfuric acid (eg, methyl sulfuric acid, ethyl sulfuric acid, etc.), sulfonic acid (eg, methanesulfonic acid). , P-toluenesulfonic acid, etc.). The reaction with compound (IX) is usually carried out in a solvent such as water, acetonitrile, acetone, ethanol, ether, ethyl acetate, dimethylformamide or other solvent which does not adversely influence the reaction, and is preferably a base such as alkali. Metal hydroxides (eg sodium hydroxide, potassium hydroxide,
Etc.), inorganic bases such as alkali metal hydrogen carbonates (eg sodium hydrogen carbonate, potassium hydrogen carbonate, etc.) or alkali metal carbonates (eg sodium carbonate, potassium carbonate, etc.), alkali metal alkoxides (eg sodium methoxide, sodium, etc.). The presence of organic bases such as ethoxide, etc.), trialkylamines (eg trimethylamine, triethylamine, etc.), triethanolamine, N, N-dimethylaniline, N, N-dimethylbenzylamine, N-methylmorpholine or pyridine. It is carried out below. The reaction temperature is not particularly limited, and a preferable example of the compound (X) which is usually subjected to cooling or heating is a diazo (lower) alkane (eg, diazomethane, diazoethane, etc.) and the like. The reaction using the compound (X) is usually carried out in a solvent such as ether or tetrahydrofuran. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or at room temperature. Compound (X
The reaction using I) is usually carried out in a solvent such as alcohol (eg methanol, ethanol, etc.), water, a mixed solvent thereof, or other solvent which does not adversely influence the reaction,
It is preferably carried out in the presence of a base. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature, or under heating.

Method 3 Compound (V) or a salt thereof can be produced by subjecting compound (IV) or a salt thereof to a dehydration reaction. Suitable salt of the compound (V) may be a salt with the same base as exemplified for the compound (I). The dehydrating agent used in this dehydrating reaction includes phosphoryl chloride, thionyl chloride, phosphorus pentoxide, phosphorus pentachloride, phosphorus pentabromide and the like. This reaction is usually dioxane, chloroform,
It is carried out in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile, dimethylformamide, or other solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, and the reaction is usually performed at room temperature or under heating or heating.

Method 4 Compound (VI) or a salt thereof can be prepared by reacting compound (V) or a salt thereof with an ammonia and / or ammonium salt. Suitable ammonium salts include ammonium acetate, ammonium sulfate, ammonium halides (eg ammonium chloride, ammonium bromide, etc.) and the like. Suitable salts of the compound (VI) may be the same as those exemplified for the compound (I). This reaction is usually carried out in a solvent such as water, alcohol (eg, methanol, ethanol, etc.), acetone, chloroform, dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, or other solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or at room temperature.

Method 5 Compound (VIII) or a salt thereof is reacted with compound (VI) or a salt thereof with a halogenating agent, and then compound (VI) is added.
Suitable halogenating agents used in this reaction which can be prepared by reacting with I) include bromine, chlorine and the like. Suitable salts of the compound (VIII) may be the same as those exemplified for the compound (I). Suitable alkali metals as M include sodium, potassium and the like. This reaction is preferably carried out in the presence of a base such as an inorganic or organic base, eg alkali metal carbonates, alkali metal alkoxides, trialkylamines and the like. This reaction is usually carried out in a solvent such as alcohol (eg methanol, ethanol, etc.) or other solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling to room temperature.

Method 6 Compound (I) or its salt can be prepared by hydrolyzing compound (VIII) or its salt. This hydrolysis is preferably carried out in the presence of bases or acids. Suitable bases include alkali metals (eg sodium, potassium, etc.) alkaline earth metals (eg magnesium,
Calcium, etc.), their hydroxides, carbonates or bicarbonates, trialkylamines (eg trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo [4,3,0] non-5-ene. , 1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] undecene-7, etc. are included. Suitable acids include organic acids (eg formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, etc.). The reaction is usually carried out in a solvent such as water, alcohol (eg methanol, ethanol, etc.), mixtures thereof, or other solvent that does not adversely influence the reaction. A liquid base or acid can also be used as a solvent. The reaction temperature is not particularly limited, and the reaction is usually carried out under heating or heating. The present invention also includes within the scope of the present invention when the protected carboxy group and / or cyano group in R ₁ is converted into a free carboxy group during the reaction. And if necessary, R ₁
The carboxy group in can be converted to the protected carboxy group by conventional methods.

Method 7 Compound (V) or a salt thereof can be prepared by subjecting compound (XII) or a salt thereof to a reaction for introducing a substituent on the hydroxyimino group. Suitable salts of the compound (XII) include alkali metal salts (eg sodium salt, potassium salt) and the like. For the reagents that can be used in the reaction for introducing a substituent onto the hydroxyimino group, those exemplified in Method 2 can be referred to. This reaction for introducing a substituent into the hydroxyimino group can be carried out in the same manner as in the above-mentioned method 2. In the method of the present invention, compounds (III), (IV), (V), (V
I) and (VIII) can be used in their next step without isolation.

The object compound (I) and its salt are 7- [2-substituted hydroxyimino-2] s having excellent antibacterial activity.
-(5-Amino-1,2,4-thiadiazol-3-yl) acetamido] cephalosporin compounds are useful as important intermediates for the production of these 7-aminocephalosporin compounds. It can be produced by reacting a phosphorus compound with the object compound (I) of the present invention as an acylating agent, a reactive derivative thereof or a salt thereof. It is known that the target compound (I) or a salt thereof can be produced by using 1-alkoxycarbonylformamidine as a starting compound. Therefore, an object of the present invention is to provide a novel method for producing compound (I) or a salt thereof as described above. The present invention is based on the finding that these novel methods are superior to known methods in the following points. (1) Known methods require several steps to prepare a starting compound, namely 1-alkoxycarbonylformamidine, from a commercially available compound, but these novel method starting compounds are As such they are commercially available compounds, which means that known methods require longer steps than these new methods. (2) The known methods require expensive and dangerous reagents for the reaction, but these new methods do not require such expensive and dangerous reagents, so that they are more industrially used than known methods. Is also much more preferable and safe.

The following examples are provided for purposes of illustrating the invention. Example 1 2-Cyanoacetamide (67.
0 g) and sodium nitrite (66.1 g) were cooled in an ice bath and acetic acid (95.8 g) was added dropwise at 10 to 15 ° C. with stirring, and stirring was continued at the same temperature for 3 hours. A mixture containing 2-cyano-2-hydroxyiminoacetamide was added to a 4N aqueous sodium hydroxide solution (35
The pH was adjusted to 8.5 with 0 ml) and diethyl sulfate (14
7.5 g) was added. Mix the mixture at 45-50 ° C.
The mixture was stirred for 5 hours, and during this heating, a 4N sodium hydroxide aqueous solution was added to maintain the pH at 8.5. The mixture was cooled in an ice bath and the precipitate was collected, washed with cold water and dried to give 2-cyano-2-ethoxyiminoacetamide (70.0g). Melting point 125-127 [deg.] C. IR (Nujol): 3400, 3300, 3180,
1705, 1600, 1560, 1160, 1045c
_{^{m -1 NMR (DHSO-d 6}} , δ): 1.37 (3H, t,
J = 8Hz), 4.53 (2H, q, J = 8Hz),
7.93 (2H, s) Example 2 A mixture of 2-cyano-2-ethoxyiminoacetamide (65.0 g) and phosphoryl chloride (141.5 g) in 1,2-dichloroethane (283 ml) was stirred for 9 hours. Refluxed. The mixture was cooled and cold water (1
Injected into 1). The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated to an oily product (7
4.7 g) was obtained. The oily product was purified by vacuum distillation to give 2-ethoxyiminopropanedinitrile (57.8).
g) colorless oil was obtained. Boiling point: 65-67 ° C at 13 mmHg. IR (film): 3000, 2250, 1520, 1
390, 1250, 1170, 1060, 785cm
^-1 NMR (CDCl ₃ , δ): 1.43 (3H, t, J =
7 Hz), 4.67 (2H, q, J = 7 Hz) Example 3 The following compounds were obtained in the same manner as in Examples 1 and 2. (1) 2-Cyanomethoxyiminopropanedinitrile, boiling point: 90-105 ° C at 5 mmHg. IR (film): 3050, 2950, 2250, 1
550, 1430, 1250, 1060 cm ⁻¹ (2) 2-methoxyiminopropanedinitrile, boiling point: 47-48 ° C. at 12 mmHg. IR (film): 3030, 2980, 2260, 1
528, 1455, 1395 cm ⁻¹ (3) 2- (2-propyloxyimino) propanedinitrile IR (film): 3320, 2960, 2250, 2
150,1532,1438 cm ⁻¹ (4) 2-allyloxyiminopropanedinitrile IR (film): 2220,1520,1420,1
350,1242,1050 cm ⁻¹ (5) 2-methoxycarbonylmethoxyiminopropanedinitrile, boiling point: 90-9 at 5.5 mmHg
9 ° C. IR (film): 3050, 3000, 2250, 1
765 cm ^-1

Example 4 Sodium salt of 2-hydroxyiminopropanedinitrile (45 g) in acetonitrile (225 ml),
A mixture of chloroacetic acid methyl ester (41.8 g) and sodium iodide (5.8 g) was stirred at 50 ° C. for 3 hours and left at room temperature overnight. The reaction mixture was evaporated,
The residue was dissolved in a mixture of diisopropyl ether and water. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated to give a crude oil of 2-methoxycarbonylmethoxyiminopropanedinitrile (45.0
g) was obtained, which was purified by distillation. Boiling point: 5.5
90-99 ° C in mmHg. IR (film): 3050, 3000, 2250, 1
765 cm ^-1 Example 5 (1) In the same manner as in Example 4, the sodium salt of 2-hydroxyiminopropanedinitrile was reacted with chloroacetonitrile to obtain the following compound. 2-Cyanomethoxyiminopropanedinitrile, boiling point:
90-105 ° C at 5 mmHg. IR (film): 3050, 2950, 2250, 1
550, 1430, 1250, 1060 cm ⁻¹ (2) According to the same method as in Example 4, the sodium salt of 2-hydroxyiminopropanedinitrile was reacted with dimethylsulfate to obtain the following compound. 2-methoxyiminopropanedinitrile, boiling point: 4 at 12 mmHg
7-48 ° C. IR (film): 3030, 2980, 2260, 1
528, 1455, 1395 cm ⁻¹ (3) In the same manner as in Example 4, the following compound was obtained by reacting the sodium salt of 2-hydroxyiminopropanedinitrile with 2-propynyl bromide. 2- (2-propynyloxyimino) propanedinitrile IR (film): 3320, 2960, 2250, 2
150, 1532, 1438 cm ^-1 NMR (CDCl ₃ , δ): 2.72 (1H, t, J =
3 Hz), 5.10 (2H, d, J = 3 Hz) (4) The following compound was obtained by reacting the sodium salt of 2-hydroxyiminopropanedinitrile with allyl bromide in the same manner as in Example 4. Obtained. 2-allyloxyiminopropanedinitrile IR (film): 2220, 1520, 1420, 1
_{^{350,1242,1050cm -1 NMR (CCl 4, δ}} ): 4.97 (2H, d, J = 6
Hz), 5.3-5.6 (2H, m), 5.6-6.3
(1H, m) (5) According to the same manner as in Example 4, the following compound was obtained. 2-Ethoxyiminopropanedinitrile, boiling point: 13m
65-67 ° C at mHg. IR (film): 3000, 2250, 1520, 1
390, 1250, 1170, 1060, 785cm
^-1

Example 6 (1) Ammonium chloride (3.2 g) and concentrated aqueous ammonium hydroxide solution (20 ml) in ethanol (20 ml).
2-Ethoxyiminopropanedinitrile (3.7 g) was added to the solution (ml) under stirring at -5 to 0 ° C and stirring was continued at the same temperature for 1.5 hours. The mixture was diluted with a mixture of water (40 ml) and methylene chloride (40 ml).
The organic layer was separated, and the aqueous layer was replaced with methylene chloride (20 m
Extracted twice with l). These organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with petroleum ether to give 2-cyano-2-ethoxyiminoacetamidine (2.4g). Melting point 110-11
1 ° C IR (Nujol): 3450, 3280, 2250,
1655, 1620, 1600, 1220, 1045c
m ^-1 NMR (CD ₃ OD, δ): 1.40 (3H, t, J =
7Hz), 4.50 (2H, q, J = 7Hz) (2) Ammonium chloride (159g), concentrated aqueous ammonium hydroxide solution (21) and ethanol (900m)
2) Ethanol (600 ml) in the mixture of 1) 2
A solution of -methoxyiminopropanedinitrile (325g) was added with stirring at -15 to -10 ° C during 1.5 hours, and after addition, stirring was continued for 30 minutes. The reaction mixture was poured into a mixture of methylene chloride (21) and water (21). The organic layer was separated, the aqueous layer was salted out, and extracted with methylene chloride. Combine the organic layer and the extract,
It was dried over magnesium sulphate and evaporated. The residual oil was dissolved in ethyl acetate (71) and glacial acetic acid (7
7.6 g) was added dropwise with stirring. The precipitate obtained is filtered off, washed with ethyl acetate and dried to give 2-cyano-
2-Methoxyiminoacetamidine acetate (160.7
7 g) was obtained. Melting point 150-155 [deg.] C (decomposition). IR (Nujol): 3250, 2700, 2350,
2250, 1675, 1580, 1548, 1530,
1495 cm ^-1 NMR (DMSO-d ₆ , δ): 1.90 (3H,
s), 4.17 (3H, s), 7.65 (4H, s) (3) 2-Methoxycarbonylmethoxyiminopropane in a solution of ammonium acetate (4.62g) in methanol (10ml) under stirring. Dinitrile (3.34
g) was added and stirring was continued for 2 hours at room temperature, then the mixture was left overnight. Isopropyl alcohol (15 ml) was added to the reaction mixture, and the mixture was stirred for 15 minutes. The obtained precipitate was collected by filtration, washed with isopropyl alcohol, and dried to give 2-cyano-2-methoxycarbonylmethoxyiminoacetamidine acetic acid salt (3.4 g). This was recrystallized from methanol. Melting point 157-158 [deg.] C (decomposition). IR (Nujol): 2800-2200, 1750,
1680, 1550 cm ⁻¹ NMR (DMSO-d ₆ , δ): 1.90 (3H,
s), 3.73 (3H, s), 5.10 (2H, s),
7.0-7.5 (4H, broads) Example 7 The following compound was obtained according to the same method as in Example 6. (1) 2-Cyano-2-allyloxyiminoacetamidine, melting point 78 ° C. IR (Nujol): 3450,
3330, 3220, 3110, 2220, 1650,
1645, 1635 cm ^-1 NMR (CDCl ₃ + D ₂ O, δ): 4.90 (2H,
d, J = 5.5 Hz), 5.2-5.7 (2H, m),
5.7-6.3 (1H, m) (2) 2-Cyano-2- (2-propynyloxyimino) acetamidine, melting point 105-108 ° C (decomposition). IR (Nujol): 3450, 3270, 3150,
2210, 2100, 1630, 1560, 1420c
_{^{m -1 NMR (CDCl 3, δ}} ): 2.63 (1H, t, J =
3 Hz), 4.95 (2H, d, J = 3 Hz), 5.8
3 (3H, broad s) (3) 2-Cyano-2-cyanomethoxyiminoacetamidine, melting point 60-65 ° C. IR (Nujol): 3450, 3300, 3150,
1640, 1600, 1570 cm ^-1

Example 8 (1) A solution of 2-cyano-2-ethoxyiminoacetamidine (8.0 g) and triethylamine (11.5 g) in methanol (120 ml) under stirring-
Bromine (9.1 g) was added dropwise at 10 ° C, and the stirring was -1.
Continued at 0--5 ° C for several minutes. A solution of potassium thiocyanate (5.5 g) in methanol (55 ml) was added dropwise to the reaction mixture at -10 to -5 ° C with stirring, and stirring was continued at 0 to 5 ° C for 2 hours. The precipitate obtained is filtered off, washed with methanol and water and dried to obtain 2
A brown powder (10.15 g) of -ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetonitrile (syn isomer) was obtained. Melting point 2
70-273 ° C (decomposition). IR (Nujol): 3400, 3260, 3150,
2250, 1620, 1540, 1190, 1050,
1040 cm ^-1 NMR (DHSO-d ₆ , δ): 1.37 (3H, t,
J = 7Hz), 4.50 (2H, q, J = 7Hz),
8.37 (2H, s) (2) A suspension of 2-cyano-2-methoxycarbonylmethoxyiminoacetamidine acetic acid salt (495 g) in methanol (4.951) under stirring and cooling-1
Triethylamine (512.6 g) was added dropwise at 0 ° C., and bromine (357.3 g) was added to the above mixture at the same temperature. The reaction mixture was stirred for 15 minutes, then a solution of potassium thiocyanate in methanol (2.161) was added dropwise with stirring at -10 to -5 ° C and the stirring was reduced to 0.
Continued at ~ 5 ° C for 30 minutes. The resulting precipitate was collected by filtration, washed with water (51), dried and dried over 2-methoxycarbonylmethoxyimino-2- (5-amino-1,2,4-
Thiadiazol-3-yl) acetonitrile (syn isomer) (430 g) was obtained. It was recrystallized from aqueous methanol. Melting point 225-227 [deg.] C (decomposition). IR (Nujol): 3400, 3250, 3100,
1740, 1630, 1550 cm ⁻¹ NMR (DMSO-d ₆ , δ): 3.77 (3H,
s), 5.17 (2H, s), 8.33 (2H, s)

Example 9 The following compound was obtained according to a method similar to that in Example 8. (1) 2-methoxyimino-2- (5-amino-1,
2,4-thiadiazol-3-yl) acetonitrile (syn isomer), mp 210-215 ° C (decomposition). IR (Nujol): 3460, 3270, 3140,
2260, 1632, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 4.24 (3H,
s), 8.32 (2H, s) (2) 2- (2-propynyloxyimino) -2-
(5-Amino-1,2,4-thiadiazol-3-yl) acetonitrile (syn isomer), melting point 193-19
5 ° C (decomposition). IR (Nujol): 3460, 3270, 3180,
3160, 2690, 2150, 1625, 1560,
1538 cm ^-1 NMR (DMSO-d ₆ , δ): 3.70 (1H, t,
J = 3 Hz), 5.12 (2H, d, J = 3 Hz),
8.35 (2H, broad s) (3) 2-allyloxyimino-2- (5-amino-)
1,2,4-thiadiazol-3-yl) acetonitrile (syn isomer), mp 180-184 ° C (decomposition). IR (Nujol): 3430, 3260, 3140,
2220, 1625, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 4.90 (2H, d,
J = 6 Hz), 5.1-5.6 (2H, m), 5.7-
6.4 (1H, m), 8.27 (2H, s) (4) 2-Cyanomethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetonitrile (syn isomer ), Melting point 190-195 ° C (decomposition). IR (Nujol): 3450, 3300, 3150,
1630, 1540 cm-1

Example 10 (1) 2-Ethoxyimino-2- (5-amino-1,2,4-thiadiazole-3 in water (142 ml)
-Yl) acetonitrile (syn isomer) (10.1 g)
And a mixture of sodium hydroxide (22.8 g) and 50
The mixture was stirred at -55 ° C for 5 hours. Cool the reaction mixture to 6N
Adjust the pH to 1 with hydrochloric acid and ethyl acetate (50 ml)
It was extracted 3 times with. The extracts were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethyl acetate to give 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazole-) having a melting point of 187 ° C. (decomposition).
Colorless fine needle crystals of 3-yl) acetic acid (syn isomer) (8.
2 g) was obtained. IR (Nujol): 3450, 3250, 3150,
1720, 1620, 1535, 1040, 1010c
_{^{m -1 NMR (DMSO-d 6}} , δ): 1.23 (3H, t,
J = 7 Hz), 4.22 (2H, q, J = 7 Hz),
8.17 (2H, s) (2) 2-methoxycarbonylmethoxyimino-2- (5-amino-1,2,4) was added to a solution of sodium hydroxide (334.5g) in water (8.361). -Thiadiazol-3-yl) acetonitrile (syn isomer) (5
50 g) was added at room temperature and the mixture was stirred at 60-65 ° C for 5 hours. The reaction mixture was cooled in an ice bath, adjusted to pH 3.0 with 50% aqueous sulfuric acid and washed with ethyl acetate. The aqueous solution was salted out, adjusted to pH 1.0 with 50% sulfuric acid aqueous solution, and extracted with acetonitrile (2.51 × 6) (extract A). The combined extract A was mixed with magnesium sulfate (1
0 kg) and filtered. The filtrate was charged with methanol (1.
A solution of sodium acetate (109 g) in 21) was added with stirring and stirring was continued for 15 minutes. The resulting precipitate is collected by filtration, washed with acetonitrile and diisopropyl ether, and dried to give 2-carboxymethoxyimino-2- (5-amino-1,2,2) having a melting point of 155-160 ° C (decomposition).
Sodium 4-thiadiazol-3-yl) acetate (syn isomer) (342.8 g) was obtained. IR (Nujol): 3320, 3180, 1720,
1630, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 4.48 (2H,
s), 8.08 (2H, broad s) The extract A obtained above was evaporated to dryness. If the residue is recrystallized from methanol, 2-carboxymethoxyimino-2- (5-amino-) having a melting point of 193-194 ° C (decomposition) is obtained.
1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) was obtained. IR (Nujol): 3400, 3250, 3100,
2800-2200, 1730, 1630, 1540c
m ^-1 NMR (DMSO-d ₆ , δ): 4.65 (2H,
s), 8.15 (2H, s) Elemental analysis value Calculated value for C ₆ H ₆ N ₄ O ₅ S: C, 29.27; H 2.46, N 22.76 Found value: C, 29.18. H 2.58, N 22.09 The same target compound as above was prepared using 2-methoxycarbonylmethoxyimino-2- (5-amino-1,
2,4-Thiadiazol-3-yl) acetonitrile (syn isomer) instead of 2-cyanomethoxyimino-2
Obtained following the same method as above using-(5-amino-1,2,4-thiadiazol-3-yl) acetonitrile (syn isomer).

Example 11 Examples 1, 2, 6, 8 and 10 or Example 4,
The following compounds were obtained according to a method similar to 6, 8 and 10. (1) 2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 173 ° C IR (nujol): 3400, 3300, 3200,
1720, 1620, 1600, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.50, -2.17.
(6H, m), 4.53-4.83 (1H, m), 5.
57-6.13 (2H, m), 8.18 (2H, s) (2) 2-cyclopentyloxyimino-2- (5-
Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 160-165 ° C (decomposition) IR (nujol): 3470, 3290, 3200,
2400, 1715, 1615, 1600, 1520c
_{^{m -1 NMR (DMSO-d 6}} , δ): 1.17-2.10
(8H, m), 4.60-4.97 (1H, m), 8.
22 (2H, s) (3) 2-cycloheptyloxyimino-2- (5-
Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 116-119 ° C (decomposition). IR (Nujol): 3250, 3200, 1650,
1600, 1520, 1400, 1260, 1150,
1000,820,720 cm ^-1 (4) 2-mesylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) IR (nujol): 3450,3400, 3270,
2600, 2460, 1735, 1640, 1620
1530 cm ^-1 NMR (DMSO-d ₆ , δ): 3.00 (3H,
s), 5.38 (2H, s), 8.22 (2H, broad) (5) 2-allyloxyimino-2- (5-amino-)
1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 93-95 ° C (decomposition). IR (Nujol): 3430, 3100, 1710,
1615, 1525 cm ^-1 NMR (d ₆ -DMSO, δ): 4.72 (2H, d,
J = 6 Hz), 5.1-5.5 (2H, m), 5.7-
6.3 (1H, m), 8.17 (1H, broad s) (6) 2-benzyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn Isomer), melting point 158-160 [deg.] C (decomposition). IR (Nujol): 3430, 3380, 3260, 173
0, 1640, 1610, 1535 cm ^-1 NMR (DMSO-d ₆ , δ): 5.22 (2H,
s), 7.33 (5H, s), 8.17 (2H, broad s) (7) 2- (2-propynyloxyimino) -2-
(5-Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 155-157 ° C (decomposition). IR (Nujol): 3500, 3310, 3160,
2600, 2480, 1745, 1610, 1535c
_{^{m -1 NMR (DMSO-d 6}} , δ): 3.53 (1H, t,
J = 2Hz), 4.87 (2H, d, J = 2Hz),
8.23 (2H, broad s) (8) 2- (2-phenoxyethoxyimino) -2-
(5-Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 150-153 ° C (decomposition). IR (Nujol): 3470, 3300, 3150,
2550, 1750, 1620, 1600, 1540,
1500 cm ^-1 NMR (DMSO-d ₆ , δ): 4.0-4.7 (4
H, m), 6.7-7.5 (5H, m), 8.20 (2
H, broad s) (9) 2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 140-143
° C (decomposition). IR (Nujol): 3450, 3350, 3260,
1745, 1670, 1645, 1615, 1515c
_{^{m -1 NMR (DMSO-d 6}} , δ): 4.72 and 4.9
5 (2H, AB _q , J = 9 Hz), 8.25 (2H, broad s) (10) 2-methylthiomethoxyimino-2- (5-
Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 140-143 ° C (decomposition) IR
(Nujol): 3500, 3300, 3150, 26
70, 2580, 1740, 1615, 1605, 15
30 cm ^-1 NMR (DMSO-d ₆ , δ): 2.22 (3H,
s), 5.33 (2H, s), 8.20 (2H, broad s) (11) 2- (2-methylthioethoxyimino) -2
-(5-Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 140-143 [deg.] C (decomposition). IR (Nujol): 3430, 3340, 3230,
2650, 2450, 1720, 1610, 1520c
_{^{m -1 NMR (DMSO-d 6}} , δ): 2.08 (3H,
s), 2.72 (2H, t, J = 7Hz), 4.28.
(2H, t, J = 7Hz), 8.17 (2H, broad s)

(12) 2-phenoxyimino-2-
(5-Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 145-147 ° C (decomposition). IR (Nujol): 3350, 3170, 2500,
1730, 1710, 1645, 1630, 1595,
1535 cm ^-1 NMR (DMSO-d ₆ , δ): 7.0-7.5 (5
H, m), 8.30 (2H, broad s) (13) 2- [2- (2-hexyloxyethoxy)
Ethoxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer). IR _(CHCl 3): 3350,3230,2600,
2500, 1730, 1620, 1520, 1460c
m ^-1 NMR (DMSO-d ₆ , δ): 0.87 (3H, t,
J = 5 Hz), 0.87-1.73 (8H, m), 3.
20-3.90 (8H, m), 4.13-4.47 (2H, m), 8.
17 (2H, broad s) (14) 2-Trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 173-174 ° C (decomposition) . IR (Nujol): 3450, 1735, 1620,
1540 cm ^-1 NMR (DMSO-d ₆ , δ): 7.35 (15H,
s), 8.22 (2H, s) (15) 2-trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (anti isomer), melting point 170-171 ° C. IR (Nujol): 3300, 3150, 1680,
1635, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 7.33 (15H,
s), 8.13 (2H, s) (16) 2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomerism Body), melting point 150 ° C
(Disassembly). IR (Nujol): 3300, 3150, 1710,
1620, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.80-2.50
(4H, m), 5.30-5.50 (1H, m), 5.
83-6.30 (2H, m), 8.20 (2H, s) (17) 2- (1-carboxy-3-hydroxypropoxyimino) -2- (5-amino-1,2,4-thiadiazole -3-yl) acetic acid (syn isomer), melting point 18
6-188 ° C (decomposition). IR (Nujol): 3400, 3250, 3100,
1710, 1620, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 1.73-2.10
(2H, m), 3.50 (2H, t, J = 6Hz),
4.73 (1H, t, J = 6Hz), 8.13 (2H,
s) (18) 2-methoxyimino-2- (5-amino-
1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 180-182 ° C (decomposition). IR (Nujol): 3450, 3250, 3100,
1715, 1610, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 3.90 (3H,
s), 8.10 (3H, broad s) (19) 2-propoxyimino-2- (5-amino-
1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp 100-103 ° C (decomposition). IR (Nujol): 3620, 3520, 3350,
3120, 2600, 2500, 1720, 1620,
1550 cm ^-1 NMR (DMSO-d ₆ , δ): 1.00 (3H, t,
J = 6 Hz), 1.3-2.0 (2H, m), 4.13
(2H, t, J = 6Hz), 8.17 (2H, broad s)

(20) 2-isopropoxyimino-2
-(5-Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 152-155 ° C (decomposition). IR (Nujol): 3450, 3300, 3200,
1730, 1620, 1530 cm ⁻¹ NMR (DMSO-d ₆ , δ): 1.22 (6H, d,
J = 6 Hz), 4.1-4.6 (1H, m), 8.20
(2H, broad s) (21) 2- (thiolane-1,1-dioxide-3-
Iloxyimino) -2- (5-amino-1,2,4-
Thiadiazol-3-yl) acetic acid (syn isomer), melting point 200-205 ° C (decomposition). IR (Nujol): 3300, 1720, 1620,
1530 cm ^-1 NMR (DMSO-d ₆ , δ); 2.20-2.50
(2H, m), 3.00-3.50 (4H, m), 5.
00-5.27 (1H, m), 8.20 (2H, s) (22) 2- (4-chlorophenoxyimino) -2-
(5-Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 150-155 ° C (decomposition). IR (Nujol): 3300, 3200, 1710,
1640, 1580, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 7.37 (2H, d,
J = 9 Hz), 7.67 (2H, d, J = 9 Hz),
8.50 (2H, broad s) (23) 2- (4-fluorophenoxyimino) -2
-(5-Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 140-145 ° C (decomposition). IR (Nujol): 3450, 3300, 3200,
1730, 1630, 1530, 1500 cm ^-1 NMR (DMSO-d ₆ , δ): 7.17 (2H,
s), 7.27 (2H, s), 8.27 (2H.s) (24) 2- (1-phenylethoxyimino) -2-
(5-Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 103-107 ° C (decomposition). IR (Nujol): 3250, 3150, 1710,
1610,1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.57 (3H, d,
J = 6Hz), 5.42 (1H, q, J = 6Hz),
7.40 (5H, m) 8.20 (2H, m) (25) 2- (2-methoxy-5-nitrophenoxyimino) -2- (5-amino-1,2,4-thiadiazole-3- Ill) acetic acid (syn isomer), melting point 125-1
28 ° C (decomposition). IR (Nujol): 3400, 3280, 1740,
1720, 1690, 1630, 1590, 1510,
1340, 1275, 970, 720 cm ^-1 NMR (DMSO-d ₆ , δ): 3.93 (3H,
s), 7.27 (1H, d, J = 8Hz), 8.01
(1H, d, J = 8Hz), 8.07 (1H, s),
8.30 (2H, broad s)

(26) 2- (3,4-dichlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 177
-178 ° C. IR (Nujol): 3300, 1710, 1625,
1585, 1530, 1300, 1210, 1120,
980 cm ^-1 NMR (DMSO-d ₆ , δ): 6.83-7.73.
(3H, m), 8.38 (2H, broad s) (27) 2- (3-trifluoromethylphenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (Syn isomer), melting point 167-16
8 ° C (decomposition). IR (Nujol): 3250, 1645, 1620,
1590, 1450, 1320, 1170, 1140,
1010,995,845,730 cm ^-1 NMR (DMSO-d ₆ , δ): 7.63 (4H,
m), 8.44 (2H, broad s) (28) 2- (3-carboxyphenoxyimino)-
2- (5-amino-1,2,4-thiadiazole-3-
(Il) acetic acid (syn isomer), melting point 186-188 ° C (decomposition). IR (Nujol): 3420, 3150, 1735,
1690, 1620, 1580, 1265, 1200,
1000,980,760 cm ^-1 NMR (DMSO-d ₆ , δ): 7.3-8.0 (4
H, m), 8.30 (2H, broad s) (29) 2- (4-fluorobenzyloxyimino)
-2- (5-amino-1,2,4-thiadiazole-3
-Yl) acetic acid (syn isomer). _{NMR (DMSO-d 6, δ} ): 8.10 (2H, broad s), 7.63-6.98 (4H, m ), 5.2
0 (2H, s) (30) 2-hexyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 158-161 ° C. NMR (DMSO-d ₆ , δ): 0.67-2.00
(11H, m), 4.20-4.38 (2H, m)

Example 12 Sodium 2-carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetate (syn isomer) (5) in methanol (935 ml).
Concentrated hydrochloric acid (56 ml) was added to a solution of 0.0 g) under stirring and stirring was continued at room temperature for 7 hours. Sodium hydrogen carbonate (23.6 g) and water (100 ml) were added to the reaction mixture.
Was added and then the mixture was evaporated to remove methanol. The aqueous residue was extracted with ethyl acetate, the extract was dried over magnesium sulfate and evaporated to dryness. The residue was pulverized in methanol, collected by filtration, washed with isopropyl alcohol, and dried to give a melting point of 179-181 ° C (decomposition) of 2
-Methoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (15.5 g) was obtained. IR (Nujol): 3400, 3300, 3200,
2800-2200, 1750, 1710, 1615,
1520 cm ^-1 NMR (DMSO-d ₆ , δ): 3.63 (3H,
s), 4.77 (2H, s), 8.10 (2H, s)

Claims (1)

[Claims] 1. A general formula [Wherein R ₁ is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cyclo (lower) alkenyl optionally substituted with an appropriate substituent, aryl optionally substituted with an appropriate substituent, or Or a salt thereof, which is an S-containing 5-membered heterocyclic group substituted with an oxo group], and then, if necessary, R ₁ of the obtained compound is substituted with a carboxy group. When it is a lower alkyl, it is converted to R by a conventional method.
_A compound of the general formula 1, characterized in that ₁ is a lower alkyl substituted with a protected carboxy group. [Wherein R ₁ is as defined above] or a method for producing a salt thereof.