KR880001762B1 - Processes for preparing 2-substituted hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic or tis salt - Google Patents

Abstract

The title compds. (I) or its salts are prepd. by hydroly sis of (II), where R1 is substituteable lower alkyl, lower alkenyl, cycloalkyl or substd. five membered hetero ring contg. sulfur. Stir a soln. contg. water 268 mL, 2-cyanoacetamide 67.0g and sodium nitrite 66.1g in an ice bath for 3hrs add acetic acid 95.8g into the rxn. mixt. at 10-15 deg.C and then diethyl sulfate 147.5g after adjusting pH 8.5 with 4N NaOH 350 mL, restir for 1h at 40-50 deg.C, cool in ice bath, filter and wash with ice water to give 2-cyano-2-ethoxyiminoacetamide 70.0g.

Description

Method for preparing 2-substituted hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid or salts thereof

The present invention relates to a novel process for the preparation of 2-substituted hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid or salts thereof and to intermediates thereof.

In particular, the present invention provides a process for preparing 2-substituted hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid or salts thereof, and intermediates useful for the preparation method and It relates to a method for producing an intermediate.

Accordingly, an object of the present invention is a 2-substituted hydroxy imino-2- (5-amino-1,2,4-thiadiazole which is useful as an acylating agent to prepare 7-acylamino sephalosporin with good antibacterial activity. -3-yl) acetic acid or its salts to provide a new method of preparation.

It is another object of the present invention to provide novel intermediates useful for the preparation of 2-substituted hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid or salts thereof. .

Another object of the present invention is to provide a method for preparing the new intermediate. 2-substituted hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid can be represented by the following structural formula.

Wherein R ₁ is lower alkyl substitutable with a suitable substituent or lower alkenyl, lower alkynyl cycloalkyl, cyclo (lower) alkenyl, aryl substitutable with a suitable substituent, or S-containing 5-membered hetero substituted with oxo group It is a cyclic group.

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

Way

Where R ₁ is as defined above and M is an alkali metal. In target compound (I) and intermediates (III), (IV), (VI), and (iii),

Partial structural formulas represented by include the geometry represented by the following structural formula.

(Wherein R ₁ is as defined above)

In the present specification, for all compounds having the partial structural formula, the compound having the geometric structure of formula (A) is called a syn isomer, and the compound having the geometric structure of the structural formula (A ′) is an anti isomer. It is called.

Suitable salts of the desired compound (I) include salts containing base or acid addition salts, for example salts with inorganic bases, ie alkali metal salts (e.g. sodium salts, potassium salts, etc.), alkaline earth metal salts ( For example, calcium salts, magnesium salts, etc.) ammonium salts, salts with organic bases, i.e. organic amine salts (e.g. triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanol amine salts, dishes) Clohexylamine salt, N, N'-dibenzylethylenediamine salt, etc.); Inorganic acid addition salts (for example, hydrochloride, bromate, sulfate, phosphate, and the like); Organic acid addition salts, ie, organic carboxylic acid addition salts or sulfonic acid addition salts (eg, formate, trifluoroacetate, methanesulfonate, benzenesulfonate, acetate, P-toluenesulfonate, etc.); Salts having a basic amino acid (eg arginine).

In the detailed description of this specification, descriptions of suitable embodiments and various definitions are within the scope of the present invention, which will be described in detail below.

Unless stated otherwise, the term "lower" means a group having 1-6 carbon atoms.

Suitable lower alkyls are straight or branched chain alkyls having 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, t-pentyl, hexyl and the like.

For 'lower alkyl' substitutable with suitable substituents, 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 (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, pentyloxymethoxy, hexyloxymethoxy, hexyloxyethoxy , Etc) ; Hydroxy; Lower alkanesulfonyl (eg, mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); Aryl substituted with halogen (eg, chlorophenyl, fluorophenyl, etc.); Cyano; Protected carboxyl groups as described below.

Suitable “protected carboxys” include esterified carboxys, and examples of suitable ester groups in the esterified carboxy include lower alkyl esters (eg, methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl) Esters, t-butyl esters, pentyl esters, hexyl esters, 1-cyclopropyl esters, etc.), which are lower alkanoyloxy (lower) alkyl esters (e.g. acetoxymethyl ester, propionyloxymethyl ester, Butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyl oxyethyl-ester, hexanoyloxymethyl ester, etc., lower alkanesulfonyl (lower) Alkyl esters (eg, 2-methylethyl ester, etc.) or mono (or di or tri) halo (lower) alkyl groups; Termini Figure gajilsu at least one suitable substituent, such as (for example, 2-iodo-ethyl, 2,2,2-trichloroethyl ester, etc.), and; Lower alkenyl esters (eg, vinyl esters, allyl esters, etc.); Lower alkynyl esters (eg, ethynyl esters, propynyl esters, etc.); Ar (lower) alkyl esters having at least one suitable substituent (eg, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (meth) Oxyphenyl) -methyl ester, 3,4-dimethoxy benzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); Aryl esters having at least one suitable substituent (eg, phenyl esters, 4-chlorophenyl esters, tolyl esters, t-butylphenyl esters, xylyl esters, mesityl esters, cumenyl esters, and the like).

Suitable lower alkenyls include vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl, and the like, with those having 2 to 4 carbon atoms being preferred.

Suitable lower alginyls include those having 2 to 4 carbon atoms, for example ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl, and the like, and those having 2 to 4 carbon atoms It is preferable.

Suitable cycloalkyls include those having from 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, preferably having from 4 to 7 carbon atoms.

Suitable cyclo (lower) alkenyls include those having 3 to 6 carbon atoms, such as cyclopentenyl, cyclohexenyl, and the like, and those having 5 to 6 carbon atoms are preferred.

Suitable aryls include phenyl, tolyl, xylyl, mesityl, cumenyl, and the like, wherein the aryl group can be substituted with one to three substituents as follows. Preferably as halogen (e.g. chlorine, bromine, fluorine or iodine), nitro, lower alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.) Having from 1 to 4 carbon atoms, halo (lower) alkyl (e.g., chloromethyl, thichloromethyl, trichloromethyl, trifluoromethyl, trichloroethyl, etc.), preferably from 1 to 3 carbon atoms It has a ruler, carboxyl.

Suitable S containing 5-membered heterocyclic groups include thiol anyl and the like, which are substituted with 1 or 2 oxo groups.

The following describes in detail the preparation of the target compound (I) or salt thereof.

Method 1

It can manufacture by nitrosing compound (II) of compound (III) or its salt.

Suitable salts of compound (III) include alkali metal salts (eg sodium salts, potassium salts).

Nitrogenating agents used during the reaction are conventional, which react with the active methylene compound to form C-nitroso compounds, ie their salts such as nitrous acid or nitrite alkali metals (eg sodium nitrite, etc.) or lower alkyl nitrites. To produce their esters (e.g., t-butyl nitrite, isopentyl nitrite, etc.). When nitrite is used as the nitrosizing agent, the reaction is carried out in the presence of inorganic or organic acids such as hydrochloric acid, sulfuric acid, acetic acid and the like. In contrast, when nitrite ester is used as the nitrosigating agent, the reaction is preferably carried out in the presence of a rather strong base such as alkali metal alkoxides (eg sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.).

The reaction is generally carried out in solvents such as water, acetic acid, alcohols (eg ethanol, methanol, etc.), ethers, tetrahydrofuran or other solvents that do not adversely affect the reaction.

Although the reaction temperature is not limited, the reaction is generally carried out under cooling or heating.

Method 2

Compound (IV) and salts thereof can be prepared by addition of a substituent to the hydroxyimino group of compound (III) or salts thereof.

Suitable salts of compound (IV) are the same as the salts of the bases given in compound (I).

The reagent used for the reaction which adds a substituent to a hydroxyimino group contains the compound of the following structural formula (i) or (i).

R ₁ ― Y (Ⅸ)

Wherein R ₁ is as defined above and Y is an acid residue.

R _1a = N ₂

Wherein R _1a is a group in which one hydrogen is removed from R ₁ .

When the added substituent is an aryl which can be substituted with a suitable substituent, the compound of the following structural formula (XI) can be used in the reaction of adding a substituent to the hydroxy amino group in addition to the above reagent.

－R_1bY

(ⅩⅠ)R _1b -X

-R _1b Y

(ⅩⅠ)

Wherein Y is as defined above, R _1b is aryl which may be substituted with a suitable substituent and X is halogen.

Suitable acid residues include hydrofluoric 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-toluene sulfonic acid, etc.).

The reaction using the compound (iii) is generally carried out in water, acetonitrile, acetone, ethanol, ethyl acetate, dimethylformamide or a solvent which does not adversely affect the reaction, and may be a base such as an alkali metal hydroxide (e.g. Inorganic bases such as sodium hydroxide, potassium hydroxide, etc.), alkali metal bicarbonates (eg sodium bicarbonate, potassium bicarbonate, etc.) or alkali metal carbonates (eg sodium carbonate, potassium carbonate, etc.), or alkalis Metal alkoxides (eg sodium methoxide, sodium ethoxide, etc.), trialkylamines (eg trimethylamine, triethylamine, etc.), triethanol amines, N, N-dimethylaniline, N, N- It is preferable to carry out in an organic base such as dimethylbenzylamine, N-methylmorpholine or pyridine.

The reaction temperature is not limited and the reaction is carried out under cooling or heating.

Representative examples of the compound (VII) are diazo (lower) alkales (for example, diazomethane, diazoethane). The reaction using the compound (VII) is generally carried out in a solvent such as ether or tetrahydrofuran.

The reaction temperature is not limited and the reaction is carried out under cooling or at room temperature.

The reaction using the compound (XI) is generally carried out in alcohol (for example, methanol, ethanol, etc.) water, their mixed solvent or a solvent which does not adversely affect the reaction, and is preferably carried out in the presence of a base.

The reaction temperature is not limited and the reaction is carried out under cooling to heating.

Method 3

Compound (V) and salts thereof can be prepared by dehydrating Compound (IV) and salts thereof.

Suitable salts of compound (V) are the same as the salts of the bases exemplified in compound (I).

The dehydrating agent used in this dehydration reaction is phosphoryl chloride, thionyl chloride, phosphorus pentoxide, phosphorus pentachloride, phosphorus oromide and the like. The reaction is generally carried out in solvents such as dioxane, chloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile, dimethylformamide or other solvents that do not adversely affect the reaction.

The reaction temperature is not limited and the reaction is generally carried out at room temperature or under heating.

Method 4

Compound (VI) or compound (V) or salt thereof can be prepared by reacting with ammonia and / or ammonium salt.

Suitable ammonium salts include ammonium acetate, ammonium sulfate, ammonium-halides (eg ammonium chloride, ammonium bromide, etc.). Suitable salts of compound (VI) are as exemplified for compound (I).

The reaction is generally carried out in water, alcohol (eg methanol, ethanol, etc.) acetone, chloroform, dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, or a solvent that does not adversely affect the reaction. do. The reaction temperature is not limited and the reaction is generally carried out under cooling or at room temperature.

Method 5

Compound (VII) or compound (VI) or salt thereof can be prepared by reacting with a halogenating agent and compound (VII).

Suitable halogenating agents for use in this reaction are bromine, chlorine, and the like. Suitable salts of compound (iii) are the same as those exemplified for compound (I).

Suitable alkali metals corresponding to M are sodium, potassium and the like.

The present reaction is preferably carried out in the presence of a base such as an inorganic base or an organic base such as an alkali metal carbonate, an alkali metal alkoxide, trialkylamine or the like.

The reaction is generally carried out in alcohol (eg methanol, ethanol, etc.) or other solvent that does not adversely affect the reaction.

The reaction temperature is not limited and the reaction is generally carried out under cooling or at room temperature.

Method 6

Compound (I) or a salt thereof can be prepared by hydrolyzing compound (VII) or a salt thereof.

Hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases include alkali metals (eg sodium, potassium, etc.), hydroxides, carbonates, or bicarbonates thereof, trialkylamines (eg trimethylamine, triethylamine, etc.), picoline, 1,5 -Diazabicyclo [4,3,0] is -5-ene, 1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] Inorganic bases and organic bases such as undecene-7. Suitable acids are organic acids (eg formic acid, acetic acid, propionic acid, trifluoroacetic acid) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

The reaction is generally carried out in water, alcohols (e.g. methanol, ethanol, etc.), mixtures thereof or solvents which do not adversely affect the reaction. Liquid bases or acids can also be used as solvents.

The reaction temperature is not limited, but the reaction is generally performed under heating.

The present invention includes the case where the protected carboxyl group and / or cyano group of R ₁ is converted into the free carboxyl group during the reaction within the scope of the present invention. In addition, if necessary, the carboxy group of R ₁ may be converted into a protected carboxy group by a known method.

Method 7

Compound (V) or a salt thereof can be prepared by carrying out a substituent addition reaction on the hydroxyimino group of compound (XII) or a salt thereof.

Suitable salts of compound (XII) are alkali metal salts (eg sodium salts, potassium salts) and the like.

The reagent used for the substituent addition reaction on the hydroxyimino group can be carried out by a method similar to that in Method 2. Substituent addition reaction on a hydroxy imino group can be performed by the method similar to the above-mentioned method.

In the present invention, compounds (III), (IV), (V), (VI) and (iii) can be used in the next step without separation.

The desired compound (I) and salts thereof are 7- [2-substituted hydroxy imino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] cephalo It is useful as a major intermediate in the preparation of a sporin compound, which has good antibacterial properties and is prepared by reacting a 7-aminocephalosporin compound with the target compound (I), an acylating agent thereof, a reaction derivative thereof, or a salt thereof. Can be.

The desired compound (I) or salt thereof can be prepared using 1-alkoxy carbonyl-formamidine as starting material. One of the objects of the present invention is therefore to provide a new process for the preparation of compound (I) or a salt thereof, as described above.

The present invention is based on the discovery that the new method is superior to known methods in the following aspects.

(1) Known methods require several steps to prepare starting materials, i.e., 1-alkoxycarbonyl-formamidine, from commercially available compounds, while the new methods of dispatching materials themselves are commercially available compounds. It requires longer steps than the method.

(2) Known methods require reagents that are both expensive during the reaction and high in risk, while the new methods do not require the high-risk reagents described above. Even more desirable and safe way.

The following describes the present invention based on the examples, which are for the purpose of explanation.

Example 1

To a mixture of 2-cyanoacetamide (67.0 g) and sodium nitrite (66.1 g) in water (268 ml) was added dropwise acetic acid (95.8 g) at 10 ° C. to 15 ° C. under cooling and stirring in an ice bath. Was maintained for 3 hours.

The mixture containing 2-cyano-2-hydroxyimino acetamide was adjusted to pH 8.5 with 4N aqueous sodium hydroxide solution (350 ml), followed by addition of diethyl sulfate (147.5 g).

The mixture was stirred at 45-50 [deg.] C. for 1 hour, while maintaining 4N aqueous sodium hydroxide solution at pH 8.5 during heating.

The mixture was cooled in an ice bath to collect the precipitate, then washed with cold water and dried to give 2-cyano-2-ethoxyimino acetamide (70.0 g). Melting point 125-127 ° C.

IR (Nujol): 3400, 3300, 3180, 1705, 1600, 1560, 1160, 1045cm ^-1

NMR (DMSO-d ₆ , δ): 137 (3H, t, J = 8 Hz), 4.53 (2H, q, J = 8 Hz), 7.93 (2H, s).

Example 2

A mixture of 2-cyano-2-ethoxyimino acetamide (65.0 g) and phosphonyl chloride (141.5 g) in 1,2-dichloro-ethane (283 ml) was refluxed for 9 hours under stirring. This mixture was cooled and mixed in chilled water (1 L).

The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated to give an oily substance (74.7 g).

The oily material was purified by vacuum distillation to give a colorless oily 2-ethoxy-iminopropane dinitrile (57.8 g). Boiling point at 13 mmHg. 65 to 67 ° C.

IR (Film): 3000, 2250, 1520, 1390, 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

In the same manner as in Examples 1 and 2, the following compounds were obtained.

(1) Boiling point of 2-cyanomethoxyiminopropanedinitrile in 5 mmHg. 90-105 ° C.

IR (Film): 3050, 2950, 2250, 1550, 1430, 1250, 1060cm ^-1

(2) The boiling point of 2-methoxyiminopropanedinitrile in 12 mmHg. 47-48 ° C.

IR (Film): 3030, 2980, 2260, 1528, 1455, 1395cm ^-1

(3) 2- (2-propynyloxyimino) propanedinitrile

IR (Film): 3320, 2960, 2250, 2150, 1532, 1438cm ^-1

(4) 2-allyloxyiminopropanedinitrile

IR (Film): 2220, 1520, 1420, 1350, 1242, 1050cm ^-1

(5) 2-methoxycarbonylmethoxyiminopropanedinitrile, boiling point 90-99 ° C. at 5.5 mmHg.

IR (Film): 3050, 3000, 2250, 1765, cm ^-1

Example 4

After stirring a mixture of sodium salt of 2-hydroxy-iminopropane dinitrile (45 g), methyl chloroacetate (41.8 g) and sodium iodide (5.8 g) in acetonitrile (225 ml) for 3 hours, It was allowed to stand overnight at room temperature.

After evaporation of the reaction mixture the residue was dissolved in a mixture of diisopropyl etherified water.

The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated to obtain crude oil (2-5.0 g) of 2-methoxycarbonylmethoxyiminopropanenitrile, which was purified by distillation. Boiling point 90-99 ° C. at 5.5 mmHg.

IR (Film): 3050, 3000, 2250, 1765Cm ^-1

Example 5

(1) The following compound was prepared by reacting sodium and chloroacetnitrile of 2-hydroxyiminopropanedinitrile in a similar manner to Example 4.

2-cyanomethoxyiminopropanedinitrile, boiling point 90-105 degreeC in 5 mmHg.

IR (Film): 3050, 2950, 2250, 1550, 1430, 1250, 1060cm ^-1

(2) The following compound was prepared by reacting the sodium salt of 2-hydroxy aminopropanedinitrile with dimethyl sulfate in a similar manner as in Example 4.

2-methoxyiminopropanedinitrile, boiling point 47-48 ° C. at 12 mm Hg.

IR (Film): 3030, 2980, 2260, 1528, 1455, 1395cm ^-1

(3) The following compound was prepared by reacting the sodium salt of 2-hydroxy iminopropanedinitrile with 2-propynylbromide in a similar manner to Example 4.

2- (2-propynyloxyimino) propanedinitrile

IR (Film): 3320, 2960, 2250, 2150, 1532, 1438cm ^-1

NMR (CDCl ₃ , δ): 2.72 (1H, t, 3 Hz), 5.10 (2H, d, J = 3 Hz).

(4) The following compound was prepared by reacting allyl bromide with sodium salt of 2-hydroxy iminopropanedinitrile in a similar manner to Example 4.

2-allyloxyiminopropanedinitrile

IR (Film): 2220, 1520, 1420, 1350, 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) The following compound was prepared in a similar manner to Example 4.

2-ethoxyiminopropanedinitrile, boiling point 65-67 ° C. at 13 mmHg.

IR (Film): 3000, 2250, 1520, 1390, 1250, 1170, 1060, 785cm ^-1

Example 6

(1) To a solution of ammonium chloride (3.2 g) and concentrated aqueous ammonium hydroxide solution (20 ml) in ethanol (20 ml) was added 2-ethoxyimino propanedinitrile (3.7 g) at −5 ° to 0 ° C. under stirring, It was kept at this temperature for 1 hour 30 minutes. 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 extracted twice with methylene chloride (20 ml). The organic layer was mixed, dried over anhydrous magnesium sulfate, and evaporated to dryness. The residue was triturated with petroleum ether to give 2-cyano-ethoxyiminoacetamine (2.4 g) which was m.p. 110 ° -111 ° C.

IR (Nujol): 3450, 3280, 2250, 1655, 1620, 1600, 1220, 1045cm ^-1

NMR (CD ₂ OD, δ): 1.40 (3H, t, J = 7 Hz), 4.50 (2H, q, J = 7 Hz).

(2) 2-methoxy iminopropane in ethanol (600 ml) for 1 hour and 30 minutes at -15 ° to -10 ° C with stirring to a mixture of ammonium salt (159 g), concentrated aqueous solution of ammonium hydroxide (2 L) and ethanol (900 ml). A solution of dinitrile (325 g) was added and held for 30 minutes.

The reaction mixture was mixed with a mixture of methylene chloride (2 L) and water (2 L). The organic layer was separated and the aqueous layer was removed with salt and extracted with methylene chloride. The organic layer and the extract were mixed, dried over magnesium sulfate, and evaporated. The residue oil was dissolved in ethyl acetate (7 L) and glacial acetic acid (77.6 g) was added dropwise under stirring.

The resulting precipitate was collected, washed with ethyl acetate and dried to give 2-cyano-2-methoxyiminoacetamide acetate (160.77 g). m.p. 150 ° -155 ° 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) To a solution of ammonium acetate (4.62 g) in methanol (10 ml) under stirring was added 2-methoxycarbonyl-methoxyiminopropanedinitrile (3.34 g), held at room temperature for 2 hours, and then overnight Stopped.

Isopropyl alcohol (15 ml) was added to the reaction mixture and stirred for 15 minutes.

The resulting precipitate was collected by filtration, washed with isopropyl alcohol and dried to give 2-cyano-2-methoxycarbonylmethoxyimino-acetamide acetate (3.4 g), which was recrystallized from methanol. . m.p. 157 ° -158 ° C. (decomposition).

IR (Nujol): 2800-2200, 1750, 1680, 1550cm ^-1

NMR (DMSO-d ₆ , δ): 1.90 (3H, s), 3.73 (3H, s), 5.10 (2H, s), 7.0-7.5 (4H, broad, s).

Example 7

The following compounds were prepared in a similar manner to Example 6.

(1) 2-cyano-2-propynyloxyimino acetamidine mp.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 Hz), 5.2-5.7 (2H, m), 5.7-6.3 (1H, m).

(2) 2-cyano-2- (2-propynyloxyimino) acetamidine, mp. 105-108 ° C. (decomposition).

IR (Nujol): 3450, 3270, 3150, 2210, 2100, 1630, 1560, 1420cm ^-1

NMR (CDCL ′, δ): 2.63 (1H, t, J = 3 Hz), 4.95 (2H, d, J = 3 Hz), 5.83 (3H, broad, s).

(3) 2-cyano-2-cyanomethoxyimomoacetamine, mp60-46 ° C.

IR (Nujol): 3450, 3300, 3150, 1640, 1600, 1570cm ^-1

Example 8

(1) To a solution of 2-cyano-2-ethoxyiminoacet amidine (8.0 g) and triethylamine (11.5 g) in methanol (120 ml) was added dropwise bromine (9.1 g) at -10 deg. And maintained at -10? -5 占 폚 for a few minutes.

To the reaction mixture was added dropwise a solution of potassium thiocyanate (5.5 g) in methanol (55 ml) at −10 ° -5 ° C. under stirring and maintained at 0 ° -5 ° C. for 2 hours.

The resulting precipitate was filtered, washed with methanol and water and dried to give a brown powder of 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetonitrile (syn Isomers) (10.15 g). m.p. 270 ° -273 ° C. (decomposition).

IR (Nujol): 3400, 3260, 3150, 2250, 1620, 1540, 1190, 1040cm ^-1

NMR (DMSOd ₆ , δ): 1.37 (3H, t, J = 7 Hz), 4.50 (2H, q, J = 7 Hz), 8.37 (2H, s).

(2) To a suspension of 2-cyano-2-methoxycarbonyl-methoxyiminoacetamide acetate (495 g) in methanol (4.95 L) triethylamine (512.6 g) at −10 ° C. under stirring and cooling. Was added dropwise and bromine (357.3 g) was added to the mixture at the same temperature. After the reaction mixture was stirred for 15 minutes, a solution of potassium thiocyanate (216 g) in methanol (2.16) was added dropwise at -10 ° to -5 ° C under stirring, and maintained at 0 to 5 ° C for 30 minutes.

The resulting precipitate was collected by filtration, washed with water (5 L) and dried to give 2-methoxy carbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl). 430 g of acetonitrile (syn isomer) were obtained and recrystallized from aqueous methanol. m.p. 225 ° -227 ° C. (decomposition).

IR (Nujol): 3400, 3250, 3100, 1740, 1630, 1550cm ^-1

NMR (DMSO-d ₆ , δ): 3.77 (3H, s), 5.17 (2H, s), 8.33 (2H, s)

Example 9

The following compounds were prepared in a similar manner to Example 8.

(1) 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetonitrile (syn isomer), mp. 210-215 degreeC (decomposition).

IR (Nujol): 3460, 3270, 3140, 2260, 1632, 1540cm ^-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), mp. 193-195 degreeC (decomposition).

IR (Nujol): 3460, 3270, 3180, 3160, 2690, 2150, 1625, 1560, 1538 cm ^-1

NMR (DMSO-d ₆ δ): 3.70 (1H, t, J = 7 Hz), 5.12 (2H, d, J = 7 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, 1540cm ^-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), mp. 190-195 ° C. (decomposition).

IR (Nujol): 3450, 3300, 3150, 1630, 1540cm ^-1

Example 10

(1) 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetonitrile (syn isomer) (10.g) and sodium hydroxide in water (142 ml) 22.8 g) of the mixed solution was stirred at 50 ° -55 ° C for 5 hours.

The reaction mixture was cooled, adjusted to pH 1 with 6N hydrochloric acid and extracted three times with ethyl acetate (50 ml).

The extract was mixed, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was recrystallized with ethyl acetate to obtain fine needle-like 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (8.2 g). m.p. 187 ° C (decomposition)

IR (Nujol): 3450, 3250, 3150, 1720, 1620, 1535, 1040, 1010 cm ^-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-methoxycarbonylmethoxy-imino-2- (5-amino-1,2,4-thiadiazole-3- in a solution of sodium hydroxide (334.5 g) in water (8.36 L) at room temperature I) Acetonitrile (syn isomer) (550 g) was added and the mixture was stirred at 60 ° -65 ° C. for 5 hours. The reaction mixture was cooled on an ice bath, adjusted to pH 3.0 with 50% aqueous sulfuric acid solution and washed with ethyl acetate. The aqueous solution was salted out, adjusted to pH 1.0 with 50% aqueous sulfuric acid solution, and extracted with acetonitrile (6 × 2.5 L). (Extract A)

Extract A was dried over magnesium sulfate (10 kg) and filtered. Under stirring, a solution of sodium acetate (109 g) in methanol (1.2 L) was added to the filtrate and held for 15 minutes.

The resulting precipitate was collected by filtration, washed with acetonitrile and diisopropyl ether and dried to give sodium-2-carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl. ) Acetate (syn isomer) (342.8 g) was obtained. m.p. 155 ° -160 ° C (decomposition)

IR (Nujol): 3320, 3180, 1720, 1630, 1530cm ^-1

NMR (DMSO-d ₆ , δ): 4.48 (2H, s), 8.08 (2H, broad s)

Extract A obtained above was evaporated to dryness. Recrystallization with methanol gave 2-carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer).

m.p. 193 ° -194 ° C (decomposition)

IR (Nujol): 3400, 3250, 3100, 2800-2200, 1730, 1630, 1540cm ^-1

NMR (DMSO-d ₆ , δ): 4.65 (2H, s), 8.15 (2H, s)

Analytical calculation for C ₆ H ₆ N ₄ O ₅ S: C 29.27, H 2.46 N 22.76

Found: C 29.18, H 2.58 N 22.09

2-cyanomethoxy-imino instead of 2-methoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetonitrile (syn isomer) as starting compound The same target compound was obtained by a method similar to the above using 2- (5-amino-1,2,4-thiadiazol-3-yl) acetonitrile (syn isomer).

Example 11

The following compounds were obtained by methods analogous to Examples 1,2,6,8 and 10 or Examples 4,6,8 and 10.

(1) 2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 173 ° C.

IR (Nujol): 3400, 3300, 3200, 1720, 1620, 1600, 1520cm ^-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-cyclopenteneoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 160-165 ° C. (decomposition).

IR (Nujol): 3470, 3290, 3200, 2400, 1715, 1615, 1600, 1520 cm ^-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), mp. 116-119 degreeC (decomposition).

IR (Nujol): 3250, 3200, 1650, 1600, 1520, 1400, 1260, 1150, 1000, 820, 720cm ^-1

(4) 2-methylmethoxyimino-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 (d ₆ -DMSO, δ): 3.00 (3H, s), 5.38 (2H, s), 8.22 (2H, broad S)

(5) 2-allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 93-95 ° C. (decomposition).

IR (Nujol): 3430, 3100, 1710, 1615, 1525cm ^-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), mp. 158-160 degreeC (decomposition).

IR (Nujol): 3430, 3380, 3260, 1730, 1640, 1610, 1535cm ^-1

NMR (d ₆ -DMSO, δ): 5.22 (2H, s), 7.38 (5H, s), 8.17 (2H, broad s)

(7) 2- (2-propynyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 155-157 ° C. (decomposition).

IR (Nujol): 3500, 3310, 3160, 2600, 2480, 1745, 1610, 1535cm ^-1

NMR (d ₆ -DMSO, δ): 3.53 (1H, t, J = 2 Hz), 4.87 (2H, d, J = 2 Hz), 8.23 (2H, broad s)

(8) 2- (2-phenoxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 150-153 ° C. (decomposition).

IR (Nujol): 3470, 3300, 3150, 2550, 1750, 1620, 1600, 1540, 1500cm ^-1

NMR (d ₆ -DMSO, δ): 4.0-4.7 (4H, m), 6.7-7.5 (5H, m), 8.20 (2H, broad s)

(9) 2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 140-0143 ° C (decomposition).

IR (Nujol): 3450, 3350, 3260, 1745, 1670, 1645, 1615, 1515 cm ^-1

NMR (d ₆ -DMSO, δ): 4.72 and 4.95 (2H, ABq, J = 9 Hz), 8.25 (2H, broad s)

(10) 2-methylthiomethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 140-143 ° C. (decomposition).

IR (Nujol): 3500, 3300, 3150, 2670, 2580, 1740, 1615, 1605, 1530 cm ^-1

NMR (d ₆ -DMSO, 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), mp. 140-143 ° C. (decomposition).

IR (Nujol): 3430, 3340, 3230, 2650, 2450, 1720, 1610, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 2.08 (3H, s), 2.72 (2H, t, J = 7 Hz), 4.28 (2H, t, J = 7 Hz), 8.17 (2H, broad s)

(12) 2-phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 145-147 ° C. (decomposition).

IR (Nujol): 3350, 3170, 2500, 1730, 1710, 1645, 1630, 1595, 1535 cm ^-1

NMR (d ₆ -DMSO, δ): 7.0-7.5 (5H, 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 (Nujol): 3350, 3230, 2600, 2500, 1730, 1620, 1520, 1460 cm ^-1

NMR (d ₆ -DMSO, 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), mp. 173-174 ° C. (decomposition).

IR (Nujol): 3450, 1735, 1620, 1540cm ^-1

NMR (d ₆ -DMSO, 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), mp. 170-171 ° C.

IR (Nujol): 3300, 3150, 1680, 1635, 1520cm ^-1

NMR (d ₆ -DMSO, 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 isomer), mp. 150 ° C. (decomposition).

IR (Nujol): 3300, 3150, 1710, 1620, 1520cm ^-1

NMR (d ₆ -DMSO, 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-thiadiazol-3-yl) acetic acid (syn isomer), mp. 186-188 ° C (decomposition).

IR (Nujol): 3400, 3250, 3100, 1710, 1620, 1540cm ^-1

NMR (DMSO-d ₆ , δ): 1.73-2.10 (2H, m), 3.50 (2H, t, J = 6 Hz), 4.73 (1H, t, J = 6 Hz), 8.13 (2H, s)

(18) 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (syn isomer), mp. 180-182 ° C. (decomposition).

IR (Nujol): 3450, 3250, 3100, 1715, 1610, 1530cm ^-1

NMR (d ₆ -DMSO, 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, 1550cm ^-1

NMR (d ₆ -DMSO, δ): 1.00 (3H, t, J = 6 Hz), 1.3-2.0 (2H, m), 4.13 (2H, t, J = 6 Hz), 8.17 (2H, broad, s)

(20) 2-isopropoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 152-155 degreeC (decomposition).

IR (Nujol): 3450, 3300, 3200, 1730, 1620, 1530cm ^-1

NMR (d ₆ -DMSO, δ): 1.22 (6H, d, J = 6 Hz), 4.1-4.6 (1H, m), 8.20 (2H, broad s)

(21) 2- (thioran-1,1-dioxide 3-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 200-205 ° C. (decomposition).

IR (Nujol): 3300, 1720, 1620, 1530cm ^-1

NMR (d ₆ -DMSO, 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), mp. 150-155 ° C. (decomposition).

IR (Nujol): 3300, 3200, 1710, 1640, 1580, 1530cm ^-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), mp. 140-145 ° C. (decomposition).

IR (Nujol): 3450, 3300, 3200, 1730, 1630, 1530, 1500cm ^-1

NMR (DMSO-d ₆ , δ): 7.17 (2H, s), 7.27 (2H, s), 8.27 (2H, s)

(24) 2- (1-phenylepoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 103-107 ° C. (decomposition).

IR (Nujol): 3250, 3150, 1710, 1610, 1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.57 (3H, d, J = 6 Hz), 5.42 (1H, q, J = 6 Hz), 7.40 (5H, m), 8.20 (2H, m)

(25) 2- (2-methoxy-5-nitropenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 125-128 ° C. (decomposition).

IR (Nujol): 3400, 3280, 1740, 1720, 1690, 1630, 1590, 1510, 1340, 1275, 970, 720cm ^-1

NMR (DMSO-d ₆ , δ): 3.93 (3H, s), 7.27 (1H, d, J = 8 Hz), 8.01 (1H, d, J = 8 Hz), 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), mp. 177-178 degreeC.

IR (Nujol): 3300, 1710, 1625, 1585, 1530, 1300, 1210, 1120, 980cm ^-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), mp. 167-168 ° 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-thiadiazol-3-yl) acetic acid (syn isomer), mp. 186-188 ° C (decomposition).

IR (Nujol): 3420, 3150, 1735, 1690, 1620, 1580, 1265, 1200, 1000, 980, 760cm ^-1

NMR (DMSO-d ₆ , δ): 7.3-8.0 (4H, m), 8.30 (2H, broad s)

(29) 2- (4-fluorobenzyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer),

NMR (DMSO-d ₆ , δ): 8.10 (2H, b, s), 7.63-6.98 (4H, m), 5.20 (2H, s)

(30) 2-hexyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp. 158-161 degreeC.

NMR (DMSO-d ₆ , δ): 0.67-2.00 (11H, m), 4.20-4.38 (2H, m)

Example 12

Conc. Hydrochloric acid under stirring to a solution of sodium 2-carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetate (syn isomer) (50.0 g) in methanol (935 ml) (50 ml) was added and kept at room temperature for 7 hours.

Sodium bicarbonate (23.6 g) and water (100 ml) were added to the reaction mixture, and the mixture was evaporated to remove methanol. The aqueous residue was extracted with ethyl acetate.

The extract was dried over magnesium sulfate and then evaporated to dryness. The residue was triturated with methanol, filtered, washed with isopropyl alcohol and dried to give 2-methoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid. (syn isomer) (15.5 g) was obtained.

m.p. 179 ° -181 ° C (decomposition)

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 (2)

A method for preparing a compound of formula (I) or a salt thereof by hydrolysis of a compound of formula (II) or a salt thereof:

Wherein R ¹ is a sulfur-containing hetero five-membered ring group substituted with lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cyclo (lower) alkenyl, aryl or oxo groups which may be substituted with suitable substituents to be. Method for producing the following structural formula (Ia) or a salt thereof, consisting of the following (a) and (b): (a) hydrolyzing the compound of formula (VIIa) or a salt thereof to prepare the following formula (Ib) or a salt thereof, and (b) compound (Ib) or a salt thereof obtained by a conventional method Switch to (Ia).

Wherein R _1a is lower alkyl substituted with protected carboxy, R _1b is lower alkyl substituted with carboxy or lower alkoxycarbonyl and R _1c is lower alkyl substituted with carboxy.