GB2094794A - Processes for preparing 2- substituted hydroxyimino-2-(5- amino-1,2,4-thiadiazol-3-yl)acetic acid or its salt, and intermediates thereof - Google Patents

Abstract

Compounds of the formula I <IMAGE> wherein R1 is optically substituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cyclo(lower) alkenyl, optionally substituted aryl or an oxo substituted S-containing 5- membered heterocycle, or its salt are prepared by subjecting a novel compound of the formula II <IMAGE> or its salt, to hydrolysis. Compounds of the formula I are useful as intermediates in the preparation of valuable synthetic cephalosporin antibacterial agents.

Description

SPECIFICATION Processes for preparing 2-substituted hydroxyimino-2-(5-amino-l ,2,4-thiadiazol-3-yl)acetic acid or its salt, and intermediates thereof The present invention relates to new processes for preparing 2-substituted hydroxyimino-2-(5 amino-I ,2,4-thiadiazol-3-yl)acetic acid or its salt, and to intermediates thereof. More particularly, it relates to new processes for preparing 2-substituted hydroxyimino-2-(5-amino-1,2-4-thiadiazol- 3-yl)acetic acid or its salt, to new intermediates which are useful in said processes and to processes for the preparation of said intermediates.

Accordingly, it is one object of the present invention to provide new processes for preparing 2-substituted hydroxyimino-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetic acid or its salt, which is useful as acylating agent for preparing 7-acylaminocephalosporin compounds having superior antibacterial activity.

Another object of the present invention is to provide new intermediates which are useful in said processes for preparing 2-substituted hydroxyimino-2-(5-amino- 1 , 2,4-thiadiazol-3-yl)acetic acid or its salt.

A further object of the present invention is to provide processes for preparing said new intermediates.

The object 2-substituted hydroxyimino-2-(5-amino- 1, 2,4-thiadiazol-3-yl)acetic acid can be represented by the following general formula:

wherein R, is lower alkyl which may be substituted with suitable substituent(s), lower alkenyl, lower alkynyl, cycloalkyl, cyclo(lower)alkenyl, aryl which may be substituted with suitable substituent(s), or S containing 5-membered heterocyclic group substituted with oxo group(s).

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

(Process)

wherein R, is defined above, and M is an alkali metal.

In the object compound (I) and the intermediates (III), (IV), (VI) and (VIII), the partial structure represented by the formula:

is to be understood to include both of the geometrical structures represented by the formulae:-

wherein R1 is as defined above).

In this specification, with regard to all the compounds having the above mentioned partial structure, the compounds having the geometrical structure shown by the formula (A) are referred to as "syn isomer" and the compounds having the alternative one shown by the formula (A') as "anti isomer".

Suitable salt of the object compound (I) may include salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g.

triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.) etc.; an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic acid addition salt, for example, organic carboxylic or sulfonic acid addition salt (e.g. formate, trifluoroacetate, methanesulfonate, benzenesulfonate, acetate, p-toluenesulfonate, etc.); a salt with a base amino acid (e.g. arginine, etc.); and the like.

In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.

The term "lower" is used to intend a group having 1 to 6 carbon atom(s), unless otherwise provided.

Suitable lower alkyl may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, tert-pentyl, hexyl or the like.

Suitable substituent(s) in the term "lower alkyl which may be substituted with suitable substituent(s)" may include halogen (e.g. chlorine, bromine, fluorine or iodine); carboxy; lower alkylthio (e.g. methylthio, ethylthio, propylthio, butylthio, etc.); aryl (e.g. phenyl, tolyl, xylyl, mesityl, cumenyl, etc.); aryloxy (e.g., phenoxy, tolyloxy, mesityloxy, etc.); lower alkoxy(lower)alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, pentyloxymethoxy, hexyloxymethoxy, hexyloxyethoxy, etc.); hydroxy; lower alkanesulfonyl (e.g, mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); aryl substituted with halogen (e.g., chlorophenyl, fluorophenyl, etc.); cyano; protected carboxy group as illustrated below; and the like.

Suitable "protected carboxy" may include an esterified carboxy and the like, and suitable examples of the ester moiety in said esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) which may have at least one suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.), lower alkanesulfonyl(lower)alkyl ester (e.g. 2-mesylethyl ester, etc.) or mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); ar(lower)alkyl ester which may have at least one suitable substituent(s) (e.g. benzyl ester, 4methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)-methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3, 5-di-tert-butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.), and the like.

Suitable lower alkenyl may include vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl and the like, preferably one having 2 to 4 carbon atoms.

Suitable lower alkenyl may include one having 2 to 6 carbon atoms, for example, ethynyl, 2propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl, or the like, preferably one having 2 to 4 carbon atoms.

Suitable cycloalkyl may include one having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like, preferably one having 4 to 7 carbon atoms.

Suitable cyclo(lower)alkenyl may include one having 3 to 6 carbon atoms, for example, cyclopentenyl, cyclohexenyl, or the like, preferably one having 5 or 6 carbon atoms.

Suitable aryl may include phenyl, tolyl, xylyl, mesityl, cumenyl and the like, and said aryl group may be substituted with 1 to 3 suitable substituent(s) such as halogen (e.g., chlorine, bromine, fluorine or iodine), nitro, lower alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.) preferably one having 1 to 4 carbon atom(s), halo(lower)alkyl (e.g., chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, trichloroethyl, etc.) preferably one having 1 to 3 carbon atom(s), carboxy, or the like.

Suitable S containing 5-membered heterocyclic group may include thiolanyl or the like, which is substituted with 1 or 2 oxo group(s).

The processes for preparing the object compound (I) or its salt are explained in details in the following.

Process 1 The compound (III) or its salt can be prepared by subjecting the compound (II) to nitrosation.

Suitable salt of the compound (III) may include an alkali metal salt (e.g., sodium salt, potassium salt), and the like.

The nitrosating agent to be used in the reaction is conventional ones, which can react with an active methylene compound to produce C-nitroso compound, including for example, nitrous acid or its salt such as alkali metal nitrite (e.g., sodium nitrite, etc.) or its ester such as lower alkyl nitrite (e.g., tert-butyl nitrite, isopentyl nitrite, etc.), and the like.

The reaction, when a salt of nitrous acid is used as the nitrosating agent, is usually carried out in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, acetic acid or the like. On the contrary, when an ester of nitrous acid is used as the nitrosating agent, the reaction is preferably carried out in the presence of a rather strong base such as an alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.) and the like.

The present reaction is usually carried out in a solvent such as water, acetic acid, alcohol (e.g., ethanol, methanol, etc.), ether, tetrahydrofuran or any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out from under cooling to under heating.

Process 2 The compound (IV) or its salt can be prepared by subjecting the compound (liy) or its salt to introduction reaction of the substituent on hydroxyimino group.

Suitable salt of the compound (IV) may include the same salt with a base as exemplified for the compound (I).

The reagent to be used in the introduction reaction of the substituent on hydroxyimino group may include the compound of the formula: R,-Y (IX) (wherein R, is as defined above and Y is an acid residue, or the compound of the formula: R1a=N2 (X) (wherein Ria is a group in which a hydrogen is eliminated from "tri").

In case that substituent to be introduced is aryl which may be substituted with suitable substituent(s), in addition to the above reagent, the following compound of the formula: R,,-X,-R,, YO (Xl) (wherein Y is as defined above, Rib is aryl which may be substituted with suitable substituent(s) and X is halogen) can also be used in the introduction reaction of the substituent on hydroxyimino gorup.

Suitable acid residue may include a residue of an acid such as hydrohalogenic acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, alkylsulfuric acid (e.g., methylsulfuric acid, ethylsulfuric acid, etc.), sulfonic acid (e.g., methanesulfonic acid, ptoluenesulfonic acid, etc.) or the like.

The reaction using the compound (IX) is usually carried out in a solvent such as water, acetonitrile, acetone, ethanol, ether, ethyl acetate, dimethylformamide or any other solvent which does not adversely affect the reaction, and is preferably carried out in the presence of a base, for example, an inorganic base such as an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide etc.), an alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.) or an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an organic base such as an alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide etc.), a trialkylamine (e.g. trimethylamine, triethylamine, etc.), triethanolamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N-methylmorpholine or pyridine, or the like.

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

Preferable example of the compound (X) may be diazo(lower)alkane (e.g., diazomethane, diazoethane, etc.) or the like.

The reaction using the compound (X) is usually carried out in a solvent such as ester, tetrahydrofuran or the like. The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.

The reaction using the compound (Xl) is usually carried out in a solvent such as alcohol (e.g., methanol, ethanol, etc.), water, mixed solvent thereof, or any solvent which does not adversely affect the reaction, and preferably carried out in the presence of a base.

The reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or under warming.

Process 3 The compound (V) or its salt can be prepared by subjecting the compound (IV) or its salt to dehydration.

Suitable salt of the compound (V) may include the same salt with base as exemplified for the compound (I).

The dehydrating agent to be used in this dehydration reaction may include phosphoryl chloride, thionyl chloride, phosphorus pentoxide, phosphorus pentachloride, phosphorus pentabromide and the like.

The present reaction is usually carried out in a solvent such as dioxane, chloroform, methylene chloride, 1 ,2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile, dimethylformamide or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out at ambient temperature, under warming or heating.

Process 4 The compound (Vl) or its salt can be prepared by reacting the compound (V) or its salt with ammonia and/or ammonium salt.

Suitable ammonium salt may include ammonium acetate, ammonium sulfate, ammonium halide (e.g., ammonium chloride, ammonium bromide, etc.) and the like.

Suitable salt of the compound (VI) may include the same one as exemplified for the compound (I).

The present reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), acetone, chloroform. dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.

Process 5 The compound (VIII) or its salt can be prepared by reacting the compound (VI) or its salt with halogenating agent and the compound (VII).

Suitable halogenating agent to be used in the present reaction may include bromine, chlorine and the like.

Suitable salt of the compound (VIII) may include the same one as exemplified for the compound (I).

Suitable alkali metal for M may include 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, for example, alkali metal carbonate, alkali metal alkoxide, trialkylamine or the like. The present reaction is usually carried out in a solvent such as an alcohol (e.g., methanol, ethanol, etc.) or any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.

Process 6 The compound (() or its salt can be prepared by subjecting the compound (VIII) or its salt to hydrolysis. Hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an inorganic base and an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkaline earth metal (e.g., magnesium, calcium, etc.), the hydroxide or carbonate or bicarbonate thereof, trialkylamine (e.g., trimethylamine, triethylamine, etc.), picol ine, 1.5-diazabicyclo[4, 1,5-diazabicyclo[4,3,0]none-5-ene, 1,4-diazobicyclo[2,2,2]octane, 1 ,8-diazabicy- clo5,4,0Jundecene-7, or the like.Suitable acid may include an organic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.) and an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

The reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol, ethanol, etc.), a mixture thereof or any other solvent which does not adversely affect the reaction. A liquid base or acid can be also used as the solvent.

The reaction temperature is not critical and the reaction is usually carried out under warming or under heating.

The present invention includes, within its scope, the cases that protected carboxy group and/or cyano group in R, are converted into the corresponding free carboxy group during the reaction. And, if desired, carboxy group in R, can be converted into protected carboxy group by conventional manner.

Process 7 The compound (V) or its salt can be prepared by subjecting the compound (XII) or its salt to introduction reaction of the substituent on hydroxyimino group.

Suitable salt of the compound (XII) may include an alkali metal salt (e.g., sodium salt, potassium salt), and the like.

The reagent to be used in the introduction reaction of the substituent on hydroxyimino group can be referred to the ones exemplified in Process 2.

The present introduction reaction of the substituent on hydroxyimino group can be carried out in a similar manner to that of aforementioned Process 2.

In the present invention, the compounds (III), (IV), (V), (VI) and (VIII) can be used without isolation for their next steps.

The object compound (I) and its salt are useful, as key intermediate, for preparing 7-[2substituted hydroxyimino-2-(5-amino-1 , 2,4-thiadiazol-3-yl)-acetamido]cephalosporin compounds, which have superior antibacterial activity and can be prepared by reacting the 7-aminocephalosporin compounds with the object compound (I), its reactive derivatives or its salt as acylating agent.

It is known that the object compound (I) or its salt can be prepared by using 1-alkoxycarbonylformamidine as a starting compound. Accordingly, one of the object of the present invention is, as mentioned above, to provide new processes for preparing the compound (I) or its salt.

The present invention is based on the observation that said new processes are superior to the known processes in the following aspects.

That is to say: (1) that the known processes need several steps to prepare the starting compound; i.e., 1 alkoxycarbonyl-formamidine, from a commercially available compound, while the starting compound of the new processes is per se a commercially available compound, which means that the known processes need longer steps than the new processes; (2) that the known processes need high cost and dangerous reagent(s) during the reactions, while the new processes do not require said expensive and dangerous reagent(s), so that the new processes are much more favorable and safer processes than the known processes in industrial use.

The following examples are given for the purpose of illustrating the present invention.

Example 1 To a mixture of 2-cyanoacetamide (67.0 g) and sodium nitrite (66.1 g) in water (268 ml) was dropped acetic acid (95.8 g) at 10 to 15"C under cooling in an ice bath and stirring, which was continued for 3 hours at the same temperature. The mixture containing 2-cyano-2-hydroxyiminoacetamide was adjusted to pH 8.5 with 4N aqueous sodium hydroxide (350 ml) and followed by an addition of diethyl sulfate (147.5 g). The mixture was stirred for 1.5 hours at 45 to 50"C, keeping pH 8.5 with an addition of 4N aqueous sodium hydroxide during heating. The mixture was cooled in an ice bath and the precipitates were collected, washed with cold water and dried to give 2-cyano-2-ethoxyiminoacetamide (70.0 g), mp. 1 25 to 127"C.

IR (Nujol): 3400, 3300, 3180, 1705, 1600, 1560, 1160, 1045 cam~' NMR (DMSO-d6, 8): 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 refluxed for 9 hours under stirring. The mixture was cooled and poured into cold water (1 I). The organic layer was separated out, washed with water, dried over anhydrous magnesium sulfate and concentrated to give an oily product (74.7 g). The oily product was purified by vacuum distillation to give a colorless oil of 2-ethyoxyiminopropanedinitrile (57.8 g), bp. 65 to 67"C at 13 mmHg.

IR (Film): 3000, 2250, 1520, 1390, 1250, 1170, 1060, 785 cm- NMR (CDCl3, S): 1.43 (3H, t, J = 7Hz), 4.67 (2H, q, J = 7Hz) Example 3 The following compounds were obtained according to similar manners to those of Examples 1 and 2.

(1) 2-Cyanomethoxyiminopropanedinitrile, bp. 90 to 105"C at 5mmHg.

IR (Film): 3050, 2950, 2250, 1550, 1430, 1250, 1060 cam~' (2) 2-Methoxyiminopropanedinitrile, bp. 47 to 48C at 1 2 mm Hg.

IR (Film): 3030, 2980, 2260, 1528, 1455, 1395 cm-' (3) 2-(2-Propynyloxyimino)propanedinitrile.

IR (Film): 3320, 2960, 2250, 2150, 1532, 1438 cam~' (4) 2-Allyloxyiminopropanedinitrile.

IR (Film): 2220, 1520, 1420, 1350, 1242, 1050 cam~' (5) 2-Methoxycarbonylmethoxyiminopropanedinitrile, bp. 90 to 99"C at 5.5 mmHg.

IR (Film): 3050, 3000, 2250, 1765 cam~' Example 4 A mixture of sodium salt (45 9) of 2-hydroxyiminopropanedinitrile, methyl chloroacetate (41.8 g) and sodium iodide (5.8 9) in acetonitrile (225 ml) was stirred for 3 hours at 50"C and allowed to stand overnight at room temperature. The reaction mixture was evaporated and the residue was dissolved in a mixture of diisopropyl ether and water. The organic layer was separated out, washed with water, dried over magnesium sulfate and evaporated to give crude oil (45.0 9) of 2-methoxycarbonylmethoxyiminopropanedinitrile, which was purified by distillation, bp. 90 to 99C at 5.5 mmHg.

IR (Film): 3050, 3000, 2250, 1765 cam~' Example 5 (1) The following compound was obtained by reacting sodium salt of 2-hydroxyiminopropanedinitrile with chloroacetonitrile according to a similar manner to that of Example 4.

2Cyanomethoxyiminoprnpanedinitrile, bp. 90 to 105C at 5 mmHg.

IR (Film): 3050, 2950, 2250, 1550, 1430, 1250, 1060 cm ~ ' (2) The following compound was obtained by reacting sodium salt of 2-hydroxyiminopropanedinitrile with dimethyl sulfate according to a similar manner to that of Example 4.

2-Methoxyiminopropandeinitrile, bp. 47 to 48C at 1 2 mmHg.

IR (Film): 3030, 2980, 2260, 1528, 1455, 1395 cam~' (3) The following compound was obtained by reacting sodium salt of 2-hydroxyiminopropanedinitrile with 2-propynyl bromide according to a similar manner to that of Example 4.

2-(2-Propynyloxyimino)propanedinitrile.

IR (Film): 3320, 2960, 2250, 2150, 1532, 1438 cam~' NMR (CDCI3,8): 2.72 (1H, t, J = 3Hz), 5.10 (2H, d, J = 3Hz) (4) The following compound was obtained by reacting sodium salt of 2-hydroxyiminopropanedinitrile with allyl bromide according to a similar manner to that of Example 4.

2-Allyloxyiminopropanedinitrile.

IR (Film): 2220, 1520, 1420, 1350, 1242, 1050 cam~' NMR (CCl4, 8): 4.97 (2H, d, J = 6Hz), 5.3-5.6 (2H, m), 5.6-6.3 (1 H, m) (5) The following compound was obtained according to a similar manner to that of Example 4.

2-Ethoxyiminopropanedinitrile, bp. 65 to 67C at 1 3 mmHg.

IR (Film): 3000, 2250, 1520, 1390, 1250, 1170, 1060,785cm-1 Example 6 (1) To a solution of ammonium chloride (3.2 9) and concentrated aqueous ammonium hydroxide (20 ml) in ethanol (20 ml) was added 2-ethoxyiminopropanedinitrile (3.7 9) at - 5 to O"C under stirring, which was continued for 1.5 hours at the same temperature. The mixture was diluted with a mixture of water (40 ml) and methylene chloride (40 ml). The organic layer was separated out and the aqueous layer was extracted twice with methylene chloride (20 ml). 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 (2.4 9), mp. 110 to 111 C.

IR (Nujol): 3450, 3280, 2250, 1655, 1620, 1600, 1220, 1045 cam~' NMR (CD3OD, 5): 1.40 (3H, t, J = 7Hz), 4.50 (2H, q, J = 7Hz) (2) To a mixture of ammonium chloride (159 9), concentrated aqueous ammonium hydroxide (2 I) and ethanol (900 ml) was added a solution of 2-methoxyiminopropanedinitrile (325 9) in ethanol (600 ml) at - 1 5 to - 10"C during 1.5 hours under stirring, which was continued for 30 minutes after the addition. The reaction mixture was poured into a mixture of methylene chloride (2 I) and water (2 I). The organic layer was separated out, and the aqueous layer was salted out and extracted with methylene chloride. The organic layer and the extract were combined, dried over magnesium sulfate and evaporated.The residual oil was dissolved in ethyl acetate (7 1), and glacial acetic acid (77.7 9) was dropped thereto under stirring. The resulting precipitates were collected by filtration, washed with ethyl acetate and dried to give 2-cyano-2methoxyiminoacetamidine acetate (160.77 9), mop. 150 to 155"C (dec.).

IR (Nujol):3250, 2700, 2350, 2250, 1675, 1580, 1548, 1530, 1495 cm-' NMR (DMSO-d6, 8): 1.90 (3H, s), 4.17 (3H, s), 7.65 (4H, s) (3) To a solution of ammonium acetate (4.62 9) in methanol (10 ml) was added 2 methoxycarbonylmethoxyiminopropanedinitrile (3.34 9) under stirring, which was continued for 2 hours at room temperature and allowed to stand overnight. To the reaction mixture was added isopropyl alcohol (15 ml) and stirred for 1 5 minutes. The resulting precipitate was collected by filtration, washed with isopropyl alcohol and dried to give 2-cyano-2-methoxycarbonylmethoxyiminoacetamidine acetate (3.4 9), which was recrystallized from methanol, mp. 1 57 to 158C (dec.).

IR (Nujol): 2800-2200, 1750, 1680, 1550 cm-' NMR (DMSO-d6, 5): 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 obtained according to a similar manner to that of Example 6.

(1) 2-Cyano-2-allyloxyiminoacetamidine, mp. 78 C.

IR (Nujol): 3450, 3330, 3220, 3110, 2220, 1650, 1645, 1635 cam~' NMR (CDCI3 + D20, 5): 4.90 (2H, d, J = 5Hz), 5.2-5.7 (2H, m), 5.7-6.3 (1 H, m) (2) 2-Cyano-2-(2-propynyloxyimino)acetamidine, mp. 1 05 to 1 08'C (dec.).

IR (Nujol): 3450, 3270, 3150, 2210, 2100, 1630, 1560, 1420 cam~' NMR (CDCI3, 5): 2.63 (1 H, t, J = 3Hz), 4.95 (2H, d, J = 3Hz), 5.83 (3H, broad s) (3) 2-Cyano-2-cyanomethoxyiminoacetamidine, mp. 60 to 65"C.

IR (Nujol): 3450, 3300, 3150, 1640, 1600, 1570 cm-' Example 8 (1) To a solution of 2-cyano-2-ethoxyiminoacetamidine (8.0 9) and triethylamine (11.5 9) in methanol (120 ml) was dropped bromine (9.1 9) at - 10"C under stirring, which was continued for several minutes at - 10 to - 5"C. To the reaction mixture was dropped a solution of potassium thiocyanate (5.5 9) in methanol (55 ml) at - 10 to - 5"C under stirring, which was continued for 2 hours at O to 5"C. The resulting precipitate was filtered, washed with methanol and water, and dried to give a brownish powder of 2-ethoxyimino-2-(5-amino-1 ,2,4-thiadiazol-3- yl)acetonitrile (syn isomer) (10.1 5 9), mp. 270 to 273C (dec.).

IR (Nujol): 3400, 3260, 3150, 2250, 1620, 1540, 1190, 1050, 1040 cm-' NMR (DMSO-d6,8): 1.37 (3H, t, J = 7Hz), 4.50 (2H, q, J = 7Hz), 8.37 (2H, s) (2) To a suspension of 2-cyano-2-methoxycarbonylmethoxyiminoacetamidine acetate (495 g) in methanol (4.95 1) was dropped triethylamine (512. 6 g) at - 10"C under stirring and cooling, and further, bromine (357.3 9) was added to the above mixture at the same temperature.After the reaction mixture was stirred for 1 5 minutes, a solution of potassium thiocyanate (216 g) in methanol (2.16 I) was dropped thereto at - 10 to - 5"C under stirring, which was continued for 30 minutes at O to 5"C. The resulting precipitates were collected by filtration, washed with water (5 1) and dried to give 2-methoxyCarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl)acetonitrile (syn isomer) (430 9), which was recrystallized from aqueous methanol, mp. 225 to 227C (dec.).

IR (Nujol): 3400, 3250, 3100, 1740, 1630, 1550 cam~' NMR (DMSO-d6,6): 3.77 (3H, s), 5.17 (2H, s), 8.33 (2H, s) Example 9 The following compounds were obtained according to a similar manner to that of Example 8.

(1) 2-Methoxyimino-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetonitrile (syn isomer), mp. 210 to 215C (dec.).

IR (Nujol): 3460,3270,3140,2260, 1632, 1540 cam~' NMR (DMSO-d6,8): 4.24 (3H, s), 8.32 (2H, s) (2) 2-(2-Propynyloxyimino)-2-(5-amino-l ,2,4-thiadiazol-3-yl)acetonitrile (syn isomer), mp. 1 93 to 195C (dec.).

IR (Nujol): 3460, 3270, 3180, 3160, 2690, 2150, 1625, 1560, 1538 cam~' NMR (DMSO-d6, 6): 3.70 (1 H, t, J = 3Hz), 5.12 (2H, d, J = 3Hz), 8.33 (2H, broad s) (3) 2-Allyloxyimino-2-(5-amino-1 ,2,4-thiadiazol-3-yl)-acetonitrile (syn isomer), mp. 1 80 to 184"C (dec.).

IR (Nujol): 3430, 3260, 3140; 2220, 1625, 1540 cm-1 NMR (DMSO-d6, 5):4.90 (2H, d, J = 6Hz),5.1-5.6 (2H, m), 5.7-6.4 (1 H, m), 8.27 (2H, s) (4) 2-Cyanomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetonitrile (syn isomer), mp. 190 to 1 95'C (dec.).

IR (Nujol): 3450, 3300, 3150, 1540 cm-' Example 10 (1) A mixture of 2-ethoxyimino-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetonitrile (syn isomer) (10.1 9) and sodium hydroxide (22.8 9) in water (142 ml) was stirred for 5 hours at 50 to 55 C. The reaction mixture was cooled, adjusted to pH 1 with 6N hydrochloric acid and extracted three times with ethyl acetate (50 ml). The extracts were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethyl acetate to give colorless fine needles of 2-ethoxyimino-2-(5-amino-1 ,2,4-thiadiazol-3-yI)acetic acid (syn isomer) (8.2 9), mop.187 (dec.).

IR (Nujol): 3450, 3250, 3150, 1720, 1620, 1535, 1040, 1010 cm-' NMR (DMSO-d6, 6):1.23 (3H, t, J = 7Hz), 4.22 (2H, q, J = 7Hz), 8.1 7 (2H, s) (2) To a solution of sodium hydroxide (334.5 g) in water (8.36 1) was added 2-methoxycarbonyl methoxyimino-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetonitrile (syn isomer) (550 9) at room temperature and the mixture was stirred for 5 hours at 60 to 65"C. 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 sealed out, adjusted to pH 1.0 with 50% aqueous sulfuric acid and extracted with acetonitrile (6 x 2.5 1) (extract A).

The combined extract A was dried over magnesium sulfate (10 kg) and filtered. To the filtrate was added a solution of sodium acetate (109 9) in methanol (1.2 I) under stirring, which was continued for 15 minutes. The resulting precipitates were 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 9), mp. 155 to 160C (dec.).

IR (Nujol): 3320, 3180, 1720, 1630, 1530 cm-' NMR (DMSO-d6, 5): 4.48 (2H, s), 8.08 (2H, broad s) The above obtained extract A was evaporated to dryness. The residue was recrystallized from methanol to give 2-carboxymethoxyimino-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetic acid (syn isomer), mp. 193 to 194"C (dec.).

IR (Nujol): 3400, 3250, 3100, 2800-2200, 1730, 1630, 1540 cm-' NMR (DMSO-d6, 5): 4.65 (2H, s), 8.15 (2H, s) Analysis Calcd. for C6H6N4O5S: C 29.27, H 2.46, N 22.76 Found: C 29.18, H 2.58, N 22.09 The same object compounds were obtained according to a similar manner to the above by using 2-cyanomethoxyimino-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetonitrile (syn isomer) instead of 2-methoxycarbonylmethoxyimino-2-(5-amino- 1,2, 4-thiadiazol-3-yl)acetonitrile (syn isomer) as a starting compound.

Example ii The following compounds were obtained according to similar manners to those of 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, 1520 cm-' NMR (DMSO-d6, 5): 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), mp. 160 to 165C (dec.).

IR (Nujol): 3470, 3290, 3200, 2400, 1715, 1615, 1600, 1520cm-1 NMR (DMSO-d6, 8): 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 to 11 9'C (dec.).

IR (Nujol): 3250, 3200, 1650, 1600, 1520, 1400, 1260, 1150, 1000, 820, 720 cm-l (4) 2-Mesylmethoxyimino-2-(5-amino-l , 2,4-thiadiazol-3-yl)acetic acid (syn isomer).

IR (Nujol): 3450, 3400, 3270, 2600, 2460, 1735, 1640, 1620, 1530 cm-1 NMR (d6-DMSO, 5): 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 to 95C (dec.).

IR (Nujol): 3430, 3100, 1710, 1615, 1525 cm-l NMR (d6-DMSO,8): 4.72 (2H, d, J = 6Hz), 5.1-5.5 (2H, m), 5.7-6.3 (1H, m), 8.17 (1H, broad s) (6) 2-Benzyloxyimino-2-(5-amino-1 ,2,4thiadiazol-3-yl)acetic acid (syn isomer), mp. 158 to 160C (dec.).

IR (Nujol): 3430, 3380, 3260, 1730, 1640, 1610, 1535 cm-' NMR (d6-DMSO, 5): 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-yI)acetic acid acid (syn isomer). mp. 155 to 1 57'C (dec.).

IR (Nujol): 3500, 3310, 3160, 2600, 2480, 1745, 1610, 1535 cm-' NMR (d6-DMSO,8): 3.53 (1 H, 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), mp. 150 to 153C (dec.).

IR (Nujol): 3470, 3300, 3150, 2550, 1750, 1620, 1600, 1540, 1500 cm-' NMR (d6-DMSO,#):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 to 143 C (dec.).

IR (Nujol): 3450, 3350, 3260, 1745, 1670, 1645, 1615, 1515 cm-' NMR (d6-DMSO,8): 4.72 and 4.95 (2H, ABq, J = 9Hz), 8.25 (2H, broad s) (10) 2-Methythiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), mp.

140 to 143"C (dec.).

IR (Nujol): 3500, 3300, 3150, 2670, 2580, 1740, 1615, 1605, 1530 cm-1 NMR (d6-DMSO, 5): 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 to 143"C (dec.).

IR (Nujol): 3430, 3340, 3230, 2650, 2450, 1720, 1610, 1520 cm-1 NMR (d8-DMSO, 5): 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) ,mp. 145 to 147C (dec.).

IR (Nujol): 3350, 3170, 2500, 1730, 1710, 1645, 1630, 1595, 1535 cm-l NMR (d6-DMSO, 5):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 (CHCl3): 3350, 3230, 2600, 2500, 1730, 1620, 1520, 1460 cm-1 NMR (d6-DMSO, 8): 0.87 (3H, t, J = 5Hz), 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 to 174"C (dec.).

IR (Nujol): 3450, 1735, 1620, 1540 cm-' NMR (d5-DMSO, 5): 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 to 171 C.

IR (Nujol): 3300, 3150, 1680, 1635, 1520 cm-' NMR (d6-DMSO, 8): 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 (dec.).

IR (Nujol): 3300, 3150, 1710, 1620, 1520 cm-' NMR (d6-DMSO,#): 1.80-2.50 (4H, m), 5.30-5.50 (1 H, m), 5.83-6.30 (2H, m), 8.20 (2H, s) (17) 2-(1 -Carboxy-3-hydroxypropoxyimino)-2-(5-amino- ,2,4-thiadiazol-3-yl)acetic acid (syn isomer), mp. 186 to 188"C (dec.).

IR (Nujol): 3400, 3250, 3100, 1710, 1620, 1540 cm-' NMR (DMSO-d6, 5): 1.73-2.10 (2H, m), 3.50 (2H, t, J = 6Hz), 4.73 (1 H, t, J = 6Hz), 8.13 (2H, s) (18) 2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3yl)-acetic acid (syn isomer). mp. 180 to 182"C (dec.).

IR (Nujol): 3450, 3250, 3100, 1715, 1610, 1530 cm-' NMR (d6-DMSO, 5): 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 to 103 C (dec.).

IR (Nujol): 3620, 3520, 3350, 3120, 2600, 2500, 1720, 1620, 1550 cm-' NMR (d6-DMSO,8): 1.00 (3H, t, J = 6Hz), 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), mp. 152 to 1 55'C (dec.).

IR (Nujol): 3450, 3300, 3200, 1730, 1620, 1530 cm-' NMR (d6-DMSO, 5)1.22 (6H, d, J = 6Hz), 4.1-4.6 (1 H, m), 8.20 (2H, broad s) (21) 2-(Thiolan-1,1 -dioxide-3-yloxyimino)-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetic acid (syn isomer). mp. 200 to 205C (dec.).

IR (Nujol): 3300 1720, 1620, 1530 cm-' NMR (d6-DMSO, 8): 2.20-2.50 (2H, m), 3.00-3.50 (4H, m), 5.00-5.27 (1 H, m), 8.20 (2H, s) (22) 2-(4-Chlorophenoxyimino)-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetic acid (syn isomer), mp.

150-1 55"C (dec.).

IR (Nujol): 3300, 3200, 1710, 1640, 1580, 1530 cm-' NMR (DMSO-d6, S):7.37 (2H, d, J = 9Hz), 7.67 (2H, d, J = 9Hz), 8.50 (2H, broad s) (23) 2-(4-Fluorophenoxyimino)-2-(5-amino-l ,2,4-thiadiazol-3-yl)acetic acid (syn isomer), mp.

140-145"0 (dec.).

IR (Nujol): 3450, 3300, 3200, 1730, 1630, 1530, 1500 cm-' NMR (DMSO-d6, 5): 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), mp.

103-107 C (dec.).

IR (Nujol): 3250, 3150, 1710, 1610, 1520 cm-' NMR (d,-DMSO, 6): 1.57 (3H, d, J = 6Hz), 5.42 (1 H, q, J = 6Hz), 7.40 (5H, m), 8.20 (2H, m) (25) 2(2-Methoxy-5-nitrophenoxyimino)-2-(5-amino- 1 ,2,4-thiadiazol-3-yl)acetic acid (syn isomer), mp. 125-128"C (dec.).

IR (Nujol): 3400, 3280, 1740, 1720, 1690, 1630, 1590, 1510, 1340, 1275, 970, 720 cm -' NMR (DMSO-d6, 6): 3.93 (3H, s), 7.27 (1 H, d, J = 8Hz), 8.01 H, d, J = 8Hz), 8.07 (1 H, 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 to 178"C.

IR (Nujol): 3300, 1710, 1625, 1585, 1530, 1300, 1210, 1120, 980 cm-' NMR (DMSO-d6, 5): 6.83-7.73 (3H, m), 8.38 (2H, broad s) (27) 2-(3-Trifluoromethylphenoxyimino)-2-(5-amino-1 , 2,4-thiadiazol-3-yI)acetic acid (syn isomer, mp. 167 to 168"C (dec.).

IR (Nujol): 3250, 1645, 1620, 1590, 1450, 1320, 1170, 1140, 1010, 995, 845, 730 cm-' NMR (DMSO-d6, 5): 7.63 (4H, m), 8.44 (2H, broad s) (28) 2-(3-Carboxyphenoxyimino)-2-(5-amino-l ,2,4-thiadiazol-3-yl)acetic acid (syn isomer), mp.

186 to 188 C (dec.).

IR (Nujol): 3420, 3150, 1735, 1690, 1620, 1580, 1265, 1200, 1000, 980, 760 cm-' NMR (DMSO-d6, 5): 7.3-8.0 (4H, m), 8.30 (2H, broad s) (29) 2-(4-Fluorobenzyloxyimino)-2-(5-amino-l ,2,4-thiadiazol-3-yl)acetic acid (syn isomer).

NMR (DMSO-d6, 8): 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. 1 58 to 161"C.

NMR (DMSO-d6,8): 0.67-2.00 (11 H, m), 4.20-4.38 (2H, m) Example 12 To a solution of sodium 2-carboxymethoxyimino-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetate (syn isomer) (50.0 9) in methanol (935 ml) was added concentrated hydrochloric acid (56 ml) under stirring, which was continued for 7 hours at room temperature. To a reaction mixture were added sodium bicarbonate (23.6 9) and water (100 ml) 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 triturated in methanol, filtered, washed with isopropyl alcohol and dried to give 2-methoxycarbonylmethoxyimino-2-(5 amino-I ,2,4thiadiazol-3-yl)acetic acid (syn isomer) (15.5 9), mp. 179 to 181 "C (dec.).

IR (Nujol): 3400, 3300, 3200, 2800-2200, 1750, 1710, 1615, 1520 cam~' NMR (DMSO-d6, 8): 3.63 (3H, s), 4.77 (2H, s), 8.10 (2H, s).

Claims (2)

1. A process for preparing a compound of the formula:

wherein R, is lower alkyl which may be substituted with suitable substituent(s), lower alkenyl, lower alkynyl, cycloalkyl, cyclo(lower)alkenyl, aryl which may be substituted with suitable substituent(s), or S containing 5-membered heterocyclic group substituted with oxo group(s), or its salt, which comprises subjecting a compound of the formula:

wherein R, is as defined above, or its salt, to hydrolysis, and, if desired, the resultant compound wherein R, is lower alkyl substituted with carboxy is converted into a compound wherein R, is lower alkyl substituted with protected carboxy.

2. A compound of the formula:

wherein R, is lower alkyl which may be substituted with suitable substituent(s), lower alkenyl, lower alkynyl, cycloalkyl, cyclo(lower)alkenyl, aryl which may be substituted with suitable substituent(s), or S containing 5-membered heterocyclic group substituted with oxo group(s); and its salt.