KR830002742B1 - Process for preparing thiadiazole compound - Google Patents

Abstract

The title compds. I (R1=(protected) amino; X1=carbonyl, (A); R2=H, acyl, aryl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocyclic pentane contg. S or O) were prepd. Thus, a mixt. contg. 2-(2-cyclopenten-1-yl)oxyimino-2-(t-formamido-1,2,4-thiadiazol-3-yl) acetate and 1N-NaOH was stirred at 50o-55≰C for 1 hr. and cooled. Resulting mixt. was extd. with ethylacetate, washed with satd. NaCl soln., and dried by MgSO4 to give syn-2-(2-cyclopenten-1-yl)-oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid.

Description

Process for preparing thiadiazole compound

The present invention relates to a method for preparing a thiadiazole compound. This relates in particular to thiadiazole compounds which are intermediates in the preparation of 7-substituted-3-cepem and cefam-4-carboxylic acids and bactericidal salts which exhibit bactericidal properties.

It is therefore an object of the present invention to provide a process for the preparation of novel thiadiazole compounds for use in the preparation of pharmaceutically active 7-substituted-3-cepem and cefam-4-carboxylic acids and their scientifically suitable salts. . Thiadiazole as the target compound can be represented by the following general formula (1).

In the above formula

R ¹ is amino or protected amano.

의 기인데 여기서.X ₁ is carbonyl or

It's a group here.

R ² is hydrogen, acyl, aryl which may be substituted. Lower alkyl, lower alkenyl which may be substituted. Lower alkynyl, cycloalkyl which may be substituted. Cyclo (lower) alkenyl or 5-membered ring heterocyclic group having S or O and substituted with oxo group

Thiadiazole (1), the target compound according to the present invention, can be prepared by the following method.

In the above formula

R ¹ and R ² are each as defined above

R ⁶ is a protecting group of a carboxyl group,

M is an alkali metal,

R ^1a is protected amino,

R7 is lower alkyl.

으로 표시된 부분구조는 하기 두식의 기하구조를 모두 포함하는 것으로 믿어진다.

및

General formula in the target compound (1)

It is believed that the substructures indicated by include all of the following two geometries.

And

In all the compounds having the partial structure in the present invention, the compound having the geometry shown by the formula (A) is an anti (isomer), the compound of the structure shown by the formula (A ') is "anti (anti) ) Isomer ".

In the compound of the formula (1), the target compound described above includes the tautomer isomer related to the thiadiazolyl group.

Transplantation is based on the structure

(R ^{l '} may be represented as imino or protected imino).

That is, the groups (B) and (B ') may be in a parallel state in the form of a toetom head which can be expressed by the following equation.

( ^Wherein R ^l and R ^{l '} are as defined above, respectively.)

In the present invention, the following formula for convenience and starting material having the two

Expressed as

Examples of suitable embodiments and various definitions in the description of the present invention are described below.

"Lower" means a group of 1-6 carbon atoms unless otherwise indicated.

Suitable protected amino groups are known protecting groups other than acyl groups such as ar (lower) alkyl (e.g. benzyl, trityl), ar (lower) alkylidene (e.g. benzylidene), lower alkoxy carbonyl or di Lower alkylidene substituted with (lower) alkyl amino (eg 1-ethoxycarbonyl-2-propylidene, dimethylamino methylene, etc.).

Suitable protected aminos include acylimino and imino groups substituted with known protecting groups other than acyl groups such as ar (lower) alkyl described above.

Suitable acyls in the terms "acyl amino" "acyl imino" "acyloxy (lower) alkyl" and "acylthio (lower) alkyl" are carbamoyl, aliphatic acyl groups, aromatic and heterocyclic acyl groups. .

Suitable examples of acyl include lower alkanoyls (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succiryl, pivalyl, etc.), preferably 1 -4 carbon atoms, particularly suitable are 1-2 carbon atoms, lower alkoxy carbonyls of 2-7 carbon atoms (e.g. methoxy carbonyl, ethoxy carbonyl, propoxycarbonyl, 1-cyclopropylethoxy Carbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.), 3-6 carbon atoms , Lower alkanesulfonyl (eg belsen sulfonyl, tosyl, etc.); Aroyl (eg benzoyl, toluoyl, naphthoyl, phthaltoyl, indacarbonyl, etc.); Ar (lower) alkanoyl) such as phenyl acetyl, phenylpropionyl, etc .; cyclo (lower) alkyl (lower) alkanoyl, such as cyclohexylacetyl cyclopentyl acetyl, etc .; ar (lower) alkoxycarbonyl (e.g. Benzyloxycarbonyl, phenethyloxycarbonyl and the like).

The acyl and acyl moieties are halogen (e.g. chlorine, bromine or fluorine), hydroxy, cyano, nitro, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, etc.), lower alkyl (e.g. Have suitable substituents 1-3 such as methyl, ethyl, propyl, isopropyl, butyl, etc., lower alkenyl (e.g. vinyl, allyl, etc.), aryl (e.g. phenyl, tolyl, etc.), amino, protected amino, etc. Can be.

Examples of preferred acyls having such substituents are di (lower) alkyl carbamoyl (e.g. methylcarbamoyl, diethylcarbamoyl dipropylcarbamoyl, etc.), phenyl substituted with amino and low alkoxycarbonyl amino ( Low) alkanoyl.

Suitable examples of acyl of R ² are halo (lower) alkanols, more preferably dihalo (lower) alkanoyls (e.g. dichlororoacetyl dibromoacetyl, etc.).

Suitable acyls may have phenyl, tolyl, xylyl, mesylyl, cumenyl and the like and the above acyl groups are halogen (e.g. chlorine, bromine, fluorine, iodine), nitro lower alkoxy (e.g. methoxy, e. Methoxy, propoxy, butoxy, pendyloxy hexyloxy, etc.) Preferably, alkyl of 1-3 carbon atoms, the following protected carboxy, preferably lower aloxycarbonyl, more preferably 2-4 carbon atoms, etc. to be.

"Acyloxy (lower) alkyl". "Acylthio (lower) alkyl" "pyridylium (lower) alkyl" protected amino (lower) alkyl "" amino (lower) alkyl "" protected carboxy (lower) alkyl "" carboxy (lower) alkyl "" heterocycle Lower alkyl in "thio (lower) alkyl" and "ar (lower) alkyl" refers to 1-6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, tertiary pentyl, hexyl Linear or branched alkyl.

Suitable substituents in “lower alkyl substituted with appropriate substituents” include halogen (eg chlorine, bromine, fluorine or iodine); cyano; carboxy; protected carboxy; Lower alkyl thio (eg, methylthio, ethylthio, propylthio, butylthio), aryl (eg, phenyl, tolyl, xylyl, mesryl, cumenyl, etc.); Aryloxy (e.g., phenoxy, tolyloxy, mesyloxyl, etc.); acyl, lower alkoxy (lower) alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxymethoxy, propoxyoxy, Butoxyethoxy, pentyloxymethoxy, hexyloxymethoxy, hexyloxyethoxy and the like; aryl (substituted with the above-mentioned protected amino, preferably acylamino, more preferably lower alkoxycarbonyl amino or amino ( Lower) alkano alamino, lower alkoxy carbonylamino, cyclo (lower) alkyl substituted with amino, (lower) alkanoyl amino; Amino, etc., wherein the aryl groups described above may be substituted with amino (lower) alkyls (eg, aminomethyl, aminoethyl, aminopropyl, etc.) or protected amino (lower) alkyl.

Suitable number of substituents in the lower alkyl group may be 1-3.

Suitable protected carboxyl groups may have the following esterified carboxyl groups.

Lower alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) Wherein the lower alkyl moiety is preferably 1-4 carbon atoms; Lower alkenyl esters (eg, vinyl esters, aryl esters, etc.) lower alkynyl esters (eg, ethylyl esters, propynyl esters, etc.); Lower alkynyl esters (eg ethylyl ester, propynyl ester, etc.); Lower alkynyl esters (e.g. ethylyl esters, propynyl esters, etc.); mono (nadi or tri) -halo- (lower) alkyl esters (e.g. 2-urodoethyl esters, 2,2,2-trichloroethyl Esters, etc.): lower alkanoyl oxy (lower) alkyl esters (e.g. acetoxymethyl ester, propionyl oxymethyl ester, 2-acetoxypropyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxy Methyl ester, 1-acetoxyethyl ester, 2-propionyloxyethyl ester 1-isobutyryloxyethyl ester, lower alkanoyloxy (lower) alkyl ester (e.g. acetoxymethyl ester, propionyloxymethyl ester, 1 Acetoxypropyl ester, valeryloxymethyl ester, pivaloyl oxymethyl ester, hexanoyl oxymethyl ester, 1-acetoxyethyl ester, 2-propionyloxymethyl Esters, 1-isobutyryloxyethyl esters; lower alkyl sulfonyl (lower) alkyl esters (e.g., mesylmethyl ester, 2-mesylethyl ester, etc.); ar (lower) alkyl esters, for example, substituted with one or two suitable substituents Phenyl (lower) alkyl esters, such as benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester bis (methoxyphenyl) methyl ester, which may be , 4-methylsibenzyl ester, 4-hydroxy-3, 5-3 tert-butylbenzyl ester, etc.) Lower alkoxy carbonyloxy (lower) alkyl esters (e.g., methoxycarbonyl oxy) Methyl esters, ethoxycarbonyloxymethyl esters, ethoxycarbonyloxymethyl esters, and the like), heterocyclic esters, benzotetrahydrofuryl esters, which may be optionally substituted with oxo groups, More preferably phthalidyl esters, azolyloxy (lower) alkyl esters (e.g., benzoyloxymethyl ester, benzoyloxyethyl ester toluoyloxyethyl ester, etc.); aryl esters which may be substituted with one or two suitable substituents (Eg phenyl ester tolyl esters, tertiary butylphenyl esters, xylyl esters, mesityl esters, cumenyl esters, etc.) The protected carboxyl group is a lower alkoxy carbonyl having a 2-7 carbon atom, in particular a 2-5 carbon factor (eg Methoxycarbonyl, ethoxycarbonyl propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.), phenyl which may be substituted with natro (Lower) alkoxycarbonyl (e.g. 4-niprobenzyloxy carbonyl, benzyloxycarbonyl, 4-nitrofenalyl, etc.), lower alkanoyloxy (lower) alkoxycarbonyl (e.g. acetoxy methoxy carbonyl , Blood Roil oxy a methoxycarbonyl, hex alkanoyl oxy-methoxycarbonyl, 1-acetoxy-ethoxycarbonyl; 1-acetoxy propoxycarbonyl 1-isobutyryloxy ethoxycarbonyl, etc.), preferably lower alkoxycarbonyloxy (lower) alkoxycarbonyl which may be substituted with carbonyl, azido of 3-8 carbon atoms (Eg, ethoxy carbonyl. Oxyethoxycarbonyl oxyethoxycarbonyl ethoxycarbonyl oxypropoxy carbonyl, etc.) Preferably 5-7 carbon atoms; Phthalidioxy carbonyl; And arryl oxy (lower) alkoxy carbonyl (eg benzoyloxy methoxycarbonyl, benzoyloxy ethoxycarbonyl, etc.).

Suitable lower alkenyl are vinyl, aryl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl, preferably 2-4 carbon atoms.

Suitable lower alkynyl is alkynyl of 2-6 carbon atoms such as ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl, preferably alkynyl of 2-4 carbon atoms

Suitable cycloalkyls are cycloalkyls of 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohelyl, preferably cycloalkyl of 4-7 carbon atoms.

Suitable substituents for cycloalkyl may be referred to as those exemplified by substituents of lower alkyl, preferably carboxy or protected carboxy.

Suitable cyclo (lower) alkenyls are 3-6 carbon atoms such as cyclopentenyl, cyclohexenyl, preferably cyclo alkenyl of 5-6 carbon atoms.

Suitable 5-membered ring heterocyclic groups containing sulfur and oxygen may be saturated or unsaturated groups of, for example, dihydrofuryl, tetra hydrofuryl, thioranyl, substituted with 1-2 oxo groups.

Preferred examples of the target compound (1) are as follows.

R 1 is amino, acylamino (more preferably lower alkanoyl amino) or di (lower) alkyl amino (lower) alkylidene amino; R2 is hydrogen; aryl (preferably pentyl); Lower alkenyl; Lower alkenyl; Cyano (lower) alkyl, ar (lower alkyl, preferably phenyl (lower) alkyl or triphenyl (lower) alkyl: halo (lower) alkyl (preferably thiohalo (lower) alkyl; lower alkylthio (lower) ) Alkyl; esterified carboxy (lower) alkyl carbamoyl (lower) alkyl; lower alkoxy (lower) alkoxy (lower) alkyl; lower alkanesulfonyl (lower) alkyl; acylamino (lower) alkyl (preferably low Alkoxycarbonylamino (lower) alkyl; amino (lower) alkyl; carboxy (lower) alkyl; cycloalkyl, cyclo (lower) alkenyl; halogen, nitro, loweralkoxy, halo (lower) alkyl or loweralkoxycarbonyl Substituted aryl (preferably phenyl); Thioranyl substituted with its oxo group; Ar (lower) alkyl substituted with carboxy or lower alkoxy carbonyl; Cycloalkyl substituted with carboxy or lower alkoxy carbonyl; Amino (lower) Alkyl or lower alkoxy Carbonyl amino (lower) alkyl substituted ar (lower) alkyl (preferably phenyl (lower) alkyl); cycloalkyloxy carbonyl (lower) alkyl; ar (lower) alkoxy carbonyl (lower) alkyl; aminona lower Ar (lower) alkanoylamino (lower) alkyl, cyclo (lower) alkyl (lower) alkanoylamino (lower) alkyl substituted with alkoxycarbonylamino; tetrahydrofuryl substituted with oxo group; It will be described in detail below.

[Method 1]

Compound (VIII) can be produced by reacting Compound (V) or a salt thereof with a halogenating agent and Compound (VI).

Suitable halogenating agents used in this reaction are bromine, chlorine and the like.

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

The reaction is carried out in alcohol (eg methanol, ethanol) or other solvents that do not adversely affect the reaction. The reaction temperature is not critical and usually proceeds at cooling or room temperature.

In the present reaction, R 6 of compound (V) is converted to a different carboxy protecting group depending on the reaction conditions and the type of protecting group and falls within the scope of the present invention.

[Method 2]

Compound (VIII) can be manufactured by introducing and reacting an amino protecting group into compound (VIII).

The method is carried out in a conventional manner, in the case where the amino protecting group introduced into the yamino group is acyl, water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, The reaction can be carried out in N-dimethylformamide, pyridine or an organic solvent suitable for the reaction. Among these solvents, the hydrophilic solvent can be mixed with water. When an introducing agent is used in the form of the free acid or its salt, the reaction is carried out in the presence of the following conventional condensing agents.

N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethyl carbodiimide, N, N-diethylcarbodiimide, N, N-diisopropyl carbodiimide, N- Ethyl-N '-(3-dimethylaminopropyl) carbodiimide, N, N-carbonylbis (2-methylimidazole), pentamethylene-ketene-N-cyclohexylimine, difinylkerene-N-cyclo Hexylimine, ethoxyacetylene, ethylpolyphosphate, isopropyl polyphosphate, diethyl tospochloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxal chloride, ryltriphenyl phosph Fin, N-ethyl-7-hydroxybenzisoxazolium fluorochelate, N-ethyl-5-phenylisoxazolium-3'-sulfonate, 1- (P-chlorobenzenesulfonyloxy) -6-chloro- 1H-benzotriazole, Vilsmeier reagent, eg thionyl chloride or half of phosgene with dimethylformamide The as-produced (chloro-methylene) ammonium chloride, by the reaction of dimethylformamide with phosphorus oxy chloride generates compounds.

The reaction includes alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal acetates, tri (lower) alkylamines, pyridine, N- (lower) alkylmorpholines, N, N-di (lower) alkylbenzylamines, It can be carried out in the presence of an inorganic or organic base such as N, N-di (lower) alkylaniline.

It can also be used as a solvent when the base or condensing agent is a liquid. The reaction temperature is not critical and is usually performed at cooling or acid temperature.

[Method 3]

Compound (X) can be manufactured by making compound (V) react with compound (V).

The process proceeds in the presence of bases such as alkali metal hydrates (eg sodium, hydrate, calcium hydrate), alkaline earth metal hydrates (calcium hydrate) and is carried out in the presence of dimethyl formamide or a solvent that is harmless to the reaction. The reaction temperature is not critical and proceeds under cooling, room temperature or temperature.

[Method 4]

Compound (XI) can be prepared by reacting compound (X) with an acid or an acid anhydride such as acetic acid and acetic anhydride.

The reaction method includes alkali metals and halogenides (e.g. sodium, perchlorate, sodium periodate, potassium perchlorate), alkaline earth metal perchlorates (e.g. magnesium perchlorate, calcium perchlorate), organic acids (e.g. formic acid) or inorganic acids (e.g. In the presence of an acid such as hydrochloric acid). The reaction temperature is not critical and is usually carried out under warming.

[Methods (5) and (7)]

Methods (5) and (7) can be carried out by conventional methods such as hydrolysis. Hydrolysis is carried out in the presence of the following bases or acids.

Suitable bases include alkali metals (e.g. sodium, potassium), alkaline earth metals (e.g. magnesium, calcium), hydroxides, carbonates or bicarbonates thereof, trialkyl amines (e.g. trimethylamine, triethylamine), picoline, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] Inorganic or organic bases such as undecene-7 and the like.

Suitable acids are organic acids (eg formic acid, acetic acid, propionic acid, trifluoroacetic acid) and inorganic acids (eg hydrochloric acid, hydrochloric acid, sulfuric acid).

The reaction is usually carried out in water, alcohols (eg methanol, ethanol), mixtures thereof or in solvents that do not have a deleterious effect on the reaction. Liquid bases and acids are also used as solvents. The reaction temperature is not critical and is usually carried out under cooling or warming.

In method (5), one having R ^1a (XI _a ) or one having amino instead of R ^lb (XI _b ) can be prepared and reacted with compound (XII) or a salt thereof as illustrated in method (6). Compounds (III _a ) or (II _b ) can be prepared respectively.

[Method 6]

Suitable salts of compound (XII) are salts of conventional acids such as inorganic acid salts such as hydrochloric acid and organic acid salts such as P-toluenesulfonate. When a salt of compound (XII) is used in the process, the reaction is usually carried out in the presence of a base such as an alkali metal hydroxide (eg sodium hydroxide, potassium hydroxide). The reaction is usually carried out in water, alcohols (e.g. methanol, ethanol) or other solvents which do not have a detrimental effect on the reaction. The temperature of the reaction is not critical and is usually carried out at room temperature.

In the above-mentioned reactions and in the treatment of the reactions of the present invention, the designated tautomeric isomers can be converted to other forms of tautomeric isomers, and such cases are also within the scope of the present invention.

The following examples are intended to illustrate the invention.

Example 1

(1) A mixture of N-hydroxyphthalimide (8.15 g), trimethylamine (5.05 g), NN-dimethylformamide (60 ml) and 1-bromo-2-cyclohexene (8.05 g) at room temperature Stir for 3.5 hours.

Water (300 ml) was poured into the reaction mixture, and the precipitated crystals were collected by filtration, washed successively with water and n-hexane, and dried to form N- (2-cyclohexen-1-yloxy) phthalimide (9.8 g) is obtained. Melting point 87 ℃

IR (New sol): 1770,1720,1610cm ^-1

NMR (DMSO-d6, δ): 1.50 = 2.17 (6H, m), 4.60-4.77 (1H, m)

5.73-6.27 (2H, m), 7.90 (4H, S)

(2) A mixture of N-hydroxyphthalimide (52.16 g), bromocycloheptane (62.41 g) dimethylsulfoxide (385 ml) and potassium carbonate (44.16 g) is stirred at 70 ° C. for 74 hours.

The reaction mixture is cooled under ice cooling and ice-water (1.5 L) is added. The precipitate is collected by filtration, washed with ice-water (twice) and dried to give N- (cycloheptyloxy) phthalimide (63 g).

Melting point 110-112 ℃

NMR (DMSO-d6, δ): 1.57 (8H, m), 1.90 (4H, m), 4.20 (1H, m), 7.93 (4H, S)

(3) A mixture of N-hydroxyphthalimide (58.20 g), 1-chloro-2-cyclopintene (36.9 g) and trimethylamine (53.9 g) dissolved in acetonitrile (370 ml) was prepared. Treatment was carried out in the same manner as in 1) and 3- (2) to obtain N- (2-cyclopenten-1-yloxy) phthalimide (56.5 g).

IR (New sol): 1780,1730.1610cm ^-1

NMR (DMSO-d6, δ): 7.92 (4H, s), 6.28 (1H, m), 6.00 (1H, m), 5.42 (1H, m), 2.9-1.98 (4H, m)

Example 2

A mixture of N- (cycloheptyloxy) phthalimide (2.59 g) and hydrazine hydride (0.45 g) dissolved in ethanol (12 ml) was refluxed for 5 minutes. The reaction mixture is cooled and filtered to give a filtrate comprising cycloheptyloxy amine.

[Example 3]

(1) A mixture of N- (2-cyclopenten-1-yloxy) phthalimide (22.9 g) and hydrazine hydrate (4.75 g) dissolved in ethanol (115 ml) was refluxed for 5 minutes. Sodium 2- (5-formamido-1,2,4-thiadiazol-3-yl) in which the reaction mixture was filtered (2-cyclopenten-1-yl) oxyamine and the filtrate containing water dissolved in water. ) To a solution of glyoxylate (22.4 g). The mixture is adjusted to pH 2 with 10% hydrochloric acid, stirred for 2 hours and concentrated. The concentrate was adjusted to pH 1 with 10% hydrochloric acid and the precipitate collected by filtration and dried to give 2- (2-cyclopenten-1-yl) oxyimino-2- (5-formamido-1,2,4-thia Diazol-3-yl) acetic acid (syn isomer) (20.0 g) is obtained.

Melting Point 150 ° C (decomposition)

IR (New sol): 3400,3100,1720,1690,1540cm ^-1

NMR (DMSO-d6, δ): 1.80-2.50 (4H, m), 5.30-5.50 (1H, m), 5.83-6.30 (2H, m), 8.90 (1H, S)

(2) A mixture of N- (2-cyclohexen-1-yloxy) -phthalimide (7.2 g) and hydrazine hydrate (1.5 g) dissolved in ethanol (40inf) was refluxed for 5 minutes. The reaction mixture is cooled and filtered to afford a filtrate comprising (2-cyclohexen-1-yl) -oxyamine (filtrate A).

On the other hand, S-methyl-3- (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (6.93 g) dissolved in IN-aqueous solution of sodium hydroxide (90 ml) The mixture of is stirred at room temperature for 30 minutes. The reaction mixture comprising sodium 2- (5-formamido-1,2,4) thiadiazol-3-yl) glyoxylate was adjusted to pH7 with 10% hydrochloric acid and to which filtrate A was added followed by pH Is adjusted to pH 3 with 10% hydrochloric acid. The mixture is stirred at room temperature for 3 hours to concentrate the reaction mixture, and ethyl acetate is added to the concentrate.

The mixture was adjusted to pHl with 10% hydrochloric acid and the precipitate collected by filtration to collect 2- (2-cycloxen-1-yl) oxyimino-2- (5-formamido-1,2,4-thiadiazole- 3-yl) acetic acid (syn isomer) (2.5 g) is obtained.

On the other hand, the ethyl acetate layer is separated from the filtrate and evaporated. The residue is treated with diethyl ether to give the same title compound (1.5 g).

Total yield: 4.0g Melting point 190 ~ 192 ℃ (decomposition)

IR (New sol): 3500,3400,3200,2500,1690,1350,1540cm ^-1

NMR (DMSO-d6, δ): 1.5-2.3 (6H, m), 4.73-5.0 (1H, m), 5.76-6.23 (2H, m), 8.97 (1H, s), 13.60 (1H. Broads)

(3) S-methyl-2- (5-formamido-1,2,4-thiadiazol-3-yl) thio in a solution of sodium hydroxide (11.2 g), dissolved in water (140 ml) at 10 ° C. Glyoxylate (27 g) is added and the mixture is stirred at 20 ° C. for 30 minutes.

The reaction mixture comprising sodium 2- (5-formamido-1,2,4-thiadiazol-3-yl) glyoxylate was cooled, adjusted to pH 7 with 10% hydrochloric acid and dissolved in ethanol (150 ml). A solution of cyclopentyloxyamine (15.3 g) is added.

The mixture is adjusted to pH 3 with 10% hydrochloric acid and stirred for 1.5 hours. The reaction mixture is adjusted to pH 7 with an aqueous solution of sodium bicarbonate and then evaporated to remove ethanol. The residue is washed with ethyl acetate and ethyl acetate is added to the aqueous layer and the mixture is adjusted to pH 1 with 10% hydrochloric acid.

The precipitate is collected by filtration to give 2-cyclopentyloxy imino-2- (5-form amido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (3.99 g). The filtrate is extracted with ethyl acetate and the extract is dried over magnesium sulfate and concentrated. The precipitate is collected by filtration and washed with diethyl ether to give the same title compound (8.1 g).

Total yield: 12.09g Melting point 180-185 ℃ (decomposition)

IR (New sol): 3130, 3040, 2680, 2610, 2520, 1720, 1690, 1660, 1600, 1550cm ^-1

NMR (DMSO-d6, δ): 1.33-2.10 (8H, m), 4.67-5.10 (1H, m) 8.88 (1H, S), 13.50 (1H, S)

(4) The following compound is obtained according to the same method as in Example 3 (1) to 3 (3). 2-cycloheptyloxyamino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

NMR (DMSO-d ₆ , δ): 1.50 (8H, m), 1.80 (4H, m), 4.37 (1H, m), 8.81 (1H, s), 9.88 (1H, s)

Example 4

2- (2-cyclopenten-l-yl) oxyimino-2- (5-formamido-l, 2,4-thiadiazol-3-yl) acetic acid (syn isomer) (20.0 g) and sodium hydroxide The 1N aqueous solution (200 ml) is stirred at 50 to 55 ° C. for 1 hour. The reaction mixture is cooled, adjusted to pH 7 with 10% hydrochloric acid, and ethyl acetate is added thereto.

The mixture is adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated.

The residue was triturated with diisopropyl ether to give 2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer Get)

Melting Point 150 ℃ (Decomposition)

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

NMR (DMSO-d6, δ): 1.80-2.50 (4H, m), 5.30-5.50 (1H, m) 5.83-6.30 (2H, m), 8.20 (2H, s)

Example 5

The following compounds are obtained according to the same method as in Example 4. (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 (New sol): 3400, 3300, 3260, 1720, 1620, 1600, 1520cm ^-1

NMR (DMSO-d6, δ): 1.53-2.11 (6H, m), 4.53-4.82 (1H, m), 5.57-6.13 (2H, m), 8.18 (2H, m)

(2) 2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting point 160-165 ° C (decomposition)

IR (new sol): 3470, 3290, 3200, 2400, 1715, 1615, 1600, 1520cm ^-1

NMR (DMSO-d6, δ): 1.17-2.10 (8H, m), 4.60 = 4.97 (1H, m), 8.22 (2H, s)

(3) 2-cyclopeptyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting point 116-119 ° C (decomposition)

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

Example 6

(1) To a mixture of tetrabutylammonium bromide (3.22 g) dissolved in methylene chloride (200 ml), ethylchloroformate (108.5 g) is added at -20 ° C.

A solution of sodium cyanate (49 g) dissolved in water (200 ml) was added to the mixture at -10 to -13 占 폚 over 15 minutes and the resulting mixture was stirred at -13 占 폚 for 1 minute.

The organic layer is separated from the reaction mixture, dried over magnesium sulfate and raised to room temperature.

The methylene chloride layer is decanted off and the refractory is washed with methylene chloride. The mixed methylene chloride layer (370 ml) is distilled at atmospheric pressure to obtain a solution containing methyl cyanoformate (335 ml). Boiling Point 42-117 ℃

(2) A solution of hydrochloric acid (32.5 g) dissolved in ethanol (34.5 g) was obtained in Example 6 (1) (335m1) containing ethylcyanoformate cooled at −10 ° C. and precooled to −10 ° C. To the solution.

The resulting solution was stirred at −5 to 5 ° C. for 6 hours, cooled to −10 ° C., and methylene chloride (400 ml) was added thereto.

To the mixture was added dropwise a solution of triethylamine (85.8 g) dissolved in methylene chloride (80 ml) and water (200 ml) at -5 to 0 ° C. The methylene chloride layer is separated, washed with water (200 ml x 2), dried over magnesium sulfate and evaporated to give a product (112 g) comprising 78.8% ethyl 2-amino-2-ethoxyacetate.

The product is purified by distillation (boiling point 80 to 88 ° C./40 mm Hg) to give pure product.

(3) A mixture of ethyl 2-imino-2-ethoxyacetate (60 g) (78.8% purity) and ammonium chloride (17.4 g) dissolved in methanol (180 ml) was stirred at room temperature for 3 hours and then -15 to -10. Cool to ° C.

The resulting mixture containing 1-methoxycarbonylformamidine hydrochloric acid bromine (51.2 g) for 10 minutes. Potassium thiocyanate (31.0 g) in which triethylamine (71.1 g) was dissolved in methanol (150 ml) for 30 minutes was added dropwise over 30 minutes.

The resulting mixture is stirred at −10 to −5 ° C. for 15 minutes and further at 1.5 ° C. for 5 hours.

The precipitate is collected by filtration, washed with methanol and ice water (200 ml) is added. The mixture is stirred and the precipitate is collected by filtration, washed with ice water and dried to afford 5-amino-1,2,4-thiadiazole-3-carboxylate (32.5 g).

(4) To a solution of ethyl cyanoformate (25.0 g) dissolved in methylene chloride (55 ml) was added 43.5% ethanol solution of hydrochloric acid (16.8 g) and stirred at 3 ° C.

The mixture is stirred for 5 h at 3-5 ° C. and left overnight at −5 to −3 ° C.

Methylene chloride (120 ml) is added to the resulting mixture at 6 캜 or lower, and a solution of triethylamine dissolved in methylene chloride (20 ml) is added at 6 캜 or lower for 30 minutes. The mixture is stirred for 40 minutes and water (40 ml) is added below 6 ° C. The resulting mixture was stirred for 3 minutes, the methyl chloride layer was separated, dried over magnesium sulfate and evaporated. After addition of diisopropyl ether (40 ml) to the residue, the insoluble material is separated by filtration and washed with diisopropyl ether (10 ml). The filtrate and washings are mixed and evaporated to afford ethyl yellowimino-2-ethoxyacetate (26.2 g) as a pale yellow oil.

The mixture of the obtained oil (26.2 g) and ammonium chloride (5.42 g) dissolved in methanol (90 ml) was stirred at room temperature for 2 hours, and diisopropylate (450 ml) was added thereto.

The mixture is stirred for 30 minutes under ice cooling.

The precipitate is collected by filtration to give 1-methoxycarbonylform amidine hydrochloric acid (13.8 g) as a white powder.

Melting Point 150-155 ℃ (Decomposition)

IR (New sol): 3350-3050, 1780, 1710, 1695, 1290, 1270, 1070, 980, 800cm ^-1

N.M.R (d6-DMSO, δ): 3.97 (3H, s), 9.8 (4H, broad s)

(5) Bromine (8.89) was added dropwise over 5 minutes at -5 to 0 DEG C in a solution of 1-ethoxycarbonyl fullamidine hydrochloric acid (7.6 g) dissolved in methanol (55 ml).

Triethylamine (11.1 g) was added to the mixture for 10 minutes, and a solution of potassium cyanide sulfate (5.3 g) dissolved in methanol (30 ml) was added at -5 to 0 DEG C over 20 minutes. The mixture is stirred at 0-5 [deg.] C. for 1.5 h and the precipitate is washed by filtration with methanol (11 ml), dried and water (15.5 ml) is added thereto.

The mixture was stirred for 30 minutes and the precipitate was collected by filtration, washed with water (5 ml × 3) and dried to give methyl 5-amino-1,2,4-thiadiazole-3-carboxylate (6.3 g) as a white powder. Get)

(6) A mixture of ethyl 2-imino-3-ethoxyacetate (36.2 g) and ammonium bromide (21.2 g) dissolved in methanol (180 ml) was stirred at room temperature for 4 hours, followed by diisopropyl ether (400 ml). ) Is added with stirring. The mixture is left for 30 minutes and the precipitate is removed by filtration. Diisopropyl ether (200 ml) is added to the filtrate and the mixture is left for 10 minutes. The precipitate was collected by filtration to give a white powder of methoxycarbonylformamide hydrobromide (16.1 g) as a white powder, and the filtrate was concentrated to 150 ml. Diisopropyl ether (200 ml) is added to the concentrate and the mixture is left for 30 minutes.

The precipitate is collected by filtration to give the same compound (11.6 g) as a white powder. Total yield: 27.7g

IR (New sol): 3350-3150, 1780, 1750, 1690, 1290, 1270, 1060, 980, 850, 800, 730cm ^-1

N.M.R (d6-DMSO, δ): 3.91 (3H, 5), 11.0 (4H, broad s)

(7) A mixture of ethyl 2-imino-2-ethoxyacetate (18.1 g) and ammonium chloride (5.8 g) dissolved in ethanol (90 ml) was stirred at room temperature for 6 hours, and the insoluble substance was separated by filtration. And wash with ethanol. The filtrate and washings are mixed, evaporated and acetone (50 ml) is added to the residual oil. The precipitate is collected by filtration and washed with acetone (110m1 × 2) to give 1-methoxycarbonylformamide hydrochloric acid (1.2 g) as a white powder.

The filtrate and washings are mixed and evaporated, the residue is decomposed into acetone (30 ml), collected by filtration, washed successively with acetone, methylene chloride and diisopropyl ether to give the same compound (7.3 g) as a white powder. .

Total yield: 8.5g

IR (New sol) 3400-3100, 1770, 1730-1680, 1650, 1300, 1260, 1120, 1010, 860, 760cm ^-1

Example 7

Method for preparing methyl 5-amino-1,2,4-thiadiazole-3-carboxylate

To a solution of 1-methoxycarbonylformamide bromic acid (16.6 g) dissolved in methanol anhydride (84 ml) is added a solution of sodium (1.92 g) dissolved in methanol anhydride (42 ml) at 0 ° C.

To the mixture was added a solution of sodium (1.93 g) dissolved in bromine (12.8 g) and anhydrous methanol (42 ml) in turn at 0 ° C, and then potassium cyanide sulfate (8.1 g) dissolved in anhydrous methanol (100 m1) in suspension. Add. The reaction mixture is stirred at 0 ° C. for 1 hour and further stirred at room temperature for 6 hours.

The mixture is filtered through cellulose powder and the filtrate is evaporated to dryness.

The residue was dissolved in a mixture of ethyl acetate and water, and then the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent is evaporated and the residue is treated with diethyl ether to give the title compound (9.0 g).

Melting point 202-205 ℃

IR (New sol): 3400, 3250, 3100, 1710, 1610, 1540cm ^-1

N.M.R. (d6-DMSO) δ: 3.85 (3H, s), 8.25 (2H, s)

Example 8

Method for preparing methyl 5-formamido-1,2,4-thiadiazole-3-carboxylate

Methyl 5-amino-1,2,4-thiadiazole-3-carboxylate (6.2 g) is added to a mixture of formic acid (33 g) and acetyl anhydride (22 g), and then the mixture is stirred at room temperature for 2 hours.

The reaction mixture is concentrated under reduced pressure and the residue is treated with a mixture of dimethyl ether and n-hexane to give the title compound (7.2 g).

Melting Point 210-215 ℃

IR (new sol): 3100, 1720, 1680cm ^-1

N.M.R. (d6-DMSO, δ): 3.90 (3H, s), 8.85 (1H's)

Example 9

Method for preparing 5-formamido-3- (2-methylthio-2-methylsulfurylacetyl) -1,2,4-thiadiazole

Methyl methyl thiomethyl sulfoxide (6.1 g) dissolved in methyl 5-formamido-1,2,4-thiadiazole-3-carboxylate (9.2 g) and N, N-dimethylformamido (100 ml) The mixture is stirred at room temperature for 1 hour with ice-cooling 50% sodium hydride (7.1 g) and further at 40 ° C. for 1 hour.

After cooling to room temperature, methylene chloride (200 ml) is added to the reaction mixture and the resulting precipitate is vertical by filtration and washed with methylene chloride. The precipitate is added to a stirred mixture of hydrochloric acid (14.7 ml), ice-water (200 m and methylene chloride (200 ml)), the insolubles are filtered off and the ethylene chloride layer is separated from the filtrate The solution is dried over anhydrous magnesium sulfate , Evaporated and the residue was treated with diethyl ether to give the title compound (4.5 g).

Melting point 130-132 ℃

IR (new sol): 3100, 1680, 1670cm ^-1

NMR (d6-DMSO) δ:

Example 10

Process for preparing S-methyl (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate

Natrified iodide dissolved in 5-formamido-3- (2-methylthio-2-methylsulfonylacetyl) -1,2,4-thiadiazole (0.85 g) and glacial acetic acid (10 ml) (0.2 g) ) Mixture is stirred at 70 ° C. for 45 minutes. The reaction mixture is evaporated and the residue is dissolved in a mixture of ethyl acetate and water. The mixture is adjusted to pH 7 with aqueous sodium bicarbonate solution and treated with an aqueous solution of sodium thiosulfate.

The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is treated with a mixture of diethyl ether and petroleum ether to give the title compound (280 ml).

Melting point 18-187 ℃

IR (new sol): 3100, 1680, 1660cm ^-1

N.M.R. (d6-DMSO) δ: 2.55 (3H, s), 8.95 (1H, s)

Example 11

Sodium iodide (2.0 g) dissolved in 5-formamide-3- (2-methylthio-2-methylsulfinylacetyl) -1,2,4-thiadiazole (10 g) and glacial acetic acid (50 ml) The mixture is stirred at 70 ° C. for 50 minutes. The solvent is evaporated and the residue is washed with n-hexane. To the residue is added 1 N aqueous sodium hydroxide (160 ml) solution and the mixture is stirred at room temperature for 1 hour.

0-allyl hydroxylamine hydrochloric acid (4.31 g) is added to the reaction mixture, the solution is adjusted to pH 3-4 with 10% hydrochloric acid, and then stirred at room temperature for 1 hour.

After filtering off the insoluble substance, the filtrate was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated to dryness. The residue was treated with a mixture of diethyl ether and diisopropyl ether to give 2-allyloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer). (5.6 g) is obtained.

Melting Point 169 ℃ -172 ℃ (Decomposition)

IR (new sol) 3130, 2500, 1720, 1690, 1590, 1550cm ^-1

N.M.R. (d6-DMSO) δ: 4.79 (2H, d, J = 6 Hz), 5.1-5.6 (2H, m), 5.8-6.4 (1H, m), 8.88 (1H, s)

Example 12

The following compound is calculated in a similar manner to Example 11.

(1) B-benzyloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 90 ℃ -95 ℃ (Decomposition)

IR (New sol): 1720, 1680, 1590, 1550,1530cm ^-1

N.M.R. (d6-DMSO) δ: 5.28 (2H, s), 7.37 (5H, s), 8.83 (1H, s),

(2) 2- (2-propynyloxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 150-155 ℃ (Decomposition)

IR (new sol): 3570, 3360, 3260, 3120, 1720, 1670, 1550, 1530cm ^-1

N.M.R. (d6-DMSO) δ: 3.55 (1H, t, J = 2 Hz), 4.88 (2H, d, J = 2 Hz), 8.85 (1H, s)

(3) 2- (2-phenoxyethoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 147-150 ℃ (Decomposition)

IR (new sol) 3200, 1740, 1720, 1640, 1590, 1530 cm ^-1

N.M.R. (d6-DMSO) δ: 4.0-4.7 (4H, m), 6.7-7.5 (5H, m), 8.83 (1H, s)

(4) 2-hydroxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 240-241 ℃ (Decomposition)

IR (new sol): 3350, 3460, 1665, 1635, 1560cm ^-1

Example 13

A solution of s-methyl (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (6.64 g) dissolved in 1N aqueous solution of sodium hydroxide (80 ml) was diluted with 10% hydrochloric acid. Adjust the pH to 8.5 and stir at room temperature for 30 minutes.

On the other hand, a mixture of N- (2,2,2-trifluoroethoxy) phthalimide (8.78 g) and hydrazine hydrate (1.7 g) dissolved in ethanol (40 ml) was refluxed for 5 minutes, followed by ice cooling. The resulting precipitate is filtered off and washed with ethanol. The filtrate and washings are mixed and a mixed solution comprising 0- (2,2,2-trifluoroethyl) hydroxylamine is added to the aqueous solution. The mixture is adjusted to pH 3-4 with 10% hydrochloric acid and stirred at room temperature for 1.5 hours. The solution is neutralized with aqueous sodium bicarbonate solution and the volume is concentrated in half under vacuum and washed with ethyl acetate. The aqueous solution is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated to dryness and the residue treated with diisopropyl ether to give 2- (2,2,2-trifluoroethoxyimino) -2 (5-formamido-1,2.4 -Thiadiazol-3-yl) acetic acid (syn isomer) (2.46 g) is obtained.

Melting Point 180-185 ℃ (Decomposition)

N.M.R. (d6-DMSO) δ: 4.80 and 5.07 (2H, ABq, J = 9 Hz), 8.85 (1H, s)

Example 14

The following compounds are calculated in the same manner as in Example 13.

(1) 2-Medylthiomethoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 146-148 ℃ (Decomposition)

IR (new sol): 3300, 2600, 2550, 1730, 1705, 1680, 1600, 1530cm ^-1

N.M.R. (d6-DMSO) δ 7: 2.23 (3H, s), 5.40 (2H, s), 8.87 (1H, s)

(2) 2- (2-methylthio ethoxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

IR (new sol): 3230, 1720, 1690, 1590, 1520cm ^-1

N.M.R. (d6-DMSO) δ: 2.17 (3H, s), 2.82 (2H, t, J = 7 Hz), 4.42 (2H, t, J = 7 Hz), 8.87 (1H, s)

(3) 2-phenoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 145-147 ℃ (Decomposition)

IR (new sol): 3130,1720, 1690, 1585, 1550cm ^-1

N.M.R. (d6-DMSO) δ: 7.0-7.6 (5H, m), 8.88 (1H, s)

(4) 2- [2- (2-hexyloxyethoxy) ethoxyimino] -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

IR (CHCl3): 3420, 3180, 1740, 1700, 1600, 1530, 1460 cm ^-1

N.M.R. (d6-DMSO) δ: 0.87 (3H, t, J = 5 Hz), 0.87-1.73 (8H, m), 3.20-3.90 (8H, m), 4.23-4.53 (2H, m), 8.84 (1H, s ), 13.55 (1H, broad s)

(5) 2-trityloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 188-190 ℃ (Decomposition)

IR (new sol): 3150, 1620, 1500, 1540cm ^-1

N.M.R. (d6-DMSO) δ: 7.00 (15H, s), 8.92 (1H, s)

Example 15

A mixture of S-methyl (5-formamido-1,2,4-thiadiazone-3-yl) thioglyoxylate (6 g) and sodium hydroxide (4.2 g) aqueous solution (50 ml) was heated to 50 ° C to 55 ° C. Stir for 1 h at. The mixture is cooled to room temperature and adjusted to pH 7 with 10% hydrochloric acid. On the other hand, a mixture of hydrazine hydrate (2.08 g) dissolved in N- (ethoxycarbonylphenoxy) phthalimide (12.9 g) and ethanol (60 ml) is refluxed for 5 minutes and ice-cooled. The resulting precipitate is filtered off and washed with ethanol. The filtrate and washes are mixed and a mixed solution comprising 0- (ethoxycarbonyl) -phenylhydroxylamine is added to the aqueous solution. The mixture is adjusted to pH 3-4 with 10% hydrochloric acid and stirred for 1,5 hours at room temperature.

The solution is neutralized with aqueous sodium bicarbonate solution and the volume is concentrated in half under vacuum and washed with ethyl acetate. The aqueous solution is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated to dryness and the residue was treated with diisopropylether to give 2-ethoxycarbonylphenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl). Acetic acid (syn isomer) (1.8 g) is obtained.

Melting Point 135-140 ℃ (Decomposition)

IR (New sol): 3500, 3350, 3210, 2670, 2550, 1740, 1610, 1540cm ^-1

N.M.R. (d6-DMSO) δ: 1.24 (3H, f.J = 7 Hz), 4.14 (2H, q, J = 7 Hz), 4.89 (2H, s), 8.15 (2H, broad s)

Example 16

The following compounds were obtained according to the same method as in Example 15.

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

Melting Point 130-135 ℃ (Decomposition)

IR (New sol): 3350,3150,1730,1630,1540cm ^-1

N.M.R. (d6-DMSO) δ: 5.17 (2H, s), 8.28 (2H, broad s)

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

Melting Point 165-168 ℃ (Decomposition)

IR (New sol): 3450,3350,3240,1750,1730,1630,1530cm ^-1

N.M.R. (d6-DMSO) δ: 1.18 (3H, t, J = 7 Hz), 1.50 (6H, s), 4.15 (2H, q, J = 7 Hz), 8.23 (2H, broad s)

(3) 2- (N, N-diethylcarbamoylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 150-155 ℃ (decomposition)

IR (New sol): 3400,3150,1745,1635,1610,1595.1535cm ^-1

N.M.R. (d6-DMSO) δ: 1.03 (3H, t, J = 7 Hz), 1.10 (3H, t, J = 7 Hz), 3.28 (4H, q, J = 7 Hz), 4.90 (2H, s), 8.23 (2H , broad s)

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

IR (New sol): 3450, 3400, 3270, 2600, 2460, 1735, 1640, 1620, 1530cm ^-1

N.M.R. (d6-DMSO) δ: 3.00 (3H, s), 5.38 (2H, s), 8.22 (2H, broad s)

Example 17

The following compounds are obtained following the method analogous to Example 4.

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

Melting Point 93-95 ℃ (Decomposition)

IR (New sol): 3430,3100,1710,1615,1525cm ^-1

N.M.R. (d6-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)

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

Melting Point 158-l60 ℃ (Decomposition)

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

N.M.R. (d6-DMSO) δ: 5.22 (2H, s), 7.33 (5H, s), 8.17 (2H, broad s)

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

Melting Point 155-157 ℃ (Decomposition)

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

N.M.R. (d6-DMSO) δ: 3.53 (1H, t, J = 2 Hz), 4.87 (2H, d, J = 2 Hz), 8.23 (2H, broad s)

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

Melting Point 150-153 ℃ (Decomposition)

IR (new sol): 3470, 3300, ε150, 2550, 1750, 1620, 1600, 1540, 1500cm ^-1

N.M.R. (d6-DMSO) δ: 4.0-4.7 (4H, m), 6.7-7.5 (5H, m), 8.20 (2H, broad s)

(5) 2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) Melting point 140-143 ℃ (decomposition)

IR (new sol): 3450, 3350, 3260, 1745, 1670, 1645, 1615, 151 ^-1

N.M.R. (d6-DMSO) δ: 4.72 and 4.95 (2H, ABq, J = 9 Hz), 8.25 (2H, broad s)

(6) 2-methylthiomethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 140-143 ℃ (Decomposition)

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

N.M.R. (d6-DMSO) δ: 2.22 (3H, s), 5.3 (2H, s), 8.20 (2H, broad s)

(7) 2- (2-methylthiomethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 140-143 ℃ (Decomposition)

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

N.M.R. (d6-DMSO) δ: 2.08 (3H, s), 2.72 (2H, tJ = 7 Hz), 4.28 (2H, t, J = 7 Hz), 8.17 (2H, broad, s)

(8) 2-phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 145-147 ℃ (Decomposition)

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

N.M.R. (d6-DMSO) δ: .7.0-7.5 (5H, m), 8.30 (2H, broad s)

(9) 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, 1460 cm ^-1

N.M.R. (d6-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)

(10) 2-trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 173-174 ° C (Decomposition)

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

N.M.R. (d6-DMSO) δ: 7.35 (1H, s), 8.22 (2H, s)

(11) 2-trityl oxoimino-2- (5-amino-1,2,4-piadiazol-3-yl) acetic acid (syn isomer)

Melting Point 170-171 ℃

IR (New sol): 3330,3150,1680, 1635,1520cm ^-1

N.M.R. (d6-DMSO) δ: 7.33 (15H, s), 8.13 (2H, s),

Example 18

Potassium iodide (20.0 g) is added to a stirred solution of iodine (7.7 g) dissolved in concentrated sulfuric acid (70 ml) at room temperature and the mixture is stirred at 35-40 ° C. for 1.5 hours. Acetic anhydride (30 ml) was added thereto at 10 ° C. for 0.5 hours, and then 1,2-dichlorobenzene (44.69 g) was added at 10 ° C. for 0.5 hours. The mixture is stirred at the same temperature for 1 hour and then at room temperature for 19 hours.

The reaction mixture is poured into ice-water (500 ml) and washed with diethyl ether. Salt (8.9 g) aqueous solution (50 ml) is added to the aqueous layer and the precipitate is collected by filtration and washed with ice water to give 3,4,3 ', 4'-tetrachlorodiphenyl iodonium chloride (58 g).

Melting Point 183-186 ° C (Decomposition)

IR (New sol) 1555,1490,1250,1210,1170,1125,1030cm ^-1

Example 19

The following compounds are obtained following methods analogous to Example 18.

(1) 3,3'-di (trifluoromethyl) diphenyl iodonium chloride

I.R. (New sol): 3600-3200, 1600, 1420, 1320, 1310, 1190, 1170, 1120, 1095, 1085, 800, 700, 685cm-1

(2) 3,3'-dicarboxydiphenyl iodonium bromide

IR (New sol): 3400,1700,1290,1250,1210,1170,1050,75Ccm ^-1

(3) 3,3'-di (ethoxycarbonyl) diphenyl iodonium bromide

Melting Point 154-157 ℃

IR (New sol): 1730,1295,1280,1255,1110,1020,750cm ^-1

Example 20

The following compounds are obtained following methods analogous to Examples 1- (1) and 1- (2).

(1) N- (2-phthalimidopropoxy) phthalimide

Melting point 168-170 ℃

IR (New sol): 1790,1770,1730,1710,1390,1060,725,705cm ^-1

(2) N- (1-cyclohexyloxycarbonylethoxy) phthalimide

Melting point 50-54 ℃

N.M.R. (d6-DMSO,) δ: 1.51 (3H, d, J = 7 Hz), 0.9-2.1 (10H, m), 4.7 (1H, m), 4.82 (19, q, J = 7 Hz), 7.87 (4H, s)

(3) N- (α-t-butoxycarbonylbenzyloxy) phthalimide

(4) N- (1-t-butoxycarbonyl-2-methylpropoxy) phthalimide

Melting point 84-87 ℃

IR (New sol): 1790,1730,1360.1160,1140,1000,800,780,700cm ^-1

(5) N- (1-t-butoxycarbonylpropoxy) phthalimide

Melting Point 49-52 ℃

N.M.R. (d6-DMSO, δ): 1.02 (3H, t, J = 7 Hz), 1.40 (9H, s), 1.9 (2H, m), 4.55 (1H, t, J = 6 Hz), 7.82 (4H, s)

(6) N- (1-t-butoxycarbonylethoxy) phthalimide

Melting point 80-82 ℃

N.M.R. (d6-DMSO): δ 1.42 (9H, s), 1.48 (3H, d, J = 7 Hz), 4.72 (1H, q, J = 7 Hz), 7.86 (4H, s)

(7) N- (1-t-butoxycarbonyl-1-methoxyethoxy) phthalimide

Melting point 96-100 ℃

N.M.R. (d6-DMSO, δ): 1.42 (9H, s), 1.48 (6H, s), 7.87 (4H, s)

(8) N- (1-butoxycarbonylethoxy) phthalimide

Melting point 48-53 ℃

IR (New sol): 1755,1720,1210,1140,1110,1080,875,695cm ^-1

(9) N- (1-benzyloxycarbonylethoxy) phthalamide

Melting point 63-68 ℃

I.R. (New sol): 1790, 1740, 145, 1210, 1190, 1110, 1080, 980, 880, 735, 700cm-1

(10) N- (2-oxo-3-tetrahydroperyloxy) phthalimide

Melting point 140-142 ℃

I, R. (New sol): 1785,1760,1605,1215,1185,870,695cm ^-1

Example 21

The following compounds are obtained according to methods analogous to Example 2.

(1) 3-aminopropoxyamine dihydrochloride

NMR (d ₂ O, δ): 2.29 (2H, m), 3.27 (2H, t, J = 7 Hz), 4.33 (2H, t, J = 6 Hz).

(2) 1-phenylethoxyamine

(3) 1-t-butoxycarbonyl-2-methylpropoxyamine

(4) α-t-butoxycarbonyl benzyloxyamine

(5) 1-butoxycarbonylethoxyamine

Example 22

The following compounds are obtained following methods analogous to Example 15 above.

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

Melting Point 150-155 ℃ (Decomposition)

IR (New sol): 3420,3230,3100,1725,1610,1530cm ^-1

N.M.R. (DMSO-d6, δ): 1.45 (9H, S), 4.70 (2H, S), 8.12 (2H, brood S)

(2) 2- (2-cyclohexyloxycarbonyl ethoxyimino) -2- (5-amino-1.2,4-thiadiazol-3-yl acetic acid (syn isomer melting point 175-180 ° C. (decomposition)

IR (New sol): 3380,3170,3170,1720,1610,1520,1220,990,710cm ^-1

NMR (d ₆ -DMSO, δ): 0.9-2.1 (13H, m), 4.7 (1H, m), 4.85 (1H, b, J = 6Hz), 8.13 (2H, broad S)

(3) 2- (thioran-1,1-dioxide-3-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting point 200-205 ℃)

IR (New sol) 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)

(4) -2- (α-t-butoxycarbonylbenzyloxyimino) -2- (5-amino-1,2,4-thiadiylzol-3-yl) acetic acid (syn isomer)

Melting Point 155-160 ℃ (Decomposition)

IR (New sol): 3440,3350,3250,1750,1730,1640,1535cm ^-1

NMR (d ₆ -DMSO, δ): 1.37 (9H, S), 5.67 (1H, S), 7.45 (5H, S), 8.25 (2H, broad S)

(5) 2- (1-t-butoxycarbonyl-2-methylpropoxyimino) -2- (5-amino-1,2.4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting point 158-162 ℃)

IR (New sol): 3600,3400,1720,1630crn ^-1

NMR (d ₆ -DMSO, δ): 0.95 (6H, d, J = 7 Hz), 1.8-2.4 (1H, m), 4.33 (1H, d, J = 6 Hz), 8.13 (2H, broad S)

(6) 2- (1-t-butoxycarbonylpropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 152-l56 ℃ (decomposition)

N.M.R. (d6-DMSO, δ): 0.94 (3H, t, J = 7H9), 1.42 (9H, S), 1.80 (2H, m), 4.51 (1H, t, J = 6 Hz), 8.16 (2H, broad S )

(7) 2- (1-t-butoxycarbonyl ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 155-156 ℃ (decomposition)

IR (New sol): 3400,3300,3200,1720,1710,1620,1520cm ^-1

NMR (d ₆ -DMSO, δ): 1.2-1.7 (12H, m), 4.72 (1H, q, J = 7 Hz), 8.2 (2H, broad S)

(8) 2- (1-t-butoxycarbonyl-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer).

Melting Point 180-181 ℃ (Decomposition)

I.R. (New sol): 3400,3300,3200,1745,1715,1630,1530

NMR (d ₆ -DMSO, δ): 1.38 (9H, S), 1.43 (6H, S), 8.15 (2H, broad S)

(9) 2- (1-butoxycarbonyl ethoxyinoamino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 120-123 ° C (decomposition)

IR (new sol): 3400, 3300, 3200, 1725, 1615, 1510, 1410, 1210, 1170, 1135, 1100, 1040, 990, 870, 720cm ^-l

NMR0d ₆ -DMSO, δ): 0.85 (3H, d, J = 6 Hz), 1.43 (3H, d, J = 7 Hz), 1.0-1.7 (4H, m), 4.12 (2H, t, J = 6 Hz), 4.85 (1H, q, J = 7 Hz), 8.04 (2H, broad s)

(10) 2- (1-benzyloxycarbonyl ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), melting point 129-133 ° C (decomposition) )

I.R. (New sol): 3300,3200,1720,1620,1530

N.M.R. (DMSO-d6, δ): 1.45 (3H, d, J = 6 Hz), 4.97 (1H, q, J = 6 Hz), 5.18 (2H, s), 7.31 (5H, s), 8.17 (2H, broad s )

Example 23

The following compounds are obtained according to the method of Example 13.

(1) 2- (thiolane-1,1-dioxide-3-yloxyimino) -2- (5-formamido-1,2.4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 214 ℃ (Decomposition)

IR (New sol): 3200,1720,1680,1600,1530cm ^-1

NMR (DMSO-d ₆ , δ): 2.30-2.50 (2H, m), 2.93-3.83 (4H, m), 5. 10-5.50 (1H, m), 8.92 (1H, s)

(2) 2- (1-phenylethoxyimino) -2- (5-formamido-1,2,4-thiadiazol-1-yl) acetic acid (syn isomer)

Melting Point 174-175 ° C (Decomposition)

IR (New sol): 3100,1720,1690,1550cm ^-1

NMR (DMSO-d ₆ , δ): 1'58 (3H, d, J = 6 Hz), 5.44 (1H, q, J = 6 Hz), 2.32 (5H, m), 8,18 (1H, m), 13.34 (1 H, broad s)

Example 24

The following compounds are obtained according to methods analogous to the above examples.

(1) 2- [2- (N-t-butoxycarbonylamino) ethoxyimino] -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 139-154 ℃ (Decomposition)

IR (New sol): 3400,3150,1748,1700,1690,1540cm ^-1

NMR (DMSO-d ₆ , δ): 1.45 (9H, s), 3.40 (2H, t, J = 6 Hz), 4.32 (2H, t, J = 6 Hz), 8.07 (1H, s)

(2) 2- [4- (N-t-butoxycarbonylamifinomethyl) benzyloxyimino2-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

IR (New sol): 3300,3150,1700cm ^-1

NMR (DMSO-d ₆ , δ): 1.65 (9H, s), 4.12 (2H, d, J = 5.5 Hz), 5.19 (2H, s), 7.21 (4H, s)

Example 25

The following compounds are obtained following methods analogous to Example 4.

(1) 2- [2- (N-t-butoxycarbonylamino) ethoxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 172-177 ℃ (Decomposition)

IR (New sol): 3300, 3140, 1738, 1680, 1628, 1595, 1550, 1527, 1285, 1245, 1165, 1120cm ^-1

NMR (DMSO-d ₆ + D ₂ O, δ): 1.42 (9H, s), 3.35 (2H, d, J = 6 Hz),

(2) 2- [3- (N-t-butoxycarbonylamino) propoxyimino] -2- (5-amino-1,2.4-thiadiazol-3-yl) acetic acid (syn isomer)

IR (new sol): 3300, 3150, 2600-2400, 1720-1660, 1620, 1530, 1250, 1160, 1030, 720cm ^-1

NMR (DMSO-d ₆ , δ): 1.33 (9H, s), 1.82 (2H, m), 3.03 (2H, m), 4.17 (2H, t, J = 6 Hz), 6.73 (1H, broad s), 8.13 (2H, broad s)

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

Melting Point 150-l55 ℃ (Decomposition)

IR (New sol): 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)

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

Melting Point 140-145 ℃ (Decomposition)

I.R. (New sol): 3450,3300,3200, 1730,1630,1530,1500

NMR (DMSO-d ₆ , δ): 7.17 (2H, s), 7.27 (2H, s), 7027 (2H, s), 8.27 (2H, s)

(5) 2- [1- (t-butoxycarbonyl-1-cyclopentyl) oxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer )

Melting Point 174-175 ° C (Decomposition)

IR (New sol): 3400,3300,3200,1745,1715,1630,1530cm ^-1

NMR (DMSO-d ₆ , δ): 1.37 (9H, s), 1.65 (4H, m), 1.97 (4H, m), 8.17 (2H, broad s)

(6) 2- (1-phenoxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

Melting Point 103-107 ℃ (Decomposition)

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

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

Example 26

S-methyl (5-formamido-1,2,4-thiadiazol-3-yl) -thioglyoxylate (64.8 g) and N- (2-oxo-3-tetrahydroperyloxy) phthal 1-carboxy-3-hydroxypropoxyamine prepared by refluxing a mixture of mead (65.0 g), concentrated hydrochloric acid (50 ml) and water (200 ml) for 1 hour was treated in a similar manner to Example 15 to give 2- (1 -Carboxy-3-hydroxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (33.2 g).

Melting Point 186-183 ℃ (Decomposition)

IR (New sol) 3400,3250,3100,17101620 '1540cm ^-1

NMR (DMSO-d ₆ , δ): 1.73-2.10 (2H, m), 350 (2H, t, J = 6 Hz),

4.73 (1H) t, J = 6 Hz) 8.13 (2H, s).

Claims (1)

The compound of formula (2) is hydrolyzed to prepare a compound of formula (3) or a salt thereof, or the compound or salt thereof is reacted with a formula R ² -ONH ₂ or a salt thereof to formula (4) A process for preparing the compound of formula (1) or a salt thereof by preparing a compound of formula (I) or a salt thereof or removing an amino protecting group from the compound of formula (5) .

Wherein R ¹ is amino or protected amino, X ¹ is carbonyl or

Wherein R ² is hydrogen, acyl, optionally substituted aryl, optionally substituted lower alkyl, lower alkynyl, optionally substituted cyclolower) alkenyl or 5 substituted with oxo A heterocyclic heterocyclic group, R ^la is a protected amino, R ⁷ is a rating alkyl.