JPH0625187B2 - Thiadiazole derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] The present invention relates to a novel thiadiazole derivative useful as an intermediate for an antibacterial agent.

Conventionally, in JP-A-59-172493 and JP-A-61-5084, an ammoniopropenyl group is present at the 3-position,
A cephem derivative having a thiadiazolylacetic acid derivative residue or a thiazolylacetic acid derivative residue at the 7-position is known.

The present inventors have found that a cephem derivative having a thiadiazolylacetic acid derivative residue substituted with an ammoniopropenyl group at the 3-position and a fluoromethoxyimino group at the 7-position has more excellent antibacterial activity. The present invention relates to a novel thiadiazole derivative which is an intermediate thereof.

Therefore, an object of the present invention is to provide a novel compound useful as an intermediate for antibacterial agents and a method for producing the same.

[Structure of Invention]

The present invention has the general formula: [Wherein, R ₁ represents a carboxyl group, a halogenocarbonyl group, a carbamoyl group or a cyano group], a thiadiazole derivative, a compound in which an amino group and / or a carboxyl group is protected by a protecting group, or a salt thereof. .

Examples of the halogen atom in the halogenocarbonyl group of R ₁ include chlorine atom, bromine atom and iodine atom.

Examples of the amino-protecting group include formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, phenylacetyl group, thienylacetyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, trityl group, p-methoxy group. Examples thereof include a benzyl group, a diphenylmethyl group, a benzylidene group, a p-nitrobenzylidene group, an m-chlorobenzylidene group and a trimethylsilyl group.

Examples of the protective group for the carboxyl group include p-methoxybenzyl group, p-nitrobenzyl group, t-butyl group, methyl group, ethyl group, 2,2,2, -trichloroethyl group, diphenylmethyl group, pivaloyloxy group. Examples include methyl group and trimethylsilyl group.

Examples of the salt of the compound of the formula (I) include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt;
Quaternary ammonium salts such as tetraethylammonium salt and betaine salt; hydrochloride, hydrobromide, hydroiodide,
Inorganic acid salts such as sulfates, carbonates and bicarbonates; organic carboxylates such as maleates, lactates, tartrates and monofluoroacetates; methanesulfonates, hydroxymethanesulfonates, hydroxyethanesulfones Acid salts, taurine salts, benzene sulfonates, toluene sulfonates and other organic sulfonates; trimethylamine salts, triethylamine salts, pyridine salts, procaine salts, picoline salts,
Amine salts such as dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) methane salt, phenethylbenzylamine salt; arginine salt, It can be appropriately selected from salts such as amino acid salts such as aspartate, lysine salt, glutamate, serine salt and glycine salt.

The compound of the present invention can be produced by the following method.

In the above formula, X represents a halogen atom. In addition, each compound in the above-mentioned production process may be a compound in which its amino group and / or carboxyl group is protected by a protecting group, or a salt thereof. This manufacturing process will be described in more detail.

(1) Production of compound of formula (I-1) a) (II) → (I-1) A compound represented by formula (II) whose amino group is protected by a protecting group, and further its carboxyl group is protected. Group-protected compounds or salts thereof are reacted with halogenofluoromethane, and the protecting groups are optionally removed to remove the thiadiazole derivative represented by formula (I-1), its amino group and / or carboxyl group. A compound in which is protected by a protecting group, or a salt thereof can be obtained.

In the above manufacturing method, examples of halogenofluoromethane include bromofluoromethane, iodofluoromethane, and chlorofluoromethane.

Moreover, the protecting groups and salts of amino groups and carboxyl groups are as described above.

The above reaction is carried out in an inert solvent such as sulfoxides such as dimethylsulfoxide, amides such as N, N-dimethylacetamide, formamide and hexamethylphosphortriamide, ketones such as acetone, or a mixed solvent thereof. It can be carried out at a temperature of -30 ° C to 100 ° C.

Desorption of the protecting groups for the carboxyl group and the amino group can be carried out by an ordinary method such as hydrolysis or reduction depending on the type of the protecting group used.

b) (I-3) → (I-1) After hydrolyzing a compound represented by the formula (I-3), a compound whose amino group is protected by a protecting group, or a salt thereof in the presence of a base. The thiadiazole derivative represented by the formula (I-1), a compound having an amino group and / or a carboxyl group protected by a protecting group, or a salt thereof can be obtained by removing the protecting group as necessary.

The protective groups and salts for amino and carboxyl groups are as described above.

The above reaction can be carried out in water, a buffer solution or a mixed solvent of these and a lower alcohol at a reaction temperature of 0 ° C to 70 ° C. As the base, sodium hydroxide, potassium hydroxide or the like can be used.

c) (III) → (I-1) A compound represented by the formula (III), a compound in which an amino group and / or a carboxyl group is protected by a protecting group, or a salt thereof is reacted with fluoromethoxyamine or a salt thereof. Then, if necessary, by removing the protecting group,
A thiadiazole derivative represented by the formula (I-1) or a salt thereof can be obtained.

The protective groups and salts for amino and carboxyl groups are as described above. As a salt of methoxyamine,
Among the above salts, acid addition salts such as inorganic acid salts, organic carboxylic acid salts and organic sulfonic acid salts can be mentioned.

The above reaction can be carried out in an inert solvent such as a lower alcohol or a mixed solvent thereof with water at a reaction temperature of -20 ° C to 80 ° C.

d) (IV) → (I-1) Required after reacting a compound represented by the general formula (IV), a compound whose carboxyl group is protected with a protecting group, or a salt thereof with an alkali metal thiocyanate. By removing the protecting group with, a thiadiazole derivative represented by the formula (I-1), a compound having a carboxyl group protected by a protecting group, or a salt thereof can be obtained.

Examples of the halogen atom represented by X in the general formula (IV) include chlorine atom, bromine atom, and iodine atom. The protective group and salt for the carboxyl group are as described above.

The above reaction can be carried out in an inert solvent such as a lower alcohol at a reaction temperature of −50 ° C. to room temperature. It is desirable to carry out this reaction in the presence of a base such as triethylamine.

(2) Production of Compound of Formula (I-2) A compound represented by the formula (I-1), a compound whose amino group is protected by a protecting group, or a salt thereof is reacted with a halogenating agent (I It is possible to obtain the thiadiazole derivative of -2), a compound whose amino group is protected by a protecting group, or a salt thereof.

Examples of the halogenating agent include phosphorus pentachloride, thionyl chloride, thionyl bromide, phosphorus oxychloride and the like. The protecting groups and salts are as described above.

The above reaction can be carried out in an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, chloroform or a mixed solvent thereof at a reaction temperature of -50 ° C to 50 ° C.

(3) Production of compound of formula (I-3) A compound represented by formula (I-4), a compound whose amino group is protected by a protecting group, or a salt thereof is hydrolyzed in the presence of an oxidizing agent and a base. After the decomposition, if necessary, the protecting group can be removed to obtain a thiadiazole derivative of the formula (I-3), a compound whose amino group is protected with a protecting group, or a salt thereof.

Examples of the oxidizing agent include hydrogen peroxide and oxygen, and examples of the base include sodium hydroxide and potassium hydroxide. The protecting groups and salts are as described above.

The above reaction is carried out in an inert solvent such as water, a buffer solution, or a mixed solvent of these and a lower alcohol at a reaction temperature of 0 ° C to
It can be performed at 70 ° C.

(4) Production of Compound of Formula (I-4) The compound represented by the general formula (V), or a salt thereof is reacted with an alkali metal thiocyanate salt, and a thiadiazole derivative represented by the formula (I-4) or a salt thereof. Can be obtained.

Regarding reaction conditions, etc., (IV) → (I-1) in the above (1) d)
It is similar to the reaction of.

This compound is prepared by halogenating a compound represented by the formula (VI) or a salt thereof to obtain a compound of the general formula (V), which is not isolated from the reaction site, but is then subjected to the above reaction. You can also do it.

The reaction of (VI) → (V) will be described later.

(5) Production of other compounds e) Compound of formula (IV) The compound of formula (IV) or a salt thereof is hydrolyzed in the presence of a base to give a compound of formula (IV) or a salt thereof. Obtainable.

Examples of the base include sodium peroxide, potassium peroxide, sodium hydroxide, potassium hydroxide and the like.

The above reaction is carried out in an inert solvent such as water, a buffer solution, or a mixed solvent of these and a lower alcohol at a reaction temperature of 0 ° C to
It can be performed at 70 ° C.

f) Compound of formula (V) A compound of formula (V) or a salt thereof can be obtained by reacting a compound of formula (VI) or a salt thereof with a halogenating agent.

Examples of the halogenating agent include bromine, chlorine, sodium hypochlorite, potassium hypochlorite and the like.

The above reaction is carried out in an inert solvent such as water, buffer solution, lower alcohol or a mixed solvent thereof at a reaction temperature of -20 ° C to 50 ° C.
It can be performed at ° C.

g) Compound of formula (VI) A compound of formula (VI) or a salt thereof can be obtained by reacting a compound of formula (VII) with ammonia and / or an ammonium salt.

Examples of ammonium salts include ammonium chloride, ammonium acetate, ammonium sulfate and the like.

The above reaction can be carried out in an inert solvent such as water, lower alcohol, acetone, chloroform or a mixed solvent thereof at a reaction temperature of -20 ° C to room temperature.

h) Compound of formula (VII) The compound of formula (VII) can be obtained by reacting the compound of formula (VIII) with a dehydrating agent in an inert solvent such as acetonitrile. Examples of the dehydrating agent include phosphorus oxychloride and thionyl chloride. The reaction temperature is preferably room temperature or higher.

i) Compound of formula (VIII) 2-Cyano-2-hydroxyiminoacetamide can be reacted with halogenofluoromethane to give a compound of formula (VIII).

Regarding the reaction conditions, etc., (II) of (1) a) → (I-1)
Is the same as.

The compound of the present invention is useful as an intermediate for β-lactam antibiotics, especially cephem compounds. For example, a compound represented by the formula (I-1) or the general formula (I-2) of the present invention for the amino group at the 7-position of a 7-amino-3-cephem derivative, a compound in which the amino group is protected by a protecting group, Alternatively, an excellent antibacterial agent or its intermediate can be obtained by acylation with a salt thereof. In particular, by introducing the compound of the present invention at the 7-position of cephem having an ammonium propenyl group at the 3-position, a compound having extremely excellent antibacterial activity can be obtained. The above acylation can be carried out by a conventional method. As described above, the other compound of the present invention may be a compound represented by the formula (I-1) or the general formula (I-2), a compound whose amino group is protected by a protecting group, or a salt thereof. You can

Next, the present invention will be described in more detail by showing Examples and Experimental Examples.

Example 1 Ethyl 2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetate 60.4 g of ethyl 2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-hydroxyiminoacetate was dissolved in 210 m of dimethyl sulfoxide,
Under ice cooling, 96.48 g of potassium carbonate was added, and the mixture was stirred for 10 minutes.
Then, add 19 g of bromofluoromethane, and at room temperature,
Stir for 3 hours. Ethyl acetate 1 was added to the reaction solution, which was washed with water and then saturated brine, dried over anhydrous magnesium sulfate, and dried. The solvent was distilled off, and 120 m of ethanol was added to the residue.
Was added. The precipitated crystals were collected and washed with ethanol to obtain 58.2 g of the desired product.

Infrared absorption spectrum (cm ^-1 _1, Nujol): 1735,1530 NMR spectrum _{(δ, DMSO-d 6)} : 1.19 (3H, t, J = 7Hz), 4.21 (2H, q, J = 7Hz), 5.79 ( 2H, d, J
= 55 Hz), 7.30 (15H, s), 10.03 (1H, s) Example 2 2- (5-Tritylamino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetic acid Sodium hydroxide 2.04g, ethanol 146m and water 29
17.87 g of the compound of Example 1 was added to the mixed solution of m, and the mixture was stirred under reflux for 20 minutes. The reaction mixture was concentrated under reduced pressure and then ethyl acetate
200m and 1N hydrochloric acid 77m were added. The ethyl acetate layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and dried. The solvent was distilled off to obtain crystals. Petroleum ether was added to this crystal, which was then crushed and collected to obtain the desired product 16.5.
5 g was obtained.

Melting point: 144 to 146 ° C Mass spectrum (m / e): M ⁺ + 1 …… 463 Elemental analysis value: C ₂₄ H ₁₉ N ₄ O ₃ SF ・ 1 / 2H ₂ O Infrared absorption spectrum (cm ^-1 , Nujol): 1720, 1585 NMR spectrum (δ, DMSO-d ₆ ): 5.78 (2H, d, J = 55Hz), 7.31 (15H, s), 10.06 (1H, s) Example 3 2- (5-Tritylamino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetic acid chloride hydrochloride Dissolve 395 mg of phosphorus pentachloride in 2.9 m of dichloromethane,
Cooled to 5 ° C. 627 mg of the compound of Example 2 was added to this solution, and the mixture was stirred at the same temperature for 2 hours and 30 minutes. N-
It was added to a mixed solution of 9.4 m of hexane and 9.4 m of n-octane. The resulting crystals were collected and washed with n-octane to obtain 325 mg of the desired product.

Mp: 139-140 ° C. (decomposition) Mass spectrum ^{(m / e): M +} ...... 480 (35 Cl), 482 (37 3 Cl) Infrared absorption spectrum (cm ^-1, nujol): 1795,1780,1740, 1630 NMR spectrum (δ, DMSO-d ₆ ): 5.79 (2H, d, J = 54Hz), 7.31 (15H, s), 10.09 (1H, s) Example 4 2- (5-amino-1,2,2) 4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid ethyl ester 2.00 g of the compound of Example 1 was stirred in trifluoroacetic acid at room temperature for 30 minutes. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 405 mg of the desired product.

Melting point: 172-173 ° C. Infrared absorption spectrum (cm ^-1 , Nujol): 1730, 1615 NMR spectrum (δ, DMSO-d ₆ ): 1.28 (3H, t, J = 7.0Hz), 4.34 (2H, q, J = 7.0Hz), 5.83 (2H, d, J = 54.5Hz), 8.27 (2H, brs) Example 5 2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z)- 2-fluoromethoxyiminoacetic acid 200 mg of the compound of Example 4 was added to 6 m of ethanol and 2 m of water.
Suspended in a mixed solution of 1N sodium hydroxide aqueous solution 1.75m
Was added and the mixture was stirred at 60 ° C. for 1 hour. Ethanol was distilled off from the reaction solution, and the solution was adjusted to pH 2 with 1N hydrochloric acid. This was purified with Diaion SP207 (trademark, a nonionic adsorption resin manufactured by Mitsubishi Kasei Co., Ltd.) to obtain 30 mg of the target product.

Infrared absorption spectrum (cm ^-1 , Nujol): 1720, 1620 NMR spectrum (δ, DMSO-d ₆ ): 5.76 (2H, d, J = 55,8Hz), 8.12 (2H, brs) Experimental example 1 (raw material compound) Synthesis of 2-diano-2-fluoromethoxyiminoacetamide 2-Cyano-2-hydroxyiminoacetamide 22.6 g
Was dissolved in 100 m of dimethyl sulfoxide, 55.2 g of potassium carbonate was added with stirring at room temperature, and the mixture was further stirred for 20 minutes. Then, a solution of 27 g of fluorobromomethane in 20 m of dimethylformamide was added, and the mixture was stirred at room temperature for 20 hours and allowed to cool. The reaction mixture was added to ice water 1 and ethyl acetate 150m
It was extracted twice with. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue is washed with ethyl ether and dried to give the desired product 1
Obtained 4.4 g.

Melting point: 124-125 ° C Infrared absorption spectrum (cm ^-1 , Nujol): 3410, 3290, 3150, 1690, 1590 NMR spectrum (δ, DMSO-d ₆ ): 5.94 (2H, d, J = 54.0Hz), 7.85 ~ 9.40 (2H, br) Experimental Example 2 (Synthesis of Starting Compound) 2-Fluoromethoxyiminopropanedinitrile A mixture of 14.0 g of the compound of Experimental Example 1, 15 m of acetonitrile, 15 g of sodium chloride, and 14 m of phosphoryl chloride was reacted under reflux for 2 hours, and 5 m of phosphoryl chloride was further added and reacted for 2 hours. After cooling the reaction mixture, ice water 200m
The mixture was added to the mixture and stirred at room temperature for 1 hour. Methylene chloride
Extracted twice at 50 m. The extract was washed with 5% aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The oily product was distilled under reduced pressure to obtain 9.1 g of the colorless oily product.

Boiling point: 69 to 70 ° C./25 mmHg NMR spectrum (δ, CDCl ₃ ): 5.85 (2H, d, J = 52.0 Hz) Experimental Example 3 (synthesis of starting material compound) 2-cyano-2-fluoromethoxyiminoacetamidine A mixture of 50 m of 28% aqueous ammonia, 8 g of ammonium chloride and 50 m of ethanol was cooled to -5 ° C, 9.1 g of the compound of Experimental Example 2 was added with stirring, and the mixture was further stirred at the same temperature for 3 hours. Add 100 m of water to the reaction mixture and add 50 methylene chloride.
Extracted 3 times with m. After extraction, anhydrous magnesium sulfate was added and dried, and then the solvent was distilled off. The residue was washed with ethyl ether and dried to obtain 3.4 g of the desired product.

A part of the product was dissolved in ethanol, and glacial acetic acid was added dropwise with stirring. The resulting precipitate was collected, washed with ethanol and then dried to obtain the acetate salt of the title compound. The following physical properties are the values of acetate.

Melting point: 125-127 ° C Infrared absorption spectrum (cm ^-1 , Nujol): 3200, 1670, 1570 NMR spectrum (δ, DMSO-d ₆ ): 1.90 (3H, s), 5.95 (2H, d, J = 54.0Hz ), 7.40 (3H, br) Example 6 2- (5-Amino-1,2,4-thiadiazol-3-yl)-(E) -2-fluoromethoxyiminoacetonitrile 3.0 g of the compound of Experimental Example 3 was dissolved in 50 m of methanol, and 4.2 g of triethylamine was added under ice cooling. After cooling the solution to -5 ° C, 3.5 g of bromine was added dropwise. Then, -3 ℃ ~ -5 ℃
Then, 2.1 g of potassium thiocyanate in methanol was added dropwise, and the mixture was stirred at the same temperature for 2 hours. The resulting precipitate was removed and washed with water and methanol. This was recrystallized from acetone to obtain 3.4 g of the desired product.

Melting point: 236 to 238 ° C Infrared absorption spectrum (cm ^-1 , Nujol): 3450, 3250, 1610, 1520 NMR spectrum (δ, DMSO-d ₆ ): 6.02 (2H, d, J = 54.0Hz), 8.38 (2H) , br) Example 7 2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide To 18m aqueous solution of 0.23g of sodium hydroxide, 7.4m of 35% hydrogen peroxide solution was added, and the compound of Example 6 was added under stirring at room temperature.
g was added and the mixture was stirred at 25 ° C to 30 ° C for 8 hours. The precipitated crystals were collected, washed with water and acetone, and dried to obtain 1.3 g of the desired product.

Melting point: 210 ° C to 211 ° C Infrared absorption spectrum (cm ^-1 , Nujol): 3450, 3260, 3180, 1690, 1610 NMR spectrum (δ, DMSO-d ₆ ): 5.73 (2H, d, J = 55.0Hz), 7.69 (2H, br), 7.98 (1H, br), 8.10 (1H, br) Example 8 2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoro Methoxyiminoacetic acid A mixture of 1.1 g of the compound of Example 7 and 10 m of 2N aqueous sodium hydroxide solution was stirred at 50 ° C. for 5 hours. The reaction mixture was cooled and adjusted to pH 1.0 with concentrated hydrochloric acid, and then ethyl acetate 20m
It was extracted 3 times with. After extraction, anhydrous magnesium sulfate was added and dried, and then the solvent was distilled off. The residue was washed with isopropyl ether to obtain 0.8 g of a crude product. This was purified by reverse phase silica gel column chromatography to obtain 0.4 g of the desired product.

The infrared absorption spectrum and the NMR spectrum were in agreement with those of Example 5.

Experimental Example 4 (Production of raw material compound) N-fluoromethoxyphthalimide N-Hydroxyphthalimide (80 g) and bromofluoromethane (63.2 g) cooled to 0 ° C. to give dry dimethyl sulfoxide 350
m. 135 g of potassium carbonate was added, and the mixture was stirred at room temperature for 4 hours. Then, nitrogen gas was introduced for 1 hour. The reaction solution was added to 800 m of ice-cooled water, and extracted with 500 m of ethyl acetate three times. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and dried. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with isopropyl ether and petroleum ether to obtain 55 g of the desired product.

Melting point: 126-127 ° C Mass spectrum (m / e): M ⁺ ... 195 Infrared absorption spectrum (cm ^-1 , Nujol): 1785, 1730, 1700, 1600 NMR spectrum (δ, CDCl ₃ ): 5.64 (2H, d, J = 54.0Hz), 7.60 to 7.95 (4H, m) Experimental Example 5 (Production of starting compound) Fluoromethoxyamine and its hydrochloride H ₂ NOCH ₂ F (· HCl) a) Fluoromethoxyamine ethanol 180 m, water 20 g of the compound of Experimental Example 4 and 5.39 g of hydrazine monohydrate were added to the 5.2 m mixture, and the mixture was refluxed for 1 hour. The reaction solution was cooled and the precipitate was removed. The liquid was distilled to obtain the desired product as an ethanol solution (the desired product and ethanol were distilled together). The NMR spectrum of this product is shown below (the peak of ethanol was excluded).

NMR (δ, CDCl ₃ ): 5.29 (2H, d, J = 56.6Hz), 5.85-6.20 (2H, brs) b) Fluoromethoxyamine hydrochloride 1) to the ethanol solution of fluoromethoxyamine obtained in the above a). 200 ml of a molar hydrochloric acid ethanol solution was added, and ethanol was distilled off under reduced pressure. Ethanol and ethyl ether are added to the residue to crystallize, collect and dry to obtain 5 g of the desired product.
Got

Melting point: 152-154 ° C Mass spectrum (m / e): M ⁺ ... 101 ( ³⁵ Cl), 103 ( ³⁷ Cl) NMR spectrum (δ, DMSO-d ₆ ): 5.73 (2H, d, J = 54Hz) , 10.80 to 11.25 (3H, brs) Example 9 2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-oxoacetic acid (1 g) was added to a solution of fluoromethoxyamine (0.58 g) in ethanol (25 m) and water (0.45 m) to give 10%.
After adjusting the pH to 4 to 5 with an aqueous sodium hydroxide solution, the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and 20 m of water was added to the residue.
, 10 g of sodium chloride was added, and the pH of the solution was adjusted to 1 with concentrated hydrochloric acid. This was extracted four times with 30 m of ethyl acetate, and the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and dried. The solvent was distilled off, and the residue was crystallized from acetone-isopropyl ether (1: 3) to obtain 0.38 g of the desired product.

The infrared absorption spectrum and the NMR spectrum were in agreement with those of Example 5.

Example 10 2- (5-Tritylamino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetic acid A solution of 0.58 g of fluoromethoxyamine in 25 m of ethanol and 0.45 m of water in 2- (5-tritylamino-1,2,4-
Thiadiazol-3-yl) -2-oxoacetic acid (1 g) was added, the pH was adjusted to 4 to 5 with a 10% aqueous sodium hydroxide solution, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, 20 m of water and 10 g of sodium chloride were added to the residue, and the pH of the solution was adjusted to 1 with concentrated hydrochloric acid. This was extracted four times with 30 m of ethyl acetate, and the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and dried. The solvent was distilled off, and the residue was crystallized from acetone-isopropyl ether (1:10) to obtain 0.55 g of the desired product.

The infrared absorption spectrum and the NMR spectrum were in agreement with those of Example 2.

Example 11 2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid 13 g of 2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid was added to 100 m of trifluoroacetic acid, and the mixture was stirred at room temperature for 24 hours. Trifluoroacetic acid was distilled off under reduced pressure, and water was added to the residue.
m was added and the insoluble material was removed. The solvent was distilled off under reduced pressure from the liquid, and the residue was mixed with acetone-isopropyl ether (1:
Crystallization from 3) gave 2.18 g of the desired product as white crystals.

The infrared absorption spectrum and the NMR spectrum were in agreement with those of Example 5.

Experimental Example 6 (Production of raw material compound) 2- (N-chloro) amidino-2-fluoromethoxyiminoacetonitrile 2.04 g of 2-amidino-2-fluoromethoxyiminoacetonitrile acetate was dissolved in 30 m of methanol and cooled with ice. 24m of 3N hydrochloric acid was added to a mixed solution of 60m of a 5% sodium hypochlorite aqueous solution and 30m of ethyl ether, and the ethyl ether layer was separated to obtain 30m of an ethyl ether solution of hypochlorous acid.

30 m of this ethyl ether solution of hypochlorous acid was added dropwise to the above solution with stirring. 5 minutes later, the solvent was distilled off under reduced pressure,
After adding 30 m of a saturated sodium hydrogen carbonate aqueous solution to the residue, the mixture was extracted 3 times with 30 m of ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and dried. The solvent was distilled off under reduced pressure to obtain crystals. This was washed with petroleum ether and isopropyl ether to obtain 1.72 g of the desired product.

Melting point: 97 to 98 ° C Mass spectrum (m / e): M ⁺ 178 ( ³⁵ Cl), 180 ( ³⁷ Cl) Infrared absorption spectrum (cm ^-1 , Nujol): 3470, 3330, 1630, 1570 NMR spectrum ( δ, DMSO-d ₆ ): 5.97 (2H, d, J = 54Hz), 7.69 (2H, brs) Experimental Example 7 (Production of starting compound) 2- (N-chloro) amidino-2-fluoromethoxyiminoacetic acid 1.1% of 85% sodium peroxide was dissolved in 20 m of water and cooled with ice. The compound of Experimental Example 6 (1 g) was added thereto, and the mixture was stirred for 3 hours and then at room temperature for 24 hours. Cool the reaction mixture to ice and add 10
g, and after adjusting the pH to 1 with 6N hydrochloric acid, ethyl acetate
It was extracted 4 times at 20 m.

Anhydrous magnesium sulfate was added to the extract and dried. The solvent was distilled off under reduced pressure, and isopropyl ether and petroleum ether were added to the residue (oil) for solidification to obtain 350 mg of the desired product.

Melting point: 112-114 ° C (decomposition) Infrared absorption spectrum (cm ^-1 , Nujol): 3300, 3150, 2650, 1720, 1590 NMR spectrum (δ, DMSO-d ₆ ): 5.79 (2H, d, J = 54Hz) Example 12 2- (5-Amino-1,2,4-thiadiazole-3-
Yl)-(Z) -2-fluoromethoxyiminoacetic acid Potassium thiocyanate 50mg, triethylamine 127mg,
A mixture of 3 m of methanol was cooled to -10 ° C, 99 mg of the compound of Experimental Example 7 was added, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 20 hours. The solvent was distilled off under reduced pressure, and the residue was saturated brine 5 m.
Was added and the pH was adjusted to 1 with 1N hydrochloric acid, then ethyl acetate was added.
It was extracted 4 times at 10 m. Anhydrous magnesium sulfate was added to the extract and dried, and then the solvent was distilled off under reduced pressure. 2-Butanone and isopropyl ether were added to the residue to solidify it,
to obtain mg.

The infrared absorption spectrum and the NMR spectrum were in agreement with those of Example 5.

Example 13 2- (5-amino-1,2,4-thiadiazole-3-
Yl)-(Z) -2-fluoromethoxyiminoacetic acid chloride hydrochloride Dissolve 500 mg of phosphorus pentachloride in 5 m of dry methylene chloride,
After cooling to -10 ° C, 2- (5-amino-1,2,4-
Thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid (325 mg) was added, and the mixture was stirred at the same temperature for 30 minutes. Isopropyl ether (20 m) was added to the reaction solution, and the resulting precipitate was collected to obtain 130 mg of the desired product.

Mass spectrum (m / e): M ⁺ ... 238 ( ³⁵ Cl), 240 ( ³⁷ Cl) Infrared absorption spectrum (cm ^-1 , Nujol): 1780, 1625 NMR spectrum (δ, DMSO-d ₆ ): 5.85 ( 2H, d, J = 55 Hz) Experimental Example 8 (Synthesis of cephem intermediate using the compound of the present invention) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl )-(Z)
-2-Fluoromethoxyiminoacetamide] -3-
[(Z) -3-Chloro-1-propen-1-yl] -3-
Cephem-4-carboxylate Dimethylformamide (348 µm) and tetrahydrofuran (4.1 m) were cooled to -10 ° C, phosphorus oxychloride (418 µm) was added, and the mixture was stirred under ice cooling for 90 minutes. Example 2 was added to this solution.
A solution of 1.73 g of the compound of 5.5
The mixture was cooled to 0 ° C and added, and the mixture was stirred under ice cooling for 90 minutes. The reaction solution was cooled to -20 ° C, and p-methoxybenzyl 7β was added thereto.
-Amino-3-[(Z) -3-chloro-1-propene-1
-Yl] -3-cephem-4-carboxylate hydrochloride
1.78g, N- (trimethylsilyl) acetamide 2.95g,
A mixed solution of 18 m of ethyl acetate and 5.5 m of tetrahydrofuran was added, and the mixture was stirred at -10 ° C for 1 hour. Ethyl acetate (100 m) was added to the reaction solution, and the mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography, and 2.65 g of the desired product was obtained.
Got

Infrared absorption spectrum (cm ^-1 , Nujol): 1765, 1725, 1680, 1610 NMR spectrum (δ, DMSO-d ₆ ): 3.45 (1H, d, J = 18Hz), 3.63 (1H, d, J = 18Hz) , 3.75 (3H, s), 3.95 (1H, dd, J = 8Hz, 12Hz), 4.12 (1H, dd, J = 8Hz, 12Hz), 5.07 (1H, d, J = 12Hz), 5.14 (1H, d , J = 12Hz), 5.24 (1H, d, J = 5Hz), 5.70 (1H, m), 5.78 (2H, d, J = 55Hz), 5.85 (1H, m), 6.26 (1H, d, J = 12Hz), 6.92 (2H, d, J = 9Hz), 7.25 ~ 7.4 (17H, m), 9.74 (1H, d, J = 8Hz), 10.08 (1H, s) Experimental Example 9 (using the compound of the present invention Synthesis of cephem intermediate) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)
-2-Fluoromethoxyiminoacetamide] -3-
[(Z) -3-Chloro-1-propen-1-yl] -3-
Cephem-4-carboxylate 8.17 g of N- (trimethylsilyl) acetamide and p-methoxybenzyl 7β were added to a mixed solution of 37 m of ethyl acetate, 5 m of tetrahydrofuran and 15.7 m of dichloromethane.
-Amino-3-[(Z) -3-chloro-1-propene-1
-Yl] -3-cephem-4-carboxylate hydrochloride
3.33 g was added and dissolved. The solution was cooled to −20 ° C., 3.80 g of the compound of Example 3 was added, and the mixture was stirred at 10 ° C. for 1 hour.
After adding 500 m of ethyl acetate to the reaction mixture, the mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 4.33 g of the desired product.

The infrared absorption spectrum and the NMR spectrum were in agreement with those of Experimental Example 8.

Experimental Example 10 (Synthesis of Cephem Intermediate) p-Methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)
-2-Fluoromethoxyiminoacetamide] -3-
[(E) -3-iodo-1-propen-1-yl] -3-
Cephem-4-carboxylate 10.11 g of the compound of Experimental Example 8 was dissolved in 212 m of acetone,
Under ice cooling, 9.03 g of sodium iodide was added, and the mixture was stirred for 15 minutes and then at room temperature for 90 minutes. The solvent was distilled off, and the residue was extracted with 500 m of ethyl acetate. The extract was washed with saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and dried. This was concentrated under reduced pressure and n-hexane was added. The resulting precipitate is removed and the target product is 10.92g.
Got

Infrared absorption spectrum (cm ^-1 , Nujol): 1770, 1715, 1685, 1610 NMR spectrum (δ, CDCl ₃ ): 3.51 (1H, d, J = 18Hz), 3.60 (1H, d, J = 18Hz), 3.81 (3H, s), 3.98 (2H, d, J = 8Hz), 5.04 (1H, d, J = 5Hz), 5.19 (1H, d, J = 12Hz), 5.24 (1H, d, J = 12Hz), 5.82 (2H, d, J = 55Hz), 5.90 (1H, m), 6.14 (1H, dt, J = 8Hz, 16Hz), 6.77 (1H, d, J = 9Hz), 6.90 (2H, d, J = 9Hz), 7.00 (1H, d, J = 16Hz), 7.2 to 7.4 (17H, m), 7.80 (1H, s) Experimental Example 11 (Synthesis of cephem compound) 7β- [2- (5-amino-1, 2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (carbamoylmethyldimethylammonio) -1-propen-1-yl] -3
-Cephem-4-carboxylate The compound of Experimental Example 10 (500 mg) was dissolved in a mixed solution of methanol (3 m) and dimethylformamide (1 m), and the mixture was cooled with ice to give N, N-.
71.3 mg of dimethylglycinamide was added, and the mixture was stirred at room temperature overnight. This reaction solution was added to a mixed solution of 50 m of ethyl acetate and 50 m of ethyl ether, and the resulting precipitate was collected and dried to obtain 382 mg of yellow powder.

This compound was treated with trifluoroacetic acid 2.7m and anisole 2.3
m, and the mixture was stirred for 2 hours under ice cooling. 25m ethyl ether and 25m isopropyl ether
The resulting precipitate was collected and washed with ethyl ether. This precipitate was suspended in 4.5 m of water, the solution was adjusted to pH 5.5 to 6.5 with sodium acetate, and the insoluble matter was removed.
The liquid was purified by reverse phase silica gel column chromatography to obtain 94 mg of the desired product.

Infrared absorption spectrum (cm ^-1 , Nujol): 1760, 1670, 1590 NMR spectrum (δ, DMSO-d ₆ ): 3.14 (3H, s), 3.15 (3H, s), 3.47 (1H, d, J = 17Hz ), 3.65 (1H, d, J = 17Hz), 4.02 (2H, s), 4.16 (2H, d, J = 8Hz), 5.06 (1H, d, J = 5Hz), 5.65 (1H, dd, J = 5Hz, 8Hz), 5.70 (1H, m), 5.80 (2H, d, J = 55Hz), 7.16 (1H, d, J = 15H)
z), 7.64 (1H, s), 8.19 (1H, s), 8.22 (2H, s), 9.70 (1H, d, J = 8Hz) Antibacterial activity MIC (μg / m) Staphylococcus aureus 0.2 209− P Escherichia coli ≤0.025 NIHJ Klebshera pneumoniae ≤0.025 EK-6 Serratia marcescens 0.1 ES-75 Morganella morgani ≤0.025 EP-14 Chadmonas aeruginosa 0.4 EP-01

Front Page Continuation (72) Inventor Isao Sugiyama 29-4 Higashiarai, Tsukuba City, Ibaraki Prefecture (72) Inventor Yoshimasa Machida 500-81 Shimohirooka, Tsukuba City, Ibaraki Prefecture 72-72 Inventor Kyosuke Kito 1 Tokodai, Tsukuba City, Ibaraki Prefecture 10-8 (72) Inventor Kamamasa 672-165 Koshirashi, Tsukuba City, Ibaraki Prefecture 72-165 (72) Hiroshi Yamauchi 500-105 Shimohirooka, Tsukuba City, Ibaraki Examiner Shinji Matsuura (56) Reference JP-A-57-158769 (JP, A) JP 61-165391 (JP, A) JP 61-243090 (JP, A) JP 58-126877 (JP, A) JP 62-205066 (JP, A)

Claims (9)

[Claims] 1. A general formula: [Wherein, R ₁ represents a carboxyl group, a halogenocarbonyl group, a carbamoyl group or a cyano group], a compound in which the amino group and / or the carboxyl group is protected by a protecting group, or a salt thereof. 2. The compound according to claim _{1, wherein} R ₁ is a carboxyl group. 3. The compound according to claim _{1, wherein} R ₁ is a halogenocarbonyl group. 4. The compound according to claim _{1, wherein} R ₁ is a carbamoyl group. 5. A method according to claim 1, wherein R ₁ is a cyano group.
The compound according to the item. 6. The formula: A compound of which the amino group is protected by a protecting group,
Further, a compound characterized by reacting a compound whose carboxyl group is protected with a protecting group, or a salt thereof with halogenofluoromethane, and then removing the protecting group if necessary: A thiadiazole derivative represented by, a compound whose amino group and / or carboxyl group is protected by a protecting group,
Or the manufacturing method of those salts. 7. The formula: The compound represented by the formula (1), a compound whose amino group is protected by a protecting group, or a salt thereof is hydrolyzed in the presence of a base, and then the protecting group is optionally eliminated: A thiadiazole derivative represented by, a compound whose amino group and / or carboxyl group is protected by a protecting group,
Or the manufacturing method of those salts. 8. The formula: A compound represented by the formula (1), a compound having an amino group and / or a carboxyl group protected by a protecting group, or a salt thereof is reacted with fluoromethoxyamine or a salt thereof, and then the protecting group is optionally eliminated. Expression: A thiadiazole derivative represented by, a compound whose amino group and / or carboxyl group is protected by a protecting group,
Or the manufacturing method of those salts. 9. A general formula: [Wherein X represents a halogen atom], a compound in which the carboxyl group is protected by a protecting group,
Alternatively, those salts are reacted with an alkali metal thiocyanate, and then a protecting group is optionally eliminated: A method for producing a thiadiazole derivative represented by, a compound having a carboxyl group protected by a protecting group, or a salt thereof.