JP2859630B2 - Method for producing thiadiazolylacetic acid derivative and intermediate thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] The present invention relates to a thiadiazolylacetic acid derivative useful as an intermediate of an antibacterial agent and an intermediate thereof.

Conventionally, JP-A-59-172493 and JP-A-61-5084
In the official gazette, there is an ammonium propenyl group at the 3-position,
Cephem derivatives having a thiadiazolylacetic acid derivative residue or a thiazolylacetic acid derivative residue substituted with a methoxyimino group or the like at the position are 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 fluoromethoxyamine group at the 7-position has excellent antibacterial activity.

An object of the present invention is to provide a method for producing a thiadiazolylacetic acid derivative useful as an intermediate of an antibacterial agent and an intermediate.

[Configuration of the invention]

The compound of interest according to the invention has the formula: Or a compound in which the amino group is protected by a protecting group, or a salt thereof.

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

Examples of carboxyl-protecting groups include p-methoxybenzyl, p-nitrobenzyl, t-butyl, methyl, ethyl, 2,2,2-trichloroethyl, diphenylmethyl, pivaloyloxymethyl And trimethylsilyl groups.

Salts of the compound of general formula (I) include sodium salts,
Alkaline metal salts such as potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; tetraethylammonium salts, betaine salts and the like;
Grade ammonium salt; inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, sulfate, carbonate, bicarbonate; maleate, lactate, tartrate, monofluoroacetate, etc. Organic carboxylate; organic sulfonate such as methanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate, taurine, benzenesulfonate, toluenesulfonate; trimethylamine salt, triethylamine salt, pyridine salt; Procaine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) methane salt, phenethylbenzylamine salt, etc. Amine salts; arginine salts, aspartates,
It can be appropriately selected from salts such as amino acid salts such as 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, R ₁ represents a hydrogen atom or a lower alkyl group, R ₂ represents a lower alkyl group, and X represents a halogen atom. The compound represented by the above formula may be a compound in which the amino group is protected by a protecting group, or a salt thereof.

Examples of the lower alkyl group for R ₁ and R ₂ include C ₁ -C ₄ alkyl groups such as methyl, ethyl and propyl. Examples of the halogen atom for X include a chlorine atom, a bromine atom and an iodine atom. The protecting group for the amino group is the same as the protecting group in the compound of the above formula (I). As for the salt, the compound having an amino group and a carboxyl group is the same as the salt of the compound of the formula (I), and the compound having only an amino group is the same as the salt of the compound of the formula (I). Among these, acid addition salts such as inorganic acid salts, organic carboxylate salts, organic sulfonic acid salts and amino acid salts are exemplified.

 These manufacturing steps will be described in more detail.

(III) → (I) A compound represented by the formula (III), a compound whose amino group is protected by a protecting group, or a salt thereof reacted with fluoromethoxyamine or a salt thereof, and if necessary, the protection is eliminated. As a result, a compound represented by the formula (I), a compound in which the amino group is protected by a protecting group, or a salt thereof can be obtained.

Examples of the salt of fluoromethoxyamine include those represented by the above formula (I)
And acid addition salts such as inorganic acid salts, organic carboxylic acid salts, organic sulfonic acid salts and amino acid salts.

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.

(III) → (II) A compound represented by the formula (II) obtained by oxidizing a compound represented by the general formula (III), a salt thereof, or a compound whose amino group is protected by a protecting group, wherein the amino group is A compound protected with a protecting group, or a salt thereof can be obtained.

Oxidation is performed by first oxidizing to an aldehyde using ozone as an oxidizing agent, and then oxidizing to a compound of formula (II) using hydrogen peroxide, potassium permanganate, chromic acid, oxygen, etc. as an oxidizing agent. Can be.

The above reaction can be carried out in an inert solvent such as dichloromethane, chloroform, lower alcohol, ethyl acetate, benzene, toluene, tetrahydrofuran, and ethyl ether at a reaction temperature of -50 ° C to 40 ° C.

(IV) → (III) A compound represented by the general formula (IV) or a salt thereof,
Reaction of an alkali metal thiocyanate with a compound of the general formula (II
Compound (I) or a salt thereof can be known.

Examples of the alkali metal salt include a potassium salt and a sodium salt.

The above reaction can be carried out in an inert solvent such as a lower alcohol at a reaction temperature of -50 ° C to 50 ° C.

(V) → (I) a compound represented by the general formula (V), a salt thereof, or a compound having an amino group protected by a protecting group is hydrolyzed;
If necessary, the protecting group can be removed to obtain a compound represented by the formula (I), a compound in which the amino group is protected by the protecting group, or a salt thereof.

A base such as sodium hydroxide or potassium hydroxide can be used for the hydrolysis.

The above reaction can be carried out in an aqueous solvent such as water or a buffer solution or a mixed solvent thereof with a lower alcohol at -10 ° C to 100 ° C.

(VI) → (V) The compound of the general formula (V) is hydrolyzed by hydrolyzing the compound of the general formula (VI), a salt thereof, or a compound in which the amino group is protected by a protecting group, and if necessary, removing the protecting group. Or a salt thereof, or a compound in which the amino group is protected with a protecting group.

Acids such as hydrochloric acid, sulfuric acid, trifluoroacetic acid and p-toluenesulfonic acid can be used for the hydrolysis.

The above reaction can be carried out in an aqueous solvent such as water or a buffer solution or a mixed solvent thereof with a lower alcohol at -10 ° C to 100 ° C.

(VII) → (VI) A compound of the formula (VII), a salt thereof, or a compound in which the amino group is protected by a protecting group is reacted with an alkali metal lower alcoholate and, if necessary, the protecting group is eliminated. Compound (VI), a salt thereof, or a compound in which the amino group is protected with a protecting group can be obtained.

Examples of the alkali metal lower alcoholate include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, and the like.

The above reaction can be carried out in an inert solvent such as a lower alcohol at a reaction temperature of -50 ° C to 0 ° C.

(VIII) → (VII) The compound of the general formula (VII) or a salt thereof can be obtained by reacting the compound of the general formula (VIII) or a salt thereof with an alkali metal thiocyanate.

The reaction conditions and the like are the same as in the step (IV) → (III).

(IX) → (VIII) The compound of the general formula (VIII) or a salt thereof can be obtained by reacting the compound of the formula (IX) or a salt thereof with a halogenating agent.

Halogenating agents include halogens such as bromine and chlorine, N
N-halogenosuccinimides such as chlorsuccinimide and N-bromosuccinimide; and alkali metal hypochlorites such as sodium hypochlorite and potassium hypochlorite can be used.

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

In this step, the process can proceed to the next step without isolating the compound of the formula (VIII).

(X) → (IX) The compound of the formula (IX) or a salt thereof can be obtained by reacting the compound of the formula (X) with ammonia and / or an ammonium salt.

Examples of the ammonium salt 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.

(XI) → (X) By reacting the compound of formula (XI) with a dehydrating agent,
The compound of formula (X) can be obtained.

Examples of the dehydrating agent include phosphorus oxychloride and thionyl chloride.

The above reaction can be performed in an inert solvent such as acetonitrile at a reaction temperature of room temperature or higher.

(XII) → (V) The compound of the general formula (V) or a salt thereof can be obtained by reacting the compound of the general formula (XII) or a salt thereof with an alkali metal thiocyanate.

The reaction conditions and the like are the same as in the step (IV) → (III).

(XIII) → (XII) The compound of the general formula (XII) can be obtained by reacting the compound of the general formula (XIII) or a salt thereof with a halogenating agent.

The reaction conditions and the like are the same as in the step (IX) → (VIII). In this step, it is possible to proceed to the next step without isolating the compound of the general formula (XII).

(XIV) → (XIII) The compound of the formula (XIV) can be reacted with ammonium halide to obtain the compound of the formula (XIII) or a salt thereof.

Ammonium halides include ammonium chloride,
Ammonium bromide.

The above reaction can be carried out in an inert solvent such as a lower alcohol at a reaction temperature of 10 ° C to a reflux temperature.

(XV) → (XIV) The compound of the general formula (XIV) can be obtained by reacting the compound of the general formula (XV) with an alkali metal lower alcoholate.

The reaction conditions and the like are the same as those in the step (VII) → (VI).

(XVI) → (XV) The compound of the general formula (XV) can be obtained by reacting the compound of the general formula (XVI) with a dehydrating agent.

 As the dehydrating agent, trifluoroacetic acid or the like is used.

The above reaction is carried out in an inert solvent such as pyridine at a reaction temperature of-
It can be performed at 20 ° C to 50 ° C.

(XVI) → (XVII) A compound of the general formula (XVI) is reacted with a sulfurizing reagent to give a compound of the formula (XVI)
The compound of VII) can be obtained.

As the sulfurizing reagent, Lawson's reagent ([2,4-bis (4
-Methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide)], diphosphorus pentasulfide and the like.

The above reaction can be carried out in an inert solvent such as dimethoxyethane, acetonitrile, dimethylsulfoxide, dimethylformamide and the like at a reaction temperature of -20 ° C to 50 ° C.

(XVII) → (XVII) The compound of the general formula (XVII) is reacted with an alkylating agent,
The compound of the general formula (XVIII) can be obtained.

As the alkylating agent, lower alkyl iodide, di-lower alkyl sulfate or the like is used.

The above reaction can be carried out in an inert solvent such as dimethoxyethane, acetonitrile, dimethylsulfoxide, dimethylformamide and the like at a reaction temperature of 0 ° C to 100 ° C.

(XVIII) → (XIII) The compound of the general formula (XIII) or a salt thereof can be obtained by reacting the compound of the general formula (XVIII) with an ammonium halide.

The reaction conditions and the like are the same as in the step of (XIV) → (XIII).

(VIII) → (XIX) The compound of the general formula (XIX) or a salt thereof can be obtained by reacting the compound of the general formula (VIII) or a salt thereof with an alkali metal lower alcoholate.

The reaction conditions and the like are the same as those in the step (VII) → (VI).

(XIX) → (XII) The compound of the general formula (XII) or a salt thereof can be obtained by hydrolyzing the compound of the general formula (XIX) or a salt thereof.

Acids such as hydrochloric acid, sulfuric acid, trifluoroacetic acid and p-toluenesulfonic acid can be used for the hydrolysis.

The above reaction can be carried out in an aqueous solvent such as water or a buffer solution or a mixed solvent thereof with a lower alkali at -10 ° C to 10 ° C.

The compound of formula (I) can be obtained by the method shown above. In addition, among the compounds of (I) to (XIX), formula (II)
Compounds other than are new compounds.

The compound of the formula (I), a compound in which the amino group is protected by a protecting group, or a salt thereof is useful as an intermediate of a β-lactam antibiotic, particularly a cephem compound. For example, the amino group at the 7-position of a 7-amino-3-cephem derivative can be prepared by a conventional method using a compound of the formula (I), a compound in which the amino group is protected by a protecting group, a salt thereof, or an acid halide thereof. The cephem derivative having excellent antibacterial activity can be obtained by acylation of the compound and, if necessary, removal of the protecting group. In particular, the above-mentioned cephem derivative having an ammonium lophenyl group at the 3-position has very excellent antibacterial activity.

Next, the present invention will be described in more detail with reference to Examples and Experimental Examples.

Experimental Example 1 2-cyano-2-hydroxyiminoacetamide 22.6 g of 2-cyano-2-fluoromethoxyiminoacetamide was dissolved in 100 ml of dimethyl sulfoxide, and 55.2 g of potassium carbonate was added with stirring at room temperature, followed by further stirring for 20 minutes. Then, a solution of 27 g of fluorobromomethane in 20 ml of dimethylformamide was added, and the mixture was stirred at room temperature for 20 hours and allowed to cool. Add the reaction solution to ice water 1 and add 150 ml of ethyl acetate.
Extracted times. The organic layer was washed twice with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The residue was washed with ethyl ether and dried, yielding 14.4 g of the desired product
I got

Melting point: 124 to 125 ° C Infrared absorption spectrum (cm ^-1 , Nujol): 3410, 3290, 3150, 1690, 1590 NMR spectrum (δ, DMSO-d ₆ ): 5.94 (2H, d, J = 54.0 Hz), 7.85 to 9.40 (2H, br) Experimental Example 2 2-fluoromethoxyiminopropanedinitrile A mixture of 14.0 g of the compound of Experimental Example 1, 15 ml of acetonitrile, 15 g of sodium chloride and 14 ml of phosphoryl chloride was refluxed under reflux for 2 minutes.
The reaction was allowed to proceed for another 2 hours. After cooling, the reaction solution was added to 200 ml of ice water and stirred at room temperature for 1 hour. Extracted twice with 50 ml of methylene chloride. The extract was washed with a 5% aqueous sodium bicarbonate solution and then with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The oily product was distilled under reduced pressure to obtain 9.1 g of the target compound as a colorless oil.

Boiling point: 69-70 ° C./25 mmHg NMR spectrum (δ, CDCl ₃ ): 5.85 (2H, d, J = 52.0 Hz) Experimental Example 3 2-cyano-2-fluoromethoxyiminoacetamidine A mixture of 50% of 28% aqueous ammonia, 8 g of ammonium chloride and 50 ml 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. 100 ml of water was added to the reaction solution, and the mixture was extracted three times with 50 ml of methylene chloride. The extract was dried over anhydrous magnesium sulfate, and 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 dried to give the acetate of the title compound. The following physical property values are for acetate.

Melting point: 125 to 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 = 54.0) Hz), 7.40 (3H, b
r) Experimental Example 4 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 ml 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. Subsequently, -3 ° C to -5 ° C
Then, a methanol solution of 2.1 g of potassium thiocyanate was added dropwise thereto, 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, 3075, 1610, 1520 NMR spectrum (δ, DMSO-d ₆ ): 6.02 (2H, d, J = 54.0 Hz), 8.38 (2H, br) Example 1 Methyl 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetimidate 10 ml of methanol was added to 500 mg of the compound of Experimental Example 4, and 0.29 g of a 28% methanol solution of sodium methoxide was added with stirring at room temperature. After stirring for further 24 hours, methanol was distilled off under reduced pressure, and a small amount of methanol and isopropyl ether were added to the residue to obtain 146 mg of the desired product.

Melting point: 157-158 ° C Infrared absorption spectrum (cm ^-1 , Nujol): 3270, 3100, 1645, 1600, 1110, 1050 NMR spectrum (δ, DMSO-d ₆ ): 3.68 (3H, s), 5.74 (2H) , d, J = 54Hz), 8.16 (2H, br
s), 8.9 (1H, s) Example 2 methyl 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetate To 100 mg of the compound of Example 1 was added 10 ml of 2N hydrochloric acid, and the mixture was added at room temperature.
Stirred for 0 minutes. The reaction solution was extracted three times with 20 ml of ethyl acetate, and the extract was washed with water. This was dried over anhydrous magnesium sulfate and dried. The solution was evaporated under reduced pressure, and a small amount of isopropyl ether was added to the residue. The precipitated crystals were collected to give 75 mg of the desired product.

Infrared absorption spectrum (cm ^-1 , Nujol): 3400, 3250, 3100, 1730, 1680, 1610 NMR spectrum (δ, DMSO-d ₆ ): 3.83 (3H, s), 5.78 (2H, d, J = 54 Hz) , 8.24 (2H, s) Example 3 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid 40 mg of sodium hydroxide was dissolved in 2 ml of water. This solution was heated to 70 ° C., and a solution of 59 mg of the compound of Example 2 in 2 ml of methanol was added dropwise with stirring. After stirring at the same temperature for 20 minutes and cooling with ice, methanol was distilled off under reduced pressure. After adding 5 ml of water, adjusting the pH to 1 with 1N hydrochloric acid, the mixture was extracted three times with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off. Add a small amount of isopropyl ether to the residue,
mg was obtained.

Infrared absorption spectrum (cm ^-1 , Nujol): 1720,1620 NMR spectrum (δ, DMSO-d ₆ ): 5.74 (2H, d, J = 55 Hz), 8.18 (2H, brs) Example 5 Dimethyl fluoromethoxyiminomalo Nate 7.0 g of dimethylhydroxyiminomalonate was dissolved in 20 ml of acetonitrile, and 11.9 g of potassium carbonate was added. To this, a solution of 5.9 g of bromofluoromethane in 20 ml of acetonitrile was added dropwise over 30 minutes. After stirring at room temperature for 5 hours, insoluble materials were removed, and the mixture was washed with ethyl acetate. The solution and the washing solution were combined, and the solvent was distilled off. 200 ml of ethyl ether was added to the residue, and the precipitate was removed. The solvent was distilled off to obtain 7.45 g of the target compound as a colorless oil.

Infrared absorption spectrum (cm ⁻¹ , neat): 2950,1740,1620 NMR spectrum (δ, CDCl ₃ ): 3.91 (6H, s), (2H, d, J = 54 Hz) Experimental Example 6 Methyl 2-carbamoyl- ( Z) -2-Fluoromethoxyiminoacetate 7.45 g of the compound of Experimental Example 5 was dissolved in 19 ml of methanol, and 28
6.25 g of aqueous ammonia was added dropwise over 10 minutes. Then, the mixture was stirred at the same temperature for 1 hour and 30 minutes. After adjusting the pH to 7 with concentrated hydrochloric acid, the solution was concentrated under reduced pressure.
The above procedure was repeated for the liquid. The obtained crystals were combined, dissolved in chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 5,04 g of the desired product.

Infrared absorption spectrum (cm ^-1 , Nujol): 3450, 3300, 3150, 1720, 1690, 1620, 1590 NMR spectrum (δ, DMSO-d ₆ ): 3.79 (3H, s), 5.78 (2H, d, J = 54Hz), 7.98 (1H, br),
8.02 (1H, br) Experimental Example 7 Methyl 2-cyano- (Z) -2-fluoromethoxyiminoacetate 2.5 g of the compound of Experimental Example 6 was dissolved in 24 ml of pyridine, and 5 ml of trifluoroacetic anhydride was added dropwise over 20 minutes under ice-cooling.
The mixture was further stirred at room temperature for 40 minutes. The reaction solution was added to 100 ml of ice water, adjusted to pH 7 with concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the desired product was obtained as a pale brown oil.
0 g was obtained.

Infrared absorption spectrum (cm ^-1 , neat): 2950, 1750, 1570 NMR spectrum (δ, CDCl ₃ ): 3.94 (3H, s), 5.78 (2H, d, J = 54 Hz) Experimental Example 8 Methyl 3-imino- 3-methoxy- (Z) -2-fluoromethoxyiminopropionate Dissolve 3.22 g of the compound of Experimental Example 7 in 80 ml of methanol,
10 ml of a 1M methanol solution of sodium methoxide was added dropwise at room temperature over 45 minutes, and then stirred for 30 minutes. After the reaction solution was neutralized with acetic acid, the solvent was distilled off. Isopropyl ether was added to the residue to remove insolubles. The liquid was purified by silica gel column chromatography to obtain 1.9 g of the desired product as a pale yellow oil.

Infrared absorption spectrum (cm ⁻¹ , neat): 3320, 2950, 1740, 1650 NMR spectrum (δ, CDCl ₃ ): 3.85 (3H, s), 3.89 (3H, s), 5.67 (2H, d, J = 54 Hz) ),
7.32 (1H, br) Experimental Example 9 Methyl 3-imino-3-methoxy- (Z) -2-fluoromethoxyiminopropionate 358 mg of the compound of Experimental Example 6 was dissolved in 10 ml of dichloromethane, and 592 mg of trimethyloxonium tetrafluoroborate was added under a nitrogen stream, followed by stirring at room temperature for 1.5 days. Under ice-cooling, 404 mg of triethylamine and then 30 ml of water were added, and after stirring, the organic layer was separated. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 350 mg of the desired product as an oil.

The infrared absorption spectrum and the NMR spectrum were identical to those of the compound of Experimental Example 8.

Experimental Example 10 Methyl 3-imino-3-ethoxy- (Z) -2-fluoromethoxyiminopropionate To 3.58 g of the compound of Experimental Example 6, 40 ml of a 1 M dichloromethane solution of triethyloxonium tetrafluoroborate was added under a nitrogen stream, followed by stirring at room temperature overnight. Under ice-cooling, 6.06 g of triethylamine and then 40 ml of water were added, and the mixture was stirred and the organic layer was separated. This was purified by silica gel column chromatography to obtain 1.03 g of the target compound as a colorless oil.

Infrared absorption spectrum (cm ⁻¹ , neat): 3320, 2970, 1740, 1660, 1610 NMR spectrum (δ, CDCl ₃ ): 1.33 (3H, t, J = 7.2 Hz), 3.90 (3H, s), 4.28 ( 2H, q, J
= 7.2Hz), 5.67 (2H, d, J = 54Hz), 8.26 (1H, brs) Experimental Example 11 Methyl 2-amidino- (Z) -2-fluoromethoxyiminoacetate hydrochloride 1.03 g of the compound of Experimental Example 10 was dissolved in 16 ml of methanol.
802 mg of ammonium chloride was added and stirred for 6 days. Ethyl acetate (80 ml) was added to the reaction solution to remove insolubles. The solution was concentrated under reduced pressure, and the precipitated crystals were collected. The residue was washed with ethyl ether to obtain 400 mg of the target substance as white crystals.

Infrared absorption spectrum (cm ^-1 , Nujol): 1740, 1680, 1620 NMR spectrum (δ, DMSO-d ₆ ): 3.87 (3H, s), 5.88 (2H, d, J = 53 Hz), 9.70 (3H, brs) Experimental Example 12 Methyl 2-amidino- (Z) -2-fluoromethoxyacetate hydrochloride 230 mg of the compound of Experimental Example 8 was dissolved in 5 ml of methanol, 191 mg of ammonium chloride was added, and the mixture was boiled for 6 hours. After cooling,
Ethyl acetate was added to remove insolubles. Concentrate the liquid,
The precipitated crystals were collected. After washing with ethyl ether, 150 mg of the target product was obtained as white crystals.

The infrared absorption spectrum and NMR spectrum were consistent with those of the compound of Experimental Example 11.

Experimental Example 13 Methyl 2-amidino- (Z) -2-fluoromethoxyiminoacetate bromate 193 mg of the compound of Experimental Example 8 was dissolved in 5 ml of methanol, 234 mg of ammonium bromide was added, and the mixture was stirred at 50 ° C. for 6 hours. Subsequently, the reaction solution was treated in the same manner as in Experimental Example 12 to obtain the target compound 13
2 mg were obtained.

Infrared absorption spectrum (cm ^-1 , Nujol): 1740, 1670, 1610 NMR spectrum (δ, DMSO-d ₆ ): 3.87 (3H, s), 5.88 (2H, d, J = 53 Hz), 9.46 (3H, brs) Experimental Example 14 Methyl 2- (N-chloro) amidino- (Z) -2-fluoromethoxyiminoacetate 400 mg of the compound of Experimental Example 11 was dissolved in 20 mg of methanol.
Under ice-cooling, 5 ml of a 0.5 M solution of hypochlorous acid in ethyl ether
The mixture was added dropwise over a period of 15 minutes and stirred for another 15 minutes. The solvent was distilled off, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution.
It was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was solidified with petroleum ether.
I got

Infrared absorption spectrum (cm ⁻¹ , Nujol): 3480, 3370, 1720, 1630, 1600 NMR spectrum (δ, CDCl ₃ ): 3.95 (3H, s), 5.73 (2H, d, J = 54 Hz), 5.75 (2H) Experimental Example 15 2- (N-chloro) amidino- (E) -2-fluoromethoxyiminoacetonitrile 2.04 g of 2-cyano-2-fluoromethoxyiminoacetamidine acetate was dissolved in 30 ml of methanol and cooled with ice. 24 ml of 3N-hydrochloric acid was added to a mixture of 60 ml of a 5% aqueous sodium hypochlorite solution and 30 ml of ethyl ether, and the ethyl ether layer was separated to obtain 30 ml of an ethyl ether solution of hypochlorous acid.

30 ml of this ethyl ether solution of hypochlorous acid was added dropwise to the above solution with stirring. After 5 minutes, the solvent was distilled off under reduced pressure.
After adding 30 ml of saturated aqueous sodium hydrogen carbonate solution to the residue,
The mixture was extracted three times with 30 ml of ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate. 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: 97-98 ° C Mass spectrum (m / e): M ⁺ …… 178 ( ³⁵ Cl), 180 ( ³⁷ C
l) Infrared absorption spectrum (cm ^-1 , Nujol): 3470, 3330, 1630, 1570 NMR spectrum (δ, DMSO-d ₆ ): 5.97 (2H, d, J = 54 Hz), 7.69 (2H, brs) 16 Methyl 2- (N-chloro) amidino- (Z) -2-fluoromethoxyiminoacetimidate 535 mg of the compound of Experimental Example 15 was dissolved in 14.4 ml of methanol, 0.6 ml of a 1M methanol solution of sodium methoxide was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. The solution was neutralized with dilute hydrochloric acid-methal. The solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 500 mg of the desired product.

Infrared absorption spectrum (cm ^-1 , Nujol): 3460, 3270, 1660, 1630, 1600 NMR spectrum (δ, CDCl ₃ ): 3.89 (3H, s), 5.74 (2H, d, J = 54 Hz), 5.80 (2H) , br),
7.56 (1H, brs) Experimental Example 17 Methyl 2- (N-chloro) amidino- (Z) -2-fluoromethoxyiminoacetate Dissolve 180 mg of the compound of Experimental Example 16 in 2 ml of methanol and add 1N
Hydrochloric acid (2 ml) was added under ice cooling, and the mixture was returned to room temperature and stirred for 2 hours. Ethyl ether (50 ml) was added to the reaction solution, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 84 mg of the desired product. The infrared absorption spectrum and NMR spectrum were identical to those of the compound of Experimental Example 14.

Experimental Example 18 Methyl 2-thiocarbamoyl- (E) -2-fluoromethoxyiminoacetate 0.89 g of the compound of Experimental Example 6 was added to 20 ml of 1,2-dimethoxyethane.
And dissolved in Lawson's reagent ([2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,
4-Disulfide]) was added under a nitrogen stream, and the mixture was heated with stirring at 50 ° C for 4 hours and 30 minutes. The reaction solution was cooled, diethyl ether was added, and insolubles were removed. The solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography to give 0.83 g of the desired product
I got

Infrared absorption spectrum (cm ^-1 , Nujol): 3400, 3270, 3160, 1710, 1590 NMR spectrum (δ, CDCl ₃ ): 3.94 (3H, s), 5.74 (2H, d, J = 54 Hz), 7.36 (1H) , br),
7.82 (1H, br) Experimental Example 19 Methyl 2-thiocarbamoyl- (E) -2-fluoromethoxyiminoacetate 178 mg of the compound of Experimental Example 6 was added to 5 ml of 1,2-dimethoxyethane.
And 222 mg of diphosphorus pentasulfide was added thereto, followed by stirring at 70 ° C. for 4 hours. The reaction solution was extracted with ethyl ether, and the extract was washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 90 mg of the desired product. The infrared absorption spectrum and NMR spectrum were consistent with those of the compound of Experimental Example 18.

Experimental Example 20 Methyl 3-imino-3-methylthio- (E) -2-fluoromethoxyiminopropionate 194 mg of the compound of Experimental Example 18 was dissolved in 10 ml of acetonitrile, and 276 mg of potassium carbonate and 1 ml of methyl iodide were added.
The mixture was stirred at room temperature for 5 hours and 30 minutes. Ethyl ether 50
ml was added and the insolubles were removed. The solvent was distilled off to obtain 190 mg of the target compound as an oil.

Infrared absorption spectrum (cm ^-1 , neat): 3290,2950,1740,1610,1560 NMR spectrum (δ, CDCl ₃ ): 2.30 (3H, s), 3.89 (3H, s), 5.66 (2H, d, J = 54Hz),
9.48 (1H, br) Experimental Example 21 Methyl 2-amidino- (Z) -2-fluoromethoxyiminoacetate hydrochloride 190 mg of the compound of Experimental Example 20 was dissolved in methanol, 147 mg of ammonium chloride was added, and the mixture was refluxed for 4 hours. After cooling the reaction solution, 50 ml of ethyl acetate was added to remove insolubles. The solution was concentrated, and the precipitated crystals were collected and washed with ethyl ether to obtain 108 mg of the desired product.

The infrared absorption spectrum and NMR spectrum were consistent with those of the compound of Experimental Example 11.

Example 4 Methyl (Z) -2-fluoromethoxyimino-2-
(5-amino-1,2,4-thiadiazol-3-yl) acetate 214 mg of methyl 2-amidino- (Z) -2-fluoromethoxyiminoacetate hydrochloride was dissolved in 3 ml of methanol, and 253 mg of triethylamine was added. To this solution, a solution of 160 mg of bromine in 2 ml of methanol was added dropwise over 5 minutes under ice cooling, followed by stirring for 20 minutes. (Methyl 2- (N-bromo)
Amidino- (Z) -2-fluoromethoxyiminoacetate is produced).

5 ml of a solution of 103 mg of potassium thiocyanate in 3 ml of methanol
It was added dropwise over a period of minutes. After stirring at the same temperature for 2 hours and 30 minutes, the solvent was distilled off, and the residue was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was distilled off to obtain 210 mg of the desired product.

Infrared absorption spectrum (cm ^-1 , Nujol): 3400, 3250, 3100, 1730, 1680, 1610 NMR spectrum (δ, DMSO-d ₆ ): 3.84 (3H, s), 5.78 (2H, d, J = 53 Hz) , 8.23 (2H, brs) Experimental Example 22 3- (N-chloroamidino) furan 1.5 g of 3-amidinofuran hydrochloride and 1.37 g of N-chlorosuccinimide were dissolved in 20 ml of methanol. Under ice cooling, a solution of 1.07 g of triethylamine in 5 ml of methanol was added dropwise, and the mixture was stirred for 45 minutes. The solvent was distilled off under reduced pressure, and 50 ml of ethyl acetate was added to the residue.
Washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the desired product 1.30.

Melting point: 88-91 ° C Mass spectrum (m / e): 144 (M ⁺ ) Infrared absorption spectrum (cm ^-1 , Nujol): 3460,3260,1615,1590,1545,1510 NMR spectrum (δ, CDCl ₃ ) : 6.68 (1H, dd, J = 1.8Hz, 0.8Hz), 7.48 (1H, t, J = 1.8H
z), 7.88 (1H, dd, J = 1.8 Hz, 0.8 Hz) Example 5 3- (5-amino-1,2,4-thiadiazol-3-yl) furan 1.1 g of the compound of Experimental Example 22 was dissolved in 22 ml of methanol, and 0.75 g of potassium thiocyanate was added under ice-cooling.
Stirred for hours. The solvent was distilled off under reduced pressure.
Then, the mixture was washed with water and then with a saturated saline solution. Anhydrous magnesium sulfate and activated carbon were added thereto, and the solvent was distilled off under reduced pressure to obtain 0.82 g of the desired product.

Melting point: 150-151 ° C Mass spectrum (m / e): 167 (M ⁺ ) Infrared absorption spectrum (cm ^-1 , Nujol): 3300, 1640, 1600, 1530, 1515 NMR spectrum (δ, DMSO-d ₆ ) : 6.78 (1H, brs), 7.66 (1H, brs), 7.92 (2H, brs), 8.0
4 (1H, brs) Example 6 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-oxoacetic acid 167 mg of the compound of Example 5 was dissolved in a mixture of 12 ml of dichloromethane and 1.5 ml of methanol, and the mixture was cooled to −30 ° C. and passed with ozone. To the reaction solution, 2 ml of 31% aqueous hydrogen peroxide and 2 ml of acetic acid were added under ice cooling, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected to obtain 66 mg of the desired product. Further, 2 g of sodium sulfite was added to the solution, and the solvent was distilled off. 5 ml of methanol in the residue
Was added and the mixture was concentrated. Dichloromethane was added thereto, and the precipitated crystals were collected to obtain 70 mg of the desired product.
A total of 136 mg of the desired product was obtained.

Infrared absorption spectrum (cm ^-1 , Nujol): 3430, 3320, 3250, 3180, 1700, 1615 NMR spectrum (δ, DMSO-d ₆ ): 8.18 (3H, brs) Experimental Example 23 (2-methyl-3-furyl) ) Ethyl formimidate hydrochloride 3.22 g of 3-cyano-2-methylfuran, 1.41 of ethanol
After absorbing 1.14 g of hydrogen chloride in a mixture of g and 8 ml of ethyl ether, the mixture was stirred at 0 ° C. for 2 days. The solvent is distilled off under reduced pressure,
40 ml of isopropyl ether was added to the residue. The precipitated crystals were collected to obtain 1.20 g of the desired product.

Melting point: 135-136 ° C Mass spectrum (m / e): 153 (M ⁺ -HCl) Infrared absorption spectrum (cm ^-1 , Nujol): 1645, 1640, 1615, 1530 NMR spectrum (δ, CDCl ₃ ): 2.56 (3H, t, J = 7.2Hz), 3.56 (3H, s), 4.81 (2H, q, J
= 7.2Hz), 7.23 (1H, d, J = 1.8Hz), 7.74 (1H, d, J = 1.8H)
z), 11.76 (2H, brs) Experimental Example 24 3-Amidino-2-methylfuran hydrochloride 1.49 g of the compound of Experimental Example 23 was dissolved in 50 ml of a saturated aqueous solution of sodium hydrogen carbonate and extracted with 10 ml of ethyl ether. The extract was washed with water and then with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is methanol
Dissolved in 9 ml. Add 378mg of ammonium chloride and 2 hours
Refluxed for 30 minutes. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl ether to obtain 1.04 g of the desired product.

Melting point: 172 to 173 ° C Mass spectrum (m / e): 124 (M ⁺ -HCl) Infrared absorption spectrum (cm ^-1 , Nujol): 3200, 3050, 2730, 1665, 1620, 1605, 1525 NMR spectrum (δ _{, DMSO-d 6): 2.51} (3H, s), 6.74 (1H, d, J = 1.8Hz), 7.65 (1H, d, J
= 1.8 Hz), 9.00 (2H, brs), 9.11 (2H, brs) Experimental Example 25 3- (N-chloroamidino) -2-methylfuran 800 mg of the compound of Experimental Example 24, N-chlorosuccinimide 665
520 mg of triethylamine in a mixture of 8 mg and methanol 8 ml
Was added dropwise and stirred for 45 minutes. The solvent was distilled off under reduced pressure, 30 ml of ethyl acetate was added to the residue, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline.
After adding anhydrous magnesium sulfate and drying, the solvent was distilled off under reduced pressure to obtain 597 mg of the desired product.

Melting point: 85-88 ° C Mass spectrum (m / e): 158 (M ⁺ ) Infrared absorption spectrum (cm ^-1 , Nujol): 3470,3300,3270.3070,2700,1770,1705,1635,1620,157
5,1555,1515 NMR spectrum (δ, CDCl ₃ ): 2.46 (3H, s), 5.38 (2H, brs), 6.36 (1H, d, J = 1.8H)
z), 7.18 (1H, d, J = 1.8 Hz) Example 7 3- (5-amino-1,2,4-thiadiazol-3-yl) -2-methylfuran 560 mg of the compound of Experimental Example 25 was dissolved in 10 ml of methanol.
Under ice-cooling, add 347 mg of potassium thiocyanate, and add
Stirred for hours. After evaporating the solvent under reduced pressure, the residue was treated with ethyl acetate 40
Then, the mixture was washed with water and saturated saline. Anhydrous magnesium sulfate and activated carbon were added to the mixture, and the mixture was filtered. The solvent was distilled off under reduced pressure to obtain 463 mg of the desired product as an oil.

Mass spectrum (m / e): 181 (M ⁺ ) Infrared absorption spectrum (cm ⁻¹ , Nujol): 3450,3300,3150.2160,1705,1610,1510 NMR spectrum (δ, CDCl ₃ ): 2.64 (3H, s) , 5.82 (2H, brs), 6.70 (1H, d, J = 1.8H
z), 7.19 (1H, d, J = 1.8 Hz) Example 8 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-oxoacetic acid 200 mg of the compound of Example 7 was dissolved in 14 ml of dichloromethane, and ozone was passed while cooling at -30 ° C. The reaction was cooled on ice,
1 ml of methanol, 1 ml of 31% aqueous hydrogen peroxide and 2 ml of acetic acid were added, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected to obtain 58 mg of the desired product. Further, 1 g of sodium sulfite and magnesium sulfate were added to the solution, and the mixture was filtered. After the solution was concentrated under reduced pressure, dichloromethane was added, and the precipitated crystals were collected to obtain 48 mg of the desired product. In total, 106 mg of the desired product was obtained.

The infrared absorption spectrum and the NMR spectrum were identical to those of the compound of Example 6.

Example 9 2- (5-amino-1,2,4, thiadiazol-3-yl)
-(Z) -2-fluoromethoxyiminoacetic acid To a solution of 0.58 g of fluoromethoxyamine in 25 ml of ethanol and 0.45 ml of water, add 1 g of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-oxoacetic acid and adjust the pH with a 10% aqueous sodium hydroxide solution. Was adjusted to 4 to 5 and then stirred at room temperature overnight. The solvent was distilled off under reduced pressure.
10 g of salt was added, and the pH of the solution was adjusted to 1 with concentrated hydrochloric acid. This was extracted four times with 30 ml of ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous magnesium sulfate. 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 NMR spectrum were the same as those of Example 3.

Example 10 2- (5-formylamino-1,2,4-thiadiazole-
Methyl 3-yl)-(Z) -2-fluoromethoxyiminoacetate 75 g of the compound of Example 2 was suspended in a mixed solution of 180 ml of formic acid and 150 ml of acetic anhydride and stirred at room temperature for 1 day. 350 ml of diisopropyl ether was added to the reaction solution, and the precipitate was collected. This was washed with diisopropyl ether and dried to obtain 69 g of the desired product.

Melting point: 221-223 ° C. (decomposition) Infrared absorption spectrum (cm ⁻¹ , Nujol): 1720,1675 NMR spectrum (δ, DMSO-d ₆ ): 3.93 (3H, s), 5.60 (1H, s), 6.20 (1H, s), 8.86 (1H,
s) Example 11 2- (5-formylamino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetic acid 250 mg of the compound of Example 10 was suspended in 1 ml of ethanol, and 2 ml of a 2N aqueous sodium hydroxide solution and methanol were added at room temperature.
2 ml was added and stirred for 1 hour. Water was added to the reaction solution, and 3N sulfuric acid 1.
The solution was acidified with 5 ml and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 193 mg of the desired product.

Melting point: 165 to 166 ° C Infrared absorption spectrum (cm ^-1 , Nujol): 1715,1680 NMR spectrum (δ, DMSO-d ₆ ): 5.57 (1H, s), 6.17 (1H, s), 8.86 (1H, s) Example 12 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid 1N-aqueous sodium hydroxide solution 1 in 50 g of the compound of Example 11
Then, the mixture was heated at 50 ° C. for 1 hour. Add water to this and add 4N
The solution was acidified with 1 ml of sulfuric acid and extracted with ethyl acetate.
After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain 40 mg of the desired product.

The infrared absorption spectrum and the NMR spectrum were identical to those of the compound of Example 3.

Example 13 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid 10 g of the compound of Example 10 was added to 27 ml of a 3N aqueous sodium hydroxide solution under ice-cooling, followed by stirring for 30 minutes. To this solution was added 9 ml of an 8N aqueous sodium hydroxide solution, and the mixture was further stirred under ice-cooling for 24 hours. 40 ml of 4N sulfuric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was recrystallized from chloroform to obtain 7.0 g of the desired product.

The infrared absorption spectrum and the NMR spectrum were identical to those of the compound of Example 3.

Example 26 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid chloride hydrochloride Dissolve 500 mg of phosphorus pentachloride in 5 ml of dry methylene chloride.
After cooling to 10 ° C., 325 mg of 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid was added, and the mixture was stirred at the same temperature for 30 minutes. 20 ml of isopropyl ether 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 C
l) Infrared absorption spectrum (cm ^-1 , Nujol): 1780,1625 NMR spectrum (δ, DMSO-d ₆ ): 5.85 (2H, d, J = 55 Hz) Experimental example 27 p-methoxybenzyl 7β- (2-phenyl) Acetamide) -3-triphenylphosphoniomethyl-3-cephem-4-carboxylate iodide 250 g of p-methoxybenzyl 7β- (2-phenylacetamido) -3-chloromethyl-3-cephem-4-carboxylate was suspended in 1.5 of acetone, 200 g of triphenylphosphine and 78 g of sodium iodide were added, and the mixture was added at room temperature. Stir for 1 hour. The insoluble material was removed, and the solution was added dropwise to a mixed solution of ethyl acetate 6-isopropyl ether 3 with stirring, and the resulting precipitate was collected. The precipitate was washed with 600 ml of isopropyl ether and dried to obtain 420 g of the desired product.

Infrared absorption spectrum (cm ⁻¹ , Nujol): 1780,1710,1670,1610 NMR spectrum (δ, DMSO-d ₆ ): 3.50 (2H, s), 3.71 (3H, s), 4.3 to 5.3 (5H, m ), 5.56
(1H, dd, J = 5.2Hz, 7.2Hz), 6.82 (2H, d, J = 8.0Hz), 7.0
-7.4 (7H, m), 7.4-8.0 (15H, m), 9.00 (1H, d, J = 7.5H
z) Experimental Example 28 p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(Z) -3-chloro-1-propenyl]
-3-Cephem-4-carboxylate 120 g of the compound of Experimental Example 27 was dissolved in chloroform 0.8,
223 ml of 1N sodium hydroxide aqueous solution and 200 ml of saturated saline
Was added and stirred. The organic layer was separated, washed with water, and dried over potassium carbonate. Remove potassium carbonate,
Under ice cooling, N, O-bis (trimethylsilyl) acetamide 1
8.4 ml was added and stirred for 5 minutes. 150 ml of a chloroform solution containing 67 g of chloroacetaldehyde was added and stirred for 30 minutes. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 32.4 g of the desired product.

Infrared absorption spectrum (cm ^-1 , Nujol): 1760, 1720, 1660, 1610 NMR spectrum (δ, DMSO-d ₆ ): 3.55 (2H, s), 3.76 (3H, s), 3.93 (1H, dd, J) = 8.0Hz, 1
2.0Hz), 4.16 (1H, dd, J = 8.0Hz, 12.0Hz), 5.14 (2H, AB
q, J = 12.0Hz), 5.21 (1H, d, J = 5.0Hz), 5.70 (1H, dt, J
= 11.3Hz, 8Hz), 5.74 (1H, dd, J = 5.0Hz, 8.0Hz), 6.30
(1H, d, J = 11.3Hz), 6.94 (2H, d, J = 8.5Hz), 7.28 (5H,
s), 7.33 (2H, d, J = 8.5 Hz), 9.14 (1H, d, J = 8.0 Hz) Experimental Example 29 p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -3 -Iodo-1-propenyl]
-3-Cephem-4-carboxylate 200 g of the compound of Experimental Example 28 was suspended in 2.5 ml of dry acetone, 290 g of sodium iodide was added, and the mixture was stirred at room temperature for 3 hours. The solution was concentrated, and the precipitated crystals were collected and washed with a dilute aqueous solution of sodium thiosulfate, water, and then acetone to obtain 133.4 g of the desired product.

Infrared absorption spectrum (cm ^-1 , Nujol): 1775,1715,1650 NMR spectrum (δ, DMSO-d ₆ ): 3.50 (1H, d, J = 13.8 Hz), 3.56 (1H, d, J = 13.8 Hz) , 3.
59 (1H, d, J = 17.8Hz), 3.74 (3H, s), 3.90 (1H, d, J = 1
7.8Hz), 4.30 (2H, d, J = 7.0Hz), 5.15 (1h, d, J = 4.8H)
z), 5.19 (1H, d, J = 12.0Hz), 5.23 (1H, d, J = 12.0Hz),
5.70 (1H, dd, J = 4.8Hz, 8.4Hz), 6.22 (1H, dt, J = 15.4H
z, 7Hz), 6.79 (1H, d, J = 15.4Hz), 6.93 (2H, d, J = 8.4H
z), 7.2 ~ 7.35 (5H, m), 7.36 (2H, d, J = 8.4Hz), 9.18
(1H, d, J = 8.4 Hz) Experimental Example 30 p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -3-[(R) -1-carbamoyl-2-hydroxyethyl] dimethyl Ammonium)-
1-propenyl] -3-cephem-4-carboxylate iodide 5.0 g of the compound of Experimental Example 29 was N, N-dimethylformamide 1
Suspended in 9 ml and cooled with ice to give (R) -2-dimethylamino-
1.42 g of 3-hydroxypropionamide was added, and the mixture was stirred for 2 hours while gradually returning to room temperature. Isopropyl ether
After adding 200 ml and stirring, the supernatant was removed and the oily precipitate was dissolved by adding 80 ml of chloroform. This is ethyl ether
300 ml was added dropwise, and the resulting precipitate was removed to obtain 3.89 g of the target substance as a pale yellow powder.

Infrared absorption spectrum (cm ^-1 , Nujol): 1775,1690,1655 NMR spectrum (δ, DMSO-d ₆ ): 3.11 (3H, s), 3.17 (3H, s), 3.52 (2H, s), 3.73 ( 3H,
s), 3.85 to 4.1 (3H, br), 4.1 to 4.35 (2H, m), 5.15 (1H,
d, J = 4.8Hz), 5.18 (2H, s), 5.5 ~ 5.8 (1H, br), 5.69
(1H, dd, J = 4.8Hz, 8.0Hz), 5.95-6.4 (1H, m), 6.90 (2
H, d, J = 8.5Hz), 7.23 (5H, s), 7.32 (2H, d, J = 8.5Hz),
7.80 (1H, br), 8.01 (1H, br), 9.09 (2H, d, J = 8.0 Hz) Experimental Example 31 7β- (2-phenylacetamide) -3-[(E)-
3-[(R) -1-carbamoyl-2-hydroxyethyl) dimethylammonio] -1-propenyl] -3-cephem-4-carboxylate trifluoroacetate 3.65 g of the compound of Experimental Example 30 were suspended in 22 ml of anisole,
Under ice cooling, 25 ml of trifluoroacetic acid was added dropwise over 30 minutes, and the mixture was stirred for 1 hour. 200 m of isopropyl ether in the reaction solution
l was added and the resulting precipitate was removed. This was washed with ethyl acetate and ethyl ether to obtain 2.67 g of the desired product as a pale yellow powder.

Infrared absorption spectrum (cm ^-1 , Nujol): 1770,1680 NMR spectrum (δ, DMSO-d ₆ ): 3.11 (3H, s), 3.17 (3H, s), 3.52 (2H, s), 3.6 to 4.4
(7H, m), 5.11 (1H, d, J = 5.0Hz), 5.65 (1H, dd, J = 5.0H
z, 8.0Hz), 5.9 ~ 6.35 (1H, m), 7.02 (1H, d, J = 15.3H
z), 7.23 (5H, s), 7.77 (1H, brs), 8.09 (1H, brs), 9.0
9 (1H, d, J = 8.0 Hz) Experimental Example 32 7β-amino-3-[(E) -3-[((R) 1-carbamoyl-2-hydroxyethyl) dimethylammonio] -1-propenyl] -3-Cephem-4-carboxylate perchlorate 8.0 g of the compound of Experimental Example 31, 8.0 g of sodium acetate trihydrate
Was dissolved in 12 ml of water. Add 0.3g of activated charcoal to this and at room temperature
After stirring for 15 minutes, the mixture was filtered and the solution was adjusted to pH 7.
Adjusted to 7. 2 g of carrier-fixed penicillin G amidase (trade name, penicillin G amidase derived from Escherichia coli (carrier: polyacrylamide) manufactured by Boehringer Maiheim Yamanouchi Co., Ltd.) is added to the mixture at 30 ° C., and the pH of the solution is adjusted to 7.5 to 7.8 with aqueous ammonia. While stirring at the same temperature for 1 hour. Take this solution and add Sepabeads SP
The product was purified by column chromatography on 207 (trade name, styrene-divinylbenzene copolymer adsorbent, manufactured by Mitsubishi Kasei Corporation), and the target fraction was concentrated to 20 ml. To this 70
% Perchloric acid was added to adjust the pH to 2.5, and 150 ml of isopropanol was added dropwise with stirring. The resulting precipitate was collected and washed with acetone and ethyl ether to obtain 1.485 g of the desired product as pale yellow crystals.

Infrared absorption spectrum (cm ^-1 , Nujol): 1775,1690,1585 NMR spectrum (δ, DMSO-d ₆ ): 3.11 (3H, s), 3.18 (3H, s), 3.4-4.1 (5H, m), 4.25
(2H, br, d, J = 6.8Hz), 4.89 (1H, d, J = 5.2Hz), 5.10 (1
H, d, J = 5.2Hz), 5.9-6.3 (1H, m), 7.06 (1H, d, J = 15.8
Hz), 7.78 (1H, brs), 8.15 (1H, br) Experimental Example 33 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetaomido] -3-[(E) -3-[(R) -1-carbamoyl-2-hydroxyethyl] dimethylammonio]
-1-propenyl] -3-cephem-4-carboxylate 5.5 ml of methanol containing 230 g of sodium oxide trihydrate
150 mg of the compound of Experimental Example 32 and 100 mg of the compound of Experimental Example 26 were added to 1 ml of water, and the mixture was stirred at room temperature for 1 hour. The methanol was distilled off, and the residue was purified by reverse-phase silica gel column chromatography to obtain 46 mg of the desired product.

Infrared absorption spectrum (cm ^-1 , Nujol): 1765,1670,1600,1530 NMR spectrum (δ, DMSO-d ₆ ): 3.08 (3H, s), 3.14 (3H, s), 3.49 (1H, d, J = 17.2H
z), 3.62 (1H, d, J = 17.2Hz), 3.87 (1H, dd, J = 5.5Hz, 1
2.5Hz), 4.06 (1H, dd, J = 5.5Hz, 12.5Hz), 4.1 ~ 4.2 (1
H, m), 4.19 (2H, d, J = 7.3Hz), 5.08 (1H, d, J = 5.0Hz),
5.67 (1H, dd, J = 4.8Hz, 8.4Hz), 5.70-5.85 (1H, m), 5.
79 (2H, d, J = 55.0Hz), 7.11 (1H, d, J = 15.4Hz), 7.76
(1H, s), 8.22 (2H, s), 8.52 (1H, s), 9.73 (1H, d, J =
8.4Hz) Antibacterial activity MIC (μg / ml) Staphylococcus aureus 0.2 209-P Escherichia coli ≤ 0.025 NIHJ Klebsiella pneumoniae ≤ 0.025 EK-6 Serratia marcescens ≤ 0.025 ES-75 Morganella morgani ≤ 0.025 EP-14 Pseudomonas aeruginosa 0.8 EP-01 Experimental Example 34 p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -3-carbamoylmethylethylmethylammonio-1-propenyl] -3-cephem-
4-carboxylate iodide In the same manner as in Experimental Example 30, 20 g of the compound of Experimental Example 29 was added to 2-
Reacted with 4.22 g of ethyl methylacetamide to obtain 23.
0 g was obtained.

Infrared absorption spectrum (cm ^-1 , Nujol): 1770,1650 NMR spectrum (δ, DMSO-d ₆ ): 1.15 to 1.4 (3H, m), 3.14 (3H, s), 3.25 to 3.8 (3H,
m), 3.55 (2H, s), 3.77 (3H, s), 4.0 ~ 4.2 (4H, m), 5.1
6 (1H, d, J = 5.2Hz), 5.23 (2H, s), 5.71 (1H, dd, J = 5.2
Hz, 8.0Hz), 5.95 to 6.4 (1H, m), 6.96 (2H, d, J = 8.8H
z), 7.30 (5H, s), 7.41 (2H, d, J = 8.8Hz), 7.75 (1H, b
r), 8.43 (1H, br), 9.21 (1H, d, J = 8.0 Hz) Experimental Example 35 7β- (2-phenylacetamido) -3-[(E)-
3-carbamoylmethylethylmethylammonio) -1
-Propenyl] -3-cephem-4-carboxylate trifluoroacetate In the same manner as in Experimental Example 31, 23 g of the compound of Experimental Example 34 was suspended in 130 ml of anisole, and 140 ml of trifluoroacetic acid was added to obtain 15.9 g of the desired product.

Infrared absorption spectrum (cm ⁻¹ , Nujol): 1775,1690 NMR spectrum (δ, DMSO-d ₆ ): 1.26 (3H, brt, J = 6.8 Hz), 3.10 (3H, s), 3.52 (2H,
s), 3.90 to 4.15 (4H, m), 5.08 (1H, d, J = 4.8 Hz), 5.62
(1H, dd, J = 4.8Hz, 8.0Hz), 5.9 ~ 6.4 (1H, m), 6.97 (1
H, d, J = 15.7Hz), 7.20 (5H, s), 7.63 (1H, brs), 8.31
(1H, brs), 9.08 (1H, d, J = 8.0Hz) Experimental Example 36 7β-amino-3-[(E) -3- (carbamoylmethylethylmethylammonio) -1-propenyl] -3-
Cephem-4-carboxylate paratoluenesulfonate In the same manner as in Experimental Example 32, 5.9 g of the compound of Experimental Example 35 was hydrolyzed using 5.9 g of carrier-fixed penicillin G amidase to obtain 0.85 g of the desired product. However, para-toluenesulfonic acid monohydrate was used instead of perchloric acid in Experimental Example 32.

Infrared absorption spectrum (cm ^-1 , Nujol): 1779,1690,1590 NMR spectrum (δ, DMSO-d ₆ ): 1.25 (3H, brt, J = 6.5 Hz), 2.26 (3H, s), 3.07 (3H ,
s), 3.3 to 4.05 (6H, m), 4.18 (2H, br d, J = 6.8 Hz), 4.7
7 (1H, d, J = 5.0 Hz), 4.98 (1H, d, J = 5.0 Hz), 5.8 to 6.2
(1H, m), 0.97 (1H, d, J = 16Hz), 7.05 (2H, d, J = 8.0H
z), 7.43 (2H, d, J = 8.0Hz), 7.60 (1H, brs), 7.93 (1H,
br) Experimental Example 37 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (carbamoylmethylethylmethylammonio) -1-propenyl] -3-cephem-4-carboxylate In the same manner as in Experimental Example 33, 60 mg of the compound of Experimental Example 36 was reacted with 32 mg of the compound of Experimental Example 26 to obtain 18 mg of the desired product.

Infrared absorption spectrum (cm ⁻¹ , Nujol): 1760, 1675, 1590, 1520 NMR spectrum (δ, DMSO-d ₆ ): 1.26 (3H, t, J = 7.2 Hz), 3.08 and 3.09 (3 in total)
H, s), 3.4 to 3.6 (2H, m), 3.47 (1H, d, J = 16.8Hz), 3.65
(1H, d, J = 16.8Hz), 4.01 (2H, s), 4.05-4.2 (2H, m),
5.06 (1H, d, J = 4.8Hz), 5.6 ~ 5.75 (2H, m), 5.79 (2H, b
r, d, J = 55.3Hz), 7.17 (1H, d, J = 15.8Hz), 7.66 (1H,
s), 8.23 (2H, s), 8.33 (1H.s), 9.71 (1H, d, J = 8.4H
z) Antimicrobial activity MIC (μg / ml) Staphylococcus aureus 0.2 209-P Escherichia coli ≦ 0.025 NIHJ Klebsiella pneumoniae ≦ 0.025 EK-6 Serratia marcescens 0.1 ES-75 Morganella morgani ≦ 0.025 EP-14 Shodomonas. Elginosa 0.8 EP-01

Continuation of the front page Examiner Junko Uchida (56) References JP-A-63-264470 (JP, A) JP-A-1-156983 (JP, A) JP-A-1-156984 (JP, A) JP-A 61 -243090 (JP, A) JP-A-57-158769 (JP, A) JP-A-58-126877 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 285/00- 285/38 C07D 417/00-417/14 CA (STN) REGISTRY (STN)

Claims (8)

(57) [Claims] (1) a general formula: [Wherein R ₁ represents a hydrogen atom or a lower alkyl group], a salt thereof, or a compound in which the amino group is protected by a protecting group is oxidized, and if necessary, the protecting group is removed to form a compound represented by the formula: A compound of which the amino group is protected by a protecting group, or a salt thereof, and after reacting with fluoromethoxyamine or a salt thereof, if necessary, removing the protecting group. : A method for producing a thiadiazolylacetic acid derivative represented by the formula (I), a compound having an amino group protected with a protecting group, or a salt thereof. 2. The general formula: [Wherein R ₁ represents a hydrogen atom or a lower alkyl group], a salt thereof, or a compound in which the amino group is protected by a protecting group, is oxidized, and if necessary, the protecting group is removed. Features, expression: A method for producing a compound represented by the formula (I), a compound in which the amino group is protected by a protecting group, or a salt thereof. 3. The general formula: [Wherein, R ₁ represents a hydrogen atom or a lower alkyl group], a salt thereof, or a compound in which the amino group is protected by a protecting group. 4. The general formula: Wherein R ₂ represents a lower alkyl group, a salt thereof, or a compound having an amino group protected by a protecting group, which is hydrolyzed by a general formula: [Wherein R ₂ represents a lower alkyl group], a salt thereof, or a compound in which the amino group is protected by a protecting group, and then the compound is hydrolyzed to remove the protecting group if necessary. An expression characterized by separating: A method for producing a compound represented by the formula (I), a compound in which the amino group is protected by a protecting group, or a salt thereof. 5. The general formula: Wherein R ₂ represents a lower alkyl group, a salt thereof, or a compound in which the amino group is protected with a protecting group, and the protecting group is removed if necessary. The general formula: Wherein R ₂ is the same as defined above,
A method for producing a salt thereof or a compound in which the amino group is protected by a protecting group. 6. The general formula: [Wherein R ₂ represents a lower alkyl group], a salt thereof, or a compound wherein the amino group is protected by a protecting group. 7. A general formula: Wherein R ₂ represents a lower alkyl group, a salt thereof, or a compound in which the amino group is protected with a protecting group, and the protecting group is removed if necessary. The expression: A method for producing a compound represented by the formula (I), a compound in which the amino group is protected by a protecting group, or a salt thereof. 8. The formula: Or a salt thereof, or a compound in which the amino group is protected by a protecting group.