JPS63264470A - Thiadiazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R1 is COOH, halogenocarbonyl, CONH2 or CN), a compound obtained by protecting the amino group and/or carboxyl group thereof with a protecting group or a salt thereof. EXAMPLE:Ethyl 2(5-triethylamino-1,2,4-thiazol-3-yl)-(Z)-2-fluoromethoxyiminoace tate. USE:An intermediate for antibacterial agents. PREPARATION:A compound shown by formula II (or formula III) which may contain NH2 protecting group and/or COOH protecting group or a salt thereof is reacted with a halogenofluoromethane (or NH2OCH2F or a salt thereof) or a compound shown by formula IV which may contain NH2 protecting group or a salt thereof is hydrolyzed in the presence of a base or a compound shown by formula V (X is halogen) which may contain COOH protecting group or a salt thereof is reacted with an alkali metallic salt of thiocyanic acid and then, if necessary, deprotected to give a compound shown by formula I (R1=COOH) or a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention relates to novel thiadiazole derivatives useful as intermediates for antibacterial agents.

Previously, JP-A No. 59-172493 and JP-A No. 6
No. 1-5084 discloses a cephem derivative having an ammoniopropenyl group at the 3-position and a thiadiazolyl acetic acid derivative residue or a thiazolyl acetic acid derivative residue at the 7-position.

The present inventors have an ammoniopropenyl group at the 3-position.

It has been found that a cephem derivative having a thiadiazolyl acetic acid derivative residue substituted with a fluoromethoxyimino group at the 7-position has superior antibacterial activity. The present invention relates to novel thiadiazole derivatives that are intermediates 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 the invention]

The present invention relates to a thiadiazole derivative represented by the general formula: [wherein R2 represents a carboxyl group, a halogenocarbonyl group, a carbamoyl group, or a cyano group], a compound whose amino group and/or carboxyl group is protected with a protecting group, or It is their salt.

Examples of the halogen atom in the halogenocarbonyl group of R1 include a chlorine atom, a bromine atom, and an iodine atom.

Protecting groups for amino groups include 2, for example, formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, phenylacetyl group, chenylacetyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, trityl group, p- Methoxybenzyl group, diphenylmethyl group, benzylidene group.

Examples include p-nitrobenzylidene group, 9m-chlorobenzylidene group, and trimethylsilyl group.

Protective groups for carboxyl groups include p-methoxybenzyl group, p-nitrobenzyl group, t-butyl group, methyl group, ethyl group, 2,2,2. -9 chloroethyl group,
Examples include diphenylmethyl group, pivaloyloxymethyl group, and trimethylsilyl group.

The salt of the compound of the general formula (Il) is the sodium salt.

Alkali metal salts such as potassium salts; calcium salts.

Alkaline earth metal salts such as magnesium salts; ammonium salts; quaternary ammonium salts such as tetraethylammonium salts and betaine salts; hydrochlorides, hydrobromides, hydroiodides, sulfates, carbonates 9 bicarbonates Inorganic acid salts such as maleate, lactate, tartrate, organic carboxylate such as monofluoroacetate; methanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate,
Organic sulfonates such as taurate, benzenesulfonate, toluenesulfonate; trimethylamine salt, )! j Ethylamine salt, pyridine salt, prolactine salt,
Picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, jetanolamine salt.

Amine salts such as triethanolamine salt, tris(hydroxymethylamino)methane salt, phenethylbenzylamine salt; arginine salt, aspartate, lysine salt,
It can be appropriately selected from salts such as amino acid salts such as glutamate, serine salts, and glycine salts.

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

(VI) (V) (I-4) ■ (■) (■) (IV) ↓ In the above formula, X represents a halogen atom. Further, in the above production process, each compound may be a compound whose amino group and/or carboxyl group is protected with a protecting group, or a salt thereof.This production process will be explained in more detail.

(1) Production of compound of formula (I-1) a) (ml-(I-1)) A compound represented by formula (II) whose amino group is protected with a protecting group, and whose carboxyl group is protected with a protecting group. A thiadiazole derivative represented by formula (I-1) is obtained by reacting the compound protected with or a salt thereof with halogenofluoromethane, and then removing the protecting group as necessary.
A compound whose amino group and/or carboxyl group is protected with a protecting group, or a salt thereof can be obtained.

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

Also, protecting groups for amino and carboxyl groups.

Regarding salt, it is as described above.

The above reaction is carried out in an inert solvent 9, such as sulfoxides such as dimethyl sulfoxide, amides such as N,N-dimethylacetamide, formamide, hexamethylphosphortriamide, ketones such as acetone, or a mixed solvent thereof. It can be carried out at a temperature of -30°C to 100°C.

The protective groups for carboxyl and amino groups can be removed by conventional methods such as hydrolysis and reduction, depending on the type of protective group used.

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

The protecting 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 06C to 70C. As the base, sodium hydroxide, potassium hydroxide, etc. can be used.

C) aID - (I-1) After reacting a compound represented by a sigma, a compound whose amino group and/or carboxyl group is protected with a protecting group, or a salt thereof with fluoromethoxyamine or a salt thereof, the necessary By removing the protecting group, the formula 2 (
A thiadiazole derivative represented by I-1) or a salt thereof can be obtained.

The protecting 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 sulfonate salts are mentioned.

The above reaction is carried out in an inert solvent such as a lower alcohol or a mixed solvent with water at a reaction temperature of -200C to 80C.
It can be done with

d) (EV) → (I-1) After reacting the salt with an alkali metal thiocyanate,
By removing the protecting group if necessary, formula (I-1')
A thiadiazole derivative represented by, a compound whose carboxyl group is protected with a protecting group.

Or you can get their salt.

Examples of the halogen atom for X in the general formula (2) include a chlorine atom, a bromine atom, and an iodine atom. carboxyl group protecting group,
Regarding salt, it is as described above.

The above reaction is carried out in an inert solvent such as a lower alcohol.

The reaction can be carried out at a temperature of -50°C to room temperature.

This reaction is preferably carried out in the presence of a base such as triethylamine.

(2) Production of compound of formula (I-2) A compound represented by formula (I-1), a compound whose amino group is protected with a protecting group, or a salt thereof is reacted with a halogenating agent to form a compound represented by formula (I-2). I-2) thiadiazole derivative,
Compounds whose amino groups are protected with a protecting group, or salts thereof can be obtained.

Examples of the halogenating agent include phosphorus pentachloride, thionyl chloride, thionyl bromide, and phosphorus oxychloride. 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 -50QC to 50C.

(3) Production of compound of formula (I-3) A compound represented by formula (I-4), a compound whose amino group is protected with a protecting group, or a salt thereof is hydrated in the presence of an oxidizing agent and a base. After disassembling.

If necessary, the protecting group can be removed to obtain the thiadiazole derivative of 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.

The reaction can be carried out at a temperature of 00C to 70C.

(4) Production of compound of formula (I-4) A thiadiazole derivative represented by formula (I-4) or a salt thereof is obtained by reacting a compound represented by general formula (1) or a salt thereof with an alkali metal thiocyanate salt. be able to.

Regarding the reaction conditions, etc., refer to (1) d) above - (I-1
) is similar to the reaction.

This compound is obtained by halogenating a compound represented by 2M or a salt thereof to obtain a compound of the general formula (2).

It can also be produced by subsequently carrying out the above reaction without isolating it from the reaction site.

The reaction from ■→■ will be described later.

e) Te (screaming combination) It is possible to obtain a compound or a salt thereof.

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

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.

The reaction can be carried out at a temperature of 00C to 70C.

r) Compound of formula (2) A compound of formula (2) or a salt thereof can be obtained by reacting a compound of formula (2) or a salt thereof with a halogenating agent.

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

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.
It can be carried out at ~50°C.

g) Compound 2M A compound represented by formula (2) or a salt thereof can be obtained by reacting a compound represented by formula (2) with ammonia and/or an ammonium salt.

Ammonium chloride is an ammonium salt.

Examples include ammonium acetate and ammonium sulfate.

The above reaction involves water, lower alcohol, and acetone.

In an inert solvent such as chloroform or a mixed solvent of these 9
The reaction can be carried out at a temperature of -200C to room temperature.

h) Compound of Formula (2) A compound of Formula (2) can be obtained by reacting a compound of Formula (9) with a dehydrating agent in an inert solvent such as acetonitrile.

Examples of the dehydrating agent include phosphorus oxychloride and thionylfluoro-N'ide. The reaction temperature is preferably room temperature or higher.

i) Compound of Formula (2) A compound represented by Formula (2) can be obtained by reacting 2-cyano-2-hydroxyiminoacetamide with halogenofluoromethane.

Regarding the reaction conditions, etc., (III→(
It is the same as I-1').

The compounds of the present invention are useful as intermediates for β-lactam antibiotics, especially cephem compounds.

An excellent antibacterial agent or an intermediate thereof can be obtained by acylating the represented compound, a compound whose amino group is protected with a protecting group, or a salt thereof. In particular, 7 of cephems with an ammonium propenyl group in the 3-position
By introducing the compound of the present invention into this position, a compound having extremely excellent antibacterial activity can be obtained. The above-mentioned acylation can be induced in a conventional manner into a compound represented by , a compound whose amino group is protected with a protecting group, or a salt thereof.

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

Example 1 Ethyl 2-(5-)ritylamino-1.2.4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetate Ethyl 2-(5-tritylamino-1,2,4-thiadiazole) -3-yl')-(Zl-2-hydroxyiminoacetate 60.4 g was dissolved in dimethyl sulfoxide 2
Dissolved in 10 rnL and cooled with water, potassium carbonate 96.4
8° was added and stirred for 10 minutes. Then, bromofluoromethane19. was added and stirred at room temperature for 3 hours.

Ethyl acetate IL was added to the reaction solution, washed with water and then with saturated brine, and dried by adding anhydrous magnesium sulfate. The solvent was distilled off, and 120 ml of ethanol was added to the residue. The precipitated crystals were poured into the bottom of the furnace and washed with ethanol to obtain the desired product 58.
2, was obtained.

Infrared absorption spectrum (Offl', Nujol): 1
735,153O NMR spectrum (δ, DMSO-d6): 1.1
9 (3H, t, J = care), 4.21 (2H, q,
J=7 out).

5.79 (2H, d, J = 557) t 7.30 (1
5H,s).

10.03 (IH,s)' Example 2 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Zl-2-fluoromethoxyiminoacetic acid sodium hydroxide 2-04 y* ethanol 146
Compound 17.87y of Example 1 was added to a mixture of rnL and 29 trtL of water, and the mixture was stirred under reflux for 20 minutes. After the reaction solution was concentrated under reduced pressure, 200 rnL of ethyl acetate and 77 TILL of IN hydrochloric acid were added. Separate the ethyl acetate layer and wash with saturated brine.

It was dried by adding anhydrous magnesium sulfate. The solvent was distilled off to obtain crystals. Petroleum ether was added to the crystals, the crystals were ground, and P was removed to obtain the desired product (16.55%).

Melting point: 144-1466C Mass x vector (m/e): M” + 1
-...463 elemental analysis value: C, 4H1, N, 0
5SF -1/2 a,o,! : LTEHNF Theoretical value (96) 61.14 4.28 11.8
8 4.03 Actual value (%”) 61.30 4.3
7 11.61 3.91 Infrared absorption spectrum (Cm
”, Nujol): 1720, 1585 NMR spectrum (δ, DMSO-d6): 5.7
8 (2H, d, J=55Hz), 7.31 (15H
,s).

10.06 (IH,s) Example 3 2-(5-)rithylamino-1.2.4-thiadiazol-3-yl)-(Zl-2-fluoromethoxyiminoacetic acid chloride hydrochloride phosphorus pentachloride 395 rng was dissolved in dichloromethane 2.9.m
The solution was dissolved in L and cooled to -5°C. Example 2 to this solution
627 mg of the compound was added thereto, and the mixture was stirred at the same temperature for 2 hours and 30 minutes. The reaction solution was mixed with 9.4rnL of n-hexane and n-
It was added to a mixture of 9.4 mL of octane. The resulting crystals were collected and washed with n-octane to obtain 325 mg of the desired product.

Melting point: 139-140°C (decomposition) Mass x hect/l/ (m/e): M'・
-...480 ("C1) t482 (17C1) Infrared absorption spectrum ((m', Nujol): 179
5, 1780.1740.163ON1viR spectrum (δ, DMSO-d,): 5.79 (2H, d,
J=54Hz), 7.31 (15H, s).

10.09 (IH,s) Example 4 2-(5-amino-1,2,4-thiadiazole-3-
yl)-(Zl-2-fluoromethoxyiminoacetic acid ethyl ester 2.00% of the compound of Example 1 in trifluoroacetic acid.

Stirred for 30 minutes at room temperature. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the desired product 4.
05 rny was obtained.

M point: 172-173'C Infrared absorption spectrum ((m', Nujol): 173
0,1615 NMR7,hexyl(a,DMSO-d,):
1.28 (3 bows t, J=7.ωt).

4.34 (2H, q, J=7.0 ratio).

5.83 (2H, d, J-54, 5Hz), 8.2
7(2H,brs)Example 5 2-(5-amino-1,2,4-thiadiazole-3-
200 μl of the compound of Example 4)-(Zl-2-fluoromethoxyiminoacetic acid) was suspended in a mixture of 6 rttL of ethanol and 2 mL of water, and 1 liter of IN aqueous sodium hydroxide solution was added.
．． 75 ml was added and stirred at 60°C for 1 hour.

Ethanol was distilled off from the reaction solution, and the solution was diluted with IN hydrochloric acid.
) Adjusted to H2. This is Diaion SP 207 (
The product was purified using a nonionic adsorption resin (trade name, manufactured by Mitsubishi Chemical Industries, Ltd.) to obtain 30 mg of the target product.

Infrared absorption spectrum (Cm', Nujol): 172
0,162O NMR spectrum (δ, DMSO-d6): 5.7
6 (2H, d, J=55.8Hz), 8.12 (2
H, brs) Experimental Example 1 (Synthesis of raw material compound) 2-Cyano-2-fluoromethoxyiminoacetamide No-C-CONH.

``'CH,F 2-cyano-2-hydroxyiminoacetamide 22.
6y was dissolved in 100 mL of dimethyl sulfoxide.

While stirring at room temperature, 55.2 y of potassium carbonate was added, and the mixture was further stirred for 20 minutes. Next, 27g of fluorobromomethane
A 20 rnL solution of dimethylformamide was added thereto, and after stirring at room temperature for 20 hours, the mixture was allowed to cool. The reaction solution was added to ice water and extracted twice with 150 mL of ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was washed with ethyl ether and dried to obtain the desired product 14.4.

Melting point: 124-125°C Infrared absorption spectrum (CM!-l, Nujol): 3
410, 3290.3150.1690.159ONM
R spectrum (δ, DMSO-ds): 5.94 (
2H, d, J=54.0Hz), 7.85-9.4
0(2H,br) Experimental Example 2 (Synthesis of Raw Material Compound) 2-Fluoromethoxyiminopropanedinitrile NC-C-CN Compound of Experimental Example 1 14.0 Q, Acetonitrile) 15 mL.

A mixture of 15 g of sodium chloride and 14 phosphoryl chloride was reacted under reflux for 2 hours, and then 5 W of phosphoryl chloride was added.
Ll was added and reacted for 2 hours. Cool the reaction solution and add the liquid to 59
6 Wash with aqueous sodium bicarbonate solution and then with saturated saline,
After drying by adding anhydrous magnesium sulfate, the solvent was distilled off. The oily product was distilled under reduced pressure to obtain the desired product 9.1 as a colorless oil.
I got g.

Boiling point: 69-70°C 125mmHg NMR spectrum (δ, CDCl5): 5.85 (
2H, d, J = 52.0 ratio) Experimental Example 3 (Synthesis of raw material compounds) 2-cyano-2-fluoromethoxyiminoacetamidine 28% ammonia water 50 g, ammonium chloride 8 g
.

A mixture of 50 zL of ethanol was cooled to -5°C and stirred.

9.1 g of the compound of Experimental Example 2 was added, 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. After drying the extract by adding anhydrous magnesium sulfate, 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 to the solution while stirring. The resulting precipitate was filtered to the bottom of the furnace, washed with ethanol, and then dried to obtain the acetate salt of the title compound. The following physical property values are for acetate.

Melting point: 125-127°C Infrared absorption spectrum (Cm-1, Nujol) = 32
00, 1670.157O NMR spectrum (δ, DMSO-d,): 1.9
0(3H,s), 5.95(2H,d, J=54.
t).

7.40 (3H, br) Example 6 2-(5-amino-1,2,4-thiadiazole-3-
yl')-(E)-2-fluoromethoxyiminoacetonitrile 360 g of the compound of Experimental Example 3 was dissolved in 50 mL of methanol, and 4.2 g of triethylamine was added to the solution under ice cooling.

After cooling the solution to -5° C., 3.5 g of bromine was added dropwise.

Subsequently, potassium thiocyanate 2 was added at -30C to -5°C.
．． 1 g of methanol solution was added dropwise, and the mixture was stirred at the same temperature for 2 hours. The resulting precipitate was separated and washed with water and methanol. This was recrystallized from acetone to obtain 3.4 g of the desired product.

Melting point = 236-238℃ Infrared absorption spectrum (C7+1-', Nujol)
:3450, 3250.3075.1610.152O
NMR spectrum (δ, DMSO-da): 6.0
2 (2H, d, J=54.0Hz), 8.38 (2
H, br) Example 7 2-(5-amino-1,2,4-thiadiazole-3-
yl)-(Zl-2-fluoromethoxyiminoacetamide 3 to 181!LL aqueous solution of 0.23 g of sodium hydroxide
Add 7.4 rnL of 596 hydrogen peroxide solution and stir at room temperature.
Add 2.0 g of the compound of Example 6 and heat at 25°C to 30°C.
The mixture was stirred for 8 hours. The precipitated crystals were poured into the bottom of the furnace, washed with water and acetone, and then dried to obtain 1.3 g of the desired product.

Melting point = 210°C ~ 211°C Infrared absorption spectrum (CI=, Nujol): 345
0,3260.31B0.1690.161ONMR spectrum (δ, DMSOda): 5.73 (2H,
d, J=55.0Hz), 7.69 (2H, br)
.

7.98 (IH, br), 8.10 (IH, br) Example 8 2-(5-amino-1,2,4-thiadiazole-3-
A mixture of 1.1 g of the compound of Example 7 and 10 mL of a 2N aqueous sodium hydroxide solution was stirred at 50° C. for 5 hours.

After cooling the reaction mixture and adjusting the pH to 1.0 with concentrated hydrochloric acid.

Extracted three times with 20 zl of ethyl acetate. After drying the extract by adding anhydrous magnesium sulfate, the solvent was distilled off.

The residue was washed with isopropyl ether to give a crude product of 0.8
I got g. This was purified by reverse phase silica gel column chromatography to obtain the desired product 0.49.

The infrared absorption spectrum and NMR spectrum matched those of Example 5.

Experimental Example 4 (Production of raw material compound) 63.2 ml of N-fluoromethoxyphthalimidoolomethane was added to 350 mL of dry dimethyl sulfoxide cooled to 0°C. potassium carbonate 13
5 g was added and stirred at room temperature for 4 hours. Then nitrogen gas was introduced for 1 hour. The reaction solution was added to 800 mL of ice-cold water and extracted three times with 500 mL of ethyl acetate. After washing the extract with saturated brine, anhydrous magnesium sulfate was added to dry it. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with isopropyl ether and petroleum ether to obtain the desired product 55.
I got y.

Melting point = 126-1276C Mass x hector (m/e): M”-・-1
95 infrared absorption spectrum (Cm-1, Nujol):
1785, 1730.1700.160ONMR spectrum (δ, CDCl,): 5.64 (2H, d,
J=54.0Hz), 7.60-7.95 (4H, m
) Experimental Example 5 (Production of raw material compound) Fluoromethoxyamine and its hydrochloride H2N0CR
2F (・HCI) a) Experimental Example 4 in a mixture of 180 fluoromethoxyamine ethanol and 5.2 ml of water
20 g of the compound and 5.39 y of hydrazine hydrate were added.

It was refluxed for 1 hour. The reaction solution was cooled and the precipitate was removed.

The p-liquid was distilled to obtain the target product as an ethanol solution (
The target product and ethanol were distilled together). The NMR of this product is shown below (the ethanol peak is excluded).

NMR (δ, CDCl5): 5.29 (2H, d, J=56.6Hz), 5.8
5-6.20 (2H, brs) b) Fluoromethoxyamine hydrochloride To the ethanol solution of fluoromethoxyamine obtained in a) above, 200 ml of 1M hydrochloric acid in ethanol was added, and the ethanol was distilled off under reduced pressure. Add ethanol and ethyl ether to the residue to crystallize it.

The bottom of the furnace was dried to obtain 5 g of the target product.

Melting point: 152-154°C Mass spectrum/I/ (m/e): M”--
101("CI)s103 (37C1) NMR spectrum (δ, DMSO-d,): 5.7
3 (2H, d, J=54Hz), 10.80~11
．． 25(3H,brs) Example 9 2-(5-amino-1,2,4-thiadiazole-3-
2-fluoromethoxyiminoacetic acid fluoromethoxyamine 0.58, ethanol 25
tnL solution, 2-(5-amino-1
, 2,4-thiadiazol-3-yl)-2-oxoacetic acid was added, and the mixture was diluted with 1096 sodium hydroxide aqueous solution.
After adjusting H to 4 to 5, the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and 20 ml of water and 10 g of common salt were added to the residue.

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 brine and dried by adding 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 matched those of Example 5.

Example 10 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Zl-2-fluoromethoxyiminoacetic acid fluoromethoxyamine 0.58% in ethanol 25m
1 solution, add 1 g of 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid to 0.45 rnL of water, and adjust the pH to 4-5 with 1096 aqueous sodium hydroxide solution. After adjustment, the mixture was stirred overnight at room temperature.

The solvent was distilled off under reduced pressure, and 20 rttL of water and 10 liters of salt were added to the residue.
．． 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 brine and dried by adding anhydrous magnesium sulfate. 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 NMR spectrum matched those of Example 2.

Example 11 2-(5-amino-1,2,4-thiadiazole-3-
yl)-(Z)-2-fluoromethoxyiminoacetic acid Trifluoroacetic acid 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)=(Zl
-13 g of 2-fluoromethoxyiminoacetic acid was added.

The mixture was stirred at room temperature for 24 hours. Trifluoroacetic acid was distilled off under reduced pressure, 100 tnL of water was added to the residue, and insoluble matter was removed in an oven. The solvent was distilled off from the furnace liquid under reduced pressure, and the residue was crystallized from acetone-isopropyl ether (1:3).

The target product 2.18y was obtained as white crystals.

The infrared absorption spectrum and NMR spectrum matched those of Example 5.

Experimental Example 6 (Production of raw material compound) 2.04 ml of 2-(N-chloro)amidino-2-fluoromethoxyiminoacetonitrile 2-amidino-2-fluoromethoxyiminoacetonitrile acetate was dissolved in methanol 30 resistant,
Ice cold. 596 Sodium hypochlorite aqueous solution 60 m
l, 3N-hydrochloric acid 2 in a mixture of 30 nL of ethyl ether
4 zL was added, and the ethyl ether layer was separated to obtain 30 mL of an ethyl ether solution of hypochlorous acid.

One drop of this ethyl ether solution of hypochlorous acid was added dropwise into the above solution while stirring. After 5 minutes, the solvent was distilled off under reduced pressure, and the residue was added with a saturated aqueous solution of sodium hydrogen carbonate at 30 rt.
After adding tL, extraction was performed three times with 30rrgL of ethyl acetate.

The extract was washed with saturated brine and dried by adding anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crystals. Wash this with petroleum ether and isopropyl ether to obtain the object 1.
．． 72, was obtained.

Melting point = 97~98°C Mass x hect/l/ (m/e): M”-
・-・-178 (3℃l).

180 ("CI) Infrared absorption spectrum (cm", Nujol): 347
0, 3330.1630.157ONMR spectrum (
δ, pMso-d, ): 5.97 (2H, d, J
= 54Hz), 7.69 (2H, brs) Experimental Example 7 (
Production of raw material compound) 1.1 g of 2-(N-chloro)amidino-2-fluoromethoxyiminoacetic acid 8596 sodium peroxide was dissolved in 20 rnL of water.

Ice cold. To this was added 1 g of the compound of Experimental Example 6, and the mixture was stirred for 3 hours, and then stirred at room temperature for 24 hours. The reaction solution was ice-cooled, 10 g of 9 chloride salt was added, the pH was adjusted to 1 with 6N hydrochloric acid, and the mixture was extracted 4 times with 20 ml of ethyl acetate.

Anhydrous magnesium sulfate was added to the extract to dry it.

1'- The solvent was distilled off under reduced pressure, and the residue (oil) + isopropyl ether and petroleum ether were added to solidify, and the target product was 350 m
I got g.

Melting point: 112-114°C (decomposed) Infrared absorption spectrum (Cm-', Nujol) = 33
00, 3150.2650.1720.159ONMR
Spectrum (δ, DMSO-ds): 5.79 (2
H, d, J=547) Example 12 2-(5-amino-1,2,4-thiadiazole-3-
A mixture of 50 mg of potassium thiocyanate, triethylamine 127, and 3 ml of methanol was cooled to -10°C.

Add 99 mg of the compound of Experimental Example 7 and keep at the same temperature for 1 hour.

The mixture was then stirred at room temperature for 20 hours. The solvent was removed under reduced pressure.

After adding 5 sL of saturated saline to the residue and adjusting the pH to 1 with IN-hydrochloric acid, the mixture was extracted four times with 10 ml of ethyl acetate.

After adding anhydrous magnesium sulfate to the extract and drying.

The solvent was removed under reduced pressure. 2-butanone and isopropyl ether were added to the residue to solidify it, yielding 56 tons of the desired product.

The infrared absorption spectrum and NMR spectrum matched those of Example 5.

Example 13 2-(5-amino-1,2,4-thiadiazole-3-
2-(5-amino-1,2,
Add 325 μl of 4-thiadiazol-3-yl'-(Z)-2-fluoromethoxyiminoacetic acid.

The mixture was stirred at the same temperature for 30 minutes. 20 zL of isopropyl ether was added to the reaction solution, and the resulting precipitate was separated to obtain the desired product 13ON.

MasS hector Cm/e): M”...23
8 (“CI).

240 ('C1) Infrared absorption spectrum (C1i-', Nujol):
1780, 1625 NMR spectrum (δ, DMSO-d6): 5.8
5<2H, d, J=55) Experimental Example 8 (Synthesis of cephem intermediate using the compound of the present invention) p-methoxybenzyl 7β-(2-(5-)ditylamino-1,2,4-thiadiazole- 3-yl)-(Z
l-2-fluoromethoxyiminoacetamide) -3
-((Z) -3-chloro-1-propen-1-yl]
348 μt of -3-cephemu 4-carboxylate dimethylformamide and 4.1 μt of tetrahydrofuran were cooled to -10°C, and phosphorus oxychloride 4.
18 μt was added, and the mixture was stirred for 90 minutes under water cooling. To this solution was added 1.73. Add 5.5 aL warm solution of tetrahydro7ran after cooling to 10°C, under water cooling,
Stirred for 90 minutes. The reaction solution was cooled to -20°C.

This was added to p-methoxybenzyl 7β-amino-3-((
Z)-3-chloro-1-propen-1-yl2-3-cephem-4-carboxylate hydrochloride 1.78 g,
N-(trimethylsilyl)acetamide 2.95 y
+ 18 mL of ethyl acetate and tetrahydrofuran5.
5 mL of the mixed solution was added and stirred at -10°C for 1 hour.

After adding 100 mL of ethyl acetate to the reaction solution and washing sequentially with water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine,
It was dried by adding anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the desired product 2.65.

Infrared absorption spectrum (C1m', Nujol):
1765, 1725.1680.1610 traced spectrum (δ, DMSO-d,): 3.45 (IH, tun J=
18Hz), 3.63 (IH, d, J=187).

3.75 (3H, s), 3.95 (IH, dd, J
=8Hz, 12Hz).

4.12 (IH, dtun J = 4 ox, 127).

5.07 (IH, d, J=1st edition (z), 5.14 (
IH, d, J=12-).

5.24 (IH, d, J=5Hz), 5.70 (I
H, m).

5.78 (2H, d, J=55Hz), 5.85
(IH, m).

6.26 (IH, d, J=12Hz), 6.92 (
2H, d, J=9Hz) -7,25~7.4 (17
H, m), 9.74 (IH, d, J=8Hz)
.

10.08 (IH,s) Experimental Example 9 (Synthesis of cephem intermediate using the compound of the present invention) p-methoxybenzyl 7β-C2-(5-)cutylamino-1,2,4-thiadiazol-.3-yl )−(
Zl-2-fluoromethoxyiminoacetamide)-3
-((Z)-3-chloro-1-propen-1-yl]-
3-cephemu 4-carboxylate ethyl acetate 37 ml. In a mixture of 5 iL of tetrahydrofuran and 15.7 ml of dichloromethane, 8.17 ff of N-(trimethylsilyl)acetamide and p-methoxybenzyl 7β-amino-3-CTZI-3-chloro-1 were added.
3.33 y of -propen-1-yltu 3-cephem-4-carboxylate hydrochloride was added and dissolved.

After cooling the solution to -20'C, compound of Example 3 3.80
g and stirred at 10°C for 1 hour. After adding 500 rnL of ethyl acetate to the reaction solution, the mixture was washed sequentially with water, saturated aqueous sodium bicarbonate solution, IN hydrochloric acid, and saturated brine.
It was dried by adding anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the desired product (4.33y).

The infrared absorption spectrum and NMR spectrum matched those of Experimental Example 8.

Experimental Example 10 (Synthesis of cephem intermediate) p-methoxybenzyl 7β-(2-(5-)IJ thylamino-1,2,4-thiadiazol-3-yl)-(
Z)-2-fluoromethoxyiminoacetamide)-3
-(ni)-3-iodo-1-propen-1-yl)-3
-cephem-4-carboxylate Compound 10.11 of Experimental Example 8, in 212 mL of acetone
(dissolved in water and iodized under water cooling) IJium 9.03 y
was added and stirred for 15 minutes, then stirred at room temperature for 90 minutes.

The solvent was distilled off, and the residue was extracted with 500 rnL of ethyl acetate. The extract was washed with a saturated aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. This was concentrated under reduced pressure, and n-hexane was added. The resulting precipitate was counted to obtain 10.92 y of the desired product.

Infrared absorption spectrum (CIl+-', Nujol):
1770, 1715i 16B5.161ONMR spectrum (δ, CDCl,): 3.51 (IH, d
, J=18Hz), 3.60 (IH,d, J=
18Hz).

3.81 (3H, s), 3.98 (2H, d,
J=8Hz).

5.0 ((IH, d, J=5Hz), 5.19 (
IH, d, J=12Hz).

5.24 (IH, d, J=12Hz), 5.
82 (2H, d, J=55Hz).

5.90 (IH, m), 6.14 (IH, dt,
J=8Hz, 16Hz).

6.77 (LH, d, J=9Hz), 6.90
(2H, d, J=9Hz).

7.00 (IH, d, J=16Hz), 7.2~
7.4 (17H, m).

7.80 (1B, s) Experimental Example 11 (Synthesis of Cephem Compound) 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamide )-3-C(El-3-(carbamoylmethyldimethylammonio)-1-propen-1-yl)
-3-cephem-4-carboxylate 500 μl of the compound of Experimental Example 10 was dissolved in a mixture of 3 mL of methanol and 1 mL of dimethylformamide, and the mixture was cooled with water.

Add 71.3 μ of N,N-dimethylglycinamide.

Stir overnight at room temperature. This reaction solution was mixed with 50% ethyl acetate.
mL and 50 ml of ethyl ether, and the resulting precipitate was dried at the bottom of a furnace to obtain 382 rng of yellow powder.

This compound was mixed with 2.7 h of trifluoroacetic acid and 2 h of ayosol.
．． It was added to 3 mL of a mixed solution and stirred for 2 hours under water cooling.

The reaction solution was added to a mixture of 25 mL of ethyl ether and 25 mL of isopropyl ether, and the resulting precipitate was poured into the bottom of the furnace and washed with ethyl ether. This precipitate was suspended in 4.5 liters of water, and the pH of the solution was adjusted to 5.5 to 6.5 with sodium acetate.
Insoluble matter was removed. The filtrate was purified by reverse phase silica gel column chromatography to obtain the target product 94T! Obtained Lg.

Infrared absorption spectrum (α″!, !, Nujiol 760
, 1670.1590 Island spectrum (δ, DMSO-d6): 3.14
(3H,s), 3.15 (3H,s).

3.47 (IH, d, J = 1 view), 3.65 (
IH, d, J = 1 view h).

4.02 (2H, s), 4.16 (2H, d,
J=87).

5.06 (IH, d, J=57).

5.55 (IH, dd, J=5Hz, 8Hz),
5.70 (IH, m).

5.80 (2H, d, J=55Hz), 7.16
(IH, d, J = 15 wires).

7.64 (LH, s), 8.19 (IH, s),
8.22 (2H, s).

9.70 (IH, d, J=8Hz) Antibacterial power MI
C (pyhrtL) Staphylococcus 0 aureus 0.209-P Escherichia coli ≦0.025IH
J Klebsiella φ pneumoniae ≦0.025K-6 Serratia marcescens 0.1 Morganella morganii ≦0.025P-14 Shortmonas aeruginosa 0.4P-01

Claims (5)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 represents a carboxyl group, halogenocarbonyl group, carbamoyl group, or cyano group] Thiadiazole derivative, its amino group and/or carboxyl group is protected with a protecting group, or their salts. (2) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound whose amino group is protected with a protecting group,
Further, a compound whose carboxyl group is protected with a protecting group, or a salt thereof, is reacted with halogenofluoromethane, and then the protecting group is removed if necessary: ▲ Formulas with mathematical formulas, chemical formulas, tables, etc. There are thiadiazole derivatives represented by ▼, compounds whose amino groups and/or carboxyl groups are protected with protecting groups,
or the method of manufacturing those salts. (3) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Compounds whose amino groups are protected with a protecting group, or their salts are hydrolyzed in the presence of a base, and then protected if necessary. Formulas characterized by elimination of groups: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Thiadiazole derivatives represented by, compounds whose amino groups and/or carboxyl groups are protected with protecting groups,
or the method of manufacturing those salts. (4) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ By reacting a compound represented by , a compound whose amino group and/or carboxyl group is protected with a protecting group, or a salt thereof with fluoromethoxyamine or a salt thereof. Thiadiazole derivatives represented by the following formulas, which are characterized by removing the protecting group if necessary: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, compounds whose amino groups and/or carboxyl groups are protected with protecting groups,
or the method of manufacturing those salts. (5) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Compounds represented by [in the formula, Thiadiazole derivatives whose carboxyl group is protected with a protecting group are formulas characterized by removing the protecting group if necessary after reacting with an acid alkali metal salt: A method for producing compounds or their salts.