JPH0228170A - Production of thiadiazolylacetic acid derivative and intermediate of the same derivative - Google Patents

Abstract

PURPOSE:To obtain the title compound useful as an intermediate for antimicrobial agents by oxidizing a novel 3-(5-amino-1,2,4-thiadiazol-3-yl)-2-(alkyl) furan as an intermediate raw material and then reacting the oxidized compound with a fluoromethoxyamine. CONSTITUTION:A novel compound shown by formula I (R1 is H or lower alkyl), a salt thereof or a compound containing a protected amino group thereof is oxidized and optionally the protecting group is eliminated to give a compound shown by formula II, a compound containing a protected amino group thereof or a salt thereof, which is reacted with a fluoromethoxyamine or a salt thereof and optionally the protecting group is eliminated to give a thiadiazolylacetic acid derivative shown by formula III, a compound containing a protected amino group thereof or a salt thereof. The novel compound shown by formula I is obtained by reacting a compound shown by formula IV or a salt thereof with an alkali metallic salt of thiocyanic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] The present invention relates to thiadiazolyl acetic acid derivatives and intermediates thereof useful as intermediates for antibacterial agents.

Previously, JP-A No. 59-172493 and JP-A No. 6
1-5084, 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 substituted with a methoxyimino group or the like at the 7-position is known. .

The present inventors have an ammoniopropenyl group at the 3rd 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 excellent antibacterial activity.

An object of the present invention is to provide a method and intermediate for producing thiadiazolyl acetic acid derivatives useful as intermediates for antibacterial agents.

[Structure of the invention]

The target compound of the present invention is a compound represented by the formula: A compound whose amine group is protected with a protecting group, or a salt thereof.

Examples of protective groups for amine groups include formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, phenylacetyl group, thienylacetyl group, t-bu!・Xycarbonyl group, pendyloxycarbonyl group, 17thyl group, p-methoxybenzyl group, diphenylmethyl group, benzylidene group.

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

Examples of carboxyl group protecting groups include p-methoxyhensyl group, p-nitrobenzyl group, t--1f group,
Methyl group, ethyl group, 2. 2. 2-t! Examples include J chloroethyl group, sifenylmethyl group, pivaloyloxymethyl group, and trimethylsilyl group.

As a salt of a compound of the general formula (Il): IJum 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, 9-hydriodides, sulfates, carbonates, 9-bicarbonates Inorganic acid salts such as; organic carboxylic acid salts such as maleate, lactate, tartrate, monofluoroacetate; methanesulfonate, hydroxymethanesulfonate.

Organic sulfonates such as hydroxyethane sulfonate, taurine salt, Hensensulfonate, toluene sulfonate; trimethylamine salt, triethylamine salt, pyridine salt, prohydroline salt, picoline salt, dicyclohexylamine [,N, N'-dibenzylethylenediamine 4
1 N-methylglucamine salt, jetanolamine salt,
Amine salts such as triethanolamine salt, tris(hydroxymethylamine)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.

In the above formula, IR+ is a hydrogen atom or a lower alkyl group.

R2 represents a lower alkyl group, and X represents a halogen atom.

Further, the compound represented by the above formula may be a compound whose amino group is protected with a protecting group, or a salt thereof.

As the lower alkyl group in R1 and R7.

Examples include C1 to C4 alkyl groups such as methyl, ethyl, and propyl. Furthermore, 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 formula (I) above. In addition, regarding the salt, in the case of a compound having an amino group and a carboxyl group, it is the same as the salt of the compound of formula (■) above.

In compounds having only amine groups, the formula (I
), inorganic acid salts, organic carboxylic acid salts,
Examples include acid addition salts such as organic sulfonates and amino acid salts.

These manufacturing steps will be explained in more detail.

(■)-1 → (I) After reacting a compound represented by formula (■), a compound whose amine group is protected with a protecting group, or a salt thereof with fluoromethoxyamine or a salt thereof, protection may be applied if necessary. By elimination, a compound represented by Formula 2 (I), a compound whose amine group is protected with a protecting group, or a salt thereof can be obtained.

Examples of the salt of fluoromethoxyamine include acid addition salts of the compound of formula fI) such as inorganic acid salts, organic carboxylic acid salts, organic sulfonate salts, and amino acid salts.

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

Field-1-→(II) A compound represented by the general field, a salt thereof, or a compound whose amine group is protected with a protecting group is oxidized to form a compound represented by the formula (ml, whose amine group is protected with a protecting group). A protected compound, or a salt thereof, can be obtained.

As for the oxidation method, first, ozone is used as an oxidizing agent to oxidize to the aldehyde form, and then hydrogen peroxide, potassium permanganate, and chromic acid are used as oxidizing agents.

Compounds of formula (river) can be oxidized using oxygen, etc.

The above reaction uses dichloromethane and chloroform.

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

σVl−−→field 1 tbsp of the compound represented by General Extract ■ or its salt.

By reacting with an alkali metal thiocyanate salt, -killing ([
Ten compounds or salts thereof can be obtained.

Examples of alkali metal salts include potassium salts and sodium salts.

The above reaction can be carried out in an inert solvent such as a lower alcohol at a reaction temperature of -506C to 50C.

M-11 (I) A compound represented by the general formula M, a salt thereof, or a compound whose amino group is protected with a protecting group is hydrolyzed, and if necessary, the protecting group is removed to form a compound represented by the formula 2 (Il). Compound,
A compound whose amine group is protected with a protecting group or a salt thereof can be obtained.

For hydrolysis, a base such as sodium hydroxide, potassium hydroxide, etc. can be used.

The above reaction is carried out at -10°C to 100°C in an aqueous solvent such as water, a buffer solution, or a mixed solvent of these and a lower alcohol.
It can be done with

■□(■ General formula ■ Compound, its salt, or a compound whose amine group is protected with a protective group is hydrolyzed, and if necessary, the protective group is removed to form a compound of general formula ■, its salt, or A compound whose amino group is protected with a protecting group can be obtained.

Hydrochloric acid, sulfuric acid, trifluoroacetic acid for hydrolysis.

Acids such as para-toluenesulfonic acid can be used.

The above reaction is carried out at -10°C to 100°C in an aqueous solvent such as water, a buffer solution, or a mixed solvent of these and a lower alcohol.
It can be done with

～m-(Vll By reacting the compound of the formula (■), its salt, or the compound whose amine 7 group is protected with a protecting group with an alkali metal lower alcoholade, and removing the protecting group if necessary, the compound of the general formula (■) is prepared. , its salt, or a compound whose amine group is protected with a protecting group can be obtained.

Examples of alkali metal lower alcoholades include sodium methoxide and sodium ethoxide.

Examples include potassium methoxide and potassium ethoxide.

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.

■----→■ The compound or salt thereof of general depletion (1) can be reacted with an alkali metal thiocyanate to obtain the compound of -demolition (2) or its salt.

Reaction conditions and the like are the same as in the step of (IV)-CIIO.

UJ ■ A compound of formula (II) or a salt thereof can be reacted with a halogenating agent to obtain a compound of formula (II) or a salt thereof.

Halogenating agents include halogens such as bromine and chlorine, N
- N-halogen succinimides such as chlorsuccinimide, N-bromosuccinimide.

Alkali metal hypochlorite salts 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 solution, a lower alcohol, or a mixed solvent thereof at a reaction temperature of -20°C.
It can be carried out at ~50°C.

In addition, in the nine steps, it is possible to proceed to the next step without isolating the compound of Formula 1 (1).

m-1→■ A compound of formula (1) or a salt thereof can be obtained by reacting the compound of (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 1
The reaction can be carried out at a temperature of -20°C to room temperature.

(to)----→■ By reacting the compound of formula with a dehydrating agent.

A compound of formula (1) can be obtained.

Examples of dehydrating agents include phosphorus oxychloride and thionyl chloride.

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

Hata --- → ■ The compounds in the general logging area or their salt can react alkaline metal salt to obtain a compound or its salt of -killing.

Reaction conditions, etc. are the same as in the process of ■-→field.

(XIII) --→(4) A compound of general formula (X) can be obtained by reacting a compound of the general formula (X HD) or a salt thereof with a halogenating agent.

The reaction conditions and the like are the same as in the (IX)-hetoto process.

In addition, in one step, it is possible to proceed to the next step without isolating the -killing compound.

(XIV) -(XIII) -A compound of (XIV) can be reacted with ammonium halide to obtain a compound of (XI[) or a salt thereof.

Examples of ammonium halides include ammonium chloride and 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 reflux temperature.

(XV)-+(XIV) A compound of -killing (XIV) can be obtained by reacting a compound of -killing (XV) with an alkali metal lower alcoholade.

The reaction conditions, etc. are the same as in the step ①→(vl).

(XVI)□→(X　V) By reacting the compound of general formula (XVI) with a dehydrating agent.

- Compounds of killing (XV) can be obtained.

Trifluoroacetic acid or the like is used as a dehydrating agent.

The above reaction is carried out in an inert solvent such as pyridine at a reaction temperature of -2
It can be carried out at a temperature of 0.8°C to 50°C.

(XVI)--→(X■) The compound of general formula (XVi) is reacted with a sulfurizing reagent.

A compound of formula (X■) can be obtained.

As a sulfurizing reagent, Lawson's reagent ((2,4-bis(4)
-methoxyphenyl)-1,3-dithia-2゜4-diphosphethane-2,4-disulfy)')).

Examples include niline trisulfide.

The above reaction can be carried out in an inert solvent such as dimethquinethane, acetonitrile, dimethylsulfoxide, dimethylformamide, etc. at a reaction temperature of -20°C to 500°C.

(X■)□(X■) A compound of general formula (X■) is reacted with an alkylating agent, -
A compound of killing (X■) can be obtained.

As the alkylating agent, lower alkyl iodide, di-lower alkyl sulfate, etc. are used.

The reaction can be carried out in an inert solvent such as dimethoxyethane, acetonitrile, dimethyl sulfoxide, dimethylformamide, etc. at a reaction temperature of O0C to 10CrC.

(X■)--<xm) A compound of formulas (X to M) is reacted with ammonium halide to obtain a compound of -saccharide (XIII) or a salt thereof.

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

(~Button---->(XIX)1) A compound of general oxidation (XIX) or a salt thereof can be obtained by reacting an alkali metal lower alcoholade with a compound of oxidation (XIX) or a salt thereof.

The reaction conditions, etc. are the same as in the step ①-NI).

(XIX) --→(4) By hydrolyzing the compound of general formula (XIX) or a salt thereof, a compound of -Serahata or a salt thereof can be obtained.

Hydrochloric acid, sulfuric acid, trifluoroacetic acid for hydrolysis.

Acids such as para-toluenesulfonic acid can be used.

The above reaction is carried out in an aqueous solvent such as water, a buffer solution, or a mixed solvent of these and a lower alcohol at -10"C to 109"C.
It can be done in C.

A compound of formula (I) can be obtained by the method shown above. In addition, among the compounds of H) to (XIX), 2 (II)
Compounds other than are new compounds.

A compound of formula (II, a compound whose amino group is protected with a protecting group, or a salt thereof is used as an intermediate for β-lactam antibiotics, especially cephem compounds. For example,
The amine group at the 7-position of the 7-amino-3-cephem derivative is replaced by 9
Compounds of formula (I) according to the invention.

Cephem derivatives with excellent antibacterial activity can be obtained by acylating the amino 7 group with a compound protected with a protecting group, a salt thereof, or an acid halide thereof, and removing the protecting group if necessary. Obtainable.

In particular, the above-mentioned cephem derivatives having an ammonium propenyl group at the 3-position have very excellent antibacterial activity.

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

Experimental Example 1 2-cyano 2-fluoromethoquinoiminoacetamide NC-C-CONH2 2-cyano-2-hydroxyiminoacetamide 22.
69 was dissolved in 100 nLt of dimethyl sulfoxide.

While stirring at room temperature, 55.2 g 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 IL, and 150 ml of ethyl acetate was added. Extracted twice with LL. 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 14.4 g of the desired product.

Melting point: 124-125°C Infrared absorption spectrum (Qll-', Nujol): 3
410, 3290.3150.1690.159ONM
R spectrum (δ, DMSO-d4): 5.94 (
2H, d, J=54.0) fzle 7.85~9.4
0(2H,br) Experimental Example 2 2-Fluoromethoxyiminopropanedinitrile NC-C-CN Compound 14.09 of Experimental Example 1, Acetonitrile 1
5mL.

Sodium chloride 15g, phosphoryl chloride], 4+nL
The mixture was reacted under reflux for 2 hours, and 5 nL of phosphoryl chloride was added and reacted for 2 hours. After cooling the reaction solution, it was added to 200 at of ice water and stirred at room temperature for 1 hour. Extracted twice with 50 rnL of methylene chloride. The extract was washed with a 5% aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The oily product was distilled under reduced pressure to obtain 9.1g of the desired product as a colorless oil.

Boiling point: 69-70'C/25mmHg NMR spectrum (δ, CDCl, ): 5.85 (2H, d, J
=52.0Hz) Experimental Example 3 2-cyano-2-fluoromethoquiniminoacetamidine 28% ammonia water! 50m1. Ammonium chloride 8
g.

A mixture of 50 ml 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 rnl of water was added to the reaction solution, and the mixture was extracted three times with 50 nl 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 collected, washed with ethanol, and then dried to obtain the acetate of the title compound. The following physical property values are for acetate.

Melting point: 125-127°C Infrared absorption spectrum (Cm-', Nujol): 3
200, 1670.157O N~1R spectrum (δ, DMSO-mountain): 1.90 (
3I(,s), 5.95(2H,d, J=54.0
Hz).

7.40 (3H, br) Experimental example 4 2-(5-amino-1,2,4-thiadiazole-3-
yl)-(E)-2-fluoromethoxyiminoacetonitrile. This was recrystallized from acetone to obtain the desired product 3.4.
I got g.

Melting point: 236-238uC Infrared absorption spectrum (cm-', Nujol): 3
450, 3250.3075.1610.152ONM
R spectrum (δ, DMSO-d6): 6.02 (
2H, d, J=54.0Hz), 8.38 (2H,
br) Example 1 2-(5-amino-1,2,4-thiadiazole-3-
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 water cooling.

After cooling the solution to -5°C, 3.5 g of bromine was added dropwise. Subsequently, potassium thiocyanate 2.
1 g of methanol solution was added dropwise, and the mixture was stirred at the same temperature for 2 hours. The resulting precipitate was stabilized, 101 FLL of methanol was added to 500 rug of the compound of Experimental Example 4 with water and methanol, and 0.299 of a 28% methanol solution of sodium methoxide was added while stirring at room temperature. After further stirring for 24 hours, methanol was distilled off under reduced pressure, and a small amount of methanol and isopropyl ether were added to the residue to make it constant.

The target product 146■ was obtained.

Melting point: 157-158°C Infrared absorption spectrum (C7+1-', Nujol):
3270, 3100.1645.1600.1110.
10105ON x vector (a, DMSO-d
6): 3.68 (3H, s), 5.74 (2H, d
, J=54Hz).

8.16 (2H, brs), 8.9 (IH, s) Example 2 2-(5-amino-1,2,4-thiadiazole-3-
yl)-(Z)-2-fluoromethoxyiminoacetate methyl infrared absorption spectrum (cm-'nujol): 3
400, 3250.3100.1730.1680.1
61ONMR spectrum (δ, DMSO-d6):
3.83 (3H, s), 5.78 (2H, d, J=
54) Lz).

8.24(2H,s) Example 3 2-(5-amino-1,2,4-thiadiazole-3-
yl)-(Z)-2-fluoromethoxyiminoacetic acid To 100 mg of the compound of Example 1 was added 1 orrLL of 2N hydrochloric acid.

Stirred at room temperature for 20 minutes. The reaction solution was diluted with ethyl acetate 2o! I
Extracted with LL three times and washed the extract with water. This was dried by adding anhydrous magnesium sulfate and filtered. The solvent was distilled off under reduced pressure, and a small amount of isopropyl ether was added to the residue. The precipitated crystals were constantized to obtain 75 mg of the target product.

40 rng of sodium hydroxide was dissolved in 2 rILL 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 while stirring. After stirring at the same temperature for 20 minutes and cooling with water, methanol was distilled off under reduced pressure. After adding 5 mL of water and adjusting the pH to l with IN hydrochloric acid.

Extracted three times with ethyl acetate. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off. A small amount of isopropyl ether was added to the residue, and the mixture was filtered to obtain 30 mg of the desired product.

Infrared absorption spectrum (Cm-', Nujol):
1720, 162O NMR spectrum (δ, DMSO-d,): 5.74 (
2H, d, J-55Hx), 8.18 (2H, br
s) Example 5 Dimethyl fluoromethoxyiminomalonate 7.0 g of dimethyl hydroxyimino malonate was dissolved in acetonitrile 20, and 9 g of potassium carbonate was added thereto. Add 5.9 g of bromofluoromethane and 20 g of acetonitrile to this.
mL solution was added dropwise over 30-min.

After stirring at room temperature for 5 hours, insoluble materials were removed and washed with ethyl acetate. The furnace liquid and washing liquid were combined, and the solvent was distilled off. 200 rnL of ethyl ether was added to the residue, and the precipitate was removed in the oven. The solvent was distilled off to obtain the desired product as a colorless oil 7.45. I got it.

Infrared absorption spectrum (01-', neat): 2950
, 1740.162O NMR spectrum (δ, CDCl, ): 3.91(
6H,s), 5.74(2H,d, J=54F(
z) Experimental Example 6 Methyl 2-carbamoyl-(Z)-2-fluoromethoxyiminoacetate H, N-C-C-Co○CH3 ゝ・. -61,2° Compound 7.459 of Experimental Example 5 was dissolved in 19 mL of methanol, and 6.25 mL of 28% aqueous ammonia was added dropwise over 10 minutes. The mixture was then stirred at the same temperature for 1 hour and 30 minutes. After adjusting the pH to 7 with concentrated hydrochloric acid, the mixture was concentrated under reduced pressure, and the precipitated crystals were taken to the bottom of the furnace and washed with water. The above operation was repeated for the furnace liquid. The obtained crystals were combined, dissolved in chloroform, and dried by adding anhydrous magnesium sulfate. The solvent was distilled off to obtain the desired product 5.049.

Infrared absorption spectrum (Ca11-', Nujol):
3450, 3300.3150.1720.1690.
1620.159ONMR spectrum (δ, DMSO
-d4): 3.79 (3H, s), 5.78 (2
H, d, J = 54H illusion.

7.90 (LH, br), 8.02 (LH, br)
Experimental Example 7 Methyl 2-cyano-(Zl-2-fluoromethoxyiminoacetate NC-C-CoOCH.

2.5 g of the compound of Experimental Example 6 was dissolved in 24 ml of pyridine.

While cooling with water, 5rrtL of trifluoroacetic anhydride was added dropwise over 20 minutes, and 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. After sequentially washing the extract with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated saline,
It was dried by adding anhydrous magnesium sulfate. The solvent was distilled off to obtain 2.0 g of the target product as a light brown oil.

Infrared absorption spectrum (C1l"', neat): 295
0, 1750.157O NMR spectrum (δ, CDCl,): 3.94 (
3H, s), 5.78 (2H, d, J=54±)
Experimental Example 8 Methyl 3-imino-3-methoxy-(Z)-2-fluoromethoxyiminopropionate Compound 3.229 of Experimental Example 7 was added to 80 rnL of methanol.
10 tnL of a 1M methanol solution of sodium methoxide was added dropwise at room temperature over 45 minutes, followed by stirring for 30 minutes. After neutralizing the reaction solution with acetic acid, the solvent was distilled off. Add isopropyl ether to the residue.

Insoluble matter was removed. The furnace solution was purified by silica gel chromatography to obtain 1.9 g of the target product as a pale yellow oil.
I got it.

Infrared absorption spectrum ((m”, neat): 3320
, 2950.1740.165ONMR spectrum (δ
, CDCl, ): 3.85 (3H,s), 3.8
9 (3H, s).

5.67 (2H, d, , J=541-fz), 7
．． 32(LH,br) Experimental Example 9 Methyl 3-imino-3-methoxy-(Z)-2-fluoromethoxyiminopropionate 358+ng of the compound of Experimental Example 6 was dissolved in dichloromethane 10
ml of trimethyloxonium tetrafluoroborate under a nitrogen atmosphere. g at room temperature.

Stirred for 10 and a half hours. Under water cooling, triethylamine 404ml
ll + Subsequently, 30++ tL of water was added, and after stirring, the organic layer was separated. After drying by adding anhydrous magnesium sulfate, the solvent was distilled off to obtain 350 my of the target product in the form of an oil.

The infrared absorption spectrum, NMR7, and vector matched those of the compound of Experimental Example 8.

Experimental Example 10 Methyl 3-imino-3-ethoxy-(Z)-2-fluoromethoxyiminopropionate N Q -CH2F Triethyl Axonium te[-rafluoroborate was added to the compound 3.589 of Experimental Example 6 under a nitrogen stream. 1M dichloromethane solution (40 rnL) was added, and the mixture was stirred at room temperature overnight. Under water cooling, 6.06 Q of triethylamine and then 40 rnl of water were added, and after stirring, the organic layer was separated. This was purified by silica gel column chromatography to obtain the desired product 1.039 as a colorless oil.

Infrared absorption spectrum (Cm-', knee!-): 332
0,2970.1740.1660.161ONMR spectrum (δ, CDCl,): 1.33(3H,t
, J=7.2Hz), 3.90 (3H, s).

4.28 (2H, q, J=7.2Hz), 5.67
(2H, d, J=54Hz).

8.26 (IH, brs) Experimental Example 11 Methyl 2-amidino-(Z)-2-fluoromethoxyiminoacetate hydrochloride Compound 1.039 of Experimental Example 10 was dissolved in methanol 16 rn
802 mg of ammonium chloride was added, and the mixture was stirred for 6 days. 80 mL of ethyl acetate was added to the reaction solution, and the insoluble matter was removed in an oven. The furnace liquid was concentrated under reduced pressure, and the precipitated crystals were poured into the furnace. Washing with ethyl ether gave 400 mg of the desired product as white crystals.

Infrared absorption spectrum (α-1, Nujol): 174
0, 1680.162O NMR spectrum (δ, DMSO-d4): 3.8
7 (3H, s), 5.88 (2H, d,, J=53
±).

9.70 (3H, brs) Experimental Example 12 Methyl 2-amidino-(Z)-2-fluoromethoxyacetate hydrochloride Compound of Experimental Example 8 230. g was dissolved in 5 yaL of methanol, 191 gg of ammonium chloride was added, and the mixture was boiled for 6 hours. After cooling, ethyl acetate was added and insoluble matter was removed in the oven. The furnace liquid was concentrated, and the precipitated crystals were poured into the furnace.

Washing with ethyl ether gave 150 grams of the desired product as white crystals.

Infrared absorption spectrum and NMR spectrum are Experimental Example 11
It was consistent with that of the compound.

Experimental Example 13 Methyl 2-amidino-(Zl-2-fluoromethoxyiminoacetate bromate i) 193.g of the compound of Experimental Example 8 was dissolved in 5rrLL of methanol, 234.g of ammonium bromide was added, and the mixture was heated at 500C.
The mixture was stirred for 6 hours. Subsequently, the reaction solution was treated in the same manner as in Experimental Example 12 to obtain the target product 132. I got g.

Infrared absorption spectrum (Cm-', Nujol):
1.740.1670.1610 NMRx vector (a, DMSO-d,):
3.87 (3H, s), 5.88 (2H, d, J
=53Hz).

9.46 (3H, brs) Experimental Example 14 Methyl 2-(N-chloro)amidino-(Z)-2-fluoromethoxyiminoacetate NMR spectrum (δ, CDCl5): 3.95 (
3H,s), 5.73(2H,d, J=54Hz
).

5.75 (2H, br) Experimental Example 15 2-(N-chloro)amidino-(E)-2-fluoromethoxyiminoacetonitrile 400 mg of the compound of Experimental Example 11 was added to 20 atm of methanol.
5+++L of a 0.5M solution of 9 hypochlorous acid in ethyl ether was added dropwise over 5 minutes under water cooling, and the mixture was further stirred for 15 minutes. The solvent was distilled off, and the residue was extracted with ethyl acetate. Add the extract to saturated aqueous sodium bicarbonate solution.

Subsequently, the mixture was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, petroleum ether was added to the residue to solidify it, and the mixture was filtered to obtain the desired product 320.9.

Infrared absorption spectrum (CIm-', Nujol)
:3480, 3370.1720.1630.1600
2.049 ml of 2-cyano-2-fluoromethoxyiminoacetamidine acetate was dissolved in 30 mL of methanol and cooled on ice. 596 hypochlorous acid) IJium aqueous solution 60
mL and 30 mL of ethyl ether were added with 24 mL of 3N hydrochloric acid, and the ethyl ether layer was separated to obtain 30 mL of a solution of hypochlorous acid in ethyl ether.

30 ml of this ethyl ether solution of hypochlorous acid was added dropwise to the above solution while stirring. After 5 minutes, the solvent was distilled off under reduced pressure, and 30 mL of saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction three times with 30 mL of ethyl acetate. The extract was washed with saturated brine and dried by adding anhydrous magnesium sulfate. The solvent was removed under reduced pressure.

Obtained 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 2 hect/l/ (m/e): M”
--178 ("CI)".

180 (3) C1) Infrared absorption spectrum (C7!'', Nujol)
:3470, 3330.1630.157ONMR spectrum (δ, DMSO-d4)25.97(2H,d
, J=54Hz), 7.69 (2H, brs) Experimental Example 16 Methyl 2-(N-chloro)amidino-(Z)-2-fluoromethoxyiminoacetimidate Compound 535 of Experimental Example 15 was dissolved in methanol 14. 4
1 of sodium methoxide dissolved in rnL and cooled with water.
0.6 ml of M methanol solution was added, and the mixture was stirred at the same temperature for 2 hours. The solution was neutralized with dilute hydrochloric acid-metal.

The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the desired product, 50 g.

Infrared absorption spectrum (CTl-', Nujol):
3460, 3270.1660.1630.160ON
MR spectrum (CDCI, ): 3.89 (3H, s), 5.74 (2H, d, J=
54Hz).

5.80 (2H, br), 7.56 (LH, brs)
Experimental Example j7 Methyl 2-(N-chloro)amidino-(Z)-2-fluoromethoxyiminoacetate Compound 180B of Experimental Example 16 was dissolved in 21 nL of methanol, 2 rttL of IN hydrochloric acid was added under water cooling, and the temperature was returned to room temperature. Stirred for 2 hours. Add 50 mL of ethyl ether to the reaction solution.
was added thereto, washed successively with a saturated aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 84 mg of the desired product. The infrared absorption spectrum and NMR spectrum matched those of the compound of Experimental Example 14.

Experimental Example 18 Methyl 2-thiocarbamoyl-(E)-2-fluoromethoxyiminoacetate NMR spectrum (δ, CDCl,): 3.94
(3H, s), 5.74 (2H, cl, J=54
Hz).

7.36 (LH, br), 7.82 (LH, br)
Experimental Example 19 Methyl 2-thiocarbamoyl-(E)-2-year-old methoxyiminoacetate 0.89 g of the compound of Experimental Example 6 was dissolved in 20 mL of 1,2-dimethoxyethane, and Lawesson's reagent ([:2,4 −
Bis(4-methoxyphenyl)-1,3-dithia-2゜4-diphosphethane-2,4-disulfide]) 1.
019 was added under a nitrogen stream and heated at 50'C for 4 hours 30 minutes.
The mixture was heated and stirred for 1 minute. The reaction solution was cooled, diethyl ether was added, and insoluble matter was removed. The furnace solution was washed with water and dried over anhydrous magnesium sulfate. Distill the solvent.

The residue was purified by silica gel column chromatography to obtain the desired product 0.839.

Infrared absorption spectrum (Rho 1 Nujol): 340
0, 3270.3160.1710.1590 Experimental example 6
Compound 178rn9 of 1,2-dimethoxyethane 5r
nL and added 222 mg of niline trisulfide.

Stirred at 70°C for 4 hours. The reaction solution was extracted with ethyl ether, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the desired product 90. I got it. Infrared absorption spectrum.

The NMR spectrum matched that of the compound of Experimental Example 18.

Experimental Example 20 Methyl 3-imino-3-methylthio-(E)-2-fluoromethoxyiminopropionate 194 rng of the compound of Experimental Example 18 was dissolved in 10 mL of acetonitrile, 276 μ of potassium carbonate and 1 rnL of methyl iodide were added, The mixture was stirred at room temperature for 5 hours and 30 minutes. 50 mL of ethyl ether was added to the reaction solution, and the insoluble matter was removed in an oven. The solvent was distilled off to obtain an oily target product (190.9%).

Infrared absorption spectrum (α-1, neat): 3290,
2950.1740.1610.156ONMR spectrum (δ, CDCl,): 2.30 (3H, s),
3.89 (3H, s).

5.68 (2H, d, J=54Hz), 9.48 (
LH, br) Experimental Example 21 Methyl 2-amidino-fZ)-2-fluoromethoxyiminoacetate hydrochloride 190 mg of the compound of Experimental Example 20 was dissolved in methanol.

Ammonium chloride 147+B was added and the mixture was refluxed for 4 hours.

After cooling the reaction solution, 50 ml of ethyl acetate was added, and the insoluble matter was removed in the oven. Concentrate the furnace liquid, remove the precipitated crystals from the bottom of the furnace,
After washing with ethyl ether, 108 mu of the target product was obtained.

Infrared absorption spectrum and NMR spectrum are Experimental Example 11
It was consistent with that of the compound.

Example 4 Methyl (Zl-2-fluoromethoxyimino-2-(5
-Amino-1,2,4-thiadiazol-3-yl)acetate methyl 2-amidino-(Zl-2-fluoromethoxyiminoacetate hydrochloride 214 liters and methanol 3rnL
and 253 tons of triethylamine were added.

To this solution, 160 mg of bromine and 2 methanol were added under water cooling.
The rLL solution was added dropwise over 5 minutes and stirred for 20 minutes.

(Methyl 2-(N-bromo)amidino-(Z)-2-
fluoromethoquine iminoacetate).

A solution of 103 mg of potassium thiodiionate in 3 iL of methanol was added dropwise over 5 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 saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 210Tng of the target product.

Infrared absorption spectrum (Low Nujol): 340
0, 3250.3100.1730.1680.161
ONMR spectrum (δ, DMSO-d6): 3.
84 (3H, s), 5.78 (2H, d, J=53
Hz).

8.23 (2H, brs) Experimental Example 22 3-(N-chloroamidino)furan was distilled off under reduced pressure, 50 ml of ethyl acetate was added to the residue, and saturated sodium bicarbonate solution, water, and saturated brine were added. Washed with. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the desired product (1.30%).

Melting point: 288-91°C Mass spectrum (m/e): 144 (M”)
Infrared absorption spectrum (Cm”, Nujol): 3
460, 3260.1615.1590.1545.1
51ONMR spectrum (δ, CDCl,): 6.
68 (LH, dd, J4.8Hz, 0.8I(z)
.

7.48 (LH, t, J=1.8Hz).

7.88 (LH, dd, J=1.8Hz, 0.8H
z) Example 5 3-(5-amino-1,2,4-thiadiazole-3-
1.5 g of furan-3-amidinofuran hydrochloride, 1.37 g of N-chlorosuccinimide, and 20 liters of methanol! Dissolved in LL.

To this, 5 iL of methanol solution of 1.079 J ethylamine was added dropwise under ice cooling, and the mixture was stirred for 45 minutes. Solvent 1.1 g of the compound of Experimental Example 22 was added to 22 ml of methanol.
Potassium thiocyanate 0.75, dissolved in water and cooled with water.
Add.

Stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and 50 mL of ethyl acetate was added to the residue, which was washed with water and then with saturated brine. Anhydrous magnesium sulfate and activated carbon were added to this and filtered, and the solvent was distilled off under reduced pressure to obtain the desired product (0.82%).

Melting point = 150-151°C Mass spectrum (m/e): 167 (M”)
Infrared absorption spectrum (cm-1, Nujol): 33
00, 1640.1600.1530.1515NMR
Spectrum (δ, DMSO-d6): 6.78 (I
H, brs), 7.66 (LH, brs).

7.92 (2H, brs), 8.04 (IH, brs)
) Example 6 2-(5-amino-1,2,4-thiadiazole-3-
yl)-2-oxoacetic acid and stirred overnight. The precipitated crystals were collected in a furnace and 66 mg of the target material was obtained.
I got it. Furthermore, 2 g of sodium sulfite was added to the furnace solution, and the solvent was distilled off. 51 rLL of methanol was added to the residue, filtered, and the filtrate was concentrated. Dichloromethane was added to this and the precipitated crystals were poured into the bottom of the furnace to obtain 70 rng of the desired product. A total of 136 rng of the target product was obtained.

Infrared absorption spectrum ((1m-', Nujol) =
3430, 3320.3250.3180.1700.
1615 NMR spectrum (δ, DMSO-d6)
:8.18 (3H, brs) Experimental Example 23 Ethyl (2-methyl-3-furyl)formimidate hydrochloride 167 ml of the compound of Example 5 was dissolved in a mixture of 12 ml of dichloromethane and 1.5 nL of methanol, and -30 'C
Ozone was passed through the solution under cooling. Add 31% to the reaction solution under water cooling.
Add 2 mL of hydrogen peroxide and 2 mL of acetic acid, and stir at room temperature.
A mixture of 3.22 Q of 3-cyano-2-methylfuran, 1.41 Q of ethanol, and 8 WLL of ethyl ether was made to absorb 1.149 Q of hydrogen chloride, and then stirred at 0°C for 2 days. The solvent was distilled off under reduced pressure, and 40 rrLL of isopropyl ether was added to the residue. The precipitated crystals were poured into the bottom of the furnace to obtain the desired product 1.299.

Melting point: 135-136°C Mass spectrum (m/e): 153 (M”
-HCI) Infrared absorption spectrum (Cm-', Nujol): 1.645.1640.1615.153O
NMR spectrum (δ, cDc13): 2.56 (3H
,t, J=7.21(z), 3.56(3H,s)
.

4.81 (2H, q, J = 7.2Hz 7.23 (L
H, d, J = 1.8Hz).

7.74 (LH, d, J4.8H, s), 11.7
6(2H,brs) Experimental Example 24 3-amidino-2-methylfuran hydrochloride. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl ether to obtain the desired product (1.04).

Melting point: 172-1738C Mass spectrum (m/e): 124 (M4
-HCI) Infrared absorption spectrum (Cm=, Nujol): 3200, 3050.2730.1665.16
20.1605.1525 NMR spectrum (δ, DM
SO-4): 2.51 (3H, s), 6.74 (LH
, d, J4.8Hz).

7.65 (IH, d, J=1.8Hz), 9.00
(2H, brs).

9.11 (2H, brs) Experimental Example 25 3-(N-Chloramidino)-2-methylfuran Compound 1.499 of Experimental Example 23 was dissolved in 50 rnL of a saturated aqueous sodium bicarbonate solution, and 100 rnL of ethyl ether was added.
Extracted with L. After washing the extract with water and then saturated saline,
It was dried with anhydrous magnesium sulfate. Remove the solvent under reduced pressure,
The residue was dissolved in 9 mL of methanol. Ammonium chloride 378. , and refluxed for 2 hours and 30 minutes, 800 mg of the compound of Experimental Example 24, and 665 N-chlorsuccinimide.
A solution of 520 rng of triethylamine in 2 rnL of methanol was added to a mixture of 8 mL of triethylamine and 8 mL of methanol.
Stir for 5 minutes. The solvent was distilled off under reduced pressure, and 30 WLL of ethyl acetate was added to the residue, which was washed successively with a saturated aqueous solution of hydrogen carbonate (II) rum, water, and saturated brine. After drying by adding anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the target product 597.
I got m9.

Melting point: 85-88°C Mass spectrum (m/e): 158 (M”
) Infrared absorption spectrum (Cff!-', Nujol): 3470, 3300.3270.3070.270
0.1770.1705°1635, 1620.157
5.1555.1515 NMR spectrum (δ, CD
Cl, ): 2.46 (3H, s), 5.38 (2H
,brs).

6.36 (LH, d, J=1.8Hz), 7.18
(LH, d, J=1.8Hz) Example 7 3-(5-amino-1,2,4-thiadiazole-3-
yl)-2-methylfuran, 560 mg of the compound of Experimental Example 25 was added to 10 rI of methanol.
Potassium thiocyanate 34Tt was dissolved in LL and cooled with water.
ng and stirred at room temperature for 3 hours. After removing the solvent under reduced pressure.

40 tnL of ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine. Anhydrous magnesium sulfate and activated carbon were added to this, filtered, and the solvent was distilled off under reduced pressure to obtain the target product 463 in the form of an oil.
I got +119.

Mass x vector (m/e): 181 (M
”) Infrared absorption spectrum (Cm-', Nujol)
:3450, 3300.3150.2160.1705
．． 1610.151ONMR spectrum (δ, CDC
l, ): 2.64 (3H, s), 5.82 (2H,
brs).

6.70 (LH, d, J=1.8Hz), 7.19
(LH, d, J=1.8Hz) Example 8 2-(5-amino-1,2,4-thiadiazole-3-
200 mg of the compound of Example 7) was dissolved in dichloronotane 14r.
nL and passed through ozone while cooling at -30°C. The reaction solution was cooled with water, 1 mL of methanol, 1 rnL of 31% hydrogen peroxide solution and 2 TLL of acetic acid were added, and the mixture was stirred at room temperature overnight.

The precipitated crystals were counted and 58 mg of the target product was obtained. Further, 1 g of sodium sulfite and magnesium sulfate were added to the furnace solution and filtered. After concentrating the furnace liquid under reduced pressure, dichloromethane was added, and the precipitated crystals were collected at the bottom of the furnace to obtain 48m9 of the target product.

A total of 106 mg of the target product was obtained.

The infrared absorption spectrum and NMR spectrum matched those of the compound of Example 6.

Example 9 2-(5-amino-1,2,4-thiadiazole-3-
yl)-(Zl-2-fluoromethoxyiminoacetic acid ether (1:3) to give 0.38 g of
I got it.

The infrared absorption spectra and NIviR spectra were consistent with those of Example 3.

Example 10 2-(5-formylamino-1,2,4-thiadiazol-3-yl)-(Zl-2-fluoromethoxyiminoacetic acid methylfluoromethoxyamine 0.589% solution of 25% ethanol, 0.0% water. 1 g of 2-(5-amino-1,2゜4-thiadiazol-3-yl)-2-oxoacetic acid per 45 strips
and adjust the pH to 4-5 with 10% sodium hydroxide aqueous solution.
After adjusting to the desired temperature, the mixture was stirred at room temperature overnight.

The solvent was distilled off under reduced pressure, and 20 mL of water + 10.
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 converted into acetone-isopropyl compound 75. 180 rrtL of formic acid and 150m of acetic anhydride
The suspension was suspended in a mixed solution of L and stirred at room temperature for 1 day. 350 mL of diisopropyl ether was added to the reaction solution, and the precipitate was poured into the bottom of the furnace. After washing this with diisopropyl ether,
Dry to obtain the target 69. I got it.

Melting point: 221-223°C (decomposed) Infrared absorption spectrum (C711-', Nujol) = 1720, 1675 NMR spectrum (δ, DMSO-d6): 3.93 (
3H,s), 5.60(LH,s), 6.20
(LH,s).

8.86 (LH,s) Example 11 2-(5-formylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetic acid NMR spectrum (δ, DMSO-d6 ) :5.5
7 (LH, s), 6.17 (IH, s), 8.8
6(LH,s) Example 12 2-(5-amino-1,2,4-thiadiazole-3-
yl)-(Z)-2-fluoromethoxyiminoacetic acid 250 rng of the compound of Example 10 was added to 1 rn methanol.
At room temperature, 2TrLL of 2N sodium hydroxide aqueous solution and 2mL of methanol were added, and the mixture was stirred for 1 hour.

Water was added to the reaction solution, the solution was made acidic with 1.5 ml of 4N sulfuric acid, and then extracted with ethyl acetate. After drying this with anhydrous magnesium sulfate, the solvent was distilled off to obtain 1931 g of the target product.

Melting point: 165-166°C Infrared absorption spectrum (Cm-', Nujol): 17
15,1680 1 mL of IN-sodium hydroxide aqueous solution was added to 50 g of the compound of Example 11, and the mixture was heated at 50°C for 1 hour.

Water was added to this, the solution was made acidic with 1 ml of 4NIA acid, and then extracted with ethyl acetate. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off to obtain the target product 40 Melon 9.

The infrared absorption spectrum and NMR spectrum matched those of the compound of Example 3.

Example 13 2-(5-amino-1,2,4-thiadiazole-3-
yl)-(Z)-2-fluoromethoxyiminoacetic acid Compound 10v of Example 10 was added to 27 mL of a 3N aqueous sodium hydroxide solution under water cooling, and the mixture was stirred for 30 minutes.

Add 8N hydroxide to this solution) 9 rrcL of IJium aqueous solution
was added, and the mixture was further stirred for 24 hours under water cooling. 4 to the reaction solution
40ml of N sulfuric acid was added and extracted with ethyl acetate. After drying the extract 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 NMR spectrum matched those of the compound of Example 3.

Experimental Example 26 2-(5-amino-1,2,4-thiadiazole-3-
2-(5-amino-1,
2゜4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetic acid 325 +++9 was added and stirred at the same temperature for 30 minutes. 20 rnL of isopropyl ether was added to the reaction solution, and the resulting precipitate was poured into the bottom of the furnace to obtain the desired product 1.
Obtained 30 my.

Mass spectrum/L/ (m/e): M”-・
-・238 (35C1).

240 (3 cylinders C1) Infrared absorption spectrum (cm-'+ Nujol): 1
780, 1625 NMR spectrum (δ, DMSO-d6): 5.8
5 (2H, d, J=55 output) Experimental Example 27 p-methoxybenzyl 7β-(2-phenylacetamido)-3-triphenylphosphoniomethyl-3-cephem-4-carboxylate iosito p-methoxybenzyl 7β 250 g of -(2-phenylacetamide)-3-chloromethyl-3-cephem 4-carboxylate was suspended in 1.5 L of acetone, and 200 g of triphenylphosphine and 78 g of sodium iodide were suspended in 1.5 L of acetone.
g was added thereto, and the mixture was stirred at room temperature for 1 hour. Insoluble matter was removed in the furnace, and the P solution was added dropwise into a mixed solution of 6 L of ethyl acetate and 3 L of isopropyl ether with stirring, and the resulting precipitate was poured into the bottom of the furnace. The precipitate was washed with 600 mL of inpropyl ether and dried to obtain 420 g of the desired product.

Infrared absorption spectrum (1:m”l Nujol):
1780, 1710.1670.161ONMR spectrum (δ, DMSO-d6): 3.50 (2■(,
s), 3.71 (3H, s), 4.3-5.3 (5
H, m).

5.56(H(, dd, J=5.2Hz, 7.2H
z).

6. 82 (2H, d, J=8.0Hz), 7.
0-7.4 (7H, m).

7.4-8.0 (15H, m), 9.00 (LH,
d, J=7.5Hz) Experimental Example 28 p-Methoxybenzyl 7β-(2-phenylacetamide) -3-(fZ)-3-chloro-1-propenylcou 3-cephem-4-carboxylate 120 g of the compound was dissolved in 0.8 Ll of chloroform,
223 mL of IN aqueous sodium hydroxide solution and 200 rnL of saturated saline were added and stirred. The organic layer was separated, washed with water, and then dried over potassium carbonate. Potassium carbonate was removed, and 18.4 WLL of N,0-bis(trimethylsilyl)acetamide was added under water cooling, followed by stirring for 5 minutes. 150 g 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 the desired product 32.49.

Infrared absorption spectrum ((1m-', Nujol):
1760, 1720.1660.161 ONMR spectrum (δ, DMSO-tun): 3.55 (2H, s),
3.76 (3H, s).

3.93 (LH, dd, J=8.0Hz, 12.0
Hz).

4.16 (IH, dd, J=8.0Hz, 12.0
Hz).

5.14 (2H, ABq, J=12.0F(z).

5.21 (LH, d, J=5.0Hz).

5.70 (LH, dt, J=11.3Hz, 8Hz
).

5.74 (LH, dd, J=5.0Hz, 8.0)
Lz).

6.30 (LH, d, J=11.3Hz).

6.94 (2H, d, J=8.5Hz), 7.28
(5H, s).

7.33 (2H, d, J-8, 5Hz).

9.14 (LH, d, J = 8.0 Hz) Experimental example 29 p-methoxybenzyl 7β-(2-phenylacetamide) -3-((E)-3-iodo-1-propenyl)-3-cephem- 200 g of the compound of 4-carboxylate Experimental Example 28 was suspended in 2.5 ml of dry acetone, and 290 g of IJium was added thereto, and the mixture was stirred at room temperature for 3 hours. The solution was concentrated, and the precipitated crystals were collected at the bottom of the furnace and washed with a dilute aqueous solution of thiosulfuric acid, water, and then acetone to obtain the desired product 133.49.

Infrared absorption spectrum ccm-', Nujol):
1775, 1715.165O NMR spectrum (δ, DMSO-c16): 3.
50 (IH, d, +43.8Hz), 3.56 (L
H, d, J = 13.8Hz).

3.59 (IH, d, +47.8Hz), 3.74
(3H, s).

3.90 (IH, d, J-17,8Hz), 4.3
0 (2H, d, J=7.0Hz).

5.15 (lh, d, J=4.8Hz), 5.1
9 (LH, d, J=12.0Hz).

5.23 (LH, d, J = 12.07).

5.70 (LH, da, J=4.8Hz, 8.4H
z).

6.22(LH, dt, J=15.4Hz, 7I(
z).

6.79 (LH, d, J=15.4Hz), 6.9
3 (2H, d, J=8.4Hz).

7.2-7.35 (5H, m), 7.36 (2H, d
, J-8,4Hz).

9.18 (LH, d, J = 8.4 Hz) Experimental example 30 p-methoxybenzyl 7β-(2-phenylacetamido)-3-((E)-3-(■-1-rubamoyl-2-hydroxyethyl ) Dimethylammonio)-1-propenyl)-3-cephem-4-carboxylate 5.0 g of the compound of Experimental Example 29 was suspended in 1'haL of N,N-dimethylformamide, and under water cooling, (R1-2 -dimethylamino-3-hydroxypropionamide 1.4
2 g was added, and the mixture was stirred for 2 hours while gradually returning to room temperature.

After adding 200rrLL of isopropyl ether and stirring,
The supernatant was removed, and 80 ml of chloroform was added to the oily precipitate to dissolve it. Add 300 tLL of ethyl ether dropwise to this.

The resulting precipitate was poured into the bottom of the furnace to obtain 3.89 g of the target material as a pale yellow powder.
I got it.

Infrared absorption spectrum (C7+1'', Nujol): 1775, 1690.1655 NMR spectrum (δ, DMSO-d,): 3.1
1 (3H, s), 3.17 (3H, s), 3.52
(2H, s).

3.73 (3H, s), 3.85-4.1 (3H, b
r).

4.1-4.35 (2H, m), 5.15 (LH, d
, J=4.8Hz).

5.18 (2H, s), 5.5-5.8 (LH, br
).

5.69 (IH, dd, J=4.8Hz, 8.0L
r), 5.95-6.4 (IH, m).

6.90 (2H, d, J=8.5Hz), 7.23
(5H, s).

7.32 (2H, d, J=8.5Hz), 7.80
(LH, br).

8.01(LH,br), 9.09(2I(,d,
J=8.0Hz) Experimental Example 31 7β-(2-phenylacetamide)-3-((E)-
3-(U-1-carbamoyl-2-hydroxyethyl)
Dimethylammonio]-1-propenyl]=3-cephem-4-carboxylate Trifluoroacetate, CF, COOH Compound 3.659 of Experimental Example 30 was suspended in 22 mL of anisole, and 25 ml of trifluoroacetic acid was added to 30 ml of trifluoroacetic acid under water cooling. The mixture was added dropwise over a period of minutes, and then stirred for 1 hour. 200 rnL of isopropyl ether was added to the reaction solution, and the resulting precipitate was collected. This was washed with ethyl acetate and ethyl ether to obtain the desired product 2.679 as a pale yellow powder.

Infrared absorption spectrum ((?m-', Nujol)
:1770, 168O NMR spectrum (δ, DMSO-d4) 23.1l
(3H,s), 3.17(3H,s), 3.52(
2H,s).

3.6-4.4 (7H, m), 5.11 (IH, d,
J=5.0Hz).

5.65 (IH, dd, J = 5.0 city, 860 city).

5.9-6.35 (LH, m), 7.02 (LH, d
, J45.3Hz).

7.23 (5H, s), 7.77 (LH, brs),
8.09 (IH, brs).

9.09 (1) I, d, J = 8.0 ratio) Experimental Example 32 7β-Amino-3-[(E) -3-C((R)-1-
Carbamoyl-2-hydroxyethyl)dimethylammonio)-1-propenyl)-3-cephem-4-carboxylate perchlorate 8.0 g of the compound of Experimental Example 32 and 8.0 g of sodium acetate trihydrate were added to 121 rLL of water. dissolved in. Activated carbon 0 in this
．． Add 3g and stir at room temperature for 15 minutes, then filter.
The p solution was adjusted to pH 7.7 with 5% aqueous ammonia. To this, 2 g of carrier-fixed penicillin G amidase [trade name, penicillin G amidase derived from Escherichia coli (carrier: polyacrylamide) manufactured by Boehringer Meiheim Yamanouchi Co., Ltd.] was added at 300C, and the pH of the solution was adjusted to 7.5 to 7.5 with aqueous ammonia. While maintaining it at 7.8.

The mixture was stirred at the same temperature for 1 hour. This was filtered, and the P solution was purified by column chromatography using Sepabeads 5p2o7 (trade name, styrene-divinylbenzene copolymer adsorbent, manufactured by Mitsubishi Kasei Corporation), and the target fraction was concentrated to 20 ml. Add 70% perchloric acid to this and adjust the pH to 2.
, 5 and add isopropanol 150 rn under stirring.
L was added dropwise. Count the resulting sediment.

Washing with acetone and ethyl ether gave the desired product 1.4859 as pale yellow crystals.

Infrared absorption spectrum (C1l11', Nujol)
=1775, 1690.1585 NMR spectrum (δ, DMSOd,): 3.11
(3H, s), 3.18 (3H, s), 3.4-4
．． 1 (5H, m).

4.25 (2H, br, d, J = 6.8Hz 4.89
(LH, d, J-5, 2Hz), 5.10 (LH,
d, J=5.2I(z).

5.9-6.3 (LH, m), 7.06 (IH, d,
J45.8Hz).

7.78 (LH, brs), 8.15 (IH, br)
Experimental Example 33 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamide) -3-((E)-3-[(■ Methanol containing 230 g of sodium acetate trihydrate 5.
150 mL of the compound of Experimental Example 32 was added to 5 mL of a 1-proof solution of water.

100 mg of the compound of Experimental Example 26 was added, and the mixture was stirred at room temperature for 1 hour. Methanol was distilled off, and the residue was purified by reverse phase silica gel column chromatography to obtain the target product 46r.
Rg was obtained.

Infrared absorption spectrum (Cm-', Nujol): 1
765, 1670.1600.153ONMR spectrum (δ, DMSO-d6): 3.08 (3H, s)
, 3.14 (3H, s).

3.49 (IH, d, J=17.2Hz), 3.6
2 (LH, d, J=17.2Hz).

3.87 (LH, dd, J=5.5Hz, 12.5
Hz).

4.06 (IH, dd, J=5.5Hz, 12.5
Hz).

4.1-4.2 (LH, m), 4.19 (2H, d,
J=7.3Hz).

5.08 (II-I, d, J=5.0Hz).

5.67 (LH, dd, J=4.8Hz, 8.4H
z).

5.70~. 5.85 (IH, m), 5.79 (2
H, d, J=55.0Hz).

7.11 (LH, d, J=15,4Hz), 7
．． 76 (LH, s).

8.22 (2H, s), 8.52 (LH, s),
9.73 (IH, d, J=8.414z) Antibacterial power M
IC (μg/mL) Staphylococcus aureus 0.209-P Escherichia coli ≦0.025II
-fJ Klebsiella pneumoniae ≦0.025K-6 Serratia marcescens ≦0.025 Morganella e Morgani ≦0.025P-14 Shortmonas aerugino-f 0.8P-01 Experimental example 34 p-methoxybenzyl 7β-( 2-phenylacetamide) -3-((E)-3-(carbamoylmethylethylmethylammonio)-1-propenyl]-3-cephem-4 Carboxylate yossite In the same manner as Experimental Example 30, Experimental Example 29 20 g of the compound was reacted with 4.229 g of 2-ethylmethylaminoacetamide to obtain the desired product 23.OQ.

Infrared absorption spectrum (α-1, Sujoor): 177
0,165O NMR spectrum (δ, DMSO-4,): 1.1
5-14 (3H, m,), 3.14 (3H, s).

3.25-3.8 (4I-I m), 3.55 (2H
, s), 3.77 (3H, s).

4.0-4.2 (4H, m), 5.16 (IH, d,
J=5.2Hz).

5.23 (2H, s), 5.71 (IH, d, d,
J=5.2Hz, 8.0Hz).

5.95-6.4 (LH, m), 6.96 (2H, d
, J=8.8Hz).

7.30 (5H, s), 7.41 (2H, d, J=
8.8Hz).

7.75 (LH, br), 8.43 (LH, br),
9.21 (LH, d, J = 8.0 Hz) Experimental example 35 7β-(2-phenylacetamide)-3-((E)-
3-C carbamoylmethylethylmethylammonio)-
1-propenyl)-3-cephem-4-carboxylate trifluoroff)4Hf Experimental example 36 7β-amino-3-((E)-3-(carbamoylmethylethylmethylammonio)-1-propenyl]-3-
Cephem-4-carboxylate paratoluenesulfonate In the same manner as in Experimental Example 31, compound 23° of Experimental Example 34 was suspended in 130 mj of anisole, and trifluoroacetic acid 14
By adding 0 at, the desired product 15.99 was obtained.

Infrared absorption spectrum (C7m-', Nujol):
1775, 169O NMR spectrum (δ, DMSO-4): 1.26 (
3H, br, t, J=6.8)Lz), 3.10
(3H, s).

3.52 (2H, s), 3.90-4.15 (4H,
m).

5.08 (LH, a, J=4.8Hz).

5.62 (LH, dd, J-4, 8Hz, 8.0H
z).

5.9-6.4 (LH, m), 6.97 (IH, d, J
= 15.7Hz).

7.20 (5H, s), 7.63 (LH, brs),
8.31 (LH, brs).

9.08 (LH, d, J = 8.0 Hz) 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 0.9 g of the target product. 85 g was obtained.

However, in place of perchloric acid in Experimental Example 32, para-toluenesulfonic acid hydrate was used.

Infrared absorption spectrum (c7I+”, Nujol)
: 1770, 1690.159O NMR spectrum (δ, DMSO-tun): 1.25 (3
H, br t, J=6.5E(z), 2.26(3
H,s).

3.07 (3H, s), 3.3~4.05 (6H, m
).

4.18 (2H, br d, J=6.8Hz).

4.77 (IH, a, J=5.0I(z), 4.9
8 (LH, d, J”5.0Hz).

5.8-6.2 (IH, m), 0.97 (LH, d
, J=16)Lz).

7.05 (2H, d, J=8.0H2), 7.4
3 (2H, d, J=8.0Hz).

7.60 (II (, brs), 7.93 (LH, b
r) Experimental Example 37 7β-(2-(5-amino-1,2,4-thianazol-3-yl')-(Z)-2-fluoromethoxyiminoacetamide)-3-[:(E)- 3-(carbamoylmethylethylmethylammonio)-1~propenyl]
-3-cephem-4-carboxylate Compound 6 of Experimental Example 36 (Jr.
ng and 32 mg of the compound of Experimental Example 26 were reacted to obtain 18 rng of the target product.

Infrared absorption spectrum (α-1, Nujol): 176
0, 1675.1590.152ONMR spectrum (
δ, DMSO-d4): 1.26 (3H, t, J
=7.2±).

3.08 and 3.09 (total 3H,s).

3.4-3.6 (2H, m), 3.47 (LH, d
, J=16.8Hz).

3.65 (LH, d, J=16.8I-(z),
4.01 (2H, s).

4.05-4.2 (2H, m), 5.06 (LH,
d, J=4.8Hz).

5.6-5.75 (2H, m), 5.79 (2H,
br d, J=55.3Hz).

7.17 (LH, d, J=15.8Hz), 7.
66 (LH, s).

8.23(2I-(,s), 8.33(LH,s)
, 9.71 (18, d, J=8.4Hz) Antibacterial power
MIC (μg/,,LL) Staphylococcus aureus 0.209-P Escherichia coli ≦0.025IH
J Klebsiella skewer pneumoniae ≦0.025K-6 Serratia Φ marcescens 0.1 Morganella morgani ≦0.025P-14 Shortmonas aeruginosa 0.8p-oi

Claims (8)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by [In the formula, R_1 represents a hydrogen atom or a lower alkyl group], its salt, or its amino group protected with a protective group The compound is oxidized and the protecting group is removed if necessary to obtain a compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, a compound whose amino group is protected with a protecting group, or a salt thereof, and then a fluorocarbon compound is obtained. Thiadiazolyl acetic acid derivatives, whose amino group is a protecting group, are represented by formulas such as ▲mathematical formulas, chemical formulas, tables, etc.▼, which are characterized by removing the protecting group if necessary after reacting with methoxyamine or its salt. A method for producing a protected compound or salt thereof. (2) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by [In the formula, R_1 represents a hydrogen atom or a lower alkyl group], its salt, or its amino group protected with a protective group A compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, a compound whose amino group is protected with a protecting group, or its Method of manufacturing salt. (3) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by [In the formula, R_1 represents a hydrogen atom or a lower alkyl group], its salt, or its amino group protected with a protective group Compound. (4) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by [In the formula, R_2 represents a lower alkyl group], its salt, or a compound whose amino group is protected with a protecting group is hydrated. By decomposition, the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R_2 represents a lower alkyl group. , then this compound is hydrolyzed and the protecting group is removed if necessary.Compounds represented by: ▲Mathematical formulas, chemical formulas, tables, etc.▼ Compounds whose amino groups are protected with a protecting group , or a method for producing its salt. (5) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by [In the formula, R_2 represents a lower alkyl group], its salt, or a compound whose amino group is protected with a protecting group is hydrated. A compound represented by the following general formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_2 is the same as the above definition], which is characterized by decomposition and removing the protective group if necessary, and salts thereof; Or a method for producing a compound whose amino group is protected with a protecting group. (6) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by [In the formula, R_2 represents a lower alkyl group], its salt, or a compound whose amino group is protected with a protecting group. (7) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by [In the formula, R_2 represents a lower alkyl group], its salt, or a compound whose amino group is protected with a protecting group is hydrated. A compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, a compound whose amino group is protected with a protecting group, or a salt thereof, which is characterized by decomposition and removing a protecting group if necessary. Production method. (8) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by, its salt, or a compound whose amino group is protected with a protecting group.