JPS6388187A - 3-ammoniopropenylcephem derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 represents lower alkyl; A represents formulae II-IV (R2 represents lower alkyl; R3 represents lower alkyl, sulfamoyl, forminidoyl or carbamoyl), etc.] and salt thereof. EXAMPLE:7beta-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoace tamido]-3-[(E)-3-(1-methyl-4-sulfamoyl-1-piperazinio)-1-propen-1-yl]-3 -cephem- 4-carboxylate. USE:An antibacterial agent against Gram-positive bacteria and Gram-negative bacteria (Pseudomonas aeruginosa). PREPARATION:A compound expressed by formula V (X represents halogen atom) is reacted with a compound expressed by formulae VI-VII, etc., and protecting groups are eliminated, as necessary.

Description

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

Previously, JP-A-58-174387, JP-A-58-
198490, JP 59-130295, JP 59-219292, JP 60-97
Publication No. 983.

Cephalosporin derivatives having a quaternary ammonio group similar to the compounds of the present invention are known in JP-A-60-197693 and the like. However, it cannot be said that a sufficiently satisfactory compound has been obtained in terms of being effective against both Durham-positive bacteria and Durham-negative bacteria (particularly Pseudomonas aeruginosa).

The present inventors applied nine compounds of the present invention to Duram-positive seedlings.

The present invention was completed based on the discovery that it has excellent antibacterial activity against both Durham-negative bacteria (Pseudomonas aeruginosa).

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

[Structure of the invention]

The present invention is based on the general formula: [wherein R1 is a lower alkyl group, A represents the following group 2,
& represents a lower alkyl group, R5 represents a lower alkyl group, a sulfamoyl group, a formimidoyl group, or a carbamoyl group] and a nontoxic salt thereof.

The lower alkyl groups of R, R2 and R5 in the general formula fIl include methyl, ethyl, n-propyl,
i-propyl, n-butyl, 5ec-butyl.

Examples include t-butyl.

Non-toxic salts of the compound of general formula tI+ include pharmaceutically acceptable salts such as alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and hydrochlorides.

Hydrobromide, hydroiodide, sulfate, carbonate.

Inorganic acid salts such as bicarbonate; vinegar salt, maleate salt.

Organic carboxylates such as lactate and tartrate; organic sulfonates such as methanesulfonate, benzenesulfonate and toluenesulfonate; arginine salt, lysine salt,
Serine salts, aspartates.

Amino acid salts such as glutamate; trimethylamine salt, triethylamine salt, pyridine salt, flocaine salt, picoline salt, dicyclohexylamine salt, N, N'-
Dibenzylethylenediamine salt, N-methylglucamine salt, jetanolamine salt, triethanolamine salt,
Examples include amine salts such as tris(hydroxymethylamino)methane salt and phenethylbenzylamine salt.

Concerning the configuration of the following moiety of the compound of the present invention of general formula (Il).

C- I \Q-R.

There is a syn isomer (Zl) and an anti-isomer El. Although both isomers are included in the present invention, the syn isomer is preferred from the standpoint of antibacterial activity.

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

General formula: [In the formula, R1 is a lower alkyl group, 2A' plate) [A' represents the following compound: R2 horse, horse is a lower alkyl group, R8 is a lower alkyl group,
sulfamoyl group, formimidoyl group or carbamoyl group] or a salt thereof, and if necessary, the protecting group is removed to obtain a compound of the general formula (Il) or a non-toxic salt thereof.

Examples of the halogen atom for X in the above general formula tm include an iodine atom, a bromine atom, and a chlorine atom.

The above reaction can be carried out at a reaction temperature of -10°C to 60°C, preferably 0°C to 40°C. Further, as the reaction solvent, an anhydrous organic solvent is preferable. Organic solvents that can be used include lower alkylnitrile such as acetonitrile and propionitrile; chloromethane,
Lower alkyl halides such as dichloromethane and chloroform; ethers such as tetrahydrofuran, dioxane, and ethyl ether; amides such as N,N-dimethylformamide; esters such as ethyl acetate; ketones such as acetone; hydrocarbons such as benzene, or mixtures thereof solvent! 1) Elimination of the protecting group depends on the type of protecting group used.

This can be carried out by conventional methods such as hydrolysis and reduction.

As protecting groups for the amino group and carboxyl group of the salt of the compound of the general formula (ml and saliva) and the compound of the general formula (III), commonly used groups can be used as long as they do not interfere with the above reaction. .

For example, protective groups for amine groups include formyl group, 'acetyl group, chloroacetyl group, dichloroacetyl group, t-
butoxycarbonyl group, benzyloxycarbonyl group,
Trityl group, p-methoxybenzyl group, diphenylmethyl group, etc.; protective groups for carboxy 1 include p-methoxybenzyl group, p-nitrobenzyl group, t-butyl group,
Methyl group.

2, 2. Examples include 2-toIJ chloroethyl group, diphenylmethyl group, and pivaloyloxymethyl group.

Also, bis(trimethylsilyl)acetamide, N-methyl-N-(1-limethylsilyl)acetamide, N-
It is convenient to use a silylating agent such as methyl-N-trimethylsilyl-trifluoroacetamide because it can hold the amino group and carboxy A at the same time.

Salts of compounds of the general formula (ml and saliva) include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; hydrochlorides, hydrobromides, Inorganic acid salts such as sulfates, carbonates, hydroiodides and 9 bicarbonates; organic carboxylates such as acetates, trifluoroacetates, maleates, lactates, tartrates; methanesulfonates, Organic sulfonates such as benzenesulfonate and toluenesulfonate; trimethylamine salt, triethylamine salt, pyridine salt,
Propylene salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, jetanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt, phenethylbenzyl Amine salts such as amine salts; salts such as amino acid salts such as arginine salts, aspartate salts, lysine salts, glutamate salts, and serine salts can be selected as appropriate.

Next, the present invention will be explained in more detail by showing experimental examples and examples.

Experimental Example 1 (Synthesis of raw material compound) p-methoxybenzyl 7β-C2-(5-)cutylamino-1,2,4-thiadiazol-3-yl)-17
1-2-methoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylate 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-iZl-2-methoxyiminoacetic acid 10
0g was dissolved in dimethylformamide IL.

Under water cooling, p-methoxybenzyl 7β-amino-3-4
0-Lomethyl-3-cephem-4-carboxylate 〇-Toluenesulfonic acid 'L'l-70-triethylamine 22.77y and N-ethyl-N'-3-dimethylaminopropylcarpodiimide hydrochloride 139.6
y was added and stirred at the same temperature for 8 hours. After adding 4 L of ethyl acetate to the reaction solution, water, saturated brine, saturated aqueous sodium bicarbonate solution, and saturated brine.

It was washed successively with IN hydrochloric acid and saturated saline. After drying by adding anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution: chloroform) to obtain 115 g of the desired product.

Experimental Example 2 (Synthesis of raw material compound) p-methoxybenzyl 7β-(2-(5-)cutylamino-1,2,4-thiadiazol-3-yl")-1
ZI-2-methoxyiminoacetamide] = 3-iodomethyl-3-cephem-4-carboxylate 60 g of the compound of Experimental Example 1 was added to 1.21 g of methyl ethyl ketone.
Dissolve 56.5% of sodium iodide in this.

was added and stirred at room temperature for 1 hour. Distill the solvent.

After dissolving the residue in ethyl acetate, the solution was washed successively with water, saturated aqueous sodium thiosulfate solution, and saturated brine.

It was dried by adding anhydrous magnesium sulfate. This was concentrated under reduced pressure, n-hexane was added, and the resulting precipitate was drained to the bottom of the furnace to obtain 61.0 g of the target product.

Experimental Example 3 (Synthesis of raw material compound) p-methoxybenzyl 7β-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-1Z
)-2-Methoxyiminoacetamide]-3-IJ phenylphosphoniomethyl-3J,7emu 4-carboxylate Compound 9.54 of Iodide Experimental Example 2, in 190 ml of benzene
Dissolved in triphenylphosphine 5.64. was added and stirred at room temperature for 1 hour. Add 10% n-hexane to this reaction solution.
0 mL was added dropwise, and the resulting precipitate was poured into the bottom of the furnace. This was washed with a benzene-n-hexane (1:1) mixture and n-hexane to obtain 11.30 g of the desired product.

Experimental Example 4 (Synthesis of raw material compound) p-methoxybenzyl 7β-(2-(5-tritylamino-1,2,4-thiadiazol-3-yl')-f
Zl-2-methoxyiminoacetamide]-3-(fZ
l-3-Chloro-1-propen-1-yl2-3-cephem-4-carboxylate Compound 30 of Experimental Example 3. O
y to chloroform 250 rrtL and ethyl acetate 300
Dissolve in mL of mixed solution and hydrate in water under water cooling) IJ
78.3 ml of an aqueous solution of umum was added and stirred. Separate the organic layer and wash it with saturated saline.

It was dried by adding anhydrous magnesium sulfate. To this organic layer was added a solution of 6.15 g of chloroacetaldehyde in 10 rnL of chloroform under water cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, 300 ml of ethyl acetate was added, and the resulting precipitate was evaporated. Concentrate the p solution to obtain crude product 29.
3g was obtained. This was purified by silica gel column chromatography (elution: chloroform) to obtain the target product 7.73.
I got y.

Experimental Example 5 (Synthesis of raw material compound) p-methoxybenzyl 7β-(2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z
l-2-Methoxyiminoacetamide]-3-((El
-3-Iodo-1-propen-1-yl)-3-cephem-4-carboxylate Compound 7.97 of Experimental Example 4
was dissolved in 167 ml of acetone, 4.37 g of sodium iodide was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was dissolved in 150 mA of ethyl acetate, washed with a saturated aqueous sodium thiosulfate solution and saturated brine, and dried by adding anhydrous magnesium sulfate. Concentrate this under reduced pressure.

Add n-hexane and petroleum ether to the residue to solidify it, and P
8.42 g of the target product was obtained.

Example 1 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl')-(Zl-2-methoxyiminoacetamide) -3-((E) -3-(1-methyl -4-
Sulfamoyl-1-piperazinio)-1-propene-
1.0 g of the compound of 1-ilcy 3-cephem-4-carboxylate Experimental Example 5 was dissolved in 5 ml of dichloromethane, 255 mg of N-sulfamoyl-N'-methylpiperazine was added under water cooling, and the mixture was stirred at room temperature overnight. Add 10 mL of ethyl acetate + 10 Tn of ethyl ether to the reaction solution.
L was added, and the resulting precipitate was counted. Dissolve this in a small amount of methanol-tetrahydrofuran mixture and
Added 0 aL. The resulting precipitate was collected in a furnace to obtain yellow powder 731.
I got door g.

This compound was added to a mixed solution of 5.2 ml of trifluoroacetic acid and 4.4 ml of anisole, and stirred for 2 hours under water cooling. The reaction solution was poured into a mixture of 50 nL of ethyl ether and 50 rrtL of isopropyl ether, and the resulting precipitate was washed in portions with ethyl ether. Add 1 ml of water to the obtained precipitate, add acetic acid to pH 5,
Adjusted to 5. Insoluble matter was removed. The reactor liquid was purified by reverse-phase silica gel column chromatography, and 30 m
I got g.

Example 2 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide:]-3-[(E)-3-(1- Methyl-4-formimidoyl-1-piperazinio)-1-propene-1
-ilcy 3-cephem-4-carboxylate 1.5 g of the compound of Experimental Example 5 was dissolved in a mixture of 10 tnL of methanol and 4 mL of dimethylformamide ML, 323 mg of N-methyl-N'-formimidoylpiperazine hydrochloride
was added and stirred overnight. The reaction solution was diluted with ethyl acetate at 20Orr.
tL, and the resulting precipitate was collected (594 mg).
.

This precipitate was added to a mixed solution of 4.2 ml of trifluoroacetic acid and 3.6 ml of anisole, and stirred for 2 hours under water cooling. The reaction solution was added to a mixed solution of 50 ml of ethyl ether and 50 ml of isopropyl ether, and the resulting precipitate was filtered out. Add 1 liter of water to this precipitate! LL was added and the insoluble matter was removed in the oven. The r liquid was purified using reverse phase silica gel column chromatography and E to obtain 20 Mg of the target product.

Example 3 7β-C2-(5-amino-1,2,4-thiadiazol-3-yl)-(Zl-2-methquiniminoacetamide]-3-((El-3-(1-methyl-4 -Rubamoyl-1-piperazinio)-1-7'mouth pen-1-1
)-3-cephem-4-carboxylate 1.0 g of the compound of Experimental Example 5 was added to 50 rrLl of ethyl acetate.
204 mg of N-methyl-N'-rubamoylpiperazine was added thereto, and the mixture was stirred overnight at room temperature with a trowel. The resulting precipitate was filtered to obtain 867 mg of yellow powder.

This compound was added to a mixed solution of 6.2 TLL of trifluoroacetic acid and 5.3 rnL of anisole, and stirred for 2 hours under water cooling. The precipitate was collected, 1 mL of water was added thereto, and the pH was adjusted to 5 with acetic acid. Insoluble matter is removed by furnace,
The P solution was purified by reverse phase silica gel column chromatography to obtain the target product 40H.

Example 4 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl')-(Zl-2-methoxyiminoacetamide) -3-(fE]-3-(1,2- dimethyl-
1-Vyrazolidinio)-1-propene-1-ylcu 3
-Cephem-4-carboxylate Compound 1 of Experimental Example 5
．． 0g was suspended in 150rnL of ethyl ether, tN,
143+ng of N'-dimethylpiperaziridine was added, and the mixture was stirred at room temperature overnight. The resulting precipitate was poured into the bottom of the furnace and dissolved in 1.5 mL of tetrahydrofuran. Add 20 mL of ethyl acetate to the solution, drain the resulting precipitate to the bottom of the oven, and make a yellow powder.
91 mg was obtained.

This compound was added to a mixed solution of 3.5 ml of trifluoroacetic acid and 3.0 ml of anisole, and the mixture was stirred for 2 hours under water cooling. The reaction solution was added to a mixed solution of 50 ml of ethyl ether and 50 ml of isopropyl ether, and the resulting precipitate was poured into the bottom of the furnace. 1 mL of water was added to this precipitate, and the pH was adjusted to 6.0 with sodium acetate. Insoluble materials were removed, and the P solution was purified by reverse phase silica gel column chromatography to obtain the desired product 1.
9 mg (total of two stereoisomers A and B, A:
8 my, B: 11 mg) was obtained.

Example 5 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-fZ)-2-methoxyiminoacetamide)-3-(to 1-3-(1,1-dioxo -4
-Methyl-4-thiomorpholinio')-1-propene-
1-yl)-3-cephem-4-carboxylate Compound i, og of Experimental Example 5 was dissolved in 3 ml of dichloromethane, 327 mg of 4-methylthiomorpholine 1,1-dioxide was added, and the mixture was stirred at room temperature overnight.

10 rILL of ethyl acetate was added to the reaction solution, and the resulting precipitate was poured into the bottom of the furnace (783 mg).

This compound was added to a mixed solution of 5.6 rnl of trifluoroacetic acid and 4.8 mL of anisole, and stirred for 2 hours under water cooling. Add the reaction solution to 100 mL of ethyl ether.

The resulting precipitate was drained to the bottom of the furnace. 1 rnL of water was added to this, and the pH was adjusted to 7.0 with IJ acetate. Insoluble matter was removed in the oven, and the P solution was purified by reverse phase silica gel column chromatography to obtain 29 mg of the target product.

Example 6 7β-C2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide)-3-((E)-3-(1,4- DiazabicycloC2,2]octane-1-io)-1-propene-1
-yl]-3-cephemu-4-carboxylate 1.0 g of the compound of Experimental Example 5 was added to 150 rr of ethyl ether.
Dissolve in tL, 1,4-diazabicyclo[2.2゜2]
148 mg of octane was added, and the mixture was stirred at room temperature overnight. The resulting precipitate was taken to the bottom of the furnace and dissolved in 2 ml of tetrahydrofuran. This solution was added to 20 mL of ethyl acetate, and the resulting precipitate was separated to obtain 746,111 g of yellow powder.

This compound was added to a mixture of 5.3 mL of trifluoroacetic acid and 3.4 mL of 7-nisole, and stirred for 2 hours under water cooling. Add the reaction solution to 100 mL of ethyl ether.

The resulting precipitate was drained to the bottom of the furnace. Add 1.8 mL of water to this.

Insoluble matter was removed. The reaction solution was purified by reverse phase silica gel column chromatography to obtain 83 mg of the target product.

The primary compounds of Examples 7 to 12 were produced in the same manner as Examples 1 to 6.

Example 7 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-tZl-2-methoxyiminoacetamide)-3-(CEI-3-(1,4-dimethyl-1 −
Piperazinio)-1-propen-1-yl)-3-cephem-4-carpoxylate 1.0 g of the compound of Experimental Example 5
and 3 μL of 1,4-dimethylpiperazine,
The protecting group was removed to obtain 15 mg of the target product.

Example 8 7β-['2-(5-amino-1,2,4-thiadiazol-3-yl>-(z+-12-methoxyiminoacetamide)-3-1:(Ej-3-(1-methyl -4-
Carbamoyl-1,2,3,6-titrahydrohyridinio)-1-propen-1-yl)-3-cephem-4
-Carboxylate Compound 600 my of Experimental Example 5 and 1-methyl-4-carbamoyl-1,2,3,6-titrahydrobiridine 1
37zg was reacted and the protecting group was removed to obtain 45mg of the target product.
I got it.

Example 9 7β-C2-(5-amino-1,2,4-thiadiazol-3-yl)-(Zl-2-methoxyiminoacetamide:]-3-(Ej-3-[N, N-dimethyl- N
-(2-Carbamoylethyl)ammonio]=1-propen-1-yl]-3-cephem-4-carboxylate 500 μl of the compound of Experimental Example 5 and 127 mg of 3-dimethylaminopropioamide were reacted to remove the protective group. After desorption, 12 mg of the target product was obtained.

Example 10 7β-C2-(5-amino-1,2,4-thiadiazol-3-yl')-12)-2-methoxyiminoacetamide)-3-[(El-3-(1,1-dimethyl -1
-Hydrazinio)-1-flopen-1-yl]-3-cephemu 4-carboxylate Compound 600 of Experimental Example 5
mg and 60 mg of 1,1-dimethyl-1-hydrazine
was reacted and the protecting group was removed to obtain the target product 50 ryg.

Example 11 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-fZl-2-methoxyiminoacetamide)-3-11:(E)-3-(N, N- dimethyl-N-hydrazinocarbonylmethylammonio)-1
-propen-1-yl]-3-cephemu 4 500 mg of the compound of Experimental Example 5 was reacted with 110 mg of N,N-dimethylacetohydrazide to remove the protecting group and obtain the target compound 14.
mg was obtained.

Example 12 7β-1:2-(5-amino-1,2,4-thiadiazol-3-yl)-(Zl-2-methoxyiminoacetamide)-3-C(Ej-3-(1,5- Diazabicyclo[3,3,O)octane-1-io)-1-propen-1-yl]-3-cephemu 4-carboxylate 750 mg of the compound of Experimental Example 5 and 1,5-diazabicyclo[3,3,0 ) 280 mg of octane was reacted and the protecting group was removed to obtain 35 mg of the target product.

Claims (7)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R_1 is a lower alkyl group, A is the following group: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas ,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
3-Ammoniopropenyl cephem derivatives and non-toxic salts thereof, represented by ▼, R_2 is a lower alkyl group, R_3 is a lower alkyl group, a sulfamoyl group, a formimidoyl group or a carbamoyl group. (2) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide]-3-[(E)-3-(1-methyl -4-
Sulfamoyl-1-piperazinio)-1-propene-
1-yl]-3-cephem-4-carboxylate and its non-toxic salts. (3) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide]-3-[(E)-3-(1,2 -dimethyl-1-pyrazolidinio)-1-propen-1-yl]-
The compound according to claim 1, which is 3-cephem-4-carboxylate and its non-toxic salt. (4) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide]-3-[(E)-3-(1-methyl -4-
Carbamoyl-1-piperazinio)-1-propene-1
-yl]-3-cephem-4-carboxylate and its non-toxic salts. (5) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide]-3-[(E)-3-(1,4 -The compound according to claim 1, which is diazabicyclo[2,2,2]octane-1-io)-1-propen-1-yl]-3-cephem-4-carboxylate and its nontoxic salt. . (6) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamide]-3-[(E)-3-(1,1 -Dioxo-4-methyl-4-thiomorpholinio)-1-propen-1-yl]-3-cephem-4-carboxylate and its non-toxic salts. (7) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R_1 is a lower alkyl group and X is a halogen atom] Compounds whose amino and/or carboxyl groups are protected A compound protected by a group or a salt thereof has the general formula: A'(III) [A' is the following compound: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, where R_2 is a lower alkyl group, R_3 is a lower alkyl group, a sulfamoyl group, a formimidoyl group, or a carbamoyl group] or a salt thereof is reacted, and if necessary, a protecting group is added. General formulas characterized by elimination: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R_1 is as described above, and A represents a quaternary ammonio group corresponding to A'] A method for producing a compound or a non-toxic salt thereof.