JPS5914026B2 - 2-Carbalkoxyamino-benzimidazolyl-5(6)-sulfonic acid-phenyl ester compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION 5(6) 2-carboalkoxy-amino- with alkyl, acyl, phenoxy and 5-phenylthio groups in the 1-position
Benzimidazolyl derivatives are known as anthelmintic agents (Nature 215, 321 (1967) and West German Publications (DOS) Nos. 2029637 and 21646).
(See the specifications of No. 90 and f0 No. 2363348).

The present invention relates to the formula (1) (wherein R1 means alkyl having 1 to 4 C atoms, and R2 and R3 are independently hydrogen, 1 to 4 C atoms, respectively).
anthelmintic 2-carbalkoxyamino-benzimidazolyl-5 (meaning alkoxy with 4 C atoms, halogen, trifluoromethyl, alkyl with 1 to 4 C atoms, or CN); 6)-
Relating to sulfonic acid phenyl ester.

Substitution Rl. Examples of the alkyl residues in R2 and R3 include methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, and tertiary butyl.

Examples of the alkoxy group for substituents R2 and R3 include methoxy, ethoxy, propoxy, isopropoxy and butoxy. Examples of the halogen atoms in the substituents R2 and R3 include fluorine, chlorine, bromine, and iodine. Particularly preferred are compounds in formula (1) in which R1 represents methyl, R2 represents hydrogen, and R3 represents hydrogen, chlorine, bromine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy; It is particularly preferred that R3 is present in the 3-position of the phenyl ring.

Furthermore, the present invention provides a 0-J-G nylene diamine derivative represented by formula (2) (wherein R2 and R3 have the same meanings as in formula (1)).
a) alkyl-R-methyl-thiourea carboxylate represented by formula (3) (wherein R1 has the same meaning as in formula (1)); or,) formula (4) (wherein R1 is cyanamide carboxylate represented by (having the same meaning as in formula (1)) and 1 to 1, respectively.
6 or by condensation in the pH range of 6 or by formula (
5) N-dichloromethylene carbamic acid ester represented by (wherein R1 has the above-mentioned meaning) and -100 to +
react in the presence of a base at a temperature of 40°C or l)
Formula (6) [wherein R1 has the meaning described for formula (1),
R4 and R5 are the same or different and are an alkyl residue having 1 to 4 C atoms, an alkenyl residue having 3 to 5 C atoms, a cyclohexyl residue or a formula (7) or (8) (formula In the middle, X each independently represents a halogen atom,
Represents a methyl group or a nitro group, and also represents np011 or 2
optionally substituted phenyl or benzyl residue, or R4 and R5 can also be joined to form a ring containing two or three methylene groups. 2-Carboalkoxy- represented by formula (1) (wherein R1, R2 and R3 have the above-mentioned meanings), characterized in that it is reacted with a bis-alkyl mono- or bis-arylthio-methylene-amino monoformate ester. The present invention relates to a method for producing amino-benzimidazole-5(6) sulfonic acid phenyl ester.

The progress of the reaction can be represented by the following scheme.
To carry out the reaction according to (a) above, first, S-methyl-thiourea sulfate of formula (9) and chloroformic acid of formula 00) (wherein R1 has the same meaning as in formula (1)) The ester is mixed in water and a strong base, for example a 25% caustic soda solution, is added dropwise, the temperature preferably being kept at a low temperature, for example about 0.degree.

The alkyl-S-methyl-thiourea carboxylate of formula (3) formed does not need to be isolated. Examples of the chloroformic acid ester of formula (sub) include chloroformic acid methyl ester, chloroformic acid ethyl ester, chloroformic acid propyl ester, chloroformic acid isopropyl ester, chloroformic acid butyl ester, chloroformic acid isobutyl ester, chloroformic acid tertiary butyl ester, etc. can be mentioned.

The pH range of the reaction mixture obtained as described above is then adjusted, preferably to a value of 2 to 5, conveniently by addition of an organic acid such as acetic acid or lactic acid.

The o-phenylenediamine derivative of formula (2) is then added as the free base or as an acid addition salt, for example as a hydrochloride. In the latter case it may be advantageous to add alkaline salts of organic acids as buffers. As the o-phenylenediamine derivative of formula (2), for example, 3.4
-Diaminobenzenesulfonic acid-phenyl ester 3
・4-Diaminobenzenesulfonic acid-4chlorophenyl ester 3,4-diaminobenzenesulfonic acid-
3-chlorophenyl ester 3,4-diamino-benzenesulfonic acid-2-chlorophenyl ester 3,4-
Diaminobenzenesulfonic acid-2,5-dichlorophenyl ester 3,4-Diaminobenzenesulfonic acid-3,5-dichlorophenyl ester 3,4-Diaminobenzenesulfonic acid-4 promorphhenyl ester 3,4 ~Diamino-benzenesulfonic acid-3-promorph phenyl ester 3,4-diamino-benzenesulfonic acid-2-promorph phenyl ester 3,4-diamino-
Benzenesulfonic acid-4methyl-phenyl ester 3.
4-Diamino-benzenesulfonic acid-3 methyl-phenyl ester 3,4-diamino-benzenesulfonic acid-2-methyl-phenyl ester 3,4-diamino-benzenesulfonic acid-4 tertiary butyl ~ phenyl ester 3
・4-Diamino-benzenesulfonic acid-2,4-dimethyl-phenyl ester 3.4-Diamino-benzenesulfonic acid-2chloro-4-methyl-phenyl ester 3.
4-Diaminobenzenesulfonic acid-2-chloro-6-
Methylphenyl ester 3,4-diamino-benzenesulfonic acid-3-chloro-4-methyl-J-G-methyl ester 3,4-diamino-benzenesulfonic acid-3-chloro-
6-Methyl-phenyl ester 3,4-diamino-benzenesulfonic acid-4chloro-2-methyl-phenyl ester 3,4-diamino-benzenesulfonic acid-4-chloro-3-methyl-phenyl ester 3,4-diamino −
Benzenesulfonic acid-4chloro-3,5-dimethyl-phenyl ester 3,47 Diaminobenzenesulfonic acid-3,5-bistrifluoromethyl-phenyl ester 3,4-Diaminobenzenesulfonic acid-4methoxyphenyl ester 3・4-Diamino-benzenesulfonic acid-3methoxyphenyl ester 3,4-diamino-
Benzenesulfonic acid-2-methoxyphenyl ester 3,4-diaminobenzenesulfonic acid-4-propoxyphenyl ester 3,4-Diamino-benzenesulfonic acid-4-isopropoxyphenyl ester 3,4-
Diamino-benzenesulfonic acid-4-butoxyphenyl ester 3,4-diamino-benzenesulfonic acid-4
Examples include isobutoxy phenyl ester.

A temperature of 30 to 100°C is convenient for the reaction of this reaction partner, and the reaction time may be 30 minutes to 10 hours.

Methyl mercaptan is liberated as a by-product. Formula (1)
2-carbalkoxyamino-benzimidazolyl-
Isolation of the 5(6)-sulfonic acid phenyl ester is carried out in a customary manner, for example by diluting the reaction mixture with water and separating off the precipitated product. The following compound is thus obtained. 2-carbomethoxyamino-5
-Benzimidazole-sulfonic acid monophenyl ester 2-carbomethoxyamino-5-benzimidazole-
4-Chlorophenyl ester 2-carbomethoxyamino-5-benzimidazole-3-chlorophenyl ester 2-carbomethoxyamino-5-benzimidazole-2-chlorophenyl ester 2-carbomethoxyamino-5-benzimidazole -2,5-dichlorophenyl ester 2-carbomethoxyamino-5-benzimidazole-3,5-dichlorophenyl ester 2-carbomethoxyamino-5-benzimidazole-4-promorphhenyl ester 2-carbomethoxyamino -5-Benzimidazole-3-promorphenyl ester 2-carbomethoxyamino-5-benzimidazole-2-promorphenyl ester 2-carbomethoxyamino-5-benzimidazole-4-methyl-phenyl ester 2-carbomethoxy Amino-5-benzimidazole-3-methyl-phenyl ester 2-carbomethoxyamino-5-benzimidazole-2-methyl-phenyl ester 2-carbomethoxyamino-5-
Benzimidazole-4-tertiary butyl phenyl ester 2-carbomethoxyamino-5-benzimidazole-2,4-dimethyl-phenyl ester 2-carbomethoxyamino-5-benzimidazole-2-chloro-
4-Methyl-phenyl ester 2-carbomethoxyamino-5-benzimidazole-2-chloro-6-methyl-phenyl ester 2-carbomethoxyamino-5-
Benzimidazole-3-chloro-4-methyl-phenylene ester 2-carbomethoxyamino-5-benzimidazole-3-chloro-6-methyl-phenylene ester 2-carbomethoxyamino-5-benzimidazole-4- Chloro-2-methyl-phenyl ester 2
-carbomethoxyamino-5-benzimidazole-4
-Chloro-3-methyl-phenyl ester 2-carbomethoxyamino-5-benzimidazole-4-chloro-
3,5-dimethyl-phenylene ester 2-carbomethoxyamino-5-benzimidazole-3,5-bistrifluoromethyl-phenylene ester 2-carbomethoxyamino-5-benzimidazole-4-methoxyphenyl ester 2-carbomethoxyamino-5-
Benzimidazole-3-methoxyphenyl ester 2-carbomethoxyamino-5-benzimidazole-
2-methoxyphenyl ester 2-carbomethoxyamino-5-benzimidazole-4-propoxyphenyl ester 2-carbomethoxyamino-5-benzimidazole-4-isopropoxyphenyl ester 2
-carbomethoxyamino-5-benzimidazole-4
-butoxyphenyl ester 2-carbomethoxyamino-5-benzimidazole-4-isobutoxyphenyl ester 2-carboethoxyamino-5-benzimidazole -sulfonic acid monophenyl ester 2-carbopropoxyamino 5- Benzimidazole-sulfonic acid monophenyl ester 2-carboisopropoxyamino 5-benzimidazole-sulfonic acid phenyl ester 2-carbobutoxyamino 5-benzimidazole sulfonic acid monophenyl ester 2-carboisobutoxyamino -5-benzimidazole-sulfonic acid-phenyl ester 2-carbo-tertiary butoxyamino-5
-Benzimidazole-sulfonic acid monophenyl ester To carry out the reaction according to (b) above, first a chloroformate of formula σ0) [for example, also used for the reaction according to (a)] is mixed with a salt, preferably a calcium salt. is added to an aqueous suspension of cyanamide a1) in the form of , the reaction temperature being kept at 40 DEG to 60 DEG C. by cooling.

After separating the precipitated dark-colored by-product, cyanamide carboxylate of formula (4) is obtained in the slurry. The cyanamide carboxylate (4) so obtained is mixed with the o-phenylenediamine derivative (2) and the mixture is adjusted to a pH of 1 to 6 by addition of a mineral acid such as concentrated hydrochloric acid.
The value is preferably adjusted to 2-4. For this reaction,
The reaction mixture is conveniently kept at 30 DEG to 100 DEG C., and preferably for 30 minutes to 10 hours, depending on the reactivity of the 0-phenylenediamine derivative. After cooling the reaction mixture, the precipitated reaction product (1) is isolated by separation of P and washing. The 0-phenylenediamine derivatives 2) can be used as free amines with alkyl-S-methyl-thiourea carboxylates (3) in the manner described above or with suitable inorganic or organic acids such as hydrochloric acid, sulfuric acid, acetic acid. It can also be used in the form of an acid addition salt with , oxalic acid, etc.

To carry out the reaction according to (c) above, 1 mole of the o-phenylene diamine derivative of formula (2) is reacted with 1 mole of N-dichloromethylenecarbamate ester of formula (5) in the presence of 2 moles of base. It is convenient to do so.

Examples of the base include alkali or alkaline earth hydroxides, carbonates and hydrogen carbonates, and tertiary organic bases. Examples include sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, triethylamine, pyridine, and methyl-substituted pyridine. The N-dichloromethylene-carbamate ester of formula (5) is disclosed in West German Publication No. 19322.
97, from known dichloromethylene-carbamic acid chlorides and alcohols to inert organic solvents such as ether, dioxane, tetrahydrochloride, etc.
In the presence of benzene, toluene, etc.
It can be produced at temperatures of °C.

Examples of the N-dichloromethylenecarbamate ester of formula (5) include methyl ester, ethyl ester, isopropyl ester, propyl ester, n-butyl ester, and secondary butyl ester of N-dichloromethylenecarbamate. It will be done. The reaction temperature can be varied over a wide range.

Generally, the range is -100 to 60°C, preferably 0 to 30°C. To carry out the reaction according to (d) above,
One mole of o-phenylene diamine derivative of formula (2) is converted into formula (
6) is reacted with 1 mol of bis-alkyl mono- or bis-arylthio-methylene amino monoformate in an inert solvent such as tetrahydrofuran, dioxane, isopropyl ether or chloroform at elevated temperature, preferably at the boiling point of the solvent used. It's convenient.

In the method of the present invention, the bis-alkyl or arylthio-methyleneamino monoformate is prepared from the hydrochloride of iminodithiocarbonate in advance in a reaction vessel (
It can also be produced by addition of a chloroformic acid ester of formula (sub) such as that used in the reaction according to a).

In this case an acid acceptor must be present, which may be an organic or inorganic base, such as sodium hydroxide, sodium bicarbonate or triethylamine.

Polar and non-polar solvents such as ether, acetone, dioxane, water, dimethylformamide,
Benzene or cyclohexane are suitable, and the temperature preferably does not exceed 20°C. Bis-alkyl- or bis-arylthio-
Methylene amino monoformates can be obtained by reacting the corresponding dithio-imino carbonate esters with the chloroformates of 0) according to the method described in US Pat. No. 3,562,290.

Bis-alkyl- or bis-arylthio- of formula (6)
Examples of methylene amino monoformate include the following. Bis-methylthio-methylene-amino monoformic acid methyl ester, bis-methylthio-methylene-amino monoformic acid monoethyl ester, bis-methylthio-methylene-amino monoformic acid propyl ester, bis-
Methylthio-methylene-aminomonoformic acid-isopropyl ester, bis-methylthio-methylene-aminomonoformic acid-
Butyl ester, bis-methylthio-methylene-aminomonoformic acid monomethyl ester, bis-butylthio-methyleneaminomonoformic acid monomethyl ester, methylthio-butylthiomethylene-aminomonoformic acid-methyl ester, allylthio-cyclohexylthio-methyleneamino -Formic acid monomethyl ester, methylthiophenylthio-methyleneamino monoformic acid monomethyl ester, methylthio mono(3.4
-dichlorobenzylthio)-methyleneamino-formic acid methyl ester or methylthio-(2-chloro-4-methylthio)methyleneaminomonoformic acid methyl ester.

Formula (2) used as starting material for reactions (a) to (d)
The 0-phenylenediamine derivative of formula () can be obtained by reducing the corresponding aminonitro derivative of formula (self) (
Here R2 and R3 have the same meaning as in formula (1)).

This reduction can be carried out by hydrogenation in the presence of Raney nickel and a solvent such as methanol or dimethylformamide at a temperature of 20 DEG to 60 DEG C., or by treatment with a reducing agent such as sodium dithionite. formula(
The amino-nitro derivative of formula A3) (in which R
2 and R3 have the same meaning as in formula (1)) with ammonia in a suitable solvent such as dioxane or methanol at elevated temperature and elevated pressure. It will be done.

The chloro-nitro compound of formula (self) is 3-nitro-
4-Chloro-benzenesulfonic acid chloride A5 was converted to formula 04
) (wherein R2 and R3 have the same meanings as in formula (1)) in the presence of a base such as triethylamine in an inert solvent. The 2-carbalkoxyamino-benzimidazole-5(6)-sulfonic acid phenyl esters according to the present invention are valuable chemotherapeutic agents and are useful in the eradication of parasitic diseases of humans and animals, such as worms and liver ants. suitable for eradication.

These are particularly useful for a large number of insects, such as Haemonchus (
Haem Onchus), Trichostrongylus (Tr.
ichOetrOngylus), Ostertagia (0
stertagia), Strongyloides (StrO
ngylOides), COoperia
), Chabertia, 1st Sofa 0゛3 Tomamu (0es0p11ag0st0mum),
HyOstrOngylns,
Ankylostoma Ascaris and Heteralc
is), etc.

In particular, it has a remarkable effect on gastrointestinal nematodes that especially affect anti-shearing animals. Since infestation of animals with these parasites results in great economic losses, the compounds according to the invention are used in particular as veterinary medicines. The active substance of formula (1) is administered in doses of 0.5 to 50 m'/kg body weight for 1 to 14 days, depending on the respective condition. Oral applications include tablets, dragees, capsules, powders, granules or pastes.

These contain the active substance together with the customary auxiliary and carrier substances such as starch, cellulose powder, talc, magnesium stearate, sugar, gelatin, calcium carbonate, finely divided silicic acid, carboxymethyl cellulose or similar substances. . For parenteral applications, mention may be made of solutions, such as oil solutions, using sesame oil, castor oil or synthetic triglycerides, optionally with the addition of tropherol as an antioxidant and/or with interfacial agents such as zorbitan fatty acid esters. Prepared with active substances. In addition, aqueous suspensions can also be used, which are prepared using ethoxylated sorbitan fatty acid esters, optionally with the addition of thickening agents such as polyethylene glycol or carboxymethylcellulose. The concentration of the active substance according to the invention in the prepared formulation is preferably between 2 and 20% by weight when used as veterinary medicine, and when used as human medicine the active substance concentration is preferably between 20 and 80% by weight.

In order to confirm the action of the compounds according to the invention, Haemonchus contortus (HaemOnchuscOntOr
tus) or Trichostrongylus colubriformis (TrichOstrOngluscOlubrifO
rmis) larvae weighing approximately 3
Chemotherapy experiments were performed on female lambs weighing 0 kg.

The test animals were kept in isolation boxes, which were thoroughly cleaned every day. Wetz
Modification of the McMaster method by El [Tierarztiiche Umschau, . Hunger 2
09-210 (1951)], the number of eggs per feces 1f7 was measured. The sheep were treated immediately thereafter (generally 4-8, at least 2 per agent). The products according to the method of the invention were each applied to these animals as a suspension in 10 ml of 1% TylOse suspension. On the 7th, 14th and 28th day after treatment, the number of eggs per 17 feces was determined again by the method described above and its percentage reduction relative to the starting value before treatment was calculated. The products according to the process of the invention have a significant effect when applied orally, but are also effective parenterally at dosages below 2 W/Kg.

These therefore include similar benzimidazole derivatives, in particular all known 5(6)-substituted 2-benzimidazoles.
Much better than carbaminate. Example a) Example 1 S in 44 ml of water and 13 ml of chloroformic acid methyl ester
-Methyl-thiourea sulfate 27.8f7 was added to a well-stirred mixture under ice cooling at a temperature not exceeding 10°C. of 25% caustic soda is added dropwise.

Stir for a further half hour, then add 10a of glacial acetic acid and 100ml
Add a mixture consisting of: 24.2 f of 3,4-diamino-benzenesulfonic acid phenyl ester dissolved in 100 ml of isopropanol are then added thereto and heated under reflux for 2 hours, at which point a solid precipitate begins to separate.

Separately, thoroughly washed with methanol and then with water, and after drying, 19f7 of 2-carbomethoxyamino-5-benzimidazole sulfonic acid phenyl ester is obtained. For purification, the crude product is dissolved in 250 mi of dioxane, filtered with carbon and the F solution is mixed with water 50a.

The yield of analytically pure product is 14f7 and its decomposition point is 242°C. The 3,4-diaminobenzenesulfonic acid phenyl ester is obtained by hydrogenating 3-nitro-4-amino-benzenesulfonic acid phenyl ester of 27f7 using Raney nickel in 300 ml of methyl glycol at normal pressure and room temperature. Manufactured by

After separating off the catalyst and concentrating, 3,4-diamino-benzenesulfonic acid phenyl ester is obtained as a crude product in the form of a dark oil of 257, which can also be used directly for ring closure. To produce the 3-nitro-4-amino-benzenesulfonic acid phenyl ester, 54f7
The 3-nitro-4-chloro-benzenesulfonic acid phenyl ester of is kept at 50 DEG C. under 500 atu of gaseous ammonia in dioxane for 5 hours, then the solvent is removed in vacuo. When the residue is mixed with 200 ml of a mixture of equal proportions of methanol and water, a solid precipitate forms after a while and is separated. After several recrystallizations from methanol and then benzene, 28t of 3-nitro-4-
Aminobenzenesulfonic acid phenyl ester (melting point 1
04°C) is obtained.

The 3-nitro-4-chloro-benzenesulfonic acid phenyl ester is 51f7 3-nitro-4-chloro-
Benzene sulfonic acid chloride was mixed with 18.8 f7 of phenol in 120 ml of acetone and cooled for 10
Obtained by dropwise addition of triethylamine 28a at an internal temperature not exceeding .degree.

Stirring is continued for a few more hours at room temperature and then on mixing with water an oil separates out which is worked up in ether. After recrystallization from methanol, 3-nitro-4-chloro-benzenesulfonic acid phenyl ester 54t having a melting point of 71 DEG C. is obtained. The following compounds are obtained analogously using the corresponding different starting materials (Examples 2 to 12).

Example 2 3-nitro-4-chloro-benzenesulfonic acid 4-chlorophenyl ester (melting point 84°C) and 3-nitro-
2 via 4-amino-benzenesulfonic acid 4-chlorophenyl ester (melting point 156°C) and 3,4-diamino-benzenesulfonic acid 4-chlorophenyl ester.
-Carbomethoxyamino-5-benzimidazole-sulfonic acid 4-chlorophenyl ester [touch point 2500
C (decomposition)] is obtained.

Example 3 3-nitro-4-chloro-benzenesulfonic acid 3-chlorophenyl ester (melting point 68°C) and 3-nitro-
4-Amino-benzenesulfonic acid 3-chlorophenyl ester (melting point 138°C) and 3,4-diamino-benzenesulfonic acid 3-chlorophenyl ester (melting point 8
2-Carpomethoxyamino-5-benzimidazole-sulfonic acid 3-chlorophenyl ester [melting point: 234° C. (decomposed)] is obtained through “C).

Example 4 3-nitro-4-chloro-benzenesulfonic acid 3,5-
Dichlorophenyl ester (melting point 104°C) and 3-
2-carboxylic acid via nitro-4-amino-benzenesulfonic acid 3-5-dichlorophenyl ester (melting point 164°C) and 3,4-diaminobenzenesulfonic acid 3,5-dichlorophenyl ester (melting point 116°C). Methoxyamino-5-benzimidazole-sulfonic acid 3,5-
Dichlorophenyl ester [melting point 2500C (decomposition)
] is obtained.

Example 5 3-nitro-4-chloro-benzenesulfonic acid 3-promorphenyl ester (melting point 72°C) and 3-nitro-
4-amino-benzenesulfonic acid 3-promorph phenyl ester (melting point 141°C) and 3,4-diaminobenzenesulfonic acid 3-promorph phenyl ester (melting point 9
4°C) to obtain 2-carbomethoxyamino-5-benzimidazole-sulfonic acid 3-promorphenyl ester [melting point 242°C (decomposition)].

Example 6 3-nitro-4-chloro-benzenesulfonic acid 4-methyl-phenyl ester (melting point 68°C) and 3-nitro-
2 via 4-amino-benzenesulfonic acid 4-methyl-phenyl ester (melting point 135°C) and 3,4-diamino-benzenesulfonic acid 4-methyl-phenyl ester.
-Carbomethoxyamino-5-benzimidazole sulfonic acid 4-methyl-phenyl ester [melting point 2400C
(decomposition)] is obtained.

Example 7 3-nitro-4-chloro-benzenesulfonic acid 3-methyl-phenyl ester (melting point 60°C) and 3-nitro-
4-Amino-benzenesulfonic acid 3-methyl-phenyl ester (melting point 138°C) and 3,4-diamino-benzenesulfonic acid 3-methyl-phenyl ester (melting point 8
4°C) to obtain 2-carbomethoxyamino-5-benzimidazole sulfonic acid 3-methyl-phenyl ester [melting point: 234°C (decomposition)].

Example 8 3-nitro-4-chloro-benzenesulfonic acid 4-methoxyphenyl ester (melting point 88°C) and 3-nitro-4-aminobenzenesulfonic acid 4-methoxyphenyl ester (melting point 140°C) and 3 - 2-Carbomethoxyamino-5-benzimidazole sulfonic acid 4-methoxyphenyl ester [melting point 228°C (decomposition)] is obtained via 4-diaminobenzenesulfonic acid 4-methoxyphenyl ester.

Example 9 3-Nitro-4-chloro-benzenesulfonic acid 3-methoxyphenyl ester (oil) and 3-nitro-4
-Amino-benzenesulfonic acid 3-methoxy phenyl ester (melting point 116°C) and 3,4-diamino-benzenesulfonic acid 3-methoxy phenyl ester (oil)
2-carbomethoxyamino-5-benzimidazole sulfonic acid 3-methoxyphenyl ester [melting point: 227°C (decomposition)] is obtained.

Example 10 3-Nitro-4-chloro-benzenesulfonic acid 3-ethoxyphenyl ester (oil) and 3-nitro-4
-2carbomethoxyamino-5-benzimidazole sulfone via amino-benzenesulfonic acid 3-ethoxyphenyl ester (melting point 86°C) and 3,4-diamino-benzenesulfonic acid 3-ethoxyphenyl ester (oil) Acid 3-ethoxyphenyl ester [melting point 212°C (decomposition)] is obtained.

Example 11 3-nitro-4-chloro-benzenesulfonic acid 3-cyanophenyl ester (melting point 118°C) and 3-nitro-4-aminobenzenesulfonic acid 3-cyanophenyl ester (melting point 183°C) and 2-carbomethoxyamino-5-benzimidazole- via 3,4-diaminobenzenesulfonic acid 3-cyanophenyl ester.
Sulfonic acid 3-cyanophenyl ester C melting point 265
°C (decomposition)] is obtained.

Example 12 3-nitro-4-chloro-benzenesulfonic acid 3-trifluoromethyl-phenyl ester (melting point 65°C) and 3-nitro-4-amino-benzenesulfonic acid 3-trifluoromethyl-phenyl ester (melting point 132°C) and 2-carbomethoxyamino-5-benzimidazole-sulfonic acid 3-trifluoromethyl-phenyl ester [melting point 250°C (
decomposition)] is obtained.

Method (5) Example 13 To a solution of cyanamide 427 in 210 ml of water is added chloroformic acid methyl ester of 907 and 33% caustic soda of 218y.

The mixture is stirred for one and a half hours at a temperature of 30-35°C.
A solution of 3,4-diamino-benzenesulfonic acid phenyl ester 2137 in isopropanol 11 is then added and the temperature is then raised to 80°C. After adding 200 ml of glacial acetic acid, the reaction mixture is kept at 90 DEG C. for a further 3-4 hours.

The reaction mixture is allowed to cool and stored in the refrigerator overnight. The precipitated 2-carbomethoxyamino-5-benzimidazole-sulfonic acid phenyl ester is separated and washed with isopropanol and water. For purification, the crude product is dissolved in dioxane, filtered with carbon and mixed with water. Yield 807, decomposition point 242°C. 3.4- above
The diamino-benzenesulfonic acid phenyl ester was prepared in the same way as described in Example 1 in three of the intermediate steps described in Example 1.
-Nitro-4-cucarobenzenesulfonic acid phenyl ester and 3-nitro-4-aminobenzenesulfonic acid phenyl ester.

The following compounds are obtained analogously using the corresponding different starting materials (Examples 14-19).

Example 14 3-Nitro-4-chloro-benzenesulfonic acid 3-chlorophenyl ester (melting point 68°C) and 3-nitro-4-amino-benzenesulfonic acid 3-chlorophenyl ester (melting point 138°C) and 3・4
-diaminobenzenesulfonic acid 3-chlorophenyl ester (melting point 8'C), 2-carbomethoxyamino-5-benzimidazole-sulfonic acid 3-chlorophenyl ester [according to Example 3, melting point 234°C ( decomposition)] is obtained.

Example 15 3-nitro-4-chloro-benzenesulfonic acid 3-promorphenyl ester (melting point 72°C) and 3-nitro-
2-carbomethoxyamino-5 via 4-amino-benzenesulfonic acid 3-promorphhenyl ester (melting point 141°C) and 3,4-diamino-benzenesulfonic acid 3-promorphhenyl ester (melting point 94°C) -benzimidazole-sulfonic acid 3-promorphenyl ester [according to Example 5, melting point 242 DEG C. (decomposed)] is obtained.

Example 16 3-nitro-4-chloro-benzenesulfonic acid 3-methyl-phenyl ester (melting point 60°C) 3-nitro-4-amino-benzenesulfonic acid 3-methyl-phenyl ester (melting point 138°C) and 3.4 -Diamino-benzenesulfonic acid 3-methyl-phenyl ester (melting point 84 fc)
) to obtain 2-carbomethoxyamino-5-benzimidazolesulfonic acid 3-methyl-phenyno L ester [according to Example 7, melting point 234° C. (decomposed)].

Example 17 3-Nitro-4-chlorobenzenesulfonic acid 3-methoxy-J-G-nyl ester (oil) and 3-nitro-4
2-carbomethoxyamino-5-benzimidazole-sulfone via -amino-benzenesulfonic acid 3-methoxyphenyl ester (melting point 116°C) and 3,4-diamino-benzenesulfonic acid 3-methoxyphenyl ester (oil) Acid 3-methoxyphenyl ester [
A melting point of 227° C. (decomposed), consistent with Example 9, is obtained.

Example 18 3-Nitro-4-chlorobenzenesulfonic acid 3-ethoxyphenyl ester (oil) and 3-nitro-4
- 2-carbomethoxyamino-5-benzimidazole sulfonic acid via aminobenzenesulfonic acid 3-ethoxyphenyl ester (melting point 86 °C) and 3,4-diamino-benzenesulfonic acid 3-ethoxyphenyl ester (oil) A 3-ethoxyphenyl ester (according to Example 10, melting point 212 DEG C. (decomposed)) is obtained.

Example 19 3-nitro-4-chloro-benzenesulfonic acid 3-trifluoromethyl-phenyl ester (melting point 65°C) and 3-nitro-4-amino-benzenesulfonic acid 3-trifluoromethyl-phenyl ester (melting point 132 ) and 2-carbomethoxyamino-5-benzimidazole-sulfonic acid 3-trifluoromethyl-phenyl ester [melting point 250°C (decomposition)] ] is obtained.

Method c) Example 20 264t of 3,4-diaminobenzenesulfonic acid phenyl ester, 2027 of triethylamine and 300
Mix 1 m of chloroform and 50 m of chloroform
A solution of N-dichloromethylene-carbamic acid methyl ester 156y in No. 1 is added gradually at a temperature of up to 20 DEG C. while stirring.

Stir for an additional hour, separate the precipitate and wash with additional chloroform. For purification, the crude product is dissolved in dioxane, filtered over carbon and mixed with water.

After separation, washing and drying, the decomposition point is 242°C.
-Carbomethoxyamino-5-benzimidazole, sulfonic acid phenyl ester 5y is obtained. 3.4 above
-diamino-benzenesulfonic acid phenyl ester and 3-nitro-4-aminobenzenesulfonic acid phenyl ester in the intermediate step described in Example 1 as described in Example 1. -obtained via benzenesulfonic acid phenyl ester.

The following compounds are obtained analogously using the corresponding different starting materials (Examples 21-26).

Example 21 3-Nitro-4-chloro-benzenesulfonic acid 3-chlorophenyl ester (melting point 68°C) and 3-nitro-4-amino-benzenesulfonic acid 3-chlorophenyl ester (melting point 138°C) and 3. 4-Diaminobenzenesulfonic acid 3-chlorophenyl ester (melting point 84°C)
5-benzimidazole sulfonic acid 3-chlorophenyl ester [according to Example 3, melting point 234°C (decomposed)
] is obtained.

Example 22 3-Nitro-4-chloro-benzenesulfonic acid 3-promorphenyl ester (melting point 72C) and 3-nitro-4-aminobenzenesulfonic acid 3-promorphenyl ester (melting point 141°C) and 3・4-diamino-benzenesulfonic acid 3-promorphenyl ester (melting point 9
2-carbomethoxyamino-5-benzimidazole-sulfonic acid 3-promorph phenyl ester via “C)
A melting point of 242° C. (decomposed), consistent with Example 5, is obtained.

Example 23 3-nitro-4-chlorobenzenesulfonic acid 3-methyl-phenyl ester (melting point 60°C) and 3-nitro-4-amino-benzenesulfonic acid 3-methyl-phenyl ester (melting point 138°C) and 3,4-diamino-benzenesulfonic acid 3-methyl-phenyl ester (melting point 8
4°C) to obtain 2-carbomethoxyamino-5-benzimidazole-sulfonic acid 3-methyl-phenyl ester [according to Example 7, melting point 234°C (decomposed)].

Example 24 3-Nitro-4-chloro-benzenesulfonic acid 3-methoxyphenyl ester (oil) and 3-nitro-4
-2-carbomethoxyamino-5-benzimidazole sulfone via amino-benzenesulfonic acid 3-methoxyphenyl ester (melting point 116°C) and 3,4-diaminobenzenesulfonic acid 3-methoxyphenyl ester (oil) Acid 3-methoxyphenyl ester [
A melting point of 227° C. (decomposed), consistent with Example 9, is obtained.

Example 25 3-Nitro-4-chloro-benzenesulfonic acid 3-ethoxyphenyl ester (oil) and 3-nitro-4
2-carbomethoxyamino-5-benzimidazole via -amino-benzenesulfonic acid 3-ethoxyphenyl ester (melting point 86°C) and 3,4-diamino-benzenesulfonic acid 3-ethoxyphenyl ester (oil). -sulfonic acid 3-ethoxyphenyl ester [according to Example 10, melting point 212 DEG C. (decomposed)] is obtained.

Example 26 3-nitro-4-chloro-benzenesulfonic acid 3-trifluoromethyl-phenyl ester (melting point 65°C) and 3-nitro-4-amino-benzenesulfonic acid 3-trifluoromethyl-phenyl ester (melting point 132 °C) and 2-carbomethoxyamino-5-benzimidazole-sulfonic acid 3-trifluoromethyl-phenyl ester via 3,4-diamino-benzenesulfonic acid 3-trifluoromethyl-phenyl ester [according to Example 12, A melting point of 250°C (decomposition) is obtained.

Method (6) Example 27 The bis-methylthio-methyleneamino formic acid methyl ester of 17.97 was dissolved in 26.97 in tetrahydrofuran 200a.
4f7 of 3,4-diamino-benzenesulfonic acid phenyl ester is added and the mixture is heated to reflux for 3 hours.

After cooling, the 2-carbomethoxyamino-5-benzimidazole sulfonic acid phenyl ester is separated off and purified by dissolving it in dioxane, filtering it with carbon and precipitating it with water. Yield 12f7, decomposition point 2
42℃. The 3,4-diamino-benzenesulfonic acid phenyl ester is prepared in the same manner as described in Example 1, but also in the intermediate step 3-nitro-4-chloro-benzenesulfonic acid phenyl ester and as described in Example 1. Obtained via 3-nitro-4-amino-benzenesulfonic acid phenyl ester.

Example 28 19.7 t of iminodithiocarbonate methyl ester hydrochloride and 1257 t of chloroformic acid methyl ester in 50 WLI of water are added dropwise to a cooled solution with 10% caustic soda, the temperature being 1
Do not exceed 0℃.

As soon as the pH value has been set to 7.5, 26.4 t of 3,4-diamino-benzenesulfonic acid phenyl ester in 50 ml of glacial acetic acid are added thereto and the mixture is heated under reflux with stirring for 2 hours. Allow to cool and form 2
-Carbomethoxyamino-5-benzimidazole-sulfonic acid phenyl ester is separated ▲. Its properties are the same as the reaction product described in Example 27. The following compounds are obtained analogously using a variety of corresponding starting materials (
Examples 29-34).

Example 29 3-Nitro-4-chloro-benzenesulfonic acid 3-chlorophenyl ester (melting point 68°C) and 3-nitro-4-amino-benzenesulfonic acid 3-chlorophenyl ester (melting point 138°C) and 3. 4-diamino-benzenesulfonic acid 3-chlorophenyl ester (melting point 84°C) to 2-carbomethoxyamino-
5-benzimidazole-sulfonic acid 3-chlorophenyl ester [according to Example 3, melting point 234°C (decomposition)
] is obtained.

Example 30 3-nitro-4-chloro-benzenesulfonic acid 3-promorphenyl ester (melting point 72°C) and 3-nitro-
4-Amino-benzenesulfonic acid 3-promorph phenyl ester (melting point 141°C) and 3,4-diamino-benzenesulfonic acid 3-promorph phenyl ester (melting point 94
2-carbomethoxyamino-5-benzimidazole-sulfonic acid 3-promorph phenyl ester [
A melting point of 242° C. (decomposed), consistent with Example 5, is obtained.

Example 31 3-nitro-4-chloro-benzenesulfonic acid 3-methyl-phenyl ester (melting point 60°C) and 3-nitro-
4-Amino-benzenesulfonic acid 3-methyl-phenyl ester (melting point 138°C) and 3,4-diamino-benzenesulfonic acid 3-methyl-phenyl ester (melting point 84
2-carbomethoxyamino-5-benzimidazole-snohyphonic acid 3-methyl-phenyl ester (according to Example 7, melting point 234°C (decomposition)) is obtained.

Example 32 3-Nitro-4-chloro-benzenesulfonic acid 3-methoxyphenyl ester (oil) and 3-nitro-4
-2-carbomethoxyamino-5-benzimidazole via amino-benzenesulfonic acid 3-methoxyphenyl ester (melting point 116°C) and 3-4-diamino-benzenesulfonic acid 3-methoxyphenyl ester (oil) A sulfonic acid 3-methoxyphenyl ester (according to Example 9, melting point 227 DEG C. (decomposed)) is obtained.

Example 33 3-nitro-4-chloro-benzenesulfonic acid 3-ethoxyphenyl ester (oil) and 3-nitro-4
-Amino-benzenesulfonic acid 3-ethoxyphenyl ester (melting point 86°C) and 3,4-diamino-benzenesulfonic acid 3-ethoxyphenyl ester (oil)
2-Carbomethoxyamino-5-benzimidazole-sulfonic acid 3-ethoxyphenyl ester [according to Example 10, melting point 212 DEG C. (decomposed)] is obtained.

Example 34 3-nitro-4-chloro-benzenesulfonic acid 3-trifluoromethyl-phenyl ester (melting point 65°C) and 3-nitro-4-amino-benzenesulfonic acid 3-trifluoromethyl-phenyl ester (melting point 132 °C) and 2-carbomethoxyamino-5-benzimidazole-sulfonic acid 3-trifluoromethyl-phenyl ester [according to Example 12,
A melting point of 250°C (decomposition) is obtained.

Claims (1)

[Claims] 1 Formula (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1) (In the formula, R_
1 means alkyl having 1 to 4 carbon atoms, R
_2 and R_3 are each independently hydrogen, 1-
2-carbalkoxyamino-benzimidazolyl-5(6)-sulfonic acid, alkoxy with 4 carbon atoms, halogen, trifluoromethyl, alkyl with 1 to 4 carbon atoms or CN) Phenyl ester compound.