CH634565A5 - Process for the preparation of phenyl- and naphthylpyridazinone derivatives - Google Patents

Description

The invention relates to a new process for the preparation of a phenyl or naphthylpyridazinone derivative of the formula

R

2nd

R

3rd

wherein Rj, R2, R3 and R4 are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a lower alkylthio group, a hydroxy group, a cycloalkyl group, an amino group or a group

RsCONH-

wherein R5 represents a lower alkyl group having 1 to 3 carbon atoms, or Rt and R2, R2 and R3 or R3 and R4 with each other to form a benzene ring which is condensed with the benzene ring to which they are linked and forms a naphthalene ring as a whole , are connected and Rs represents a hydrogen atom or a lower alkyl group.

In the above general formula (I), the lower alkyl group means an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, , tert-butyl, n-amyl, isoamyl, sec.-amyl, n-hexyl group and the like, and the lower alkoxy group is an alkoxy group having 1 to 4 carbon atoms, such as a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy group and the like. The lower alkylthio group is an alkylthio group having 1 to 4 carbon atoms, such as, for example, a methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio group and the like. The halogen atom consists of chlorine, bromine. Fluorine or iodine and the cycloalkyl group is a cycloalkyl group having 3 to 6 carbon atoms, such as a cyclopropyl, cyclopentyl, cyclohexyl group and the like.

If the group has the formula R6CONH-, R6 denotes a methyl, ethyl, n-propyl or isopropyl group.

The compound of general formula (I) above, which can be prepared by the process of the invention, is a very useful compound as an agricultural fungicide as such or as an intermediate for other agricultural chemicals and drugs.

With regard to the production of 6-phenyl-3 (2H) pyridazi-nonen, a) a process for the oxidation of the corresponding 4,5-dihydropyridazinone with bromine (J. Am. Chem. Soc., 75, 1117), b) a process for Oxidation of the corresponding 4,5-dihydropyridazinone with bromine (J. Am. Nitrobenzenesulfonate (Japanese Patent Publication No. 12740/1969), c) a process for reacting the corresponding 3-benzoyiacrylic acid ester with an excess of hydrazine (Japanese Provisionai Publication No. 34178 / '976), d) a process for reacting a salt of the corresponding benzoylacrylic acid with an excess of methanol in the presence of a base, releasing the corresponding acid from the salt reaction product and then heating the acid thus released with a hydrazine compound (Japanese Provisionai Patent Publi-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

3rd

634565

cation No. 43776/1976), e) proposed a process for reacting the corresponding 2-morpholino-4-phenyl ~.-oxobutyric acid with a hydrazine compound (Bull. Soc. Chim. France, 1973, 625) and similar processes. However, the previous processes mentioned above, for example processes a) and b), involve complicated measures and they also use complex oxidizing agents (bromine and sodium m-nitrobenzenesulfonate), which are also difficult to handle. And methods c) and d) require longer reaction times and rather tedious cleaning measures, which are caused by the contamination by undesired products. Process e) has the disadvantage of poor product yield.

As a result of extensive research into an economical process for producing a 6-phenyl-3 (2H) pyridazinone derivative, the present process was found, which is considerably improved in terms of economic performance and ease of synthesis.

Of the compounds of the above general formula

(I) which are prepared by the process of the invention, typical examples of the compounds are listed below:

(1) 6- (3,5-dichloro-4-methylphenyl) -3 (2H) pyridazinone

(2) 6-phenyl-3 (2H) pyridazinone

(3) 6- (p-tolyl) -3 (2H) pyridazinone

(4) 6- (3,4-dichlorophenyl) -3 (2H) pyridazinone

(5) 6- (3-bromophenyl) -3 (2H) pyridazinone

(6) 6- (3-chlorophenyl) -3 (2H) pyridazinone

(7) 6- (4-bromophenyl) -3 (2H) pyridazinone

(8) 6- (4-chlorophenyl) -3 (2H) pyridazinone

(9) 6- (3-chloro-4-fluorophenyl) -3 (2H) pyridazinone (10) 6- (3-bromo-4-fluorophenyl) -3 (2H) pyridazinone

(II) 6- (3,5-dichloro-4-hydroxyphenyl) -3 (2H) pyiridazinone

(12) 6- (3-chloro-4-methoxyphenyl) -3 (2H) pyridazinone

(13) 6- (4-fluorophenyl) -3 (2H) pyridazinone

(14) 6- (4-Hydroxyphenyl) -3 (2H) pyridazinone

(15) 6- (3,4-Dimethoxyphenyl) -2 (2H) pyridazinone

(16) 6- (4-ethylphenyl) -3 (2H) pyridazinone

(17) 6- (4-isopropylphenyl) -3 (2H) pyridazinone (18) 6- (2,5-dimethylphenyl) -3 (2H) pyridazinone (19) 6- (β-naphthyl) -3 (2H) pyridazinone

(20) 6- (4-Cyclohexylphenyl) -3 (2H) pyridazinone

(21) 6- (3-Chloro-4-methylphenyl) -3 (2H) pyridazinone

(22) 6- (2,3,5-trichloro-4-methylphenyl) -3 (2H) pyridazinone

(23) 6- (4-MethoxyphenyI) -2 (2H) pyridazinone

(24) 6- (3,5-dichloro-4-ethylphenyl) -3 (2H) pyridazinone

(25) 6- (4-Methylthiophenyl) -3 (2H; pyridazinone

(26) 6- (3-Nitro-4-methylphenyl) -3 (2H) pyridazinone

(27) 6- (4-Acetamidophenyl) -3 (2H) pyridazinone

(28) 6- (3-Chloro-4-methylphenyl) -2-methyl-3 (2H) pyridazinone

(29) 6- (p-TolyI) -2-methyl-3 (2H) pyridazinone

(30) 6- (4-aminophenyl) -3 (2H) pyridazinone

(31) 6- (n-hexylphenyl) -3 (2H) pyridazinone

(32) 6- (3-Jphenphenyl) -3 (2H) pyridazinone

(33) 6- (4-n-Butylthiophenyl) -3 (2H) pyridazinone

(34) 6- (4-Cyclopropylphenyl) -3 (2H) pyridazinone.

Of the above compounds, compounds Nos. (1), (5), (6), (9), (10), (11), (21), (22), (24), (28). (31), (32), (33) and (34) new compounds.

According to the process of the invention, the compounds of the general formula (I) above are obtained by reacting a 3-halo-4-phenyl-4-oxobutyric acid derivative of the general formula

R,

2nd

—CH - CH- C00R,

R

3rd

R,

wherein Rj, R2, R3 and R4 have the meaning given above, R7 represents a hydrogen atom or a lower alkyl group with the proviso that R- is a hydrogen atom when R5 is a lower alkyl group and X is a halogen atom, e.g. Chlorine or bromine means with a hydrazine of the general formula

Rg-NHNH ;, (III)

in which R5 has the meaning given above, or with hydrazine hydrate, hydrazine hydrochloride or hydrazine sulfate in the presence of a base and a solvent, and

if R is a lower alkyl group, treatment of the reaction mixture thus obtained with an acid is carried out at elevated temperature.

The process according to the invention can easily be carried out by contacting the compound of the formula (II) with the hydrazine of the formula (III) in the presence of a base and a solvent. The base used is an alkali or alkaline earth carbonate, such as potassium carbonate, sodium carbonate or calcium carbonate; an alkali hydrogen carbonate such as potassium hydrogen carbonate or sodium hydrogen carbonate; an alkali hydroxide such as sodium hydroxide or potassium hydroxide; an alkali acetate such as sodium acetate or potassium acetate; an alkali alkoxide such as sodium methoxide or potassium ethoxide; a tertiary amine such as triethylamine or pyridine; aqueous ammonia and the like, preferably alkali carbonates or more preferably sodium carbonate.

The hydrazine (III) used as the reactant can also be used as the base. As the hydrazine (III) which can be used in the reaction, there may be mentioned, for example, hydrazine, methylhydrazine, ethylhydrazine, isopropylhydrazine and the like. The amount of the hydrazine used is usually 1 to 6 moles to 1 mole of the compound (II). An equivalent of the base is preferably present when the hydrazine is used to one equivalent. The use of a large excess of hydrazine does not require any other base. The reaction temperature is not particularly critical, but the reaction can usually be carried out at room temperature up to the reflux temperature of the solvent used. The response time ranges from several minutes to dozens of hours. When the compound of formula (II) in which R is a lower alkyl group is used as a starting material, the reaction mixture obtained above is acidified with an acid, e.g. Hydrochloric acid and hydrobromic acid, heated.

The phenyl or naphthylpyridazinone compound of the general formula (I) given above is e.g. separated and then excess hydrazine in the mother liquor released by adding an alkali, the used hydrazine can be supplemented and is again useful for this reaction. The hydrazine can also be separated from the mother liquor, for example, as a sparingly soluble salt which can be used for a new reaction. The reaction is carried out in the presence of a solvent5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

634565

4th

guided. There is no particular limitation on the solvents that can be used if they do not participate in the present reaction; e.g. can water; an alcohol such as methanol, ethanol or isopropanol; an organic acid such as acetic acid or propionic acid; a cyclic ether such as dioxane or tetrahydrofuran; a dialkyl sulfoxide such as dimethyl sulfoxide and a dialkylformamide such as dimethylformamide and mixtures of such organic solvents with water and the like can be used. Of the above solvents, water is used advantageously.

After the reaction has ended, the desired compound of the process according to the invention can be obtained from the reaction mixture by conventional methods. For example, the crystalline substance separated off in the reaction mixture after the reaction is filtered off, washed with water and dried to obtain the desired product. The product is further processed by a conventional method, e.g. Recrystallization, column chromatography and the like. Purified to obtain the pure product.

The starting compound of the above-mentioned general formula (II), in which X is a chlorine atom, is a new compound and can be obtained by chlorination of a 4-phenyl-4-oxobutyric acid of the general formula

R,

2nd

R.

3rd

R>

wherein Rj, R2, R3, R4 and R, which have the meaning given above, are prepared.

With regard to the process for the preparation of 4-phenyl-3-bromo-4-oxobutyric acids, the preparation has hitherto been stated in which the corresponding 4-phenyl-4-oxobutyric acid (IV) bromination of the side chain using bromine in one inert solvents such as chloroform or ether is subjected [The Journal of the Chemical Society, page 455 (1945)]. However, this method requires the use of expensive bromine and difficult handling.

An improved process has now also been developed by which the new compounds 4-phenyl-3-chloro-4-oxo-butyric acids can be produced in good yield by a simple reaction process using cheap chlorine or sulfuryl chloride.

The process for producing the compound of the formula (II) by reacting the compound of the above formula (IV) with a halogenating agent can be carried out in an inert solvent. As the halogenating agent usable in this reaction, chlorine, bromine, iodine, iodine monochloride, sulfuryl chloride and sulfuryl bromide can be given, and chlorine and bromine, especially chlorine, are particularly preferred for use.

The molar ratio of the compound of the formula (IV) to the halogenating agent is preferably from 1: 1 to 1: 3. Alkyl halides, such as, for example, dichloromethane, dichloroethane, chloroform or tetrachloroethane; Ethers such as diethyl ether or diisopropyl ether and organic acids such as acetic acid or propionic acid can be used. This reaction is preferably carried out in the presence of a catalytic

Amount of Lewis acid performed, and as the Lewis acid usable in this case, aluminum chloride, ferric chloride, titanium tetrachloride, zinc chloride and tin chloride or the like can be mentioned. The reaction temperature can be from room temperature to the reflux temperature of the solvent used. The response time is e.g. 0.5 to 24 hours.

The starting compound of formula (IV) above can be prepared by any method known per se, for example by the so-called Friedel-Crafts reaction, in which a substituted benzene is subjected to the reaction with succinic anhydride together with a Lewis acid [the above mentioned organic reactions,

Volume 5, page 229 (1949)] or by the method in which a 4-phenyl-4-oxobutyric acid is treated in the presence of a Lewis acid to bring about the halogenation of the benzene ring [Arzneimittel-Forschung, volume 24, page 1360 (1974 )] or similar processes.

Alternatively and preferably, the starting compound of formula (IV) in which the halogen atoms are located either in the 3- or 5-position of the benzene ring or in both positions can be reacted by reacting benzene or a substituted benzene with succinic anhydride in the presence of anhydrous aluminum chloride of the product thus obtained with a halogenating agent without isolating the product and treating the complex produced with an acid, for example Hydrochloric acid and hydrobromic acid, and, if necessary, esterification of the product. The reaction of benzene with succinic anhydride can take place at a reaction temperature of from -10 ° C. to 50 ° C. in an inert organic solvent, such as, for example, carbon disulfide, nitrobenzene, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane . The molar ratio of benzene to anhydrous aluminum chloride is e.g. 1: 1 to 1: 4, preferably 1: 2 to 1: 3. Chlorine, bromine, iodine, iodine monochloride, sulfuryl chloride and sulfuryl bromide can be used as the halogenating agent. The molar ratio of benzene to halogenating agent is e.g. 1: to 1: 4.

Of the compounds of the formula (II) given above, the 4-phenyl-3-halogeno-4-oxobutyric acids in which there is a halogen atom in at least one of the positions 3 and 5 of the benzene ring can also be obtained continuously by halogenation of the 4-phenyl 4-oxobutyric acid of the formula (IV), in which there is a hydrogen atom in at least one of the 3- and 5-positions of the benzene ring, in its side chain by the method mentioned in the above process and subsequent halogenation reaction in the 3- and / or 5-positions of the benzene ring are prepared in the presence of an excess of Lewis acid.

As mentioned above, the compounds of formula (I) prepared by the process of the invention are useful as agricultural fungicides and provide a preventive and curative effect against plant diseases without any damage to the host plants.

More specifically, they could be particularly effective in controlling leaf rot of rice plants, which is a serious disease of the rice plant, by using these fungicides as sprays or as surface sprays.

They are also particularly effective in combating the disease of various crops such as beets, cotton plants, the pumpkin family caused by pathogenic fungi Rhizoctonia, and they are effective in controlling infectious soil-borne diseases, e.g. the southern arid 5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

634 565

rot of eggplant plants and plants of the pumpkin family, black scab of potatoes and the like by using a soil fungicide or seed disinfectant.

In a practical dosage, no phyto-toxicities were found in crops such as rice plants, tomatoes, potatoes, cotton plants, eggplant plants, cucumbers, white beans and the like.

Furthermore, the compounds of the above formula (I) can be effectively used as fungicides in an orchard, an undeveloped land or pasture land, a forest and the like.

The compounds produced by the process of the invention can be used for the preparations which are usually used as agricultural fungicides, such as, for example, powdery dusts, coarse dusts, fine granules, granules, wettable powders, emulsifiable concentrates, aqueous liquids, water-soluble powders, oil suspensions and the like Mixture can be formulated with a carrier and optionally other auxiliaries. The carrier used here is e.g. a synthetic or natural and inorganic or organic substance which is mixed with an active compound and can assist the active compound in its access to the part to be treated and facilitates storage, transport or handling.

The compounds prepared according to the method of the invention, which are formulated into various types of preparations as indicated above, can be used in a rice field or in a field of 1 to 5000 g, preferably 10 to 1000 g, of the active ingredient per 10 ares for leaf spraying or after emergence or to soak or spray the water to effectively combat disease.

Furthermore, the compounds made by the method of the invention, when used to disinfect or coat seeds, can effectively control soil infectious diseases by 0.1 to 2%, preferably 0.2 to 0, seeds , 5% of active ingredient per weight of the seed are coated.

The method of the invention is explained in more detail by the examples and reference examples given below.

The following compounds were prepared using the measures of Example 1 above:

6-phenyl-3 (2H) pyridazinone

5 6- (p-tolyl) -3 (2H) pyridazinone

6- (3,4-dichlorophenyl) -3 (2H) pyrid azinone

Mp 205 to 206.5 ° C mp 233 to 235 ° C

10th

Mp 258 to 262 ° C 6- (3-bromophenyl) -3 (2H) -pyridazinone mp 202 to 204 ° C 6- (3-chlorophenyl) -3 (2H) -pyridazinone mp 226.5 to 227 ° C 6- (4-bromophenyl) -3 (2H) pyridazinone mp 252 to 256 ° C 6- (4-chlorophenyl) -3 (2H) pyridazinone mp 273 ° C

15

20th

25th

6- (3-Chloro-4-fluorophenyl) -3 (2H) pyridazinone

6- (3-bromo-4-fluorophenyl) -3 (2H) pyridazinone

6- (3,5-dichloro-4-hydroxyphenyl) -3 (2H) pyridazinone

6- (3-chloro-4-methoxyphenyl) -3 (2H) pyridazinone

Mp 237 to 239 ° C mp 251 to 253 ° C mp over 300 ° C mp 287 to 288 ° C

6- (4-fluorophenyl) -3 (2H) -pyridazinone mp 267-268 ° C

6- (4-hydroxyphenyl) -3 (2H) pirid-

azinon mp above 300 ° C

30 6- (3,4-dimethoxyphenyl) -3 (2H) -

pyridazinone mp 225-228 ° C

6- (4-ethylphenyl) -3 (2H) pyridazinone mp 185-187 ° C

6- (4-isopropylphenyl) -3 (2H) pyrid-

35

azinone

Mp 202 to 204 ° C

6- (2,5-dimethylphenyl) -3 (2H) pyride-

azinon mp 179 to 179.5 ° C

40 6- (β-naphthyl) -3 (2H) pyridazinone mp 256 ° C

6- (4-cyclohexylphenyl) -3 (2H) pyrid-

azinon mp 240 to 244 ° C

6- (3,5-dichloro-4-ethylphenyl) -3 (2H) -

pyridazinone mp 254 ° C

45

6- (3-iodophenyl) -3 (2H) pyridazinone mp 232 ° C

example 1

6- (3,5-dichloro-4-methylphenyl) -3 (2H) pyridcizinone

To a cold solution of 0.53 g of sodium carbonate in 5 ml of water was added 2.96 g of 4- (3,5-dichloro-4-methylphenyl) -3-chloro-4-oxobutyric acid and then a solution of 0.5 g Hydrazine hydrate in 5 ml of water and the resulting mixture was heated under reflux and stirring for 2 hours. After the reaction had ended, the separated crystalline substance was filtered off from the reaction mixture, washed with water and dried, giving 2.42 g of the desired product as crystals (94.9% of the theoretical amount). This product was pure enough for practical use. Recrystallization from 40 ml of dioxane gave 1.68 g of the pure product, which melted at 254 to 258 ° C (66.0% of the theoretical amount).

Analysis (%) for: CnH8OCl2N2 calculated: CI 27.80 found: Cl 27.48 IR spectrum (Nujol) cur1: 1705 (^ C = 0).

Example 2 6- (3-bromophenyl) -3 (2H) pyridazinone

50

A mixture of 2.91 g of 4- (3-bromophenyl) -3-chloro-4-oxo-butyric acid, 10 ml of water and 1.0 g of hydrazine hydrate was heated under reflux for 2 hours, during which time the reaction mixture was initially suspended and 55 was dissolved and then crystalline substance was separated in situ. At the end of the reaction, the reaction mixture was again in the suspended state. After the reaction had ended, the reaction mixture was allowed to cool, the crystalline substance was filtered off, washed with water and dried 60 g, and 2.39 g of the desired product were obtained as crystals (95.0% of the theoretical amount). The product was recrystallized from dioxane to give 1.76 g of the pure product with a melting point of 202 to 204 ° C (70.0% of the theoretical amount).

65 Analysis (%) for: C10H7OBrN2 calculated: Br 31.82 found: Br 31.60 IR spectrum (Nujol) cm-1: 1710 (^; C = 0).

634565

6

The following compounds were prepared using the measures of Example 2 above:

6-phenyl-3 (2H) pyridazinone

6- (p-tolyl) -3 (2H) pyridazinone

6- (3-chloro-4-methylphenyl) -3 (2H) pyridazinone

6- (3,5-dichloro-4-methylphenyl - 3 (2H) pyridazinone

6- (2,3,5-trichloro-4-methylphenyl) -3 (2H) pyridazinone

6- (3,4-dichlorophenyl) -3 (2H) pyrid azinone

6- (4-Acetamidophenyl) -3 (2H) pyrid azinone

6- (4-aminophenyl) -3 (2H) pyrid azinone

Mp 205 to 206.5 ° C mp 233 to 235 ° C

Mp 276 to 277 ° C

Mp 254 to 258 ° C

Mp 299 ° C

Mp 258-262 ° C

Mp 297.5 to 299 ° C

Mp 295 to 297 ° C

6- (3,5-dichloro-4-methylphenyl) -3 (2H) pyridazinone

6- (p-tolyl) -3 (2H) pyridazinone

6- (4-chlorophenyl) -3 (2H) pyridazinone

6- (4-bromophenyl) -3 (2H) pyridazinone

6- (3,4-dichlorophenyl) -3 (2H) pyrid azinone

6- (3-Chloro-4-methoxyphenyl) -3 (2H) pyridazinone

6-phenyl-3 (2H) pyridazinone

6- (4-methoxyphenyl) -3 (2H) pyrid-azinone

6- (4-Methylthiophenyl) -3 (2H) pyrid azinone

6- (3-nitro-4-methylphenyl) -3 (2H) pyridazinone

Example 4 6- (p-Tolyl) -3 (2H) pyridazinone

A mixture of 4.53 g of 4- (p-tolyl) -3-chloro-4-oxo-but-5-acidic acid, 1.2 g of hydrazine hydrate and 25 ml of ethanol was heated under reflux for 3.5 hours. After cooling, the crystalline substance thus separated was filtered off, washed with water and dried to obtain 1.5 g of the desired product. The solvent was distilled off from the io filtrate under reduced pressure, the residue was washed with ether and then with water and dried, whereby 0.45 g of the desired product was obtained. Total yield 1.95 g (52.5% of the theoretical amount). Mp 233 to 235 ° C (recrystallized from di-15 oxane).

Analysis (%) for: CUH10ON2

20th

calculated: C 70.95 found: C 70.62 IR spectrum (Nujol) cm-1: 1650 (~

Example 5

: C = 0).

Example 3

6- (3-chloro-4-methylphenyl) -3 (2 H) pyridazinone

A mixture of 1.52 g of isopropyl 4- (3-chloro-4-methylphenyl) -3-chloro-4-oxobutyrate, 10 ml of water and 1.25 g of hydrazine hydrate was heated under reflux for 1 hour. Then the reaction mixture was added by adding

2 ml of concentrated hydrochloric acid was acidified and the resulting mixture was further refluxed for 2 hours. After cooling, the crystalline substance thus separated was filtered off, washed thoroughly with water and then dried (80% of the theoretical amount) to obtain 0.88 g of the desired compound having a melting point of 276 to 277 ° C.

Analysis (%) for: CnH9OClN2 calculated: Cl 16.07 found: Cl 15.96 IR spectrum (Nujol) cm-1: 1680 (^ C = 0), 1665.

Using the measures of the example above

3 the following connections were made:

Mp 254 to 258 ° C mp 233 to 235 ° C mp 273 ° C mp 252 to 256 ° C

Mp 258-262 ° C

Mp 287 to 288 ° C mp 205 to 206.5 ° C

Mp 195 to 198 ° C

Mp 213 ° C

Mp 279 to 280 ° C

6- (3-chloro-4-methylphenyl) -2-methyl-3 (2H) pyridazinone

0.92 g of methylhydrazine was added to a suspension of 2.61 g of 4- (3-chloro-4-methyl-25-phenyl) -3-chloro-4-oxobutyric acid in 10 ml of water, and the resulting mixture was refluxed and Stir heated for 2 hours. After the reaction was completed, the crystalline substance thus separated was filtered off, washed with water and dried, and 2.02 g of the desired product were obtained as crude crystals (86% of the theoretical amount).

Mp 125.5 to 128.5 ° C (recrystallized from benzene-n-hexane).

35 Analysis (%) for: C, 2HnOClN2 calculated: Cl 15.11 found: Cl 15.66 IR spectrum (Nujol) cm-1: 1660 (^; C = 0).

The following connection was made using the measures of Example 40 5 above:

6- (p-tolyl) -2-methyl-3 (2H) pyridazinone, mp 120-124 ° C.

Reference Example 1 4- (3,5-dichloro-4-methylphenyl) -3-chloro-4-oxobutyric acid

45

8.64 g of directly evaporated liquid chlorine were slowly added to a suspension of 13.06 g of 4- (3,5-dichloro-4-methylphenyl) -4-oxobutyric acid in 50 ml of acetic acid at 50 ° C. with stirring for 3 hours blown in. After the reaction had ended, the reaction mixture was poured into 100 g of ice water, the resulting mixture was left to stand overnight, the crystalline substance thus separated off was filtered off, washed thoroughly with water and dried, and 14.16 g of the desired product (95, 8% of the 55 theoretical amount).

Mp 130 to 134 ° C (recrystallized from benzene-n-hexane) Analysis (%) for: CnH ^ C ^

calculated: Cl 35 99 found: Cl 35.83 60 IR spectrum (Nujol) cmJ: 2800 to 2500 (-COOH), 1715, 1685 (^ C = 0).

The following compounds were prepared using the measures of Reference Example 1 above:

65 4- (p-tolyl) -3-chloro-4-oxobutyric acid, mp 100 to 101.5 ° C

4- (3-chloro-4-fluorophenyl) -3-chloro - 4-oxobutyric acid

Mp 98-101 ° C

7

634 565

4- (3-chloro-4-methylphenyl) -3-chloro - 4-oxobutyric acid

4-phenyl-3-chloro-4-oxobutyric acid

4- (2,3,5-trichloro-4-methylphenyl) -3-chloro-4-oxobutyric acid

4- (3,4-dichlorophenyl) -3-chloro-4-oxo-butyric acid

Mp 102 to 105 ° C mp 69 to 73 ° C

Mp 121 to 124.5 ° C

Mp 118 to 121 ° C

Reference Example 2 4- (3-Bromophenyl) -3-chloro-4-oxobutyric acid

1.8 g of sulfuryl chloride were added to a suspension of 2.57 g of 4- (3-bromophenyl) -4-oxo-butyric acid in 10 ml of dichloroethane and the eG mixture obtained was heated under reflux for 7 hours. Then 10 ml of hot water was added to the reaction mixture, and the resulting mixture was stirred for a while and was left at room temperature. The reaction mixture was extracted with benzene, the benzene extract was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off from the extract, whereby 2.72 g of the desired product was obtained as an oily substance (93.2% of the theoretical amount) . This substance solidified after standing at room temperature and was then recrystallized from benzene, whereby the pure product with a melting point of 123 to 127 ° C was obtained.

Analysis (%) for: CwH803BrCl calculated: Cl 12.16 found: Cl 11.99 IR spectrum (Nujol) cnr1: 2750 to 2500 (-COOH), 1710, 1690 (^ C = 0).

Using the measures of Reference Example 2 above, the following compound was prepared: 4- (3-chlorophenyl) -3-chloro-4-oxobutyric acid, mp 109-115 ° C.

Reference Example 3 4- (p-Tolyl) -3-chloro-4-oxobutyric acid

To 50 ml of dry dichloroethane was added 9.6 g of 4- (p-tolyl) -4-oxobutyric acid and 0.5 g of anhydrous aluminum chloride, and to the resulting mixture was added dropwise 14 g of sulfuryl chloride at room temperature with stirring. After the dropwise addition was completed, the resulting mixture was stirred at 50 ° C for 7 hours. Then 20 ml of hot water and 200 ml of n-hexane were added to the reaction mixture, and after stirring for a while and standing, the separated organic layer was collected, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off from the layer, whereby 11.3 g of the desired product were obtained as an oily substance, which was then recrystallized from n-hexane and showed a melting point of 100 to 101.5 ° C.

Analysis (%) for: CnHn03Cl calculated: Cl 15.64 found: Cl 15.72 IR spectrum (Nujol) cm-1: 2800 to 2500 (-COOH), 1730, 1660 (^ C = 0).

Reference example 4

4- (3-bromophenyl) -3-bromo-4-oxobutyric acid

To a suspension of 2.57 g of 4- (3-bromophenyl) -4-oxo-butyric acid in 20 ml of acetic acid was added dropwise 1.6 g of bromine at 50 ° C. with stirring over 30 minutes and then the resulting mixture was added at 50 ° C stirred for a further 1.5 hours. After stirring was stopped, the reaction mixture was poured into 150 g of ice water, and the crystalline substance thus separated was filtered off, washed thoroughly with water and then dried, whereby 3.11 g of the desired product was obtained (90% of the theoretical amount).

Mp 138 to 141 ° C (recrystallized from benzene).

Analysis (%) for: C10H8O3Br2 io calculated: Br 46.18 found: Br 47.45 IR spectrum (Nujol) cm-1: 2750 to 2550 (-COOH), 1700, 1680 C ^ C = 0).

Using the measures of reference 15 example 4 above, the following compounds were made:

4- (3-bromo-4-fluorophenyl) -3-bromo - 4-oxobutyric acid

4- (3,5-dichloro-4-ethylphenyl) -3-20 -bromo-4-oxobutyric acid

Mp 122 to 124 ° C mp 125 ° C

Reference Example 5 4- (3,5-dichloro-4-hydroxyphenyl) -3-bromo-4-oxobutyric acid

25 To a suspension of 2.3 g of 4- (3,5-dichloro-4-hydroxy-phenyl) -4-oxobutyric acid in 10 ml of dry ether was added dropwise 1.53 g of bromine at room temperature over 15 minutes, and the resulting one The mixture was stirred at room temperature for a further 5 hours. After stirring was stopped, the reaction mixture was extracted with ether, the extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off from the extract, whereby 2.96 g (99.5% of the theoretical amount) of the desired 35 product remained as an oily substance. This substance solidified after treatment with hot benzene and showed a melting point of 170 to 174 ° C.

Analysis (%) for: CI0H7O4BrCl2 calculated: Cl 20.73 40 found: Cl 20.20

IR spectrum (Nujol) cm-1: 3420 (OH), 2800 to 2500 (-COOH), 1715, 1675 (^; C = 0).

The following compounds were produced using the measures of reference example 5 above:

45

50

4- (4-cyclohexylphenyl) -3-bromo-4-oxobutyric acid

4- (4-acetamidophenyl) -3-bromo-4-oxobutyric acid

4- (n-hexylphenyl) -3-bromo-4-oxo-butyric acid

4- (3-iodophenyl) -3-bromo-4-oxo-55 butyric acid

Mp 155-159 ° C

Mp 195 to 198 ° C (with decomposition)

Mp 85-87 ° C mp 132-137 ° C

60

Reference Example 6 Ethyl 4- (p-tolyl) -3-chloro-4-oxobutyrate

To a solution of 19.2 g of 4- (p-tolyl) -4-oxobutyric acid in 100 ml of ethanol were introduced 18.8 g of chlorine at 40 ° C with stirring for 2 hours. After the reaction was completed, the excess ethanol was distilled off from the reaction mixture under reduced pressure, and the residue was extracted with benzene. The extract was then treated in the same manner as in Reference Example 2, with 25.3 g of the desired product

634565

8th

were obtained as an oily substance (nD23's 1.5241). Yield: 99%.

Analysis (%) for: C13H1503C1 calculated: Cl 13.92 found: Cl 14.09 IR spectrum (liquid film) cm-1: 1740 (-COOC2H5), 1700 (^ C = 0).

Reference Example 7 Methyl 4- (3,5-dichloro-4-methylphenyl) -3-chloro-4-oxobutyrate

To a solution of 6.2 g of 4- (3,5-dichloro-4-methylphenyl) -3-chloro-4-oxobutyric acid in 60 ml of methanol was added 0.5 ml of concentrated hydrochloric acid and the resulting mixture was added to Reflux heated for 1.5 hours. After completion of the reaction, the reaction mixture was then treated in the same manner as in Reference Example 6, whereby 5.3 g of the desired product was obtained as an oily substance (nD21 1.5580). Yield: 82.3%.

Analysis (%) for: C12Hn03Cl3 calculated: Cl 34.36 found: Cl 34.56 IR spectrum (liquid film) cm-1: 1730 (-COOCH3), 1695 OC = 0).

The following compounds were prepared using the measures of Reference Example 7 above:

Methyl? 4- (4-methylthiophenyl) -3-bromo-

-4-oxobutyrate nD19 1.6127

Isopropyl-4- (3-chloro-4-methylphenyl) -

-3-chloro-4-oxobutyrate nD22 1.5278

Methyl-4- (3-nitro-4-methylpheny]) - 3-

-bromo-4-oxobutyrate nX) 21'8 1.5632

Reference Example 8 4- (3-Chloro-4-methylphenyl) -3-chloro-4-oxobutyric acid

3.9 g of chlorine were introduced at 40 to 45 ° C. with stirring for 1 hour to a suspension of 9.6 g of 4- (p-tolyl) -4-oxobutyric acid in 50 ml of dichloroethane. After complete formation of the intermediate 4- (p-tolyl) -3-chloro-4-oxobutyric acid, confirmed by thin-layer chromatography, 20 g of powdery anhydrous aluminum chloride were added with cooling to -5 ° C. In the obtained mixture, 8.6 g of chlorine was introduced at -5 to 0 ° C with stirring for 1 hour, and the obtained mixture was stirred at -5 to 0 ° C for an additional hour. After complete formation of the final product, which was confirmed by high pressure liquid chromatography, the reaction mixture was added to 200 g of ice and 40 ml of concentrated hydrochloric acid with vigorous stirring. Then, the obtained mixture was extracted with dichloroethane and the extract was treated in the same manner as in Reference Example 2 above to obtain 12.1 g of the desired product. Yield: 95%.

Mp 102 to 105 ° C (recrystallized from benzene).

The following connections were made using the measures of reference game 8 above:

4- (3,5-dichloro-4-methylphenyl) -3-

-chloro-4-oxobutyric acid mp 130 to 134 ° C 4- (3-bromophenyl) -3-chloro-4-oxo-

butyric acid mp 123 to 127 ° C 4- (3-bromophenyl) -3-bromo-4-oxo-

butyric acid mp 138 to 141 ° C

Reference Example 9 4- (4-aminophenyl) -3-bromo-4-oxobutyric acid hydrochloride

A suspension of 1.57 g of 4- (4-acetamidophenyl) -3-bromo-4-oxobutyric acid in 18% aqueous hydrochloric acid was heated under reflux for 1 hour. After the reaction was completed, the clear reaction mixture was ice-cooled, and the separated crystalline substance was filtered and dried, whereby 0.94 g of the desired product was obtained as pink flakes (60.9% of the theoretical amount).

Mp 155 to 164 ° C (with decomposition).

Analysis (%) for: C10HnO3BrClN calculated: Br 25.90 found: Br 25.78 IR spectrum (Nujol) cm-1: 3000, 2550, 1930, 1650 (NH3 +), 1730, 1680 (^ C = 0).

Reference Example 10 4- (3-Chloro-4-methylphenyl) -4-oxobutyric acid

(1) To a mixture of 100 ml of dry dichloroethane, 32 g of anhydrous aluminum chloride powder and 10 g of succinic anhydride in a 300 ml four-necked flask was added dropwise 10 g of toluene with stirring over about 30 minutes, and the resulting mixture was further stirred for 1.5 hours Room temperature stirred. 8 ml (12.56 g) of chlorine gas enclosed in dry ice acetone was gradually blown into the mixture until the peak due to the intermediate, 4- (p-tolyl) -4-oxo-butyric acid, disappeared on high pressure liquid chromatography . The reaction mixture was added to a mixture of 500 g of ice and 60 ml of concentrated hydrochloric acid with vigorous stirring. The product obtained was filtered, washed with water and dried, and 24.4 g of crude crystals were obtained, which were recrystallized from benzene-n-hexane (1: 1) to give 16.2 g of the desired product, which was obtained at 151 to 153 ° C melted. Yield: 72%.

Analysis (%) for: CUHU03C1 calculated: Cl 15.64 found: Cl 15.67 IR spectrum (Nujol) cm-1: 2800 to 2500 (-COOH), 1695, 1690 C; C = 0).

(2) 50 ml of dry dichloroethane, 16 g of anhydrous aluminum chloride powder, 5 g of succinic anhydride and 5 g of toluene were treated using the same measures as in (1) above, and 7.4 g of sulfuryl chloride was added dropwise to the reaction mixture at 35 ° C . After stirring at 50 ° C for about 4 hours, another 7.4 g of sulfuryl chloride was added dropwise and the whole mixture was stirred at 50 ° C for 4 hours. After the reaction was completed, the reaction mixture was treated in the same manner as in (1) above to obtain 9 g of the desired product. Yield: 83%.

Reference Example 11 4- (3-bromo-4-methylphenyl) -4-oxobutyric acid

10 g of succinic anhydride were added to a suspension of 32 g of anhydrous aluminum chloride powder in 110 ml of dry dichloroethane. To the mixture, 10 g of toluene was added dropwise, and the mixture was stirred at room temperature for 2 hours. A mixture of 22.4 g of bromine and 20 ml of dichloroethane was added dropwise to the reaction mixture over 45 minutes, followed by stirring at room temperature for 20 hours

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

9

634565

connected. After a further 4.8 g of bromine had been added, the reaction mixture was stirred at 50 to 55 ° C. for 3 hours. Upon complete disappearance of the intermediate, i.e. 4-p-Tolyl-4-oxobutyric acid, which was confirmed by high pressure liquid chromatography, the mixture was treated in the same manner as in Reference Example 10 (1) to obtain 27.6 g of crude crystals. The crude crystals were extracted with hot acetone and the extract was filtered to give 20.3 g of the desired product by evaporating the solvent under reduced pressure. Yield: 75%.

Mp 165 to 171 ° C (recrystallized from acetonitrile). Analysis (%) for: CnHnOgBr calculated: Br 29.47 found: Br 29.29 IR spectrum (Nujol) cm-1: 2800 to 2500 (-COOH), 1695, 1690 (^: C = 0).

Reference Example 12 4- (3,5-dichloro-4-methylphenyl) -4-oxobutyric acid

130 g of succinic anhydride were added to a suspension of 400 g of anhydrous aluminum chloride powder in 1 liter of dry dichloroethane. 92 g of toluene was added dropwise to the mixture over about 20 minutes while maintaining the internal temperature at 10-15 ° C. After the addition was complete, the mixture was stirred for 1 hour and 50 ml (78.5 g) of chlorine gas was introduced into the mixture over 3 hours while keeping the internal temperature at 0 to -3 ° C. After allowing the mixture to stand at room temperature overnight, 131 ml (205.7 g) of chlorine gas was introduced into the mixture over 6 hours while the internal temperature was kept at 0 to -3 ° C. After the relative ratio of the peak height reached a maximum in high pressure liquid chromatography due to the desired product, the reaction mixture was added to a mixture of 2 kg of ice and 500 ml of concentrated hydrochloric acid with vigorous stirring. Excess dichloro-15 ethane was distilled off under reduced pressure, and the solid so produced was filtered off, washed with water, dried and recrystallized from toluene to obtain 163 g of the desired product. Yield: 54%.

20 mp 185 to 187 ° C (colorless needles, recrystallized from acetonitrile).

Analysis (%) for: CnH10O3Cl2 calculated: Cl 27.16 found: Cl 26.77 25 IR spectrum (Nujol) cm-1: 3000 to 2500 (-COOH), 1710 OC = 0).

v

Claims (6)

634565 2. The method according to claim 1, characterized in that X is a chlorine atom. 2nd C CH - CH0 - COOR, R wherein Rj, R2, Rs and R4 have the meaning given above, R represents a hydrogen atom or a lower alkyl group with the proviso that R is a hydrogen atom when R5 is a lower alkyl group and X represents a halogen atom with a hydrazine the general formula R5-NHNH2 (III) wherein R5 has the meaning given above, or is reacted with hydrazine hydrate, hydrazine hydrochloride or hydrazine sulfate in the presence of a base and a solvent, and if R, represents a lower alkyl group, the reaction mixture thus obtained is treated with an acid at elevated temperature. 2nd PATENT CLAIMS 1. Process for the preparation of a phenyl or naphthylpyridazinone derivative of the formula: wherein R1 (R2, R3 and R4 are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a lower alkylthio group, a hydroxy group, a Cycloalkyl group, an amino group or a group R6CONH- wherein R6 represents a lower alkyl group having 1 to 3 carbon atoms, or R 1 and R 2, R 2 and R 3 or R 3 and R are joined together to form a benzene ring which is fused to the benzene ring to which they are linked and forms a naphthalene ring as a whole, and R-, a hydrogen atom or a lower alkyl group, characterized in that a compound of formula E, 3. The method according to claim 1 or 2, characterized in that an alkali carbonate is used as Bas °. 4. The method na; h claim 3, characterized in that sodium carbonate is used as the base. 5. The method according to claim 1 or 2, characterized in that the same hydrazine used as the reactant is used as the base. 6. The method according to any one of claims 1 to 5, characterized in that water is used as the solvent.