HU194544B - Improved process for production of derivatives of phenil-piridasine - Google Patents

Abstract

Phenylpyridazine cpds. of formula (I) are prepd. by reacting alkali metal salts of 3-phenyl-4-hydroxy-6-chloropyridazine with alkylthioformate in H2O/acetone at 5-60≰C , removing aq. phase contg. alkali metal chloride, and evaporizing acetone. In (I), R is C1-18 alkyl radical.

Description

The present invention relates to an improved process for the preparation of phenylpyridazine derivatives in aqueous acetone.

No. 23,3138. It is known from the disclosure of the Federal Republic of Germany that 3-phenyl-6-chloropyridazine thiocarbonates have valuable hybicidal properties. The same publication discloses its preparation by reacting 3-phenyl-4-hydroxy-6-chloropyridazine or salts thereof with alkylthiochloroformates; the reaction is optionally carried out by adding an acid acceptor, namely a tertiary amine. The addition of an acid acceptor can be dispensed with especially when it is used in the form of its 3-phenyl-4-hydroxy-6-chloropyridazine salt with tertiary amines. The reaction is preferably carried out in the presence of an inert solvent, such as aromatic hydrocarbons, and it is desirable to provide for the presence of hydroxyl group compounds such as alcohols or water.

In practice, this process leaves a lot to be desired, since the tertiary amines which serve as acid acceptors, whether used as such or in the form of salts with the pyridazine compound, are converted into the hydrochloride during the reaction which must be discarded it is contaminated or has to be processed in a separate process, which places a heavy economic burden on the whole process. It has also been found that even small amounts of tertiary amines, especially in the presence of water, degrade phenyl hydrazine derivatives. Inert aromatic hydrocarbons, as the reaction medium, which are difficult to remove completely from the active ingredient, have already a small amount of undesirable plant toxicity and should therefore be avoided. Finally, avoiding as much water as possible requires starting from dried, anhydrous compounds, which is disadvantageous because 3-phenyl-4-hydroxy-6-chloropyridazine contains water from its preparation.

It has been found that the compounds of formula (I) can be prepared very well in the presence of water, provided that they are carried out in an aqueous-acetone solvent system. In this way, the otherwise necessary and costly drying of 3-phenyl-4-hydroxy-6-chloropyridazine can be avoided. The use of alkali metal salts as starting materials has not been considered so far, since they crystallize with 2 molecules of crystalline water, which are very difficult to remove completely by drying.

The present invention therefore relates to a process for the preparation of phenylpyridazine derivatives of the formula I:

R is a linear or branched C 1 -C 18 alkyl group, which is reacted with the alkylthiochloroformates of the formula (II) in which the salts of the 3-phenyl-4-hydroxy-6-chloropyridazine have the formula: reagdltatásával; The process is characterized in that the alkali metal salt is used as the salt and the reaction is carried out in an aqueous-acetone solution at a temperature of 5 to 60 ° C, followed by separation of the reaction with the higher aqueous phase containing the alkali metal chloride. The phenylpyridazine slag of Formula I is recovered by evaporating the acetone from the remaining acetone solution.

The starting material of 3-phenyl-4-hydroxy-6-chloropyridazine is obtained in a known manner by heating 3-phenyl-4,6-dichloropyridazine with sodium hydroxide, followed by acidification and centrifugation. It has been found to be particularly advantageous if the starting compound is not dried, but suspended in the acetone-water mixture while still being centrifuged wet, mixed with a known concentration of aqueous alkali metal hydroxide until a clear solution is formed and the theoretical amount of alkali is consumed. This occurs at a pH of 8.8 to 9.7. Thus, the exact concentration of the starting compound is known, without prior drying and measurement, and the amount of alkylthiochloroformate required for the reaction can be easily calculated from the amount of alkali consumed. Particularly, the alkali metal hydroxide is aqueous sodium or potassium hydroxide.

The starting compound can be first suspended in water and then mixed with acetone, first suspended in acetone and then mixed with water, and finally suspended in a mixture of acetone and water. The acetone-water mixture preferably contains 50-75% by weight of acetone and 25-50% by weight of water; 60-70% by weight of acetone and 30-40% by weight of water are particularly preferred.

The alkali metal salt of the starting compound may also be prepared separately and as such is soluble in acetone-water, but in situ preparation of the solution of the alkali metal salt is particularly preferred.

To the solution of the alkali metal salt of the starting compound, the calculated amount of alkylthiochloroformate is added as quickly as possible and with vigorous stirring. The reaction is carried out at a temperature of 5 to 60 ° C, in particular 10 to 40 ° C. Since the reaction is slightly exothermic, cooling may be used to maintain the desired temperature range. After a reaction time of 1 to 2 hours, the agitator is stopped and then easily and without formation of an intermediate layer, 2 phases are formed: a lower organic phase, which is 0- [3-phenyl-6-chloropyridazine-4 (4)] - S- alkyl thiocarbonate and acetone; and a higher specific gravity phase consisting of water, alkali metal chloride and little acetone. The aqueous phase is separated off, the acetone contained therein is distilled off and reused to produce only one aqueous solution of common salt or alkali metal chloride.

From the organic phase, which contains only traces of water, the acetone is distilled off along with traces of water to leave the phenylchloropyridazinylalkylthiocarbonate in substantially 100% yield.

Example 1

Into a 1500 liter mixing vessel was made 550 liters of acetone, with stirring added 300 kg of centrifuged wet 3-phenyl-4-hydroxy-6-chloropyridazine followed by 220 liters of water. Thereafter, 51.0% sodium hydroxide solution was added until a pH of 9.5 was reached and a clear solution was formed. The amount of alkali used is 93.7 kg. Thereafter, 254.6 kg of 98% octylthiochloroformate was added over a period of 4-5 minutes at 30 ° C. The temperature rises to 35 ° C in a few minutes. The reaction temperature is maintained between 35 and 37 ° C using cooling. The pH drops to about 4.5 over 1 hour. The reaction was allowed to react for a total of 2 hours, then the stirrer was stopped, allowed to stand for 30 minutes, and the higher specific gravity aqueous phase was removed. Acetone is rapidly distilled off from the organic phase. 456 kg techn.

Yield 194,544, 99.6% yield.

Example 2 A mixture of 550 ml of acetone and 320 ml of water was prepared in a 1 liter four-necked flask and suspended in 300 g of wet 3-phenyl-4-hydroxy-6-chloropyridazine with stirring in 44.7% aqueous potassium hydroxide. solution is adjusted to pH 9.5 with jθ. A clear solution is formed; use of potassium hydroxide solution is 174.4 g. The solution was cooled to 25 ° C and n-octylthiochloroformate (98%) (295 g) was added over 1 minute with vigorous stirring. The temperature rises to 40 ° C over 15 minutes and then returns to 31 ° C over 105 minutes.

Stop the mixer and settle for 10 minutes! after a period of time, the layers are separated.

The organic phase is concentrated in a Rotavapor evaporator and the remaining acetone is removed under vacuum at 80 ° C. 20.536 g of an oily product are obtained. Yield = 99.2%.

Physical data for the product obtained in Examples 1 and 2: n ^ ⁰ = 1.5774

IR (5% in chloroform): 25

1732 cm ^-1 (C = O);

1060 cm ¹ : strongest band.

Example 3 In a 30 liter three-necked flask, 350 g of centrifuged wet 3-phenyl-4-hydroxy-6-chloropyridazine were suspended in 935 ml of acetone and 144 g of 48.1% sodium hydroxide at pH 9.5. is set to 35.

Ethyl thiochloroformate (222 g) was added at 2 ° C over 2 minutes. The temperature rises to 39 ° C in 10 minutes. the reaction was allowed to react for a total of 2 hours, then the stirrer was stopped and the phases were separated. The organic phase of lower specific gravity was removed by rotary evaporation under reduced pressure to yield 511 g of oily O- [3-phenyl-6-chloropyridazinyl (4)] - S-ethylthiocarbonate in an oil. Yield 100%.

IR (KBr): 1730 cm ^-1 (C = O) 45

1050 cm ¹ : strongest band.

Propyl thiocarbonate is obtained which corresponds to a 100% yield. r £ ° = 1.5700 '

IR (KBr): 1730 cm ^-1 (C = O)

1045 cm ' ¹ : strongest band.

Example 5

As described in Example 4, 100 g of centrifuged-wet 3-phenyl-4-hydroxy-6-chloropyridazine was adjusted to 9.6 ρΗ with 39.0 g of 48.1% sodium hydroxide at 25 ° C. you. 73 g of 98% isobutylthiochloroformate were added and the reaction was stirred for 2 hours. The maximum reaction temperature reached was 40 ° C and the pH reached 4.2.

After separation of the phases and separation of the aqueous phase, the solvent is evaporated from the organic phase of lower specific gravity. 151 g of 0- [3-phenyl-6-chloropyridazinyl (4)] - isobutylthiocarbonate are obtained in the form of an oily product in a yield of 100%.

n ^ ⁰ = 1.5752

IR (KBr): 1730 cm ^-1 (C = O)

1055 cm ¹ : strongest band.

By reacting equivalent amounts of the corresponding alkylthiochloroformates with 3-phenyl-4-hydroxy-6-chloropyridazine in an analogous manner to Example 1, the following compounds were prepared:

Example 6

0- [3-phenyl-6-chloro-pyridazinyl (4)] - S-5-n-decyl-thiocarbonate

Yield: 99.7% of theory.

n ^ ⁰ = 1.5600. . .

Example 7

0- [3-phenyl-6-chloro-pyridazinyl (4)] - S-n-dodecenyl thiocarbonate

Yield: 99.8% of theory.

n ™ = 1.5498

Example 4 In a 3-L three-necked flask, acetone (200 mL), water (100 mL), and 3-phenyl-4-hydroxy-6-chloropyridazine (100 g) were added to the suspension, followed by the addition of 39.4 g of 48.1% sodium pH is adjusted to 9.6, the solution is cooled to 25 ° C and 67.0 g of 98% isopropylthiochloroformate are added over 30 seconds. .

After 40 minutes, the temperature was 40 ° C and the pH was 7.5.

The reaction mixture was stirred for 2 hours, during which time the pH dropped to 4.5. After stopping the mixer, the layers were separated and the higher specific sodium chloride-containing phase was separated. The lower specific phase was freed from solvent on a rotary evaporator under vacuum to give 146.0 g of oily O- [3-phenyl-6-chloropyridazinyl (4)] - S-8. example

0- [3-phenyl-6-chloro-pyridazinyl (4)] - S-n-octadecenyl-thiocarbonate

Yield: 99.7% of theory.

M.p. 56-58 ° C.

Claims (5)

Claims A process for preparing a phenylpyridazine derivative of formula (I) wherein: R is a straight or branched C 1 -C 18 alkyl group A process according to claim 1, wherein the aqueous acetone solution contains 50-75% by weight of acetone and 25-50% by weight of water. A process according to claim 2, wherein the aqueous acetone solution contains 60-70% acetone and 30-40% water. Salts of 3-phenyl-4-hydroxy-6-chloropyridazine with alkylthiochloroformates of formula (II) - wherein R 3 194,544 Yen as described above, characterized in that the alkali metal salt is used as the salt and the reaction is carried out in an aqueous acetone solution at a temperature between 5 ° C and 60 ° C and then separating the higher specific aqueous phase containing the alkali metal chloride. recovering the phenylpyridazine derivative of formula (I) by evaporating the acetone from the residual acetone solution. 4. Process according to any one of claims 1 to 5, characterized in that the reaction is carried out at a temperature of 10 to 40 ° C. The process according to any one of claims 1 to 4, wherein the alkali metal salts are prepared in situ from 3-phenyl-4-hydroxy-6-chloropyridazine and an aqueous solution of a known concentration of alkali metal hydroxide.