CS216930B2 - Method of preparation of the pyrazoles - Google Patents

Abstract

Pyrazoles are prepared by reaction of 1,3-dicarbonyl compounds with hydrazines and a sub-equivalent amount of acid at a pH between 0 and 6.9. The pyrazoles which can be prepared by the process of the invention are useful starting substances for the preparation of dyes, plant protection agents and pharmaceuticals.

Description

The present invention relates to a novel process for preparing pyrazoles by reacting 1,3-dicarbonyl compounds with hydrazines and with an insufficient amount of acid at a pH between 0 and 6.9.

A variety of pyrazole syntheses are known in the literature, see Rodd, Chemistry of Carbon Compounds, Volume IVa (Elsevier, NY, 1957 J, pp. 246-249), for example by reacting hydrazines with 1,3-dicarbonyl compounds, dehydrating β-ketoester hydrazones, cyclizing hydrazones α-cyanoketone, by reaction of aldehyde phenylhydrazones with β-ketoesters in the presence of zinc chloride, condensation of α-halohydrazones with sodium salt of keto compounds or diazo compounds with acetylene derivatives Important synthesis methods lead through reaction of 1,3-dicarbonyl acid compounds with hydrazine or hydrazine Thus, according to J. Am. Chem., Soc. Part 71 (1949) p. 3997, the stoichiometric reaction of 1,1,3,3-tetraethoxypropane with hydrazine dihydrochloride is carried out in admixture with a mixture of hydrazines or hydrazine derivatives. The solution is then evaporated, the residue is taken up in water and the solution is treated with sodium bicarbonate solution. The mixture was filtered, the filter cake was washed thoroughly with ether, and the etherate filtrate was used to extract the aqueous filtrate.

In these syntheses starting from hydrazine salts (or derivatives thereof) in solution, it is inevitable that stoichiometric amounts of waste salts are generated after use of, for example, inorganic bases. When carried out on a large technical scale, these salts lead to considerable waste water problems and environmental problems. For example, more than 2 kg of sodium chloride is released per kg of pyrazoles prepared according to the above-mentioned working method (J. A. Ch. S. cit. Above).

The present invention provides a process for the preparation of the pyrazoles of formula (I)

wherein the individual radicals R 1, R ² and R ² are the same or different, namely a hydrogen atom or a C 1 -C 18 alkyl, by reacting the 1,3-dicarbonyl compounds with hydrazine in the presence of water and an acid, characterized in that

with a 1,3-dicarbonyl compound of formula II

OR ² O

II I II

R1 — С — С — C — R ¹ (II),

AND

H wherein R ¹ and R ² are as defined above, are reacted with a hydrazine of formula III

R ³ -NH-NH ₂ (III), wherein R ³ is as defined above, in the presence of less than 2 equivalents of acid per mole of hydrazine of formula III, at a temperature of -10 to 100 ° C, wherein the pH of the reaction mixture during the reaction is between 0 and 6.9.

It has further been found that the process according to the invention is preferably carried out by reacting a proportion of the pyrazole of the formula I in the reaction mixture according to the nature of the pyrazole salt with an additional amount of the hydrazine of the formula III to form the free pyrazole of the formula I.

In view of the prior art, the process of the invention surprisingly provides a simpler and more economical way for preparing pyrazole in better yield and purity. Considerable amounts of acid and the corresponding costly neutralization and waste water purification operations are saved. The procedure corresponds to environmental protection requirements. All these advantageous properties are surprising in view of the prior art. In view of the prior art, less conversion, lower yields, and the formation of a heterogeneous mixture of starting and end bases and their salts must be envisaged.

The starting compound of the formula II is reacted with the starting compound of the formula III in a stoichiometric amount or with an excess of one component relative to the other, preferably in a ratio of 0.1 to 1.5, in particular 0.9 to 1.1 mol, of the starting compound of the formula III per mole of the starting compound of formula II. Preferred starting compounds of the formulas II and III and the corresponding preferred final compounds of the formula I are those in which the individual radicals R ¹ , R ² and R ³ are the same or different, namely hydrogen, alkyl of 1 to 18 carbon atoms. Instead of the 1,3-dicarbonyl compounds of the general formula II, substances which form these 1,3-dicarbonyl compounds under the reaction conditions can generally be used. They are predominantly bisacetals, monoacetals, bisacyl compounds and monoacyl compounds.

The reaction for the use of 1,1,3,3-tetramethoxypropane and hydrazine is as follows:

OCHj OCHj

CH.OC-CH3C-OCH3 + H _from N-NH2-i- ⁴⁷

H ti —-> П, ♦ 4CH ₃ OH.

in

H

Particularly preferred are 1,1,3,3-tetramethoxypropane, 1,1,3,3-tetraethoxypropane, 1,1,3,3-tetraisobutoxypropane, 1,1,3,3-tetraisopropoxypropane, 1,1,3,3 -tetrabutoxypropane,

1,1,3,3-tetrapropoxypropane.

Suitable hydrazines of the formula III are, for example, hydrazine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl-substituted hydrazines. Instead of the hydrazine of the formula III, compounds which form these hydrazines under the reaction conditions, for example hydrazine hydrates, salts of hydrazines such as sulfates or disulfonates, for example dibenzenesulfonates, are also suitable; hydrazones, for example formaldehyde, acetaldehyde, together with amines such as ethylamine. In the case of salts, the total amount of free and hydrazine bound amount of acid is always less than 2 equivalents of acid per mole of hydrazine.

The reaction is carried out at a temperature of from -10 to 10 ° C

4-100 ° C, preferably from 0 to 100 ° C, in particular from 30 to 70 ° C, at atmospheric pressure or under pressure, continuously or intermittently. Optionally, the reaction is carried out in an organic solvent inert under the reaction conditions.

Examples of suitable solvents are: aromatic hydrocarbons, for example chlorobenzene, o-, m-, p-chlorotoluene, 1,2,4-tritoluene, ethylbenzene, o-, m-, p-xylene, isopropylbenzene, methylnaphthalene, halogenated hydrocarbons, especially chlorinated hydrocarbons, for example tetrachlorethylene, 1,1,2,2- or 1,1,1,2-tetrachloroethane, amyl chloride, dichloropropane, methylene chloride, dichlorobutane, carbon tetrachloride, 1,1,1- or 1,1,2- trichloroethane, trichlorethylene, pentachloroethane, 1,2-dichloroethane, 1,1-dichloroethane, n-propyl chloride, 1,2-cis-dichloroethyl, n-butyl chloride, 2-, 3- and iso-butyl chloride, chlorobenzene, o- p- and m-dichlorohenzene, o-, m-, p -chlorotoluene, 1,2,4-trichlorobenzene; an ether, for example ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, diisopropyl ether, cyclohexylmethyl ether, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, alkanols and methanol such as ethanol, cycloalkanols, butanol, isobutanol, tert-butanol, glycol, n-propanol, isopropanol, amyl alcohol, cyclohexanol, 2-methyl-4-pentanol, ethylene glycol monoethyl ether, 2-ethylhexanol, methyl glycol, especially those containing 1 to 4 carbon atoms, aliphatic or cycloaliphatic hydrocarbons such as heptane, pinane, nonane, gas fractions at 70 DEG-190 DEG C., cyclohexane, methylcyclohexane, decalin, petroleum ether, hexane, ligroin, 2,2,4-trimethylpentane, 2,2,3-trimethylylpentane,

2,3,3 - trimethylpentane, octane and corresponding mixtures.

The solvent is preferably used in an amount of 400 to 10,000 wt.%, Preferably 100 to 500 wt.%, Based on the starting compounds II.

Water is always used, preferably in an amount of from 1 to 70, preferably from 1 to 10 moles of water, based on hydrazine III. It is preferably added to the starting mixture together with another component, for example an acid and / or a starting compound of formula III.

The reaction is carried out in the presence of less than 2 equivalents of acid, preferably in an amount of from 0.05 to 1.9, in particular from 0.25 to 1.25 equivalents of acid, based on 1 mole of the starting compound III. Inorganic or organic acids may also be used. Equivalent amounts of polybasic acids can also be used in place of monohydric acids. For example, the following acids are suitable: inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid, boron-containing acids such as boric acid, fluoroboric acid, aliphatic carboxylic acids, such as: chloroacetic acid, dichloroacetic acid, trichloroacetic acid, oxalic acid, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, glycolic acid, α- and β-respectively. , 3-chloropropionic or corresponding mixtures. The acids can be used in concentrated form, in mixtures thereof and / or in a solvent, especially in water. Hydrochloric acid is preferred. The reaction is carried out at a pH between 0 and 6.9, preferably 0.5 to 4, in particular 0.9 to 2.5.

The reaction is carried out as follows:

The mixture of hydrazine III, acid and water is adjusted to the desired pH while additional starting compound III and starting compound II are added, optionally together with water and / or an organic solvent, so as to maintain the pH of the reaction. Preferably, the reaction is carried out at a temperature of from -10 to + 60 ° C and the addition time is between 5 and 30 minutes. The total reaction time is between 0.1 and 12 hours. It has proven to be highly advantageous that in the process according to the invention a minimum amount of acid equivalents, based on the hydrazine derivative, is used. The final product can be isolated from the reaction mixture in a conventional manner, for example by neutralizing and extracting the mixture and distilling the extract. The neutralization can be carried out discontinuously, for example with an inorganic base, whereby in the process according to the invention only a small amount of salt, corresponding to the reduced amount of the acid used, is dispensed as by-product. However, in particular in the continuous process, the release of the pyrazole I according to the invention takes place by adding the corresponding hydrazine III to the reaction mixture, preferably adjusting the pH to 6 to 10 prior to extraction. The pyrazole example shows that the re-usable hydrazine salt remains in solution. .

x HCl + h ₂ n-h ₂ * h ₂ o ---->

^^ a ₊ a / ₂ and NH ₂ on xHCpa

H

Losses per acid equivalent preferably occur in the distillation and extraction processes by transition from the aqueous phase. The release of the products of formula I by addition of hydrazine preferably takes place at 0 to 40 ° C. In the above-mentioned manner, the resulting hydrazine salt solution can be further used in any number of repetitions, which is a considerable and surprising advantage of the process.

The pyrazoles of the formula I according to the invention are valuable starting compounds for the preparation of dyes, plant protection agents and pharmaceutical preparations. As far as the use is concerned, these are mentioned in the already published literature.

The parts given in the examples are parts by weight. The parts by weight shall be expressed as kilograms per liter.

Example 1

320 parts of water and 20 parts (0.4 mol) of hydazine hydrate are placed in the stirred apparatus and the pH is adjusted to 1 by adding 59 parts of 36% by weight aqueous hydrochloric acid (0.5 mol) at 40 ° C. 1.5 parts (392 parts by volume) 380 parts (7.6 moles) of hydrazine hydrate, 354 parts by weight of 36% by weight, hydrochloric acid (3.54 moles) and 1312 parts (8 moles) were added simultaneously from three containers 1 1,3,3-tetramethoxypropane is maintained such that the pH is maintained at 2 to 3 (43-55 ° C without cooling) while the rate of addition is adjusted such that 1,1,3,3-tetramethoxypropane is added at a constant rate of 540 parts per hour and hydrazine hydrate at a constant rate of 153 parts per hour The pH is controlled by the addition of hydrochloric acid. After stirring for 7 hours, the mixture is adjusted to pH 8 by adding 320 parts (4 mol) NaOH and at 2 kPa / 50 degrees Celsius. 1553 parts of methanol-water were distilled off for 5 hours.

The residue is stirred with 2000 parts by volume of methylene chloride and filtered. 250 parts of sodium chloride are filtered off and 445 parts (82% of theory) of pyrazole, b.p. 60-70 [deg.] C./30 mbar, are obtained from the filtrate by distillation.

Example 2

а) 12.9 parts (0.258 mol) of hydrazine hydrate are placed in a stirred apparatus with a pH electrode and neutralized with 50.6 parts of aqueous hydrochloric acid (0.506 mol) under cooling. First, hydrazine hydrochloride precipitates. Then 1,1,3,3-tetramethoxypropane and other hydrazine hydrate are added simultaneously at 45 to 50 ° C to maintain a pH of 1-2, namely 82 parts (0.5 mol) of 1,1, 3,3-tetramethoxypropane a

15.5 parts (0.31 mol) of hydrazine hydrate. After the addition was complete, the pH of the reaction mixture was 1. The reaction mixture was then stirred at 22 ° C for two hours.

(b) 120 parts (3/4) of this solution are adjusted to pH 6.8-7.2 with 20.6 parts (0.426 mol) of hydrazine hydrate, followed by extraction with 2 x 200 parts of CH ₂ Cl ₂ (hydrazine hydrate phase / extract). Distillation of the extract was obtained

23.2 parts of pyrazole (85% of theory), b.p. 60-70 ° C / 10 Pa.

c) The remaining quarter, finely 40 parts by volume in Example 2a of the reaction solution obtained (pH 1), is reacted with

61.5 parts (0.375 mol) of 1,1,3,3-tetramethoxypropane and according to b) an extracted hydrazine hydrate phase (pH 6.9 to 7.2). The pH is again maintained at 1 and 2. After a further 2 hours, the mixture is worked up as in Example 2b. Distillation yielded 21.45 parts (0.36 mol) of pyrazole (corresponding to 84% yield), bp 60-70 ° C / 10 Pa.

(d) The procedure referred to in paragraph (c) shall be carried out ten times. Even in the 10th repetition, a reaction mixture having a pH of 1.6 to 1.6 was obtained

1.7 and the same results as in Example 2c.

Claims (2)

A process for the preparation of pyrazoles of the general formula I wherein the individual radicals R ¹ , R ² and R ³ are the same or different, namely a hydrogen atom or a C 1 -C 18 alkyl, by reacting the 1,3-dicarbonyl compounds with hydrazine in the presence of water and an acid characterized in that the 1,3-dicanbonyl compounds of the formula II of the invention wherein R ¹ and R ² are as defined above are reacted with a hydrazine of the formula III R ³ -NH-NH ₂ (III), wherein R ³ is as defined above, in the presence of less than 2 equivalents of acid per mole of hydrazine of formula III, at a temperature of -10 to 100 ° C, wherein the pH of the reaction mixture during the reaction is between 0 and 6.9. 2. A process according to claim 1, wherein the pyrazole fraction of formula I present in the reaction mixture in the form of a pyrazole salt is converted to the free pyrazole by reaction with a further amount of hydrazine of formula III. OR ² O ri — с — с — C — R ¹ (II),