MXPA98000412A - Preparation of 3-hidroxipirazoles n-substitui - Google Patents

Abstract

The N-substituted 3-hydroxypyrazoles of the formula (I), wherein, R1 is unsubstituted or substituted alkyl, aryl or heteroaryl, and R2 and R3 is hydrogen, cyano, halogen or unsubstituted or substituted alkyl, aryl or heteroaryl is prepare by oxidation of a corresponding pyrazolidin-3-one

Description

"PREPARATION OF N-SUBSTITUTE 3-HYDROXYPYRAZOLES" The present invention relates to a process for preparing N-substituted 3-hydroxypyrazoles of the formula I wherein R 1 is unsubstituted or substituted alkyl, aryl or heteroaryl, and R 2, R 2 is hydrogen, cyano, halogen or unsubstituted or substituted alkyl, aryl or heteroaryl, by oxidation of a pyrazolidin-3-one of the formula II, H II It is known from the literature that N-substituted 3-hydroxypyrazoles are obtained by oxidation of the corresponding pyrazolidinones [J. Gen. Chem. USSR, Engl. Trans. 31, 1770 (1961); Chem. Heterocycl. Comp. 5, 527 (1969) / J. Prakt. Chem 313, 115 (1971); J. Prakt. Chem. 318, 253 (1976); J. Med. Chem. 34, 1560 (1991); J. Prakt. Chem. 313, 1118 (1971); DE-A 34 15 385]. The oxidants used here are elemental sulfur [J. Gen. Chem. USSR, Engl. Trans. 31, 1770 (1961)], elemental halogens [Chem. Heterocycl. Comp. 5, 527 (1969); J. Prakt. Chem 318, 253 (1976); J. Prakt. Chem. 313, 1118 (1971)], peroxides [J. Med. Chem. 34, 1560 (1991); DE-A 34 15 385] and atmospheric oxygen [J. Prakt. Chem. 313, 115 (1971); J. Prakt 313, 1118 (1971)]. For purposes of industrial preparation of the 3-hydroxypyrazoles, the oxidation being elemental sulfur has the disadvantage that considerable amounts of sulfur reduction products are formed, and these require complicated treatment and disposal. The use of elemental halogens, likewise, is not appropriate for the industrial synthesis of the 3-hydroxypyrazoles, since the yields leave much to be desired. In addition, the use of large amounts of elemental halogen as the oxidant is an inconvenience both for environmental reasons and also in view of the costs.

The known oxidation processes using peroxides require, on the one hand, complicated purifications and on the other hand, the use of expensive reagents that provide only unsatisfactory yields so that they are not suitable for industrial synthesis. Only the use of atmospheric oxygen as an oxidant offers a sensible alternative. However, processes of this type that are known have the disadvantage that the reaction has to be carried out in a strongly acidic medium. In the treatment this results in a considerable base consumption resulting in significant salt formation which is undesirable from an ecological point of view. According to the literature, oxidation by means of atmospheric oxygen is carried out in the presence of double molar amounts of iron salts or catalytic amounts of copper salts, manifesting in the latter case that the iron salts are inferior under catalytic conditions. to copper salts. An object of the present invention is to provide a safe and simple economic and industrial process for preparing the 3-hydroxypyrazoles. We have found that this object is achieved by a process for preparing the N-substituted 3-hydroxypyrazoles of the formula I, - - where R! is unsubstituted or substituted alkyl, aryl or heteroaryl, and R2, R3 is hydrogen, cyano, halogen or alkyl, aryl or heteroaryl unsubstituted or substituted by oxidation of a pyrazolidin-3-one of the formula II, wherein the oxidation is carried out in the presence of metal salts using as the oxidant the atmospheric oxygen. In the oxidation of pyrazolidinones II, the procedure is usually to first mix an essentially neutral solution of II with catalytic amounts of a metal salt subsequently passing air into this mixture. Suitable metal salts with in particular iron salts in oxidation state II or III (e.g., iron (II) chloride, iron (III) chloride, iron (II) sulfate and iron sulfate ( III)), the salts of copper in oxidation state I or II (eg, copper (I) chloride, copper (II) chloride), copper (I) sulfate and copper (II) sulfate and also the corresponding salts of the main group or transition metals. Metal salts are generally used in amounts of 0.01 mole percent to 20 mole percent, preferably 0.5 mole percent to 10 mole percent, particularly 1 mole percent to 5 mole percent based on IV [sic] This oxidation is usually carried out at a temperature of 0 ° C up to the boiling point of the solvent used, preferably from 20 ° C to 100 ° C. Suitable solvents are water and aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons such as toluene, o-, m- and p-xylene, halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene, alcohols such such as methanol, ethanol, n-propanol, iso-propanol, n-butanol and tertiary butanol, carboxylic esters such as ethyl acetate and also N-methylpyrrolidone and dimethylformamide, particularly preferably dimethylformamide and N-methylpyrrolidone. Mixtures of these solvents can also be used.

The reaction mixtures are treated in the usual manner, e.g., by mixing with water, separating the phases and if desired, purifying the crude products by chromatography. The intermediate and final products are sometimes obtained in the form of colorless or slightly brownish viscous oils which are purified or released from the constituents or volatiles under reduced pressure at moderately elevated temperature. If the intermediate and final products are obtained as solids, the purification can also be carried out by recrystallization or digestion. The 3-hydroxypyrazoles obtainable by the process of the present invention are suitable as intermediates for preparing dyes or active compounds in the pharmaceutical or crop protection sector.

Comparison Examples 1. Oxidation of pyrazolidinones using FeCl3 [J. Prakt. Ch. 313, 1118 (1991)]. A solution of 23 grams (0.142 mol) of FeCl3 in 40 milliliters of H2O was added dropwise at room temperature to a mixture of 14 grams (0.071 mol) of l- (4-chlorophenyl) pyrazolidin-3-one and 100 milliliters of HCl of 1 N. After stirring overnight, 24 grams of NaOH were added in portions, the mixture was heated to 90 ° C and filtered while suction while hot. The precipitated material was washed with boiling water. After acidification of the filtrate at a pH of 5-6 and subsequent extraction of CHCl3, a small amount of a dark residue of the ornate phase was obtained. No product of this residue could be detected. It was also not possible to isolate any product having sufficient purity for quantitative or qualitative characterization of the solid obtained from the aqueous phase and filtration. 2. Oxidation of pyrazolidinones using CUCI2 [J. Prakt. Ch. 213, 115 (1971)] 2.1 Oxygen was passed for 8 hours at 50 ° C to a mixture of 19.6 (0.1 mol) of l- (4-chlorophenyl) pyrazolidin-3-one, 200 milliliters of HCl of 1 N and 0.05 gram of CuCl • 2 H20 (0.293 millimole). The mixture was stirred overnight subsequently and the brown solid formed was filtered off with suction. This provided 17.7 grams of a mixture of pyrazolinone and pyrazolidinone in a ratio of 4: 1. Calculated yield: 73 percent. 2. 2 A similar experiment in which oxygen was passed for 24 hours at 50 ° C provided 17.8 grams of a mixture whose spectroscopic and physical data were identical to those obtained under 2: 1. This thin layer chromatographic analysis carried out during the reaction showed that the amount of the by-product increased steadily over time. An additional extension of the reaction time was therefore not examined.

Examples of the process according to the present invention: 1. Synthesis of p? Razol? Dm-3-ones 1-subst? Tu? Das 1.1 1- (4-chlorophen? L) p? Razol? Dm-3-one 90 g (0.9 mol) of acrylate were added by drops of ethyl at a temperature of 40 ° C to 45 ° C to a mixture of 15.9 grams (234 millimoles) of sodium ethoxide, 110 milliliters of ethanol, 110 milliliters of toluene and 25.7 grams (180 millimoles) of 4-chlorofemlh? drazma and the mixture was subsequently stirred for one hour at 40 ° C. The reaction mixture was evaporated to 100 milliliters and the residue was absorbed in water. The resulting mixture was washed a number of times with toluene and the combined organic phases were extracted with NaOH at a concentration of 5 hundred. The combined aqueous phases were adjusted to a pH of 6.5 and cooled to 10 ° C. The solid formed was filtered off with suction, washed with water and dried under reduced pressure. Yield: 26.4 grams (75 percent of the theoretical amount). Melting temperature: 117 ° C to 120 ° C (with decomposition). 1. 2 1- (2,4-dichlorophenyl) pyrazolidin-3-one 105.0 grams (1.05 mol) of ethyl acrylate were added dropwise to a mixture of 37.3 grams (211 millimoles) of 2, -dichlorophenylhydrazine, 18.6 grams (273 millimoles) ) of sodium ethoxide, 150 milliliters of ethanol and 150 milliliters of toluene and the mixture was subsequently stirred for one hour. The reaction mixture was evaporated to 100 milliliters and the residue was absorbed in water. The organic phase was separated and extracted with NaOH of 5 percent concentration. The combined aqueous phases were adjusted to a pH of 6.5 and the solid formed was filtered off with suction, washed with water and dried under reduced pressure. Yield: 39.1 grams (81 percent of the theoretical amount).

Melting temperature: 197 ° C to 199 ° C (with decomposition). 1. 3- 1- (6-chloro-2-pyridyl) pyrazolidin-3-one A solution of 20.1 grams (140 millimoles) of 6-chloro-2-pyridylhydrazine (synthesis: Chem. Ber. 103, (1970) 1960) was added by drops at a temperature of 15 ° C to 20 ° C to a mixture of 12.4 grams (182 millimoles) of sodium ethoxide, 100 milliliters of ethanol and 100 milliliters of toluene. After stirring for 2 hours at 25 ° C, the reaction mixture was evaporated, the residue was taken up in water and extracted with MTBE. The aqueous phase was adjusted to a pH of 6.5 and cooled to 5 ° C. The precipitated material formed was filtered and dried under reduced pressure at 40 ° C. Yield: 21.6 grams (78 percent of the theoretical amount). Melting temperature: 116 ° C to 118 ° C (with decomposition). 2. Oxidation of pyrazolidinones using FeCl3 2.1 1- (4-chlorophenyl) -2H-pyrazol-3-one 29.5 grams (150 millimoles) of 1- (4-chlorophenyl) pyrazolidin-3-one were dissolved in 100 milliliters of dimethylformamide and mixed with 2.4 grams (15 millimoles) of FeCl3. While air was being passed, the The mixture was heated to 80 ° C, this temperature was maintained for 1 hour and the mixture was subsequently stirred for an additional 12 hours without heating. The reaction mixture was emptied into 1 liter of water, the precipitated material formed was filtered, washed with water and dried under reduced pressure. Yield: 27.0 grams (92 percent of the theoretical amount). Melting temperature: 181 ° C to 182 ° C (with decomposition). 2. 2 1- (2,4-dichlorophenyl) -2H-pyrazolidin-3-one 39.0 grams (169 millimoles) of 1- (2,4-dichlorophenyl) pyrazolidin-3-one and 1.4 grams (8.6 millimoles) of FeCl3 were dissolved. in 220 milliliters of N-methylpyrrolidone were heated to 80 ° C and air was passed through the reaction mixture for 18 hours. The mixture was subsequently poured into ice water. The solid formed is filtered off with suction, washed with water and dried under reduced pressure at 40 ° C. Yield: 33.5 grams (87 percent of the theoretical amount). Melting temperature: 236 ° C to 237 ° C (with decomposition). 2. 3 l- (6-chloro-2-pyridyl) -2H-pyrazolin-3-one 10.1 grams (51 millimoles) of 1- (6-chloro-2-pyridyl) pyrazolidin-3-one and 0.41 gram (2.5 millimoles) of FeCl3 in 50 milliliters of dimethylformamide. While air was being passed, the mixture was first stirred for 1 hour at 25 ° C, and then for 3 hours at 50 ° C. The reaction mixture was poured into 300 milliliters of ice water, the precipitated material formed was filtered, washed with water and dried under reduced pressure at 40 ° C. Yield: 9.6 grams (96 percent of the theoretical amount). Melting temperature: 196 ° C to 199 ° C. 3. Oxidation of pyrazolidinones using CuCl 3.1 1- (4-chlorophenyl) -2H-pyrazolin-3-one Air was passed for 2 hours at 25 ° C through a solution of 9.8 grams (50 mmol) of 1- (4 -chlorophenyl) pyrazolidin-3-one and 0.25 gram (2.5 millimoles) of CuCl in 50 milliliters of dimethylformamide. The reaction mixture was poured into water and stirred for 1 hour. The precipitated material formed was filtered, washed with water and dried under reduced pressure at 50 ° C. According to the melting temperature and the Nuclear Magnetic Resonance spectrum of ^ -H, the product is identical to that described under 2.1. Yield: 86 percent of the theoretical amount. 3. 2 1- (2,4-dichlorophenyl) -2H-pyrazolin-3-one 23.1 grams (100 millimoles) were dissolved 1 (2,4-dichlorophenyl) pyrazolidin-3-one and 0.5 gram (5 millimoles) of CuCl in 230 milliliters of dimethylformamide were heated to 80 ° C and air was passed through the reaction mixture for 9 hours. After stirring for 15 hours without heating and without passing air, the mixture was heated while air was passed at a temperature of 80 ° C for 2 hours and 100 ° C for 2 hours. The reaction mixture was evaporated and the residue was stirred for 3 hours with 500 milliliters of H2O. The solid was filtered with suction, washed with n-hexane, with water and dried under reduced pressure at 60 ° C. In accordance with the melting temperature and the Nuclear Magnetic Resonance spectrum of ^ H, the product is identical to that described under 2.2. Performance: 85 percent of the theoretical amount.

Claims (3)

- - R E I V I N D I C A C I O N E S:

1. A process to prepare 3-hydroxypyrazoles

N-substituted of the formula I, wherein R1 is unsubstituted or substituted alkyl, aryl or heteroaryl, and R2, R3 is hydrogen, cyano, halogen or alkyl, aryl or heteroaryl unsubstituted or substituted by oxidation of a pyrazolidin-3-one of the formula II, wherein the reaction is carried out in the presence of 0.01 mole percent to 20 mole percent based on II, of the metal salts using atmospheric oxygen as the oxidant in an essentially neutral pH medium. 2. A process according to claim 1, wherein the metal salt used is an iron salt.

3. A process according to claim 1, wherein the metal salt used is a copper salt.