EP1230221A1

EP1230221A1 - Method for producing n-substituted 2-pyrazoline-5-one

Info

Publication number: EP1230221A1
Application number: EP00979592A
Authority: EP
Inventors: Hans Rupert Merkle; Erich Fretschner; Knut Koob
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1999-11-19
Filing date: 2000-11-17
Publication date: 2002-08-14
Also published as: AU1702601A; HUP0302107A3; WO2001036389A1; TW553935B; AR026475A1; US6515139B1; CA2391907A1; IL149265A0; JP2003514800A; HUP0302107A2

Abstract

The invention relates to a method for producing N-substituted 2-pyrazoline-5-one of the general formula (I), wherein R is defined as per claim 1. Said method is characterised in that a compound of the general formula (II), wherein R, X and Y are defined as per claim 1, is reacted with a molar excess of alkali hydroxide at a high temperature in an aqueous reaction medium and the pH value is subsequently adjusted to </= 6 by adding an acid.

Description

Process for the preparation of N-substituted 2-pyrazolin-5-ones

description

The present invention relates to a process for the preparation of N-substituted 2-pyrazolin-5-ones of the general formula I.

R where

R represents Ci-Cs-alkyl, C ₅ -C ₈ cycloalkyl, phenyl, naphthyl or phenyl-Cχ-C4-alkyl, which optionally have one or more substituents which are inert to aqueous alkali.

N-substituted pyrazolinones are valuable intermediates in the manufacture of pharmaceuticals and crop protection products. For example, US Pat. No. 4,557,753 describes the preparation of benzoyl-substituted 5-benzyloxy-l-methylpyrazoles, which are prepared starting from l-methylpyrazolin-5-one.

As a rule, N-substituted pyrazolones are prepared by cyclization of β-functionalized acid derivatives with substituted hydrazines. EP-A 240 001 provides an overview of various synthetic methods. This document also describes a process in which a hydrazone of a β-hydrazinopropionic acid derivative is cyclized in the presence of a base. The aforementioned methods all make use of substituted hydrazines. Substituted hydrazines are difficult to access and therefore expensive. In addition, substituted hydrazines are usually very toxic. The preparation of N-substituted pyrazolinones from known or otherwise accessible pyrazole precursors is therefore desirable.

Dorn et al. (J. Pract. Chem. 313, 1971, pp. 115-128) describe a process in which 3-pyrazolidones are first acylated on 1-nitrogen, then alkylated on 2-nitrogen with alkyl chlorides or dialkyl sulfates and then with oxidizing agents condi- the acyl group is split off again. This gives N-substituted 5-hydroxypyrazoles or their tautomers 2-pyrazolin-5-one. However, the manufacturing process is not economical due to the large number of reaction steps. Dialkyl sulfates are also very toxic.

The object of the present invention is to provide an economical process for the preparation of the 2-pyrazolin-5-ones of the general formula I defined at the outset, which is based on already known or easily accessible pyrazoles.

It has surprisingly been found that the compounds of the general formula I are obtained in good yields if 5-halopyrazole-4-carboxylic acids or their basic saponifiable derivatives are reacted with aqueous alkali metal hydroxide solutions at elevated temperature and the reaction mixture is then acidified.

Accordingly, the present invention relates to a process for the preparation of N-substituted 2-pyrazolin-5-ones of the formula I defined at the outset, which is characterized in that a compound of the general formula II

wherein

for halogen, and

Y is CN or a group of the formula R '(O) C, in which R' is a hydroxyl group or a radical which can be saponified with alkali metal hydroxide,

and in which R has the meanings given for formula I,

reacted at elevated temperature with a molar excess of alkali hydroxide in an aqueous reaction medium and then adjusted to a pH <6 by adding an acid.

In the following, compounds of general formula II with

Y = R '(O) C and R' = OH also as 5-halopyrazole-4-carboxylic acids and the compounds with Y = CN or Y = R '(0) C with R' φ OH as

Designated 5-halopyrazole-4-carboxylic acid derivatives. The compounds of the formula I are in equilibrium with the 5-hydroxypyrazoles of the formula Ia

The process according to the invention thus also includes the preparation of the compounds Ia.

Organic radicals R 'which can be saponified under basic reaction conditions, such as alkali metal hydroxide, are known to the person skilled in the art. Examples of suitable radicals R 'are C ₁ -C ₄ alkoxy, such as methoxy, ethoxy, n-propoxy and n-butoxy, which can also be substituted, furthermore phenyloxy and benzyloxy, which can also be substituted on the phenyl ring. Examples of substituents are halogen, such as fluorine, chlorine or bromine, nitro and C _! -C ₄ alkoxy. further basic saponifiable radicals R 'are NH ₂ and halogen. Preferred basic saponifiable radicals R 'are -CC ₄ alkoxy, especially methoxy and ethoxy. If Y stands for a CN group, ie the compound II is a nitrile derivative, the saponification of the nitrile group to form the carboxyl group takes place under the reaction conditions of the first stage. The same applies if Y is R '(0) C and R' is a group which can be saponified with alkali metal hydroxide.

Particularly preferred compounds II are the carboxylic acids, ie radical R 'stands for hydroxy (= OH). Likewise preferred are compounds II in which Y is R '(0) C and R' is C 1 -C ₄ -alkoxy, in particular methoxy or ethoxy.

Halogen X preferred according to the invention is chlorine or bromine, in particular chlorine.

The nature of the substituent R is of minor importance for the reaction according to the invention. The meanings given for R are collective terms for individual residues. Here:

-C-C ₈ alkyl: a linear or branched alkyl chain with 1 to 8 carbon atoms, for. B. methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl , 1-methylpentyl, 2-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, n-heptyl, n-octyl and 2-ethylhexyl. C ₃ -C ₈ cycloalkyl: mono- or bicyclic hydrocarbon radicals having 3 to 8 carbon atoms, e.g. B. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl and 2.2.2-bicyclooctyl.

Phenyl -CC-C ₄ alkyl represents a Cχ-C ₄ alkyl group which is substituted with phenyl, for. B. benzyl, 1-phenylethyl and 2-phenylethyl.

The aforementioned radicals, as well as phenyl and naphthyl, can have one or more substituents which are inert to aqueous alkali metal hydroxide solutions. Examples of such radicals are -CC ₄ alkoxy, such as methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, furthermore trifluoromethyl, pentafluoroethyl, trifluoromethoxy and pentafluoroethoxy. In addition, as the alkali-stable substituents for the radicals cycloalkyl, phenyl, naphthyl, and phenyl-C ₁ -C ₄ alkyl and Ci-C ₄ alkyl considered. The three last-mentioned substituents can also have one or more chlorine or fluorine atoms as alkali-inert substituents on the phenyl group or on the naphthyl group.

R preferably represents Ci-Cs-alkyl and in particular C 1 -C ₄ -alkyl, which are preferably unsubstituted, and particularly preferably methyl or ethyl.

The starting compounds of the formula II are known to the person skilled in the art and are readily accessible (see EP-A 350176). Unknown compounds of the formula II can be prepared, for example, in a simple manner by oxidation of N-substituted 5-halo-4-methylpyrazoles by the process described in EP-A 350 176.

In a first step in the process according to the invention, a compound of the general formula II is reacted with alkali metal hydroxide in molar excess in an aqueous reaction medium. A molar excess of alkali metal hydroxide is ensured in the case of the compounds of the general formula II if more than 2 mole of alkali metal hydroxide is used per mole of compound II. In the first stage, one mole for the replacement of the halogen X by hydroxy and one mole for the saponification or neutralization of the

Group C (0) R 'required. According to the invention, preference is given to using 3 to 20 mol of alkali metal hydroxide and in particular 5 to 12 mol of alkali metal hydroxide per mole of compound II. Preferred alkali hydroxides are sodium hydroxide and potassium hydroxide, especially sodium hydroxide. Both aqueous and mixtures of water and water-miscible organic solvents are suitable as aqueous reaction media. The water-miscible organic solvents are preferably inert to alkali hydroxide under the reaction conditions. Examples of suitable organic solvents are

C 1 -C ₄ -alkanols, in particular methanol and ethanol, furthermore diethyl sulfoxide, tetrahydrofuran, dioxane, glycol, glycerol, diethylene glycol, triethylene glycol and similar. As a rule, the aqueous reaction medium will not contain more than 50% by volume, preferably not more than 30% by volume and in particular not more than 10% by volume of an organic, water-miscible solvent. In a preferred embodiment of the present invention, water is the sole solvent.

The first reaction step is particularly preferably carried out in an aqueous alkali metal hydroxide solution which contains 10 to 50% by weight and in particular 20 to 40% by weight of alkali metal hydroxide.

According to the invention, the first reaction step is carried out at an elevated temperature. An elevated temperature is understood to mean heating to generally at least 50 ° C. and preferably at least 90 ° C. As a rule, the reaction temperature will not exceed 200 ° C. The reaction is very particularly preferably carried out at temperatures in the range from 120 to 200.degree.

Depending on the reaction temperature, the first reaction step will be carried out without pressure or under increased pressure. At reaction temperatures above 100 ° C, a reaction pressure of 1 to 10 bar is generally established. Typical reaction conditions are, for example, in a purely aqueous reaction medium 150 to 180 ° C and 5 to 7 bar.

As a rule, the reaction will lead to almost complete conversion of the starting compound II. By conversion is meant here the conversion of the halogen group X in pyrazole II into a hydroxyl group or the formation of the corresponding alcoholate and the saponification of the nitrile group (X = CN) or the group -C (0) R 'if R' Φ OH. The time required to achieve almost complete conversion naturally depends on the reaction conditions chosen and can vary between 0.5 h and 24 h. Typical reaction times in purely aqueous systems are usually in the range of 2 to 10 hours.

In the second reaction step, the reaction product obtained in the first reaction step is reacted under acidic conditions. In this case, the formation of compound I occurs under C0 ₂ development. The C0 ₂ development is based on the splitting off of the 4-position ιf- if * K> t

LΠ O tπ o Ul o Ul O Ul

xylation, the reaction conditions are maintained for a certain period of time, which can be from a few minutes to a few hours.

The compound I is isolated in the customary manner by working up the reaction mixtures of the second reaction step by customary workup methods, for example by extractive working up of the liquid reaction mixture with an organic solvent or by removing the solvent and isolating the target compound from the residue obtained in this way. Before working up, it is advisable to mix the reaction mixture of the second reaction stage with a base to pH> 6, e.g. neutralize pH 6 to 7. Suitable bases are alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, alkaline earth metal carbonates and alkaline earth metal hydroxides. Alkali metal hydroxides and in particular sodium hydroxide solution are usually used for neutralization.

In the process according to the invention, it is often advantageous, because of the salt load, to remove the aqueous reaction medium of the second reaction stage, preferably after neutralization, by distillation or by evaporation in vacuo, to remove the compound I, or to remove the residue with a suitable organic solvent. The person skilled in the art will select the solvents in such a way that the desired product is soluble in them, but not the salts resulting from the neutralization. Typical organic solvents for extraction are C ₂ -C ₆ alcohols, such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol, amyl alcohol and isoamyl alcohol, aromatic hydrocarbons such as toluene, ethylbenzene and xylene. After the extract has been evaporated to dryness, the target compound I is obtained and can be further purified and worked up in the customary manner.

The aqueous reaction medium of .2. Work up the reaction stage, preferably after neutralization, extractively with a polar solvent which is immiscible or only miscible with water, for example by extraction with a C ₆ -C ₆ alcohol such as n-butanol, isobutanol, amyl alcohol or isoamyl alcohol, or with one of the abovementioned aromatic hydrocarbons. The extraction can be carried out in portions or continuously.

To explain the method according to the invention, a typical procedure for the implementation of the compounds II to the 2-pyrazolin-5-ones is described below: * »4 * O l to t in O Ul 0 Ul 0 Ul O l

CD 3 "σ μ- <μ-

3 a Φ

CD H o <

X Φ

P> μ-

3 rt a er μ- tr ιQ 3

CD Φ

3 a

3 rt O: 3 μ- 0) i

01 rt Φ

O 3

3 '

CD σ H

3 µ- H φ J s;

H w Φ

O he 0 H

3

CD a

N Φ

Φ 3 μ- 3 art μ- D h 3

3 P rt et Φ μ- μ- μ-

Hh O 3 μ- 3 φ

N H µ- a

CD Φ Z

Hj Hi p: rt 01

HH 01

0: H

01 μ-

3 i

3 Φ m 3 tr ¹ μ- θ:

Φ 01 in 3 and 3 n μ-

3 a

01 a 01

Φ h

M to X

Φ P m M

Φ μ-

H- ¹ 1

Example 2 (Preparation of 1-ethyl-2-pyrazolin-5-one = 5-hydroxy-1-ethylpyrazole)

4 g of 5-chloro-1-ethyl-4-pyrazolecarboxylic acid were dissolved in 40 g of 25% strength by weight sodium hydroxide solution and reacted analogously to the procedure described in Example 1. The reaction temperature of the first reaction stage was 170 ° C., the reaction pressure 7.5 bar. The reaction time was 8 hours. Working up in the manner described for Example 1 gave 2.3 g of the target compound with a content of 99.7% (determined by means of gas chromatography). This corresponds to a yield of 89.4% of theory. The melting point was 88 ° C. The product was identified by mixed melting point with an authentic sample.

Example 3 (Preparation of l-methyl-2-pyrazolin-5-one, work-up by liquid-liquid extraction)

10 g of 5-chloro-1-methylpyrazole-4-carboxylic acid were first reacted with 100 g of 25% strength by weight sodium hydroxide solution as in Example 1 and then under acidic conditions. After the acidic reaction mixture had been neutralized to pH 6.5 with 25% strength by weight sodium hydroxide solution, the reaction mixture was transferred to a liquid-liquid extractor and extracted with isobutanol at the boiling point of the solvent. After isolation of the organic phase and distillation of the isobutanol, 5.8 g of l-methyl-2-pyrazolinone remained (purity according to GC: 98.1%). The melting point was 112 ° C. The yield was 92.5% of theory.

Claims

claims

1 . Process for the preparation of N-substituted 2 -pyrazolin-5-ones of the general formula I.

wherein

R represents Cx-Cs-alkyl, C ₅ -C ₈ -cycloalkyl, phenyl, naphthyl or phenyl-Cχ-C ₄ -alkyl, which may have one or more substituents which are inert to aqueous alkali,

characterized in that a compound of the general formula II

wherein

X for halogen, and

y represents CN or a group R '(O) C,

in which R 'denotes a hydroxyl group or a radical saponifiable with alkali metal hydroxide,

and R has the meanings given for formula I, reacts alkali hydroxide in an aqueous reaction medium at elevated temperature with a molar excess and then adjusts a pH <6 by adding an acid.

2. The method according to claim 1, characterized in that reacting the compound of general formula II with at least 3 moles of alkali metal hydroxide, based on 1 mole of compound II.

3. The method according to any one of the preceding claims, characterized in that one carries out the reaction with aqueous alkali hydroxide at a temperature above 90 ° C.

4. The method according to any one of the preceding claims, characterized in that the acid is added at a temperature in the range from 0 to 100 ° C.

5. The method according to any one of the preceding claims, characterized in that compounds of general formula II are used, wherein

Y represents a group R '(O) C;

R 'is Cχ-C alkyloxy or OH; X represents chlorine or bromine; and

R has one of the meanings given for formula I.

6. The method according to any one of the preceding claims, characterized in that one carries out the reaction in an aqueous, 10 to 50 wt .-% sodium hydroxide solution.