Method for producing N-substituted 2-pyrazoline-5-one

Details Method for producing N-substituted 2-pyrazoline-5-one Method for producing N-substituted 2-pyrazoline-5-one

2002-05-13

2003-02-04

Ramsuer, Robert W. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06515139

ABSTRACT:

The present invention relates to a process for preparing N-substituted 2-pyrazolin-5-ones of the formula I
in which
R is C
1
-C
8
-alkyl, C
5
-C
8
-cycloalkyl, phenyl, naphthyl or phenyl-C
1
-C
4
-alkyl which may be unsubstituted or may carry one or more substituents which are inert towards aqueous alkali.
N-Substituted pyrazolinones are useful intermediates for preparing pharmaceuticals and crop protection agents. Thus, for example, U.S. Pat. No. 4,557,753 describes the preparation of benzoyl-substituted 5-benzyloxy-1-methylpyrazoles which are prepared starting from 1-methylpyrazolin-5-one.
In general, N-substituted pyrazolones are prepared by cyclization of &bgr;-functionalized acid derivatives with substituted hydrazines. A review of various synthesis methods is given in EP-A 240 001. This publication furthermore describes a process in which a hydrazone of a &bgr;-hydrazinopropionic acid derivative is cyclized in the presence of a base. In all of the processes mentioned, substituted hydrazines are employed. Firstly, substituted hydrazines are difficult to obtain and thus expensive. Secondly, substituted hydrazines are usually highly toxic. Accordingly, it is desirable to prepare N-substituted pyrazolinones from already known or otherwise obtainable pyrazole precursors.
Dorn et al. (J. Pract. Chem. 313 (1971), 115-128) describe a process in which 3-pyrazolidone is initially acylated at the 1-nitrogen, then alkylated with alkyl chlorides or dialkyl sulfates at the 2-nitrogen, followed by removal of the acyl group under oxidizing conditions. This gives N-substituted 5-hydroxypyrazoles or their tautomers, i.e. 2-pyrazolin-5-ones. However, owing to the large number of reaction steps, the preparation process is uneconomical. Moreover, dialkyl sulfates are highly toxic.
It is an object of the present invention to provide an economical process for preparing the 2-pyrazolin-5-ones of the formula I defined at the outset, which process uses pyrazoles which are already known or easily obtainable as starting materials.
We have found that this object is achieved and that compounds of the formula I are obtained in good yields by reacting 5-halopyrazole-4-carboxylic acids or derivatives thereof which can be hydrolyzed with bases at elevated temperature with aqueous alkali metal hydroxide solutions and then acidifying the reaction mixture.
Accordingly, the present invention relates to a process for preparing N-substituted 2-pyrazolin-5-ones of the formula I defined at the outset, which process comprises reacting a compound of the formula II
in which
X is 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 hydrolyzed using alkali metal hydroxide,
and R has the meanings mentioned for formula I,
at elevated temperature with a molar excess of alkali metal hydroxide in an aqueous reaction medium, and then adjusting the pH to pH≦6 by adding an acid.
Hereinbelow, compounds of the formula II where Y=R′(O)C and R′=OH are also referred to as 5-halopyrazole-4-carboxylic acids, and the compounds where Y=CN or Y=R′(O)C where R′≠OH are referred to as 5-halopyrazole-4-carboxylic acid derivatives.
The compounds of the formula I are in an equilibrium with the 5-hydroxypyrazoles of the formula Ia
Accordingly, the process according to the invention also embraces the preparation of the compounds Ia.
Organic radicals R′ which can be hydrolyzed 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 may also be substituted, and furthermore phenyloxy and benzyloxy, which may also be substituted at the phenyl ring. Examples of substituents are halogen, such as fluorine, chlorine or bromine, furthermore nitro and C
1
-C
4
-alkoxy. Further radicals R′ which can be hydrolyzed with base are NH
2
and halogen. Preferred radicals R′ which can be hydrolyzed with base are C
1
-C
4
-alkoxy, in particular methoxy and ethoxy. If Y is a group CN, i.e. the compound II is a nitrile derivative, under the reaction conditions of the first step the nitrile group is hydrolyzed to the carboxyl group. This also applies when Y is R′(O)C and R′ is a group which can be hydrolyzed with alkali metal hydroxide.
Particularly preferred compounds II are the carboxylic acids, i.e. the radical R′ is hydroxyl (═OH). Also preferred are compounds II in which Y is R′(O)C and R′ is C
1
-C
4
-alkoxy, in particular methoxy or ethoxy.
According to the invention, preferred halogen X is chlorine or bromine, in particular chlorine.
For the reaction according to the invention, the nature of the substituent R is of minor importance. The meanings mentioned for R are collective terms for individual radicals. These meanings are:
C
1
-C
8
-alkyl: a linear or branched alkyl chain having 1 to 8 carbons, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, 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, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl and 2.2.2-bicyclooctyl.
Phenyl-C
1
-C
4
-alkyl is a C
1
-C
4
-alkyl group which is substituted by phenyl, for example benzyl, 1-phenylethyl and 2-phenylethyl.
The abovementioned radicals, and phenyl and naphthyl, may have one or more substituents which are inert towards aqueous alkali metal hydroxide solutions. Examples of such radicals are C
1
-C
4
-alkoxy, such as methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, furthermore trifluoromethyl, pentafluoroethyl, trifluoromethoxy and pentafluoroethoxy. Another suitable alkali-stable substituent for the radicals cycloalkyl, phenyl, naphthyl and phenyl-C
1
-C
4
-alkyl is C
1
-C
4
-alkyl. The three last-mentioned substituents may also have one or more chlorine or fluorine atoms as alkali-inert substituents at the phenyl group or the naphthyl group.
R is preferably C
1
-C
8
-alkyl and in particular C
1
-C
4
-alkyl, which are preferably unsubstituted, and is particularly preferably methyl or ethyl.
The starting materials of the formula II are known to the person skilled in the art and readily obtainable (see EP-A 350176). Compounds of the formula II which are not known 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 the process according to the invention, in a first step, a compound of the formula II is reacted with alkali metal hydroxide in molar excess in an aqueous reaction medium. In the case of the compounds of the formula II, a molar excess of alkali metal hydroxide is ensured when more than 2 mol of alkali metal hydroxide are employed per mole of the compound II. In the first step, one mole is required for exchanging the halogen X with hydroxyl and one mole is required for hydrolysis or neutralization of the group C(O)R′. 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 the compound II. Preferred alkali metal hydroxides are sodium hydroxide and potassium hydroxide, in particular sodium hydroxide.
Suitable aqueous reaction media are both water and mixtures of water and water-miscible organic solvents. The water-miscible organic solvents are preferably inert to alkali metal hydroxide under the reaction conditions. Examples of suitable organic solvents are C
1
-C
4
-alkanols, in particular methanol and ethanol, and furthermore dimethyl sulfoxide, tetrahydrofuran, dioxane, glycol, glycerol, diethylene glycol, triethylene glycol and the like. In general, the aqueous reaction medium does not contain more than 50% by volume, preferably not mo

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