DE4127111A1 - Prepn. of 3-pyrrolin-2-one derivs. - by reacting 3-formyl-carboxylic acid deriv. with ammonia or amine - Google Patents

Abstract

The prepn. of 3-pyrrolin-2-one derivs. of formula (I) comprises reacting a 2-formylcarboxylic acid deriv. of formula (III) with ammonia or an amine of formula R1NH2 (III). R1 and R4 = each H, alkyl, cycloalkyl, aralkyl or aryl, R2 and R3 each = R1 or COOH, alkoxycarbonyl or halogen. USE/ADVANTAGE - (I) are intermediates in the synthesis of pharmaceuticals and plant protecting agents. The process is simpler and more economical than previous processes. In an example, a soln. of 47 g. ammonia (as the ethanoate) in 760 g. glacial ethanoic acid was heated to 70 deg.C and mixed within 30 min. with 44 g. 3-formyl-valerianic acid methyl ester. The mixt. was stirred for 30 min. at 70 deg.C and for a further 2 hrs. at 115 deg.C. Work up gave 17.5 g. (51% yield) of 4-ethyl -3-pyrrolin-2-one derivs. of m.pt. 84 deg.C.

Description

The present invention relates to a new process for the production of 3-pyrrolin-2-ones of the general formula I

in the
R¹ is hydrogen or alkyl, cycloalkyl, aralkyl or aryl radicals and
R² and R³ denote one of the radicals R¹ or carboxyl, alkoxycarbonyl or halogen radicals.

The compounds I are known and serve as intermediates for Synthesis of pharmaceutical and crop protection products.

In DE-A 36 30 613 their production is by implementation of 3-alkenylamides with carbon monoxide and hydrogen in the presence of Cobalt and / or rhodium carbonyl complexes described.

From Tetrahedron Letters, No. 14, pp. 1271-74 (1974) the reaction of 4-Chloromethyl-4-methyl-azetidin-2-one with aqueous alkali solution 4-methyl-3-pyrrolin-2-one known.

The oxidation of pyrroles is another possibility for synthesis Hydrogen peroxide (Gazz. Chim. Ital. 1972, 102, pp. 91-101) and the Reaction of N-substituted acetamides with basic compounds (DE-A 29 23 553).

However, these previously known methods are difficult because of their difficulty accessible starting connections and the high technical effort not to satisfy.

The invention was therefore based on the object of 3-pyrrolin-2-one I. making it easier and more economical to access.  

Accordingly, a new process for the production of 3-pyrrolin-2-ones has been developed of the general formula I

in the
R¹ is hydrogen or alkyl, cycloalkyl, aralkyl or aryl radicals and
R² and R³ denote one of the radicals R¹ or carboxyl, alkoxycarbonyl or halogen radicals,
found, which is characterized in that a 3-formyl carboxylic acid or its ester of the general formula II

inn the R⁴ means one of the radicals R¹, with ammonia or an amine general formula III

R¹-NH₂ (III)

implements.

The process according to the invention can be illustrated as follows:

The starting compounds II are known or by known methods available, e.g. B. by hydroformylation of corresponding alkene carboxylic acids and their esters (New Synthesis with Carbonmonoxide, J. Falbe, Springer-Verlag, pp. 116-123 (1980)).

Under the definition compounds II from economic For reasons preferred those in which the radicals have the following meaning:

• - hydrogen;
• - C₁-C₈-alkyl, preferably C₁-C₄-alkyl, including preferably C₁-C₂ alkyl such as methyl and ethyl;
• - C₅-C₁₂-cycloalkyl, preferably C₅-C₇-cycloalkyl such as cyclopentyl, Cycloheptyl and especially cyclohexyl;
• - C₇-C₁₂ arylalkyl, preferably phenylethyl and very particularly benzyl;
• Aryl such as preferably phenyl;
• - C₁-C₁₂-alkoxycarbonyl, preferably C₁-C₈-alkoxycarbonyl, including preferably C₁-C₂ alkoxycarbonyl such as ethoxycarbonyl and whole especially methoxycarbonyl;
• - Halogen such as preferably chlorine.

The alkyl, cycloalkyl and aryl groups can in turn Bear substituents, preferably C₁-C₁₂ alkyl groups, C₁-C₁₂ alkoxy groups and halogen.

Preferred starting materials II are:

• Methyl 3-formylpropionate,
• Ethyl 2-methyl-3-formylpropionate,
• Methyl 2-methoxycarbonyl-3-formylpropionate,
• N-butyl 3-formylbutyrate,
• - cyclohexyl 3-formylvalerate,
• - Benzyl 3-formylvalerate and
• - 2-chloro-3-formylvaleric acid methyl ester.

With regard to the desired process products I is the 3-formylvaleric acid methyl ester particularly preferred.

Preferred compounds III are C₁-C₆ alkylamines, especially Methylamine, ethylamine, n-hexylamine, cyclohexylamine and benzylamine and especially ammonia.

The molar ratio of III to II is advantageously 1: 1 to 20: 1, especially 1.5: 1 to 10: 1.

In general, the reaction is carried out at 20 to 200 ° C., preferably at 70 to 150 ° C through.

The implementation is usually carried out at normal pressure, but can one can also work at reduced or slightly increased pressure, for example in the range of 0.1 to 10 bar. A pressure in the range of 2 is preferred up to 10 bar.

The reaction times are normally 0.1 to 20 hours, usually 1 up to 5 hours.

It may be expedient to implement the reaction using solvents carry out, using polar solvents such as dimethylformamide, Acetonitrile or nitrobenzene are preferred. Are particularly well suited Carboxylic acids and their anhydrides.

Basically, the type of alkyl radical is important for carboxylic acids not, provided that they are liquid under the reaction conditions, as is the case mostly applies to carboxylic acids with alkyl radicals of up to 6 carbon atoms. Carboxylic acids with longer alkyl radicals, e.g. B. those of 6 to 12 carbon atoms, usually require working at higher temperatures.

Preferred solvents are therefore monocarboxylic acids such as formic acid, Propionic acid, butyric acid, 2-ethylhexanoic acid, cyclohexane carboxylic acid, Benzoic acid, pivalic acid and very particularly preferably acetic acid. Besides suitable dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, Glutaric acid and adipic acid.

The amount of solvent, e.g. B. the carboxylic acids is not critical and therefore variable within a wider range. Generally is so much carboxylic acid necessary that the ammonium salt formed from the amine is dissolved under the respective reaction conditions. Usually is used 1 to 50 times, preferably 5 to 30 times that Starting compound III.  

An economically very advantageous embodiment of the invention Process consists in the use of carboxylic acids as Solvent. A solution of amine III and solvent are heated and mixed with component II. Then the implementation at completed higher temperature.

Working up the reaction mixture to process products I takes place in a manner known per se, as a rule, by Distillation or fractional distillation and if desired by subsequent recrystallization.

The simple and economical according to the inventive method 3-Pyrrolin-2-one I available as intermediates for the Synthesis of pharmaceutical and crop protection products.

Examples Preparation of 3-pyrrolin-2-ones of the formula

A solution of a g ammonia or an amine III or its salt in 760 g of glacial acetic acid was heated to 70 ° C and then within 44 g of methyl 3-formylvalerate II were added for 30 minutes. After that was first for 30 minutes at 70 ° C and then for more Stirred at 115 ° C for 2 hours. After cooling and pre-cleaning Kugelrohr distillation at 220 ° C and 0.1 mbar was recrystallized or fractionally distilled.

The details of these experiments and their results are the see the table below.  

table

Production of 3-pyrrolin-2-ones

Claims (3)

1. Process for the preparation of 3-pyrrolin-2-ones of the general formula I in the
R¹ is hydrogen or alkyl, cycloalkyl, aralkyl or aryl radicals and
R² and R³ denote one of the radicals R¹ or carboxyl, alkoxycarbonyl or halogen radicals,
characterized in that a 3-formyl carboxylic acid or its ester of the general formula II in which R⁴ is one of the radicals R¹, reacted with ammonia or an amine of the general formula IIIR¹-NH₂ (III). 2. The method according to claim 1, characterized in that the radicals R² and R³ in process products I and the starting compounds II for hydrogen, methyl, ethyl, cyclohexyl, benzyl, phenyl, Methoxycarbonyl or chlorine are available.   3. The method according to claim 1 or 2, characterized in that the rest R¹ in process products I and the starting compounds III Means hydrogen.