CH671762A5 - - Google Patents

Description

671,762

2

DESCRIPTION

1. Process for the preparation of a compound of general formula

(I)

in which R1 represents a hydrogen atom or an optionally substituted alkyl or cycloalkyl group, R2 has an optionally substituted alkyl or cycloalkyl group, R3 and R4 each independently represent an optionally substituted alkyl or cycloalkyl group and R5 and R6 each independently represent a group alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl optionally substituted, characterized by the reaction of a hydrazone of general formula

(II)

The present invention relates to the preparation of certain substituted derivatives of dihydropyridine and pyridine and of new dihydropyridines themselves. These compounds are useful as intermediates for the preparation of pyridyl imidazolinones having herbicidal activity.

Pyridyl imidazolinones have been described as herbicides and plant growth regulators in various documents. For example, EP-A-4I623 describes a wide range of compounds and their use as herbicides, while EP-A-41624 describes their use as agents for controlling plant growth. Among the compounds specifically described by each of these specifications are 2- (5-isopropyl-5-methyl-4-oxo-2-imida-zolin-2-yl) -5-ethyl-nicrotinic acid and acid 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) -5-methyl-nicotinic.

EP-A-95105 teaches that such pyridyl imidazolinones can be prepared by synthesis from 2,3-pyri-dine carboxylic anhydrides and it is known that the dicarboxylated compounds from which these anhydrides are easily prepared can themselves be prepared by subjecting quinolines to oxidizing conditions.

EP-A-161221 teaches that compounds of formula A

i

/NOT

'2 \ 4

R R

with a dicarboxylate of general formula

/ COjR5

vs

III

NxjjR6.

(III)

2. Method according to claim 1, characterized in that R1 represents a hydrogen atom and each of R2 to R5 represents an alkyl group in CM.

3. Method according to claim 2, characterized in that each of R3 to R6 represents a methyl group and R2 represents a methyl or ethyl group.

4. Method according to one of the preceding claims, characterized in that the hydrazone is in molar excess relative to the dicarboxylate.

5. Method according to one of the preceding claims, characterized in that the reaction takes place in an inert organic solvent in the range of 50 ° C at reflux temperature.

6. Process for the preparation of a compound of general formula

(IV)

characterized by deamination of a compound of formula I obtained by the process according to claim 1.

7. Compound of general formula I, obtained by the process according to one of claims 1 to 3.

8. Compound of general formula IV, obtained by the process according to claim 6, with the exception of the diethyl ester of 5-methyl-2,3-pyridinecarboxylic acid.

HORN,

HORN.

(AT)

30

can be prepared by reacting a hydrazone of formula B with a maleic acid derivative of formula C to form a compound of formula D

35

CH

(1

CH

/

\\ NOT

(B)

X-C II HC \

CO-R3

(VS)

"X * 3

AT

* 9 "10

HORN,

fl

CH

* He

CH C-COR,

\ / 4

# 1

NOT / \

* 9 * 10 -

(D)

from which H-NR9R10 is eliminated. A wide range of possibilities is claimed for the R portions! to R10.

The X portion of the compounds of formula C is a chlorine or bromine atom, so that the reaction produces the di-50 hydropyridyl compounds D. The presence of a base is indicated as preferable, and is used in all the examples, to fix the hydrochloric or hydrobromic acid formed. Deamination is carried out by using an acid in dioxane.

In the compounds of examples of EP-A-161221, the groups R3 55 and R4 always represent a combined portion, which is usually a group of formula ^ N — R, R usually being a phenyl, alpha-cyanoalkyl or alpha-carbamoylalkyl group . In one example, the combined portion is an oxygen atom. EP-A-161221 also aims to provide the 2,3-pyridine carboxyli-60 anhydrides from which the pyridyl imidazolinones can be prepared. The manner in which these anhydrides are prepared, according to EP-A-161221, involves the decyclization of the pyridylic compounds derived by deamination of the compounds of formula D in which R3 and R4 jointly represent a group of formula —R, with 65 loss of the compound R— NH2, to form dicarboxylated compounds, this being followed by dehydration.

The compounds of formula C necessary for the reactions described in EP-A-161221 must themselves be prepared by syn-

3

671,762

thesis, and this can be done by treatment of maleic anhydride with a compound of formula R-NH2, followed by treatment with acetic anhydride and then halogenation (see EP-A-41624).

The present invention relates to a simple process for the preparation of dihydropyridines, from which such 2,3-pyridine carboxylic anhydrides can be easily prepared.

According to the present invention, there is provided a process for the preparation of a compound of general formula

(I)

in which R1 represents a hydrogen atom or an optionally substituted alkyl or cycloalkyl group, R2 has an optionally substituted alkyl or cycloalkyl group, R3 and R4 each independently represent an optionally substituted alkyl or cycloalkyl group and R5 and R6 each individually represent a group alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl optionally substituted, which comprises the reaction of a hydrazone of general formula ai)

NOT*

i

/NOT

'3 M R R

with a dicarboxylate of general formula

/ C02R5

vs

III

\ n6.

(III)

While the prior art provides a method of preparing 2,3-pyridine carboxylic anhydrides which requires a large number of steps from maleic acid anhydride, including in particular the formation of a cyclic compound containing a group N — R, halogenation, base catalyzed addition, acid catalyzed deamination and decyclization of the resulting compound with loss of the R — NH2 compound, the present invention provides a simple and direct route to these compounds which does not require not halogenation, the use of a base or a decyclization step with resulting loss of material.

According to the process of the present invention, an alkyl, alkenyl or alkynyl group preferably has 1 to 6, especially 1 to 4 carbon atoms, while a cycloalkyl group preferably has 3 to 8 carbon atoms. An aryl group is preferably a phenyl group and an aralkyl group is preferably a benzyl group. When a group is substituted, possible substituents may include, for example, halogen atoms, alkoxy or haloalkoxy groups in CM and hydroxy, cyano, amino, alkyllamino, phenyl, phenoxy, carboxy and alkoxycarbonyl groups. In general, however, unsubstituted groups are preferred for each substituent R2 to Ra, and preferably unsubstituted CM alkyl groups, methyl and ethyl groups being particularly preferred, while Rx is preferably a hydrogen atom .

Preferably, the reaction takes place in an inert organic solvent, such as tetrahydrofuran, acetonitrile or dioxane, or conveniently an alkylated benzene such as toluene or xylene. The reaction can take place in the range of 0 ° C at reflux temperature (which can be suitably between 70 ° C and 140 ° C depending on the solvent used) and advantageously takes place in the range of 50 ° C at the reflux temperature, in particular at the reflux temperature.

It is preferred that the hydrazone is in molar excess relative to the dicarboxylate, although the reaction may develop sufficiently if this is not the case. In general, a preferred molar ratio of hydrazone to dicarboxylate is between 1: 1 and 2: 1, especially between 1: 1 and 1.5: 1.

According to another aspect, the invention relates to compounds of formula I themselves.

A compound of general formula I can be transformed into a Pyridine of general formula

(IV)

under deamination conditions. Preferably, the reaction takes place in an inert organic solvent, such as benzene, toluene or xylene, in the presence of a catalyst such as palladium or platinum, which can conveniently be deposited on a carbon support. wood. Preferably, the reaction takes place at elevated temperature, suitably in the range of 50 ° C at reflux temperature, preferably at reflux temperature.

In another aspect, the present invention relates to the novel pyridines themselves, with the exception of the diethyl ester of 5-methyl-2,3-pyridine dicarboxylic acid.

The compounds of general formula IV can be used to produce pyridyl imidazolynic compounds having herbicidal activity, for example by converting them, in aqueous sodium hydroxide, into corresponding dicarboxylic acids, by converting the acids into their anhydrides. acid, suitably by refluxing the acids in the presence of acetic anhydride, and then by the methods described in EP-A-95105.

The invention will now be further described with reference to the following 45 examples.

Example 1

Preparation of 4H-1-dimethylamino-2,3-dicarboxy-5-methyldihydropyridine dimethyl ester

Dimethyl acetylene dicarboxylate (17.3 g; 0.122 mole) and 2-methylprop-2-enal dimethylhydrazone (15.0 g; 0.134 mole) were added to 20 ml of anhydrous toluene. The reaction mixture was heated to reflux under a nitrogen atmosphere for 1 hour. The solvent was removed by evaporation. Column chromatography on silica using 35-40% (v / v) ethyl acetate / n-hexane as the eluent gave the title compound as a yellow oil (6.9 g ) which crystallized on cooling (melting point around 50 ° C).

Analysis:

Calculated: C56.7 H 7.1 N11.0%

Found: C 56.5 H 7.2 N11.0%

60

Example 2

6S Preparation of 4-H-1-dimethylamino-2,3-dicar-boxy-5-ethyldihydropyridine dimethyl ester

Dimethyl acetylene dicarboxylate (20.5 g; 0.144 mole) and 2-ethylprop-2-enal dimethylhydrazone (20.0 g; 0.159 mole) have

671762

4

added to 25 ml of anhydrous toluene. The reaction mixture was heated at reflux for 1 hour. The solvent was removed by evaporation. Column chromatography on silica using 40.5% (v / v) ethyl acetate / n-hexane as the eluent gave the title compound as an orange oil (7.7 g ). 5

Analysis:

Calculated: C58.2 H 7.5 N 10.4%

Found: C 56.8 H 7.7 N 9.6%

Example 3 10

Preparation of 2,3-carboxy-5-methylpyridine dimethyl ester

The tire compound of Example 1 (6.5 g) was dissolved in 50 ml of anhydrous toluene and 0.6 g of catalyst 5% by weight of palladium on charcoal was added. The reaction mixture was heated at reflux for 14 hours with replenishment of catalyst every 2 hours. The reaction mixture was filtered and the solvent was evaporated to leave a reddish-brown oil (7.0 g). Column chromatography on silica using 40% (v / v) ethyl acetate / n-hexane as the eluent gave the title compound (3.35 g) as a solid , melting point 59-60 ° C.

Analysis:

Calculated: C 58.9 H 3.1 N 8.6% '25

Found: C 58.7 H 3.7 N 8.0%

Example 4

Preparation of 2,3-dicarboxy-5-ethylpyridine dimethyl ester

The title compound of Example 2 (7.45 g) was dissolved in 75 ml of anhydrous toluene and 0.75 g of catalyst 5% by weight of palladium on charcoal was added. The reaction mixture was heated at reflux under a nitrogen atmosphere for 21 hours, with replenishment of catalyst after 17 and 19 hours. The reaction mixture was filtered and the solvent was evaporated. Column chromatography of the resulting oil (6 g)

on silica using 35-40% (v / v) ethyl acetate / n-hexane gave the title compound as an orange oil (3.4 g).

Analysis:

Calculated: C 59.2 H 5.8 N 6.3%

Found: C57.8 H 5.8 N6.5%

When the above procedure was repeated, 3.49 g of the title compound was produced from 6.4 g of starting material.

The following example shows how a compound of formula IV can be transformed into an acid anhydride, which can be used for the synthesis of a pyridyl imidazolinic compound of EP-A-95105.

Example 5

Preparation of 2,3-carboxy-5-methylpyridine anhydride

The title compound of Example 3 (7.95 g) was added to a 10% by weight aqueous sodium hydroxide solution (35 ml). The reaction mixture was heated at reflux for 1.5 hours and cooled. Concentrated hydrochloric acid was added until the pH of the reaction mixture was 2. A pale brown precipitate which formed on cooling was separated by filtration and dried (2.15 g). Hydrochloric acid was added further until the pH was 1. The additional precipitate which formed (0.95 g) was separated by filtration and dried.

The 2.15 g precipitate (2,3-dicarboxy-5-methylpyri-dine) was dissolved in acetic anhydride (35 ml; density 1082 g / 1). The reaction mixture was heated at reflux for 2.5 hours. The acetic anhydride was separated first by evaporation and then by a hot water bath and a vacuum pump, leaving a pale gray solid.

Analysis:

Calculated: C58.9 H 3.1 N8.6%

Found: C58.7 H 3.7 N8.0%

R