DE3707530A1 - NEW SUBSTITUTED DIHALOGENPYRIDINE AND METHOD FOR THE PRODUCTION THEREOF AND ITS OTHER IMPLEMENTATION FOR PYRIDINE DICARBONIC ACID DIESTERS - Google Patents

Description

The present invention relates to the manufacture of certain substituted dihydropyridines and pyridine compounds as well as new dihydropyridine compounds per se. Such compounds are valuable as intermediates for the preparation of herbicidally active pyridylimidazolinone compounds.

Pyridylimidazolinone compounds as such and their use as herbicides and regulators for plant growth are disclosed in a wide variety of documents been. For example, EP-A-41 623 discloses publication a variety of such connections and their use as herbicides, while in EP-A-41 624 publication  their use as a regulatory tool for plant growth is indicated. In the above Publications in particular will be the following Compounds revealed: 2- (5-isopropyl-5-methyl-4-oxo 2-imidazolin-2-yl) -5-ethyl-nicotinic acid and 2- (5-isopropyl- 5-methyl-4-oxo-2-imidazolin-2-yl) -5-methyl-nicotinic acid. From EP-A-95 105 publication it is known that such Pyridylimidazolinone compounds from 2,3-pyridinecarboxylic acid anhydrides can be synthesized and it continues it is known that dicarboxylic acid compounds from which such Anhydrides are easily accessible in a simple manner can be made by using quinoline compounds subject to oxidizing conditions.

EP-A-1 61 221 publication claims that Compounds of Formula A below

can be prepared by using a hydrazone Formula B with a maleic acid derivative of the formula C. reacting to form a compound of formula D,

wherein an amine of the formula H-NR ₉ R _{10 is} split off from the last-mentioned compound. A wide range of possible embodiments is disclosed for the meaning of the molecular parts R ₁ to R ₁₀ .

The molecular part X in the compounds of formula C is a Chlorine or bromine to make sure that through the Reaction formed the dihydropyridyl compounds D. will. It is stated that the presence of a Base is preferred and such is also used in all exemplary embodiments used to form the hydrochloric acid formed or to take hydrobromic acid. Deamination is carried out using a Acid carried out in dioxane.

In the compounds of the exemplary embodiments of EP-A-1 61 221 publication, the groups R ₃ and R ₄ each represent a common part of the molecule, which is generally a group of the formula

is
wherein R is usually a phenyl group, an α-cyanoalkyl group or an α-carbamoylalkyl group. In one example, this common part of the molecule is also an oxygen atom. EP-A-1 61 221 is also concerned with making available the 2,3-pyridinecarboxylic anhydrides from which the pyridylimidazolinone compounds can be synthesized. According to the teaching of EP-A-1 61 221 publication, the synthetic route by means of which such anhydrides can be prepared comprises ring opening of the pyridyl compounds formed by deamination of compounds of the formula D, the substituents R ₃ and R in the compounds of the formula D. ₄ together a group of the formula

are, wherein a compound R-NH _{2 is} separated by the deamination. Water is then split off from the dicarboxy compounds thus formed, as a result of which the anhydrides are formed.

The compounds of the formula C required for the reactions as described in EP-A-1 61 221 publication have to be synthesized themselves and this can be done by treating maleic anhydride with a compound of the formula R-NH ₂ and then with Treated acetic anhydride and then halogenated the reaction product (see. EP-A-41 624).

The present invention now provides a simple method for the production of dihydropyridine compounds for Available, which are easily 2,3-pyridinecarboxylic anhydride compounds have it made.

The method according to the invention for producing a compound the general formula

in which R ^{1 represents} a hydrogen atom or an optionally substituted alkyl or cycloalkyl group, R ^{2 represents} an optionally substituted alkyl or cycloalkyl group, each group R ³ and R ⁴ independently of one another represents an optionally substituted alkyl or cycloalkyl group and each group R ⁵ and R ⁶ independently of one another represents an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl group, is characterized in that a hydrazone of the following general formula

with a dicarboxylate compound of formula III below

implements.

While 2,3-pyridinecarboxylic anhydrides according to the prior art are only accessible by means of a procedure, which comprises a plurality of process stages, starting from Maleic anhydride, and among other things the formation of a ring compound with a group

halogenation, a base-catalyzed addition reaction, an acid-catalyzed deamination and a ring opening of the finally obtained compound with the loss of a compound R-NH ₂ , the present invention offers a simple and direct process to such compounds, which neither halogenation nor the use of a base nor requires a ring opening step with loss of material.

According to the process of the present invention, an alkyl, alkenyl or alkynyl group preferably has 1 to 6 and in particular 1 to 4 carbon atoms, while a cycloalkyl group preferably has 3 to 8 carbon atoms. An aryl group is preferably the phenyl group and an aralkyl group is preferably the benzyl group. If a group is substituted, possible substituents include, for example, halogen atoms, C _1-4 alkoxy or halogenoxy groups, the hydroxyl, cyano, amino, alkylamino, phenyl, phenoxy, carboxy and alkoxycarbonyl groups. In general, however, unsubstituted groups are preferred for each substituent R ² to R ⁶ and unsubstituted C _1-4 alkyl groups are preferably used for this, with methyl and ethyl groups being particularly preferred, while R ^{1 is} preferably a hydrogen atom.

The reaction is preferably carried out in an inert organic Solvents such as tetrahydrofuran, acetonitrile or dioxane, or in an alkylated benzene, such as toluene or xylene, carried out. The reaction can take place at a temperature in the range from 0 ° C to the reflux temperature,  the latter suitably in the range of 70 to 140 ° C depending on the solvent used. Especially The reaction at a temperature in the range is advantageous from 50 ° C to the reflux temperature and in particular performed at the reflux temperature itself.

According to a preferred embodiment, the hydrazone used in molar excess over the dicarboxylate compound, although the implementation is also easy can if this condition is not met. Generally a preferred molar ratio of hydrazone is to dicarboxylate in the range from 1: 1 to 2: 1, in particular in the range of 1: 1 to 1.5: 1.

The present invention also relates to those which can be produced in this way Compounds of formula I as such. A connection of formula I can under deaminating conditions also in a simple manner in a pyridine compound of the following general formula to be converted.

Such a reaction is preferably carried out in an inert manner organic solvents such as benzene, toluene or xylene, in the presence of a catalyst, such as palladium or platinum, performed, these precious metals very conveniently Activated carbon is available as a substrate. Preferably the Reaction at elevated temperature, suitably in the range  from 50 ° C to the reflux temperature instead the reflux temperature itself is particularly preferred.

The invention also relates to those which can be produced in this way new pyridine compounds of formula IV with the exception the compound 5-methyl-2,3-pyridinecarboxylic acid diethyl ester.

The compounds of general formula IV can be used are used to prepare herbicidally active pyridylimidazolinyl compounds, for example by placing them in aqueous sodium hydroxide solution to the corresponding dicarboxylic acids then converts these acids into the acid anhydrides transferred, suitably by heating the acids in the presence of acetic anhydride under reflux conditions, and then continue to implement them according to the methods described in the EP-A-95 105 publication.

The invention is illustrated by the examples below explained.

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

17.3 g (0.122 mol) of dimethylacetylene dicarboxylate and 15.0 g (0.134 mol) of 2-methylprop-2-enaldimethylhydrazone become Added 20 ml of anhydrous toluene. The reaction mixture is under under a nitrogen atmosphere for 1 hour Heated to reflux. The solvent is then evaporated. Column chromatography on silica using from 35 to 40% (v / v) ethyl acetate / n-hexane as eluent gives the title compound in an amount of 6.9 g as  yellow oil that crystallizes on cooling (melting point: approx. 50 ° C).

analysis

Theory (%) 56.7 C 7.1 H 11.0 N found (%) 56.5 C 7.2 H 11.0 N

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

20.5 g (0.144 mol) of dimethylacetylene dicarboxylate and 20.0 g (0.159 mol) of 2-ethylprop-2-enaldimethylhydrazone become 25 ml of anhydrous toluene added. The reaction mixture heated to reflux for 1 hour. The solvent will then evaporated. Column chromatography on silica using 40.5% (v / v) ethyl acetate / n-hexane as Eluent gives the title compound in the form of a orange colored oil (yield: 7.7 g).

Analysis:

Theory (%): 58.2 C 7.5 H 10.4 N found (%): 56.8 C 7.7 H 9.6 N

Example 3 Preparation of 2,3-dicarboxy-5-methylpyridine dimethyl ester

6.5 g of the title compound from Example 1 are dissolved in 50 ml anhydrous toluene and then 0.6 g of a Activated carbon containing 6% by weight of palladium Catalyst added. This reaction mixture is heated At reflux for 14 hours, with the catalyst every 2 hours is added. The reaction mixture is then filtered and the solvent is evaporated. There remain  7.0 g of a red-brown colored oil. Column chromatography of silica using 40% (v / v) Ethyl acetate / n-hean as eluent gives 3.35 g of the title compound in the form of a solid body with a melting point from 59 to 60 ° C.

Analysis:

Theory (%): 58.9 C 3.1 H 8.6 N found (%): 58.7 C 3.7 H 8.0 N

Example 4 Preparation of 2,3-dicarboxy-5-ethylpyridine dimethyl ester

7.45 g of the title compound of Example 2 are dissolved in 75 ml anhydrous toluene dissolved and then 0.75 g with one 5% by weight of palladium-loaded activated carbon as a catalyst added. The reaction mixture is under for 21 hours heated to reflux under a nitrogen atmosphere and after 17 or 19 hours, the catalyst is added. The reaction mixture was filtered and the solvent evaporated. Column chromatography on silica using from 25 to 40% (v / v) ethyl acetate / n-hexane results from the 6 g of crude oil obtained the title compound in the form of a orange oil (yield: 3.4 g).

Analysis:

Theory (%): 59.2 C 5.8 H 6.3 N found (%): 57.8 C 5.8 H 6.5 N

When repeating this operation using 4.6 g of the starting material gave the title compound in an amount of 3.49 g.  

The example below explains how to connect the Formula IV further converted to an acid anhydride compound can be used as a starting material for synthesis a pyridylimidazolinyl compound according to EP-A-95 105 Publication can be used.

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

7.9 g of the title compound of Example 3 become 35 ml a 10 weight percent aqueous sodium hydroxide solution added. The reaction mixture is 1 1/2 hours heated under reflux and then cooled. Then you bet concentrated hydrochloric acid until the pH of the Reaction mixture has dropped to 2. When cooling forms a light brown colored precipitate that filters off and dried (yield: 2.15 g). Then it will continue Add hydrochloric acid until the pH is 1. This forms a further 0.95 g of precipitate, which is filtered off and be dried.

The amount of 2.15 g of precipitate (2,3-dicarboxy-5- methylpyridine) in 35 ml of acetic anhydride (density: 1.082 g / l) dissolved. This reaction mixture is 2 1/2 hours heated at reflux for a long time. The acetic anhydride will first by evaporation and then in a hot water bath Vacuum removed. A light gray color remains Solid.

Analysis:

Theory (%): 59.8 C 3.1 H 8.6 N found (%): 58.7 C 3.7 H 8.0 N

Claims (8)

1. A process for the preparation of a compound of the general formula in which R ^{1 represents} a hydrogen atom or an optionally substituted alkyl or cycloalkyl group, R ^{2 represents} an optionally substituted alkyl or cycloalkyl group, each group R ³ and R ⁴ independently of one another represents an optionally substituted alkyl or cycloalkyl group and each group R ⁵ and R ^{6 is} independently an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl group, characterized in that a hydrazone compound of the following general formula with a dicarboxylate compound of the general formula implements. 2. The method according to claim 1, in which R ^{1 is} a hydrogen atom and each of the groups R ² to R ⁵ independently of one another is a C _1-4 alkyl group. 3. The method according to claim 2, characterized in that each of the groups R ³ to R ^{6 represents} a methyl group and R ^{2 represents} a methyl or ethyl group. 4. The method according to any one of the preceding claims, characterized in that the hydrazone in one molar excess over the dicarboxylate is used. 5. The method according to any one of the preceding claims, characterized in that the reaction in one inert organic solvents at a temperature in the Range from 50 ° C to the reflux temperature performed becomes. 6. The method according to any preceding claim, characterized in that the compound of formula I then to a compound of general formula IV is deaminated. 7. A compound according to general formula I, such as defined in any of claims 1 to 3. 8. A compound of general formula IV, as in Claim 6 defines, except for the connection 5-methyl-2,3-pyridinecarboxylic acid diethyl ester.