BACKGROUND OF THE INVENTION 0001 The present invention relates to an improved process for preparing substituted pyridines by oxidation (i.e., aromatization) of the corresponding 1,4-dihydropyridines. 0002 Substituted pyridines are important products for the preparation of pharmaceutics, crop protection agents and dyes. 0003 A large number of oxidizing agents, for example, supported iron nitrates and copper nitrates, if appropriate with the action of ultrasound, cerium ammonium nitrate, pyridinium chlorochromate, nitric acid, and nitrogen monoxide (see J. Org. Chem., 62, 3582 (1997) are known to be suitable for oxidizing (i.e., aromatizing) 1,4-dihydropyridines. Some of these oxidation methods are expensive, others require complicated apparatus and safety precautions, and others require ecologically objectionable oxidizing agents. The nitrogen monoxide recommended in the above literature reference for use as oxidizing agent must be handled under argon since it reacts with atmospheric oxygen and is expensive. According to J. Med. Chem., 29, 1596 (1986), the oxidation is carried out using nitric acid, but large amounts of nitric acid are required (12 ml of aqueous nitric acid for 0.66 g of starting material), and the product must be isolated by three extractions with ether. 0004 To prepare 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)pyridine, it is known to oxidize the corresponding 1,4-dihydropyridine with sulfur (see U.S. Pat. No. 4,950,675). In addition to the problematic handling of sulfur, this process has the major disadvantage that yields of only considerably less than 40% are possible and that highly toxic hydrogen sulfide is formed as by-product. 0005 Thus, there is currently no process that is easy to carry out and cost-effective and gives high yields for preparing substituted pyridines by oxidation of the corresponding 1,4-dihydropyridines.

SUMMARY OF THE INVENTION 0006 This invention accordingly provides a process for preparing substituted pyridines of formula (I) 1

0007 wherein 0008 R1 and R5 are identical or different and each represents C1-C10-alkyl or C6-C10-aryl, 0009 R2 and R4 are identical or different and each represents hydrogen, C1-C10-alkyl, CN, or COOR6 wherein R6 is C1-C10-alkyl, and 0010 R3 represents hydrogen, C1-C10-alkyl or represents C6-C10-aryl that is optionally substituted by halogen, nitro, COOR6 (wherein R6 is C1-C10-alkyl), CN, or C1-C10-alkyl, 0011 comprising reacting a substituted 1,4-dihydropyridine of formula (II) 2

0012 wherein R1 to R5 are as defined for formula (I), with methyl nitrite in the presence of an acid containing less than 20% by weight of oxidizing components.

DETAILED DESCRIPTION OF THE INVENTION 0013 In formulas (I) and (II), R1 and R5 are preferably identical and each preferably represents straight-chain or branched C1-C6-alkyl; R2 and R4 are preferably identical, and each preferably represents COOR6 wherein R6 is straight-chain or branched C1-C6-alkyl; and R3 preferably represents fluorine- and/or chlorine-substituted phenyl. 0014 In formulas (I) and (II), R1 and R5 particularly preferably represent isopropyl; R2 and R3 particularly preferably represent COOR6 wherein R6 is methyl or ethyl; and R3 particularly preferably represents 4-fluorophenyl. 0015 The methyl nitrite that is required can be prepared in a simple known manner by reacting alkali metal nitrites with methanol in the presence of a strong acid. In this preparation method, the methyl nitrite is obtained in gaseous form and can be used in this form for the process according to the invention. It is advantageous to use at least the amount of methyl nitrite that is stoichiometrically required. Even relatively large excesses of methyl nitrite do not interfere with the reaction. Preference is given to using from 1 to 20 mol of methyl nitrite per mole of 1,4-dihydropyridine of formula (II). 0016 A very wide variety of mineral and carboxylic acids are suitable for use as acids. Preference is given to using gaseous hydrogen chloride, aqueous hydrochloric acid, aqueous sulphuric acid and C1-C4-carboxylic acids in substance or as aqueous solution. 0017 The amount of acid can be varied within relatively wide limits. It is possible, for example, to use catalytic, stoichiometric, or superstoichiometric amounts of acid. Preference is given to using from 0.01 to 2 mols of acid per mole of 1,4-dihydropyridine of formula (II). It is also possible to use mixtures of different acids. Carboxylic acids can also act as solvent and therefore can be set in in higher molar ratios, for example up to 50 mols, preferably up to 30 mols per mol of 1,4-dihydropyridine of the formula (II). 0018 The acid to be used contains less than 20% by weight of oxidizing components. Oxidizing components can be, for example, nitric acid or salts having oxidizing action. The content of oxidizing components in the acid is preferably below 5% by weight. Particularly preferably, the acid is free of oxidizing components. 0019 The 1,4-dihydropyridine of formula (II) can also be employed in the form of 1,4-dihydropyridinium salts of non-oxidizing acids, for example, in the form of 1,4-dihydroxypyridine hydrochlorides. In such cases, it is possible to dispense with the separate addition of an acid. 0020 If the acid is used in the form of an aqueous solution in such an amount that the reaction mixture forms a suspension or solution that is easy to stir, it is not necessary to add other solvents. Otherwise, it is expedient to add solvents. Suitable solvents are those that do not take part in any undesirable side reactions. Examples are water, aromatic hydrocarbons such as toluene, alcohols such as methanol, ethers such as dibutyl ether, halogenated hydrocarbons such as dichloroethane and chlorobenzene, sulfoxides such as dimethyl sulfoxide, and sulfones such as tetramethylene sulfone. Carboxylic acids can also act as solvent (see above). 0021 If appropriate, the solvents are added in such amounts that the reaction mixture forms a suspension or solution that is easy to stir. 0022 The process according to the invention can be carried out in different ways. For example, the 1,4-dihydropyridine of formula (II) can be suspended or dissolved in a solvent, followed by addition of the acid and introduction of gaseous methyl nitrite. It is also possible to admix the 1,4-dihydropyridine of formula (II) with such an amount of an aqueous solution of the acid that a readily stirrable suspension or solution is formed and then to introduce gaseous methyl nitrite. It is also possible to meter in the acid simultaneously but separately from the methyl nitrite. 0023 Furthermore, it is also possible, for example, to suspend 1,4-dihydropyridine of formula (II) in water and then to introduce gaseous hydrogen chloride and then methyl nitrite. Other ways of carrying out the process according to the invention are also feasible. 0024 Suitable reaction temperatures for the process according to the invention are, for example, between 30 and 100 C., in particular from 10 to 65 C. 0025 The reaction mixture that is present after the reaction has ended can be worked up in a simple manner. If the reaction has been carried out substantially in aqueous medium, the reaction mixture can first be neutralized using any base, and the substituted pyridine of formula (I) that has been prepared can then be separated off, for example, by filtration. 0026 If the reaction has been carried out substantially in alcoholic medium or in another water-miscible solvent, water can, after neutralization with any base, be added to the reaction mixture, and the substituted pyridine of formula (I) that has been prepared can be separated off, for example, by filtration. 0027 If the reaction has been carried out in a water-immiscible medium, some or all of the solvent can, following neutralization with any base, be removed from the reaction mixture, thus giving the substituted pyridine of formula (I) that has been prepared. 0028 Other simple alternatives for working up the reaction mixtures are also feasible. 0029 The base used for neutralizing the reaction mixture can be any base that does not take part in undesirable side reactions. Suitable bases are, for example, aqueous lyes, alkoxides as such or in alcoholic solution, and amines. If the reaction is carried out in aqueous medium, preference is given to using aqueous lyes. If the reaction is carried out in an alcoholic medium, preference is given to alkoxides. 0030 In cases where carboxylic acids are set in the neutralization can be omitted. 0031 The process according to the invention has a number of advantages. Thus, the obtainable yields, which are generally between 90 and 99% of theory, are high, the practice is simple, the methyl nitrite can be prepared in a simple manner as required, no ecologically objectionable heavy metal salts are used for the oxidation and, as a consequence, no highly toxic by-products are formed, and work-up of the reaction mixture is simple.

EXAMPLES

Example 1

Not According to the Invention 0032 The methyl nitrite used in the examples below was prepared as required by treating a solution of I part by weight of 25% by weight strength of aqueous sodium nitrite solution and 0.14 part by weight of methanol with 0.37 part by weight of 48% by weight strength aqueous sulfuric acid and used in gaseous form for the oxidation (i.e., aromatization) according to the invention of substituted 1,4-dihydropyridines of formula (II).

Example 2 0033 In a 4 liter glass reactor, 750 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)-1,4-dihydropyridine were initially charged in 2250 g of water and 207 g of 37% by weight strength of aqueous hydrochloric acid. 15 mol of methyl nitrite were then introduced at 60 C. After cooling to 20 C., the pH was adjusted to pH 8 using 198 g of 45% by weight strength of aqueous sodium hydroxide solution. The resulting suspension was filtered and the product that had been filtered off was washed twice with in each case 800 ml of water and then dried at 55 C. under reduced pressure. 736 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)pyridine were isolated, which corresponds to a yield of 98% of theory.

Example 3 0034 In a 2 liter glass reactor, 375 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)-1,4-dihydropyridine were dissolved in 711.6 g of methanol at 5 C. 4 g of gaseous hydrogen chloride and 2 mol of methyl nitrite were then introduced at from 3 to 10 C. After warming to 20 C., the mixture was neutralized by adding 19.5 g of 30% by weight strength of methanolic sodium methoxide solution. The solution was heated to boiling and then admixed with 170 g of water. After cooling to 5 C., the resulting suspension was filtered and the product that had been filtered off was washed twice with in each case 400 ml of methanol/water (1:4) and then dried at 55 C. under reduced pressure. This gave 338 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)pyridine, which corresponds to a yield of 90.5% of theory. 0035 Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.

Example 4 0036 In a 4 l glass reactor, 750 g 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxy-carbonyl)-1,4-dihydropyridine were mixed with 2250 g water and 245 g of acetic acid. Thereafter 7 mols of methyl nitrite were introduced at 58 to 60 C. After cooling to 20 C. 363 g of 45% by weight strength aqueous sodium hydroxide were added to result in an increase of the pH up to 9. The resulting suspension was filtered and the product that has been filtered off was washed twice with in each case 800 ml of water and then dried at 50 to 60 C. under reduced pressure. 708 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxy-carbonyl)-pyridine were isolated, which corresponds to a yield of 95% of theory.

Example 5 0037 In a 4 l glass reactor, 750 g 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxy-carbonyl)-1,4-dihydropyridine were mixed with 1470 g water and 1470 g of acetic acid. Thereafter 7 mols of methyl nitrite were introduced at 58 to 60 C. After cooling to 20 C. the resulting suspension was filtered and the product that has been filtered off was washed twice with in each case 800 ml of water and then dried at 50 to 60 C. under reduced pressure. 643 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxy-carbonyl)-pyridine were isolated, which corresponds to a yield of 86% of theory.