DD154537A1 - PROCESS FOR THE PREPARATION OF 3,6-DISUBSTITUTED 2,4-DIHALOGEN PYRIDINES - Google Patents

Abstract

Substituted dihalopyridines are particularly useful as intermediates for the preparation of 5-substituted pyridine-2-carboxylic acids having antihypertensive activity of Intresse.D. Previously known processes for their preparation are carried out as pressure reactions or in the presence of basic nitrogen compounds a technically simple and economical method of synthesis such compounds having the general formula I in the R hoch1 hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aralkyl, aryl, halogen, nitro, cyano, alkoxy, aryloxy, alrylthio, carboxyl and carbalkoxy and R hoch2 Hydrogen and alkyl mean to produce in high yield, compounds of the general formula II in the R 1 and R 2 high have the meaning given, with Phorphoroxyhalogeniden invention in the presence of acid amides, such as DMF, dimethylacetamide, dimethylbenzamide, N-formyl-morpholine , implemented without pressure.

Description

2 1 A 6 7 6 -ι-

Title of the invention

Process for the preparation of 3,6-disubstituted 2,4-dihalo-pyridines

Field of application of the invention

The invention relates to a process for the preparation of 3,6-disubstituted 2,4-dihalopyridines. These compounds are intermediates for the manufacture of medicines and pesticides. They are particularly suitable for the preparation of 5-substituted pyridine-2-carboxylic acids, which are distinguished by an intensive and long-lasting hypotensive action. The preparation of such pyridine-2-carboxylic acids via 3,6-disubstituted 2,4-dihalo-pyridines has not attained any practical significance because of the considerable lack of the known synthesis of these intermediates.

Characteristic of the known technical solutions

It is known to represent pyrid-2-ones and pyrid-4-ones by the action of halogenating agents, in particular phosphorus halides, halopyridines (E. Klingsberg, Pyridine and its derivatives, Interscience Publishers, Inc., New York 1960, Part II, p 326-334 and pp 646-651; RA Abramovitch, Pyridine and its derivatives, Dobn- Wiley and Sons, Inc., New York-London-Sydney-Toronto 1974, Supplement Part 2, pp. 407-488, and Supplement Part 3, S. 784 to 793. The transfer of these pyridones in

₂ 2 14 6 76

the corresponding halogen compounds are, apart from special cases of strong steric hindrance, usually in good yields.

Suitable halogenating agents are a number of compounds such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride , phosphorus tribromide, phosphorus oxybromide, phosphorus pentabromide, phenylphosphonic dichloride, thionyl chloride or phosgene. The implementation oer 4-hydroxy-pyrid-2-one with these halogenating agents to the corresponding Dihalogenpyridinen prepares, however, difficulties.

It is also known to carry out the reaction between hydroxypyridones and halogenating agents with the aim of increasing the yields of dihalopyridines under pressure, in solvents or in the presence of free amines. The execution of the reaction as a pressure reaction requires a considerable technical and economic effort for autoclaves, which are suitable for working with the said aggressive halogenating agents, especially under industrial conditions, as well as extensive safety measures. Nevertheless, the goal of a high yield is only partially achieved, and as a rule a strongly gummed product is obtained at the high reaction temperatures used.

Thus, Sn-butyl, for example, ^ -hydroxy-ö-methyl-pyrid-2-one is heated with phosphorus oxychloride in a sealed tube at 180 ° to 200 ⁰ C (K. Schreiber, and G. Adam, Chem. Ber. 93, 1848 (I960) ). The yield of 3-n-butyl-2,4-dichloro-6-methyl-pyridine, despite complex apparatus operation, is only 51%. In addition, there is a large amount of tarry products which makes the work-up extraordinarily aggravating (H. Mayer, Vol. Dissertation, TH Karlsruhe 1967, p. 3).

An additional economic and technical burden means the use of solvents.

For the reaction of hydroxypyridones with phosphorus oxychloride and oxybromide, the addition of basic nitrogen compounds

3 2 14 6 76

compounds, in particular tertiary amines, proposed in order to avoid working in an autoclave and in order to be able to convert certain pyridones into the dihalogen compounds in the first place with usable yields; see DE-PS 2 127 521, 2 305 045, 2 307 444, US-PS 2 742 478. However, this procedure also has a number of disadvantages. The use of free amines in the required large quantities is associated because of their toxicity and flammability with appropriate, the procedure burdening labor and fire safety measures. In addition, the addition of free amines to the reaction mixture containing phosphorus halides entails operational risks as a result of an exothermic reaction. Since this procedure is aimed at increasing the boiling point of the reaction mixture by addition of the amine to temperatures at which high yields are achieved under the chosen conditions even without the use of pressure vessels, the use of high-boiling expensive amines is a condition. However, the beneficial effect of adding these basic nitrogen compounds is apparently limited to certain hydroxypyridones. Thus, for example, when 2,3-D-ichloro-4-hydroxypyrid-6-one is heated with phosphorus oxychloride in the presence of N, N-dimethylaniline, only one chlorine is introduced to form 2,3,6-trichloropyrid-4 on (OA Elvidge and NA Zaidi, 0. ehem. Soc. (C) 1968 , 2188).

, In contrast to the described, sometimes extremely difficult reaction conditions in the synthesis of the dihalogen compounds, the preparation of monohalogenopyridines according to A. Signor et al., (Gazz, Chim., Ital., 93 (1963) 65) proceeds by reacting certain pyridones, such as 3-nitropyridine. 2- or 4-one, with the usual halogenating agents, regardless of the presence of other additives, such as dimethylformamide, but without limitation in good yields, so that the use of such additives for an advantageous reaction in the halogenation of pyridones generally and especially hydroxypyridones not was clearly visible. in the

214 6 76

On the contrary, the teaching of DD-PS 80 209 clearly indicates that the halogenation reaction to form 2-chloronicotinic acid from nicotinic acid N-oxide and phosphorus oxychloride in the presence of triethylamine leads to significantly higher yields of the target product than in the presence of dimethylformamide or the case is ·

Object of the invention

It is an object of the invention to provide a technically simple and economical method of synthesis for the production of disubstituted dihalopyridines, wherein both the use of pressure vessels and the use of additional organic solvents and basic nitrogen compounds avoided and beyond the yield of the target products is increased.

Explanation of the essence of the invention

This object is achieved by a process for the preparation of 3,6-disubstituted 2,4-dihalopyridines of general formula I

in the mean

X are identical or different halogens, such as chlorine or bromine R is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl having 1 to 10 carbon atoms, aryl, halogen, nitro, cyano, alkoxy, aryloxy, alkylthio, arylthio, carboxyl and carbalkoxy, wherein the hydrocarbon radicals alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl are optionally substituted by substituted amino or aryl groups, halogen, nitro, cyano, alkoxy, aryloxy, alkylthio, arylthio, carboxyl and carbalkoxy

and 2 ·

R is hydrogen and alkyl having 1 to 4 carbon atoms

.214676

by halogenation of 3,6-disubstituted 4-hydroxypyrid-2-ones of the general formula II

Dft '· -

12 in which R and R have the abovementioned meaning,

with phosphorus oxyhalides, according to the invention, the halogenation reaction at atmospheric pressure in the presence of |

Acid amides of the general formula III V

 ,8th*

in the mean

3 R is hydrogen, alkyl having 1 to 4 carbon atoms and aryl, which is optionally substituted

R and R are alkyl having 1 to 4 C atoms, wherein R and R together may also represent an alkylene radical having 4 to 6 C atoms, internally methylene groups optionally substituted by oxygen or the imino radical, and aryl which is optionally substituted,

is carried out"

The halogenating agents used are the phosphoroxyhalides phosphorus oxychloride and phosphorus oxybromide, which are optionally used with an addition of phosphorus trichloride, phosphorus pentachloride and phosphorus tribromide.

Suitable acid amides of the general formula III are, for example, dimethylformamide, N-formylmorpholine, N-formylpiperidine, dimethylacetamide, N-methylformanilide, N, N-dimethylbenzamide U, a. as well as their mixtures in question ·

The reaction of the 3,6-disubstituted 4-hydroxy-pyrid-2-ones with the halogenating agents takes place in the presence of

Compounds according to formula ILI suitably by heating to temperatures between 70 ° · and 150 ⁰ C, preferably 90 ° to 130 ° C. The halogenating agents are used in an equivalent amount or in excess, wherein the excess also serves as a solvent and can be recovered easily after completion of the reaction conveniently by vacuum distillation. An amount of from 2 to 6 mol of halogenating agent per mole of hydroxypyridone is favorable. While the preferred mode of operation is to use excess halogenating agent as the solvent, on the other hand, the addition of inert organic solvents of suitable boiling point, for example, alkylaromatics such as toluene and xylenes, chlorobenzene and dichlorobenzene, is not excluded and can be optionally realized.

The acid amides according to formula III or mixtures thereof are used in amounts of from 0.1 to 3 mol, preferably from 1 to 2 mol, per mole of 4-hydroxy-pyrid-2-one. In most cases, the use of significantly more than 2 mol of the compound of formula III per mole of 3,6-disubstituted 4-hydroxy-pyrid-2-one not only leads to no increase in yield, but due to partial resinification of the reaction mixture to a decrease in yield ,

The conversion to the dihalopyridines according to formula I is carried out by heating the component mixture at the defined reaction temperatures until the end of the halogenation. It is also possible first to react hydroxypyridone and halogenating agent to form corresponding hydroxypyridone halophosphoric acid esters until the hydrogen halide elimination is complete, then to introduce acid amide according to formula III and to continue the reaction to give the desired dihalopyridines. The addition of hydroxypyridone to the optionally heated mixture of halogenating agent and compound of formula III is feasible.

After completion of the reaction, the workup of the reaction mixtures to obtain the Dihalogenpyridine carried out in the usual manner. Generally applicable is the treatment of the

7 2 14 6 7 6

Reaction mixtures with ice, expediently after distillative removal of excess halogenating agent, and isolation of the dihalopyridine by filtration or extraction, if appropriate after setting a favorable for the separation of the product ρ ,, - value.

Compared with the known methods which dictate the operation under pressure and the addition of basic nitrogen compounds for the preparation of dihalopyridines, the process according to the invention surprisingly has a number of decisive technical and economic advantages.

The beneficial effects of the addition of the non-basic compounds of general formula III in the synthesis of 3,6-disubstituted 2,4-dihalo-pyridines are therefore surprising, aa the representation of 2,4-dihalogeno compounds even by addition of basic nitrogen compounds only partially could be improved.

Also from the running in very good yields known overhead of certain pyridones by halogenating agent in the presence of dimethylformamide in Monahalogenpyridine was not to conclude on the decisive favorable influence of the acid amides according to formula III in the synthesis of 3,6-disubstituted 2,4-dihalo-pyridines since the abovementioned monohalogenopyridines are also formed without the addition of dimethylformamide in very high yields.

The decisive favorable influence, which is brought about by the addition of the compounds according to formula III with respect to the increase in yield anpihalogenpyridinen according to the inventive method is also insofar as far as not predictable estimate, as is known, the acid amide dimethylformamide in the case of Her- ' Position of 2-chloronicotinic acid from nicotinic acid-N-oxide and phosphorus oxychloride over oer basic nitrogen compound triethylamine has shown significantly weaker in its respective effect. ·

8 214676

Last but not least, the high yield increase of 3,6-disubstituted 2,4-dihalogenopyridines by acid amides according to formula III is also surprising because the pyridones themselves form cyclic cyclic acid amides and thus exert an autocatalytic action. The ability to work according to the inventive method without using pressure vessels in conventional equipment, eliminates a number of hazards and brings significant economic benefits by eliminating expensive printing equipment and the cost of protective measures.

The use of acid amides of the general formula III in place of basic nitrogen compounds leads not only to significantly higher yields but also to simplified workup of the reaction mixtures since resinous by-products virtually no longer form.

The use of compounds of the general formula III also entails a considerably lower wastewater load because of the substantially smaller amount required in comparison to basic nitrogen compounds.

EXECUTIVE EXAMPLES

Example 1:

To the mixture of 36.2 g (0.2 mol) of 3-n-butyl-4-hydroxy-6-methyl-pyrid-2-one and 110 ml (1.2 mol) of phosphorus oxychloride are added with stirring 7.3 g ( 0.1 mol) of dimethylformamide is added dropwise. It is stirred at H8 ° C for 4.5 hours at reflux. Excess phosphorus oxychloride is distilled off in vacuo and the residue is added to 500 g of ice. It is extracted with methylene chloride, the extract washed with water, dried with magnesium sulfate and distilled. Colorless liquid

. Kp 132 ° to 133 ⁰ C / 8 Torr;

Yield: 33.3 g (76.4%) of 3-n-butyl-2,4-dichloro-6-methylpyridine; C ₁₀ H ₁₃ Cl ₂ N (218.1).

9 2 14 6 76

Example 2:

In the manner described in Example 1, but using 29.2 g (0.4 mol) of dimethylformamide, a yield of 37.6 g (86.2 %) of 3-n-butyl-2,4-dichloro 6-methyl-pyridine obtained ·

Example 3:

The mixture of 36.2 g (0.2 mol) of 3-n-butyl-4-hydroxy-6-methyl-pyridi-2-one and 110 ml (1.2 mol) of phosphorus oxychloride is heated under reflux for 2 hours. 29.2 g (0.4 mol) of dimethylformamide are added dropwise. The mixture is stirred for a further 2.5 hours at 118 C and worked up as described in Example 1.

Yield: 29.8 g (68.3 %) of 3-n-butyl-2'-dichloro-e-methylpyridine.

Example 4:

In the manner described in Example 1, but using 34.9 g (0.4 mol) of dimethylacetamide, a yield of 31.2 g (71.5%) of 3-n-butyl-2'-dichloro-e -methyl pyridine obtained.

Example 5: Comparative Example

The mixture of 10.0 g (0.055 mol) of 3-n-butyl-4-hydroxy-6-methyl-pyrid-2-one and 15 ml (0.164 mol) of phosphorus oxychloride is 5 hours in a bomb tube at 180 ° to 190 ⁰ C. heated. The procedure is as described in Example 1. Colorless liquid. . "Kp 139 ° to 141 ⁰ C / 10 torr;

Yield: 5.7 g (47.5 %) of 3-n-butyl-2,4-dichloro-6-methylpyridine. ,

Example 6: Comparative Example

85.1 g (0.47 mol) of 3-n-butyl-4-hydroxy-6-methylpyrid-2-one and 170 ml (1.86 mol) of phosphorus oxychloride are heated at reflux for 12 hours. It is described as in Example 1

worked up. Colorless liquid · bp. 135 ° to 137 ⁰ C / 10 Torr; Yield: 46.4 g (45.2 %) of 3-n-r-butyl-2-pyridine.

Example 7: Comparative Example

To a mixture of 35.2 g (0.2 mol) of 3-n-butyl-4-hydroxy-6-methyl-pyrid-2-one and 110 ml (1.2 mol) of phosphorus oxychloride are added with stirring 40.5 g Dropped (0.4 mol) of triethylamine. After the exothermic reaction has subsided, the mixture is heated at 123 ° to 125 ⁰ C for 12 hours at reflux and worked up as described in Example 1. Colorless liquid "bp. 137 ° to 140 ⁰ C / 10 Torr; Yield: 21.3 g (48.8 %) of 3-n-butyl-2,4-dichloro-5-methylpyridine.

Claims (2)

invention claim 1 _# Process for the preparation of 3,6-disubstituted 2,4-dihalo-pyridines of the general formula I. in the mean. X are identical or different halogens, such as chlorine or bromine R is hydrogen, alkylcycloalkyl, alkenyl, cycloalkenyl, alkynyl having 1 to 10 C atoms, aryl, halogen, nitro, cyano, alkoxy, .Aryloxy, alkylthio, arylthio, carboxyl and carbalkoxy where the hydrocarbon radicals are alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, optionally substituted by amino or aryl groups. Halogen, nitro, cyano, alkoxy, aryloxy, alkylthio, arylthio, carboxyl and carbalkoxy are substituted and . 2
R is hydrogen and alkyl having 1 to 4 C atoms, by halogenation of 3,6-disubstituted 4-hydroxy-pyrid-2-ones of general formula II 12 in which R and R have the abovementioned meaning, with phosphorus oxyhalides, characterized in that the halogenation reaction at atmospheric pressure in the presence of acid amides of the general formula III in the mean R is hydrogen, alkyl having 1 to 4 carbon atoms and aryl which is optionally substituted,
and R and R are alkyl having 1 to 4 carbon atoms, wherein R and R together also an alkylene radical having 4 to 6 carbon atoms, in which 2 1 Λ 6 76 Can methylene groups are optionally replaced by oxygen or the imino group, showing, and aryl which is optionally substituted, mol with amounts of 0.1 to 3 mol _# preferably between 1 and 2 per mol of compound of general formula II at temperatures ranging between 70 ° and 150 ⁰ C, preferably from 90 ° to 130 ⁰ C, is performed. Process according to item 1, characterized in that phosphorus oxychlorides or phosphorus oxybromide are used as phosphorus oxyhalides.