DD154538A1 - PROCESS FOR PREPARING SUBSTITUTED 2,4 AND 2,6 DIHALOGEN PYRIDINES - Google Patents

Abstract

Substituted dihalopyridines are of particular interest as intermediates for the preparation of 5-substituted pyridine-2-carboxylic acids having antihypertensive activity. The previously known processes for their preparation are carried out as pressure reactions in the presence of basic nitrogen compounds. According to the aim of the invention, by means of a technically simple and economic synthesis method, compounds of the general formula I in which X and Y are in the 4- or 6-position chlorine or bromine and R is high 1 and R is high 2 in 3,5-, 3,6- or 5,6- and 3,4-position identical or different substituents in the series hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aralkyl, aryl, halogen, nitro, cyano, alkoxy, aryloxy, alkylthio, arylthio , Carboxyl and carbalkoxy mean to produce in high yield, compounds of general formula II in which R is high in 4-or 6-position hydroxyl and R is high 1 and R 2 have the meaning given above, with Phosphoroxyhalogeniden invention in the presence of Hydrogen halides of secondary or tertiary amines or the halides of quaternary ammonium bases reacted without pressure.

Description

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Title of the invention

Process for the preparation of substituted 2,4- and 2,6-dihalopyridines

Field of application of the invention

The invention relates to a process for the preparation of substituted dihalopyridines. These compounds are intermediates for the preparation of medicines and pesticides · They are particularly suitable for the preparation of 5-substituted pyridine-2-carboxylic acids, which are characterized by an intensive and long-lasting hypotensive effect. The preparation of such pyridine-2-carboxylic acids via substituted dihalopyridines has hitherto not achieved any practical significance because of the considerable lack of the known synthesis of these intermediates.

Characteristic of the known technical solutions

It is known from pyrid-2-ones and pyrid-4-o> NEN by the action of halogenating agents, in particular Phcsphorhalogeniden. Halphyridines (E. Klingsberg, Pyridine and its Derivatives, Interscience Publishers, Inc. · New York 1960, Part II, pp. 326-334 and pp. 646-651; RA · Abramovitch, Pyridine And Its Derivatives, publisher Oohn Wiley and Sons, Inc., New York-London-Sydney-Toronto 1974, Supplement Part 2, pp. 407-488, and Supplement Part 3, pp. 784-793). The conversion of these pyridones into the corresponding halogen compounds proceeds, except

qn.ψ.) iqvq * Kn9Nt-

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special cases of severe disability, mostly 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. However, the reaction of the 4-hydroxy- and 6-hydroxy-pyrid-2-ones with these halogenating agents to form the corresponding dihalopyridines causes difficulties.

It is also known to carry out the reaction between hydroxypyridones and halogenating agents with the aim of increasing the yields of dihalogen compounds 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 achieved only partially and obtained at the high reaction temperatures usually a strongly gummed product. For example, 3-n-butyl-4-hydroxy-6-methyl-pyrid -2-one with phosphorus oxychloride is heated in a sealed tube at 180 ° to 200 ⁰ C (K. Schreiber, and G. Adam, Chem. Ber. 1848 93_ _t (I960)). The yield of 3-n-butyl-2- _t 4-dichloro-6-methylpyridine is, in spite of complex apparatus operation, only 51 %. In addition, there is a large amount of tarry products which makes the processing extremely difficult (H. Mayer, Dissertation, TH Karlsruhe 1967, p. 3).

An additional economic and technical burden also means the use of solvents. For the reaction of hydroxypyridones with phosphorus oxychloride and oxybromide, the addition of basic nitrogen compounds, in particular tertiary amines, is proposed in order to avoid working in an autoclave and to obtain certain pyridones in the first place with usable yields

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be able to convert into halogen compounds; see: DE-PS 2,127,521, 2 306 045, 2 307 444, US-PS 2,742,478. However, this procedure has a number of disadvantages · The use of free amines in the required large quantities is because of their toxicity and flammability with corresponding costs for work and fire protection measures which burden the procedure. 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 without the use of pressure vessels, the use of high-boiling expensive amines condition. However, this means the exclusion of the particularly cheap, but low-boiling amine trimethylamine. In addition, the beneficial effect of adding basic nitrogen compounds is apparently limited to certain dihydroxypyridines. Thus, for example, when 2,3-dichloro-4-hydroxypyrid-6-one is heated with phosphorus oxychloride in the presence of N, N-dimethylaniline, only one chlorine can be introduced to form 2,3,6-trichloropyrid-4-one (OAElvidge and NA Zaidi, 3rd ed. Soc. (C) 1968 , 2188)).

Object of the invention

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

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Explanation of the essence of the invention

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

in the mean

X in the 2-position and Y in the 4- or 6-position identical or different halogens such as chlorine or bromine

R ¹ and R ² in the 3,5-, 3,6-, 3,4- or 5,6-position are identical or different substituents of the series hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl each 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 can be substituted by halogenation of 4-hydroxy and 6-hydroxy-pyrid-2-ones of the general formula II

1 2 in which R and R have the abovementioned meaning and R is in the 4- or 6-position hydroxyl, with phosphorus oxyhalides, according to the invention the ^ halogenation reaction at atmospheric pressure in the presence of

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Halogen compounds of the general formula III

in which Z "is chloride or bromide and

A, B, C, D are the same or different radicals of the series alkyl having 1 to 20 C atoms, where A and B may together form an alkylene radical having 2 to 7 C atoms, which, if appropriate, including C, 1 to 3 May contain double bonds. Cycloalkyl, aryl, which are optionally substituted by amino groups, halogen, aryl and acyl, and up to two of the radicals A, B, C, D and hydrogen, is carried out.

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

Suitable halogen compounds of the general formula III are non-basic nitrogen compounds in the form of the hydrohalides of secondary and tertiary amines or of the halides of quaternary ammonium bases. The hydrochlorides or hydrobromides of secondary and tertiary aliphatic and cycloaliphatic amines, anilines and heterocyclic amines such as pyridines and quinolines, which may be partially or completely hydrogenated in the core, are suitable. Examples of these are trimethylamine hydrochloride, diethylamine hydrochloride, triethylamine hydrobromide, diisopropylamine hydrobromide, ethylmethylcyclohexylamine hydrochloride, dodecyldimethylamine hydrochloride, N, N-dimethylaniline hydrochloride, pyridine hydrochloride, 2,6-dimethylpyridine hydrochloride, 4-dimethylaminopyridine hydrochloride, N-methylpiperidine hydrobromide, N-ethyl-hexamethyl

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lenimin hydrochloride, quinoline hydrochloride and the hydrochlorides of technical amine, pyridine or Chinolingemische · Furthermore, the chlorides and bromides of the quaternary ammonium \ vie tetraethylammonium chloride, trimethyl-hexylammoniumbromid and tetrabutylammonium bromide can be used.

The reaction of the hydroxypyridones of the formula II with the halogenating agents is conveniently carried out in the presence of the halogen compounds of the formula III by heating to temperatures between 70 and 150 C, preferably 100 to 130 C. The halogenating agents are used in an equivalent amount or in excess, the excess being at the same time serves as a solvent and can be recovered easily after completion of the reaction by vacuum distillation. Conveniently, an amount of 2 to 6 moles of phosphorus oxyhalides per mole of hydroxypyridine. Although the preferred procedure 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 xylene, chlorobenzene and dichlorobenzene, is not excluded and can optionally be realized.

Halogen compounds of the formula III or mixtures thereof are used in amounts of 0.1 to 3 mol, preferably 1 to 2 mol, per mole of hydroxypyridone.

The reaction to form the 2,4- or 2,6-dihalopyridines according to the invention of 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 hydroxypyridone and halogenating agent to form corresponding Hydroxypyridonhalogenphosphorsaureester to complete the elimination of hydrogen halide, then to enter halogen compound according to formula III and continue the reaction to the desired Dihalogenpyridinen.

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 reaction

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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 ρ ,, value for the separation of the product

For the preparation of the dihalopyridines, the same halogen in the halogenating agent and in the added halogen compound according to formula III will generally be chosen. On the other hand, for example in the preparation of dihalopyridines for the hydrogenolytic dehalogenation, unequal halogens can also be used in the abovementioned components and dihalopyridines having different halogen substituents can be prepared.

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

The beneficial effects of the addition of halogen compounds of general formula III are therefore surprising, since an addition of basic nitrogen compounds according to the prior art actually shows certain favorable effects and then expect no positive effects from the nonbasic compounds according to formula III were·

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 halogen compounds of general formula III in place of basic nitrogen compounds also leads to significantly higher yields and simplified work-up of the reaction mixtures, since resinous by-products practically no longer form · the use of said halogenides

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Compounds in place of basic nitrogen compounds allows the use of smaller amounts of this excipient e, of which it is necessary to apply by known method so much that an increase in the boiling point is preferably reached to 150 C.

Further economic advantages are achieved when using the method according to the invention by making it possible to use inexpensive auxiliaries. Thus, the use of the particularly cheap trimethylamine due to d ^ es boiling point according to the conventional procedure of adding basic nitrogen compounds for technical reasons was out of the question. On the other hand, it is now easy to use also triraethylamine hydrohalides, of which due to the low molecular weight in comparison to other hydrohalides in addition much smaller amounts by weight are needed.

While the use of basic nitrogen compounds due to their flammability and their high vapor pressure peculiar safety and toxicological problems, halogen compounds according to formula III are easy and safe to handle.

Exemplary embodiments Example 1

27.8 g (0.2 mol) of 4-hydroxy-3,6-dimethyl-pyrid-2-one are reacted with 110 ml (1.2 mol) of phosphorus oxychloride and 55.1 g (0.4 mol) of triethylamine hydrochloride Stirred at 115 ° to 126 ⁰ C at reflux for 12 hours. Excess phosphorus oxychloride is distilled off in vacuo and the residue is added to 500 g of ice. It is extracted three times with 100 ml of ether, the extract washed with sodium bicarbonate solution, dried with magnesium sulfate and distilled. The residue forms a colorless liquid. Bp 103-106 ° C / 10 Torr;

Yield: 26.0 g (73.7 %) of 2,4-dichloro-3,6-dimethylpyridine; C ₇ H ₇ Cl ₂ N (176.1).

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Example 2:

36.2 g (0.2 mol) of Sn-butyl - ^ - hydroxy-δ-methyl-pyrid ^ -one, 110 ml (1.2 mol) of phosphorus oxychloride and 21.9 g (0.2 mol) of diethylamine hydrochloride are reacted as described in Example 1. It is worked up in the same way · colorless liquid · bp. 135 ° to 140 ° C / 9 Torr;

Yield: 25.4 g (58.2 %) of Sn-butyl - ^^ - dichloro-e-methylpyridine.

^C l0 ^H l3 ^C1 2 ^N i ²¹⁸ ' ¹ ) ·

Example 3:

The mixture of 36.2 g (0.2 mol) of 3-n-butyl-4-hydroxy-6-methylpyrid-2-one, 110 ml (1.2 mol) of phosphorus oxychloride and 38.2 g (0, 4 moles) of trimethylamine hydrochloride is stirred for 12 hours at 115 ° to 126 ⁰ C at reflux. It is worked up analogously to Example 1. After distilling off the solvent, 43.7 g (100 %) of a brownish oil are obtained.

Bp, 136 ° to 138 ° C / 8 torr. Colorless liquid · Yield: 38.6 g (88.5 %) of 3-n-butyl-2,4-dichloro-6-methylpyridine

N (218,1).

Example 4:

The mixture of 36.2 g (0.2 mol) of 3-n-butyl-4-hydroxy-6-raethyl-pyrid-2-one, 110 ml (1.2 mol) of phosphorus oxychloride and 55.1 g (0, 4 mol) of triethylamine hydrochloride is stirred for 12 hours at 126 ° to 130 ⁰ C at reflux. The procedure is as described in Example 1. Colorless liquid. Bp. 136 ° to 140 ° C / 9 Torr;

Yield: 34.6 g (79.3 %) of 3-n-butyl-2,4-dichloro-6-methylpyridine.

N (218,1).

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Example 5:

227 g (1.25 mol) of 3-n-butyl-4-hydroxy-6-methyl-pyrid-2-one and 687 ml (7.5 mol) of phosphorus oxychloride at temperatures between 100 ° and 117 ⁰ C for 2 hours Reflux, 345 g (2.5 mol) of triethylamine hydrochloride are added. The mixture is stirred at reflux for 15 hours, excess phosphorus oxychloride is distilled off in vacuo and the residue is added to 4300 g of ice. It is extracted three times with 500 ml of methylene chloride, the extracts are washed twice with water and dried with magnesium sulfate with the addition of sodium carbonate. After distilling off the solvent remain 266.3 g (97.6 %) of a brownish oil.

Kp x 135 ° to 141 ° C / 9 Torr. Colorless liquid · Yield: 217.0 g (79.5 %) of 3-n-butyl-2,4-dichloro-6-methylpyridine.

^C l0 ^H l3 ^C1 2 ^N i ²¹⁸ » ¹ ) ·

Example 6: 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

 Bp. 139 ° to 141 ° C / 10 torr;

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

C ₁₀ H ₁₃ Cl ₂ N (218.1).

Example 7: 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. The procedure is as described in Example 1 · Colorless liquid. Bp 135 ° to 137 ° C / 10 torr;

Yield: 46.4 g (45.2 %) of 3-n-butyl-2,4-dichloro-6-methylpyridine

C ₁₀ H ₁₃ Cl ₂ N (218.1).

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Example 8: Comparative Example

To a 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 40.5 g Dropped (0.2 mol) of triethylamine. After the exothermic reaction has subsided for 12 hours at 123 ° to 125 ⁰ C heated to reflux, distilled off excess phosphorus oxychloride in vacuo, the residue was added to 500 g of ice and worked up as described in Example 1 · colorless liquid

 Bp. 137 ° to 140 ° C / 10 Torr;

Yield: 21.3 g (48.8 %) of 3-n-butyl-2,4-dichloro-6-methylpyridine;

^C l0 ^H l3 ^C1 2 ^N (2 ¹⁸ » ¹ ) ·

Example 9;

36.2 g (0.2 mol) of Sn-butyl - ^ - hydroxy-e-methyl-pyrid - ^ - on, 72.8 g (0.4 mol) of triethylamine hydrobromide and .110 ml (1.2 mol ) Phosphorus oxychloride are heated at reflux for 12 hours. After usual work-up, 21.7 g of a mixture of 74.2 % of 3-n-butyl-2,4-dichloro-6-methyl-pyridine and 25.8 % of 4-bromo-3-n-butyl-2-chloro -6-methyl-pyridine, b.p. 135 ° to 150 ° C / 8 torr.

Example 10:

When 33.1 g (0.2 mol) of tetraethylammonium chloride are used in place of the diethylamine hydrochloride in Example 2, the yield is 32.1 g (73.6 %) of 3-n-butyl-2,4-dichloro-6- methyl-pyridine.

Example 11:

36.0 g (0.2 mol) of 2,3-dichloro-4-hydroxy-pyrid-6-one are reacted with 110 ml (1.2 mol) of phosphorus oxychloride and 38.2 g (0.4 mol) of trimethylamine hydrochloride implemented as described in Example 1. It is worked up by steam distillation and recrystallized from dilute methanol. Yellowish crystals

F. 40 ^° C;

Yield: 28.2 g (65.0 %) of 2,3,4,6-tetrachloropyridine. C ₅ HCl ₄ N (216.9).

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Example 12:

30.0 g (0.2 mol) of 3-cyano-6-hydroxy-4-methyl-pyrid-2-one are mixed with 172.0 g (0.6 mol) of phosphorus oxybromide and 56.0 g (0.4 mol ) Trimethylamine hydrobromide as described in Example 1 implemented. After customary work-up and suction, 42.1 g (76.2 %) of 2,6-dibromo-3-cyano-4-methylpyridine are obtained. The recrystallization from glacial acetic acid gives

32.8 g (59.4 %) of the product as colorless crystals. F. 120 ° to 122 ⁰ C.

C ₇ H ₄ Br ₂ N ₂ (276.0).

Example 13:

42.4 g (0.2 mol) of 3-cyano-5-hydroxy-4-phenyl-pyrid-2-one are reacted with 110 ml (1.2 mol) of phosphorus oxychloride and 38.2 g (0.4 mol) of trimethylamine hydrochloride as described in Example 1 implemented. Yellowish crystals.

F. 173 ⁰ C;

Yield: 39.0 g (78.3 %) of 2,6-dichloro-3-cyano-4-phenylpyridine.

^C 12 ^H 6 ^Cl 2 ^N 2 i ²⁴⁹ x ¹ ) · Example 14

41.6 g (0.2 mol) of S-cyano-e-hydroxy - ^ - methoxycarbonylmethylpyrid-2-one are reacted with 110 ml of phosphorus oxychloride and 38.2 g (0.4 mol) of trimethylamine hydrochloride as described in Example 1 , Yellowish crystals.

F. 92 ⁰ C;

Yield; 33.0 g (67.4 %) of 2,6-dichloro-3-cyano-4-methoxycarbonylmethyl-pyridine.

C ₉ H ₆ Cl ₂ N ₂ O ₂ (245.1).

Example 15:

31.0 g (0.2 mol) of 4-carboxy-6-hydroxy-pyrid-2-one, 9.6 g (0.1 mol) of trimethylamine hydrochloride and 91.5 ml (1.0 mol) of phosphorus oxychloride Heated to reflux for 5 hours.

It is poured on ice, filtered off with suction, washed with water and dried. Yellowish crystals.

F. 201 ° to 204 ⁰ C;

Yield: 35.1 g (91.3 %) of 2,6-dichloroisonicotinic acid.

C ₆ H ₃ Cl ₂ NO ₂ (192.0).

Claims (1)

6 7 Erfindungsansprueh 1 «Process for the preparation of substituted 2,4- and 2,6 · Oihalogenpyridine the general formula I. rf R ² in the mean X in the 2-position and Y in the 4- or 6-position identical or different halogens such as chlorine or bromine and R ¹ and R ² in the 3,5-, 3,6-, 3,4- or 5,6-position are identical or different substituents of the series hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl each having 1 to 10 C- Atoms, aryl, halogen, nitro, cyano, alkoxy, aryloxy, alkylthio, arylthio, carboxyl and. Carbalkoxy, wherein the hydrocarbon radicals alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl may optionally be substituted by substituted amino or aryl groups, halogen, nitro, cyano, alkoxy, aryloxy, alkylthio, arylthio, carboxyl and carbalkoxy, by halogenation of 4- Hydroxy and 6-hydroxy-pyrid-2-ones of the general formula II 12 in which R and R have the abovementioned meaning and R is in the 4- or 6-position hydroxyl, with phosphorus oxyhalides, characterized in that the halogenation reaction at atmospheric pressure in the presence of halogen compounds of general formula III 14 6 7 D - N - β 2 ^Θ in the mean Chlor "chloride or bromide and A, B, C, D _{1 are the} same or different radicals of the series alkyl having 1 to 20 carbon atoms, wherein A and B may together form an alkylene radical having 2 to 7 carbon atoms, which, optionally with the inclusion of C, 1 to 3 double bonds, cycloalkyl, aryl, which are optionally substituted by amino groups, halogen, aryl and acyl, and up to two of the radicals A, B, C, D and hydrogen, with amounts of 0.1 to 3 mol, preferably between 1 and 2 moles per mole of compound of general formula II at temperatures in the range between 70 and 150 C _# preferably from 100 ° to 130 ⁰ C, is performed. Process according to item 1, characterized in that phosphorous oxychloride or phosphorus oxybromide are used as phosphorus oxyhalides.