RU2266900C2 - Methods for preparing derivatives of 2-aminomethylpyridine and 2-cyanopyridine - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved methods for preparing compounds of the formulae (I)

and (II)

or their salts wherein X represents halogen atom; Y represents halogen atom, halogenalkyl, alkoxycarbonyl or alkylsulfonyl; n = 0-3. Method for preparing compound of the formula (I) involves catalytic hydrogenation of compound of the formula (II) in the presence of a catalyst, such as palladium in solvent medium at temperature from 0°C to 60°C. Method provides preparing the end compounds with high yields (95-97%) and high purity degree due to minimization of by-side dehalogenation reaction of the parent reagents. Method for preparing compound of the formula (II) involves treatment of the corresponding derivative of 2-fluoro-derivative with the cyanide source in the presence of a catalyst, such as tetraalkyl ammonium salt in an aqueous solvent or without solvent at temperature from 10°C to 60°C. Method provides preparing the end compounds with high yields (80-90%), high purity (98%) at moderate temperatures.

EFFECT: improved preparing methods.

23 cl, 3 ex

Description

The invention relates to new methods for producing 2-aminomethylpyridines (especially 2-aminomethyl-3-chloro-5-trifluoromethylpyridine), as well as for the preparation of 2-cyanopyridines used for their preparation, i.e. compounds that are useful as intermediates in the preparation of pesticides.

The catalytic reduction of cyanopyridines with the aim of producing aminomethylpyridines is known. However, when the cyanopyridine compound contains additional halogen atom (s), the reduction may be complicated by a parallel dehalogenation reaction. PNRylander, Hydrogenation Methods (Best Synthetic Series, Academic Press), (1985), p. 148 indicates that palladium is usually chosen when they want to carry out a dehalogenation reaction, and that platinum and rhodium are relatively ineffective and therefore are often used in reactions hydrogenation where it is necessary to preserve halogen.

In contrast to the aforementioned prior art, applicants have found that the use of a palladium catalyst gives particularly good results in the reduction of cyanopyridines which contain additional halogen atom (s). Applicants have developed a new method for producing 2-aminomethylpyridines that contain additional halogen atom (s), at which minimal dehalogenation occurs and which is suitable for industrial processes.

A number of techniques have been published for introducing a cyano group into the 2-position of the pyridine component. Typically, they include the substitution of halogen, in particular bromine or fluorine, in a polar solvent, for example in dimethyl sulfoxide or dimethylformamide. In addition, there are numerous methods where activated pyridine N-oxide or N-alkylpyridine is used as starting materials. Many of these cyanidation pathways use heavy metal reagents containing copper or nickel. For example, EP0034917 describes the preparation of 2-cyano-3-chloro-5-trifluoromethylpyridine from an analog containing bromine in the 2-position by reaction with monovalent copper cyanide in dimethylformamide at 120 ° C.

However, many of these prior art methods suffer from one or more disadvantages, including low yields, the use of heavy metals that produce toxic waste streams, or polar solvents that are difficult to regenerate. In addition, methods that include the formation of pyridine N-oxide or N-alkylpyridine include several steps. These shortcomings become critical when the scale of production increases to industrial.

GB Patent Publication No. 117970 describes the cyanation of 2-halo-pyridine compounds with an activating reagent and a cyanide source in a polar solvent, and thus avoids many of the disadvantages described above. However, when carrying out this procedure, there remains a need for recycling an activating reagent and an aprotic solvent to minimize the cost of an industrial-scale process.

Applicants have developed an alternative and improved method for producing 2-cyanopyridines, which can be used for industrial processes.

According to a first aspect of the present invention, there is provided a method (A) for preparing a compound of general formula (I):

or its salts, including catalytic hydrogenation of the compounds of General formula (II):

or its salt,

where X is halogen; each of Y may be the same or different and represent halogen, haloalkyl, alkoxycarbonyl or alkylsulfonyl; and n is from 0 to 3.

In the present invention, halogen means a fluorine, chlorine or bromine atom. A preferred halogen atom is chlorine.

Halogenated alkyl usually means a C ₁ -C ₆ alkyl group substituted with one or more halogen atoms. For example, the C ₁ -C ₆ alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl. The C ₁ -C ₆ alkyl group is preferably substituted with one or more chlorine or fluorine atoms. A more preferred haloalkyl group is trifluoromethyl.

The alkoxycarbonyl group is typically C ₁ -C ₆ alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or iso-propoxycarbonyl.

The alkylsulfonyl group is typically C ₁ -C ₆ alkylsulfonyl, wherein the C ₁ -C ₆ group is as defined above.

Preferably, X is chlorine.

Preferably, Y is halogen or haloalkyl (more preferably trifluoromethyl).

Compound (II) is preferably 3-chloro-2-cyano-5-trifluoromethylpyridine.

Typically, the catalyst includes a metal selected from palladium, platinum, ruthenium, nickel or cobalt. The amount of metal in the catalyst used (which is usually deposited, for example, on charcoal) is typically 0.05-0.7% by weight relative to the amount of the compound of formula (II), preferably 0.05-0.3%, more preferably 0.1-0.2%. A preferred catalyst contains palladium, for example, finely divided palladium on an inert carrier such as charcoal. It has been found that this provides both a suitable reaction rate and a minimum of adverse reactions. Thus, when the compound of formula (II) is 3-chloro-2-cyano-5-trifluoromethylpyridine, minimal dechlorination occurs using the method of the invention. Other examples of suitable catalysts include catalysts containing oxides and other compounds of the above metals.

Typically, the method is carried out in the presence of a solvent, such as an alcohol, for example methanol, ethanol, propanol or butanol, or such as an ester, for example ethyl acetate, or such as an ether, for example tetrahydrofuran. Alcohol solvents are preferred (methanol is most preferred). Preferably, the method is carried out in the presence of a strong acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid (preferably hydrochloric acid). The presence of acid helps prevent poisoning of the catalyst by the amino group of the product of formula (I), and also prevents the interaction of intermediate amino compounds, which, as you know, otherwise occurs during the catalytic hydrogenation of nitriles.

Reaction conditions typically include combining all reagents in a suitable reaction vessel and stirring, for example, at a temperature of from 0 to 60 ° C, preferably from 20 to 30 ° C. An additional advantage of the method is that low pressure is used, and, as a rule, a hydrogen pressure of 1 to 4 atmospheres is used (preferably, the method is carried out at 1 atmosphere).

Optionally, the reaction is carried out in the presence of a catalyst inhibitor, which can lead to an additional improvement in the selectivity of the reaction, reducing the degree of dehalogenation that can occur as an adverse reaction. Such catalyst inhibitors are known in the art, for example, as described in PNRylander, Hydrogenation Methods (Best Synthetic Series, Academic Press), (1985), p.125-126, and include alkali metal bromides or iodides such as potassium bromide or potassium iodide; or ammonium bromide or ammonium iodide; or hydrogen bromide or hydrogen iodide; or phosphorus compounds such as triphenylphosphite, hypophosphorous acid, phosphorous acid or alkylphosphinic acids; or thiodiglycol (2,2'-thiodiethanol); or thiourea; or sulfur. Preferably, the catalyst inhibitor is selected from alkali metal bromide or iodide, ammonium bromide or iodide and hydrogen iodide.

Thus, the present invention provides a high-performance selective and convenient method for producing 2-aminomethylpyridines.

It is also convenient to obtain the compound of formula (I) in the form of a salt, also a hydrochloride salt. When used as an intermediate in the production of a pesticide, the salt can be fed directly to the next reaction step without first isolating the corresponding free amine. Therefore, salt production and its subsequent reaction can be easily carried out in one vessel. A particularly preferred salt is 2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride.

According to a further aspect of the present invention, there is provided a process (B) for preparing a compound of general formula (II) as defined above, which comprises treating a compound of general formula (III):

a cyanide source and a catalyst in an aqueous solvent or in the absence of a solvent,

where X, Y and n are as defined above; and where the source of cyanide is hydrogen cyanide, alkali metal cyanide, alkaline earth metal cyanide or optionally substituted ammonium cyanide.

The catalyst is typically an interfacial catalyst such as a tetraalkylammonium salt, for example benzyltrimethylammonium chloride, tricaprylmethylammonium chloride, tetramethylammonium chloride, tetra-n-propylammonium bromide, tetra-n-ammonium tetra-n-butomonium-tetra-n-butomonium-butomide-butomide-butomide-butride tetra-n-bromide, tetra-n-tetra-ammonium butomide, tetra-n-tetra-ammonium-tetra-n-tetra-ammonium chloride, tetra-n-ammonium tetra-n-tetra-ammonium chloride, tetra-n-ammonium chloride, tetra-n-ammonium chloride, tetra-n-ammonium tetra-ammonium chloride, tetra-n-ammonium chloride, tetra-n-ammonium chloride, tetra-n-ammonium chloride, tetra-n-ammonium tetra-ammonium chloride tetra-n-octylammonium bromide or n-tetradecyltrimethylammonium bromide; or a tetraalkylphosphonium salt, for example tetra-n-butylphosphonium bromide or tetraphenylphosphonium bromide; or crown ether or an acyclic analogue thereof, for example TDA-1 (tris [2- (2-methoxyethoxy) ethyl] amine); or an amine such as 4-dimethylaminopyridine.

Preferably, the catalyst is selected from tricaprylmethylammonium chloride and tetra-n-octylammonium bromide.

The amount of catalyst used is usually from about 0.01 to 10 mol%, preferably from about 0.1 to 5 mol%, more preferably from about 1 to 5 mol%.

Compound (III) is preferably 3-chloro-2-fluoro-5-trifluoromethylpyridine.

The above method (B) according to the invention is a method for producing 2-cyanopyridines, providing a high yield, which is easy to implement, operates at moderate temperatures and does not suffer from the disadvantages of many prior art methods. In particular, the method according to the invention does not require heavy metal cyanides, such as copper cyanide or nickel cyanide, which when used on an industrial scale lead to the formation of toxic effluent flows and are difficult to regenerate. The method (B) according to the invention provides waste streams that are easy to process.

In addition, the method does not require the preparation of activated pyridine N-oxide or N-alkyl pyridine for high degrees of conversion, which is necessary for many prior art processes. The method (B) according to the invention does not require an activating agent, such as 4-dimethylaminopyridine and, therefore, eliminates the need for additional stages of regeneration and recycling. A further advantage of the method (B) according to the invention is that no organic solvents are used in the reaction, thus eliminating the need for recycling of expensive solvents such as dimethyl sulfoxide.

Preferably, the source of cyanide is sodium cyanide or potassium cyanide, preferably potassium cyanide. The amount of cyanide source used is typically from about 1.0 to 2.0 molar equivalents (however, if desired, a larger amount can be used), preferably from 1.0 to 1.5 molar equivalents, more preferably from 1 , 0 to 1.1 molar equivalents.

Typically, and preferably, the reaction is carried out using water as a solvent, however, it can also be carried out in the absence of a solvent.

Reaction conditions typically include combining all reagents in a suitable reaction vessel and stirring at a temperature of from 10 to 60 ° C, preferably from 20 to 40 ° C.

Thus, the present invention provides a method (B) for producing 2-cyanopyridines, providing a high yield. Since the reaction uses moderate reaction temperatures, all that is needed is simple and inexpensive reactors and the processing equipment located behind them to divert the reaction products. Moreover, since reagents are readily available, the method is inexpensive to operate. In addition, the present method provides waste streams that are easy to recycle.

According to a further aspect of the invention, methods (B) and (A) can be combined to prepare a compound of formula (I) from a compound of formula (III).

According to a further aspect of the invention, method (A) or the combined methods (B) and (A) are followed by an additional step of method (C), which comprises acylating said compound (I) with a benzoyl compound of formula (IV):

where L represents a leaving group; R ¹ and R ² each represent halogen, the same or different; and m is 0, 1 or 2, in order to obtain a compound of formula (V):

Preferably L is chlorine.

The compounds of formula (V) are valuable pesticidal active ingredients described, for example, in the publication of international patent number WO 99/42447.

Preferred compounds of formula (V) are:

N - [(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2,6-dichlorobenzamide;

N - [(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2,6-difluorobenzamide;

N - [(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2-chloro-6-fluorobenzamide;

N - [(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2,3-difluorobenzamide;

N - [(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2,4,6-trifluorobenzamide

or

N - [(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2-bromo-6-chlorobenzamide.

The stage of method (C) is described in the publication of international patent number WO 99/42447.

According to a further aspect of the invention, method (B) or combined methods (B) and (A), or (B), (A) and (C) can be combined with an earlier step of method (D), which comprises fluorinating a compound of formula (VI) :

where X, Y and n are as described above.

Step (D) is usually carried out using an appropriate fluorinating agent such as alkali metal fluoride, preferably potassium fluoride or sodium fluoride, in an aprotic solvent such as dimethyl sulfoxide or sulfolane, at a temperature of from 50 ° C to 150 ° C.

The compounds of formulas (I) and (II), obtained by the above methods according to the invention, are especially useful to obtain fungicidal active derivatives of 2-pyridylmethylamine of formula (V) according to the following reaction scheme:

Further, the present invention is illustrated by the following production examples.

Example 1 (method step A)

A mixture of 3-chloro-2-cyano-5-trifluoromethylpyridine (5.1 g) and 5% palladium-charcoal (5.1 mg metal palladium) was stirred at 20 ° C with methanol and concentrated hydrochloric acid (2, 5 ml) in a hydrogen atmosphere under a pressure of 1 atmosphere. Based on the HPLC data, it is believed that after 4 hours the reaction is complete. The mixture was filtered through Celatom, washed with methanol and water and evaporated to give 2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride in 95-97% yield. NMR (in D ₂ O) 4.6 (s, 2H), 8, 35 (s, 1H); 8.9 (s, 1H).

Example 2 (stage of method B)

To a stirred mixture of 3-chloro-2-fluoro-5-trifluoromethylpyridine (199.5 g) and Aliquat 336 (tricaprylmethylammonium chloride, 12.1 g) at 30 ° C. potassium cyanide solution (71.6 g) was added over 1 hour in water (215 g). Stirring at this temperature is continued for 4 hours, after which the amount of starting fluoride is less than 1% according to HPLC. The lower organic phase is separated, washed with an aqueous solution of sodium chloride and distilled, obtaining 3-chloro-2-cyano-5-trifluoromethylpyridine (185.8 g, 90% yield) T _bp = 90 ° C at 15 mbar. The purity of this product is 98%.

Example 3 (method step B)

Solid sodium cyanide (0.29 g) was added to a stirred mixture of 3-chloro-2-fluoro-5-trifluoromethylpyridine (0.8 g) and tetrabutylammonium bromide (0.06 g) at 20-25 ° C and stirred for 23 hours, obtaining 3-chloro-2-cyano-5-trifluoromethylpyridine (0.68 g, 82% yield by HPLC).

An example of a stage of method D

To a stirred mixture of anhydrous potassium fluoride (320 g) and anhydrous dimethyl sulfoxide at 110 ° C was added 2,3-dichloro-5-trifluoromethylpyridine (800 g), then heated at 120 ° C for 2 hours and subjected to fractional distillation under reduced pressure, obtaining 3-chloro-2-fluoro-5-trifluoromethylpyridine (685 g) in 92% yield (98% purity).

Claims (26)

1. The method of obtaining the compounds of General formula (I)

or its salt, including catalytic hydrogenation of the compounds of General formula (II)

or its salt, where X is halogen; each of Y, which may be the same or different, is halogen, haloalkyl, alkoxycarbonyl or alkylsulfonyl and n is 0 to 3; in the presence of a catalyst such as palladium, the process being carried out in a solvent at a temperature of from 0 to 60 ° C. 2. The method according to claim 1, in which X represents chlorine. 3. The method according to claim 1 or 2, in which Y represents halogen or halogenated. 4. The method according to claim 3, in which Y represents trifluoromethyl. 5. The method according to claims 1 to 4, in which the compound of formula (II) is 3-chloro-2-cyano-5-trifluoromethylpyridine. 6. The method according to claims 1-5, in which the amount of metal in the catalyst is 0.05-0.7% by weight relative to the amount of the compound of formula (II). 7. The method according to claim 6, in which the amount of metal in the catalyst is 0.05-0.3% by weight relative to the amount of the compound of formula (II). 8. The method according to claim 7, in which the amount of metal in the catalyst is 0.1-0.2% by weight relative to the amount of the compound of formula (II). 9. The method according to any one of claims 1 to 8, which is carried out in the presence of an alcohol solvent. 10. The method according to claim 9, in which the alcohol solvent is methanol. 11. The method according to any one of claims 1 to 9, which is carried out in the presence of a strong acid selected from hydrochloric, hydrobromic, sulfuric or phosphoric acids. 12. The method according to claim 11, wherein said strong acid is hydrochloric acid. 13. The method according to any one of claims 1 to 12, which is carried out at a hydrogen pressure of from 1 to 4 atmospheres. 14. The method according to any one of claims 1 to 13, which is carried out in the presence of a catalyst inhibitor. 15. The method according to 14, in which the catalyst inhibitor is selected from alkali metal bromide or iodide, ammonium bromide or iodide and hydrogen bromide or hydrogen iodide. 16. A method of obtaining a compound of General formula (II), as defined in any one of claims 1 to 4, comprising treating a compound of general formula (III)

a cyanide source in the presence of a catalyst representing a tetraalkylammonium salt in or without an aqueous solvent, where X, Y and n are as defined in claim 1, and where the source of cyanide is hydrogen cyanide, alkali metal cyanide, alkaline earth metal cyanide or optionally substituted ammonium cyanide. 17. The method according to clause 16, in which the catalyst is selected from tricaprylmethylammonium chloride and tetra-n-octylammonium bromide. 18. The method according to any one of p. 16 or 17, in which the amount of catalyst used is from 0.01 to 10 mol.%. 19. The method according to any one of paragraphs.16-18, in which the source of cyanide is potassium cyanide. 20. The method according to any one of claims 16-19, wherein the amount of the source of cyanide used is from 1.0 to 2.0 molar equivalents. 21. The method according to any one of claims 16 to 20, wherein the solvent is water. 22. The method according to any one of paragraphs.16-21, in which the temperature is from 10 to 60 ° C. 23. The method according to any one of claims 16 to 22, wherein the compound of formula (III) is 3-chloro-2-fluoro-5-trifluoromethylpyridine. Priority on points: 08/25/2000 according to claims 1-13; 10/19/2000 according to claims 14 and 15; 06/07/2001 according to claims 16-23.