Catalytic hydrogenation of nitriles

Abstract

The present invention relates to a novel catalytic hydrogenation of substituted 2-methyl cyanopyridyl derivatives, in particular 3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile [=Py-CN] to substituted 2-ethylaminopyridine derivatives, in particular 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine [=Py-ethanamine] or salts thereof in the presence of Raney catalysts, in particular Raney nickel or cobalt.

Claims

1. A process for preparing 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine or corresponding salts thereof, comprising (A1) hydrogenating [3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile in the presence of Raney cobalt catalyst.

2. The process according to claim 1 further comprising (A2) reacting the 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine obtained in step (A1) with a benzoyl halide according to formula (IV) ##STR00008## wherein Hal is fluorine, chlorine or bromine; q is an integer equal to 1, 2, 3 or 4; and each substituent Y is chosen, independently of the others, as being halogen, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl; to produce a compound having the formula ##STR00009## wherein q is an integer equal to 1, 2, 3 or 4; and each substituent Y is independently halogen, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl.

Description

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

(1) Process (A) may comprise an additional step (A2) after steps (A1),

(2) wherein the isolated product according to formula (III) is reacted with a benzoyl halide according to formula (IV)

(3) ##STR00006##

(4) wherein

(5) Hal is fluorine, chlorine or bromine;

(6) q is an integer equal to 1, 2, 3 or 4;

(7) each substituent Y is chosen, independently of the others, as being halogen, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl;

(8) to the compound according to formula (I)

(9) ##STR00007##

(10) wherein p and X are defined as above;

(11) q is an integer equal to 1, 2, 3 or 4;

(12) each substituent Y is chosen, independently of the others, as being halogen, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl.

(13) p is preferably 1 or 2.

(14) p is very preferably 2.

(15) In each case, X is preferably independently of the others, as being fluorine, chlorine, bromine, C.sub.1-C.sub.2 alkyl or C.sub.1-C.sub.2 haloalkyl having 1 to 5 halogen atoms selected independently from each other from fluorine, chlorine;

(16) In each case, X is more preferably independently of the others, as being fluorine, chlorine, methyl, ethyl or C.sub.1-C.sub.2 haloalkyl having 1 to 5 halogen atoms selected independently from each other from fluorine, chlorine;

(17) In each case, X is particular preferably independently of the others, as being fluorine, chlorine, or difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl;

(18) In each case, X is very particular preferably independently of the others, as being chlorine, or trifluoromethyl.

(19) As regards the positions in which the 2-pyridyl moiety is substituted by X, the 2-pyridyl moiety is preferably substituted by X in 3- and/or in 5-position. Preferably, the 2-pyridyl moiety is substituted by X in 3- and 5-position.

(20) q is preferably 1 or 2.

(21) q is very preferably 1.

(22) Y is preferably independently of the others, as being fluorine, chlorine, bromine, C.sub.1-C.sub.2 alkyl or C.sub.1-C.sub.2 haloalkyl having 1 to 5 halogen atoms selected independently from each other from fluorine, chlorine;

(23) Y is more preferably independently of the others, as being fluorine, chlorine, methyl, ethyl or C.sub.1-C.sub.2 haloalkyl having 1 to 5 halogen atoms selected independently from each other from fluorine, chlorine;

(24) Y is particular preferably independently of the others, as being fluorine, chlorine, or difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl;

(25) Y is very particular preferably trifluoromethyl.

(26) Y is very particular preferably chlorine.

(27) As regards the positions in which the phenyl moiety is substituted by Y, the phenyl moiety is preferably substituted by Y in 2- and/or in 6-position. Preferably, the phenyl moiety is substituted by Y in 2-position.

(28) Very particular preferably the compound according to formula (II) is 3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile and the compound according to formula (III) is 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine. Very preferably the compound according to formula (IV) is 2-trifluoromethyl-benzoyl chloride.

(29) Very preferably the compound according to formula (I) is fluopyram as defined in formula (Ia).

(30) In one embodiment the compounds according to formula (III) may be present as free amines or salts thereof.

(31) The corresponding salts of the compounds according to formula (III) are preferably phosphates, formiates, or acetates.

(32) In one embodiment step (A2) is performed in the presence of a base.

(33) In another embodiment step (A2) is performed under reduced pressure without a base being present.

(34) In another embodiment step (A2) is performed under reduced pressure and in the presence of a base.

(35) Useful bases which may be used in the process according to the present invention, such as in particular in step (A2) are inorganic or organic bases such as Na.sub.2CO.sub.3, NaHCO.sub.3, K.sub.2CO.sub.3, KHCO.sub.3, NaOH, KOH, Ca(OH).sub.2, Mg(OH).sub.2, triethyl amine, N,N-diisopropylethylamine, dimethylcyclohexylamine.

(36) The following bases are particularly preferred for step (A2): Na.sub.2CO.sub.3, NaHCO.sub.3, K.sub.2CO.sub.3, KHCO.sub.3, NaOH, KOH, Ca(OH).sub.2. More preferred are NaOH, KOH, Ca(OH).sub.2. Mostly preferred are NaOH, KOH. Preferably, in step (A6) a base as defined herein is added until adjustment of the pH value of the reaction solution to pH 4 to 14, preferably pH 5 to 13 is achieved.

(37) The metal catalyst is any hydrogenation catalyst selected from the group of Raney catalysts. In one embodiment the metal catalyst is a Raney catalyst selected from the group of Raney nickel and Raney cobalt.

(38) In one embodiment the metal catalyst is any Raney cobalt catalyst.

(39) The Raney catalysts may be present in different forms, for example as a powder, a fixed bed catalyst, as hollow spheres, extrudates, granulates, fiber tablets or shell-activated tablets

(40) In one embodiment the Raney catalyst has a density of 0.1 to 2 g/ml.

(41) The catalyst alloy of the catalysts used in accordance with the invention is preferably composed of up to 20-80 wt % of one or more catalytically active metals, preferably cobalt and nickel and up to 20-80 wt % of one or more alkali-leachable metals, preferably aluminum. A fast or slow cooled alloy can be used as catalyst alloy. Fast cooling is understood to mean, for example, cooling at a rate from 10 to 105 K/sec.

(42) The cooling media can be various gases or liquids such as water. Slow cooling is understood to mean methods with lower cooling rates.

(43) Raney catalysts doped with other metals may be used. The doping metals are frequently also called promoters. The doping of Raney catalysts is described, for example, in the documents U.S. Pat. No. 4,153,578, DE 21 01 856, DE 21 00 373 or DE 20 53 799. Preferred elements for doping are elements of groups 1A, 2A, 3B through 7B, 8, 1B, 2B and 3A of the periodic system and germanium, tin, lead, antimony and bismuth. Particularly preferred are chromium, manganese, iron, vanadium, tantalum, titanium, tungsten, molybdenum, rhenium and/or metals of the platinum group. The amount of promoters in the Raney catalyst can preferably be 0-20 wt %. The promoters can already be contained as an alloy component, or can be added only later, especially after activation.

(44) In one embodiment hollow catalysts with a diameter from 0.05 to 20 mm and a shell thickness from 0.05 to 7 mm may be used. The catalyst shells can be impermeable, or they can have a porosity of 80% and higher.

(45) The catalysts are available from commercial sources like the companies BASF, Acros, Evonik.

(46) The catalysts can be used in any form, for example dry, or wet (water-wet). Preferably, the catalysts are used several times. More preferably, the catalysts are used more than two times. Most preferably, the catalysts are used between once and ten times. The catalysts can be used in in a batch, semibatch or fixed bed hydrogenation reaction as well as in a continuous hydrogenation reaction process. More preferably the catalysts can be used in in a batch or fixed bed hydrogenation reaction.

(47) In the process according to the invention, the catalyst is used in a concentration of about 0.01 mol % to about 50 mol % catalyst with respect to the amount of cyanopyridyl derivative according to formula (II). The catalyst is preferably used in a concentration of about 0.1 to about 50 mol %, more preferably the catalyst is used in a concentration of about 0.5 mol % to about 3 mol %.

(48) Whilst not being bound by theory, in the process of the present invention the Raney catalysts allow a reduction of the formation of the unwanted dehalogenated, particularly the dechlorinated, side-products. One the one hand, this reduces the toxicity and on the other hand enhances the yield of the desired reaction products.

(49) By using the Raney catalyst in the process of the present invention a reduction of the dehalogenated, particularly dechlorinated, side-products is achieved, preferably to equal or less than 25%, more preferably equal or less than 20%, even more preferably equal or less than 15%, particular more preferably equal or less than 10%, even particular more preferably equal or less than 5%, most preferably equal or less than 3%, most particular preferably equal or less than 1%, can be achieved compared to the reaction as described in the prior art in WO 2004/016088 and EP-A 1674455.

(50) The Raney cobalt catalyst may be present in different forms, for example as a powder, a fixed bed catalyst, as hollow spheres, extrudates, granulates, fiber tablets or shell-activated tablets.

(51) In one embodiment the Raney cobalt catalyst has a density of 0.1 to 2 g/ml.

(52) The catalyst alloy of the catalysts used in accordance with the invention is preferably composed of up to 20-80 wt % of one or more catalytically active metals, preferably cobalt and nickel and up to 20-80 wt % of one or more alkali-leachable metals, preferably aluminum. A fast or slow cooled alloy can be used as catalyst alloy. Fast cooling is understood to mean, for example, cooling at a rate from 10 to 105 K/sec. The cooling media can be various gases or liquids such as water. Slow cooling is understood to mean methods with lower cooling rates.

(53) Raney cobalt catalyst doped with other metals may be used. The doping metals are frequently also called promoters. The doping of Raney cobalt catalyst is described, for example, in the documents U.S. Pat. No. 4,153,578, DE 21 01 856, DE 21 00 373 or DE 20 53 799. Preferred elements for doping are elements of groups 1A, 2A, 3B through 7B, 8, 1B, 2B and 3A of the periodic system and germanium, tin, lead, antimony and bismuth. Particularly preferred are chromium, manganese, iron, vanadium, tantalum, titanium, tungsten, molybdenum, rhenium and/or metals of the platinum group. The amount of promoters in the Raney cobalt catalyst can preferably be 0-20 wt %. The promoters can already be contained as an alloy component, or can be added only later, especially after activation.

(54) In one embodiment hollow catalysts with a diameter from 0.05 to 20 mm and a shell thickness from 0.05 to 7 mm may be used. The catalyst shells can be impermeable, or they can have a porosity of 80% and higher.

(55) The catalysts are available from commercial sources like the companies BASF, Acros, Evonik.

(56) The catalysts can be used in any form, for example dry, or wet (water-wet). Preferably, the catalysts are used several times. More preferably, the catalysts are used more than two times. Most preferably, the catalysts are used between once and ten times. The catalysts can be used in in a batch, semibatch or fixed bed hydrogenation reaction as well as in a continuous hydrogenation reaction process. More preferably the catalysts can be used in in a batch or fixed bed hydrogenation reaction.

(57) In the process according to the invention, the catalyst is used in a concentration of about 0.01 mol % to about 50 mol % catalyst with respect to the amount of cyanopyridyl derivative according to formula (II). The catalyst is preferably used in a concentration of about 0.1 to about 50 mol %, more preferably the catalyst is used in a concentration of about 0.5 mol % to about 3 mol %.

(58) Whilst not being bound by theory, in the process of the present invention the Raney cobalt catalyst allow a reduction of the formation of the unwanted dehalogenated, particularly the dechlorinated, side-products.

(59) One the one hand, this reduces the toxicity and on the other hand enhances the yield of the desired reaction products.

(60) By using the Raney cobalt catalyst in the process of the present invention a reduction of the dehalogenated, particularly dechlorinated, side-products is achieved, preferably to equal or less than 25%, more preferably equal or less than 20%, even more preferably equal or less than 15%, particular more preferably equal or less than 10%, even particular more preferably equal or less than 5%, most preferably equal or less than 3%, most particular preferably equal or less than 1%, can be achieved compared to the reaction as described in the prior art in WO 2004/016088 and EP-A 1674455.

(61) The Raney nickel catalyst may be present in different forms, for example as a powder, a fixed bed catalyst, as hollow spheres, extrudates, granulates, fiber tablets or shell-activated tablets

(62) In one embodiment the Raney nickel catalyst has a density of 0.1 to 2 g/ml.

(63) The catalyst alloy of the catalysts used in accordance with the invention is preferably composed of up to 20-80 wt % of one or more catalytically active metals, preferably cobalt and nickel and up to 20-80 wt % of one or more alkali-leachable metals, preferably aluminum. A fast or slow cooled alloy can be used as catalyst alloy. Fast cooling is understood to mean, for example, cooling at a rate from 10 to 105 K/sec. The cooling media can be various gases or liquids such as water. Slow cooling is understood to mean methods with lower cooling rates.

(64) Raney nickel catalyst doped with other metals may be used. The doping metals are frequently also called promoters. The doping of Raney nickel catalyst is described, for example, in the documents U.S. Pat. No. 4,153,578, DE 21 01 856, DE 21 00 373 or DE 20 53 799. Preferred elements for doping are elements of groups 1A, 2A, 3B through 7B, 8, 1B, 2B and 3A of the periodic system and germanium, tin, lead, antimony and bismuth. Particularly preferred are chromium, manganese, iron, vanadium, tantalum, titanium, tungsten, molybdenum, rhenium and/or metals of the platinum group. The amount of promoters in the Raney nickel catalyst can preferably be 0-20 wt %. The promoters can already be contained as an alloy component, or can be added only later, especially after activation.

(65) In one embodiment hollow catalysts with a diameter from 0.05 to 20 mm and a shell thickness from 0.05 to 7 mm may be used. The catalyst shells can be impermeable, or they can have a porosity of 80% and higher.

(66) The catalysts are available from commercial sources like the companies BASF, Acros, Evonik.

(67) The catalysts can be used in any form, for example dry, or wet (water-wet). Preferably, the catalysts are used several times. More preferably, the catalysts are used more than two times. Most preferably, the catalysts are used between once and ten times. The catalysts can be used in in a batch, semibatch or fixed bed hydrogenation reaction as well as in a continuous hydrogenation reaction process. More preferably the catalysts can be used in in a batch or fixed bed hydrogenation reaction.

(68) In the process according to the invention, the catalyst is used in a concentration of about 0.01 mol % to about 50 mol % catalyst with respect to the amount of cyanopyridyl derivative according to formula (II). The catalyst is preferably used in a concentration of about 0.1 to about 50 mol %, more preferably the catalyst is used in a concentration of about 0.5 mol % to about 3 mol %.

(69) Whilst not being bound by theory, in the process of the present invention the Raney nickel catalyst allow a reduction of the formation of the unwanted dehalogenated, particularly the dechlorinated, side-products.

(70) One the one hand, this reduces the toxicity and on the other hand enhances the yield of the desired reaction products.

(71) By using the Raney nickel catalyst in the process of the present invention a reduction of the dehalogenated, particularly dechlorinated, side-products is achieved, preferably to equal or less than 25%, more preferably equal or less than 20%, even more preferably equal or less than 15%, particular more preferably equal or less than 10%, even particular more preferably equal or less than 5%, most preferably equal or less than 3%, most particular preferably equal or less than 1%, can be achieved compared to the reaction as described in the prior art in WO 2004/016088 and EP-A 1674455.

(72) The hydrogenation reaction can be conducted at any suitable reaction conditions. In general the hydrogenation reaction will be conducted under batch, semi/batch or fixed bed conditions as well as in a continuous hydrogenation reaction process.

(73) In one embodiment the hydrogenation reaction will be conducted under batch or fixed bed conditions.

(74) Therein, the hydrogenation reaction is performed in either batch, semi-batch or continuous slurry reactors. Semi-batch hydrogenation involves the feeding of the nitrile to a slurry of catalyst in a solvent (or without). In this mode the ratio of nitrile to the catalyst is lower compared to batch process. In contrast to the batch or semi-batch process in the continuous mode the product is removed at the same rate as nitrile as is added.

(75) Pressure

(76) The catalytic hydrogenation according to the invention is preferably performed under elevated pressure (i.e. up to about 600 bar), preferably in an autoclave in a hydrogen gas atmosphere, preferably in a semi batch hydrogenation process. The (additional) pressure increase can be brought about by supply of an inert gas, such as nitrogen or argon. The hydrogenation according to the invention is effected preferably at a hydrogen pressure in the range from about 0 to about 300 bar, more preferably at a hydrogen pressure in the range from about 5 to about 200 bar. Preferred ranges of hydrogen pressure are also e from about 0.5 to about 50 bar.

(77) In one embodiment the catalytic hydrogenation according to the invention is preferably performed under elevated pressure (i.e. up to about 200 bar).

(78) The hydrogen pressure according to the invention can also vary during the process.

(79) If necessary, suitable measures for dissipating heat from the exothermic reaction can be applied.

(80) Temperature

(81) The catalytic hydrogenation according to the invention is performed preferably at a temperature in the range from about 20 C. to about 200 C., more preferably at a temperature in the range from about 0 C. to about 100 C., most preferably in the range from about 5 to 70 C.

(82) Solvents

(83) The catalytic hydrogenation can also be performed without a solvent. However, it is generally advantageous to perform the process according to the invention in the presence of solvents (diluents). Solvents are advantageously used in such an amount that the reaction mixture remains efficiently stirrable over the entire process. Advantageously, based on the nitrile used, 1 to 50 times the amount of solvent, preferably 2 to 40 times the amount of solvent and more preferably 2 to 30 times the amount of solvent is used.

(84) Useful solvents for the performance of the hydrogenation process according to the invention include water and all organic solvents which are inert under the reaction conditions, the type of solvent used depending on the type of reaction procedure, more particularly on the type of catalyst used and/or the hydrogen source (introduction of gaseous hydrogen or generation in situ). Solvents are also understood in accordance with the invention to mean mixtures of pure solvents.

(85) Solvents suitable in accordance to the invention are water, acids such as acetic acid, acetic anhydride, alcohols such as methanol, ethanol, isopropanol, 1-propanol, butanol, tert. butanol, 1-butanol, 2-butanol, t-amyl alcohol, benzyl alcohol, 1,3-butanediol, 1,4-butandiol, 2-butoxyethanol, cyclohexanol, diethylene glycol, diethylen glycol methyl ether, dipropylene glycol, dipropylene glycol methyl ether, 2-ethoxyethanol, ethanolamine, ethylene glycol, glycerol, hexanole, hexylene glycol, isoamyl alcohol, isobutanol, 2-methoxyethanol, 1-octanol, pentanol, propylene glycol, tetraethylene glycol, triethylene glycol; ethers, such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethylglycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methyl cyclopenthylether, dioxane, dichlorodiethyl ether, petroleum ether, ligroin and polyethers of ethylene oxide and/or propylene oxide; ketones such as acetone, cyclohexanone, 3-pentanone, amines, such as trimethyl-, triethyl-, tripropyl-, and tributylamine, tert-amyl methyl ether (TAME), N-methyl morpholine, aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, methyl cyclohexane heptane, octane, nonane, and technical-grade hydrocarbons which may be substituted by fluorine and chlorine atoms, such as dichloromethane, fluorobenzene, chlorobenzene or dichlorobenzene, for example white spirits having components with boiling points in the range, for example, from 40 C. to 250 C., cymene, petroleum fractions within a boiling range from 70 C. to 190 C., toluene, xylenes, ethylbenzene. esters such as amyl acetates, butyl acetates, ethyl acetate, isobutyl acetate, isopropyl acetate, 2-methoxyethyl acetate, methyl acetate, propyl acetate, prop glycol methyl ether acetate, carbonate such as propylene carbonate, dimethyl carbonate, diethyl carbonate; N,N-Dimethylacetimide, N,N-Dimethylformamide, 2-pyrrolidone and N-methyl pyrrolidone.

(86) In the process according to the invention, it is preferred to use alcohols, esters or ethers as solvent. Preferred are methanol, ethanol, isopropanol, 1-propanol, butanol, tert. butanol, 1-butanol, 2-butanol, t-amyl alcohol, benzyl alcohol, 1,3-butanediol, 1,4-butandiol, 2-butoxyethanol, cyclohexanol, diethylene glycol, methyl-tert-butyl ether, amyl acetates, butyl acetates, ethyl acetate, isobutyl acetate, isopropyl acetate, 2-methoxyethyl acetate, methyl acetate, propyl acetate, prop glycol methyl ether acetate.

(87) The solvents which can be used in step (A1) can be the same or different and can independently in each case be used as mixtures of solvents, in particular mixtures comprising water or as solvents consisting of only one component.

EXAMPLES

(88) The examples shown below further illustrate the invention without limiting it.

(89) Examples regarding Process (A):

Example 1: Hydrogenation with Raney Cobalt Catalyst

(90) The water-comprising Raney cobalt catalyst (Actimet Cobalt (BASF)) is washed three times with water and another three times with tert-butyl methyl ether (MTBE).

(91) An autoclave is charged with 30% (w/w) of the washed Raney cobalt catalyst and 66 g of [3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile solved in 340 g of MTBE. Another 50 g of MTBE is added. The contents are then stirred at an elevated hydrogen pressure of 20 bar at 25 C. until the hydrogen uptake ceased after about three hours. Stirring is then continued for another hour. The reaction mixture is removed by filtration from the autoclave. The removed reaction mixture is analyzed by HPLC to quantify the content of amine.

(92) The product 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine was obtained at 76.59% yield in a first example, and at 74.74% in a second example.