Title of Invention	PROCESS FOR THE PREPARATION OF PYRIDYLCARBOXYLIC AMIDES AND ESTERS
Abstract	The invention relates to a process for the preparation of pyridylcarboxylic amides and esters I wherein Hal, X and R1 have the meanings given in claim 1, which comprises the following steps: (a) heating a mixture consisting essentially of trichloromethylpyridine II, wherein Hal has the meaning given, and 1.0 to 1.5 equivalents of concentrated sulfuric acid, characterized in that the trichloromethylpyridine II in a liquid form is added to the concentrated sulfuric acid at a temperature from 110°C to 160°C; and (b) reacting the intermediate product obtained in step (a) with an amine or alcohol III, HXR1 III, wherein X and R1 have the meaning given, optionally in the presence of a solvent and/or a base.

Title of Invention

PROCESS FOR THE PREPARATION OF PYRIDYLCARBOXYLIC AMIDES AND ESTERS

Abstract

The invention relates to a process for the preparation of pyridylcarboxylic amides and esters I wherein Hal, X and R1 have the meanings given in claim 1, which comprises the following steps: (a) heating a mixture consisting essentially of trichloromethylpyridine II, wherein Hal has the meaning given, and 1.0 to 1.5 equivalents of concentrated sulfuric acid, characterized in that the trichloromethylpyridine II in a liquid form is added to the concentrated sulfuric acid at a temperature from 110°C to 160°C; and (b) reacting the intermediate product obtained in step (a) with an amine or alcohol III, HXR1 III, wherein X and R1 have the meaning given, optionally in the presence of a solvent and/or a base.

Full Text	The present invention relates to a process for the preparation of pyridylcarboxylic am- ides and esters I wherein Hal represents a halogen atom; X represents O or NR2; R1 represents a C1-C6-alkyl or aryl group, wherein both groups may be sub- stituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6- haloalkyl or C1-C6-alkoxy groups;, R2 represents a hydrogen atom or a C1-C6-alkyl group; which comprises the following steps: (a) heating a mixture consisting essentially of a trichloromethylpyridine II, wherein Hal has the meaning given, and 1.0 to 1.5 equivalents of concentrated sulfuric acid, characterized in that the trichloromethylpyridine II in a liquid form is added to the concentrated sulfuric acid at a temperature from 110 to 160 °C; and (b) reacting the intermediate product obtained in step (a) with an amine or alco- hol III, wherein X and R1 have the meaning given, optionally in the presence of a solvent and/or a base. Another aspect of the present invention is a process for the preparation of (aryloxy)pyridylcarboxylic amides and esters IV wherein R1 and X have the meaning given, and R3 represents an aryl group, which may be substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy groups; wherein the pyridylcarboxylic amides and esters I or a salt thereof are prepared from a trichloromethylpyridine II according to the present invention and (c) are further reacted with an aromatic alcohol V, R3-OH v, wherein R3 has the meaning given, optionally in the presence of a base. Pyridylcarboxylic amides and esters I are suitable intermediates for the preparation of a broad variety of compounds which are useful as agrochemicals or pharmaceuticals. In particular, they are key intermediates in the preparation of herbicidal phenoxypyridyl- carboxamides which are described for example in EP 0 447 004. The European patent application EP 0 646 566 suggests to hydrolyze trichloromethyl heteroarenes with water in the presence of chlorinated hydrocarbons and a Lewis acid and to react the resulting heteroarylcarbonyl chloride with an amine. However, this process causes problems with respect to the dosing rate and the exact equimolar dosing of water. Any excess of water will cause hydrolysis of the desired acid chloride compound and therefore reduce the yields. Moreover, in these days using chlorinated hydrocarbons is not desired because of environmental problems, and the amount of solvent used in the prior art procedure is high. Furthermore, the reaction time needed using water/1,2-dichloroethane is very long (24 h). The European patent application EP 0 899 262 discloses a process for the preparation of pyridylcarboxylic amides and esters in which sulfuric acid is added to a pyridyltri- chloromethane compound. However, this process causes problems since the intermediate formed solidifies at temperatures below 100 °C, but re-melting of this solidified intermediate is difficult due to decomposition under evolution of hydrochloric acid and sulphurtrioxide. It is, therefore, an object of the present invention to provide an efficient new process for the preparation of pyridylcarboxylic amides and esters in high yield and purity. The novel improved process avoids the disadvantages of the processes of the prior art and enables to carry out the production of pyridylcarboxamides and esters in technical scale and high yields using ready-available educts. Moreover the process according to the present invention has several advantages with respect to process safety compared to the process disclosed by EP 0 899 262 A: The mixture obtained in step (a) is not as sensitive to cooling during adding of the tri- chloromethypyridine II. The reaction mixture obtained during adding time is more stable and loss of heating would not cause solidification problems. Furthermore, when the sulfuric acid is added to the trichloromethylpyridine II as dis- closed by EP 0 899 262, the trichloromethylpyridine II shows the tendency to evaporate from the reaction mixture into the overhead system and is condensing and/or solidifying there. In addition to potential loss of yield, this may cause blockage of valves and vent lines representing a safety risk. So the process of the present invention clearly reduces the evaporation of the richloromethylpyridine II. Other objects and advantages of the present invention will be apparent to those skilled in the art from the following description and the appended claims. In general terms, unless otherwise stated herein, the term "the trichloromethylpyridine of formula II in a liquid form" includes trichloromethylpyridines II, which are liquid at room temperature; and trichloromethylpyridines II, which are solid at room temperature but are utilized either in form of a solution in an inert solvent or at a temperature above their melting point, i.e. they are used in molten form. In general terms, unless otherwise stated herein, the term "pyridylcarboxylic amides I" stands for ".pyridylcarboxylic amides and esters I, wherein X represents NR2". In general terms, unless otherwise stated herein, the term "pyridylcarboxylic esters I" stands for .pyridylcarboxylic amides and esters I, wherein X represents O". In general terms, unless otherwise stated herein, the term "amine III" stands for ..amine or alcohol III, wherein X represents NR2". In general terms, unless otherwise stated herein, the term "alcohol III" stands for ..amine or alcohol III, wherein X represents O". In general terms, unless otherwise stated herein, the term "(aryloxy)pyridylcarboxylic amides IV" stands for „(aryloxy)pyridylcarboxylic amides and esters IV, wherein X re- presents NR2". In general terms, unless otherwise stated herein, the term "(aryloxy)pyridylcarboxylic esters IV" stands for „(aryloxy)pyridylcarboxylic amides and esters IV, wherein X represents O". The organic moieties mentioned in the definition of the substituents R1, R2 and R3 or as substituents on phenyl, naphthyl or anthranyl rings are - like the term halogen - collec- tive terms for individual enumerations of the individual group members. All hydrocarbon chains, i.e. all alkyl, haloalkyl and alkoxy groups can be straight-chain or branched, the prefix Cn-Cm denoting in each case the possible number of carbon atoms in the group. Halogenated substituents preferably carry one, two, three, four or five identical or dif- ferent halogen atoms. The term halogen denotes in each case fluorine, chlorine, bro- mine or iodine. Examples of other meanings are: C1-C4-alkyl: CH3, C2H5, n-propyl, CH(CH3)2, n-butyl, CH(CH3)-C2H5, CH2- CH(CH3)2 and C(CH3)3; C1-C6-alkyl: C1-C4-alkyl as mentioned above, and also, for example, n-pentyl, 1- methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n- hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3- dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1- ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1- methylpropyl or 1-ethyl-2-methylpropyl, preferably methyl, ethyl, n-propyl, 1- methylethyl, n-butyl, 1,1—dimethylethyl, n-pentyl or n-hexyl; C1-C4-haloalkyl: a C1-C4-alkyl radical as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, i.e., for example, CH2F, CHF2, CF3, CH2CI, dichloromethyl, trichloromethyl, chlorofluormethyl, di- chlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-brom- oethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluor-oethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-tri-chloroethyl, C2F5, 2- fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoro-propyl, 2-chloro- propyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3- trifluoropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoro- propyl, 1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or non- afluorobutyl; C1—C6—haloalkyl: a C1-C4-haloalkyl radical as mentioned above and also, for example, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undeca- fluoropentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6-iodohexyl and dode- cafluorohexyl; C1-C4-alkoxy: for example OCH3, OC2H5, n-propoxy, OCH(CH3)2, n-butoxy, OCH(CH3)-C2H5, OCH2-CH(CH3)2 or OC(CH3)3, preferably OCH3, OC2H5 or OCH(CH3)2; C1-C6-alkoxy: a C1-C4-alkoxy radical as mentioned above, and also, for exam- ple, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methoxylbutoxy, 1,1- dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-tri- methylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1 -ethyl-2- methylpropoxy; aryl: a mono-, bi- or tricyclic aromatic carbocycle containing 6 to 14 ring mem- bers, for example phenyl, naphthyl und anthracenyl; As a rule aromatic groups are preferred, which are substituted by at least one electron- withdrawing group, in particular by one or more halogen atoms, nitro, cyano or C1-C6- haloalkyl groups. In a particular embodiment of the process according to the present invention the radi- cals of the compounds according the present invention are as defined below, these definitions being both on their own and in combination with one another, particular embodiments of the present invention: Preference is given to a process according to the present invention wherein Hal represents fluorine, chlorine or bromine; preferably chlorine or bromine; particular preferably chlorine. Preference is also given to a process according to the present invention wherein X represents oxygen. Preference is also given to a process according to the present invention wherein X represents NR2. Preference is also given to a process according to the present invention wherein R1 represents C1-C6-alkyl, which may be substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy groups; preferably C1-C6-alkyl, which may be substituted by one or more halogen atoms; particularly preferably C1-C6-alkyl; very particularly preferably C1-C4-alkyl. Preference is also given to a process according to the present invention wherein R1 represents an aryl group, which may be substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyi or C1-C6-alkoxy groups; preferably a phenyl group, which may be substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6- alkoxy groups; particularly preferably a phenyl group, which may be substituted by one or two halogen atoms selected from fluorine and chlorine; very particular preferably a phenyl group, which may be substituted by one halogen atom; especially preferably a phenyl group, which may be substituted by one fluorine atom. Preference is also given to a process according to the present invention wherein R2 represents hydrogen. Preference is also given to a process according to the present invention wherein R2 represents C1-C6-alkyl; preferably C1-C4-alkyl. Preference is also given to a process according to the present invention wherein X represents O; and R1 represents C1-C6-alkyl, which may be substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy groups; preferably C1-C6-alkyl, which may be substituted by one or more halogen atoms; particularly preferably C1-C6-alkyl; very particularly preferably C1-C4-alkyl; most preferably isopropyl. Preference is also given to a process according to the present invention wherein X represents NR2; R1 represents an aryl group, which is substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy groups; preferably a phenyl group, which is substituted by one or more halo- gen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy groups; particularly preferably a phenyl group, which is substituted by one or two halogen atoms and/or C1-C6-haloalkyl groups; very particular preferably a phenyl group, which may be substituted by one or two halogen atoms selected from fluorine and chlorine; very particular preferably a phenyl group, which may be substituted by one halogen atom; especially preferably a phenyl group, which may be substituted by one fluorine atom; and R2 represents hydrogen. Preference is also given to a process according to the present invention wherein R3 represents an aryl group, which may be substituted by one or two halogen atoms or C1-C6-haloalkyl groups; preferably an aryl group, which may be substituted by one C1-C6- haloalkyl group. Preference is also given to a process according to the present invention wherein R3 represents a phenyl group, which may be substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy groups; preferably a phenyl group, which may be substituted by one or more halogen atoms or C1-C6- haloalkyl groups; particularly preferably a phenyl group, which may be substituted by a C1-C6- haloalkyl group; very particularly preferably a phenyl group, which may be substi- tuted by a C1-C6- haloalkyl group in 3-position of the phenyl moiety; especially preferably a phenyl group, which may be substituted by a C1-C4- haloalkyl group in 3-position of the phenyl moiety. Preference is also given to a process according to the present invention wherein the trichloromethylpyridines II are substituted by one halogen atom, preferably by a chlorine atom. Particular preference is given a process according to the present invention wherein the trichloromethylpyridines II are represented by trichloromethylpyridines HA Most preference is given a process according to the present invention wherein the trichloromethylpyridines II are represented by nitrapyrin (NP), a compound IIA, wherein Hal is CI. Step (a) of the process according to the present invention comprises heating a mix- ture consisting essentially of a trichloromethylpyridine II and 1.0 to 1.5 equivalents of concentrated sulfuric acid, characterized in that the trichloromethylpyridine II in a liquid form is added to the concentrated sulfuric acid at a temperature from 110 to 160 °C: The intermediate product formed in step (a) comprises a compound of formula VI and/or formula VII, or a structural isomeric form thereof: The reaction of the trichloromethylpyridine II with the sulfuric acid is carried out from 110 °C to 160°C, preferably from 120 °C to 150 °C, most preferred at 135°C. Preference is given to a process according to the present invention wherein in step (a) the mixture of the trichloromethylpyridine II and the concentrated sulfuric acid is kept at temperatures from 120 to 150°C for 30 to 300 minutes, more preferably for 30 to 240 minutes. Step (a) can be carried out under reduced or elevated pressure, preferably it is car- ried out at ambient pressure. Step (a) can be carried out in an inert organic solvent with a suitable boiling point or in the absence of any solvent. Suitable solvents are aliphatic hydrocarbons such as mixtures of C5-C8-alkanes, aro- matic hydrocarbons such as toluene, o-, m- and p-xylene, and halogenated hydrocar- bons such as chlorobenzene. It is also possible to use mixtures of the solvents mentioned. Preference is given to a process according to the present invention wherein step (a) is carried out in the absence of any solvent. Preference is given to a process according to the present invention wherein in step (a) the concentrated sulfuric acid contains less than 3 % by weight of water. Step (a) is carried out in the presence of 1.0 to 1.5 equivalents, preferably of 1.1 to 1.4 equivalents, particularly preferably of 1.25 to 1.35 equivalents of concentrated sulfuric acid. Preference is given to a process according to the present invention wherein in step (a) the trichloromethylpyridine II is added slowly, more preferably added in a time range of 1 to 5 hours to the concentrated sulfuric acid. Under these preferred reaction conditions the reaction of step (a) is as a rule com- pleted within 30 to 300 minutes, preferably within 45 to 240 minutes, in particular within 60 to 210 minutes. The trichloromethylpyridines II required are commercially available or can be prepared by halogenation of 2-trichloromethylpyridine (e.g. A. R. Katritzky, C. D. Johnson, Angew. Chem. Int. Ed. 1967, 6, 608-615). Step (b) of the process according to the present invention comprises reacting the in- termediate product obtained in step (a) with an amine or alcohol III optionally in the presence of an inert solvent and/or a base: The reaction of the intermediate product obtained in step (a) with an amine or alco- hol III is usually carried out at a temperature between ambient temperature and the reflux temperature of the reaction mixture, preferably at from 0 °C to 140 °C, particu- larly preferably at from 20 °C to120°C, most preferred at 40 °C to 100 °C in the pres- ence of an inert solvent and/or a base. As a rule step (b) can be carried out under reduced or elevated pressure, preferably it is carried out at ambient pressure. Step (b) of the reaction according to the invention may be carried out in the absence or presence of a solvent, which promotes the reaction or at least does not interfere with it. Suitable solvents are apolar solvents including aliphatic hydrocarbons such as pen- tane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons such as toluene, o-, m- and p-xylene, halogenated hydrocarbons such as dichloro- methane, chloroform, 1,2- dichloroethane and chlorobenzene, nitroalkanes such as nitroethane. It is also possible to use mixtures of the solvents mentioned. Step (b) of the reaction according to the invention may be carried out in the absence or presence of a base. Suitable bases are, in general, organic bases, e.g. tertiary amines such as tri(CrC6- alkyl)amines (e.g. trimethylamine, triethylamine, diisopropylethylamine), N- methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine, N- methylmorpholine and 4-dimethylaminopyridine and also bicyclic amines. The bases are generally employed in equimolar amounts, in excess or, if appropriate, they can be used as solvent. Preferably the bases are used in equimolar amounts. In general, the intermediate product obtained in step (a) and the amine or alcohol III are used in equimolar amounts. It might be advantageous to employ an excess of III based on the intermediate product. The resulting intermediate product obtained in step (a) is preferably reacted with the amine or alcohol III in a liquid form or upon dilution with an inert solvent. In a preferred embodiment the intermediate product of step (a), preferably in a liquid form, is transferred to the amine or alcohol III. The reaction of step (b) with an alcohol III is preferably carried out from 40°C to 70°C, most preferred at 65°C. In the event that the intermediate product formed in step (a) is reacted with an alco- hol III, step (b) is preferably carried out with an excess of said alcohol. Preferably the intermediate product formed in step (a) is reacted with an alcohol III as a solvent. Alternatively, the intermediate product obtained in step (a) may be treated with an alcohol III in the presence of an inert solvent such as toluene. Preference is given to a process according to the present invention wherein in step (b) the intermediate product obtained in step (a) is treated with an alcohol III wherein R1 represents C1-C6-alkyl, which may be substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy groups; preferably C1-C6-alkyl; more preferably ethyl or isopropyl. The reaction of step (b) with an amine III is preferably carried out from 50 °C to 140 °C, most preferred at 80°C. In the event that the intermediate product formed in step (a) is reacted with an amine III, step (b) is preferably carried out in the presence of a base as listed above; particularly preferably in the presence of tri(C1-C6-alkyl)amines (e.g. trimethylamine, triethylamine, diisopropylethylamine), N-methylpiperidine, pyridine, substituted pyri- dines such as collidine, lutidine, N-methylmorpholine and 4-dimethylaminopyridine; very particular preferably tri(C1-C6-alkyl)amines; especially preferably triethylamine. Preferably the intermediate product formed in step (a) is reacted with an amine III as a solvent. Alternatively, the intermediate product obtained in step (a) may be treated with an amine III in the presence of an inert solvent, preferably an aromatic hydrocarbon such as toluene. Preference is given to a process according to the present invention wherein the inter- mediate product obtained in step (a) is treated with an amine III in the presence of a base and an aromatic hydrocarbon as a solvent. Preference is also given to a process according to the present invention wherein the intermediate product obtained in step (a) is treated with an amine III wherein R1 represents a phenyl group, which is substituted by one or two halogen atoms and/or C1-C6-haloalkyl groups; preferably a phenyl group, which may be substituted by one or two halogen atoms selected from fluorine and chlorine; particular preferably a phenyl group, which may be substituted by one halogen atom; especially preferably a phenyl group, which may be substituted by one fluorine atom; and R2 represents hydrogen. Under this preferred reaction conditions step (b) is as a rule completed within 0.5 to 5, in particular 1 to 4 hours. The amines or alcohols III required are commercially available. The obtained pyridylcarboxylic amides and esters I may be purified by standard proce- dures, as for example by crystallization or chromatography, in particular by crystalliza- tion. However, since the pyridylcarboxylic amides and esters I are obtained in high purity with the process according to the invention, it is also possible to use the obtained prod- uct without further purification to prepare (aryloxy)pyridylcarboxylic amides and esters IV. Pyridylcarboxylic amides I can also prepared from pyridylcarboxylic esters I, which have been prepared in step (b) by treating the intermediate product ob- tained in step (a) with an alcohol III as mentioned above, by treating the pyridylcarboxylic esters I with an amine III as hereinbefore defined, in the presence of a base: The reaction of the pyridylcarboxylic ester I with an amine 111 is usually carried out at a temperature between ambient temperature and the reflux temperature of the reaction mixture, preferably at from 25 °C to 140 °C, particularly preferably at from 50 °C to 110°C, most preferred at 80 °C to 100 °C in the presence of an inert solvent and a base. As a rule step (b) can be carried out under reduced or elevated pressure, preferably it is carried out at ambient pressure. This reaction according to the invention may be carried out in the absence or pres- ence of a solvent, which promotes the reaction or at least does not interfere with it. Suitable solvents are apolar solvents including aliphatic hydrocarbons such as pen- tane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons such as tolene, o-, m- and p-xylene, halogenated hydrocarbons such as dichloro- methane, chloroform, 1,2- dichloroethane and chlorobenzene. Particular preference is given to aliphatic hydrocarbons, halogenated hydrocarbons and aromatic hydrocarbons. It is also possible to use mixtures of the solvents mentioned. Suitable bases are, in general Inorganic compounds such as alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hy- droxide and calcium hydroxide, alkali metal and alkaline earth metal oxide such as lith- ium oxide, sodium oxide, calcium oxide and magnesium oxide, as well as alkali metal and alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potas- sium ethoxide, potassium tert-butoxide, potassium tert-pentoxide and dimethoxymag- nesium, and furthermore organic bases, such as tertiary amines such as trimethyl- amine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substi- tuted pyridines such as collidine, lutidine, N-methylmorpholine and 4- dimethylaminopyridine and also bicyclic amines. Preferred bases are metal alkoxides such as sodium methoxide or sodium ethoxide. The bases are generally employed in catalytic amounts, however they can also be em- ployed in equimolar amounts, in excess or, if appropriate, be used as solvent. In general, the pyridylcarboxylic ester I and the amine III are used in equimolar amounts. It might be advantageous to employ an excess of III based on the pyridylcar- boxylic ester I. Preference is given to a process according to the present invention wherein a pyridyl- carboxylic ester I is treated with an amine III in the presence of a base as mentioned above and an aromatic hydrocarbon as solvent. In the event that pyridylcarboxylic amides I are prepared from pyridylcarboxylic esters I by treating the pyridylcarboxylic esters I with an amine III, wherein R2 represents a hydrogen atom, in the presence of a base, salts of formula 1.1 are formed: Preference is given to a process according to the present invention wherein a pyridyl- carboxylic ester IA, is reacted with an amine III, wherein R2 represents a hydrogen atom, to give the salts 1.1 A Another aspect of the present invention is a process for the preparation of (aryl- oxy)pyridylcarboxylic amides and esters IV wherein X represents O or NR2; R1 represents a C1-C6-alkyl or aryl group, wherein both groups may be sub- stituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6- haloalkyl or C1-C6alkoxy groups; R2 represents a hydrogen atom or a C1-C6-alkyl group; R3 represents an aryl group, which may be substituted by one or more halo- gen atoms, nitro, cyano, C1-C6-alkyI, C1-C6-alkoxy or C1-C6-haloalkyl groups; which comprises the following steps: (a) heating a mixture consisting essentially of a trichloromethylpyridine II as here- inbefore defined, and 1.0 to 1.5 equivalents of concentrated sulfuric acid, characterized in that the trichloromethylpyridine II in a liquid form is added to the concentrated sulfuric acid at a temperature from 110 to 160 CC; (b) reacting the intermediate product obtained in step (a) with an amine or alco- hol III as hereinbefore defined, optionally in the presence of a solvent and/or a base; and (c) reacting the pyridylcarboxylic amides and esters I or a salt thereof obtained in step (b) with an aromatic alcohol V, R3-OH v, wherein R3 has the meaning given; optionally in the presence of a base: The reaction of the pyridylcarboxylic amides and esters I or a salt thereof with an aro- matic alcohol V is usually carried out at from 0°C to the boiling point of the reaction mixture, preferably at from 60 °C to 200 °C, particularly preferably at from 140 °C to 180 °C, in an inert organic solvent optionally in the presence of a base. Suitable solvents are apolar solvents including aliphatic hydrocarbons such as pen- tane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons such as toluene, o-, m- and p-xylene, halogenated hydrocarbons such as dichloror- methane, 1,2-dichlororethane, chloroform and chlorobenzene, as well as amides such as dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone. Particular preference is given to apolar or polar aprotic solvents like aliphatic hydro- carbons, halogenated hydrocarbons, aromatic hydrocarbons or amides such as di- methylformamide, N,N-dimethylacetamide or N-methylpyrrolidone or mixtures of any of these solvents. It is also possible to use mixtures of the solvents mentioned. Suitable bases are, in general Inorganic compounds such as alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hy- droxide and calcium hydroxide, as well as alkali metal and alkaline earth metal alkox- ides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert- butoxide, potassium tert-pentoxide and dimethoxymagnesium, and furthermore organic bases such as tertiary amines such as trimethylamine, triethylamine, diisopropylethyl- amine and N-methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine, N-methylmorpholine and 4-dimethylaminopyridine and also bicyclic amines. Particular preference is given to metal alkoxides or metal hydroxides such as sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide. The bases are generally employed in equimolar amounts, however they can also be employed in excess or, if appropriate as solvent. Preference is given to a process according to the present invention wherein in step (c) the pyridylcarboxylic amides and esters I or a salt thereof obtained according to the present invention are reacted with an aromatic alcohol V without further purification. Preference is also given to a process according to the present invention wherein a pyridylcarboxylic ester IA is reacted with an aromatic alcohol V in the presence of a base to give (aryloxy)pyridylcarboxylic esters IVA: In a particularly preferred embodiment according to the present invention the liquid obtained in step (a) is added to 5 to 15 equivalents of an alcohol III, in particular isopropanol, at a temperature between 20 and 85 °C. The resulting reaction mixture is diluted with an aromatic hydrocarbon and washed with water. The resulting solution is added at temperatures from 120 to 160°C to a solution of the salt of an aromatic alcohol V, which is obtained by treating 1.01 to 1.30 equivalents, in particular about 1.22 equivalents, of an aromatic alcohol V, and a solution of sodium alkoxide, preferably 1.01 to 1.30 equivalents sodium alkoxide, in particular 1.22 equivalents sodium alkoxide, most preferred sodium methoxide, in an alcohol; in an aromatic hydrocarbon, in particular xylene, at 100-140°C. Preferably the excess of the remained alcohol V is distilled off before the pyridylcar- boxylic ester I is added to the solution of the salt of an aromatic alcohol V. The reaction mixture is as rule heated to 140 - 160°C and kept at this temperature for 2-8 hours to complete the reaction. In a preferred embodiment of the present invention a pyridylcarboxylic ester I or the salt 1.1 thereof obtained according to the present invention in step (b) is reacted with an aromatic alcohol V in the presence of a base [step (c)], and the resulting (ary- loxy)pyridylcarboxylic ester IV is subsequently treated with an amine III [step (d)] to give (aryloxy)pyridylcarboxylic amides IV: Particular preference is given to a process according to the present invention, wherein in step (c) a pyridylcarboxylic ester IA, wherein R1 represents a C1-C6-alkyl group; preferably an isopropyl group, is reacted with an aromatic alcohol V in the presence of a base; and treating the resulting (aryloxy)pyridylcarboxylic ester IVA, wherein R1 and R3 have the meaning given, with an amine III as hereinbefore defined in the presence of a base. In a further preferred embodiment of the present invention a pyridylcarboxylic ester I is reacted with an amine III, wherein R2 is hydrogen, and the resulting salts 1.1 are sub- sequently treated with an aromatic alcohol V to give (aryloxy)pyridylcarboxylic amides IV wherein R2 is hydrogen: Particular preference is also given to a process according to the present invention wherein a pyridylcarboxylic ester IA, wherein R1 represents a C1-C6-alkyl group; preferably an isopropyl group, is reacted with an amine III, wherein R2 represents a hydrogen atom, to give the salts 1.1 A which are subsequently treated with an aromatic alcohol V to give the (ary- loxy)pyridylcarboxylic amides IV.A wherein R2 is hydrogen without using any additional base. In a further particularly preferred embodiment according to the present invention an amine III, in particular 0.9 to 1.2 equivalents, preferably a halogenated aniline, in particular 4-fluoroaniline is added to the resulting reaction mixture at 120-150°C, in particular at 135 °C; optionally followed by adding a sodium alkoxide solution, in particular sodium methoxide solution, preferably catalytical amounts, more preferably 0.05 to 0.20 equivalents, mostly preferably about 0.13 equivalents in 10 to 60 minutes with simultaneous distillation of the alcohol used [step (d)]. The reaction mixture is stirred for 1 to 4 hours at 120 to 150 °C, in particular at about 135°C to complete the reaction. In another preferred embodiment of the present invention a pyridylcarboxylic amide of I or the salt 1.1 thereof obtained according to the present invention is treated with an aromatic alcohol of formula V: The reaction of the pyridylcarboxylic amides I or 1.1 with an aromatic alcohol V is car- ried out at a temperature from 0 °C to 250 °C, preferably at elevated temperatures from 60 to 200 °C, in particular from 140 to 180 °C, most preferred at 160 °C. Particular preference is given to a process according to the present invention wherein the pyridylcarboxylic amide of I or the salt thereof obtained according to the present invention is treated with an aromatic alcohol of formula V, wherein R3 represents a phenyl group, which is substituted by one or more halogen at- oms, nitro, cyano, C1-C6-alkyl, C1-C6-alkoxy or C1-C6-haloalkyl groups; in particular a phenyl group which is substituted by C1-C6-haloalkyl; preferred a phenyl group which is substituted by C1-C4-haloalkyl; most preferred a phenyl group which is substituted by 3-trifluoro- m ethyl; optionally in the presence of a base and an inert solvent. In a particularly preferred embodiment according to this invention the solution of the pyridylcarboxylic amides I, in particular N-(4-fluorophenyl) 2-chloro-pyrid-6-ylinecarbox-amide, in a aromatic hydrocarbon solvent, is added to a mixture of - a base, preferably a alkali hydroxide, in particular potassium hydroxide; - a polar aprotic solvent, in particular N,N-dimethylacetamide; and - an aromatic alcohol of formula VII, in particular 3-hydroxybenzotrifluoride; at 100 to 140 °C. The resulting mixture is heated to temperatures from 140 to 200 °C and the aromatic hydrocarbon and water formed during the reaction is distilled off. Subsequently, the mixture is stirred at elevated temperatures for 1 to 4 hours. The solvent is distilled off under reduced pressure. The residue is diluted with an apolar solvent, in particular a mixture of aromatic and aliphatic hydrocarbons and washed with water or an aqueous alkali hydroxide. The aqueous phase is separated off and the organic phase is dried. The resulting crystals are collected by filtration, washed and dried at elevated tempera- tures and reduced pressure. In order to facilitate a further understanding of the invention, the following illustrative examples are presented. The invention is not limited to the specific embodiments de- scribed or illustrated, but encompasses the full scope of the appended claims. 231 g (1 mol) molten 2-chloro-6-trichloromethylpyridin (= nitrapyrin = NP) is dosed to 98.1 g (1 mol) concentrated sulfuric acid (98 % by weight) within 3 hours at 135 °C. The resulting mixture is stirred for 3 hours at 135 °C. A viscous melted mass is formed which is added to a mixture of 122.0 g (1.1 mol) 4- fluoroaniline, 202.0 g (2 mol) triethylamine and toluene at temperatures between 20 and 100 °C within 45 minutes. The resulting reaction mixture is heated to tempera- tures between 80 and 120 °C and stirred for 1 hour. The mixture is treated with 500 ml of hydrochloric acid (7.5 % by weight) at 80 °C and the phases are separated. The resulting solution of N-(4-fluorophenyl) 2-chloro-pyrid-6-ylinecarboxamide in toluene is used for the preparation of N-(4-fluorophenyl) 2-(3-trifluoromethyl-phenoxy)-pyrid- 6-ylinecarboxamide (example 3) without further purification. 924 g (4 mol) molten NP is dosed to 510.2 g (5.2 mol) concentrated sulfuric acid (98 % by weight), within 3 hours at 135 °C. The resulting mixture is stirred for 3 hours at135°C. A viscous melted mass is obtained which is dosed to 2145 g (35.7 mol) isopropanol within 30 minutes starting at ambient temperature which raises to 60-65 °C. Re- mained isopropanol is distilled off under reduced pressure in 3 hours. The resulting product mixture is added to a mixture of xylene and water. Upon heating to 50 °C the organic phase is separated and washed with water. The obtained organic phase is dried and concentrated by distillation of xylene under reduced pressure. The resulting product (2070 g) contains 34.1 wt% of isopropyl 2-chloro-pyrid-6- ylcarboxylate in xylene which corresponds to a yield of 88.4 % based on NP and is used for the preparation of N-(4-fluorophenyl) 2-(3-trifluoromethylphenoxy)-pyrid-6- ylinecarboxamide without further purification (examples 4 and 5). The solution of 13.5 % (0.226 mol) N-(4-fluorophenyl) 2-chloro-pyrid-6- ylinecarboxamide in toluene obtained according to example 1 is added to a mixture of 19.8 g (0.300 mol) potassium hydroxide, 47.1 g (0.291 mol) 3-hydroxy-benzotrifluoride and 200 ml N,N-dimethylacetamide at 120 °C with stirring. The resulting mixture is heated to 160 °C and toluene and water formed during the reaction is distilled off. Sub- sequently, the mixture is stirred at 160 °C for two hours. The solvent is distilled off. The residue is diluted with xylene and isooctane and washed with water at 80 °C. The aqueous phase is separated off and the organic phase is dried, diluted with isooctane and cooled down to 10 °C within 4 hours. The resulting crystals are collected by filtra- tion and washed with isooctane and dried at 45 °C and 100 mbar. 73.2 g (0.195 mol) N-(4-fluorophenyl) 2-(3-trifluoromethylphenoxy)-pyrid-6- ylinecarboxamide is obtained as a white solid with a purity of 97 % representing an overall yield of 83.5 % based on the amide obtained in example 2. A 30 %wt solution of 212.5 g sodium methoxide in methanol (1.22 equivalents NaOMe) is dosed in 1 h to a solution of 194.5 g (1.24 equivalents) 3- hydroxybenzotrifluoride in 856 g (8.31 equivalents) xylene at 120-110°C, with simul- taneous distillation of methanol. The .resulting phenolate mixture is slowly heated to 140X to distill off remained methanol. A solution of 194.5 g (0.97 mol) isopropyl 2-chloro-pyrid-6-ylcarboxylate in xylene obtained from example 2 is dosed at 140°C to the phenolate mixture in 30 min, fol- lowed by further heating and distillation of xylene to get a batch temperature of 150- 155°C which is kept for 4-6 h to complete the reaction. The resulting reaction mixture is cooled to 135°C and directly used in example 5. 111.1 g (1.03 equivalents) 4-Fluoroaniline is added to the reaction mixture from ex- ample 4 at 135°C, followed by dosing in 30 %wt solution of 24.3 g (0.13 equivalents) sodium methoxide in 30 min with simultaneous distillation of methanol. The reaction mixture is stirred for 2 h at 135°C to complete the reaction. The reaction mixture is then added to a mixture of isooctane and water at 70°C, resulting in a final tempera- ture of 80°C. The aqueous phase is separated off, the organic phase is washed with water at 80°C. The resulting product solution is dried azeotropically under Dean-Stark conditions to a final batch temperature of 105-110°C. The product solution is cooled to 5°C in 5 h, including seeding at 68°C. The crystallized product is filtered, washed with isooctane and dried at 45°C and 100 mbar. 316.5 g trifluoromethylphenoxy)-pyrid-6-ylinecarboxamide is obtained as a white solid with a purity of 99.3 % representing an overall yield of 75.8 % an NP. We Claim: 1. A process for the preparation of pyridylcarboxylic amides and esters I wherein Hal represents a halogen atom; X represents O or NR2; R1 represents a C1-C6-alkyl or aryl group, wherein both groups may be substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy groups; R2 represents a hydrogen atom or a C1-C6-alkyl group; which comprises the following steps: (a) heating a mixture consisting essentially of a trichloromethylpyridine II, wherein Hal has the meaning given, and 1.0 to 1.5 equivalents of concentrated sulfuric acid, characterized in that the trichloromethylpyridine II in a liquid form is added to the concentrated sulfuric acid at a temperature from 110°C to 160 °C; and (b) reacting the intermediate product obtained in step (a) with an amine or alcohol III, HXR1 III, wherein X and R1 have the meaning given, optionally in the presence of a solvent and/or a base. 2. A process as claimed in claim 1, wherein the trichloromethylpyridines II are represented by the trichloromethylpyridines IIA wherein Hal represents a halogen atom. 3. A process as claimed in claim 1 or 2, wherein X represents O; and R1 represents a C1-C6-alkyl group. 4. A process as claimed in claims 1 to 3, wherein X represents NR2; R1 represents a phenyl group which is substituted by one or two halogen atoms and/or C1-C6-haloalkyl groups; and R2 represents a hydrogen atom. 5. A process as claimed in claims 1 to 4, wherein the trichloromethylpyridine II is added to the concentrated sulfuric acid at a temperature from 120 to 150°C. 6. A process as claimed in claims 1 to 5, wherein the mixture of the trichloromethylpyridine II and the concentrated sulfuric acid is kept at a temperature from 120 to 150°C for 30 to 300 minutes. 7. A process as claimed in claims 1 to 6, wherein the sulfuric acid used contains less than 3 % by weight of water. 8. A process as claimed in claims 1 to 7, wherein the intermediate product formed in step (a) comprises a compound of formula VI and/or VII or a structural isomeric form thereof, wherein Hal represents a halogen atom. 9. A process as claimed in claims 1 to 8, wherein the intermediate product formed in step (a) is added to the amine or alcohol III in a liquid form. 10. A process as claimed in claims 1 to 9, wherein the intermediate product obtained in step (a) is treated with an amine III in the presence of a base and an aromatic hydrocarbon as solvent. 11. A process as claimed in claims 1 to 10, wherein an pyridylcarboxylic ester I is treated with an amine III in the presence of a base and an aromatic hydrocarbon as solvent. 12. A process for the preparation of (aryloxy)pyridylcarboxylic amides and esters IV wherein X represents O or NR2; R1 represents a C1-C6-alkyl or aryl group, wherein both groups may be substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyI, C1-C6-haloalkyl or C1-C6-alkoxy groups; R2 represents a hydrogen atom or a C1-C6-alkyl group; R3 represents an aryl group, which may be substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-alkoxy or C1-C6-haloalkyl groups; which comprises the following steps: (a) heating a mixture consisting essentially of a trichloromethylpyridine II as hereinbefore defined, and 1.0 to 1.5 equivalents of concentrated sulfuric acid, characterized in that the trichloromethylpyridine II in a liquid form is added to the concentrated sulfuric acid at a temperature from 110 to 160 °C; (b) reacting the intermediate product obtained in step (a) with an amine or alcohol III as hereinbefore defined, optionally in the presence of a solvent and/or a base; and (c) reacting the pyridylcarboxylic amides and esters I or a salt thereof obtained in step (b) with an aromatic alcohol V, R3-OH V, wherein R3 has the meaning given; optionally in the presence of a base. 13. A process as claimed in claim 12, wherein in step (c) the pyridylcarboxylic amides and esters I or a salt thereof are reacted with an aromatic alcohol V without further purification. 14. A process as claimed in claim 12 or 13 wherein in step (c) a pyridylcarboxylic ester IA, wherein R1 represents a C1-C6-alkyl group, is reacted with an aromatic alcohol V in the presence of a base. 15. A process as claimed in claims 12 to 14 for the preparation of (aryloxy)pyridylcarboxylic amides IV which comprises (c) reacting the pyridylcarboxylic ester I or the salt thereof obtained in step (b) with an aromatic alcohol V in the presence of a base, and (d) treating the resulting (aryloxy)pyridylcarboxylic ester IV with an amine III. 16. A process as claimed in claim 12 for the preparation of (aryloxy)pyridyl-carboxylic amides IV wherein R2 is hydrogen, wherein step (c) comprises reacting an pyridylcarboxylic ester I with an amine III, wherein R2 is hydrogen, and treating the resulting salts 1.1 with an aromatic alcohol V. Abstract PROCESS FOR THE PREPARATION OF PYRIDYLCARBOXYLIC AMIDES AND ESTERS The invention relates to a process for the preparation of pyridylcarboxylic amides and esters I wherein Hal, X and R1 have the meanings given in claim 1, which comprises the following steps: (a) heating a mixture consisting essentially of trichloromethylpyridine II, wherein Hal has the meaning given, and 1.0 to 1.5 equivalents of concentrated sulfuric acid, characterized in that the trichloromethylpyridine II in a liquid form is added to the concentrated sulfuric acid at a temperature from 110°C to 160°C; and (b) reacting the intermediate product obtained in step (a) with an amine or alcohol III, HXR1 III, wherein X and R1 have the meaning given, optionally in the presence of a solvent and/or a base.

Full Text

The present invention relates to a process for the preparation of pyridylcarboxylic am-
ides and esters I

wherein
Hal represents a halogen atom;
X represents O or NR2;
R1 represents a C1-C6-alkyl or aryl group, wherein both groups may be sub-
stituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-
haloalkyl or C1-C6-alkoxy groups;,
R2 represents a hydrogen atom or a C1-C6-alkyl group;
which comprises the following steps:
(a) heating a mixture consisting essentially of a trichloromethylpyridine II,

wherein Hal has the meaning given,
and 1.0 to 1.5 equivalents of concentrated sulfuric acid,
characterized in that the trichloromethylpyridine II in a liquid form is added to the
concentrated sulfuric acid at a temperature from 110 to 160 °C; and
(b) reacting the intermediate product obtained in step (a) with an amine or alco-
hol III,

wherein X and R1 have the meaning given,
optionally in the presence of a solvent and/or a base.
Another aspect of the present invention is a process for the preparation of
(aryloxy)pyridylcarboxylic amides and esters IV

wherein R1 and X have the meaning given, and

R3 represents an aryl group, which may be substituted by one or more halogen
atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy groups;
wherein the pyridylcarboxylic amides and esters I or a salt thereof are prepared from
a trichloromethylpyridine II according to the present invention and
(c) are further reacted with an aromatic alcohol V,
R3-OH v,
wherein R3 has the meaning given,
optionally in the presence of a base.
Pyridylcarboxylic amides and esters I are suitable intermediates for the preparation of a
broad variety of compounds which are useful as agrochemicals or pharmaceuticals. In
particular, they are key intermediates in the preparation of herbicidal phenoxypyridyl-
carboxamides which are described for example in EP 0 447 004.
The European patent application EP 0 646 566 suggests to hydrolyze trichloromethyl
heteroarenes with water in the presence of chlorinated hydrocarbons and a Lewis acid
and to react the resulting heteroarylcarbonyl chloride with an amine.
However, this process causes problems with respect to the dosing rate and the exact
equimolar dosing of water. Any excess of water will cause hydrolysis of the desired
acid chloride compound and therefore reduce the yields. Moreover, in these days using
chlorinated hydrocarbons is not desired because of environmental problems, and the
amount of solvent used in the prior art procedure is high. Furthermore, the reaction
time needed using water/1,2-dichloroethane is very long (24 h).
The European patent application EP 0 899 262 discloses a process for the preparation
of pyridylcarboxylic amides and esters in which sulfuric acid is added to a pyridyltri-
chloromethane compound.
However, this process causes problems since the intermediate formed solidifies at
temperatures below 100 °C, but re-melting of this solidified intermediate is difficult due
to decomposition under evolution of hydrochloric acid and sulphurtrioxide.
It is, therefore, an object of the present invention to provide an efficient new process
for the preparation of pyridylcarboxylic amides and esters in high yield and purity.
The novel improved process avoids the disadvantages of the processes of the prior art
and enables to carry out the production of pyridylcarboxamides and esters in technical
scale and high yields using ready-available educts.

Moreover the process according to the present invention has several advantages with
respect to process safety compared to the process disclosed by EP 0 899 262 A:
The mixture obtained in step (a) is not as sensitive to cooling during adding of the tri-
chloromethypyridine II. The reaction mixture obtained during adding time is more stable
and loss of heating would not cause solidification problems.
Furthermore, when the sulfuric acid is added to the trichloromethylpyridine II as dis-
closed by EP 0 899 262, the trichloromethylpyridine II shows the tendency to evaporate
from the reaction mixture into the overhead system and is condensing and/or solidifying
there. In addition to potential loss of yield, this may cause blockage of valves and vent
lines representing a safety risk.
So the process of the present invention clearly reduces the evaporation of the
richloromethylpyridine II.
Other objects and advantages of the present invention will be apparent to those
skilled in the art from the following description and the appended claims.
In general terms, unless otherwise stated herein, the term "the trichloromethylpyridine
of formula II in a liquid form" includes
trichloromethylpyridines II, which are liquid at room temperature;
and
trichloromethylpyridines II, which are solid at room temperature but are utilized either in
form of a solution in an inert solvent or at a temperature above their melting point, i.e.
they are used in molten form.
In general terms, unless otherwise stated herein, the term "pyridylcarboxylic amides I"
stands for ".pyridylcarboxylic amides and esters I, wherein X represents NR2".
In general terms, unless otherwise stated herein, the term "pyridylcarboxylic esters I"
stands for .pyridylcarboxylic amides and esters I, wherein X represents O".
In general terms, unless otherwise stated herein, the term "amine III" stands for ..amine
or alcohol III, wherein X represents NR2".
In general terms, unless otherwise stated herein, the term "alcohol III" stands for
..amine or alcohol III, wherein X represents O".
In general terms, unless otherwise stated herein, the term "(aryloxy)pyridylcarboxylic
amides IV" stands for „(aryloxy)pyridylcarboxylic amides and esters IV, wherein X re-
presents NR2".

In general terms, unless otherwise stated herein, the term "(aryloxy)pyridylcarboxylic
esters IV" stands for „(aryloxy)pyridylcarboxylic amides and esters IV, wherein X
represents O".
The organic moieties mentioned in the definition of the substituents R1, R2 and R3 or as
substituents on phenyl, naphthyl or anthranyl rings are - like the term halogen - collec-
tive terms for individual enumerations of the individual group members. All hydrocarbon
chains, i.e. all alkyl, haloalkyl and alkoxy groups can be straight-chain or branched, the
prefix Cn-Cm denoting in each case the possible number of carbon atoms in the group.
Halogenated substituents preferably carry one, two, three, four or five identical or dif-
ferent halogen atoms. The term halogen denotes in each case fluorine, chlorine, bro-
mine or iodine.
Examples of other meanings are:
C1-C4-alkyl: CH3, C2H5, n-propyl, CH(CH3)2, n-butyl, CH(CH3)-C2H5, CH2-
CH(CH3)2 and C(CH3)3;
C1-C6-alkyl: C1-C4-alkyl as mentioned above, and also, for example, n-pentyl, 1-
methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-
hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-
methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-
dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-
ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-
methylpropyl or 1-ethyl-2-methylpropyl, preferably methyl, ethyl, n-propyl, 1-
methylethyl, n-butyl, 1,1—dimethylethyl, n-pentyl or n-hexyl;
C1-C4-haloalkyl: a C1-C4-alkyl radical as mentioned above which is partially or
fully substituted by fluorine, chlorine, bromine and/or iodine, i.e., for example,
CH2F, CHF2, CF3, CH2CI, dichloromethyl, trichloromethyl, chlorofluormethyl, di-
chlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-brom-
oethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluor-oethyl,
2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-tri-chloroethyl, C2F5, 2-
fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoro-propyl, 2-chloro-
propyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-
trifluoropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoro-
propyl, 1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl,
1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or non-
afluorobutyl;

C1—C6—haloalkyl: a C1-C4-haloalkyl radical as mentioned above and also, for
example, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undeca-
fluoropentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6-iodohexyl and dode-
cafluorohexyl;
C1-C4-alkoxy: for example OCH3, OC2H5, n-propoxy, OCH(CH3)2, n-butoxy,
OCH(CH3)-C2H5, OCH2-CH(CH3)2 or OC(CH3)3, preferably OCH3, OC2H5 or
OCH(CH3)2;
C1-C6-alkoxy: a C1-C4-alkoxy radical as mentioned above, and also, for exam-
ple, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methoxylbutoxy, 1,1-
dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy,
hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy,
1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy,
2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-tri-
methylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1 -ethyl-2-
methylpropoxy;
aryl: a mono-, bi- or tricyclic aromatic carbocycle containing 6 to 14 ring mem-
bers, for example phenyl, naphthyl und anthracenyl;
As a rule aromatic groups are preferred, which are substituted by at least one electron-
withdrawing group, in particular by one or more halogen atoms, nitro, cyano or C1-C6-
haloalkyl groups.
In a particular embodiment of the process according to the present invention the radi-
cals of the compounds according the present invention are as defined below, these
definitions being both on their own and in combination with one another, particular
embodiments of the present invention:
Preference is given to a process according to the present invention wherein
Hal represents fluorine, chlorine or bromine;
preferably chlorine or bromine;
particular preferably chlorine.
Preference is also given to a process according to the present invention wherein
X represents oxygen.
Preference is also given to a process according to the present invention wherein
X represents NR2.

Preference is also given to a process according to the present invention wherein
R1 represents C1-C6-alkyl, which may be substituted by one or more halogen
atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy
groups;
preferably C1-C6-alkyl, which may be substituted by one or more
halogen atoms;
particularly preferably C1-C6-alkyl;
very particularly preferably C1-C4-alkyl.
Preference is also given to a process according to the present invention wherein
R1 represents an aryl group, which may be substituted by one or more halogen
atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyi or C1-C6-alkoxy
groups;
preferably a phenyl group, which may be substituted by one or more
halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-
alkoxy groups;
particularly preferably a phenyl group, which may be substituted by
one or two halogen atoms selected from fluorine and chlorine;
very particular preferably a phenyl group, which may be substituted
by one halogen atom;
especially preferably a phenyl group, which may be substituted by
one fluorine atom.
Preference is also given to a process according to the present invention wherein
R2 represents hydrogen.
Preference is also given to a process according to the present invention wherein
R2 represents C1-C6-alkyl;
preferably C1-C4-alkyl.
Preference is also given to a process according to the present invention wherein
X represents O; and
R1 represents C1-C6-alkyl, which may be substituted by one or more halogen
atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy
groups;
preferably C1-C6-alkyl, which may be substituted by one or more
halogen atoms;
particularly preferably C1-C6-alkyl;
very particularly preferably C1-C4-alkyl;
most preferably isopropyl.

Preference is also given to a process according to the present invention wherein
X represents NR2;
R1 represents an aryl group, which is substituted by one or more halogen
atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy
groups;
preferably a phenyl group, which is substituted by one or more halo-
gen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy
groups;
particularly preferably a phenyl group, which is substituted by one or
two halogen atoms and/or C1-C6-haloalkyl groups;
very particular preferably a phenyl group, which may be substituted
by one or two halogen atoms selected from fluorine and chlorine;
very particular preferably a phenyl group, which may be substituted
by one halogen atom;
especially preferably a phenyl group, which may be substituted by
one fluorine atom; and
R2 represents hydrogen.
Preference is also given to a process according to the present invention wherein
R3 represents an aryl group, which may be substituted by one or two halogen atoms
or C1-C6-haloalkyl groups;
preferably an aryl group, which may be substituted by one C1-C6-
haloalkyl group.
Preference is also given to a process according to the present invention wherein
R3 represents a phenyl group, which may be substituted by one or more halogen
atoms, nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy
groups;
preferably a phenyl group, which may be substituted by one or more
halogen atoms or C1-C6- haloalkyl groups;
particularly preferably a phenyl group, which may be substituted by
a C1-C6- haloalkyl group;
very particularly preferably a phenyl group, which may be substi-
tuted by a C1-C6- haloalkyl group in 3-position of the phenyl moiety;
especially preferably a phenyl group, which may be substituted by a
C1-C4- haloalkyl group in 3-position of the phenyl moiety.
Preference is also given to a process according to the present invention wherein
the trichloromethylpyridines II are substituted
by one halogen atom,
preferably by a chlorine atom.

Particular preference is given a process according to the present invention wherein
the trichloromethylpyridines II are represented by trichloromethylpyridines HA

Most preference is given a process according to the present invention wherein the
trichloromethylpyridines II are represented by nitrapyrin (NP), a compound IIA, wherein
Hal is CI.
Step (a) of the process according to the present invention comprises heating a mix-
ture consisting essentially of a trichloromethylpyridine II and 1.0 to 1.5 equivalents of
concentrated sulfuric acid, characterized in that the trichloromethylpyridine II in a liquid
form is added to the concentrated sulfuric acid at a temperature from 110 to 160 °C:

The intermediate product formed in step (a) comprises a compound of formula VI
and/or formula VII, or a structural isomeric form thereof:

The reaction of the trichloromethylpyridine II with the sulfuric acid is carried out from
110 °C to 160°C, preferably from 120 °C to 150 °C, most preferred at 135°C.
Preference is given to a process according to the present invention wherein in step (a)
the mixture of the trichloromethylpyridine II and the concentrated sulfuric acid is kept
at temperatures from 120 to 150°C for 30 to 300 minutes, more preferably for 30 to
240 minutes.

Step (a) can be carried out under reduced or elevated pressure, preferably it is car-
ried out at ambient pressure.
Step (a) can be carried out in an inert organic solvent with a suitable boiling point or in
the absence of any solvent.
Suitable solvents are aliphatic hydrocarbons such as mixtures of C5-C8-alkanes, aro-
matic hydrocarbons such as toluene, o-, m- and p-xylene, and halogenated hydrocar-
bons such as chlorobenzene.
It is also possible to use mixtures of the solvents mentioned.
Preference is given to a process according to the present invention wherein step (a)
is carried out in the absence of any solvent.
Preference is given to a process according to the present invention wherein in step
(a) the concentrated sulfuric acid contains less than 3 % by weight of water.
Step (a) is carried out in the presence of 1.0 to 1.5 equivalents, preferably of 1.1 to 1.4
equivalents, particularly preferably of 1.25 to 1.35 equivalents of concentrated sulfuric
acid.
Preference is given to a process according to the present invention wherein in step (a)
the trichloromethylpyridine II is added slowly, more preferably added in a time range
of 1 to 5 hours to the concentrated sulfuric acid.
Under these preferred reaction conditions the reaction of step (a) is as a rule com-
pleted within 30 to 300 minutes, preferably within 45 to 240 minutes, in particular
within 60 to 210 minutes.
The trichloromethylpyridines II required are commercially available or can be prepared
by halogenation of 2-trichloromethylpyridine (e.g. A. R. Katritzky, C. D. Johnson,
Angew. Chem. Int. Ed. 1967, 6, 608-615).
Step (b) of the process according to the present invention comprises reacting the in-
termediate product obtained in step (a) with an amine or alcohol III optionally in the
presence of an inert solvent and/or a base:

The reaction of the intermediate product obtained in step (a) with an amine or alco-
hol III is usually carried out at a temperature between ambient temperature and the
reflux temperature of the reaction mixture, preferably at from 0 °C to 140 °C, particu-
larly preferably at from 20 °C to120°C, most preferred at 40 °C to 100 °C in the pres-
ence of an inert solvent and/or a base.
As a rule step (b) can be carried out under reduced or elevated pressure, preferably it
is carried out at ambient pressure.
Step (b) of the reaction according to the invention may be carried out in the absence
or presence of a solvent, which promotes the reaction or at least does not interfere
with it.
Suitable solvents are apolar solvents including aliphatic hydrocarbons such as pen-
tane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons
such as toluene, o-, m- and p-xylene, halogenated hydrocarbons such as dichloro-
methane, chloroform, 1,2- dichloroethane and chlorobenzene, nitroalkanes such as
nitroethane.
It is also possible to use mixtures of the solvents mentioned.
Step (b) of the reaction according to the invention may be carried out in the absence
or presence of a base.
Suitable bases are, in general, organic bases, e.g. tertiary amines such as tri(CrC6-
alkyl)amines (e.g. trimethylamine, triethylamine, diisopropylethylamine), N-
methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine, N-
methylmorpholine and 4-dimethylaminopyridine and also bicyclic amines.
The bases are generally employed in equimolar amounts, in excess or, if appropriate,
they can be used as solvent. Preferably the bases are used in equimolar amounts.
In general, the intermediate product obtained in step (a) and the amine or alcohol III
are used in equimolar amounts.
It might be advantageous to employ an excess of III based on the intermediate product.

The resulting intermediate product obtained in step (a) is preferably reacted with the
amine or alcohol III in a liquid form or upon dilution with an inert solvent.
In a preferred embodiment the intermediate product of step (a), preferably in a liquid
form, is transferred to the amine or alcohol III.
The reaction of step (b) with an alcohol III is preferably carried out from 40°C to 70°C,
most preferred at 65°C.
In the event that the intermediate product formed in step (a) is reacted with an alco-
hol III, step (b) is preferably carried out with an excess of said alcohol.
Preferably the intermediate product formed in step (a) is reacted with an alcohol III as
a solvent.
Alternatively, the intermediate product obtained in step (a) may be treated with an
alcohol III in the presence of an inert solvent such as toluene.
Preference is given to a process according to the present invention wherein in step (b)
the intermediate product obtained in step (a) is treated with an alcohol III wherein
R1 represents C1-C6-alkyl, which may be substituted by one or more halogen atoms,
nitro, cyano, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-alkoxy groups;
preferably C1-C6-alkyl;
more preferably ethyl or isopropyl.
The reaction of step (b) with an amine III is preferably carried out from 50 °C to
140 °C, most preferred at 80°C.
In the event that the intermediate product formed in step (a) is reacted with an amine
III, step (b) is preferably carried out in the presence of a base as listed above;
particularly preferably in the presence of tri(C1-C6-alkyl)amines (e.g. trimethylamine,
triethylamine, diisopropylethylamine), N-methylpiperidine, pyridine, substituted pyri-
dines such as collidine, lutidine, N-methylmorpholine and 4-dimethylaminopyridine;
very particular preferably tri(C1-C6-alkyl)amines;
especially preferably triethylamine.
Preferably the intermediate product formed in step (a) is reacted with an amine III as
a solvent.

Alternatively, the intermediate product obtained in step (a) may be treated with an
amine III in the presence of an inert solvent, preferably an aromatic hydrocarbon such
as toluene.
Preference is given to a process according to the present invention wherein the inter-
mediate product obtained in step (a) is treated with an amine III in the presence of a
base and an aromatic hydrocarbon as a solvent.
Preference is also given to a process according to the present invention wherein the
intermediate product obtained in step (a) is treated with an amine III wherein
R1 represents a phenyl group, which is substituted by one or two halogen atoms
and/or C1-C6-haloalkyl groups;
preferably a phenyl group, which may be substituted by one or two
halogen atoms selected from fluorine and chlorine;
particular preferably a phenyl group, which may be substituted by
one halogen atom;
especially preferably a phenyl group, which may be substituted by
one fluorine atom; and
R2 represents hydrogen.
Under this preferred reaction conditions step (b) is as a rule completed within 0.5 to
5, in particular 1 to 4 hours.
The amines or alcohols III required are commercially available.
The obtained pyridylcarboxylic amides and esters I may be purified by standard proce-
dures, as for example by crystallization or chromatography, in particular by crystalliza-
tion.
However, since the pyridylcarboxylic amides and esters I are obtained in high purity
with the process according to the invention, it is also possible to use the obtained prod-
uct without further purification to prepare (aryloxy)pyridylcarboxylic amides and esters
IV.
Pyridylcarboxylic amides I can also prepared from pyridylcarboxylic esters I,
which have been prepared in step (b) by treating the intermediate product ob-
tained in step (a) with an alcohol III as mentioned above,
by treating the pyridylcarboxylic esters I with an amine III as hereinbefore defined,
in the presence of a base:

The reaction of the pyridylcarboxylic ester I with an amine 111 is usually carried out at a
temperature between ambient temperature and the reflux temperature of the reaction
mixture, preferably at from 25 °C to 140 °C, particularly preferably at from 50 °C to
110°C, most preferred at 80 °C to 100 °C in the presence of an inert solvent and a
base.
As a rule step (b) can be carried out under reduced or elevated pressure, preferably it
is carried out at ambient pressure.
This reaction according to the invention may be carried out in the absence or pres-
ence of a solvent, which promotes the reaction or at least does not interfere with it.
Suitable solvents are apolar solvents including aliphatic hydrocarbons such as pen-
tane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons
such as tolene, o-, m- and p-xylene, halogenated hydrocarbons such as dichloro-
methane, chloroform, 1,2- dichloroethane and chlorobenzene.
Particular preference is given to aliphatic hydrocarbons, halogenated hydrocarbons
and aromatic hydrocarbons.
It is also possible to use mixtures of the solvents mentioned.
Suitable bases are, in general Inorganic compounds such as alkali metal and alkaline
earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hy-
droxide and calcium hydroxide, alkali metal and alkaline earth metal oxide such as lith-
ium oxide, sodium oxide, calcium oxide and magnesium oxide, as well as alkali metal
and alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potas-
sium ethoxide, potassium tert-butoxide, potassium tert-pentoxide and dimethoxymag-
nesium, and furthermore organic bases, such as tertiary amines such as trimethyl-
amine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substi-
tuted pyridines such as collidine, lutidine, N-methylmorpholine and 4-
dimethylaminopyridine and also bicyclic amines.
Preferred bases are metal alkoxides such as sodium methoxide or sodium ethoxide.

The bases are generally employed in catalytic amounts, however they can also be em-
ployed in equimolar amounts, in excess or, if appropriate, be used as solvent.
In general, the pyridylcarboxylic ester I and the amine III are used in equimolar
amounts. It might be advantageous to employ an excess of III based on the pyridylcar-
boxylic ester I.
Preference is given to a process according to the present invention wherein a pyridyl-
carboxylic ester I is treated with an amine III in the presence of a base as mentioned
above and an aromatic hydrocarbon as solvent.
In the event that pyridylcarboxylic amides I are prepared from pyridylcarboxylic esters I
by treating the pyridylcarboxylic esters I with an amine III,
wherein R2 represents a hydrogen atom,
in the presence of a base,
salts of formula 1.1 are formed:

Preference is given to a process according to the present invention wherein a pyridyl-
carboxylic ester IA,

is reacted with an amine III, wherein R2 represents a hydrogen atom,
to give the salts 1.1 A

Another aspect of the present invention is a process for the preparation of (aryl-
oxy)pyridylcarboxylic amides and esters IV

wherein
X represents O or NR2;
R1 represents a C1-C6-alkyl or aryl group, wherein both groups may be sub-
stituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl, C1-C6-
haloalkyl or C1-C6alkoxy groups;
R2 represents a hydrogen atom or a C1-C6-alkyl group;
R3 represents an aryl group, which may be substituted by one or more halo-
gen atoms, nitro, cyano, C1-C6-alkyI, C1-C6-alkoxy or C1-C6-haloalkyl
groups;
which comprises the following steps:
(a) heating a mixture consisting essentially of a trichloromethylpyridine II as here-
inbefore defined, and 1.0 to 1.5 equivalents of concentrated sulfuric acid,
characterized in that the trichloromethylpyridine II in a liquid form is added
to the concentrated sulfuric acid at a temperature from 110 to 160 CC;
(b) reacting the intermediate product obtained in step (a) with an amine or alco-
hol III as hereinbefore defined, optionally in the presence of a solvent and/or a
base; and
(c) reacting the pyridylcarboxylic amides and esters I or a salt thereof obtained in
step (b) with an aromatic alcohol V,
R3-OH v,
wherein R3 has the meaning given;
optionally in the presence of a base:

The reaction of the pyridylcarboxylic amides and esters I or a salt thereof with an aro-
matic alcohol V is usually carried out at from 0°C to the boiling point of the reaction

mixture, preferably at from 60 °C to 200 °C, particularly preferably at from 140 °C to
180 °C, in an inert organic solvent optionally in the presence of a base.
Suitable solvents are apolar solvents including aliphatic hydrocarbons such as pen-
tane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons
such as toluene, o-, m- and p-xylene, halogenated hydrocarbons such as dichloror-
methane, 1,2-dichlororethane, chloroform and chlorobenzene, as well as amides such
as dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone.
Particular preference is given to apolar or polar aprotic solvents like aliphatic hydro-
carbons, halogenated hydrocarbons, aromatic hydrocarbons or amides such as di-
methylformamide, N,N-dimethylacetamide or N-methylpyrrolidone or mixtures of any
of these solvents.
It is also possible to use mixtures of the solvents mentioned.
Suitable bases are, in general Inorganic compounds such as alkali metal and alkaline
earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hy-
droxide and calcium hydroxide, as well as alkali metal and alkaline earth metal alkox-
ides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-
butoxide, potassium tert-pentoxide and dimethoxymagnesium, and furthermore organic
bases such as tertiary amines such as trimethylamine, triethylamine, diisopropylethyl-
amine and N-methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine,
N-methylmorpholine and 4-dimethylaminopyridine and also bicyclic amines.
Particular preference is given to metal alkoxides or metal hydroxides such as sodium
methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide.
The bases are generally employed in equimolar amounts, however they can also be
employed in excess or, if appropriate as solvent.
Preference is given to a process according to the present invention wherein in step (c)
the pyridylcarboxylic amides and esters I or a salt thereof obtained according to the
present invention are reacted with an aromatic alcohol V without further purification.
Preference is also given to a process according to the present invention wherein a
pyridylcarboxylic ester IA is reacted with an aromatic alcohol V in the presence of a
base to give (aryloxy)pyridylcarboxylic esters IVA:

In a particularly preferred embodiment according to the present invention the liquid
obtained in step (a) is added to 5 to 15 equivalents of an alcohol III,
in particular isopropanol,
at a temperature between 20 and 85 °C.
The resulting reaction mixture is diluted with an aromatic hydrocarbon and washed with
water.
The resulting solution is added at temperatures from 120 to 160°C to a solution of the
salt of an aromatic alcohol V,
which is obtained by treating 1.01 to 1.30 equivalents, in particular about 1.22
equivalents, of an aromatic alcohol V,
and a solution of sodium alkoxide,
preferably 1.01 to 1.30 equivalents sodium alkoxide,
in particular 1.22 equivalents sodium alkoxide,
most preferred sodium methoxide,
in an alcohol;
in an aromatic hydrocarbon, in particular xylene,
at 100-140°C.
Preferably the excess of the remained alcohol V is distilled off before the pyridylcar-
boxylic ester I is added to the solution of the salt of an aromatic alcohol V.
The reaction mixture is as rule heated to 140 - 160°C and kept at this temperature for
2-8 hours to complete the reaction.
In a preferred embodiment of the present invention a pyridylcarboxylic ester I or the
salt 1.1 thereof obtained according to the present invention in step (b) is reacted with
an aromatic alcohol V in the presence of a base [step (c)], and the resulting (ary-
loxy)pyridylcarboxylic ester IV is subsequently treated with an amine III [step (d)] to
give (aryloxy)pyridylcarboxylic amides IV:

Particular preference is given to a process according to the present invention,
wherein in step (c) a pyridylcarboxylic ester IA,

wherein R1 represents a C1-C6-alkyl group;
preferably an isopropyl group,
is reacted with an aromatic alcohol V in the presence of a base; and
treating the resulting (aryloxy)pyridylcarboxylic ester IVA,

wherein R1 and R3 have the meaning given,
with an amine III as hereinbefore defined in the presence of a base.
In a further preferred embodiment of the present invention a pyridylcarboxylic ester I is
reacted with an amine III, wherein R2 is hydrogen, and the resulting salts 1.1 are sub-
sequently treated with an aromatic alcohol V to give (aryloxy)pyridylcarboxylic amides
IV wherein R2 is hydrogen:

Particular preference is also given to a process according to the present invention
wherein a pyridylcarboxylic ester IA,

wherein R1 represents a C1-C6-alkyl group;
preferably an isopropyl group,

is reacted with an amine III, wherein R2 represents a hydrogen atom,
to give the salts 1.1 A

which are subsequently treated with an aromatic alcohol V to give the (ary-
loxy)pyridylcarboxylic amides IV.A wherein R2 is hydrogen

without using any additional base.
In a further particularly preferred embodiment according to the present invention
an amine III, in particular 0.9 to 1.2 equivalents,
preferably a halogenated aniline,
in particular 4-fluoroaniline
is added to the resulting reaction mixture
at 120-150°C,
in particular at 135 °C;
optionally followed by adding a sodium alkoxide solution,
in particular sodium methoxide solution,
preferably catalytical amounts,
more preferably 0.05 to 0.20 equivalents,
mostly preferably about 0.13 equivalents
in 10 to 60 minutes
with simultaneous distillation of the alcohol used [step (d)].
The reaction mixture is stirred for 1 to 4 hours at 120 to 150 °C, in particular at about
135°C to complete the reaction.
In another preferred embodiment of the present invention a pyridylcarboxylic amide of
I or the salt 1.1 thereof obtained according to the present invention is treated with an
aromatic alcohol of formula V:

The reaction of the pyridylcarboxylic amides I or 1.1 with an aromatic alcohol V is car-
ried out at a temperature from 0 °C to 250 °C, preferably at elevated temperatures
from 60 to 200 °C, in particular from 140 to 180 °C, most preferred at 160 °C.
Particular preference is given to a process according to the present invention wherein
the pyridylcarboxylic amide of I or the salt thereof obtained according to the present
invention is treated with an aromatic alcohol of formula V, wherein
R3 represents a phenyl group, which is substituted by one or more halogen at-
oms, nitro, cyano, C1-C6-alkyl, C1-C6-alkoxy or C1-C6-haloalkyl
groups;
in particular a phenyl group which is substituted by C1-C6-haloalkyl;
preferred a phenyl group which is substituted by C1-C4-haloalkyl;
most preferred a phenyl group which is substituted by 3-trifluoro-
m ethyl;
optionally in the presence of a base and an inert solvent.
In a particularly preferred embodiment according to this invention the solution of the
pyridylcarboxylic amides I,
in particular N-(4-fluorophenyl) 2-chloro-pyrid-6-ylinecarbox-amide,
in a aromatic hydrocarbon solvent,
is added to a mixture of
- a base, preferably a alkali hydroxide, in particular potassium hydroxide;
- a polar aprotic solvent, in particular N,N-dimethylacetamide; and
- an aromatic alcohol of formula VII, in particular 3-hydroxybenzotrifluoride;
at 100 to 140 °C.
The resulting mixture is heated to temperatures from 140 to 200 °C and the aromatic
hydrocarbon and water formed during the reaction is distilled off. Subsequently, the
mixture is stirred at elevated temperatures for 1 to 4 hours. The solvent is distilled off
under reduced pressure. The residue is diluted with an apolar solvent, in particular a
mixture of aromatic and aliphatic hydrocarbons and washed with water or an aqueous
alkali hydroxide. The aqueous phase is separated off and the organic phase is dried.
The resulting crystals are collected by filtration, washed and dried at elevated tempera-
tures and reduced pressure.

In order to facilitate a further understanding of the invention, the following illustrative
examples are presented. The invention is not limited to the specific embodiments de-
scribed or illustrated, but encompasses the full scope of the appended claims.

231 g (1 mol) molten 2-chloro-6-trichloromethylpyridin (= nitrapyrin = NP) is dosed to
98.1 g (1 mol) concentrated sulfuric acid (98 % by weight) within 3 hours at 135 °C.
The resulting mixture is stirred for 3 hours at 135 °C.
A viscous melted mass is formed which is added to a mixture of 122.0 g (1.1 mol) 4-
fluoroaniline, 202.0 g (2 mol) triethylamine and toluene at temperatures between 20
and 100 °C within 45 minutes. The resulting reaction mixture is heated to tempera-
tures between 80 and 120 °C and stirred for 1 hour. The mixture is treated with 500
ml of hydrochloric acid (7.5 % by weight) at 80 °C and the phases are separated. The
resulting solution of N-(4-fluorophenyl) 2-chloro-pyrid-6-ylinecarboxamide in toluene
is used for the preparation of N-(4-fluorophenyl) 2-(3-trifluoromethyl-phenoxy)-pyrid-
6-ylinecarboxamide (example 3) without further purification.

924 g (4 mol) molten NP is dosed to 510.2 g (5.2 mol) concentrated sulfuric acid
(98 % by weight), within 3 hours at 135 °C. The resulting mixture is stirred for 3 hours
at135°C.
A viscous melted mass is obtained which is dosed to 2145 g (35.7 mol) isopropanol
within 30 minutes starting at ambient temperature which raises to 60-65 °C. Re-
mained isopropanol is distilled off under reduced pressure in 3 hours. The resulting
product mixture is added to a mixture of xylene and water. Upon heating to 50 °C the
organic phase is separated and washed with water. The obtained organic phase is
dried and concentrated by distillation of xylene under reduced pressure.
The resulting product (2070 g) contains 34.1 wt% of isopropyl 2-chloro-pyrid-6-
ylcarboxylate in xylene which corresponds to a yield of 88.4 % based on NP and is

used for the preparation of N-(4-fluorophenyl) 2-(3-trifluoromethylphenoxy)-pyrid-6-
ylinecarboxamide without further purification (examples 4 and 5).

The solution of 13.5 % (0.226 mol) N-(4-fluorophenyl) 2-chloro-pyrid-6-
ylinecarboxamide in toluene obtained according to example 1 is added to a mixture of
19.8 g (0.300 mol) potassium hydroxide, 47.1 g (0.291 mol) 3-hydroxy-benzotrifluoride
and 200 ml N,N-dimethylacetamide at 120 °C with stirring. The resulting mixture is
heated to 160 °C and toluene and water formed during the reaction is distilled off. Sub-
sequently, the mixture is stirred at 160 °C for two hours. The solvent is distilled off. The
residue is diluted with xylene and isooctane and washed with water at 80 °C. The
aqueous phase is separated off and the organic phase is dried, diluted with isooctane
and cooled down to 10 °C within 4 hours. The resulting crystals are collected by filtra-
tion and washed with isooctane and dried at 45 °C and 100 mbar.
73.2 g (0.195 mol) N-(4-fluorophenyl) 2-(3-trifluoromethylphenoxy)-pyrid-6-
ylinecarboxamide is obtained as a white solid with a purity of 97 % representing an
overall yield of 83.5 % based on the amide obtained in example 2.

A 30 %wt solution of 212.5 g sodium methoxide in methanol (1.22 equivalents
NaOMe) is dosed in 1 h to a solution of 194.5 g (1.24 equivalents) 3-
hydroxybenzotrifluoride in 856 g (8.31 equivalents) xylene at 120-110°C, with simul-
taneous distillation of methanol. The .resulting phenolate mixture is slowly heated to
140X to distill off remained methanol.
A solution of 194.5 g (0.97 mol) isopropyl 2-chloro-pyrid-6-ylcarboxylate in xylene
obtained from example 2 is dosed at 140°C to the phenolate mixture in 30 min, fol-
lowed by further heating and distillation of xylene to get a batch temperature of 150-
155°C which is kept for 4-6 h to complete the reaction. The resulting reaction mixture
is cooled to 135°C and directly used in example 5.

111.1 g (1.03 equivalents) 4-Fluoroaniline is added to the reaction mixture from ex-
ample 4 at 135°C, followed by dosing in 30 %wt solution of 24.3 g (0.13 equivalents)
sodium methoxide in 30 min with simultaneous distillation of methanol. The reaction
mixture is stirred for 2 h at 135°C to complete the reaction. The reaction mixture is
then added to a mixture of isooctane and water at 70°C, resulting in a final tempera-
ture of 80°C. The aqueous phase is separated off, the organic phase is washed with
water at 80°C. The resulting product solution is dried azeotropically under Dean-Stark
conditions to a final batch temperature of 105-110°C. The product solution is cooled
to 5°C in 5 h, including seeding at 68°C. The crystallized product is filtered, washed
with isooctane and dried at 45°C and 100 mbar.
316.5 g trifluoromethylphenoxy)-pyrid-6-ylinecarboxamide is obtained as a white solid
with a purity of 99.3 % representing an overall yield of 75.8 % an NP.

We Claim:
1. A process for the preparation of pyridylcarboxylic amides and esters I

wherein
Hal represents a halogen atom;
X represents O or NR2;
R1 represents a C1-C6-alkyl or aryl group, wherein both groups may be
substituted by one or more halogen atoms, nitro, cyano, C1-C6-alkyl,
C1-C6-haloalkyl or C1-C6-alkoxy groups;
R2 represents a hydrogen atom or a C1-C6-alkyl group;
which comprises the following steps:
(a) heating a mixture consisting essentially of a trichloromethylpyridine II,

wherein Hal has the meaning given,
and 1.0 to 1.5 equivalents of concentrated sulfuric acid,
characterized in that the trichloromethylpyridine II in a liquid form is added
to the concentrated sulfuric acid at a temperature from 110°C to 160 °C; and
(b) reacting the intermediate product obtained in step (a) with an amine or
alcohol III,
HXR1 III,
wherein X and R1 have the meaning given,
optionally in the presence of a solvent and/or a base.
2. A process as claimed in claim 1, wherein the trichloromethylpyridines II are
represented by the trichloromethylpyridines IIA

wherein Hal represents a halogen atom.

3. A process as claimed in claim 1 or 2, wherein
X represents O; and
R1 represents a C1-C6-alkyl group.
4. A process as claimed in claims 1 to 3, wherein
X represents NR2;
R1 represents a phenyl group which is substituted by one or two halogen atoms
and/or C1-C6-haloalkyl groups; and
R2 represents a hydrogen atom.
5. A process as claimed in claims 1 to 4, wherein the trichloromethylpyridine II is
added to the concentrated sulfuric acid at a temperature from 120 to 150°C.
6. A process as claimed in claims 1 to 5, wherein the mixture of the trichloromethylpyridine II
and the concentrated sulfuric acid is kept at a temperature from 120 to 150°C for 30 to
300 minutes.
7. A process as claimed in claims 1 to 6, wherein the sulfuric acid used contains
less than 3 % by weight of water.
8. A process as claimed in claims 1 to 7, wherein the intermediate product
formed in step (a) comprises a compound of formula VI and/or VII or a structural
isomeric form thereof,

wherein Hal represents a halogen atom.
9. A process as claimed in claims 1 to 8, wherein the intermediate product formed
in step (a) is added to the amine or alcohol III in a liquid form.
10. A process as claimed in claims 1 to 9, wherein the intermediate product obtained
in step (a) is treated with an amine III in the presence of a base and an aromatic
hydrocarbon as solvent.
11. A process as claimed in claims 1 to 10, wherein an pyridylcarboxylic ester I is
treated with an amine III in the presence of a base and an aromatic hydrocarbon
as solvent.

12. A process for the preparation of (aryloxy)pyridylcarboxylic amides and esters IV

wherein
X represents O or NR2;
R1 represents a C1-C6-alkyl or aryl group, wherein both groups may be substituted
by one or more halogen atoms, nitro, cyano, C1-C6-alkyI, C1-C6-haloalkyl
or C1-C6-alkoxy groups;
R2 represents a hydrogen atom or a C1-C6-alkyl group;
R3 represents an aryl group, which may be substituted by one or more halogen
atoms, nitro, cyano, C1-C6-alkyl, C1-C6-alkoxy or C1-C6-haloalkyl groups;
which comprises the following steps:
(a) heating a mixture consisting essentially of a trichloromethylpyridine II as
hereinbefore defined, and 1.0 to 1.5 equivalents of concentrated sulfuric acid,
characterized in that the trichloromethylpyridine II in a liquid form is added
to the concentrated sulfuric acid at a temperature from 110 to 160 °C;
(b) reacting the intermediate product obtained in step (a) with an amine or
alcohol III as hereinbefore defined, optionally in the presence of a solvent
and/or a base; and
(c) reacting the pyridylcarboxylic amides and esters I or a salt thereof obtained
in step (b) with an aromatic alcohol V,
R3-OH V,
wherein R3 has the meaning given;
optionally in the presence of a base.
13. A process as claimed in claim 12, wherein in step (c) the pyridylcarboxylic amides
and esters I or a salt thereof are reacted with an aromatic alcohol V without further
purification.
14. A process as claimed in claim 12 or 13 wherein in step (c) a pyridylcarboxylic
ester IA,

wherein R1 represents a C1-C6-alkyl group,
is reacted with an aromatic alcohol V in the presence of a base.
15. A process as claimed in claims 12 to 14 for the preparation of (aryloxy)pyridylcarboxylic
amides IV which comprises
(c) reacting the pyridylcarboxylic ester I or the salt thereof obtained in step (b)
with an aromatic alcohol V in the presence of a base, and
(d) treating the resulting (aryloxy)pyridylcarboxylic ester IV with an amine III.
16. A process as claimed in claim 12 for the preparation of (aryloxy)pyridyl-carboxylic
amides IV wherein R2 is hydrogen, wherein step (c) comprises
reacting an pyridylcarboxylic ester I with an amine III,
wherein R2 is hydrogen, and
treating the resulting salts 1.1 with an aromatic alcohol V.

Abstract

PROCESS FOR THE PREPARATION OF PYRIDYLCARBOXYLIC AMIDES AND ESTERS
The invention relates to a process for the preparation of pyridylcarboxylic amides and
esters I
wherein Hal, X and R1 have the meanings given in claim 1,
which comprises the following steps:
(a) heating a mixture consisting essentially of trichloromethylpyridine II,

wherein Hal has the meaning given,
and 1.0 to 1.5 equivalents of concentrated sulfuric acid,
characterized in that the trichloromethylpyridine II in a liquid form is added to the
concentrated sulfuric acid at a temperature from 110°C to 160°C; and
(b) reacting the intermediate product obtained in step (a) with an amine or alcohol
III,
HXR1 III,
wherein X and R1 have the meaning given,
optionally in the presence of a solvent and/or a base.

Documents:

01645-kolnp-2008-abstract.pdf

01645-kolnp-2008-claims.pdf

01645-kolnp-2008-correspondence others.pdf

01645-kolnp-2008-description complete.pdf

01645-kolnp-2008-form 1.pdf

01645-kolnp-2008-form 3.pdf

01645-kolnp-2008-form 5.pdf

01645-kolnp-2008-international exm report.pdf

01645-kolnp-2008-pct priority document notification.pdf

01645-kolnp-2008-pct request form.pdf

1645-KOLNP-2008-(01-05-2013)-CORRESPONDENCE.pdf

1645-KOLNP-2008-(01-05-2013)-FORM 3.pdf

1645-KOLNP-2008-(06-12-2012)-ABSTRACT.pdf

1645-KOLNP-2008-(06-12-2012)-ANNEXURE TO FORM 3.pdf

1645-KOLNP-2008-(06-12-2012)-CLAIMS.pdf

1645-KOLNP-2008-(06-12-2012)-CORRESPONDENCE.pdf

1645-KOLNP-2008-(06-12-2012)-DESCRIPTION (COMPLETE).pdf

1645-KOLNP-2008-(06-12-2012)-FORM-1.pdf

1645-KOLNP-2008-(06-12-2012)-FORM-2.pdf

1645-KOLNP-2008-(06-12-2012)-OTHERS.pdf

1645-KOLNP-2008-(06-12-2012)-PETITION UNDER RULE 137.pdf

1645-KOLNP-2008-(30-11-2012)-CORRESPONDENCE.pdf

1645-KOLNP-2008-(30-11-2012)-OTHERS.pdf

1645-KOLNP-2008-ASSIGNMENT.pdf

1645-KOLNP-2008-CANCELLED PAGES.pdf

1645-KOLNP-2008-CORRESPONDENCE 1.1.pdf

1645-KOLNP-2008-CORRESPONDENCE.pdf

1645-KOLNP-2008-EXAMINATION REPORT.pdf

1645-KOLNP-2008-FORM 18.pdf

1645-KOLNP-2008-FORM 3 1.1.pdf

1645-KOLNP-2008-GPA.pdf

1645-KOLNP-2008-GRANTED-ABSTRACT.pdf

1645-KOLNP-2008-GRANTED-CLAIMS.pdf

1645-KOLNP-2008-GRANTED-DESCRIPTION (COMPLETE).pdf

1645-KOLNP-2008-GRANTED-FORM 1.pdf

1645-KOLNP-2008-GRANTED-FORM 2.pdf

1645-KOLNP-2008-GRANTED-FORM 3.pdf

1645-KOLNP-2008-GRANTED-FORM 5.pdf

1645-KOLNP-2008-GRANTED-SPECIFICATION-COMPLETE.pdf

1645-KOLNP-2008-INTERNATIONAL SEARCH REPORT & OTHERS.pdf

1645-KOLNP-2008-OTHERS.pdf

1645-KOLNP-2008-PETITION UNDER RULE 137.pdf

1645-KOLNP-2008-PRIORITY DOCUMENT.pdf

1645-KOLNP-2008-REPLY TO EXAMINATION REPORT.pdf

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Patent Number

257790

Indian Patent Application Number

1645/KOLNP/2008

PG Journal Number

45/2013

Publication Date

08-Nov-2013

Grant Date

04-Nov-2013

Date of Filing

24-Apr-2008

Name of Patentee

BASF SE

Applicant Address

67056 LUDWIGSHAFEN

Inventors:

#	Inventor's Name	Inventor's Address
1	BRINK MONIKA	VORDERER BOHL 31A, 55218 INGELHEIM
2	WEVERS JAN HENDRIK	GARTENSTR. 11, 67591 HOHEN-SULZEN
3	KNELL MARCUS	UNTERGASSE 8, 65239 HOCHHEIM

PCT International Classification Number

C07D 213/81

PCT International Application Number

PCT/EP2006/067818

PCT International Filing date

2006-10-26

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/733755	2005-11-07	U.S.A.