Title of Invention	"PROCESS FOR THE PREPARATION OF 2- AMINOMETHYLPYRIDINE DERIVATIVES"
Abstract	Process for the preparation of 2-aminomethylpyridine derivative of general formula (I), in which: n represents 0, 1, 2 or 3; X is a halogen atom; Y may be the same or different and may be a halogen atom, a halogenalkyl, a alkoxycarbonyl or a alkylsulphonyl.

Full Text

The present invention relates to a novel process for the preparation of 2-aminomethylpyridine derivative which is useful as intermediate compound for .the preparation of pesticides, starting with benzophenone and 'glytine alkyl ester hydrochloride. Patent application WO 99/42447 discloses1 the preparation of 2-aminomethylpyridines starting from benzophenone glycine imine alkyl ester. This document does not disclose a method for the preparation of benzophenone gjycine imine alkyl ester. Certain methods for the preparation of benzophenone glycine imine alkyl ester have been reported in Journal ofPeptide Research (2000), 55(4), page 300-307. This article discloses the reaction of benzophenone imine with alkyl glycinate hydrochlbride to prepare benzophenone glycine imine alkyl ester. The use of benzophenone is not disclosed in that document. The use of benzophenone imine presents the.drawback in that it is expensive. Furthermore, this compound converts into the benzophenone compound during the preparation of 2-aminomethylpyridine compounds thus resulting in an additional step in the process to convert benzophenone into benzophenone imine before recycle, which is undesirable on a commercial plant. We have now found an alternative method to prepare 2-aminomethylpyridine derivatives which. overcomes these problems and which is applicable to industrial scale operation. Accordingly, the present invention relates to a process for the preparation of a 2-aminomethylpyridine derivative of general formula (I) or a salt thereof: (Formula Removed) in which : - n represents 0, 1,2 or 3, - X is halogen atom, - Y may be the same or different, and may a halogen atom, a halogenoalkyl, a alkoxycarbonyl or a alkylsulphohyl; , said process comprising: (A)- a first step according to reaction scheme 1 : Scheme I (Scheme Removed) in which benzophenone (BP) is reacted with glycine alkyl ester hydrochloride (GAE.HC1) at reflux in a non polar solvent, said solvent being capable of forming an azeotrope with water, in the presence of an acid catalyst and a trialkylamine base, in a BP / GAE.HC1 molar ratio of from 1 to 4, to provide a benzophenone glycine inline derivative (BPGI); Us" (B)- a second step according to reaction scheme 2 : Scheme 2 (Scheme Removed) in which: - X, Y and n are as defined above, - z is a leaving group, comprising the reaction of the benzophenone glycine inline derivative (BPGI) solution obtained in step one with a pyridine derivative (Py-z) in the presence of a dry inorganic base, in the presence of a catalyst and an aprotic polar solvent, the mixture being heated at reflux, to provide a pyridine glycine imine derivative (PyGI); (C)- a third step according to reaction scheme 3 : Scheme 3 (Scheme Removed) in which X, Y and n are as defined above comprising the addition to the previous pyridine glycine imine derivative (PyGI). solution of an aqueous hydrochloric acid at a temperature up to 25°C, in a HC1 / PyGI molar ratio of at least 1, to provide a pyridine glycine ester hydrochloride derivative (PyGE.HCl); (D)- a fourth step comprising the conversion of the pyridine glycine ester hydrochloride derivative (PyGE.HCl) into a compound of general formula (I) by heating under reflux of water. For the purposes of the present invention : - Alk represents a C1-C6 alkyl moiety, preferably ethyl; - haloalkyl means C1-C6 alkyl moiety substituted by one or more halogen atoms; - alkoxycarbonyl means C1-C6 alkoxycarbonyl. Suitable examples of such a moiety may be methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl and i- propoxycarbonyl; - alkylsulphonyl means C1-C6 alkysulphonyl; - "Catalyst" means a compound which is used in an amount of 0,01 to 0,2 molar equivalent preferably from 0,01 to 0,1 molar equivalent of the respective reagent or intermediate compound; - a halogen atom may be a bromine atom, a chlorine atom, a iodine atom or a fluorine atom. During the preparation of PyGE.HCl from PyGI according to the present invention, benzophenone can be recovered and ready to be directly recycled for benzophenone glycine imine alkyl ester preparation. According to the present invention, benzophenone does not need to be recycled into benzophenone imine, avoiding an expensive additional step. Furthermore, the yield of product obtained by the process according to the present invention is greater than the yield achievable with the processes known from the prior art. The present invention relates to a process for the preparation of compound of general formula (I). Preferably, the different characteristics of compound of formula (I) may be chosen independently from each other as being: - as regards X, X is chlorine; - as regards n, n is 1; - as regards Y, Y is haloalkyl; more preferably, Y is trifluoromethyl. » More preferably, the present invention relates to a process for the preparation of compound of general formula (I) in which: - X is chlorine; -nis 1; - Y is trifluoromethyl. The process of the present invention is particularly suitable for the preparation of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine. The first step (step A) of the process according to the present invention requires the use of a solvent which is capable of forming an azeotrope with water. Suitable solvent includes toluene or ethylbenzene. StepjA of the process according to the present invention requires the use of ani acid catlayst, preferably i-paratoluenesulfonic acid catalyst. Step A of the process according to the present invention requires also the use of a trialkylamine base. The preferred trialkylamine base is N,N-diisopropyl N-ethylamine. The second step (step B) of the process according to the present invention comprises the reaction of the benzophenone glycine imine derivative (BPGI) obtained in step one with a pyridine derivative (Py-z), wherein z is a leaving group, preferably a halogen atom and more preferably a chlorine atom. Step B of the process according to the present invention requires the use of a dry inorganic base. Suitable dry inorganic base includes dry K2CO3 or NaH. Step B of the process according to the present invention requires the use of a catalyst, preferably a phase transfer catalyst. Suitable phase transfer catalyst may be NEUBr. Step B of the process according to the present invention also requires the use of an aprotic polar solvent. Suitable solvent may be propionitrile. The third step (step C) of the process according "to the present invention is carried out at a temperature up to 25°C, preferably at a temperature of from 20 to 25°C. Step C is carried out in a HC1 / PyGI molar ratio of at least 1, preferably in a HC1 / PyGI molar ratio of from 1 to 5. The product stream obtained in the different steps of the process according to the present invention may be treated to separate and to recycle useful compounds. Such post treatment steps may be carried out according to methods well known by the man ordinary skilled in the art. Particularly, the mixture obtained following to step A may be cooled down and washed with water to dissolve trialkylamine base hydrochloride salt. The two liquid phases may then be separated. The bottom aqueous layer containing the trialkylamine base hydrochloride salt may be separated and treated with aqueous sodium hydroxide to recover trialkylamine base for recycle. The solvent layer which contains the BPGI and the excess of benzophenone may be dried by azeotropic distillation of the solvent and water. The dry solution of BPGI in solvent may then be ready for the coupling reaction with Py-z. On completion of step B, the aprotic polar solvent is distilled under vacuum for possible recycle. The mixture of PyGI, non polar solvent and excess dry inorganic base may be cooled down at about 20°C and then washed with water to separate the two phases. A bottom aqueous layer containing excess dry inorganic base may be discarded. The solution of PyGLin non polar solvent and the excess of benzophenone from the previous step may then be ready for the acidification reaction of the step C. j On completion of the step C, two phases may be separated. The bottom aqueous phase containing PyGE.HCl which is ready for the decarboxylation step (step D), and a top non polar solvent phase containing benzophenone. The non polar solvent and benzophenone may be recovered for recycle to the BPGI preparation. The conversion of PyGE.HCl into compound of general formula (I) according to part D of this process may be performed by known methods such the one described in WO 99/42447 herein incorporated by reference. During the preparation of PyGE.HCl from PyGI according to the present invention, benzophenone can be recovered for direct recycle into benzophenone glycine inline alkyl ester preparation. According to the present invention, benzophenone does not need to be recycled into benzophenone imine, avoiding an expensive additional step. Thus, according to another aspect of the present invention there is provided a process for the preparation of pyridine glycine ester hydochlorlde derivative v (PyGE.HCl) according to reaction schemes 1 to 3 as above described. The present invention will now be illustrated with reference to the following examples. Example 1; Preparation of benzophenone glyctne Imine ethyl ester In a 1 litre glass reactor equipped with a distillation section and a Dean and Stark separator, 182g (1 mole) of benzophenone, 70.1g (0.5 mole) of glycine ethyl ester hydrochloride, 4.75g (0.05 mole) of paratoluenesulfonic acid and 249g of toluene were loaded. The mixture was heated at 110-115°C at atmospheric pressure to give a good reflux in toluene. 97g (1.05 mole) of N,N-diisopropyl N-ethyl amine was added by pump over 4 hours. During the reaction, water was formed and was distilled off as water-toluene azeotrop. Water was decanted in the Dean and Stark seprator and toluene was returned to the reactor. Reaction was pursued for 1 hour after the end of the amine addition and completion of the reaction was monitored by liquid chromatography. When reaction was complete, the reaction mixture was cooled down to 20°C. The mixture was then washed with 33 5g of water and the 2 liquid phases were separated by decantation. The bottom aqueous phase containing all N,N-diisopropyl N-ethyl amine hydrochloride was kept for treatment by aqueous sodium hydroxide to recover N,N-diisopropyl N-ethyl amine for recycle. The upper toluen phase containing benzophenone glycine imine ethyl ester and the excess benzophenone was concentrated during which operation water was removed as an azeotrope with toluene. The dry solution, of benzophenone glycine imine ethyl ester in toluene was assayed by liquid chromatography : a 91% yield of benzophenone glycine imine ethyl ester was obtained with respect to glycine ethyl ester hydrochloride. Example 2 ; Preparation of ethyl N-(diphenylrnetbvlene)--2-(3-chloro-5-trifluoromethyl-2-pyridvnglvcinate In a glass reactor equipped with a distillation section and a Dean and Stark separator, 185g (3 molar equivalent) of potassium, carbonate and 300g of toluene were loaded. Potassium carbonate was dried of water by refluxing in toluene and distilling off water-toluene azeotrop at a pot temperature of 110°C. 15Qg of toluene were removed. To the dry suspension of potassium carbonate, 4.75g (0.05 molar equivalent) of tetraethylarnmoniurn bromide, 310g of propionitrile and 380g (I molar equivalent of BPGI intermediate) of the previous solution of dry benzophenone glycine imine ethyl ester in toluene were added. The mixture was heated at reflux (105°C), and 99g (1 molar equivalent of benzophenone glycine imine ethyl ester intermediate) of 2,3-dichloro-5-trifluoromethyl-pyridine was added by pump over 3 hours, maintaining reflux and separating the condensate in the Dean and Stark condensator, returning solvent to the reaction vessael and discarding water. The reaction completion was monitored by liquid chromatography. Reflux with water removal was continued for a further 3 hours after the end of the pyridine addition. Propionitrile was then distilled off under a reduced pressure of 300 mbar. The reaction mixture was cooled down to ,* 20°C. 315g of water was added and the 2 liquid phases were separated. The bottom aqueous phase contains all the unreacted potassium carbonate and was discarded. The upper toluene phase of ethyl N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate was assayed by liquid chromatography. A yield bf 85% in ethyl N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate with respect to 2,3-dichloro-5-trifluoromethyl-pyridine was obtained. Example 3 ; Preparation of ethyl 2-(3-chloro-5-trlfluoromethYl-2-PYridvl)glycinate '.V To the ethyl N-(diphenyhnethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate solution in toluene obtained in the previous example, 290g of aqueous 10% hydrochloric acid were added at 20°C. The reaction was stirred for 1 hour. Conversion of ethyl N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate to ethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate hydrochloride salt was monitored by liquid chromatography for completion. Two liquid phases were separated. The bottom aqueous phase containing ethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate hydrochloride salt was separated and was ready for the following decarboxylation reaction (preparation of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride). The top organic phase contains all the benzophenone from ethyl N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate and the excess from the BPGI preparation, and was recovered for recycle at step 1. A 93% recovery yield of benzophenone with respect to the 182g (1 mole) introduced in behzophenone glycine imine ethyl ester preparation was obtained. Example 4 : Preparation of 2-aminomethvl-3-chloro-5-trifluoromethylpyrldine hydrochloride The previous aqueous solution of ethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate was heated under reflux for 7 hours'. COa formed during the reaction was vented off. After reaction completion, the recovery yield of 2-aminomethylpyridine hydrochloride with respect to PyGI was 86%. We claim: 1. Process for the preparation of pyridine glycine ester hydrochloride (PyGE.HCl) (Formula Removed) in which: -n represents 0, 1, 2 or 3, -X is halogen atom, -Y may be the same or different and may a halogen atom, a halogenoalkyl, a alkoxycarbonyl or a alkylsulphonyl; said process comprising (A)- a first step according to reaction scheme 1: Scheme 1 (Scheme Removed) in which benzophenone (BP) is reacted with glycine alkyl ester hydrochloride (GAE.HCl) at reflux in the presence of 0,01 to 0,2 molar equivalent an acid catalyst and a trialkylamine base, in a mm polar solvent, said solvent being capable of forming an azeotrope with water, in a. BP / GAE.HC1 molar ratio of 1 to 4, to provide a benzophenone glycine imine derivative (BPGl); (B)- A second step according to reaction scheme 2 : (Scheme 2 Removed) in which: -X, Y and n are as defined above, -z is a leaving group. comprising the reaction of the benzophenone glycine imine derivative (BPGI) solution obtained in step one with a pyridine derivative (Py-z) in. the presence of a dry inorganic base, in which is added a catalyst and an aprotic polar solvent, the mixture being heated at reflux, to provide a pyridine glycine imine derivative fPvGH: (C)- a third step according to reaction scheme 3 : (Scheme 3 Removed) comprising me auamon to tne previous pynoine gtycine imine derivative (PyGI) solution of an aqueous hydrochloric acid at up to 25°C, in a HC1 / PyGl molar ratio from 1 to 5, 10 provide a pyridine glycine ester hydrochloride derivative (PyGE.HCl). 2. Process as claimed in claim 1, wherein X is chlorine. 3. Process as claimed in claim 1, wherein n is 1. 4. Process as claimed in any of the claims 1 to 3, wherein Y is haloalkyl. 5. Process as claimed in claim 4, wherein Y is trifluoromethyl. 6. Process as claimed in claim 1, wherein X is chlorine, n is 1 and Y is trifluoromethyl. 7. Process as claimed in claim 6, wherein compound of general formula (I) is 2- aminomethyl-3-chloro-5-trifluoromethylpyridine. 8. Process as claimed in any of the claims 1 to 7, wherein, in the first step, the acid catalyst is paratoluenesulfonic acid catalyst. 9. Process as claimed in any of the claims 1 to 8, wherein, in the first step, the solvent capable of forming an azeotrope with water is toluene or ethylbenzene. 10.Process as claimed in any of the claims 1 to 9, wherein the trialkylamine base is N,N-diisopropyl N-ethylamine. 11.Process as claimed in any of the claims 1 to 10, wherein, in the second step, z is a halogen atom. 12.Process as claimed in claim 11, wherein z is a chlorine atom. 13.Process as claimed in any of the claims 1 to 11, wherein, in the second step, the dry inorganic base is K2CO3 or NaH. 14.Process as claimed in any of the claims 1 to 13, wherein, in the second step, the catalyst is a phase transfer catalyst. 15.Process as claimed in claim 14, wherein the phase transfer catalyst is Net4Br. 16.Process as claimed in claims 1 to 15, wherein, in the second step, the polar solvent is propionitrile. 17.Process as claimed in any of the claims 1 to 16, wherein, in the third step, the temperature is of from 20 to 25°C. 18.Process as claimed in any of the claims 1 to 17, wherein, in the third step the Hcl/PyGI molar ratio is of from 1 to 5.

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1179-DELNP-2005-Abstract-23-04-2008.pdf

1179-DELNP-2005-Abstract-28-04-2008.pdf

1179-delnp-2005-abstract.pdf

1179-delnp-2005-claims-02-05-2008.pdf

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1179-DELNP-2005-Description (Complete)-28-04-2008.pdf

1179-delnp-2005-description (complete).pdf

1179-DELNP-2005-Form-1-23-04-2008.pdf

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1179-delnp-2005-petition-138.pdf