JP2008512495A - Process for preparing N- (substituted arylmethyl) -4- (disubstituted methyl) piperidines and intermediates - Google Patents

Abstract

（式中、Ｒ^１、Ｒ^２、ＢおよびＺは本明細書中に定義される。）の化合物を調製するための改良された方法が記載される。これらの化合物はＮ−（置換アリールメチル）−４（二置換メチル）ピペリジンの調製において有用である。Formula (B, C, F, H)

An improved method for preparing the compounds of which R ¹ , R ² , B and Z are defined herein is described. These compounds are useful in the preparation of N- (substituted arylmethyl) -4 (disubstituted methyl) piperidines.

Description

  The present invention is in the field of chemical methods, and more specifically is a method for preparing intermediates useful in the preparation of N- (substituted arylmethyl) -4- (disubstituted methyl) piperidines. .

  N- (substituted arylmethyl) -4- (disubstituted methyl) piperidines are disclosed as useful insecticides in PCT Publications 2004/060371 and 2004/060865, the disclosures of which are incorporated herein by reference. take in. PCT Publication 2004/060371 discloses the following general method for synthesizing N- (substituted arylmethyl) -4- (disubstituted methyl) piperidines,

ｉ）Ｍｇ／Ｉ_２／ＴＨＦ／≦４０℃、ｊ）ＨＣｌｇ）／ＥｔＯＡｃ、ｋ）Ｈ_２／ＰｔＯ_２／ＭｅＯＨ、ｌ）Ｎ，Ｎ−ジイソプロピルエチルアミン／ＤＭＳＯ（ｍ）Ｅｔ_３Ｎ／ＣＨ_２Ｃｌ_２／３５℃、
式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、およびＲ^６は独立して、水素、ハロゲン、アルキル、ハロアルキル、ヒドロキシル、アルコキシ、ハロアルコキシ、ペンタハロチオ、アルキルチオ、シアノ、ニトロ、アルキルカルボニル、アルコキシカルボニル、アリール、またはアリールオキシから選択され、但し、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、およびＲ^６のうち少なくとも１つは水素以外であり；および、Ｒ^２およびＲ^３、またはＲ^３およびＲ^４のうちいずれかは、−ＯＣＦ_２Ｏ−、−ＯＣＦ_２ＣＦ_２、−ＣＦ_２ＣＦ_２Ｏ−、またはＣＨ＝ＣＨＣＨ＝ＣＨ−と一緒になってベンゾ縮合環を形成し；Ｒ^１７、Ｒ^１８、Ｒ^１９、Ｒ^２０、およびＲ^２１は独立して、水素、ハロゲン、アルキル、ハロアルキル、アルコキシ、ハロアルコキシ、アルキルチオ、ハロアルキルチオ、シアノ、ニトロ、アルキルカルボニル、アルコキシカルボニル、アルコキシカルボニルアミノ、アリール、アリールオキシ、および２−アルキル−２Ｈ−テトラゾールから選択され、ここでＲ^１７およびＲ^１８、またはＲ^１８およびＲ^１９のいずれかは、−ＣＨ_２ＣＨ＝ＣＨＣＨ_２−、−ＯＣＦ_２Ｏ−、−ＯＣＦ_２ＣＦ_２−、またはＣＦ_２ＣＦ_２Ｏ−と一緒になってベンゾ縮合環を形成し；および、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２５、およびＲ^２６は独立して、水素、ハロゲン、アルキル、ヒドロキシ、アルコキシ、アルコキシアルキル、ジアルコキシアルキル、トリアルコキシアルキル、アルコキシイミノアルキル、アルケニルオキシイミノアルキル、アルキニルオキシイミノアルキル、シクロアルキルアルコキシ、アルコキシアルコキシ、アルキルチオ、ジチオアルコキシアルキル、トリチオアルコキシアルキル、アルキルスルホニル、アルキルアミノスルホニル、ジアルキルアミノスルホニル、シクロアルキルアミノスルホニル、アルケニルオキシ、アルキニルオキシ、ハロアルケニルオキシ、アルキルスルホニルオキシ、場合により置換されたアリールアルコキシ、シアノ、ニトロ、アミノ、アルキルアミノ、アルキルカルボニルアミノ、アルコキシカルボニルアミノ、アルケニルオキシカルボニルアミノ、アルキニルオキシカルボニルアミノ、ハロアルキルカルボニルアミノ、アルコキシアルコキシカルボニルアミノ、（アルキル）（アルコキシカルボニル）アミノ、アルキルスルホニルアミノ、場合により置換された（ヘテロアリール）（アルコキシカルボニル）アミノ、場合により置換されたアリールカルボニルアミノ、ホルミル、場合により置換された１，３−ジオキソラン−２−イル、場合により置換された１，３−ジオキサン−２−イル、場合により置換された１，３−オキサゾリジン−２−イル、場合により置換された１，３−オキサアザペルヒドロイン−２−イル、場合により置換された１，３−ジチオラン−２−イル、場合により置換された１，３−ジチアン−２−イル、アルコキシカルボニル、アルキルアミノカルボニルオキシ、アルキルアミノカルボニルアミノ、ジアルキルアミノカルボニルアミノ、アルキルアミノ（チオカルボニル）アミノ、ジアルキルホスホロウレイジル、場合により置換されたチエニル、場合により置換された１，３−チアゾリルアルコキシ、場合により置換されたアリール、場合により置換されたアリールオキシ、場合により置換されたアリールオキシアルキル、場合により置換されたアリールアミノカルボニルオキシ、場合により置換されたヘテロアリール、場合により置換されたヘテロアリールオキシ、場合により置換されたピロリル、場合により置換されたピラゾリル、場合により置換されたピラジニルオキシ、場合により置換された１，３−オキサゾリニル、場合により置換された１，３−オキサゾリニルオキシ、場合により置換された１，３−オキサゾリニルアミノ、場合により置換された１，２，４−トリアゾリル、場合により置換された１，２，３−チアジアゾリル、場合により置換された１，２，５−チアジアゾリル、場合により置換された１，２，５−チアジアゾリルオキシ、場合により置換された２Ｈ−テトラゾイル、場合により置換されたピリジル、場合により置換されたピリジルオキシ、場合により置換されたピリジルアミノ、場合により置換されたピリミジニル、場合により置換されたピリミジニルオキシ、場合により置換された３，４，５，６−テトラヒドロピリミジニルオキシ、場合により置換されたピリダジニルオキシ、または場合により置換された１，２，３，４−テトラヒドロナフタレニルから選択され、ここでこの場合による置換基は、ハロゲン、アルキル、ハロアルキル、アルコキシ、ジアルコキシアルキル、ジチオアルコキシアルキル、シアノ、ニトロ、アミノ、またはアルコキシカルボニルアミノの１つまたはそれ以上から選択され、但し、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２５、およびＲ^２６のうち少なくとも１つは水素以外である。

i) Mg / I ₂ / THF / ≦ 40 ° C. j) HCl g) / EtOAc, k) H ₂ / PtO ₂ / MeOH, l) N, N-diisopropylethylamine / DMSO (m) Et ₃ N / CH ₂ Cl _2/35 ℃,
Wherein R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are independently hydrogen, halogen, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, pentahalothio, alkylthio, cyano, nitro, alkylcarbonyl, alkoxy Selected from carbonyl, aryl, or aryloxy, provided that at least one of R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ is other than hydrogen; and R ² and R ³ , or R ³ and the one of ^{_{R 4, -OCF 2 O -,}} - OCF 2 CF 2, -CF 2 CF 2 O-, or CH = CHCH = CH- and taken together to form a benzo fused ^{ring; R 17 , R 18, R 19, R} 20, and ^{R 21} are independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, Haroa Kokishi, alkylthio, haloalkylthio, cyano, nitro, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylamino, aryl, aryloxy, and 2-alkyl -2H- tetrazole, wherein ^{R 17} and ^{R 18} or ^{R 18} and, Any of R ¹⁹ together with —CH ₂ CH═CHCH ₂ —, —OCF ₂ O—, —OCF ₂ CF ₂ —, or CF ₂ CF ₂ O— forms a benzo-fused ring; and R ²² , R ²³ , R ²⁴ , R ²⁵ , and R ²⁶ are independently hydrogen, halogen, alkyl, hydroxy, alkoxy, alkoxyalkyl, dialkoxyalkyl, trialkoxyalkyl, alkoxyiminoalkyl, alkenyloxyiminoalkyl, Alkynyloxy Noalkyl, cycloalkylalkoxy, alkoxyalkoxy, alkylthio, dithioalkoxyalkyl, trithioalkoxyalkyl, alkylsulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cycloalkylaminosulfonyl, alkenyloxy, alkynyloxy, haloalkenyloxy, alkylsulfonyloxy, Optionally substituted arylalkoxy, cyano, nitro, amino, alkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, haloalkylcarbonylamino, alkoxyalkoxycarbonylamino, (alkyl) (alkoxycarbonyl) ) Amino, alkylsulfonylamino, in some cases Substituted (heteroaryl) (alkoxycarbonyl) amino, optionally substituted arylcarbonylamino, formyl, optionally substituted 1,3-dioxolan-2-yl, optionally substituted 1,3-dioxane 2-yl, optionally substituted 1,3-oxazolidine-2-yl, optionally substituted 1,3-oxaazaperhydroin-2-yl, optionally substituted 1,3-dithiolane- 2-yl, optionally substituted 1,3-dithian-2-yl, alkoxycarbonyl, alkylaminocarbonyloxy, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkylamino (thiocarbonyl) amino, dialkylphosphoroylidyl Optionally substituted thienyl, optionally Substituted 1,3-thiazolylalkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxyalkyl, optionally substituted arylaminocarbonyloxy, optionally substituted Heteroaryl, optionally substituted heteroaryloxy, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted pyrazinyloxy, optionally substituted 1,3-oxazolinyl, optionally substituted 1,3-oxazolinyloxy, optionally substituted 1,3-oxazolinylamino, optionally substituted 1,2,4-triazolyl, optionally substituted 1,2,3-thiadiazolyl, case 1,2,5-thiadiazolyl substituted by 1,2,5-thiadiazolyloxy optionally substituted, optionally substituted 2H-tetrazoyl, optionally substituted pyridyl, optionally substituted pyridyloxy, optionally substituted pyridylamino, optionally substituted Pyrimidinyl optionally substituted pyrimidinyloxy, optionally substituted 3,4,5,6-tetrahydropyrimidinyloxy, optionally substituted pyridazinyloxy, or optionally substituted 1,2, Selected from 3,4-tetrahydronaphthalenyl, wherein the substituent in this case is one of halogen, alkyl, haloalkyl, alkoxy, dialkoxyalkyl, dithioalkoxyalkyl, cyano, nitro, amino, or alkoxycarbonylamino Or more Is, ^{however, R 22, R 23, R} 24, R 25, and at least one of ^{R 26} is other than hydrogen.

  The disadvantages of this method are that it does not meet the optimum yield, cannot achieve the optimum cycle time, and has a high catalyst load. Another disadvantage is that the first stage of the reaction is very exothermic. This marked exothermic reaction occurs due to the presence of Mg and fluorine. A very exothermic reaction that is difficult to control affects yield and cycle time and requires expensive equipment.

  The present invention improves yield, cycle time and catalyst loading and reduces the exothermic nature of certain reactions in the production of N- (substituted arylmethyl) -4- (disubstituted methyl) piperidines.

  The present invention relates to an improved method for preparing intermediates useful in the preparation of N- (substituted arylmethyl) -4- (disubstituted methyl) piperidines.

(Detailed description of the invention)
In one embodiment, the present invention provides compounds of formula B:

(Wherein R ¹ is selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ )
An improved method for preparing a compound of formula (A):

(Wherein X is a halogen and R ¹ is as defined above.)
Wherein said substituted aryl halide and pyridine-4-carbaldehyde are reacted in the presence of an alkylmagnesium halide.

  This reaction can be carried out in a solvent, preferably in tetrahydrofuran, dioxane or monoglyme. Preferably, the alkylmagnesium halide is i-propyl magnesium chloride or i-propyl magnesium bromide.

  A second embodiment of the present invention provides a compound of formula C:

（式中、Ｒ^１はハロゲン、ＣＦ_３、ＯＣＦ_３、ＯＣＨＦ_２、ＯＣＦ_２ＣＨＦ_２およびＳＦ_５からなる群より選択される。）
の化合物を調製するための改良された方法であって、式Ｂ：

(Wherein R ¹ is selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ )
An improved process for preparing the compound of formula B:

の化合物を高圧下で水和することを含む前記の方法である。

Wherein the compound is hydrated under high pressure.

  Hydration can be performed in an alcohol solvent using a metal catalyst. Preferably, the metal catalyst is platinum, palladium or rhodium and the alcohol solvent is methanol or ethanol. Preferably, the high pressure is in the range of 25 pounds per square inch to 200 pounds per square inch.

  A third embodiment of the present invention provides the formula F:

（式中、Ｒ^１はハロゲン、ＣＦ_３、ＯＣＦ_３、ＯＣＨＦ_２、ＯＣＦ_２ＣＨＦ_２およびＳＦ_５からなる群より選択され、ＺおよびＢは独立してＣＨおよびＮからなる群より選択される。）
の化合物を調製するための改良された方法であって、式Ｃ：

Wherein R ¹ is selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ , and Z and B are independently selected from the group consisting of CH and N. )
An improved method for preparing the compound of formula C:

（式中、Ｒ^１は上記に定義されるとおりである。）
の化合物と、ｉ）式Ｄ：

(Wherein R ¹ is as defined above.)
I) Formula D:

（式中、ＺおよびＢは上記に定義されるとおりである。）
の化合物およびｉｉ）式Ｅ：

(Wherein Z and B are as defined above.)
And ii) Formula E:

（式中、Ｙはハロゲンであり、ＺおよびＢは上記に定義されるとおりである。）
の化合物からなる群より選択される化合物とを反応させることを含み、但し、式Ｅの化合物が使用される場合、前記反応は炭酸塩、溶媒、および場合により相間移動触媒の存在下で行われる前記の方法である。

(Wherein Y is halogen and Z and B are as defined above.)
Reacting with a compound selected from the group consisting of: wherein a compound of formula E is used, said reaction being carried out in the presence of a carbonate, a solvent, and optionally a phase transfer catalyst. This is the method described above.

  This reaction can be carried out at a temperature within the range of ambient temperature to 80 ° C. The solvent is preferably toluene or methyl isobutyl ketone. The phase transfer catalyst may be a phase transfer catalyst such as polyethylene glycol, dimethylaminopyridine, triethylamine, p-toluenesulfonic acid, diphosphorus pentoxide, pyridine or quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof. it can. Preferably, the reaction of the compound of formula C with the compound of formula D is carried out in the presence of a solvent selected from the group consisting of sodium borohydride and 1,2-dichloroethane, dichloromethane, acetonitrile and tetrahydrofuran.

  A fourth embodiment of the present invention provides the formula H:

（式中、Ｒ^１およびＲ^２は独立してハロゲン、ＣＦ_３、ＯＣＦ_３、ＯＣＨＦ_２、ＯＣＦ_２ＣＨＦ_２およびＳＦ_５からなる群より選択され、ＺおよびＢは独立して、ＣＨおよびＮからなる群より選択される。）
の化合物を調製するための改良された方法であって、式Ｆ：

Wherein R ¹ and R ² are independently selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ , and Z and B are independently from CH and N Selected from the group of
An improved method for preparing the compound of formula F:

（式中、Ｒ^１、ＺおよびＢは上記に定義されるとおりである。）
の化合物と式Ｇ：

(Wherein R ¹ , Z and B are as defined above.)
And a compound of formula G:

（式中、Ｒ^２は上記に定義されるとおりである。）
の化合物とを１，２−ジクロロエタン、アセトニトリルおよびジオキサンからなる群より選択される溶媒の存在下で縮合させることを含む前記方法である。

(Wherein R ² is as defined above.)
Wherein said compound is condensed in the presence of a solvent selected from the group consisting of 1,2-dichloroethane, acetonitrile and dioxane.

  This condensation can be carried out at a temperature in the range of 40 ° C to 80 ° C.

In all embodiments of the present invention, preferably R ¹ and R ² are independently selected from the group consisting of halogen, CF ₃ , and OCF ₃ , X is bromine or chlorine, and Y is bromine, iodine or chlorine It is. More preferably, R ¹ is CF ₃ , R ² is Cl, and X is bromine. Furthermore, it is preferable that Z is N and B is CH.

  The modifier “about” is used herein to indicate that certain preferred operating ranges, such as, for example, ranges of reactant molar ratios, material usage, and temperature, are not fixedly determined. This meaning is often obvious to those skilled in the art. For example, an enumeration of a temperature range of about 120 ° C. to about 135 ° C. with reference to an organic chemical reaction includes other similar temperatures that can be expected to be beneficial to the useful reaction rate of the reaction, eg 105 ° C. or 150 ° C. It is interpreted as including. If there is no guidance from the experience of a person skilled in the art, no guidance from the context of the text, and more specific rules are not listed below, the “about” range is the absolute value of the end value of the range. The lesser of either not exceeding 10% or not exceeding 10% of the indicated range.

  As used herein and unless otherwise indicated, the substituent terms “alkyl”, “alkoxy”, and “haloalkyl” used alone or as part of a larger portion are suitable as substituents. Includes straight or branched chain having at least 1 or 2 carbon atoms, preferably up to 12 carbon atoms, more preferably up to 10 carbon atoms, most preferably up to 7 carbon atoms . The term “aryl” refers to phenyl or naphthyl optionally substituted with one or more halogen, alkyl, alkoxy or haloalkyl. “Halogen”, “halide” or “halo” refers to fluorine, bromine, iodine or chlorine. The term “ambient temperature” refers to a temperature in the range of about 20 ° C. to about 30 ° C. Certain solvents, catalysts, etc. are known by their initials. They include the acronym “EDC” meaning 1,2-dichloroethane and “THF” meaning tetrahydrofuran. The term “glyme” refers to a class of solvents composed of monoglyme, diglyme, triglyme, tetraglyme and polyglyme.

  The following examples illustrate the methods of the present invention and the overall method for preparing N- (substituted arylmethyl) -4- (disubstituted methyl) piperidines of formula (I) using these methods. .

（ａ）ｉ−ＰｒＭｇＣｌ／ＴＨＦ／５℃から室温 （ｂ）Ｈ_２／２５ｐｓｉから３５ｐｓｉ／ＭｅＯＨ （ｃ）Ｋ_２ＣＯ_３／Ｃｕ_２Ｏ／１４５℃から１７０℃／１２から２０時間 （ｅ）ＥＤＣ／ＮａＢＨ（ＯＡｃ）_３／３５℃から４０℃／３から２０時間 （ｆ）ＥＤＣ／３５℃から５０℃／２から１８時間 （ｇ） ８０％Ｈ_２Ｏ_２／ＭｅＯＨ／４０℃から４５℃ ９から４４時間

(A) i-PrMgCl / THF / 5 ℃ from room temperature _(b) H 2 / 25psi from _{35psi / MeOH (c) K 2} CO 3 / Cu 2 O / 145 ℃ from 170 ° C. / 12 from 20 hours (e) EDC _{/ NaBH (OAc) 3/35} ℃ from 40 ° C. / 3 from 20 hours (f) EDC / 35 ℃ from 50 ° C. / 2 to 18 hours _{(g) 80% H 2 O} 2 / MeOH / 40 ℃ from 45 ° C. 9 44 hours from

  As shown in Example 1, in the first step, appropriately substituted aryl halides, such as the known compounds 4-bromo-1- (trifluoromethyl) benzene (A) and pyridine-4 Carbaldehyde was reacted with a Grignard reagent to produce hydrochloride (B) of 4-pyridyl [4- (trifluoromethyl) phenyl] methane-1-ol. The intermediate (B) was then hydrogenated under high pressure to produce the corresponding hydrochloride salt (C) of 4-piperidyl [4- (trifluoromethyl) phenyl] methane-1-ol. Next, an appropriately substituted phenol, such as the known compound 4-hydroxybenzaldehyde, in the range of 145 ° C. to 170 ° C. in the presence of halopyridine, eg 2-chloropyridine, potassium carbonate and a catalytic amount of copper oxide. To give 4- (2-pyridyloxy) benzaldehyde (D). The intermediate (C) is then reacted with the intermediate (D) in the presence of sodium triacetoxyborohydride at a temperature in the range of 35 ° C. to 40 ° C. to give {1-[(4- (2-pyridyl Oxy) phenyl) methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methane-1-ol (F) was produced. The intermediate (F) is then condensed with an appropriately substituted aryl halide, such as the known compound 4-chlorobenzene isocyanate (G)) at a temperature in the range of 35 ° C. to 50 ° C., and N- (4 -Chlorophenyl) ({1-[(4- (2-pyridyloxy) phenyl) methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methoxy) carboxamide (H) was produced. The intermediate (H) is then oxidized with hydrogen peroxide at a temperature in the range of 40 ° C. to 55 ° C. to give N- (4-chlorophenyl) ({1-oxo-1-[(4- (2-pyridyloxy ) Phenyl) methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methoxy) carboxamide (Formula I) was obtained.

（ｃ）Ｋ_２ＣＯ_３／Ｃｕ_２Ｏ／１４５℃から１７０℃／１２から２０時間 （ｄ）Ｂｒ_２ （ｅ）Ｋ_２ＣＯ_３／トルエン／３５℃から４０℃／３から２０時間 （ｆ）ＥＤＣ／３５℃から５０℃／２から１８時間 （ｇ）８０％Ｈ_２Ｏ_２／ＭｅＯＨ／４０℃から４５℃ ／９から４４時間

(C) K ₂ CO ₃ / Cu ₂ O / 145 ° C. to 170 ° C./12 to 20 hours (d) Br ₂ (e) K ₂ CO ₃ / toluene / 35 ° C. to 40 ° C./3 to 20 hours (f) EDC / 35 ° C. to 50 ° C./2 to 18 hours (g) 80% H ₂ O ₂ / MeOH / 40 ° C. to 45 ° C./9 to 44 hours

  In the first stage of Example 2, an appropriately substituted phenol, such as the known compound 4-methylphenol, in the presence of halopyridine, for example 2-chloropyridine, potassium carbonate and a catalytic amount of copper oxide, The reaction can be carried out at a temperature ranging from 145 ° C. to 170 ° C. to produce 2- (4-methylphenoxy) pyridine (D2). The intermediate (D2) can then be halogenated, for example with bromine, to produce 2- [4- (bromomethyl) phenoxy] pyridine (E). Intermediate (C) (prepared as in Example 1) is then reacted with Intermediate (E) in the presence of potassium carbonate at a temperature in the range of 35 ° C. to 40 ° C. to give {1- [ (4- (2-Pyridyloxy) phenyl) methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methane-1-ol (F) can be produced. The intermediate (F) is then condensed with an appropriately substituted aryl halide, such as 4-chlorobenzene isocyanate (G), a known compound, at a temperature in the range of 35 ° C. to 50 ° C. to give N- (4 -Chlorophenyl) ({1-[(4- (2-pyridyloxy) phenyl) methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methoxy) carboxamide (H) can be produced. The intermediate (H) is then oxidized with hydrogen peroxide at a temperature in the range of 40 ° C. to 55 ° C. to give N- (4-chlorophenyl) ({1-oxo-1-[(4- (2-pyridyl Oxy) phenyl) methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methoxy) carboxamide (Formula I) can be formed.

  Although the invention has been described with emphasis on preferred embodiments, various modifications of the preferred embodiments can be used and in ways other than those specifically described herein. It will be apparent to those skilled in the art that it can be implemented. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the appended claims.

Claims (19)

Formula B:

(Wherein R ¹ is selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ )
A process for preparing a compound of formula (A):

(Wherein X is a halogen and R ¹ is as defined above.)
Wherein said substituted aryl halide and pyridine-4-carbaldehyde are reacted in the presence of an alkylmagnesium halide. The method of claim 1, wherein R ¹ is CF ₃ , R ² is Cl, Z is N, and B is CH.   The method of claim 1, wherein X is bromine or chlorine.   The method of claim 1, wherein the alkylmagnesium halide is i-propyl magnesium chloride or i-propyl magnesium bromide.   The method of claim 1, wherein the reaction is performed in a solvent.   6. A process according to claim 5, wherein the solvent is tetrahydrofuran, dioxane or monoglyme. Formula C:

(Wherein R ¹ is selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ )
A process for preparing a compound of formula B:

A process as described above comprising hydrating said compound under high pressure.   The process according to claim 7, wherein the hydration is carried out in an alcohol solvent using a metal catalyst.   The method of claim 8, wherein the metal catalyst is platinum, palladium, or rhodium.   The method of claim 8, wherein the alcohol solvent is methanol or ethanol.   8. The method of claim 7, wherein the high pressure is in the range of 25 pounds per square inch to 200 pounds per square inch. Formula F:

Wherein R ¹ is selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ , and Z and B are independently selected from the group consisting of CH and N. )
A process for preparing a compound of formula C:

(Wherein R ¹ is as defined above.)
I) Formula D:

(Wherein Z and B are as defined above.)
And ii) Formula E:

(Wherein Y is halogen and Z and B are as defined above.)
Comprising reacting with a compound selected from the group consisting of: wherein a compound of formula E is used, the reaction being carried out in the presence of a carbonate, a solvent, and optionally a phase transfer catalyst. Said method.   13. A method according to claim 12, wherein Y is bromine, iodine or chlorine.   13. The reaction of a compound of formula C with a compound of formula D is performed in the presence of a solvent selected from the group consisting of sodium borohydride and 1,2-dichloroethane, dichloromethane, acetonitrile, and tetrahydrofuran. Method.   The process according to claim 12, wherein the reaction is carried out at a temperature in the range from ambient temperature to 80 ° C.   13. A process according to claim 12, wherein the solvent is toluene or methyl isobutyl ketone.   The method of claim 12, wherein the phase transfer catalyst is polyethylene glycol. Formula H:

Wherein R ¹ and R ² are independently selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ , and Z and B are independently CH and N Selected from the group.)
A process for preparing a compound of formula F:

(Wherein R ¹ , Z and B are as defined above.)
And a compound of formula G:

(Wherein R ² is as defined above.)
Wherein said compound is condensed in the presence of a solvent selected from the group consisting of 1,2-dichloroethane, acetonitrile and dioxane.   The process according to claim 18, wherein the condensation is carried out at a temperature in the range of 40 ° C to 80 ° C.