KR20070052319A - Processes for preparing n-(substituted methyl)-4-(disubstituted methyl)piperidines and intermediates - Google Patents

Abstract

Improved methods of preparing compounds of formula (B, C, F, H) have been described in which R ¹ , R ² , B and Z have been defined herein. These compounds are useful in the preparation of N- (substituted arylmethyl) -4- (disubstituted methyl) piperidine.

Description

Processes for Preparing N- (Substituted methyl) -4- (Disubstituted Methyl) Piperidines and Intermediates} -N- (substituted arylmethyl) -4- (disubstituted methyl) piperidine

The present invention claims the benefit of US Provisional Application No. 60 / 609,539, filed September 13, 2004.

The present invention is a process for preparing useful intermediates in the field of chemical processes, more specifically, N- (substituted arylmethyl) -4- (disubstituted methyl) piperidine.

In PCT Publication Nos. 2004/060371 and 2004/060865, the disclosures of which are incorporated herein by reference, N- (substituted arylmethyl) -4- (disubstituted methyl) piperidine have been disclosed as useful pesticides. PCT Publication 2004/060371 discloses the following general method for synthesizing N- (substituted arylmethyl) -4- (disubstituted methyl) piperidine:

(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, alkoxycarbonyl, aryl, or aryloxy, provided that at least one of R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ is other than hydrogen; Wherein R ² and R ³ or R ³ and R ⁴ are taken together with -OCF ₂ O-, -OCF ₂ CF _2- , -CF ₂ CF ₂ O-, or -CH = CHCH = CH-, -Form a benzo-fused ring; R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , and R ²¹ are independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, cyano, nitro, alkylcarbonyl, alkoxy Carbonyl, alkoxycarbonylamino, aryl, aryloxy, and 2-alkyl-2H-tetrazole, wherein R ¹⁷ and R ¹⁸ , or R ¹⁸ And R ¹⁹ is taken together with —CH ₂ CH═CHCH ₂ —, —OCF ₂ O—, —OCF ₂ CF ₂ —, or —CF ₂ CF ₂ O— to form a benzo-fused ring; R ²² , R ²³ , R ²⁴ , R ²⁵ , and R ²⁶ are independently hydrogen, halogen, alkyl, hydroxy, alkoxy, alkoxyalkyl, dialkoxyalkyl, trialkoxyalkyl, alkoxyiminoalkyl, alkenyloxyiminoalkyl, Alkynyloxyiminoalkyl, cycloalkylalkoxy, alkoxyalkoxy, alkylthio, dithioalkoxyalkyl, trithioalkoxyalkyl, alkylsulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cycloalkylaminosulfonyl, alkenyloxy , Alkynyloxy, haloalkenyloxy, alkylsulfonyloxy, optionally substituted arylalkoxy, cyano, nitro, amino, alkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyl Oxycarbonylamino, haloalkylcarbonylamino, alkoxyalkoxycarbonylamino, (alkyl) (alkoxycarbonyl) amino, alkylsulfonylamino, optionally substituted (heteroaryl) (alkoxycarbonyl) amino, optionally substituted Arylcarbonylamino, formyl, optionally substituted 1,3-dioxolan-2-yl, optionally substituted 1,3-dioxan-2-yl, optionally substituted l, 3-oxazolidin-2-yl , Optionally substituted l, 3-oxazahydrohydroin-2-yl, optionally substituted l, 3-dithiolan-2-yl, optionally substituted l, 3-dithia-2-yl, alkoxycarbonyl, alkyl Aminocarbonyloxy, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkylamino (thiocarbonyl) amino, dialkylphosphoroeuridyl, 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, optionally substituted 1,2,5-thiadiazolyl, optionally substituted 1,2,5-thiadiazolyloxy, optionally substituted 2H-tetrazolyl, 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 1,2,3,4-tetrahydronaphthalenyl, wherein any substituent is one or more halogen, alkyl, haloalkyl, alkoxy, dialkoxyalkyl, dty Selected from an alkoxyalkyl, cyano, nitro, amino, or alkoxycarbonylamino, provided that At least one of R ²² , R ²³ , R ²⁴ , R ²⁵ , and R ²⁶ is other than hydrogen. Disadvantages of this method include suboptimal yields, suboptimal cycle recovery and high catalyst loadings. Another disadvantage is that the first stage of the reaction is high fever. This marked exothermic reaction is due to the presence of Mg or fluorine. Highly controllable high heat reactions not only require expensive equipment, but can also affect yield. The present invention not only reduces the exothermicity of certain reactions involved in preparing N- (substituted arylmethyl) -4- (disubstituted methyl) piperidine but also improves yield, circulation recovery and catalyst loading.

Summary of the Invention

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

Detailed description of the invention

In one embodiment, the present invention is directed to an improved process for preparing a compound of formula B, which method comprises the reaction of a substituted aryl halide and pyridine-4-carbaldehyde of formula ( A ) in the presence of an alkyl magnesium halide. :

Wherein R ¹ is selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ ;

X is halogen.

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

A second embodiment of the invention is an improved process for preparing compounds of formula C, which comprises hydrating the compounds of formula B at elevated pressure:

Wherein R ¹ is selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ .

Hydration can be performed in an alcoholic solvent, such as a metal catalyst. Preferably, the metal catalyst is platinum, palladium or rhodium; The alcohol solvent is methanol or ethanol. Preferably, the upward pressure ranges from 25 pounds per square inch to 200 pounds per square inch.

A third embodiment of the present invention is an improved method for preparing a compound of formula F, wherein the method comprises reacting a compound selected from the group consisting of a compound of formula C and i) a compound of formula D and ii) a compound of formula E Provided that compounds of formula E are used, the reaction is carried out under carbonate, a solvent and optionally a phase transfer catalyst:

Where

R ¹ is halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ And SF ₅ ;

Z and B are independently selected from the group consisting of CH and N;

Y is halogen.

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

A fourth embodiment of the invention is an improved process for preparing compounds of formula H, which process compounds of formula F in the presence of a solvent selected from the group consisting of 1,2-dichloroethane, acetonitrile and dioxane Condensation with a compound of G:

Where

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 ;

Z and B are independently selected from the group consisting of CH and N.

Can be condensed at a temperature in the range from 40 ° C to 80 ° C.

In all embodiments of the 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; Y is bromine, iodine or chlorine. More preferably, R ¹ is CF ₃ and R ² is Cl. Also preferably Z is N and B is CH.

The modifier “about” is used herein to indicate any desired operating range that is not firmly determined, such as the molar ratio for the reactants, the amount of material, and the temperature range. The meaning will often be apparent to those skilled in the art. For example, the specification of the temperature range of about 120 ° C.-135 ° C. in relation to organic chemical reactions is to include other similar temperatures, such as 105 ° C. or 150 ° C., which can be expected to give a useful reaction temperature for the reaction. Can be interpreted. Where there is no guidance in the experience of the person skilled in the art, no guidance in the context, and no more specific rules are described below, the range of "about" is 10% of the absolute value of the endpoint, or 10% or more of the stated range. It can't be, and either is smaller.

As used herein, unless otherwise stated, the substituent terms “alkyl”, “alkoxy”, and “haloalkyl”, used alone or as part of a larger moiety, are at least one or two carbon atoms suitable for substituents. Straight or branched chains, 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" means fluorine, bromine, iodine, or chlorine. The term “room temperature” means a temperature in the range of about 20 ° C.-30 ° C. Certain solvents, catalysts, and the like are known by their acronyms. These include the acronym "EDC" for 1,2-dichloroethane and "THF" for tetrahydrofuran. The term "glyme" means a solvent group consisting of monoglyme, diglyme, triglyme, tetraglyme, and polyglyme.

The following examples illustrate the process of the present invention and the overall process for preparing N- (substituted arylmethyl) -4- (disubstituted methyl) piperidine of formula (I).

Example 1

(a) i-PrMgCl / THF / 5 ℃ - RT b) H 2/25 psi - 35 psi / MeOH c) K 2 C0 3 / Cu 2 O / 145 ℃ - 170 ℃ / 12-20 sigan e) EDC / _{NaBH (OAc) 3/35 ℃} - 4O ℃ / 3-20 sigan f) EDC / 35 ℃ - 5O ℃ / 2-18 sigan _{g) 80% H 2 O 2} / MeOH / 40 ℃ - 45 ℃ / 9-44 time)

In the first step depicted in Example 1, Grignard is suitably substituted aryl halides such as the known compounds 4-bromo-l- (trifluoromethyl) benzene (A) and pyridine-4-carbaldehyde Reaction with the reagents formed a hydrogen chloride salt of 4-pyridyl [4- (trifluoromethyl) phenyl] methane-ol (B). Intermediate (B) was then hydrogenated under elevated pressure to yield the corresponding hydrogen chloride salt of 4-piperidyl [4- (trifluoromethyl) phenyl] methane-ol (C). Next, a suitably substituted phenol, such as the known compound 4-hydroxybenzaldehyde, is reacted at a temperature in the range of 145 ° C.-170 ° C. in the presence of halopyridine, for example 2-chloropyridine, potassium carbonate and a catalytic amount of copper oxide. To form 4- (2-pyridyloxy) benzaldehyde (D). The intermediate (C) is then reacted in the presence of intermediate (D) with sodium triacetoxyborohydride at a temperature in the range of 35 ° C.-40 ° C. to yield {1-[(4- (2-pyridyloxy ) Phenyl) methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methan-1-ol (F). Thereafter, the intermediate (F) is condensed at a temperature in the range of 35 ° C.-50 ° C. with an aryl halide, for example, the known compound 4-chlorobenzeneisocyanate (G), to appropriately substituted N- (4-chlorophenyl) ({l-[(4- (2-pyridyloxy) phenyl) methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methoxy) carboxamide (H) was formed . The intermediate (H) is then oxidized with hydrogen peroxide at a temperature ranging from 40 ° C.-55 ° C. to give N- (4-chlorophenyl) ({l-oxo-1-((4- (2-pyridyloxy) phenyl) Methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methoxy) carboxamide (Formula I).

Example 2

(c) K ₂ CO ₃ / Cu ₂ O / 145 ° C-170 ° C / 12-20 hours d) Br ₂ e) K ₂ CO ₃ / toluene / 35 ° C-4O ° C / 3-20 hours f) EDC / 35 ℃-50 ℃ / 2-18 hours g) 80% H ₂ O ₂ / MeOH / 40 ℃-45 ℃ / 9-44 hours)

In the first step of Example 2, an appropriately substituted phenol, for example, known compound 4-methyl phenol, is selected from 145 ° C-170 ° C in the presence of halopyridine, for example 2-chloropyridine with potassium carbonate and a catalytic amount of copper oxide It can be reacted at a temperature in the range, forming 2- (4-methylphenoxy) pyridine (D2). The intermediate (D2) can then be halogenated, for example with bromine, to form 2- [4- (bromomethyl) phenoxy] pyridine (E). The intermediate (C) made in Example 1 can then be reacted in the presence of intermediate (E) with potassium carbonate at a temperature in the range of 35 ° C.-40 ° C., and {l-[(4- (2-pyridyloxy ) Phenyl) methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methan-1-ol (F). Intermediate (F) can then be condensed at temperatures ranging from 35 ° C. to 50 ° C., with appropriately substituted aryl halides, for example the known compound 4-chlorobenzeneisocyanate (G), and N- (4-chlorophenyl ) ({l-[(4- (2-pyridyloxy) phenyl) methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methoxy) carboxamide (H) It was. The intermediate (H) can then be oxidized with hydrogen peroxide at a temperature in the range of 40 ° C.-55 ° C., with N- (4-chlorophenyl) {1-oxo-1-[(4- (2-pyridyloxy) Phenyl) methyl] (4-piperidyl)} [4- (trifluoromethyl) phenyl] methoxy) carboxamide (Formula I).

Although the invention has been described as emphasizing preferred embodiments, those skilled in the art can use variations of the preferred embodiments and it is intended that the invention may be practiced other than as specifically described herein. Accordingly, the present invention is intended to embrace all such modifications as come within the spirit and scope defined by the following claims.

Claims (19)

A process for preparing a compound of formula B comprising reacting a substituted aryl halide of formula ( A ) and pyridine-4-carbaldehyde in the presence of an alkyl magnesium halide:

Wherein R ¹ is selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ ; X is halogen. The method of claim 1, R ¹ is CF ₃ ; R ² is Cl; Z is N; B is CH. The method of claim 1 wherein X is bromine or chlorine. The method of claim 1 wherein the alkyl magnesium halide is i-propyl magnesium chloride or i-propyl magnesium bromide. The process of claim 1 wherein the reaction is carried out in a solvent. The method of claim 5 wherein the solvent is tetrahydrofuran, dioxane or monoglyme. A process for preparing a compound of Formula C, comprising hydrating the compound of Formula B at elevated pressure:

Wherein R ¹ is selected from the group consisting of halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ and SF ₅ . 8. The method of claim 7, wherein the hydration is performed with a metal catalyst in an alcohol solvent. 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 elevated pressure ranges from 25 pounds per square inch to 200 pounds per square inch. Reacting a compound selected from the group consisting of a compound of formula C and i) a compound of formula D and ii) a compound of formula E, provided that when a compound of formula E is used, the reaction is a carbonate, a solvent and optionally a phase change Process for preparing a compound of formula F, carried out in the presence of a catalyst:

Where R ¹ is halogen, CF ₃ , OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ And SF ₅ ; Z and B are independently selected from the group consisting of CH and N; Y is halogen. 13. The method of claim 12, wherein Y is bromine, iodine or chlorine. 13. The solvent of claim 12, wherein the reaction of the compound of formula C and the compound of formula D is selected in the presence of sodium borohydride and from the group consisting of 1,2-dichloroethane, dichloromethane, acetonitrile and tetrahydrofuran The method is carried out in the presence of. 13. The process of claim 12, wherein the reaction is carried out at a temperature in the range of ambient temperature-80 ° C. 13. The process of claim 12 wherein the solvent is toluene or methyl isobutyl ketone. The method of claim 12, wherein the phase transfer catalyst is polyethylene glycol. A process for preparing a compound of Formula H comprising condensing a compound of Formula F with a compound of Formula G in the presence of a solvent selected from the group consisting of 1,2-dichloroethane, acetonitrile and dioxane:

Where 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 ; Z and B are independently selected from the group consisting of CH and N. The method of claim 18, wherein the condensation is carried out at a temperature in the range 40 ° C.-80 ° C. 19.