MX2007002910A - Processes for prepating n-(substituted arylmethyl)-4-(disubstituted methyl)piperidines and intermediates - Google Patents

Abstract

Improved processes are described for preparing compounds of formulae:(B, C, F, H) wherein R1, R2, B and Z are defined herein. These compounds are useful in the preparation of N-(substituted arylmethyl)-4­(disubstituted methyl)piperidines.

Description

PROCEDURES FOR THE PREPARATION OF N- (SUBSTITUTED ARTIST METHYL) -4- (METHYL DISUSED) PIPERIDINES AND ITS INTERMEDIATES FIELD OF THE INVENTION This invention pertains to the field of chemical processes; more specifically, processes for the preparation of intermediates useful in the preparation of N- (substituted aryl methyl) -4- (methyl disubstituted) piperidines.

BACKGROUND OF THE INVENTION N- (substituted aryl methyl) -4- (methyl disubstituted) piperidines are described in PCT publications 2004/060371 and 2004/060865 as useful insecticides, the descriptions of which are incorporated herein by reference. PCT Publication 2004/060371 discloses the following general procedure for the synthesis of N- (substituted aryl methyl) -4- (methyl di-substituted) piperidines: Ref .: 179545 ?? i) Mg / I2 / THF / < 40 ° C; j) HC1 (g) / EtOAc; k) H2 / Pt02 / MeOH; I) N, -diisopropylethylamine / DMSO m) Et 3 N / CH 2 Cl 2/35 ° C wherein R 2, R 3, R 4, R 5, and R 6 are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, pentahalothio, alkylthio, cyano, nitro, alkylcarbonyl, alkoxycarbonyl, aryl, or aryloxy, with the proviso that at least one of R2, R3, R, R5, and R6 is other than hydrogen; and, wherein any of R2 and R3, or R3 and R4 are taken together with -OCF20-, -OCF2CF2-, -CF2CF20-, or -CH = CHCH = CH-, forming a benzocondensate ring; R17, R18, R19, R20, and R21 are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, cyano, nitro, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylamino, aryl, aryloxy, and 2-alkyl-2H -tetrazole, and, wherein any of R17 and R18, or R18 and R19 can be taken together with -CH2CH = CHCH2-, -OCF20-, -OCF2CF2-, or -CF2CF20-, to form benzocondensate rings; and R22, R23, R24, R2, and R26 are independently selected from hydrogen, halogen, alkyl, hydroxy, alkoxy, alkoxyalkyl, dialkoxyalkyl, trialcoxialquilo, alkoxyiminoalkyl, alkenyloximinoalkyl, alquiniloxiiminoalquilo, cycloalkylalkoxy, alkoxyalkoxy, alkylthio, ditioalcoxialquilo, tritioalcoxialquilo, 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, (heteroaryl) (alkoxycarbonyl) amino optionally substituted, optionally substituted arylcarbonylamino, formyl, optionally substituted 1,3-dioxolan-2-yl, optionally substituted 1,3-dioxan-2-yl, 1,3-oxazolidin-2-yl optionally substituted, optionally substituted 1, 3-oxazaperhidroin-2-yl, optionally substituted 1,3-dithiolan-2-yl, optionally substituted 1,3-dithian-2-yl, alkoxycarbonyl, alkylaminocarbonyloxy, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkylamino (thiocarbonyl) amino, dialkylphosphoroureidyl, optionally substituted thienyl, optionally substituted 1,3-thiazolylalkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxyalkyl, optionally substituted arylaminocarbon loxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted pyrrolyl, optionally substituted pyrazolyl, pyrazinyloxy optionally substituted, 1,3-oxazolinyl or optionally substituted, 1,3-oxazolinyloxy optionally substituted, optionally substituted 1,3-oxazolinylamino, optionally substituted 1,2-triazolyl, 1,2,3-thiadiazolyl optionally substituted, optionally substituted 1, 2, 5-thiadiazolyl, 1,2,5-thiadiazolyloxy optionally substituted , 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 the optional substituent is selected from one or more of halogen, alkyl, haloalkyl, alkoxy, dialkoxyalkyl, dithioalkoxyalkyl, cyano, nitro, amino, or alkoxycarbonylamino, with the proviso that at least one of R22, R23, R24, R25, and R26 is other than hydrogen. The disadvantages of this process include less than optimum yields, less than optimum cycle lengths and high catalyst loads. Another disadvantage is the first very exothermic reaction stage. This significantly exothermic reaction is the result of the presence of Mg and fluorine. Marginally controllable and highly exothermic reactions can affect yields and cycle lengths while requiring equipment expensive. The present invention improves the yield, cycle times and catalyst loading while reducing the exothermic nature of certain reactions involved in the production of N- (substituted aryl methyl) -4- (methyl disubstituted) piperidines.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to improved processes for the preparation of intermediates useful in the preparation of N- (substituted aryl methyl) -4- (methyl disubstituted) piperidines.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the present invention relates to an improved process for the preparation of a compound of formula B: B wherein R is selected from the group consisting of halogen, CF3, OCF3, OCHF2, OCF2CHF2 and SF5; said process comprising reacting a substituted aryl halide of formula (A): Formula (A) wherein X is halogen; and R1 is as defined above; and pyridine-4-carbaldehyde in the presence of an alkylmagnesium halide. The reaction can be carried out in a solvent, preferably tetrahydrofuran, dioxane or monoglyme. Preferably, the alkylmagnesium halide is i-propylmagnesium chloride or i-propylmagnesium bromide. A second embodiment of the present invention is an improved process for the preparation of a compound of formula C: wherein R is selected from the group consisting of halogen, CF3, OCF3, OCHF2, OCF2CHF2 and SF5; said method comprising the hydration of a compound of formula B: at high pressure. The hydration can be carried out with a metal catalyst; in an alcohol solvent. Preferably, the metal catalyst is platinum, palladium or rhodium; The alcohol solvent is methanol or ethanol. Preferably, the elevated pressure is in the range of 25 psi to 200 psi (172, 4 to 1378, 9 kPa). A third embodiment of the present invention is an improved process for the preparation of a compound of formula F: F wherein R1 is selected from the group consisting of halogen, CF3, OCF3, OCHF2, OCF2CHF2 and SF5; and Z and B are independently selected from the group constituted by CH and N; said method comprising reacting a compound of formula C: wherein R is as defined above; and a compound selected from the group consisting of i) a compound of formula D: D wherein Z and B are as defined above; and ii) a compound of formula E: E in which Y is halogen; and Z and B are as defined above; with the proviso that when a compound of formula E is used the reaction is carried out in the presence of a carbonate, a solvent and optionally a phase transfer catalyst.

The reaction can be carried out at a temperature in the range of room temperature to 80 ° C. The solvent is preferably toluene or methyl isobutyl ketone. The phase transfer catalyst can be polyethylene glycol, < ± ü ^ ethylannopyridine, triethylamine, p-toluenesulfonic acid, phosphorus pentoxide, pyridine or phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof. Preferably, the reaction of a compound of formula C and a compound of formula D is carried out in the presence of a sodium borohydride and a solvent selected from the group consisting of 1,2-dichloroethane, dichloromethane, acetonitrile and tetrahydrofuran. A fourth embodiment of the present invention is an improved process for the preparation of a compound of formula H: H in which and R are independently selected from the group constituted by halogen, CF3, OCF3 / OCHF2, OCF2CHF2 and SF5; and Z and B are independently selected from the group consisting of CH and N; said method comprising the condensation of a compound of formula F: F wherein R1, Z and B are as defined above; with a compound of formula G: wherein R2 is as defined above; in the presence of a solvent selected from the group consisting of 1,2-dichloroethane, acetonitrile and dioxane. The condensation can be carried out at a temperature in the range of 40 ° C to 80 ° C. In all the embodiments of the present invention: preferably, R1 and R2 are independently selected from the group consisting of halogen, GF3, and OCF3; X is bromine or chlorine; And it's bromine, iodine or chlorine. More preferably, R1 is CF3 and R2 is Cl; X is bromine. Also preferably Z is N and B is CH. The "about" modifier is used herein to indicate that certain preferred ranges of operation, such as the ranges for the molar ratios for reagents, amounts of materials, and temperatures, are not determined in a fixed manner. The meaning will often be evident to someone with ordinary knowledge. For example, a ratio of a temperature range of between about 120 ° C and about 135 ° C in reference to, for example, an organic chemical reaction will be interpreted to include other similar temperatures that can be expected to favor a reaction rate useful for the reaction, such as 105 ° C or 150 ° C. When the guidance of the experience of those with ordinary knowledge is lacking, the guidance of the context is lacking, and when a more specific rule is not mentioned below, the "approximately" interval should not exceed 10% of the absolute value of an extreme value or 10% of the mentioned interval, whichever is less. As used in this specification and unless it is to the contrary, the substituent terms "alkyl", "alkoxy", and "haloalkyl", used alone or as part of a larger moiety, include straight or branched chains of at least one or two carbon atoms, as convenient for the substituent, and 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 of halogen, alkyl, alkoxy, or haloalkyl. "Halogen", "halide" or "halo" refer to fluorine, bromine, iodine, or chlorine. The term "room temperature" refers to a temperature in the range of about 20 ° C to about 30 ° C. Certain solvents, catalysts, and the like are known by their acronyms. These include the acronyms "EDC" which means 1,2-dichloroethane and "HF" which means tetrahydrofuran. The term "glimes" refers to a class of solvents comprising monoglyme, diglyme, triglyme, tetraglime, and polyglide. The following examples illustrate processes of the present invention and an overall process using such processes to prepare N- (substituted aryl methyl) -4- (methyl disubstituted) piperidines of formula (I).

?? Formula I a) i-Pr gCl / THF / 5 ° C a ta b) H2 / 25 psi at 35 psi (172.4-241.3 kPa) / MeOH c) K2C03 / Cu20 / 145 ° C at 170 ° C / 12-20 hours e) EDC / NaBH (OAc) 3/35 ° C at 40 ° C / 3-20 hours f) EDC / 35 ° C at 50 ° C / 2-18 hours g) H202 at 80% / MeOH / 40 ° C at 45 ° C / 9-44 hours In the first step as depicted in Example 1, a suitably substituted aryl halide, for example, the known compound 4-bromo-l- (trifluoromethyl) benzene ( A), and pyridine-4-carbaldehyde were reacted with a Grignard reagent to form the hydrogen chloride salt of 4- pyridyl [4- (trifluoromethyl) phenyl] methan-1-ol (B). Then intermediate (B) was hydrogenated under elevated pressure to give the hydrogen chloride salt of the corresponding 4-piperidyl [4- (trifluoromethyl) phenyl] methan-1-ol (C). Next, a suitably substituted phenol, for example, the known compound 4-hydroxybenzaldehyde, was reacted with a halopyridine, for example 2-chloropyridine, in the presence of potassium carbonate and a catalytic amount of copper oxide at a temperature in the range of 145 ° C to 170 ° C to form 4- (2-pyridyloxy) benzaldehyde (D). Then intermediate (C) was reacted with intermediate (D) in the presence of sodium triacetoxyborohydride at a temperature in the range of 35 ° C to 40 ° C to form. { l - [(4- (2-pyridyloxy) phenyDmethyl] (4-piperidyl).]. [4- (trifluoromethyl) phenyl] methan-l-ol (F). Then intermediate (F) was condensed with a halide of suitably substituted aryl, for example, the known compound 4-chlorobenzeisocyanate (G), at a temperature in the range of 35 ° C to 50 ° C to form N- (4-chlorophenyl) (. {1- 1- (4 - (2-pyridyloxy) phenyl) methyl] (4-piperidyl).} - [4- (trifluoromethyl) phenyl] methoxy) carboxamide (H) Then intermediate (H) was oxidized with hydrogen peroxide at a temperature of the range from 40 ° C to 55 ° C to form N- (4-chlorophenyl) (. {1-oxo-l- [(4- (2-pyridyloxy) phenyl) methyl] (4- piperidil)} [4- (trifluoromethyl) phenyl] methoxy) carboxamide (Formula I). Example 2 (D2) wherein Z is N wherein R3 is CH3 B is CH where R2 is Cl Formula I c) K2C03 / Cu20 / 1450C at 170 ° C / 12-20 hours d) Brz e) K2C03 / toluene / 35 ° C at 40 ° C / 3-20 hours f) EDC / 35 ° C at 50 ° C / 2-18 hours g) 80% H202 / MeOH / 40 ° C at 45 ° C / 9-44 hours In the first step of Example 2, a suitably substituted phenol, for example, the known compound 4-methylphenol, is it can react with a halopyridine, for example 2-chloropyridine, in the presence of potassium carbonate and a catalytic amount of copper oxide at a temperature in the range of 145 ° C to 170 ° C to form 2- (4-methylphenoxy) ) iridine (D2). The intermediate (D2) can then be halogenated with, for example, bromine, to form 2- [4- (bromomethyl) phenoxy] pyridine (E). Then intermediate (C), prepared as in Example 1, can be reacted with intermediate (E) in the presence of potassium carbonate at a temperature in the range of 35 ° C to 40 ° C to form. { 1- [(4- (2-pyridyloxy) phenyl) methyl] (4- piperidil)} [4- (trifluoromethyl) phenyl] methan-l-ol (F). Intermediate (F) can then be condensed with a suitably substituted aryl halide, for example, the known compound 4-chlorobenzeisocyanate (G), at a temperature in the range of 35 ° C to 50 ° C to form N- ( 4-chlorophenyl) ( { 1- [(4- (2-pyridyloxy) phenyl) methyl] (4-piperidyl).}. [4- (trifluoromethyl) phenyl] methoxy) carboxamide (H). Then the intermediate (H) can be oxidized with hydrogen peroxide at a temperature in the range of 40 ° C to 55 ° C to form N- (4-chlorophenyl) (. {1-oxo-l- [(4 - (2-pyridyloxy) phenyl) methyl] (4-piperidyl).] - [4- (trifluoromethyl) phenyl] methoxy) carboxamide (Formula I). Although this invention has been described with emphasis in relation to preferred embodiments, it will be obvious to those of ordinary skill in the art that variations of the preferred embodiments may be used and that the invention is intended to be practical. other than those specifically described in this document. Accordingly, this invention includes all modifications encompassed within the spirit and scope as defined by the following claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (19)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A process for the preparation of a compound of formula B: B characterized in that R is selected from the group consisting of halogen, CF3, OCF3, OCHF2, OCF2CHF2 and SF5; said process comprising reacting a substituted aryl halide of formula (A): Formula (A): wherein X is halogen; and R1 is as defined above; and pyridine-4-carbaldehyde in the presence of an alkylmagnesium halide.
2. 2. The method according to claim 1, characterized in that R1 is CF3; R2 is Cl; Z is N; and B is CH.
3. 3. The process according to claim 1, characterized in that X is bromine or chlorine.
4. The process according to claim 1, characterized in that the alkylmagnesium halide is i-propylmagnesium chloride or i-propylmagnesium bromide.
5. 5. The process according to claim 1, characterized in that the reaction is carried out in a solvent.
6. 6. The process according to claim 5, characterized in that the solvent is tetrahydrofuran, dioxane or monoglyme.
7. 7. A process for the preparation of a compound of formula C: c characterized in that R1 is selected from the group consisting of halogen, CF3, 0CF3, OCHF2, OCF2CHF2 and SF5; said method comprising the hydration of a compound of formula B: at high pressure.
8. 8. The process according to claim 7, characterized in that the hydration is carried out with a metal catalyst in an alcoholic solvent.
9. 9. The process according to claim 8, characterized in that the metal catalyst is platinum, palladium or rhodium.
10. 10. The process according to claim 8, characterized in that the alcohol solvent is methanol or ethanol.
11. The method according to claim 7, characterized in that the high pressure is in the range of 25 psi to 200 psi (172.4 to 1378.9 kPa).
12. 12. A process for the preparation of a compound of formula F: F characterized in that R is selected from the group consisting of halogen, CF3, OCF3, OCHF2, OCF2CHF2 and SF5; and Z and B are independently selected from the group consisting of CH and N; the method comprising reacting a compound of formula C: wherein R1 is as defined above; and a compound selected from the group consisting of i) a compound of formula D: D wherein Z and B are as defined above; and ii) a compound of formula E: E in which Y is halogen; Y Z and B are as defined above; with the proviso that when a compound of formula E is used the reaction is carried out in the presence of a carbonate, a solvent and optionally a phase transfer catalyst.
13. 13. The process according to claim 12, characterized in that Y is bromine, iodine or chlorine.
14. The process according to claim 12, characterized in that the reaction of a compound of formula C and a compound of formula D is carried out in the presence of a sodium borohydride and a solvent selected from the group consisting of 1,2-dichloroethane , dichloromethane, acetonitrile and tetrahydrofuran.
15. 15. The process according to claim 12, characterized in that the reaction is carried out at a temperature in the range of room temperature to 80 ° C.
16. 16. The process according to claim 12, characterized in that the solvent is toluene or methyl isobutyl ketone.
17. 17. The process according to claim 12, characterized in that the phase transfer catalyst is polyethylene glycol.
18. 18. A procedure for the preparation of a composed of formula H: H characterized in that R1 and R2 are independently selected from the group consisting of halogen, CF3, OCF3, OCHF2, OCF2CHF2 and SF5; and Z and B are independently selected from the group consisting of CH and N; said method comprising the condensation of a compound of formula F: F wherein R1, Z and B are as defined above; with a compound of formula G: G wherein R2 is as defined above; in the presence of a solvent selected from the group consisting of 1,2-dichloroethane, acetonitrile and dioxane.
19. 19. The process according to claim 18, characterized in that the condensation is carried out at a temperature in the range of 40 ° C to 80 ° C.