This invention is in the field of chemical processes; more specifically, an improved process for preparing N-(substituted arylmethyl)-4-substituted-4-(disubstituted methyl)piperidines, processes for preparing intermediates useful in this process and novel intermediates useful in this process.
N-(substituted arylmethyl)-4-substituted-4-(disubstituted methyl)piperidines are useful insecticides and have been described in PCT published application WO 2005/036961 the disclosure of which is incorporated herein by reference. Disadvantages of processes disclosed in WO 2005/036961 to produce these compounds include less than optimal yields, highly exothermic reactions due to the presence of fluorine, less than optimal cycle times and high catalyst loadings. The present invention improves yield, cycle times and catalyst loading and reduces the exothermic nature of certain of the reactions involved in producing N-(substituted arylmethyl)-4-substituted-4-(disubstituted methyl)piperidines.
The present invention is directed to (a) an overall process for preparing N-(substituted arylmethyl)-4-substituted-4-(disubstituted methyl)piperidines of formula I:
wherein
(b) individual steps involved in the process, and (c) novel intermediates.
The overall process comprises the following eight steps:
a) forming intermediate (B) :
wherein
with a Grignard reagent and an alkyl formate;
b) halogenating intermediate (B) to form intermediate (C):
wherein
c) reacting intermediate (C) with a compound of formula (D):
wherein R3 is selected from the group consisting of hydrogen, benzyl, substituted benzyl, t-butoxycarbonyl and trimethylsilyl; to form intermediate (E):
wherein R1, R2 and R3 are as defined above;
d) reacting intermediate (E) with an acid in the presence of a catalyst to form intermediate (F):
wherein R1 and R2 are as defined above;
e) reacting a substituted phenol and a compound selected from the group consisting of 2-halopyridine, 2-halopyrimidine and halobenzene to form intermediate (G):
wherein
f) when R4 in intermediate (G) is —CH3, halogenating intermediate (G) to form intermediate (H):
wherein
g) reacting intermediate (F) and a compound selected from the group consisting of i) intermediate (G) wherein R4 is —CHO and ii) intermediate (H) to form intermediate (J):
wherein R1, R2, Z and B are as defined above; and
h) oxidizing intermediate (J) to form a compound of formula I.
Steps a, c and g, as well as the compound identified as formula E, are also part of the invention.
The present invention relates to an overall process, individual steps of the process and novel intermediates involved in preparing a N-(substituted arylmethyl)-4-substituted-4-(disubstituted methyl)piperidine of formula I:
wherein
The overall process comprises the following eight steps:
a) forming intermediate (B):
wherein
with a Grignard reagent and an alkyl formate;
b) halogenating intermediate (B) to form intermediate (C):
wherein
c) reacting intermediate (C) with a compound of formula (D):
wherein R3 is selected from the group consisting of hydrogen, benzyl, substituted benzyl, t-butoxycarbonyl and trimethylsilyl;
to form intermediate (E):
wherein R1, R2 and R3 are as defined above; d) reacting intermediate (E) with an acid in the presence of a catalyst to form intermediate (F):
wherein R1 and R2 are as defined above;
e) reacting a substituted phenol and a compound selected from the group consisting of 2-halopyridine, 2-halopyrimidine and halobenzene to form intermediate (G):
wherein
f) when R4 in intermediate (G) is —CH3, halogenating intermediate (G) to form intermediate (H):
wherein
g) reacting intermediate (F) and a compound selected from the group consisting of i) intermediate (G) wherein R4 is —CHO and ii) intermediate (H) to form intermediate (J):
wherein R1, R2, Z and B are as defined above; and
h) oxidizing intermediate (J) to form a compound of formula I.
Preferably, R1 and R2 are independently selected from the group consisting of CF3, OCF3 and OCHF2; X and D are bromine or chlorine; Y is bromine, iodine or chlorine; R3 is benzyl, t-butoxycarbonyl or trimethylsilyl. More preferably, R1 and R2 are OCF3; X and D are bromine. Also preferred, Z is N and B is CH.
The reacting of step a) can be conducted with ethyl formate or methyl formate as the alkyl formate; the Grignard reagent used in step a) is formed by reacting an alkyl magnesium halide with one of the substituted aryl halides. Preferably, the reacting of step a) is conducted at a temperature in the range of from −20° C. to 30° C.; and the alkyl magnesium halide is i-propyl magnesium chloride or i-propyl magnesium bromide.
The halogenating of step b) can be conducted with hydrogen bromide and acetic acid; in an organic solvent. Preferably, the organic solvent is a hydrocarbon solvent such as heptane, hexane or petroleum ether or an aromatic solvent such as toluene or xylene.
The reacting of step c) can be conducted in the presence of an organometallic reagent. Preferably, the reacting of step c) is conducted at a temperature in the range of from −20° C. to −100° C., more particularly from −50° C. to −100° C.; and the organometallic reagent is t-butyl lithium, sec-butyl lithium or n-butyl lithium.
The reacting of step d) can be conducted with formic acid; with a palladium catalyst; in the presence of alcohol solvents. Preferably, the reacting of step d) is conducted at a temperature in the range of from ambient temperature to 130° C., more particularly from ambient temperature to 100° C.; the alcohol solvents are methanol, ethanol, propanol or butanol; and the palladium catalyst is palladium on a support such as Pd(OH)2/C, Pd/C, Pd/SiO2 or Pd/Al2O3. More preferably, the alcohol solvent is methanol.
The reacting of step e) can be conducted in the presence of a base and a catalytic amount of copper catalyst. The substituted phenol reacted in step e) is 4-methylphenol or 4-hydroxybenzaldehyde. Preferably, the reacting of step e) is of 4-methylphenol or 4-hydroxybenzaldehyde and 2-chloropyridine; the reacting is conducted at a temperature in the range of from 125° C. to 180° C.; the base is carbonate or hydroxide; and the copper catalyst is copper, copper chloride, copper oxide, copper bromide or copper carbonate.
The reacting of step g) when R4 is CHO can be conducted in the presence of sodium borohydride and a solvent. Preferably, the solvent is tetrahydrofuran, dioxane, dichloroethane, dichloromethane or acetonitrile. The reacting of step g) when intermediate (F) and intermediate (H) are reacted can be conducted in the presence of a carbonate, a solvent and optionally a phase transfer catalyst. The solvent can be toluene or methyl isobutyl ketone. The phase transfer catalyst can be polyethylene glycol, dimethylaminopyridine, triethylamine, p-toluenesulfonic acid, phosphorous pentoxide, pyridine or phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof.
The oxidizing of step h) can be conducted in the presence of an oxidizing agent and a solvent. Preferably, the oxidizing of step h) is conducted at a temperature in the range of from ambient temperature to 60° C.; the oxidizing agent is peroxide and the solvent is selected from alcohol solvents such as methanol, ethanol, propanol and butanol.
Another embodiment of the present invention is an improved process (step a above) for preparing a compound of formula B:
wherein R1 and R2 are independently selected from the group consisting of halogen, CF3, OCF3, OCHF2, OCF2CHF2 and SF5;
said process comprising reacting two substituted aryl halides of formula (A-1) and formula (A-2):
wherein
with a Grignard reagent and an alkyl formate.
Another embodiment of the present invention is a process (step c above) for preparing a compound of formula E:
wherein
said process comprising reacting a compound of formula C:
wherein
wherein R3 is as defined above.
Another embodiment of the present invention is a process (step g above) for preparing a compound of formula J:
wherein
said process comprising reacting a compound of formula F:
and a compound selected from the group consisting of i) a compound of formula G:
wherein Z and B are as defined above;
and ii) a compound of formula H:
wherein
Yet another embodiment of the present invention is a compound of formula E:
wherein
which may be prepared by the process described above.
The modifier “about” is used herein to indicate that certain preferred operating ranges, such as ranges for molar ratios for reactants, material amounts, and temperature, are not fixedly determined. The meaning will often be apparent to one of ordinary skill. For example, a recitation of a temperature range of about 120° C to about 135° C. in reference to, for example, an organic chemical reaction would be interpreted to include other like temperatures that can be expected to favor a useful reaction rate for the reaction, such as 105° C. or 150° C. Where guidance from the experience of those of ordinary skill is lacking, guidance from the context is lacking, and where a more specific rule is not recited below, the “about” range shall be not more than 10% of the absolute value of an end point or 10% of the range recited, whichever is less.
As used in this specification and unless otherwise indicated the substituent terms “alkyl”, “alkoxy”, and “haloalkyl”, used alone or as part of a larger moiety, includes straight or branched chains of at least one or two carbon atoms, as appropriate to the substituent, and preferably up to 12 carbon atoms, more preferably up to ten carbon atoms, most preferably up to seven 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, and the like are known by their acronyms. These include the acronyms “DMF” meaning N,N-dimethylformamide and “THF” meaning tetrahydrofuran.
The following examples illustrate the processes of the present invention.
In the first step as depicted in Example 1, two molecules of a substituted aryl halide, for example, the known compound 4-bromo-1-(trifluoromethoxy)benzene (A), were reacted with a Grignard reagent and an alkyl formate, for example, ethyl formate to form bis[4-(trifluoromethoxy)phenyl]methan-1-ol (B). Intermediate (B) was then reacted under acidic conditions with hydrogen bromide, to afford the corresponding (4-{bromo[4-(trifluoromethoxy)phenyl]methyl}phenoxy)trifluoromethane (C). Intermediate (C) was then lithiated, for example with butyl lithium, and then reacted with an appropriately N-substituted piperidin-4-one, formula (D), for example 1-benzylpiperidin-4-one, at a temperature in the range of −85° C. to −60° C. to afford the corresponding 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-benzylpiperidin-4-ol (E). Intermediate (E) was then reacted with an acid, for example formic acid, in the presence of a catalyst, for example a palladium catalyst, to form the hydrogen chloride salt of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-ol (F). Next, an appropriately 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 (G). Intermediate (F) was then reacted with Intermediate (G) in the presence of sodium triacetoxyborohydride to form 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[4-(2-pyridyloxy)phenyl)methyl]piperidin-4-ol (J). Intermediate (J) was then oxidized with hydrogen peroxide at a temperature in the range of 40° C. to 55° C. to form 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-4-hydroxy-1-[(4-(2-pyridyloxy)phenyl)methyl]piperidin-1-one (Formula I).
Steps a) through d) are the same as in Example 1 to form (F)
In the first step of Example 2, an appropriately substituted phenol, for example, the known compound 4-methyl phenol, can be 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 2-(4-methylphenoxy)pyridine (G2). Intermediate (G2) can then be halogenated with, for example bromine, to form 2-[4-(bromomethyl)phenoxy]pyridine (H).
Intermediate (F), made as in Example 1, can then be reacted with Intermediate (H) in the presence of potassium carbonate to form 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[(4-(2-pyridyloxy)phenyl)methyl]piperidin-4-ol (J). Intermediate (J) can then be oxidized as in Example 1 to form 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-4-hydroxy-1-[(4-(2-pyridyloxy)phenyl)methyl]piperidin-1-one (Formula I).
While this invention has been described with an emphasis upon 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 it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly this invention includes all modifications encompassed within the spirit and scope as defined by the following claims.
This application claims the benefit of U.S. Provisional Application No. 60/609,533, filed Sep. 13, 2004.
Filing Document | Filing Date | Country | Kind | 371c Date |
---|---|---|---|---|
PCT/US05/32279 | 9/12/2005 | WO | 7/18/2007 |
Number | Date | Country | |
---|---|---|---|
60609533 | Sep 2004 | US |