HCID 11497364, compound → 4-{Bis[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-ol

HRID 1642017Notes

Reaction equation

HRID 1642017 reaction equation
[F:1][C:2]([F:37])([F:36])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:11]2([OH:24])[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1>[Pd].C(O)=O>[F:34][C:32]([F:33])([F:35])[O:31][C:28]1[CH:27]=[CH:26][C:25]([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:37])([F:1])[F:36])=[CH:5][CH:6]=2)[C:11]2([OH:24])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:30][CH:29]=1

Participants

4

Reactant 1

HCID 11497364HCID 11497364, compound

Product 1

HCID 166562744-{Bis[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-ol

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 284Formic AcidSolvent

Procedure

In the first step as depicted in Scheme 4, two appropriately substituted aryl halides, for example, the known compound 4-bromo-1-(trifluoromethoxy)benzene (A3), were cross-coupled with a Grignard reagent and an alkyl formate, for example, ethyl formate to form bis[4-(trifluoromethoxy)phenyl]methan-1-ol (B3). Intermediate (B3) was then reacted under acidic conditions with hydrogen bromide, to afford the corresponding bis(trifluoromethoxyphenyl)bromomethane (C3). Intermediate (C3) was then lithiated, for example with butyl lithium, and then reacted with an appropriately N-substituted piperidin-4-one, formula (D3), 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 (E3). Intermediate (E3) 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 (F3). Next, an appropriately substituted phenol, for example, the known compound 4-hydroxybenzaldehyde, was cross-coupled 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 (G3). Intermediate (F3) was then cross-coupled with Intermediate (G3) in the presence of sodium triacetoxyborohydride to form 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[(4-(2-pyridyloxy)phenyl)methyl]piperidin-4-ol (I-A). Intermediate (I-A) was then oxidized with hydrogen peroxide at a temperature in the range of 40° C. to 55° C. to form a compound of formula I-C.

Sources & evidence

ORD record
ord-36043e9b79374f6390b6d2291b5cffce
Source dataset
uspto-grants-2012_02
Patent number
US08119563B2

Reaction notes

Loading…