Process for preparing N-(substituted arylmethyl)-4-substituted-4- (disubstituted methyl) piperidines and intermediates
An intermediate and two-substituted technology, applied in the field of chemistry, can solve the problems of suboptimal yield, suboptimal cycle time, high catalyst loading, etc.
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Embodiment 1
[0174]
[0175] Embodiment 1 (continued)
[0176]
[0177] a-i)THF / I-PrMgCl / 15°C to room temperature / 24h a-ii)HCO 2 Et / -10~0℃a-iii)10%NH 4 Cl b) octane / HBr / acetic acid / room temperature / 3h c-i) tert-butyllithium / THF / -85~-60℃ / 12h c-ii) HCl(g) d)MeOH / HCOOH / 'Pd(OH) 2 / C' / 40~55℃ / 4h e)K 2 CO 3 / Cu 2 O / 145~170℃ / 3.5h g)THF / NaBH(OAc) 3 / room temperature / 12h h)50%H 2 o 2 / MeOH / 40~55℃ / 9-44h
[0178] As shown in Example 1, in the first step, two molecules of a substituted aryl halide, for example, the known compound 4-bromo-1-(trifluoromethoxy)benzene (A), and a Reaction of Riya reagent with an alkyl formate, eg, ethyl formate, forms bis[4-(trifluoromethoxy)phenyl]methanol-1 (B). Afterwards, intermediate (B) reacts with hydrogen bromide under acidic conditions to generate the corresponding (4-(bromo[4-(trifluoromethoxy)phenyl]methyl)phenoxy)trifluoromethane (c) . Intermediate (c) is then lithiated, for example with butyl lithium, and then reacted with a suitable N-subst...
Embodiment 2
[0180] The process of generating (F) from steps a) to d) is the same as in Example 1.
[0181] Example 2
[0182]
[0183] Embodiment 2 (continued)
[0184]
[0185] e)K 2 CO 3 / Cu 2 O / 145~170℃ / 3.5h f)Br 2 j) K 2 CO 3 / DMF h)50%H 2 o 2 / MeOH / 40~55℃ / 9-44h
[0186]Example 2 In the first step, a suitable substituted phenol, such as the known compound 4-methylphenol, and a halogenated pyridine, such as 2-chloropyridine, can be oxidized in potassium carbonate and a catalytic amount In the presence of copper, react at a temperature of 145-170°C to form 2-(4-methylphenoxy)pyridine (G2). Intermediate (G2) can then be halogenated using eg bromine to form 2-[4-(bromomethyl)phenoxy]pyridine (H). In the presence of potassium carbonate, intermediate (F) as prepared in Example 1 can react with intermediate (H) 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 ...
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