US 5,294,744 AGranted

Formylation process for aromatic aldehydes

AssigneePfizer Inc.

InventorsDennis M. Godek, William M. Synder, Andrew M. Stewart

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Abstract

A novel two-step reaction process for preparing 5-substituted-2-methoxybenzaldehyde compounds is disclosed wherein the substituent group is either isopropyl or trifluoromethoxy. The process involves (1) reacting a corresponding 4-substituted phenol compound with dimethyl carbonate in the presence of a tertiary-amine base to form the corresponding 4-substituted anisole compound, and (2) thereafter subjecting the latter intermediate product obtained in the first step to aromatic C-formylation on the ring with hexamethylenetetramine in the presence of trifluoroacetic acid, followed by hydrolysis, to ultimately yield the desired aldehyde compound. The two aromatic aldehyde compounds so obtained, viz., 2-methoxy-5-trifluoromethoxybenzaldehyde and 2-methoxy-5-isopropylbenzaldehyde, are known to be useful as intermediates that specifically lead to (2S,3S)-cis-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine and (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-5-isopropylphenyl)methyl]-1-a zabicyclo[2.2.2]octane-3-amine, respectively. The latter final products, in turn, are both known to be useful in the field of medicinal chemistry as substance P receptor antagonists.

Claims10

Dependent claims

A process for preparing a 5-substituted 2-methoxybenzaldehyde compound having the formula:

##STR4## wherein R is isopropyl or trifluoromethoxy, which comprises the steps of (a) reacting a corresponding 4-substituted phenol compound of the formula:
##STR5## wherein R is as hereinbefore defined, with dimethyl carbonate in the presence of a tertiary-amine base and in the presence or absence of a reaction-inert polar organic solvent, with the proviso that said solvent is always present when R is isopropyl, said reaction being conducted at a temperature that is in the range of from about 120.degree. C. up to about 170.degree. C. until the O-methylation reaction to form the corresponding 4-substituted anisole compound of the formula:
##STR6## wherein R is as previously defined, is substantially complete;
and (b) thereafter subjecting the intermediate 4-substituted anisole compound of the formula III obtained in step (a) to aromatic C-formylation on the ring by initially reacting said anisole compound at the desired ortho-position with hexamethylenetetramine in the presence of trifluoroacetic acid at a temperature that ranges from between about 65.degree. C. and the reflux temperature of the reaction mixture until the ortho-substitution reaction is substantially complete, followed by hydrolysis of the resulting mixture at ambient temperatures by addition of water thereto to ultimately yield the desired aldehyde compound of structural formula I.

1 more element

Dependencies are inferred from the claim text.