Thionyl Chloride → [4-(Chloromethyl)phenoxy]acetonitrile

Schema 5 illustrates yet another route for preparing the compounds of the present invention wherein R1 is a disubstituted amino. In schema 5, the appropriately substituted (4-hydroxyphenyl)methan-1-ol (SM4) was reacted with a bromomethylisocyanate and a reducing agent, for example potassium carbonate, in a solvent, for example, DMF, in the manner disclosed above to form the corresponding (4-(cyanomethoxy)phenyl)methan-1-ol (BBB). The methan-1-ol (BBB) was then reacted with sulfinyl chloride in a solvent, for example, chloroform, at 0° C. to form the corresponding 4-(cyanomethoxy)-1-(chloromethyl)benzene (CCC), which was in turn reacted with the appropriately substituted naphthol or phenol (SM14) and a reducing agent, for example, potassium carbonate, in a solvent, for example DMF, in the manner described above to yield the corresponding 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(cyanomethoxy)benzene (DDD). The 4-(cyanomethoxy)benzene (DDD) was reacted with borane in a solvent, for example, THF, at 0° C. to form the appropriately substituted 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(aminomethoxy)benzene (EEE). The 4-(aminomethoxy)benzene (EEE) was in turn reacted with the appropriate oxoalkyl chloride, for example, acetyl chloride, in a solvent, for example, pyridine or THF, at 0° C. to yield the corresponding 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(oxoalkylaminomethoxy)benzene (FFF). The 4-(oxoalkylaminomethoxy)benzene (FFF) was then reacted with borane in a solvent in the manner described above to yield the targeted 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(alkylaminomethoxy)benzene (VIII). At this point, additional moieties can be optionally added to the amino group by reacting the 4-(alkylaminomethoxy)benzene (VIII) with the appropriate substituted alkyl, alkoxy, or alkoxyalkyl halide and a base, for example, triethylamine, to yield the target 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-((disubstituted amino)methoxy)benzene (IX).

ORD record

ord-9e443d95c7244365957f291520bf77a3

Source dataset

uspto-grants-2007_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07247756B2