Tamibarotene synthesis

Several synthesis of tamibarotene have been disclosed in the literature including the process scale synthesis as shown in the scheme. The synthesis started with preparation of dichloride 134 in 82% yield from diol 133 by treating with concentrated HCL in DCM. Friedal Crafts reaction of dichloride 134 with acetanilide in the presence of aluminum chloride at -15°C for 2h provided acetanilide derivative 136 in 78% yield. In a single pot, the acetanilide was reacted with PCl5 and dimethylaniline at -25°C for 1.5h followed by quenching the reaction with methanol for 2h after addition at -25°C. Addition of dimethylaniline and terepthalic chloride mono-methylester at -30 - - 20°C for 1 hr provided the tamibarotene methyl easter 137 in 81% yield. Hydrolysis of the ester by heating with sodium hydroxide in MeOH:water mixture for 1h followed isolation and crystallization gave tamibarotene (XIX) in 92% yield.