| SYNTHESIS |
The compd features a benzoic acid unit whose benzene ring is bonded to enantiomeric chromane (benzopyran).
Researchers realized that biaryl coupling of an iodo compd with a boronic acid (Suzuki coupling) would form such a bond. First they tried an iodobenzoate ester with a chromane
boronic acid. But the iodobenzoate ester was unstable. And the chromaneboronic acid was amorphous, which made it hard to characterize for regulatory purposes.
In a switch of functional groups for coupling, a carboxybenzeneboronic acid with a bromochromane was a successful combination, but new problems arose. Coupling worked with an amide-protected -COOH, but hydrolysis of the amide afterwards was too hard.
Esters were more easily cleaved after coupling. Of various esters tried, the 2-pentyl ester gave 99% yield. But 2-pentyl is an asymmetric group, & adding the ester to the asymmetric chromane gave 2 diastereoisomers. Co.'s analytical dept objected to that.
Finally researchers discovered that a neopentyl benzoate gave just the right directing influence to guide the boronic acid group into the ortho position. And the neopentyl ester coupled with the bromochromane in 100% yield. Moreover, the Pd catalyst loading was so low for the coupling that it was not necessary to carry out Pd removal to reach purity standards
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