Indacrinone

Indacrinone is a chiral drug, with one chiral center and hence exists as mirror-image twins. (R)-enantiomer, the eutomer, is diuretic whereas the mirror-image version (S)-enantiomer counteracts side effect of the eutomer. Here both the enantiomers contribute to the overall desired effect in different ways.

As indicated earlier, the (R)- enantiomer is the pharmacologically active diuretic. Like most other diuretics, the (R)-isomer possesses an undesirable side-effect of retaining uric acid. But the (S)-enantiomer, the distomer, has the property of assisting uric acid secretion (uricosuric effect), and, therefore, antagonizing the undesirable side-effects of the eutomer (uric-acid retention). It affords a good argument for the marketing of a racemic mixture. But studies exemplify that 9:1 mixture of the two enantiomers provides optimal therapeutic value.

The Friedel-Crafts acylation of 2,3-dichloroanisole [1984-59-4] (1) with phenylacetyl chloride [103-80-0] (2) gives 2,3-dichloro-4-phenylacetylanisole [59043-83-3] (3). A variation of the Mannich reaction is performed employing tetramethyldiaminomethane [51-80-9] (this is an aminal of dimethylamine and formaldehyde). The intermediate reaction product (5), which is not isolated, would undergo a β-Hydride elimination with concomitant loss of dimethylamine and formation of the corresponding enone, 2,3-Dichloro-4-(2-phenylacryloyl)anisole (PC10924810) (6). Acid catalyzed (H₂SO₄) intramolecular cyclization gives the indanone (PC10990444) (7). This is O-demethylated under acidic conditions to give 2-Phenyl-5-hydroxy-6,7-dichloro-1-indanone, PC12774089 (8). The phenol thus obtained is then alkylated on oxygen by iodoacetic acid [64-69-7] (9) affording PC20520826 (10). Alkylation with iodomethane [74-88-4] in the presence of sodium hydride completed the synthesis of indacrinone (11).