Development of a scalable synthetic process for selective bromination of 4-methyl-3,7-substituted coumarins

摘要

The hydroxyl-protected coumarin derivatives 6a-e of 4-methyl3-(2,4-dihydroxyphenyl)-7-hydroxycoumarin (4) are key intermediates in the synthesis of unsymmetrical benzopyranobenzopyran compounds, a novel series of selective estrogen receptor modulators (SERMs). Free radical bromination of the 4-methyl group on 7-acetoxy-3-[(2,4-diacetoxy)phenyl]-4-methylcoumarin (6a) with NBS resulted in incomplete reactions and low to moderate yields (25-44%) of 4-bromomethyl product 7a. Lithiation of the 4-methyl group of coumarins 6b (R = SEM), 6c (R = MOM) and 6d (R = Bz) with LDA (1.1 - 1.7 equiv) or LHMDS (1.2-1.7 equiv) generated carbanion in THF at -76 degrees C, which was quenched with bromine (1.5-2.0 equiv) to afford 4-bromomethyl derivatives 7b-d in good yields (80-90%) in small scale reactions (2-20 g). The reaction yields declined to similar to 70% when the scale was increased to >= 80 g. Furthermore, treatment of 3-[(2,4-dimethoxy)phenyl]-7-methoxy-4-methylcoumarin (6e) with LHMDS (1.08 equiv) in THF followed by rapid inverse quenched with NBS (1.10 equiv) in THF at -76 degrees C, selectively produced the desired 4-bromomethyl compound 7e in excellent yield (> 90%) in both small (2-8 g) and large (80-150 g) scale reactions. A non-chromatographic process was developed to prepare 6e. This selective and efficient procedure was successfully transferred to the pilot plant to produce multikilograms of 4-bromomethyl coumarin 7e.