Isoquinoline Alkaloids. 2. Preparation of d,l-Glaucine 1.5 Phosphate from d,l-Laudanosoline Hydrobromide

A high-yield, commercially viable synthesis of d,l-glaucine 1.5 phosphate (1) from d,l-laudanosoline hydrobromide (2) is described. Oxidation of 2 with ferric chloride in ethanol/ water buffered with sodium acetate gave d,l-1,2,9,10-tetrahydroxyaporphine hydrochloride (3) in 76−83% yield. This was converted to the free base, 4, which was methylated with phenyltrimethylammonium hydroxide (5) in 1,2-dichlorobenzene to give, after precipitation with 48% hydrobromic acid, crude d,l-glaucine hydrobromide (6) in 74% yield. The crude 6 was purified by recrystallization from 50/50 (v/v) ethanol/water to remove by-product 1-(2-(dimethylamino)ethyl)-3,4,6,7-tetramethoxyphenanthrene hydrobromide (7). The purified 6 was converted to 1 in 86−88% yield by formation of the free base followed by treatment with 85% phosphoric acid in 80% ethanol and subsequent crystal digestion for 6 h.