(Hive Addict)
07-31-03 03:38
No 450864
(Rated as: excellent)

GJ Kapadia, YN Vaishnav, MBE Fayez. Peyote alkaloids IX: Identification and synthesis of 3-demethylmescaline, a plausbile intermediate in the biosynthesis of the cactus alkaloids. J Pharm Sci 58(9) (1969) 1157-1159. (as requested by Potter)

3-Hydroxy-4,5-dimethoxybenzoic acid (II)

A solution of methyl gallate (120 g) in 10% sodium hydroxide solution (550 mL) was treated at 5 with DMS (238 g) added dropwise over 1.5 h (N2 atmosphere). After basification with sodium hydroxide and heating to 60 for 10 min, a deposit (43 g) was formed which was shown to be trimethyl gallic acid methyl ester, mp 81-82C (undepressed); reported [10] mp 82.5. The alkaline filtrate was washed with ether, acidified with HCl, then extracted with chloroform. The residue from the latter extract was methylated with methanol-sulfuric acid (20 h reflux) and, after neutralization with sodium bicarbonate solution, methanol was removed and the aqueous concentrate treated with sodium hydroxide solution, then extracted with ether to remove trimethyl gallic acid methyl ester. A stream of carbon dioxide was passed through the alkaline solution followed by extraction with chloroform; this extract was shown (by GLC) to contain essentially methyl 4-hydroxy-3,5-dimethoxybenzoate. Acidification of the aqueous layer with HCl gave 3-hydroxy-4,5-dimethoxybenzoic acid as a precipitate (44 g, with an additional 1.5 g by extraction of the filtrate), mp 189-191. Reported [5] mp 193-194.

3-Benzyloxy-4,5-dimethoxybenzoic acid (V)

A solution of 16.36 g of compound II in 270 mL of acetone containing 24 g of anhydrous potassium carbonate was treated with benzyl bromide (32.7 g) under reflux for 24 h. After the usual work-up, the product (benzyl ester-ether) was saponified with 6% methanolic potash (7 h reflux) and the reaction mixture washed with chloroform. The material (20.8 g) which deposited upon acidification of the aqueous layer was crystallized from methanol to give 17.6 g (an additional 1 g was obtained by chloroform extraction), mp 176. Reported [5] mp 170-172.

3-Benzyloxy-4,5-dimethoxybenzoyl chloride (VI)

A solution of V (2.25 g) in dry benzene (20 mL) was briefly heated with oxalyl chloride (11 mL) and the mixture then left at room temperature for 16 h. The residue remaining after evaporation in vacuo was crystallized from benzene-light petroleum to give fine needles (2.21 g), mp 69-70. A pure sample had mp 83-84.

3-Benzyloxy-4,5-dimethoxyphenylacetamide (VIII)

A solution of the acid chloride VI (1.83 g) in ether (100 mL) was treated with an ethereal solution (50 mL) of diazomethane (about 1 g). After standing at room temperature overnight and evaporation, an oily product (1.9 g) was obtained which could not be induced to crystallize. This material (presumably the diazoketone VII) was directly treated in a dioxane solution (20 mL) with concentrated ammonia solution (20 mL) and 10% aqueous silver nitrate solution (2.5 mL) under reflux (steam bath) for 17 h. After filtration the reaction mixture was decolorized with activated carbon (Norite) then concentrated to a small volume. The crude product which deposited was repeatedly crystallized from methanol-water then from benzene to give prisms (0.82 g), mp 117-118.

3-Benzyloxy-4,5-dimethoxy-β-phenylethylamine hydrochloride (IX)

To a stirred suspension of 1 g of LAH in ether (70 mL) was added portionwise a solution of the acid amide (VIII, 0.8 g) in benzene (25 mL). After 3.5 h reflux and standing overnight at room temperature, the mixture was worked up in the usual manner. The crude product was treated with a benzene solution of hydrogen chloride and the material which deposited (0.41 g) was crystallized from benzene to give matted needles, mp 150-152.

3-Hydroxy-4,5-dimethoxy-β-phenylethylamine hydrochloride (I)

A solution of the benzyl ether IX (0.3 g) in acetic acid (15 mL) containing 0.1 g of 10% palladized charcoal was shaken with hydrogen (26 psi) at room temperature for 90 min. After removal of the catalyst, the solution was evaporated and the residue crystallized from ethanol-benzene to give flat needles (0.195 g), mp and mixed mp with an authentic sample 178-179; identical IR spectra.

[5] E Spaeth et al. Monatsh Chem 43 (1922) 93
[10] I Heilbron. Dictionary of Organic Compounds. Oxford University Press, 3 (1965) 1494

Dirty old man