3,4 Dimethoxyphenylacetic acid

A 500-nil., round-bottomed flask equipped with a mechanical stirrer, a dropping funnel, a thermometer, and a reflux condenser is charged with 49.0 g. (0.25 mole) of 3,4-dimethoxyphenylacetic acid (Note 1) and 125 ml. of acetic acid. The solution is stirred and heated at 80° on a steam bath, while 40 ml. of aqueous concentrated hydrochloric acid is added rapidly and followed immediately by 40 ml. of 37% formalin (Notes 2 and 3). The yellow solution is stirred and heated on a steam bath for 1 hour, during which time the reaction temperature reaches 90° (Note 4) and the solution assumes a dark brown oolor. 

The 3,4-dimethoxyphenylacetic acid was purchased from Mathe-son Coleman and Bell. The checkers prepared material of m.p. 97-98° according to the procedure described in an earlier volume of this series.2... 

Intermolecular acylation of 3,4-dimethoxyphenylacetic acid occurs in polyphosphoric acid, leading to 2-(3,4-dimethoxyphenylacetyl)-4,5-dimethoxyphenylacetic acid (622). Cyclization to the isochromanone takes place when the keto acid is heated in decalin (Scheme 240) (72JHC853). 

A chemical modification of DMPEA that has been explored in this quest on of pink spots, mental pathology, and diagnostic markers, is the corresponding acetami de. One of the metabolites of DMPEA was found to be the N-acetyl derivative, N-acetyl-3,4- dimethoxyphenethylamine. It was found to be demethylated in man, and to have pharmacological activity in animals. Maybe this was the active compound that could be involved in the schizophrenic process. But human trials with it, as with the principal metabolite 3,4-dimethoxyphenylacetic acid, showed nothing at all in man. 

Nitroveratric aldehyde and 3 4-dimethoxyphenylacetic acid were condensed to give the acid [xv, R = H]. Reduction and Pschorr phenanthrene ring-closure of this gave two tetramethoxyphenanthrene carboxylic acids one of these, also accessible from the bromo-acid [iv, R = Br], must be the 3 4 5 6-isomer [v] and the other the 3 4 6 7-isomer [yi]. The latter on decarboxylation afforded dimethylsinomenol [u, R = Me]. 

The positions of the oxygen substituents in sinomenine was demonstrated by the identity of dimethylsinomenol [xcvil] with 3 4 6 7-tetramethoxyphenanthrene. This was synthesized by Pschorr s method from 2-nitroveratric aldehyde and 3 4-dimethoxyphenylacetic acid, a synthesis that afforded two tetramethoxyphenanthrene-9-carboxyhc acids, [xcvm] and [xoix], one of which, [xcvm], being also accessible from the bromo-acid [c] must be the 3 4 5 6-isomer the other [xcix], which must therefor be the 3 4 6 7-isomer, gave dimethylsinomenol on decarboxylation [103, 105-6],... 

In the realm of synthesis, two groups74,75 have reported a facile preparation of the 3-isoquinolone derivative (40) by the same method, and one of these has used this compound as an intermediate for entries into tetrahydropapaverine (41 R = H) and ( )-laudanosine (41 R = Me) as shown in Scheme 3.75 Inter-molecular acylation of 3,4-dimethoxyphenylacetic acid with polyphosphoric acid gave (39) in 60 %75 or 95 %74 yield. The latter compound was readily converted into tetrahydropapaverine (41 R = H) in three steps. On the other hand, treatment of (42), prepared by dehydration of (39) in refluxing decalin, with methylamine followed by identical steps to those used in the synthesis of (41 R = H) gave (+)-laudanosine (41 R = Me). 

With the related 6-methoxy compound shown the cyclisation to a morphinan with hydrochloric acid proceeded to the unwanted product C in 37% yield and the desired one in only a 3% yield (ref. 179). The same precursor, synthesised from 2-(3-methoxyphenyl)ethylamine and 3,4-dimethoxyphenylacetic acid by amide formation and ring closure by the Bischler-Napieralski cyclisation, followed by reduction, methylation and Birch reduction, was used by others with similar results (ref. 180). The route constitutes a synthesis of morphine by the use of the final steps of earlier work (refe. 169,171), albeit in low yield, although in considerably fewer steps than the earlier syntheses. 

But human trials with it, as with the principal metabolite 3,4-dimethoxyphenylacetic acid, showed nothing at all in man. 

Coned. HCl added rapidly at 80° to a stirred soln. of 3,4-dimethoxyphenylacetic acid and acetic acid, then 37%-formalin added immediately, stirred and heated 1 hr. on a steam bath 6,7-dimethoxy-3-isochromanone. Y 56-85%. F. e. s. J. Finkelstein and A. Brossi, Org. Synth. 55, 45 (1976). 

Procedures. The preparation of 3,4-dimethoxyphenylacetic acid (homoveratric acid) is described in Organic Syrdheses ... 

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