Apomorphine synthesis

Hedberg MH, Linnanen T, Jansen JM, Nordvall G, Hjorth S, Unelius L, Johansson AM. 11-Substituted (R)-apomorphines—synthesis, pharmacology, and modeling of D-2A and 5-HT1A receptor interactions. J Med Chem 1996 39 3503-3513. 

Further complicating the picture is the induction of autoreceptor supersensitivity with chronic neuroleptic administration, as well as the fact that at least one tract-the mesocortical, which projects to the prefrontal cortex-may lack such autoreceptors. Some of the authors conducted preliminary, single-dose studies with apomorphine at a dose that stimulated presynaptic DA autoreceptors that reduced synthesis and NT release, producing a measurable acute antipsychotic effect ( 9, 10). 

The synthesis of three l,2,10,ll-tetrasubstituted./V-(n-propyl)noraporphines, using either the Bischler-Napieralski-Pschorr sequence or a Reissert alkylation-Pschorr cyclization, has been achieved.29 Patents have been taken out on the morphine-apomorphine rearrangement that is induced by phosphoric acid and which leads to N- alkylated norapomorphines.30 Other patents concern the vanadium-trichloride-induced cyclization of tetrahydrobenzylisoquinolines that are hydroxylated at C-7, to furnish a series of 1-hydroxylated aporphines such as thaliphorphine. 31,32... 

The synthesis of a number of radiolabelled apomorphine derivatives has been described.59-62 A full paper has appeared on the preparation of (—)-2,10,11-trihydroxy-/V-(n-propyl)noraporphine, a dopaminergic compound with anticonvulsant activity.63 The potential dopamine-inhibiting properties of (—)-N-(2-chloroethyl)norapomorphine and related compounds have been assessed. A-Chloroethylation in the aporphine series can abolish dopamine agonist action, and can confer a long-lasting dopamine antagonist potential.64... 

Mattingly, B.A. Fields, S.E. Langfels, M.S. Rowlett, J.K. Robinet, P.M. Bardo, M.T. (1996) Repeated 7-OH-DPAT treatments behavioral sensitization, dopamine synthesis and subsequent sensitivity to apomorphine and cocaine. Psychopharmacology Berl. 125, 33-42. 

Further degradation of the methine and isomethine yields the same 3 4-dimethoxy-8-vinylphenanthrene [v], which can be oxidized, first to 3 4-dimethoxy-8-(a /3-dihydroxyethyl)-phenanthrene [vi] and finally to 3 4-dimethoxyphenanthrene-8-carboxylic acid [vn] [16, 66]. The latter has been converted via the 8-amino compound to 3 4 8-tri-methoxyphenanthrene [vm] [67], shown to be identical with an authentic specimen [68]. Two ethylphenanthrenes, not identical with 9-othylphenanthrene, are obtained by distilling [v] with zinc-dust [66]. Position 8 of the phenanthrene system was thus established as the point of attachment of thecarbon end of the side-chain in apomorphine. Position 9 as point attachment of the nitrogen was assumed on the basis of evidence derived from the chemistry of morphine and was finally proved by synthesis. 

The use of 2-nitrobenzyl halides in the Reissert alkylation, followed eventually by the Pschorr cyclization, has provided an attractive route to various aporphines (31). Thus this procedure had led to the synthesis of apomor-phine, ° apomorphine derivatives, atheroline, imenine, N-methyl-ovigerine, oconovine, 8-hydroxyaporphines, 10-hydroxyaporphines, ... 

Morphine alkaloids. 113. Synthesis of C-3 halogen-substituted apocodeines and apomorphines... 

The metabolism of apocodeine to apomorphine and norapomorphine was shown to occur in rats. The clinical application of apomorphine has been discussed. The synthesis and pharmacological testing of several aporphine alkaloid analogues have been reported. The pharmacology of liriodenine, thalicminine, corydine, and isocorydine hydrochloride has been investigated. The synthesis of tritium- and deuterium-labelled apomorphine has been reported. " Under controlled conditions, exclusive introduction of label into the catechol ring of the molecule was achieved. 

Borgman, R.J., Smith, R.V. and Keiser, J.E. (1975) The acetylation of apomorphine. An improved method for the selective preparation of diacetylapomorphine utilizing trifluoroacetic acid/acetyl bromide. Synthesis 249-250. 

These cycloadditions can be highly regioselective, as in a recent synthesis of apomorphine analog 693 from 691 and 3,4-dimethoxybenzyne 693 was isolated in 34% yield, and none of its regioisomer could be detected in the reaction mixture. Thus initial attack is by the more nucleophilic site of the diene on the more electrophilic (and less hindered) site of the aryne. 

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