11- Hydroxy aporphines

The drugs were dissolved in degassed ultra pure water with approximately 0.5 mg/ml ascorbic acid to prevent oxidation of the compounds and stocked in a concentration of 300 nmol/ml for subcutaneous administration and 10 pmol/2 ml for oral administration and diluted, if necessary, with degassed ultra pure water before administration. To dissolve R-(-)-ll-hydroxy-aporphine a drop of glacial acetic acid was added. Drugs used were R-(-)-apomorphine.HCl (11), R-(-)-ll-hydroxyaporphine (79), R-(-)-N- -... 

Later Goto and Shishido prepared di-3-ethoxy-5 6-dimethoxy-A -ethylnoraporphine ethiodide, m.p. 186-7°, and this, by the Hofmann degradation process, gave the ethiodide of the de-At-ethyl base, m.p. 194°, from which the dimethoxyethoxyvinylphenanthrene, m.p. 108°, was obtained, identical with that from natural Z-tuduranine. The latter is therefore 3-hydroxy-5 6-dimethoxy-A -H0)aporphine. A later paper (1941) also relating to tuduranine is not yet accessible. 

A novel and efficient synthesis of aporphinic alkaloids has been developed by Kupchan and O Brien (55) via oxidative photocyclization of l-(a-hydroxy-2-iodobenzyl)-6-hydroxy-7-methoxyisoquinolines such as 120, 121, or 122, all prepared by the Reissert method shown in Scheme 17. N-Methylation of oxo-aporphines 124 and 125 yielded corunnine (127) and nandazurine (128), respectively. Reduction of 124 with Zn-AcOH resulted in thalicmidine (130), and similar reduction of 125 gave domesticine (131) in racemic form. Caaverine (129) has also been prepared by this route (55). 

Thalifasine (516), C40H46N2O9, [a] [67.9° (c 0.80, MeOH), is the last of the six 12 —8 ether-linked aporphine-benzylisoquinoline dimers (the others being 302,304,473, 514, and 515) isolated from Thalictrum faberi. The UV base shift of the alkaloid and a NMR study of its O, O-diacetate suggested the indicated location of the hydroxy substituents. The CD curve, closely resembling that of thalifaberine (302), indicated the same configuration (545). 

A careful investigation of the alkaloidal content of the Brazilian plant Ocotea minarum (Lauraceae) has led to five new aporphines, namely ocotominarine (3), ocominarine (4), norleucoxylonine (5), iso-oconovine (6), and 4-hydroxy-dicentrine (7).4... 

The new aporphine alkaloid oliveroline (13) exhibits antiparkinsonian activity, while oliveridine (AT-methyl-14) and oliverine (N-deoxy-18) cause a dose-dependent hypotension in normal rats followed by a secondary hypertension. In the isolated rabbit ear, oliveridine has a vasodilating effect comparable to that of papaverine.55 Cabudine, which corresponds to l,2-methylenedioxy-3-hydroxy-methyl-9-methoxydehydroaporphine, possesses adrenolytic activity.56... 

Isothebaine (= 1-Hydroxy-2,1 1-dimethoxyaporphine) (aporphine isoquinoline) Laudanosine (= Laudanine methyl ether) (benzylisoquinoline)... 

Pschorr aporpMne synthesis, K upchan el at have reported an improved synthesis of aporphines by using (1) for condensation with o-nitrotolucncs (2) in the presence of potassium /-butoxide in DMA to give l-(2-nitrobenzyl)-6-methoxy-7-hydroxy-l,2,3.4-tetrahydroisoquinolincs (3) in yields of 88 95%. These are hydrogenated to the... 

PSCHORR APORPHINE SYNTHESIS 6-Methoxy-7-hydroxy-3,4-dihydroisoquino-linium melhiodide. 

ANILINES 4-Chloro-2-pbenylquliiazolme. ANNULENES Propaigyl aldehyde. ANTHRONES Pyiidene hydrochloride. APORPHINES 6-Methoxy-7-hydroxy-3,4-dihydroisoquinoliniuin methiodide. ARYLACETIC ACIDS Ceric acetate. ARYLACETYLENES n-Butylamine. Iodoethynyl(trimethyl)siIane. 

In 1965, the actual synthesis of (+ )-l-hydroxy-2,9,10-trimethoxy-aporphine (XXIV) (mp 190°-192°) by an unambiguous route was reported, and the synthetic material was found to be different from natural glaucentrine (16). It was then found that natural glaucentrine and natural corydine (XXVI) are identical, so that the name glaucentrine should be eliminated from the record (16). 

The UV-spectrum of thaliporphine exhibits A 305, 280, and 220 mp, (log e 4.12, 4.12, and 4.52) characteristic of a 1,2,9,10-tetrasubstituted aporphine, and undergoes a bathochromic shift in base. The NMR-spectrum revealed the presence of three methoxyl and one A-methyl groups. Spectral and thin-layer chromatographic comparisons then showed that thaliporphine is identical with l-hydroxy-2,9,10-tri-methoxyaporphine which had been previously synthesized (16, 43). It follows that the unnamed alkaloid from Fagara tinguassoiba (see Section III,B) corresponds to the A-methylthaliporphinium cation. 

The steroidal dienone (170) can be induced to undergo the relatively unusual reorganization to the 2-hydroxy-4-methylandrosta-l,3,5-triene (171), by irradiation in refluxing acetic acid although only 48% of the acetate (171) was isolated, the related 17-ketone (36%) was also formed. The p-dienones (172) and (173) are restructured on irradiation in cyclohexane with net relocation of methyl and t-butyl groups to afford the phenols (174) and (175) in 55% and 73% yield, respectively. A photo-induced aryl shift in the benzylisoquinoline dienone (176) was employed to prepare the aporphine (177 44%) en route to ( )-boldine. The p-dienones (178 X = Cl, X = Ns) aromatize on irradiation to yield the alkylated p-hydroxybenzoates (179 e.g. X = Ns, 57%) as well as minor quantities, of their isomers (180). Mechanistic aspects of these reactions are discussed in the literature cited. 

In a new variation on the above theme, it was determined that treatment of the intermediate quinol acetate with TFA resulted in a substantial increase in the yield of the aporphine, while no C-4 oxygenated aporphine could be detected. Racemic domestidne, thaliporphine and 1-hydroxy-2,9,10,11-tetramethoxyaporphine were thus prepared in 84, 96, and 48% yield, respectively, from the corresponding tetrahydrobenzylisoquinolines. The mechanism of such transformations may be viewed as shown in Scheme 5. 

Aporphines synthesized via benzyne intermediates obtained from treatment of appropriately substituted 6-methoxy-7-hydroxy-2 -halo-N-methyltetrahydro-benzylisoquinolines with KNH2 in liquid ammonia include N-methylcaaverine (1-hydroxy-2-methoxyaporphine), thaliporphine and domestidne. The upper limit on the yields by this route appears to be 24%, a by-product being the corresponding dibenzopyrrocoline salt resulting from cyclization on nitrogen. ... 

Reaction of the bromophenol (31) with KNH2 in liquid ammonia furnished 1-hydroxy-2,10-dimethoxyaporphinein 18% yield. Reactants devoid of the necessary phenolic function in ring A do not afford aporphines on treatment with the strong... 

Immonium salts can also be used in the benzyne reaction. Treatment of salt (32) with dimsyl sodium in DMSO gave a 25% yield of dehydrodomesticine which was reduced to domesticine. Similarly, salt (33) furnished 1-hydroxy-2,10-dimethoxydehydroaporphine which was readily reduced to the corresponding aporphine. ... 

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