Adrenochrome preparation

The syntheses of the monoxime [mono- or di-hydrate, m.p. 178° (decomp.)] and monosemicarbazone [m.p. 223° (decomp.)] of DL-adrenochrome have recently been described by Remizov.191 The majority of previous publications referring to these compounds have dealt with derivatives of adrenochrome prepared initially from L-adrenaline. The picrates obtained from the DL-oxime and dl-semicarbazone of adrenochrome were described as yellow powders, decomposing at 124 and 150°, respectively.191 Remizov also described the formation of highly colored complexes from the interaction of the DL-oxime and DL-semicarbazone with certain metal ions (e.g. Co++, Ni++, Cr+++ Fe++ and Fe+++).191... 

Most of the work so far reported has been carried out with adrenochrome synthesised from (—)-adrenaline. However, some workers consider that the sign of rotation is altered during the oxidation process, giving rise to the dextrorotatory form of adrenochrome [26, 379]. The conunercial samples used by Grof, Vojtechovsky and Vitek in their investigations were apparently prepared from ( )-adrenaline, whereas the material synthesised by this group was obtained from (—)-adrenaline [374, 376]. Holfer has reported that adrenochrome prepared from (-t-)-adrenaline exhibits somewhat more pronounced psychological effects than that prepared from (—)-adrenaline [33, 34, 348]. 

The main procedure used for the preparation of adrenochrome (1) in the laboratory involves the oxidation of adrenaline by silver oxide in methanol. This method, which was first described by Veer in 194262,63 and subsequently used by many other workers (see refs. 2 and 3 for early references), is still the simplest procedure available for obtaining adrenochrome (1) and similar non-halogenated amino-... 

Adrenochrome methyl and ethyl ethers (8 and 9 respectively), first isolated by Hukki and Seppalainen as their semicarbazones,66 have now been obtained in crystalline form by oxidation of the corresponding catecholamine ethers with silver oxide in dry acetonitrile.65 A-Ethylnoradrenochrome (6) has also been prepared in crystalline form by the oxidation of N-ethylnoradrenaline in 90% methanol with the calculated quantity of iodic acid65 (cf. the preparation of adrenochrome by Macciotta67). Adrenochrome 08-acetate (3-acetoxy-epinochrome) (10) was obtained by the oxidation of acetyladrena-line [j3-acetoxy-j8-(3,4-dihydroxyphenyl)ethylmethylamine].68... 

Several new iodoaminochromes have been described recently, including N-ethyl-7-iodonoradrenochrome (13A),65 7-iodoadreno-chrome methyl ether (14A),6B and 7-iodoadrenochrome ethyl ether (14B).6B Improved procedures for the preparation of 7-iodonor-adrenochrome (15A),70,71 7-iodo-2-methylnoradrenochrome (15B),70 and 7-iodo-JV-isopropylnoradrenochrome (13B)6B have also been reported. 

The higher decomposition points were obtained when adrenochrome methyl and ethyl ethers were prepared by oxidation of the appropriate catecholamine in methanol with silver oxide. The BOlid aminochromes were then obtained as microcrystalline solids on addition of dry ether and cooling the resultant solution to — 80°. The slightly less pure products were obtained when the oxidation was carried out in acetonitrile. [R. A. Heacock and B. D. Scott, loc. cit. (footnote c )]. 

No simple oxidation products of adrenochrome have been obtained in crystalline form. The evidence for and against the existence of oxoadrenochrome was summarized in an earlier review.3 Although the preparation of a substance described as 2-iodooxoadrenochrome (70) by the oxidation of adrenaline with iodic acid was reported,87,187 it was subsequently shown by an exhaustive consideration of its physical and chemical properties to be identical with 7-iodoadreno-chrome (12)109 (cf. ref. 70). 

Addition products have been obtained from aminochrome derivatives such as the semicarbazone, with sodium bisulfite. Recently Correia Alves reported the preparation of a compound described as adrenochrome semicarbazone sodium sulfonate (m.p. >300°) by treating a solution of adrenochrome monosemicarbazone (90) in sodium carbonate solution with sulfur dioxide at 40° for several days192 this compound was apparently different from the substance (m.p. 227-228°) obtained in a somewhat similar manner by Iwao193-194 and may be comparable to the compound (83) (m.p. > 300°) previously described in a Belgian patent179 (see Section IV,F). Iwao established the structure of his compound as the sodium salt of epinochrome-3-sulfonic acid monosemicarbazone (93).193... 

Chlorobenzonitrile and adrenaline, our second example, both give electrode products that are unstable with respect to subsequent chemical reaction. Because the products of these homogeneous chemical reactions are also electroactive in the potential range of interest, the overall electrode reaction is referred to as an ECE process that is, a chemical reaction is interposed between electron transfer reactions. Adrenaline differs from/ -chlorobenzonitrile in that (1) the product of the chemical reactions, leucoadrenochrome, is more readily oxidized than the parent species, and (2) the overall rate of the chemical reactions is sufficiently slow so as to permit kinetic studies by electrochemical methods. As a final note before the experimental results are presented, the enzymic oxidation of adrenaline was known to give adrenochrome. Accordingly, the emphasis in the work described by Adams and co-workers [2] was on the preparation and study of the intermediates. 

A common mechanism may underlie the psychogenic action of the indole type hallucinogens on the one hand and the compounds related to adrenaline on the other, but it is not yet possible to say whether this action is related to 5-hydroxytryptamine or to adrenaline. Adrenochrome and adrenolutin have structural similarities with the indoles and, under similar conditions, both LSD and mescaline similarly antagonize the action of 5-hydroxytryptamine on isolated preparations . There is some evidence that LSD... 

An improved method for the preparation of 7-iodonorepinochrome (61) has been reported [141] as has an unsuccessful attempt to prepare nor-adrenochrome methyl ether (62) [141]. 

Adrenochrome monosemicarbazone (96) is not very soluble in aqueous solution and this sometimes creates a problem in preparing solution for clinical use. To overcome this problem by chemical means, attempts have been made to introduce solubilising groups into the molecule. It was found, for example, that when adrenochrome semicarbazone (96) was allowed to react with sodium bisulphite at 30 C for several days sodium l-methyl-5-semicarbazono-6-oxo-2,3,5,6-tetrahydroindole-3-sulphonate (Adona, AC-17, 97)[183, 184] was formed. On the other hand, when a solution of adrenaline was boiled under reflux with sodium bisulphite for 1 hour and the product oxidised and then treated with semicarbazide, a compound isomeric with (97) having the sulphonate group in the 2-position (AC-44, 98), was obtained [185, 186]. The synthesis of a compound described as sodium 1-methyl-2,3,5,6-tetrahydro-5-semicarbazido-6-hydroxyindole-3-sulphonic acid (99) has recently been claimed in a British patent [187]. The procedure followed was similar to that used by Tomino [18 in the synthesis of (98) and the validity of the structure proposed for (99) is therefore questionable. 

Whilst there are no reports in the literature of crystalline products having been obtained from the interactions of adrenochrome with o-phenylenedi-amine. Auterhoff and Hamacher have prepared a phenazine derivative (103) by the interaction of o-phenylenediamine with rubreserine (66) (a compound structurally similar to the aminochromes) [193]. In the same paper, the authors describe the reaction of rubreserine with ammonia in alcohol at reflux temperatures. A complex mixture of products including the phenoxazone derivative, eserine blue was obtained [193]. 

The semicarbazone (134) was too water-soluble to isolate readily, but it was possible to isolate other derivatives of the aminochrome-thiol addition products of this type one such compound was the p-nitrophenylhydrazone of the addition product between adrenochrome and )S-mercaptopropionic acid which was readily obtained in pure crystalline form. The structure of this compound (135) was established by consideration of the microanalytical data and spectroscopic (u.v. visible, i.r. and n.m.r) properties. A total of five derivatives of this type have been prepared and fully identified (see Table 63) [249]. 

In their original paper on adrenochrome, published in 1937, Green and Richter reported that the oxidation of adrenaline to adrenochrome is catalysed by (a) a cyanide-insensitive system present in heart and skeletal muscle and b) the cytochrome-indophenol oxidase system present in all tissues [22]. Since that time, there have been numerous reports of in vitro studies dealing with adrenaline to adrenochrome oxidations catalysed by mammalian body fluid and tissue preparations. 

Grof, Vojtechovsky and Vitek have attempted to clarify some of the confusion and contradiction that exists in the literature concerning adrenochrome in this regard [374, 376]. They suggest that different samples of adrenochrome, possibly prepared by different procedures, may be of variable purity or they may have contained trace quantities of psychoactive contaminants, which could lead to variable psychological effects. It is also apparent that a wide range of subject reactivities to adrenochrome exists [374, 376]. 

In 1960 Mason and Shulman described a product claimed to prevent vascular damage due to the effects of radiation, snake venom and thermal burns [431]. This product, which was not defined chemically was almost certainly a mixture, the composition of which varied from preparation to preparation. Their product, which they were unable to purify was obtained by treating adrenochrome firstly with mineral acid and then with thiosemi-carbazide [431]. 

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