Promazine, oxidation

The generation of a eoloured product upon the oxidation of promethazine with Ce was used in the development of a FIA method. Promethazine in tablet form could be analysed by this method with a precision of + 1% and at a rate of 122 samples per h. In a similar method promazine was oxidised by passing through a short column containing Mn02 and then the oxidation product was measured. ... 

Oxidation of promazine and chlorpromazine with hexaimidazolecobalt(III) in acidic solution results in the formation of Co(II) and a cationic radical. The kinetic and activation parameters have been determined and mechanistic aspects have been discussed.75... 

The volumes of activation were AV (k ) = — 6.2 cmVmol and AV (kr) = —11.4 cm3/mol and are very close in value to those obtained for oxidation of promazine, and clearly show that a combination of intrinsic and solvation changes are very closely matched for the two similar reactions. An identical value to the reaction volume determined kinetically, +5.2 cm3/mol, was found for the reaction volume determined from a pressure dependence study of the system at equilibrium. The volume profile is shown in Figure 7.11. 

Fishman and Goldenberg have isolated phenothiazine, A-unsubsti-tuted phenothiazine-5-oxide (as the main product), and 3-hydroxy-phenothiazine from human and canine urine, after administration of promazine the corresponding 2-chloro derivatives were found in the case of chlorpromazine. 

Photolysis of chlorpromazine (1). The photolysis of 1 results mainly in oxidation to the corresponding sulfoxide. Irradiation in the presence of a cyclodextrin (CD), however, results mainly in dechlorination to promazine (2), which is also converted into a sulfoxide, (3), on photolysis. The rate of conversion of 1 to 2 depends on the cyclodextrin used, the rates following the order /3-cyclodextrin >y-cyck)dextrin> a-cyclodextrin. Since these cyclodextrins differ in the size of the cavity, it appears that the conversion of 1 to 2 takes place within the inclusion complex. ... 

Sulfur is readily oxidized, nonenzymatically as well as enzymatically (Scheme 11.21). Chlorpromazine metabolism provides an example of S-oxidation by CYP3A (Scheme 11.22). Chlor promazine is also metabolized by N-oxidation and N-dealkylation pathways, resulting in a multiplicity of excreted products. 

Perfluoro-cfv-2,3-dialkyloxaziridines (64a) also selectively oxidizes sulfides to sulfoxides at — 40°C in CFC13 <94JOC2762>, for example, the hydrochloride of promazine (67), a neuroleptic drug, is oxidized to (68) in 90-94% yield (Equation (14)). At higher temperatures and/or with excess oxidant the corresponding sulfones are rapidly formed even at —20 to 0°C. 

Simultaneous chlorpromazine, chloiprothixene, phenothiazine-5-oxide, promazine, tri-meprazine... 

A good example of a solvent extraction scheme combined with po-larographic determination is given by the determination of chlor-promazine (Largactil) and its three metabolites (the S-oxide, the N-oxide and the S-oxide-N-oxide) in blood plasma. The details of this method are not important and you should make no effort to remember them. However it does serve as a good illustration of a complete polarographic method. 

N-oxidation and S-oxidation, This can be used for heterocyclic nitrogen and sulphur compounds. Oxidising agents could include hydrogen peroxide, bromine and chloroperbenzoic acid. A good example would be the oxidation of electroinactive chlor-promazine to its electroactive S-oxide. 

Figure 10. Mechanism proposed " for the electrochemical oxidation of 7-hydroxychlor-promazine at pH 2.

The electrochemical (and chemical and enzymic) oxidation of 7-hydroxychlorpromazine leads to the eventual formation of 7,8-dioxochlor-promazine which, according to the mechanism proposed by Neptune and McCreery, " proceeds through a trihydroxylated intermediate (VI, Figure 10). It has been suggested " that the oxidized form of the latter compound (i.e., VII, Figure 10) could react with neuromembrane proteins, particularly at thiol sites, in the same way described for the p-quinone of 6-hydroxy-dopamine (see p. 143) and hence cause some neurophysiological effect. 

The side chain can also affect electronic events of the tricyclic ring system. Electron spin resonance experiments allowed Fenner S to suggest that the influence of the side chain of phenothiazine on the formation of free radicals showed a correlation between the redox activity of the phenothiazine nucleus and dynamic aspects of stereochemistry. For example, there was a difference in the formation of cationic free radicals between promazine and alimemazine. The latter has a branched side chain, and forms cationic free radicals only under irradiation. It differs from promazine in pharmacodynamic properties, reported s to result in considerably shifted ion exchange equilibria. A kinetic study of the oxidation of dopamine by dialkylaminoalkyl phenothiazine cationic free radicals showed that a strong correlation existed between side-chain structures and oxidation rates phenothiazine free radicals with two carbon side chains had faster rates than those with three carbon side diains, albeit both were very rapid at physiological pH. 

Ascorbic acid vitamin K3 promazine Pharmaceutical formulation Oxidation with Fe(lll). Determination of released Fe(ll) through a colored complex... 

An example of a simple oxidatiim reaction is the craiver-sion of Fe " into Fe. Examples of active substances that are prone to oxidation are acetylcystein, adrenaline, apomorphine, clioquinol, dithranol, dobutamine, ergotamine, hydroquinone, isoniazid, mesalazine, naloxone, neomycin, oxycodone, paracetamol, peptides, salbutamol, phenothiazine derivatives (promazine, promethazine, chlorpromazine), phenylephrine, physostigmine, tetracycline, tretinoin, the vitamins A and D, and the excipients flavouring agents, fragrances and unsaturated fats (vegetable oils, suppository bases). 

Scheme 1.54 Oxidation of promazine, chloropromazine, and promethazine using oxaziridines...

Figure 7.6 The metabolic pathways for conversion of chlorpromazine into phenolic metabolites. The route in which the arene oxide undergoes ring opening to put the cationic center in conjugation with the nitrogen is preferred, leading to 7-hydroxychlor-promazine as a major metabolite [2]. The alternate route requires stabilization of the positive charge by sulfur, which is less favorable due to the relatively poor orbital overlap between sulfur and carbon.

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