Phenothiazines preparation

Authors are designed row sensitive and selective test-systems for analysis of heavy metals, active chlorine, phenols, nitrates, nitrites, phosphate etc. for analysis of objects of an environment and for control of ions Ee contents in the technological solutions of KH PO, as well as for testing some of pharmacological psychotropic daigs alkaloids (including opiates), cannabis as well as pharmaceutical preparations of phenothiazines, barbiturates and 1,4-benzodiazepines series too. 

The parent drug of this series, promazine (24), was prepared originally as an antihistamine. Following the identification of the more potent chloro analog as an antipsychotic, it too came into use for that indication. The drug is prepared by straightforward alkylation of phenothiazine with w-C3-chloropropyl)di-methylamine by means of sodium hydride in xylene. ... 

Chlorpromazine (33) can probably be considered the prototype of the phenothiazine major tranquilizers. The antipsychotic potential of the phenothiazines was in fact discovered in the course of research with this agent. It is of note that, despite the great number of alternate analogs now available to clinicians, the original agent still finds considerable use. The first recorded preparation of this compound relies on the sulfuration reaction. Thus, heating 3-chlorodiphenylamine (30) with sulfur and iodine affords the desired phenothiazine (31) as well as a lesser amount of the isomeric product (32) produced by reaction at the 2 position. The predominance of reaction at 6 is perhaps due to the sterically hindered nature of the 2 position. Alkylation with w-C3-chloropropyl)dimethylamine by means of sodium amide affords chlorpromazine (33). ... 

The most complex side chain of the piperazine phenothiazines is to be found on chlorimpiphenine (86). The side chain is prepared by first alkylating monocarbethoxypiperazine with the chlorobenzimidazole 83 [itself attainable by alkylation of methylbenzimidazole with a dihalide). Removal of the carbethoxy group affords the substituted piperazine, 85. Alkylation of this base with the chloropropyl phenothiazine, 58, affords finally the desired compound (86). ... 

Replacement of the terminal nitrogen of the piperazine by carbon is said to enhance the antiemetic activity of the phenothiazines at the expense of the other pharmacologic effects. The simplest compound in this series, pipamazine (88), is prepared by alkylation of nipecotamide (87) with the chloropropyl phenothiazine (58). Preparation of the analogous sulfoxide begins with acetylation of the thiomethyl compound, 89 [prepared by a route... 

The requisite intermediate. 10-(3-chloropropyl)-2-acety(phenothiazine is prepared as follows To a suspension of sodamide (from 3 grams of sodium) in 300 ml of liquid ammonia is added 30 grams of 2-acetylphenothiazine. After stirring for one hour, there is added 19 grams of 1-bromo-3-chloropropane. The ammonia is allowed to evaporate and the residue is diluted with 200 ml of water. The mixture is extracted with ether and the ether solution is dried over anhydrous sodium sulfate, filtered and concentrated. 

The thiazine dyes used in the preparation of this type of leuco are obtained through oxidative coupling of phenothiazine with an active methylene compound or an aniline. The reduction of the dye 23 with zinc powder in acetic acid is straightforward.9 Treatment of the leuco 24 with acetic anhydride at 40°C yields a more air stable leuco 25.9 Addition of arylsulfinic acid to thiazine dyes such as 26 produces directly leuco dyes such as 27.Sb... 

Analogously prepared are the diesters of TV-methyl-phenothiazine diacetic acid and mono-/7-toluenesulfonyl-, chloro- or iodooligoethylene glycols.[144]... 

Nowhere, perhaps, is this phenomenon better illustrated than in the phenothiazine class. The earlier volume devoted a full chapter to the discussion of this important structural class, which was represented by both major tranquilizers and antihistamines. The lone phenothiazine below, flutiazin (130), in fact fails to show the activities characteristic of its class. Instead, the ring system is used as the aromatic nucleus for a nonsteroidal antiinflammatory agent. Preparation of 130 starts with formylation of the rather complex aniline 123. Reaction with alcoholic sodium hydroxide results in net overall transformation to the phenothiazine by the Smiles rearrangement. The sequence begins with formation of the anion on the amide nitrogen addition to the carbon bearing sulfur affords the corresponding transient spiro intermediate 126. Rearomatization... 

Phenothiazines are well-known as intermediates for pharmaceuticals, and are also active as insecticides and antioxidants. These compounds are usually prepared by the thiation of diphenylamines with elemental sulfur. In this context, the group of Toma has elaborated a synthesis of 3-phthalimidophenothiazine, as shown in Scheme 6.265 [455]. Using a variety of high-boiling solvents under conventional thermal reflux conditions, low isolated yields of the desired product were obtained. The highest conversion and isolated product yield (55%) was achieved by microwave irradiation of a mixture of the starting N-(4-phenylaminophenyl)phthalimide with... 

Stemetil is a proprietary preparation of prochlorperazine, a phenothiazine used in vertigo and labyrinthine disorders. Stemetil is available as tablets, syrup and injection. There is no contraindication to the concurrent use of paracetamol and prochlorperazine. 

An alternative synthesis of 4-nitrodibenzothiophene involves heating 2-amino-2 -nitrodiphenyl sulfide in a sealed tube at 190° (20%). The reaction probably proceeds via homolytic cleavage of the derived diazonium ion which could have been formed from nitrous acid liberated during the formation of phenothiazines, which were also detected. Similarly, 2-methyl-4-nitrodibenzothiophene is formed from 2-amino-2 -nitro-4 -methyldiphenyl sulfide (10%), and in this case the intermediacy of the diazonium ion was further indicated in that the same material was obtained by pyrolysis of the separately prepared diazonium salt of the sulfide. Although yields are poor in this reaction, it nevertheless represents the only route to substituted dibenzothiophenes containing a nitro substituent in the 4-position and as such is worthy of further attention. 

Preparative scale electrochemical oxidation of phenothiazine in aqueous acetonitrile, with no added acid, leads to the radical formed by proton loss from the radical-cation. The radical dimerizes and further oxidation leads to the green qui-nonoid cation 67 [230]. 

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