Phenothiazine-10-carboxylic acid chloride

Phenothiazine-10-carboxylic acid chloride Dimethylaminoethoxy ethanol Hydrogen chloride... 

Dimethoxanate [477-93-0] (47) and pipazethate [2167-85-3] (48) are related phenothiazine derivatives that have shown antitussive activity. Unlike many phenothiazines, these do not produce central nervous system depression or analgesia at therapeutic doses. They are both somewhat less potent than codeine. It has been suggested that the unique side chain that is similar to, but shorter than, the one on benzonatate, may be at least pardy responsible for the antitussive effects. Both dimethoxanate and pipazethate are the result of molecular modifications of classical phenothiazines, such as promethazine [60-87-7], which possess antitussive activity in addition to central nervous system depressant activity. Dimethoxanate can be prepared by the reaction of phenothiazine- 10-carboxylic acid chloride with p-dimethylaminoethoxyethanol (66). 

The acid chloride of phenothiazine-1-carboxylic acid has been prejDared by treating the acid with the calculated amount of PCI5 in benzene, thus avoiding ring chlorination -(see Section V, A, 1, d). Another way to prevent ring chlorination in this reaction is first to acylate at position 10. ° Some amides have been prepared from phenothiazine carboxylic acid chlorides - ° and Curtius degradations performed. ... 

Attempts to prepare phenothiazine-1- and phenothiazine-2-car-boxylic acid chlorides with SOCI2 gave acid chlorides ring-chlorinated in positions 3,7,9 and 1,3,7,9, respectively. The preparation of a dichlorophenothiazine-1-carboxylic acid chloride of unknown orientation from SOCI2 and a suspension of 1-carboxyphenothiazine in benzene has recently been reported. ... 

A C-substituted product was formed on treating phenothiazine with ferrocene carboxylic acid chloride even in the absence of AICI3... 

When lithiated phenothiazine is treated with methyl sulfate, acetyl chloride, and ethylene oxide 10-substituted derivatives are obtained. Lithium salts of carboxylic acids, however, lead to 1-phenothiazinyl ketones Scheme 14 presents the evidence for the structures assigned to these substances. 

Activation of the carboxylic acid as the acyl chloride permits direct reaction with azide anion to form the acyl azide substrates for Curtius rearrangement. Sodium azide is commonly used, and the reaction has been used on the process chemistry scale for the synthesis of benzyl-A-vinyl carbamate. Acryloyl chloride was combined with sodium azide in a biphasic system with phase-transfer catalysis (PTC), providing acyl azide 25. Upon heating, Curtius rearrangement provided vinyl isocyanate, which was distilled directly into benzyl alcohol containing phenothiazine (27) to inhibit polymerization of 26 and triethylamine to catalyze addition of the alcohol to the isocyanate. The vinyl carbamate product 28 was isolated by crystallization. As the autiior clearly pointed out, preparation and reaction of acyl azides, particularly on large scales, require appropriate safety precautions. 

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