Phenothiazine carboxylic acids

The availability of phenothiazine carboxylic acids makes them very convenient starting materials for the preparation of other derivatives. 

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. ... 

Chemical Name 10H-Phenothiazine-10-carboxylic acid 2-[2-(dimethylamino)ethoxy] ethyl ester... 

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

The most commonplace substrates in energy-transfer analytical CL methods are aryl oxalates such as to(2,4,6-trichlorophenyl) oxalate (TCPO) and z s(2,4-dinitrophenyl) oxalate (DNPO), which are oxidized with hydrogen peroxide [7, 8], In this process, which is known as the peroxyoxalate-CL (PO-CL) reaction, the fluorophore analyte is a native or derivatized fluorescent organic substance such as a polynuclear aromatic hydrocarbon, dansylamino acid, carboxylic acid, phenothiazine, or catecholamines, for example. The mechanism of the reaction between aryl oxalates and hydrogen peroxide is believed to generate dioxetane-l,2-dione, which may itself decompose to yield an excited-state species. Its interaction with a suitable fluorophore results in energy transfer to the fluorophore, and the subsequent emission can be exploited to develop analytical CL-based determinations. 

Apart from valpromide derivatives, there are only few other drugs with a primary amide group that undergo metabolic hydrolysis. One example is that of metopimazine (4.23), a phenothiazine with antiemetic properties. Its carboxylic acid 4.24 was the major urinary metabolite in rabbits, but was not formed in dogs [8],... 

Pr Pro ptz pvp py pyca pycaH pyo pyr pys pySH pySSpy iso-propyl = 2-propyl proline phenothiazine polyvinyl pyridine pyridine pyridine-2-carboxylato(l -) pyridine-2-carboxylic acid pyridine iV-oxide pyrimidine pyridine-2-thiolato(l -) pyridine-2-thiol 2,2 -bis(pyridyl) disulfide... 

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). 

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... 

Phenothiazine gives exclusively phenothiazine-l-carboxylic acid on treatment with butyllithium followed by carbonation with 10-alkyIphenothiazines the same reaction leads to a mixture of almost equal quantities of the 1- and 4-carboxylic acids. 10-Acylphenothia-zines undergo deacylation in the metalation reaction, so that the same results are obtained as with A-unsubstituted phenothiazines. 

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. 

These findings suggest the intermediate formation of a 1,10-dilithio derivative, which reacts either in position 1 or 10 depending on the reagent. This is supported by the optimal yields of phenothiazine-l-carboxylic acid obtained by using 2 moles of butyllithium to 1 of... 

A Grignard reaction has been used to convert 3-bromo-lO-ethyl-phenothiazine into lO-ethylphenothiazine-3-carboxylic acid. ... 

Schmitt et worked out an interesting procedure, applicable on a large scale, for introducing alkylaminoalkyl residues in position 10, via the esters of phenothiazine-lO-carboxylic acid (136). On thermal decomposition, the latter eliminate CO2 and give the deri-... 

Of particular importance is the conversion of phenothiazine-2-carboxylic acids into aldehydes, because this is the only route to... 

Attempts to a iply the Curtius reaction to phenothiazine-1-carboxylic acid yielded a very hydrolysis-resistant pyrazolone. - ... 

Using the calculated amount of hydrogen peroxide the 5-oxides of many phenothiazine drugs have been prepared. - Chlorproma-zine (179) yields the V-oxide of the 5-oxide (180) without oxidation at sulfur to the 5,5-dioxide. Chlorpromazine-5,5-dioxide (181) was prepared indirectly, as shown in Scheme 19 it may be further oxidized to the V-oxide (182). m-Chloroperbenzoic acid oxidation has been used with 2-trifluoromethylphenothiazine-l-carboxylic acid. ... 

Interest in close auialogs of fen-amates is illustrated by 8-tri-fluoromethyl phenothiazine-1-carboxylic acid (XIV) (an S-bridged analog) and the acetic acid homologs. Heterocyclic analogs are exemplified by several pyrimidine (XV) and pyridine (XVI) 7 iso-sters. Replacement of the carbox-resulted in a slightly less active but posit is noteworthy that the optimal activity O... 

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. 

Phenothiazine-l-carboxylic acid, P-70055 10//-Phenothiazine-2-carboxylic acid, P-70056 10//-Phenothiazine-3-carboxylic acid, P-70057 10//-Phenothiazine-4-carboxylic acid, P-70058... 

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