MAY
1961
PYILROLIDINES. 111
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~ Y N 1 ’ I I U T I CO I t G A N l C CHEMIBTIZY, I{LSUAllCli 1)IVISION,
1520 MEADJOIINSON AND CO.1
Pyrrolidines. 111. lo-( 1- Substitiitcd 3-Pyrrolidinylme thy1)phenothiazines’ YAO-IIUA W u
AND
R. F. E’ELL)KA,MP
Received J u n e f 3,1060
A new serics of lo-( I-substitutcd 3-pyrrolidinylmcthy1)phenotliiazincs was prcparcd by coiidcnsiiig 1-sulJstitutcd3-chloromcthylpyrrolidines with appropriate plienothiazincs. EXPERIMENTAL The physiological properties of 10-(aminoalky1)phenothiazines have been shown t o vary considerMclting points and boiling points are uncorrccted. Microably in respect to both the aminoalkyl groups and analyses by Clark Microanalytical Laboratory, Urbana, Ill. Phenothiazines. Commercial phenothicuinc (Eastinaii) the substituents attached t o the phenothiazine nucleus.2 This diversity of activity prompted us was used without further purification. 2-Chlorophenothiazine, n1.p. 199-200” (reported,S m.p. 106-197O), was to synthesize a series of 10-(1-substituted 3-pyr- prepared by the method of Charpentier, et aL5 2-Methoxyrolidinylmethy1)pheriothiazines (I) using l-sub- phenothiazine was similarly prepared by the process uf stituted 3-chloromethylpyrrolidines3 to introduce Cymerman-Craig, et al.,6 m.p. 178-180” 184.5”). General procedure for the preparation of 10-( 1-subslituled these novel basic groups a t the 10-position of the S-pyrrolidinylmethy1)phenothiazines.A mixture of 1 mole of phenothiazine nucleus.
h r I
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I11 gcnertll tlicse cornpounds wore prepared by tlie condensation of the appropriate chloroniethylpyrrolidine with a phenothiazine in the presence of an acid binding agent such as sodium amide or sodium hydride in an inert solvent such as benzene or toluene. The crude free bases were either purified by vacuum distillation prior to crystallization from n-heptane or converted directly to their hydrochlorides in the usual manner. The physical properties of thcse compounds are listed in Table I. l’harmacological tests have indicated that t h e 10 - (1 - substituted 3 - pyrrolidinylmethy1)phenothiazines are primarily antiallergenic agents. 10( 1-Methyl-3-pyrro1idinylmethyl)phenothiazine hydrochloride (“Tacaryl”) is now undergoing extensive clinical evaluation.
( 1 ) Prcsciitcd iii part :It the lhtlcrick 11’. Uliclie Symposium of thc Division of hlcdicinal Chcinistry at the 138th National hlceling of the American Cherniwl Socicty, New York, N. Y., September 19G0. (2) H. Friebel, H. Flick, and C. Reichlc, ArzneiniillelPorsch., 4, 171 (1954). (3) Yno-Hua Wu and R. F. Feldkamp, J . Org. Chem., 26, 1510 (1961). (4) “Tacaryl” is the trade mark of the Mead Johnson and Co. brand of “Methdilazine.”
phenothiazine, 1 mole of 1-substituted 3-chloromcthylpyrrolidine, 1 mole (39 6.) of sodium amide, and 600 ml. of dry toluene was heated a t reflux temperature for 20 hr. After cooling, the reaction mixture waR treated with 250 ml. of water and thoroughly shaken. The toluene layer was scparated, washed once with water, and extracted with several portions of 350 to 400 ml. of 3N hydrochloric acid. The combined aqueous acid extracts were made strongly basic with 56% potassium hydroxide to liberate the basc as an oil. The oil was extracted into ether and the ethereal extract dried with anhydrous magnesium sulfate. After filtration and removal of solvent, the residual dark oil was distilled under reduced pressure. Residual traces of phcnot,liiazine were removed by treating the viscous ycllow-brown distillatc with 500 ml. of 3N hydrochloric acid, diluting with 2.5 1. of watcr and filt.ering. Thc clear solution was m:idc hasic with 150 ml. of 58% potassium hydroxide and thc 1il)eratcd oil cstrwtcd with ctlier. The ether solution was dricd with anhydrous magnesium d f a t e , filtered, and distilled to remove solvent. Thc residual product was either crystallized from n-heptitne or used directly to prepare the hydrochloride. IO-( 1-Subslifnted 3-pyrro~idinylmelhy~phenothiazine hydrochloride. A solution of the free base (0.1 mole) in 300 ml. of 2-propanol was t r c a t d with 4 g. of dry hydrogen chloride in 115 ml. of the same solvcnt. After cooling overnight a t Oo, 1Iic c+rystallincproduct was collectcd on a Gltcr, washed \villi 2-propanol and ailhydrous ctlicr, and tlicri dried in a vxuiim ovcn. Altcrnntivcly the Iiytlrochloridc salt can bc prepared by saturating a solution of 0.1 mole of thc free hasc in 400 nil. of n-hept:tnc with dry hydrogen chloride. The separated crude hydrochloride was recrystallizcd from a suitable solvent. IO-(l-Meth~l-S-p~rrolidinylmelhyl)phenothiazine melhobromide. A Folution of IO-( I-methyl-3-pyrrolidinylmethy1)phenothiazine (6 g., 0.02 mole) in 50 ml. of acetone was cooled in an ice bath and treated with 10 g. of methyl bromide. On standing crystalline 10-(1-methyl-3-pyrrolidinylmethy1)phenothiazine mcthobromide separated. Two rccrystallizntions of the crude compound from hot methanol yielded 5.5 g. (67%) of the pure product, m.p. 215-217’.
EVANSVILLE 21, IND. (5) P. Charpenticr, P. Gaillot, R. Jacob, J. Gnudechori, and P. Buisson. Cornwt. rend. Acad. sci. Paris., 235., 50 (1952). (6) J. Cymermnn-Craig, W. P. Rogers, and M. E. Tate, Australian J . Chem., 9, 397 (1956).
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