3640
HOWARD J. GLENNAND BRUCEW. HORROM
Vol. 76
[CONTRIBUTION FROM ABBOTTLABORATORIES)
Analgesics Derived from Tetrahydroacenaphthonesl BY HOWARD J. GLENNAND BRUCEW. HORROX RECEIVED XfARCII 1, 1954
A series of klannich derivatives of S-methosy-2a,3,4,5-tetrahydroacenaphthone-l ( I )has been prepared from formaldehyde and the folloning amines: dimethylamine, piperidine (111), morpholine and pyrrolidine. One of the AIannich products (111) was reduced t o the carbinol which in turn was acylated with propionic anhydride. The compound SI1 when treated with phenylmagnesium bromide gave l - p h e n y l - 2 - p i p e r i d i n o r n e t h y l - 8 - n ~ c t h o ~ ~ - ~ a , 3 , 4 , ~ - t e t r ~ h ~ d r o a c e n a pas h t hay l ~ n e result of carbinol dehydration.
As part of a systematic investigation of the an& gesic properties of basic ketone derivatives, a series of Xannich products and derivatives of S-methoxy2a,3,4,5-tetrahydroacenaphthone-l (I) was prepared. The formal similarity between this ketone (I) and a portion of the codeine molecule (11) is apparent on comparison of the two structural formulas.
Two different procedures were used in the prepar.ition of these c:mpmntls. \\'hen cyclic amines were used (procedure A), the best yields were obtained without solvent by stirring formalin, the ketone and the cyclic amine hydrochloride under nitrogen on a steam-bath. I t wzs found advantageous to add a small amount of hydrochloric acid occasionally t o keep the reaction acidic. This proCH3 cedure is approximately the same as t h a t given by Xosettig and May3 for Mannich products of a-tetralone. IVhen dimethylkmine hydrochloride was used, the best yield was obtained by refluxing the amine hydrochloride, ketone, paraformaldehyde 0 cr%,o' '011 and a trace of hydrochloric acid in isoamyl alcohol (procedure B). llannich products could not be I SI The parent ketone I was prepared by the method isolated from the reactions with diethylamine, diof Jehnson and Glenn.? When treated with n-butylamine, 2-methylpiperidine or N-methylpiformaldehyde and certain secondary amines, I gave perazine. Since 2-piperidinomethyl-8-methoxy-2a,3,4,5-tenormal AIarinich products 111-VI, the physical trahydroacenaphthone-1 (111) possessed outstandconstants of which are given in Table I. ing analgesic activity in dogs, the syntheses of sevO= --CHJSRZ eral modifications of this structure were attempted. Interestingly enough, this compound could not CH20 C H a O b b be reduced catalytically with hydrogen ; however, lithium aluminum hydride reduction gave the corresponding carbinol VIII which was acylated with I' 111, XRZ = piperidino propionic anhydride to the ester IX. Reaction of IV,iYR2 = morpholino Compound I11 with phenylmagnesium bromide gave V, SR2 = pyrrolidino a colorless unstable carbinol hydrochloride which \'I, X R J = dimethylamino Y
Yi:!d, Sa.
111
III .I%c1 SY
Y VI VI1
Comp
