Synthesis of alkoxybenzhydryl akylamines, local anesthetics from Schiff bases and phenyllithium

Abstract

The use of PhLi instead of PhMgBr gave improved yields of the title compds. (I). Thus, a soln. of 0.3 mole 0-, m-, or p-HOC6H4CHO in 150 ml. 2N KOH was treated with 0.103 mole Me2SO4 or Et2SO4 and shaken 5 min. The procedure was repeated twice, then the mixt. was shaken 0.5 hr., treated with 30 ml. 2N KOH and refluxed 0.5 hr. The cooled soln. was extd. with CHCl3, which ext. was dried and evapd. to dryness in vacuo to give the corresponding ethoxy- or methoxybenzaldehyde. The propoxy and butoxy derivs. were prepd. by refluxing 6 hrs. a mixt. of 0.3 mole aldehyde, 0.35 mole alkyl halide, 0.4 mole KOH, and 180 ml. EtOH. The soln. was dild. with 3 times its vol. of H2O, and worked up as described. For the prepn. of the alkoxybenzylidenalkylamines (II), 0.1 mole amine was added dropwise with cooling to 0.1 mole ROC6H4CHO. The following II were prepd. (R1, R2, % yield, and b.p./mm. given): Me, m-Me, 81, 120-2 Deg/12; Me, m-Et, 86, 118-22 Deg/12; Me, m-Pr, 78, 140-3 Deg/12; Et, m-Et, 84, 82-5 Deg/0.3; Pr, m-Me, 80, 136-8 Deg/12; Pr, m-Et, 80, 140-3 Deg/12; Pr, m-Pr, 75, 156-7 Deg/12; Bu, m-Et, 80, 123-30 Deg/1.5; Bu, m-Bu, 86, 184-8 Deg/12; Me, p-Me, 83, 118-20 Deg/12; Pr, p-Me, 84, 133-6 Deg/12; Me, 0-Pr, 75, 120-5 Deg/12; Pr, 0-Bu, 76, 153-8 Deg/12. For the prepn. of I 32 g. PhBr was added with stirring and cooling under N to a mixt. of 2.8 g. Li wire in 100 ml. dry Et2O. The soln. was filtered through glass wool, shaken 2 hrs. under N with a soln. of 0.07 mole II in 50 ml. dry Et2O, and decompd. with ice water. The org. phase was sepd. and the aq. phase was extd. with CHCl3. The combined org. exts. were dried and evapd. to dryness in vacuo. The residue was dissolved in Et2O, treated with HCl and evapd. to dryness. The residue was crystd. from MeOH-Et2O. The following I were prepd. (R1, R2, % yield, b.p. base/mm., and m.p. HCl salt given): Me, 0-Pr, 76, 185-91 Deg/12, 157-8 Deg; Pr, 0-Bu, 77, 164-7 Deg/0.5, 123-5 Deg; Me, m-Me, 72, 186-9 Deg/12, 223 Deg; Me, m-Et, 72, 192-4 Deg/12, 232 Deg; Me, m-Pr, 78, 148-50 Deg/0.1, 153 Deg; Me, m-Bu (III), 74, 145-8 Deg/0.3, 94-5 Deg; Et, m-Et, 78, 175-80 Deg/2, 165 Deg; Pr, m-Me, 75, 197-200 Deg/12, 193 Deg; Pr, m-Et, 80, 200-2 Deg/12, 200 Deg; Pr, m-Pr, 80, 154-5 Deg/0.2, 175 Deg; Bu, m-Et, 80, 169-71 Deg/0.2, 176-7 Deg; Bu, m-Pr, 74, 174-7 Deg/0.2, 160 Deg; Bu, m-Bu, 78, 192-8 Deg/2, 152 Deg; Me, p-Me, 81, 192-5 Deg/12, 175 Deg; Pr, p-Me, 82, 199-202 Deg/12, 164-5 Deg. Five compds. were compared with Novocain (IV) in infiltration, surface, and intravenous anesthesis. III was effective at .apprx.5%, 7%, and 12%, resp., of the concn. of IV. 14 references.