:\lay 1969
443
1-SUBSTITUTED 3-(O-~IETHOXYPHESOXY)PYRROLIDIKES
bCHJ X TABLEI l-SCBSrITCTED 3-(O-~~ETliOXYPFIENOXY)PYRROLIDINES
NO.
Yield,
Mp or bp
%
(mm), ‘C
n
53 155-158 (0.16) 3 92 94-97 3 96 143-145 3 93 107-110 3 69 99-101 3 88 143-145 3 70 102-104 2 70 154-156 2 85 124-126 2 2 63 95-98 94 3 90 78-83 3 62 119-121 4 OC6H3-2-OCH3-4COCHa 3 88 113-116 OC6Hr2-OCHa-PCOCH3 4 41 125-127 Osalate. a I = i-PrOH, EA = EtOAC, E = i-PrsO. * All compounds analyzed for C, H, N. Fumarate. J! Analytical sample molecularly distilled. Hydrochloride. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
’
toxic, with LD6O’sof about 50 mg, kg or less, were 6-8 and 13-15. Compounds with LDM values in the 75175 mg kg range were 1-3, 5, 9, 10, and 12. The least toxic with LDM’s in excess of 300 mg’kg were 4 and 11.
Experimental Section General procedures are given below for the preparation of the compounds described in this paper. Analyses, yields, and physical properties are recorded in Table I and significant variations in the procedure are noted in the table footnotes. Temperatures are uncorrected. Microanalyses were done by Micro-Tech Laboratories Inc., Skokie, Ill.
Purificn solventa
I I I I I EA I I I I I-E
I I
Cs6H3iS0gc Cs6H33S09‘ Fumarate monohydrate. e Maleate.
Hydroxyalkylpyrrolidines.-.4 mixture of 0.4 mole of 3-(0methoxyphenosy)pyrrolidine, 0.44 mole of a bromohydrin, and 0.88 mole of anhydrous &Cos in 600 ml of i-PrOH was allowed to reflux for 16 hr. After cooling, the mixture was filtered and concentrated under vacuum. The residual oil was dissolved in EtzO, and the solution was extracted with dilute HC1. The aqueous layer was made basic and extracted with EtZO. The collected Et20 extracts were dried (XanS04),treated with charcoal, filtered, and concentrated under vacuum. The residual oil was purified by vacuum distillation. Carbamoy1oxyalkylpyrrolidines.-To a stirred solution of 0.04 mole of a 1-(hydroxyalky1)-3-(o-methoxyphenoxy)pyrrolidine in 50 ml of dry CsHe under Kz was slowly added 0.04 mole of an isocyanate. The solution was stirred at room temperature for an
Dibenz [c,d,h]azulenes. 11.
“Bridged” Amitriptyline Analogs’
It is geiierally k i i o ~ n ithat witliiii the class of tiiv so-called tricyclic drugs, several of the estahlisheti riiig systems (like the dihenzocycloheptylidelle riiig system in the antidepressant tlrugs amitriptyline and nortriptyline, 1) are not plaiiar but are skewed :uid lieiit :? therefore, a convex and a c o i i c a v ~side may be distiiiguishctl with such ring systems. So oiie seems to linvcl tlrawii attention, however, to ai1 additional featuw tleduciltle from models: that th(. iiitrogeii atom 111 1, iii a11 possiblc coiiformatioiis of the seveii-mem~)erc.ti always stays above thc coiiv~xside of the h i i t surface tlcfinetl hy the tri le. Illtleed, the letrgth alltl rotational freedom of the sidc chain is such that thr, iiitrogenous group cainiot assuine positions helow ( 1 .e.. 0 1 1 the concave side of) that surface. This rerognition aiiti the desirability to test its potential significaiicc led us to caonstruct molecules 2 :uid 3. On one hand, as again studied on models, thv geometry of the moiety formed 1)yrings A, 13, and (’ i i i
h C H , R la, R = H . nortriptyline b, R =CH,, amitriptyline
3a. K = H b. R =C‘H
’CH,NCH, R 2a.
R-H
b, R = C H 4
4a,
R=H
b, R = C H ,
