DIBENZOCYCLOHEPTESE ASTIDEPRESSASTS. I1
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191
Antidepressants. 1I.l Bridged Ring Ether Derivatives in the Dibenzocycloheptene Series' ~ \ ~ A R C IE. A
CHRISTY, CSROLE
c. BoL.k?rD, JUNEG. WILLIAMS, AND EDWARD L. ENGELHARDT
Merck Sharp R- Dohine Research Laboratories, Division of Merck R- Co., Inc., W e s t Point, Pennsylvania Received October 31, 1969 The synthesis and proof of structure of novel 11-substituted 5,lO-epoxy-5H-dibenzo[a,d] cycloheptene-5propplamirie derivatives is reported. These compounds exhibit potent tetrabenzazine-antagonizing activity.
5H-Dibenzo [a,d ]cycloheptene-5-propylamine derivatives relat'ed to amitriptyline and protriptyline have been the subject of a synthet'ic program in our laboratories.' I n an extension of this investigation to 10- and 11-subs ti t u t ed dibenzocyclo hep t'enes, novel bridged ring ether derivat$ives that have shown significant antidepressant act,ivit#ywere synthesized and are described in t'his paper. The carbinol 2a mas obtained by the Grignard reactmionof t'he known acetonide of cis-l0,ll-dihydro-10,11-di hydroxy-5H-dibenzo [a,cl ] cyclohep t en-5-one3 (1a) with 3-dimet~hylaminopropylniagnesiumchloride. When 2a was subjected to p-toluenesulfonic acid catalyzed hydrolysis in refluxing MeOH, the product was a crystalline base t'hat was not the expected 5,lO,ll-t,riol 10. The empirical formula, C20H23S02, corresponded with the loss of one molecule of HzO from this struct'ure. The uv spectrum of the product showed no strong maximum in the 230-240-mh region characterist'ic of unsaturation a t the 5,a-posit'ions4and the ir spectrum, showing strong C-0 stretching bands at, 1020 and 1080 em-', was consistent with an et,her linkage in addition to OH. The product afforded a monoacet'yl derivat'ive upon treatment wit8h d c 2 0 , but' fa,iled to react with LAH, n'aOcH3 in refluxing MeOH, or BOH in et'hylene glycol. This behavior eliminated 10,l1-dihydroxy-5,aunsat'urated and 10,ll-epoxide structures from consideration and seemed consist,ent only wit'h the 5,lObridged ether 3a. A similar sequence s t a r h g from the trans acet'onide l b afforded the isomeric t m z s ether 3b (Scheme I). The significant nmr charact,eristics of the carbinols 3a and 3b and the corresponding acetates 4a and 4b are summarized in Table I and are in accord with the chemical nonequivalence of the 10 and 11 protons, t'he (1) Previous paper: E. L. Engelhardt, M. E. Christy, C. D. Colton. 1'1. B. Freedman, C. C. Boland, L. 31. Halpern, V. G . Vernier, and C. A . Stone, J . .Wed. Chem., 11, 325 (1968). ( 2 ) Presented in p a r t a t the 10th National RIedicinal Chemistry Symposium of the American Chemical Society, Bloomington, Ind., June 27, 1966. (3) G . L. Buchanan and D . B. Jhareri, J. Org. Chem., 26, 4295 (1961). (4) S.0. Winthrop, 11. A . Davis, G. S. Myers, J. G. Gai.in, R . Thomas, and R. Barber, i b i d . , 27, 230 (1962).
PH 2a,b
a = cis isomer b = trans isomer
position of the secondary alcohol bubstituent, and the 5,lO-epoxy linkage in the bridged ring ether structure. The lack of spin coupling between the 10 and 11 protons in the cis isomers 3a and 4a as compared t o their trans counterparts is also shown by the precurzor acetonide 2a and apparently is attributable to the H-Clo-Cll-H bond ang1es.j The downfield position of the OH signal ( 5 ) Examination of Dreiding models rei eals t h a t the dihedral angle a t the intersection of the planes formed b y HCioCll and CiuCnH is approximatelk 76" in t h e czs isomer 3a and 25' in t h e trans isomer 3b. From the Karplus equation, J would be expected t o approach zero as t h e dihedral angle approaches 90' and to have its largest value as t h e dihedral angle approaches 0'.
the cis-wlculiol 3a relative t o the t i m s i;.onier 3b probshlj. reflect. the deahieldiiig effect of the more piusiinal ethcr ( ) in the cis i.omei, 111
~
\
0
HO
OH
10
0H 6
The furimitioii of ux;.geii-t)i,idged clibcnzocycloheptciie deriviiti\-cs hiis beeii reported previously h\. Buch:in:in a i i c l .Jhur-eri3 wlio obtaincd the bridged 1xt:iIs 8a m t l b from the ihonieric diol. 7a nnd b.
OCH 8a.b
(I
7a.b a = 1 1 5 isomei
b = iron, isomei
Other tr:in.:iiiiiulnr reactioii- oi clitic~izt~cycloheptenc clerivutive. have been reported recent 1; ." I t heeiii. prohhle that t h e 5,lO.ll-triol iz an interiiiedi:ttc in t h e tormitiori ot tlic .i.lO-epo\;> derivativcl, 2 -
tl ->lt
IO
DIBEXZOCTCLOHEPTESE ANTIDEPRESYAXTS.I1
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193
I
NH2
I
17
(CH.1 X‘
‘R’
NO.
3a 3b 13 14 18 19
R R
c~s-OH,R’ = CH, = trans-OH, R’ = CH3 R = CWOH, R’ = H R = tr~ns-OH,R’ = H R = =O, R’ CHI R = NOH, R’ = CII3 R = ~ v u T z s - S HR’ ~ , = CHI Protriptyline Amitriptyline Imipramine =
Tetrabenazine antagonism exploratory EDso ( m g h P 0.)
0.9 0.07 1.6 0.016 0.2.5 0.03 0.038 0.3 1.3 2.37
Experimental Section8 cis-3a,l2b-Dihydro-2,2-dimethyl-8-( 3-dimethylaminopropy1)8H-dibenzo[3,4 :6,7]cyclohepta[l,2-d]-1,3-dioxol-8-01. 2a.The Grignard reagent was prepared from 1.47 g (12 mmol) of 3-dimethylaminopropyl chloride and 290 mg (12 mg-at,) of l l g in 12 ml of dry T H F under Nz and using 110 mg (1 mmol) of ( 8 ) AI1 melting points were determined with calibrated thermometers in a Thomas-Hoover capillary melting point apparatus. Where analyses are indicated only by symbols of elements, analytical results obtained for those elements were within &0.4% of the theoretical value. Unless noted other\rise, all concentrations were carried out in a rotary evaporator a t reduced pressure.
EtBr as init,iat,or. A solutioii of 1.7 g (6.1 mmol) of &-3a,12bdihydro-2,2-dimethyl-8H- dibenzo [3,4:6,7]cycltrhepta [ 1,2-d]- 1,sdioxol-%one3 in 13 nil of dry T H F was added dropwise over 30 min t,o the stirred solution of the Grignard reagent cooled in ice. After 2 hr at room temperature, the bulk of the T H F was evaporated, the residue dissolved in C6H6,and M-ith ice-cooling, 6 nil of H20 was added dropwise. The C ~ Hlayer G wa.. decanted from the gelat,inous precipitate which then was extracted repeatedly with boiling C6H6. The combined C6H6 extract- were washed (HuO), dried (r\’a2S04),and evaporated. Crgst~allizationof the residual solid from 9570 EtOH gave 1.56 g (70%) of white needles, mp 181-188”. Recryst,allizations from 9.ic; EtOH and from iPrOH afforded a purified sample, mp 189-190’: n n (CDCL), ~ 6 1.60 and 1.65 (s, 3 each, C(CH,)?), 2.15 ( - . 6. S(CH3),), 5 . Z (s, 2, 10 and 11-H). =Inal. ( C ~ ~ H Z S KC.OH, ~ )S. trans Isomer. 2b.-The trans ket,one l b 3 wa- reacted with an excess of hIezN(CHz),lIgC1 as described for the cis isomer. The product. was obt,ained as a viscous yellow oil in quantit,at,ive yield. 4 sample of the base was converted into rhe hydrogen oxalate t,hat had constant mp 173.3-170..-1~dec after repeated recryst,allizations from i-PrOH-Et&; nnir (,C‘DClr1. 6 1.57 Is, 6, C(CKB)z), ‘2.20 (s, 6, N(CH3)2), 4.53 (d, J = 9 Hz, 1, 11-€I), 3.37 (d, J = 9 Hz, 1, 10-H). Anal. (CZ3Hz&O?.C~H?O4) C, H, S . cis-lO,ll-Dihydro-5-( 3-dimethylaminopropyIr-5,1O-epoxy-5Hdibenzo[a,d]cyclohepten-11-01. 3a.-cis-2a t 2.9.5 g, 8 mmol) and 3.0 g (15.8 mmol) of p-toluenesulfonic acid hydrate in 300 ml of MeOH were heated tmorefluxing for 4 hr. Aft,er neut,ralization with 1 .If KOH in lIeOH, solvent was di-tilled and the residue was part,itioned between CsH6 and H,O. The CsH6 lager was washed (H,O), dried (Na2S04), and evaporated to dryness. Crystallization of the residual solid from 505; EtOH gave 1.9 g (81%,),mp 145-152’. Recrystallization from cyclohexane yielded 1.75 g, final mp 131-153”. A n a l . (CZOK&O?I C . H, S . trans Isomer. 3b.-Hydrolysis of the trans-acetonide 2b as
March 1970
DIBETZOCYCLOHEPTENE ASTIDEPKESSINTY.I1
3 , CHa), 3.15 (d, J = 6 Hz, 1, 11-H), 3.46 (d, J = 6 Hz, 1, 10-H). d n d . (CigHziNOZ)C, H, S . This product (13) was obtained also in 35% yield by basic hydrolysis according to the above procedure for the oily urethan 12 prepared in 98% yield by refluxing the trans-carbinol 3b i n ethyl chloroformate for 30 hr. Identity of the product was established by conlparisoii (mixture melting point, ir) of the hydrogen maleate salts prepared from samples of the base; dnal. (CisH21N02.C4H404) mp 15'2-154" (i-PrOH-Et?O). C, H, X . cis Isomer.-Basic hydrolysis of cis-1 1-acetoxy-S-carbethoxymet,hyl- 5H - dibeiizo [a,d]cyclohep10,ll-dihydro - 5,lO-epoxy --Yteiie-&propylamine as described for the trans isomer gave 33yG of the cis isomer of the secondary amine. The aiialyt,ical sample, nip 138-139", n-as obtained by repeated recrystallizationu from Et20 and sublimation a t 130" (0.03 mm); rimr (CIlC11), 6 2.28 (s, 3, CHa), 4.31 (3, 1, ll-H), 5.45 (s,1, 10-H). h a / .( C I ~ H ? I S O B ) C, H, N. 10,11-Dihydro-5-( 3-dimethylaminopropyl)-5,lO-epoxy-5H-dibenzo[a,d]cyclohepten-11-one(14).-A solution of 49 g (0.158 mol) of trans-3b and 494 ml of freshly dist,illed cyclohexanone in 3 1. of dry P h l l e was dried by distillation of about 600 ml of PhMe. Slow distillation was continued while a sollition of 64 g (0.314 mol) of Al(i-OPr)p iii 370 ml of dry P h l l e was added dropwise over 1.6 hr and for a n additioiial 43 min. After cooling, the mixture was hydrolyzed with 1 1. of saturated aqueous NaKC4H406 and t,he aqueous phase was separated and reextracted with t,oluene. The combined organic layers were washed (H20) and extracted with three 350-ml portions of 0.5 J I citric acid. The ice-cold acid extract was made strongly basic with 40% aqueous NaOH arid the base was extracted into CsH,. Evaporation of the washed and dried extract and crystallization of the residual solid from hexane gave 33 g (6SCc) of analytically pure product, mp 76.3-78". Anal. (CinHpiNOz) C, H, ?IT. The ketone 14 was reduced readily to the parent trans-carbinol 3b by refluxirig with excess KHB, in CHIOH (67% yield). 10,ll-Dihydro-5-(3-dimethylaminopropyl)-5,lO-epoxy-l1methyl-5H-dibenzo[a,d]cyclohepten-ll-ol(15).-A solutioii of the Grigiiard reagent prepared from 0.X g (0.033 g-at) of l l g and excess lleC1 in 123 ml of dry T H F was added rapidly dropwise to a stirred solution of 3 g (0.0162 mol) of 14 iti 75 ml of dry THF cooled iii ice. After 1.3 hr at, room t,emperature, tmhebiilk of the T H F was evaporated; the residue was diswlved in CsHs; and, wit,h ice-cooliiig, 3 ml of H?O was added dropwise. The CsHs layer was decaiited from t,he gelatiiioiL:, precipitate which theii was extracted repeatedly with boiliiig CsH6. The combined CsH6 layers were ext,racted wit,h 0.5 J I citric acid. The ice-cold acid extract was made basic with 4 0 5 aqiieoiis S a O H and the base was extracted iiito C6H6. Upoii evaporatioii, the washed and dried extract yielded a crj-stalliiie rexidue. Recrystallization from Et&petroleum ether (30-60") gave 4.2 g (go?), mp 125127". .hd.iC,iH,;SOz) C, H . A sample of this base was converted into the hydrogen maleate salt, mp 181-182" (EtOH). Anal. (C2lH,jKO2.CdH,Oa) C, H, N. Spiro[10,11-dihydro-5-( 3-dimethylaminopropyI)-5,lO-epoxy5H-dibenzo[a,d]cycloheptene]-11,2'-na-dithiane (16).-Compoiuid 14 (900 mg, 3 mmol) and 1 ml of 1,3-propaiiedit.hiol in 20 ml of glacial HOAc were stirred with 2 ml of BF, etherate for l..i hr and theii allowed to stand overnight, at, room temperat,iire. The solution was poured int,o 300 ml of ice-cold 5% aqueous NaOH. The precipitat,e of t,he produrt was collected, washed thoroughly with H,O, air-dried, aiid dissolved in 150 ml of Et2O. Evaporation of the filtered solution left 1.1 g (92%), mp 122-126". A sample for analysis melted at 130.5-1:32° after recrystallizations from EtOH-HrO and i-PrOH; nmr (CI>c13),S2.20 (s, 6, N ( C H ~ ) Z ) , 3.W (a, 1 , 10-H). ilnal. (C23H2,XOS?)C, H, X.
195
lO,ll-Dihydro-S,~~-dimethyl-5,lO-epoxy-5H-dibenzo[a,~~] cycloheptene-5-propylamine (17).-A solution of 600 mg ( l..i mmol) of 16 in 75 ml of Et,OH was st.irred at reflux wit,h ca. 7 g of W-2 Raiiey Ni for 24 hr. The mixture was filtered and t8he filtrate evaporat,ed, leaving the colorless oily base that. was converted into the hydrogen maleate salt, in Et,OH-EtzO; 2x0 mg ( 4 . 5 5 ) , mp 135-138'. Recrystallizations from i-PrOH-Et20 aiid EtOHEt20 gave purified material: mp 141.5-143.3': nmr (CDCl:]), 6 2.21 (s, 6, S(CHa)2),3.45 and 3.71 (d, J = 6 Hz, 1 each, ll-CHZ), 5.57 (d, J = 6 Hz, 1, 10-H). < l d .ICmHyaNO.C4H404) C, H, K. 10,ll-Dihydro-5-(3-dimethylaminopropyI)-5,lO-epoxy-5H-dibenzo[a,d]cyclohepten-11-oneOxime (18).-A solutioii of T,..i g (18 mmol) of 14, 1.4 g (20 mmol) of HBKOH.HC1,aiid 2.7 g (20 mmol) of KaOAc.3H20 in 160 ml of 11eOH-20 ml of H i 0 was heated under reflux for 2..i hr. Solvent, was di,stilled aiid the residid syrup was dissolved in 300 ml of HzO. The solution was made st,rongly basic with 4 0 5 , aqiieons 3 a O H and the precipit#atewas collect.ed, washed ( H 2 0 ) ,parttially dried in a vaciiiim oven at 70°, and recrystallized from 95% EtOH t o yield 4.7 g (XlC;'c), mp 206-210O.B The analytical sample from a previous experiment had the same melting point range after repeated recrystallizatioiis from 95% EtOH; nmr (llllSO-d6), 2.23 (.*, 6, X(CHa)z), 6..53 (s, 1, 10-H), 7.80 (m, 1, OH). .!nul. ( C ~ O H ~ K ~ O P ) C, H, S. A sample of this base was converted into the hydrogen maleate salt, mp 184-186" dec (EtOH). .lnal. (CinH?2V2Or. CIHaOi) C, H, ?;. trans-lO,ll-Dihydr0-5-( 3-dimethylaminopropyI)-5,lO-epoxy5H-dibenzo[a,d]cyclohepten-ll-amine(19).--Under N?, a soliit.ion of 4.15 g (12.9 mmol) of 18 in 200 ml of dry T H F was added dropwise over 1 hr to a stirred swapension of X00 mg (21 mmol) of LAH in 30 ml of THF. After 22 hr of st,irring at room temperat.ure, the mixture x a s cooled in ice and hydrolyzed by the eiiccessive dropwise additioli of 0.8 ml of H20, 0.h mi of 1.75 ayueoiis NaOH, axid 2.4 ml of H,O. The precipit,ate wa?; filtered and washed with 75 ml of boiling CsH6. Evaporation of the combined filtrate and washings left 3.9 g of the oily base that was converted int.0 the dihydrogen dimaleate salt in Et.OH-Et?O, yieldiiig 4.1 g (58%), mp 162-165" dec. Repeated recrystallizations from i-PrOH-EtiO gave purified material, nip 171-172" dec. A n a l . (CpoHz,N?O'2C4H,O4) C, H, N. trans-ll-Acetamido-lO,ll-dihydro-5-( 3-dimethylaminopropy1)5,10-epoxy-5H-dibenzo[a,d]cycloheptene (20).-trans-19 (2.0g, 6.5 mmol) was dissolved in 10 ml of A4cz0at. room temperat,iire. In a mildly exothermic reaction, a whitmeprecipit,ate separat,ed. After several hours, t,he mixt w e was evaporated t,o dryness and the residue dissolved ill HzO. The H,O soliition was cooled in ice and made basic,with 3cG aqueorts SaOH, and the solid base was ext,ract,ed into CsH,. Upon evaporation, the washed CsH, ext,ract. yielded 2.2 g ( 9 6 5 ) of white cryst,als, nip 177-1S0°. The analytical sample from a previous experiment melted at 179-181" after repeated recrystallizations fiom 1IeCN. .Inal. (CnHuN2Os) C, H.
Acknowledgment.-The authors n ish to thank I< B. Streeter, T.C. Lee, and their staff for the microanalytical data, W.R. ;\lcGaughran, and E. L. Creison for the spectroscopic measurements, aiid Dr. S. R. Treririer for his help in the interpretatioii of the iinx spectra. We are also indebted to Dr. L. 11. Halpern for the pharmacological data. (9) TIC of the oxtine slioned a major component of R f 0 50 and a trace minor component of Rr 0 45 (fluorescent silica gel CHCls-MeOH-concentrated ?iHroH, 60 8 1) Its stereochemlcal Identlt, v a s not determined.
