The Synthesis and Stereochemistry of (±)-(4a,13b-trans)-2,3,4,4a,8,9,13b,14-Octahydro-1H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]-isoquinoline Hydrochloride (Taclamine Hydrochloride), a Novel Psychotropic Agent

Abstract

in experimental animals. Preliminary pharmacological res~llts have been described (1)and a fill1 paper is in preparation. In this report we describe the synthesis a n d stereochemistry of taclamine hydrochloride.T h e synthesis of taclamine.HC1 1 has been accomplislied through two independent pathways (see Scheme I). In the first, 10,1 I-dihydro-(2) (2) was condensed with 8-valerolactone t o give the hydroxyamide 3, which o n treatment with p h o s p h o r o~~s oxychloride undergoes a double cyclization to afford the pentacyclic pyridoisoquinolini~~m salt 4. R e d~~c t i o n of 4 with hydrogen and platinum, or, with sodium borohydride generates the 4a,13b-cis isomer of taclamine~free base which was converted to the hydrochloride salt 5. O n the other hand, reduction of 4 with zinc and hydrochloric acid affords predominately the 4a, l3b-trans isomer, 1. (See disc~lssion of stereochemistry below.) T h e isomeric nature of the two reduction products was confirmed by the oxidation of each, with 'Nonproprietary name selected by the U.S. Adopted Names Council. This compound has also been designated AY-22,214. (3). A mixt~lre o f the 4a,l3b-trar~s-and 4a, I3b-cis-pentacyclic aniino ketones 7 a and 80, respectively, were formed in a ratio of 6 : 1. The m i x t~~r e was readily separated into its components by column chromatography and the amino ketones 7 a and 8a were converted t o 1 and 5, respectively, through desulfi~rization of the corresponding ethylenethioketal derivatives, 76 and 86. T h e pure ethylenethioketal derivatives, 76 and 86 were also obtained by column chromatographic separation o f the m i x t~~r e o f 76 and 86 obtained by direct treatment of t h e amino ketone mixt~lre (7a a n d 8a) with ethaneditliiol and boron trifluoride etherate.Configurational assignments at the 4a and 13b centers o f 1 and 5 were made by interpretation of their n.m.r. spectra a n d , independently, by a consideration of the stereochemical controls operative in the reductions of the iminium salt 4. Thus, the isomer 5 obtained via catalytic hydrogenation of 4 is assigned a 4a,13b-cis relative configuration since examination of molecular models shows that the substrate for reduction, 4, contains an iminium center, which causes rings C, D, a n d E t o be virtually coplanar while the phenyl ring A is located on the cr-side at the Can. J. Chem. Downloaded from www.nrcresearchpress.com by 54.202.233.140 on 05/12/18For personal use only.

Neuroleptics related to butaclamol. An investigation of the effects of chlorine substituents on the aromatic rings

“…The 4a,13b relative configuration of the dechloro amino ketones related to 24-27 and to 28-32 has been confirmed indirectly by crystallographic studies,23 and it had been noted28 that the NMR signal of the C13b hydrogen of the 4a,13b-trans isomer appears as a triplet while that of the 4a,13b-cis isomer is a doublet. Similar splitting patterns for the C13b hydrogens of the amino ketones [24][25][26][27][28][29][30][31][32] (see Table I) lend support to the configurational assignments shown in Scheme II and Table I.…”

“…The Schiff bases were reacted, as their hydrochloride salts, with methyl vinyl ketone to afford the pentacyclic amino ketones shown in Scheme II and Table I. The 6-, 9-, 10-, and 11-chloro Schiff bases 19-23 gave mixtures of the cis (24)(25)(26)(27) and trans (28)(29)(30)(31) amino ketones with a preponderance of the trans isomers being formed. No cis isomer could be isolated on reaction of the 4-chloro Schiff base 23 with methyl vinyl ketone.…”

Crystal structure and absolute configuration of the neuroleptic agent (+)-isobutaclamol hydrobromide

“…Various chemical and pharmacological studies have been undertaken in recent years at the AYERST Research Laboratories of Canada, in order to determine the topography of the central dopamine receptor and its mode of interaction with neuroleptic agents of the benzocycloheptapyridoisoquinoline series. Some of these studies have been reported by Bruderlein, Humber & Pelz (1974) on synthetic procedures; Humber, Bruderlein & Voith (1975) on the mode of interaction; Humber, Bruderlein, Philipp, G6tz & Voith (1979) on the effect of modifications to ring E of the neuroleptic butaclamol (Ia); and on the effect of modifications to the regions occupied by the A and B rings of (Ia). Besides the chemical synthesis and pharmacological evaluation of the compounds, the studies include stereochemical * NRCC Publication No.…”

Neuroleptics related to butaclamol. Synthesis and some psychopharmacological effects of a series of 3-aryl analogues

“…Percent inhibition was calculated with the formula, % = 100(1 -a/b), where a is the sum or the reaction diameters in the treated animals and b the sum of the reaction diameters in the control animals.21 Each variable was tested in groups of five rats. 3b,4,5,7,8b,9,6-cT dipyrazole (1). A mixture of 1.11 g (5 mmol) of 4,11 1 mL (ca.…”

“…Anal. (C14H18N4) C, , 4,5,8b,9,dipyrazole (6). This compound was prepared in 26% yield by a similar procedure as for 1 and 5.…”