:\lay 1967 atid acetoiie cyatioliydriti iii the itsiial niatiiier3), aiid 1-piperidiiiolohexaiietiitrile~with pheiiyllithium acwrdirig t,o t,he above cediire gave the followiiig conipoiiiids iii 86845; yield. 1-(2-Imino-l,l-dimethyl-2-phenylethyl)dimethylamine, bp 9506' ( 2 mm). Anal. Calcd for C1UH18N2:N, 14.72. Fouiid: ?I, 14.50. 1-(2-Imino-l,l-dimethyl-2-phenylethyl)morpholine, bp 115120' (0.2 mm),mp 4 S 4 i o (hexaiie). Anal. Calcd for ClrH,,YpO: S , 12.06. FoLilid: 5 ,12.13. 1-( 1-Benzimidoylcyclohexyl)piperidine,hp 148-151' ( 0 . 2 mm), nip 88-90" (hexane). A n a l . Calcd for Ci~H26N2:S, 10.36. Foimd: S, 10.24. 1- [2-Imino-l,1-dimethyl-2-(p-chlorophenyl)ethyl] piperidine.% . so1rit)ioiiof 115 g (0.6 mole) of p-chlorobromobeiizeiie in 600 ml of ether was stirred and cooled to -15' iii an ice-salt bat,h and treated drop\\-ise, over a period of 1.5 miii, with 380 ml of 1.6 S n-biityllithiiim in hexaiie (0.6 mole) while maiiitaiiiiiig the temperature a t -7 to -12". The pale yellow solution was stirred for m i additional 30 miti at -10' aiid theii was treated with a soliitioii of 76.0 g ( 0 . 5 mole) of cu-piperidirioisobiityroiiit~rilein 300 ml of ether. 9 yellow-oraiige precipitate began to separate from the mixtiire after aboiit 30 miii. A4fterstanding for 4 days a t room temperatiire, the mixture \vas added to a cold Y H C I soliitioti aiid proces.ed iii the maiiiier described for Ia to give 96.2 g (73'';) of pale yellow prodiict, bp 1.55-158' ( 0 . 5 mm). ;Lnal. Calcd for Cl:1321ClS2: N, 10.38. Fouiid: X, 10.73. 1 -( 1,l -Dimethyl-2-phenacetylimino-2-phenylethyl)piperidine Hydrochloride (4).-.4 stirred solutioii of 40.0 g (0.17 mole) of I a iii 200 ml of beiizeiie was maiiitaiiied at 15-20' during the dropwise additioii of a wliitioii of 27.0 g ( 0 . l i mole) of freshly diutilled pheiiacetyl chloride in 100 ml of benzene. The mixture was refltixed for 1 hr, cooled, mid filtered t o give 62.5 g (93ci) of prodiict, mp 160-165'. ilfter two crystallizatiotis from 250-nil yl alcohol, the material weighed 39.3 g, mp and 5.98 p iC=O and C = S ) . 1-( p-Amino-cu,cu-dimethylphenethyl)piperidine.--A solutioti of 29.9 g (0.13 mole) of Ia in 100 ml of ethaiiol was treated with 0.9 g of PtO?. The mixtiire was placed in a Parr apparatiis iinder 3 atm of hl-drogeii and heated to .No. The theoretical qiiaiitity of hydrogeii \\-as coiisiimed iii 6 hr. The mixtiire was filtered atid the filtrate was concentrated iinder rediiced preshure to give 25.1 g 1 8 2 C i ) of colorless prodiict, bp 105-10io (0.1 mm), nip .56-39O. After crystallizatioii from hexane, it, melted at 61.563 O . .2nal. Calcd for CljH?4S2:S , 12.06. Foiuid: S, 11.83. The HCl ralt is 14 aiid the phenaretyl derivat,ive is 15. The dimethylamino analog (above) was hydrogeiiated it1 a 4milar matitier to give 64c1 yield of the amine, bp 87-89' (0.5 nini). The HC1 salt is 16. 2-Methyl-2-piperidinopropiophenoneHydrochloride (17).-T11 170 ml of cold concentrated HC1 was added 34.9 g (0.15 mole) of Ia: the mixtiire was refliixed for 24 hr, cooled, and treated with a aolutioii of 100 g of NaOH it] 130 ml of water. The prodlict was extracted with ether aiid t,he combined ethereal solutiolis were dried (lIgH04). A4fterevaporation of the solvetit, the residiie was fractionated to give 31.8 g (ill(-;)of pale yellow liquid, bp 100101' 10.2 mm) [lit.6bp 110-112° ( 0 . 5 mni)]. Thic base was coiivertsed to the HC1 salt, iii the usiial maiiiier (see preparation of Ia). The ketones 19 and 20 were obtained iii the same nianiier by hydroly5is of the correspondiiig imino compoiinda. Appetite Depressant Test Procedure.-Mice were deprived of food (water ad l i b i t u m ) for aboiit 18 hr. Aqueous solutions of the te-t drugs were admiiiistered orally to groups of mice (lo/ dohe) atid after 1.5 miti they were offered food pellets (Rockland l\[oiise Iliet) for a period of 1 hr. The amolitit of food consumed diiritig this period was theii deterniiiied. The anorectic activity, espres.-ed iti milligrami. per kilogram, is the approximate dobe which caiised a 50yc decrease in the normal food iiitake. A 5irnilar test procedure was iised wheii a compound was tested iii dogs.
Acknowledgments.-The
4'3'7
KOTES
authors are indebted to
h.Szaho, C. F. Turk, and ,J. Williams for the preparation of some of the c.onipounds and to .J. Xliciiio and his associates for the analyses reported herein. ( 5 ) .I. l k t z and 1'. lIerkel, .I. I'rokt. Chern., 113, 4g (lY26). (CI) C. L. Stevens and C. 11. Cliang, J . Ory. Chem., 27, 4892 (1962).
To study the biological effect5 of replacement of the aromatic rings by pyridine rings in the antidepressant drug, 5-(3-dimethylaminopropyl)-1O.ll-dihydro-5H-dibenzo [b,f]azepine. the diaza compound I was prepared as shown in Chart I. CH \111
I
' 0 .'.'H,PO,
+
NHI NHL I1
I11
Pyrolysis of ~,~'-dianiiiio-8,3'-dipirol\-l~ a s the diphosphate salt' (11) at temperatures in the range of 3OOo3 gave the t,ricyclic aniine 111, which was converted into I by alkylation with dimethylaminopropyl chloride and sodium hydride. The latter was cahararterized as t'he tetrahydrochloride and dinialeate salts. The nnir spect'rum of I,4 measured in CDC1, with TJIS as internal st,andard 011 the T'arian A-GO, is consistent with t'he assigned structure and shorn: (:I) t'he protons a t positions 1 and 9 of the ring, being tlic least' shielded are furthest downfield. shon- a singlet a t 6 S.31 (2 H); (b) the doublets centered at 6 S.2((i ( 2 H ) and 6.95 ( 2 H) are assigned to the proton:: nt positions 3,7 and 4,6 of t,he ring, respertively; (c) the bridge protons a t C-10 and -11 appear as a singlet at' 6 3.11 (4 H); (d) the t'riplet's centered at, 6 3.92 ( 2 H) and 2.30 ( 2 H) and the quintet a t 1 . i i ( 2 H) are the a , y , arid p protons, respectively, of tmhepropyl side chain; (e) the strong singlet, a t 6 2.18 corresponds t o the six protons of the S ( C H & group. Compound I was remarkably inactive in most hiological testing procedures. The compound at an oral dose of 10 mg/kg did not a,ritagoriize tetra,benazineinduced sedat'ionj in mice. The standard' had uii EDSO of 0.5 nig/lig in this test procedure. At oral doses of 2-15 mg/lig in the cat. no significmit behavioral changes were not,ed. The EDjo I'n tit/,o (1) Imipramine; S i 2 (1954).
\V. Schindler and F. Hafliger, Heli,. Ciiim. d c t a , 37,
(2) E. C. Taylor, -1.J. Crovetti, and X. E. Boyer. J . d m . Ciiem. S o r . , 19,3549 ( 1 9 5 i ) . (3) TY. Schindler and F. Haflirer, C . P. Patent 2,i64,.580 ( I Y X j , (4) T h e aiitlior is iniieljred ti1 l l r , l l i l t o n I ) . YiiCIi- of tiie l'ii3sicnl Organic Chemistrj- Ilepartment of t h e iclierine C'oru f o r tlir intrri)rerat i o n of the nmr data. ( 5 ) For a revie\\. of this lxocedure, see V . G . Vernier, II. AI. H a n w r i and C . 1.Stone in "I'~yc11oso1~iaiicAledicine," .J. 1 3 . NuiIinc unci .J. 11. AIoyer, E d . , Lea and l;cl,iuer. l'liiladel~,l~ia, P a , , liiii5, C'lliIlJler80.
