J u l y 1967

KEWPSYCHOTROPIC AGEXTS. TIII

Anal. Calcd for 71.6; H, 8.4.
C23H32N203:

627
C, 71.8; H, 8.4. Found: C,

Anal. Calcd for CZEH~ZNZO~:70.7; H, 7.6; 11, 424. C, Found: C, 69.i; H, 7.6; R.I (by mass spectrometry), 424. Reduction of Brucidine to X1V.-Materials used were brucidine (4g), S a ( 3 . 5 g), ?jH3 (400 ml), methanol (4ml), NH&l (4.09). Time intervals were A, 30 min; B, 45 min. The product was recrystalllzed from acetone to give the 215,22-dihydro-23,24secobriicidine a5 a solvate ( 2 g); mp 192-196; one major spot Ri 0.11, with a trace of a second, Rf 0.16. The desolvated substance, prepared by drying zn caczm, had mp 195-202.

Acknowledgments.-We thank Dr. Larry Stein and his associates of the Psychopharmacology Section of these laboratories for the biological testing data, and Dr* DeJongh and J. Hribar, State University, Detroit, Nich., for the mass spectra.

New Psychotropic Agents. VIII. Analogs of Amitriptyline Containing the Normeperidine Group
AI. A. DAVIS, HERR, A. F. R.
THOMAS, ASD

~IARIE-~AULE CHAREST

A yerst Research Laboratories, Montreal, Canada

Received iVovember 3, 1966

A series of compounds related to the previously reported 5- [3-(4-carbethoxy-4-phenylpiperidino)propylidene] lO,ll-dihydro-5K-dibenzo [a,d] cycloheptene has been prepared. These include analogs in which the tricyclic ring and piperidino group were separated by one- to three-carbon side chains in differing states of oxidation. I n several cases the corresponding reversed esters were also prepared. Related compounds were made in which the dibenzocycloheptene ring was replaced by an iminodibenzyl, a phenothiazinyl, or a benzhydryl grouping. The preparation of a number of novel intermediates is discussed including that of a dibenzocycloheptene &piroepoxide. Analgetic testing showed that several of the compounds had activities in the range of morphine.

The preparation, in these laboratories, of a series of dibenzocycloheptenes possessing distinct psychotropic activities has been reported.2 Two of the compounds, amitriptyline (Ia) and nortriptyline (Ib), have been used successfully in the treatment of depressive disorders.; One of the analogs which me had studied was IC, in which the terminal amino function, XRlR2, formed part of the 4-carbethoxy-4-phenylpiperidine or nornieperidirie group. When the sparingly watersoluble hydrochloride salt of IC was given intraperitoneally to mice and rats, it exhibited some of the pharmacological properties of the antidepressant drugs, but appeared to lack significant analgetic effects. The influence of the normeperidine group was seen, however, on subsequent oral administration. Due, possibly, to better absorption from the gastrointestinal tract (at large doses a portion of the unchanged compound had tieen found in the intraperitoneal cavity), it exhibited an analgetic action in the range between morphine and meperidine. I t is well known that replacement of the S-methyl moiety of meperidine by appropriate groups can lead to conipourids with markedly enhanced analgetic activities.* On occasion it has been possible to dissociate the morphine-like effects of the parent drug to obtain agents which possess antiperistaltic4 or antitussive6 actions together with minimal or no narcotic properties. Accordingly, a series of compounds related to IC was prepared having the Common structural features shown in 11. Those derived from the dibenzocgcloheptene ring ( A = CH2CH2 or CH-CH; B = carbon) carrying
(1) P a r t VI1 M . A. Davis, G. Beaulieu, J . R. \Tatson, and 31 -P. Charest. J . .?fed. Chem , 9 , 860 (1966). (2) (a) S 0. Ninthrop, hl. A. Davis, G S Myers, J. G Gaxin, R. A. Thomas. and R Barber, J. Org Chem., 27, 230 (1962); (b) J. S t e n a r t , M.-P Charest, and F. Herr, J . M e d Chem , 6 , 338 (1963). (3) F. Hafliger and V. Burckhardt in Psqchopharmacological Agents, Vol. 4-1, 11.Gordon, E d , Academic Press Inc., K e n Tork, ?;. Y., 1964, p 35. (4) R A Hardy, Jr., and RI. G. Howell in Analgetics, G. destevens, 11 , Academic Piess Inc., New York, N. Y., 1965, p 179. .1 ( 5 ) BI. A. Daiis, U. S. Patent, 3,094,528 (1963).

Ia, R1=R2= CH3 b, R I = H ; R2=CH3 I1 c, NR,R,= 4-carbethoxy-4-phenylpiperidino

a one- to three-carbon side chain, Y,in differing states of oxidation are listed in Table I . As well as the usual normeperidine group (2 = CO2C,HS), we have also prepared some of the compounds in the form of their reversed esters (2 = OCOC,HJ in the hope of increasing the analgetic potency. Table I1 lists compounds where the dibenzocycloheptene ring has been replaced by a heterocycle, viz., 5-iminodibenzyl or 10-phenothiazinyl. A series of related compounds derived from iminodibenzyl has been claimed to possess antipsychotic propertiesJ6while 2-substituted 10-phenothiazinyl analogs of IC exhibited antihypertensive activity. Several compounds were prepared in which the bridging group , A, is absent; these benzhydryl analogs are listed in Table 111. They are related to 2,2-diphenylbutyronitrile derivatives having antidiarrheal (IIIa)8a and

IIta, R = C6HS; R=C02CPHB (diphenoxylate)

b, R=piperidino; R=CONHZ (pirinitramide)
(6) Yoshitomi Pharmaceutical Industries, Ltd., British Patent 1,017,986 (1966); Chem. Abstr., 64, 17559 (1966). (7) H . S. Lowrie, U. S.Patent 3,112,308 (1963). ( 8 ) (a) P. A . J. Janssen, A. H. Jageneau, and J. Huygens, J . Med. PhaTm. Chem., 1, 299 (1959); (b) C. van de Westeringh, P. Van Daele, B. Hermans, C. Van der Eycken, J. Boey, and P. A. J. Janssen, ibtd., 7 , 619 (1964).

Juljr 19G7
c r i =

KEWPSYCHOTROPIC XGEKTS. 1 7 1 1 1
g
'a??
-3,s:
m s 3. y . .
' 9

629

analgetic (IIIb)8b activities. A recent patent9 claims long-acting analgetic act'ivit'y and low toxicity for analogs of IIIa in which the a-cyano group is replaced c c c;."-E .t CiCDrnC UlC - %F s + by hydrogen. 12 5.1 3oCy?c.3 Ulrr .N o & $ A : s . . A variety of methods was eniployed to prepare the & wmmccti pis X L ~ L C % ~ ~ $ zdibenxocycloheptene derivatives listed in Table I. 32 E E a +,%a 9 c =e c : s : ?5 P- L C t- 5.1 5.1 c I9. x . 3c. c ~9 s 0 . . : 5 3 5 5 g 5.1 ? The most general one involved treatment, of arl apj,,,,, ,,,,, ,,,,, m3g5 1 propriate 5-(w-haloalkylene or -alkylidene)dibenzo1 9 m s c1 2 m LC , s L m m t- =?.I e c.1 . _.CD ts : 5.1 C lr: : C W P- - c & $ E Y a = % cycloheptene with secondary amines (method A). 1 u . . . . . . . . . . . . . . . . With normeperidine, it was preferred to carry out, the 5 . i g 2 E p 2 g 2 3 % g 3 2 2 % ,P % Lw= reactions in boiling benzene or tolueiie containing tri- 3 C b s d g24 E [+?% . . 2 N. C. -4-W et'hylamine, while the condensations Tvith 4-phenyl-40 ?corny x - $ . . . i z z x X .I x t.zt-0 a E5 *aj piperidinol were best effected in boiling 1-butanol and E 3 2 : I Sa2C03. For certain conipounds, especially those I ? E a 0 , @ l-E h m - : g % t - 1 . . % g2: 6 5.- & s . carrying a hydroxy group on the 5 poshion of the tri12 tt .- . , q 0 c. . . g m 0 1 5 ' 1 ? ? m r : 5.15.1 & , Q : : * 2 2. 2 8 cyclic ring, a p-toluenesulfonate was used in place of E B the halogen compound (method B). Tields were fair rn t zrn a 0 2 ? e mm. _.* L ?0 g t L9, s gc.3 m zr: 5.1 L t 9 3 2 E tc 0 _.I W . + to poor, but it was shown that' little or no dehydration of the carbinols to the corresponding alkylidenes had occurred. These alkylidenes could, however, be obtained by heating the 5-hydroxy compounds lt-ith niinera1 acid (method C) and could in turn be reduced catalytically to the corresponding saturated side chains (method D). Both of these latter approaches ivere less satisfactory than method A. The reversed esters were obtained from the appropriate piperidinols by heating with propionic anhydride cont'aining a little H2SOI (about 90") (method E). The products, as their hydrohalide salts, tenaciously retained water or solvent of crystallization and required careful drying. Some = difficulties were incurred in finding suitable conditions 0 $?ab4 E 4 4 4 4 '= W X H for the acylations. Treatment of the piperidinol, 8A, + 64 2 o 5% for example, with propionyl chloride in CHC1, either at 2 s a * room temperature'O or at the boiling point of the solvent h .- s , ,$-e z s 3 h b -=r 2 gave either incomplete reaction or concomitant dee2 J ~ ~ 3 d ~ . a ~ ~ i .-.E3 i . ~ ~ - u ~ ~ ~ ~ 2 .+ * hydration of the 4-hydroxyl group to form 10. Prior 2 - 8 - 5 treatment of the piperidinol with ethereal methyl2 + 0 v v pR-:.E a magnesium bromide'l or with NaH in benzene followed u"v y o

/=

mzc x

"S$&b

t-x

t-jt-0

' 9

-8

- L i 3

a w z E
I

'i

ri

L ?

i .

$&*~

F 4 .n g

c H

= 2 5 2 - S.L+ F.2 AtLtL&&t.~&L$&&&&Y-l.& 4 8 56s 2 g f g 2 =; =: 4 5 g 2 c 5:;

x m ~ & o o ~ y i L Q - o

34
2
1

' J - c

2g

2 1

3 $$ 5 %

5:

2
id

2 3

i-

V J*,e I

c c

2~ 5
h -N *I

; g l b T c8 w o E , g " x =u . - 3 g su 2% c,:s$h s3 E ., g 2 g 4 s p s u ? r dde Zd se d , T " T q ~ & ~ d ~ q q csl o$ 2 o i, ~ j LCC."62c ~ ~ o u c 3 o u o u o u u u2 ' = c d2. 2

- ,
i d d o
. " M T

. -: - : .

c)

. ..

9 gh 4-c 63 . - 3 2h gc ud ::T= z
Y

.-A

by the acid chloride was unsatisfactory, while the action of propionic anhydride in pyridine at, 50" gave only unchanged carbinol. Other workers'* were unable to esterify a related compound (IV), attributing this to steric hindrance caused by the benzhydryl group.

F - c

" ?

I I

e: i , i I

N C

- S % W W

c
IV

& S f

i"i"c

-N

m , z 2 , z A N
N N

G4ZEES a
w v v w
N

k9 1

$-,$

SE

- e

22
555
Z K Z
$ S S

uuu
3 C F

-52
N N

z ; f i r ; u u u En,2$.2< 0 c s sxgas : v v v i -v : u u u ' ; u u &$

c

Y *

H C S CH2N3(c"5
COGH, COCH,R

=<g # $ $ 7 :.
53; & $ 0 :,a 2 E 4 3 A "A .k a ' g
3

VI

uu
* e

VIIa, R-H b, R==CH,N(CHJ,

; i i ;

uu3 I1 11 I!

uu

I1 11

x E=;
C' s

3;g
Ln

2-$& E 6.5

Z 8 FI + 8 :-c,E's??
gJ-c.1"-

Three ot'her syntheses mere employed for the normeperidine derivatives. Interaction of the piperidine with the spiroepoxide V (method F) gave compound
(1966).

u \ O O (9) ~ E rG" ~ Lm sm m ~ C "b C a 6 1 Farbwerke Hoechst A.-G., Belgian P a t e n t 673,267

4ffi 4rqcm crsS g 0 1 m b i e ~ 0 t - w ? 3 C C i 3 T M e m m m 01 c1 5.1 5.1 c1 h m m m m m 5 m

cie

&g
+ 6 9 :

(10) P. M. Carabateas and L. Grumbach, J . M e d . Phnrm. Chem., 5, 913 (1962). (11) R. T. Major and F. Diirsch. J. Org. Chem., 26, 1 8 6 i (1961). (12) B. G. Boggiano, V. Petrow, 0. Stephenson, and A. RI. IVild, J . Chem. Soc., 1143 (1959).

July 1967

KEWPSYCHOTROPIC AGESTS. VI11

TABLE

63 1

Iv
Spontaneous motility Effect, Dose % mdkg 3Iydriasis Dose, Effert, unitsC mdkg .intispasmodica Dose, EtTect, mg 5 %

PHARMACOLOGICAL OF REPRESENTATIVE PROFILE COMPOUXDS

Cornpd Route of admin LDjo, m g h Analgesia (tail flick), mdkg

EDsa (hot plate),

mdkg

iP
PO

600 f 42 >1200

7 f0.7 18 f 3 8 i0 . 2 13f 1 1 . 4 i0 . 2 2 . 8 f0.3 >l50

19 f 4

7 15

+1 i 5
+241 973

+32

7
2. i

1.7 4.2 1 0 G 12 86 238 9 18 118 146

81 i 11 .
13 i 0 . 2 32 f 6 1.1 f 0 . 0 7 2.8 f0.5 >200 >300 14 28 23 f 4 6 f0.5 l l f 2 145 f 17 400 14 f 2 36 f 4 4.5 f 14 67 f 10 118 f 0 5 f 2 13 i 3 67 f 10 i 6 f4
2% 4i

iP
PO

450
i30

8 15

12 1.5 3 22 +11i

iP
PO

450 730 280

1 4
2.8

3.S
6.4 0 0 0 1 -5 3 70 00 1 .,j 3
205

3-30

10

iP
PO

150

- 6S

100
22.j

>1200

>300 >loo
14 i 2 1 . 6 f 0.2 2.6 f0.4 140f 10 430 12 f 0 . 6

12B

iP
PO

> 1000 > 1200

125 175

+222
+990

14 14

0
1.2 0 2 14 0.6 1.6 4.2 4.6 4.2
0

14

iP
PO

1. . i 3

+44

+ 10
- 85

14

130 360

1.6 2.6 14,;

280

19
20

iP
PO

> 1200
180 830 550
GO0

1.3 2.6

220 200

14,;
12 24

iP
PO

T-52 +2i8

12
22

22 f 4
20 f 4 42 f 8

11 '22

3i0 310

218

iP
PO

20 40

+ 10,i
-71

- 38

20

40
94 3 10
120 120 4 3

29B Xorphine sulfate

iP
PO

iP
PO

380 >1200 275

1000 14jb 26Sb

> 160 58 f 3 4.3f0 5

20 f 2 22 f 2 81 f 5

21 42

146 208

+ 1,::; +i 8 + 167 + $6

3 .6 4
in 20
,

20
22

3Ieperidine HC1

iP
PO

!>

370 360

b
c

40 230 80 790 5 I11 rats. The effect is the per cent increase in residual BaSOd o n the stomachs of treated rats c.~mparedto untreated cJntrols. Values in agreement with the findings of C. 31. Gruber, E. R. Hart, and C. AI. Gluber, Jr., J . Pharmaco!. Espil. Therap., 73,310 (1941). Units of increase over pupil diameter in control groups; a score of 40 represents maximal dilatation.

81

1q.G

finyl carbanionj29 but efforts to trap any ring-derived anion by treatment with C 0 2 also pave unchangPd Icetone. The observation that 1,l-diphenylethylene did not' form the epoxide with perbenzoic acid"0 was paralleled in the case of 5-methylene-l0,1l-dih\-dro-5H-

QJ \

CHPX
XIa, X = OH b, X=Br C, X-OTos
(29) E. J. Cores and RI. Chaykovsky, J . Am. Chem. Soc., 84, 866 (1962): J . Org. Chem., 28, 254 (1863); C. Walling and L. Bollyky, ibid., 28, ?A6 (1963); G . A. Russell, H. D . Becker, and J. Schoeb, ibid., 28, 3684 (1963). (30) G . T. Kewbold and F. S.Spring, J. Chem. Suc., 247 (1946).

dibenzo [a,d]cycloheptene on treatment 1 ith 3-chloro1 perbenzoic acid. 3-(2-Bromoeth>lene)- 10,11-dihydro-3H-dibe1lzo[a,d]cycloEeptene, required for the preparation of 3 arid 4, was prepai ed from the corresponding hydroxy compound. This was obtained from the unsaturated acid (XIV) n hich was first hydropcnated to XV and then reduced with LiBlH,. The olefinic acid has been previously describedj2J1 but a preferred route involved the action of HBr on either the isopropyl (XIIIa) or the f-butyl ester (XIIIb) of the related &hydroxy acid. Decarboxylation became import ant if the reaction was carried out at elevated temperatures and an attempted one-step conversion of X I I I b to the saturated acid (XV) using hydriodic acid gave no acidic product.
( 3 1 ) C. \ a n der Stelt .I. Haasjes, H. 11. Tersteege, and \Y,T1 K a u t a , 1 IZec Trau. Chim., 1466 (1965). 84,

July 1967

NEWPSYCHOTROPIC AGENTS. VI11

(V). A.Anal. Calcd for CliHlsO: C, 85.67; H, 7.61. 85.78: H, 7.40.
Found:

633
C,

Spiro{ 5H-dibenzo[a,d]cycIoheptene5,2'-Epoxide )

N a H (50% dispersion, 1.15 g, 0.024 mole) was freed of mineral

oil and added to dry dimethyl sulfoxide (DMSO) (30 ml). The mixture was heated a t 60-75" for 45 miii, cooled to O", and diluted with dry tetrahydrofuran (TI-IF) (30 ml). A solution of trimethylsulfoiiium iodide (4.9 g, 0.02 mole) in DlISO ( 2 5 ml) and T I I F (10 ml) was added followed by 5H-dibenzo[a,d]cyclohepten-3-01~~9 (4.1 g, 0.02 mole) dissolved in T H F (10 ml). The reaction mixture, which was a light red color, was kept a t 0' for 30 min and allowed to warm to room temperature (1 hr). It was poured into cold water to give 4.0 g (91%) of material, nip 85-89 ', which contained no residual ketone. Recrystallization from cyclohexane gave the pure epoxide: m p 91-93'; CHCh ( A 287 mp (E 15,500). urnax 350, 800 em-1 (epoxide); :? Anal. Calcd for ClsH120: C, 87.24; H, 5.49. Found: C, 87.28; H, 5.33. B.-Dimethylsulfoxonium methylide was generated from trimethylsulfoxoriiuni iodide (6.1 g, 0.03 mole) and N a H (507,) 1.32 g, 0.03 mole) in DAIS0 (25 ml) a t room temperature. The preceding ketone (4.7 g, 0.02 mole) was added, and the mixture was stirred for 1 hr a t 25" followed by 1 hr a t 50-55". The solid obtained by dilution with water contained the product plus a little ketone; oiie recrystallization from cyclohexane gave 2.1 g (42%)of the epoxide, mp 89-00'. 10,l l-Dihydra-5-hydroxy-5H-dibenzo cycloheptene-5-acetic [a$] Acid Isopropyl Ester (XIIIa).-Following a procedure of Sisido,*3 the Grignard reagent prepared from ethyl bromide (43.5 g, 0.4 mole) and Mg (9.8 g, 0.4 g-atom) in ether (200 ml) was cooled to 5" while diet,hylamine (29.4 g, 0.4 mole) in ether (100 ml) was added dropwise. The mixture was then heated under reflux for 0.5 hr, cooled again to 5 O , aiid treated dropwise with a solution of 10,1l-dihydro-5H-dibeiizo[a,d]cyclohepten-5-one4~ (41.6 g, 0.2 mole) and isopropyl acetate (20.4 g, 0.2 mole) in ether (200 nil). After heating under reflux for a n additional 2 hr the mixt,iire was hydrolyzed with ice-water and NI-IICl. The aqueous layer was separated and ext'racted with ethylene dichloride (emiilsioiis u-ere broken by the addition of dilute H&Oa to p I I 3). The extracts were combined with the ether layer, then dried and evaporated. There was obtaiiied 36.0 g (58%) of product, nip 101-103 (from 2-propanol), 264 mp (e 5 0 2 ) . dnal. Calcd for CyoIIT?Oa:C, 76.98; II, 7 . 3 2 . Found: C, 77.39; TI, 7.14.

'5-(2-Bromoethylene)-lO,ll-dihydro-5H-dibenzo[a,d] cycloheptene.-A solution of PBr3 (11.9 g, 0.04 mole) in dry benzene (50 ml) was added dropwise and with cooling to a solution of the preceding carbinol (10.5 g, 0.04 mole) iii benzene (50 nil) coiitaining pyridine (0.1 ml). The mixture was stirred for 2 hr a t room temperatiire aiid then heated under reflux for 0.5 hr. It was cooled aiid poiired into water, and the organic layer was distilled to afford 6.4 g ( 4 8 7 ) of the bromide, bp 154-158' (0.01 mm). The oil solidified o n standiiig: mp 54-53', unchanged on recrystallization from pentane,":!,A : 266 m p ( e 545). Anal. Calcd for CliH,iBr: C, 67.93: H, 5.69; Br, 26.53. Found: C, 67.69: H, 3.50: Br, 26.54.
5-(2-Bromoethylidene)-lO,ll -dihydro-5H-dibenzo[a,d]cycloheptene.-The interaction of 10,1l-dihydro-5-hydroxy-5H-dibe~izo[a,cl]cycloheptei~e-S-ethai~ol~~ g, 0.04 mole) and PBr3 (10.0 (34 g, 0.12 mole) in beiizeiie (100 nil) was carried out as above except that the heating time a a b decreaded to 10 niiii. There JYas obtained 11.3 g (98%;) of product, nip 110-lll', michaiiged on recrystallization from hexane; 246 nip ( E 13,800). For material prepared by a different' method, the reported46 melting point was 105-110". An attempted preparation from the diol and boiling 4S(7 I-TBrwas unsuccessful. 5 4 2-Bromoethyl)-lO,ll -dihydro-5H-dibenz [b,f] azepine.-A solution of lO,ll-dihydro-5H-dibeiiz [h,f!azepiii-j-ethaiio147 (7.5 g, 0.03 mole) iii dry beiizeiie (70 ml) \vas cooled to 3" and treated with PBr3 (8.4 g, 0.03 mole) iii benzeiie (30 nil). The mixtiire was processed as described above to give 4.0 g ( g 2 5 , )of material: nip 90-91" (from hexane); ":> A : 211, 2 2 mp (E 26,100, 9450). The compound could not be obtained completely pure and was used as such for the preparation of 18. 5-(3-Chloropropyl)-lO,ll-dihydr0-5H-dibenz[~,~]azepine was prepared in 33% yield as d e s c ~ i b e d bp ~160-166" (0.3 mm), ,~ lit.**bp 150-160" (0.2-0.3 mm). Anal. Calcd for CliH&l?r': C1, 13.06; K, 5.16. Found: C1, 12.82; i , Y 4.81. l,l-Diphenyl-1,3-propanediol.-4 solution of 3J-diphenyl-3hydroxypropionic acid t-biityl ester43(44.1)g, 0.15 mole) in T H F (600 ml) was reduced with LiAlH, (8.6 g, 0.22 mole) giving 32.0 g (947,) of the diol, mp Si-90". A pure sample was ohtailled from 2-propanol-hexane: m p 91-93"; lit.49 for a mixture of . isomers, mp 87-90". -Anal. Calcd for ClsH1,O?: C, 7S.92; H, 7.06. Found: C, 79.03: H , 7.14. A 3-p-tolueiies,ilfoiiate eater was prepared followilig a procedure used for the corresponding dibeiizocycloheptelie analog.28 It rapidly decomposed on attempted isolation and was used ill the crude form for the preparation of 22 by method B. 3-Bromo-1,l-diphenyl-1-propene.A.-A solution of the preceding diol (15.0 g, 0.07 mole) in dry benzene (100 ml) was kept a t 5" while PBrs (18.4 g, 0.07 mole) dissolved iii the same solveiit (100 ml) was added dropwise. The mixture was heated uiider reflux for 2 hr, cooled, aiid poured into mater. Ilistillatioii of the organic layer afforded 13.5 g ( 8 6 5 ) of prodiict, bp 13%' mm), (0.1 mp 41-42', raised to 4 2 4 3 " on recrystallizatioii from peiitaiie; lit.59mp 37-39"; ?:A : 254 mp (E 17,900). B.-A solution of l,l-dipheiiyl-l-propeiie51 (24.2 g, 0.125 mole), S-bromosuccinimide ( 2 2 . 2 g, 0.125 mole), and beiizoyl peroxide (0.1 g ) ill CCla (100 ml) w a s heated uiider reflux for 16 hr. The precipitate was filtered, the solveiit was evaporated, mid the residue was recrystallized from pentane t o give 22.9 g (67%) of the bromo olefin, mp 44-48'. Using this procedure, Ziegler5' obtained an oil, bp 96-08" (0.0.5 mm), whicah corild iiot be solidified due to the presence of an impurity. dnai. Cnlcd for C16TT,,Br: Br, 29,30. Foiiiid: Br, 20.31.

Az ?

10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylideneacetic
Acid (XIV). A.-A solution of XIIIb23. (108.0 g, 0.33 mole) in acetic acid ( 1 1.) was cooled in an ice bath and saturated with gaseoiis FTBr. It was kept overnight, part of the solvent, was removed in uucuo, aiid water (1 1.) was added. The precipitate was dissolved in CIIC13 and extracted with dilute, aqueous XaOH. Acidification of the alkaline layer gave 77.0 g (93'3 ) of product, mp 169-l7Oo (from benzene-hexane); lit.2&131 172-173", 168170". If the reaction mixture was heated 011 the steam bath for 0.5 hr, the yield of carboxylic acid dropped to 44%, while heating for 3.5 hr gave only the decarboxylated product, 5-methylene-l0,1l-dihydro-5H-dibenzo [a,cl] cycloheptene, 12 mp aiid mmp 634.7". B.-A solution of X I I I a (5.0 g ) in CHC13 (25 ml) was kept a t 10" and treated with HBr for 2 hr. It, was then kept a t room temperature overnight, poured into water (50 ml), and processed as above to give 2.6 g (66%) of the unsaturated acid, mp 168170". The reaction was repeated a t 0" for 15 min, and the mixture was processed a t once. The only isolated product in t,his case was the isopropyl ester of XIV (3.5 g, 74%,), mp 63-64' (from hexane), A : : 261 nip (e 12,750).44 Anal. Calcd for C~IX,OZ: C, 82.16; IT, 6.90. Found: C, 82.43; I T , 6.69. 10,11-Dihydro-5H-dibenzo[a,d] cycloheptene-5-ethanoI.-A solution of l0,11-dihydro-5H-dibeiizo[~,d]cyclohepteiie-5-acetic acid (X\')31145(31.7 g, 0.13 mole) in T H F (200 ml) was added dropwise to LiAlH, (10.6 g, 0.28 mole) in the same solvent (300 ml). The mixture was heated under reflux for 1.5 hr, cooled, and treated sriccessively with water (11 ml), 2076 NaOH (8 ml), and water (37 ml). Removal of the precipitate and evaporation of the solvent gave 18.5 g (sa%), mp 5 9 4 0 " (from cyclohexane), :? A 266 mp (E 604).
(42) A. C. Cope and S. W. Fenton, J . Am. Chem. Soc., 7 3 , 1673 (1Y.51). (43) K. Sisido, H. Nozaki, and 0. Kurihara, ibid., 74, 6254 (1952). (44) Preparation carried o u t by M r . R. Otson. (45) L. G. Humber, .\I. A Davis, R . A. Thomas, R . Otson, and J. R. \Vatson, J . H e f s r o c g c l i c Chem.. 3, 2 4 i (1966).

(46) R. D. I I o f f ~ o m m e rD. T a u h , and K. L. \Vender, J . . > f e d , Cliem., , 7, 392 (1964). (47) (a) Rhhne-Poulenc, French Patent 1,215,590 (1960); Chem. $ b s l ~ . , 66, 14488 (1961); (b) J. R. Geig-y, .I.-G., 15ritish Patent 907,T85 (1962); Chem. A b s f r . , 6 8 , 5616 (1963). (18) J. \V. Cusic. U. S. Patent 3,123,610 (1961). (49) H. If.Walborsky and C . Columbini, J . O r g . Chem., 2 7 , 2387 (1962). ( 5 0 ) K . Ziegler and P. Tiernann, Ber., 66, 3406 (1922). (51) S. C. Husses, C. 5. Marvel, and F. D . Hagar, J . A m . Chrm. SOC. 62, 1122 (1930). ( 5 2 ) K. Ziegler, .\. Spath, E. Sclirraf, \I-. Srlirimann, and E. \l-inkelmann, Ann. Cham., 661,80 (19.52).

,July 19G7

XEWPSYCHOTROPIC AGENTS. VI11

635

acetate to give 0.2 g of material, mp 191-1(32", v:;:l3 1623 c111-l 238 mp ( c i 2 3 ) . (amide C=O), 1 -( 4,4-Diphenyl-3-oxobutyl)-~-carbethoxy-4-phenylpiperidine Hydrobromide (30A).-The Maiinich reaction between ljl-diphenvl-2-propaiioiie (8.4 g, 0.04 mole), 4-carbethoxv-4-phenylpiperidine hydrochloride (11.3 g, 0.04 mole), aiid paraformaldeThe reaction mixture was heated under reflux for 1 hr, treated with a n additional 1.0 g of paraformaldehyde, and heated for hyde (2.4 g, 0.08 mole) i n 1,2-dimethoxyethaiie(45 ml) coiitainiiig another 2 hr. After cooling, a little insoluble material was re5 drops of coiicentrated HC1 was carried out as described for method H . The mixture was heated for 3.5 hr, cooled, and dimoved hj- filtration, and the solvent was evaporated. The luted with ether. The precipitated hydrochloride was combined residrie, on shaking with CHCl3 and N a H C 0 3 solution afforded with a further amount obtaiiied by evaporatioii of the solvents the criide base as a n oil. Conversion to the hydrobromide salt gave 7.8 g, m p 186-188". hi1 analytical sample had mp 192and trituration of the residue with ether, giviiig a total of 16.1 g. 193")' ?A , : 264 mp ( e 890). The spectrum of an aqueous solution It was converted via the free base to the hydrobromide: mp remailred the same after keeping for 1 week at room temperature. 193-195' dec; 258, 290 mp ( e 515, 20%). 0 1 1 keeping Regeiieratioii of the base gave material, mp 109-11O0, A ": % this solution for 1 week at room temperature or for 2 hr at 70' the two peaks were obscured bv eiid absorptioii a11d the shape of 264 m p (E 910). I t was converted to the hydrochloride salt, mp 181-182'. Heating this salt (0.1 g ) with 37y0 aqueous the resulting curve was very similar to the oiie descrihed by Wilformaldehyde ( 5 drops) aiid a little HC1 in acetone ( 3 ml) 011 the son aiid Kyi26 for the decompositioii of a related AIaniiich base. steam bath for 10 min gave only unchanged material; mp and A portiori of the purified salt was converted to the hydrochloride mmp 181-1S2". This stability may be compared to that of 30B, mp 169-171" (see Table 111). the rioribridged analog (30,see below). 1 -( 3-Oxobutyl)-4-carbethoxy-4-phenylpiperidine Hydrochloride Method I. 5-13-(4-Hydroxy-4-phenylpiperidino)propionyl] (XI). A.-A portion of the crude base described in the precediiig experiment (which coiitaiiied some uiichanged p:tr:tform:tldeh!de) 10,11-dihydro-5H-dibenzo[a,d]cycloheptene Hydrochloride (16). -5-( 3-l~imethylami1iopropioiiyl)-l0,ll-dihydro-5H-dibeii~o [a,d]- was dissolved i n acetone and treated dropwise with ethereal lohepteiie (VIIb) hydrochloride was prepared as deHCI. During the addition an exothermic reaction s in aiid the t : initially formed precipitate redissolved. The mixtiire was chilled from VIIa except that the heating time was increased to 48 hr. The product, mp 177-178' (lit.I8 mp 175-176"), was and the deposited prodiict was recrystallized from acetonitrileconverted to the methiodide which could not be readily purified. ether: mu 160-161" dec, uiidepressed by the sample prepared Powdered Na&3& ( 2 . 0 g) was added to a solution of 4-phenylbelow;: A ": 258 mp ( L 3 2 2 ) . 4-piperidinol (0.53 g, 0.003 mole) in dry D l I F (1: ml) followed by And. Calcd for ClsH&1N03: C, 63.54; H, 7.71 ; C1, 10.43; the above methiodide salt (1.63 g, 0.004 mole); a strong odor of K , 4.12. Found: C, 63.90; H, i . 9 7 : C1, 10.48; 5 , 4.01. t~rimethylamine was evolved. The mixture was stirred overnight, When a sample of purijiecl base in acetoiie was treated with filtered, and added to water (100 nil). The precipitate thus ethereal HCI, only the expected hydrochloride of 1-(4,4-dipheiiylformed was collected in ether, and the solution was dried and 3-oxobnty1)-4-carbethoxy-4-phenylpiperidine (30B) was obevaporated to give 1.2 g of an amorphons solid. This was tained; mp and mmp 165-167O. converted to the hydrochloride (0.6 g), X2z 263 mp (E 826). B.-A mixture of 4-carbethoxy-4-pheiiylpiperidine hydroMethod J. l,l-Diphenyl-3-(4-hydroxy-4-phenylpiperidino)-l- chloride (10.8 g, 0.04 mole) and paraformaldehyde (2.4 g, 0.0s propanol Hydrochloride (23).-A solution of 1-(3-oxo-3-phenylmole) i i i acetoile (40 nil) aiid ethanol (15 ml) contaiiiing 5 drops propyl)-4-pheii~~1-4-piperidinol~~g, 0.025 mole) in dry T H F (7.8 of coiicentrated HC1 was heated under reflux for 10 hr. Filtra( 2 5 ml) was added dropwise to pheriyllit,hium from Li ( 2 . 2 g, tion arid evaporatiun.opthe solvent gave 13.4g (9(3yc) product, of 0.032 g-atom) and bromobenzene (24.7 g, 0.16 mole) in T H F mp 162-163" dec. 1lecrystrt.llizatioii from acetone gave a snmple, (100 ml). The reaction mixture was heated under reflux for m p 162-164" dec. For material prepared by a different roirte, 1 hr, cooled, and poured into ice-cold NHaC1 solution. ExtracProtiva, et report mp 147-1,jO'. tion of the product illto beiizene followed by removal of the Method K. 2-(4-Carbethoxy-4-phenylpiperidino)ethyl 2,2-Disolvent gave 15.0 g of a gummy solid which contained iione of the phenyl-2-ethoxyiicetate (32).-A solution of 2,2-dipheny1-2starting ketoiie. I<ecrystallization from ethyl acetate or nitroethoxyacetic acid60 (5.12 g, 0.02 mole) and 1-(2-chloroethy1)-4met,haiie-ether gave 0.8 g of material, mp 176-177", which was carbet,hoxy-4-pht:nylpiperidiiie(from 6.7 g, 0.02 mole, of the iiot the desired product. It was eventnally obtained, as the hydrochloride)61in 2-propanol (40 ml) was heated under reflux hydrochloride (1.6 g), from the mother liqiiors;: A ": 238 m P for 16 hr. The solvent was evaporated, and the residue was (E 672). shaken with NaHCOs solution and ether. Evaporatioii of the l-(3,3-Diphenyl-2-oxopropyl)-4-phenyl-4-piperidinol Hydroether gave an oil which crystallized from peiitane; mp 81-86' chloride (27).--8 mixture of 3-bromo-l,l-dipheiiyl-2-proparioiie~~ (5.0 g). Ai1 analytical sample had nip 8i-8Xa. (1.1 g, 0.004 mole) and 4.phenyl-4-piperidinol (1.3 g, 0.008 mole) in dioxane (15 ml) was stirred for 16 hr at, room temperature. Acknowledgment.-The authors wish t~othank A h . Ether (25 ml) was added, the precipitate was filtered, and the W. J. Turnbull for the microanalyses, JIrs. J. Jnchner solvent was evaporated leaving 1.3 g, mp 167-169'. This prodand Mr. 11. Boulerice for the spectral data, and A h . J. uct was dissolved in acetorie-ether and the hydrochloride (0.2 g) Pavlenyi for technical assistance. Dr. G. S. Nyers was prepared; nip 193-196", 1733 em-1 (C=O), and his staff provided several of the intermediates in - < I ( mp (E 815). l-(3,3-Diphenyl-l-oxopropyl)-4-phenyl-4-piperidinol (28).quant'ity. The filtrate from the preparation of the preceding hydrochloride (59) 11. Protiva. J. 0. Jilek. J. PomykQCeii, J. Jirkovskf. and Z. J. was evaporated and the residue was recrystallized from ethyl

Method H. 5-[3-(4-Carbethoxy-4-phenylpiperidino)propionyl]-l0,11-dihydro-5H-dibenzo[a,d]cycloheptene ( E A ) . Paraformaldehyde (1.8 g, 0.06 mole) was added to a mixture of VIIa18.5' (7.1 g, 0.03 mole) and 4-carbethoxy-4-phenylpiperidine hydrochloride (8.6 g, 0.03 mole) in l,2-dimethoxyethane (40 ml).

.,--

v:' ;:

Az %

( 5 7 ) I V e wish to thank Dr. P. 1 Petersen of Lundbeck Co., Copenhagen, ' . for a generous sample of this ketone. (58) C. L. Stevens and C. T. Lenk, J . Org. Chem., 19, 538 (1954).

Vejdelsk, Collection Czech. Chem. Commun., 28, 2627 (1963). (60) 13. Wladislav and .L AI. J. Ayers. J . O w . Chem.. 27, 281 (1962). (61) 13. Elpern, P. Carabateas. .L E. Soria, L. N. Gardner. a n d L. Grumbach, J . A m . Chem. Soc., 81, 3784 (1959).