CEKTRAL N E R V O ~SYSTEM S DEPRESSANTS. T'I
May, 19G.1
(1.3 9.) was recrystallized from a methanol-acetone mixture and finally from 2-propanol, m.p. 169-170". AnaE. Calcd. for C?SH33N305: C, 65.85; H , 7.3; N, 9.22. Found: C, 65.74; H , 7.32; h',9.16. 5 4 3-Bis[2-hydroxyethyl] aminopropyl)-6,7,8,9,10,11-5Hcyclooct [blindole (IX, 7t = 6).-5-(3-Amino~ro~yl)-6,7,8,9,10,115H-~yclooct[bIindole (11.5 g., 0.045 mole) l$%s dissolved in methanol (50 ml.), and ethylene oxide (4.4 g., 0.1 mole) was added slowly. The solution \vas allowed to stand for 2 days and the solvent then distilled. The residue was transferred to a small
319
( 2 5 ml.) pear-shaped flask and distilled in U U C I I O . The product (12 g., i7.570) was an extremely viscous liquid, b.p. 245-250' (0.01 mm.), and i t was necessary to apply heat to the condenser to maintain a flow.
Acknowledgments.-The authors wish to thank Drs. ;\lelvin Gluckmali and Larry Stein for the pharmaDr. Gordon and his cO1Ogicdata Staff for miCl.oallalySeS.
Central Nervous System Depressants. VI. Polymethoxyphenyl Esters and Amides ROBERT BRUCEMOFFETT Research Laboratories, T h e U p j o h n Company, Kalamazoo, X i c h i g a n Received ,Vovember 16. 1963 A large number of esters and amides were prepared from 3,4,5-trimethoxy-, 3,4-dimethoxy-, and 3,4-niethylenedioxybenzoic, -phenylacetic, -cinnamic, and -hydrocinnamic acids (I, 11,and 111). Most of these were made by reaction of the acid chlorides with the appropriate alcohol or amine, but some involved the rearrangements shown in Chart I. The compounds generally produced central nervous system (CYS) depressant effects as shown by gross observation of intact animals and confirmed by avoidance behavior and motor activity studies.
The interesting central nervous system depressant activity found for certain di- and trimethoxyacetophenones, described in paper TT of this series,' eiicouraged us to continue the study. I n previous, somewhat related work, acids, esters, and especially amides were found t o be active depressants. Therefore a considerable number of conipouiids of the types I, 11, and I11 were prepared. COOR'
ACON(R1)2
OCH3
OCH3
I .4=single bond, -CH,-,
ACON(R1)2
I1 -CH,CH,-,
or -CH-CH-;
I11 R = H or 5-OCHB
In general the esters aiid amides were prepared from the corresponding acid chlorides by treatment with the appropriate alcohol or amiiie in the presence of a proton acceptor. In the preparation of the amides an excess of the amiiie usually served for this purpose. The preparation of several compounds involved rearrangement of oxazoline hydrohalides to N-(P1ialoethyl)amides. These in turn rearranged during hydrolysis to P-aminoethyl esters as is shown in Chart I. These findings confirm and extend the work of Fry3 mho carried out some similar rearrangements from Sbeiizoylethanolamine. It i s interesting to note that whereas the oxazoline hydrochloride 18 rearranged essentially completely to the P-chloroethylamide 16 on heating, either the corresponding oxazoliiie hydrobromide 19 or the 6-bromoethylamide 17 went to an equilibrium mixture when heated under the same
conditions. This doubtless reflects the difference between the C-C1 and C-Br bond energies. Pharmacology.-Table I lists the compounds prepared in this work with some of their central nervous system actiirities in mice and rats. A number of old compounds are included for comparison. Methodology detail3 may be found in paper T' of this series.' It may be noted that most of these compounds are depressants. This was observed in intact mice and rats during 1,oxicitystudies and confirmed by avoidance behavior studies4 aiid in some cases by motor activity tests.2 In general, the amides are more depressive than the esters and the 3,4,5-trimethoxyphenyl compounds are more active than the corresponding dimethoxy compounds. The methoxybenzamides and cinnamides are better than the phenylacetamides or hydrocinnaniides. It seems that small substituents, for example hydrogen, niethyl or allyl, on the amide nitrogen are desirable. Larger radicals, especially those containing functional groups, decrease the depressant activity. Experimental5 1-Methyl-4-piperidyl 3,4,5-Trimethoxyben~oate~ [2 (base)].A solution of 23.0 g. (0.1 mole) of 3,4,5-trimethoxybenzoyl chloride and 23.0 g. (0.2 mole) of X-methyl-4-hydroxypiperidinein 300 ml. of benzene was heated under reflux for 2 hr. A white solid separated and after cooling the mixture was extracted a i t h cold dilute hydrochloric acid. The free base was liberated with sodium hydroxide and extracted with ether. Bfter washing with vater and saturated sodium chloride, the ether solution was dried over sodium sulfate, filtered, and evaporated. The
(4) T o be reported b y D r . D. G . Anger, The Upjolin Co., Kalaniazoo,
hlich.
(1) R. I3 hloffett, A . R. Hanze, and 1'. 11. Seay, J . M c d . Chern., 7 , 178 (1964). (2) R. 13. Moffett, P. Ii. Seay, and . ' ; 1 13. Reid, iliid.. a , 17!1 (1960). (3) E. Ar. Fry, J . 01.0. ~ h e r n . .14, 887 ( I Y U ) .
(.5) .\felting points were taken in capillary tubes with a partial immersion thermometer. ('alibration of the apparatus against standard compounds slioued no need for correction. Infrared spectra were obtained on all pure compounds and unless otherwise noted were in accordance n i t h the yroposed structures. (6) Prepared by Dr. R. P. IIolysz in these laboratories.
\
1:"
101l
2iHl
12
>IO00
i3
3Ol1
I4
--s
IO0
0
I ,j"
I ii
I7 18
I0(i1'
I !J
.i-OC€€+
> 1000 > IO00
IO0
32 1
CENTRAL NERVOCS SYSTEM DEPRESSANTS. VI
May, 1964
DepresMouse L D K Q , ~ sion,
R'
KO.
A
mg./kg.
nig./kg.
28
CH3
...
>1000
-
29
CH3
...
650
-
30
CH3
...
650
-
31
CH3
...
>1000
-
...
1000
-
...
>1000 >1000
32 33 34 35'" 36 37
3s"'
650
CH3
- -CH&H:CH2 H CHI
I . .
...
650 230
...
-CH,
... ...
39 41 42
- -CH,--CHg-CHz-
43
-CHz-
44"J 45" 4GPs' 47" 48"
-CH=CH-CH=CH-CH=CH-CH=CH--CH=CH-
49
-CH=CH
50P
-CH=CH-
51
-CH=CH-
52" 53 54t 55 56 57' 5SM 59" 60" 61' 62 63" 64 65
-CH=CH-CH=CH-CH=CH-CH=CH-CH=CH-CH*CH*-CH&H*-CHZCH*-CHzCHr-CH(CHa)CHz.--CH(CHs)CHz-CH(CHa)CH*-CH( CH3)CHr-C(CHs)=CH--
40"
0-R=H CH3 CH3 CH3 -CH*-
-CH*-
>1000 >1000 -N
n 0
U
SH* -NHCHZ --N(CH3)2 -NH( CHz)aCH3 --SHCHzCH=CHz
--N
1000 650
300 200 100
>1000
300
1000 650 750 1000 1000
loo* 300 100
650
100
560
-
650
100 300 30 300 300 200
n 0
do NH
U
-NH-CsHs *"K Hz --NHCHaCH=CH* -SH2 -N( CH3)2 --?U"CH( CH,)CH*OH --P\"C( CH,)*CH*OH --NHCH( CH?CH,)CHzOH -OH -0CHzCH3 -NHz -COR'"=-CHzSHz.HCI -0CH2CH3
loo* 100
> > >1000
W
-N
l00J -1 100 100
>1000 500 760 1000 1000 6-50
> >
-
-
-CH*30" 1000 CH3 CH3 iio 100" CH3 CH3 1000 10og CHI CH3 200 CH3 CH3 1000 300 CH3 CH3 a Compounds were administered t o mice intraperitoneally. The values (mg./kg. ) are approximations with an accuracy of about Mice (or rats) were observed during the toxicity tests (footnote a ) . The lowest dose a t which significant de+loo%, to -507,. pression was noted in mice is recorded in this column. Depression a t doses greater than 40c/, of the LDw is not considered significant and is indicated as negative ( -). For the most part the rat toxicity studies were not carried to doses as low as 40YGof the LD, but in cases where depression was noted a t such a dose i t is recorded in footnotes. Any ot,her significant effect,s on the C S S which were obSee footnote 7. See footnote 6. e Available commercially but included for cumserved are also noted in footnotes in this column. See foot'note 11. parison. !R. B. Moffett, U. S. Patent 3,036,128 (1962). Sleep in rats a t 500 mg./kg. (705; of the rat LD,,). * Trioxazine, see L. Vargha, E. Kasztreiner, J. Borsy, L. Farkas, J. Kuszmann, and B. Dumbovich, Biochem. Pharmacol., 11, 639 (1962); J. Borsy, M. Feketa, and Zs. Csizmedia, Acta. Physiol. Acad. Sci. Hung., 19, 27 (1961). j Sleep in mice a t 370 mg./kg. and in rats a t 500 mg./kg. Extreme depression in rats a t 250 mg./kg. (50% of the rat LDjo). Motor activity of mice 50% decrease See footnote 13. This a t 60 mg./kg. IC See Table 11, footnote gg. Depression in rats a t 100 mg./kg ( < l o % of the rat LDbo). amide has been prepared by several workers by a Wolff rearrangement [for example by G. P. Schiemenz and H. Engelhard, Chem. Her., 92, 1336 (1959)]. We prepared i t via the acid chloride and ammonia from the commercially available (Aldrich Chem. Co.) 3,4,5-triG. P. Schiemenz and H. Engelhard, Chem. Ber., 93, 1751 (1960). * C. M . Hofmann, methoxyphenylacetic acid, m.p. 124-125'. Motor activity of mice 507, Union of South Africa Patent Spec. 4314 (1960); Brit. Patent 906,319 (1962). KOanalysis is given. decrease a t 30 mg./kg. ' See footnote 14. K. W. Gopinat'h, Mot,or activity of mice 99% decrease at, 100 mg./kg. Depression in rats at 325 mg./kg. ( 3 Govindachari, K. Nagarajan, and K. K. Purushothaman, J . Chem. Soc., 1144 (1957). ?,rotor activity of mice 50% decrease the rat LD.5,). " See foot,note 15. (' Motor activity of mice 50% decrease a t 50 mg./kg. a t 150 mg./kg. Motor activity of mice 50% decrease a t 300 mg./kg.
> >
\
resulting solid \vas recrystallized from 130 1111. of metliylcycloIiexane giving 23.8 g. of nearly wliite rrystals, m.p. 83-85".? Hydrochloridefi (2).-A sctlutirrn of 23.5 g. (0.076 mole) of t h e free base in 300 nil. of ethyl acetate \\-as acidified with etliariolica hydrogen chloride. The white cryst:& \\-ere collected and dried: \\eight 23.24 g., m.p. 225" der. This \vas recrystallized from 225 nil. of ?-propanol containing 20 ml. of methanol giving 20.8 g. of \\)lite crystals, m.p. 2:3:3-234' dec. P:ilazzir! ~t d . , 7 report,
01
T
liour, suiiicient v\.ater was :tdded t o tiissiilve tlie inurg:inic s:ilts. The ether layer \vas separated, dried, and the solvent WLS removed. The oily product was distilled under reduced pressure g. of product, k1.p. 121" (6.0 mrn.). A saniple w:is further purified by careful redistillation, b.p. 140" (15 mni.). .lnal. Calcd. for CliH,vNOS: C, 61.92; H, 8.08; S , 6.57; S , 15.03. Found: C, 62.39; H, 8 . Z ; N,6.22; S, 14.80. 3,4,5-Trimethoxybenzoate Ester of l-(Z-Thieny1)-3-diethylt11.p. "30". amino-2-propanol Hydrochloride (6).--A solution of 23 g. (0.1 inole) of 3,4,5-triniethosybcnzoyl chloride, and 21.3 g. (0.1 mole) Methobromide8 (3).-Tii ii [*oldberizerie solution C J crude ~ frw II:ISC(from 0.06 nio!e of 3,4,5-tririiethi~syl~enz:oyl (,kiloride) v-:is in 100 ml. of benzenv of l-(ry-tliieii?-l)-3-diethylariiino-2-propanol added 20 nil. of cold niethyl brcrniide. After standing for 3 days, \\-as heated under reflux for 0.5 hr. and allowed to stand for 6 days. 100 nil. of ether !vas added and the crystalline qwtternnry salt Tlie mixture n-as poured into ice-\\-:iter and acidified x i t h hydrirchloric acid. The resulting crystalline solid was collected, washed \\:IS cctllec,ted. After 3 c:rystallizatioIis from methanol, 9.4 g. iritli water and benzene, dried, and recrystallized from methanol, of ivliite crystals \\-as obtained, 11i.p.237.5-238'. ni.p. 156-158'. This \\-as s l i o ~ v n ,by romparison of its infrared I-Phenethyl-4-piperidyl 3,4,5-Trimethoxybenzoate Hydrospectrum with that of 1111autlientic sample, to he 3,4,5-trirnethoxychloridefi (4).-A solution of 13.84 g. (0.06 mole) of 3,4,5-triniet,hosyltenzoyl chloride in 40 nil. of toluene u;as added drop\\-isc Itenzoic anhydride. IXlution of the niethanolic fi1trat.ewith ether during 3 lir. t o a solution of 10.26 g. of 1-phenetliyl-4-piperidiriol g:tve 1 4 3 g. of the desired ester hydrochloride. The aqueous in 40 nil. of anhydrous pyridine. The mixture \vas stirred for solution \viis sep:rrated, wished with benzene, and made basic: with IS lir., and diluted w-itli 300 ml. of toluene and 10 ml. of x i t e r . sodium hydroxide. Tlie oily free base was extracted \Tit11 ether, T h e niisture \vas mxslied ivith dilute sodiuiii hydroxide solutioii \vashed with water, ; i d dried over sodium sulfate. Aftor fi1tr:t:(rid wat,er. Tlie toluene solution w i e filtered and evaporated t i t tion tlic ether solution of the free Imse was aridified with etlidryncw under reduced pressure leaving lS.5 g . of red oil. This :uiolic Ilydrogen clilriride. Tlic resulting Irydrochloride s l ~ \ v l y h e \vas dissolved in 30 i d . of :tbsohite etlianol, decolorized carystallized and n-as rerrystallizcd from 75 ml. of 2-propanol givwit11 activated charcoal, and 10 nil. of concentrated Iiydroc~liloric ing :in additional 9.8 g. of ester Iiydrocliloride, ni.p. 160--162.5". :wid and 50 nil. of et,her were added. Refrigeration of the soluticin General Method for the Preparation of Amides.-To ii solutioii ( i f 0.2 mole of the acid chloride in a niisture of absolute ether :inti yielded 16.30 g. of cryst&, I I I . ~ .222-223". I)enzene was :idded shJ\Vl>-, n-ith stirring, a solution of 0.4 niolo of Methobromide6 ( F i ) . - h ether solution of frer Ituse Eroiii 5 p. of the hydrochloride ( 4 ) was c~mledto 0" iind 20 nil. of ( ~ ~ 1 d the requisite amine in the smie solvents. The misture I)ecanic. \\arm and usually reached reflux, and :I solid separated. -4ftcr nicthyl I>romide \\.:IS added. The solution n x s :iIlo\ved to st:rntl stirring for :in additionnl 2 hr. icewater was :idded, and t,he for scvrral d:~ysand the resulting white solid \vas cwl1ec.te.d. This mixture \\-as acidified with hydrochloric acid. If solid aniide \v:ts rerryst:illized f r o m :t niistrire o f niet.hano1 and et,her yielding reniained insoluble in both layers it was collected, washed wit 11 5 g. of the qunterniLry salt, 1ii.p. 226-227" tie(*. 1-(2-ThienyI)-3-diethylamino-2-propanol.q-2-T1-lic~iyllithiu~~iYcold dilute sodium carbonate solution, water, and ether, and re\VAS prepitred in :t 22-1. flask froni 200 g , of lithium, 1360 g. of lrutyl i-rystallized from the solvent indicated in Table 11. If the aniitlc n-as appreciably soluhle, it was extr:rcted from the aqueous soluIrroiriide, S40 g . o f thiophene, m d S 1. of alisolute ether. To this sirlut ion ivits added slon-ly, a t reflus, 1040 g. of 3-dieth~1:imirio-1,2tion lvith etlier, wished with cold dilute podium carbonzite soluc'poxypropane.'o After stirring under reflux for an additionxl tion, water, and saturated sodium chloride. After drying ovcr nodiurn sulfate, filtering, and removing the solvent, the residue \vas cryst,allized from the indicated solvctnt. 2-(3,4,5-Trimethoxyphenyl)-oxazoline Hydrochloride (la).--To 100 nil, of thionyl chloride nxs added portioiiwise at, 5-7" iiiiritig 1 5 iiiin. 25.5 g. 10.1 niole) of S-(P-]iydrosyethy1)-3,4,5t riiiicthcisyl,enn;iii(li!.~~ After stirriiig the solution for 2 hr. :it
CENTRAL SERVOUS SYSTEM DEPRESSANTS. VI
Vay, 1964
323
TABLEI1 CHEMICAL PROPERTIES No. from Table I 1 Ze*f base 2etf 3f 41
5f 6 8CC
9 10 11 12 13 14 16 17 18 19 20 21 22 23 24 26 27 28 29 30 31 32 33 34 35 36 37 3811
39 41
42 43 4.5' 46S.P 475 48' 49 5ns 51
525 53 55 66
57u 5811
59ff 601f 62 64 65
Yield,a
%
M . P . . 0C.b
56'
166.5-168.5 83-85 233-234 237.5-238 222-223 226-227 (dec.) 160.5-162.5 123.5-126 134-136 101-102 78-80 147-149 67-69 66-69 132-134.5 160-162.5 135.5-137.5 162.5-165 137-139 139-141 115-1 1 7 . 5 173-177 126-1 2 8 . 5 100-103
770 80' 39c 7 5' 89C 56'
96 81 83 941
68 68" 58* 84' 52C 82C 6ZC 32' 92' 86 43c 68 89 94bb
...
189-19 1 138-140 62.5-64. 5 170-171 243-245,s c 182.5-1 84 85C.U 159-161 181-11(3 . Y o 120.5-122 7OU 99-100 74" C 94-95.5 232-233 82% 73-75 58" 45 81 , 5 8 3 104..i-106 82 120-123 7 8 ' ~ ~ 125.5-127 6su 153-154.5 8C 100" 148-150 162-163.5 49u 132-133.5 64'' 56% 169-171 53" 128-130.5 71'8" 183-185 131-133 92" 172-1 74 44u 86-87 92C 111-113 50' sU 81-83 28'*" 38C'U 81-83 63' 197.5-199.5 33c 55. 5-il7.5 60' 40' 90 66 68 74c
...
Crystallizing solvent z-PrOH hfeCsH11° a-PrOH MeOH EtOH EtnO MeOH Et20 z-PrOH EtOH z-PrOH z-PrOH h\IeC6H11!' C&I" E-PrOH C;Hisee RfeCsHllQ
+ +
+
BuOH C6H6 RIeOH EtOH z-PrOH z-PrOH Et90 Cs€lizaa EtOAc EtOH MeOH CEH~Z"~
+ +
z-PrOH z-PrOH CsHirQ EtOIc DhIFr EtOH FtOH hIeOH a-PrOH RIeOH a-PrOH EtOAc NPOH Et0.h Et04c z-PrOH CtOAc C'5Hlaq iLleC04Ie EtOH hIeOH z-PrOH a-PrOH
+
+
H.0 EtOH a-PrOH MeOH hleOH
nieconie
EtOAc EtOAc EtOAc a-PrO€I a-PrOH
+ C6H1ai
Carbon, 70 Calcd. Found
Calcd.
Found
49.40 62.12 55.550.50 63.36 58.30 56.81 62.14 63.38 63.38 65 95 64.96 68.12 fi8.44 52.65 4 5 . 30 52.66 45.30 52.74 47.75 58.70 53.72 62.12 62.12 62.12 57.13 61.85 69.70 62.21 61.62 52.84 60.75 54.82 65.14 64.38 61.64 61.52 63.38 66.36 63.38 62.14 63.39 6.5.51 64.R6 67.31 62.52 59.99 68.99 59.18 67.99 63.75 62.90 62.13 63.38
49.29 61.70 55.43 50.48 63.20 57.63 56.77 62.31 63,43 63.74 60.00 65.19 68.10 68.52 52. 50 45.75 52.83 46.57 53.17 47.47 58.69 53,70 62.29 62.28 62.28 56,91 61.73 69.70 62.49 62.01 53.11 60.78 54.91 65.13 64.59 60.67 61.69 63,23 66.24 63.13 62.40 63.44 65,61 65.07 67.37 62.84 59.61 69.16 59.43 67.87 64.02 63.10 62.19 63.37
6.22 7.49 6.99 6.48 6.94 6.52 6.81 6.82 7.22 7.22 7.27 6.91 7.31 8.16 5.89 5.07 5.89 5.07 7.27 6.68 7.70 6.01 7.49 7.49 7.49 6.17 5.88 6.47 6.10 5.17 5.76 6.37 5.62 6.83 5.40 7.56 6.71 7.22 7.28 7.22 6.82 7.22 7.90 6.91 6.98 6.88 6.29 6.11 5.87 6.93 6.32 7.92 6.82 7.22
6.20 7.20 7.11 6.13 6.95 6.71 6.45 6.67 6.83 7 16 7.3.3 7,22 6.98 8 02 5 . 8.4 4.99 5.83 5.00 7.10 6.63 7.70 5.74 7.30 7.42 7.79 6.00 5.72 6.54 6.22
66.64 58.64 64.27
66.71 59.07 64.27
7.09 8.20 7.19
7.78 8.32 6.86
4.Y5
3.56 6 46 5.82 6 56 5.15 7.43 6.72 6.95 7.21 7.09 6.66 7.00 7.65 7.01 6.93 6.74 6.28 5.99 5.99 6.63 6.33 7.75 6.88 7.60
Nitrogen, % Found Calcd. 4.80 4.53 4.05 3.46 3.21 2.83 3.16 5 . *57 5.28 5.28 4.81 5.05 4.41 4.20 5.12 4.40 5.12
7.10 6.33 6.83 5.53 7.18 5.28 5.95 5.28 5.57 5.28 4.78 5.05 4.62 4.56 8.75 4.47 6.28 5.66 6.76 5.24 5.58 5.28 5,28
4.86 4.63 3.95 3.20 3.16 3.25 3.16 5.51 5.16 5.40 4.92 4.99 4.47 4.27 5.29 4.28 5.00 4.27 8.70 7.32 4.25 10.29 4.67 4.57 4.58 9.50 5.00 4.21 3.75 4.30 6.02 6.01 7.10 6.62 6.81 5.39 7.08 5.50 6.03 5.09 5 72 5.50 4.93 4.81 4.64 4.64 8.86 4.71 5.99 5.68 6.64 5.36 5.46 5.38 5.03
5.70
5,99
4.40
8 79 7.43 4.28 10.44 4.53 4.53 4.53 9 52 4.81 4.28 4.03 4 23 6.16 5,YO
...
...
...
...
Unless otherwise indicated the amides in this Table were prepared by the general method described in the Experimental section. Yields are based on the starting acid chloride and are calculated for material melting not less than 2" below the highest melting point See experimental section for specific preparation of this compound. Anal. Calcd.: C1, 12.15; 0, obtained. * See footnote 5 . 27.42. Found: C1, 12.14; 0 , 26.22. e See footnote 7. 1 See footnote 6. hleC6H11 = methylcyclohexane. Anal. Calcd.: C1 Anal. Calcd.: Br, 19.77. Found: Br, 19.31. Anal. Calcd.: C1, 8.13. Found: C1, 8.07. 10.25. Found: C1, 10.34. Anal. Calcd.: Br, 16.16. Found: Br, 16.40. Anal. Calcd.: C1, 7.99; S, 7.22. Found: C1, 8.10 S, 7.26. llZ Anal. Calcd.: C1, 12.95; 0, 23.88. Found: C1, 13.14; 0, 22.88. Anal. Calcd.: Br, 25.12; 0, 20.11. Found: Br, 25.41; 0, 19.83. rlnal. Calcd.: C1, 14.43. Found: C1, 14.22 Extracted from the aqueous solution with chloroform. The product was repeatedly fractionally crystallized from methylcyclohexane. C6H14 = petroleum hexane (Skellysolve B). ' D N F = See Table I, footnote p . dimethylformamide. Extracted from the aqueous solution with chloroform and benzene. The acid chloride was prepared from the corresponding acid and thionyl chloride and was used without purification. The yield is calculated from the starting acid. See footnote 14. Anal. Calcd.: C1, 12.95; 0, 23.38. Found: C1, 12.65; 0, 23.64. Anal. Calcd.: Br, 25.12; 0, 20.11. Found: Br, 25.03; 0, 19.04. YAnal. Calcd.: C1, 11.12; 0, 20.08. Found: C1, 11.22; 0, 20.18. ZAnal: Calcd.: Br, 21.18. Found: Br, 21.02. a a C6H12 = cyclohexane. bb This product failed to crystallize and was distilled in ashortpath distillation apparatus a t 170" (bath temp.) (0.02 mm.) giving a 9470 yield of colorless gum. cc See Table I, footnotef. d d Extracted from the aqueous solution with ether and then with methylene chloride. After removing the solvent the residue was dissolved in benzene and passed through a column of 250 g. of acid-washed alumina which was eluted with more benzene. The solvent was retnoved and the product crystallized from heptane. B e CiH1, = petroleum heptane (Skellysolve C). 11 See footnote 13. 0~ Commerical syringamide was obtained from Aldrich Chemical Co. Inc., Milwaukee, Wis. A sample was sublimed a t 170" (bath, 0.01 mm.) giving white solid which was crystallized from 2-propanol. hh Anal. Calcd.: S , 14.11. Found: S, 14.02. 5
May, 1964
CEXTRAL SERVOUS S Y ~ T EDEPRESSASTS. M VI
with pentane and water giving 16.7 g. of white solid, m.p. 159161'. This was recrystallized from 150 ml. of methanol yielding 11.6 g. of solid, m.p. 159-161". N- [ (1-Hydroxymethyl)propyl]-3,5-dimethoxybenzamide13 (38).-A mixture of 3.83 g. (0.0182 mole) of ethyl 3,5-dimethoxybenzoate and 1.61 g. (0.0182 mole) of 2-aminobutanol was heated under reflux for 5 hr., cooled, and extracted with hexane. Warming t'he lower layer renioved solvent and caused it to crystallize yielding 2.5 g. of tan solid. Four recrystallizations from ethyl acetate gave colorless needles, m.p. 94-05.5'. 4-Hydroxy-3,5-dimethoxycinnamamide (53).-A mixture of 20.0 g. (0.089 mole) of 3,5-dimethoxy-4-hydroxycinnamic acid, 1 g. of sodium :wetate, and 150 nil. of acetic anhydride \vas imrnicd slightly to effect solution and allowed to stand overnight. The excess acetic anhydrid,e was distilled under reduced preesure on a ste:ini bath. The oily residue was diluted with 50 nil. of i)cxnzene and 50 nil. of thionyl chloride \vas added. The mixture was stirred under reflux for 2 hr. and the solvent \ws renioved under reduced pressure. Tlie resulting solid was suspended in absolute etlier and :tniniiiniiL gas \\:is pnssed in with stirring f o r 3 Iir. After standing overnight, the tliivk niixture \vas sltaken lvitli xi-ater :ind filtered. Tlie solid \vas well \\aslied xvitti M-ater and ether, and dried, giving 20.85 g. crude l-acetoxy-:i,;i-ciinietlioxyt~erixamide,ni.p. 151-185". Tttis was Iiydrolyxed a-itli dilute :tqueous sodium liydrcrxide at about S5" for 15 niin. The solution \\-asfiltered, acidified, and cirnrent,rated,giving crystalline solid. After recrystallixatiori froin 2-propand there was obtained 14 g. of light, tan cq-stals, ni.p. 183-186'. N,N-Dimethyl-3,4,5-trimetho~yhydrocinnamamide~~ (57).-A solution of 10.3 g. of K,N-dimethyl-3,4,5-trimetho amide in 100 nil. of methanol was hydrogenated Tvith 0.5 g. of 5% palladiurn-on-cliarcoal a t 3.5 kg./cma2 pressure and room teniperature. In 40 min. about the theoretical amount of hydrogen was taken up. -4fter filtration and evaporation, the oily residue was crystallized from ether-hexane giving 9.53 g. of colorless prisms, m.p. 85.9-87.2'. Recrystallization from acetonehexane gave large colorless prisms, m.p. 86.5-87.2". 3,4-Dimethoxyphenylacetyl Chloride.--A solution of 160.8 g. (0.86 mole) of 3,4-dimethoxyphenylacetic acid, and 146 ml. (2.0 moles) of thionyl chloride, in 11. of benzene, \vas heated under reflux n.ith stirring for 6 hr. The solvent n'as removed and the product was distilled giving 82.7 g. (45%) of liquid, b.p. 124' (0.05 nini.). N-( 2-Hydroxy-2-propyl)-3,4-methylenedioxyhydrocinnamamide13 (58).-A solution of 20.8 g. (0.1 mole) of methyl 3,4niethylenedioxyhydrocinnamate and 7.5 g. (0.1 mole) of 2aminopropanol was heated under reflux for 3 hr., cooled, and extracted with hexane. The lower layer was warmed to remove solvent and on cooling it crystallized. This material was recrystallized t,wice from ethyl acetate giving 10 g. of colorless crystals, m.p. 111-113'. N- [ (2-Hydroxy-1 -( 2-methyl)propyl]-3,4-methylenedioxyhydrocinnamamide13 (59).-This was prepared from 20.8 g. (0.1 mole) of methyl 3,4-methylenedioxyhydrocinnamateand 8.9 g. (0.1 mole) of 2-amino-2-methylpropanol. Recrystallization from ethyl acetate yielded 7.5 g. of colorless crystals, m.p. 81-93'. (13) Prepared b y Dr. 11. 1;. Zienty i n these lahoraturies. (14) Prepared h y Dr. Gilbert A. Youngdale in these laboratorieb
325
N- [( 1-Hydroxymethyl)-2-propyl] -3,4-methylenedioxyhydrocinnamamide13 (go).-This was prepared from 20.8 g. (0.1 mole) of methyl 3,4-methylenedioxyhydrocinnamate and 8.9 g. (0.1 mole) of 2-aminobutanol. Recrystallization from ethyl acetate gave 10 g. of product, m.p. 76-79". Aft,er two more recrystallizations from ethyl acetate colorless material was obtained, m.p. 81-83". Ethyl p-(3,4-Dimethoxyphenyl)butyrate (62).-.4 mixture of 11.8 g. (0.052 mole) of p-(3,4-dimethoxyphenyl)butyric acid,Is 73 ml. (1 mole) of thionyl chloride, and 100 nil. of benzene was heated under reflus for 5 hr. and the solvent was distilled under reduced pressure. This crude acid rhloride was dissolved in 50 ml. of benzene and 100 nil. of absolute ethanol and 5.7 nil. of pyridine \+-ereadded. After boiling for 15 min. the solution was evaporated under reduced pressure. The oil was mixed with ether and Jvashed with dilute liydrocliloric arid, water, dilute sodium hydroxide, ivater, and saturated salt solution. After drying over sodium sulfate and distilling the solvent, the product was distilled twice t,lirougli a short column giving 8.27 g. of colorless liquid, b.p. 107" (0.008 inin.); nY5l)I.50T8. 3-(3,4-Dimethoxyphenyl)butylamineHydrochloride (64).k'roin L: Soxhlet extr:trtcrr, 9.9 g. (0.045 mole) of p-(3,4-dimethoxyp h e r i y l ) t ~ ~ i t y r : ~ r u W:IS i d e ~reduced ~ with 3.S g. (0.1 mole) of lithium aluniinurii hydride iri 300 nil. of :thsolutc ether. After extracting for 2 1 lir. there n-ere cilrefully added in suwession 10 nil. of ethyl acetate, 4 nil. of water, 3 nil. of 'LO'/c scidiutn hydroxide, and 14 nil. of water. After thorough mixing the solution was filtered and the solid ~vasliedwith ether. The ether solution was extracted with dilute hydrochloric acid which was washed with ether and made basic XTith sodium hydroxide. The free base was extracted with ether, washed with saturated salt solution, and dried. After removal of the solvent an oil remained which was taken up in absolute ether, and acidified with ethanolic hydrogen chloride. The white solid hydrochloride was cdlected and recrystallized from 2-propanol yielding 3.04 g. of white crystals, n1.p. 197.5-199.5'. An additional 0.62 g. was obtained from the filtrates. Ethyl 3,4,5-Trimethoxy-p-methylcinnamate(65).-A mixture of 53.1 g. (0.253 mole) of 3,4,5-trimethoxyacetophenone, 50 g. (0.3 mole) of ethyl bromoacetate, 280 ml. of benzene, and 20 g. of zinc t,urnings was heated under reflux R.ith stirring for 2 hr. The solution \%-asdecanted from unchanged zinc and shaken with 14 ml. of concentrated sulfuric acid in 100 ml. of iyater. The benzene layer \vas separated, well washed with water, and dried over sodium sulfate. After filtration and removal of the solvent, the product was distilled giving 60.8 g. of crystalline solid, b.p. 134" (0.05 mm.). This was recrystallized from 2propanol yielding 42.5 g. of nearly white crystals, m.p. 55.557.5O.
Acknowledgments.-The author wishes to thank the following people who contributed to this work: our Department of Physical and Aiialytical Chemistry for analytical and spectral data; Dr. P. H. Seay, A h . Wm. T'eldkamp, and associates for biological data; Dr. R. V. Heiiizelmaii for guidance; and Mr. It. F. Tripp for technical assistance. (1.3 E. H. JToodruff, J . Am. Chem. Soc., 64, 285Y (1942)
