July, 1961
O-(%PYRIDYL)-
A N D 0-(%PIPERIDYL)-PROPIONAMIDES
with that of the “abnormal” product. After two recrystallizations from ethanol, the melting point was 109-110’. The melting point was not depressed by admixture with the 1,3-diphenylisochromaneobtained previously.
3165
A n d . Calcd. for CnHisO: C, 88.08; H, 6.34. Found: 87.45; H, 6.12.
C,
CHICAGO 16, ILL.
[CONTRIBUTION FROM THE WARNER INSTITUTE FOR
RECEIVED NOVEMBER 11, 1950
THERAPEUTIC RESEARCH]
Some p- (2-Pyridy1)- and p- (&Piperidyl)-propionamides * BY FREEMAN H. MCMILLAN AND
JOHN
A. KING
Series of the substances named in the title were prepared for pharmacological evaluation of their central stimulant action. 3-(2-Pyridy1)-propanol-1was oxidized to 3-(2-pyridyl)-propionic acid which was converted to 17 amides. Eight of these were catalytically hydrogenated to the corresponding piperidyl amides.
Although the physiological actions of N,N- azolez0series. It is noteworthy that in practically diethylnicotinamide, assigned the non-proprietary all of the amides claimed to have analeptic properties name nikethamide by the Council on Pharmacy and the carboxyl group is attached directly to the heteroChemistry of the American Medical Association, cyclic nucleus; the few exceptions are a small were first reported in 1924283and this compound has number of substituted malondiamides, a few furan subsequently enjoyed considerable use in medical derivatives, a single pyridine derivative,6 and, as practice as a respiratory stimulant and analeptic, the only mention of heterocyclic substituted alkanthere has been relatively little study of its homologs, amides higher than acetamides as analeptics, a l3 analogs and isosteres. In the pyridine series series of w-(3,5-dimethylisoxazolyl)-alkanamides. amides of pyridine-2,3- and -3,4-dicarboxylic acid It seemed desirable to us to learn if this neglect of are claimed4 as analeptics, as are the amides of- N- higher alkanamides was justified and, particularly, substituted - 2,3 - dimethylpiperidine - 4,4 - di- to learn if the 3-carboxylic and -acetic amides were carboxylic and N,N-diethylpyridine-3-acet- unique in the pyridine series in their display of amide.6 Several fury1 carboxylic and acetic acid stimulant properties. In connection with other workz1which required amides5p7i8and amides of a pyranyl malonic acid5 and pyrone carboxylic a c i d ~ ~are ~ ~reported O to have the preparation of p- (2-piperidyl)-propionic acid stimulant properties. Other amides so reported dimethylamide and cyclic lactam (3-ketooctaare those of several isoxazole“-l6 and benzisox- hydropyrrocoline) it was desirable to have a ready azole” carboxylic acids, of methyl-p-( l-morphol- source of the requisite corresponding acid or its iny1)-ethylmalonic acid,5 and of nuclear car- pyridyl precursor. The most frequently mentioned boxylic acids of the pyrazole,l8 pyrazineIg and thi- synthesis of P-(2-pyridyl)-propionic acid consistsz2 * Presented before the Division of Medicinal Chemistry at the 119th of the condensation of chloral with a-picoline, folmeeting of the American Chemical Society, Cleveland, Ohio, April 9 , lowed by hydrolysis, dehydration and reduction ; 1951. this method was used by us a t the start of our work (1) “New and Nonofficial Remedies,” J. B. Lippincott Company, and, while the over-all yield of 30 to 40% was conPhiladelphia, Pa., 1950, p. 239. sidered satisfactory, the initial condensation re(2) E. S. Faust, Sckweis. med. Wochschr., 64, 229 (1924); Lancet, 108, 1336 (1925); c. A , . i 9 , 3 i i 4 ~ 9 2 5 ) . action was somewhat troublesome. Other methods (3) S. J . Thannhauser and W. Fritzel, ibid., 64, 232 (1924); C. A , , which have been described in the literature for the 19, 3114 (1925). preparation of the acid are: condensation of a(4) M. Hartmann and H. Ensslin (to Society of Chemical Industry picoline with mesoxalic ester, giving a 40% yield in Bade), U. S. Patent 2,136,502, November 15, 1938. (3) H. Martin and H. Gysin (to J. R. Geigy A.-G.), U. S. Patent of ethyl 8-(Bpyridy1)-acrylate which could be 2,447,194, Aug. 17, 1948. reduced to the p r ~ p i o n a t e ~preparation ~; of 8(6) M. Hartmann and W. Bosshard, Hciu. Chim. Acta, 34, 28E (2-pyridyl)-ethyl bromide, its metathesis with (1941). sodium cyanide, then hydrolysis to the acidz4; (7) H. Martin, W. Baumann and H. Gysin (to J. R. Geigy A.-G.), U. S. Patent 2,317,286, April 20, 1943. and the addition of hydrogen cyanide to 2-vinyl(8) J. R. Geigy A.-G. Swiss Patent 226,786; C. A . , 43, 2643 (1949). pyridine followed by hydrolysis, giving the acid in (9) H. Martin, W. Baumann, H. Zaeslin and H. Gysin ( t o J. R. 30y0over-all yield.26 Geigy A.-G.), U. S. Patent 2,364,304, Dec. 5 , 1944. Because objections were to be had to each of the (10) J. R. Geigy A.-.G. Swiss Patent 215,240. Sept. 1, 1941; C. A . , 4a, 3782 (1948). above methods, a more convenient synthesis of (11) M. Hoffer (to Hoffmann-La Roche Inc.); U. S. Patent 2,115,P- (2-pyridyl)-propionic acid was sought and was 681, April 26, 1938. found in the acid permanganate oxidation of the (12) M. Hoffer and M. Reinert, Arch. intern. gharmacodynamie, 66, 211 (1937); c. A , , sa, 1326 (1938). (13) F. Hoffmann-La Roche and Co. A,-G., German Patent 673,111, Mar. 16, 1939; C. A , , 88, 4380 (1939). (14) F. Hoffmann-La Roche and Co. A,-G., Swiss Patent 194,109, Veb. 1, 1938; C. A , , 33,7214 (1938). (15) F. Hoffmann-La Roche and Co. A.-G., Swiss Patent 194,368, Feb. 16, 1938; C. A . , 39, 7214 (1938). (16) F. Hoffmann-La Roche and Co. A,-G., Swiss Patent 215,778, NOV. 1, 1941; c. A , , 4a, 4013 (1948). (17) U. P . Basu and S. P . Dhar, J . Indian Chem. Soc., 48, 189 (1946). (18) C. Musante and P. Pino, Gas% chim. ila!., 77, 199 (1947). (19) 0. Dalmer and E. Walter (to Merck and Co., Inc.), U. S. Patent 2,149,279, March 7, 1939.
(20) H. Erlenmeyer and C. J. Morel, Hclu. Chim. A d a , 38, 362 (1945). (21) J. A. King, V. Hofmann and F. I€. McMillan, J . Org. Chem., in press. (22) (a) A. Einhorn and A. Liebrecht, Bcr., 30, 1593 (1887); (b) G. R. Clemo and G. R . Ramage, J . Chcm. SOC.,2969 (1932); (c) K. Winterfeld and F. W. Holschneider, Arch. Pkarm., 479, 192 (1939); (d) C. W. Tullock and S. M McElvain, THISJOURNAL, 61,961 (1939). 63, 2213 (23) S. M. McElvain and H G. Johnson, THISJOURNAL, (1941). (21) L. A. Walter, W. H. Hunt and R. J. Fosbinder, ibid., 68, 2771 (1941). (25) W. E. Doering and R. A. N Weil, ibid., 69, 2461 (1947).
TABLE I
fi
~ - ( % - I ' Y R I D S L ) -PROPIUSAMIDES
PxJCHrCH2COSR1R' No. 1' -11
It2
KI
-11
2 3
-CHa -CzIIs 4 -CaHi-ra 2 --CaHi-i Bd -CdHe-w 7' - 6 H 6 8 --CHzCHzOH 9 -CHaCH?NEiz 1@' --CHa 110 -CZHS 12 -CaHi-n 13 -CaH7-i 14" -C,Hu-li 15 16
Preparative Yield, methoda
.~ ~
31 p., OC.6
"C
-11
63.545
-€1
47.;-48.5
--H
132 119-121 114-11:
11111
~
H
C
S
-
'.;------~
Analyses,
CdlCd.
~ 1 ~ ' ~ ;C
if'^
122 102-104 122 154
.3
133-135 126-130
.4
1 5413
.2
1 5444
124-130
109.5-1 10 102.5-104
-H -H
1.io 113- 117 107
CHI -CnH5 -c3H7-71 421H7-i C4Hs-11
-
-CHI
B7-G9
0 .1 . 15 .I
17.06 15.72 1 5200 1.0482 14, ;I7 68.72 8 . 3 9 14.57 . l > It3157 (59, 95 8 . 8 0 1 3 . 5 8 74.31 6 . 2 4 12.38 01.83 7 . 2 6 14.42 . O B 1 ilL54 1 ,0283 16.85 .8 1 5304 1 ,0833 .I I 5152 1 . OR86 13.,58 ..I 1 5073 1.0046 11.90 1 5 1 3074 1.0101 11.90 .1 1 5009 10 68
7 5 77
-H -H
Piperidine Morpholine
17
,"
Found H
S
128-120
-H
-CaH6
1) I J
63.90 7 . 3 7 67,39 7.92
7 4 . 9 7 6.71 1.0907 1.1690 65.43 7 . 3 2
65.81 7 . 6 4 66.91 i . 7 5 68.85 7 0 . 00 74.10 61.50
8.21 8.92 6.08 7.26
16.85 15.85 14.61 14.46 13.84 12.47 14.68 16.88 13.S4
11.NI 11.67 10.$4 74.82
6.41
65.27
7.06
12.85 12.72
12.69 12.80
a See Experimental. Melting points and boiling points are uncorrected. Ref. 24; m.p. reported, 129-130'. Hy drochloride, m.p. 103-104'. Anal. Calcd. for C1pH18N20.HCl: C1, 15.09. Found: C1, 14.89. e Hydrochloride, m.p' 203-204'. Anal. Calcd. for C,dH~d?r'~o.HCi:C1. 13.50. Found: C1. 13.57. f Ref. 21. 0 Methiodide. m.u. 107.6108.5'. Am:. Calcd. for C ~ ~ H Z I I ~ \ T I,~36.45. O; 'Found: I, 36.54. h'Dihydrochloride (prepared in anhydrois ether), m.p. 72.5-73 Anal. Calcd. for
[email protected]: C1, 21 2. Found: C1, 20.4.
.
TABLE I1
8-(2-PIPERIDYL)-PRoPIoSAMIDES
ii (
x
J
~
~
2
~
~
2
~
~
~
~
1
~
?
H &TO.
K'
K?
Ygld,
A.I.p., OC."
,t
n.p.,a oc.
RIm.
I Z ~ ~ D
Analyses, % pi Calcd. Found
18 -C4Ho-n -13 51 4U-41 110-144 0. 0,; 13.19 13.23 19' -C& -H fi0 85-86 12.06 12.16 20" -CH, -CH., 31 9-9? 2 1.1042 1.0128 60 101-101i ,:j 1.4877 0.9809 13.19 13.23 21d -C?HS -CZH:, 22 -C,H,-n - C ~ H ~ - T Z71 110 .% 1.4815 0.9546 11.66 11.41 23 -C4Hg-n -C4Hp+ 6fi 116-118 .1 1.4791 10.44 10.48 24 -C& -CHa 71 131 .1 1.5393 1.0573 11.37 11.59 25 Piperidine 69 llh .13 1.5096 1.0368 12.49 12.76 a Melting points and boiling points are uncorrrctcd. Hydrochloride, m.p. 202.5". .4nal. Calcd. for C~~HZON~O.HCI : C1, 13.52. Found: C1, 13.46. Ref. 21. Methiodide, m.p. 161.5-162.5'. Anal. Calcd. for C , ~ H P ~ I N ~I,O 35.8. : Found: I, 36.0.
commercially available 3-(2-pyridyl)-propanol- 1. Although this gave us no better yield (35-5070) than other methods the ease of the one-step reaction rendered it the most desirable synthesis of the acid. With a supply of the desired pyridyl acid thus assured, we proceeded with the preparation of series of K-substituted amides, all of which are new compounds. Although the three isomeric unsubstituted pyridyl propionamides are known (2-24,3-26,4-24),none of the X-substituted substances are reported in the literature, and in the piperidine series even the N-unsubstituted 2-, :i-or &propionamides are unreported. The two iiietliods used by us for conversion of the pyridyl acid to its amides were: (1) aminolysis of an ester; and (2) thermal dehydration of a substituted ammonium salt. The reaction between methyl /3- (2-pyridy1)propionate and low-boiling aiiiines (airiirioniu, methylatnine atid the like i was satisfactory but ' 2 0 ~ I., Lraef I R I FrerIcii
