AMINOETHYL ESTERSOF SUBSTITUTED GLYCOLIC AND ACETICACIDS
March 20, 1955
TABLE I11 (Continued)
No. of
base (Table 1)
1565
Yield,
%"
Salt
Crystallizing solvent
M.p., "C.b
Empirical formula
Halogen, % Found Calcd.
Br, 19.98 ClgHssBrNO~ Br, 20.47 19 CHaBr 75 181-183 Benzene C1. 9.29 20 HC1 65 120-132 C22Ha2ClN02 C1, 9 . 3 5 EtOAc C1, 10.25 21 HC1 56 153-154 CigH36ClN02 C1, 10.23 EtOAc C1, 8.89 81 148.5-150 CzaHa4ClNOz C1, 9.05 22 HC1 MeEtCO EtOAc Br, 17.99 Benzene C Z ~ H S ~ B ~ NBr, O ~17.74 ~ 22 CHzBr 52 164-166 C1, 9.32 23 HCl 73 153-156.5 Cz2Hs~ClN02 C1, 9.38 Me-i-BuCO C1, 9.48 25 HCl 83 108-112 CzzHs2ClNOz C1, 9.38 EtOAc c1, 10.19 26 HCl 41 95-97.5 CigHa6Cl~0~ c1, 10.02 EtOAc Et20 C1, 8.92 Cz3HarClNO2 C1, 9 . 0 5 27 HC1 75 138-140 EtOAc C1, 9.25 28 HCl 91 137-138 CzzHs6ClNO2 C1, 9.28 EtOAc C1, 9.34 86 140-141 C22Ha2ClN02 C1, 9.38 29 HCl EtOAc C1, 10.10 89 145.5-146.5 Cl~H&lN02 C1, 10.02 30 HCl MeEtCO 4-EtOAc C1, 9.38 MeEtCO C22H3zClN02 C1, 9.38 31 HCl 76 146.5-149 C1, 9.70 81 120-125 EtOAc C2iH30ClN02 C1, 9.74 32 HCl C1, 9.56 MeEtCO CziH32ClN02 C1, 9.69 33 HCl 62 138-144 C1, 10.68 C1, 10.59 34 HC1 81 96.5-98.5 EtOAc Et20 CisHa4ClNOz C1, 9.35 C1, 9.37 Me2CO CzzHazCliYO~ 35 HCl 73 165-167 C1, 10.23 Cl, 10.23 21 148-150 EtOAc Ci&~ClN02 36 HCl C1, C1, 9.75 55 109-112 Tetrahydrofuran 4- C ~ H U CZOH~SC~NO ~ ~ 9.85 37 HCI The yields of the quaternary salts 0 The yields of the hydrochlorides are based on the distilled free bases (Table 11). are based on the pure hydrochlorides. * Melting points are uncorrected. See footnote b Table 11. Calcd.: C, 62.55; H , 7.64; N, 3.32. Found: C, 62.42; H , 7.87; N, 3.58. * Calcd.: C, 61.76; H, 7.40; N, 3.43. Found: C, 61.47; H, Calcd.: C, 57.44; H, 9.11; 7.66; N, 3.44. f Calcd.: C,62.55; H,7.64; N, 3.32. Found: C, 61.83; H, 7.17; N, 3.32. N, 3.72. Found: C, 56.96; H, 9.09; N, 3.67. Calcd.: C, 62.55; H, 7.64; N, 3.32. Found: C, 62.74; H, 7.70; N, 3.51. i Calcd.: C, 63.29; H, 7.85; N, 3.21. Found: C, 63.47; H, 8.00; N, 3.40. i Calcd.: C, 62.25; H, 8.07; N, 3.30. This Calcd.: C, 58.15; H, 9.76; N,3.57. Found: C, 57.99; H, 9.59; N, 3.51. Found: C, 62.17; H, 7.87; N, 3.44. compound was prepared by the low pressure hydrogenation of free base No. 14 (Table 11)with PtOz catalyst. The reduced free base was not isolated but was converted t o its hydrochloride. Calcd.: C, 63.29; H, 7.85; N, 3.21. Found: C, 63.35; H, 7.69; N, 2.99. Calcd.: C, 62.55; H, 7.64; N, 3.32. Found: C, 62.07; H , 7.57; N, 3.34. Calcd.: C, 58.43; H, 9.30; N, 3.59. Found: C, 58.39; H, 9.51; N, 3.75. p Calcd.: C, 63.99; H, 8.06; N, 3.11. Found: C, 64.17; Calcd.: N, 3.89. Found: N, 3.91. H, 7.84; N, 3.32.
+
+
+
Q
ester in 94 ml. (1.0 mole) of isopropyl bromide was heated in a bomb a t 100' for 24 hours. Addition of ether to the reaction mixture caused the separation of 15 g. (36%) of crude quaternary salt. This was recrystallized from ethyl
[CONTRIBUTION FROM
THE
acetate giving a product with the properties of the first compound in Table 111. KALAMAZOO, MICHIGAN
RESEARCH LABORATORIES O F THE UPJOHN COMPANY]
Antispasmodics. VII. Aminoethyl Esters of Substituted Glycolic and Acetic Acids BY ROBERT BRUCEMOFFETT,JOHN L. WHITE,BROOKED. ASPERGREN AND FRANK E. VISSCHER RECEIVED OCTOBER 27, 1954 A series of tertiary aminoethyl esters of a-substituted mandelic acids has been prepared. Also disubstituted acetic acid esters have been made from hexamethyleneaminoethanol and from several methyl substituted piperidinoethanols. Most of these compounds were less active as antispasmodic or gastric antisecretory agents than those previously reported, but a few have interesting biological properties.
For many years it has been known that aminoalkyl esters of benzilic acid are very active antispasmodics.' However their toxicity is usually high. The report by Blicke and Tsao2of a remarkably active series of esters of thienylglycolic acids kindled renewed interest in basic esters of a-hydroxy acids and a number have been reported recently. Since we have found that pyrrolidyl, and methyl substituted pyrrolidyl, ethyl esters of disubstituted acetic acids are good antispasmodic and gastric antisecretory agents3 it seemed desirable to prepare some substituted glycolic esters of some of these (1) R.Fromherz, Arch. e x p l l . Path. P ~ Q Y ~ Q 178, ~ 86 o ~(1933). . , (2) F. F. Blicke and M. U.Tsao, THISJOURNAL, 66, 1645 (1944). (3) R. B. Moffett, J. L. White, R. D. Aspergren and F. E. Visscher, i b i d . . 77 1562 (1955). and preceding papers.
amino alcohols. These basic esters were obtained as hydrochlorides and a few were also converted t o their methyl bromide salts. They are listed with some of their pharmacological properties in Table I and their physical properties are given in Table 11. One of these esters, 2-(2,2-dimethyl-l-pyolidyl)ethyl a-cyclopentylmandelate methyl bromide (U0371) (No. 7 methyl bromide in Table I), had sufficiently interesting properties to warrant clinical study. Our study of antispasmodic esters has been extended by the preparation of a number of methyl substituted piperidyl, and hexamet'hyleniminoethyl esters. The disubstituted acetic acids used to make these esters were those previously found to give good antispasmodic^.^ The salts of these basic
1566
R. B. L
M
~J. L.~ WHITE, ~ ~B. D. ~ ASPERGREN ~ , AND F. E. VISSCHER
1-01. 77
TABLE I PHARMACOLOGICAL ACTIVITIES AntiAntispas- secretory modic activity, ED60 (w.1 activity, (At. I.) b (mg./kg.) 0 kg.1 .Z .. 3.0
3
(CHa)rCHCHzCHzC(CeHs)(OH)COOCHzCHzNCH(CHs)CHzCHaCHz
HCI
fi-ld
0.5
>3.0
5
(CHdzCHCHzCHC(C6Ha)(OH)COOCHICH:NCH(CHI)CHZCH~CHZ
CHsBr
..
1.0
2 0
G
(CHi)zCHCHzCHrC(CsHs)(OH)COOCHzCHzNC(CHs)zCHnCH~CHz
HCI
2x3
0.14
4 0
7
CHzCHzCHzCHzCHC(CeHd (OH)COOCHzCHrNC(CHa)zCHzCHzCHz
HCl
ll3d
1.0
0 , r,
7
CHZCHZCHICHICHC(CBH,) (OH)COOCHzCH~NC(CHa)zCHzCH~CH:
CHsBr
0.2
CHaC(C6Hs)(OH)COOCHzCHzN(CHa)(C6Ha) CBH~~H(CH~OH)COOCHZCHZNCHICHICHZCHZCHZ
CHsBr Citrate
63 21d 167
0.73
8 9
L
'
1
L
L
..
10
HCI
G50
11
HC1
G O
13
HClf
12
CHaBr
13
HCl
I
I
I
13
CH=CHCHICHZCHCH(COH~) COOCHzCHa~CH(CHa)CHtCHzCHKHCHi
14
~HzCHzCHzCHa~HCH(CHzCHzCHa)COOCHzCH~NC(CHa)zCHzCH(CHa~CHzCHCH~ HCI
CHaBr
2.0" 0.01
....
>1.0
1 .o >5.0
0.2
2.0
