4396
VOI. i 0
HOWARD B. WRIGHTAND M. B. MOORE [CONTRIBUTION FROM ABBOTTLABORATORIES]
V. 4-Morpholinylalky1 Aryl Ether'
Local Anesthetics.
BY HOWARD B. WRIGHTAND hl. B. MOORE RECEIVED APRIL 17, 1954 Sixty-four 4-morpholinylalkyl aryl ethers have been prepared and tested for local anesthetic activity. The method of synthesis has been described in previous papers. The compound 4-n-butoxyphenyl -y-4'-morpholinylpropyl ether seems to combine maximum anesthetic efficiency with minimum toxicity.
In previous papers,2 we have reported some aryl alkamine ethers of the general formula
O
E
O
R
R' alkyl, aryl or ether substituents K = various alkamine residues 5
TABLE I n ~-MORPHOLINYLALKYL ARYLETHERSr $ ~ O C , F , , , Y < ,0 Hydro-
\-/
I
chloride
No. 1 >
3 4 fi 8
9 in 11
12 13 14 15 1t i 17 18 19
20 21 '>,I
--
Yield,
%
99 53 58 100 84
B . p . or m.p. OC. Mrn. 155-156 2 . 0 90 195-l9(i 2 . 5
149
45 48
78-79 196 20&201
55
84-85
78 50 75 31 23 52.5 94 51 72 100 51 29.4 46 38
m.p., OC.
0.0 3.8
97-98 18~'-1844 . 2 170 171-172 165 192
0.75 1.4 3 0
177
1.4
1 fi4-167
90-91 200-201 170-172 171-173 07-68 226-227
2.8 2.5 1.9 0.9
c
Analyses, ' S ?rl
H ? ; 8.42 9.63 4 03 8.91 4 59 8.79 4.28 7.70 9.27 8.65
C 06,79 75,36 70.84 62.83 73.72' 69.79 69.92
05.91
8.85
65. 87b
9.00
76.74 74.71 65.96 70.07 74.19 70.07 53.62 74.19
7.79 10.23 10 20 8 65 10.03 8.65 6.23 10.03
76. 75h 74.34 66.23 70.03 74.18 70.21 53.88 74.39
7.58 10.32 9.94 8 50 10.05. 8.38 6.40 9.98
61.88
7.19
61.95
7.22
76.74 61.05 58.63 07.47 73.82
7.79 7.09 6.81 8.81 7.12
70.52 61.35 58.63 67.26 73,59
7.77 0.83 6.62 8.74 7.18
65.87
8.63
23
22
217-218
65.91
8.85
24 23
50
"fj
50
103-104 208-210 238-240 334-135 82-84
65.80 73.87 73.28 70.55 58.63 57.23 74.27 74.00 69.59 73.04 73.58 69.59 73.04 77.13 70.56 56.74 75.63 62.90
8.07 7.97 7.44 8.65 6.81 7.76 7.17 7.86 9.27 7.74 8.03 9.27 7.74 8.09 7.11 7.00 10.65 7.92
55.89 65.99 65.99 76.21
8.27 8.79 8.80 7.23
'7 28 29
30 31 32 33 31 35 36 37 38 39 40 41 42
60
33 17 7'2 43 70.5 f
22 35.2 45 I
1.2 3.7 3.3 213
75-76 88 193-194 80--81 52-53 19&191 255-257 184-185 159-161
4.3
2.1 5.0 2.3
I
121-122
68 47 I
190
43 41
59 58
4.5
f
164-166 219-221 98-99
165
1.5 0.7 214-215 (dec.) 0.15 3.2
Found H N 8.16 9 . 6 3 4.67 8 . 9 8 4.62 8.88 7 . 3 5 4.38 9.m 8.45
C 66.90 75.26 70.79 62.86 73.37 69.59 70.07
5 . 9 0 06.0@ 73.80 73.38 70.75 58.68 10.27 57.41 74 5? 8 . 5 8 73.58 69.44 73.33 8 . 5 8 73.46 69.87 73.20 77.06 70.77 56.66 75.57 62.72 55.87 65.66 65.89 76.07
7.93 8.08 7.35 8.85 6.59 7.64 7.18 8.03 9.10 7.50 7.75 9.22 7.48 8.05 6.84 7.01 10.45 7.87
5.76
10.13
8.77
8.96
8.43 8.83 8.87 7.31
Catalytic reduction of 2 to Catalytic reduction of 3. Average of two analyses. 0 2-(l'-Methylbutyl)-4-methyl. give p-cyclohesylcyclohesyl alkamiric ether. e Chlorine calcd. 21.35, found 24.09. f Obtained in low yield. 0 n7 n CJ~~O-SHC~HBX 0 does not fit iiito the above general formula. n-CIHrO oCaHeNL, 0 does L~-' r o t fit into the above general formula. 6 - S a p h t h y l m h o radical. -_ ____ a
(1) Paper presented before t h e Division of M e d i c i n a l Chemistry a t t h e 125th hleeting of the American Chemical Society, Kansas City, h l o , hIdrch, 1954 (2) (a) H. R. Wright and A I . B. hioore, THISJ O U R N A L , 73, 2281 1951); (b) { b i d . , 73, 5525 (1951).
and some aryloxyalkyl alkamine ethers of general
ArOR'OR"NR2 Ar = aryl or arylalkyl residue, R' and R" = bivalent alkylene radicals and NR2 = a tertiary amine residue
Sept. 5, 1954
LOCAL ANESTHETICS : 4-RfORPHOLINYLALKYL
ARYL
4397
ETHERS
TABLE I1
u0
4-MORPHOLINYLALKYL ARYLETHERSArOCxHA -T No.
46 47 48 49 50 51
Ar
CIDHf CoH6NC C&Nd C5339d CioHiig CioHi?
Yield,
%
B.p. or m.p. O C .
52 23.2 #
18.3 24 32.7
193-194 64-66 195-196 135 150-152 147
Carbon, % Calcd. Found
Mm.
Formula
1.2
CnH2iNOz C1eH20N202 Ci~,H2oNzOx C12H23N03 Ci7&N01 Ci7Hd02
2.0
1.8 0.35 0.2
75.24 70.56 70.56 62.85 74.14 74.14
75.01 70. 9gb 69.EGb 63.06 74.25 74.26
Hydrogen, “c Calcd. Found
7.80 7.40 7.40 10.11 9.15 9 . l
