Local Anesthetics. V. 4-Morpholinylalkyl Aryl Ether1 - Journal of the

Local Anesthetics. V. 4-Morpholinylalkyl Aryl Ether1. Howard B. Wright, and M. B. Moore. J. Am. Chem. Soc. , 1954, 76 (17), pp 4396–4398. DOI: 10.10...
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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