3734
s. L. SRAPIRO, K. ~ ~ E I N B E RT.G ,B A Z GA. ~K D L.FR1: EChl is 1
[CONTRIBUTION FROM
THE
RESEARCH LABORATORIES O F THE
Val.
so
u. S. VITAMIN CORPORATION]
N,N’-Polymethylene-bis-anilinesand Related Compounds BY SEYMOUR L. SHAPIRO,KURTWEINBERG, THEODORE BAZGA AKD LOVEFREEDMAS RECEIVED JANUARY 24, 1958 Series of N,S’-polymethylene-(2,6-dialkylanilines) and 1\T-methyl-w-2,6-dialkylariilinoalkylene halides have been synthesized for pharmacologic evaluation. Significant effects have been noted upon examination as anesthetics, central nervous system depressants and hypotensive agents.
It is generally accepted that steric factors as- methylation. The structures of the type I have sociated with N,N-disubstituted-2,6-dialkylanilines been compiled in Table I result in loss of planarity with inhibition of resoThe compounds of the type I, R1 = CH3,did not nance and hindrance to solvation’ in these systems. yield crystalline quaternary compounds with The pharmacologic response to such hindered methyl iodide or methyl sulfate, which is attribfunctions would be anticipated to differ from that utable to steric hindrance.lt4 The di-acid salts of typical aryl or alkylamines and could contribute of the polymethyl-bis-anilines of the type I , R1 = distinctive therapeutic properties. I n this paper H, formed readily (see Table I, compounds 4, 6, the synthesis of a series of N,N’-polymethylene- 7, 9, 10, 21 and 23). bis-(2,6-dialkylanilines) was undertaken to exThe reaction of the N-methyl-2,6-dialkylaniline amine the effects of such structures on pharmaco- with an excess of the a,w-polymethylene dibromide logic activity. or dichloride provided a convenient synthesis of The most convenient synthesis of the required the N-methyl-w-2,6-dialkylanilinoalkyl halides (11). compounds was by treatment of the selected poly- These compounds darkened rapidly on standing, methylene dihalide with an excess of the 2,6- and even upon storage a t 10’ became contaminated dialkylaniline.2 and the scope of reactions studied by a crystalline p r e ~ i p i t a t e . ~On reaction with has been detailed in Scheme I . tertiary amines, the freshly distilled aminoalkyl halide I1 yielded compounds (111) containing a SCHEME I quaternary nitrogen function and the hindered tertiary amine function. The compounds I1 and XI1 have been described in Table 11. An alternative synthetic approach to structures ‘R R’ R ‘ of the type I was via the bis-anilides IV which were I, Ri = H I11 readily obtainable by the reaction of the dibasic acid chloride and the appropriately substituted aniline. The anilides so prepared have been described in Table 111. Inspection of the physical data shown in Table I11 indicates an interesting melting point pattern. HCOOH-HCHO The structures IV, RI = H, have high melting Method C points, with IV, R = ethyl, melting lower than IV, R = methyl, in each instance. The melting points approach one another as “n” is increased (compounds 1 us. 6, 2 LIS. 7 , 3 vs. 8, 4 vs. 9). Compound 4, wherein R1 = methyl, melts 155’ lower than its congener, compound 3, wherein R1 = hydrogen. The melting point peak is reached when n = 2 (compounds 3 and 8). These factors, coupled with the poor solubility of the compounds in organic solvents, and the high steric strain of I, RI= CHI I1 R = CHI, CzH6; Y = -(CHz)n-; 72 = 2-6; Y -CH*CH= structures as formally shown would indicate that CHCH2-; -CHzC-CCHzthe bis-2,B-dialkylanilides described in Table III This method proved to be serviceable for most (with the exception sf compound 4) exist largely in of the variants of U but did not yield the desired the form The existence of the bis-anilides in the form 1’ structure I, R1 = H, Y = -(CH2)4-, probably as a result of pyrrolidine formation. The correspond- would foretell difficulties with the projected use of ing structure I, RI = CH3, Y = (CH2)4-, was (4) Sommrrs and Aaland (ref. 2) found t h a t N,N’-bis-(Z,ti-diobtained readily. The compounds of the type I, methoxypheny1)-pentamethylenediamine gave only an oily hydrochloride salt, a n d t h e picrate derivative re!!ected a mixture of monoR1 = H, could be converted to I. R1= CH3, by N- and dipicrates.
’ 1 D-KH
(1) (a) B. l f . Wepster, Rec. ~ Y U Z J chim., . 7 6 , 357 (1957): (b) G. Thomson, J . C h e m . S O L . , 1113 (1940); (c) R. N. Beale, ibid, 4494 (3954); (d) M. S . Newman, “Steric Effects in Organic Chemistry,” John Wiley and Sons, Inc., New York, pi. Y.,1956, p. 174; (e) H. C . Brown, J . Chcm Joc.. 1248 (1950); (f, W. G. Brown and S. Fried, THISJOURNAL, 66, 1841 (1943). (2) A. H. Sommers and S. E . Aaland, ibid., 75, 5280 11953). (31 A H . Sommers, ibid., 78, 2439 (1956).
( 5 ) T h e nature of t h e precipitate mas not established, b u t it is unlikely t h a t steric factors would permit intramolecular quaternization and it is believed t h a t dehydrohalogenation occurs with iormntion of the hydrochloride salt of t h e parent compound or of t h e dehydrohalogenated amine. (6) A somewhat similar rationalization of melting point. d a t a was advanced by W. M. Pearlman and C. I(. Hanks, THISJ O U R N A L , 70, 3726 (1948), in a study of chlorodianii~o-syin-triarines.
3735
N,N, -POLYMETHYLENE-~~S-ANILINES
July 20, 1958
TABLE I RI R POLYMETHYLENE-BIS-(2,6-DIALKYLANILINES)AND SALTS 0
R - ' h ( C H z ) . I & ' a .2HXi R/
\R R = CHa, Ri = H HX No. n
1 2 3 4 5' 6' 7 8 9 10
2 3 4 4 5 5 5 6 6
B.P., OC.
R'Zbp.,a.b
Mm.
168 172-174 172-184
0.2 .2 .ll
190-194
0.1
HPicU HCl HPic.' 200-210
Yield,
C.
0.1
HCl HC1
yo Method
37-40' 6 50 71-73' 25 61-63c 193-196b1 17 40-42c 249-250b2 116-118b1 40 198-205*2 226-227b2 17
A A B
15 43 13 28
Formula
Carbon Calcd. Found
81.1 81.1 81.1 51.3
Analyses,d yo Hydrogen Calcd. Found
9.0 9.3 9.5 4.5
Nitrogen Calcd. Found
9.0 8.9 9.4 4.6
10.4 9.0 9.5 14.8
9.8 10.0 9.7 14.8
7.3 14.6 8.6 7.1 7.7
7.2'1 14.8 8.8 7.2'2 7.8
A
A
81.5
9.9
9.9
A
66.1
7.1
7.3
A
81.1 81.2 81.1 81.5 81.6 81.9
9.5 9.7 9.9 10.1 10.3 8.8
9.5 10.0 9.7 10.1 10.4 8.9
9.4 9.0 8.6
9.2 9.0 8.7
8.0 8.7
8.0 8.7
81.7 81.9 82.0 68.0 81.8 68.5
9.9 10.1 10.4 9.2 10.6 9.3
9.6 10.0 9.8 8.7 10.4 9.2
8.6
8.7
6.4 7.4 6.2
6.4 7.3 6.1c3
R = CHI, Ri = CHa
12 13 14 15 16 17
2 3 4 5 6
18 19 20 21 22 23
2 3
5 5 HCI
148-152 158-163 150-154 156-164 184 158-162
0.2 .05 .06 .03 .04 .08
178-184 243-258 186-194
0.08 .16 .07
220-240
.3
48-51'
c
A C
52 18
c
33 6 19
A A A
18
A
A
188-195b2
6 6 HC1
179-185b2
CizHazNz 81.4 CzaHaaNt 81.6 Cz6H38Nz 81.9 CzsH40ClzNz 68.2 CzsHtoNz 82.0 C&~~C~ZN 6 8Z. 8
R = CIHS,
RI = CHa
7.9 7.6 81.8 81.8 10.3 10.3 168-173 0.12 C24H36N2 24 2 22 C 8 . 4 10.5 10.5 81.9 81.4 7.6 Cz~,HasNz 166-176 .l8 9 C 25 3 7.1 6.9 82.2 82.1 10.7 10.9 174-184 .15 C27HzzNz 26 5 47 C b1 water, b Z methaRecrystallizing solvent: a Melting points were determined on a Fisher-Johns melting point block. nol-ethyl acetate. Melting points represent unrecrystallized material. The compounds were characterized as the liquids, Analyses by Weiler and Strauss, Oxand these on prolonged standing crystallized to yield solids melting as indicated. Reported b.p. 175-183' (0.1 18.5, 18.5; 6 2 17.9, 18.3; s 3 15.6, 15.!. ford, England. e Halogen, % calcd., % found: -(CHz),- is CHZC= mm.), m.p. 41-42'; the dihydrochloride, reported m.p. 247-248' in ref. 2. 0 HPic. = picric acid. CCH1-. i Compound not characterized under the HX column are free bases. TABLEI1 x-(2,6-DIALKYLPHENYL),N-METHYLAMINOALKYL HALIDES
No.
1 2 3 4 5 6 7 8 9 10
R = CHI n
3 3 3 4 4 4 5 6 6 b
X
Br Brd Br' c1 Br Brd Br Br Br'
c1
B.P., OC.
90-94
Mm.
M.P.,~ OC.
0.2 142-144 185-187
94-98 98-102
.07 .18 150-152
124-128 146-154
.4
.5 133-134
92-96
.08
Yield,
%
29 52 38 7 21 75 22 35 31 29
Formula
C1zHdrN C~sHaaBrKz C18H3I BrNz C13HzoClN CBHZOB~N CIQH~+& CI4H22BrN ClbHtaBrN CzlHa7BrNz C13Hi8C1
Nitrogen, % Calcd. Found
5.5 7.8 7.9 6.2 4.8 7.6 4.9 4.7 7.1 6.3
5.6"
7 .7 7.9 6.2 5.2 7.6 5.3 4.6 7.0 6.4
R = C2HS
11 3 Br 108-112 CUHZZB~N 4.9 5.1 .1 26 b 12 c1 104-106 .26 26 C1,HzzCIN 5.6 5.7 Found: 30.7. * -( CH?) - in generic formula is replaced by -CH2CH=CHCH2-. Compounds a Bromine, calcd. : 30.8. Quaternary ammonium salt with for which melting points are shown were recrystallized from ethyl acetate-acetonitrile. Quaternary ammonium salt with N-methylpiperidine. triethylamine,
S.I,. SI-IAPIRO, K. WEINBERG, T. RAZGAAND I,. F R E E D M ~ S
3736
Val. 80
TABLE 111
SI.p.,ii
n
oc.
Tield,C v /O
I'ormu 1a
Carbon, 5% Calcd. Found
Hydrogen, yo Calcd. Found
Nitrogen. yo Calcd. Found
0" 1 2
264-265 65 72.9 73.0 6.8 7.0 9.4 9.2 266-267 71 73.5 73.1 7.1 i.3 9.0 8.0 322-323 83 74.0 73.8 i,5 6.9 8.0 8.6 0 165 41'* 75.n 75.0 s.0 8.4 8.0 7.i 4 290-292 72 i0.0 '75.1 8.0 5.2 7.9 8.2 0' 224-225 Of) i5.0 i5.3 3.0 8.0 8.1) 7.8 1 237-242 75.4 75.1 82 64 7.8 7.6 8.2 2 300-302 75.7 754 ST, 8.3 44 7.4 6.9 4 284-283 58 76.4 76.7 X 9 9.0 6.9 7.1 RI = hydrogen it1 all instances except compound 4 where RI = CIII. Ir Melting points :ire not corrected. The recrystallizing solvent was methyl Cellosolve unlesq otherwise indicated. d Solvent, methanol. e Compounds where n = 0 represent bis-oxanilides.
--
I
,R
OH
0
R
anilide VI forms an insoluble complex with the lithium aluminum hydride which hinders further reduction, but which does not reconstitute when compound VI is isolated and again treated with R ' lithium aluminum hydride. t Pharmacology.-The compounds in this study were examined for their propertiesg as anesthetics, central nervous system depressants, hypotensive agents and adrenergic blocking agents. Significant pharmacologic findings with 2,6R ' v R' dialkyl substituted anilines are confined largely to these compounds as reactants for the preparation of the excellent local anesthetic effect obtained with I by lithium aluminum hydride reduction. Such xylocaine.'O Examination for anesthetic potency1' in the compounds would be expected to form unreactive polymethylene-bis-anilines described in Table I complexes of the type --N=C(0A1H3)--87 leading indicates that gond anesthetic response is obtained to very slow reductions. This proved to be the case and, accordingly, only with selected structures. Thus, the following data, one system was studied in detail, involving the Table I compound no., EDSo mg. 'ml., LD,,,,. preparation of N,N'-tetramethylene-bis-(2,6-di- mg.,'kg. (mice), were obtained: 3, 0.44, > 1000; methylaniline) which was not obtained by method 5 , 0.34, > 1000; 8: 3.2. > 1000; 15, 12, > 1000. The following compounds, evaluated by this proceA. The attempted synthesis of I, R1= CH3, R1 = dure, did not show any response: 10, 13, 14, 16, H, Y = -(CH2)4-, from the diamide IV via lithium 18, 19, 22, 2-2 and 26. ,Ilso negative was the realuminum hydride resulted in but partial reduction sponse of N-methyl-S-(,3-phenethyl)-3!C,-dimethylaniline which had been prepared to assess the need to the mono-anilide VI3 as shown in Scheme 11. for two anilino groups in structures of this type; comparable data noted for xylocaine: EDjo 6.S SCHEME I1 (METHUD B) mg./ml., L D m i n , 225 mg.,'kg. H CH, \ Selected structures show good local anesthetic response when compared to xylocaine. The best activity appears to be confined to structures I , I
