2965
NOTES
June, 1951
T ~ L I1 E PROPmTIES OF HBTEROCYCLIC QUATERNARY AMMONIUM: SALTS OF TYPE1 R
1 Lauryl 2 Myristyl 3 Cetyl
C. K. D.“ 1000 pts. H i 0 Stadh. E . lyphosa auicur
10-20 1-10 1
10-20 10-20 1-10
...
...
4 Lauryl 5 Myristyl 6 Cetyl
...
...
1.0
1-10
7 Lauryl 8 Myristyl 9 Cetyl
1-10 10-20 1-10
20-30 30
10 Myristyl
10-20
10-20
11 Lauryl 12 Myristyf
24.0 10-20
20 10-20
13 Lauryl 14 Myristyl 15 Cetyl
20 20 1-10
40
1
v&,
I Analyses, % Recrystn. Nitrogen Carbon Hydrogen solvent Formula Calcd. Found Calcd. Found Calcd. Found E s t e r of N-carboxymethyl-N-methylmorpholiniumchloride 113-114de. 65 M-CO CioHisNOaCl 3.85 3.71 62.70 62.90 10.52 10.25 CnHUNOaCl 3.58 3.45 64.34 63.96 10.80 10.66 118-119 dec. 67 MeCO 119-120 dm. 66 MeCO CrrHMNOiCl 3.34 3.38 65.76 65.74 11.04 10.74
Yield,
%
Esters of N,N‘-dicarboxymethyl-N,N‘-dimethylpiperaziniumdichloride 157-158 66 EtOH-MeCO CiiHuNrOiCle 4.38 4.58 63.95 166-167 69 EtOH-MerCO GsH7aNtO4Cli 4.03 3.96 65.58 175-177 dec. 74 EtOH-MerCO CuH~tNsOtClr 3.73 3.91 67.12
63.98 65.43 67.as
10.71 11.01 11.27
10.62 10.91 11.09
Esters of 120-121 dec. 123-124 121-122 dec.
69.40 70.47 71.41
69.42 70.73 71.59
10.13 10.41 10.66
10.13 10.17 10.77
Esters of N-carboxymethyl-N-(2-benzyloxy)-ethylmorpholinium chloride 158-159 40 MeCO CsHwNOtCl 2.74 2.76 68.00
68.25
9.84
9.93
60.67 61.80
9.96 10.16
10.06 10.22
carboxymethyldimethylbenzylammoniumchloride 3.52 3.31 CnaHloNOrCl 89 MerCO CriHuNOpCl 3.29 3.30 85 MaCO 3.09 2.92 CnHoNOpCl 79 MenCO
Es-
30 10
of N-carboxymethyl-N-methyl-N’-carbethoxypiperazinium chloride 125-127 dec. 40 EtrO-MrCO CnHtrNiOtCl 6.44 6.18 60.73 136-138 dec. 75 EtrO-MqCO CztHnNg01Cl 6.06 5.79 62.27 Esters of N-carboxymethyl-N-methylpiperidiniumchloride 156-157dec. 87 MeCO CmHloNOzCl 3.87 3.62 158-159 dec. 72 MeCO CrrHitNOrCl 3.60 3.42 160-161 dec. 74 MerCO CIIH~NO~CI 3.35 3.34
66.35 67.74 68.95
66.05 67.62 68.95
11.14 11.37 11.57
10.86 11.41 11.33
a Critical Killing Dilution-that concentration of the substance which will kill organisms of standard phenolic resistance in ten minutes but not in five minutes, at 37”, determined by the method described in Circular 198 of the U. S. Department Determined on a Fisher-Johns melting point aooaratus. of Agriculture.
..
Quaternary ammonium salts were prepared by adding the equivalent quantity of the alkyl chloroacetate to 0.05 mole of the tertiary amine in 20 ml. of acetone. This mixture was refluxed for from two to 30 hours on a steam-bath. The cooled mixture was then filtered and the solid recrystallized. Compounds 11 and 12 in Table I1 were best recrystallized from a mixture of acetone and ether containing a trace of alcohol. If the melting points of compounds 11 and 12 were taken in a capillary tube, they appeared to melt at 88 and 78”, respectively. If a Fisher-Johns melting point apparatus was used, much higher melting points were obtained; however, a change in crystalline structure was observed at the lower temperatures which seem to be the transition points for the compounds. Most yields were very good, but the primary objective was to obtain pure compounds rather than to determine the h u m yield attainable. DEPARTMENT OF CHEMISTRY JAMES MILLIKIN UNIVERSITY OCTOBER19,1950 DECATUR, ILLINOIS RECEIVED
Quaternary Carbon Compounds. V. Trisubstituted Carbinylcarbamates BY NATHANSPERBER,ROSEMARIE FRICANO, ERWIN SCHWENK AND DOMENICK PAPA
Although the majority of compounds synthesized as antispasmodics are basic esters of alicyclic and/or aromatic acidsJ1a limited number of diversified structures have also shown this interesting pharmacological action. Of the latter group, carbamic acid derivatives may be viewed as intermediate in structure between the basic esters and the non-ester type of antispasmodic compounds, Only one series of carbamic acid esters has been reported to exhibit antispasmodic activity.2 Of a number of derivatives of carbamylcholine, the dibutylcarbamate of dimethylethyl-8-hydroxy(1) F. F. Blicke, Ann. Rev. Biochem., 18, 549 (1944). (2) K. C. Swan and N. G. Wbite, Proc. Soc. Exptl. Biol. Med., 58, 164 (1943); Arch. Opthalmol., 88, 16 (1945); R. M. Featherstone and N. G . White, J . Pharmacol. Erptl. Thcrap., 84, 105 (1945).
ethylammonium sulfate, the most active member of t h i s series, exhibited a quick-acting atropinelike action. Two other series of carbamates, the alkamine esters of disubstituted methylcarbamic acids, RIRzCHNHCOO(CHa)nNRzwhere R1 and Rz are either aliphatic or aromatic radicals3 and the dialkylaminoalkyl esters of a-naphthylphenylcarbamic acid4 have been reported to possess local anesthetic activity. In continuation of studies on quaternary carbon compounds,5 it appeared of interest to investigate the pharmacological action of carbamic acid derivatives of the general formula RR’R’’CNHCO0(CHJnRt” (I)6 where R is an alkyl, diethylaminomethyl or a N-piperidinomethyl group, R’ and R” are alkyl groups containing two to five carbon atoms, R“‘ is a dialkylamino group, and n is two or three (Table I). In addition, the tributylcarbinylcarbamates from 8-(2-pyridy1)-ethanoland 8-(N-piperidin0)-ethanol were prepared as examples of cyclic amino alcohols. The carbamates were prepared by refluxing the trisubstituted carbinylisocyanate and the amino alcohol in xylene. Upon removal of the solvent, and fractionation of the residual oil in vacuo, the carbamates were obtained as viscous, yellow liquids. The in vitro antispasmodic activity of the carbamates was determined on isolated rabbit intestinal muscle by measuring the relaxation produced by the test compound against Dory1 and barium chloride-induced spasms using atropine and papaverine as standards. The most active compounds were those in which R, R’ and R” were butyl or amyl, R”’ was dimethylamino, diethylamino or (3) J. J. Donleavy and J. English, Jr., THIS JOURNAL, 61, 218 (1940). (4) A. B. Boese, Jr., and R. T. Major, i b i d . , 57, 175 (1935). (5) For paper IV in this series, see N. Sperber, D. Papa and E. Scbwenk, ibid., 72, 2012 (1950). (6) U. S. Patent 2,536,079,Jan. 2, 1951.
Vol. 73
NOTES
2966
TABLE I TRISUBSTITUTED CARBINYLCARBAMATES OF FORMULA RR'R"C-NHCOO(CHZ),R'" R
R'
R"
R"'
x
'CB"'
t,
Mm
2 128-129 1 C2HS CzHs C2HO N(CsH6)2 2 164-166 2.5 CzHr C4H9 C4H9 S(CzHs)z N(CH3)z 2 175-176 5 C4Ho C4Ho Ci" 2 164-165 2 C4H9 C4Ho C4Ho N(C2Hs)s 2 181-183 2 C4H9 CiHo C4H9 N(C&)L 3 185-190 3 C4H9 C4H9 C4Ho N(CiH0)z :3 175-177 2 C4H9 C4Hs CIHO N(CzHs)z C4H9 C4Hp C4H9 CHzCH(CHs)N(CnH& 0 164-165 1 5 0 185-188 3 CiHo C4H9 C4H9 CHzCHzNCsHi: 0 198900 2 C4HO C4H9 C4H9 CH2CH2CaH4Nb 2 180-183 2.5 GHii CaHil CaHu X(CzHs)z 1 186-187 4 5 (CzHs)zNCHz C4Ho C4H9 S(CaHs)z 2 186-188 4 CsHioNCHz' C4H9 C4H9 S(C2H& E 6-(N-Piperidyl)-ethyl ,3-(2-PyridyI)-ethyl. S-Piparidylinethyl
x,,
"C.
1.4560 1.4568 1.4570 1 4567 1.4550 1.4531 1.4558 1.4548 1 4682 1.4877 1.4564 1 4603 1.4720
25 25 22 25 22 24 22 23 25 24 25 25 22
Yield,
%
62 C14H3002Nz 10 85 10 85 83 CisHa80zN~ 8 91 8 87 83 Ci8H~80zNz 8 91 9 31 87 CzoH420Z~z 8.18 8 31 7 17 N~ 83 C Z ~ H ~ O O Z7.0.3 80 C2sH6202NL 6 79 ii 78 75 GlHu02N~ 7 86 7 78 7 86 Y Of) 46 CZlH4@2NZ 7 911 8 0 4 64 C2iHtzOzNz 61 CziH,,OJX> 8.04 8.05 CzJH4802N2 7.29 11 32 CZ~H~SOZK~ 32 Cn&Iij02N3 10 96 88
85
_ I _ _
dibutylamino and n was two. &Diethylaminoethyl tributylcarbinylcarbamate, the most active member of the series, was twenty times more active than papaverine and possessed one-thirtieth the activity of atropine. In general, the structural requirements for antispasmodic activity observed in the quaternary carbon compounds described previously6 apply to the dialkylaminoalkyl trisubstituted carbinylcarbamates. Experimental The synthesis of the trialkylcarbinylisocyanateshas been described.7 The dialkylaminoalkanols were obtained either from commercial sources or were prepared by standard proredures.
Dialkylaminoalkyl Trialkylcarbiny1carbamates.-The
preparation of 8-diethylaminoethyl tributylcarbinylcarbamate will illustrate the general method: A solution of 11.3 g. (0.05 mole) of tributylcarbinylisocyanate and 8.2g. (0.07 mole) of 8-diethylaminoethanol in 50 ml. of dry xylene was refluxed for 48-72 houri. The xylene was removed in vacuo and the residue was fractionated. After a small forerun, the carbamate was collected as a yellow, viscous oil. The rnethiodide melted at 1 1 8 118.5"after two recrystallizations from benzene-petroleum ether. 4nnl Calcd. for CZ,FI~,OZNZI. S , 5.78; I , 26.8 Found:
Nitrogen, o/; Calcd. Found
Formula
T 17 11 10 10.84
__
pound containing both anomers in a ratio a : 6 = 3 : 1. When held a t a temperature of 135-140' the liquid beta isomer is converted to a crystalline solid which after recrystallization from suitable solvents appears to be identical with that reported by Bergmann and Freudenberg; m.p. 175-178', [ a ] " ~ 36" (chloroform), [ C Y ] ~ * D 35" (pyridine). The rotation data in pyridine indicate that this material is approximately an equilibrium mixture of the alpha and beta aiioiners. -4pplying Hudson's3 rules of isorotation, the rotational value of a-gentiobiose heptaacetate can be calculated from values for @-gentiobiose heptaacetate and the .mnmeric forms of gentiobiose octaacetate.
+-
+
et,tte, -4 $-Gentiobiose octaacetate, - A
++ BB
2B
= = =
35,500 -3,600 '31,900
A represents the rotational contribution of thc carbonyl group and B that of the remainder of the a-Gentiobiose heptaacetate, A ' &Gentiobiose heptaacetate, -A'
Y, .5 50; I, 27.2.
+A +A
=
x
=
1,800
Then it follows that the value of x, the molecular rotation of a-gentiobiose heptaacetate, is 30,100° ID $. 47.40, The rotation of 23,000' ( [ a ] ~ 36.1', chloroform) found for the equilibrium mixture would indicate the (7) N. Sperber and R. Fricano, r m s JOURNAL, 71, 3352 (1949). presence of approximately three parts of the alpha CHEMICAL RESEARCH Drvrcro\ to one of the beta anomer. The specific reaction SCHERINC CORPORATION RECEIVED M~~~ 15, 19.51 constant of the mutarotation in pyridine of the BLOOMFIELD, N. J. beta anomer was first order, indicating the presence __ -_---- -- .oI esseritiallv onlv a b h a and beta anomers in solution. HowGver, X-riy powder diffraction diagrams The Gentiobiose Heptaacetates showed that the material isolated from the equilibB Y ALVA'SHUMPSOS1 ANI) M. L.XvOLPROM rium mixture contained no admixed crystalline Bergmann and W. Freudenberg2 prepared a &gentiobiose heptaacetate. This equilibrium masubstance designated a-gentiobiose heptaacetate, terial must therefore be a crystal compound from m.p. 178' (cor.), [ Q ] ~ ~ D 35.1' -+ +31.6" (pyri- the two isomers. Similar molecular compounds dine), from amygdalin. We wish to report the between anomers have been reported by Hockett synthesis of @-gentiobioseheptaacetate, m.p. 113- and Hudson for methyl D-xyloside and for lactose.4 115', [ C X ] ~ ~ D 2.9" (chloroform), [ c Y ] ~ * D- 7.0" Experimental (initial, extrapolated) +34.1 O (5 hr., pyridine), p-Gentiobiose Heptaacetate .-Five grams of @-gentiotogether with evidence that the "alpha" form pre- biose octaacetate was converted to heptaacetyl-a-gentiobromide by the method of Zemp16n6; yield 3.9 g. viously reported is a crystalline molecular com- hiosyl --
Acknowledgment. --\\*e are grateful to Dr. Richard Tislow and hlrs. Annette LaBelle of our Biological Laboratories for the pharmacological data described herein.
+
+
+
(1) Corn Industries Research Foundation Associate of 'The Ohio State University Research Foundation (Project 203) (2) M. Berpinann and W. Freudenberg, Rfr , 61,3783 (1929)
(3) C S. Hudson, THIS JOURNAL, S1, 66 (1909) (4) R. C TIockrtt rrid C 5 Hudson, abid , 63, 4454, 4455 (19dl .J I . / I lllplrrl H I , 61, 648 irl2+)
