Nov., 1946
DERIVATIVES OF 1-PHENYLCYCLOPARAFFINCARBOXYLIC ACIDS
by hot acetylation with sodium acetate and acetic anhydride. N-Methyl-L-glucosaminic Acid.-Fifty grams of Nmethyl-L-glucosaminic acid nitrile was dissolved in 100 cc. of concentrated hydrochloric acid (d. 1.19) with cooling. The solutioii was then evaporated under reduced pressure t o a sirup. All but traces of the hydrochloric acid were removed by alternate solution in water and evaporation under reduced pressure. The sirup was dissolved in 200 cc. of water, 95 g. of barium hydroxide octahydrate added, and the solution boiled until the odor of ammonia could no longer be detected. The barium ion was precipitated exactly by the addition of sulfuric acid. Activated carbon was added and the hot mixture filtered. The solution was treated with lead carbonate until it no longer effervesced. Decolorizing carbon was added again, the solution filtered, and evaporated under reduced pressure to 100 cc. It was allowed to stand in the ice-box overnight. The separated lead chloride was removed by filtration. The solution was warmed and treated with silver carbonate t o remove the remainder of the chloride ion and the mixture filtered. The lead and silver ions were precipitated with hydrogen sulfide and the colorless liquid evaporated under reduced pressure at a temperature below 50" t o a thin sirup. Absolute ethanol was added and the evaporation continued until a heavy crop of crystalline acid formed. The crystalline material was removed by filtration. More crystals were obtained by the addition of ethanol t o the mother liquor and further evaporation; yield 32 g., m. p.
2345
234-236" (dec.), [a]'lD -3.0" (c 4.1,water); no mutarotation. Pure material was obtained on two recrystallizations from water-ethanol; m. p. 236" (dec.), [ a I z 4 D -4.6" ( c 4.0, water); [ci]"D -3.0" (initial, extrapolated) -,-9.1" (final) (c 10.8,2.5% hydrochloric acid). These constants are in agreement (opposite sign) with those cited by Votdek and LukeS7for the enantiomorph and with the melting point cited by Folkers and co-worker~.~ The substance is soluble in water, very slightly soluble in ethanol and is insoluble in ether. Anal. Calcd. for C~H150sN: C, 40.19; H , 7.23; 5 , 6.70. Found: C,40.22; H , 7.25; N, 6.64.
Acknowledgment.-We are indebted to Mr. W. J. Polglase for the analytical data recorded. Summary 1. An effective method for the preparation of N-methyl-L-glucosaminicacid is reported. 2. L-Arabinosyl-N-methylamine and Nmethyl-L-glucosaminicacid nitrile (and its pentaacetate) have been synthesized in crystalline form. 3. Postulations are made concerning the nature of the isomeric forms of D-gluconic acid nitrile. COLUMBUS, OHIO RECEIVED AUGUST12, 1946
[CONTRIBUTION FROM THE ORGANIC RESEARCH DEPARTMENT OF ABBOTTLABORATORIES]
Antispasmodics. Derivatives of 1-Phenylcycloparaffincarboxylic Acids BY ARTHUR W. WESTON amined for their antispasmodic activity. For purposes of comparison, some basic alkyl thioesters and amides of these acids were also prepared. After this work was completed, a report2 on tfie investigation of a series of compounds derived from 1-phenylcyclohexanecarboxylic acid appeared. One of the esters prepared in the present work, @-diethylaminoethyl l-phenylcyclohexanecarboxylate, was described therein. 1- Phenylcyclohexanenitrile, one of the starting I materials, was obtained by a modification of the published method3 in which phenylacetonitrile was condensed with pentamethylene bromide in the presence of sodamide. By employing a relatively large volume of solvent, it was found #at the tendency for intermolecular condensation was diminished. This resulted in an increased yield of the 1-phenylcyclohexanenitrile. Whether higher dilutions would have still further improved this conversion was not investigated. Hydrolysis of the nitrile was accomplished with 48% hydrobromic acid. Casea reported a 22.2% over-all yield of 1-phenylcyclohexanecarboxylic acid from phenylacetonitrile. By the present method a 52% In an effort to find a potent antispasmodic yield was realized. drug, basic alkyl esters of l-phenylcyclohexaneThe 1-phenylcyclopropanenitrilewas prepared, carboxylic acid (111) and l-phenylcyclopropane- according to the directions of Knowles and Cloke4 carboxylic acid (IV), which are somewhat related as modified by Case,afrom phenylacetonitrile and structurally to 1 and 11, were synthesized and ex(2) Rubin a n d Wishinsky, THIS JOURNAL, 68, 828 (1946).
Basic alkyl esters of substituted acetic acids have been studied extensively in a search for a synthetic antispasmodic drug which would combine both a musculotropic and neurotropic action within the same molecule.' Two compounds possessing this dual activity to an appreciable degree are Trasentin-6H (I) and Propavine (11).
(1) For recent reviews see Raymond, J . A.m. Pharm. Assoc. Sci. Ed., 34, 249 (1943); :Blicke, Ann. Rn. B k h c m . . I S , 649 (1944).
(3) Case, i&id., 66, 716 (1934). (4) Knowles and Cloke, ibid., S4, 2028 (1932).
2346
VOl. 68
ARTHURW. WESTON TABLE I
BASICALKYLESTERSOF
1-PIWNYLCYCLOPROPANE- AND 1-PHENYLCYCLOHEXANECAR-
BOXYLIC
APbno.
m
ACIDSAND HYDROCHLORIDESO R
53 68
2 6
OCHzCH2N(C&r)r OCHzCHzN(C:Hds
139 143 155 140 144 142 141 119 113
5 2
OCH2CHzN(C&)t SCHzCH,N(C&s): SCHoCHzN(GHd z NHCHXH2N( Ws), OCH2CHzNHCHtCeH~ OCHaCH&HrNCJI# OCHnCH2CHtNClHaOO OCHzC(CH.&CHzNC4N~W OCHZ(CH~)~CH~NCJI@'
APb no.
5
5 2 2 5 5
5
HCI
M. p., OC.
Cryst. solventC
B. P., OC.
oz:y-R 8O
Ref. index Mm.
I, 'C.
nD
..
....
155-157
2
1.5110
.....
..
....
..
164-165 185-186 202-203
2 2
.....
3
..
1.5398 1.5149 1.5280
26 23 24
173-175 202-203
. . . . .h
2 2
..
1.5193 1.5238
26 26
228-230
4
1.5166
24
.....
Formula
Calcd.
..
25
....
....
Base
..
..
Method of prepn.
Yield
Ib Ia I1
76d 80 70d
Ia Ia Ia IC IV I11 Ia IV Ia
94
...
%
..
78 94 70d 73 92 88 86 87
Nitrogen, % Found
Hydrochloride Calcd. Found
53 132-133 Et CleHuNOrHCI .. .. 4.70 4.73 68 162-103 Et ClrHmNOs(HC1) 4.62 4.65 4.12 4.12 .. .. 3.15 3.16 139 101.5-1024 AA-E CtoH2oNOp.CHsI" 143 137-138 Et ClsHwNOS(HC1)' 5.05 5.04 4.46 4.40 155 140-141 Et CIOHIONOS(HCI) 4.30 4.16 3.94 3.90 140 166.5-167 AA-E CIQHSNZO(HCI) 9.30 9.34 8.28 8.14 AA CloHz1NOz.HCI .. .. 4.22 4.16 144 171-172 142 168-169 AA CnHnaNOs(HC1) 4.84 4.86 4.30 4.38 3.81 3.96 141 174-175 AA CzoH2oN4(HCI) 4.23 4.25 AA ClzHarNO; (HCl) 119 180-181 3.90 3.97 3.54 3.53 113 121-122 Et Cn3HasNOs(HCl) 3.75 3.79 3.42 3.47 4 Compound 139 is the methiodide. Antispasmodic code number. Legend: Et, ethyl acetate; AA, absolute alcohol; E, ether. Crude yield. Decomposition. Sulfur anal., calcd., 10.21; found: 10.32. 0 NCIHsO represents M. p., 53-54' (dil. alc.). the morpholina group. @
ethylene dibromide. Alcoholic potassium hydroxThe pertinent data on the free basic esters and ide gave the amide which was then converted to their hydrochlorides are recorded in Table I. the acid by refluxing with concentrated hydroIn Table I1 some of the pharmacological results' chloric acid. obtained with the compounds prepared in this inThe oxygen esters were synthesized by a variety TABLE I1 of methods: I, by condensation of the acid chloride (a) with excess of the aminodcohol, (b) with TOXICITIES AND ANTISPASMODIC ACTIVITIESOF PRODUCTS one equivalent of the aminoalcohol, (c) with the AP' LDa Antispasmodic activity against no. m d k . Acetylcholine BaClr aminoalcohol hydrochloride; 11, by heating the 53 225 1/250 1 /8 acid with the dialkylaminoalkyl halide6; 111, by heating the potassium salt of the acid with the 68 170 1/15 1.0 dialkylaminoalkyl halide and IV, by amination of 139 100 1/50 I '? the correspondingbromoalkyl esters. 143 2'0 1/15 2.0 One of the bromoalkyl esters, the w-bromo155 1-10 1/50 2.0 hexyl 1-phenylcyclohexanecarboxylate,was made 140 200
