428
F. F. B L I c r a AND CHARLES E. MAXWRLL
Vol. 64
Summary
The titration of several hydrocarbon picrates is reported and the advantages of this method of analysis are pointed out.
The nitric acid oxidation of some yomatic hydrocarbons and derivatives is described.
DECEMBER 15, 1941 HARVARD UNIVERSITY RECEIVED CAMBRIDGE, MASSACHUSETTS
hydroxide solution to the end-point described above. The results are listed in Table I.
CONVERSE MEMo*AL
LABORATORY
[CONTRIBUTION FROM THE COLLEGE OF PHARMACY, UNIVERSITY OF MICHIGAN]
Synthetic Mydriatics. I BY F. F. BLICKEAND CHARLES E. MAXWELL''' The great majority of substances which exhibit methobromide of P-diethylaminoethyl benzilate, marked mydriatic activity, and especially those when tested on the rabbit's eye, were described by which find practical application as mydriatics, Dr. F. Bruce Fralick and Dr. Harold F. Falls, to are of two types: esters of a hydroxy acid such as whom we are indebted for all of the animal tests, as tropic, CeHbCH(CH20H)COOH, or mandelic, excellent mydriatics; the hydrochlorides of the CsH&H(OH)COOH, and an amino alcohol; aryl- P-diethylaminoethyl and the y-piperidinopropyl alkylamines similar to epinephrine or ephedrine ester of benzilic acid, as well as the methobromide of the latter, produced good mydriasis. in structure. Some of the ester hydrochlorides were found to We have discovered that the benzilic acid ester (C&I&C(OH)CO- be so insoluble in water that satisfactory 1-2y0 of /3-piperidinoethyl O C H ~ C H ~ N C Jis~ a~ strong O, mydriatic. This ob- solutions could not be prepared. In these inservation shows that the alcoholic hydroxyl in the stances the methobromides of the esters proved to acid radical, which seems to be quite essential for be much more soluble. Furthermore, the quaterstrong mydriasis in the ester type, may be tertiary nary compounds have been found to be much less as well as secondary (mandelic acid) or primary irritant and are as active or even more active than the corresponding tertiary amine hydrochlorides. (tropic acid). The esters were prepared by the methods of Recently four other esters of benzilic acid-the tropyl,* the pse~dotropyl,~ the 8-diethylamino- Horenstein and Pahlicke,'O according to which ethyl6 and the -pdiethylamino-/3,/3-dirnethylpro-the potassium salt of the required acid was heated pyl' ester-have been shown to be not only my- with the hydrochloride or hydrobromide of the driatics but also local anesthetics and antispas- basic-substituted alkyl halide, or the acid, dismodics.8 solved in isopropyl alcohol, was allowed to react The substituted ethyl and propyl esters of ben- with the basic-substituted alkyl halide. zilic acid, which we prepared, are listed in Table In view of the statement in the literature" that XI. Three compounds, P-piperidinoethylbenzilate aminomethyl phenyl ketone produces mydriasis,l 2 hydrochloride, the ester methobromide and the it seemed desirable to prepare and test a few (1) This paper represents part of a dissertation submitted to the amino ketones and some of the corresponding Horace H. Rackham School of Graduate Studies by Charles E Maxwell in partial fulfillment of the requirements for the degree of secondary alcohols. It was found that no, or Doctor of Philosophy in the University of Michigan. only slight, mydriasis was obtained with 1 4 % (2) Lilly Endowment Fellow. (3) Von Brucke and Juucrer [Arch. crpll. Path. Pharmacol , 190, solutions of the hydrochlorides of the ketones and 516 (1938)) stated that this ester is an antispasmodic but no desecondary alcohols listed below. scription of ita preparation seems to have been published (4) Kreitmair, Klioe. Wschr., 16, 676 (1936). Ketones : aminomethyl phenyl,l8diethylamino(5) groner, ibid., 16, 678 (1936). (6) Hdpern, Arch, in;. Pharmaccdynarn. ThnaD., 69, 179 (1938) (7) Fromherz, Arch. cxptl. Path. Pharmacol , 178, 113, 126 (1933) (8) During the lost few years a number of esters have been prepared primarily in the hope that they might be found to be antispasmodis; their mydriatic activity was discovered more or less incidentally during routiw: pbsrmacological tests. Among the very few studies which deal with the relatbnshlp between chemical structure and mydriatic activity those of Pymao [ J . Chem. SoC., 111, 1108 (1917)l and of von Braun, Braunsdorf and RIith [Bcr., 66, 1666 (1922)l deserve mention
(9) As early as 1808. Crum, Brown and Fraser [Trans. Roy. Soc Edinburth, 96, 708 (1888)l discovered that the mydriatic action of methylatropinium sulfate is about the same as that of atropine Y U I fate. (10) Horenstein and Pahlicke, Ber., 71, 1654 (1938) (11) Pitini, Arch. itrlernat. de pharmacodyn. et de Thrrapie, 14, 72 (1905).
(12) A 10% solution was required. (13) Mannich and Hahn, Bcr., 44, 1616 (1911). bromid+2.
Used as hydro-
SYNTHETIC MYDIUATICS
Feb., 1942
429
methyl phenyl,I4 8-dimethylaminoethyl phenyl,l6 found 119' (11 mm.)], 8 g. of cyclohexyldi-(p-hydroxy6-diisoamylaminoethyl phenyl, piperidinomethyl ethyl)-amine which boiled at 175-178' (12 mm.) (the boiling point reported is 180-184' (14 mm.) [British Patphenyl. ent 297, 484; Chem. Zentr., 99, I, 1683 (1929)l and 42 g. of unchanged cyclohexylamine. A mixture of 58 g. of 8Experimental The alcohols were obtained by the processes indicated below. The chloride hydrochlorides were produced when the alcohol, dissolved in chloroform, was treated with thionyl chloride. When the basic chloride was required, the latter was liberated from an aqueous solution of the salt and used immediately. The two procedures, A and B, used for the preparation of the esters are illustrated in the case of p-piperidinoethyl benzilate hydrochloride. TABLE I ALCOHOLS AND CHLORIDE HYDROCHLORIDES Alcohol B . p., " C . #-Aminoethyl 8-Butylaminoethyl @-Diethylaminoethyl 8-Dibutylaminoethyl @-(Methy1cyclohexylamino)ethyl 6 @-(Dicyc1ohexylamino)-ethyl 7 8-Methylphenylaminobethyl 8 #-PiperidinoethyI 9 #-Morpholinoethyl 10 y-Piperidinopropyl 11 6-Piperidinoisopropyl 12 8,@-Dimethyl-y-piperidinopropyl 1 2 3 4 5
. I . . .
. . . . .0
.....
8
.....n
Chloride hydrochloride M. p.. OC.a
.....b . . . . .d
21&211'
. . . . .h
115-116 (13 mm.)i . . .. .i 165-167 (6 mm.)b 185-186' 151-153 ( 1 5 m n 1 . ) ~ . . . .n 196-199' 229-231' 220-2229 . . . . .I
.
.....
.....
191-194'
203-204u
. . . . .v
. . . . .w
B
Salts 3 and 6 were dissolved in alcohol and precipitated by ether; 8 was recrystallized from a mixture of alcohol and ethyl acetate; 11 was recrystallized from amyl acetate. * We used the bromide hydrobromide ("Organic Syntheses," Vol. 18, p. 13). Matthes, Ann., 315, 112 (1901). The chloride boils a t 113-116' (23 mm.). Anal. Calcd. for CaHlrNCl: N, 10.33. Found: N, 10.34. Incidentally the alcohol hydrochloride was prepared by passing hydrogen chloride into an ether solution of the alcohol; the precipitated salt was recrystallized from a mixture of acetone and alcohol; m. p. 135136'. Anal. Calcd. for CsHleONCl: C1,23.21. Found: 54, 2928 Cl, 23.09. Horne and Shriner [THISJOURNAL, (1932)l prepared this substance but did not report a Gough and King [J. Chem. Sac., 2436 melting point. (1928)l found the same melting point; Slotta [Ber., 68, 758 (1935)l reported 212'. Barnett, Jenkins, Peet, Dreger and Adams, THIS JOURNAL,59, 2248 (1937). The chloride boils a t 114-115' (23 rnm.). Anal. Calcd. for CloHzlNCl: N, 7.31. Found: N, 7.15. When a mixture of 99 g. of cyclohexylamine, 25 cc. of ethylene oxide and 9 cc. of water was t r a t e d according to the general procedure of Matthes (Ref. c ) there was obtained 50 g. of B-(cyclohexy1amino)-ethanol which boiled at 127-130' (15 mm.) [Wedekind and Bruch, Ann., 471, 91 (1928),
'
(14) Adams and du Vigneaud [THIS JOURNAL, 46, 2098 (1924)j desfsihed the base. This product was tested a8 the lactate. (15) Mannich and Heilner, Bel., S6, 359 (1922). (16) Blicke and Blake, THISJOURNAL, Sa, 235 (1930); we found the melting point of the hydrochloride to be 220-221' instead of 210-2110.
(cyclohexy1amino)-ethanol and 58 g. of formalin was heated on a steam-bath for twelve hours, sodium hydroxide added and the (3-(methylcyclohexylamino)-ethanol extracted with ether; yield 51 g. Wedekind and Bruch [Ann., 471, 94 (1928)l found the boiling point to be 106" (10 mm.). The chloride boils at 99-100' (11 mm.1. Anal. Calcd. for CoHlsNCI: N, 7.92. Found: N, 7.98. When a mixture of 90.5 g. of dicyclohexylamine and 20 g. of ethylene chlorohydrin was heated for five hours at 150', the base liberated with 40% sodium hydroxide solution and extracted with ether, there was obtained 30.8 g. of 8(dicyclohexy1amino)-ethanol; b. p. 165-167' (6 mm.). The boiling point reported is 135' (2 mm.) [British Patent 351,605, Chem. Zentr., 103, I, 102 (1932)l. ' T h e reported melting point is 186' (Ref. k). m From 53.5 g. of methylaniline and 40.0 g. of ethylene chlorohydrin there was obtained 42 g. of 6-(methylphenylamin0)-ethanol; b. p. 151-153' (15 mm.). Laun [Be?., 17, 676 (1884)J reported 218-219' (110 mm.). " The chloride boiled at 126-128' (8 mm.); von Braun and Kirschbaum [Ber., 52, 1719 (1919)l found 134' (13 mm.). Twenty-seven grams of ethylene chlorohydrin was added to 58 g. of piperidine in a flask fitted with a reflux condenser. After the initial reaction had subsided, the mixture was heated for three hours on a steam-bath, dissolved in water, 40% sodium hydroxide solution added and the p-piperidinoethanol extracted with ether; yield 37 g.; b. p. 196--199'. Ladenburg, Ber., 14, 1877 (1881) ] found 199'. Dunlop [ J . Chem. Sac., 101, 2002 (1912)l found 231". This alcohol was obtained in 85% yield by Knorr's general method [Knorr, Ann., 301, 9 (1898)] from morpholine, ethylene oxide and water; b. p. 220-222". The chloride boiled at 104-106' (29 mm.). Mason and Block [THISJOURNAL, 62, 1446 (1940)l reported 93-94' (12 mm.). Anal. Calcd. for CeH1zONCl: N, 9.36. Found: N, 9.28 a We used the bromide hydrobromide; m. p. 210-211 '. Gabriel and Stelzner [Ber., 29, 2389 (1896)l found 212'. To ohtain this substance, 73.5 g. of N-(y-phenoxypropy1)piperidine and 350 cc. of 48% hydrobromic acid were refluxed in an all glass apparatus for six hours, the mixture evaporated t o dryness and the hydrobromide (70 g., 76%) dissolved in alcohol and precipitated with ether. N-(7Phenoxypropy1)-piperidinewas prepared in 84% yield in the following manner: 72.0 g. of y-phenoxypropyl bromide ("Organic Syntheses," 9, 72) was added to 56.5 g. of piperidine and, after the initial reaction had subsided, the mixture was heated for three hours on a steam-bath, water added, the mixture acidified and unchanged bromide extracted with benzene. The aqueous layer was made strongly alkaline, the oily layer separated and the water extracted with ether. The product boiled at 152-154" (5 mm.); von Braun [Ber.. 42,2041 (1909)] reported 172" (13 mm.); yield 64 g. Laun [ibid., 17, 682 (1884)) found 194". Wenker [THIS JOURNAL, 60, 158 (1938)l found 204'. Mannich, Lesser and Silten, Ber., 65, 384 (1932). Mannich and Baumgarten, ibid., 70, 213 (1937).
'
F. F. BLICKEAND CHARLES E. MAXWELL
430
Vol. 64
TABLE I1 ESTERSO F BENZILIC ACID(HYDROCHLORIDES AND METROBROMIDES) (CBH&C(OH)-COO--R-HCl (or CHaBr) CsHll = cyclohexyl; NC&O = morpholino; NCsHlo = piperidino. Tested on the rabbit's cornea, compounds 2 , 4, 6, 11, 13, 17 and 19 were found to be inactive as local anesthetics; compounds 3, 7, 8 and 9 showed some activity while compound_20proved to be a strong anesthetic. Compounds 1and 10 were recrystallized from alcohol; 2 and 5 from ethyl acetate; I and 17 from amyl acetate; 3, 6, 9, 11, 12, 13, 15 and 19 from a mixture of alcohol and ethyl acetate; 4, 8, 14, 16 and 18 were precipitated from an alcoholic solution by the addition of ether. % Halogen K 1A,R 1 -CHzCHzNHz 2 -CH&HzNH(C4Ho).HCl B 4 '% 3 -CHzCHzN(QHs)z'HCl 4 --CHZCHZN(CZH~)~CH~B~~ 6 -CH~CH~N(C~HS)~'HC~ 1% 6 -CHL!HZN(C~H&CH~B~ 7 ---CHzCHJV(CHs)(CsH11).HCl B 8 -CHzCH2N(CH3) (CeH11)CH3Br 9 --CH&HgN(CsHii)2.HCl u 10 --CH2CHzN(CH3) (CeH6) u 11 -CHsCH2N(CHa) (CeH6).CH3Br B 12 ---CH~CH~NC~HSO.HC~ 13 . - C H Z C H ~ N C ~ H B O , C H ~ B ~ -4,B 14 -CHzCHzNC6Hio,HCi 15 ---CHzCH2NC5H~o,CH3Br 16 -CH&H$H&C6H10.HBr A 17 --CH~CH~CHZNC&O.CH~B~ 18 --CH(C&)C&NCsHio.HCl A 19 -CH(CH&2HpNC5H10CHBBr 20 -CHzC(CHs),.CHzNC,Hio.HCl A
a
?VI. p . , o c .
IIb
-0
+++
+ +
3. f 0
0
--
+ 0
--
0
7-
++
f+ff
t
++ +
+++ +++
-_
0
++
170-171 121-122 174-175' 169-170 126-127 138-139 154-155 153-154 197-198 78-79 170-180 180-181 203-204 175-176 202-203 168-169 168-169 167-168 176-177 170-171
+
Calcd.
C1eH1703~ (5.16 C2oHzeOsNCI 9.75 CZOHZBO~NC~9.75 C Z I H Z S O ~ N B 18.92 ~ CtrHarOaNCl 8.44 C26H3603NBr 16.70 C23H3oOBNCl 8.78 CzrHa2OaNBr 17.28 CzsH.&NCl 7.51 C23HZ303N (3.88 GrHzs03NBr 17.51 CzoHzr04,"Cl 9.38 Cz~Hza04NBr 18.32 C2iHzaOsNCI 9.69 CnzH2gOaNBr 18.40 C22H2803NBr 18.40 G3Ha03NBr 17.82 GzHz808NCl 9.09 C23H3~03NBr 17.82 '&H3?03NCl 8.48
++
Method of preparation. 'Mydriatic activity: 0 = inactive; = poor; = moderate; = excellent. ' The same melting point has been reported (Ref. 8). Methobromide.
+ +++
Found
5.13N) 9.70 9.80 18.81 8.35 16.81 8.68 17.19 7.48 3.84N) 17.53 9.31 18.22 9.64 18.42 18.42 17.86 9.09 17.78 8.57 = good;
+++
S-Piperidinoethyl Benzilate Hydrochloride. -(A) A mixture of 31.9 g. (0.12 mole) of potassium benzilate17 and 22.5 g. (0.12 mole) of 6-piperidinoethyl chloride hydrochloride was heated for two hours a t 140". The material was extracted with hot alcohol, the extract concentrated, cooled and ethyl acetate added whereupon the ester hydrochloride precipitated; yield of crude product 44 g. (99%). (B) The hydrochloride of 6-piperidinoethyl chloride was dissolved in nTater, a saturated solution of sodium carbonate added, the base extracted with ether, the solution dried with fused sodium sulfate and the ether removed in a current of dry air. The product was used immediately. To 7.4 g. (0.05 mole) of the basic chloride there was added 11.4 g. (0.05 mole) of benzilic acid, dissolved in 50 cc. of isopropyl alcohol. The mixture was refluxed for twelve hours, the solvent removed under diminished presSure on a steam-bath and the residue washed with ethyl acetate; yield 13 g. (70%). The crude product was purer than that obtained by process A. p-fiperihoethyl Bazfiate Methobromide.--X solution of 3.4 g. (0.01 mole) of the ester in 25 cc. of absolutc alcoho1 was poured into a magnesium citrate bottle, cooled to 0 O and 10 cc. of methyl bromide added. After several hours a t ordinary temperature about two-thirds of the alcohol was removed and the ~nethobroitiideprrcipitated with absoiute ether; yield 4.0 g. (940h). The hydrobromide and the methobromide of Y -piperi-
dinopropyl benzilate both melt a t 168-169 O and even though the mixed melting point was 152-157', the methobromide was hydrolyzed in order to establish its identity. A mixture of 4.58 g. of the methobromide, 1.68 g. of potassium hydroxide and 10 cc. of absolute alcohol was refluxed for three hours, the precipitated potassium benzilate (2.73 g. or 97%) filtered, dissolved in water and the solution acidified; 2.21 g. of benzilic acid was obtained. The alcoholic filtrate was neutralized with hydrobromic acid, evaporated t o dryness, the residue treated with hot alcohol and the undissolved potassium bromide removed by filtration. Upon addition of ethyl acetate to the filtrate 2.11 g. (950j0) of the methobromide of ypiperidinopropyl alcohol precipitated; m. p. 138-139'. The hitherto unknown methobromidewas obtained when a mixture of 14.3 g. of 7-piperidinopropyl alcohol, 19.0 g. of methyl bromide and W cc. of absolute alcohol was allowed to remain a t ordinary temperature for three hours and ether then added; the precipitated product weighed 22.58. (93%) and melted at 138-139" after recrystallization from acetone which contained a small amount of alcohol. A n d . Calcd. for CsHgoONBr: Br, 33.56. Found: Br, 33.51. p-Diisoamylaminoethyl Phenyl Ketone Hydrochtoride.18 --A mixture of 13.8 g. of acetophenone, 23 g. of diisoamylamine hydrochloride, 3.4 g. of trioxymethylene and 20 cc. of absolute alcohol was heated for two hours on a steambath; the trioxymethylene dissolved gradually. Upon
(17) Benzilic acid was prepared by oxidation of benzoin with Tmlassiiim bromate i"0rganic Syntheses," roll. Yo1 I p 8 2 )
(18) Prepared by the general mcthod of Mannirh and Heilner, Ner.. 65, :
