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ERICHMOSETTIG, FORREST W. SHAVER AND ALFREDBURGER
Vol. BO
3-7, 35.5 g., 85" (29 mm.), 1.4260; residue, 0.8 g. Frac- hours gave a crude carbinol which, on fractionation through tions 3-7 were a 92% yield of n-propylneopentylcarbinol. column VI, gave: 1-2, 3.4 g., 80-94' (12 mm.), 1.4271A n d Calcd. for CQHZOO: C, 75.0; H, 14.0. Found: C , 1.4326; 3-12, 80.7 g., 96" (13 mm.), 1.4338, dad 0.8225. Fractions 3-12 represented an 89% yield of n-amylneo74.5; H, 14.5. The phenylurethan had m. p. 82". Preparation of n-Butylneo~ntylcarbinol.-n-Butyi neo- pentylcarbinol. Anal. Calcd. for CllH~40:C , 76.7, pentyl ketone, b. p. 69' (13 mm.), n*%1.4204, d 9 0.8143, H, 14.0. Found: C, 76.9; H, 14.0. Phenylurethan, m. p was prepared in 77% yield by the action of n-butylmag- 60.5-61'; a-naphthylurethan,m. p. 63-63.5'. nesium bromide on t-butylacetamide,m. p, 132'. Heating Summary of 26.7 g. (0.17 mole) of the ketone with 20.4 g. (0.I mole) of aluminum isopropylate in 120 CC. of dry isopropyl alco1. The action of n-propyl-, n-butyl- and nhol was conducted for twenty-four hours with the removal amylmagnesium bromides on t-butylacetyl chloof acetone, during the course of the reaction, through column VI: 1-2, 3.1 g., 90-99' (30 mm.), 1.4254-1.4300; ride produced, together with the expected tertiary 3-522.2 g., 95" (24 mm.), 1.4308, d l 0.8212; residue, 2.0 carbinols and olefins, n-propylneopentylcarbinol g. Fractions 3-5 represented a 93% yield of n-butylneo- in 24.4% yield, n-butylneopentylcarbinol in 20.5% pentylcarbinol. Anal. Calcd, for C10H320:C , 75.9; H, yield, n-amylneopentylcarbinol in 19.3% yield, re13.9. Found: C, 76.7; H, 14.1. The a-naphthylurethan spectively. No reduction product could be isohad m. p. 70-70.5". Preparation of n-Amylneopentyle~b~ol.~-Amylneo-lated when ethylmagnesium bromide was used. pentyl ketone, b. p. 86" (13 mm.), 1.4247, d% 0.8184, 2. The preparation aiid physical constants of was prepared in 60% yield from n-amylmagnesium bro- n-propylneopentyl-, n-butylneopentyl-, and nmide and t-butylacetamide. Heating of 51 g. (0.25 mole) of aluminum isopropyiate in 400 cc. of dry isopropyl alco- amylneopentylcarbinols have been reported. hol with 90 g. (0.53 mole) of the ketone for thirty-three STATE CQLLEGE,PENNA RECEIVEDJUNE 29, 1938
[CONTRIBUTION FROM
THE
COBBCHEMICAL LABORATORY,UNIVERSITY OF VIRGINIA]
Studies in the Phenanthrene Series. XXI. Morpholino Alcohols Derived from Phenanthrene'
w.
BY ERICH MOSETTIG,FORREST SHAVER
As part of a systematic search for substances with central narcotic action, which, eventually, rphine, we have synthesized in previous years a large variety of amino alcohols derived from phenanthrene.2 Dr. N. B. Eddy a t the University of Michigan has shown3that some of these phenanthryl amino alcohols produce in the cat marked analgesia and a physiological pic(1) (a) The work reported in this paper is part of a unification of effort by a number of agencies having responsibility for the solution
University of Virginia, and the University of Michigan. (b) Communications XIX and XX of this series have been submitted to the Journal of Organic Chemistry. TEIS JOURNAL, 56, 3448 6, 1745 (1934); (c) van de 1935); (d) Mosettig and Kamp and Mosettig. ibid , mettig, ibid., 58, 1570 (1936); 1036); (h) van de Kamp, 38); (i) Burger, ibid., 60,
1533 (1838). (3) (a) Eddy, J . Pharmacol., 56, 410 (1085); (b) Eddy, ibid., wettig. Eddy and co-workers, "Ats with Central Narcotic and, in Partempts ticular, pplement 138 to the U S. Public Health Reports, Government Ptinting Office, Washington. D C , in press. ( Proc.)
AND
ALFREDBURGER
ture very like that of morphine. Furthermore, a distinct interdependence of degree of analgesic action and nature of the tertiary amino group became evident when, in the various groups of amino alcohols, individual members differing only in the basic group were compared. Thus, for example, the diethylamino derivatives of types I and I1 are superior to the dimethylamino derivatives.4 Extension of these studies to morpholino alcohols (I-VI) seemed justified, in order that comparison with the corresponding diethyl and piperidin0 compounds might be made. The preparation of the various amino alcohols proceeded quite normally except that in the catalytic hydrogenation of 2morpholino- 1-keto-1,2,3,4-tetrahydrophenanthrene the two diastereoisomeric forms (A and B) of the corresponding amino alcohol (type 111) were formed. We have (4) Such regularities have been observed ulso in the dibenzofuran series [Eddy, J . Phormacoi., R8, 158 (1938); Mosettig and Robinson, THISJOURNAL, 57, 2186 (1935); Robinson and Mosettig, ibid., SS, 088 (1036)l and in the carbazole series [Ruberg and Small, ibid , 60, 1591 (1938))
Oct., 1938
MORPHOLINO ALCOHOLSDERIVEDFROM PHENANTHRENE
2466
2466
ERICHMOSETTIG. FORREST W. SHAVER AND ALFREDBURGER
Vol. 60
' To a solution of 5 g. of 2-w-bromoa~etyIphenathrene~~in 30 ml. of benzene for forty-eight hours. The red mixin 40 ml. of dry benzene was added 3.5 g. of morpholine ture was extracted with water and a crystalline residue was ( n m 1.4547), ~ and the mixture was allowed to stand over- obtained by evaporation of the benzene layer; yield 55%. night. I t was diluted with ether, the solution was washed e Seventeen and five-tenths grams of No. 22 in 400 ml. of with water, and the solvent was evaporated under reduced methanol and 0.5 g. of platinum oxide absorbed approximately the calculated amount of hydrogen in a week. The pressure; yield 89%. The hydrochloride was obtained by adding an ethereal mixture of crystalline hydrochlorides was converted to the solution of hydrogen chloride to an acetone solution of the bases, m. p, 95-127'; yield 16 g. This mixture was distree base. solved in 100 ml. of hot ethanol and allowed to crystallize. ' Liberated from No. 4 with sodium hydroxide solution The first crop (A) was filtered when the temperature of the and extracted into ether solution had reached 30'. Another crop (B) was obtained " A suspension of 4 g. of No. 2 and 0.16 g. of platinum by allowing the filtrate to crystallize slowly. The base A oxide in 160 ml. of ethanol absorbed the required amount was recrystallized from ethanol three times to the constant yield 1 g. The hydrochloride was of hydrogen in about ten hours. The catalyst was filtered m. p. 179-180'; out and the solvent was evaporated under reduced pres- formed from the base in acetone suspension with ethereal sure. The residue was dissolved in acetone, the acetone hydrogen chloride. The acetyl derivative was obtained by solution was diluted with ether, and allowed to crystallize; the action of acetic anhydride in pyridine solution. The vield 75%. base B was recrystallized from ethanol three times to the e Obtained like No. 1, by employing 8.3 g. of 3-w-bromoconstant m. p. 139-140.5'; yield 1 g. In a second experiacetylphenanthrene, 40 ml. of benzene, and 5.6 g. of ment, similarly, two bases were obtained. The one was morpholine. The amino ketone was purified through the base A of m. p. 179-180', the other one melted a t 153-1,54" hydrochloride; yield 85%. (B,). A new determination of the melting point of B Prepared like No. 4; yield 70%. showed that this compound had changed, in the meantime, LJ A mixture of 3 g. of 2-acetylphenanthrene,5 1 g. of parato the higher-melting form. ' Prepared by the Mannich reaction, by heating to formaldehyde, 2 g. of morpholine hydrochloride (prepared by neutralizing morpholine with alcoholic hydrogen chlo- boiling a solution of the reactants (10 g. of I-ketotetraride and precipitating the salt with ether), and 12 ml. of hydrophenanthrene, 12 g. of paraformaldehyde, and 7 g. of isoamyl alcohol was boiled under reflux for six minutes. morpholine hydrochloride) in 50 ml. of isoamyl alcohol for The amino ketone hydrochloride precipitated out within four minutes. The crude hydrochloride was washed with this time, and the precipitation was completed by addition acetone; yield 41%. Prepared by catalytic hydrogenation of No. 31; yield of ether to the cooled reaction mixture. The free base was liberated from the salt with ammonium hydroxide, and 94%. Prepared like No. 21 by allowing 3-bromo-4-ketoextracted into ether. The ether solution was washed with water. The base was purified by sublimation in an oil- 1,2,3,+tetrahydrophenanthrene to react with morpholine in benzene solution; yield 63%. pump vacuum, and cqstallization; yield 73%. * Prepared from No. 12 and purified by sublimation in " Prepared by catalytic hydrogenation of No. 35; yield an oil-pump vacuum. 68%. " Six grams of 4-keto-1,2,3,4-tetrahydrophenanthrene Prepared like No. 4; yield 63%. was boiled with 4.2 g. of morpholine hydrochloride, 7.2 g. A suspension of 0.3 g. of the amino alcohol in 5 ml. of dry pyridine and 1 ml. of acetic anhydride was allowed to of paraformaldehyde, and 24 ml. of isoamyl alcohol for stand for forty-eight hours. The solvent was evaporated twenty-five minutes. The reaction mixture was worked under reduced pressure, the reqidiie was washed with up in the usual manner; yield 30%. acetone and recrystallized. never observed in our previous work the simulIr Prepared from No. 15. Prepared like No. 9, except that the hydrochloride, as taneous formation of diastereoisomeric amino precipitated from the reaction mixture, was purified by alcohols under analogous conditions. When a crystallization; yield 76%. Prepared by catalytic hydrogenation of No. 15; yield noble metal catalyst is employed in the reduction of amino ketones, generally only one of the two 82%. * Ten and two-tenths grams of 3-methoxy-9-w-bromo- possible amino alcohols is formed, while in the acetylphenanthrene2bwas allowed to react with 7.5 g. of sodium amalgam reduction both forms may be morpholine in 50 ml. of benzene for one hour. The mix- obtained. ture was extracted with water, the benzene solution was The possibility that one of the two compounds dried, evaporated in a vacuum, and the oily residue was converted to the hydrochloride in acetone solution; yield A or B is a hexahydro derivative cannot be excluded entirely, since, because of lack of material, 82%. Prepared by catalytic hydrogenation of No. 19 (metha- we did not attempt to demonstrate the isomerism nol, platinum oxide); yield 70%. The free base could by converting A and B to identical desoxy comnot be obtained crystalline. Nine grams of l-keto-2-bromo-l,2,3,4-tetrahydrophe- pounds. ( 6 ) See Hyde, Browning and Adam, ibid., SO, 2287 (1928), end rianthrene2d and 7.5 g. of morpholine were allowed to react
'
'
'
Mannich, Borkowskp and Wan Ho Lin, Arch. Pharm., 275, 54 (1937). ( 5 ) Mosettig and van de Kamp. THISJOURNAL, 68,3704 (1930)
See also Shriner and Teeters. THIS J O V R S A L , 60, 4.16 (19381
CHEMICAL STRUCTURE AND ANESTHETIC ACTIONOF DIOTHANES
Oct., 1938
2467
/--
OH RzNCHz
HZC-CH~
NRz =
-4 \ /
'0
HzC-CHa
All of the amino alcohols that have been tested so far (Nos. 4,8, 20, 24, 27, 33, 37, 40 of the accompanying table)7 show only low analgesic action or none at all. In the instances where a comparison with analogous diethylamino and piperidino compounds was possible, it became apparent that replacement of the diethyl or piperidino group by the morpholino group resulted
UNIVERSITY, VIRGINIA
(7) Eddy, unpublished results.
[CONTRIBUTION FROM THE
in a decrease of analgesia in the ratio from 2:l to about 8:l. summary The synthesis of a series of morpholino alcohols from 2-acetylphenanthrene, 3-acetylphenanthrene, l-ketothrene, 3-methoxy-9-acetylphenar. tetrahydrophenanthrene and 4-keto-tetrahydrophenanthrene is described. RECEIVED JULY 9, 1938
DEFT. OF CHEMICAL ENGINEERING, UNIVERSITY OF CINCINNATI, AND THE RESEARCH LABORATORIES OF THE WM. s. MERRELL COMPANY]
An Investigation of the Effect of Chemical Structure on Local Anesthetic Action of Diothane Analogs' BY ELSIEM. WALTER* Most local anesthetics in general use contain alkyl esters of 2-furoic acid where the alkyl vara benzene ring somewhere in their structure. In ied from methyl to amyl. They found that all fact, many early experimenters claimed that a of the compounds possess local anesthetic action compound must contain a benzoyl group to ex- which increases with the size of the alkyl from hibit anesthetic action. In 1925, Gilman and methyl to amyl. The amyl furoate has approxiPickens3 studied the effect of various aromatic mately the same activity as cocaine. It was rings on the anesthetic action of procaine. They pointed out by the authors that the correspondprepared the furan, thiophene, and pyrrole ana- ing benzoates show either incomplete or no aneslogs of procaine. Their results indicate that the thetic action. Since very little work has been done on the order of decreasing activity is benzene > pyrrole > thiophene > furan > methyl. More recently, effect of substituting various aromatic rings for however, Phatak and Emerson4 prepared various the benzene ring in the structure of local anesthetics, it was decided to prepare some furan (1) Prom a thesis in partial fulfilment of the requirements for the degree of Chemical Engineer, University of Cincinnati, June, 1938. analogs of Diothane (piperidinopropanediol di(2) Present address: Institutum Divi Thomae, Cincinnati, Ohio. phenylurethan hydrochloride6)and compare their (3) H. Gilman and R. M. Pickens, Tam JOURNAL., 47,245 (1925). (4) N. M. Phatak and G . A. Emerson, J . Pharmacol., 68, 174 (1936).
(5) T.H.Rider, THISJOURNAL., 63, 2115 (1930); T.H.Rider and E. S . Cook, J . Phavmacol., in press.
