[CONTRIBUTION FROM THE CHEMISTRY LABORATORY
OF THE
UNIVERSITY OF MARYLAND]
SSNTHETIC ANTIMALARIALS. SOME P-DIALKYLAMINOETHANOLS -4ND CY-ALKYLAMINOBORNEOLS’ NATHAN L. DRAKE, JOHN A. GARMAN, RICHARD M. PECK, WALTON
AND
EDWARD
Received June 17, 19.46
The present paper presents an extension of earlier work (1) in these laboratories, and is part of an extensive investigation of aryl dialkylaminoalkanols initiated a t the National Institute of Health (2). The preparation of the compounds described herein follows in general the methods of earlier work (1, 2). The two monoalkylaminoborneols were synthesized by reductive alkylamination of “camphor quinone” and subsequent reduction of the remaining carbonyl group by the Meernrein-Ponndorf method. The compounds prepared and submitted for testing are a-(4-biphenyl)-@diethylaminoethanol hydrobromide (SN-5371-13), a-(4-biphenyl)-p-di-n-butylaminoethanol hydrobromide (SN 5372-13), (~-(4’-bromo-4-biphenyl)-@-diethylaminoethanol hydrobromide (SN 6989-13), a-(4’-bromo-4-biphenyl)-P-di-nbutylaminoethanol hydrochloride (SN 5881-4), N-ethyl-a-aminoborneol hydrochloride (SN 9025-4), and K-n-butyl-a-aminoborneol hydrochloride (SN 8600-4) .z
The structures of the biphenyl-substituted compounds are clear from their method of preparation and earlier work on p-phenylphenacyl bromide (3). The structures of the alkylaminoborneolsare apparent from the work of Rupe and di Vignano (4). EXPEFSMENTAL3
a-(4-Biphenyl)-j3-diethylaminoethanol hydrobromide (SN-6371-25). Reduction of 12.5 g. of 4-biphenyl diethylaminomethyl ketone hydrochloride, prepared from p-phenylphenacyl bromide by a method quite similar to that described earlier (l),and purified by recrystallization from alcohol-ether, was accomplished with 15 g. of aluminum isopropoxide in 100 ml. of anhydrous 2-propanol. The mixture was boiled and the acetone formed was removed through a three-foot helix-packed column; when a negative test for acetone was obtained in a small test portion of the distillate, the reaction was considered complete. The remaining solvent was removed under diminished pressure and the residue was taken up in 10% hydrochloric acid. The acid solution was then made strongly basic and the organic base was extracted with ether. After the ether solution had been thoroughly dried, the hydrobromide of SN-5371 was precipitated by means of dry hydrogen bromide. The crude salt was recrystallized from alcohol-ether; after one recrystallization, the salt melted at 139140’; the yield in the reduction was 55%. Anal. Calc’d for ClsH2,BrNO: C, 61.9; H, 6.93. Found: C, 61.9; H, 6.77. 1 This work was carried out under a contract recommended by the Committee on Medical Research between the Office of Scientific Research and Development and the University of Maryland. 2 See “Antimalarial Drugs, 1941-1945”, F. Y. Wiselogle, Editor, in press. The Survey Number (SN) identifies the drug in the Survey Office and in the monograph. 8 Semi-micro analyses by J . Daniel Draper of this laboratory. 795
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DRAKE, GARMAN, PECK, AND WALTON
u-(.$-Biphenyl) -8-di-n-but ylaminoethanol hydrobromide (SNdS7r8-13). The preparation of this substance was carried out by the method described directly above. From 23.0 g. of crude amino ketone hydrochloride was obtained 14.5 g. of twice recrystallized hydrobromide (61.5%). SN-5372-13 melts at 110.4-111.3”. Anal. Calc’d for ClaH,ZBrNO: C, 65.01; H, 7.95; Br, 19.66. Found: C, 64.9; H, 7.94; Br. 19.58. a-(4’-Bromo-4-biphenyl)-~-diethylaminoethanol hydrobromide (SN-6989-IS). The hydrochloride of SK-6989 is sufficiently sparingly soluble in aqueous hydrochloric acid so that i t can be separated by filtration after the residue from the reduction of the amino ketone has been poured into cold hydrochloric acid; otherwise the preparation of SN-6989 from 4-(4‘bromopheny1)phenacyl bromide followed the scheme earlier described. The hydrochloride was converted into base, taken up in ether, and precipitated by means of dry hydrogen bromide from the dried ether solution. After recrystallization from alcohol-ether to constant melting point, the hydrobromide melted a t 193-195’. The over-all yield from the substituted phenacyl bromide was 55%. Anal. Calc’d for C18H23BrZXO: C, 50.34; H, 5.36; Br (ionic), 19.06. Found: C, 50.33, 50.76; H, 5.60, 5.55; Br (ionic), 18.81, 18.85. a-(4’-Bromo-4-biphenyl)-p-di-n-butylaminoethanol hydrochloride (XN-6881-4). This substance was obtained from the corresponding phenacyl bromide in the usual way. The product melts at 171.6-172.4”; the over-all yield from the bromide was 58%. Anal. Calc’d for Cz2HJ1BrClXO:C, 60.00; H, 7.04. Found: C, 60.06, 59.32; H , 6.55, 6.48. N-n-Butyl-a-antinocamphor hydrohloride (4). Amixture of 30 g. of “camphor quinone” and 14.6 g. of n-butylamine in 60 ml. of absolute alcohol was boiled under reflux for 2 hours and then hydrogenated in the presence of Raney nickel a t about 40-60 p.s.i. gauge pressure. After separation of the catalyst by filtration, the solution was evaporated t o remove the alcohol, and the residue was taken up in dry ether. Dry hydrogen chloride precipitated the amine salt; the yield was 44 g. of hydrochloride which melted at 257-260” (95%). Recrystallization of the crude substance from alcohol-ether yielded a product whose melting point was 272-273”. N-n-Butyl-a-aminoborneol hydrochloride (SN-8600-.4). Reduction of 34 g. of the above hydrochloride in a mixture of 120 g. of aluminum isopropoxide and 500 ml. of dry 2-propanol yielded 27 g. (78.5y0) of N-n-butyla-aminoborneol hydrochloride after the crude product had been once recrystallized from 80% alcohol. The hydrochloride melted at 313-314”. The crude hydrochloride crystallized from the reduction mixture after the latter had been poured into aqueous hydrochloric acid. Anal. Calc’d for C1,H&lNO: C, 64.14; H, 10.69. Found: C, 64.37, 64.35; H, 10.63, 10.71. N-Ethyl-a-aminocamphor. The hydrochloride of this amine (4) was obtained by a method like that described above for the corresponding N-n-butyl derivative; 34 g. of hydrochloride , m.p. 255-256” after recrystallization from alcohol-ether, was obtained from 41 g. of “camphor quinone” (60y0). The salt was converted to free base, taken up in ether, and used in the next step, after removal of the ether, without further purification. N-Ethyl-a-aminoborneol hydrochloride (SN-9026-4). From 17 g. of the amine described directly above was obtained 12 g. (60%) of once-recrystallized hydrochloride (alcoholether). K-Ethyl-or-aminoborneol hydrochloride melts with decomposition in a sealed capillary a t 369-370”. Anal. Calc’d for C12H2LXNO: C, 61.7; H, 10.0. Found: C, 61.8; H, 10.0. SUMMARY
The preparation of four a-aryl-P-dialkylnmioethanols and two N-alkyl-aaminoborneols has been described.
ALKAMINES OF BIPHENYL AND BORNEOL
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In five of the six cases studied, the final Meerwein-Ponndorf reduction was advantageously carried out on a salt of the amino ketone. COLLB~QPJ PABK,MD. REFERENCES (1) DRAKE AND GOLDMAN, J. Org. Chem., 11, 100 (1946). (2) MAYAND MOSETTIG, J . Org. Chem., 11, 1 (1946). (3) DRAKE AND BRONITSKY, J . Am. Chem. Soc., 62,3715 (1930): (4) RUPEAND DIVIGNANO, Helu. Chim. Acta, 20, 1078 (1937).
