Resolutions. A. Ic.-(i)-Ic6 ( 2 . 2 g), 1.8 g (1.1.5 eqiiiv) of I-mandelic acid (Aldrich Chemical Co., Inc.), 10 nil of RIe2C0, and 1 nil of Me011 i5ei.e heated to d u t i o n and left at 2.5" for 3 hr and at -,5' for 18 hr; yield 1.7 g, mp 173-1Y5°. This white solid, recrystallized from RIeOH, gave 1.2 g of ( - )-IC I-mandelate, mp 190-192", which in LIeOH-aqueous NH, yielded 0.65 g (60%) of (-)-IC, mp 211-212', [aIZnn-72..5", atter a recrystallization from ;\IezCO or LfeOH [ilnal. (ClaHIqNO) C, IT] ; hydrochloride (from absoliite EtOH-HCl then rerryhtallizal i o n fiom absolute EtOH), nip 262-265', [a120n-49.6'. dnnl. (CirHLoClXO)C, H. The cwnbined filtrates (from the 1.7 p. of /-mandelate and from .tallization of this 1.i g) were concentrated to 2-3 ml and treated with excess aqueous KH, to give 1.5 g of base mixtiire. This material, 1.2 g of d-mandelic acid (Aldrich), 6 ml of XenCO, and 2 ml of LleOH were warmed to solution, cooled, and kept at 5'' for 1 hr to give 1.7 g of white solid, mp 184-188'. One rerrystallization from 3-6 ml of MeOH gave 1.3 g of (+)-ICdmandelate, nip 1(31-192.5", in turn converted t o 0.7 g (63%) of (+)-IC,mp 20!)-210.5°, [ " ] ~ O D +74,s0,after a recrystallization from LIenCO [ilnal. (C14HI9?;0) C, H ] ; hydrochloride (from j l\IeOIT-RIe2CO), mp 262-26*5", [ a ]2 f l ~$49.1". B. Id.-Racemate Id6 (.i.0 g), 3.3 g of d-mandelic acid, 13 ml of absoliite EtOH, and 5 ml of lZIezCO were heated to solution, filtered, and left at 23" overnight to give 1.7 g (41yc) of white solid which was recrystallized from AIeOH-MesCO ( 4 : 15 ml). Cooling to 0" gave 0.9 g of (-)-Id d-mandelate, mp 170.5-li2°, [cT]~"D +2,5.1°. Anal. (C23H?9N04)C, H. It gave 0.5 g of (-)-Id from aqlieoiis NHa; mp 208-210°, [ C ~ ! ~ O D -49.7". Anal. (C16H21N;0) C,H. The hygroscopic hydrochloride (from ethereal HCI) was recryptalliaed from hIeOH-Me&O and carefully dried for 3 hr at 100' in z'acuo just prior to analysis; mp 186.5-188.3", sealed capillary. Anal. (C13H2;C1SO)C, H. The combined filtrates (from isolation and recrystallization of (-)-Id d-mandelate) were concentrated to 7-10 ml, made basic with diliite ?iH40H, diluted with H?O, and cooled to give 4.3 g of a mixture of ( i)- and( +)-Id. This mixture, 2.8 g of I-mandelic acid, 8 ml of XIeOH, and 3;i ml of Me&O, was warmed to solution and filtered and the filter was washed with XIe2C0. The combined filtrate and washings were distilled to half-voliime, diluted (hlenCO). and again distilled to half-volume. Addition of Lle.CO to 75 ml and refrigeration gave a white solid which was recrystallized from absolute EtOH-RIeCCO (1 1: 25 ml) giving 1.3 g (31%) of (+)-Id I-mandelate, mp 170..5-171.5", ( a I z o D -21.3". Anal. (CP.,HPYN04) C, H . The (+)-Id base melted at 209.5-211.,5' and had [ L Y ] ~ +,5l0. ~D dnal. (C1;HzlSO) C, H. The hydrochloride had mp 188-18!1" and was hygroscopic like ( 5 ) K. 13. Eddy, J. G. Murphy, and E. L. May, , J . O r g . Chrm., 22, 13TO (l95i);E . 11. Fry and E. L. AIay, ihid., 26, 252 (lW.31). (6) 5 . Saito and E. L. M a y . ihid.. 27, 948 (1962).
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PII.iI{M.\(Y>LOGIC P I ~ I I I ' I ~ X ' I ' I P O : ~F
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Nod 0.02-0,033 nalorphine - )-Ia 0.9 Yo +)-Ia Inactive S o -)-Ib 1. 2 Noe 0 . 1 nalorphiiie Intermediate So )-Ih 7 ,$1 So! 0.0" nalorphiiic 1. s - )-IC T.ery low No (+)-IC 2 % .9 0.6 SOQ 0.02.5-0.0.5 nalorphine ( - )-Id Low so (+)-Id 21.8 0.8 Noh 0.2 rralorphine ( - )-Ie High So ( + )-Ie 12.3 1.2 High so 3lorphiiie 7.3 Iiitermediate So Codeine Administered as HC1 salts in water except for morphine (as sulfate). h X. B. Eddy and 1). Leimbach, J . Pharnmcol. E ~ p f lThrrap., . 107, 38.5 (1953), and A. E.Jacobson and E. L. l l a y , J . J I p d . Chrm., 8,563 (1963). Sf. ref 2 4 . From 0.5-8 mg'kg. e From 0.5-32 mg/kg. J From 1.0-20 mg 'kg. From 2-16 mg 'kg. h From 0.3-3 mg/kg.
+
cf.
Q
the enantiomer. Anal. (Cl;H&INO) C, H. (&)-Id was recovered EL? in the cme of Ic. C. 1e.-Absolute EtOH (20 ml), 2.0 g of (=k)-Ie,7 and 2.0 g of cl-10-camphorsdfonic acid (Eastman) were heated to soliltion and left at room temperature for 6 hr to give 1.3 g of squaie plates, mp 243-247" after filtration and washing with cold EtOH. This salt yielded 0.65 g (6,5%) of (+)-Ie (from aqiieoiis lIeOHNH,), mp 235-237", [ a ]2 0 ~+69.8", after a recrystallization from hIeOH. Anal. (Cl;H&O) C, H, N. The hydrochloride +50.8". Anal. (from CPrOH-Et20) had mp 166-169", [ L Y ] * ~ D (Ci;H2&1NO) C, H, CI. The filtrate and washings from the 1.3 g of square plates above were made basic with XHeOH and diluted with an eqilal volume of HPO. Cooling gave 1.2 g of ( - )- and ( i ) - I e which, with 0.8 g of d-mandelic acid, was heated to solution in 5 ml of 31egCO. After 6 hr at 25", 1.1 g of (-)-Ie mandelate, mp 209-211", was filtered and converted to 0.63 g (6353) of (-)-Ie, mp 236with LIeOH-diliite ?jH,OH. Anal. 238", [ a ]2 0 ~ -70.0', (CliH2jNO) C, H, S . The hydrochloride melted at, 106-16R0, [ a ] * O D -49.3'. Anal. (CiiH26ClSO) C , H. ( 7 ) J. H. Aaer, R. E. Fullerton, and E. L. May, .I. X e d . Chrm., 6, 322 F.Chianell, J. H. A m r , and E. I.. )lay, ilind., 8 , 23.5 (1961j).
(1963): C.
