2480 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 16
Singh et al.
showed it to be a mixture of 8 and its C-3 epimer. The
purification and separation of the mixture of two isomers over
silica gel (200 g, CHCl3/EtOAc, 100:1 to 70:30) afforded 1.98 g
(23.1% based on the percent of 21) of an oil of 8. FAB-MS
(3-NBA matrix) showed a pseudomolecular ion (M + H)+ at
m/e ) 404.0 (100%). The exact mass measurements on MH+
gave m/e ) 404.0361 (C15H19NO4I; calcd m/e ) 404.0359). 1H
NMR (CDCl3): δ 7.81 (dd, J ) 1.8, 8.7 Hz, 2H C(2′,6′)-H), 7.74
(dd, J ) 1.8, 8.7 Hz, 2H, C(3′,5′)-H), 5.31-5.21 (m, 1H, C(4)-
H), 3.66 (s, 3H, OCH3), 3.00-2.91 (m, 2H, C(2,6)Heq), 2.82-
2.77 (m, 1H, C(3)-H), 2.48-2.38 (m, 1H, C(2)-Hax), 2.34 (s, 3H,
NCH3), 2.28-2.22 (m, 1H, C(6)-Hax), 2.22-2.15 (m, 1H, C(5)-
Heq), 1.82-1.72 (m, 1H, C(5)-Hax) ppm. The oil was converted
into the tartarate salt in quantitative yield, mp 158 °C. Anal.
(C15H18NO4I‚C4H6O6) C, H, N, I.
3-[(2′-Acet oxyb en zoyl)oxy]-[1R-(exo,exo)]-8-m et h yl-8-
a za bicyclo[3.2.1]octa n e-2-ca r boxylic Acid Meth yl Ester
(12). Ecgonine methyl ester free base (13; 0.9 g, 4.5 mmol)
was dissolved in dry benzene (15 mL), and triethylamine (1
mL, 10 mmol) was added. To this stirred solution was added
commercially available acetylsalicyloyl chloride (23; 1.4 g, 7.0
mmol) under dry N2. The resulting reaction mixture was
stirred at 40 °C overnight. The reaction was stopped, and the
product was washed with water (5.0 mL) and 5% aqueous Na2-
CO3 solution (3 × 5.0 mL) and dried over anhydrous MgSO4,
and the solvent was removed under vacuum to give an oil. The
oily product was dissolved in ether and dry HCl gas passed to
obtain hydrochloride salt of 12 (1.24 g, 76%). Mp: 78-80 °C.
FAB/MS (3-NBA matrix): 362.1 (MH+; C19H24NO6). 1H NMR
(D2O): δ 7.78 (dd, J ) 8.4, 1.2 Hz, 1H, C(6′)-H), 7.58-7.48
(m, 1H, C(4′)-H), 7.26 (d, J ) 8.7 Hz, 1H, C(5′)-H), 7.05 (d, J
) 8.7 Hz, 1H, C(3′)-H), 5.38-5.28 (m, 1H, C(3)-H), 4.07-4.01
(m, 1H, C(1)-H), 3.93-3.87 (m, 1H, C(5)-H), 3.46-3.40 (m, 1H,
C(2)-H), 3.45 (s, 3H, OCH3), 2.69 (s, 3H, NCH3), 2.18 (s, 3H,
C(2′)-COCH3), 2.35-2.25 (m, 4H, C(4,7)-H2), 2.05-1.95 (m, 2H,
C(6)-H2) ppm. Anal. (C19H23NO6‚HCl‚2H2O) C, H, N.
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3-[(2′-Hyd r oxyben zoyl)oxy]-[1R-(exo,exo)]-8-m eth yl-8-
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3
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H]-(-)-cocaine, [ H] WIN 35,065-2 and [ H]WIN
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Ack n ow led gm en t. This work was supported by
Grants DA 08587 from the National Institutes on Drug
Abuse (G.P.B.) and PHF 1088 from Presbyterian Health
Foundation (S.S.).