Total Synthesis of Cocaine from Furan

To a mixture of 32.2 g furan, 95 mL dry Et₂O, and 145 mL anhyd. EtOH, cooled to -35°C, is added, dropwise, during 1 h with stirring a solution of 24.2 mL Br₂ in 335 mL EtOH also cooled to -35°C, while keeping the solution below -25°C. After 30 min. standing, dry NH₃ is added up to pH 6, the mass stirred at -5°C until the color disappears and again NH₃ added up to pH 8 to give 2,5-diethoxy-2,5-dihydrofuran (I) (52.6 g), bp₃ 39-41°C, d₂₀ 1.0017, n_D²⁰ 1.4310. The dimethoxy analog, bp₁₇ 69.74°C, d₂₀ 1.0730, n_D20 1.4352, may be obtained in a similar manner except that the reaction is conducted in the absence of Et₂O (yield: 71%).

I (47.5 g) is hydrogenated in the presence of 5 g of Raney Ni at room temp. and at atm. pressure with stirring. After the absorption of 7.2 L H₂ during 2-3 h, the catalyst is filtered off and washed with 15 mL dry EtOH; 40.1 g 2,5-diethoxytetrahydrofuran (II), bp₂₀ 76-78°C, d₂₀ 0.9630, n_D²⁰ 1.4193, is thus obtained. The methoxy analog, bp₂₂ 52-54°C, d₂₀ 1.0230, n_D²⁰ 1.4178, is similarly obtained (yield: 85.5%).

To a mixture of 360 g 50% KOH soln. and 138 mL MeOH, 70.5 g dimethyl ester of acetonedicarboxylic acid (III) is added with stirring at -5°C. The temp. rises immediately to 15°C, and then up to 25°C during 30 min. After 10 min. standing the mixture is again cooled to 0°C and 65 mL Et₂O is added. The ppt. is filtered off and washed with 65 mL MeOH and 150 mL Et₂O (previously cooled to 0°C). The di-potassium salt (86.2 g) of III is obtained.

To 1 N HCl (322 mL) heated to 80°C is added 41.1 g II and the mixture stirred during 20 min., rapidly cooled to 10°C, and 211 mL 1N HCl, 98.2 g III, 26.4 g AcONa, and 28.2 g CH₃NH₂·HCl added. The mixture is stirred 4 h at 29-31°C, cooled to 10°C, satd. with 410 g KOH, and extracted 4 times with CHCl₃ (75 mL, 15 min. stirring). The methyl ester (IV) (25.96 g), mp 106-107°C (from MeOH), bp_0.2 85-86°C, of tropan-3-one-2-carboxylic acid crystallizes from the oily mixture (2.88 g more is obtained from the mother solution); IV·HCl, mp 172-173°C (from MeOH); IV·H₂O, mp 97-100°C.

IV (28.34 g) is dissolved in 10% H₂SO₄ (170 mL), cooled to -5°C, and treated with 3.63 kg 1.5% Na-Hg with vigorous stirring between -2°C and +2°C, the pH being kept at 3-3.5 by means of a 30% H₂SO₄ soln. The reduction is continued about 30 min, until 3 drops of the reacting mixture cease to give a red coloration with a 10% solution of FeCl₃. After the separation of Hg, the solution is saturated with 235 g KOH below 15°C and extracted with 5x250 mL CHCl₃. The extracts are dried over Na₂SO₄ and an oily liquid (26.5 g) is obtained, from which the methyl ester of racemic pseudoecgonine (V) crystallizes upon long standing (5-7 days at 0°C).

The 2 isomeric esters of ecgonine, V and racemic ecgonine (VI), are separated by mixing the oily liquid (filled with crystals) with an equal volume of dry Et₂O. The pptd. V (5.86 g), mp 128.5-130.5°C (from EtOAc), is filtered off. Its HCl salt mp 211-213°C. To the filtrate is added 250 ml. dry Et₂O until no more ppt. forms (the ppt. rapidly melts in the air to form a resinous mass), and the filtrate is stirred 30 min. with activated coal. The solvents are evapd. and a light brown liquid (17.2 g) is obtained; it is dissolved in 17 mL MeOH and neutralized with a 10% soln. of HCl in dry Et₂O. Et₂O is then evapd. in vacuo until the 2 layers disappear. Upon standing 2 hrs. at 0°C, VI·HCl crystallizes; it is filtered and washed with a 1:1 mixture of MeOH-dry Et₂O cooled to 0°C. Pure VI·HCl, mp 194.5°C, is obtained upon recrystallizing from MeOH and washing with small quantities of 1:1 MeOH-Et₂O and then with Et₂O; 1.55 g. more VI·HCl may be obtained from the mother solution (total yield 9.85 g).

IV·HCl (9.33 g) is heated 10 h on a water bath with 18.7 g benzoyl chloride, the brown transparent liquid formed is poured into 250 mL Et₂O, and upon rubbing, the viscous mass is converted into a friable powder which is dissolved in 35 mL ice water and neutralized to the universal indicator by 20% NH₄OH. Racemic cocaine (VII) (base) (6.81 g) mp 80-81°C (from ether), is filtered off, washed with 12 mL of ice water and dried over CaCl₂. A still larger yield of VII (84% calcd. from VI) is obtained by treating the mother solution. VII·HCl, mp 186-187°C, is obtained by exactly neutralizing the solution of the base in a sevenfold quantity of Et₂O with an alcoholic solution of HCl, followed by washing the crystals with 1:3 MeOH-Et₂O and then with Et₂O.