(Rhodium (Chief Bee) 10-16-04 04:31 No 536032) Russian Synthesis of Cocaine

Synthesis of Cocaine
G. I. Bazilevskaya, M. S. Bainova, D. V. Gura, K. M. Dyumaev, and N. A. Preobrazhenskii
CA 53, 423h (1959) [Izvest. Vysshikh Ucheb. Zavedenii, Khim. i Khim. Tekhnol. 75-81 (1958)]

To a mixt. 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 soln. of 24.2 mL Br2 in 335 mL EtOH also cooled to -35°C, while keeping the soln. 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, nD20 1.4310. The dimethoxy analog, bp17 69.74°C, d20 1.0730, nD20 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, nD20 1.4193, is thus obtained. The methoxy analog, bp22 52-54°C, d20 1.0230, nD20 1.4178, is similarly obtained (yield: 85.5%).

To a mixt. 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 mixt. 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 mixt. 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 mixt. 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), bp0.2 85-86°C, of tropan-3-one-2-carboxylic acid crystallizes from the oily mixt. (2.88 g more is obtained from the mother soln.); 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 ½ hr. until 3 drops of the reacting mixt. cease to give a red coloration with a 10% soln. of FeCl3. After the sepn. of Hg, the soln. is satd. with 235 g KOH below 15°C and extd. with CHCl3 (250 ml., 5 times). The extracts are dried over Na2SO4 and an oily liquid (26.5 g) is obtained, from which the Me 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 sepd. 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 Et acetate), 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 mixt. 1:1 MeOH-dry Et2O cooled to 0°C. Pure VI·HCl, mp 194.5°C, is obtained upon recrystg. 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 soln. (total yield 9.85 g).

IV·HCl (9.33 g) is heated 10 h on a water bath with 18.7 g PhCOCl, 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 soln. VII·HCl, m. 186-187°C, is obtained by exactly neutralizing the soln. of the base in a sevenfold quantity of Et2O with an alc. soln. of HCl, followed by washing the crystals with 1:3 MeOH-Et2O and then with Et2O.

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If anyone can access an English Language version of that paper it would be gold.

Succindialdehyde

To 400 ml of 0.2 N sulfuric acid was slowly added 44.2 g (0.334 mol) of 2,5-dimethoxytetrahydrofuran (Aldrich) and stirred for 15 min. The succindialdehyde was allowed to stand for 4 h without further treatment.[/url]

Dimethyl B-ketoglutarate.

Powdered, anhydrous citric acid (192 g., 1.00 mole), m.p. 153", was added in 32-g. portions to fuming sulfuric acid (383 g., 202 ml., 21%) with stirring, the first two cautiously at 0' and the other four at 15-20' during 1.5 hrs. The mixture was stirred 1 hr. at 25", 3 at 35', and 17 at 25'.

To the stirred, yellow mixture absolute methanol (500 ml.) was added dropwise at -5 to 0" (3 hrs.). The mixture was kept 13-20 hrs. at 25" and added to a stirred mixture of sodium bicarbonate (700 g.), ice (500 g.), and water (200 g.). The precipitated salts were immediately filtered off and washed with 50% aqueous methanol (150 ml.). The slightly alkaline yellow filtrates were extracted with ether (7 X 400 ml.), the extracts dried (NalS04), and the solvent removed on the water bath and then in vacuo. The residual oil, which contained some water, was distilled in vacuo: after two distillations 112 g. ,(64%, b.p. 85"/1 mm....)

Monomethyl B-ketoglutarate, dipotassium salt.

A solution of potassium hydroxide (33.6 g., 0.600 mole) in absolute methanol (150 ml.) was added dropwise at 0' during 35 min. to a mixture of dimethyl b-ketoglutarate (43.5 ml., 0.300 mole) and methanol (10 ml.). When about one fifth of the alkali had been added a granular precipitate began to separate, and a yellow color appeared when the addition was about half complete.' The mixture was kept 3 hours at room temperature during which period it became thicker. After storing overnight in the refrigerator, the salt was collected and washed with cold methanol (15 ml.): 56.5 g.

From Findlay S.P.,Regarding Carbomethoxytropinone* J. Org. Chem., 22, 1385-1394 (1957), pp.1389-90.

I am looking for anything to do with the reduction of 2-CMT that leads to the precursor of the natural product using something OTHER than Na/Hg (which would be a fucking nightmare - imagine trying to source 1kg of fucking Hg so as to make a 1.5% amalgam...).