taken from the vespiary, check the link if u want the reference used >_< pls note that furan is super flammable and its boiling point is around room temperature!! im not sure how useful this synth is 4 the new (or even average) chemist, but i figured id post it anyway just 4 the sake of the information being available
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, 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 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), bp0.2 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.
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, 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 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), bp0.2 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.
