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SYNTHESIS
To a solution of 5.0 g 4-hydroxyindole in 20 mL pyridine there was added 10 mL acetic anhydride and the reaction heated on the steam bath for 10 min. The reaction was quenched by pouring over chipped ice to which was added an excess of NaHCO3.
After being stirred for 0.5 h the product was extracted with ethyl acetate and the extracts washed with brine and the solvent removed under vacuum.
The residue weighed 6.3 g (95%) which, after crystallization from cyclohexane, had a melting point of 98-100 °C. IR (in cm-1): 1750 for the carbonyl absorbtion.
To a solution of 0.50 g 4-acetoxyindole in 4 mL Et2O, that was stirred and cooled with an external ice bath, there was added, dropwise, a solution of 0.5 mL oxalyl chloride in 3 mL anhydrous Et2O.
Stirring was continued for 0.5 h and the intermediate indoleglyoxylchloride separated as a yellow crystalline solid but it was not isolated.
There was then added, dropwise, a 40% solution of diethylamine in Et2O until the pH was raised to 8-9.
The reaction was then quenched by the addition of 100 mL CHCl3, and the organic phase was washed with 30 mL of 5% NaHSO4 solution, with 30 mL of saturated NaHCO3, and finally with 30 mL of saturated brine.
After drying with anhydrous MgSO4, the solvent was removed under vacuum. Theresidue set up as crystals and, after recrystallization from Et2O, provided 0.62 g (72%) 4- acetoxyindol-3-yl-N,N-diethylglyoxylamide with a mp of 150-151 °C.
A suspension of 0.5 g LAH in 10 mL anhydrous THF was held in an inert atmosphere and vigorously stirred. To this there was added, dropwise, a solution of 0.6 g of 4-acetoxyindol-3-yl-N,N-diethylglyoxylamide in 10 mL anhydrous THF at a rate that maintained a gentle reflux.
After the addition was complete, the refluxing was maintained for an additional 15 min, cooled to 40°C, and the excess hydride killed by the addition of 1.0 mL EtOAc, followed by 2.3 mL H2O.
The reaction mixture was filtered free of solids under a N2 atmosphere, washed with THF, and the filtrate and washings combined and stripped of solvent under vacuum. The residue was distilled in a KugelRohr apparatus and the solid distillate recrystallized from EtOAc/hexane to give 0.24g (52%) 3-[2-(diethylamino)ethyl]-4-indolol (4-HO-DET) as white crystals with a mp of 103-104°C.
The product discolored quickly in the presence of air, and was best stored under an inert atmosphere at -30 °C. Conversion to the phosphate ester was achieved by reaction of the sodium salt of 3-[2-(diethylamino)ethyl]-4-indolol with dibenzylchlorophosphonate, followed by the reductive removal of the benzyl groups with catalytic hydrogenation.
DOSAGE : 10 - 25 mg, orally
DURATION : 4 - 6 hrs
To a solution of 5.0 g 4-hydroxyindole in 20 mL pyridine there was added 10 mL acetic anhydride and the reaction heated on the steam bath for 10 min. The reaction was quenched by pouring over chipped ice to which was added an excess of NaHCO3.
After being stirred for 0.5 h the product was extracted with ethyl acetate and the extracts washed with brine and the solvent removed under vacuum.
The residue weighed 6.3 g (95%) which, after crystallization from cyclohexane, had a melting point of 98-100 °C. IR (in cm-1): 1750 for the carbonyl absorbtion.
To a solution of 0.50 g 4-acetoxyindole in 4 mL Et2O, that was stirred and cooled with an external ice bath, there was added, dropwise, a solution of 0.5 mL oxalyl chloride in 3 mL anhydrous Et2O.
Stirring was continued for 0.5 h and the intermediate indoleglyoxylchloride separated as a yellow crystalline solid but it was not isolated.
There was then added, dropwise, a 40% solution of diethylamine in Et2O until the pH was raised to 8-9.
The reaction was then quenched by the addition of 100 mL CHCl3, and the organic phase was washed with 30 mL of 5% NaHSO4 solution, with 30 mL of saturated NaHCO3, and finally with 30 mL of saturated brine.
After drying with anhydrous MgSO4, the solvent was removed under vacuum. Theresidue set up as crystals and, after recrystallization from Et2O, provided 0.62 g (72%) 4- acetoxyindol-3-yl-N,N-diethylglyoxylamide with a mp of 150-151 °C.
A suspension of 0.5 g LAH in 10 mL anhydrous THF was held in an inert atmosphere and vigorously stirred. To this there was added, dropwise, a solution of 0.6 g of 4-acetoxyindol-3-yl-N,N-diethylglyoxylamide in 10 mL anhydrous THF at a rate that maintained a gentle reflux.
After the addition was complete, the refluxing was maintained for an additional 15 min, cooled to 40°C, and the excess hydride killed by the addition of 1.0 mL EtOAc, followed by 2.3 mL H2O.
The reaction mixture was filtered free of solids under a N2 atmosphere, washed with THF, and the filtrate and washings combined and stripped of solvent under vacuum. The residue was distilled in a KugelRohr apparatus and the solid distillate recrystallized from EtOAc/hexane to give 0.24g (52%) 3-[2-(diethylamino)ethyl]-4-indolol (4-HO-DET) as white crystals with a mp of 103-104°C.
The product discolored quickly in the presence of air, and was best stored under an inert atmosphere at -30 °C. Conversion to the phosphate ester was achieved by reaction of the sodium salt of 3-[2-(diethylamino)ethyl]-4-indolol with dibenzylchlorophosphonate, followed by the reductive removal of the benzyl groups with catalytic hydrogenation.
DOSAGE : 10 - 25 mg, orally
DURATION : 4 - 6 hrs