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JACS, 78, 3087 (1956). 3-Indolepropionic acid, 94.5 g (0.5 mole) is dissolved in 600 ml of water containing 20 g of NaOH. The solution is mixed with 100 g of Raney Nickle catalyst and hydrogenated at room temp in a steel bomb at about 3,500 psi until the uptake of hydrogen stops (about 20-30 hours). Filter off the catalyst and wash it with a little water to remove the product that is clinging to it. Add 85 ml of concd HCl acid to the filtrate, and cool. If your reduction is incomplete, you will now have unreacted starting material separate, and this must be removed by filtration. Benzoylate the filtrate (the Schotten and Baumann method is preferable), using 210 ml of 12 N NaOH 180 ml of benzoyl chloride. Keep the solution alkaline throughout the benzoylation, and keep the temp below 40°C by cooling. When the benzoyl chloride is fully reacted, the reaction mixture is cooled and acidified with 300 ml of HCl acid. Filter the crude product by filtration, wash with water, and extract with four 1 liter portions of hot water. Separate, and crystallize the resulting syrupy product from a few volumes of methanol. Filter and wash with a little cold methanol to get a little over 100 g that melts at 151-153°. This is l-Benzoyl-3-beta-carboxyethyl-2,3-dihydroindole. This can be purchased to eliminate this step.

1-Benzoyl-5-keto-1,2,2a,3,4,5,-hexahydrobenzindole. 118 g of the above product (1-benzoyl-3-B-carboxyethyl-2,3-dihydroindole) is mixed with 200 ml of pure thionyl chloride. This solution is allowed to stand for 30 min, then it is warmed gently for 15-21 min on a steam bath. Excess thionyl chloride is completely evaporated with the temp maintained between 22-26°C in vacuo. The crude acid chloride is dissolved in dry carbon disulfate. This solution is added, in a thin stream, to a well stirred suspension of 240 g of aluminum chloride in 1750 ml of carbon disulfate in a 5,000 cc flask. Note: this must be done under a fume hood. A complex will separate and bog down the stirring device. Heat this mixture under reflux with stirring for 1 hour. Decompose this mixture by adding 500 g of ice, 250 ml of concd HCl acid, and 500 ml of water, all while good stirring is continued. Cooling of this operation is affected by periodic distillation of the carbon disulfate in vacuo. After the decomposition is complete, any remaining carbon disulfate is removed completely in vacuo, and the product is extracted with 2 liters of benzene. The extract is washed well with 500 ml of 2 N NaOH in three portions, and then with water. Dry (with the usual magnesium sulfate), and evaporate to a small volume in vacuo. Add this small volume to several portions of ether to get the ketone to crystallize (add slowly), and filter, then wash with ether to get 85 g of pure title product, mp: 146-147°C.

1-Benzoyl-4-bromo-5-keto-1,2,2a,3,4,5-hexahydrobenzindole. A solution of the above indole (305 g) in 2,200 ml of glacial acetic acid is warmed to 40°C. While the reaction is illuminated with a 250 watt bulb, 352 g of pyridine hydrobromide perbromide is added in portions, over 5 min with shaking. The solution is then heated to 60° and is held between there and 55°C for 30 min. Treat the mixture with carbon, and evaporate to a small volume in vacuo. The residue is taken up with 2,200 ml of chloroform, and wash this solution with several portions of water, dry as above, and concentrate in vacuo. Crystallize the residue from 2,200 ml of 50% acetic acid and 50% ether to get 270 g of title product that melts at 180.5-181.5°C. Another crop can be obtained from concentrating the fltrates. Yield: 30 g of less pure product.

1-Benzoyl-2,2a,3,4-tetrahydro-4-methyl-2-methyl-1,3-dioxolan-2-yl-methyl-aminobenzindol-5-(1H)one. A solution of the last indole product above (270 g) and 307 g of methylaminoacetone ethylene ketol in 4,500 ml of dry benzene is refluxed for 21 hours under a slow stream of nitrogen. The mixture is cooled and 151 g of methylaminoacetone ethylene ketol hydrobromide is filtered off. The filtrate is washed with ice water, then extracted with 2.5 liters of cold dilute HCl acid containing 150 ml of the concd acid. The acid extracts are immediately added to an excess of ice cold dilute NaOH. Extract with 1 1iter of chloroform, dry over magnesium sulfate, treat with carbon and concentrate by evaporation in vacuo. The residual ketol-ketone is crystallized from acetone to yield 220 g, mp: 135-136°C.








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