Recrystallization collection

Purification and Characterization. RecrystaUize all but 5 mg of the crude extract from acetone/95% efhanol (10 1). Dissolve the crystals in the minimum amount of hot acetone, keeping the recrystaUization vessel hot, and add the appropriate volume of 95% ethanol. Allow the mixture to cool to room temperature and then place the flask in an ice bath to complete the recrystallization. Collect the golden-yeUow crystals by vacuum filtration ( ) and wash them with cold acetone. Dry the crystals on a porous clay plate or on a sheet of filter paper. As an alternative and more efficient procedure, the crude material may be recrystallized using a Craig tube, avoiding the filtration step with the Hirsch funnel. 

The hydrazone prepared above (153 g. 0.42 mol) was heated at reflux for 5 h in 5% H2SO4 (750ml). The solution was cooled to 4 "C and after 12h the precipitate was collected by filtration. Recrystallization from MeOH/water (70 30) gave the product (145 g, 99%). 

A solution of 2,3-dibromo-5-methoxyaniline (32 g, 0.17 mol) in CHjClj (300 ml) was stirred and cooled in an icc bath. Boron trichloride (1 M in CH2CI2, 180 ml, 0.18 mol), chloroacetonitrile (14.3 g, 0.19 mol) and TiC (1 M in CH CIj, 190ml, 0.19 mol) were added. The resulting mixture was refluxed for 1.5 h. The solution was cooled to room temperature and poured carefully on to a mixture of icc and 20% aq. HCl (700 ml). The organic layer was separated and the CH Clj removed by distillation. The residue was heated to 90°C on a water bath for 30 min. The solution was cooled and the solid collected by filtration. It was partitioned between ether (1.41) and 1 N NaOH (500 ml). The ether layer was washed with brine, dried over Na2S04 and evaporated. The residue was recrystallized from ethanol to give 2-amino-3,4-dibromo-6-methoxy-a-chloroacetophenone (55 g) in 90% yield. 

The above product (24 g, 0.067 mol) was dissolved in 90 10 dioxane-water (300 ml) and sodium borohydride (92.5 g, 0.067 mol) was added. The mixture was refluxed for 4h. The cooled solution was poured into 0.1 N HCl (1.11). A solid precipitated and was collected by filtration, dried and recrystallized from ether hexane to give 6,7-dibromo-4-methoxyindole (18.5 g, 90%). 

Phenylmagnesium bromide (2.8 mol) was prepared in anhydrous ether (21) from bromobenzene (440 g, 2.9 mol) and magnesium turnings (68.0 g 2.8 g-atom). To this solution was added dropwise a solution of indole (328 g, 2.8 mol) in benzene (8(X)ml). The resulting solution was stirred for 10 min and then a solution of cyclopentanoyl chloride (322 g, 2.4 mol) in benzene (800 ml) was added dropwise. The solution was stirred for 1 h and then water (11) was added carefully. The precipitate which formed was collected by filtration and dried to give 169 g of crude product. Additional product (97 g) was obtained by evaporation of the organic layer of the filtrate. The combined products were recrystallized from toluene to give 250 g (49% yield) of pure product. 

This material Is purified by recrystallization from ethyl acetate acetone 2 1 (v v) to give a first crop (6.8 g), and by flash chromatography of the residue from the mother liquor, using 150 g of 230-400 mesh silica gel (Merck), a 40-mm diameter column, and elution with 10 1 (v v) ethyl acetate methanol. A fast moving orange band and a slower moving lemon-yellow band can be clearly seen on the column. The lemon-yellow hand is collected from the column and evaporation gives a second crop (1.4 g) of comparably pure material. The total yield of the pale yellow isoquinoline is 8.2 g (86t), mp 135-137°C (Note 10). 

D. 3,3-Diahlarothietane 1,1-dioxide. Thietane 1,1-dioxide (5.0 g, 0.047 mol) Is placed In a 500-mL, three-necked, round-bottomed flask equipped with a reflux condenser, magnetic stirrer, and chlorine gas bubbler. Carbon tetrachloride (350 mL) Is added and the solution Is irradiated with a 250-watt sunlamp (Note 5) while chlorine Is bubbled through the stirred mixture for 1 hr (Note 9). Irradiation and chlorine addition are stopped and the reaction mixture is allowed to cool to room temperature. The product Is collected by filtration as a white solid (4.0-4.4 g, 49-53%), mp 156-158°C (Note 10). The product can be used without further purification or It can be recrystallized from chloroform. 

B. Diethyl aminomalonate hydrochloride. The crude diethyl aminomalonate is diluted with 80 ml. of dry ether and filtered to remove a small amount of white solid. The filtrate is collected in a 250-ml. Erlenmeyer flask and cooled in an ice bath. Dry hydrogen chloride is passed just over the solution while it is being stirred mechanically (Note 6). The fine white crystals which precipitate are collected by suction filtration and washed three times with a total of 60 ml. of dry ether (Note 7). The filtrate and washings are treated again with hydrogen chloride, and a second crop of diethyl aminomalonate hydrochloride is collected and washed as before. This process is repeated until no further precipitation results from passing hydrogen chloride into the solution. A total of 16.5-17.4 g. (78-82% yield based on diethyl malonate) of diethyl aminomalonate hydrochloride, m.p. 162-163°, is obtained. Recrystallization from alcohol-ether affords a purer product, 164-165°. 

The product is collected on a suction filter. The yield of air-dried product, as yellow-orange crystals, m.p. 87-89°, is 38-42 g. (65-71%) (Note 8). A purer, lemon-yellow product, m.p. 88.5-90°, is obtained by an additional recrystallization from 1 1. of petroleum ether (b.p. 90-100°) with use of carbon the yield after this second crystallization is 28-34 g. (48-58%). 

A solution of the 3-ketone hydrate (0.15 g) in acetone- -heptane is heated to boiling. After the acetone has been boiled off, a trace of concentrated hydrochloric acid is added to the -heptane solution and boiled for an additional 2 min. After cooling, the resulting crystals are collected by filtration, washed with dry -heptane and dried in vacuo overnight. Recrystallization from dry -heptane gives 17 -hydroxy-4,4-difluoroestr-5-en-3-one 0.98 g mp 123.5-124.5° [a] 134° (CHCI3). 

Periodic Acid Degradation 17a,20 -Dihydroxy-4,4,6,16a-tetramethyl-pregn-5-en-3-one (0.3 g) is dissolved in 30 ml of methanol and treated with an aqueous solution of 0.25 g of periodic acid in 5 ml of water at room temperature for 17 hr. On dilution with water, the resultant crystals are collected by filtration, washed well with water, and dried to give 0.26 g mp 158-160°. Recrystallization from hexane-acetone gives 0.24 g (90%) of 4,4,6,16a-tetramethylandrost-5-ene-3,17-dione mp 160-161° [aj —6° (CHCI3). 

A solution of the bromo ketone (1 g) and sodium iodide (1 g) in 40 ml of acetone is refluxed for 20 min. The hot solution is filtered and the filtrate added to a mixture of 5 g of potassium bicarbonate and 4 ml of acetic acid. This mixture is then refluxed overnight, cooled and poured into a large excess of water. The resulting white precipitate is collected by filtration, dried in vacuo and finally recrystallized twice from methanol to afford 0.49 g of 3, 21-diacetoxypregna-5,16-dien-20-one mp 153-155° [a]jj —40° (CHCI3). 

A solution of 1.1 g of the cyanohydrin in 6 ml of pyridine is treated with 0.6 ml of phosphorus oxychloride and allowed to stand at room temperature overnight. The reaction mixture is quenched with ice and water and the resulting crystalline precipitate is collected, washed with water and dried to yield 1.05 g. Recrystallization from aqueous pyridine affords 0.88 g (83%) of 20-cyano-21-hydroxy-3,3-ethylenedioxypregna-5,17(20)-dien-l l-one acetate mp 197-200°. 

Monoadduct 17-ketal (43b), mp 160-162°, is hydrolyzed to the corresponding 17-ketone by treatment with methanolic 1 N hydrochloric acid for 1 hr at room temperature. The product is precipitated from the reaction mixture by careful addition of water and collected by suction filtration. Recrystallization of the crude product from acetone affords prisms mp 182-184°. 

Methoxy-D-Homo-estra-l,3,5(10)-trien-17a-one (96)" (/) Acetic acid (6.4 ml) is added to a stirred solution of estrone methyl ether (93 1.1 g) in ethanol (35 ml) containing potassium cyanide (6 g) at 0°. After being stirred for 1 hr at 0° and 2.5 hr at room temperature, the reactants dissolve and potassium acetate preciptates. Water (65 ml) is added to the reaction mixture and the precipitated solid is collected by filtration. The crude product is dissolved in ethyl acetate and the ethyl acetate solution is washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. Recrystallization of a portion of the crude product from cyclohexane-acetone gives 3-methoxy-17a-cyano-estra-l, 3,5(10)-trien-17j5-ol (94a) as needles mp 158.5°. 

Imine 24 was dissolved in sulfuric acid and the solution heated at 60 °C for 2h. The mixture was poured into cold water and the precipitate collected, washed with water and recrystallized from methanol to yield 25. 

The mixture is decanted into an Erlenmeyer flask, the residual green salts are washed with two 15-ml portions of acetone, and the washings are added to the main acetone solution. Cautiously, sodium bicarbonate (approx. 13 g) is added to the solution with swirling until the pH of the reaction mixture is neutral. The suspension is filtered, and the residue is washed with 10-15 ml of acetone. The filtrate is transferred to a round-bottom flask and concentrated on a rotary evaporator under an aspirator while the flask temperature is maintained at about 50°. The flask is cooled and the residue transferred to a separatory funnel, (If solidification occurs, the residue may be dissolved in ether to effect the transfer.) To the funnel is added 100 ml of saturated sodium chloride solution, and the mixture is extracted with two 50-ml portions of ether. The ether extracts are combined, washed with several 5-ml portions of water, dried over anhydrous magnesium sulfate, and filtered into a round-bottom flask. The ether may be distilled away at atmospheric pressure (steam bath) or evaporated on a rotary evaporator. On cooling, the residue should crystallize. If it does not, it may be treated with 5 ml of 30-60° petroleum ether, and crystallization may be induced by cooling and scratching. The crystalline product is collected by filtration and recrystallized from aqueous methanol. 4-r-Butylcyclohexanone has mp 48-49° (yield 60-90 %). 

A solution of resorcinol (11 g) in sodium hydroxide solution (4.8 g of sodium hydroxide in 20 ml of water) is hydrogenated in the presence of 1.1 g of 5 % rhodium on alumina for 16-18 hours at 50 psi initial pressure in a Parr apparatus. The reduction stops after the absorption of 1 equivalent of hydrogen. The catalyst is removed by filtration through celite, and the aqueous solution is carefully acidified with concentrated hydrochloric acid at 0°. The crude product is collected by filtration, dried in air, and recrystallized from benzene to give 1,3-cyclohexanedione, mp 105-107. ... 

---