Reaction and recrystallization

Imidazole quaternary salts (9) are frequently quite hygroscopic and need to be kept dry if storage is intended. In their synthesis all apparatus must be scrupulously dry, solvents must be dried before use, and reactions and recrystallizations need to be carried out under dry nitrogen. Liquid reagents are best added using a syringe through a serum cap, and Schlenk apparatus is recommended for filtrations. 

Methylene chloride is used as an effective reaction and recrystallization solvent in the extraction of several pharmaceutical compounds and in the production of many antibiotics and vitamins. The chemical also has been used as a carrier for pharmaceutical tablet coatings. In these applications, essentially no methylene chloride is left in the coating of the tablet. Residue tolerances have been established by the Food and Drug Administration (FDA) for this particular use. 

Phenylacetic acid. Use 5 0 g. of magnesium, 25 g, (23 ml.) of redistilled benzyl chloride (Section IV,22) and 75 ml. of sodium-dried ether. Allow the reaction mixture to warm to 15° and then decompose it with dilute hydrochloric or sulphuric acid. Filter off the crude acid and recrystallize it from water. The yield of pure phenylacetic acid, m.p. 76-77°, is 11 g. 

Ethyl 4,5-Dlbenzamldopent-4-enoate (2) Ethyl 3-lmidazol-4(5)-ylpropanoale 1 (9.2 g, 54 mmol) In ElOAc (140 mL) was treated with benzoyl chloride (15 7 g, 112 mmol) In ElOAc (40 mL) and 1M NaHCOa (380 mL) added simultaneously In 1 h under Ice-cooling. The reaction mixture was stirred for 1 h, then a further portion of benzoyl chloride (IS 7 g, 112 mmol) in ElOAc) and iM NaHCOa (280 mL) was added m the same manner, followed by an additional portion o( 1M NaHCOa (200 mL) The reaction mixture was stirred for 24 h, then the organic layer was separated, concentrated, and the residue dissolved in THF (300 mL) The THF solution was stirred with 10% NaHCOa (600 mL) for 24 h to decompose any N-lormyl intermediate and to remove benzoic acxl Extraction with EtOAc, drying (Na2S04), solvent evaporation and recrystallization of the residue from EtOAc hexane afforded 16 24 g of 2 (84%), mp 128-129°C... 

Vinyllithium Reaction To a cooled solution of 80 g of 3y -hydroxy-5a-androstan-17-one in 1.5 liters of tetrahydrofuran is added 400 ml of 2 4/ vinyllithium in tetrahydrofuran. The solution is stirred at 0° for 0.5 hr, allowed to warm to room temperature, and stirred an additional hr. Cone ammonium chloride solution is added, and the mixture is concentrated under reduced pressure until a precipitate begins to form. The slurry is poured into water, and the precipitate is filtered and recrystallized twice from methanol, affording 52.2 g (60%) of 17a-vinyl-5a-androstane-3, 17i -diol mp 205-207.5°. 

P4S3 is the most stable compound in the series and can be prepared by heating the required amounts of red P and sulfur above 180° in an inert atmosphere and then purifying the product by distillation at 420° or by recrystallization from toluene. The retention of a P3 ring in the structure is notable. Its reactions and commercial application in match manufacture are discussed on p. 509. 

To an ethanolic solution of sodium ethoxide prepared by addition of 0.46 g (0.02 mole) of freshly cut sodium metal in 100 mL of absolute ethanol was slowly added 5.10 g (0.02 mole) of ethyl 4-nitrobenzylthioacetate 28 with stirring at 5°C. The mixture was refluxed for about 4 to 6 hours until the reaction was complete (monitored by tic). The resultant mixture was allowed to cool to room temperature and then added into an ice-water mixture. The solution was neutralized with slow addition of dilute aqueous hydrochloric acid (10%). The precipitated solid was removed by filtration, washed with water, and recrystallized from a dimethylformamide-ethanol (T.l) mixture yielding 2.10 g (76 %) of 29 as a light brown crystalline solid, mp 227°C ir (nujol) (neat (1710 cm ms m/z Til (NT). Anal. Calcd. For C13H11NO4S C, 56.31 H, 3.97 N, 5.05 S, 11.55. Found C, 56.36 H, 3.95 N, 5.01 S, 11.49. 

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 %). 

The reaction mixture is allowed to stand at room temperature for 30 minutes, during which time crystals of the product form. The product is collected by filtration, washed with a little cold ethanol, and recrystallized from ethanol or methylcyclohexane. The faintly yellow product has mp 150-151°. 

Solid sodium nitrite (0.97 g) was added at room temperature with stirring over a period of one hour to a solution of 2-chloro-9-(2-hydroxyethoxymethyl)adenine (0.5 g) in glacial acetic acid (10 ml). The reaction mixture was stirred for an additional A A hours. The white solid was removed by filtration, washed with cold acetic acid and then well triturated with cold water to remove the sodium acetate present. The solid product was retained. The combined acetic acid filtrate and wash was evaporated at reduced pressure and 40°C bath temperature and the residual oil triturated with cold water. The resulting solid material was combined with the previously isolated solid and the combined solids dried and recrystallized from ethanol to give 2chloro-9-(2-hydroxyethoxymethyl)+iypoxanthine (0.25 g), MP>310°C. Elemental analysis and NMR spectrum were consistent with this structure. 

A mixture of 2.0 g (0.064 mol) of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-qulnazolinone, Oi g of 5% palladium-carbon and 100 ml of acetic acid is shaken for 30 minutes in hydrogen gas. The initial pressure of hydrogen gas is adjusted to 46 lb and the mixture is heated with an infrared lamp during the reaction. After 30 minutes of this reaction, the pressure of hydrogen gas decreases to 6 lb. After the mixture is cooled, the mixture is filtered to remove the catalyst. The filtrate is evaporated to remove acetic acid, and the residue is dissolved in chloroform. The chloroform solution is washed with 5% aqueous sodium hydroxide and water, successively. Then, the solution is dried and evaporated to remove solvent. The oily residue thus obtained is dissolved in 2 ml of chloroform, and the chloroform solution is passed through a column of 200 g of silica gel. The silica gel column is eluted with ethyl acetate-benzene (1 1). Then, the eluate is evaporated to remove solvent. The crude crystal obtained is washed with isopropylether and recrystallized from isopropanol. 0.95 g of 2-fluoromethyl-3-(o-tolyl)-6-amino-4(3H)-quinazolinone Is obtained. Yield 52.5% MP 195°-196°C. 

Preparation of cholesta-5,7-diene-ia,3/3-diol a solution of 500 mg of the 1,4-cyclized adduct of cholesta-5,7-dien-3/3-ol-ia,2a-epoxideand 4-phenyl-1,2,4-triazoline-3,5-dione in 40 ml of tetrahydrofuran is added dropwise under agitation to a solution of 600 mg of lithium aluminum hydride in 30 ml of THF. Then, the reaction mixture liquid Is gently refluxed and boiled for 1 hour and cooled, and a saturated aqueous solution of sodium sulfate is added to the reaction mixture to decompose excessive lithium aluminum hydride. The organic solvent layer is separated and dried, and the solvent Is distilled. The residue Is purified by chromatography using a column packed with silica gel. Fractions eluted with ether-hexane (7 3 v/v) are collected, and recrystallization from the methanol gives 400 mg of cholesta-5,7-diene-la, 3/3-diol. 

ICj Preparation of 3-Bemyl-6-Trifluoromethyl-7-Sulfamyl-3,4-Dihydro-1, 4 Ben othiadiazine 1,1-Dioxide A grams of 5-trifluoromethyl-2,4-disulfamylaniline is dissolved in 12 ml of dioxane. 2.7 ml of phenylacetaldehyde and a catalytic amount of p-toluenesulfonic acid are added. After boiling for a short time under reflux, the reaction mixture crystallizes, and, after filtration and recrystallization from dioxane, the desired product is obtained with a MP of 224.5°-225.5 C,... 

Preparation of Bisacodyl 5 grams of (4,4 -dihydroxy-diphenyl)-(pyridyl-2)-methane are heated with 5 grams of anhydrous sodium acetate and 20 cc of acetic anhydride for three hours over a boiling waterbath. The cooled reaction mixture is poured into water, whereby after a while a colorless substance precipitates, which Is filtered off with suction, washed with water and recrystallized from aqueous ethanol. Colorless bright crystals, MP 138°C are obtained. 

A suspension of 45 g 3-phenoxycarbonyloxy-1 -methyl-7-chloro-5-pheny -1,3-dihydro-2H-1,4-benzodiazepin-2-one in 450 ml methanol is treated with stirring, with 43 ml of a solution of dimethylamine in methanol (containlng31 gdimethylamine in 100 ml). Stirring ismaintained at 20°C to 25°C during 5 hours. The reaction mixture is filtered, and the filtrate is diluted with 450 ml water. The precipitate thus formed, is 3-(N,N-dimethylcarbamoyloxy)-1-methy -7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, which is collected on a filter, dried and recrystallized from ethyl acetate, and has a melting point of 173°C to 174°C. 

An alternative purification can be effected by dissolving the reaction product in water. The ester base is liberated by rendering the clarified aqueous solution alkaline. Removal of the base from the alkaline solution is achieved by extraction with a Suitable solvent such as benzene or ether. The pure hydrochloride of diethylaminoethyl 2-chloro-4-aminobenzoate Is then precipitated from the dried extract by the addition of dry hydrogen chloride. After removal by filtration and recrystallization from ethanol it is found to have a melting point of 173° to 174°C. 

To a stirred suspension of 10 grams (35 mmol) of 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H) one 4-oxide in approximately 150 ml of methanol was added in portions an excess of a solution of diazomethane in ether. After about one hour, almost complete solution had occurred and the reaction mixture was filtered. The filtrate was concentrated in vacuo to a small volume and diluted with ether and petroleum ether. The reaction product, 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1 H)-one 4-oxide, crystallized in colorless prisms. The product was filtered off and recrystallized from acetone, MP 188°-189°C. 

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