Crystallin residues

The dry methosulfate, dissolved in about 30 ml. of water, is made alkaline with 2-3 ml. of 10% sodium hydroxide, and the solution is then extracted exhaustively with successive 15-ml. portions of chloroform until no more blue substance is remov ed from the aqueous solution (Note 12). The combined chloroform solutions are extracted three times with 20-ml. portions of 5% hydrochloric acid. The combined acid extracts are made alkaline to phenolphthalein with 10% sodium hydroxide and reextracted exhaustively with 25-ml. portions of chloroform until no more blue substance is removed from the aqueous solution (Note 12). The combined chloroform solutions are dried over anhydrous sodium sulfate and decanted, and the chloroform is removed by distillation under reduced pressure. The blue crystalline residue is recrystallized by dissohnng it in the least possible amount of water at 60° and then cooling the solution in an ice bath. The product is filtered on a 5-cm. Buchner funnel and dried in the dark in a v acuum desiccator over calcium chloride. The yield is 1.35 g. (58%) of dark blue needles that melt at 133° (Note 13). 

Androst-4-ene-3,17-dione. Testosterone (0.58 g, 2 mmoles) is dissolved in a solution prepared from 3 ml of benzene, 3 ml of dimethyl sulfoxide, 0.16 ml (2 mmoles) of pyridine and 0.08 ml (1 mmole) of trifluoroacetic acid. After addition of 1.24 g (6 mmoles) of dicyclohexylcarbodiimide, the sealed reaction flask is kept overnight at room temperature. Ether (50 ml) is added followed by a solution of 0.54 g (6 mmoles) of oxalic acid in 5 ml of methanol. After gas evolution has ceased ( 30 min) 50 ml of water is added and the insoluble dicyclohexylurea is removed by filtration. The organic phase is then extracted twice with 5 % sodium bicarbonate and once with water, dried over sodium sulfate and evaporated to a crystalline residue (0.80 g) which still contains a little dicyclohexylurea. Direct crystallization from 5 ml of ethanol gives androst-4-ene-3,17-dione (0.53 g, 92%) in two crops, mp 169-170°. 

Hydroxyandrosta-4,6-dien-3-one. A suspension of 42 g of crude androsta-4,6-diene-3j ,17j -diol in 2000 ml of chloroform is treated with 250 g of activated, manganese dioxide. The mixture is then shaken vigorously for 15 min in a stoppered flask. The mixture is filtered and the manganese dioxide washed well with chloroform in order to elute material which initially remains adsorbed on the solid phase. The filtrate is concentrated to a pale yellow, crystalline residue. Recrystallization from acetonitrile gives 38 g (90%) of 17/ -hydroxyandrosta-4,6-dien-3-one as plates mp 211-214°. 

A solution of 0.7 g (18 mmoles) of potassium in 35 ml of /-butanol is added to a boiling solution of 5 g (13 mmoles) of 5a-cholestan-3-one in 50 ml of benzene and 25 ml of /-butanol. A total of 5 ml (11.4 g, 80 mmoles) of methyl iodide in 50 ml of benzene is then added and refluxing is continued for 3 min. The solution is cooled, ice is added and the product is isolated by extraction with ether. The crystalline residue in light petroleum solution is chromatographed on 300 g of alumina. Elution with light petroleum yields initially 0.55 g (10%) of 2,2-dimethyl-5a-cholestan-3-one mp 111-113° [o(]d 77° (CHCI3), after crystallization from ether-methanol. Further elution affords 1.01 g (20%) of 2a-methyl-5a-cholestan-3-one mp 119-120° [a]o 32° (CHCI3), after crystallization from ether-methanol. 

The residue (12 g) which contains the 18-iodo-18,20-ether is dissolved in 200 ml of acetone, 5 g of silver chromate is added Note 3) and after cooling to 0°, 11.8 ml of a solution of 13.3 g of chromium trioxide and 11.5 ml of concentrated sulfuric acid, diluted to 50 ml with water is added during a period of 5 min. After an additional 60 min, a solution of 112 g of sodium acetate in 200 ml of water is added and the mixture diluted with benzene (400 ml), filtered and the benzene layer separated. The aqueous phase is reextracted with benzene, washed with half-saturated sodium chloride solution, dried and evaporated to yield 11.2 g of a crystalline residue. Recrystallization from ether gives 7.2 g (72%) of pure 3/5, 1 la, 20/5-trihydroxy-5a-pregnan-18-oic acid 18,20 lactone 3,11-diacetate mp 216-218°. 

A solution of the crude cyanohydrin (94a ca. 1 g) in pyridine (15 ml) and acetic anhydride (15 ml) is allowed to stand at room temperature for 52 hr. The solvents are evaporated under reduced pressure below 60°. The residue is dissolved in ether, and the ether solution is washed successively with 5 % hydrochloric acid, water and saturated salt solution. The solvent is evaporated under reduced pressure to give a crystalline residue. Recrystallization of the crude product from cyclohexane-acetone gives 3-methoxy-17a-cyano-estra-l,3,5(10)-trien-17i5-ol acetate (94b 0.9 g), mp 130-132°, as large prisms. 

A mixture of a-naphthol 41 (15.0 g, 0.1 mol), phenylhydrazine 42 (11.0 g, 0.1 mol) and sodium bisulfite solution (36 %, 250 g) was heated at reflux for 15 h. A further 4 g of phenylhydrazine was added and heating continued for 15 h, after which time the majority of the a-naphthol was consumed. After cooling, the mixture was extracted with ether. The oily, ether and aqueous insoluble residue was warmed with cone. HCl until a dark crystalline mass developed. After cooling, the mixture was extracted with ether. The organic extract was dried and concentrated to afford a crystalline residue which was purified by recrystallisation from ethanol to afford the product 43 as a white crystalline solid, mp 225 °C. A reaction yield is not given. 

A 500-ml rcund-bottom flask is equipped with a reflux condenser, a gas inlet tube, and a gas outlet leading to a bubbler. The flask is charged with a solution of rhodium (III) chloride trihydrate (2 g) in 70 ml of 95 % ethanol. A solution of triphenylphosphine (12 g, freshly recrystallized from ethanol to remove the oxide) in 350 ml of hot ethanol is added to the flask, and the system is flushed with nitrogen. The mixture is refluxed for 2 hours, following which the hot solution is filtered by suction to obtain the product. The crystalline residue is washed with several small portions of anhydrous ether (50 ml total) affording the deep red crystalline product in about 85% yield. 

A solution of 10 g of 9 10-dihydro-9 10-ethano-(1 2)-anthracene-(9)aldehyde (made from anthracene and acrolein) and 10 g of monomethylamine in 100 cc of ethanol is heated at 80°C for 4 hours in an autoclave. The reaction mixture is then evaporated to dryness under reduced pressure to leave a crystalline residue which is dissolved in 150 cc of ethanol and, after the addition of 2 g of Raney nickel, hydrogenated at 40°C under atmospheric pressure. When the absorption of hydrogen has subsided, the catalyst is filtered off and the filtrate evaporated under reduced pressure. An oil remains which is covered with 100 cc of 2N hydrochloric acid. The 9-methylamino-methyI-9 10-dihydro-9 10-ethano-(9 10)-anthracene hydrochloride crystallizes immediately after crystallization from methanol it melts at 320°-322°C. 

Ninety-eight grams of 6-chloro-2-chloromethyl-4-phenylquinazoline 3-oxide hydrochloride were introduced into 600 cc of ice cold 25% methanolic methylamine. The mixture was initially cooled to about 30°C and then stirred at room temperature. After 15 hours the reaction product which precipitated was filtered off. The mother liquor was concentrated in vacuo to dryness. The residue was dissolved in methylene chloride, washed with water and dried with sodium sulfate. The methylene chloride solution was concentrated in vacuo and the crystalline residue was boiled with a small amount of acetone to dissolve the more soluble impurities. The mixture was then cooled at 5°C for 10 hours and filtered. The crystalline product, 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide, was recrystallized from ethanol forming light yellow plates, MP 236° to 236.5°C. 

The precipitate was then mixed with diatomaceous earth, collected on a filter, and washed with water and extracted with two 100 ml portions of boiling benzene. The aqueous filtrate was extracted with 50 ml of benzene, the combined benzene extracts washed with water and evaporated to dryness under reduced pressure. The crystalline residue, MP 140° to 147°C, weighed 30.8 g. Recrystallization from a mixture of benzene and hexane gave 27.6 g (83%) of 2-chloro-10-(3-dimethylaminopropyl)-10-hydroxythiaxanthene, MP 152° to 154°C. Analytically pure material from another experiment melted at 153° to 154°C. 

After further working up there is obtained an oily crystalline residue which is subjected to chromatography on silica gel. The 16a-methyl-6a,9a-difluoro-A -pregnadien-11/3,21-diol-3,20-dione is eluated with ethyl acetatereacted with valeric acid chloride to give the valerate ester. 

The mercury plus aqueous phase was separated, after partitioning, from the ether the latter may be further washed with water, with 0.5 N sodium hydroxide, and again with water to purify the alpha glycol. Evaporation of the ethereal phase yielded a crystalline residue of the isomeric transoid (16(/3),17(a)-dihydroxy-steroid-3-methyi ether and cisoid 16(Q ),17(a)-di-hydroxy-steroid-3-methyi ether. 

Part of the solvent is then distilled off under reduced pressure and the crystalline residue is filtered to yield 53 g (= 79% of theory) of pure 5-chloro-2-(CJ-athylthioureido)-Q-methyl-Q-phenylbenzyl alcohol melting at 101°C to 103°C. On crystallization from benzene + petroleum ether a higher-melting modification melting at 112°C to 114°C is sometimes obtained. 

Filtration of the catalyst over a Hyflo pad and removal of the solvent left a yellow crystalline residue. The crude mixture of ketone and potassium acetate was partitioned between methylene chloride (300 cc) and water (1 liter), The layers were separated and the water layer washed with methylene chloride (3 x 50 cc). The organic layers were combined, washed with 3N sodium hydroxide solution (2 x 50 cc), water (3 x 100 cc), dried over anhydrous sodium sulfate and filtered. The solvent was removed and the product recrystallized from ethanol to give 2-amino-2 -fluorobenzophenone as yellow prisms melting at 126° to 128°C,... 

A solution of 50 mg of 6a-fluoro-triamcinolone acetonide in 1 ml of pyridine and 1 ml of acetic anhydride is allowed to stand at room temperature for 18 hours. Removal of the reagents in vacuo gives a crystalline residue which after crystallization from acetone-hexane gives the pure 16a,17a-isopropylidene 6o -fluoro-triamcinolone 21 acetate (fluocinonide), as described in U.S. Patent 3,197,469. 

This oil is dissolved in benzene (100 cc) and chromatographed through silica (430 g). After elution with ethyl acetate, there is collected a fraction of 21 liters, which is concentrated to dryness under reduced pressure (20 mm Hg). The crystalline residue (32.5 g) is recrystallized from acetonitrile (100 cc) and a product (16.4 g), MP 94°C, is obtained. On recrystallization from a mixture of benzene (60 cc) and petroleum ether (200 cc), there is finally obtained 2-(3-benzoylphenyl)propionic acid (13.5 g), MP 94°C. 

When all the ethyl nitrite has been added, the reaction mixture is refluxed for approximately one hour, then concentrated to dryness under reduced pressure (25 to 30 mm Hg) and at a maximum temperature of 70°C. The crystalline residue is dissolved in 35 liters of water and adjusted to a pH of 8 to 9 by addition (with cooling and stirring) of 11 to 12 kg of caustic soda. The sodium chloride formed is filtered off, and the filter cake is washed with 20 liters of normal butyl alcohol. This wash liquid is used for the first extraction of the product from the aqueous filtrate. The filtrate is then further extracted with four successive 20-liter portions of n-butyl alcohol. 

The liberated crystalline substance is extracted twice with 50 ml of dichloromethane each time. After being separated, the dichloromethane layers are combined and washed once with 30 ml of water and dried over sodium sulfate. The solvent of the layer is removed by evaporation under reduced pressure to leave a crystalline residue (72.56 mg, 53% crude yield). 

To a solution of 2 mols of methylmagnesium iodide in 1.5 liters of ether are added with vigorous stirring 107 g (0.5 mol) of ethyl p-chloroatrolactate. The reaction mixture is stirred for about sixteen hours, and is then decomposed by the addition of about 320 ml of saturated aqueous ammonium chloride solution. After standing, the ether layer is decanted from the mixture and the aqueous phase and the precipitated salts are washed with several 500 ml portions of ether. The combined ether solution and washings are washed with successive 500 ml portions of 5% ammonium chloride solution and water, are dried over anhydrous magnesium sulfate, and are evaporated to dryness in vacuo. The crystalline residue consisting of 2-p-chlorophenyl-3-methyl-2,3-butanediol, is recrystallized from a mixture of benzene and petroleum ether. 

A 15.7 g (0.1 mol) of 2,6-dihydroxy methylpy rid in e hydrochloride are suspended in 176 ml of acetonitrile, and 20fi ml (0.15 mol) of triethylamine are added to the suspension. Thereafter 13 ml (0.22 mol) of methyl isocyanate are added dropwise to the reaction mixture at 20°C to 25°C. The reaction mixture is stirred at 20°C to 30°C for one hour, thereafter boiled for 3 hours, and finally the solvent is evaporated under reduced pressure. 35 to 40 g of a greyish, crystalline residue are obtained, which Is a mixture of 2,6-dihydroxymethylpyridine-bis-(N-methylcarbamate) and triethylamine hydrochloride. The obtained residue is dissolved in 80 ml of hot water, decolorized with 2 g of activated carbon when hot, and filtered after 30 minutes of stirring. The filtrate is cooled, the resulting crystal suspension is stirred at 0°C to 5°C for 3 hours, the solids are filtered off, and dried at 50°C to 60°C. 

The excess thionyl chloride was removed under vacuum and by distilling from the residue two portions of dry benzene. The crystalline residue was crystallized twice from hexane-ether to yield 3,4,5-trimethoxycinnamoyl chloride which was obtained in the form of bright yellow prisms, MP 95° to 96°C. 

This 0 -benrylmercaptopropionylglycine (60 g) is dissolved in 400 ml of liquid ammonia, kept at about -50 C, and 12g of sodium metal is gradually added thereto. After the reaction, excess ammonia is removed therefrom, the residue is dissolved in water, washed with ether and the residual aqueous layer is adjusted to pH 1 with hydrochloric acid and concentrated in vacuo in a stream of hydrogen sulfide. The crystalline residue is dried and recrystallired from ethyl acetate to give 25 g of 0 -mercaptopropionylglycine of melting point 95°C to 97°C. 

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