Ethyl sodium, reaction with benzene

To a mixture of ethyl 5a-cholestan-3-one 2a-xanthate (2 g, 3.95 mmol) and 100 ml methanol is added sufficient ether to completely dissolve the solids. Sodium borohydride (90 mg, 2.36 mmol) is added directly to the reaction flask and the solution is stirred at room temperature for 4 hr. (The use of an excess of sodium borohydride and an extended reaction time produces 5oc-cholestan-2a,3a-thiirane.) The reaction is diluted with 200 ml ether and washed several times with ca. 100 ml water, dried (MgS04) and the solvent is removed under vacuum. The crude sticky gum is chromatographed on a column of 85 g silicic acid. The hexane eluates contain 5a-cholest-2-ene. Ethyl 5a-cholestan-3a-ol 2a-xanthate is obtained in ca. 30% yield by subsequent elution with benzene hexane (1 7) and the desired ethyl 5a-cholestan-3 -ol 2a-xanthate is eluted with ether hexane (1 3) in ca. 30% yield. 

A total of 3 g (0.13 moles) of sodium hydride is added to a solution consisting of 10 g of 17 -hydroxy-5a-androstan-3-one (36 mmoles) in 200 ml of benzene and 10 ml of ethyl formate. The reaction mixture is allowed to stand under nitrogen for 3 days followed by dropwise addition of 10 ml of methanol to decompose the excess of sodium hydride. The solution is then diluted with 300 ml water and the layers are separated. The basic aqueous solution is extracted with ether to remove neutral material. The aqueous layer is acidified with 80 ml of 3 A hydrochloric acid and the hydroxymethylene steroid is extracted with benzene and ether. The combined organic extracts are washed with water and saturated sodium chloride solution and then dried over magnesium sulfate and concentrated. The residue, a reddish-yellow oil, crystallized from 10 ml of ether to yield 9.12 g (83%) of 17 -hydroxy-2-hydroxymethylene-5a-androstan-3-one mp 162-162.5°. Recrystallization from chloroform-ether gives an analytical sample mp 165-165.5° [a]o 53° (ethanol) 2 ° 252 mjj. (g 11,500), 307 m u (e 5,800). 

The formic acid Is distilled off, and the remainder dissolved in warm benzene and washed with a bicarbonate solution to a neutral reaction. After the benzene has been distilled off, the aminomalonic ester xylidide is obtained. This Is treated with an equal quantity of sodium ethylate and boiled with twice the theoretical quantity of tetramethylene bromide in absolute alcohol. 

Sodium (9.6 parts) was dissolved in butanol (192 parts) and di-n-butyl ethyl 1 -methyl-n-butylmalonate (62,B parts) and urea (14.4 parts) were added to the warm solution with agitation. The mixture was then heated to reflux temperature in three quarters of an hour and maintained for 2 hours. The reaction mass was kept, water (150 parts) added, the aqueous portion separated, and the butanol layer extracted with water (3 x 50 parts). The combined aqueous extracts were then given 3 small extractions with benzene, the aqueous liquors separated, charcoaled,filtered and precipitated with concentrated hydrochloric acid (acid to congo-paper). The solid was collected, washed with water, dissolved in N-sodium hydroxide and reprecipitated with carbon dioxide. On recrystallization, from aqueous alcohol, the pentobarbitone was obtained. 

A suspension of 30 g of sodium hydride in benzene (30 ml) was added dropwise to 52 g of 8-chlorodibenzo[b,f] thiepin-10(11 H)-one dissolved in dimethylformamide (800 ml), and the mixture was heated at 100°C for 2 hours. To this, there were added 68 g of 2-dimethylamino-ethyl chloride, and the mixture was heated at 60°C for 39 hours. The reaction mixture, after cooled, was poured into ice-water, and the solution was extracted with ethyl acetate. The ethyl acetate layer, after washed with water, was extracted with 10% hydrochloric acid, when oil was precipitated. The aqueous layer, in which oil was precipitated, was washed with ether, made neutral with concentrated sodium hydroxide solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated to give oil, which was allowed to stand to provide solid. The solid was washed with petroleum ether and recrystallized from cyclohexane to yield 42.5 g of 8melting point 90°C to 91°C. Male-ate as colorless needle, melting point 204°C to 204.5°C. 

Silver fluoborate, reaction with ethyl bromide in ether, 46, 114 Silver nitrate, complexing with phenyl-acetylene, 46, 40 Silver oxide, 46, 83 Silver thiocyanate, 45, 71 Sodium amide, in alkylation of ethyl phenylacetate w ith (2-bromo-ethyl)benzene, 47, 72 in condensation of 2,4-pentanedione and 1 bromobutane to give 2,4-nonanedione, 47, 92 Sodium 2 ammobenzenesulfinate, from reduction of 2 mtrobenzenesul-finic acid, 47, 5... 

Lead tetraacetate is added in small quantities, with stirring, to an ice-cold suspension of 11 g. of ethyl 3-(D-arabino-tetrahydroxybutyl)-5-methyl 4-furoate in 100 ml. of benzene plus 40 ml. of glacial acetic acid. Addition is stopped when there is a positive reaction with potassium iodide-starch paper. The mixture is stirred for a further ten minutes, filtered, and the benzene solution washed twice with water. The benzene layer is then dried with anhydrous sodium sulfate, filtered, and the filtrate evaporated to dryness. The residue (6 g.) is mixed with a solution of 7.5 g. of sodium hydroxide plus 20 g. of silver nitrate in 40 ml. of water, and heated for 40 minutes on a steam bath. The aqueous solution is filtered, acidified to Congo Red while being cooled with ice, and the crystals formed are removed by filtration, washed with ice-cold water, and dried over phosphorus pentoxide in the vacuum desiccator yield, 2.2 g. After recrystallization from water, the product has m. p. 234r-235°. 

Glycolaldehyde is formed by heating 2 g. of dihydroxymaleic acid in 10 ml. of water until the evolution of carbon dioxide ceases. To the resultant solution is added 2 ml. of ethyl acetoacetate followed by 2 ml. of ethyl alcohol and 1 g. of zinc chloride. The mixture is heated for one hour on a steam bath, and the reaction mixture is extracted with benzene. The benzene extract is washed with a concentrated solution of sodium bisulfite, and evaporated, affording an oil which is saponified by heating with sodium hydroxide solution (10%) on a steam bath for one hour. It is then acidified with dilute hydrochloric acid and extracted with ether. The ethereal extract is dried with anhydrous sodium sulfate and the solvent is evaporated the residue crystallizes from ether m. p., 99°. 

The acylation of 6-indazolylaminomethylenemalonate (1470) by reaction with acetic anhydride in the presence of pyridine for 45 min, or with benzoyl chloride in a mixture of DMF and benzene in the presence of sodium ethylate for 75 min, gave 1-acyl derivatives (1504) in 72% and 58% yields, respectively (78YZ1158). 

Yet a further increase in potency is observed when the para-isobutyl group is replaced by a benzene ring. One published synthesis for that compound is quite analogous to the malonate route to the parent drug. The acetyl biphenyl (50-1) is thus converted to the corresponding arylacetic acid by reaction with sulfur and morpholine, followed by hydrolysis of the first-obtained thiomorpholide. This is then esterified and converted to malonate anion (50-2) with sodium ethoxide and ethyl formate. The anion is quenched with methyl iodide hydrolysis of the esters followed by decarboxylation yields the NSAID flubiprofen (50-3) [51]. 

In a 50-ml three-necked flask are placed the carboxylic acid (0.01 mol), ethyl polyphosphate (6g, PPE) and purified chloroform (5 ml). The mixture is cooled in an ice bath and the flask is connected to a balloon containing ammonia gas ( 3 litres). Air in the flask is replaced with ammonia and the mixture is mechanically stirred at 0-5 °C for 30 minutes and then at room temperature for one and a half hours whereupon the mixture turns very viscous (1). The balloon is removed and PPE (10 g) is added. The stirring is continued at 80 °C until the reaction is complete (usually within several hours) the dehydration is monitored by t.l.c. analysis (1). The mixture is stirred with aqueous 25 per cent sodium carbonate solution (150 ml), and then extracted with benzene (3 x 40 ml CAUTION). The combined organic extracts are dried with sodium sulphate and evaporated. The residual oil is passed through a short column packed with silica gel ( 20g) and the product eluted with benzene. The eluate is evaporated and the residue purified by short path distillation under reduced pressure (Kugelrohr apparatus). 

A solution of 4,4,17a-trimethyl-androsta-2,5-dien-17p-ol-3-one in benzene was added to sodium methoxide (from sodium and of absolute methanol, concentrating the solution and drying the residue for 1 h at 150°-160°C and 15 mm). Ethyl formate was then added with stirring in a nitrogen atmosphere. The reaction mixture was stirred for 4 h at room temperature, allowed to stand for about 15 h, stirred for 2 h and then poured into water. The reaction mixture was extracted with benzene, the aqueous layer warmed until clear, filtered and cooled below room temperature. Concentrated hydrochloric acid and ice were added to the filtrate until the mixture was acid to Congo red, and the product was extracted with chloroform. The chloroform extracts were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated vacuum, whereupon there separated 2-hydroxymethylene-4,4,17a-trimethyl-androsta-2,5-dien-17p-ol-3-one. 

A mixture of 560 g of potassium carbonate, 700 ml of ethanol (96%), 404 g of 1,3-dibromopropane and 260 g of ethyl acetoacetate was heated with stirring to go 60°C. After the reaction had subsided, the reaction mixture was refluxed for 5 hours. Then the bulk of the alcohol was distilled off under ordinary pressure and the residue was mixed with 1.5 L of water. The resulting oily layer was separated, and the aqueous phase was extracted with benzene and the benzene layer was combined with the oil. After drying with sodium sulfate the benzene was distilled off and the residue was fractionally distilled 250 g (73% of theory) of 2-methyl-3-carbethoxy-5,6-dihydropyrane of boiling point 105°-108°C were obtained. 

Cyano-10-(3-methanesulfonyloxypropyl)phenthiazine and 4-hydroxypiperidine in toluene were heated under reflux with stirring. The reaction mixture was allowed to cool and water was added. The resulting toluene solution layer was decanted and washed twice with water. The toluene solution was then stirred with 5% hydrochloric acid. The hydrochloride of the desired phenthiazine base precipitated in gummy condition in the aqueous layer. This was decanted and treated with sodium hydroxide (density 1.33). It was then extracted three times with ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated in vacuum. A resinous product was obtained. This product was dissolved in a mixture of benzene and cyclohexane and chromatographed on a column containing alumina. The chromatographed product was eluted successively with mixtures of benzene and cyclohexane and then with benzene and finally with a mixture of benzene and ethyl acetate. The eluates were evaporated to yield a crude product. This product was recrystallised from aqueous ethanol (40% water) and yielded 2-cyano-10-[3-(4-hydroxy-l-piperidyl)propyl]phenthiazine as white crystals. 

The procedure developed by Moriarty for the a-hydroxylation of ketones using iodosylbenzene or its diacetate has been extended fw use with esters.Thus treatment of methyl or ethyl esters with iodosylbenzene diacetate in a two-phase system (benzene/aqueous KOH) generates the a-hydroxy acid, while reaction in methanol in the presence of sodium methoxide provides the a-methoxy ester, (Scheme 19). Oxidation of the fnt acid was unsuccessful (Section 2.3.2.6). Both variations proceed in similar, moderately good yields, in a fashion mechanistically analogous to Ae reaction with ketones. 

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