Sodium 3- -dione

Ninhydrin (also named 1 2 3-triketoindane or 1 2 3-triketohydrindene hydrate) is prepared most simply from the inexpensive phthahc anhydride (I). The latter is condensed with acetic anhydride In the presence of potassium acetate to give phthalylacetlc acid (II) reaction of the latter with sodium methoxide in methanol yields 1 3-indanedionecarboxyhc acid, which is decomposed upon warming with dilute hydrochloric or sulphuric acid to indane-1 3-dione (or 1 3-diketohydrindene) (HI). Selenium dioxide oxidation of (III) afibrds indane-1 2 3-trione hydrate (ninhydrin) (IV). 

Indane-1 3-dione (1 3-diketohydrindene). Method A. To a solution of sodium methoxide, prepared from 6 1 g. of sodium and 200 ml. of anhydrous methanol, add 15 g. of phthalylacetic acid and allow to stand for 1 hour at room temperature collect the yellow precipitate by suction filtration. Mix the yellow solid with 150 ml. of 10 per cent, sulphuric acid, heat on a steam bath until no more carbon dioxide is evolved (15-20 minutes), filter the hot solution and allow to cool. Collect the yellow crystals by filtration at the pump, wash with a httle water and dry at 100°. The yield of crude 1 3-indanedione, m.p. 125-126°, is 7 g. RecrystaUise from hght petroleum, b.p. 80-100°, and thus obtain the pure product, m.p. 129-130°. 

Fluoro-llb,21-dihydroxy-16a-methyl-21-(phosphonooxy)-pregna-l,4-diene- 3,20-dione, disodium salt. See Dexamethasone sodium phospate. 

Cychc diacyl peroxides can be generated from suitable dibasic acid chlorides and sodium or hydrogen peroxide, especially in dilute solutions (187,205), eg, 2,3-ben2odioxin-l,4-dione [4733-52-2] from phthaloyl chloride ... 

There are two main classes here. Firstly, 5-substituted 4(6)-aminopyrimidines, e.g. the 5-ester (227), are reacted with esters in the presence of sodium (63CB1868), or with acetals in the presence of alkoxide (78KGS1549), to give pyrido[2,3-Keto esters give 6-ketones (229) (80USP4215216), whilst use of aminopyrimidine nitriles gives 7-oxo-5-amino derivatives (81USP4245094). 

Another approach uses the reaction of 6-chloro-5-nitropyrimidines with a-phenyl-substituted amidines followed by base-catalyzed cyclization to pteridine 5-oxides, which can be reduced further by sodium dithionite to the heteroaromatic analogues (equation 97) (79JOC1700). Acylation of 6-amino-5-nitropyrimidines with cyanoacetyl chloride yields 6-(2-cyanoacetamino)-5-nitropyrimidines (276), which can be cyclized by base to 5-hydroxypteridine-6,7-diones (27S) or 6-cyano-7-oxo-7,8-dihydropteridine 5-oxides (277), precursors of pteridine-6,7-diones (278 equation 98) (75CC819). 

Isatin (indoIe-2,3-dione) [91-56-5] M 147.1, m 201-203 , 205°, pK >12 (acidic NH). Crystd from amyl alcohol and sublimed at 180°/lmm. In aq NaOH the ring opens to yield sodium o-ami nobenzoy 1 formate. 

Reductants such as zinc or sodium dithionite generate the semidione from diketones. Electrolytic reduction can also be used. Enolates can reduce diones to semidiones by electron transfer. 

A solution of 2 g of sodium borohydride in 5 ml of water is added at room temperature to a solution of 1 g of 3a-hydroxy-5jS-pregnane-l 1,20-dione in 15 ml of methanol. Almost immediately, crystals begin to form. After the mixture has been kept overnight, the precipitate is collected with suction to yield 0.8 g of the diol, mp 230-232°. The analytical sample, crystallized once more from aqueous methanol, melts at 231.4-232.6° [a]p 31.2° (acetone). Reported mp 236-238°. 

Refluxing 3a-hydroxy-5)5-pregnane-ll,20-dione in methanol overnight with sodium borohydride gives the 3a,llj5,20jS-triol in 85% yield with mp 233-235°, [ ][) 38.9° (dioxane). 

When 3a,17a-dihydroxy-5jS-pregnane-ll,20-dione is allowed to react at room temperature overnight with sodium borohydride in aqueous methanol, no crystals form and only 5j5-pregnane-3a,l ljS,17a,20j5-tetrol is isolated in good yield. If the reaction is halted at the end of 3 h y the addition of water and extraction with chloroform, it is possible xo obtain a 55% yield of 3a,17a,20jS-trihydroxy-5j5-pregnan-ll-one, mp 218-220°,after recrystallization of the chloroform residue from aqueous methanol. The analytical sample, crystallized once more, has mp 219.0-220.6° [a][, 36° (acetone), reported mp 220° [aJu 38°. 

A solution of 1 g of the dione in 200 ml of methanol at 0° is treated with 75 mg of sodium borohydride and the mixture is kept for 2 hr. After addition of 0.1 ml of acetic acid the mixture is concentrated to ca. 20 ml. Dilution with water gives 0.9 g of crystals which are chromatographed on 20 g of unwashed alumina. Elution with benzene-ether (40 60) yields 0.73 g of the methyl-hydroxytestosterone, mp 245-249°, which after crystallization from acetone has mp 255-256° [a] 111° (CHCI3). 

A solution of 0.25 g sodium borohydride in 140 ml of ethanol is added to a stirred solution of 0.56 g of calcium chloride in 60 ml of ethanol at —25°. The vigorously stirred mixture is treated dropwise at —25° over 5 min with 4.87 g of 1 la-hydroxy-5/S-pregnane-3,20-dione in 100 ml of ethanol. After a further 3 hr at —20°, 10 ml of 40% aqueous acetic acid is added and the mixture is evaporated to dryness under vacuum. The residue is dissolved in 150 ml of ether and the ethereal solution is washed with 30 ml of 2 A hydrochloric acid and twice with 30 ml of water and dried over Na2S04. Removal of the solvent gives 4.6 g of crystals, which are recrystallized from 20 ml of ether to yield 2.9 g (60%) of the dihydroxy ketone, mp 182-184° [aj 110° (ethanol). 

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°. 

A solution of 16jS-methyl-l la,17a,21-trihydroxy-5j5-pregnane-3,20-dione 21-acetate (52), 45 g, in dioxane (297 ml) is cooled to 15° and treated over a 5 min period with a solution of bromine (34.2 g) in dioxane (594 ml) precooled to 18°. After 2 min a solution of sodium acetate (60 g) in water (600 ml) is added and the mixture poured into ice water (8 liters). The precipitate is filtered off, washed to neutrality with water, and dried to give the crude dibromide (53), 55.7 g mp 125-126° (dec.) [aJu 58°. A mixture of dibromide (53), 55.5 g, lithium bromide (27.8 g), lithium carbonate (27.8 g) and DMF (1.11 liters) is refluxed under rapid stirring for 6 hr. The mixture is concentrated under vacuum to about 250 ml, poured into ice water (8 liters) containing hydrochloric acid (250 ml), and extracted with methylene dichloride. The extracts are washed to neutrality with water and evaporated to dryness. The residue is dissolved in acetone, evaporated to dryness under reduced pressure, redissolved in acetone and crystallized by the additon of hexane. This gives the dienone (54) 24.4 g, mp 236-239°. 

Androst-4-ene-3,l7-dione 3-Ethylene Thioketal A solution of androst-4-ene-3,17-dione (1.42 g, 5 mmoles) in acetic acid (20 ml) is treated with ethanedithiol (0.47 g, 5 mmoles) and a solution of 0.45 of p-toluenesulfonic acid monohydrate in acetic acid (5 ml). After 1 hr at room temperature, the pale yellow solution is poured into water and the resulting suspension is extracted with chloroform. The chloroform solution is washed with water, 5 % sodium hydroxide solution and water, dried (Na2S04) and evaporated. Chromatography of the resulting oil (1.93 g) over silica gel yields androst-4-ene-3,17-dione bisethylene thioketal, mp 173-175° [0.16 g, eluted with petroleum ether-benzene (1 2)] and androst-4-ene-3,17-dione 3-ethylene thioketal, mp 173-176° [1.38 g (76%), eluted with benzene-ethyl acetate (19 1)]. 

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