Crystallization, borohydride solutions

Phenyl Phenylselenomethyl Tellurium 2.05 g (5 mmol) of diphenyl ditellurium are dissolved in dml of ethanol/benzene (3/1, v/v) and the solution is placed in a nitrogen-flushed, 250-ml flask equipped with a magnetic stirrer. 10 g (265 mmol) of sodium borohydride are dissolved in 200 w/ of 1 M aqueous sodium hydroxide solution. The sodium borohydride solution is added dropwise at 20° to the stirred diphenyl ditellurim solution until the mixture becomes colorless. Then 2.5 g (10 mmol) of phenylselenobromometh-ane are added immediately and the mixture is stirred at 20° for 30 min. 10 m/of dichloromcthane are added, the organic layer is separated, washed successively with saturated ammonium chloride solution and brine, and dried with anhydrous magnesium sulfate. The dried extract is filtered and the filtrate evaporated. The residue is dissolved in petroleum ether (b.p. 30-60°), and the solution is cooled to — 78° whereupon the product crystallizes yield 2.5 g (66%) m.p. 51°. 

Refill the separatory furmel as necessary until all 500 mL of the sodium borohydride solution has been consitmed. The initial color of the ferric chloride solution is rasty, which will go to tight green (ferric to ferrous) and eventually to black (ferric to zero valent i.e., Fe°) as the nano iron crystals are formed. 

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°. 

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 1 g of the ethyleneketal of the trione in 40 ml of methanol is treated with 0.2 g of sodium borohydride and the mixture is stirred at 20° for 2 hr. Slow drop wise addition of water precipitates the reaction product as crystals. These are filtered, washed with water and dried, to give 1.02 g of hydroxy ketone, which after crystallization from methylene dichloride-hexane has mp 182-184° (reported 184-186°) -23° (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). 

A solution of sodium borohydride (8 grams) in water (16 ml) was added to a stirred solution of 2(3,16(3-bis-piperidino-5a-androstan-3a-ol-17-one (17 grams) in tetrahydrofuran (70 ml) and methanol (30 ml) and the solution stirred at room temperature for 16 hours. The product was precipitated by the addition of water, filtered off, dried, and crystallized from acetone to give the diol (14.9 grams). 

Step D Chemical Reduction Preparation of 3-Morpholino-4-(3-tert-Butylamino-2-Hydroxy-propoxyl-l,2,5-Thiadiazole — The 3-morpholino-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole (0.01 mol) is dissolved in isopropanol (10 ml). To the solution is added sodium borohydride in portions until the initial evolution of heat and gas subsides. The excess sodium borohydride is destroyed by addition of concentrated hydrochloric acid until the mixture remains acidic. The precipitate of sodium chloride is removed, ether is added, and the solution is concentrated to crystallization. The solid material is removed by filtration and dried thus providing 3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole, MP 161° to 163°C (as hydrochloride). 

Removal of the p-methoxybenzyl group is accomplished by treatment with dichloro-dicyanoquinone (DDQ), which forms quantitatively aminal 17 in an 11.5 1 diastereomeric ratio (Yu and Levy, 1984). The solution is treated with sodium methoxide in methanol, which decomposes the aminal into the desired amine 18 and p-methoxybenzaldehyde. Due to the difficulties in separating the p-methoxybenzaldehyde from amino alcohol 18, the aldehyde is reduced in situ with sodium borohydride. The amino alcohol 18 is crystallized from the reaction mixture after neutralization with acetic acid. Additional recrystallization provides the desired amino alcohol 18 in 94% yield. 

S)-2-Amino-3-phenylpropan-1 -ol [(S)-phenylalaninol. 124 To a solution of sodium borohydride (3.5 g, 0.092 mol) in 50 per cent aqueous ethanol (50 ml) is added dropwise a solution of (S)-phenylalanine ethyl ester hydrochloride (5.0 g, 0.022 mol) in 50 per cent aqueous ethanol (50 ml). After the resulting mixture is refluxed for 4.5 hours, ethanol is evaporated in vacuo. The aqueous solution thus obtained is then extracted with ethyl acetate and the extract washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. Evaporation of the ethyl acetate under reduced pressure affords (S)-phenylalaninol (2.8 g, 84%) as a pale yellow solid m.p. 85-92 °C. Recrystallisation from ether gives colourless crystals of m.p. 91-93 °C, [oc] 5 - 25.6° (c. 1.037 in EtOH). 

To a stirred mixture of 13 parts of 2-(acetylimino)-3-(2-thienylcarbonyl)methyl]thiazoline hydrobromide and 64 parts of ethanol are added portion wise 3 parts of sodium borohydride (exothermic reaction). After the addition is complete, the whole is stirred and refluxed for one hour. The solvent is evaporated. The solid residue is dissolved in hydrochloric acid 4 N. After keeping at room temperature, it crystallizes again. The solid is filtered off and dissolved in water. The aqueous solution is rendered alkaline with ammonium hydroxide and extracted with chloroform. The chloroform extract is dried over magnesium sulfate and evaporated. The solid residue is recrystallized twice first from 4-methyl-2-pentanone and once more from 400 parts of water. After drying in vacuum, DLI-2-(acetylimino)-3-[2-hydroxy-2-(2-thienyl)ethyl]thiazoline is obtained MP 132.5°-133°C. 

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