Dioxan purification

Syntheses of a,)3-dihalogenoethers can be achieved in various ways the classical method (37), wherein a current of dry gaseous hydrochloric acid, is made to react in an equimolar mixture of ethanol and aldehyde at 20°C first to form the monochloroether (50% yield) and then by the action of bromine, the dibromoether (80 to 90% yield) can be used. The second and simpler method is the direct bromination of ethylvinylether in a chloroformic or dioxane solution if the product is used directly without purification,... 

The acetal (b 82.5°) is removed during fractional distn. Traces of benzene, if present, can be removed as the benzene/MeOH azeotrope by distn in the presence of MeOH. Distn from LiAlHa removes aldehydes, peroxides and water. Dioxane can be dried using Linde type 4X molecular sieves. Other purification procedures include distn from excess C2H5MgBr, refluxing with Pb02 to remove peroxides, fractional crystn by partial freezing and the addition of KI to dioxane acidified with aq HCl. Dioxane should be stored out of contact with air, preferably under N2. 

Dioxane available from Fisher Scientific Company was used without further purification. 

A mixture of 1.38 grams of the above compound and 15 cc of dioxane was treated with 1.9 cc of a 0.5 N aqueous solution of perchloric acid and 600 mg of N-bromoacetamide, adding the latter in the dark, in three portions, in the course of half an hour and under continuous stirring. It was then stirred for a further 1% hours in the dark, then the excess of reagent was decomposed by the addition of aqueous sodium bisulfite solution and ice water was added the product was extracted with methylene chloride, washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, thus giving a yellow oil consisting of the 16,21-diacetate of 6a-fluoro-9a-bromo-16o-hydroxy-hydrocortisone which was used for the next step without further purification. 

A solution of 1-phenyl-1//-pyrazolo[3,4-rf]pyridazinc-7-carbonitrilc (150 mg. 0.68 mmol) and A,A-diethyl-prop-l-ynamine(151 mg, 1.36 mmol) in l,4-dioxane(2 mL) was refluxed for 5 h. After cooling, the reaction mixture was poured onto excess ice, and extracted with CHC13. The extract was washed with H20, dried (Na2S04) and concentrated under reduced pressure. Purification by chromatography (silica gel, benzene then bcnzene/EtOAc 20 1) gave, from the benzene eluate, 6-diethylamino-1 -phenyl-1 //-indazole-7-carbo-nitrile [yield 81 mg (39 %) mp 104-105 C (benzene/petroleum ether)] as slightly yellow prisms and, from the second eluate, the diazocine 5 as yellow needles yield 90 mg (40 %) mp 121-122 C (benzene/ petroleum ether). 

Dioxane, palladium (II) acetate, and triphenylphosphine were purchased from Aldrich Chemical Company, Inc. and were used without further purification. 

Alternatively, 300-400 ml. of the dioxane may be transferred by this method into another flask before the hexane is added. The recovered dioxane may then be used in another preparation without purification. 

The pKs value of acetic acid is about the same as that of water therefore, in order to obtain high accuracy and greater differentiation in potentiometric titrations, Pifer and Wollish91 preferred to use acetic acid mixed with dioxan in the solvent and also in the perchloric acid titrant in view of the possible presence of peroxide, the previous purification requires great care40. Similarly, Fritz92 recommended acetic acid mixed with acetonitrile (pKs = 19.5 at 25° C)93 in both the solution and the titrant. 

Following a patented procedure for the conversion of 2,4-dinitrochlorobenzene to 5-chloro-2-nitrophenol, 2,4-difluoronitrobenzene was treated with sodium hydroxide in hot aqueous dioxane containing a phase transfer catalyst. On the small scale, the reaction and isolation of 5-fluoro-2-nitrophenol, including vacuum distillation, were uneventful. On the 20 1 scale, vacuum distillation of combined batches of the crude product led to onset of decomposition at 150°C, which could not be controlled, and the residue erupted with explosive violence and a small fire ensued. Thermal examination of fresh small-scale crude material has shown that it is capable of highly exothermic decomposition, with onset of the exotherm at 150°C (ARC). It was then realised that difficulty in controlling the reaction temperature had been experienced on the 20 1 scale. It is recommended that this procedure and purification should not be attempted on so large a scale. 

Dimethylformamide (DMF), dioxane, piperidine, methylene chloride, acetonitrile, trimethyl orthoformate (TMOF), sodium borohydride, diisopropylcarbodiimide, and trifluoroacetic acid (TFA) were purchased from Aldrich Chemical Company, Inc. and used without further purification. All of the diversity reagents were purchased from Aldrich except for Fmoc-glycine-OH, which was purchased from Novabiochem. 

General Procedure for the Hydroformylation/Carbonyl ene Reaction/O,O-acetal Forma-tion/Dehydration. Synthesis of Chromane Derivatives. A solution of the substrate (1 eq) RhCl(PPh3)3 (1 mol %) and PPh3 (3 mol %) in dry dioxane was heated for 70 h to 120 °C und an atmosphere of CO/H2 (1 1, 100 bar). The crude product was filtered through basic alumina (eluated with MTBE). After evaporation of the solvent further purification by column chromatography (silica, PE/MTBE) furnished the title compounds. 

Figure 1.6 ICH Class 2 solvents measured using GC. Purification of pravastatin sodium by preparative liquid chromatography. Reprinted from [15], copyright 2004, with permission from Elsevier. (Column 30 m X 0.53 mm i.d. 3 pm OVI-G43 (Supelco) carrier gas helium at 5 ml/min injection in split mode total flow 25 ml/min injector temperature 140 C flame ionization detector temperature 25C C and oven temperature 40°C for 20 min, to 240°C at 10°C/min, maintain at 240 C for 20 min. The components are 1 methanol, 3 acetonitrile, 4 dichloromethane, 5 hexane, 6 cw-l,2-dichloroeth-ylene, 7 nitromethane, 8 chloroform, 9 cyclohexane, 13 1,2-dimethoxyethane, 15 1,1,2-trichloroethyl-ene, 16 methylcyclohexane, 17 1,4-dioxane, 18 pyridine, 19 toluene, 20 2-hexanone, 21 chlorobenzene, 22 ethylbenzene, 23 m-xylene, 24p-xylene, 25 o-xylene, and 26 tetralin. The solvents are dissolved in DMF and heated at 80X for 60 min, and a sample of the headspace is injected.)...

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