Cooling dilution

Dibromobutane (from 1 4-butanediol). Use 45 g. of redistilled 1 4-butanediol, 6-84 g. of purified red phosphorus and 80 g. (26 ml.) of bromine. Heat the glycol - phosphorus mixture to 100-150° and add the bromine slowly use the apparatus of Fig. Ill, 37, 1. Continue heating at 100-150° for 1 hour after all the bromine has been introduced. Allow to cool, dilute with water, add 100 ml. of ether, and remove the excess of red phosphorus by filtration. Separate the ethereal solution of the dibromide, wash it successively with 10 per cent, sodium thiosulphate solution and water, then dry over anhydrous potassium carbonate. Remove the ether on a water bath and distil the residue under diminished pressure. Collect the 1 4-dibromobutane at 83-84°/12 mm. the yield 3 73 g. 

Mix 1 g. of the nitro compound with 4 g, of sodium dichromate and 10 ml. of water in a 50 ml. flask, then attach a reflux condenser to the flask. Add slowly and with shaking 7 ml. of concentrated sulphuric acid. The reaction usually starts at once if it does not, heat the flask gently to initiate the reaction. When the heat of reaction subsides, boil the mixture, cautiously at first, under reflux for 20-30 minutes. Allow to cool, dilute with 30 ml. of water, and filter oflF the precipitated acid. Purify the crude acid by extraction with sodium carbonate solution, precipitation with dUute mineral acid, and recrystaUisation from hot water, benzene, etc. 

To a mixture of 10 g. of the compound and 3-5 ml. of 33 per cent, sodium hydroxide solution in a test-tube, add 2-5 ml. of 50 per cent, chloroacetic acid solution. If necessary, add a little water to dissolve the sodium salt of the phenol. Stopper the test-tube loosely and heat on agently-boiling water bath for an hour. After cooling, dilute with 10 ml. of water, acidify to Congo red with dilute hydrochloric acid, and extract with 30 ml. of ether. Wash the ethereal extract with 10 ml, of water, and extract the aryloxyacetic acid b shaking with 25 ml. of 5 per cent, sodium carbonate solution. Acidify the sodium carbonate extract (to Congo red) with dilute hydrochloric acid, collect the aryloxyacetic acid which separates, and recrystallise it from hot water. 

Oximes (compare Section III,74,B). The following procedure has wide application. Dissolve 0-5 g. of hydroxylamine hydrochloride in 2 ml. of water, add 2 ml. of 10 per cent, sodium hydroxide solution and 0-2 g. of the aldehyde (or ketone). If the latter is insoluble, add just sufficient alcohol to the mixture to give a clear solution. Heat the mixture under reflux for 10-15 minutes, and then cool in ice. If crystals separate, filter these off, and recrystallise from alcohol, dilute alcohol, benzene or light petroleum (b.p. 60-80°). If no solid separates on cooling, dilute with 2-3 volumes of water, filter the precipitated sohd, and recrystallise. 

A mixture of l-(r-Boc)indol-2-yl-tri- -butylstannanc (1.2 mmol) and 4-bromo-benzonitrile (1.0 mmol) and Pd(PPh3)2C , (0.02 mmol) in dry dioxane (5 ml) was heated at I00°C overnight under nitrogen. The reaction mixture was cooled, diluted with EtOAc and stirred for 15 min with 15% aq. KF. The precipitate was removed by filtration and washed with EtOAc. The EtOAc layer was separated, washed with brine, dried (Na2S04) and concentrated. The residue was purified by chromatography on silica. The yield was 66%. 

A. l-THmethyleilyloxyayalopentsne. A 1-L, two-necked, round-bottomed flask is equipped with a mechanical stirrer and a reflux condenser having a drying tube (calcium chloride). The flask is charged with 200 mL of dimethylformamide (Note 1), 45 g (0.54 mol) of cyclopentanone (Note 2), 65.5 g (0.6 mol) of chlorotrimethylsilane (Note 2) and 185 mL (1.33 mol) of triethylamine (Note 1), and the mixture is refluxed for 17 hr (Note 3). The mixture is cooled, diluted with 350 mL of pentane, and washed four times with 200-mL portions of cold saturated aqueous sodium hydrogen carbonate. The... 

Dissolved in EtOH, and added to 0.25M Pb(OAc)2 in 50% aqueous EtOH. The ppted lead mercaptide was filtered off, washed with a little EtOH, and impurities were removed from the molten salt by steam distn. After cooling, dilute HCl was added dropwise to the residue, and the mercaptan was distd directly from the flask. Water was separated from the distillate, and the mercaptan was dried (Na2C03) and distd under nitrogen. [Mathias J Am Chem Soc 72 1897 1950.]... 

Dipping solution Add 50 ml perchloric acid (70%) carefully to 50 ml water and after cooling dilute the mixture with 50 ml ethanol. 

Q Preparation of 2-Acetyi-3-Methyi-5-(2-Oxo-2,5-Dihydro-4-Furyi)Benzo[b]Furan (3556 CB) (1) A suspension of 2 grams of the compound prepared according to (B) in 20 ml of concentrated hydrochloric acid, is heated to about 50°C, just until it dissolves. Thereafter it is heated for 2 minutes to 70°C, just until precipitation commences. The mixture is allowed to cool, diluted with water, filtered, the residue washed, dried, and sublimed at 200°C and 0.1 mm pressure, 1.4 grams of product (Yield 70%) Is obtained, MPc = 218°-221°C. A second sublimation produces a chemically pure product, MP = 221°-222°C. 

The following is an alternative route 19.4 parts of p-chlorophenyidicyandiamide, 9.4 parts of hexamethylenediamine dihydrochloride and 100 parts of nitrobenzene are stirred together and heated at 150°C to 160°C for 6 hours. The mixture Is cooled, diluted with 200 parts of benzene and filtered. The solid residue is washed with benzene and crystallized from 50% acetic acid. 1,6-di(Ni, Ni -p-chlorophenyldiguanido-Ns,Ns )hexane dihydrochloride Is obtained. 

To 6a-fluoro-16a-hydroxy-hydrocortisone 21-acetate, described by Mills et al, J. Am. Chem. Soc., volume 81, pages 1264 to 1265, March 5, 1959, there was added acetic anhydride in dry pyridine. The reaction mixture was left at room temperature overnight and was then poured with stirring into ice water. The resulting precipitate was filtered, washed with water and crystallized from acetone-hexane to give 6a-fluoro-16a-hydroxy-hydrocortisone-16a,21-diacetate. This was reacted with methane-sulfonyl chloride in dimethyl formamide in the presence of pyridine at 80°C for 1 hour. The mixture was cooled, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. By recrystallization of the residue from acetone-hexane there was obtained 6a-fluoro-A <" -pregnadiene-16o ,17a,21-triol-3,20-dione 16a,21 diacetate. 

A solution of 23.7 grams of 2-bromoacetamido-2 -fluorobenzophenone in tetrahydrofuran (100 cc) was added to liquid ammonia (approximately 500 cc) and allowed to evaporate overnight. The residue was treated with water (1 liter) and the crystals filtered off and refluxed in toluene (100 cc) for 30 minutes. The mixture was treated with decolorizing carbon (Norite) and filtered over Hyflo. The solution was concentrated to a small volume (25 cc) cooled, diluted with 20 cc of ether and allowed to stand. The product was re-crystallized from acetone/hexane to give 5-(2-fluorophenyl)3H-1,4-benzodiazepin-2(1 H)-one as white needles melting at 180° to 181°C. 

After the furfurel has all been added and the reaction has subsided, the residue is cooled, diluted with water, made strongly alkaline and distilled until all volatile substances are removed. The distillate is then made acid with formic acid and distilled with steam as long as nonbasic substances are carried over by the steam. The residue is then made strongly basic with caustic soda and the volatile amines again distilled with steem. The distillate is then treated with strong alkali and then extracted with ether to extract the base. The extract is dried by the addition of caustic potash, the ether removed and the residual amine purified by distillation. Furfuryl dimethyl amine boils over the range 145°C to 150°C. 

To obtain the corresponding amino derivative, 109 g of base are heated under agitation in a round-bottomed flask with 300 cc of 35-36% concentrated hydrochloric acid and 600 cc of water. It is heated on a water bath until dissolution is complete, then maintained at boiling point for 90 minutes, cooled, diluted with 1 liter of water, and neutralized with about 350 cc of 30% soda. The N-(2-diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide formed crystallizes, is centrifuged and washed in water. Its melting point is 122°C and the yield is 74%. 

Bis(3,5-di-tert-butyl-4-hydroxyphenyl) acetone mercaptole, melting at 125°C to 126°C is prepared by employing 2,6-di-tert-butyl-4-mercaptophenol and acetone as starting materials. In one representative procedure, the 2,6-di-tert-butyl-4-mercaptophenol (47.5 g, 0.2 mol) is dissolved in methanol (50 ml) heated at a temperature of 50°C. A catalytic amount of concentrated hydrochloric acid (1 ml) is added, followed by acetone (5S g,0.1 mol). The temperature of the mixture rises to about 60°C, and is maintained at about 60°C to 65°C for 1.5 hours. The mixture is cooled, diluted with water and about 10 ml of aqueous sodium bicarbonate and extracted with ether. The ether extract is evaporated, and the product is obtained as a residue, which is recrystallized from ethanol and then from isopropanol to obtain the bis(3,5-di-tert-butyl-4-hydroxyphenyl) acetone mercaptole as a crystalline solid melting at about 125°Cto 126°C. 

To the resulting solution now add a further 20 mL portion of the standard EDTA solution, add nitric acid (1M) to adjust the pH to 1-2, and then boil the solution for 15 minutes. Cool, dilute to 400 mL by the addition of de-ionised water, add hexamine to bring the pH to 5-6, add more of the indicator solution, and titrate the excess EDTA with the standard lead nitrate solution. 

A mixture of jV-[(2-benzyl-3-methyl)phenyl]formamide (24. R1 = R3 = R4 = H R2 = Me 15 g, 68 mmol) in PPA (120 g) and POC1, (32 g. 208 mmol) was stirred at 120"C for 1.5 h. The mixture was cooled, diluted with cold H20. and basified by addition of aq KOH. The alkaline mixture was extracted with Et20, the extracts were dried (MgS04), and evaporated to give the crude product as an oily residue, which was purified by distillation under reduced pressure (bp 110 Q0.025 Torr). The distillate solidified on cooling to give the product as yellow needles yield 6g (43%) mp 68 C. 

A mixture of the foregoing nitro compound 3 (0.27 g, 1 mmol), iron powder (0.25 g, 4.5 m-atom) and HOAc (20 mL) was heated at 50 C for 5 h, cooled, diluted with H20 and extracted with CH2C12. The organic phase was washed with sat. brine, dried (MgS04) and evaporated yield 0.16 g (66%) mp 259 — 262°C. 

Benzene-1,2-diamine (2.0 g. 18.5 mmol) and benzoylacetone (4.0 g. 24.6 mmol) in warm EtOH (8 mL) and HOAc (3 mL) were kept at 40 C for 30 min, cooled, diluted with EtzO (20 mL) then treated with coned H2S04 (2.5 ntL) in H,0 (5 mL) and kept overnight. The precipitated violet product was collected and washed with Et20 yield 4.9 g (75%) mp 173-175 C. 

Under N2, 6-chlorobcnzo[/]isoindolincdiiminc (5.04g, 21.9 mmol) was added to a refluxing mixture of SiCl (3.7 g, 2.5 mL, 22 mmol) and anhyd quinoline (40 mL) over 50 min. The resulting mixture was refluxed for 1.5 h, cooled, diluted with EtOH (75 mL), and the suspension was filtered. After the residue had been washed (MeOH), it was subjected to extraction (Soxhlet, pyridine) and then vacuum dried (90 C) to afford a blue-green solid yield 4.66 g (90%). 

The reaction mixture is cooled, diluted with 100 mL of sat. aq NaCI and extracted with four 50-mL portions of Ei,0. The combined ethereal extracts are washed with 50 ml. of sat. aq NaCI, dried, filtered and concentrated to a volume of a few milliliters. 20 ntL of petroleum ether arc added to precipitate the soluble salts. The mixture is filtered through a silica gel column (petroleum ether)and purified by medium-pressure liquid chromatography yield 360 mg (65%). 

A solution of the 0-silylketone (1 mmol) in chloroform (3 ml) was added to a suspension of copper(n) bromide (2 mmol) in boiling ethyl acetate (3 ml). The mixture was heated under reflux for 0.75 h, and then cooled, diluted with carbon tetrachloride (10ml), filtered, and the precipitate... 

A mixture of sarcosine (45 mg, 0.5 mmol) and bis(trimethylsilyl)acetamide 22a (272 iL, 1.1 mmol) in 0.5 mL acetonitrile is stirred at room temperature for 1 h and at 40 °C for 30 min to give 441, which is then combined with a solution of the glyoxamide 440 in 1 mL abs. toluene. The resulting mixture is heated under reflux for 18 h, cooled, diluted with CHjClj, washed with 1 M NaOH, and the aqueous layer is extracted with CH2CI2. The combined organic layers are washed with brine, dried, concentrated, and purified by chromatography to give 40 mg (40%) 444 as a yellowish oil [49] (Scheme 5.89). 

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