Acetic acid ethyl ester solution

After having been washed with 50 cc of water the benzene layer is dried over potassium carbonate, filtered, allowed to stand over 10 g of alumina for about VA hours for partial decolorization, filtered again and concentrated under reduced pressure. The oily base which remains as a residue is directly converted into the tartrate. A solution cooled to 0°C, of 6.50 g of the free base in 100 cc of acetic acid ethyl ester is thoroughly shaken and poured into an ice cold solution of 2.66 g of tartaric acid in 410 cc of acetic acid ethyl ester. The precipitated, analytically pure, tartrate of 3-methylsulfinyl-10-[2 -N-methyl-piperidyl-2")-ethyl-1 ]-phenothiazine melts at 115° to 120°C (foam formation) and sinters above B0°C. The base Is reacted with benzene sulfonic acid in a suitable solvent to give the besylate. 

A solution of 69g of sodium in 1,380 ccof absolute alcohol is mixed with 257.4 g of /3-methyl-thioethyl-d -methyl)-n-butvl-cyano-acetic acid ethyl ester and 114 g of thiourea and the whole mass boiled under reflux with stirring for six hours. After concentration under vacuum the residue is taken up in 1.5 liters of water and shaken up thrice, each time with 300 cc of ether. The aqueous alcoholic layer is stripped, under vacuum, of the dissolved ether and mixed with 300 cc of 30% acetic acid under stirring and ice cooling. The precipitated material is sucked off, washed with water, dried and recrystallized from isopropyl alcohol. The thus obtained j3-methvl-thioethyl-(1 -methyD-n-butyl-cyano-ecetyl thiourea forms yellowish green crystals having a melting point of 229°C to 230°C. 

Its hydrochloride is produced by dissolving the base in acetic acid ethyl ester and adding an ethereal hydrochloric acid solution thereto. After recrystallization from acetic acid ethyl ester, the melting point of the hydrochloride is 152-154°C. 

To 50 gms. (excess) of pure ethyl acetate (see Preparation 199) are added 23 gms. (excess) of sodium in the form of wire. The flask is cooled in ice, and, with slight shaking, 10 gms. (1 mol.) of benzaldehyde are gradually added. When all the sodium has gone into solution, the flask is set aside for 2 hours, when it is acidified with dilute acetic acid. The ester layer which separates is removed, shaken up with dilute sodium carbonate solution, and dried over calcium chloride. It is then distilled, the fraction 265°—275° being retained. 

A solution of 57.0 g (0.12 mole) of [[2-methyl-l-(l-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid, phenyl methyl ester in 300 ml of ethyl acetate was treated with 3.0 g of 10% Pd/C and hydrogenated on the Parr apparatus (45 psi) for 4 hours. The mixture was filtered through Hyflo and the solution was extracted with 5% NaHC03. The aqueous extracts were washed with ether, cooled to 5°C and treated with 36 ml of HOAc. The product was extracted into ethyl acetate, dried (MgS04) and the solvent was evaporated in vacuo. The residue was dissolved in 300 ml of toluene and the solvent was evaporated in vacuo to remove last traces of acetic acid. The oil residue became semi-solid on standing at room temperature. The yield of the product of debenzoylation - 2-[carboxymethyl)-(4-phenylbutyl)-phosphinoyloxy]-2-methylpropionic acid ethyl ester (racemic mixtures) was 39.8 g (72%). 

To a solution of 4-acethylamino-5-azido-3-(l-ethyl-propoxy)-cyclohex-l-ene-1-carboxyllic acid (crude from previous reaction, assume 0.83 mmol), ethyl alcohol (150 ml), and catalytic dimethylaminophenol in (CH2CI2 (6.0 ml) was added 2-(diethylamino)ethyl(bicyclohexyl)-l-carboxylate (172 mg, 0.83 mmol) in one portion at room temperature. After several minutes a precipitate formed and after an additional 1 h of stirring the reaction was filtered and washed with CH2CI2. Concentration in vacuo afforded a pale solid which was purified by flash chromatography on silica gel (50% hexanes in ethyl acetate) to give 272 mg (96%) of 4-acethylamino-5-azido-3-(l-ethyl-propoxy)-cyclohex-l-ene-l-carboxyllic acid ethyl ester as a white solid. 

A suspension of 5.0 g of l-bromo-4,4-bis(3-methylthien-2-yl)but-3-ene, 3.4 g of nipecotic acid ethyl ester and 3.3 g of potassium carbonate in 150 ml of dry acetone was kept under reflux for 15 h. The reaction mixture was evaporated and, after addition of 30 ml of water, the resulting solution was extracted twice with 50 ml of ethyl acetate. The ethyl acetate extracts were dried and evaporated leaving 7.3 g of an oil. By column chromatography on silica gel using methanol as eluent, N-(4,4-bis(3-methylthien-2-yl)but-3-enyl)nipecotic acid ethyl ester was isolated. 

A stirred suspension of 5 g of (S)-5-(2-oxo-l,3-oxazolidin-4-ylmethyl)-3-[(2-toluen-4-sulphoniloxy)ethyl]-lH-indol-2-carboxylic acid ethyl ester in 30 ml of a 2 N solution of dimethylamine in ethanol was stirred at 50°C for 20 hours in a closed reactor. The solvent was evaporated to dryness, the residue dissolved in 20 ml of 2 N HCI and washed three times with 15 ml of dichloromethane. The washed aqueous phase was cooled and adjusted to pH 12 with a 40% sodium hydroxide solution and extracted three times with 20 ml of dichloromethane. The combined organic phases were washed with brine and dried above anhydrous sodium sulphate. The solvent was evaporated to dryness and the residue recrystallised from ethyl acetate to give 3.4 g (91%) of the title dimethylamine as a yellow solid. Melting point 67°-70°C. 

To a solution of 1.4 g (24.9 mmoles) of KOH in 10 ml of ethanol was added 2.8 g (7.8 mmoles) of (S)-3-(2- dimethylaminoethyl)-5-[2-oxo-l,3-oxazolidin-4-ylmethyl]-lH-indol-2-carboxylic acid ethyl ester. The resulting solution was heated at reflux temperature for one hour. It was cooled and the solvent evaporated to dryness. The residue was dissolved in 6 ml of water and washed three times with 10 ml of dichloromethane. The aqueous solution was cooled to 5°C, adjusted to pH 6 with glacial acetic acid, stirred for 30 minutes at that temperature and the water evaporated to dryness. The residue was redissolved in 30 ml of water and 5 g of ionic exchange resin (Dowex50WX8-400) added. The mixture was left under stirring at room temperature for 24 hours. The resin was filtered and it was washed with water. For desorbtion the resin was suspended with 20 ml of a 10% aqueous solution of ammonia and stirred at room temperature for 5 hours. After that it was filtered and washed with water, water was evaporated to dryness under reduced pressure to give 7.75 g (94%) of the title acid as a yellow crystalline solid. Melting point 230°C. 

---