Isopropyl acetate, drying

Isopropyl acetate [108-22-5] M 102.1, b 88.4 , d 0.873, n 1.3773. Washed with 50% aq K2CO3 (to remove acid), then with saturated aq CaCl2 (to remove any alcohol). Dried with CaCl2 and fractionally distd. 

To 1,320 parts of methyl isobutyl ketone is added 570 parts of 3-diethylamino-1 -cyclohexyl-1 -phenylpropanol-1 (2 mols) and the mixture is stirred until solution is complete. Then 500 parts (3.2 mols or 60% excess) of ethyl iodide are added. After filtration, the filtrate is diluted with an additional 300 parts of methyl isobutyl ketone and the solution is then heated at the reflux temperature (108°C to 110°C) for 9 hours. After cooling to 0°C, the precipitated solid material is removed by filtration, washed with isopropyl acetate and dried. Approximately 111 parts of product is obtained or a yield of 88.6% based on as-is starting material or 92.5% based on real starting material. 

To a 12 L 3-neck round bottom flask was added isopropyl acetate (6.5 L). The solvent was cooled to 0°C in an ice-water bath and 3-amino-l-propanol (1.14 kg, 15.1 mol) was added in one portion. To this stirring solution, benzyl chloroformate (1.20 kg, 7.03 mol) was added dropwise over 2 hours while maintaining the internal temperature of the flask between 10-15°C. After the addition was complete, the reaction mixture was allowed to stir for an additional 0.3 hour after which time water (3.5 L) was added in one portion. The solution was then partitioned and washed with an additional 2 times 3.5 L of water. The organic layer was dried over potassium carbonate and concentrated to give a solid that was dissolved in excess isopropyl acetate and precipitated from solution by adding the compound to heptane. The solid was filtered under nitrogen to yield 1.20 kg (82%) of N-carbonylbenzyloxy-3-aminopropanol as a colorless solid. 

To a 5 L 3-neck round bottom flask was added the crude carbonylbenzyloxy-3-aminopropanal (115 g, 0.555 mol) followed by addition of water (400 mL) and methanol (1600 mL). The reaction mixture was maintained at 25°C throughout the course of the reaction. After the solution became homogeneous. (S)-Valine methyl ester hydrochloride (90.2 g, 0.538 mol) was added in one portion followed by rapid addition of sodium acetate trihydrate (151 g, 1.11 mol) and sodium cycanoborohydride (73.2 g, 1.17 mol). The reaction mixture was allowed to stir at room temperature for 0.5 hour and was concentrated in vacuo. To this solution, saturated aq sodium bicarbonate (400 mL) was added and the mixture was extracted with isopropyl acetate (1 L). The organic layer was washed with water, dried over sodium sulfate, and concentrated to yield 150 g of crude product, which was dissolved in isopropyl acetate (300 mL) and heptane (2400 mL). Dry HCI was bubbled in and an oily solid precipitated out of solution. The liquid was decanted away from and the solid was dissolved in dichloromethane (3 L). The solution was washed with water (600 mL) and saturated aq sodium bicarbonate (600 mL) and dried over sodium sulfate. It was concentrated in vacuo to yield 105 g (59%) of N-(N-(benzyloxycarbonyl-3-amino)-propyl)valine methyl ester as a light yellow oil. 

Isopropyl Acetate 23 0 uniatlpf. tStMlvad Easiman Tenite Butyrate dry (CAB)... 

The alcohol (1.5 L, 208 g, 280 mmol) in THF is charged to a jacketed flask followed by dimethyl sulfide (37 g, 590 mmol) and diisopropylethylamine (47 g, 364 mmol). The solution is cooled to approximately -13 °C. 7V-Chlorosuccinimide (NCC 71 g, 532 mmol) is dissolved in THF (240 mL) and added to the flask at a rate so as to maintain the internal temperature at -11 to -13 °C. The mixture is then stirred at -15 5 °C for 3 h. Isopropyl acetate (3 L) is added followed by 0.5 N NaOH (1.2 L). The mixture is warmed to room temperature and stirred for 1 h. The organic layer is washed with 5% NaCl (2 x 600 mL) and brine (2 x 600 mL). The product layer is concentrated under vacuum to obtain, at first, a yellow amorphous solid which when dried under high vacuum turns into a white foam. Slurrying the solid in warm water followed by filtration and drying afforded 196 g (94%) of the 3-ketomacrolide as a white solid after trituration with 10% EtOAc/heptane. 

Chloro-(/7-cyanophenyl)phenylphosphine 349 Dichloro(phenyl)phosphine (60 g) is added to a slurry of i -cyanobenzenediazonium tetrafluoroborate (72 g) and copper(i) bromide (2.4 g) in dry isopropyl acetate (300 ml). After about 20 min a violent reaction sets in which is moderated by external cooling so that the temperature remains between 20° and 40°. When gas evolution ceases, aluminum turnings (8 g) are added and the mixture is stirred for 2 h at 40-50°. Then the liquid is decanted from unused aluminum, and phosphorus oxychloride (51 g) is added to decompose the aluminum chloride complex. Distillation then affords a forerun (5 g), followed by the main fraction (39 g, 47%) between 15870.7 mm and 195°/ 3.1 mm (owing to unavoidable decomposition the pressure does not remain constant during the distillation). Further distillation gives a product boiling at 16270.2 mm. 

---