反应详情

温度

115.5 °C

To a stirred solution of 4,4-dimethyl-2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]oxazoline (287 g, 0.724 mol) in pyridine (1000 ml), at 5° C., phosphorous oxychloride (135 ml, 1.474 mol) is slowly added while keeping the temperature at 5 to 10° C. The mixture is heated at reflux (115-116° C.) for 3 to 4 hours. The mixture is cooled to about 10° C. and treated with deionized water (3200 mL), and the pH is adjusted to about pH 9 by addition of 28% aqueous ammonia (800 ml). The product is extracted with of toluene (1500+1000+500+500 ml) and the combined organic phases are decoloured with charcoal. The organic phase is concentrated under reduced pressure at 60-70° C. to give an oily residue to which acetone (3000 ml) is added. The acetone solution is cooled to 10° C. and treated with 60 ml 48% HBr to a pH value of 4-5. The solvent is evaporated under reduced pressure and the residue is taken up in acetone (800 ml). The mixture is heated to 40-50° C. and thereafter cooled to 5° C. After 15 hours at 5° C. the product is filtered off, washed with cold acetone (500 ml) and dried in vacuo at 50° C. 175-180 g of citalopram hydrobromide with a purity (HPLC, peak area)≧90% is obtained.

1. customat 5 to 10° C
2. temperatureThe mixture is heated
3. temperatureThe mixture is cooled to about 10° C.
4. extractionThe product is extracted with of toluene (1500+1000+500+500 ml)
5. concentrationThe organic phase is concentrated under reduced pressure at 60-70° C.
6. customto give an oily residue to which acetone (3000 ml)
7. additionis added
8. customThe solvent is evaporated under reduced pressure
9. temperatureThe mixture is heated to 40-50° C.
10. temperaturecooled to 5° C
11. filtrationAfter 15 hours at 5° C. the product is filtered off
12. washwashed with cold acetone (500 ml)
13. customdried in vacuo at 50° C