Ethyl bromoacetate → Flutazolam

A solution of 33.3g (0.1 M) of 10-chloro-11b-(2-fluorophenyl)2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one in 100 ml of dry N,N-dimethylformamide was treated with 6.6g (0.138 M) of a 50 per cent dispersion of sodium hydride in mineral oil. The mixture was stirred for 0.5 hour at room temperature, was then cooled to 5°-10° and treated with a solution of 31g (0.186 M) of ethyl bromoacetate in 25 ml of dry N,N-dimethylformamide. The resulting mixture was allowed to stir at room temperature for 18 hours when 3 ml of water was carefully added. The solution was next evaporated to dryness under reduced pressure. The residue was next treated with 50 ml of toluene and evaporated to dryness. This procedure was repeated twice in order to azeotrope any remaining water or N,N-dimethylformamide. The crude ester thus obtained was dissolved in 250 ml of dry tetrahydrofuran, cooled to 0° and was treated by the portionwise addition of 1.9g (0.05 M) of lithium aluminium hydride. The cooling bath was removed and the mixture was allowed to stir for 3 hours. Enough saturated sodium bicarbonate solution was added to coagulate the solids and the mixture was filtered. The filtrates were concentrated to dryness and dissolved in dichloromethane. The solution was washed with 1N hydrochloric acid, water, saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from toluene to give the above named product as white prisms, m.p. 142°-147°.

1. temperaturewas then cooled to 5°-10°
2. additionwas carefully added
3. customnext evaporated to dryness under reduced pressure
4. additionThe residue was next treated with 50 ml of toluene
5. customevaporated to dryness
6. customThe crude ester thus obtained
7. temperaturecooled to 0°
8. customThe cooling bath was removed
9. stirringto stir for 3 hours
10. additionEnough saturated sodium bicarbonate solution was added
11. filtrationthe mixture was filtered
12. concentrationThe filtrates were concentrated to dryness
13. dissolutiondissolved in dichloromethane
14. washThe solution was washed with 1N hydrochloric acid, water, saturated brine
15. dry with materialdried over anhydrous sodium sulfate
16. customevaporated
17. customThe residue was crystallized from toluene
18. customto give the above named product as white prisms, m.p. 142°-147°

ORD record

ord-79b2ac2e9ff940f0893baf74026e7e86

Source dataset

uspto-grants-1976_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US03965151