Toluene → 8-fluoro-12-(4-methylpiperazin-1-yl)-6H-(1)benzothieno(2,3-b)(1,5)benzodiazepine

Temperature

70 °C

12-Anino-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine hydrochloride (102 g) was suspended in toluene (600 ml), and the mixture was stirred under reflux with heating for 3 hours to remove water. The mixture was cooled to 70° C. under a nitrogen atmosphere, and N-methylpiperazine (300 ml) was added. The mixture was stirred with heating under a nitrogen atmosphere until the inside temperature reached 120° C. while removing toluene for 1.5 hours. The mixture was heated under a nitrogen atmosphere at 120° C. for 2.5 hours and cooled to 25° C. under a nitrogen atmosphere. Ethyl acetate (600 ml) and water (450 ml) were added to the reaction mixture for extraction and the obtained ethyl acetate layer was washed three times with water (300 ml). After confirming pH 7-8 of washing water, the solvent was concentrated under reduced pressure. Acetonitrile (100 ml) was added and the mixture was azeotropically concentrated to dryness under reduced pressure. To the residue was added acetonitrile (300 ml) and the mixture was heated for dissolution. The solution was cooled and stirred at −10° C.-−5° C. for 2.5 hours to allow precipitation of crystals. The precipitated crystals were filtered by suction and washed with acetonitrile (100 ml), followed by drying to give 8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (65.5 g).

1. temperatureunder reflux
2. temperaturewith heating for 3 hours
3. customto remove water
4. additionN-methylpiperazine (300 ml) was added
5. stirringThe mixture was stirred
6. temperaturewith heating under a nitrogen atmosphere until the inside temperature
7. customreached 120° C.
8. customwhile removing toluene for 1.5 hours
9. temperatureThe mixture was heated under a nitrogen atmosphere at 120° C. for 2.5 hours
10. temperaturecooled to 25° C. under a nitrogen atmosphere
11. additionEthyl acetate (600 ml) and water (450 ml) were added to the reaction mixture for extraction
12. washthe obtained ethyl acetate layer was washed three times with water (300 ml)
13. concentrationthe solvent was concentrated under reduced pressure
14. additionAcetonitrile (100 ml) was added
15. concentrationthe mixture was azeotropically concentrated to dryness under reduced pressure
16. additionTo the residue was added acetonitrile (300 ml)
17. temperaturethe mixture was heated for dissolution
18. temperatureThe solution was cooled
19. stirringstirred at −10° C.-−5° C. for 2.5 hours
20. customprecipitation of crystals
21. filtrationThe precipitated crystals were filtered by suction
22. washwashed with acetonitrile (100 ml)
23. customby drying

ORD record

ord-7ce1b43c6ecb4feb9cde780486b30da9

Source dataset

uspto-grants-2001_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06271225B1