Reacción #803859

Ecuación de reacción

olanzapine

triethylamine

chloromethyl chloroformate

→

chloromethyl 2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate

Disolventes

dichloromethane

dichloromethane

Condiciones de reacción

Tratamiento posterior

1. 1
   Otroonce a clear solution formed
2. 2
   Temperaturato warm to room temperature
3. 3
   Lavadowashed with aq satd NaHCO3 (75 mL) and water (350 mL)
4. 4
   SecadoThe organic phase was dried over MgSO4
5. 5
   Filtraciónfiltered
6. 6
   ConcentraciónThe organic phase was then concentrated under vacuum at 45° C. to a volume of −150 mL
7. 7
   workup.ADDITIONThe mixture was diluted with ethyl acetate (30 mL) and ˜20-30 mL
8. 8
   Otrofurther was evaporated under vacuum
9. 9
   TemperaturaThe mixture was cooled to room temperature
10. 10
    Filtraciónthe resulting solid precipitate filtered
11. 11
    Lavadowashed with ethyl acetate
12. 12
    SecadoAfter drying under vacuum at 35° C. for 90 min chloromethyl 2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate [A] (17.1 g, 73%)
13. 13
    Otrowas obtained as a yellow solid

Procedimiento

To a solution of olanzapine (18.0 g, 57.7 mmol) and triethylamine (16 mL, 0.12 mol) in dichloromethane (250 mL) was warmed to 35° C. and once a clear solution formed, the reaction was cooled to 5° C. To this was added chloromethyl chloroformate (7.6 mL, 86.5 mmol) over 20 minutes. The reaction was stirred at room temperature for 30 min and allowed to warm to room temperature. After 15 min at room temperature the reaction mixture was diluted with dichloromethane (100 mL), then washed with aq satd NaHCO3 (75 mL) and water (350 mL). The organic phase was dried over MgSO4 and filtered. The organic phase was then concentrated under vacuum at 45° C. to a volume of −150 mL. The mixture was diluted with ethyl acetate (30 mL) and ˜20-30 mL further was evaporated under vacuum. The mixture was cooled to room temperature and the resulting solid precipitate filtered and washed with ethyl acetate. After drying under vacuum at 35° C. for 90 min chloromethyl 2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate [A] (17.1 g, 73%) was obtained as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ 7.62-7.14 (4H, m), 6.27-6.22 (1H, m), 5.84-5.69 (1H, m), 5.47-5.23 (1H, m), 3.89-3.63 (4H, m), 2.66-2.22 (10H, m).

Fuente