Hydrochloric Acid → 3H-1,5-Benzodiazepine, 2,4-bis(4-methyl-1-piperazinyl)-3-propylidene-

Temperature

-10 °C

A suspension of 2,4-bis(4-methyl-1-piperazinyl)-3H-[1,5]benzodiazepine (45.396 g, 133.3 mmol) in tetrahydrofuran (560 ml) under constant flow of argon was cooled to −10° C. A solution of lithium diisopropylamide (LDA) (2M, 100 ml, 200 mmol) was added over a period of 20 min, maintaining the temperature at −10° C. The obtained deep red solution was stirred for 30 min. Propionaldehyde (14.6 ml, 200 mmol) was added dropwise. Triethylamine (148 ml, 1.067 mol) and pyridine (0.54 ml, 6.7 mmol) were added successively. Trifluoroacetacetic anhydride (93.1 ml, 667 mmol) was added over a period of 50 min, maintaining the temperature at −10° C. The reaction mixture was stirred for 1 h and allowed to warm to −5° C. Methanol (213 ml) and while strongly agitated NaOH (5M, 200 ml, 1.000 mol) were added maintaining the temperature at −5° C. The reaction mixture was allowed to warm to room temperature and stirred over night. The solution was made acidic with 5M HCl to a pH of 3.5. Two phases were formed and the lower layer was extracted with 600 ml and twice with 100 ml of dichloromethane. The aqueous phase was treated with brine (200 ml) and toluene (400 ml) and made alkaline with 5M NaOH to a pH of 10. The phases were separated and the aqueous phase was extracted with toluene (2×200 ml). Combined toluene phases were dried over anhydrous Na2SO4 and the solvent was evaporated at reduced pressure to give 48.38 g (95%) of the title compound as an amber resin. The product obtained was characterised using 1H-NMR spectroscopy and was found to be identical to the product obtained by method A.

1. temperaturemaintaining the temperature at −10° C
2. temperaturemaintaining the temperature at −10° C
3. stirringThe reaction mixture was stirred for 1 h
4. temperatureto warm to −5° C
5. temperaturemaintaining the temperature at −5° C
6. temperatureto warm to room temperature
7. stirringstirred over night
8. customTwo phases were formed
9. extractionthe lower layer was extracted with 600 ml and twice with 100 ml of dichloromethane
10. additionThe aqueous phase was treated with brine (200 ml) and toluene (400 ml)
11. customThe phases were separated
12. extractionthe aqueous phase was extracted with toluene (2×200 ml)
13. dry with materialCombined toluene phases were dried over anhydrous Na2SO4
14. customthe solvent was evaporated at reduced pressure

ORD record

ord-8b5675230ec94026a54d8d3d7571bd19

Source dataset

uspto-grants-2009_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07498433B2