تفاعل #442713

معادلة التفاعل

trimethylamine-N-oxide

8-Chloro-6-(2-fluorophenyl)-3a,4-dihydro-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine-5-oxide

ammonium hydroxide

trimethylamine-N-oxide

→

title compound

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-5-oxide

المذيبات

methylene chloride

ظروف التفاعل

المعالجة

1. 1
   أخرىThe layers are separated
2. 2
   استخلاصthe aqueous phase is extracted with additional methylene chloride (2×50 ml)
3. 3
   تركيزThe combined organic extracts are concentrated to dryness
4. 4
   workup.DISSOLUTIONthe solids are redissolved in acetonitrile (200 ml)
5. 5
   workup.ADDITIONTo this mixture is added
6. 6
   درجة الحرارةThe reaction mixture is heated
7. 7
   درجة الحرارةto reflux
8. 8
   درجة الحرارةThe mixture is heated
9. 9
   درجة الحرارةat reflux for 42 hr at which time HPLC
10. 10
    تركيزThe reaction mixture is concentrated to dryness and ethyl acetate (100 ml)
11. 11
    workup.ADDITIONis added back
12. 12
    أخرىThe slurry is chromatographed (magnesol, 100 g) until no more product
13. 13
    تركيزThe combined column fractions are concentrated to about 60 ml and heptane (140 ml)
14. 14
    workup.ADDITIONis added slowly
15. 15
    درجة الحرارةThe product is cooled to -15° overnight
16. 16
    ترشيحcollected by vacuum filtration
17. 17
    غسيلwashed with cold heptane
18. 18
    أخرىdried in the vacuum oven at 40°

الإجراء التجريبي

8-Chloro-6-(2-fluorophenyl)-3a,4-dihydro-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine-5-oxide (IX, EXAMPLE 7, 20.00 g, 46 mmol) is partitioned between ammonium hydroxide (10%, 100 ml) and methylene chloride (100 ml). The layers are separated and the aqueous phase is extracted with additional methylene chloride (2×50 ml). The combined organic extracts are concentrated to dryness and the solids are redissolved in acetonitrile (200 ml). To this mixture is added powdered molecular sieves (20 g) and trimethylamine-N-oxide (7.6 g, 68 mmol) followed by one activated TPAP sample from above. The reaction mixture is heated to reflux and the next sample of TPAP and an additional trimethylamine-N-oxide (7.66 g, 68 mmol) is added after 6 hr and again after 18 hr. The mixture is heated at reflux for 42 hr at which time HPLC shows only 6% starting material remaining. The reaction mixture is concentrated to dryness and ethyl acetate (100 ml) is added back. The slurry is chromatographed (magnesol, 100 g) until no more product is eluding with ethyl acetate. The combined column fractions are concentrated to about 60 ml and heptane (140 ml) is added slowly. The product is cooled to -15° overnight, collected by vacuum filtration, washed with cold heptane and dried in the vacuum oven at 40° to give the title compound.

المصدر