反应详情

温度

20 °C

To the crude solution from the previous step (solution of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal) retained in the reactor is charged 6.2 kg of 200 proof ethanol. The batch was then concentrated via vacuum distillation (Tjacket NMT 50° C.) to ˜7 L. To the batch was charged 6.2 kg of 200 proof ethanol. The batch temperature is then adjusted to 0±5° C. To the cooled batch is charged hydroxylamine (50 wt % aqueous solution, 1.0 kg, 15.4 mol, 1.5 equiv) at a rate to maintain the internal temperature of the batch <30° C. The batch is then agitated at an internal temperature of 20±5° C. for 2 h. An HPLC sample is removed to determine conversion (target >97 A % conversion 220 nm, for this batch: >99 A % conversion). To the batch is charged isopropyl acetate (19 kg) and 5 wt % aqueous sodium chloride (9.2 kg). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut (mass aqueous cut 7.6 kg). To the batch is charged 5 wt % aqueous sodium chloride (9.2 kg). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut (mass aqueous cut 14.5 kg). The batch volume is adjusted to 7 L via vacuum distillation (external temperature NMT 60° C.). To the batch is charged acetonitrile (10 L). The batch volume is adjusted to 7 L via vacuum distillation (external temperature NMT 60° C.). The batch was drained and the reactor rinsed with acetonitrile (2 L). The rinse was combined with the original batch and the resulting solution massed 7.75 kg (HPLC purity: 80.4 A % (220 nm), Karl Fisher 3.2% water and the Proton NMR wt % assay (with dimethyl fumarate as an internal standard) is 28.0 wt % (2.76 kg, 78.7% yield) of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal oxime (8) for the two step process. The solution is used as is for the following step.

1. concentrationThe batch was then concentrated via vacuum distillation (Tjacket NMT 50° C.) to ˜7 L
2. additionTo the batch was charged 6.2 kg of 200 proof ethanol
3. customis then adjusted to 0±5° C
4. temperatureto maintain the internal temperature of the batch <30° C
5. customAn HPLC sample is removed
6. additionTo the batch is charged isopropyl acetate (19 kg) and 5 wt % aqueous sodium chloride (9.2 kg)
7. stirringThe batch is agitated for 20 min
8. additionTo the batch is charged 5 wt % aqueous sodium chloride (9.2 kg)
9. stirringThe batch is agitated for 20 min
10. distillationThe batch volume is adjusted to 7 L via vacuum distillation (external temperature NMT 60° C.)
11. additionTo the batch is charged acetonitrile (10 L)
12. distillationThe batch volume is adjusted to 7 L via vacuum distillation (external temperature NMT 60° C.)
13. washthe reactor rinsed with acetonitrile (2 L)