Hydroxylamine → (R)-2-(4-bromophenyl)-2-cyclopropylpropanal oxime

Temperatur

20 °C

To a 500 mL reactor is charged the crude solution of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal (7, 230 g, 11.9 wt %, 108.1 mmol, 1.00 equiv). The batch is reduced to 75 mL (3 vols) via vacuum distillation (external temperature NMT 55° C.). To the batch is charged ethanol (denatured, 78.9 g, 100 mL, 4 vols). The batch is reduced to 75 mL (3 vols) via vacuum distillation (external temperature NMT 55° C.). To the batch is charged ethanol (denatured, 39.5 g, 50 mL, 2 vols). The batch temperature is adjusted to an internal temperature of 10±5° C. To the batch is charged 50 wt % Hydroxylamine (10.7 g, 162.2 mmol, 1.50 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: >99.5 A % conversion). To a separate vessel (vessel 2) is prepared the 5 wt % aqueous sodium chloride solution by dissolving sodium chloride (7.5 g) in water (142.5 g). To the batch is charged isopropyl acetate (157 g, 180 mL, 7 vols) and 5 wt % aqueous sodium chloride (75 g, ˜3 vols, vessel 2). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut. To the batch is charged 5 wt % aqueous sodium chloride (75 g, ˜3 vols, vessel 2). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut. The batch volume is adjusted to 2-3 vols (50-75 mL) via vacuum distillation (external temperature NMT 55° C.). To the batch is charged acetonitrile (39.3 g, 50 mL, ˜2 vols). The batch volume is adjusted to 2 vols (50-75 mL) via vacuum distillation (external temperature NMT 55° C.). The batch was drained and the reactor rinsed with acetonitrile (3.9 g, 5 mL). The rinse is combined with the original batch and the resulting solution reduced to ˜50 mL via vacuum distillation. The mass of the resulting solution: 44.4 g and the Proton NMR wt % assay (with dimethyl fumarate as an internal standard) is 65 wt % (28.9 g, 99.5% yield) of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal oxime (8). The solution is used as is for the following step.

1. distillationThe batch is reduced to 75 mL (3 vols) via vacuum distillation (external temperature NMT 55° C.)
2. additionTo the batch is charged ethanol (denatured, 78.9 g, 100 mL, 4 vols)
3. distillationThe batch is reduced to 75 mL (3 vols) via vacuum distillation (external temperature NMT 55° C.)
4. additionTo the batch is charged ethanol (denatured, 39.5 g, 50 mL, 2 vols)
5. customis adjusted to an internal temperature of 10±5° C
6. temperatureto maintain the internal temperature of the batch <30° C
7. customAn HPLC sample is removed
8. customTo a separate vessel (vessel 2) is prepared the 5 wt % aqueous sodium chloride solution
9. stirringThe batch is agitated for 20 min
10. stirringThe batch is agitated for 20 min
11. distillationThe batch volume is adjusted to 2-3 vols (50-75 mL) via vacuum distillation (external temperature NMT 55° C.)
12. additionTo the batch is charged acetonitrile (39.3 g, 50 mL, ˜2 vols)
13. distillationThe batch volume is adjusted to 2 vols (50-75 mL) via vacuum distillation (external temperature NMT 55° C.)
14. washthe reactor rinsed with acetonitrile (3.9 g, 5 mL)
15. distillationthe resulting solution reduced to ˜50 mL via vacuum distillation

ORD-Eintrag

ord-cca73f28a8c244c28eb46b70c259164d

Quelldatensatz

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09029592B2