Hydrochloric Acid → (R)-2-(4-bromophenyl)-2-cyclopropylpropanal

Temperature

25 °C

To a clean and dry 2 L reactor (vessel 1) under an inert atmosphere (nitrogen) is charged the (S)-2-(1-(4-bromophenyl)-1-cyclopropylethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution (6, 200.0 g, 24.0 wt %, 136.7 mmol, 1.00 equiv). A sample is removed and the KF is determined (target KF<350 ppm water, if >350 ppm water proceed with an azeotropic cyclopentyl methyl ether distillation). The KF of this batch was determined to be 750 ppm water, and 200 mL of cyclopentyl methyl ether was charged to the batch. The batch was vacuum distilled (external temperature <60° C.) to reduce the batch volume to 200 mL. The KF of the batch after the azeotropic distillation is: 103 ppm water. To the batch is charged tetrahydrofuran (222 g) and then the batch temperature was adjusted to an internal temperature of −25±5° C. During the cooling of the batch dichloromethane (78.9 mL, 1230 mmol, 9.0 equiv) was charged. To a separate reactor (vessel 2) was prepared the LDA solution via the following procedure: To a clean and dry reactor (1 L) under an inert atmosphere was charged tetrahydrofuran (200 mL) and diisopropylamine (78.6 mL, 560.5 mmol, 4.10 equiv). The batch temperature was adjusted to −5° C. and to the agitated solution was charged 2.4 M solution of n-butyl lithium (227.8 mL, 546.9 mmol, 4.00 equiv) at a rate to maintain the internal temperature NMT 25° C. The resulting solution was stirred at an internal temperature of 20±5° C. for NLT 15 min. The LDA solution is cooled to an internal temperature of −25±5° C. To the main batch (vessel 1) is charged the precooled (an internal temperature of −25±5° C.) LDA solution (vessel 2) at a rate to maintain the batch temperature NMT −11° C. and with a 25 min addition time. The batch is aged at an internal temperature of −25±5° C. for 30 min (NLT 20 min). The batch temperature was adjusted to an internal temperature of 0±5° C. and the batch is aged at an internal temperature of 0±5° C. for 1 h. To a separate vessel (vessel 3) is prepared the sodium hydroxide/hydrogen peroxide solution as follows: charge sodium hydroxide (12.0 g, 300.7 mmol, 2.2 equiv) and water (150 g). The solution is mixed to obtain a homogeneous solution. To the homogeneous sodium hydroxide solution is charged hydrogen peroxide (30%, 17.1 g, 150.4, 1.1 equiv). The solution is agitated to form a clear homogeneous solution. To the main batch (vessel 1) is charged the sodium hydroxide/hydrogen peroxide solution (vessel 3) at a rate to maintain the internal temperature <25° C. Note; the exotherm from the hydrogen peroxide charged is delayed by ˜1-2 mins, thus portion-wise charging is usually performed. The batch is agitated at an internal temperature of 20±5° C. for 30 min. The agitation is stopped and a sample is removed for HPLC analysis (target >95A % conversion from the rearrangement products to the aldehyde). If the oxidation is not complete, continue agitation for an additional 30 min and recheck HPLC A % conversion. To a separate vessel (vessel 4) is prepared a ˜4 N HCl aqueous solution by mixing concentrated aqueous hydrogen chloride (177.4 g) with water (273 g) until the solution is homogeneous. To the batch is charged 250 g of the ˜4 N aqueous HCl solution (vessel 4) at a rate to maintain the internal temperature <25° C. The batch is agitated at an internal temperature of 20±5° C. for 10 min. The agitation is stopped and the layers are allowed to settle (˜30 min). The aqueous layer is cut (mass: 550 g). To the batch is charged 200 g of the ˜4 N aqueous HCl solution (vessel 4) at a rate to maintain the internal temperature <25° C. The batch is agitated at an internal temperature of 20±5° C. for 10 min. The agitation is stopped and the layers are allowed to settle (˜30 min). The aqueous layer is cut (mass: 297 g). To a separate vessel (vessel 5) is prepared a 5 wt % NaCl aqueous solution by dissolving sodium chloride (10.0 g) in water (190.0 g). To the batch is charged the 5 wt % sodium chloride solution (vessel 5). The batch is agitated at an internal temperature of 20±5° C. for 10 min. The agitation is stopped and the layers are allowed to settle (˜30 min). The aqueous layer is cut (mass: 233 g). The batch volume is adjusted to ˜100 mL via vacuum distillation (external temperature <50° C.). The batch is drained and filtered through a celite plug. The reactor is rinsed with reagent grade alcohol (˜150 mL). This rinse is used to rinse the celite plug and combined with the main batch solution. The combined mass of the solution: 233 g. Proton NMR wt % assay with an internal standard (dimethyl fumarate) indicates 11.9 wt % of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal (7, 27.7 g, 80% yield). This solution is used as is for the following step.

1. customTo a clean and dry 2 L reactor (vessel 1) under an inert atmosphere (nitrogen)
2. customA sample is removed
3. distillationif >350 ppm water proceed with an azeotropic cyclopentyl methyl ether distillation)
4. additionwas charged to the batch
5. distillationdistilled (external temperature <60° C.)
6. distillationThe KF of the batch after the azeotropic distillation
7. additionTo the batch is charged tetrahydrofuran (222 g)
8. customwas adjusted to an internal temperature of −25±5° C
9. additionwas charged
10. customTo a clean and dry reactor (1 L) under an inert atmosphere
11. customwas adjusted to −5° C. and to the agitated solution
12. additionTo the main batch (vessel 1) is charged the
13. customan internal temperature of −25±5° C.
14. temperatureto maintain the batch temperature NMT −11° C.
15. additionwith a 25 min addition time
16. waitThe batch is aged at an internal temperature of −25±5° C. for 30 min
17. custom(NLT 20 min)
18. customwas adjusted to an internal temperature of 0±5° C.
19. waitthe batch is aged at an internal temperature of 0±5° C. for 1 h
20. additionThe solution is mixed
21. customto obtain a homogeneous solution
22. stirringThe solution is agitated
23. customto form a clear homogeneous solution
24. temperatureto maintain the internal temperature <25° C
25. waitis delayed by ˜1-2 mins
26. stirringThe batch is agitated at an internal temperature of 20±5° C. for 30 min
27. customa sample is removed for HPLC analysis (target >95A % conversion from the rearrangement products to the aldehyde)
28. customfor an additional 30 min
29. customTo a separate vessel (vessel 4) is prepared a ˜4 N HCl aqueous solution
30. temperatureto maintain the internal temperature <25° C
31. stirringThe batch is agitated at an internal temperature of 20±5° C. for 10 min
32. custom(˜30 min)
33. temperatureto maintain the internal temperature <25° C
34. stirringThe batch is agitated at an internal temperature of 20±5° C. for 10 min
35. custom(˜30 min)
36. stirringThe batch is agitated at an internal temperature of 20±5° C. for 10 min
37. custom(˜30 min)
38. distillationThe batch volume is adjusted to ˜100 mL via vacuum distillation (external temperature <50° C.)
39. filtrationfiltered through a celite plug
40. washThe reactor is rinsed with reagent grade alcohol (˜150 mL)
41. washto rinse the celite plug

ORD record

ord-c2875f0b92c04bcfa8273811b5d5c58a

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09029592B2