反应详情

温度

-40 °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, 7.50 kg, 47 wt %, 10.0 mol, 1.00 equiv). The batch is concentrated via vacuum distillation (Tjacket NMT 50° C.) to reduce the batch to ˜7 L (˜2 vols). To the batch is charged tetrahydrofuran (6 L) and agitation is initiated. The batch is concentrated via vacuum distillation (Tjacket NMT 50° C.) to reduce the batch to ˜5 L (˜2 vols). To the batch is charged tetrahydrofuran (15 L) and then a sample is removed and the water content is determined: Target NMT 300 ppm: this batch 270 ppm. The batch volume at this point is ˜21 L. To the batch is charged 1,4-dioxane 3.8 kg. The batch temperature was adjusted to −45±5° C. During the cooling of the batch dichloromethane (1.8 kg, 20 mol, 2.0 equiv) is charged. To the batch is charged a titrated 2 M solution of lithium diisopropylamine as a solution in THF, heptane and ethyl benzene (7.29 L, 5.75 kg, 15.4 mol, 1.5 equiv) at a rate to maintain the internal temperature NMT −40° C. (the addition required 1.5 h to complete). The batch is aged at −45±5° C. for NLT 20 min. To the batch is charged methanol (2.76 L, 2.18 kg) at a rate to maintain the internal temperature NMT −40° C. The batch temperature is adjusted to 20±5° C. and then the batch is aged at 20±5° C. for NLT 30 min. 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. To the main batch (vessel 1) is charged hydrogen peroxide solution (29-32 wt % aqueous: 1.22 kg, 10.76 mol, 1.05 equiv) 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. A sample is removed and the oxidation is monitored by HPLC analysis: Target NLT 95A %: this batch 96.5A %. To the batch is charged: 3.8 L of tert-butyl methyl ether and then 10 kg of a 4 N aqueous hydrogen chloride solution at a rate to maintain the internal temperature NMT 25° C. The resulting batch is agitated at 20±5° C. for 30 min (NMT 2 h). The agitation is stopped and the layers are allowed to settle (˜30 min). The aqueous layer is cut (mass: 35.1 kg). To the batch is charged 4.6 kg of a 20 wt % solution of sodium sulfite (prepare by mixing 0.92 kg of sodium sulfite and 3.7 kg of water and mixing until homogeneous (20 nm)). The resulting batch is agitated at 20±5° C. for 30 min (NMT 2 h). The agitation is stopped and the layers are allowed to settle (˜30 min). The aqueous layer is cut (mass: 5.28 kg). The batch is concentrated via vacuum distillation to (Tjacket NMT 50° C.) to reduce the batch volume to ˜5 L. The solution was retained in the reactor and used as is for the following step.

1. customTo a clean and dry 2 L reactor (vessel 1) under an inert atmosphere (nitrogen)
2. concentrationThe batch is concentrated via vacuum distillation (Tjacket NMT 50° C.)
3. additionTo the batch is charged tetrahydrofuran (6 L) and agitation
4. concentrationThe batch is concentrated via vacuum distillation (Tjacket NMT 50° C.)
5. additionTo the batch is charged tetrahydrofuran (15 L)
6. customa sample is removed
7. additionTo the batch is charged 1,4-dioxane 3.8 kg
8. customwas adjusted to −45±5° C
9. additionis charged
10. additionthe addition required 1.5 h
11. customis aged at −45±5° C. for NLT 20 min
12. customis adjusted to 20±5° C.
13. customis aged at 20±5° C. for NLT 30 min
14. custom(NLT 20 min)
15. customwas adjusted to an internal temperature of 0±5° C
16. temperatureto maintain the internal temperature <25° C
17. waitis delayed by ˜1-2 mins
18. customA sample is removed
19. additionTo the batch is charged
20. temperature3.8 L of tert-butyl methyl ether and then 10 kg of a 4 N aqueous hydrogen chloride solution at a rate to maintain the internal temperature NMT 25° C
21. custom(˜30 min)
22. additionTo the batch is charged 4.6 kg of a 20 wt % solution of sodium sulfite (prepare by mixing 0.92 kg of sodium sulfite and 3.7 kg of water and mixing until homogeneous (20 nm))
23. stirringThe resulting batch is agitated at 20±5° C. for 30 min (NMT 2 h)
24. custom(˜30 min)
25. concentrationThe batch is concentrated via vacuum distillation to (Tjacket NMT 50° C.)