[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8](B2OC(C)(C)C(C)(C)O2)([CH:10]2CC2)[CH3:9])=[CH:4][CH:3]=1.ClCCl.C(N[CH:29]([CH3:31])[CH3:30])(C)C.[Li].C(C1C=CC=CC=1)C.[OH:41]O>C1COCC1.CO.CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([CH:29]2[CH2:31][CH2:30]2)([CH3:9])[CH:10]=[O:41])=[CH:6][CH:7]=1To 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.
読み込み中…
