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Stage #1: With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium hydrogencarbonate; potassium bromide In dichloromethane; water at 0 - 5℃; Inert atmosphere; Large scale Stage #2: With ammonium hydroxide In dichloromethane; acetonitrile at 0 - 20℃; Large scale
A 100 L, 5 -necked round bottomed flask equipped with an overhead stirrer and a nitrogen inlet was charged with alcohol 12 (3.80 kg, 18.88 mol) and dichloromethane (6.0 vol, 30.2 kg, 22.8 L). The solution was cooled to an internal temperature below 5 °C (target range 0 - 5 °C). A solution of potassium bromide (449 g, 3.78 mol, 0.2 equiv) in water (1.2 vol, 4.56 kg, 4.56 L) was added as a single charge. TEMPO (59.0 g., 0.378 mol, 0.02 equiv) was then added as a single solid charge. Potassium bicarbonate (3.78 kg, 37.8 mol, 2.0 equiv) was added as a water (6 vol, 22.8 kg, 22.8 L) solution over 10 minutes. After 10 minutes stirring, 10 wtpercent sodium hypochlorite (14.06 kg, 11.65 L, 1.0 equiv) was added over 1 hour maintaining internal temperature between 0-5 °C. After 30 minutes stirring the organic layer was assayed for conversion of alcohol 12. When the reaction is judged to be complete, a solution of sodium thiosulfate (1.49 kg, 9.44 mol, 0.5 equiv) is added as a water (2 vol, 7.60 kg, 7.60 L) solution over 15 minutes with stirring. The mixture was then allowed to warm to room temperature and was then concentrated in vacuo. The aqueous layer is extracted with dichloromethane (3 vol, 11.4 L, 15.1 kg), and the organics combined (note: there may be precipitated salts in the organics at this point). The organics were then washed with water (5 vol, 19.0 L, 19.0 kg), and then solvent switched to acetonitrile (5 vol, 14.8 kg, 18.8L) while maintaining internal temperature at or below 30 °C during distillation. The acetonitrile solution was cooled to an internal temperature below 5 °C (target range 0 - 5 °C). NH4OH (10.5 L, 9.45 kg, 75 mol, 28percent aqueous solution, 4 equiv) was added over 1 hour to the acetonitrile solution maintaining internal temperature between 0 - 5 °C. Glyoxal (3.02 L, 3.83 kg, 26.4 mol 40percent aqueous solution, 1.4 equiv) was added over 1 hour maintaining internal temperature between 0 - 5 °C and the reaction stirred at ambient temperature for 19 hours. At this time HPLC analysis shows <2percent residual starting material by weight (note: if residual aldehyde is present a further charge of 0.2 eq. glyoxal will drive conversion). The reaction was diluted with 10 vol ethyl acetate (33.9 kg, 37.6 L), and washed with 2 volumes 20 wtpercent NaCl (7.5 L). The organics were then successively washed with 3 volumes 20 wtpercent NaCl (11.3 L) and 3 volumes water (11.3 L). The organics were solvent switched to approximately 4 volumes (15.0L, 13.0 kg) Toluene, then n-heptane (6 volumes, 15.4 kg, 22.6 L) was slowly added over 1 hour to precipitate out compound 13 which was stirred until the solution concentration of 13 was <8 mg/mL (if concentration is higher, further heptane charge should be added until the target concentration is reached). The slurry was filtered, washed with 3 volumes 40percent) Toluene/Heptane, and dried to provide compound 13 (as a mixture of rotamers) as a white solid (3.1 kg, 70percent yield). 1H NMR (DMSO, 400 MHz): 11.64 (br s, 1H), 6.85 (br s, 1H), 4.80- 4.73 (m, 1H), 3.48 (br s, 1H), 3.32 (m, 1H), 2.50 (m, 1H), 2.23-1.73 (m, 4H), 1.39/1.15 (s, 9H).
Stage #1: With sulfur trioxide pyridine complex; trifluoroacetic acid In dichloromethane for 2 h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane for 0.5 h; Stage #3: With tris-(dibenzylideneacetone)dipalladium(0); Thiosalicylic acid; 1,4-di(diphenylphosphino)-butane In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere; Sealed tube
to the Boc-L-prolinol (6.03g, 30 mmol) in dry DCM (120 mL), TEA (15 mL) and dry DMSO (33 mL) were added, then PyrS03 powder (5 g each )was added in several portions over 2 hrs until LCMS showed no starting material alcohol was present. Overall 30 g of PyrS03 was used. The mixture was then washed with 6 N NaHS04 (3 xlOO mL), water (2x lOOmL), and transferred to a flask. To the flask, N-methyl allylic amine (2.8 ml, 29 mmol) was added, followed by addition of addition of NaBH(OAc)3 ( 6.36 g, 30 mmol). After stirred 30 min, the mixture was transferred to a separation funnel. The organics were washed with water (100 mL), dried and concentrated to yield the desired product as an oil (4.5 g).The oil was re-dissolved in THF (lOOmL), then the solution was bubbled with N2 gas for 10 min, followed by addition of thiosalicylic acid (4.1g, 26.6 mmol), Pd2dba3 ( 137 mg, 0.5 mmol) and then 1,4- bis(diphenylphosphine)butane (128 mg, 0.30 mmol). The mixture was sealed and stirred at rt for 1 hr. It was then concentrated and washed with 4N NaOH (2x 50 mL), water (50mL), then dried and concentrated to offer a red oil. It was stirred with hexane (200 ml) for lOmin, then hexane was decanted to another flask and concentrated to offer the desired product (3.0 g). MS (M+l)+: 215.2.
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