3-氯-2-羟基丙基氨基甲酸叔丁酯

实验步骤: 投料: 1）碘普罗胺溶于2M 氢氧化钾溶液中，N-cbz3-氯-2-羟基丙基氨溶于少量ACN，室温滴加，反应过夜。取样LCMS监测（18324-R2-2-BOC-0922），原料原料产物约为1/1。反相柱层析纯化，hnmr(C4X-18324-R2-2-CBZ)分析反应位点正确，但钯碳还原或6 M盐酸加热反应均无法脱掉CBZ保护基，所以本路线中Cbz保护基弃用。 2) 碘普罗胺溶于2M 氢氧化钾溶液中，3-氯-2-羟基丙基氨基甲酸叔丁酯 溶于少量ACN（1 mL），室温滴加，反应过夜。取样LCMS监测（18324-R2-2-BOC-0922），原料原料产物约为1/1。反应体系用3 M盐酸调pH=1,继续反应LCMS(C4X-18324-R2-BOC-3）监测，酸性条件下boc可脱去。

实验步骤: 投料: 碘普罗胺溶于2M 氢氧化钾溶液（20 mL,0.5 M）中，3-氯-2-羟基丙基氨基甲酸叔丁酯(4.6g，2.2eq） 溶于少量ACN（5 mL），室温滴加，反应过夜。取样LCMS监测（18324-R2-2-1017），原料原料产物约为1/1。停反应，6 M盐酸调pH=7-8,反相纯化（H2O/ACN=42/58过出产物)，45℃旋蒸除去乙腈，冻干除水，得白色固体3.5g。

实验步骤: 投料: 碘普罗胺溶于2M 氢氧化钾溶液（10 mL,0.5 M）中，3-氯-2-羟基丙基氨基甲酸叔丁酯 溶于少量ACN（1 mL），室温滴加，反应过夜。取样LCMS监测（18324-R2-2-BOC-0922），原料原料产物约为1/1。50℃加热反应6小时后取样LCMS监测（18324-R2-2-BOC-0922-2）原料无明显减少，恢复至室温，补加1.2eq 3-氯-2-羟基丙基氨基甲酸叔丁酯，继续反应过夜。 取样LCMS监测（18324-R2-2-BOC-0923），体系无明显变化，停反应，6 M盐酸调pH=7-8,反相纯化（H2O/ACN=42/58过出产物)，45℃旋蒸除去乙腈，冻干除水，得白色固体2g。

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of the product of Step 2 (7.0 g, 21.3 mmol) in DMF (14 mL) is cooled at 0° C. and treated with (3-chloro-2-hydroxy-propyl)carbamic acid tert-butyl ester (5.6 g, 27 mmol) and then lithium tert-butoxide (51 mL of a 1.0 M solution in THF) dropwise over 15 min. The reaction mixture is stirred for 20 h at room temperature and then treated with 40 mL of satd. NH4Cl and 100 mL of H2O. The solution is extracted with two portions of dichloromethane and the combined organic phases washed with H2O, brine and dried (MgSO4), filtered and concentrated. The crude product is purified by column chromatography (0–50% ethyl acetate-hexanes) to provide the title compound as a foam. treated with 40 mL of satd The solution is extracted with two portions of dichloromethane the combined organic phases washed with H2O, brine dried (MgSO4) filtered concentrated The crude product is purified by column chromatography (0–50% ethyl acetate-hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of the product of Step 2 (7.0 g, 21.3 mmol) in DMF (14 mL) is cooled at 0° C. and treated with (3-chloro-2-hydroxy-propyl)carbamic acid tert-butyl ester (5.6 g, 27 mmol) and then lithium tert-butoxide (51 mL of a 1.0 M solution in THF) dropwise over 15 min. The reaction mixture is stirred for 20 h at room temperature and then treated with 40 mL of satd. NH4Cl and 100 mL of H2O. The solution is extracted with two portions of dichloromethane and the combined organic phases washed with H2O, brine and dried (MgSO4), filtered and concentrated. The crude product is purified by column chromatography (0–50% ethyl acetate-hexanes) to provide the title compound as a foam. treated with 40 mL of satd The solution is extracted with two portions of dichloromethane the combined organic phases washed with H2O, brine dried (MgSO4) filtered concentrated The crude product is purified by column chromatography (0–50% ethyl acetate-hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of the product of Step 2 (7.0 g, 21.3 mmol) in DMF (14 mL) is cooled at 0° C. and treated with (3-chloro-2-hydroxy-propyl)carbamic acid tert-butyl ester (5.6 g, 27 mmol) and then lithium tert-butoxide (51 mL of a 1.0 M solution in THF) dropwise over 15 min. The reaction mixture is stirred for 20 h at room temperature and then treated with 40 mL of satd. NH4Cl and 100 mL of H2O. The solution is extracted with two portions of dichloromethane and the combined organic phases washed with H2O, brine and dried (MgSO4), filtered and concentrated. The crude product is purified by column chromatography (0–50% ethyl acetate-hexanes) to provide the title compound as a foam. treated with 40 mL of satd The solution is extracted with two portions of dichloromethane the combined organic phases washed with H2O, brine dried (MgSO4) filtered concentrated The crude product is purified by column chromatography (0–50% ethyl acetate-hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of the product of Step 2 (7.0 g, 21.3 mmol) in DMF (14 mL) is cooled at. 0° C. and treated with (3-chloro-2-hydroxy-propyl)carbamic acid tert-butyl ester (5.6 g, 27 mmol) and then lithium tert-butoxide (51 mL of a 1.0 M solution in THF) dropwise over 15 min. The reaction mixture is stirred for 20 h at room temperature and then treated with 40 mL of satd. NH4Cl and 100 mL of H2O. The solution is extracted with two portions of dichloromethane and the combined organic phases washed with H2O, brine and dried (MgSO4), filtered and concentrated. The crude product is purified by column chromatography (0-50% ethyl acetate-hexanes) to provide the title compound as a foam. treated with 40 mL of satd The solution is extracted with two portions of dichloromethane the combined organic phases washed with H2O, brine dried (MgSO4) filtered concentrated The crude product is purified by column chromatography (0-50% ethyl acetate-hexanes)