经典合成反应标准操作— 醛酮的合成 药明康德新药开发有限公司

period, 300 g of crushed ice is added to the paste with careful stirring, producing a clear, cherry-red aqueous solution.

This solution is transferred with 100 mL of water to a 3-l. three-necked flask containing 200 g of crushed ice and fitted with an efficient mechanical stirrer and a separatory funnel containing a solution of 375 g. (9.4 mole) of sodium hydroxide in 1L of water The aqueous base is added. The remaining two-thirds is added rapidly with efficient stirring until about one-third of it has been added. The remaining two thirds is added rapidly with efficient stirring, and the resulting suspension is heated rapidly to the boiling point and allowed to cool to room temperature, after which it is placed in a refrigerator overnight. The precipitate is collected on a filter and resuspended in 1L of water. Most of the inorganic material dissolves, and the product is then collected on a filter, washed with three 300-mL portions of water and air-dried, yielding about 120 g (97%) of indole-3-aldehyde, mp 196-197 ℃. The indole-3-aldehyde resulting from this procedure is sufficiently pure for most purposes, but it may be recrystallized from ethanol if desired. Reference: Org. Syn., Vol 4, pp 539-541.

6.5.1.2 Vilsmeyer 反应示例二

OPOCl3,DMFAOCHOOO

Pyrophosphoryl chloride (1.889g, 7.5 mmol) was added dropwise to a stirred mixture of cold (ice bath) N,N-dimethylformamide (0.731g, 10.0 mmol) and p-dimethoxybenzene (0.691g, 5.0 mmol). The resulting syrup was then heated at 100 ℃ for 48 hours. The cold product was basified with an aqueous solution of 2M sodium hydroxide and extracted with dichloromethane and dried (MgSO4) and concentrated. Short-path distillation gave 2,5-dimethoxybenzaldehyde (0.332g 40%), mp 50-51 ℃. bp 80 ℃ at 0.1 mmHg. Reference: Tetrahedron 49(19) 4015-4034 (1993)

6.5.1.3草酰氯-DMF 体系Vilsmeyer 反应示例

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经典合成反应标准操作— 醛酮的合成 药明康德新药开发有限公司

CHODMF, (COCl)2OHOHOHOH

A 1-L 3-neck flask equipped with a temperature thermocouple and an efficient overhead stirrer is charged with DMF (46.37 g, 0.63 mole) and acetonitrile (350 mL). The reaction is treated dropwise with a solution of oxalyl chloride (66.12 g, 0.521 mole) in actionitrile dropwise over 20 min so that the temperature is maintained at 20~26℃ with a water bath. Gas evolution is noted and a thick precipitate forms. The reaction is stirred at ambient temperature for 1 h to insure complete conversion to the Vilsmeier reagent. The reaction is cooled in a dry-ice bath to -14?to -17?C and a solution of resorcinol (26.87 g, 0.244 mole) in acetonitrile (75 mL) is added over 20 min. The Vilsmeier reagent dissolves as the reaction with resorcinol occurs, and soon afterward the precipitation of chloride salt 4--Scheme 4 begins. The reaction is stirred at -15?C. for 35 min, then at 28~32 oC. for 2 h. The HPLC of the reaction solution shows <6% of the starting material. After cooling to 3~5℃ for 2 h, the reaction is filtered and washed with cold acetonitrile (70 mL). The solid is washed with hexane (30-40 mL) and the product dried. The Vilsmeier formamidinium chloride is dried at 30~35 oC at 0.05 mm of Hg for 24 h. The recovery is 42.3 g; the yield corrected for purity is 79%; it is a single component by HPLC, mp 170~173 ℃. Hydrolysis:

To water (250 mL) stirred at 40 oC is added the above salt (42.3 g, 0.209 mole) in three portions. The reaction is heated to 50 oC for 0.5 h, and the reaction is cooled. When the temperature had reached 35 oC, sodium thiosulfate solution (0.09M, 1-2 mL) is added to discharge the resulting pink color. The reaction is cooled to 5 oC., and stirred for 2 h. The mixture is filtered, the solid is washed with cold water, and air dried at <35 oC for 24 h giving 2,4-dimethoxybenzaldehyde (24.4 g, wt/wt assay by HPLC 97%; corrected yield: 69% from resorcinol) an off-white solid, mp 134~136oC. Reference:US5599988

6.5.1.4 二氯亚砜用于Vilsmeyer 反应示例

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