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

配合物水解则得到酮。

5.5.1 由Weinreb酰胺还原合成醛反应示例一

OOSHNONOLAH/THFOOSHNO

4-[4-(methanesulfonamido)phenyl]butyraldehyde

A mixture of 4.20 g (14 mmol) of 4-[4-(methanesulfonamido)phenyl]butyric acid,

N-methoxy-N-methylamide and 100 mL of anhydrous tetrahydrofuran was stirred under nitrogen with cooling in an ice bath as 17.5 mL (17.5 mmol) of 1M lithium aluminum hydride in tetrahydrofuran was added gradually by syringe. After 0.75 hours, 70 mL of 5percent potassium hydrogen sulfate solution (aqueous) was added cautiously by syringe. The mixture was then removed from the ice bath, diluted with 150 ML of water, and shaken with 150 mL of ethyl acetate. The milky aqueous phase was extracted with an additional 50 mL of ethyl acetate. The combined organic fractions were washed successively with 2*100 mL of 1N hydrochloric acid, then 50 ML of saturated aqueous sodium bicarbonate solution, and finally 50 ML of saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue on silica gel (elution with 3:2 hexane-EtOAc) yielded 2.47 g (73%) of an oil; homogeneous by TLC in 1:1 hexane-EtOAc).Upon storage in the freezer, solidification occurred (mp 41~44

o

C.).

Reference: US5756507

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5.5.2由Weinreb酰胺还原合成酮反应示例:

F3CF3CNOOHMgClNF3CF3CONOOH

1-(Methyl{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)-pentan-2-one

To a solution of [N-1--methoxy-N-1-N-2-dimethyl-N-2-- {4- [2,] 2,2- trifluoro-1-hydroxy- 1-(trifluoromethyl)ethyl]phenyl}glycinamide (240 mg, 0.64 mmol) in CH2Cl2 (3.5 mL) at 0

o

C under a nitrogen atmosphere was slowly added a solution of propylmagnesium chloride

(1.6 mL, 2M in Et2O). After stirring 3 hours, the reaction mixture was poured into 1 M HCI and extracted twice with EtOAc. The organic layer was washed with brine, dried (NA2SO4), filtered, and concentrated. Purification by flash chromatography (2: 1 EtOAc/hexanes) afforded the title compound as a dark yellow waxy solid (110 mg, 48%). Reference:WO2003/99769

5.6由氰合成醛酮

腈与金属氢化物反应生成醛亚胺的金属盐，由于亚胺的碳氮双键极化比较小，难以被第二个负氢进攻，则可让反应停于此阶段而得醛。Stephen 醛合成法（H. Stephen, J. Chem. Soc. 127, 1874 (1925); T. Stephen, H. Stephen, ibid. 1956, 4695）是用SnCl2/HCl将腈转化为醛亚胺的盐酸盐然后水解便得醛。此法只用于芳香醛的合成。

L. N. Ferguson, Chem. Rev. 38, 243 (1946); E. Mosettig, Org. React. 8, 246 (1954); O. Bayer, Houben-Weyl 7/1, 299 (1954); E. N. Zilberman, P. S. Pyryalova, J. Gen. Chem. U.S.S.R. (Engl. trans.) 33, 3348 (1963); C. G. Stuckwisch, J. Org. Chem. 37, 318 (1972).

低温下，加入氢化铝锂至腈中，随可得到一定收率（40-70%）的醛。但最好的方法还是向腈化物中加入等当量至稍过量的DIBAL，0℃以下进行反应。该法对缩醛及卤化物不反应，但除羧酸外会先与其它羰基化合物作用，所以通常要保护这些羰基后再进行反应。

Raney Ni 的活性作适当调节，可以催化还原腈到醛。通常用亚磷酸钠和甲酸钝化

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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

Raney Ni。也有在N，N-二苯基乙二胺或氨基脲共存下制得醛衍生物的方法。

腈与Grignard试剂反应，可以将腈变为酮。由于反应中形成了活性低的酮亚胺盐，当反应停于此阶段，则经水解便能以较好的收率得到酮。因为Grignard试剂有些碱性，它可以在连接吸电子基氰基的邻位碳上夺取一个质子，所以本法用于脂肪族腈时，收率低了些，相反自芳香腈制芳酮时，便是个高收率的优良合成法。

5.6.1DIBAL 还原腈到醛示例 （最重要的方法）

ClNCDIBAlOHC

ClPreparation of 2-chloro-6-methylbenzaldehyde

To a stirred solution of 2-chloro-6-methylbenzonitrile (1 g, 6.6 mmol) in THF (15 mL)

under argon at 0 oC a solution of DIBAL (1 M in THF, 7 ML, 7 mmol) was added dropwise over 5 minutes. After 3 hr at 0 oC, the reaction mixture was brought to room temperature and further stirred overnight. The reaction mixture was quenched with 5percent sulfuric acid at 0 oC, extracted with ether, washed with brine and dried (MgSO4). Concentration provided 2-chloro-6-methylbenzaldehyde (0.92 g) which was used without further purification.

Reference:: US6506747

5.6.2Li(EtO)3AlH 还原腈到醛示例 （较重要的方法）

CN1. Li(C2H5O)3AlH2. H3O+CHO

In a 1-liter flask equipped with a stirrer, condenser, dropping funnel, and thermometer is placed 10.2 g (0.3 mol) of lithium aluminum hydride in 300 mL of ether. The flask contains a nitrogen atmosphere throughout the reaction period. To the stirred solution is added 39.6 g (0.45 mol) of ethyl acetate over a period of 1.25 h at 3-7℃. The reaction mixture is stirred for an additional 0.5 h and then 24.9 g (0.30 mol) of trimethylacetonitrile is added over a period of 5 min. The temperature rise to 10℃, with the formation of a highly visous solution. The reaction mixture is stirred for 1 h at 0℃ and then the solution is decomposed

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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

cautiously with 300 mL of 5 N H2SO4. The ether layer is separated and the layer is extracted three times with 50 mL portions of ether. The ether extracts are washed with saturated sodium bicarbonate solution followed by ether washings with 30 mL portions of cold water in order to remove ethanol. The ether extracts are dried over sodium sulfate and distilled to yield 25.8 g (74%) of pivalaldehyde, bp 70-72.5℃ (747 mm), n20D 1.3794.

Reference: H. Stephen, J. Chem. Soc., 1925, 127, 1874

5.6.3Ranney Ni 加氢还原氰到合成醛示例

CNRaney nickelHCO2H, heatSO2NH2SO2NH2 CHOA 2-l., two-necked, round-bottomed flask fitted with a mechanical stirrer and a reflux condenser is charged with 40.0 g. (0.232 mole) of 4-cyanobenzenesulfonamide, 600 mL of 75% (v/v) formic acid, and 40 g. of Raney nickel alloy. The stirred mixture is heated under reflux for 1 hour. The mixture is filtered with suction through a Büchner funnel coated with a filter aid, and the residue is washed with two 160-mL portions of 95% ethanol. The combined filtrates are evaporated with a rotary evaporator. The solid residue is dissolved in 400 mL of boiling water and freed from a small amount of insoluble material by decantation through a plug of glass wool placed in a filter funnel. The filtrate is chilled in an ice bath, and the precipitate is collected by filtration with suction, washed with a small amount of cold water, and dried at 50° under vacuum, yielding about 32 g. of crude product, m.p. 112–114°C. The product is dissolved in 800 mL of hot 95% ethanol, 15.5 g. of activated carbon is added, and the mixture is swirled periodically while it is allowed to cool for 1 hour. The activated carbon is removed by filtration with suction through a bed of filter aid, the filter cake is washed with 50 mL of 95% ethanol, and the combined filtrates are evaporated with a rotary evaporator. The residue is dissolved in 225 mL of boiling water, and the hot solution is decanted through glass wool placed in a filter funnel. The filtrate is cooled to 0°, the product is collected by filtration with suction, washed with a small amount of cold water, and dried in

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