一、酯的堿水解

水解反應是酯化反應的逆反應，酯化反應要在酸性條件下進行的，因此多數情況下酯的水解在堿性條件下進行是有利的。一般來說非位阻酯的水解主要通過LiOH-MeOH-H2O 體系于室溫下進行反應，正常條件是氫氧化鋰的當量為2-5 當量，甲醇與水的比例為5:1~3:1。如果反應仍不能水解，可適當加熱直至回流。對于有些位阻大、惰性的酯，需要用更強的反應條件，一般可使用NaOH、KOH 的水溶液或水甲醇的混合溶液進行水解，其中最強烈的條件是用KOH 的水甲醇的混合溶液回流水解，KOH的濃度越大、溶劑甲醇的比例越高，水解條件越強，很少有在這種條件下水解不了的酯。對于該類水解反應的后處理一般先濃縮去處醇類溶劑，然后用有機溶劑提取可能未反應完的非酸類副產物，再酸化，許多酸在此時可以析出沉淀，過濾即可得到，若為油則用有機溶劑提取。有時當一個分子同時存在甲酯和叔丁酯時，用以上條件很難較好的選擇性的水解甲酯，有時需要控制堿的當量數和反應溫度。

1.1、LiOH-MeOH-H2O 水解體系的標準操作

To a solution of ester (10 mmol) in MeOH-H2O (30 mL, MeOH:H2O=3:1~5:1, 甲醇濃度越高，水解能力越強) at 0°C was slowly added LiOH.H2O (800 mg ~ 2 g, 20-50 mmol). The reaction mixture was allowed to warm to room temperature overnight (若水解不完全就加熱至反應完全). Methanol was removed in vacuo and the residual aqueous solution was partitioned with Et2O or AcOEt (~20 mL), then the organic phase was extracted with H2O (5-10 mL, two times). The combined aqueous extracts was acidified to pH 2 with 1N HCl. The aqueous phase was extracted with CHCl3 (three times) (注意若有固體析出則過濾得到相應的酸). The combined organic extract was dried over MgSO4 and concentrated to afford thedesired acid (normal yield >95%).

1.2、 LiOH-MeOH-H2O 體系的選擇性水解甲酯

To a solution of compound 1 (14.15 g, 48.1mmol) in MeOH (250 ml) at 0°C was slowly added aqueous LiOH (1M, 48 ml, 48mmol) over 15 min. The reaction mixture was allowed to warm to room temperature overnight with stirring.The organic solvent was removed in vacuo and the residual aqueous solution was partitioned with Et2O, then the organic phase was extracted with H2O (two times). The combined aqueous extract was acidified to pH 2 with 1N HCl. The aqueous phase was extracted with CHCl3 (three times). The combined organic extract was dried over MgSO4 and concentrated to afford the desired acid (11.4 g, 85%).

Reference: Publ.: US2004/6065 A1 (2004/01/08); Appl.: US2003-465426 (2003/06/19)

1.3 、KOH-H2O 體系的水解

A mixture of ethyl 3-methylcoumarilate (70 g, 0.34mol) and 10% aqueous potassium hydroxide solution (500 mL) was refluxed for 1 hour. The clear yellowish solution was acidified while hot with a slight excess of concentrated hydrochloric acid to precipitate 3-methylcoumarilic acid. The suspension was cooled to room temperature, and the colorless solid was filtered with suction. The filter cake was resuspended in 500 mL of cold water, stirred vigorously for several minutes, and filtered again with suction. The colorless powder The filter cake was dried in a desiccator under reduced pressure to give a colorless powder (54~57 g, 90~95%) which melts at 192~193°C.

Reference: Organic Syntheses: Coll. Vol. 4, 590

二、酯的酸水解

某些情況下對于一些特定結構的酯需要在酸性條件下進行水解，例如叔丁酯和一些對堿不穩定的酯。有些氨基酸酯在1 N 鹽酸回流條件下水解（一般回流1~2 小時即可），蒸干溶劑后可直接以鹽的形式進行下面的反應，而無需進一步提純，此時也可以考慮用酸進行水解。叔丁酯一般比Boc 難脫，一般要用50-100%TFA 或4N HCl/Dioxane （注意：在用HCl/dioxane 來脫除叔丁酯時，千萬不能在溶劑處理時中引入甲醇，乙醇或其他小位阻的醇，否則叔丁酯會轉變為相應的酯。

2.1 、叔丁酸酯的酸水解

1-(4-Methoxycarbonyl-2-methylbutanoyl)-L-proline t-butyl ester (3.4 g, 10.8 mmol) was dissolved in trifluoroacetic acid (25 mL) and the resulting solution was kept at room temperature for one hour. The trifluoroacetic acid was removed in vacuo and the residue was used to the next reaction directly.

Reference: US4154937

2.2 、對堿不穩定的酯的酸水解

A solution of ethyl α-chlorophenylacetate (119 g, 0.6 mol) in glacial acetic acid (238 mL) and concentrated hydrochloric acid (119 mL) was heated under reflux in a hood for 1.5 hours. At the end of the heating period the solution was concentrated by heating in an oil bath at 100°C at reduced pressure (15~20 mmHg) until no further material was distilled. The residue was allowed to cool to room temperature and poured slowly with stirring into 1 L of ice-cold saturated sodium bicarbonate solution. Solid sodium bicarbonate was added in small portions until the solution became neutral to universal indicator paper. The solution was then extracted with two 200 mL portions of ether. The aqueous phase was acidified cautiously with ice-cold 12N sulfuric acid until the mixture was acid to Congo red paper. The oily suspension was extracted with two 200 mL portions of ether. The ether extracts were washed with two 100mL portions of water and dried over 45 g of anhydrous sodium sulfate. The dried ether extract was concentrated on a steam bath until ether was no longer distilled. To the residue there was added 500 mL of warm (50~60°C) concentrated hydrochloric acid (in a hood) and the suspension was allowed to cool with occasional swirling. Crystallization was completed by chilling in ice and the product was collected on a sintered-glass funnel. After the product was dried as much as possible on the funnel it was dried to constant weight in a vacuum desiccator over solid potassium hydroxide to give the dry acid (82~84 g, 80~82%) which melts at 77.5~79.5°C.

Reference: Organic Syntheses. Coll. Vol. 4, 169

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