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%).
1.3 、KOH-H2O 体系的水解
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
某些情况下对于一些特定结构的酯需要在酸性条件下进行水解，例如叔丁酯和一些 对碱不稳定的酯。有些氨基酸酯在1 N 盐酸回流条件下水解（一般回流1~2 小时即可），蒸干溶剂后可直接以盐的形式进行下面的反应，而无需进一步提纯，此时也可以考虑用酸进行水解。叔丁酯一般比Boc 难脱，一般要用50-100%TFA 或4N HCl/Dioxane （注意：在用HCl/dioxane 来脱除叔丁酯时，千万不能在溶剂处理时中引入甲醇，乙醇或其他小位阻的醇，否则叔丁酯会转变为相应的酯。）
常见副反应：叔丁酯的酸水解和脱Boc类似，当分子中存在一些官能团（如氰基，参考Ritter反应 ）其可与副产物叔丁基碳正离子在酸性下反应时，需要添加硫酚(如苯硫酚)来清除叔丁基碳正离子，如此举可防止蛋氨酸和色氨酸的脱Boc时的烷基化。也可使用其它的清除剂，如苯甲醚、苯硫基甲醚、甲苯硫酚、甲苯酚及二甲硫醚等。
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.
2.2 、对碱不稳定的酯的酸水解
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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