1、羧酸的合成水解法060114经典化学合成反应标准操作羧酸的合成水解法编者: 杨纯道药明康德新药开发有限公司化学合成部1 前言22 酰氯的水解33 酸酐的水解44 酯的水解54.1酯的碱水解54.2酯的酸水解54.3丙二酸二乙酯合成法75 酰胺的水解85.1酰胺的直接酸水解95.2酰胺的直接碱水解95.3亚硝酸钠促进的酰胺酸水解法95.4 酰胺的间接水解法96 腈的水解106.1腈的酸水解116.2腈的碱水解116.3亚硝酸钠促进的腈的酸水解法121. 前言利用缩水的方法可以将羧酸转变为各种羧酸的衍生物,如酰氯、酸酐、酯、酰胺和腈等,反过来通过水解反应各种羧酸衍生物也可以转变为羧酸,除酰氯和酸酐
2、外,酯、酰胺和腈的水解一般都可以在酸或碱的催化下进行。羧酸衍生物水解的速度和羰基碳原子的正电性有关,一般来说正电性越大,水解速度越快。2. 酰氯的水解把羧酸制成酰氯,再通过酰氯去进行各种反应是有机合成中常用的方法,较少有用酰氯来制备羧酸的例子,但在有些条件下利用酰氯来制羧酸也是较为有效的。例如芳环通过佛克反应和草酰氯反应得到相应的酰氯。一般来讲脂肪酰氯的水解是相当快的,不用加任何催化剂即可反应。但芳香酰氯的反应要相对慢了很多,有时为了促进其水解需要加入碱和酸。2.1 酰氯的水解示例Aluminum chloride (160 g, 1.2 mol) was added to a stirred
3、 solution of the 4-n-pentylbiphenyl (224 g, 1 mol) in methylene chloride (1000 mL) at approximately -20C. Then Oxalyl chloride (96 mL) was added to the solution at a temperature below -10C. After addition, the reaction temperature was allowed to rise to approximately 0C. Stirring continued at approx
4、imately 0C untill the evolution of hydrogen chloride was ceased. The resulting reaction mixture was poured into ice water forming two nonmiscible fluid layers. The organic layer was seperated from the aqueous layer, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed
5、by distillation to yield a crude 4-n-pentylbiphenyl-4-carboxy chloride (213 g, 75%) which was used directly in the next step.The 4-n-pentylbiphenyl-4-carboxy chloride (142 g, 0.5 mol) was reacted with a hot, stirred solution of sodium hydroxide (60 g, 0.75 mol) in water (50 mL) and acetone (500 mL)
6、for about three hours. The cold reaction mixture was then acidified with concentrated hydrochloric acid solution. The acid was filtered and washed with water untill the filtrate was neutralized. The product of the reaction was purified from ethanol to yield 4-n-pentylbiphenyl-4-carboxylic acid (102.
7、4 g, 80%).Reference: US44243713. 酸酐的水解酸酐也并不常用于制备酸,由于酸酐的活性比酸强,多数情况下直接室温水解就可以转变为羧酸,在有些情况下对反应加加热可以促进反应的进行。3.1 酸酐的水解示例To citraconic anhydride (22.4 g, 0.2 mol) was added from a pipet exactly 4 mL (0.22 mole) of distilled water. The mixture was stirred on a hot plate until a homogeneous solution was form
8、ed, then covered with a watch glass and allowed to stand for forty-eight hours. At the end of this time the mixture would solidified completely. For further purification it was finely ground in a mortar, washed with 50 mL of cold benzene, dried in the air, and then dried for twenty-four hours in a v
9、acuum desiccator over phosphorus pentoxide to give citraconic acid (24.4 g, 94%) which melts at 9293C.Reference: Organic Syntheses. Coll. Vol. 2, 1404. 酯的水解在有机合成中,羧酸和酯可以很方便地相互转换,因此酯化反应是保护羧基的一种常用方法,酯水解也成为水解法制羧酸的重要方法。4.1 酯的碱水解水解反应是酯化反应的逆反应,酯化反应要在酸性条件下进行的,因此多数情况下酯的水解在碱性条件下进行是有利的。一般来说非位阻酯的水解主要通过LiOH-MeO
10、H-H2O体系于室温下进行反应,正常条件是氢氧化锂的当量为2-5 当量,甲醇和水的比例为5:13:1。如果反应仍不能水解,可适当加热直至回流。对于有些位阻大、惰性的酯,需要用更强的反应条件,一般可使用NaOH、KOH的水溶液或水甲醇的混合溶液进行水解,其中最强烈的条件是用KOH的水甲醇的混合溶液回流水解,KOH的浓度越大、溶剂甲醇的比例越高,水解条件越强,很少有在这种条件下水解不了的酯。对于该类水解反应的后处理一般先浓缩去处醇类溶剂,然后用有机溶剂提取可能未反应完的非酸类副产物,再酸化,许多酸在此时可以析出沉淀,过滤即可得到,若为油则用有机溶剂提取。有时当一个分子同时存在甲酯和叔丁酯时,用以上
11、条件很难较好的选择性的水解甲酯,有时需要控制碱的当量数和反应温度。4.1.1 LiOH-MeOH-H2O水解体系的标准操作To a solution of ester (10 mmol) in MeOH-H2O (30 mL, MeOH:H2O=3:15:1, 甲醇浓度越高,水解能力越强) at 0C was slowly added LiOH.H2O (800 mg 2 g, 20-50 mmol). The reaction mixture was allowed to warm to room temperature overnight (若水解不完全就加热至反应完全). Methano
12、l 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) (注意若有固体析
13、出则过滤得到相应的酸). The combined organic extract was dried over MgSO4 and concentrated to afford the desired acid (normal yield 95%).4.1.2 LiOH-MeOH-H2O体系的选择性水解甲酯和叔丁酯示例To a solution of compound 1 (14.15 g, 48.1mmol) in MeOH (250 ml) at 0C was slowly added aqueous LiOH (1M, 48 ml, 48mmol) over 15 min. The r
14、eaction 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
15、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)4.1.3 KOH-H2O体系的水解示例A mixture of ethyl 3-methylco
16、umarilate (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,
17、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 (5457
18、g, 9095%) which melts at 192193C.Reference: Organic Syntheses: Coll. Vol. 4, 5904.2 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12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
19、的醇,否则叔丁酯会转变为相应的酯。4.2.1 叔丁酸酯的酸水解示例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 use
20、d to the next reaction directly. Reference: US41549374.2.2 对碱不稳定的酯的酸水解示例A solution of ethyl -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
21、 was concentrated by heating in an oil bath at 100C at reduced pressure (1520 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 ad
22、ded 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 e
23、xtracted with two 200 mL portions of ether. The ether extracts were washed with two 100 mL 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 (5
24、060C) 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 c
25、onstant weight in a vacuum desiccator over solid potassium hydroxide to give the dry acid (8284 g, 8082%) which melts at 77.579.5C.Reference: Organic Syntheses. Coll. Vol. 4, 1694.3 丙二酸二乙酯合成法丙二酸二乙酯合成法是把卤代烃转变为多两个碳原子的酸的经典而有效方法,它借助丙二酸二乙酯这一特定试剂,实际包括了-H的取代、水解和脱羧三步反应。4.3.1 丙二酸二乙酯合成法示例To anhydrous butyl al
26、cohol (2.5 L) was added clean, bright sodium (115 g, 5mol) cut in small pieces at one time. After the sodium was dissolved completely, the solution was allowed to cool to 7080C and then redistilled ethyl malonate (800g, 5mol) was added rapidly with stirring. After heating the reaction solution to 80
27、90C, pure heptyl bromide (913 g, 5.1 mol) was added. The bromide should be added rather slowly at first, until precipitation of sodium bromide began; it might then be added at such a rate that the butyl alcohol refluxed gently. Usually about one hour was required for the introduction of the heptyl b
28、romide. The mixture was refluxed gently until it was neutral to litmus (about one hour).To the entire mixture, including the precipitated sodium bromide, was added a solution of 90 per cent potassium hydroxide (775 g, 12.5 mol) in an equal weight of water. The mixture was heated cautiously, with occ
29、asional shaking, until refluxing started, and refluxing was continued until saponification was complete (about four or five hours). The flask was fitted at once for steam distillation, and the mixture was distilled until no more butyl alcohol passes over. To the residue was added concentrated hydroc
30、hloric acid (1350 mL, 15.5 mol) carefully, with shaking, and the mixture was refluxed for about one hour. After cooling, the water layer was siphoned off and discarded.The oil obtained in the preceding step was heated under an air-cooled reflux condenser in an oil bath at about 180C. When the evolut
31、ion of carbon dioxide ceased (about two hours), the oil was decanted from a small amount of solid material. The solid residue on treatment with 200300 mL of concentrated hydrochloric acid gave an additional small quantity of oil which was added to the main portion.The crude pelargonic acid was distilled in a modified Claisen flask having a fractionating side arm, and the material boiling
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