1、經(jīng)典化學(xué)合成反應(yīng)標(biāo)準(zhǔn)操作羧酸的合成水解法編者： 楊純道藥明康德新藥開發(fā)有限公司化學(xué)合成部目 錄1 前言22 酰氯的水解33 酸酐的水解44 酯的水解54.1酯的堿水解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酰胺的直接堿水解95.3亞硝酸鈉促進(jìn)的酰胺酸水解法95.4 酰胺的間接水解法96 腈的水解106.1腈的酸水解116.2腈的堿水解116.3亞硝酸鈉促進(jìn)的腈的酸水解法121. 前言利用縮水的方法可以將羧酸轉(zhuǎn)變?yōu)楦鞣N羧酸的衍生物，如酰氯、酸酐、酯、酰胺和腈等，反過來通過水解反應(yīng)各種羧酸衍生物也可以轉(zhuǎn)變?yōu)轸人幔Ｂ群退狒?，酯、酰胺和腈的水?/p>

2、一般都可以在酸或堿的催化下進(jìn)行。羧酸衍生物水解的速度與羰基碳原子的正電性有關(guān)，一般來說正電性越大，水解速度越快。2. 酰氯的水解把羧酸制成酰氯，再通過酰氯去進(jìn)行各種反應(yīng)是有機(jī)合成中常用的方法，較少有用酰氯來制備羧酸的例子，但在有些條件下利用酰氯來制羧酸也是較為有效的。例如芳環(huán)通過佛克反應(yīng)與草酰氯反應(yīng)得到相應(yīng)的酰氯。一般來講脂肪酰氯的水解是相當(dāng)快的，不用加任何催化劑即可反應(yīng)。但芳香酰氯的反應(yīng)要相對(duì)慢了很多，有時(shí)為了促進(jìn)其水解需要加入堿和酸。2.1 酰氯的水解示例Aluminum chloride (160 g, 1.2 mol) was added to a stirred solution o

3、f 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 approximately 0C

4、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 by distilla

5、tion 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) for about t

6、hree 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 (102.4 g, 80%).R

7、eference: US3. 酸酐的水解酸酐也并不常用于制備酸，由于酸酐的活性比酸強(qiáng)，多數(shù)情況下直接室溫水解就可以轉(zhuǎn)變?yōu)轸人?，在有些情況下對(duì)反應(yīng)加加熱可以促進(jìn)反應(yīng)的進(jìn)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 formed, then covered w

8、ith 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 vacuum desiccator o

9、ver phosphorus pentoxide to give citraconic acid (24.4 g, 94%) which melts at 9293C.Reference: Organic Syntheses. Coll. Vol. 2, 1404. 酯的水解在有機(jī)合成中，羧酸和酯可以很方便地相互轉(zhuǎn)換，因此酯化反應(yīng)是保護(hù)羧基的一種常用方法，酯水解也成為水解法制羧酸的重要方法。4.1 酯的堿水解水解反應(yīng)是酯化反應(yīng)的逆反應(yīng)，酯化反應(yīng)要在酸性條件下進(jìn)行的，因此多數(shù)情況下酯的水解在堿性條件下進(jìn)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(jìn)行反應(yīng)，正常

10、條件是氫氧化鋰的當(dāng)量為2-5 當(dāng)量，甲醇與水的比例為5:13:1。如果反應(yīng)仍不能水解，可適當(dāng)加熱直至回流。對(duì)于有些位阻大、惰性的酯，需要用更強(qiáng)的反應(yīng)條件，一般可使用NaOH、KOH的水溶液或水甲醇的混合溶液進(jìn)行水解，其中最強(qiáng)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(qiáng)，很少有在這種條件下水解不了的酯。對(duì)于該類水解反應(yīng)的后處理一般先濃縮去處醇類溶劑，然后用有機(jī)溶劑提取可能未反應(yīng)完的非酸類副產(chǎn)物，再酸化，許多酸在此時(shí)可以析出沉淀，過濾即可得到，若為油則用有機(jī)溶劑提取。有時(shí)當(dāng)一個(gè)分子同時(shí)存在甲酯和叔丁酯時(shí)，用以上條件很難較好的選擇性的水解甲酯，有時(shí)

11、需要控制堿的當(dāng)量數(shù)和反應(yīng)溫度。4.1.1 LiOH-MeOH-H2O水解體系的標(biāo)準(zhǔn)操作To a solution of ester (10 mmol) in MeOH-H2O (30 mL, MeOH:H2O=3:15:1, 甲醇濃度越高，水解能力越強(qiáng)) 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 (若水解不完全就加熱至反應(yīng)完全). Methanol was removed in v

12、acuo 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(yīng)的酸). The c

13、ombined organic extract was dried over MgSO4 and concentrated to afford the desired acid (normal yield 95%).4.1.2 LiOH-MeOH-H2O體系的選擇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 reaction mixture wa

14、s 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 p

15、hase 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- (2003/06/19)4.1.3 KOH-H2O體系的水解示例A mixture of ethyl 3-methylcoumarilate (70 g, 0.34mol

16、) 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

17、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 g, 9095%) which melts at

18、 192193C.Reference: Organic Syntheses: Coll. Vol. 4, 5904.2 酯的酸水解某些情況下對(duì)于一些特定結(jié)構(gòu)的酯需要在酸性條件下進(jìn)行水解，例如叔丁酯和一些對(duì)堿不穩(wěn)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12小時(shí)即可），蒸干溶劑后可直接以鹽的形式進(jìn)行下面的反應(yīng)，而無需進(jìn)一步提純，此時(shí)也可以考慮用酸進(jìn)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(shí)，千萬不能在溶劑處理時(shí)中引入甲醇，乙醇或其他小位阻的醇，否則叔丁酯會(huì)轉(zhuǎn)變?yōu)橄鄳?yīng)的酯。4.2.1 叔

19、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 used to the next reaction d

20、irectly. Reference: US4.2.2 對(duì)堿不穩(wěn)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 was concentrated by heating in

21、 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 added in small portions until the

22、 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 portio

23、ns 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 (5060C) concentrated hydrochloric

24、 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 desi

25、ccator 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鹵代烴轉(zhuǎn)變?yōu)槎鄡蓚€(gè)碳原子的酸的經(jīng)典而有效方法，它借助丙二酸二乙酯這一特定試劑，實(shí)際包括了-H的取代、水解和脫羧三步反應(yīng)。4.3.1 丙二酸二乙酯合成法示例To anhydrous butyl alcohol (2.5 L) was added clean,

26、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 8090C, pure heptyl bromide (913 g

27、, 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 bromide. The mixture was refluxe

28、d 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 occasional shaking, until refluxin

29、g 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 hydrochloric acid (1350 mL, 15.5 mol)

30、 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 evolution of carbon dioxide ceased (a

31、bout 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 flas

32、k having a fractionating side arm, and the material boiling at 140142C/12 mmHg (or 188190/100 mmHg) was collected to give an oil (525590 g, 6675% of the theoretical amount). The melting point of the pure acid was 1212.5C.Reference: Organic Syntheses Coll. Vol. 2, 4745. 酰胺的水解酰胺的活性比羧酸差，因此酰胺的水解一般需要強(qiáng)酸或強(qiáng)

33、堿參與并在加熱的條件下進(jìn)行。酰胺水解也有堿水解和酸水解兩種情況，在有些情況下，加入亞硝酸鈉可以促進(jìn)酰胺水解。由于酰胺直接水解較為強(qiáng)烈，對(duì)于一些復(fù)雜的分子無法使用，因此對(duì)氮上有活潑氫的酰胺可將其衍生化后水解，一般衍生化的方法是用引入Boc，其反應(yīng)如下：以上方法也可用于保護(hù)氨基的酰胺鍵，得到相應(yīng)的Boc保護(hù)的胺：5.1 酰胺直接酸水解示例A suspension of 2-(5-oxo-10,11-dihydrodibenzoa,dcyclohepten-2-yl)propionamide (15 g, 53.7 mmol) in a mixture of sulphuric acid (d =

34、1.36, 50 mL) and water (60 mL) was heated with vigorous stirring for 3 hours at 110C. After cooling, the product which precipitated was filtered off and then added to 2 N sodium hydroxide solution (55 mL). The alkaline solution, clarified by filtration, was acidified by adding 2 N hydrochloric acid

35、(60 mL). The product which precipitated was filtered off, dried and then recrystallized from CCl4 (170 mL) to give 2-(5-oxo-10,11-dihydrodibenzoa,dcyclohepten2-yl)propionic acid (7.4 g, 49.2%) melting at 122C.Reference: US5.2 酰胺直接堿水解示例A solution of 4-(1,1-diphenylpropyl)-picolinamide (3.8 g, 0.012 m

36、ol) in ethanol (50 mL) was added 10% aqueous potassium hydroxide (100 mL) and the resulting mixture was heated at reflux overnight。 The solvent was removed under reduced pressure and the residue was added water then adjusted to about pH 5 with 10% aqueous hydrochloric acid. The resulting solid was f

37、iltered and recrystallized from ethanol to obtain the desired compound of this example (1.6 g, 42.0%) melting at 191193C.Reference: US5.3 亞硝酸鈉促進(jìn)的酰胺酸水解法示例To a solution of 4-carbamoyl-3-methoxyisothiazole (7.9 g, 0.05 mole) in 90 mL of 80% sulfuric acid at 1015C was added slowly beneath the surface of

38、 the liquid a solution of sodium nitrite (9.5 g, 0.137 mol) in water (13 mL). When the addition was complete the solution was allowed to come to 25C and then was heated to 60C for several minutes. After cooling to 25C the reaction solution was poured onto ice to afford 4-carboxy-3-methoxyisothiazole

39、 (3.64 g, 46%) as a white solid melting at 182185C.Reference: US5.4 酰胺的間接水解法示例To a 0.5 M solution of (R)-N-Methyl-3-phenylbutanamide (194 mg, 1.09 mmol) in methylene chloride was added triethylamine (0.15 ml, 1.09mmol), di-tert-butyl dicarbonate (0.5 ml, 2.18 mmol) and 4-(dimethylamino)pyridine (150

40、 mg, 1.11 mmol). The solution was stirred for 8 h at room temperature. The volatiles were removed and the residue was purified by flash chromatogramphy (1/20 (v/v) EtOAc/hexane) to afford the desired (R)-N-Boc-N-Methyl-3-phenylbutanamide (210 mg, 70%).A 0.2 M solution of (R)-N-Boc-N-Methyl-3-phenylb

41、utanamide (175 mg, 0.63 mmol) in THF (4 ml), under N2 atmosphere, was cooled to 0C. To this solution was added 1 N lithium hydroxide (2.0 ml, 2.0 mmol). The reaction mixture was allowed to stir for 6 h. After removal of THF in vacuo, the basic residue was acidified with 5% HCl and extracted with eth

42、er (3 15 ml). The combined ether layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by bulb-to-bulb distillation (110120C/1.2 mmHg) to give the desired (R)-3-phenylbutyric acid (85 mg, 85%).Reference: J. Org. Chem.; 61; 14; 1996; 454245

43、54.6. 腈的水解由于氰基很容易由鹵代烴或重氮鹽與無機(jī)氰化物反應(yīng)引入，因此腈水解是制備羧酸的很重要的方法。腈水解也有酸水解和堿水解兩種情況。腈的酸水解一般都是用濃硫酸在水或水-乙醇的溶劑中進(jìn)行，若用濃鹽酸，經(jīng)常會(huì)停留在酰胺一步。在某些特殊情況下，腈水解也會(huì)停留在酰胺這一步，此時(shí)為了水解完全，可以加入亞硝酸鈉促進(jìn)水解反應(yīng)的進(jìn)行。直接將腈水解為酸的反應(yīng)條件相當(dāng)苛刻，因此并不是一個(gè)很好的辦法，一般來說，是將腈在HCl/MeOH中轉(zhuǎn)化為甲脂，而后再水解，這樣條件就要溫和了很多。6.1 腈的酸水解示例A mixture of water (1150mL), commercial sulfuric ac

44、id (840 mL) and benzyl cyanide (700 g, 6 mol) was heated under a reflux condenser and stirred for three hours, cooled slightly, and then poured into 2 L of cold water. The mixture should be stirred so that a solid cake was not formed; the phenylacetic acid was then filtered off. The crude material w

45、as melted under water and washed by decantation several times with hot water. These washings, on cooling, deposited a small amount of phenylacetic acid which was filtered off and added to the main portion of material. The last of the hot water was poured off from the material while it was still molt

46、en, and it was then transferred to a Claisen distilling flask and distilled under reduced pressure. A small amount of water came over first and was rejected; about 20 mL, containing an appreciable amount of benzyl cyanide, then distils. This fraction was used in the next run. The distillate boiling at 176189/50 mmHg was collected separately and solidified on stan