酯化反应-020608

酯类化合物的合成 严家庆 技术部 实验员 目 录 1.概述： 　３ 2. 羧酸酯类化合物的合成： ３ 2.1 羧酸和醇的酯化反应示例： ３ 2.1.1 硫酸作催化剂的酯化反应示例： ４ 2.1.2 盐酸（氯化氢）作催化剂的酯化反应示例： ４ 2.1.3 亚硫酰氯作催化剂的酯化反应示例： ５ 2.1.4 乙酰氯作催化剂的酯化反应示例： ５ 2.1.5 对甲苯磺酸作催化剂的酯化反应示例： ６ 2.1.6 吡啶衍生物作除水剂的酯化反应示例： ７ 2.1.7 苯并三唑衍生物作除水剂的酯化反应示例： ８ 2.2 羧酸盐和卤烃作用的 酯化反应示例： ８ 2.3 羧酸（或盐）和硫酸酯、磺酸酯酯化的示例： ９ 2.4 酸酐和醇、酚的酯化反应示例： １０ 2.5 酰氯和醇、酚的酯化反应示例： １２ 2.6 酯交换的反应示例： １３ 2.7 腈的醇解反应示例： １６ 3. 其他酯类化合物的合成： １７ 4．参考文献： １８ 1.概述 酯化反应最简单的形式是： （1） 也是最常用的制备酯的方法。 反应（1）速度一般反应很慢，在常温不能觉察；在回流温度也极其缓慢，不能用于制备，必须加入催化剂加速它的进行。催化剂中最常用的是酸，如硫酸、盐酸等。如果有机酸本身酸性较强，如甲酸、草酸等，以及氨基酸的盐酸盐等，酯化时可以不加无机酸 酯化反应是可逆反应。 酯化时要把缩合所形成的水不断除去，以提高酯的产率。除去水的方法有物理方法和化学方法两类。 物理方法可用恒沸蒸馏法,即在反应系统中加入和水不相混溶的溶剂，如苯、甲苯、二甲苯、四氯化碳、氯仿等。苯：乙醇：水的成分比为74.1：18.5：7.4时可形成三组分最低共沸液，沸点为64.8℃；四氯化碳：乙醇：水的成分比为10：65：25时可形成三组分最低共沸液，沸点为61℃； 化学除水方法可以用无机盐类，如硫酸铜，它能与水形成水合晶体，但效果不甚好。硫酸和盐酸（实际上是无水氯化氢气体）是催化剂，同时也是除水剂。有效的除水剂如乙酰氯、亚硫酰氯、氯磺酸等，另外如碳二酰亚胺（R－N＝C＝N－R）是极好的除水剂，可在室温下酯化脱水。三氟化硼和它的乙醚复合物则既是催化剂又是除水剂，其他的还有利用吡啶衍生物、苯并三唑衍生物等。 酯化速度，在醇方面伯醇＞仲醇＞叔醇，叔醇的酯化一般要比脱水的速度要慢，因此用通常的酯化方法得到的是烯而不是酯；在酸方面，脂肪族酸＞芳香族酸。 2. 羧酸酯类化合物的合成 依羧酸和醇的性质可采用以下方法制取：①羧酸和醇脱水酯化；②羧酸盐和卤素作用；③羧酸盐和硫酸酯、磺酸酯作用；④酸酐和醇、酚反应；⑤酰氯和醇、酚反应；⑥羧酸酯和醇、酚酯交换反应；⑦腈的醇解反应； 2.1 羧酸和醇的酯化反应示例： 2.1.1 硫酸作催化剂的酯化反应示例： 4-Amino-3-nitrobenzoic acid (200.0 g) was suspended in ethanol (1030 g). Conc. sulfuric acid (120.0 g) was added dropwise to the mixture over 0.5 h. After the dropwise addition, the mixture was refluxed under heating for 15 h. A part (422 mL) of ethanol was distilled away at atmospheric pressure, and water (660 mL) was added dropwise to allow precipitation of crystals. To this suspension were added 25% aqueous sodium hydroxide solution (50 mL) and then 2.5% aqueous sodium hydroxide solution (262 mL), and pH was adjusted to 6.5. The precipitated crystals were collected by filtration, washed successively with ethanol (531 mL) and water (1069 mL), and dried under reduced pressure to give ethyl 4-amino-3-nitrobenzoate (200.6 g)[1]. 2.1.2 盐酸（氯化氢）作催化剂的酯化反应示例： 3,4-Diaminobenzoic acid (152 g, 1.0 mol) was stirred with ethanol (2000 mL) in a Morton flask. Hydrogen chloride gas was passed through the stirred suspension for about 2 h. As the gas was absorbed, the slurry became gel-like in character. Ethanol (500 ml.) was added to the reaction mixture to disperse the gel. The reaction mixture was refluxed 24 h. The mixture was filtered and the filtrate was evaporated to dryness in vacuo. The filter cake and the filtrate residue were dissolved in water (9 L). The aqueous solution was made basic by the addition of solid sodium carbonate. The product precipitated from the basic solution. The material was filtered and dried to yield ethyl 3,4-diaminobenzoate (130 g, 72.14%)[2] 2.1.3 亚硫酰氯作催化剂的酯化反应示例 To a suspension of 6-chloropyridine-2-carboxylic acid (8.3 g, 0.0525 mol) in dioxane (25 mL), thionyl chloride (9.4 mL, 0.13 mol) was added and the resulting mixture was stirred at 70℃ for 4 h. The reaction mixture was concentrated in vacuo and a mixture of dioxane (8.3 mL) and ethanol (16.6 mL) was added. The reaction mixture was heated to 70℃ for 2 h, triethylamine (8.3 mL), ethanol (4.1 mL) and water (8.3 mL) were added and the reaction mixture was again concentrated. The residue was distributed between diethyl ether (28 mL) and water (18 mL) and the phases were separated. The aqueous layer was extracted with diethyl ether (30 mL) and the combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to afford 6-chloropyridine-2-carboxylic acid ethyl ester (8.82 g, 91%) as oil [3]. 2.1.4 乙酰氯作催化剂的酯化反应示例： Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0℃. After 30 min, the acid (7.69 mmol) was added and the reaction mixture was heated at reflux for 15 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (20 mL) and saturated sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (20 mL × 2) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the ester in 94% yield as brown oil[4]. 2.1.5 对甲苯磺酸作催化剂的酯化反应示例： 对甲苯磺酸作酯化催化剂只比硫酸稍弱，仍是一个强酸，其用量与使用硫酸相等分子，其作用相等或相近，使用对甲苯磺酸作为酯化催化剂主要是为了避免硫酸带来的焦化和其他副反应。 A 300-mL, one-necked, round-bottomed flask was equipped with a magnetic stirrer, Dean-Stark trap, and a reflux condenser. The flask was charged with 3.0 g (20 mmol) of L-(+)-tartaric acid, 6.5 g (60 mmol) of benzyl alcohol, 47.5 mg (0.25 mmol) of p-toluenesulfonic acid monohydrate and 40 mL of toluene. The mixture was heated under reflux in an oil bath (about 130℃) for 13 h. During this period the theoretical amount of water (0.62 mL) was collected. The mixture was allowed to cool to ambient temperature, diluted with ether, and poured into 50 mL of aqueous, saturated sodium bicarbonate. The organic phase was separated and the aqueous phase was extracted twice with 20 mL of ether. The combined organic phases were dried over sodium sulfate. The solvent was removed with a rotary evaporator, and the resulting crude product was triturated with hexane-ether (20:1, 210 mL) to give white crystals of (−)-dibenzyl tartrate. The precipitate was collected by filtration and washed with hexane-ether (20:1). The filtrate was further concentrated to give a second crop. The total yield was 6.2 g (94%), mp 49–50℃[5] 2.1.6 吡啶衍生物作除水剂的酯化反应示例： A. Ricinelaidic acid S-(2-pyridyl)carbothioate In a dry, stoppered, 10-mL flask containing a magnetic stirring bar were placed 360 mg (1.2 mmol) of ricinelaidic acid, 2,2'-dipyridyl disulfide (308 mg, 1.4 mmol), benzene (1 mL), and 367 mg (1.4 mmol) of triphenylphosphine. The mixture was stirred for 30 min. The resulting slurry was then dissolved in dry acetonitrile (55 mL). B. Ricinelaidic acid lactone Dry acetonitrile (100 mL), 3.5 mL of 1 M silver perchlorate in toluene and a magnetic stirring bar were placed in a 500-mL flask equipped with a reflux condenser that carries a Hershberg dropping funnel. The solution was heated in an oil bath so that the boiling acetonitrile returns from the condenser at the rate of 5–10 drops per second. Then the acetonitrile solution of the ricinelaidic acid S-(2-pyridyl)carbothioate was added dropwise during 1 h through the condenser to the magnetically stirred refluxing silver perchlorate solution. The slightly turbid mixture was boiled for an additional 15 min and the solvent was removed under reduced pressure in a rotary evaporator. The residue was diluted with 30 mL of 0.5 M potassium cyanide solution and the mixture containing suspended solids was extracted with three 50-mL portions of benzene. The benzene extracts were washed with 30 mL of water, dried with anhydrous magnesium sulfate, and filtered, and the solvent was removed under reduced pressure. Crude product was obtained as an oil (710 mg). It can be purified by chromatography on 40 g of silica gel with benzene as eluant. Fractions of 10 mL were collected at 30 min intervals. Fractions 7–19 contain 283–296 mg (84–88%) of ricinelaidic acid lactone [6]. 2.1.6 苯并三唑衍生物作除水剂的酯化反应示例： Triethylamine (305ul, 2.2 mmol) was added at room temperature to a stirred solution of 1-phenyl-1, 2-ethanediol (280 mg, 2.0 mmol) and 1-(benzolyoxy)benzotriazole (503 mg, 2.1 mmol) in CH2Cl2 (8 mL). The reaction mixture was stirred at room temperature for 24 h, diluted with CH2Cl2 (30 mL), washed with saturated NaHCO3 solution (20 mL), dried over MgSO4, and evaporated to dryness. The crude product was subjected to silica gel column chromatography with hexane/ EtOAc (6:1) mixture as an eluent o afford the dibenzoate (34 mg, 5%), the primary monobenzoate (390 mg, 83%), and the secondary nonobenzoate (42 mg, 9%) 2.2 羧酸盐和卤烃作用的 酯化反应示例： 羧酸盐与卤代烃（或芳侧链的卤代烃）作用生成酯。 M代表金属，X代表卤素，或硫酸根、亚硫酸根、磺酸根。羧酸盐常用的为银盐或铅盐，碱金属盐、碱土金属盐也可以用。X中最活泼的是碘代物，其次是溴代物，氯化物一般不常用。硫酸酯等则与酸酸钾、钠反应比较适宜。 反应可以在溶剂中进行，常用溶剂如：苯、甲苯、乙酸、乙醇；也可以不用溶剂，在氧化亚铜、汞盐、乙酸铅或其它催化剂存在下加热（无水条件下）即可酯化。这种方法一般用来酯化比较贵重、较小量的酸，以及芳族和脂族位阻酸。 To a solution of (4-bromo-2-cyclohexyloxyphenyl)acetic acid (1.33 g) in N,N-dimethylformamide (13 mL) were added K2CO3 (0.88 g) and iodomethane (1.33 g) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 2.5 d. The resulting mixture was poured into water and the aqueous layer was extracted with a mixture of hexane and ethyl acetate (1:1). The organic layer was washed successively with water (twice) and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/toluene=1:1 to 1:2) to give ethyl (4-bromo-2-cyclohexyloxyphenyl)acetate (1.24 g)[7]. 2.3 羧酸（或盐）和硫酸酯、磺酸酯酯化的示例 2-Hydroxy-1-naphthoic acid (470.5 mg, 2.5 mmol) in dry THF (2.5 mL) was treated with LiOH.H2O (104.9 g, 2.5 mol) at room temperature for 30 min followed with Me2SO4 (0.24 mL, 2.5 mol), and the mixture was heated for 3 h. Solvent was distilled off, and the mixture was diluted with saturated aqueous NaHCO3 and the extracted with Et2O to afford the ester (485.16 mg, 96%) as a white solid [8]. Trethyl orthoacetate (16.0 mL, 87 mmol) was added dropwise to a solution of 1-naphthoic acid (5.0 g, 29 mmol) in toluene (35 mL). The reaction mixture was heated at reflux for 24 h. After the mixture has cooled, 2 N HCl (30 mL) was added. The organic extract was washed with saturated NaHCO3 (30 mL) and brine (30 mL) and dried with MgSO4. The solvent was removed in cacuo to give a brown oil. Kugelrohr distillation of the product at 100℃ (0.45 Torr) gives the ethyl ester (5.15 g, 89%)[9]. 2.4 酸酐和醇、酚的酯化反应示例： 酸酐的酰化能力很强，当加入少量的（几滴）硫酸催化反应能在很短的时间内完成，几乎是定量的。反应中，催化剂硫酸提供质子，酸酐接受质子形成酰基正离子，与醇、酚完成酰化反应后又释出质子。 To the above flask, containing 3-nitro-4-hexanol (330 g, 2.24 mol) was added a magnetic stirring egg and 1 mL of conc. sulfuric acid. The contents of the flask were stirred in an ice bath and acetic anhydride (240 g, 2.35 mol) was added in portions, keeping the temperature of the reactants below 60℃. After the addition of the acetic anhydride was complete, the contents of the flask were stirred for 1 h. The flask was then equipped for vacuum distillation. The lower boiling components (Ac2O and AcOH) were removed at 25 mm by gently heating the stirred contents of the flask (≤100℃ bath temperature). After these reagents have been removed, the system was cooled, attached to a vacuum pump, and carefully heated. The fraction boiling at 105–107℃/10 mm was collected, affording 4-acetoxy-3-nitrohexane (379 g, 90%)[10]. In a 1000mL flask, the nitrodiol (52 g, 0.323 mol) were suspended in acetic anhydride (150 mL). Without cooling, 3~6 drops of concentrated sulfuric acid were added. After stirring for 1 h, 500 mL of ice/water was rapidly added and stirring was continued for 60 min. The resulting colorless crystals were filtered, washed with water, and air-dried to give the product (75.6 g, 95.6%) of colorless crystals [11]. 5-Hydroxywasophthalic acid (360.56 g, 1.98 mol) was charged to a 2000 mL round bottom 3-neck flask with a Friedrich condenser and thermocouple under a blanket of nitrogen. Acetic anhydride (808.25 g, 7.96 mol) was added slowly. The white suspension was stirred and refluxed (~136℃) for 4 h. After cooling the white solid was filtered off and washed with toluene to afford 5-acetoxywasophthalic acid (336.95 g, 76%)[12]. 294 ml of butyric acid anhydride was treated with addition of 2 ml of concentrated aqueous sulfuric acid at room temperature, and then 122 g of 3,5-dimethyl-phenol was added to the solution at room temperature. The reaction temperature raised to 40℃ and was then raised to 80℃. The mixture was stirred for 1 h and diluted with 60 mL of water and 60 mL of ethanol, poured onto ice water and twice extracted with 500 mL of hexane each time. The hexane extract was washed with water, aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated to give butyryloxy-3, 5-dimethyl-benzene which boils at 123℃.-125℃/11 mm Hg after rectification[13]. 2.5 酰氯和醇、酚的酯化反应示例： 酰氯是强酰化剂和醇、酚作用生成酯的反应很迅速，此方法适用于由空间障碍的酯化。经常是在吡啶或其它叔胺参与下反应。 In an oven-dried, 500-mL, two-necked, round-bottomed flask equipped with a magnetic stir bar and a rubber septum was placed 1,3,5-tri-O-benzoyl-α-D-ribofuranose (5.0 g, 10.8 mmol) and 2,6-lutidine (1.4 g, 13.0 mmol) in 200 mL of dry dichloromethane under an argon atmosphere. The reaction mixture was cooled to 0℃ and 3-(trifluoromethyl)benzoyl chloride (3.3 g, 16.2 mmol) was added dropwise to the stirred solution over 30 min. After the addition, the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with 80 mL of aqueous saturated sodium bicarbonate, the phases were separated and the aqueous phase was extracted with dichloromethane (200 mL × 2). The combined organic extracts were washed with brine (100 mL × 2) and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure to give yellow oil. Purification by flash column chromatography (140 g of silica gel) and eluting with 25% ethyl acetate in hexanes gives a white solid that can be recrystallized from EtOAc/hexane to yield 1,3,5-O-tribenzoyl-2-O[(3- trifluoromethyl)benzoyl]- -α-D-ribofuranose (5.62 g, 82%) as white crystals[14]. A mixture of 28.5 g of 4-nitrobenzoyl chloride, 30.0 g of 3,5-dichlorophenol and 300 mL of pyridine was heated under reflux for 3 h. After completion of the reaction, the pyridine was distilled off under reduced pressure, the remaining reaction product was dissolved in ethyl acetate, and the solution was washed with water and then with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure to give crude crystals, which was recrystallized from ethyl acetate to give 3,5-dichlorophenyl-4-nitrobenzoate (44.2 g) as needles [15]. To the mixture of 3-Hydroxy-5-pregn-16-en-20-one (10 g) in pyridine (50 mL) was added p-methylbenzenesulfonyl chloride (10 g), and the reaction mixture was stirred at room temperature overnight and then poured into dilute hydrochloric acid. The precipitate was extracted into chloroform, and the extract was washed with dilute hydrochloric acid and with water, dried over sodium sulphate and evaporated to an oil which crystallized on standing. Recrystallisation from ethyl acetate/petrol gave 3-p-methylbenzenesulfonyloxy-5-pregn-16-en-20-one (13.3 g) as off-white prisms [16]. 2.6 酯交换的反应示例： 酯和另一种过量的醇在少量的碱或酸催化下共热，发生烷氧基转移，生成另一种酯。 A mixture of Ethyl 2-cyano-3,3-diphenylacrylate (83.1 g，0.3 mol), cyclopentanol (100 mL) and Na2CO3 (6 g) were heated at 145℃ with disstillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 3 h, the reaction mixture was filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with petroleum ether and dried to give cyclopentyl 2-cyano-3, 3-diphenylacrylate (78.1 g, 82%) as a colorless solid [17]. The mixture of 500 mg of 3-acetyloxy-7-[(5-nitro-2-pyridinyl)oxy]-1H-indene, 5 ml of benzoyl chloride and 15 mg of p-toluenesulfonic acid was stirred at 100℃. After stirring for 1.5 h, ethyl acetate was added to the reaction solution and the solution was washed in turn with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution. The solution extracted with ethyl acetate was dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10:1) to obtain 130 mg of 3-benzoyloxy-7- [(5-nitro-2-pyridinyl) oxy]-1H-indene as a white powder[18]. 1H-NMR (CDCl3): 3.34 (d, 2H, 2.31 Hz), 6.52 (t, 1H, J=2.31 Hz), 7.06-7.12 (m, 2H), 7.38-7.70 (m, 5H), 8.23-8.27 (m, 2H), 8.51 (dd, 1H, J=8.91, 2.64 Hz), 9.04 (d, 1H, J=2.64 Hz) A solution of 6-acetoxycholestan-3-one (1.215 g, 2.74 mmol) of isopropenyl acetate (15 mL) was refluxed in the presence of p-toluenesulfonic acid (20 mg) under argon for 3 h. Most of the solvent was removed and the concentrated mixture was extracted with ethyl acetate. The extract was washed with saturated NaHCO3, and brine, and dried over MgSO4. The residue obtained upon evaporation of the solvent was purified by column chromatography on silica gel (40 g) to give 2,6-Diacetoxycholest-2-ene (1.265 g, 95%)[19]. 5-Hexynoic acid (26.9 mg), 40.6 mg of 2-chloro-1, 3-dimethylimidazolinium chloride and 37.9 mg of pyridine were stirred in dichloromethane (10 mL) at room temperature for one h. Thereafter, 50 mg of 2,3-dimethyl-4-hydroxy-5, 6-difluoroquinoline was added thereto, and the mixture was stirred at room temperature for 15 h. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The dichloromethane layer obtained was washed with a saturated aqueous sodium hydrogencarbonate solution and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (10 g; elution solvent: hexane/ EtOAc=10:1) to give 77.8 mg of 2,3-dimethyl-4- (5-hexynoylcarbonyloxy)-5,6-fluroq uinoline[20]. To the solution of Biotin (1.0 g, 4.1 mmol) in 20 mL of DMF, triethylamine (1 mL, 8 mmol) was added followed by the addition of 2,3,5,6-tetrafhtororophenyl trifluoroacetate (1.76 g, 1 mmol) under argon atmosphere at 25℃. The reaction mixture was stirred at room temperature for 30 min and the solvent was removed under vacuum. The product was triturated in 10 mL of ether and filtered. The isolated product was dried under vacuum to yield biotin TFP ester (1.3 g, 80%) as a colorless solid [21]. 2.7 腈的醇解反应示例： 在酸催化下，氰基可以醇解直接生成酯。通常使用的催化剂是浓硫酸或氯化氢，只适用于伯醇，因为叔醇和仲醇在硫酸作用下会生成烯，硫酸和释放出的氨成盐。 腈的醇解，醇兼作溶剂，其用量比较大，一般是理论量的4～5倍；硫酸的用量也要超过理论用量的0.5～1倍。 1-(4-Cyanophenyl)-piperazine (11 mmol) was dissolved in 5 N a solution of concentrated sulfonic acid and methanol (15 ml) and stirred in a sealed tube at 110℃for 3 h. After evaporation of the solvent, the residue was dissolved in water and extracted with ethyl acetate. Addition of sodium carbonate to the water phase until pH 9 results in the precipitation of a white solid which was filtered off and dried (vacuum). A white powder with Rf 0.59 (CH2Cl2/MeOH = 9:1) was obtained. 4-piperazin-1-yl-benzoic acid methyl ester [22]. 1-[2,2-Bis(4-cyanobenzylthio)ethyl]-1H-imidazole hydrochloride (1.43 g) was added to methanol (50 mL) which had been saturated with hydrogen chloride at 0℃. The resulting solution was stirred under reflux for 20 h and then concentrated. The gummy residue was partitioned between CH2Cl2 and aqueous NaHCO3, and the CH2Cl2 layer was washed with brine and dried over Na2SO4. Removal of the CH2Cl2 left a gum which was hromatographed on silicic acid (60 g) with CH2Cl2 /CH3OH (95:5), to afford 1.1 g of the free base of the title compound as a viscous oil. Treatment of a solution of the base in CH3OH-ether with hydrogen chloride provided colorless crystals