酯化以及酰胺化.docx

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 hr. 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 495052.5 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-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- -D-ribofuranose (5.62 g, 82%) as white crystals14.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.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 powder18.A 500-mL, one-necked flask equipped with a calcium chloride drying tube was charged with 28.83 g (0.20 mol) of monoethyl fumarate, 200 mL of dry dichloromethane, 44.47 g (0.60 mol) of tert-butyl alcohol, and 2.00 g (0.16 mol) of 4-dimethylaminopyridine. The solution was stirred and cooled in an ice bath to 0C while 45.59 g (0.22 mol) of dicyclohexylcarbodiimide was added over a 5-min period. After a further 5 min at 0C the ice bath was removed and the dark-brown reaction mixture was stirred for 3 h at room temperature. The dicyclohexylurea that has precipitated was removed by filtration through a fritted Bchner funnel(多孔布氏漏斗) (G3), and the filtrate was washed with two 50-mL portions of 0.5 N hydrochloric acid 无化 盐酸and two 50 mL portions of saturated sodium bicarbonate solution(部分饱和碳酸氢钠溶液). During this procedure some additional dicyclohexylurea was precipitated(adj. 沉淀的), which was removed by filtration of both layers to facilitate their separation. The organic solution was dried over anhydrous sodium sulfate(无化 无水硫酸钠) and concentrated with a rotary evaporator. The concentrate was distilled under reduced pressure, affording after a small forerun, 30.532.5 (7681%) of tert-butyl ethyl fumarate, bp 105107C (12 mm)25.25: Organic Syntheses, Coll. Vol. 7, p.93 (1990); Vol. 63, p.183 (1985).例如将a-羟基乙酸及苄胺于90共热， 并蒸出生成的水及过量的苄胺，则生成a-羟基乙酰基苄胺 Rivera L S Z, Darrillo L, Mancilla T. Org. Prep. Proc. Int. 2000, 32 (1), 2952.1.4应用的磺酰氯合成酰胺示例A mixture of the benzoic acid (10 mmol), 4-methylbenzene-1-sulfonyl chloride (10 mmol), K2CO3 (5.52 g, 40 mmol) and TEBAC (0.23 g, 1mmol) in 60 mL of benzene is stirred at reflux for 40 min. Then ethyl 2-aminoacetate (10 mmol) is added and stirring is continued for 10 min at reflux temperature. The precipitate is filtered off, and the filtrate is evaporated under reduced pressure. The carboxamide 8 thus obtained is crystallized from MeOH to afford the pure product (yield 82%).2.2碳二亚胺类缩合剂法利用碳二亚胺类缩合剂缩合制备酰胺在药物合成中应用极为广泛，目前常用的缩合剂主要有三种：二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)和1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)。使用该类的缩合剂一般需要加入酰化催化剂或活化剂，如4-N,N-二甲基吡啶（DMAP）、1-羟基苯并三氮唑(HOBt)等等，其主要由于在反应的第一阶段酸对碳二亚胺的加成中间体其并不稳定，若不用酰化催化剂转化为相应的活性酯或活性酰胺，其自身会通过重排成相应的稳定的脲的副产物 (Path b).常用的缩合活化剂有以下几种，目前4-N,N-二甲基吡啶（DMAP）已被广泛应用于催化各种酰化反应。有时在用DMAP催化效果不好时，可采用4-PPY，据相关文献报道其催化能力要比DMAP高千倍左右。在三个常用的缩合剂DCC、DIC和EDCI中， DCC和DIC的价格较为便宜，一般DCC和DMAP合用，使用DCC有一个最大的缺点就是反应的另一产物二环己基脲在一般的有机相溶解度很小但又都有一些微溶，因此通过一些常用的纯化方法，重结晶，柱层析等等很难将其除得很彻底；由于二环己基脲在乙醚中的溶解度相对要比其他溶剂小， 因此处理这类反应一般蒸掉反应溶剂后加入乙醚，滤掉大部分的二环己基脲后再进一步处理。DIC由于其产生的二异丙基脲在有一般的有机溶剂中溶解度较好，因此一般在组合化学的固相合成中用的较多。目前，在药物化学中用的最多的还是EDCI，其一个主要的特点就是其反应后的生成的脲是水溶性的，很容易被洗掉，一般EDCI与HOBt合用（注意: 这一反应HOBt一般是缺不了的，否则有可能导致缩合产率太低）。有时如果酸的a-位位阻大或者连有吸电子基团，反应会停留在活性酯这一步（这一活性酯的质谱信号较强，可通过MS或LC-MS检测到）。由于HOBt也是水溶性的，其使得反应的处理和纯化相对要容易。一般在这一缩合中要加入碱，特别当用胺或氨基酸的盐酸盐等缩合，常用的是加2-3当量的N-甲基吗啡啉或二异丙基乙胺（DIEA, Hunig base）, 缩合时以二氯甲烷为溶剂，若底物的溶解度不好，可用DMF作反应溶剂，再使用该方法进行。2.2.1应用DCC缩合法合成酰胺示例To a solution of compound 11 (4.06 g, 10 mmol) in DMF (150 mL) was added N-hydroxybenzotriazole (HOBt, 5.64 g, 42 mmol), followed by dicyclohexylcarbodiimide (DCC; 8.60 g, 42 mmol). After stirring for l h, a solution of di-tert-butyl 4-amino-4-2-(tert-butoxycarbonyl)ethylheptanedioate 5 (17.34 g, 41.7 mmol) in DMF (60 mL) was added and the solution stirred at 25 for 23 h. The crystals were filtered and washed on the filter with DMF (25 mL). The solvent was distilled at 50/1mm, and the residual oil was dissolved in ether (600 mL). Crystals were filtered, the ethereal solution was washed successively with 10% HCl (2 x100 mL), saturated NaHCO3 (2 x 100 mL), and brine (2 x 50 mL), then dried (Na2SO4). The ether solution was filtered through celite and solvent was then removed in vacuo to afford 19.0 g of crude product, which was purified on a silica column eluting with toluene/EtOAc (1:1) to furnish (60%) the white, non-crystalline ester 12: 14.0 g; mp 55-60. 1H NMR 1.43 (s, CH3, 108H), 1.94-2.28 (m, CH2CH2, 64H), 5.87 (s, NH, 4H), 6.17 (s, CH=CH, 2H); 13C NMR (DMSO-d6) 28.3 (CH3), 29.3 (CH2CH2), 56.8 (CNH), 69.0 (CSO2), 171.1 (CO), 171.4 (CO). 应用DIC缩合法合成酰胺示例To a solution of amine 13 (106 mg, 0.3 mmol), Fmoc-Phe-OH (116 mg, 0.3 mmol), and HOBt (44.8 mg, 0.33 mmol) in anhydrous DMF (2 mL) was added DIC (56 L, 0.36 mmol). The resulting mixture was stirred at room temperature overnight, and DMF was then evaporated under high vacuum. The residue was dissolved in ethyl acetate (10 mL), washed sequentially with saturated aqueous NaHCO3 and brine, and then dried over Na2SO4. The evaporation of the solvent gave the crude product that was directly submitted for the Fmoc removal without purification. The crude product was dissolved in DMF (8 mL), piperidine (2.0 mL) was added, and the resulting solution was stirred at room temperature for 1 h. Following the solvent evaporation, the residue was purified by silica gel chromatography (50% ethyl acetate in hexanes to 10% methanol in chloroform) to provide product 14 (128 mg) in 85% yield as a mixture of two diastereomers. 1H NMR (CDCl3, 400 MHz) 8.12-8.00 (2H, m), 7.90-7.80 (2H, m), 7.70-7.54 (2H, m), 7.42 (2H, m), 7.35-7.20 (2H, m), 6.97-6.83 (3H, m), 5.32 (1H, m), 4.32 (1H, m), 4.20-4.03 (2H, m), 3.96-3.80 (2H, m), 3.60 (1H, m), 2.98 (3H, m), 2.88 (2H, s), 2.60 (1H, s), 2.00 (1H, m), 1.85 (2H, m), 1.77-1.55 (3H, m); MS (ES+) m/z ) 501.4 (M + 1).2.2.3应用EDC缩合法合成酰胺示例一 （二氯甲烷为溶剂）To a solution of amine16 (0.284 mg, 1.19 mmol) and 5-hexenoic acid 15(0.136 g, 1.19 mmol) in CH2Cl2 (12.0 ml) at 0 were added HOBt (0.177 g, 1.31 mmol) and EDC (0.251 g, 1.31 mmol). The reaction mixture was stirred at room temperature for 10 h, then washed with 5% aqueous HCl (315.0 ml), 5% aqueous NaHCO3 (20 .0 ml), H2O (20.0 ml), and brine (20.0 ml), and dried (Na2SO4). Purification by flash chromatography (CH3Cl/MeOH, 10%, Rf = 0.43) afforded amidoalkene 17 in 99% yield as a brown oil. 2.2.4应用EDC缩合法合成酰胺示例二 （DMF为溶剂）A DMF solution (10 mL) containing HOBt (103 mg, 0.76 mmol), EDC (192 mg, 1.0 mmol), and Boc-D-Ile (172 mg, 0.76 mmol) was stirred at room temperature for 20 h. A solution of the amino ketal 18 (0.41 g, 0.76 mmol) and 4-methylmorpholine (0.17 mL, 1.5 mmol) dissolved in 10 mL of DMF was then added to the reaction mixture. After 4 h the reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed with H2O, dried over MgSO4, and concentrated under reduced pressure. Flash chromatography (4:1 EtOAc/hexanes) afforded the Boc ketal 19 (0.44 g, 0.59 mmol, 78%). .1酰卤的制备示例3.5.1应用二氯亚砜合成酰氯示例Fit a 100 mL two-necked flask with a dropping funnel and a reflux condenser connected at the top to a gas absorption trap. Place 36 g (21.5 mL, 0.3 mol) of redistilled thionyl chloride in the flask and 22 g (23mL, 0.25 mol) of butyric acid in the separatory funnel. Heat the flask gently on a water bath, and add the butyric acid during the course of 30-40 minutes. When all the acid has been introduced, heat was on a water bath for 30 minutes. Rearrange the apparatus and distillation: collect the crude acid chloride boiling between 70 and 110 . Finally, restil from a flask provided with a short fractionating column and collect the butyryl chloride at 100-101 . The yield is 23 g (86 %).Note: Wrap a piece of absorbent cotton wool around the stem of the reflux condenser above the joint of the reaction flask to prevent condensed3.5.2用草酰氯合成酰氯示例Compound 42 (4.19 g, 13.94 mmol) was dissolved in 20 mL CH2Cl2, oxalyl chloride (4.25 mL, 48.40 mmol) was added at room temperature, the resultant mixture was stirred at room temperature for 30 min and then the mixture was gently warmed under reflux for 30 min. After the mixture was concentrated in vacuo, the residue was dissolved in THF, and the solution was again concentrated in vacuo to offer quantitatively the crude chloride 43.应用酰卤的合成酰胺3.5.1应用酰氯合成酰胺示例（有机碱）To a solution of 47 (1.09 g, 3.00 mmol) was added pyridine (1.50 g, 18.96 mmol), followed by dropwise addition of phenylacetyl chloride (0.93 g, 6.00 mmol) in CH2Cl2 (20 mL). The solution was stirred for 2h. at 25C, then it was washed successively with 10% HCl, 10% NaHCO3 and water, dried (MgSO4), filtered and the solvent was then evaporated to give the impure amide which was recrystallized from ethanol to give N-(-carboethoxy-phenylethyl)-3-phenylacetylamino-4-styryl-2-azetidinone (48, 3.86g, 80%)。3.5.2应用酰氯合成酰胺示例（无机碱）A mixture containing 8.21 g of phenylalanine, 5.565 g of Na2CO3 in 40 mL of water and 20 mL of tetrahydrofuran (THF) was stirred at room temperature. benzoyl chloride (7.73 g), dissolved in 20 mL of anhydrous THF, was added gradually over a period of 45 minutes with continued stirring at room temperature. Stirring was allowed to continue for an additional hour, at which time the reaction mixture was transferred to a rotary evaporator at 30 to remove the THF. An excess of water was then added and the reaction mixture extracted four times with ethyl acetate. The aqueous phase was then titrated to PH 2 with 3N HCl. A white crystalline precipitate formed which was recovered by filtration, washed three times with cold dilute HCl and three times with cold water, and dried in a vacuum oven over P2O5 at about 50. The product was recrystallized from aqueous ethanol, yielding 8.37 g, m.p. 183.-184., which migrated as a single compound on thin layer chromatography in five separate solvent systems. In this reaction sequence the racemate is obtained. If a NaOH solution is used in place of the Na2CO3 in this example and the procedure set forth in Carter, H. E. et al, J. Biol. Chem. 138, 627 (1941) is substantially