酯化反應(yīng) 020608

1、經(jīng)典合成反應(yīng)標準操作一酯化反應(yīng)夕藥明康德新藥開發(fā)有限公司經(jīng)典化學(xué)合成反應(yīng)標準操作酯類化合物的合成編者：李少軍藥明康德新藥開發(fā)有限公司化學(xué)合成部目 錄1. 概述： 32. 羧酸酯類化合物的合成： 32.1羧酸和醇的酯化反應(yīng)示例：32.1.1硫酸作催化劑的酯化反應(yīng)示例： 42.1.2鹽酸（氯化氫）作催化劑的酯化反應(yīng)示例： 42.1.3亞硫酰氯作催化劑的酯化反應(yīng)示例： 52.1.4乙酰氯作催化劑的酯化反應(yīng)示例： 52.1.5對甲苯磺酸作催化劑的酯化反應(yīng)示例： 62.1.6吡啶衍生物作除水劑的酯化反應(yīng)示例： 72.1.7苯并三唑衍生物作除水劑的酯化反應(yīng)示例： 82.2羧酸鹽和鹵烴作用的 酯化反應(yīng)示例：

2、 82.3羧酸（或鹽）和硫酸酯、磺酸酯酯化的示例： 92.4酸酐和醇、酚的酯化反應(yīng)示例：衛(wèi)2.5酰氯和醇、酚的酯化反應(yīng)示例：1.22.6酯交換的反應(yīng)示例：1.32.7腈的醇解反應(yīng)示例： 163. 其他酯類化合物的合成： 174 參考文獻：1.8.藥明康德內(nèi)部保密資料71. 概述酯化反應(yīng)最簡單的形式是：R COOH + ROH* R-COOR + H2O（1）也是最常用的制備酯的方法。反應(yīng)（1）速度一般反應(yīng)很慢，在常溫不能覺察；在回流溫度也極其緩慢， 不能用于制備，必須加入催化劑加速它的進行。催化劑中最常用的是酸，如硫酸、 鹽酸等。如果有機酸本身酸性較強，如甲酸、草酸等，以及氨基酸的鹽酸鹽等，

3、酯化時可以不加無機酸酯化反應(yīng)是可逆反應(yīng)。酯化時要把縮合所形成的水不斷除去，以提高酯的產(chǎn)率。除去水的方法有物理方法和化學(xué)方法兩類。物理方法可用恒沸蒸餾法，即在反應(yīng)系統(tǒng)中加入和水不相混溶的溶劑，如苯、 甲苯、二甲苯、四氯化碳、氯仿等。苯：乙醇：水的成分比為74.1: 18.5: 7.4時可形成三組分最低共沸液，沸點為648C ;四氯化碳：乙醇：水的成分比為10: 65： 25時可形成三組分最低共沸液，沸點為 61 C；化學(xué)除水方法可以用無機鹽類，如硫酸銅，它能與水形成水合晶體，但效果 不甚好。硫酸和鹽酸（實際上是無水氯化氫氣體）是催化劑，同時也是除水劑。 有效的除水劑如乙酰氯、亞硫酰氯、氯磺酸等，

4、另外如碳二酰亞胺（R-N = C=N - R）是極好的除水劑，可在室溫下酯化脫水。三氟化硼和它的乙醚復(fù)合物 則既是催化劑又是除水劑，其他的還有利用吡啶衍生物、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脫水的速度要 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. 羧酸酯類化合物的合成依羧酸和醇的性質(zhì)可采用以下方法制?。?羧酸和醇脫水酯化；羧酸鹽和鹵素 作用；羧酸鹽和硫酸酯、磺酸酯作用；酸酐和醇、酚反應(yīng)；酰氯和醇、酚 反應(yīng)；羧酸酯和醇、酚酯交換反應(yīng)；腈的醇解反應(yīng)；2.1羧酸和醇的酯化反應(yīng)示例：2.1.1硫酸作催化劑的酯化反應(yīng)示例：4-Amin

5、o-3-nitrobenzoic acid (200.0 g) was suspendedin ethanol (1030 g). Cone, 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 etha nol was distilled away at atmospheric pressure, and wate

6、r (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 successiv

7、ely with ethanol (531 mL) and water (1069 mL), and dried un der reduced pressure to give ethyl 4-am ino-3-n itrobe nzoate (200.6 g)1.2.1.2鹽酸(氯化氫)作催化劑的酯化反應(yīng)示例：H2NH2NOH巴OH2Netha nolH2NOO3,4-Diami nobe nzoic acid (152 g, 1.0 mol) was stirred with etha nol (2000 mL) in a Morton flask. Hydroge n chloride

8、gas was passedthrough the stirred suspe nsionfor about 2 h. As the gas was absorbed, the slurry became gel-like in character. Etha nol (500 ml.) was added to the react ion mixture to disperse the gel. The react ion mixture was refluxed 24 h. The mixture was filtered and the filtrate was evaporated t

9、o dryn ess in vacuo. The filter cake and the filtrate residue were dissolved in water (9 L). The aqueous soluti on was made basic by the additi on of solid sodium carb on ate. The product precipitated from the basic solution. The material was filtered and dried to yield ethyl 3,4-diaminobenzoate (13

10、0 g, 72.14%2.1.3亞硫酰氯作催化劑的酯化反應(yīng)示例OHTo a suspe nsion of 6-chloropyridi ne-2-carboxylic acid (8.3 g, 0.0525 mol) in dioxa ne (25 mL), thi onyl chloride (9.4 mL, 0.13 mol) was added and the result ing mixture was stirred at 70C for 4 h. The react ion mixture was concen trated in vacuo and a mixture of di

11、oxa ne (8.3 mL) and etha nol (16.6 mL) was added. The react ion mixture was heated to 70c 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 betwee n diethyl ether (28 mL) and water (18 mL) and

12、the phaseswere 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 to3 afford 6-chloropyrid in e-2-carboxylic acid ethyl ester (8.82 g, 91%) as oil .2.1.4乙酰氯作催化劑的酯化反應(yīng)示例：Acetyl chloride (15.3 mmo

13、l) was added dropwise to ethanol (50 mL) at 0 C . After 30 min, the acid (7.69 mmol) was added and the react ion mixture was heated at reflux for 15 h. The react ion mixture was concen trated and the residue was partiti oned betwee n dichlorometha ne (20 mL) and saturated sodium bicarb on ate (10 mL

14、). The aqueous layer was further extracted with dichloromethane (20 mL x 2) and the combined orga nic layers were dried (mag nesium sulfate) and concen trated to provide the ester in 94% yield as brown oil.2.1.5對甲苯磺酸作催化劑的酯化反應(yīng)示例：對甲苯磺酸作酯化催化劑只比硫酸稍弱， 仍是一個強酸，其用量與使用硫酸相等 分子，其作用相等或相近，使用對甲苯磺酸作為酯化催化劑主要是為了避免硫酸

15、 帶來的焦化和其他副反應(yīng)。OHCOOH、TsOH, tolueneOHCO2CH2PhCO2CH2PhA 300-mL, one-n ecked, roun d-bottomed flask was equipped with a magn etic stirrer, Dea n-Stark trap, and a reflux conden ser. 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)

16、of p-toluenesulfonic acid monohydrate and 40 mL of toluene. The mixture was heated under reflux in an oil bath (about 130 c) 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 in

17、to 50 mL of aqueous, saturated sodium bicarb on ate. The orga nic 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 solve nt was removed with a rotary evaporator, and the result ing crude product was tri

18、turated with hexa ne-ether (20:1,210 mL) to give white crystals of (-) -dibenzyl tartrate. The precipitate was collected by filtration and washed with hexa ne-ether (20:1). The filtrate was further concen trated to give a sec ond crop. The total yield was 6.2 g (94%), mp 49-50C 2.1.6吡啶衍生物作除水劑的酯化反應(yīng)示例

19、:經(jīng)典合成反應(yīng)標準操作一酯化反應(yīng)S藥明康德新藥開發(fā)有限公司_N SS N-IPPh 3, benzeneCOOHA. Ricinelaidic acid S-(2-pyridyl)carbothioateIn 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 mm

20、ol) of triphe ny Iphosph ine. The mixture was stirred for 30 mi n. The result ing slurry was the n dissolved in dry acet on itrile (55 mL).B. Rici nelaidic acid lact oneDry acet on itrile (100 mL), 3.5 mL of 1 M silver perchlorate in tolue ne and a magn etic stirring bar were placed in a 500-mL flas

21、k equipped with a reflux condenser that carries a Hershberg dropp ing funn el. The soluti on was heated in an oil bath so that the boili ng acet on itrile returns from the conden ser at the rate of 5 -0 drops per sec ond. Then the acet on itrile soluti on of the ricin elaidic acid S(2-pyridyl)carbot

22、hioate was added dropwise duri ng 1 h through the conden ser to the magn etically stirred reflux ing silver perchlorate solution. The slightly turbid mixture was boiled for an additional 15 min and the solve nt was removed un der reduced pressure in a rotary evaporator. The residue was diluted with

23、30 mL of 0.5 M potassium cyanide solution and the mixture containing suspe nded solids was extracted with three 50-mL porti ons of benzene. The benzene extracts were washed with 30 mL of water, dried with an hydrous magn esium sulfate, and filtered, and the solve nt was removed un der reduced pressu

24、re. 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 -9 contain 283 -296 mg (84 -88%) of ricinelaidic acid lactone6藥明康德內(nèi)部保密資料#經(jīng)典合成反應(yīng)標準操作一酯化反應(yīng)3藥明康德新藥開發(fā)有限

25、公司2.1.6苯并三唑衍生物作除水劑的酯化反應(yīng)示例:Et3N, CH 2CI2OTriethylamine (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 CH2CI2 (8 mL). The reaction mixture was stirred at room temperature for 24

26、h, diluted with CH 2CI2 (30 mL), washed with saturated NaHCO 3 solution (20 mL), dried over MgSO 4, and evaporated to dryness. The crude product was subjected to silica gel colu mn chromatography with hexa ne/ EtOAc (6:1) mixture as an elue nt o afford the dibe nzoate (34 mg, 5%), the primary mon ob

27、e nzoate (390 mg, 83%), and the sec on dary nonoben zoate (42 mg, 9%)2.2羧酸鹽和鹵烴作用的 酯化反應(yīng)示例：羧酸鹽與鹵代烴（或芳側(cè)鏈的鹵代烴）作用生成酯。OM +R-X R + MXRR OM代表金屬，X代表鹵素，或硫酸根、亞硫酸根、磺酸根。羧酸鹽常用的為銀鹽 或鉛鹽，堿金屬鹽、堿土金屬鹽也可以用。 X中最活潑的是碘代物，其次是溴代 物，氯化物一般不常用。硫酸酯等則與酸酸鉀、鈉反應(yīng)比較適宜。反應(yīng)可以在溶劑中進行，常用溶劑如：苯、甲苯、乙酸、乙醇；也可以不用溶劑, 在氧化亞銅、汞鹽、乙酸鉛或其它催化劑存在下加熱（無水條件下）即

28、可酯化。 這種方法一般用來酯化比較貴重、較小量的酸，以及芳族和脂族位阻酸。k2co3,dmfCH3ITo a solution of (4-bromo-2-cyclohexyloxyphenyl)acetic acid (1.33 g) in N,N-dimethylformamide (13 mL) were added K 2CO3 (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

29、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 an hydrous magn esium sulfate and evaporated un der reduced pressure. The residue wa

30、s purified by colu mn chromatography on silica gel (hexa ne/tolue ne=1:1to 1:2) to give ethyl (4-bromo-2-cyclohexyloxyphe nyl)acetate (1.24 g)7.2.3羧酸(或鹽)和硫酸酯、磺酸酯酯化的示例COOHOHMe 2SO4LiOH.H 2O, THFCOOMeOH2- Hydroxy-1- nap hthoic acid (470.5 mg, 2.5 mmol) in dry THF (2.5 mL) was treated with LiOH.H 2O (1

31、04.9 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. Solve nt was distilled off, and the mixture was diluted with saturated aqueousNaHCO3 and the extracted with Et2O to afford the ester (485.16 mg, 96%) as a white solif.Trethyl

32、orthoacetate (16.0 mL, 87 mmol) was added dropwise to a solution of 1-n aphthoic acid (5.0 g, 29 mmol) in tolue ne (35 mL). The react ion mixture was heated at reflux for 24 h. After the mixture has cooled, 2 N HCl (30 mL) was added. The orga nic extract was washed with saturated NaHCQ (30 mL) and b

33、rine (30 mL) and dried with MgSO4. The solve nt was removed in cacuo to give a brow n oil. 藥明康德內(nèi)部保密資料9Kugelrohr distillation of the product at 100 C (0.45 Torr) gives the ethyl ester (5.15 g, 89%)9.2.4酸酐和醇、酚的酯化反應(yīng)示例：ROR OH斗酸酐的?；芰軓?，當(dāng)加入少量的（幾滴）硫酸催化反應(yīng)能在很短的時間內(nèi)完 成，幾乎是定量的。反應(yīng)中，催化劑硫酸提供質(zhì)子，酸酐接受質(zhì)子形成酰基正離 子，與醇、酚

34、完成?；磻?yīng)后又釋出質(zhì)子。O OR人人+ HO R(Ar)ORorTo the above flask, containing 3-nitro-4-hexanol (330 g, 2.24 mol) was added a magnetic stirring egg and 1 mL of cone. sulfuric acid. The contents of the flask were stirred in an ice bath and acetic an hydride (240 g, 2.35 mol) was added in porti ons, keeping the tem

35、perature of the reactants below 60c . After the addition of the acetic an hydride 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 conten

36、ts of the flask 伍 100C bath temperature). After these reagents have been removed, the system was cooled, attached to a vacuum pump, and carefully heated. The fraction boiling at 105-07C /10 mm was collected, affordi ng 4-acetoxy-3-nitrohexa ne (379 g, 90%)0.Ac? OH2SO4NO2經(jīng)典合成反應(yīng)標準操作一酯化反應(yīng)夕藥明康德新藥開發(fā)有限公司I

37、n a 1000mL flask, the n itrodiol (52 g, 0.323 mol) were suspe nded in acetic an hydride (150 mL). Without cooling, 36 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

38、were filtered, washed with water, and air-dried to give the product (75.6 g, 95.6%) of colorless crystal11】OH藥明康德內(nèi)部保密資料175-Hydroxywasophthalic acid (360.56 g, 1.98 mol) was charged to a 2000 mL round bottom 3-n eck flask with a Friedrich conden ser and thermocouple un der a bla nket of n itroge n. A

39、cetic an hydride (808.25 g, 7.96 mol) was added slowly. The white suspension was stirred and refluxed (136C) 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.o294 ml of butyric acid an hydride was treated with addi

40、ti on of 2 ml of concen trated aqueous sulfuric acid at room temperature, and the n 122 g of 3,5-dimethyl-phe nol was added to the solutio n at room temperature. The react ion temperature raised to 40 C and was then raised to 80C . The mixture was stirred for 1 h and diluted with 60 mL of water and

41、60 mL of etha nol, poured onto ice water and twice extracted with 500 mL of hexa ne each time. The hexa ne extract was washed with water, aqueous sodium bicarb on ate solutio n, dried over sodium sulfate and evaporated to give butyryloxy-3, 5-dimethyl-benzene which boils at 123C .-125 C /11 mm Hg af

42、ter rectification13.2.5酰氯和醇、酚的酯化反應(yīng)示例：酰氯是強?；瘎┖痛?、酚作用生成酯的反應(yīng)很迅速，此方法適用于由空間障礙的 酯化。經(jīng)常是在吡啶或其它叔胺參與下反應(yīng)。F3CCOClBzOCH2CI2, 2,6-lutidineOBzOCF3In an oven-dried, 500-mL, two-necked, round-bottomed flask equipped with a magn eticstir bar and a rubber septum was placed1,3,5-tri-O-benzoyl- a-D-ribofuranose (5.0 g, 1

43、0.8 mmol) and 2,6-lutidine (1.4 g, 13.0 mmol) in 200 mL of dry dichlorometha ne un der an argon atmosphere. The reacti on mixture was cooled to 0C 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 reacti on mixt

44、ure was warmed to room temperature and stirred over ni ght. The react ion was que nched with 80 mL of aqueous saturated sodium bicarb on ate, the phases were separated and the aqueous phase was extracted with dichloromethane (200 mL 2). The comb ined orga nic extracts were washed with brine (100 mL

45、2) and driecMover an hydrous magn esium sulfate. After filtrati on, the solve nt was removed un der 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

46、 EtOAc/hexa ne to yield1,3,5-O-tribe nzoyl-2-O(3-trifluoromethyl)benzoyl- - aD-ribofuranose (5.62 g, 82%) as white crystal&4.A mixture of 28.5 g of 4-nitrobe nzoyl chloride, 30.0 g of 3,5-dichlorophe nol a nd 300 mL of pyridine was heated under reflux for 3 h. After completion of the reaction, the p

47、yrid ine was distilled off un der reduced pressure, the rema ining reacti on product was dissolved in ethyl acetate, and the soluti on was washed with water and the n with asaturated aqueous solution of sodium chloride and concentrated under reduced pressure to give crude crystals, which was recryst

48、allized from ethyl acetate to give3,5-dichlorophenyl-4-nitrobenzoate (44.2 g) as needle&5.HTo the mixture of 3-Hydroxy-5-preg n-16-e n-20-one (10 g) in pyrid ine (50 mL) was added p-methylbe nzen esulfo nyl chloride (10 g), and the react ion mixture was stirred at room temperature overnight and then

49、 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 gave3- p-meth

50、ylbenzenesulfonyloxy-5-pregn-16-en-20-one (13.3 g) as off-white prisms 16發(fā)生烷氧基轉(zhuǎn)移，生成另一種2.6酯交換的反應(yīng)示例:酯和另一種過量的醇在少量的堿或酸催化下共熱, 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 C with disstillative removal of the etha nol formed

51、, assisted by a stream of n itroge n. After about 3 h, the react ion mixture was filtered hot in order to remove the Na?CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with petroleum ether and dried to give cyclope ntyl 2-cya no-3, 3-diphe ny lacryl

52、ate (78.1 g, 82%) as a colorless solid17CO -p-TsOHNO2The mixture of 500 mg of 3-acetyloxy-7-(5-n itro-2-pyrid in yl)oxy-1H-i ndene, 5 ml of benzoyl chloride and 15 mg of p-toluenesulfonic acid was stirred at 100 C . After stirring for 1.5 h, ethyl acetate was added to the reaction solution and the s

53、olution was washed in tur n with a saturated sodium hydroge ncarb on ate soluti on and a saturated sodium chloride solution. The solution extracted with ethyl acetate was dried over an hydrous magn esium sulfate and the solve nt was distilled off. The result ing residue was purified by silica gel co

54、lu mn chromatography (elue nt: hexa ne/ethyl acetate=10:1) to obta in 130 mg of 3-be nzoyloxy-7- (5-n itro-2-pyridi nyl) oxy-1H-i ndene as a white.18powder .11H-NMR (CDCI3): 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,

55、2.64 Hz), 9.04 (d, 1H,A soluti on of 6-acetoxycholesta n-3-one (1.215 g, 2.74 mmol) of isoprope nyl acetate (15 mL) was refluxed in the prese nee of p-tolue nesulfo nic acid (20 mg) un der argon for 3 h. Most of the solve nt was removed and the concen trated mixture was extracted with ethyl acetate.

56、 The extract was washed with saturated NaHCO3, and brine, and dried over MgSO4. The residue obta ined upon evaporati on of the solve nt was purified by colum n chromatography on silica gel (40 g) to give 2,6-Diacetoxycholest-2-e ne (1.265 g, 95%)5-Hex ynoic acid (26.9 mg), 40.6 mg of 2-chloro-1,3-di

57、methylimidazoli nium 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 reacti o

58、n soluti on, and the mixture was extracted with dichlorometha ne. The dichlorometha ne layer obta ined was washed with a saturated aqueous sodium hydroge ncarb on ate soluti on and was the n dried over an hydrous sodium sulfate. The solve nt was the n removed by evaporati on un der the reduced pressure. The crude