1、药明康德内部保密资料经典化学合成反应标准操作醇的制备编者：李荣坡 王锋 雷庭军药明康德新药开发有限公司化学合成部经典合成反应标准操作醇的制备 药明康德新药开发有限公司药明康德内部保密资料 Page 1 of 62目 录1. 羧酸酯和羧酸还原为醇31.1 羧酸酯还原成醇31.1.1 金属钠和醇为还原剂（Bouveault-Blanc 反应） 31.1.2 金属氢化物为还原剂41.2 羧酸还原为醇71.2.1 氢化铝锂还原羧酸为醇71.2.2 硼烷还原羧酸为醇81.2.3 Lewis 酸存在下硼氢化钠还原羧酸为醇101.2.4 硼氢化钠还原活性酯或酰氟为醇112. 卤代烃的水解反应制备醇132.1
2、 在碱性水溶液中，脂肪组卤代烃的卤原子被羟基取代生成醇 133. 醛和酮转变成醇173.1 醛和酮的加氢还原173.2 金属还原183.3 金属氢化物还原223.3.1 反应机理223.3.2 试剂的主要性质及反应条件233.4 醇铝还原剂还原（Meerwein-Ponndorf-Verley 反应）263.4.1 反应机理及影响反应的因素264通过有机金属试剂对醛、酮、环氧、及羧酸衍生物加成反应得到 醇294.1 有机金属试剂对醛制备仲醇304.2 有机金属试剂对酮加成制备叔醇314.3 有机金属试剂对环氧加成制备醇334.4 有机金属试剂对酸加成制备叔醇344.5 有机金属试剂对酯加成制备
3、叔醇355. 烯烃制备醇.375.1 硼氢化反应37经典合成反应标准操作醇的制备 药明康德新药开发有限公司药明康德内部保密资料 Page 2 of 625.1.1 Mechanism385.2 烯烃双羟基化制备邻二羟基化合物415.2.1 顺式羟基化415.2.3 反式羟基化.435.3 烯烃羟卤化反应制备邻卤醇.445.4 Kennedy oxidative cyclization.455.4.1 Mechanism455.5 Baylis-Hillman reaction495.5.1 Introduction.495.5.2 Mechanism496.通过环氧制备醇.517.手性醇的合成
4、.537.1 不对称酮还原为手性的仲醇537.2 Sharpless 不对称双羟化 .567.3 Sharpless 不对称羟胺化 .56. 7.4 通过不对称环氧化引入手性.577.5 从手性氨基酸合成手性羟基酸.598 其他合成方法 .61经典合成反应标准操作醇的制备 药明康德新药开发有限公司药明康德内部保密资料 Page 3 of 621羧酸酯和羧酸还原为醇1.1 羧酸酯还原成醇羧酸酯一般来说较易被还原伯醇，其常用的方法为金属钠和醇 Na-EtOH；金属氢化物如氢化铝锂(LAH), 硼氢化钠（钾）等。其中金属氢化物是最为常用的还原剂。1.1.1 金属钠和醇为还原剂（Bouveault-B
5、lanc 反应）本反应是将羧酸酯用金属钠和无水醇直接还原生成相应地伯醇，主要用于高级脂肪羧酯的还原。由于催化氢化和氢化铝锂的广泛应用，此法在实验室中已经很少采用，但是因为其简便易行，在工业上仍然广泛应用。Bouveault-Blanc 反应的历程可能如下：ROO+Na RCOO OHROONaRCOOH ROOHNaRCOHOHRHHONaRHHO RHHOHH1.1.1.1 金属钠和醇为还原剂（Bouveault-Blanc 反应）示例 1n-C1H23OEtNa,EtOHtoluenn-C1H23OHThe central neck of a 5-l. three-necked round
6、-bottomed flask is fitted with a stopper carrying a mercury-sealed mechanical stirrer. One of the side necks is connected by means of a short piece of heavy rubber tubing to a large reflux condenser about 2 m. long, with an inner tube 2.5 cm. in diameter. The third neck is fitted with a separatory f
7、unnel.In the flask are placed 70 g. (3 moles) of sodium and 200 cc. of dry toluene. The flask is heated in an oil bath until the sodium is melted. The stirrer is then started; when the sodium is finely divided, the oil bath is removed and the mixture allowed to cool. Stirring must be continued durin
8、g the cooling in order to keep the sodium finely divided.When the mixture has cooled to about 60, there are added from the separatory funnel, first, a solution of 114 g. (0.5 mole) of ethyl laurate in 150 cc. of absolute alcohol, then 500 cc. 经典合成反应标准操作醇的制备 药明康德新药开发有限公司药明康德内部保密资料 Page 4 of 62more of
9、 alcohol, as rapidly as is possible without loss of material through the condenser. The time required for the addition of the ester solution and the alcohol is less than five minutes, usually two or three minutes. When the reaction has subsided, the flask is heated on a steam bath until the sodium i
10、s completely dissolved. The mixture is then steam-distilled to remove the toluene and ethyl alcohol. The contents of the flask are transferred to a separatory funnel while still hot and washed three times with 200-cc. portions of hot water to remove the sodium laurate. The lauryl alcohol is extracte
11、d with ether from the cooled mixture and the washings. The combined ether extracts are washed with water, sodium carbonate solution, and again with water, and dried over anhydrous magnesium sulfate. The ether is evaporated and the lauryl alcohol distilled under diminished pressure. The yield is 6070
12、 g. (6575 per cent of the theoretical amount) of a product boiling at 143146/18 mm. or 198200/135 mm.1.1.2 金属氢化物为还原剂羧酸酯用 0.5 mol 的氢化铝锂还原时，可得到伯醇。ROOR LiAlH4ROORAlH3ROHLiAlH4ROAlH3 ROORHROH-ROH如仅用 0.25mol 并在低温下或降低氢化铝锂的还原能力，可使反应停留在醛的阶段。降低氢化铝锂还原能力可以提高还原反应的选择性。常用的的方法是加入不同比例的无水三氯化铝或者加入计算量的醇，取代氢化铝锂中 1-3 个氢
13、原子而成铝烷、或烷氧基氢化铝锂。如用烷氧基氢化铝锂还原 ,-不饱和酯到 ,-不饱和醇，若单用氢化铝锂还原，则得到饱和醇。单纯使用氢化硼纳纳还原酯效果较差，若在 Lewis 酸如 AlCl3,ZnCl2 存在下，还原能力大增，可顺利的还酯，甚至可还原某些羧酸。由氢硼化钠和酰基苯胺在 -甲基吡啶中反应，生成的酰苯胺氢硼化钠是还原酯的有效试剂。其优点：反应操作简便，不需要无水条件，反应选择性好。1.1.2.1 LAH 还原羧酸酯成伯醇示例 2利用 LAH 还原羧酸酯到伯醇是一个快速，后处理较为简便的方法，一般情况下，经典合成反应标准操作醇的制备 药明康德新药开发有限公司药明康德内部保密资料 Page
14、 5 of 62酯基可在零下 30下反应 30 分钟即可被还原。因此即使分子内有酰胺或其他一些敏感的官能基存在也没什么关系。 TBSOCO2MeNMe2 TBSONMe2LiAlH4 ethr5oC OHA dry, 500-mL, three-necked, round-bottomed flask is equipped with a 150-mL pressure-equalizing addition funnel, a reflux condenser topped with an inert atmosphere line, a glass stopper, and an egg-
15、shaped magnetic stirring bar. The flask is charged with lithium aluminum hydride (2.66 g, 0.070 mol) and anhydrous ether (50 mL). The flask is cooled to 5C in an ice-water bath. A solution of (2R)-methyl 4-(tert-butyldimethylsilyloxy)-2-(dimethylamino)cyclohex-3-enecarboxylate (22.4 g, 0.072 mol) in
16、 ether (80 mL) is transferred to the addition funnel and added over a 30-min period. The reaction mixture is stirred for another 15 min, diluted with ether (100 mL), and quenched by dropwise addition of water (9 mL). The ice-water bath is removed, the resulting gray suspension is allowed to reach ro
17、om temperature, and the mixture is stirred vigorously for an additional 60 min. The mixture is transferred to a 1.0-L Erlenmeyer flask and diluted with 350 mL of ether. Anhydrous sodium sulfate (Na2SO4) (60 g) is added, the suspension is stirred for 30 min, and filtered. The filter cake is washed tw
18、ice with ether (50 mL each time). The solvent is removed on a rotary evaporator and the remaining volatile material is removed under high vacuum to afford 18.6 g (91%) of (2S)-4-(tert-butyldimethylsilyloxy)-2-(dimethylamino)cyclohex-3-enyl)methanol as a viscous clear oil.1.1.2.2 异丁醇铝还原 ,-不饱和酯到 ,-不饱和
19、醇示例 3 HNN OO lithium tri-sec-butylborhydride HNN OHTo a solution of 3-(1H-benzoimidazol-5-yl)-acrylic acid methyl ester (50 mg in 1 ML dry tetrahydrofuran) at -78.deg. C. was added 1.24 NL of a 1M solution of lithium tri-sec-butylborohydride in tetrahydrofuran and the mixture stirred at -78.deg. C.
20、for 4 hours followed by warming to -40.deg. C. for an additional 4 hours. 经典合成反应标准操作醇的制备 药明康德新药开发有限公司药明康德内部保密资料 Page 6 of 62The reaction was quenched by addition of aqueous methanol, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 87:13) to give
21、 the title compound (44 mg).1.1.2.3 硼氢化钠（钾）还原羧酸酯成伯醇示例 4利用硼氢化钠（钾）还原羧酸酯到伯醇操作较为安全，简单的方法，由于硼氢化钠的还原性不够强，因此这类反应一般需要回流过夜。反应初始阶段不要去加热，而是在室温下搅拌数小时后在，再加热缓缓回流，否则反应极容易喷出来。硼氢化钠在甲醇中分解较快，这个反应尽量不要用甲醇做溶剂。 NH3CO2 CO2H3 NOHOHNaBH4To a stirred suspension of 58.5g (300mmol) of dimethyl pyridine-2, 6-dicarboxylate in 800
22、ml of anhydrous ethanol was added in portions 53.0g (1400mmol) of sodium borohydride at 0C, after stirring for 1h at 0C, the ice bath was removed and the ongoing exothermic reaction caused the solution to boil under reflux. Stirring was continued for 3h, then the solution was heated under reflux for
23、 another 10h. The solvent was distilled off and the residue was digested with 200ml of acetone. The acetone was distilled off; to the residue was added 200ml of a saturated aqueous solution of K2CO3 and the whole was heated for 1h with a boiling water bath. The solvent was again distilled off, the r
24、esidue was dissolved in 800ml of water, and sodium chloride was added in portions with stirring until a colorless precipitate was formed. The product was extracted three times, each time with 150ml of chloroform, the combined organic phases were dried with MgSO4 and filtered. The solvent was distill
25、ed off to give 37.8g (91%)of desired product as colorless needles 1.1.2.4 NaBH4-ZnCl2 还原酯示例 5EtOCCOEtOTIPSZn(BH4)2TF OTIPSHOOHTo a suspension of ZnCl2 (80.36 g, 0.591 mol) in dry THF (1000 mL), NaBH4 (11.2 g, 经典合成反应标准操作醇的制备 药明康德新药开发有限公司药明康德内部保密资料 Page 7 of 620.3043 mol) was added in portions at 05 u
26、nder nitrogen. The mixture was stirred for 30 min at 2025 , The mixture was cooled to 05 and compound (S)-diethyl 2-(triisopropylsilyloxy)succinate (82 g, 0.2368 mol) was added dropwise at 05 . Then the mixture was warmed to 5560 and stirred for 18 hours. After confirming the completion of reaction
27、by HPLC, The result reaction mixture was cooled to -15-10 . Water (213 mL) was added dropwise to quench the reaction at -15-10 . The reaction was aged for 3 h at 2025 . Charged celite (12.3 g) to the mixture and then the solid was removed by filtration. The filtrate was concentrated under vacuum to
28、remove THF. And the filter cake was washed with CH2Cl2 (2503 mL). The combined organic layers were washed with water (200 mL) and the mixture was separated and the organic layer was dried over Na2SO4. The solution was concentrated to give compound (S)-2-(triisopropylsilyloxy)butane-1,4-diol (44.68 g
29、, 0.170 mol, yield 71.9%). 1.2 羧酸还原为醇金属氢化物如氢化铝锂、硼烷、硼氢化钠（钾）是实验室中常用的将羧酸还原成相应的伯醇的还原剂。氢化铝锂是还原羧酸的最常用试剂。硼烷是选择性的还原羧酸为醇的优良试剂，条件温和，反应速度快，且不影响分子中存在的硝基、卤素等基团。1.2.1 氢化铝锂还原羧酸为醇氢化铝锂还原羧酸，反应可在十分温和的条件下进行，一般不会停止在醛的阶段。即使位阻较大的酸，也有较好的收率，所以得到广泛的应用。1.2.1.1 LAH 还原羧酸示例 5：H2NCO2HCHMe2H LAH,TFH2NCHMe2HHOCaution! Because of th
30、e hydrogen gas evolved during this reaction, this procedure 经典合成反应标准操作醇的制备 药明康德新药开发有限公司药明康德内部保密资料 Page 8 of 62should be carried out in an efficient fume hood.An oven-dried, 3-L, three-necked flask equipped with a mechanical stirrer, a Friedrich condenser, and a nitrogen-inlet tube is flushed with ni
31、trogen, and then charged with a suspension of lithium aluminum hydride (47.9 g, 1.26 mol) in 1200 mL of tetrahydrofuran (THF). The mixture is cooled (10C, ice bath) and L-valine (100 g, 0.85 mol) is added in portions over a 30-min period from a 200-mL round-bottomed flask connected to the reaction f
32、lask via a flexible plastic sleeve so as not to produce too vigorous an evolution of hydrogen. After the addition is complete, the plastic sleeve is replaced by a stopper, the ice bath is removed, and the reaction mixture is warmed to room temperature and then refluxed for 16 hr. The reaction mixtur
33、e is then cooled again (10C, ice bath) and diluted with ethyl ether (1000 mL). The reaction is quenched over a 30-min period with water (47 mL) (Caution!, aqueous 15% sodium hydroxide (47 mL, over 20 min), and water (141 mL, over 30 min). The solution is stirred for 30 min and the white precipitate
34、is filtered. The filter cake is washed with ethyl ether (3 150 mL) and the organic filtrates are combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. Distillation of the residue under vacuum affords L-valinol (63.965.7 g, 7375%) as a clear liquid: bp 6365C (0.9 mm)
35、: D20 + 14.6 (neat); nD20 1.455; IR (neat) cm1: 3300, 1590; 1H NMR (CDCl3) : 0.92 (d, 6 H), 2.382.74 (m, 4 H), 3.133.78 (m, 2 H).1.2.2 硼烷还原羧酸为醇硼烷为亲电性还原剂，首先是由缺电子的硼原子和羰基氧原子上未共用电子相结合，然后硼原子的氢，以负氢离子形式转移到羰基碳原子上而使之还原成醇。 RR OBH3RCROBH2HRR OBH3RCHR OHRCR OBH2BH2OH+在羧酸的还原过程中，可能是先生成三酰氧基硼烷，然后酰氧基中氧原子上未共用的电子与缺电子的
36、硼原子之间可能发生相互作用。生成中间体而使酰氧基硼烷中的羰基较为活波，进一步按羰基还原的方式得到相应的伯醇。经典合成反应标准操作醇的制备 药明康德新药开发有限公司药明康德内部保密资料 Page 9 of 62COHOI 3BH3/THF COOI 3B COOI B OHI硼烷还原羧基的速度比还原其他基团快，因此，当羧酸衍生物分子中有氰基、酯基时，若控制硼烷的用量并在低温反应，可选择性地还原羧基为相应的醇，而不影响其他取代基。硼烷还原羧酸的速度，脂肪酸大于芳香酸，位阻小的羧酸大于位阻大的羧酸，但羧酸盐则不能还原。对脂肪酸酯的还原速度一般较羧酸慢，对芳香酸酯几乎不发生反应，这是由于芳环和羰基的共
37、轭效应，降低了羰基氧上的电子云密度，使硼烷的亲电进攻难于进行。1.2.2.1 硼烷还原羧酸示例 5H2NCO2HCHMe2H H2NCHMe2HHOBH3. SMe2F3. OEt2Procedure:Caution! Because of the foul odor of the methyl sulfide given off, this procedure, up to the methanol quench, should be carried out in a hood.A 2-L, three-necked, round-bottomed flask is equipped wit
38、h a mechanical stirrer, heating mantel, 250-mL graduated addition funnel, and an 8-in., air-cooled reflux condenser (West type) topped with a water-cooled distillation head and a 1-L receiving flask. It is connected to a nitrogen line through the still head. The glassware is either oven-dried and co
39、oled in a desiccator or flame-dried and assembled while still hot. The assembly is flushed with nitrogen and charged with 200 g of L-valine (1.7 mol), 400 mL of tetrahydrofuran (THF), and 210 mL of freshly distilled boron trifluoride etherate (242 g, 1.7 mol). The mixture is heated at a rate suffici
40、ent to cause the THF to reflux gently and 188 mL (1.88 mol) of boranemethyl sulfide complex (BMS) is added dropwise over the course of 2 hr. The solution is then refluxed for 18 hr. The methyl sulfide that has collected at the stillhead is discarded, and the reaction mixture is cooled to 0C and quen
41、ched by the slow addition of 200 mL of methanol. The addition funnel is replaced by a glass stopper, and the air-cooled condenser is removed, leaving the flask equipped for distillation of solvent through the distillation head. The reaction 经典合成反应标准操作醇的制备 药明康德新药开发有限公司药明康德内部保密资料 Page 10 of 62mixture
42、is concentrated under reduced pressure with heating and stirring. The distillation head is replaced by a water-cooled reflux condenser, and the residue is dissolved in 1 L of 6 M sodium hydroxide and refluxed for 4 hr. The mixture is saturated with potassium carbonate (ca. 400 g); cooled; filtered t
43、hrough a Celite pad on a coarse, fritted funnel; and extracted with three 1-L portions of chloroform. The combined extracts are washed with three portions of saturated sodium chloride (500 mL each), stirred over anhydrous potassium carbonate for 24 hr, and concentrated under reduced pressure to give
44、 a yellow oil. The crude material is vacuum distilled to give 77.5 g (44%) of purified L-valinol, bp 6267C/2.5 mm(Note 6); D20 + 14.6 (neat), nD20 1.455; IR (neat film) cm1: 3300 (OH), and 1590 (NH2); NMR : 0.92 (d, 6 H), 1.54 (m, 1 H), 2.382.74 (m, 4 H), 3.133.78 (m, 2 H).1.2.2.2 硼烷还原 ,-不饱和 acid 到 ,-不饱和醇示例 6HO2C CO2Et HO2C CO2Et-10oC t r.tBH3 .TFA dry, 2-L, one-necked, round-bottomed flask is equipped with a 1-L pressure-equalizing funnel and a large magnetic stirring bar. The system is flame-dried under an i
