CLR-124

1.     前言 腈类化合物是很多药物的合成中间体，而腈的合成是有机合成中非常重要的一部分，它一般经由如下几种方法制备： 1.      酰胺的脱水 2.      脂肪卤代烃或磺酸酯的反应        3．芳香卤代烃的氰基取代        4．其他羟基或肟到腈的转化 2.     酰胺的脱水反应 酰胺的脱水反应可在P2O5、POCl3、SOCl2、PCl5等脱水剂存在下进行脱水反应生成腈，此为实验室合成腈的方法之一。 将酰胺与P2O5的混合物加热，反应毕将生成的腈蒸出可得到良好的收率。SOCl2最适宜于处理高级的酰胺，这是由于副产物均为气体，易于除去，因而减少精制腈的困难。 同时，以上这些脱水试剂多在酸性条件下反应，对于酸敏感的底物是不实用的，因此人们也开发了许多更加温和的方法用于酰胺的脱水，如：Burgess reagent [Et3N+SO2N-COOMe]，三氟醋酸酐(TFAA)－三乙胺，(COCl)2-NEt3-DMSO等条件可以在低温和几乎中性的条件下反应。还有甲烷磺酰氯(CH3SO2Cl)，四氯化钛(TiCl4) 等等。 2.1 用P2O5为脱水剂的反应实例 Asolution of 35g (0.16 mol) of 2-(2-ethyl-3-benzofuranyl)-propionamide in 500mlof toluene was refuxed for 18 hours in the presence of P2O5.  The organic phase was decanted off and theresidue was carefully decomposed with ice-water and extracted with ether.  The organic phase was washed with water,dried over sodium sulphate and added to the toluenic phase.  The solvent was evaporated off under reducedpressure and the residue was fractionated to give 23.8g of2-(2-ethyl-3-benzofuranyl)-propionitrile (yield 74.4%, boiling point: 105.deg.C. at0.2 mmHg). Reference: US4124710 A1  (1978/11/07) 2.2 用POCl3为脱水剂的反应实例 A mixture of2-chloro-1,3,4-thiadiazole-5-carboxamide (1.4 g) in 17 ml of POCl3 is heated atreflux for 18 hours.  The reactionmixture is concentrated and the residue is suspended in 25 ml of ethyl acetate.  The suspension is cooled in an ice bath andneutralized with saturated, aqueous NaHCO3 (to pH 7).  The phases are separated and the aqueousphase is extracted with 20 ml of ethyl acetate. The combined organic phases are dried over MgSO4, filteredand concentrated.  The residue ispurified by column chromatography (using 30 percent ethyl acetate / hexane aseluent) to afford 0.832 g of 2-cyano-5-chloro-1,3,4-thiadiazole. MP: 65-67. deg.C Reference: Patent; EP883611 B1  (2002/07/31) 2.3 用SOCl2为脱水剂的反应实例 A solution of thionyl chloride (7.70 g, 0.065 mol)in dry DMF (10 ml) was added dropwise to a stirred solution of compound 13 (4.20g, 0.013 mol) in dry DMF (25 ml) at room temperature.  The stirred mixture was heated at 120C for 3h and poured into ice–water. The product was extracted into ether (twice) and thecombined ethereal extracts were washed with water, saturated sodium hydrogencarbonate solution, water, and dried (MgSO4).  The solvent was removedin vacuo and the residue was purified by column chromatography (silicagel–light petroleum (bp 40–60 8C) with the gradual introduction ofdichloromethane) to yield a colourless solid. Yield 2.88 g (68%); Reference:J. Chem. Soc.,Perkin Trans. 1, 1998,3479–3484 2.4 用PCl5为脱水剂的反应实例 4-Oxo-4H-9-oxa-1,4a-diaza-fluorene-3-carboxylic acidamide (4.58 g, 20 mmol) wassuspended in 150 ml of anhydrous DMF, PC15 (5.0 g, 24 mmol) wasadded, and the mixture was stirred for 2 h at 40-50 oC.  The reaction mixture was poured into 600 mlice-water to yield a solid, which was collected by filtration.  The solid was washed thoroughly (first withsaturated aqueous NaHCO3, then with water) and dried to give 4-oxo-4H-9-oxa-1,4a-diaza-fluorene-3-carbonitrile. Ref: J . Med. Chem.1983, 26,608-611 2.5 用Bugess试剂为脱水剂的反应实例 To a solution of 2-tetrazol-1-yl-benzamide(1.5 g, 7.9 mmol) in tetrahydrofuran (50 ml) was added Et3N+SO2N-COOMe(2.8 g, 11.8 mmol) in three portions over 1.5 h.       Water was added and the reaction mixture was extracted withethyl acetate.  The combined organic layers were washed with brine and water. Afterdrying and filtration, the solvent was evaporated to give 2-tetrazol-1-yl-benzonitrile. Reference:  J. Med.Chem. 47, 12, 2004, 2995-3008. Preparation of Bugess reagent: 将无水甲醇19.2g(0.6 mol) 和无水苯40mL的混合物在30-40分钟内，滴入ClSO2NCO85g (52.3 mL, 0.6 mol)和无水苯200mL的混合物中，控温10-15℃。加毕，室温搅拌2小时。然后加入1000mL无水苯稀释后，小心滴入190mL无水三乙胺和250mL无水苯的混合物中，控温10-15℃，约40分钟左右加完。加毕，室温搅拌2小时，析出大量固体。反应毕，过滤，固体用无水苯200mL、无水THF200mL洗后，滤液浓缩后，（控温<30℃），加入无水THF溶解后，重结晶得123g, 收率86%。注：整个操作温度要低于30℃。 2.6用TFAA-NEt3为脱水剂的反应实例 To a mixtureof compound amide (287 mg, 1 mmol), Et3N (470 mg, 4.5 mmol) inanhydrous DCM (4 mL) was added TFAA (0.44 g, 2 mmol) at 0℃ with stirring. The resulting mixture was warmed to room temperature and stirred for 12h.  The reaction was monitored by TLC(Hexane:AcOEt = 1:1) until its completion. The organic layer was washed with brine and water, dried andconcentrated to give the desiredproduct (~80% yield). 2.7 用(COCl)2-NEt3-DMSO为脱水剂的反应实例 A solution of (COCl)2(67 μL, 0.77 mmol) in CH2Cl2 (0.5 mL) was addedto the solution of 3-carbamoyl-piperidine-1-carboxylic acid tert-butylester (142.0 mmol) and DMSO (78 μL, 1.1 mol) in CH2Cl2(1.5 mL) at -78 oC.  Afterstirring for 15 min at -78 oC, Et3N (0.23 mL, 1.65 mmol)was added dropwise to the mixture.  Afterthe reaction mixture was stirred for 15 min. at -78 oC, the mixturewas quenched by addition of water (5 mL). After this mixture was warmed to room temperature, the aqueous layer wasextracted with EtOAc (3×10 mL).  The combined organiclayers were washed with brine, dried and filtered.  Concentration after filtration in vaccuofollowed by purification by column gave 3-cyano-piperidine-1-carboxylic acid tert-butyl ester (123.3 mg, 93%). Reference:T. L. 38, 12,1997, 2099-2102 2.8 用甲烷磺酰氯(CH3SO2Cl)为脱水剂的反应实例 6-(3-Methoxy-2-propyl-phenyl)-hexanoic acid amide (7.2g, 27.2 mmol) was cooled to 0 oC and added methane-sulfonyl chloride(18.5 mL, 239 mmol) dropwise over 5 min.  The mixture was stirred overnight while slowlywarming to 25 oC.  Thereaction mixture was then poured into 3 volumes of ice water.  The aqueous mixture was repeatedly extractedwith ethyl acetate.  The combined organicextracts were washed with dilute HC1 and brine, then dried over MgSO4.  After evaporation of the solvent, a brownoily residue was obtained.  The crudenitrile was purified by bulb-to-bulb distillation (bp 133-137"C (0.02mmHg)), which was pure enough for further transformation (5.50 g, 83 %). Reference: J. Med. Chem.1988, 31, 172-175 2.9 用TiCl4为脱水剂的反应实例 Toa solution of CCl4 (110μL, 1.17 mmol) and THF (6 mL) at 0 oC wasadded TiCl4 (58 μL, 0.52mmol).  After 5 min, 5,11-diethyl-8-methoxy-5,6,11,12-tetrahydro-chrysene-2-carboxylic acid amide (47 mg, 0.13 mmol) in THF (14 mL) and Et3N(72μL, 0.52 mmol) was added to thisyellow heterogeneous solution, and stirring was continued at room temperature untilno starting material remained.  Diethylether and water were added, and the organic layer was washed with brine, driedover MgSO4, and concentrated. Repeated recrystallization from diethyl ether gave 5,11-diethyl-8-methoxy-5,6,11,12-tetrahydro-chrysene-2-carbonitrile (45 mg, 99%). Reference: J. Org. Chem. 1992, 1262-1271 2.10叔丁酰胺脱水为腈 叔丁酰胺也可当作伯酰胺的替代品，在二氯亚砜，三氯氧磷或草酰氯作用下脱叔丁基脱水为腈，因此有时在制备伯酰胺不容易时，做成相应的叔丁酰胺转化为腈也不失为一个好的方法。 2.10.1叔丁酰胺脱水为腈示例一 A solution of 1.240 mmol ofN-tert-butyl-4-(6,7-dihydro-5H-[2]pyridin-7-yl)benzamide and 1.0 ml of thionylchloride in 30 ml of chloroform is stirred under reflux for 6 hours.  The reaction mixture is cooled to roomtemperature and evaporated.  The residueis taken up in dichloromethane and mixed with saturated aqueous sodiumbicarbonate solution.  The organic phaseis separated and the aqueous phase is extracted with dichloromethane (2x).  The combined organic phases are dried withsodium sulphate and concentrated.  Theresidue is dissolved in diethyl ether and the title compound is converted intothe hydrochloride salt by adding ethereal HCI solution (2N).  The solid is stirred in diethyl ether/acetone(1: 1), filtered and dried.  The titlecompound is obtained as a dark grey solid.  Rf (free base) = 0.36 (EtOAc) Reference: WO2005/118540 2.10.2叔丁酰胺脱水为腈示例二 A 5 L round bottom flask was charged with N,N'-di-tert-butyl-5-(2,3-difluoro-6-nitro- phenoxy)-isophthalamide (21; 564 g) and 1.3 L ofphosphorus oxychloride.  The mixture washeated to between 90 deg C. ~ 100.deg. C. for 2 h, after which approximately1/2 of the POCl3was removed by distillation.  Toluene was added (1 L) and additional liquidwas distilled.  After cooling the mixtureovernight, a crude was obtained by filtration. Additional material was obtained by recovery from the mother liquid.  The combined solids were stirred in MeOH (0.7L) for between 1 and 3 h, filtered and dried in a vacuum oven between 50~80 degC.at 25 Torr with a nitrogen bleed to afford 339 g of 22 (90percent theory). Reference:US2005/234236 2.10.3叔丁酰胺脱水为腈示例三 At ice-water bath, oxalyl chloride (0.345 ml) wasadded dropwise to a solution of 1.0 g of ethyl1-{4-[2-(t-butylaminocarbonyl)phenyl]phenyl}methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate in 10 ml of methylene chloride.  The mixture was stirred at the sametemperature for 2 hours.  The reactionmixture was diluted with an aqueous solution of sodium hydrogencarbonate andethyl acetate, and the ethyl acetate layer was separated, dried over anhydrousmagnesium sulfate and concentrated by evaporation under reduced pressure.  The residue was purified by silica gel columnchromatography, using 1:1 EtOAc/hex (v/v) as the eluent, to give 0.69 g of thetitle compound as crystals. Reference: US5616599 3.     脂肪卤代烃或磺酸酯与金属氰化物的亲核取代反应 脂肪体系中的亲核取代反应是最受有机化学家注意的单元反应之一，其中脂肪卤代烃或磺酸酯与金属氰化物的亲核取代合成腈得到了广泛的应用： 在转化合成过程中最有用的是在直接取代机理方面有反应活性的底物。即伯类及未受阻碍的仲类脂肪卤代烷或磺酸酯。在叔烷基体系中发生消去反应的倾向是相当显著的，从而在涉及这些体系的转化合成方面限制了亲核取代反应的应用。有时侯，当非碘代的卤代烃反应活性不够时，需要在反应体系中加入KI或NaI 增加卤代烃反应活性，或者假如氧离子络合剂，如18冠6等; 有不少文献报道用相转移催化方法完成这一取代。 脂肪卤代烃可由相应醇经卤代反应制备，而磺酸酯可由相应醇经与甲烷磺酰氯或对甲苯磺酰氯反应得来。 3.1 烷基卤代物的氰基取代反应示例 To a stirring solution ofsodium cyanide (1.62 g, 33 mmol) and potassium iodide (66 mg, 0.4 mmol) indimethyl sulfoxide (20 ml) at 40 deg C., was slowly added 1-bromo-2-ethylbutaneover 30 min.  The reaction mixture wasstirred at 80 deg C for 12 h, then at 110 deg C for 4 h.  The reaction mixture was cooled andpartitioned between Et2O and water. The organic layer was washed with brine, dried over Na2SO4, filtered andconcentrated in vacuo to yield 2.9 g (87percent yield) of 1-cyano-2-ethylbutaneas an amber oil. 1H NMR (300 MHz, CDCl3): d2.34 (d, 2 H), 1.58(m, 1 H),1.46(m, 4 H), 0.92(t, 6 H). Reference:: Bioorg. Med.Chem.  11, 18, 2003,4093-4102. 3.2 磺酸酯的氰基取代反应示例 A mixture of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-[6-[(methylsulfonyl)oxyl]-hexyl]urea (2.0 g) in a few mL of DMF was added to acooled stirring suspension of anhydrous sodium cyanide (0.50 g) in 3 mL of dryDMSO.  The mixture was heated overnightat 80 oC.  Then it was pouredinto water (100 mL) and the product was extracted with dichloromethane.  The combined extracts were washed water,dried (MgSO4) and concentrated to give 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-(6-cyanohexyl)urea. Ref: US 4623662 A1 4.     用TMSCN转化羟基到腈 对于芳基苄位的羟基，可以用TMSCN直接转化为腈，反应的好坏与邻位的碳上是否有烷基的氢质子有关。 4.1 TMSCN双芳基甲醇氰化反应示例一 Thionyl chloride (50 ml) was added tobis(4-fluorophenyl)methanol (24.2 g) at 0 deg C and after stirring for 30 min,the mixture was poured into 2N hydrochloric acid (500 ml).  The mixture was extracted with ethyl acetateand the organic layer was dried over calcium chloride and concentrated underreduced pressure.  The resulting residuewas dissolved in dichloromethane (200 ml) and after addition oftrimethylsilylcyanide (16.4 ml), titanium tetrachloride (13.4 ml) was addeddropwise at 0 degC.  The mixture wasstirred for 50 min. Methanol (5 ml) was added to the reaction mixture and themixture was poured into saturated aqueous sodium hydrogen carbonate.  The mixture was extracted with ethyl acetateand washed with saturated brine.  Theorganic layer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give the title compound (21.8 g) oil. Ref: EP1219294  A1  (2002/07/03) 4.2 TMSCN单芳基苄醇氰化反应示例二 Tosolution of 4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexane carboxylic acid ethyl ester (13.5 g, 33.9 mmol) in CH2Cl2(135 mL) cooled to 0 °C was added trimethylsilyl cyanide (22.6 mL, 169 mmol)followed by a slow addition of SnCl4 (13.6 mL of a 1.0 M solutionin CH2Cl2, 13.6 mmol).  The reaction mixture was allowed to warm toroom temperature overnight.  K2CO3(18.7 g, 136 mmol) and KFâ2H2O (12.8 g, 136 mmol) were added, followed bydropwise addition of H2O (4.30 mL, 239 mmol). The reaction mixture was stirred vigorously for 90 min, after whichsilica gel (25 g) was added. The mixture was filtered and washed thoroughlywith CH2Cl2.  The filtrate was washed withsaturated aqueous NaHCO3 (250 mL), dried over MgSO4, filtered, andconcentrated to yield 13.2 g oily product of (96% recovery)cyano-4-(1-cyclohexyl-3-ethyl- 1H-indazol-6-yl)cyclohexanecarboxylic acid ethylester as a mixture of diastereoisomers.  Forcharacterization purposes, a sample of each diastereoisomer was obtained bychromatographic purification on silica gel eluting with 4:1 hexanes/EtOAc. Reference: : Organic Process Research & Development2001, 5, 587-592 5.     用TosMIC直接从酮转化为氰基 To a 250 mL round-bottomed flask equipped withcondenser and nitrogen inlet were added 4.34 g (23.49 mmol)N-carboethoxyperhydroazepin-4-one (prepared according to the procedure given byZ. G. Finney and T. N. Riley, J. Med. Chem., 23, 895, 1980), 10.53 g(54.02 mmol) tosylmethylisocyanide and 117 mL 1,2-dimethoxyethane.  The solution was cooled to 0 deg C and 2.48 mL(54.02 mmol) ethanol and 9.21 g (82.2 mmol) potassium t-butoxide were added.  The mixture was heated at 60 deg C for 18hours, cooled and concentrated.  Theresidue was taken up in ethyl acetate, washed with brine, dried over sodiumsulfate and concentrated to give an oil. The oil was purified by chromatography on silica gel using hexane/ethylacetate as eluent to afford 4.6 g (100percent) of oil. Reference: 72800; Patent; Pfizer Inc.; Publ.:  US5373003 A1  (1994/12/13), 6. 用2,4,6-三异丙基磺酰肼-KCN将酮转化为氰基 3-Quinuclidinone (24.2 g, 0.19 mol) and 2,4,6-triisopropylbenzenesulphonohydrazide (72g, 0.24 mol) were stirred together in anhydrous MeOH (250 mL) for 3 h.  Potassium cyanide (33.8 g, 0.51 mol) was addedand the mixture was heated under reflux for 5 h.  The residue after evaporation of the solventwas partitioned between water and CH2C12.  The organic phase was dried and evaporated andthe residue was fractionally distilled under reduced pressure to give3-cyanoquinuclidine (32, 6.1 g). Reference: J.Med. Chem. 1990, 33, 1128-1138 7. 芳香卤代烃在金属催化作用下的腈化反应 芳腈化合物在有机合成中占据非常重要的地位，尤其是在染料，除草剂，农用化学品，药物及自然产品中应用非常广泛。传统方法合成芳腈化合物主要通过苯胺的重氮化接着Sandmeyer反应制得，对不是复杂的苯腈可由甲苯类化合物在NH3作用下直接氧化制备。但这些方法有较大局限性：反应条件较剧烈，底物要比较简单取代基较少，毒性很大。以下介绍的是实验室常用方法。 7.1a 芳香卤代烃与氰化亚酮作用可用来制备相应芳腈化合物 About 14.7 g (0.05 mol) of5-bromo-4-chloro-2-methoxybenzoic acid ethyl ester, 5.4 g (0.06 mol) of copper (I)cyanide and 8 ml of dimethylformamide are heated at 190 deg for three hourswhile stirring under nitrogen atmosphere. After cooling, the reaction mixture is stirred well with 250 ml ofmethylene chloride and 250 ml of 2N hydrochloric acid.  The insoluble portions are filtered off withsuction filtration and the layers are separated in a separating funnel.  The methylene chloride solution is washedneutral with water and then concentrated by evaporation.  The obtained residue was re-crystallized frommethylene chloride/hexane to give pure 4-chloro-5-cyano-2-methoxybenzoic acidethyl ester. Ref.:Frontpage/Claim:  59938; Patent; CibaGeigy Corporation; Publ.:  US4559349  A1  (1985/12/17),  Appl.: US1984-586493  (1984/03/05) 7.1b 芳香卤代烃与KCN或 Zn(CN)2在钯催化剂作用下可以实现氰基取代反应。这类反应常用的催化剂及配体有：Pd(PPh3)4,Pd(OAc)2/PPh3, Pd2dba3等。DMF或NMP为常用溶剂。 实例1 In a similar fashion, a mixture of3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4-oxadiazole (33.2 mg, 0.1 mmol), zinccyanide (17.6 mg, 0.15 mmol) and Pd(PPh3)4 (11.5 mg, 0.01 mmol) inN,N-dimethylformamide (1 ML) was heated under an argon atmosphere at 80 deg Cfor 16 hours.  After cooling the reactionmixture was poured into water and the crude product was extracted withdichloromethane.  Silica gelchromatography using 50 percent ethyl acetate in hexane afforded of3-(2-pyridyl)-5-(2-cyano-5-methoxyphenyl)-1,2,4-oxadiazole. Ref.: Patent;Wagenen, Bradford Van; Publ.:  US2003/55085 A1  (2003/03/20),  Appl.: US2002-76618  (2002/02/19) 实例2 A mixture of5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (14)(3.01 g, 7.99 mmol), 1,1'-bis(diphenylphosphino) ferrocene (dppf) (93 mg, 0.162mmol), Pd2dba3 (73 mg, 0.080 mmol) and Zn(CN)2 (573 mg, 4.78 mmol) in 1-methyl-2-pyrrolidin one (NMP: 4.5 ml) was heated in a sealed tube reactor.  After 20 hours the reaction mixture wascooled to room temperature, quenched by the addition of 8 ml 4:1:4 (volume)mixture of saturated NH4Cl, concentrated NH4OH and water. The solution was extracted with a mixture of EtOAc/THF.  The combined organic extracts were washedwith 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH4OH and water,and then brine.  The organic layer wasdried (MgSO4)and concentrated.  Purification by flashcolumn chromatography using the Biotage system (twice:100 percent hexanes to35percent CH2Cl2 in hexanes, then 30 percent CH2Cl2 in hexanes) provided 1.33 g (52 percent) ofthe desired product. Ref:Patent; Wallace, Eli; Publ.:  US2005/54701 A1  (2005/03/10),Appl: US2004-929295  (2004/08/30) 7.2 Cu催化下芳香卤代烃或（TfO-）和K4[Fe(CN)6]反应氰基取代 最近，Thornds Schdreind,Alexander zapf 报道了一种在Cu催化下芳香卤代烃或（TfO-）和K4[Fe(CN)6]反应高收率生成氰基化合物的方法。作者经过一系列实验，使用不同的铜催化剂，以及不同的配体与溶剂，从而得到了最好的实验条件。即：Cu(BF4)2.6H2O为催化剂，DMEDA为配体，DMAc为溶剂。 No condition details were available in this literature.  The general reaction conditions that theauthor gave were: 2.0 mmol aryl halide, Cu(BF4)2.6H2O(0.1eq), 20 mol% dry K4[Fe(CN)6], 2 mL DMAc, 20 mol% KI, 20mol % Na2CO3, 100 mol % DMEDA. Reference:Tetrahedron Letters. 46 (2005) 2585-2588 7.3 微波反应芳卤氰基化 在7.1反应实例中，这些直接取代大多用高温反应，最近有人开发了使用微波反应做这一取代。 A dried heavy-walled pyrex tube was charged with organo-bromide(0.2 mmol), Zn(CN)2 (23.5 mg, 0.2 mmol) and Pd(PPh3)4(6.9 mg, 6.0 ímol) in DMF (1 ml).  The reaction mixture was flushed with nitrogenand the screw cap tightened thoroughly before mixing with a Whirlimixer.  The reaction mixture was exposed to microwaveirradiation (60 W) for 2 min (for 2g 2.5 min).  The reaction tube was allowed to reach roomtemperature before the reaction mixture was diluted in EtOAc (60 mL) and washedwith water.  The organic phase was dried andthe solvent was removed under reduced pressure.  The crude product was purified by columnchromatography to give the pure nitrile. Reference:: J. Org. Chem. 2000, 65, 7984-7989. 8. 肟脱水生成腈 芳香或烷基的醛可以通过转变成肟脱水成相应的腈. Asolution of the powder (0.49 g) of diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylateand thionyl chloride (1.5 ml) in dry diethyl ether (1.5 ml) was stirred at roomtemperature for 30 minutes.  After theresultant solution was evaporated to dryness, water was added to the residueand the mixture was extracted with ethyl acetate.  The extract was washed with water, dried overmagnesium sulfate and concentrated under reduced pressure to give brown oil(0.39 g).  The oil was purified by columnchromatography on silica gel with eluent of 5:1 benzene:ethyl acetate andcrystallized with n-hexane to give a yellow powder (50 mg).  The powder was further recrystallized fromdiethyl ether / n-hexane to give crystals of diethyl 2-methyl-4-(2-trifluoromethyl-phenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate. Reference:Chem Pharm Bull. 1991,89-3201. 本文内容来源于网络，版权归原作者所有