腈的合成-060303

1、经典化学合成反应标准操作腈的合成编者： 江志赶药明康德新药开发有限公司化学合成部药明康德新药开发有限公司经典合成反应标准操作 腈的合成目录1 前言 42 酰胺的脱水 42.1 用 P2O5 为 脱水剂的反应实例42.2 用 POCl 3 为 脱水剂的反应实例52.3 用 SOCl 2 为 脱水剂的反应实例52.4 用 PCl 5 为 脱水剂的反应实例62.5 用 Bugess 试剂为脱水 剂的反应实例 62.6 用 TFAA-NEt 3 为 脱水剂的反应实例72.7 用(COCl) 2-NEt 3-DMSO 为脱水剂的反应实例72.8 用 CH 3 SO2Cl 为 脱水剂的反应实例82.9 用

2、 TiCl 4 为 脱水剂的反应实例82.10 叔丁酰胺脱水为腈 93 脂肪卤代烃或磺酸酯的反应 103.1 脂肪卤代烃的氰基取代的反应示例113.2 磺酸酯的氰基取代的反应示例114. 用 TMSCN 转化羟基到腈 124.1 TMSCN 双芳基甲醇氰化反应示例124.2 TMSCN 单芳基甲醇氰化反应示例125. 用 TosMIC 直接从酮转化为氰基 136. 用 2,4,6- 三异丙基磺酰肼 -KCN 将酮转化为氰基 14147. 芳香卤代烃在金属催化作用下的腈化反应Page 1 of 17药明康德内部保密资料经典合成反应标准操作 腈的合成 药明康德新药开发有限公司7.1 钯催化下芳香卤

3、代烃或（ TfO- ）氰基取代反应 147.2 Cu 催化下芳香卤代烃或（ TfO- ）和 K 4Fe（CN） 6反应氰基取代 167.3 微波反应芳卤氰基 化168. 肟脱水生成腈 17Page 2 of 17药明康德内部保密资料药明康德新药开发有限公司经典合成反应标准操作 腈的合成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下面分别进行阐述。2. 酰胺的脱水反应 酰胺的脱水反应可在 P2O5、POCl3、SOCl2、PCl5

4、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。OR C NH2OHHRCN-H2O R C N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 (

5、CH3SO2Cl)，四氯化钛 (TiCl 4) 等等。2.1 用 P2O5 为脱水剂的反应实例P2O5A solution of 35g (0.16 mol) of 2-(2-ethyl-3-benzofuranyl)-propionamide in 500ml of toluene was refuxed for 18 hours in the presence of P2O5. The organic phase was decantedPage 3 of 17药明康德内部保密资料药明康德新药开发有限公司经典合成反应标准操作 腈的合成off and the residue was care

6、fully 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 reduced pressure and the residue was fractionated to give 23.8g of 2-(2-ethyl-3-benzofuranyl)-propionitr

7、ile (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H2NClPOCl 3A mixture of 2-chloro-1,3,4-thiadiazole-5-carboxamide (1.4 g) in 17 ml of POCl3 is heated at reflux for 18 hours. The reaction mixture is concentrated and the residue is suspe

8、nded in 25 ml of ethyl acetate. The suspension is cooled in an ice bath and neutralized with saturated, aqueous NaHCO3 (to pH 7). The phases are separated and the aqueous phase is extracted with 20 ml of ethyl acetate. The combined organic phases are dried over MgSO4, filtered and concentrated. The

9、residue is purified by column chromatography (using 30 percent ethyl acetate / hexane as eluent) to afford 0.832 g of 2-cyano-5-chloro-1,3,4-thiadiazole. MP: 65-67. deg.CReference: Patent; EP883611 B1 (2002/07/31)2.3 用 SOCl2 为脱水剂的反应实例SOCl 2DMFOFBrA solution of thionyl chloride (7.70 g, 0.065 mol) in

10、 dry DMF (10 ml) was added dropwise to a stirred solution of compound 13 (4.20 g, 0.013 mol) in dry DMF (25 ml) at room temperature. The stirred mixture was heated at 120C for 3 h and poured into icewater. The product was extracted into ether (twice) and the combined ethereal extracts were washed wi

11、th water, saturated sodium hydrogen carbonate solution, water, and dried (MgSO4). The solvent was removedi n vacuo and the residue was purified by column chromatography (silicaPage 4 of 17药明康德内部保密资料药明康德新药开发有限公司经典合成反应标准操作 腈的合成gellight petroleum (bp 4060 8C) with the gradual introduction of dichlorome

12、thane) to yield a colourless solid. Yield 2.88 g (68%);Reference: J. Chem. Soc., Perkin Trans. 1, 1998, 347934842.4 用 PCl5 为脱水剂的反应实例PCl5DMF4-Oxo-4H-9-oxa-1,4a-diaza-fluorene-3-carboxylic acid amide (4.58 g, 20 mmol) was suspended in 150 ml of anhydrous DMF, PC15 (5.0 g, 24 mmol) was added, and the m

13、ixture was stirred for 2 h at 40-50 oC. The reaction mixture was poured into 600 ml ice-water to yield a solid, which was collected by filtration. The solid was washed thoroughly (first with saturated aqueousN aHCO3, then with water) and dried to give 4-oxo-4H-9-oxa-1,4a-diaza- fluorene-3-carbonitri

14、le.Ref: J . Med. Chem.1983, 26, 608-6112.5 用 Bugess 试剂为脱水剂的反应实例NNNN NONBugess reagentTHFNNNNNNTo a solution of 2-tetrazol-1-yl-benzamide (1.5 g, 7.9 mmol) in tetrahydrofuran (50 ml) +-was added E3tN SO2N COOMe (2.8 g, 11.8 mmol) in three portions over 1.5 h. Water was added and the reaction mixture

15、was extracted with ethyl acetate. The combined organic layers were washed with brine and water. After drying and filtration, the solvent was evaporated to give 2-tetrazol-1-yl-benzonitrile.Reference: J. Med. Chem.4 7, 12, 2004, 2995-3008.Preparation of Bugess reagent:将无水甲醇 19.2g (0.6 mol) 和无水苯 40mL

16、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，Page 5 of 17药明康德内部保密资料经典合成反应标准操作 腈的合成药明康德新药开发有限公司 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 123

17、g, 收率 86%。注：整个操作温度要低于 30。2.6 用 TFAA-NEt 3 为脱水剂的反应实例TFAA, Et 3NDCMEtOOCCNTo a mixture of compound amide (287 mg, 1 mmol), Et3N (470 mg, 4.5 mmol) in anhydrous 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 12 h. The

18、reaction was monitored by TLC (Hexane:AcOEt = 1:1) until its completion. The organic layer was washed with brine and water, dried and concentrated to give the desired product (80% yield).2.7 用(COCl) 2-NEt 3-DMSO 为脱水剂的反应实例OBoc(COCl) 2, NEt3, DMSOCH2Cl2BocCNA solution of (COCl) 2 (67L, 0.77 mmo)l in C

19、H 2Cl2 (0.5 mL) was added to the solution of 3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (142.0 mmol) and DMSO (78 L,1.1 mol) in CH 2Cl2 (1.5 mL) at -78 oC. After stirring for 15 min at -78 oC, Et3N (0.23 mL, 1.65 mmol) was added dropwise to the mixture. After the reaction mixture was

20、stirred for 15 min. at -78 oC, the mixture was quenched by addition of water (5 mL). After this mixture was warmed to room temperature, the aqueous layer was extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried and filtered. Concentration after filtration in vaccu

21、o followed by purification by column gave 3-cyano-piperidine-1-carboxylic acid tert-butyl ester (123.3 mg, 93%).Page 6 of 17药明康德内部保密资料药明康德新药开发有限公司经典合成反应标准操作 腈的合成Reference: T. L. 38, 12, 1997, 2099-21022.8 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 (7.2 g, 27.2 mmol)

22、 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 slowly warming to 25 oC. The reaction mixture was then poured into 3 volumes of ice water. The aqueous mixture was repeatedly extracted with ethyl acetate. The com

23、bined organic extracts were washed with dilute HC1 and brine, then dried over MgSO4. After evaporation of the solvent, a brown oily residue was obtained. The crude nitrile was purified by bulb-to-bulb distillation (bp 133-137C (0.02 mmHg), which was pure enough for further transformation (5.50 g, 83

24、 %).Reference: J. Med. Chem.1988, 31, 172-1752.9 用 TiCl4 为 脱水剂的反应实例TiCl 4To a solution of CCl 4 (110 L, 1.17 mmol) and THF (6 mL) at 0 oC was added TiCl4 (58 L, 0.52 mmol). 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) an

25、d Et 3N (72L, 0.52 mmol) was added to this yellow heterogeneous solution, and stirring was continued at room temperature until no starting material remained. Diethyl ether and water were added, and the organic layer was washed with brine, dried over MgSO4, and concentrated. Repeated recrystallizatio

26、n 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, 1262-1271Page 7 of 17药明康德内部保密资料药明康德新药开发有限公司经典合成反应标准操作 腈的合成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

27、叔丁酰胺脱水为腈示例一A solution of 1.240 mmol of N-tert-butyl-4-(6,7-dihydro-5H-2pyridin-7-yl)benzamide and 1.0 ml of thionyl chloride in 30 ml of chloroform is stirred under reflux for 6 hours. The reaction mixture is cooled to room temperature and evaporated. The residue is taken up in dichloromethane and m

28、ixed with saturated aqueous sodium bicarbonate solution. The organic phase is separated and the aqueous phase is extracted with dichloromethane (2x). The combined organic phases are dried with sodium sulphate and concentrated.T he residue is dissolved in diethyl ether and the title compound is conve

29、rted into the hydrochloride salt by adding ethereal HCI solution (2N). The solid is stirred in diethyl ether/acetone (1: 1), filtered and dried. The title compound is obtained as a dark grey solid. Rf (free base) = 0.36 (EtOAc)Reference: WO2005/1185402.10.2叔丁酰胺脱水为腈示例二FA 5 L round bottom flask was ch

30、arged with N,N-di- tert-butyl-5-(2,3-difluoro-6-nitro- phenoxy)-isophthalamide (21; 564 g) and 1.3 L of phosphorus oxychloride. The mixture was heated to between 90 deg C. 100.deg. C. for 2 h, after which approximately 1/2 of the POCl3 was removed by distillation. Toluene was added (1 L) and additio

31、nal liquid wasPage 8 of 17药明康德内部保密资料药明康德新药开发有限公司经典合成反应标准操作 腈的合成distilled. After cooling the mixture overnight, a crude was obtained by filtration. Additional material was obtained by recovery from the mother liquid. The combined solids were stirred in MeOH (0.7 L) for between 1 and 3 h, filtered and

32、 dried in a vacuum oven between 5080 degC. at 25 Torr with a nitrogen bleed to afford 339 g of 22 (90percent theory).Reference: US2005/2342362.10.3叔丁酰胺脱水为腈示例三At ice-water bath, oxalyl chloride (0.345 ml) was added dropwise to a solution of 1.0 g of ethyl 1-4-2-(t-butylaminocarbonyl)phenylphenylmethy

33、l-4-(1-hydroxy-1-methylethyl)- 2-propylimidazole-5-carboxylate in 10 ml of methylene chloride. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with an aqueous solution of sodium hydrogencarbonate and ethyl acetate, and the ethyl acetate layer was separat

34、ed, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using 1:1 EtOAc/hex (v/v) as the eluent, to give 0.69 g of the title compound as crystals.Reference: US56165993. 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

35、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：R-X + CN-R-CN +X-X is I- Br- Cl- or MsO- or TsO-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Page 9 of 17药明康德内部保密资料药明康德新药开发有限公司经典合成反应标准操作 腈的合成代的卤代烃反应活性不够时，需要在反应体系中加入 KI 或

36、 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NaCNKITo a stirring solution of sodium cyanide (1.62 g, 33 mmol) and potassium iodide (66 mg, 0.4 mmol) in dimethyl sulfoxide (20 ml) at 40 deg C., was slowly added 1-bromo-2-

37、ethylbutane over 30 min. The reaction mixture was stirred at 80 deg C for 12 h, then at 110 deg C for 4 h. The reaction mixture was cooled and partitioned between Et2O and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to yield 2.9 g (87percent

38、yield) of 1-cyano-2-ethylbutane as an amber oil.1H NMR (300 MHz, CDCl 3): 2.34 (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-hexylu

39、rea (2.0 g) in a few mL of DMF was added to a cooled stirring suspension of anhydrous sodium cyanide (0.50 g) in 3 mL of dry DMSO. The mixture was heated overnight at 80 oC. Then it was poured into water (100 mL) and the product was extracted with dichloromethane. The combined extracts were washed w

40、ater, dried (MgSO4)Page 10 of 17药明康德内部保密资料药明康德新药开发有限公司经典合成反应标准操作 腈的合成and concentrated to give 1-(4-butylphenyl)methyl-3-(4-chloro-2-methylphenyl)- 1-(6-cyanohexyl)urea.Ref: US 4623662 A14. 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

41、) was added to bis(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 acetate and the organic layer was dried over calcium chloride and concentrated under reduced pressure. The res

42、ulting residue was dissolved in dichloromethane (200 ml) and after addition of trimethylsilylcyanide (16.4 ml), titanium tetrachloride (13.4 ml) was added dropwise at 0 degC. The mixture was stirred for 50 min. Methanol (5 ml) was added to the reaction mixture and the mixture was poured into saturat

43、ed aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (21.8 g) oil. Ref: EP1219294 A1 (2002/07/03)4.2 TMSCN 单芳

44、基苄醇氰化反应示例二TMSCNSnCl2 / CH2Cl2To solution 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 wasPage 11 of 17药明康德内部保密资料药明康德新药开发有限公司经典合成反应标准操作 腈的合成added trimethylsilyl cyanide (22.6 mL, 169 mmol) followed b

45、y a slow addition of SnCl 4 (13.6 mL of a 1.0 M solution in CH 2Cl2, 13.6 mmol). The reaction mixture was allowed to warm to room temperature overnight. K2CO3 (18.7 g, 136 mmol) and KFa2H2O (12.8 g, 136 mmol) were added, followed by dropwise addition of H2O (4.30 mL, 239 mmol). The reaction mixture

46、was stirred vigorously for 90 min, after which silica gel (25 g) was added. The mixture was filtered and washed thoroughly with CH2Cl2. The filtrate was washed with saturated aqueous NaHCO3 (250 mL), dried over MgSO 4, filtered, and concentrated to yield 13.2 g oily product of (96% recovery) cyano-4

47、-(1-cyclohexyl-3-ethyl- 1H-indazol-6-yl)cyclohexanecarboxylic acid ethyl ester as a mixture of diastereoisomers. For characterization purposes, a sample of each diastereoisomer was obtained by chromatographic purification on silica gel eluting with 4:1 hexanes/EtOAc.Reference: : Organic Process Rese

48、arch & Development 2001, 5, 587-5925. 用 TosMIC 直接从酮转化为氰基To a 250 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 4.34 g (23.49 mmol) N-carboethoxyperhydroazepin-4-one (prepared according to the procedure given by Z. G. Finney and T. N. Riley, J. Med. Chem., 23, 895, 198

49、0), 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 18 hours, cooled and concentrated. The residue was taken u

50、p in ethyl acetate, washed with brine, dried over sodium sulfate and concentrated to give an oil. The oil was purified by chromatography on silica gel using hexane/ethyl acetate as eluent to afford 4.6 g (100percent) of oil. Reference: 72800; Patent; Pfizer Inc.; Publ.: US5373003 A1 (1994/12/13),6.

51、用2,4,6-三异丙基磺酰肼 -KCN 将酮转化为氰基Page 12 of 17药明康德内部保密资料经典合成反应标准操作 腈的合成 药明康德新药开发有限公司N 2,4,6-triisopropylbenzenesulphonohydrazine NKCNO CN3-Quinuclidinone (24.2 g, 0.19 mol) and 2,4,6-triisopropylbenzenesulphonohydrazide (72 g, 0.24 mol) were stirred together in anhydrous MeOH (250 mL) for 3 h. Potassium c

52、yanide (33.8 g, 0.51 mol) was added and the mixture was heated under reflux for 5 h. The residue after evaporation of the solvent was partitioned between water and CH2C12. The organic phase was dried and evaporated and the residue was fractionally distilled under reduced pressure to give 3-cyanoquin

53、uclidine (32, 6.1 g).Reference: J. Med. Chem. 1990, 33, 1128-11387. 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

54、 14.7 g (0.05 mol) of 5-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 hours while stirring under nitrogen atmosphere. After cooling, the reaction mixture isstirred well with 250 ml of methylene ch

55、loride and 250 ml of 2N hydrochloric acid. The insoluble portions are filtered off with suction filtration and the layers are separated in aseparating funnel. The methylene chloride solution is washed neutral with water and then concentrated by evaporation. The obtained residue was re-crystallized f

56、rom methylene chloride/hexane to give pure 4-chloro-5-cyano-2-methoxybenzoic acid ethyl ester.Ref.: Frontpage/Claim: 59938; Patent; Ciba Geigy Corporation; Publ.: US4559349 A1Page 13 of 17药明康德内部保密资料药明康德新药开发有限公司经典合成反应标准操作 腈的合成(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 1Zn(CN)2Pd(PPh 3)4In a similar fashion, a mixture of 3-(2-pyridyl)-5-(2-bromo-5-met