合成反应标准操作

1、经典化学合成反应标准操作药明康德新药开发有限公司化学合成部编写前 言有机合成研究人员在做化学反应经常碰到常规的反应手边没有现成的标准操作步骤而要去查文献，在试同一类反应时，为了寻找各种反应条件方法也得去查资料。为了提高大家的工作效率，因此化学合成部需要一份经典合成反应标准操作。 在这份材料中，我们精选药物化学中各类经典的合成反应，每类反应有什么方法，并通过实际经验对每类反应的各种条件进行点评，供大家在摸索合成条件时进行比较。同时每种反应的标准操作，均可作为模板套用于书写客户的final report，这样可以大大节省研究人员书写final report的时间，也相应减少在报告中的文法错误。另外

2、本版是初版，在今后的工作中我们将根据需要修订这份材料。药明康德新药开发有限公司化学合成部2005-6-28目 录1. 胺的合成a) 还原胺化b) 直接烷基化c) 腈的还原d) 酰胺的还原e) 硝基的还原f) 叠氮的还原g) Hoffman降解h) 羧酸通过Cris 重排2. 羧酸衍生物的合成a) 酰胺化的反应b) 酯化反应c) 腈转化为酯和酰胺d) 钯催化的插羰反应e) 酯交换为酰氨3. 羧酸的合成a) 醇氧化b) 酯水解c) 酰胺的水解d) 腈的水解e) 有机金属试剂的羰基化反应f) 芳香甲基的氧化4. 醛酮的合成a) Weinreb 酰胺合成醛酮b) 醇氧化c) 酯的直接还原d) 有机金属

3、试剂对腈加成合成酮5. 脂肪卤代物的合成a) 醇转化为脂肪溴代物通过PBr3 转化通过PPh3 与 CBr4 转化 HBr直接交换 通过相应的氯代物或磺酸酯与LiBr交换、b) 醇转化为脂肪氯代物通过SOCl2转化通过PPh3 与 CCl4 转化 HCl直接交换c) 醇转化为脂肪碘代物通过PPh3 与I2 转化 通过相应的氯代物或磺酸酯与NaI交换6. 芳香卤代物的合成a) Sandermyyer 重氮化卤代b) 直接卤代c) 杂环的酚羟基或醚的卤代7. 醇的合成a) 羧酸或酯的还原b) 醛酮的还原c) 卤代烃的水解d) 吡啶的氧化转位8. 酚的合成a) Sandermayer 重氮化反应b)

4、 醚的水解c) Bayer-vigerlar 氧化d) 硼酸的氧化9. 腈的合成a) 磺酸酯或卤代烃的取代b) 酰胺的脱水c) 芳卤代烃的氰基取代10. 硝化反应11. 醚的合成a) 芳香醚的合成酚与烷基卤代烃的直接烷基化Mitsunobu 芳香醚化Buckwald芳香醚化b) 脂肪醚的合成醇的醚化12. 脲的合成a) 胺与异腈酸酯的反应b) 用三光气合成脲c) 羰基二咪唑（CDI）合成脲d) 对硝基苯酚碳酰胺合成脲13. 烯烃的合成a) Wittig 反应b) 羟基的消除c) Wittig-Horner 反应合成a,b-不饱和酯14. 磺酸及磺酰氯的合成a) 氯磺化反应合成磺酰氯b) 从硫醇

5、合成磺酰氯c) 磺化反应15. 氨基酸的合成a) Streck 反应合成b) 手性氨基酸的合成16. 偶联反应a) Suzuki Coupling b) Buckwald 芳胺化，芳酰胺化、c) Heck 反应17. Mitsunobu 反应a) 醇的反转 b) 胺的取代18. 脱羟基反应19. 酮还原为亚甲基20. 氨的保护及脱保护策略a) 用碳酰胺作保护基 b) 苄基保护21. 醇的保护及脱保护策略a) 用硅醚进行保护b) 其他醚类保护22. 羧基的保护Boc脱保护-1格氏反应-1还原胺化-2卤化反应-2Suzuki coupling-2磺化反应-3酯化反应-3水解反应-3硝化反应-4n-

6、BuLi-4LiAlH4还原-4POCl3的杂环氯代-5NaH-5NBS-5氢化反应-6m-CPBA-6EDC-6用三光气成脲-7芳卤用n-BuLi处理后与Weinreb酰胺成酮-7Boc上保护To a solution of A (2.72 g, 13.9 mmol) and tetramethylammonium hydroxide pentahydrate (5.62 g, 31.0 mmol) in acetonitrile (270 mL) was added di-tert-butyldicarbonate (3.79 g; 17.4 mmol) and the resulting

7、 solution was allowed to stir 18 h at rt and concentrated. The residue was partitioned between Et2O/H2O; the phases were separated and the aqueous phase extracted twice more with Et2O. The aqueous phase was brought to pH 4 with solid citric acid and extracted with CHCl3 (3.x.100 mL). The organic ext

8、racts were combined, dried (Na2SO4) and concentrated to afford 2.58 g (63 percent) B as a white foam.ReturnBoc脱保护Tert-Butyl 2-(2-methoxyphenoxy)ethylcarbamate (23.8 g, 89 mmol) in dichloromethane (10 ml) was cooled to 0 deg C and stirred as a mixture of trifluoroacetic acid: dichloromethane (1:1, 40

9、 ml) was added dropwise. The mixture was allowed to warm to rt, stirred for 2 hours and concentrated in vacuo. The residue was taken back up in dichloromethane (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3*20 ml) and aqueous sodium hydroxide (10percent, 3*2

10、0 ml), dried (Na2SO4), filtered and concentrated in vacuo to provide 2-(2-methoxyphenoxy)ethylamine (13 g, 88percent yield) as a light yellow solid.Return格氏反应A stirred mixture of magnesium turnings (23.6 g, 0.98 mol) and Et2O (200 mL) under nitrogen is treated with a crystal of iodine and about 5per

11、cent of a solution of bromoethane (56.3 ml, 0.75 mol) in Et2O (375 mL). When the reaction starts, the remainder of the bromoethane solution is added, dropwise at a rate sufficient to maintain a gentle reflux. After the addition, stirring is continued for 1 hour. To this solution of ethylmagnesium br

12、omide was slowly added a solution of 4-cyanopyridine (39 g, 0.375 mol) in Et2O (750 ml). The reaction mixture was warmed at reflux for 12 hours, treated with concentrated H2SO4 (125 ml)/H2O (125 ml), and then washed three times with Et2O (250 ml). The aqueous portion was made basic (PH 9) with 15per

13、cent NaOH solution and extracted five times with 250 ml portions of Et2O. The combined Et2O extracts were dried (MgSO4), and the solvent was removed under reduced pressure to afford a brown oil (48.4 g, 95percent).Return还原胺化A solution of 2-amino-4-ethylphenol (1.00 g. 7.28 mmol), 2-naphthaldehyde (1

14、.13 g, 7.28 mmol), and p-toluenesulfonic acid (0.05 g) in methanol (50 ML) was stirred at room temp for 24 h. To the resultant solution, sodium borohydride (0.82 g, 22 mmol) was added in small portions. After addition was completed, the mixture was stirred at room temperature for 30 min and concentr

15、ated under vacuum. The residue was then subjected to column chromatography on silica gel eluted with 10percent ethyl acetate in hexane and followed by recrystallization (aqueous methanol) yielded 450 mg (22percent) of analytically pure product.Return卤化反应To a stirred solution of 8-methyl-1-nitro-naph

16、thalene (10.6g, 56.32 mmol) and iron (III) chloride (0.45 g, 2.77 mmo) in CCl4 (150 ml) heated to 60°C was added dropwise (3.0 ml, 58.23 mmol) of bromine. After one hour, the reaction mixture was poured into saturated NaHCO3 solution, and the layers were separated. The aqueous layer was re-extr

17、acted with CH2Cl2. The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure. The crude residue was recrystallized from ethanol and the mother liquors were concentrated and then flash chromatographed on silica, eluding hexanes:ethyl acetate (12: 1).ReturnSuzuk

18、i couplingTo a mixture of 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indole (2 g, 8.2 mnmol) and 3-bromobenzene (0.87 ml, 8.3 mmol) in THF (28 ml) were added palladium catalyst Pd(PPh3)4 (284 mg, 0.25 mmol) and the freshly prepared sodium hydroxide solution (984 mg in 9 ml of water).The syste

19、m was degassed and then charged with nitrogen for three times. The mixture was stirred under nitrogen at 70 °C oil bath for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and separated from water layer. The ethyl acetate solution was washed by brine, d

20、ried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluding with hexanes: EtOAc 9:1 to give 1.38 g (78%yield) of 4-phenyl-1H-indole as a colorless liquid.Return磺化反应Chlorosulfonic acid (4.66g, 40 mmol) is added dropwise to a cold (0°C) solution of 2,3-dihydro-2-tri

21、fluoroacetyl-1H-Benzdeisoquinoline (2.9g, 8 mmol) in chloroform (800 ml). The resulting solution is stirred at 0°C for 30 minutes.The cold bath is then removed and the solution is stirred at room temperature for 1 hour then cautiously poured into ice water. The organic layer is separated, dried

22、 over magnesium sulfate and concentrated to afford the title compound.The crude product is purified by column chromatography eluted with 10% acetic ether in petroleum ether (2.36 g, 81% yield).Return酯化反应A mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 ml), and concentrate H2

23、SO4 (2 ml) was refluxed overnight. The insolubles were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with aqueous NaHCO3 (2*), brine, dried over MgSO4, and concentrated to give a yellow oil. Silica gel column chromatography using ethyl acetate/h

24、exane (1/3) gave the desired product as a yellow oil (3.3 g, 35%yield).Return水解反应A solution of 1-Methyl-naphthalene-2-carboxylic acid methyl ester (7.20g, 35mmol) and 2N sodium hydroxide (35ml) in tetrahydrofuran (130ml) was stirred under reflux for 18 hours. The mixture was neutralised using 2N hyd

25、rochloric acid, and extracted with dichloromethane (3x). The combined organic solutions were dried (MgSO4), and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gelusing an elution gradient of dichloromethane: methanol (100:0 to 97:3) to afford the

26、 title compound as a solid (3.11g, 47.8%yield).Return硝化反应To a cold (0°C) suspension of 1-methylnaphthalene (5 g, 35.2 mmol) in HNO3 was added H2SO4 (5 ml) dropwise. After stirring the reaction for one hour, the solution was diluted with ethyl acetate and washed with water (3*), aqueous saturate

27、d NaHCO3 (2*) and brine, dried over MgSO4, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate: hexane (5: 95) and recrystallized from methanol to give yellow needles (0.22g, 33% yield).Returnn-BuLiTo a dry three-necked round-bottomed flask with an addi

28、tion funnel and at -78°C under inert atmosphere was charged with anhydrous THF (500 ml). A solution of n-butyllithium (2.5 M in hexane, 88 ml, 220 mmol) was added dropwise followed by addition of a solution of acetonitrile (10.43 ml, 200 mmol) in anhydrous THF (100 ml). The internal temperature

29、 was maintained below -70°C during the entire addition process. After 2 hr at -78°C a solution of Trifluoro-acetic acid ethyl ester (14.2 g, 100 mmol) in anhydrous THF (30 ml) was added dropwise and the mixture was stirred for 1.5 hr. To the mixture was added acetic anhydride to quench the

30、 reaction. The reaction mixture was allowed to warm up to rt. A precipitate was filtered and the filtrate was concentrated to give a brown oil, which was used in the next step without purification. ReturnLiAlH4还原A solution of 2,3-naphthalenedicarboxylic acid (4.6 g, 0.023 mole) in dry THF (135 ml, w

31、armed to 50° to maintain solution) is added dropwise over 15 minutes to a 1.15 M lithium aluminum hydride solution in THF (45 ml, 0.052 mole). The solution is stirred 3 hours after which TLC indicated consumption of diacid and formation of a new major product. The reaction is quenched carefully

32、 with THF-water, then 2N hydrochloric acid (40 ml) is added, and the resulting mixture is extracted 3 times with ether. The combined ether extracts are washed with water (2 times), with saturated sodium bicarbonate solution (1 time), with water, and are dried (sodium sulfate), filtered, and concentr

33、ated to give a tan solid (3.67 g). The solid is recrystallized from ethyl acetate giving the title compound (2.91 g, 67.3%yield) as a light tan crystalline material.ReturnPOCl3的杂环氯代To a suspension of 2,4-dihydroxy-5,6-dimethylpyrimidine (6.2 g, 0.044 mol) in POCl3 (25 ml) was slowly added N,N-dimeth

34、ylaniline (6.18 ml, 0.049 mol). The mixture was then refluxed at 125 °C for 3 hours. After this time, the starting material completely dissolved indicating that the reaction was completed.The reaction mixture was cooled and then poured slowly onto ice to quench the POCl3 (cautionexothermic). A

35、precipitate formed, which was filtered and washed with ice-cold water. The precipitate was dried under high vacuum overnight to yield 2,4-dichloro-5,6-dimethyl-pyrimidine (7.2 g, 0.041 mol, 92%yield) as a yellow solid.ReturnNaHSodium hydride (50% in mineral oil, 5.5 g, 0.11 mol) was added portionwis

36、e at 0 °C under a nitrogen atmosphere to a solution of 2-aminobenzenethiol (12 ml, 0.1 mol) in DMF (120 ml). After 0.5 h, benzyl chloride (11.5 ml, 0.1 mol) in DMF (80 ml) was added in 0.5 h. The solution was stirred for 3 h while the temperature was allowed to rise to rt, then it was poured in

37、to ice/water (1000 g). The precipitate was filtered, dissolved in ethyl acetate and washed with brine. The organic layer was dried over Na2SO4 and evaporated. The solid obtained was ground in pentane (19.3 g, 90% yield).ReturnNBSA mixture of 2,4-Dichloro-6-ethyl-5-fluoro-pyrimidine (27.46 g， 0.14mol

38、), AIBN (1.32 g) and n-bromosuccinimide (27.02 g， 0.152mol) in CH2Cl2 (170 ml) was refluxed under a nitrogen atmosphere for 36 h. Then washed by water, the aqueous was extracted by CH2Cl2. The combined organic layer was washed by saturated Na2S2O3 and brine, dried over Na2SO4, and evaporated to give

39、 a white solid which was purified by column chromatography eluted with 50% acetic ether in petroleum ether (34 g, 88.6% yield).Return氢化反应A mixture of ethyl 3-(N-benzylamino)-3-methylbutyrate hydrochloride (25g, 0.1 mol) and 10percent Pd-C (2g) in 250 ml of dried alcohol was hydrogenated under 55 psi

40、 H2 for four days. The reaction medium was then filtered and evaporated under reduced pressure to provide an amber oil which gradually crystallized upon standing (18 g, 100% yield).Returnm-CPBAA solution of 85% m-chloroperoxybenzoic acid (19 g, 94 mmol) in CH2Cl2 (350 ml)was added at 5 0 °C to

41、a solution of 2-Benzylsulfanyl-phenylamine (19 g, 88 mmol) in CH2Cl2 (400 ml). The mixture was allowed to warm to rt in 3 h, then it was washed with a 5% Na2S2O3 solution, 10% NaHCO3 solution and brine. The organic layer was dried over Na2SO4, and evaporated. The solid was ground in pentane (19 g, 9

42、5% yield).ReturnEDCTo a 0°C mixture of Boc-L-tyrosine (2.04 g, 7.26 mmol) and amylamine (0.63 gl, 7.26 mmol) in methylene chloride (30 ml) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (1.53 g, 9.9 mmol). The white mixture is stirred at 0°C for 5 min and at room temp for 23

43、hrs. The resulting solution is diluted with methylene chloride (30 ml) and washed successively with 0.5 M HCl (40 ml), water (20 ml) and sat aq sodium bicarbonate (25 ml). The organic phase is dried over magnesium sulfate and concentrated to a foam (1.84 g, 72.4%yield), sufficiently pure to carry in

44、to the next step. An analytical sample is obtained by HPLC.Return三光气成脲To a solution of 2-(tert-butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) in toluene (10 ml) triethylamine (0.13 ml, 1.64 mmol) and triphosgene (88.4 mg, 0.3 mmol) were added. The reaction mixture was stirred at 70 °C for 2 hours, then cooled to room temperature. Then more 2-(tert -butyldimethylsilylo