合成反應(yīng)標(biāo)準(zhǔn)操作

1、經(jīng)典化學(xué)合成反應(yīng)標(biāo)準(zhǔn)操作藥明康德新藥開發(fā)有限公司化學(xué)合成部編寫前 言有機(jī)合成研究人員在做化學(xué)反應(yīng)經(jīng)常碰到常規(guī)的反應(yīng)手邊沒有現(xiàn)成的標(biāo)準(zhǔn)操作步驟而要去查文獻(xiàn)，在試同一類反應(yīng)時(shí)，為了尋找各種反應(yīng)條件方法也得去查資料。為了提高大家的工作效率，因此化學(xué)合成部需要一份經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作。 在這份材料中，我們精選藥物化學(xué)中各類經(jīng)典的合成反應(yīng)，每類反應(yīng)有什么方法，并通過實(shí)際經(jīng)驗(yàn)對(duì)每類反應(yīng)的各種條件進(jìn)行點(diǎn)評(píng)，供大家在摸索合成條件時(shí)進(jìn)行比較。同時(shí)每種反應(yīng)的標(biāo)準(zhǔn)操作，均可作為模板套用于書寫客戶的final report，這樣可以大大節(jié)省研究人員書寫final report的時(shí)間，也相應(yīng)減少在報(bào)告中的文法錯(cuò)誤。另外

2、本版是初版，在今后的工作中我們將根據(jù)需要修訂這份材料。藥明康德新藥開發(fā)有限公司化學(xué)合成部2005-6-28目 錄1. 胺的合成a) 還原胺化b) 直接烷基化c) 腈的還原d) 酰胺的還原e) 硝基的還原f) 疊氮的還原g) Hoffman降解h) 羧酸通過Cris 重排2. 羧酸衍生物的合成a) 酰胺化的反應(yīng)b) 酯化反應(yīng)c) 腈轉(zhuǎn)化為酯和酰胺d) 鈀催化的插羰反應(yīng)e) 酯交換為酰氨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) 有機(jī)金屬試劑的羰基化反應(yīng)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) 酯的直接還原d) 有機(jī)金屬

3、試劑對(duì)腈加成合成酮5. 脂肪鹵代物的合成a) 醇轉(zhuǎn)化為脂肪溴代物通過PBr3 轉(zhuǎn)化通過PPh3 與 CBr4 轉(zhuǎn)化 HBr直接交換 通過相應(yīng)的氯代物或磺酸酯與LiBr交換、b) 醇轉(zhuǎn)化為脂肪氯代物通過SOCl2轉(zhuǎn)化通過PPh3 與 CCl4 轉(zhuǎn)化 HCl直接交換c) 醇轉(zhuǎn)化為脂肪碘代物通過PPh3 與I2 轉(zhuǎn)化 通過相應(yīng)的氯代物或磺酸酯與NaI交換6. 芳香鹵代物的合成a) Sandermyyer 重氮化鹵代b) 直接鹵代c) 雜環(huán)的酚羥基或醚的鹵代7. 醇的合成a) 羧酸或酯的還原b) 醛酮的還原c) 鹵代烴的水解d) 吡啶的氧化轉(zhuǎn)位8. 酚的合成a) Sandermayer 重氮化反應(yīng)b)

4、 醚的水解c) Bayer-vigerlar 氧化d) 硼酸的氧化9. 腈的合成a) 磺酸酯或鹵代烴的取代b) 酰胺的脫水c) 芳鹵代烴的氰基取代10. 硝化反應(yīng)11. 醚的合成a) 芳香醚的合成酚與烷基鹵代烴的直接烷基化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) 胺與異腈酸酯的反應(yīng)b) 用三光氣合成脲c) 羰基二咪唑（CDI）合成脲d) 對(duì)硝基苯酚碳酰胺合成脲13. 烯烴的合成a) Wittig 反應(yīng)b) 羥基的消除c) Wittig-Horner 反應(yīng)合成a,b-不飽和酯14. 磺酸及磺酰氯的合成a) 氯磺化反應(yīng)合成磺酰氯b) 從硫醇

5、合成磺酰氯c) 磺化反應(yīng)15. 氨基酸的合成a) Streck 反應(yīng)合成b) 手性氨基酸的合成16. 偶聯(lián)反應(yīng)a) Suzuki Coupling b) Buckwald 芳胺化，芳酰胺化、c) Heck 反應(yīng)17. Mitsunobu 反應(yīng)a) 醇的反轉(zhuǎn) b) 胺的取代18. 脫羥基反應(yīng)19. 酮還原為亞甲基20. 氨的保護(hù)及脫保護(hù)策略a) 用碳酰胺作保護(hù)基 b) 芐基保護(hù)21. 醇的保護(hù)及脫保護(hù)策略a) 用硅醚進(jìn)行保護(hù)b) 其他醚類保護(hù)22. 羧基的保護(hù)Boc脫保護(hù)-1格氏反應(yīng)-1還原胺化-2鹵化反應(yīng)-2Suzuki coupling-2磺化反應(yīng)-3酯化反應(yīng)-3水解反應(yīng)-3硝化反應(yīng)-4n-

6、BuLi-4LiAlH4還原-4POCl3的雜環(huán)氯代-5NaH-5NBS-5氫化反應(yīng)-6m-CPBA-6EDC-6用三光氣成脲-7芳鹵用n-BuLi處理后與Weinreb酰胺成酮-7Boc上保護(hù)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脫保護(hù)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格氏反應(yīng)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還原胺化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鹵化反應(yīng)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磺化反應(yīng)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酯化反應(yīng)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水解反應(yīng)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硝化反應(yīng)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還原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的雜環(huán)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氫化反應(yīng)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三光氣成脲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