药明康德_有机反应的后处理

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药明康德有机反应的后处理PPT培训课件

LAH
DIBAL-H
Lithium Aluminum Hydride
Diisobutyl Aluminum Hydride
(x g):
(x mmol):
1. 用适量乙醚稀释后冷却到0 0C； 1. 用适量乙醚稀释后冷却到0 0C；
2. 慢慢加入x mL水；
2. 慢慢加入0.04x mL水；
3. 加入x mL 15 %氢氧化钠水溶液； 3. 加入0.04x mL 15%氢氧化钠水溶液；
Boron Compounds
加入MeOH，生成了(MeO)3B，旋蒸除去
PCC/PDC 通过硅藻土、硅酸镁载体等过滤除去
Jones Reagent
加入异丙醇直至反应体系颜色从橙色或红色变成绿色
Copper Salts
用饱和NH4Cl水溶液来淬灭反应，再在室温下搅拌一段时间至溶液成深蓝色，分掉水相
E
O
~10% ~95%
常见特殊试剂的淬灭及处理
PPh3P=O
O P
极性相对较小的产物，可以将反应混合物悬浮于hexane/ether的混合溶剂中，通过非常短的硅胶柱过滤，用醚类作为洗脱剂。
OTf
B(OH)2 NHBoc
N
1
N EtOOC
N S
2
Pd(PPh3)4 /Na2CO3 1, 4-Dioxane
吸附／干燥
常见特殊试剂的淬灭及处理
在后处理前，推荐取一点反应液留作样品，以供对后处理好的反应液对照比较。
Notes:
选择合适的淬灭试剂，要充分考虑到产物的稳定性以及后处理的难易程度; 如果淬灭过程会大量放热，须在冷却下进行淬灭; 不要过分依赖文献，而不对反应进行监控。只有当TLC或其他分析手段显示反应结束，才能对反应进行淬灭; 可能的话，后处理应在淬灭后尽快进行。

经典合成反应标准操作药明康德目录

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)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α,β-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 Couplingb)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.羧基的保护格氏反应---------------------------------------------------------------------------------------------------------1还原胺化---------------------------------------------------------------------------------------------------------2卤化反应---------------------------------------------------------------------------------------------------------2 Suzuki coupling-------------------------------------------------------------------------------------------------2磺化反应---------------------------------------------------------------------------------------------------------3酯化反应---------------------------------------------------------------------------------------------------------3水解反应---------------------------------------------------------------------------------------------------------3硝化反应---------------------------------------------------------------------------------------------------------4 n-BuLi------------------------------------------------------------------------------------------------------------4 LiAlH4还原-----------------------------------------------------------------------------------------------------4 POCl3的杂环氯代----------------------------------------------------------------------------------------------5 NaH---------------------------------------------------------------------------------------------------------------5 NBS---------------------------------------------------------------------------------------------------------------5m-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OHH 2NHO OOOOOO OHN HO OHO O ABTo 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 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 extracts were combined, dried (Na2SO4) and concentrated to afford 2.58 g (63 percent) B as a white foam.ReturnBoc 脱保护OON HOOOOH 2NTert-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 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*20 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NCNNOA 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 5percent 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 bromide 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 15percent 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OHO H 2N+HON HA solution of 2-amino-4-ethylphenol (1.00 g. 7.28 mmol), 2-naphthaldehyde (1.13 g, 7.28 mmol), andp-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 concentrated 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O2N O2NBrTo a stirred solution of 8-methyl-1-nitro-naphthalene (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-extracted 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).ReturnSuzuki couplingBrBOO NH+NH To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (2 g, 8.2 mnmol) and3-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 system was degassed and then charged with nitrogen for three times. The mixture was stirred under nitrogen at 70 °Coil 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, dried 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NOFFFNOFFFSOClOChlorosulfonic acid (4.66g, 40 mmol) is added dropwise to a cold (0°C) solution of2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline (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 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HOHO O HOO OA mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 ml), and concentrate H2SO4(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/hexane (1/3) gave the desired product as a yellow oil (3.3 g, 35%yield).Return水解反应OO OHOA 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 hydrochloric 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 title compound as a solid (3.11g, 47.8%yield).Return硝化反应NO 2To 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 saturated 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-BuLiEtOCF 3O CF 3O NCTo a dry three-necked round-bottomed flask with an addition 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, 88ml, 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 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 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HOHO O OHOHOA solution of 2,3-naphthalenedicarboxylic acid (4.6 g, 0.023 mole) in dry THF (135 ml, warmed 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 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 concentrated 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NN HOOHN NClClTo a suspension of 2,4-dihydroxy-5,6-dimethylpyrimidine (6.2 g, 0.044 mol) in POCl3 (25 ml) was slowly added N,N-dimethylaniline (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(caution[exothermic]). A 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.ReturnNaHHSH 2N Cl +SNH 2Sodium hydride (50% in mineral oil, 5.5 g, 0.11 mol) was added portionwise 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 into 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).ReturnNBSNN FCl ClNBSN N FCl ClBrA mixture of 2,4-Dichloro-6-ethyl-5-fluoro-pyrimidine (27.46 g ， 0.14mol), 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 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O ONH OONH2Cl ClA 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 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-CPBAS NH2SNH2OA solution of 85% m-chloroperoxybenzoic acid (19 g, 94 mmol) in CH2Cl2 (350 ml)was added at –5 –0 °C to 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, 95% yield).ReturnEDCNH2OHNOO+HOHOHNOOTo 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). Thewhite mixture is stirred at 0°C for 5 min and at room temp for 23 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 into the next step. An analytical sample is obtained by HPLC.Return三光气成脲NH 2ONO 2Si O Cl Cl ClO O Cl Cl ClO 2NHN H NO OHOHNO 2+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-butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) was added. The resulting mixture was allowed to stir at 70 °C for 48 hours then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane: ethyl acetate, 10:1) gave 1,3-Bis-(2-hydroxy-4-nitro-phenyl)-urea (130 mg, 31%yield).Return芳卤用n-BuLi处理后与Weinreb酰胺成酮N FFFFNOO+FFFO NFTo a solution of diisopropylamine (17.69 ml, 0.135 mole) in THF (200 ml) at –78°C under argon was added n-butyllithium (54.0 ml, 2.5M in hexane, 0.135 mole), followed after 5 min by dropwise a solution of 2-fluoro-4-methylpyridine (10 g, 0.090 mole) in THF (20 ml). After stirring for 15 min at –78°C, a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 ml) was added dropwise. After stirring for more 5 min, the reaction was allowed to warm to 0°C and quenched by pouring into water (400 ml) and ethyl acetate (400 ml). The layers were separated, and the aqueous layer washed with ethyl acetate (200 ml). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel with 20percent ethyl acetate in hexane to give 21.6 g of 2-(2-Fluoro-pyridin-4-yl)-1-(3-trifluoromethyl-phenyl)-ethanone (84.8%yield).Return。

有机合成中的后处理

有机合成中的后处理后处理的几个常用而实用的方法：（1）有机酸碱性化合物的分离提纯具有酸碱性基团的有机化合物，可以得失质子形成离子化合物，而离子化合物与原来的母体化合物具有不同的物理化学性质。

碱性化合物用有机酸或无机酸处理得到胺盐，酸性化合物用有机碱或无机碱处理得到钠盐或有机盐。

根据有机化合物酸碱性的强弱，有机、无计酸碱一般为甲酸、乙酸、盐酸、硫酸、磷酸。

碱为三乙胺、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠等。

在一般情况下，离子化合物在水中具有相当大的溶解性，而在有机溶剂中溶解度很小，同时活性碳只能够吸附非离子型的杂质和色素。

利用以上的这些性质可对酸碱性有机化合物进行提纯。

以上性质对所有酸碱性化合物并不通用，一般情况下，分子中酸碱性基团分子量所占整个分子的分子量比例越大，则离子化合物的水溶性就越大，分子中含有的水溶性基团例如羟基越多，则水溶性越大，因此，以上性质适用于小分子的酸碱化合物。

对于大分子的化合物，则水溶性就明显降低。

酸碱性基团包括氨基。

酸性基团包括：酰氨基、羧基、酚羟基、磺酰氨基、硫酚基、1，3－二羰基化合物等等。

值得注意的是，氨基化合物一般为碱性基团，但是在连有强吸电子基团时就变为酸性化合物，例如酰氨基和磺酰氨基化合物，这类化合物在氢氧化钠、氢氧化钾等碱作用下就容易失去质子而形成钠盐。

中合吸附法：将酸碱性化合物转变为离子化合物，使其溶于水，用活性碳吸附杂质后过滤，则除去了不含酸碱性基团的杂质和机械杂质，再加酸碱中合回母体分子状态，这是回收和提纯酸碱性产品的方法。

由于活性碳不吸附离子，故有活性碳吸附造成的产品损失忽劣不计。

中和萃取法：是工业过程和实验室中常见的方法，它利用酸碱性有机化合物生成离子时溶于水而母体分子状态溶于有机溶剂的特点，通过加入酸碱使母体化合物生成离子溶于水实现相的转移而用非水溶性的有机溶剂萃取非酸碱性杂质，使其溶于有机溶剂从而实现杂质与产物分离的方法。

成盐法：对于非水溶性的大分子有机离子化合物，可使有机酸碱性化合物在有机溶剂中成盐析出结晶来，而非成盐的杂质依然留在有机溶剂中，从而实现有机酸碱性化合物与非酸碱性杂质分离，酸碱性有机杂质的分离可通过将析出的结晶再重结晶，从而将酸碱性有机杂质分离。

药明康德-醇的制备

+
+
-
-
O Cl
RCHO
+
+
+
+ 22
3.1 醛和酮转变为醇
反应的功能基
CN
生成的功能基
-CH2NH2 or -CH=N →-CHO
LiAlH4
+
NOH
NH2
+
R NO2
R-NH2
+
CH2OSO2Ph or -CH2Br
-CH3
+
O S
NH2
+
OH
-CH2NR2
+
NC S
-NHCH3
+
Ph NO2
PhN=NPh
+
N
o
N
+
RSSR or RSO2Cl
RSH
+
注：表中+表示功能基能被还原，-表示不能被还原。
LiBH4
+ + + + + + +
NaBH4
+ + + + + + +
KBH4
+ + + + + + +
23
3.1 醛和酮转变为醇
3.1.6 醇铝还原剂还原(Meerwein-Ponndorf-Verley Reaction):
H H2N
CHMe2 CO2H
BH3. SMe2 BF3. OEt2
H H2N
HO
CHMe2
10
1.2 羧酸还原为醇

药明康德Level 2题目-烃化反应

是非题:1.采用卤代烷对醇进行烷基化反应，氟代烷活性最高，碘代烷活性最低。

（）2.碱性条件下，烷氧负离子进攻环氧化合物开环，主要受电性控制，进攻发生在取代较多的碳原子上。

（）3.由于酚负离子亲核性比烷氧基负离子弱，以卤代烷为烷基化剂，酚的烷基化反应较醇难以进行，需要采用更强的碱。

（）4.邻羟基苯甲酸与对羟基苯甲酸相比，由于邻羟基苯甲酸含有分子内氢键，酚羟基酸性更强，烃化反应更容易进行。

（）5.硫酸二甲酯是一种常用的甲基化试剂，由于硫酸二甲酯含有两个甲基，可以甲基化两个当量的醇。

（）6.硫酸二甲酯活性较碘甲烷弱，一般只能用于甲基化醇，不能用于甲基化酚。

（）7.羧酸比酚更容易被重氮甲烷甲基化。

（）8.DCC不仅可以用于酸和醇缩合，也可用于酚和醇缩合生成醚。

（）9.Mitsunobu反应用于手性醇对酚的烷基化反应中，手性醇的构型会发生反转。

（）10.醇在碱性条件下与芳基卤代物发生亲核取代反应，碘代芳烃活性最低，氟代芳烃活性最高。

（）11.Cu催化的芳基卤化物与芳香胺的偶联反应中，碘代芳烃活性最低，氟代芳烃活性最高。

（）12.Chan-Lam偶联是铜催化下的硼酸或硼酯与胺，酚或醇等的反应，和Suzuki反应类似，Chan-Lam偶联对氧气比较敏感，需要在惰性气体保护下进行，但对水不敏感，加水一般可以促进反应。

（）13.Friedel-Crafts烷基化反应中，伯卤代烷由于位阻最小，反应活性也最高。

（）14.Friedel-Crafts烷基化反应中，氟代烷反应活性最高，碘代烷活性最低。

（）15.三氯化铝是Friedel-Crafts反应中最常用的催化剂，但一般不适用于催化富电子杂环如呋喃或吡咯的烷基化。

( )16.叔卤代烷由于在碱性条件下易消除，一般不适用于活泼亚甲基化合物的烷基化。

( )17.酮的α位碳在碱性条件下拔氢，在动力学控制条件下易于生成取代基少的烯醇负离子。

( )18.由于醛在碱性条件下易发生羟醛缩合，对醛的α位烷基化可以采用烯胺烷基化的间接方法。

药明康德英文实验记录表述(2)

Sentence Template for Notebook and Report WritingPfizer Project Management TeamApril 12, 2007Part 1: 反应前的装置描述1.1: A 3 L three-necked round bottom flask equipped with mechanical stirrer (or magnetic stirrer), addition funnel and thermometer (or Dean-Stock; drying tube)1.2: All flasks used in the reaction were heated under vacuum for 30 minutes and purged with N2 for 10 minutes. (无水反应装置)Part 2: 加料2.1: 不同的顺序和表达2.1.1: A 3 L three-necked round bottom flask equipped with mechanical stirrer (or magnetic stirrer), addition funnel and thermometer (or Dean-Stock; drying tube) were charged with A (10 mL, 1 mole), B (2 g, mole) and C (50 mL),2.1.1.1: a solution of D (10 g, 1 mole) in E (20 mL) was added dropwise (via addition funnel or syringe) at 10o C (or while maintaining gentle reflux; while keeping inner temperature between 10o C – 30o C) under N2 （液体滴加到反应液中）2.1.1.2:D (10 g, 1 mole) was added in portions during a period of 1 hr (固体分批加入到反应液中)2.1.1.3: D (10 g, 1 mole) and E (20 mL) were added in turn2.2:To a solution (mixture, suspension or slurry) of A (10 mL, 1 mole) and B (2 g, mole) in C (50 mL)2.2.1: was added dropwise a solution of D (10 g, 1 mole) in E (20 mL) with stirring at 10o C (or while maintaining gentle reflux; while keeping inner temperature between 10o C – 30o C) under N22.2.2: was added D (10 g, 1 mole) in portions during a period of 1 hr2.2.3: were added D (10 g, 1 mole) and E (20 mL) in turn2.3:2.3.1: A solution of D (10 g, 1 mole) in E (20 mL) was added dropwise into a solution (mixture or suspension) of A (10 mL, 1 mole) and B (2 g, mole) in C (50 mL) at 10o C (or while maintaining gentle reflux; while keeping inner temperature between 10o C – 30o C) under N22.3.2:D (10 g, 1 mole) was added into a solution (mixture or suspension) of A (10 mL, 1 mole) and B (2 g, mole) in C (50 mL) in portions2.3.3:D (10 g, 1 mole) and E (20 mL) were added into a solution (mixture or suspension) ofA (10 mL, 1 mole) andB (2 g, mole) inC (50 mL) in turn2.4:2.4.1: A solution of BuLi or BH3/THF (10 mL, 1 mole, 2.5 M in hexane) was cannulated into addition funnel or into a solution A in solvent B2.4.2: A solution of BuLi or BH3/THF (10 mL, 1 mole, 2.5 M in hexane) was added into a solution of A in solvent B via cannula, dropping funnel or syringe over a period of hrsPart 3: 反应3.1: 无溶剂反应A (1 g, 1 mol) andB (1 g, 1 mol) were dissolved in solvent C, evaporated to dryness and heated for x hours at x o C3.2: 催化量的反应A (20 mL, 142 mmol) and catalytic amount (a trace amount or two drops) ofB were added into a solution ofC (4.549 g, 46.4 mmol) in D(120mL) at 0 o C3.3: 闷罐反应或封管反应A solution of A (x g, x mol) in methanol (x mL) saturated with NH3 (or other gas such as: CO, CO2, H2S) was stirred under 50 Psi at x o C for x hours in a 50 mL of sealed tube or autoclave.3.4: 有气体参与的反应3.4.1: A solution of A (x g, x mol) in methanol (x mL) saturated with HCl was stirred at x ℃.3.4.2: Ozone was bubbled into a solution of A (x g, x mol) in MeOH (x mL) at x o C for 15 minutes. After excess O3 was purged by N2, Me2S (x mL) was added at x o C.3.4.3: Gas was bubbled into a solution of A (x g, x mol) and B (x g, x mol) in solvent C (x mL) at x o C for x hours.3.5: 混合溶剂参与的反应3.5.1: To a solution of A (x g, x mol) in a mixture of solvent B (mL) and solvent C (x mL) (ora mixed solvent of B and C) was added D (x g, x mol) at x o C, the reaction mixture was allowed to stir (reflux or heat) for x hrs.3.5.2: To a solution of A (x g, x mol) in 10: 1 aqueous acetone (x mL) was added B (x g, x mol) followed by addition of C (x g, x mol), the reaction mixture was allowed to stir (reflux or heat) for x hrs.3.6: 分水器分水的反应3.6.1:A (x g, x mol) and B (x g, x mol) in benzene or toluene (x mL) were refluxed for x hours with azeotropical removal of water.3.6.2; A mixture of A, B and TsOH.H2O (56.91 g, 0.3 mol) in toluene (400 mL) was heated to reflux and remove water by Dean-Stark trap.3.7: 氢化反应To a solution of A (x g, x mol) in EtOH (x mL) was added Pd-C or Ra-Ni or Pd(OH)2/C (10%, x g) under N2. The suspension was degassed under vacuum and purged with H2 several times.3.7.1: The mixture was stirred under H2 (x psi) at x ℃for x hours. [氢化瓶或高压釜]3.7.2: The mixture was stirred under H2 balloon at x ℃for x hours. [常压氢化如气球反应] 3.7.3: A mixture of A (x g, x mol) and Ra-Ni (x g) in EtOH (x mL) was hydrogenated under 50 Psi of hydrogen pressure for x hours at room temperature.Part 4: 反应条件或过程描述4.1: The reaction mixture (solution or suspension) was stirred at 5o C for 2 hrs and then kept at room temperature (or ambient temperature) for another 2 hrs (or overnight)4.2: The reaction mixture (solution or suspension) was refluxed (heated to reflux) or heated at 60o C for 2 hrs (or overnight)4.3: The reaction mixture (solution or suspension) was allowed to reflux (or heat to reflux) for 2 hrs (or overnight)4.4: The reaction mixture (solution or suspension) was allowed to warm to temperature during 2 hrs and reflux (or heat to reflux) for 2 hrs (or overnight)Part 5: 反应监测5.1: Taking sample from the reaction mixture (solution or suspension) by dropping tube or syringe. After workup, check the reaction via TLC, LC-MS or HPLC etc.. (预处理)5.2:反应状态或终点描述5.2.1: The reaction was complete (incomplete or messy) detected (determined or confirmed) by TLC (PE/EtOAc 4:1), LC-MS, HPLC or NMR5.2.2: TLC (PE:EtOAc=1:1) or HPLC (107757-088-1) showed or indicated that the reaction was complete.5.2.3: TLC (PE:EtOAc=1:1) or HPLC (107757-088-1) showed the starting material was consumed completely.5.2.4: TLC (PE:EA=1:1) or HPLC (107757-088-1) showed the reaction didn’t work at all or most of starting material was still remained.5.2.5: The starting material was consumed completely, but no desired compound was detected or determined by MS (106657-078-1) or LC-MS (106657-078-1).5.2.6: Several spots were shown on TLC.5.2.7: Only a trace amount of desired compound was detected by MS (106657-078-1) or LC-MS (106657-078-1) or HPLC (106657-078-1) or TLC (PE:EtOAc=1:1).5.2.8: The desired compound could not be isolated, separated or purified by chromatography or prep. HPLC due to poor yield or poor solubility.5.2.9:1H NMR (106675-010-2) or MS confirmed the obtained (or isolated) compound is not the desired compound. The reaction was failed.Part 6: 反应淬灭6.1: An aqueous solution of A (10 mL) was added dropwise into the reaction mixture once the reaction mixture (solution or suspension) was allowed to warm (or cool) to -5o C or room temperature (ambient temperature).6.2: The hot (or cold) reaction mixture (solution or suspension) was poured into water (ice water) or poured onto ice.6.3: The reaction mixture (solution or suspension) was concentrated (distilled) under reduced pressure (in vacuum) or evaporated to remove MeOH (THF; DMF etc.) or excess SOCl2 (reagent). Then the reaction residue (or the residual) was diluted with solvent and poured into water (ice water) or poured onto ice.Part 7: 分液提取7.1: The residue was partitioned between ethyl acetate (100 mL) and 1N aq. HCl (50 mL). The separated organic layer was washed with water, dried over (Na2SO4 or MgSO4) and evaporated to dryness.7.2: After quenching the reaction, the reaction mixture was poured into separatory funnel and separated.7.3: The aqueous layer (or phase) was extracted with organic solvent (40 mL) twice (or X times). The combined organic layers were (or the organic layers were combined and) washed with an aqueous solution of A (50 mL) or water and dried over Na2SO4 or MgSO4.7.4: The combined aqueous layers were extracted with solvent (40 mL) twice (or X times) to remove neutral impurities. The aqueous phase was acidified (or basified) with aqueous HCl (or NaHCO3) till PH = X and extracted with organic solvent.7.5: The combined organic layers were (or the organic layers were combined and) washed with an aqueous solution of A (50 mL) or water and dried over Na2SO4 or MgSO4.Part 8: 浓缩蒸发8.1: After filtration via filter paper or Celite pad, the organic layer (or extract) was concentrated under reduced pressure (or in vacuum) or evaporated to dryness to provide (afford; give or yield) an oil (or foam) (which solidified on standing) or a white solid.8.2: The organic layer (or extract) was filtered and concentrated under reduced pressure (or in vacuum) or evaporated to dryness to provide (afford or give) A (10 g, 0.5 mole) an oil (or foam) (which solidified on standing) or a white solid.8.3: After removal of solvent by evaporation or concentration, A (10 g, 0.5 mole) was obtained (or prepared) an oil (or foam) (which solidified on standing) or a white solid.8.4: The extract in CH2Cl2 was evaporated to dryness and then swapped with toluene to remove residual CH2Cl2.Part 9: 几种常见的后处理描述9.1: The reaction mixture or solution was concentrated to dryness. [适用于反应液不需要quench]9.2: After the reaction mixture was cooled to 0 ℃, the reaction mixture was quenched by addition of x mL of H2O, followed by x mL of 15% aqueous NaOH. After being stirred at room temperature for x hour, the solid was removed by filtration (or the mixture was filtered through Celite pad to remove by-product). The filtrate was concentrated to dryness to give crude product. [LiAlH4反应的经典后处理]9.3: The mixture was diluted with water (x mL), neutralized with solid K2CO3 until no CO2 was evolved. [适用于酸性反应液的后处理]9.4: The suspension was filtered through a pad of Celite or silica gel and the pad or filter cake was washed with EtOH (x mL×x). The combined filtrates were concentrated to dryness to give product (x g, x%) as. [适用氢化反应的后处理, 或者难于过滤的反应液的后处理, 但要注意的是这里需要的是滤液而不是固体才能添加助滤剂]9.5: The reaction mixture was poured into x mL of ice-water carefully and the organic layer or phase was separated. [产物在有机相里]9.6: The reaction mixture was poured into x mL of ice-water carefully and the aqueous phase was washed with Et2O (x mL×x) [产品在水相] and acidified with 1N HCl to pH=3. Theresulting precipitate was collected by filtration or the resulting solution was extracted with EA (x mL×x).9.7: The reaction mixture was filtered and the filter cake was washed with x mL of solvent, dried in vacuum to give or afford product. [这里需要的是固体而不是滤液]9.8: The reaction mixture was quenched with x mL of saturated aqueous NH4Cl. The resulting solution was extracted with EA (x mL×x). [适用于丁基锂等活泼金属有机物的后处理] 9.10: The residue was triturated with ether and filtered to afford a white solid. (磨碎)9.11: The crude product was purified by prep. HPLC to give A as a colorless thick oil which was solidified on standing. (静止固化)9.12: After prep. HPLC purification, the eluent was concentrated or evaporated to remove organic solvents. The residual aqueous solution was lyophilized to give a white solid. (冷冻干燥)9.13: After concentration, the crude product was used directly for the next step without purification.Part 10: 产品的纯化10.1: The crude product was purified by silica gel chromatography eluted with PE: EtOAc=10: 1 to give product (x g, x%) as yellow solid.10.2: The crude product was purified by re-crystallization (or re-crystallized) from x solvent (x mL).10.3: The crude product was distilled in vacuum (x o C, x pressure) to afford pure product (x g, x%) as colorless liquid.10.4: The crude product was pre-purified by column chromatography followed by prep. HPLC purification or re-crystallization to afford pure product.。

药明康德有机反应的后处理

药明康德有机反应的后处理
后处理的常规方法
反应混合物
过滤／旋干溶剂
淬灭／萃取
一般做完反应后，应该首先采用萃取的方法，先除去一部分杂质
Perfect Reaction 蒸馏（常压／减压／水蒸气）色谱技术（TLC／Column）重结晶
吸附／干燥
常见特殊试剂的淬灭及处理
在后处理前，推荐取一点反应液留作样品，以供对后处理好的反应液对照比较。
Lithium Aluminum Hydride
Diisobutyl Aluminum Hydride
(x g):
(x mmol):
1. 用适量乙醚稀释后冷却到0 0C； 1. 用适量乙醚稀释后冷却到0 0C；
2. 慢慢加入x mL水；
2. 慢慢加入0.04x mL水；
3. 加入x mL 15 %氢氧化钠水溶液； 3. 加入0.04x mL 15%氢氧化钠水溶液；
Acetonitrile
与水混溶，方便的话在后处理前预先除去
Alcohols
与水及有机溶剂都混溶，在进行水相后处理时应先除去
与水混溶，安全的做法是, 在进行水相后处理时先除去
THF/Dioxane
DMF/DMSO
大极性的高沸点溶剂，与水混溶，很难除去 a) 5% LiCl (aq); b) 0.5 N HCl
N EtOOC
SP005，酸碱化处理
N
N NH2 S 3
N
OH N
N HO
Boc N
PPh3, 1.2 eq. C2Cl6, 1.2 eq.
N
Et3N 2.0 eq. DCM, 20 0C
O NN
1
overnight
2
SP015c，先脱Boc，再分离

Suzuki反应-药明康德

经典化学合成反应标准操作Suzuki 反应编者：刘德军、武伟药明康德新药开发有限公司化学合成部目录1 前言 (3)1.1 Suzuki反应的通式 (3)1.2 Suzuki反应的机理 (3)1.3 Suzuki反应的特点及研究方向 (4)2 有机硼试剂的合成 (4)2.1 通过金属有机试剂制备单取代芳基硼酸 (4)2.1.1 通过Grinard试剂制备单取代芳基硼酸示例 (4)2.1.2 通过有机锂试剂制备单取代芳基硼酸示例 (5)2.2 通过二硼烷频哪酯制备芳基硼酸酯 (6)2.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一） (9)2.2.2 通过二硼烷频哪酯制备芳基硼酸酯示例（二） (10)2.2.3 通过芳基硼酸转化为芳基硼酸酯 (10)2.3 烯基硼酸酯的制备 (10)2.4 烷基硼酸酯的制备 (10)3 催化剂的制备 (11)3.1 Pd(PPh3)4的制备 (11)3.2 Pd(PPh3)2Cl2的制备 (12)3.3 Pd(dppf)Cl2的制备 (12)4Suzuki偶联的应用 (12)4.1 普通的芳卤和芳基硼酸的Suzuki偶联 (13)4.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 体系Suzuki偶联反应示例 (14)4.2 大位阻芳基硼酸参与Suzuki偶联反应 (14)4.3 含敏感功能团的芳基硼酸（酯）参与Suzuki偶联反应 (15)4.3.1 芳基硼酸频哪酯和芳基卤代物的Suzuki偶联 (16)4.3.2 带着酯基底物的Suzuki偶联反应示例（一） (16)4.3.3 带着酯基底物的Suzuki偶联反应示例（二） (17)4.4 杂环芳基硼酸参与Suzuki偶联反应 (17)4.5烷基硼酸参与Suzuki偶联反应 (18)4.6烯基硼酸参与Suzuki偶联反应 (19)4.7 Triflate参与Suzuki偶联反应 (19)4.7.1芳基的三氟甲基磺酸酯与芳基硼酸偶联示例 (20)4.7.2 芳基的Triflate与芳基硼酸偶联示例 (20)4.8 芳基氯参与Suzuki偶联反应 (21)4.8.1钯催化下芳基氯参与Suzuki偶联反应示例（一） (21)4.8.2钯催化下芳基氯参与Suzuki偶联反应示例（二） (22)4.9 镍催化体系用于Suzuki偶联反应 (22)4.9.1 NiCl2(dppf)和n-BuLi催化下芳基氯参与Suzuki偶联反应示例 (22)4.10 其他方法 (23)4.10.1 直接Pd/C用于Suzuki偶联反应示例 (23)4.10.2 直接Pd(OAc)2用于Suzuki偶联反应示例 (23)1 前言1.1 Suzuki 反应的通式在钯催化下，有机硼化合物与有机卤素化合物进行偶联反应，这就提供了一类常用和有效的合成碳-碳键化合物的方法，我们称之为Suzuki 偶联反应，或Suzuki-Miyaura 偶联反应。

《有机反应的后处理》课件

纯化
进一步去除目标产物中的杂质，提高其纯度，常用的方法包括重结晶、色谱分离等。
精制
对纯化后的产物进行最后的处理，以达到所需的纯度要求，常用的方法包括干燥、脱色等。
02
有机反应产物的分离与纯化
蒸馏与精馏
蒸馏
利用混合物中各组分的沸点不同，通过加热和冷凝的方法将各组分分离的物理过程。根据操作方式的不同，蒸馏可以分为简单蒸馏、连续蒸馏和精馏等。
重要性
后处理是实现有机合成目标的关键步骤，直接影响最终产物的纯度、收率和质量。
后处理的目的和任务
目的
获得高纯度的目标产物，满足后续应用或进一步合成的要求。
任务
从反应混合物中分离和纯化目标产物，同时尽可能减少副产物的生成和产物的损失。
后处理的基本步骤
分离
将目标产物从反应混合物中分离出来，常用的方法包括萃取、蒸馏、结晶等。
《有机反应的后处理》ppt课件
目录
• 有机反应后处理简介 • 有机反应产物的分离与纯化 • 有机反应产物的干燥与提纯 • 有机反应产物的分析与检测 • 有机反应后处理案例分析
01
有机反应后处理简介
定义与重要性
定义
有机反应后处理是指对反应产物进行分离、纯化和精制的过程，以获得所需纯度的目标产物。
重结晶
将晶体溶解在溶剂中，通过蒸发溶剂或加入另一种溶剂，使晶体重新析出的过程。重结晶可以去除杂质、提高产品的纯度。
03
有机反应产物的干燥与提纯
干燥剂的选择与使用
1 2
常用干燥剂
常用的干燥剂包括无水硫酸镁、硫酸钠、氯化钙等，它们具有吸水性强、不易变质等特点。
干燥剂的选用原则
根据反应产物的性质和所需的干燥程度选择合适的干燥剂，以达到最佳的干燥效果。

药企制药反应后处理流程

药企制药反应后处理流程英文回答：Pharmaceutical companies have well-defined processesfor handling pharmaceutical reactions. These processes ensure that any adverse reactions or side effects of drugs are promptly addressed and managed effectively. Let me walk you through the typical post-pharmaceutical reaction handling process.Firstly, when a pharmaceutical reaction is reported, it is important to gather all relevant information about the reaction. This includes details such as the patient's medical history, the drug involved, dosage, and any other medications the patient may be taking. This information helps in assessing the severity of the reaction and determining the appropriate course of action.Once the information is collected, it is reviewed by a team of experts, including pharmacists, toxicologists, andmedical professionals. They analyze the data to understand the cause and potential implications of the reaction. This analysis helps in determining the appropriate steps to be taken.Based on the severity of the reaction, different actions may be taken. In cases of mild reactions, such as minor skin rashes or gastrointestinal discomfort, the patient may be advised to discontinue the medication and seek symptomatic relief. The reaction is then documented for future reference and monitoring.For more serious reactions, such as severe allergic reactions or life-threatening side effects, immediate medical intervention is necessary. The patient may be referred to a healthcare facility for further evaluation and treatment. In such cases, it is crucial to ensure the patient's safety and well-being.In addition to addressing the immediate concerns, pharmaceutical companies also have a responsibility to report and document adverse reactions. These reports aresubmitted to regulatory authorities, such as the FDA in the United States, to contribute to drug safety monitoring and surveillance. This information helps in identifying patterns and trends in drug reactions and enables regulatory agencies to take appropriate actions, such as issuing warnings or recalls.Furthermore, pharmaceutical companies often conduct post-marketing surveillance studies to monitor the long-term safety and effectiveness of their drugs. These studies involve collecting data from real-world patients to assess any potential risks or benefits that may not have been identified during clinical trials. The findings from these studies can influence the labeling, dosage recommendations, or even the withdrawal of a drug from the market if necessary.Overall, the post-pharmaceutical reaction handling process involves thorough assessment, appropriate medical intervention, documentation, reporting, and ongoing monitoring. It is crucial for pharmaceutical companies to have robust systems in place to ensure the safety and well-being of patients using their medications.中文回答：药企在处理药物反应时有着明确的流程。

药明康德有机反应的后处理

酸碱化处理
O COOEt Cl N N H NEt3 , CH 2Cl2 NH O A Boc2 O (??? eq.) MeOH B N Boc COOEt
纯化: 酸洗、碱洗
纯化: 1.原料过量 --》酸洗 2.BOC2O过量 --》 H2NCH2CH2NMe2
NHBoc COOEt
NHBoc LiOH, MeOH COOH C
通过硅藻土、硅酸镁载体等过滤除去加入异丙醇直至反应体系颜色从橙色或红色变成绿色用饱和NH4Cl水溶液来淬灭反应，再在室温下搅拌一段时间至溶液成深蓝色，分掉水相可以通过KF与硅藻土的混合物过滤，也可以通过硅胶短柱，以反应溶剂（加~2-5%的Et3N）为洗脱剂来除去许多过渡态金属可以与硫化物生成沉淀除去。通常可以用 Na2S水溶液来洗涤
O
NH2 H N O 1 NH2 LiAlH 4 THF N 2 H N
O 1
H N
LiAlH 4 Boc -20 0 C HO 2
H N
Boc
N
SP010，在 0 0C加水淬灭，再加 10 %NaOH，然后过滤
SP011，在 0 0C加水淬灭，再加 10 %NaOH，然后过滤
DIBAL-H
O Boc N O 1
CONFIDENTIAL
WXPT-Schering Plough FTE Team Internal Training Notes
Workup of Org. Reaction
有机反应的后处理
March-28-2008
For Internal Use Only
主要内容
◆ 后处理的目的和评价标准 ◆ 后处理的常规方法 ◆ 常见特殊试剂的淬灭及处理 ◆ 不同溶剂反应的处理

药物有机合成后处理方法总结

药物有机合成后处理方法总结有机合成心得(3)-合成路线的选择合成路线的设计与选择是有机合成中很重要的一个方面，它反映了一个有机合成人员的基本功和知识的丰富性与灵活的头脑。

一般情况下，合成路线的选择与设计代表了一个人的合成水平和素质。

合理的合成路线能够很快的得到目标化合物，而笨拙的合成路线虽然也能够最终得到目标化合物，但是付出的代价却是时间的浪费和合成成本的提高，因此合成路线的选择与设计是一个很关键的问题。

合成路线的选择与设计应该以得到目标化合物的目的为原则，即如果得到的目标化合物是以工业生产为目的，则选择的合成路线应该以最低的合成成本为依据，一般情况下，简短的合成路线应该反应总收率较高，因而合成成本最低，而长的合成路线总收率较低，合成成本较高，但是，在有些情况下，较长的合成路线由于每步反应都有较高的收率，且所用的试剂较便宜，因而合成成本反而较低，而较短的合成路线由于每步反应收率较低，所用试剂价格较高，合成成本反而较高。

所以，如果以工业生产为目的，则合成路线的选择与设计应该以计算出的和实际结果得到的合成成本最低为原则。

如果得到的目标化合物是以发表论文为目的，则合成路线的选择与设计则有不同的原则。

设计的路线应尽量具有创造性，具有新的思想，所用的试剂应该是新颖的，反应条件是创新的，这时考虑的主要问题不是合成成本的问题而合成中的创造性问题。

如果合成的是系列化合物，则设计合成路线时，应该共同的步骤越长越好，每个化合物只是在最后的合成步骤中不同，则这样的合成路线是较合理的和高效率的，可以在很短的时间内得到大量目标化合物。

每个目标化合物的合成路线一般有多步反应，为了避免杂质放大的问题，最好的解决办法是将合成路线一分为二，转化为两个中间体，最后将两个中间体通过一步反应组装起来得到目标化合物。

尽量避免连续反应只在最后一步得到产物。

有机合成心得(4)-有机反应的实质有机合成的任务是运用已知的或可能的化学反应来形成C-C键或C-杂键，从而将两个或多个分子或离子连接起来。

药明康德化学合成部2012年3月晋升测试题II_Answer

1.3 组成有机化合物的原子许多有同位素，所以在质谱中会出现不同质量的同位素峰。有机物分子中同时含一个溴一个氯时，在质谱中会出现明显同位素峰的比例是（ D ）
A. 1: 2: 1; B. 9: 6: 1; C. 9: 3: 1; D. 3: 4: 1
第 1 页共 12 页
2012 年 3 月药明康德化学合成部晋升测试（II）试题
2H 1H 2H
O
1H
2H 2H
第 7 页共 12 页
2012 年 3 月药明康德化学合成部晋升测试（II）试题
四、机理（10 分）
4.1 请写出 Mitsunobu 的反应通式及机理（5 分）
4.2 请画出 Sonogashira coupling 的反应通式及机理（5 分）
带格式的: 行距: 单倍行距
反应完成后，将反应混合物冷却至-10 ~ 0 ℃，搅拌下，缓慢滴加1 mL 的水猝灭反应。完毕，再缓慢滴加滴 1 mL 的1 0％NaOH 溶液。滤除产生的固体，用反应溶剂洗涤数次，滤液减压浓缩即得产品。必要时，固体可用乙醇或甲醇浸泡洗涤，浓缩收更多的产品(此时多半含无机盐)。一般情况下，加完后，沙状固体悬浮于反应溶剂中，非常容易过滤。有时在加水过程中，反应物较为粘稠，可适当加入一些反应溶剂稀释。或用10水硫酸钠后处理
4-氯吡啶的活性也更高. D. Pd 直接插入 C-X 健的过程中, 反应的活性大小次序为: X=I>Br~OTf>Cl>F
1.12 按照药明康德公司安全监查部规定，无水溶剂允许存放期限为（D）
A：1 天 B：3 天
C：5 天 D：7 天
1.13 NaH、Na、LiAlH4 着火了，只能用哪种灭火器材？(A)

药明康德有机反应的后处理教程教案

OTf
B(OH)2 NHBoc
N
1
N EtOOC
N S
2
Pd(PPh3)4 /Na2CO3 1, 4-Dioxane
N EtOOC
SP005，酸碱化处理
N
N NH2 S 3
N
OH N
N HO
Boc N
PPh3, 1.2 eq. C2Cl6, 1.2 eq.
N
Et3N 2.0 eq. DCM, 20 0C
CONFIDENTIAL
WXPT-Schering Plough FTE Team Internal Training Notes
Workup of Org. Reaction
有机反应的后处理
March-28-2008
For Internal Use Only
主要内容
◆ 后处理的目的和评价标准 ◆ 后处理的常规方法 ◆ 常见特殊试剂的淬灭及处理 ◆ 不同溶剂反应的处理 ◆ 萃取操作 ◆ 酸碱化处理 ◆ 产物是氨基酸类的处理 ◆ 易燃易爆或剧毒品的后处理 ◆ 后处理常见问题的解决技巧
水的粘性铝化合物常用淬灭剂：十水硫酸钠、乙酸乙酯／乙醇、水
常见特殊试剂的淬灭及处理
LAH
DIBAL-H
Lithium Aluminum Hydride
Diisobutyl Aluminum Hydride
(x g):
(x mmol):
1. 用适量乙醚稀释后冷却到0 0C； 1. 用适量乙醚稀释后冷却到0 0C；
萃取溶剂的选择
萃取溶剂的选择，应根据被萃取化合物的溶解度而定，同时要易于和溶质分开，最好用低沸点溶剂。一般难溶于水的物质用石油醚等萃取；较易溶者，用乙醚等萃取；易溶于水的物质用乙酸乙酯等萃取。每次使用萃取溶剂的体积一般是被萃取液体的1/5～1/3，两者的总体积不应超过分液漏斗总体积的2/3

Suzuki反应-药明康德

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调pH > 9，加入饱和NaClO溶液 (1 mol 约需0.4 L) 过夜，用亚硝酸盐试纸证实NaClO已过量
调pH > 9，按1：50以上的浓度配成稀的水溶液，搅拌下慢慢加入NaClO淬灭在酸性水溶液中，用Fe2+、亚硫酸盐或二硫化物还原至淀粉 KI试纸呈阴性，中和
碱金属氢化物、悬浮在干燥四氢呋喃中，搅拌下慢慢加乙醇或异丙醇至不再钠屑放出氢气、澄清为止
CONFIDENTIAL
WXPT-Schering Plough FTE Team Internal Training Notes
ห้องสมุดไป่ตู้
Workup of Org. Reaction
有机反应的后处理
March-28-2008
For Internal Use Only
主要内容
◆ 后处理的目的和评价标准 ◆ 后处理的常规方法 ◆ 常见特殊试剂的淬灭及处理 ◆ 不同溶剂反应的处理
常用sat. NH4Cl或NaHCO3淬灭
N Boc 1
OH CH3MgBr, (1.5 eq.) Et2O, -10 0C, overnight N Boc 2
SP49b, sat. NH4Cl淬灭
CF3 CF3 O N O A C O D E O B BrMg MgBr N O + O OH CF3 CF 3
SP005，酸碱化处理极性相对较小的产物，可以将反应混合物悬浮于hexane/ether的混合溶剂中，通过非常短的硅胶柱过滤，用醚类作为洗脱剂。
N
O N H
H N O 1
N
Boc PPh3 , 1.2 eq. N C 2Cl6, 1.2 eq. Et3N 2.0 eq. DCM, 20 0C overnight
DMF/DMSO
a) 5% LiCl (aq); b) 0.5 N HCl
benzene/toluene/ xylene
di-/trialkylamines/ pyridine
用稀盐酸洗涤，或用10% CuSO4水溶液洗涤
＊ From Not Voodoo Website
萃取操作
萃取原理
利用物质在两种不互溶（或微溶）溶剂中溶解度或分配比的不同来达到
O N N 2
N Boc
SP015c，先脱Boc，再分离
常见特殊试剂的淬灭及处理
种类
Boron Compounds PCC/PDC Jones Reagent Copper Salts R3Sn-X Byproducts Metal Salts
处理方法＊
加入MeOH，生成了(MeO)3B，旋蒸除去
萃取操作
在萃取时常常出现不分层和乳化的现象
(1) 长时间静置；
How can we do?
(2) 加入适当的物质，使其密度差增大，对于水相，通常加入无机盐； (3) 因表面活性剂存在而形成的乳化，改变溶液的pH往往能使其分层； (4) 因碱性而产生乳化，可加入少量酸破坏； (5) 因少量悬浮固体引起的乳化，可将乳浊液缓慢过滤，过滤时在漏斗里铺上一层吸附剂(硅酸镁、氧化铝、硅胶)，则效果更好; (6) 因两种溶剂（水与有机溶剂）能部分互溶而发生乳化，可加入少量电解质如氯化钠等，利用盐析作用加以破坏; (7) 对于顽固的乳化，还可用离心分离，也可加热，或向有机溶剂中加入极性溶剂（如醇类或丙酮）以改变两相的表面张力。
后处理的常规方法
过滤／旋干溶剂
Perfect Reaction 蒸馏（常压／减压／水蒸气）反应混合物色谱技术（TLC／Column）淬灭／萃取重结晶一般做完反应后，应该首先采用萃取的方法，先除去一部分杂质
吸附／干燥
常见特殊试剂的淬灭及处理
在后处理前，推荐取一点反应液留作样品，以供对后处理好的反应液对照比较。
N Cbz 1
SP006, via 20 % citric acid solution
N Cbz 2
等电点 -- 两性离子所带电荷因溶液的pH值不同而改变，当两性离子正负
电荷数值相等时，溶液的pH值即为等电点。
产物是氨基酸类的处理
◆ 氨基酸又一提纯方法可以通过上Boc, 降低极性和水溶性后
再进行分离。
通过硅藻土、硅酸镁载体等过滤除去加入异丙醇直至反应体系颜色从橙色或红色变成绿色用饱和NH4Cl水溶液来淬灭反应，再在室温下搅拌一段时间至溶液成深蓝色，分掉水相可以通过KF与硅藻土的混合物过滤，也可以通过硅胶短柱，以反应溶剂（加~2-5%的Et3N）为洗脱剂来除去许多过渡态金属可以与硫化物生成沉淀除去。通常可以用 Na2S水溶液来洗涤
Al H
DIBALH toluene, -78oC 2
处理难点：反应淬灭后，产生大量不溶于
水的粘性铝化合物
Boc N O
常用淬灭剂：十水硫酸钠、乙酸乙酯／乙醇、水
SP007，在-78 0C用3 M NaOH 淬灭，升温至室温后再用3 M NaOH洗涤
常见特殊试剂的淬灭及处理
LAH
Lithium Aluminum Hydride (x g):
易燃易爆或剧毒品的后处理
Example: 1
OH POCl3 EtOOC N 1-1 N S Py.HCl EtOOC N 1-2 S Cl N
Example: 2
O O KCN, (NH 4) 2CO3 Bn N 2-1 EtOH / H 2O, 60
0C
NH HN N 2-2 O
Bn
SP005，倒入大量冰水中，EtOAc萃取
易燃易爆或剧毒品的后处理
《常见危险废物的销毁方法》
种类处理方法
酰氯、三氯氧磷、在搅拌下，加到大量冰水中，再用碱中和氯化亚砜硫酸二甲酯有机锂化物在搅拌下，滴加到稀ＮaOH或氨水中，中和溶于THF中，慢慢加入过量一倍mol的EtOH，再加水稀释，最后加稀HCl至溶液变清
氰化物
叠氮物过氧化物
SP009，倒入大量水中，产品析出
Example: 3
O
Example: 4
O R NH NH 4-1 mCPBA DMF MeO 2S N N N H NH 4-2 R
Cl N CHO
N3
CO2 Et N
Cl
O
N
(1.5 eq.)
O N3 3-2
SMe N
3-1
NaOMe (2 eq.), MeOH -30 0 C to rt
◆ 萃取操作
◆ 酸碱化处理 ◆ 产物是氨基酸类的处理 ◆ 易燃易爆或剧毒品的后处理 ◆ 后处理常见问题的解决技巧
后处理的目的和评价标准
◆ 目的
◎ 分离提纯得到纯的产品
◆ 评价标准
◎ 产品是否最大限度的保质保量得到
◎ 原料、中间体、溶剂及有价值的副产物是否最大限度的得到
回收利用
◎ 后处理步骤，无论是工艺还是设备，是否足够简化 ◎ 三废量是否达到最小
O
NH2 H N O 1 NH2 LiAlH 4 THF N 2 H N
O 1
H N
LiAlH 4 Boc -20 0 C HO 2
H N
Boc
N
SP010，在 0 0C加水淬灭，再加 10 %NaOH，然后过滤
SP011，在 0 0C加水淬灭，再加 10 %NaOH，然后过滤
DIBAL-H
O Boc N O 1
NH NH2 N 1 2 CDI N N O N H BnBr N+ Bn Br3 N O N H
NH NH2 N 1 2 CDI N N O N H (Boc) 2O N N O N Boc Puri f icati n 4 BnBr N+ Bn Br3 N O N H
* SP004, CDI 副产物咪唑导致了分离的困难
SP052a，sat. Na2CO3淬灭, Et2O萃取,
在30 0C, 用sat. NaClO 处理水相
酸碱化处理
酸碱化原理：

具有酸碱性基团的有机化合物，可以得失质子形成离子化合物，而离
子化合物与母体化合物具有不同的物理化学性质。
Questions: how to purify the product A, B and C ：
O C O O Et Cl B o c 2 O ( ?? ? e q .) N N H N E t3 , C H 2 C l2 NH O A M eO H N Boc B CO OEt
4. 再加入3x mL水；
5. 升温到室温搅拌15分钟； 6. 加入一些无水MgSO4；
4. 加入0.1x mL水； 5. 升温到室温搅拌15分钟； 6. 加入一些无水MgSO4； 7. 搅拌15分钟后过滤除盐。
7. 搅拌15分钟后过滤除盐。
常见特殊试剂的淬灭及处理
O
Grignard Reagent
萃取操作
萃取的次数
70% 70%
待处理物
30%
有机相
70% 21%
水相
30% 30%
用少量溶剂多次萃取,
通常萃取的次数是三次
有机相
70% 6.3%
水相
9% 30%
有机相
水相
2.7%
70% + 21% + 6.3% = 97.3%
在得到实验结果前，有机相、水相、不明固体一律不允许丢弃。
萃取操作
几种特殊的有机萃取溶剂
常用于萃取大极性物质的有机溶剂
n-BuOH (沸点117 0C, 油泵旋蒸方可除去); DCM : MeOH (10: 1); EtOAc : THF (10: 1); CHCl3 : i-PrOH (3: 1).
EtOAc deosn’t work; DCM/MeOH = 10 : 1 works well

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药明康德有机反应的后处理PPT培训课件

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有机合成中的后处理

药明康德-醇的制备

药明康德Level 2题目-烃化反应

药明康德英文实验记录表述(2)

药明康德有机反应的后处理

Suzuki反应-药明康德

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