药明康德有机合成讲义资料 有机氟化合物的合成共54页文档
药明内部讲义.pdf
O
O
H2O dioxane
F O NH
BO
reflux
F
Patent; US6958330 B1 (2005/10/25)
带着酯基底物的 Suzuki 偶联反应示例
OH
F
Br
B OH
Pd(dppf)Cl2
MeO2C
F
Na2CO3, DCM, reflux MeO2C
Patent; US2002/55631 A1 (2002/05/09)
X G
(RO)2B-B(OR)2
Pd(dppf)Cl2 KOAc
DMSO, 80℃
B(OR)2 G
1. 溶剂：在极性溶剂里此偶联反应的产率可以得到很大的提高：DMSO≥ DMF > dioxane > toluene。
2. 碱：经过验证，KOAc 是应用于这个反应最合适的碱，其他的如 K3PO4 或 K2CO3 这些碱性略强的碱会进一步使原料芳基卤发生自偶联反应的结果。
-加成反应生成 Pd(II) 的络合物，然后与活化的硼酸发生金属转移反应生成 Pd(II)的络合物，最后进行还原-消除而生成产物和 Pd(0)。
1.3 Suzuki 反应的特点及研究方向 这类偶联反应有一些突出的优点：1.反应对水不敏感；2.可允许多种活性官
能团存在；3.可以进行通常的区域和立体选择性的反应，尤其是，这类反应的无 机副产物是无毒的并且易于除去，这就使得其不仅适用于实验室而且可以用于工 业化生产。
三氟甲基磺酸酯和芳基硼酸的偶联反应有时候会因为在反应初期, 催化剂 配体 PPh3 容易和 Triflate 反应, 从而导致催化剂分解破坏为钯黑。如果在反应体 系中加入和催化剂等当量的 LiBr 或 KBr 就足以阻止这种分解反应。
药明康德谱图分析精品PPT课件
酯：
1250~1100 cm-1，反对称, 强 1160~1050 cm-1，对称, 强
C-X: 1400 ~ 400 cm-1，强峰
C-F: 1400 ~ 1000 cm-1 C-Cl: 800 ~ 600 cm-1 C-Br: 700 ~ 500 cm-1 C-I: 610 ~ 485 cm-1
Bionanotextile
氢核磁共振(1H NMR)
H H
H
HHH H
H H H
多少个氢？
氢的种类？
如何连接？
每种氢的数目？
Bionanotextile
各种氢的化学位移
Bionanotextile
取代基电负性：诱导效应
向低场移动的程度正比于原子的电负性和该原子与H之间的 距离
Bionanotextile
基团特征频率
根据虎克定律双原子分子的频率公式为：
基团和化学键的特征频率取决于化学键的强弱和化学键所连 接的两个原子的质量。
Bionanotextile
红外光谱吸收带的基本分区
谱带的位置：特征频率 各种基团和化学键的与化学结构有关，出现的位置有规律。
由于不同分子化学结构不同，其能级分布不同，因此从基态跃
Bionanotextile
(2) CH
不饱和CH > 3000 cm-1 饱和CH < 3000 cm-1
2962 cm-1，反对称伸缩振动
CH3
2872 cm-1，对称伸缩振动
2926 cm-1，反对称伸缩振动
CH2
2853 cm-1，对称伸缩振动
Bionanotextile
(3) NH
3500 ~ 3300 cm-1, 中强，尖峰
药明康德酰胺的合成ppt课件
HOCH2COOH
Ph
4
混合酸酐法 (一)
氯甲酸酯法:主要应用羧酸与氯甲酸乙酯或异丁酯反应生成混合酸酐,而 后再与胺反应得到相应的酰胺。这一反应如果酸的a-位位阻大或者连有 吸电子基团，有时会停留在混合酸酐这一步。但加热可以促使其反应； 这一反应也可用于无取代酰胺的合成。
稳定，若不用酰化催化剂转化为相应的活性酯或活性酰胺，其 自身会通过重排成相应的稳定的脲的副产物 (Path b).
R1 HN C N O R2 O R X X = Activator Path a R O X R3 R4 NH R O N R4 R3
R O O R1 N C H N R2
R R1 O N C O NH R2
ClCOOC2H5 , TEA, THF, then NH3 (g) -20'C to rt. 65% BnO
O O
CONH2 CH3
5
混合酸酐法 (二)
羰基二咪唑:应用羰基二咪唑(CDI)与羧酸反应得到活性较
高的酰基咪唑，许多酰基咪唑有一定的稳定性，有时可以 分离出来。但一般来说其不用分离，反应液直接与胺一锅 反应制备相应的酰胺；文献报道羰基二咪唑与三氟甲磺酸 甲酯反应得到的二甲基化的三氟甲磺酸盐(CBMIT)的缩合性 能更好。该类反应由于CDI或CBMIT会和过量的胺反应得到 脲的副产物，因此其用量一定要严格控制在1当量。最近有 人发现应用CDI合成Weinreb 酰胺是一个较好的方法。
20
鎓盐类的缩合剂法（一）
使用碳鎓盐缩合剂进行酰胺缩合，主要是通过分子内的
转移，一步得到相应的活性酯，以下以HATU的缩合反应 为例，说明其反应机理。
O N N N N O N R 1 NH2 N N N N N N O O R O N O N N N intramolecular general base catalysis enhances reactivity O O R + N N N R HO R
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。
硝基化合物和氟化物的合成-MA071124
4
1．前言
常见的硝化试剂归纳如下：
• 硝酸 Nitric acidAlone or in combination with H2SO4, H3PO4, HClO4, HF(BF3), (CH3CO)2O, (CF3CO)2O, CF3CO2H, MeSO3H, CF3SO3H, FSO3H(SbF5), NafionH, sulfonated resins, clays, molecular sieves,graphite • 硝酸盐 Nitrate salts AgNO3/BF3, KNO3/H2SO4,K(Na)NO3/TMSCl/AlCl3,Cu(NO3)2/(CH3CO)2O, NH4NO3/(CF3CO)2O, (NH4)2Ce(NO3) • 硝酸酯 Nitrate esters BuONO2/Nafion-H, MeONO2/BF3, Me3SiONO2, acetone cyanohydrin nitrate • 硝酰化合物 Nitryl compounds NO2BF4, NO2PF6, NO2ClO4, NO2Cl(F), MeCO2NO2, CF3CO2NO2, PhCO2NO2, Nnitropyridinium nitrate •氧化氮 Nitrogen oxides NO2－O3, N2O3/BF3, N2O4/H2SO4, N2O4/AlCl3, nBuLi/N2O4, N2O5, N2O5/HNO3，N2O5/SO2 • 硝烷 Nitroalkanes C(NO2)4, CH(NO2)3, (O2N)3CC(NO2)
R-NO2 or Ar-NO2
R-H
R-Nu, alkenes
R'CNO R'CO2H
R'CHO
有机氟化合物的合成
经典化学合成反应标准操作有机氟化合物的合成目录1．前言 (2)2．通过不饱和C-C键的加成合成氟化合物 (4)3．通过重氮盐合成氟化合物 (7)3.1 Balz-Schiemann 反应 (7)3.2 从α-氨基酸合成α-氟代羧酸 (10)4．亲核氟代 (12)4.1．环氧开环合成氟化合物 (12)4.2．氧被氟取代合成氟化合物 (13)4.3. 硫被氟取代合成氟化合物 (20)4.4．磺酸酯被氟取代合成氟化合物 (22)5．亲电氟代 (24)5.1 芳环的亲电氟代 (25)5.2 通过烯醇，烯醇醚，烯醇酯及烯胺合成α-氟代羰基化合物 (27)5.3 有机金属化合物的氟代 (29)5.4 不对称亲电氟代 (31)6．三氟甲基的引入（Trifluoromethylation） (34)6.1 自由基三氟甲基化 (34)6.2 亲电三氟甲基化 (35)6.3 亲核三氟甲基化 (36)参考文献 (41)1．前言1771年Scheele 第一次报导了氟化氢，1836年Dumas 和Peligot 报导了第一个有机氟化合物：一氟甲烷的合成，而元素氟的制备则在50年后，1886年Henri Moissan 分离到了氟气。
Table 1 H，F，Cl的比较H F Cl电子排布1s1 2s22p5 3s23p53d0电负性 2.1 4.0 3.0电离能(kcal/mol) 315 403 300键能C-X (kcal/mol) 99 111 78键长C-X (Å) 1.09 1.32 1.77氟原子半径小，是电负性最强的元素，这种极强烈的电负性增加了氟与碳的亲和力。
因此它们所形成的C-F键要比C-H键能大得多，明显地增强了含氟有机化合物的稳定性。
如下面三个聚合物，聚乙烯和聚四氟乙烯都很稳定，而聚四氯乙烯则不稳定。
H2CH2nF2CCF2nCl2CCCl2nstable stable unstable氟原子的引入导致有机及无机化合物具有独特的物理、化学性能及生理活性。
药明内部讲义.pdf
3.4 杂环芳基硼酸参与 Suzuki 偶联反应 杂环芳基硼酸参与 Suzuki 偶联反应同样可以得到好的结果。
MeOOC
Br +
B(OH)2 Pd(PPh3)4
COOMe
NO2
N
O2N
aq. Na2CO3 N
benzene
J . Org. Chem. 1984, 49, 5237.
3-吡啶基二乙基硼烷是一个对空气和水份稳定的化合物,可以用来作杂环的 芳化反应。
Pd 催化的偶联反应
内容简介
Pd 催化的偶联反应有较多类型，目前用途最广泛的主要有以下三类: 1. Suzuki 反应 2. Heck 反应 3. Sonogashira 反应
第一部分： Suzuki 反应
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的偶联反应，称之为
3. 催化剂：对于制备溴代物和碘代物相应的芳基硼酸酯，Pd(dppf)Cl2 一 般可以得到很好的结果，又由于其具有易于反应的后处理的优点，因此是公司目
前最常用的一类催化剂。
4. 对于氯代物，2001 年 Ishiyama 经过研究发现在 Pd(dba)2/2.4PCy3(3-6mol %) 的催化下此类反应可以接近定量的进行
TMS
2. B(OMe)3
I
-78oC-25oC, 30min (HO)2B
3. H+/HCl
Chem. Eur. J. 2003, 9, 4430-4441
2.2 通过二硼烷频哪酯制备芳基硼酸酯 对于分子中带有酯基、氰基、硝基、羰基等官能团的芳香卤代物来说, 无法
通过有机金属试剂来制备相应的芳基硼酸。1995 年由 Ishiyama 率先取得了突破: 通过二硼烷频哪酯和芳基卤发生偶联反应制备相应的芳基硼酸酯 (yield: 60-98%)。这个方法还有一个突出的优点就是还可以原位制备硼酸酯, 然后“一 锅法”和芳基卤反+ ArX
人教版化学选修5课件：3-4-2《有机合成》(54张ppt)
【预备知识回顾】
3、卤代烃的制取及其主要化引学入性一质个卤 往素相(—邻X碳)原上子引 入2个卤素原子
9
【预备知识回顾】
3、卤代烃的制取及其主要化学性质
化学性质： 请写出溴乙烷分别和NaOH水溶液、
NaOH醇溶液混合加热的化学方程式， 并指出其反应类型。
思考： 1、如何引入C=C？
2、如何引入羟基(—OH)？
试写出：
(1) 化合物A、B、C的结构简式： 、 、 。
(2) 化学方程式：A→D
，A→E
。
(3) 反应类型：A→D
，A→E
。
27
问题三 分析：
题中说“A的钙盐”，可知A含—COOH； 结合A的分子式，由A→C知，A还含有—OH， 由A在催化剂作用下被氧化的产物不能发生银 镜反应可知：A的—OH不在碳链的末端；3个 碳的碳链只有一种：C—C—C，—OH只能在中 间碳上。综上：A的结构简式C为H3：—CH—COOH
3）卤代烃的水解（碱性） 水
C2H5Br +NaOH △ C2H5OH + NaBr
4）酯的水解 稀H2SO4
CH3COOC2H5 + H2O △ CH3COOH+C2H5OH （2）官能团的消除
①通过加成消除不饱和键
②通过消去或氧化或酯化或取代等消除羟基
③通过加成或氧化消除醛基
④通过消去反应或水解反应可消除卤原子
6
【预备知识回顾】
2、苯及其同系物的化学性质
写出苯与液溴、浓硝酸和浓硫酸混合 液、浓硫酸、氢气反应的化学方程式。
思考：
如何往苯环上引入— X原子、—NO2、 —SO3H？如何将苯环转化为环己基？
7
2、苯及其同系物的化学性质
药明康德酰胺的合成
BocHN
ClCOOEt, NEt3
NH3 (gas)
Ph
CHCl3, -20~5oC, 1.5h
rt, 30min
Ph
NH2
COOH
91%
O
O OH
NMM, DMF BocHN
r.t.
OO OO
C5H11NH2 33%
BocHN
O N C5H11 H
O
COOH ClCOOC2H5, TEA, THF, then NH3 (g)
85%
THPO
O
NH2
N
Bn
OBz 15
三个常用的缩合剂的比较
用EDC缩合法合成酰胺
O OH
+ Br
NH2
EDC, HOBt, DCM
N
0OC to rt.
H
99%
O N H
Br NH
Ph R OO N
H2N O S
EDC, HOBT, NMM
DMF
BocHN
rt., 18 hr 78%
Ph O
N H
OO S
CO2Bu-t
CO2H + H2N
CO2Bu-t
CO2H
CO2Bu-t
DCC
O HN R
DMF, 25OC, 23 hr
O
60%
HN R
R
HN
OO S
O R= 1
CO2Bu-t CO2Bu-t
O NH R
CO2Bu-t
用DIC缩合法合成酰胺
THPO
H N
OBz
i) Fmoc-Phe-OH, HOBt, DIC, DMF, rt. ii) 20% piperidine, CH2Cl2
药明康德有机反应的后处理课件
CONFIDENTIAL
\\chkg14P20032\ibdshared3$\Structure\Clients\Miscellaneous Industries\Healthcare\WuXi PharmaTech\IPO Execution\03 Presentations\13 Random\Merck Template.ppt /3
6. 加入一些无水MgSO4； 7. 搅拌15分钟后过滤除盐。
5
CONFIDENTIAL
\\chkg14P20032\ibdshared3$\Structure\Clients\Miscellaneous Industries\Healthcare\WuXi PharmaTech\IPO Execution\03 Presentations\13 Random\Merck Template.ppt /6
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
O NN
1
overnight
2
SP015c，先脱Boc，再分离
文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。
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
药明康德立体化学讲义
培训目的: 理解立体化学的基本原理. 培训后有能力区分辨别镜像立体异构体(enantiomers)和非镜像立体异构体(diastereomers), 镜像立体异构体(enantiomers)和非镜像立体异构体(diastereomers)的物理化学性质, 镜像立体选择反应(enantioselective)和非镜像立体选择(diastereoselctive)反应等培训时间: 1.5 –2小时培训内容:1. 碳原子有机化合物的异构体种类(Isomerism in Carbon Compounds)2. 镜像立体异构体(enantiomers) 和非镜像立体异构体(diastereomers)的物理化学性质3. 立体选择反应(Stereochemistry in Chemical Reactions)参考文献:1. /nbauld/teach/stereo.html#stereo2. Organic Chemistry, Solomans&Fryhle, 4th editionProperties of Enantiomers and Diastereomers 手性分子使偏振光偏转对应的镜像异构体会向相反方向偏转相同的角度!!手性色谱(HPLC, GC, etc)Properties of Enantiomers and Diastereomers1.不是所有的外消旋化合物都是可以分开的2.外消旋化合物需要在手性柱上先被分开来测量反应ee%3.绝对构型无法通过手性色谱确立，除非同已知文献报道的结果相比NNH NNBocO NNH NNBocO 外消旋化合物(普通HPLC)NNH NNBoc O=+外消旋化合物(手性HPLC)OMeOMe: 你能将上图中的四组峰和下面四个化合物一一对应吗OH OMeOH OMeOH OMe OH OMe:51问题?OH。