药明康德酰胺的合成
芳酰胺化反应
降低催化剂的活性。因些，加入络合强的配体可以阻止这种配位作用，使反应顺利进行。
Kang 和 Padwa也报道了用二胺类做配体使噻酚和呋喃顺利进行酰胺化 7。
Br +
A
O HN
CuI, N,N-dimethylethylenediamine, K3PO4 110'C
O N
A
A=S A=O
A = S 99% yield A = O 80% yield
此外，对于一些特殊的条件，比如溶剂有一定的配位作用（如吡啶）或者底物自 身有配位作用（如氨基酸），不使用配体也可以得到较为理想的结果。
关于配体对反应的作用，Buchwald认为配体的存在有助于提高铜盐的溶解性，阻碍 催化剂的分解，减少副产物的生成，从而有利于反应。 然而，这样的解释目前还缺乏 具体的实验证据。 关于Cu催化偶联反应中配体如何与Cu盐及各种反应中间体相互作用 并改变它们的结构和能量，还需要更为细致的研究。
现，适量地添加配体（一般10~20%）能够显著地提高反应的活性。Buchwald比较系统 地研究了碳-氮交叉偶联反应中二齿胺配体的作用。
药明康德内部保密资料
Page 5 of 18
经典合成反应标准操作— 芳酰胺化反应
药明康德新药开发有限公司
在比较十三种配体的作用之后，发现二胺的空间结构对于催化的效率影响不大。 而 最重要的影响因素则是二胺上氮的取代基的数目及取代基的位阻，N,N’-二甲基乙二胺 3 和11比未取代的二胺1，8，9和10有更高的活性。N上有位阻较大取代基的13（异丙基） 和12（乙基）则降低了芳酰胺化的反应速率，如果在N原子上有更多的取代基如7，则配 体失去活性。在大多数情况下，作者推荐使用配体3和11，而且配体11较配体3更好一点。 当芳酰胺化难于进行时，配体的选择将会显出其重要性。
酯交换为酰胺-060123
经典化学合成反应标准操作酯交换为酰胺编者：杜晓行药明康德新药开发有限公司化学合成部目录1．前言 (2)2．酯交换为酰胺 (2)3．酯交换为N-取代酰胺 (2)1．前言酯和氨水反应可以很方便地得到酰胺。
N-取代酰胺一般可以利用相应的胺与酯直接反应得到，在有些条件下，需要有铝试剂的存在反应才能够顺利进行。
2．酯与氨交换一般酯的氨解通过氨的醇溶液或氨水来进行。
氨的醇溶剂氨解反应可通过加入适量的甲醇钠和氰化钠来催化。
用氨水直接氨解一般需要加热（当该反应温度到100度时，一定要用高压釜做这一反应），这类反应一般可以通过硫酸铜来进行催化。
反应的条件选择主要看酯的活性程度，一般脂肪酸酯的交换要比芳香羧酸酯来得容易，甲酯要比乙酯来得快。
对脂肪酸酯，α位的位阻大小也决定了反应的快慢。
酯通过甲酰胺在乙醇钠的存在下，高温也可得到相应的酰胺。
这一方法对各类的酯都比较有效，只是产品的分离比直接氨解稍微麻烦一些，但反应较快。
另外近年来，AlMe 3-NH 4Cl 或Me 2AlNH 2在多官能团及复杂化合物的合成中用的较多，该方法条件较强，各类酯都能很快的氨解。
其缺点是AlMe 3易自燃，操作不是太方便。
2.1 氨水用于脂肪羧酸酯氨解示例[1]NO OOOO NO H 2NOO NH OHTo ethyl 5-ethoxycarbonylmethyl-3-methylisoxazole-4-carboxylate (1.00 g, 4.15 mmol) was added an excess of conc. aqueous ammonia (d = 0.88 kg·dm -3, 5.0 cm 3) and EtOH (3.0 cm 3), and the suspension was stirred vigorously at room temperature for 14 h. After this period a white solid had precipitated which was filtered and recrystallized (EtOAc) to yield the desired product as a white solid (0.81 g, 92%).NO OOOO NO HNOOO MeNH 2 / toluenePrepared as described above for ethyl 5-carbamoylmethyl-3-methylisoxazole-4-carboxylate but using methyl-5-ethoxycarbonyl- 3-methylisoxazole-4-carboxylate (1.00 g, 4.15 mmol) and methylamine in toluene (30% w/v, 10.0 cm 3), to yield the desired product as a white solid (0.93 g, 99%).2.2 氨甲醇氨解脂肪羧酸酯示例[2] [3]NH O OCOOEtNH OO CONHMe MeNH / MeOHThe ester (4.11 g, 14 mmol) was dissolved in absol. methanolic ammonia (100 ml, 20 % NH 3), and the solution was allowed to stand at temperature for 3 days, the solvent was then evaporated, and the resulting crystalline was purified by recrystallization.2.3 氨水用于芳香羧酸酯氨解示例[4]NNCONH 2To an autoclave, was added methyl 6-methylniconate (500 g, 3.31 mol), sat. aq. NH 4OH (500 ml) and ethanol (500 ml). After sealing, the reaction was heated to 80℃ for 2 days. The cooled reaction mixture was filtrated, and the filter cake was recrystallized to afford white solid (247 g, 54.8%)。
胺的合成-MA070818
4.6 硝基保险粉还原示例
NH2 N N BrN N Na2S2O4, 0.2N NaOH EtOH, 40oC, 24 h 65% NO2 N
NH N N N -p-H2NC6H5CH2OH N N NH2 NH2 N N
经典有机合成反应讲座(六)
第一部分:胺的合成
化学合成部执行主任:马汝建
药明康德新药开发有限公司
药明康德版权所有
1
胺的合成(概述）
胺作为一类非常有效的药物官能团, 存在于大多数药物结构之上。 上世纪的两类重要药物：青霉素类药物及磺胺类药物都以环化或 磺化的胺基作为核心药效基团。 药效基团是药物化学中的重要概念. 药效团的基本意义在于当一 个化合物的一部分结构发生变化时, 生物活性产生相应改变, 而 其余部分结构发生变化时, 生物活性发生微小变化或者不变。现 代药物化学研究与设计已经把胺类结构定位为最重要药效基团之 一。除了对化合物生物活性的影响之外, 我们知道胺类结构对于 改善化合物的整体水油分配系数(即logP)亦有重要作用, 此外游 离的胺可以制备成盐酸盐、硫酸盐、磷酸盐或有机盐等各种盐类 结构以改善药物在生物体内的吸收和代谢。从化学合成的角度来 说, 氨基的存在有利于多样性的产生, 有利于优化过程的快速进 行。
14
5.酰胺还原合成胺
5.3.2 NaBH4-AlCl3 体系还原酰胺
Cl NaBH4-AlCl3 O NH2 S O O DME H2N N H S O O Cl
N H
5.2.3 DIBAL 还原酰胺
O H2N NH N N O O DIBAL-H O H2N NH O
有机合成酰胺的合成和反应机理
有机合成酰胺的合成和反应机理酰胺是一类重要的有机化合物，广泛应用于医药、农药、染料、涂料等领域。
通过合成酰胺，可以获得具有特定功能和性质的有机分子。
本文将介绍有机合成酰胺的几种常见方法，并探讨其反应机理。
一、酰胺的合成方法1. 酰胺的酸催化缩合反应酰胺的常见合成方法之一是酸催化缩合反应。
该反应通过羰基化合物和氨或胺的缩合反应生成酰胺。
常用的酸催化剂有硫酸、磷酸和酸性离子交换树脂等。
酸催化缩合反应适用于不对称酰胺的合成，但反应条件需要控制得当，以避免副反应的发生。
2. 酰胺的酰氯缩合反应酰胺的另一种常见合成方法是酰氯缩合反应。
该反应通过羰基化合物和酰氯的缩合反应生成酰胺。
酰氯缩合反应的优点是反应速度快，但需要具备较强的反应条件，如较高的温度和碱性条件。
3. 酰胺的酯胺交换反应酰胺的酯胺交换反应是一种常用的合成方法。
该反应通过酯和胺的反应生成酰胺。
此方法在合成中性酰胺时具有广泛的应用，并具有较好的反应活性。
酯胺交换反应的反应条件温和，无需酸催化或碱催化。
二、酰胺的反应机理酰胺的合成反应通常经历以下几个关键步骤：1. 缩合反应酰胺的合成首先涉及缩合反应，即羰基化合物和氨或胺的缩合。
在酰胺的酸催化缩合反应中，氨或胺中的氢原子会被羰基化合物中的羰基氧原子去质子化，形成中间的羰基中间体。
随后，羰基中间体经过质子化和脱水反应，生成酰胺。
2. 酰氯缩合反应酰胺的酰氯缩合反应是通过羰基化合物和酰氯的缩合反应生成酰胺。
在该反应中，羰基化合物中的羰基氧原子被酰氯中的氯原子取代，形成酰氯中间体。
酰胺的形成通过质子转移和脱氯反应完成。
3. 酯胺交换反应酰胺的酯胺交换反应是通过酯和胺的交换反应生成酰胺。
在该反应中，酯中的酯基被胺中的氨基取代，形成酰胺。
酯胺交换反应可以在中性条件下进行，并且通常伴随着水的生成。
总的来说，有机合成酰胺的方法有多种多样，每种方法都有其适用范围和优缺点。
通过合理选择反应条件和反应物，可以实现高效、高选择性的酰胺合成。
经典合成反应标准操作
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Boc脱保护-------------------------------------------------------------------------------------------------------1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---------------------------------------------------------------------------------------------------------------5 氢化反应---------------------------------------------------------------------------------------------------------6 m-CPBA----------------------------------------------------------------------------------------------------------6 EDC---------------------------------------------------------------------------------------------------------------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 OOO OOO OHN HO OHO O A BTo 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 HOO OOH 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 ofethylmagnesium 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), 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 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O 2NO 2NBrTo 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).Return Suzuki 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 °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, 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 HOOOA 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, 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 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 HOHOA 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 isrecrystallized 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NNHOOH 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).ReturnNBSN NFClCl NBSNNFClClBrA 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 wasallowed 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).ReturnEDCNH 2O+H OTo 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 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 ClO Cl ClO 2NHN H NOHOHNO 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 mixturewas 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 F FFN O O+F FF ONFTo a solution of diisopropylamine (17.69 ml, 0.135 mole) in THF (200 ml) at –78°C under argon wasadded 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。
Mitsunobu-反应
Mitsunobu-反应经典化学合成反应标准操作Mitsunobu 反应编者：谢军药明康德新药开发有限公司化学合成部目录1．前言 (2)2．醇的翻转 (3)2.1 Mitsunobu 法醇的构型翻转合成方法示例 (7)3．Mitsunobu 醚化反应 (8)3.1 Mitsunobu 法醚的合成方法示例 (9)4．Mitsunobu 氨基取代反应 (10)4.1 Mitsunobu 法利用苯磺酰胺合成胺方法示例 (13)4.2 Mitsunobu 法利用DPPA合成伯胺方法示例 (13)4.3 Mitsunobu 法分子内关环合成相应的环状胺方法示例 (14)4.4 Mitsunobu 法合成丙二烯方法示例 (14)5．Mitsunobu 硫代反应 (16)5.1 Mitsunobu 法合成硫醚方法示例 (16)6．Mitsunobu 卤代反应 (18)6.1 Mitsunobu 法合成卤代物方法示例 (18)7．其他手性翻转试剂 (20)1. 前言1967年，Oyo Mitsunobu 报导了在三苯膦（PPh3）和偶氮二甲酸二乙酯（DEAD）作用下酸和醇缩合成酯的新方法1。
当底物为仲醇的时候，与羟基相连的碳原子的构型会发生翻转。
经过多年的研究和发展，形成了一大类合成方法，我们称之为Mitsunobu 反应。
这类反应被广泛应用在有机合成，特别是天然产物的合成中2。
2．醇的翻转在Mitsunobu 反应中，DEAD 和三苯膦首先生成一个活性的甜菜碱式中间体（betaine intermediate ），这个活性中间体夺取作为亲核试剂的酸的质子并同时活化醇，随后经过S N 2取代，得到手性翻转的酯；将得到的酯水解，其净结果是醇的构型翻转。
R O R OH Ar O23反应在很温和的条件下进行，通常反应温度是在0o C 到室温，大部分基团都不会影响反应。
但亲核试剂质子的pKa 值必须小于甜菜碱式中间体（betaine intermediate ）的pKa 值（～13），否则亲核试剂的质子不能被中间体（betaine intermediate ）夺取，反应不能进行。
药明康德-酰胺的合成-图文
在使用该方法进行氨基酸缩合时，一般投料必须在零
下20－30℃下进行，并在此温度下搅拌近一小时后再室
温搅拌，否则其会引起氨基酸的消旋化。
15
三个常用的缩合剂的比较
用DCC缩合法合成酰 胺
用DIC缩合法合成酰胺
16
三个常用的缩合剂的比较
用EDC缩合法合成酰胺
17
鎓盐类的缩合剂法（一）
碳鎓盐类的缩合剂：近年来，许多盐缩合剂被相继开发出来用于 酰胺的缩合反应，从盐的种类来分，主要有两类： 一类是碳鎓盐，目前常用的为O-(7-氮杂苯并三氮唑-1-基)-二 （二甲胺基）碳鎓六氟磷酸盐（HATU）、O-（苯并三氮唑1-基)-二（二甲胺基）碳鎓六氟磷酸盐 （HBTU）、O-(5-氯 苯并三氮唑-1-基)-二（二甲胺基）碳鎓六氟磷酸盐（HCTU） 、O-（苯并三氮唑-1-基)-二（二甲胺基）碳鎓四氟硼酸盐（ TBTU）、O-(N-丁二酰亚胺基)-二（二甲胺基）碳鎓四氟硼酸 盐（TSTU）、O-(N-endo-5-降莰烯-2,3-二碳二酰亚胺)-二 （二甲胺基）碳鎓四氟硼酸盐（TNTU）等。
目前在药物化学中用的最多的是EDCI，其一个主要的特点就 是其反应后的生成的脲是水溶性的，很容易被洗掉，一般EDCI 与HOBt合用（注意: 这一反应HOBt一般是缺不了的，否则有可 能导致缩合产率太低）。有时如果酸的a-位位阻大或者连有吸电 子基团，反应会停留在活性酯这一步（这一活性酯的质谱信1号4 较 强，可通过MS或LC-MS检测到）。
6
混合酸酐法 (二)
7
混合酸酐法 (三)
磺酰氯：另一类常用的方法是羧酸和磺酰氯生成羧酸-磺酸 的混合酸酐，其与胺反应得到相应的酰胺。常用的磺酰氯 有甲烷磺酰氯（MsCl），对甲苯磺酰氯（TsCl）和对硝 基苯磺酰氯（NsCl）, 对硝基苯磺酰氯由于其吸电子性， 其与酸反应生成活性更高的混合酸酐，一般二级胺和三级 胺，甚至位阻很大的胺都能顺利反应。
氰转化为酰胺-060123
经典化学合成反应标准操作氰基转化为酯和酰胺目录1．前言 (2)2．氰基转化为酯 (2)3．氰基转化为酰胺 (2)3.1丙稀酰胺的合成 (2)3.2苯乙酰胺的合成 (3)6. 从氰基合成酰胺6.1氰基水解腈加水可以分解为伯酰胺。
由于伯酰胺会继续水解为羧酸，一般要控制水解的条件。
目前有许多方法报道，有时需要根据底物的特性选择酸性，碱性或中性的水解条件。
作为中性的条件，也有文献报道使用镍或钯催化剂的方法。
在酸性条件下与饱和碳相连的氰基，可以在酸中很方便的水解转化为酰胺，并在条件较为剧烈时，很容易进一步水解成酸。
但乙烯基或芳基腈的水解条件则要求剧烈得多，一般需要强酸条件，而且一般不会进一步水解。
在碱性条件下，利用过氧化氢氧化的方法可在室温下短时间内水解腈为伯酰胺，这是一个较为可靠的方法。
利用NaOH(aq.)-CH2Cl2相转移催化体系，DMSO-K2CO3体系[2]可以用于各种腈水解为伯酰胺。
6.1.1 盐酸水解腈为伯酰胺示例[3]HCl, H2OCN CONH2In a 3-l. three-necked round-bottomed flask equipped with glass joints are placed 200 g. (1.71 moles) of benzyl cyanide and 800 ml. of 35% hydrochloric acid. The flask is fitted with a reflux condenser, a thermometer, and an efficient mechanical stirrer. At a bath temperature of about 40° the mixture is stirred vigorously. Within a period of 20–40 minutes the benzyl cyanide goes into solution. During this time, the temperature of the reaction mixture rises about 10°above that of the bath. The homogeneous solution is kept in the bath with, or without, stirring for an additional 20–30 minutes. The warm water in the bath is replaced by tap water at about 15–20°, and the thermometer is replaced by a dropping funnel from which 800 ml. of cold distilled water is added with stirring. After the addition of about 100–150 ml., crystals begin to separate. When the total amount of water has been added, the mixture is cooled externally with ice water for about 30 minutes. The cooled mixture is filtered by suction. Crude phenylacetamide remains on the filter and is washed with two 100-ml. portions of water. The crystals are then dried at 50–80°. The yield of crude phenylacetamide is 190–200 g. (82–86%).6.1.2 浓硫酸水解不饱和腈为伯酰胺示例[4]CN CONH 21. H 2SO 42. NH 3To 106 g of 84 % sulfuric acid, was added 50 g of acrylonitrile. After stirring for 30 min at r.t., the resulting mixture was heated to 95 ℃, and stirred for 2 h. After cooling, the solid was collected by suction, and the filter cake was transferred into a beaker. To the ice-cooled solid, was added aq. ammonia with the speed that keep the temperature less than 50℃. The precipitated ammonium sulphate was filtered off, and the filtrate was cooled. The precipitate was collected by filtration, and the filter cake was washed by water, dried in vacuum to give the desired product.6.1.3 H 2O 2-K 2CO 3-DMSO 体系水解腈为伯酰胺示例[1] Cl CN30% H 2O 2, K 2CO 3DMSO, rt, 5 min ClONH 2To a stirred solution of 4-chlorobenzonitrile (1.37 g, 0.01 mol) in DMSO (3 ml), cooled in a ice bath, was added 30% H 2O 2 (1.2 ml) and K 2CO 3, the reaction was allowed to warm up to r.t. (strong exothermic effect was observed). After 5 min., distilled water (50 ml) was added, cooling applied, and the product was collected by filtration, yield 85%.6.1.4 NaOH(aq.)-CH 2Cl 2相转移催化体系水解腈为伯酰胺[2] CN (n -C 4H 9)N +HSO 4-30 % H O , CH Cl NH 2OTo a magnetically stirred dichloromethane solution (1.5 ml) of o -tolunitrile (0.5 g, 4.27 mmol) cooled in an ice ba th, are added 30% hydrogen peroxide (2.0 ml), tetrabutylammonium hydrogen sulfate (0.290 g, 0.85 mmol), and a 20% aqueous solution of sodium hydroxide (1.6 ml). Thereaction mixture is allowed to warm up to r.t. and maintained under stirring. After 1.6 h, dichloromethane is added, the organic layer is separated, washed with brine, and dried with sodium sulphate. The solvent is removed under reduced pressure to leave a white solid from which pu re o-toluamide is obtained by chromatography on silica gel. Yield 0.485 g (97%).6.2 Ritter反应碳正离子加成到腈基的氮原子上生成的腈盐加水分解得到相应的酰胺加水可以分解为酰胺。
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9 0 o C O
H O C H 2 C O O H + P h C H 2 N H 2
H O C H 2 C N H C H 2 P h
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。
目前在药物化学中用的最多的是，其一个主要的特点 就是其反应后的生成的脲是水溶性的，很容易被洗掉， 一般与合用（注意: 这一反应一般是缺不了的，否则有
OH
MsCl, (PhCH2)Et3N+.Cl-
COOH CH3CN, 50oC, 15 min
O2N
SO2Cl
CO2H
NsCl
Et3N, DMAP, CH3CN
OO O S
O
OH
H2N
N
reflux, 10 min
O
N
N
H
OH
Sy nthesis 1989, 745
OO O S
O
NO2
Ph NHMe rt, 40 min
缩合活化剂:常用的缩合活化剂有以下几种，目前4二甲基吡 啶（）已被广泛应用于催化各种酰化反应。有时在用催化效 果不好时，可采用4，据相关文献报道其催化能力要比高千倍 左右。
N N
N DMAP
N 4-PPY
OH N
N N
HOBt
OH NN
N N
HOAt
O N OH O
HOSu
O N OH O
NHPI
O
O N Ph
混合酸酐法 (四)
酸酐:通过酸与酸酐反应得到的混合酸酐与氨反应可得到相应的 伯酰胺。
B o c 2 O
O O
C b z H N C O O H
C b z H N
O O
N H 3
O
C b z H N N H 2
R C O O H .P y + ( B o c ) 2 O
OO ROO
N H 4 H C O 3 O RN H 2+B u O H +C O 2
药明康德酰胺的合成
常见合成酰胺的方法
➢ 羧酸与胺的缩合酰化反应 ➢ 氨或胺与酰卤的酰化反应 ➢ 氨或胺与酸酐的酰化反应 ➢ 其他缩合方法 ➢ 酯交换为酰胺 ➢ 氰基转化为酰胺
与胺的反应是合成酰胺的重要方法: 这一反应是 一个平衡反应，采用过量的反应物之一或除去反应中 生成的水，均有利于平衡向产物方向转移。 除去水的 方法通常是在反应物中加入苯或甲苯进行共沸蒸馏。 例如将羟基乙酸及苄胺于90℃共热，并蒸出生成的水 及过量的苄胺，则生成羟基乙酰基苄胺:
O
M eO Tf(2eq.)
NN NN
C H 3N O 2, 10oC
O
N N N N -O Tf2 C B M IT
混合酸酐法 (二)
O
NN
N
N
O
RCOOH
CDI CH2Cl2, 0oC, 30min
R
NH2 N N rt, overnight
O O
O R=
O
O N H
TBSO
HO
OH
O
1. CDI, CH2Cl2 2. HN(OMe)Me. HCl
F
F
F
N OH
F
OH
O
F
NHNI
PFPOH
三个常用的缩合剂的比较
在三个常用的缩合剂中，和的价格较为便宜。一般和 合用，使用有一个最大的缺点就是反应的另一产物二环 己基脲在一般的有机相溶解度很小但又都有一些微溶， 因此通过一些常用的纯化方法，重结晶，柱层析等等很 难将其除得很彻底；由于二环己基脲在乙醚中的溶解度 相对要比其他溶剂小， 因此处理这类反应一般蒸掉反 应溶剂后加入乙醚，滤掉大部分的二环己基脲后再进一 步处理。由于其产生的二异丙基脲在有一般的有机溶剂 中溶解度较好，因此一般在组合化学的固相合成中用的 较多。
O
CH3
-20'C to rt.
BnO
O
65%
CONH2 CH3
混合酸酐法 (二)
羰基二咪唑:应用羰基二咪唑()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()的缩合性能更好。该类反应由 于或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。最近有人发现应用合成 酰胺是一个较好 的方法。
题外引伸-那些酰胺活性高
N R
O
N N
R O
N N
R O
O N
N O
N N
R O
G O
HN R
O
N N
R O
GO S
HN O R
O
碳二亚胺类缩合剂法（一）
缩合剂:利用碳二亚胺类缩合剂缩合制备酰胺在药物合成中应 用极为广泛，目前常用的缩合剂主要有三种：二环己基碳二 亚胺()、二异丙基碳二亚胺()和1-(3-二甲胺基丙基)-3-乙基碳 二亚胺()。
TBSO
23OC, 3 hr 93%
HO
N(OMe)Me
O
混合酸酐法 (三)
磺酰氯：另一类常用的方法是羧酸和磺酰氯生成羧酸-磺酸的混合酸酐， 其与胺反应得到相应的酰胺。常用的磺酰氯有甲烷磺酰氯（），对甲 苯磺酰氯（）和对硝基苯磺酰氯（）, 对硝基苯磺酰氯由于其吸电子 性，其与酸反应生成活性更高的混合酸酐，一般二级胺和三级胺，甚 至位阻很大的胺都能顺利反应。
副产物 ( b).
R
O
O
H
R1 N C N R2
R R1 O
NC O NH
R2
Path a Path b
R1 HN
O CN
O
R2
R X
X = Activator
Path a
O
R3R4NH
RX
O
R
N R3
R4
R1
ON
C NH
RO
R2
Path b
O
R1
N N R2
R
H
O
byproduct
碳二亚胺类缩合剂法（二）
NCN DCC
NCN DIC
NC N N .HCl
EDC
碳二亚胺类缩合剂法（一）
使用该类的缩合剂一般需要加入酰化催化剂或活化剂，
如4二甲基吡啶（）、1-羟基苯并三氮唑()等等，其主
要由于在反应的第一阶段酸对碳二亚胺的加成中间体
其并不稳定，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
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
BnO
O
COOH ClCOOC2H5, TEA, THF, then NH3 (g)