CN105622302B - 一种取代连苯三酚的合成方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B41/00—Formation or introduction of functional groups containing oxygen
- C07B41/02—Formation or introduction of functional groups containing oxygen of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
- C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
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Abstract
本发明涉及一种取代连苯三酚的合成方法，属于有机合成领域。以芳氧基吡啶为原料，在钯催化剂和二醋酸碘苯作用下，在有机溶剂中于60‑120℃反应3‑12h得双乙酰氧化产物；最后处理脱除乙酰基及吡啶基得到连苯三酚类化合物。本发明反应条件温和、易操作、收率高，无废气污染且易放大生产，是一种具有较好应用前景的取代连苯三酚的合成方法。
Description
技术领域
本发明属于有机合成领域，涉及一种取代连苯三酚化合物的合成方法。
背景技术
多元酚是一类重要的有机中间体，其具有良好的抗肿瘤活性和抗菌活性，在医药领域应用非常广泛。在本发明给出之前，现有的多元酚的合成方法也有一定的报道，以连三苯酚为例，通常是以羟基取代的芳香醛为反应原料，经过Dakin反应，在双氧水和强碱体系中制备(式1，路线a,B.Saikia,P.Borah and N.C.Barua,Green Chem.2015,17,4533-4536)。然而该类反应中所涉及的原料来源较难，且所用试剂腐蚀性和污染较大，在使用过程中存在较大的安全隐患。脱羧法也是制备连三苯酚的有效方法。Baruah等以三羟基取代的苯甲酸为原料，纤维素负载纳米铜为催化剂，在微波条件下实现了脱羧反应(式1，路线b，D.Baruah,D.Konwar,Catal.Commun.2015,69,68-71)。同样，多羟基取代的苯甲酸来源较为困难，且反应所需的条件较为复杂。朱素圆等在专利CN103755529A中公开了以三甲氧基苯甲醛为原料，氢气氛围中，改性骨架镍催化的脱羰反应(式1，路线c)。该法环境友好、原料易得、反应步骤短，便于工业化，其缺点在于对于制备一些复杂的含取代基的多元酚，其原料来源仍然苛刻。因此开发一种简便、高效的制备取代多元酚的方法十分必要。
式1：反应路线
发明内容
本发明的目的在于提供一种取代连苯三酚类化合物的合成方法，旨在解决现有技术中存在的问题。
本发明采用的技术方案如下：
一种如下式所示的取代连苯三酚类化合物的合成方法，反应式如下：
一种如上式所示的取代三元酚类化合物的合成方法，其特征在于按照下述步骤进行：将芳氧基吡啶、钯催化剂、二醋酸碘苯和溶剂加入烧瓶中，于60-120℃反应3～12小时。反应结束后，混合物经水洗，甲苯重结晶得化合物2。所述的芳氧基吡啶：钯催化剂：二醋酸碘苯的投料物质的量比为：1：0.05：3。其中钯催化剂可为醋酸钯、氯化钯、硝酸钯、乙酰丙酮钯；苯环上的取代基R可以为下列之一：烷基、烷氧基、酯基、卤原子、三氟甲基。本发明所述的有机溶剂可选自下面任意一种：乙酸乙酯、乙腈、氯苯、N,N-二甲基苯甲酰胺和1,2-二氯乙烷。所述的有机溶剂用量以芳氧基吡啶摩尔浓度计推荐为0.1～1mol/L。
将制备的化合物2，三氟甲磺酸甲酯与甲苯加入烧瓶中，其中化合物2与三氟甲磺酸甲酯的比例为1:2(摩尔比)，在惰性气体条件下回流2小时，减压除去溶剂，加入金属钠及甲醇，其中化合物2与甲醇钠的比例为1:20(摩尔比)，回流反应1小时。反应结束后，减压除去溶剂，混合物经乙酸乙酯萃取、水洗、重结晶得化合物3。
本发明是一种取代三元酚的合成方法，其创新技术是采用来源方便的芳基吡啶为原料，经过钯催化的双乙酰化反应，最终脱除吡啶及乙酰基官能团。反应条件温和，易操作，收率高且污染小。与现有的其他合成途径相比，方法新颖、产品易于提纯、无废气排放，是一种具有较好推广前景的取代三元酚的合成方法。
具体实施方式
以下以具体实例来说明本发明的技术方案，但本发明的保护范围不限于此：
实例1：5-甲基连三苯酚的合成
投料物质量比2-(4-甲基苯氧基)吡啶：醋酸钯：二醋酸碘苯为：1：0.05：3，有机溶剂为乙腈，溶剂用量为0.1mol/L(2-(4-甲基苯氧基)吡啶摩尔浓度计)。
在装有温度计，回流冷凝管和机械搅拌的三口烧瓶内，室温下依次加入2-(4-甲基苯氧基)吡啶1.85g(0.01mol)、醋酸钯0.11g(0.5mmol)、二醋酸碘苯9.66g(0.03mol)和乙腈100mL。加毕，升温至60℃，保温反应12小时。反应结束后，减压蒸去溶剂，残余物倒入冰水中，乙酸乙酯萃取，去离子水洗涤，减压蒸馏得粗产物，经甲苯重结晶得纯品2.41g，收率80％。
Mp:118～120℃；1H NMR(300MHz,CDCl3)δ8.14(ddd,J＝5.0,1.9,0.7Hz,1H),7.67(ddd,J＝8.3,7.2,2.0Hz,1H),6.99(ddd,J＝7.2,5.0,0.8Hz,1H),6.94–6.92(m,3H),2.36(s,3H),2.03(s,6H)；13C NMR(75MHz,CDCl3)δ168.3,162.4,147.6,143.5,139.4,135.4,135.0,121.6,118.6,110.1,21.1,20.4.
在装有温度计，回流冷凝管和机械搅拌的三口烧瓶内，室温下依次加入上述步骤制备的二乙酰氧化产物2.41g，三氟甲磺酸甲酯2.62g和甲苯50mL，回流反应2小时；完毕，减压除去甲苯，缓慢加入甲醇钠(8.6g)的甲醇溶液(100mL)，回流反应1小时。反应结束后，减压除去溶剂、水洗、乙酸乙酯萃取、水重结晶得5-甲基连三苯酚0.84g(75％)。
实例2：5-氯连三苯酚的合成
投料物质量比2-(4-氯苯氧基)吡啶：氯化钯：二醋酸碘苯为：1：0.05：3，有机溶剂为N,N-二甲基乙酰胺，溶剂用量为1mol/L(2-(4-氯苯氧基)吡啶摩尔浓度计)。
在装有温度计，回流冷凝管和机械搅拌的三口烧瓶内，室温下依次加入2-(4-甲基苯氧基)吡啶1.85g(0.01mol)、氯化钯0.09g(0.5mmol)、二醋酸碘苯9.66g(0.03mol)和N,N-二甲基乙酰胺10mL。加毕，升温至120℃，保温反应3小时。反应结束后，减压蒸去溶剂，残余物倒入冰水中，乙酸乙酯萃取，去离子水洗涤，减压蒸馏得粗产物，经甲苯重结晶得纯品2.76g，收率86％。
Mp:103～105℃；1H NMR(300MHz,CDCl3)δ8.13(ddd,J＝5.0,1.9,0.7Hz,1H),7.70(ddd,J＝8.3,7.2,2.0Hz,1H),7.16(s,2H),7.04–6.95(m,2H),2.04(s,6H)；13C NMR(75MHz,CDCl3)δ167.7,162.0,147.5,144.2,139.6,136.5,129.8,121.6,119.0,110.2,20.4.
在装有温度计，回流冷凝管和机械搅拌的三口烧瓶内，室温下依次加入上述步骤制备的二乙酰氧化产物2.76g，三氟甲磺酸甲酯2.62g和甲苯50mL，回流反应2小时；完毕，减压除去甲苯，缓慢加入甲醇钠(8.6g)的甲醇溶液(100mL)，回流反应1小时。反应结束后，减压除去溶剂、水洗、乙酸乙酯萃取、水重结晶得5-氯连三苯酚1.14g(83％)。
Claims (4)
1.一种取代连苯三酚的合成方法，其特征在于：所述的合成方法如下，
将芳氧基吡啶、钯催化剂、二醋酸碘苯和溶剂加入烧瓶中，于60-120℃反应3～12小时，得双乙酰化产物2，然后在三氟甲烷磺酸甲酯、甲苯、甲醇钠和甲醇作用下脱除乙酰基及吡啶基，
其中，所述的钯催化剂为醋酸钯或氯化钯；所述的溶剂为乙酸乙酯、乙腈、氯苯、N,N-二甲基苯甲酰胺或1,2-二氯乙烷；
上式中，R为烷基、烷氧基、酯基、卤原子或三氟甲基，X为Cl或CH3COO。
2.根据权利要求1所述的取代连苯三酚的合成方法，其特征在于：其中，芳氧基吡啶、钯催化剂、二醋酸碘苯的投料物质的量比为1：0.05：3。
3.根据权利要求1所述的取代连苯三酚的合成方法，其特征在于：所述溶剂的用量以芳氧基吡啶摩尔浓度计为0.1～1mol/L。
4.根据权利要求1所述的取代连苯三酚的合成方法，其特征在于：将制备的双乙酰化产物2、三氟甲磺酸甲酯与甲苯加入烧瓶中，其中，双乙酰化产物2与三氟甲磺酸甲酯的摩尔比为1:2，在惰性气体条件下回流2小时，减压除去溶剂；加入甲醇钠及甲醇，其中，双乙酰化产物2与甲醇钠的摩尔比为1:20，回流反应1小时；反应结束后，减压除去溶剂，混合物经乙酸乙酯萃取、水洗、重结晶得取代连苯三酚3。
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