技术领域technical field
本发明涉及一种香豆素-3-膦酸酯衍生物的制备方法，属有机化学领域。The invention relates to a preparation method of coumarin-3-phosphonate derivatives, belonging to the field of organic chemistry.
背景技术Background technique
香豆素是一类重要的天然产物，其衍生物具有广泛的生物活性，如抗菌抗炎、抗老年痴呆、抗HIV和抗胸腺癌等。3-膦酰化香豆素作为香豆素的含磷衍生物，对人类的白血病细胞具有较好的细胞毒性，因此，研究3-膦酰化香豆素衍生物的合成具有重要的实际意义。Coumarin is an important class of natural products, and its derivatives have a wide range of biological activities, such as antibacterial and anti-inflammatory, anti-senile dementia, anti-HIV and anti-thymus carcinoma. 3-phosphonylated coumarin, as a phosphorus-containing derivative of coumarin, has good cytotoxicity to human leukemia cells. Therefore, it is of great practical significance to study the synthesis of 3-phosphonylated coumarin derivatives .
目前，香豆素-3-膦酸酯衍生物的合成通常采用Knoevenagel反应或Arbuzov反应来实现，但是这些方法需要多步反应且条件相对比较苛刻，缺乏经济性和实用性。文献“ZhouP,JiangYJ,ZouJP,etal.Mn(OAc)3-mediatedfreeradicalphosphonylationofflavonesandcoumarins[J].Synthesis,2012,44:1043-1050.”和“邹建平,姜耀甲,潘向强.一种合成香豆素-3-膦酸酯衍生物的方法[P].CN101497632A”以Mn(OAc)3为催化剂，脂肪酸为溶剂，香豆素与亚磷酸酯反应得到3-膦酰化香豆素衍生物。文献“MiX,HuangMM,ZhangJY,etal.Regioselectivepaddadium-catalyzedphosphonationofcoumarinswithdialkylH-phosphonatesviaC-Hfunctionalization[J].OrgLett,2013,15(24):6266-6269.”以金属Pd为催化剂，2，2′-联吡啶等为配体，K2S2O8为氧化剂，香豆素与亚磷酸酯通过金属活化3位氢得到3-膦酰化香豆素衍生物。文献“MiX,WangCY,HuangMM,etal.Silver-catalyzedsynthesisof3-phosphoratedcoumarinsviaradicalcyclizationofalkynoatesanddialkylH-phosphonates[J].OrgLett,2014,16(12):3356-3359.”以Ag2CO3为催化剂，以炔酯为原料，与亚磷酸酯通过自由基反应得到3-膦酰化香豆素衍生物。但是这些合成方法需要酸做溶剂，或使用贵金属为催化剂，或使用不易得到的反应前体等缺点。因此，急需探讨一种步骤简单，条件温和，收率较高的香豆素-3-膦酸酯衍生物的合成方法，这将促进香豆素-3-膦酸酯衍生物的开发利用，对保护我国自主知识产权的研发具有重要的意义。At present, the synthesis of coumarin-3-phosphonate derivatives is usually realized by Knoevenagel reaction or Arbuzov reaction, but these methods require multi-step reactions and the conditions are relatively harsh, lacking in economy and practicability. Literature "ZhouP, JiangYJ, ZouJP, etal.Mn(OAc)3 -mediatedfreeradicalphosphonylationofflavonesandcoumarins[J].Synthesis,2012,44:1043-1050." The method of ester derivatives [P].CN101497632A " takes Mn(OAc)3 as a catalyst, fatty acid as a solvent, and reacts coumarin and phosphite to obtain 3-phosphonylated coumarin derivatives. Document "MiX, HuangMM, ZhangJY, etal.Regioselectivepaddadium-catalyzedphosphonationofcoumarinswithdialkylH-phosphonatesviaC-Hfunctionalization[J].OrgLett,2013,15(24):6266-6269." Using metal Pd as catalyst, 2,2'-bipyridine etc. as Ligand, K2 S2 O8 is the oxidizing agent, and coumarin and phosphite activate the 3-position hydrogen through metal to obtain 3-phosphonylated coumarin derivatives. Document "MiX, WangCY, HuangMM, etal.Silver-catalyzedsynthesisof3-phosphoratedcoumarinsviaradicalcyclizationofalkynoatesanddialkylH-phosphonates[J].OrgLett,2014,16(12):3356-3359." Using Ag2 CO3 as a catalyst, using alkyne ester as a raw material, and Phosphites undergo radical reactions to give 3-phosphonylated coumarin derivatives. However, these synthetic methods need acid as a solvent, or use noble metals as catalysts, or use difficult-to-obtain reaction precursors and other disadvantages. Therefore, be badly in need of exploring a kind of step is simple, and condition is gentle, the synthetic method of the higher coumarin-3-phosphonate derivative of yield, this will promote the development and utilization of coumarin-3-phosphonate derivative, It is of great significance to the research and development of the protection of my country's independent intellectual property rights.
发明内容Contents of the invention
基于上述研究背景，本发明的目的在于提供一种条件温和、收率高，通过一步反应得到香豆素-3-膦酸酯衍生物的合成新方法。Based on the above-mentioned research background, the object of the present invention is to provide a new method for the synthesis of coumarin-3-phosphonate derivatives through one-step reaction with mild conditions and high yield.
为实现本发明目的，本发明以取代香豆素与亚磷酸酯为原料，在催化剂AgNO3和辅助剂共同作用下合成香豆素-3-膦酸酯衍生物。本发明所述的香豆素-3-膦酸酯衍生物有如下通式I。To achieve the purpose of the present invention, the present invention uses substituted coumarin and phosphite as raw materials, and synthesizes coumarin-3 -phosphonate derivatives under the joint action of catalyst AgNO3 and auxiliary agents. The coumarin-3-phosphonate derivatives of the present invention have the following general formula I.
其中R代表如下基团：C1-5烷基、苯基或苄基，优选-CH3，-C2H5，-CH2CH2CH3，-CH(CH3)2；R1代表氢基或如下基团之一：甲基、乙基、甲氧基或乙氧基，优选-H，-CH3、-OCH3；R2代表氢基或如下基团在苯环上单取代或双取代：甲基、乙基、甲氧基、乙氧基、硝基、氨基、羟基、乙酰氨基、乙酰氧基或卤基，R2优选如下基团在苯环上单取代：-F，-Cl，-Br，-CH3，-C2H5，-OCH3，-OC2H5，-OH，-NH2，-NHCOCH3。Where R represents the following groups: C1-5 alkyl, phenyl or benzyl, preferably -CH3 , -C2 H5 , -CH2 CH2 CH3 , -CH(CH3 )2 ; R1 represents hydrogen or one of the following groups: methyl, ethyl, methoxy or ethoxy, preferably -H, -CH3 , -OCH3 ; R2 represents a hydrogen group or the following groups are monosubstituted on the benzene ring or Disubstituted: methyl, ethyl, methoxy, ethoxy, nitro, amino, hydroxyl, acetamido, acetoxy or halo, R2 is preferably monosubstitutedon the benzene ring by the following groups: -F, -Cl,-Br ,-CH3 ,-C2H5 ,-OCH3 ,-OC2H5 ,-OH ,-NH2 ,-NHCOCH3 .
具体技术方案通过如下步骤实现：首先将取代香豆素A与亚磷酸酯B溶解在合适的有机溶剂中，然后加入催化剂AgNO3和辅助剂，在80-100℃下反应。反应结束后，冷却至室温，经洗涤，萃取，干燥，减压蒸去溶剂，得通式(I)香豆素-3-膦酸酯衍生物粗品。The specific technical solution is realized through the following steps: first, dissolve the substituted coumarin A and phosphite B in a suitable organic solvent, then add catalyst AgNO3 and auxiliary agent, and react at 80-100°C. After the reaction, cool to room temperature, wash, extract, dry, and evaporate the solvent under reduced pressure to obtain the crude product of coumarin-3-phosphonate derivative of general formula (I).
取代香豆素A和亚磷酸酯B的摩尔比优选1:2。催化剂AgNO3的量为取代香豆素摩尔量的5％。The molar ratio of substituted coumarin A and phosphite B is preferably 1:2. The amount of catalyst AgNO3 is 5% of the molar amount of substituted coumarin.
辅助剂选择Mg(NO3)2·6H2O，Fe(NO3)3·9H2O，NaNO3，Cu(NO3)2·3H2O，Cr(NO3)3·9H2O，优选Mg(NO3)2·6H2O作为辅助剂，加入的量为取代香豆素摩尔量的50％。Auxiliary agent selection Mg(NO3 )2 6H2 O, Fe(NO3 )3 9H2 O, NaNO3 , Cu(NO3 )2 3H2 O, Cr(NO3 )3 9H2 O, Mg(NO3 )2 ·6H2 O is preferably used as an auxiliary agent, and the added amount is 50% of the molar amount of substituted coumarin.
有机溶剂选择THF、甲苯、二氧六环、甲醇、氯仿、DMSO和乙腈等中一种或多种作为溶剂，优选乙腈为溶剂。优选采用90℃为最佳的反应温度，最佳的反应时间为5h。The organic solvent is selected from one or more of THF, toluene, dioxane, methanol, chloroform, DMSO, and acetonitrile as a solvent, preferably acetonitrile as a solvent. It is preferable to adopt 90° C. as the optimum reaction temperature, and the optimum reaction time is 5 hours.
式中R、R1、R2表述同上。In the formula, R, R1 and R2 have the same expressions as above.
分离和纯化香豆素-3-膦酸酯衍生物粗品，例如，将粗品通过硅胶柱层析进行分离得香豆素-3-膦酸酯衍生物(I)，使其获得更好的应用。另外，可以通过在(I)的乙酸乙酯溶液中加入适量的石油醚，使(I)结晶析出。该类衍生物在材料、化工、医药等领域具有潜在的应用。Isolate and purify the crude product of coumarin-3-phosphonate derivatives, for example, separate the crude product through silica gel column chromatography to obtain coumarin-3-phosphonate derivatives (I), so that it can be used better . In addition, crystals of (I) can be precipitated by adding an appropriate amount of petroleum ether to the ethyl acetate solution of (I). Such derivatives have potential applications in the fields of material, chemical industry, medicine and the like.
本发明所用试剂均市售可得。The reagents used in the present invention are all commercially available.
本发明原理在于：亚磷酸酯首先与硝酸银反应生成中间体((CH3)2CHO)2P(O)Ag复合物，脱去Ag(0)后形成磷自由基；然后磷自由基进攻香豆素的3位碳原子，形成碳自由基，通过Ag(I)作用，得到一个电子形成Ag(0)，从而形成一个碳正离子；最后通过消去一个质子得到目标产物香豆素-3-膦酸酯衍生物。The principle of the present invention is that: phosphite first reacts with silver nitrate to generate an intermediate ((CH3 )2 CHO)2 P(O)Ag complex, and forms a phosphorus free radical after removing Ag(0); then the phosphorus free radical attacks The 3-position carbon atom of coumarin forms a carbon free radical, and through the action of Ag(I), an electron is obtained to form Ag(0), thereby forming a carbocation; finally, the target product coumarin-3 is obtained by eliminating a proton - Phosphonate derivatives.
本发明有益效果在于：本发明合成香豆素-3-膦酸酯衍生物的方法原料廉价易得、反应条件温和、通过一步反应得到目标物，操作简便，合成产率高，达60％以上，非常有利于工业化生产，为制备具有抗菌抗炎、抗癌等活性的香豆素-3-膦酸酯衍生物提供了一条新的途径。The beneficial effects of the present invention are: the raw materials of the method for synthesizing coumarin-3-phosphonate derivatives of the present invention are cheap and easy to obtain, the reaction conditions are mild, the target object can be obtained through one-step reaction, the operation is simple, and the synthesis yield is high, reaching more than 60%. , is very beneficial to industrial production, and provides a new way for the preparation of coumarin-3-phosphonate derivatives with antibacterial, anti-inflammatory, anticancer and other activities.
具体实施方式Detailed ways
下面通过实施例对本发明进行进一步的阐述，但并不意味着本发明的内容局限于实施例。The present invention is further elaborated below through the examples, but it does not mean that the content of the present invention is limited to the examples.
实施例1.R＝-CH(CH3)2，R1＝R2＝-H时，香豆素-3-二异丙基膦酸酯衍生物的制备Example 1. Preparation of coumarin-3-diisopropylphosphonate derivatives when R=-CH(CH3 )2 , R1 =R2 =-H
在10mL反应瓶中加入香豆素(0.5mmol,73mg)和亚磷酸二异丙酯(1.0mmol,166mg)溶解在3.0mLCH3CN中，然后加入AgNO3(0.025mmol,4.2mg)和Mg(NO3)2·6H2O(0.25mmol,64mg)。在油浴中加热搅拌下反应，反应温度为90℃。通过TLC跟踪反应过程，反应时间为5h，反应结束后，减压蒸除溶剂，残液中加入10mL乙酸乙酯，用20mL饱和的NaHCO3洗涤二次，再用10mL饱和的食盐水洗涤一次，溶液浓缩后用硅胶柱层析提纯(洗脱剂：乙酸乙酯/石油醚＝1/5)，得到白色固体0.096g，产率62.0％。Add coumarin (0.5mmol, 73mg) and diisopropyl phosphite (1.0mmol, 166mg) in 10mL reaction flask and dissolve in 3.0mL CH3 CN, then add AgNO3 (0.025mmol, 4.2mg) and Mg( NO3 )2 ·6H2 O (0.25 mmol, 64 mg). React under heating and stirring in an oil bath, and the reaction temperature is 90°C. The reaction process was tracked by TLC. The reaction time was 5 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 10 mL of ethyl acetate was added to the raffinate, and20 mL of saturated NaHCO was used. Washing twice, and then washing once with 10 mL of saturated brine, After the solution was concentrated, it was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/5) to obtain 0.096 g of white solid with a yield of 62.0%.
熔点95-96℃.1HNMR(CDCl3)δ:8.49(d,JP-H＝6.9Hz,1H),7.62-7.55(m,2H),7.32-7.28(m,2H),4.87-4.79(m,2H),1.34(dd,JP-H＝12.9Hz,JH-H＝6.0Hz,12H).13CNMR(CDCl3)δ:158.1(d,JP-C＝22.9Hz),155.2,152.9(d,JP-C＝10.7Hz),134.0,129.3,124.8,119.8,118.0(d,JP-C＝22.7Hz),116.8,72.2(d,JP-C＝9.8Hz),24.0(d,JP-C＝6.8Hz),23.8(d,JP-C＝7.6Hz).31PNMR(CDCl3)δ:8.2.IR(KBr)ν(cm-1):2981,2935(-CH3),1738(C＝O),1614,1566(Ar-),1450(P-C),1248(P＝O),1105(P-O).ESIMS311.3[M+H]+(calculatedforC15H20O5P+311.1).Melting point 95-96℃.1 HNMR(CDCl3 )δ: 8.49(d, JPH ＝6.9Hz, 1H), 7.62-7.55(m, 2H), 7.32-7.28(m, 2H), 4.87-4.79(m ,2H),1.34(dd,JPH ＝12.9Hz,JHH ＝6.0Hz,12H).13 CNMR(CDCl3 )δ:158.1(d,JPC ＝22.9Hz),155.2,152.9(d,JPC ＝10.7Hz), 134.0, 129.3, 124.8, 119.8, 118.0(d, JPC ＝22.7Hz), 116.8, 72.2(d, JPC ＝9.8Hz), 24.0(d, JPC ＝6.8Hz), 23.8( d, JPC ＝7.6Hz).31 PNMR (CDCl3 ) δ: 8.2. IR (KBr) ν (cm-1 ): 2981, 2935 (-CH3 ), 1738 (C=O), 1614, 1566 ( Ar-), 1450(PC), 1248(P=O), 1105(PO).ESIMS311.3[M+H]+ (calculated for C15 H20 O5 P+ 311.1).
实施例2.R＝-CH2CH2CH3，R1＝-H，R2＝-H时，香豆素-3-二正丙基膦酸酯衍生物的制备Example 2. Preparation of coumarin-3-di-n-propylphosphonate derivatives when R=-CH2 CH2 CH3 , R1 =-H, R2 =-H
在10mL反应瓶中加入香豆素(0.5mmol,73mg)和亚磷酸二正丙酯(1.0mmol,166mg)溶解在3.0mL氯仿中，然后加入AgNO3(0.025mmol,4.2mg)和Fe(NO3)3·9H2O(0.25mmol,101mg)。在油浴中加热搅拌下反应，反应温度为80℃。通过TLC跟踪反应过程，反应时间为5h，反应结束后，减压蒸除溶剂，残液中加入10mL乙酸乙酯，用20mL饱和的NaHCO3洗涤二次，再用10mL饱和的食盐水洗涤一次，溶液浓缩后用硅胶柱层析提纯(洗脱剂：乙酸乙酯/石油醚＝1/5)，得到淡黄色粘稠状液体0.093g，产率60.0％。Add coumarin (0.5mmol, 73mg) and di-n-propyl phosphite (1.0mmol, 166mg) in 10mL reaction bottle and dissolve in 3.0mL chloroform, then add AgNO3 (0.025mmol, 4.2mg) and Fe(NO3 )3.9H2 O (0.25 mmol, 101 mg). React under heating and stirring in an oil bath, and the reaction temperature is 80°C. The reaction process was tracked by TLC. The reaction time was 5 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 10 mL of ethyl acetate was added to the raffinate, and20 mL of saturated NaHCO was used. Washing twice, and then washing once with 10 mL of saturated brine, After concentration, the solution was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/5) to obtain 0.093 g of light yellow viscous liquid with a yield of 60.0%.
1HNMR(CDCl3)δ:8.50(d,JP-H＝6.9Hz,1H),7.64-7.56(m,2H),7.34-7.29(m,2H),4.20-4.06(m,4H),1.76-1.68(m,4H),0.94(d,JH-H＝7.4Hz,6H).13CNMR(CDCl3)δ:158.1(d,JP-C＝23.4Hz),155.2,153.4(d,JP-C＝10.5Hz),134.2,129.3,124.9,118.8,117.9(d,JP-C＝22.7Hz),116.8,68.8(d,JP-C＝10.2Hz),23.8(d,JP-C＝10.4Hz),10.0.31PNMR(CDCl3)δ:10.5.IR(KBr)ν(cm-1):2968,2931,2850(-CH3,-CH2),1732(C＝O),1610,1564(Ar-),1445(P-C),1248(P＝O),1008(P-O).ESIMS311.2[M+H]+(calculatedforC15H20O5P+311.1).1 H NMR (CDCl3 ) δ: 8.50 (d, JPH = 6.9 Hz, 1 H), 7.64-7.56 (m, 2H), 7.34-7.29 (m, 2H), 4.20-4.06 (m, 4H), 1.76- 1.68(m,4H),0.94(d,JHH ＝7.4Hz,6H).13 CNMR(CDCl3 )δ:158.1(d,JPC ＝23.4Hz),155.2,153.4(d,JPC ＝10.5Hz ), 134.2, 129.3, 124.9, 118.8, 117.9 (d, JPC = 22.7Hz), 116.8, 68.8 (d, JPC = 10.2Hz), 23.8 (d, JPC = 10.4Hz), 10.0.31 PNMR ( CDCl3 )δ: 10.5. IR(KBr)ν(cm-1 ): 2968, 2931, 2850(-CH3 ,-CH2 ), 1732(C=O), 1610, 1564(Ar-), 1445( PC), 1248(P=O), 1008(PO).ESIMS311.2[M+H]+ (calculated for C15 H20 O5 P+ 311.1).
实施例3.R＝-CH(CH3)2，R1＝-H，R2＝-OCH3时，7-甲氧基香豆素-3-二异丙基膦酸酯衍生物的制备Example 3. Preparation of 7-methoxycoumarin-3-diisopropylphosphonate derivatives when R=-CH(CH3 )2 , R1 =-H, R2 =-OCH3
在25mL反应瓶中加入7-甲氧基香豆素(1.0mmol,176mg)和亚磷酸二异丙酯(2.0mmol,232mg)溶解在5.0mL甲醇中，然后加入AgNO3(0.05mmol,8.4mg)和NaNO3(0.5mmol,42.5mg)。在油浴中加热搅拌下反应，反应温度为90℃。通过TLC跟踪反应过程，反应时间为5h，反应结束后，减压蒸除溶剂，残液中加入10mL乙酸乙酯，用20mL饱和的NaHCO3洗涤二次，再用10mL饱和的食盐水洗涤一次，溶液浓缩后用硅胶柱层析提纯(洗脱剂：乙酸乙酯/石油醚＝1/3)，得到白色固体0.216g，产率64.0％。Add 7-methoxycoumarin (1.0mmol, 176mg) and diisopropyl phosphite (2.0mmol, 232mg) in 25mL reaction flask and dissolve in 5.0mL methanol, then add AgNO3 (0.05mmol, 8.4mg ) and NaNO3 (0.5 mmol, 42.5 mg). React under heating and stirring in an oil bath, and the reaction temperature is 90°C. The reaction process was tracked by TLC. The reaction time was 5 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 10 mL of ethyl acetate was added to the raffinate, and20 mL of saturated NaHCO was used. Washing twice, and then washing once with 10 mL of saturated brine, After concentration, the solution was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3) to obtain 0.216 g of white solid with a yield of 64.0%.
熔点76-77℃.1HNMR(CDCl3)δ:8.37(d,JP-H＝6.8Hz,1H),7.42(d,JH-H＝8.7Hz,1H),6.82(dd,JH-H＝2.4Hz,JH-H＝8.7Hz,1H),6.74(d,JH-H＝2.4Hz,1H),4.80-4.72(m,2H),1.33(d,JH-H＝6.2Hz,6H),1.26(d,JH-H＝6.2Hz,6H).13CNMR(CDCl3)δ:164.7,158.4(d,JP-C＝23.7Hz),157.4,152.9(d,JP-C＝11.3Hz),130.4,113.2(d,JP-C＝16.6Hz),111.7(d,JP-C＝23.2Hz),100.5,71.9(d,JP-C＝9.6Hz),55.9,24.0(d,JP-C＝6.5Hz),23.8(d,JP-C＝7.5Hz).31PNMR(CDCl3)δ:8.8.IR(KBr)ν(cm-1):2981,2935(-CH3),1738(C＝O),1614,1553(Ar-),1373(P-C),1252(P＝O),1142(P-O).ESIMS341.3[M+H]+(calculatedforC16H22O6P+341.1).Melting point 76-77℃.1 HNMR(CDCl3 )δ: 8.37(d, JPH ＝6.8Hz, 1H), 7.42(d, JHH ＝8.7Hz, 1H), 6.82(dd, JHH ＝2.4Hz, JHH ＝8.7Hz,1H),6.74(d,JHH ＝2.4Hz,1H),4.80-4.72(m,2H),1.33(d,JHH ＝6.2Hz,6H),1.26(d,JHH ＝6.2Hz, 6H).13 CNMR(CDCl3 )δ: 164.7, 158.4(d, JPC ＝23.7Hz), 157.4, 152.9(d, JPC ＝11.3Hz), 130.4, 113.2(d, JPC ＝ 16.6Hz), 111.7(d, JPC ＝23.2Hz), 100.5, 71.9(d, JPC ＝9.6Hz), 55.9, 24.0(d, JPC ＝6.5Hz), 23.8(d, JPC ＝7.5Hz ).31 PNMR (CDCl3 ) δ: 8.8. IR (KBr) ν (cm-1 ): 2981, 2935 (-CH3 ), 1738 (C=O), 1614, 1553 (Ar-), 1373 (PC ), 1252(P=O), 1142(PO).ESIMS341.3[M+H]+ (calculated for C16 H22 O6 P+ 341.1).
实施例4.R＝-CH(CH3)2，R1＝-H，R2＝-NO2时，6-硝基香豆素-3-二异丙基膦酸酯衍生物的制备Example 4. Preparation of 6-nitrocoumarin-3-diisopropylphosphonate derivatives when R=-CH(CH3 )2 , R1 =-H, R2 =-NO2
在25mL反应瓶中加入6-硝基香豆素(1.0mmol,191mg)和亚磷酸二异丙酯(2.0mmol,232mg)溶解在5.0mL二氧六环中，然后加入AgNO3(0.05mmol,8.4mg)和Cr(NO3)3·9H2O(0.5mmol,200mg)。在油浴中加热搅拌下反应，反应温度为100℃。通过TLC跟踪反应过程，反应时间为5h，反应结束后，减压蒸除溶剂，残液中加入10mL乙酸乙酯，用20mL饱和的NaHCO3洗涤二次，再用10mL饱和的食盐水洗涤一次，溶液浓缩后用硅胶柱层析提纯(洗脱剂：乙酸乙酯/石油醚＝2/1)，得到淡黄色粘稠状液体0.212g，产率60.0％。Add 6-nitrocoumarin (1.0mmol, 191mg) and diisopropyl phosphite (2.0mmol, 232mg) in 25mL reaction bottle and dissolve in 5.0mL dioxane, then add AgNO3 (0.05mmol, 8.4 mg) and Cr(NO3 )3 ·9H2 O (0.5 mmol, 200 mg). React under heating and stirring in an oil bath, and the reaction temperature is 100°C. The reaction process was tracked by TLC. The reaction time was 5 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 10 mL of ethyl acetate was added to the raffinate, and20 mL of saturated NaHCO was used. Washing twice, and then washing once with 10 mL of saturated brine, After the solution was concentrated, it was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=2/1) to obtain 0.212 g of light yellow viscous liquid with a yield of 60.0%.
1HNMR(CDCl3)δ:8.56(d,JP-H＝5.9Hz,1H),8.54(s,1H),8.48(dd,JH-H＝2.6Hz,JH-H＝9.0Hz,1H),7.50(d,JH-H＝9.0Hz,1H),4.95-4.87(m,2H),1.43(d,JH-H＝6.2Hz,6H),1.35(d,JH-H＝6.2Hz,6H).13CNMR(CDCl3)δ:158.4,156.5(d,JP-C＝22.3Hz),150.9(d,JP-C＝10.5Hz),144.1,128.2,124.9,122.9,121.0,118.1,118.0(d,JP-C＝23.5Hz),72.8(d,JP-C＝10.2Hz),24.0(d,JP-C＝6.5Hz),23.8(d,JP-C＝6.5Hz).31PNMR(CDCl3)δ:5.6.IR(KBr)ν(cm-1):3087,2965(-CH3,),1735(C＝O),1625,1578(Ar-),1376(P-C),1245(P＝O),1134(P-O).ESIMS356.1[M+H]+(calculatedforC15H19NO7P+356.0).1 H NMR (CDCl3 ) δ: 8.56 (d, JPH = 5.9 Hz, 1H), 8.54 (s, 1 H), 8.48 (dd, JHH = 2.6 Hz, JHH = 9.0 Hz, 1 H), 7.50 (d , JHH ＝9.0Hz, 1H), 4.95-4.87 (m, 2H), 1.43 (d, JHH ＝6.2Hz, 6H), 1.35 (d, JHH ＝6.2Hz, 6H).13 CNMR (CDCl3 )δ: 158.4, 156.5 (d, JPC = 22.3Hz), 150.9 (d, JPC = 10.5Hz), 144.1, 128.2, 124.9, 122.9, 121.0, 118.1, 118.0 (d, JPC = 23.5Hz), 72.8(d, JPC ＝10.2Hz), 24.0(d, JPC ＝6.5Hz), 23.8(d, JPC ＝6.5Hz).31 PNMR(CDCl3 )δ:5.6.IR(KBr)ν(cm-1 ):3087, 2965(-CH3 ,), 1735(C=O), 1625, 1578(Ar-), 1376(PC), 1245(P=O), 1134(PO).ESIMS356.1[ M+H]+ (calculated for C15 H19 NO7 P+ 356.0).
实施例5.R＝-CH(CH3)2，R1＝-CH3，R2＝-OH时，4-甲基-7-羟基香豆素-3-二异丙基膦酸酯衍生物的制备Example 5. Derivatization of 4-methyl-7-hydroxycoumarin-3-diisopropylphosphonate when R=-CH(CH3 )2 , R1 =-CH3 , R2 =-OH preparation
在25mL反应瓶中加入4-甲基-7-羟基香豆素(1.0mmol,176mg)和亚磷酸二异丙酯(2.0mmol,232mg)溶解在5.0mLCH3CN中，然后加入AgNO3(0.05mmol,8.4mg)和Cu(NO3)2·3H2O(0.5mmol,120.5mg)。在油浴中加热搅拌下反应，反应温度为90℃。通过TLC跟踪反应过程，反应时间为5h，反应结束后，减压蒸除溶剂，残液中加入10mL乙酸乙酯，用20mL饱和的NaHCO3洗涤二次，再用10mL饱和的食盐水洗涤一次，溶液浓缩后用硅胶柱层析提纯(洗脱剂：乙酸乙酯/石油醚＝5/1)，得到淡黄色粘稠状液体0.21g，产率62.0％。Add 4-methyl-7-hydroxycoumarin (1.0mmol, 176mg) and diisopropyl phosphite (2.0mmol, 232mg) into 25mL reaction flask and dissolve in 5.0mL CH3 CN, then add AgNO3 (0.05 mmol, 8.4 mg) and Cu(NO3 )2 ·3H2 O (0.5 mmol, 120.5 mg). React under heating and stirring in an oil bath, and the reaction temperature is 90°C. The reaction process was tracked by TLC. The reaction time was 5 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 10 mL of ethyl acetate was added to the raffinate, and20 mL of saturated NaHCO was used. Washing twice, and then washing once with 10 mL of saturated brine, After the solution was concentrated, it was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=5/1) to obtain 0.21 g of light yellow viscous liquid with a yield of 62.0%.
1HNMR(CDCl3)δ:10.1(s,-OH),7.64(d,JH-H＝8.9Hz,1H),6.94(dd,JH-H＝2.4Hz,JH-H＝8.9Hz,1H),6.89(d,JH-H＝2.4Hz,1H),4.89-4.80(m,2H),2.90(d,JP-H＝0.9Hz,3H),1.40(d,JH-H＝6.2Hz,6H),1.33(d,JH-H＝6.2Hz,6H).13CNMR(CDCl3)δ:163.4(d,JP-C＝20.8Hz),159.5(d,JP-C＝25.3Hz),155.7,127.5,114.1,112.6(d,JP-C＝25.2Hz),111.1,109.1,102.8,72.4(d,JP-C＝10.0Hz),24.0(d,JP-C＝7.4Hz),23.8(d,JP-C＝7.4Hz),17.1(d,JP-C＝6.2Hz).31PNMR(CDCl3)δ:10.0.IR(KBr)ν(cm-1):3105(-OH),2993,2905(-CH3),1736(C＝O),1599,1482(Ar-),1352(P-C),1198(P＝O),1005(P-O).ESIMS341.2[M+H]+(calculatedforC16H22O6P+341.1).1 HNMR (CDCl3 ) δ: 10.1 (s, -OH), 7.64 (d, JHH = 8.9 Hz, 1 H), 6.94 (dd, JHH = 2.4 Hz, JHH = 8.9 Hz, 1 H), 6.89 ( d, JHH ＝2.4Hz, 1H), 4.89-4.80(m, 2H), 2.90(d, JPH ＝0.9Hz, 3H), 1.40(d, JHH ＝6.2Hz, 6H), 1.33(d, JHH ＝6.2Hz,6H).13 CNMR(CDCl3 )δ:163.4(d,JPC ＝20.8Hz),159.5(d,JPC ＝25.3Hz),155.7,127.5,114.1,112.6(d,JPC ＝25.2Hz), 111.1, 109.1, 102.8, 72.4(d, JPC ＝10.0Hz), 24.0(d, JPC ＝7.4Hz), 23.8(d, JPC ＝7.4Hz), 17.1(d, JPC = 6.2Hz).31 PNMR (CDCl3 ) δ: 10.0. IR (KBr) ν (cm-1 ): 3105 (-OH), 2993, 2905 (-CH3 ), 1736 (C=O), 1599 , 1482(Ar-), 1352(PC), 1198(P=O), 1005(PO).ESIMS341.2[M+H]+ (calculated for C16 H22 O6 P+ 341.1).
实施例6.R＝-CH(CH3)2，R1＝-CH3，R2＝-OC2H5时，4-甲基-7-乙氧基香豆素-3-二异丙基膦酸酯衍生物的制备Example 6. When R=-CH(CH3 )2 , R1 =-CH3 , R2 =-OC2 H5 , 4-methyl-7-ethoxycoumarin-3-diisopropyl Preparation of phosphonate derivatives
在25mL反应瓶中加入4-甲基-7-乙氧基香豆素(1.0mmol,204mg)和亚磷酸二异丙酯(2.0mmol,232mg)溶解在5.0mL甲苯中，然后加入AgNO3(0.05mmol,8.4mg)和Mg(NO3)2·6H2O(0.5mmol,128mg)。在油浴中加热搅拌下反应，反应温度为90℃。通过TLC跟踪反应过程，反应时间为5h，反应结束后，减压蒸除溶剂，残液中加入10mL乙酸乙酯，用20mL饱和的NaHCO3洗涤二次，再用10mL饱和的食盐水洗涤一次，溶液浓缩后用硅胶柱层析提纯(洗脱剂：乙酸乙酯/石油醚＝5/1)，得到无色晶体0.24g，产率68.0％。Add 4-methyl-7-ethoxycoumarin (1.0mmol, 204mg) and diisopropyl phosphite (2.0mmol, 232mg) in 25mL reaction bottle and dissolve in 5.0mL toluene, then add AgNO3 ( 0.05 mmol, 8.4 mg) and Mg(NO3 )2 ·6H2 O (0.5 mmol, 128 mg). React under heating and stirring in an oil bath, and the reaction temperature is 90°C. The reaction process was tracked by TLC. The reaction time was 5 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 10 mL of ethyl acetate was added to the raffinate, and20 mL of saturated NaHCO was used. Washing twice, and then washing once with 10 mL of saturated brine, After concentration, the solution was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=5/1) to obtain 0.24 g of colorless crystals with a yield of 68.0%.
熔点83-84℃.1HNMR(CDCl3)δ:7.70(dd,JH-H＝4.7Hz,JH-H＝8.6Hz,1H),6.87-6.85(m,1H),6.74(d,JH-H＝2.5Hz,1H),4.83-4.80(m,2H),4.12-4.09(m,2H),2.96(d,JP-H＝1.1Hz,3H),1.45(d,JH-H＝5.5Hz,1H),1.41-1.38(m,6H),1.33-1.30(m,6H).13CNMR(CDCl3)δ:163.4,162.6(d,JP-C＝17.1Hz),158.8(d,JP-C＝23.3Hz),155.6,127.2,113.5(d,JP-C＝25.8Hz),113.1,111.2,100.6,71.6(d,JP-C＝9.7Hz),64.3,24.0(d,JP-C＝7.2Hz),23.9(d,JP-C＝7.2Hz),16.8(d,JP-C＝5.7Hz),14.4.31PNMR(CDCl3)δ:10.2.IR(KBr)ν(cm-1):3096,2967,2855(-CH3,-CH2),1735(C＝O),1562,1480(Ar-),1340(P-C),1178(P＝O),1025(P-O).ESIMS369.2[M+H]+(calculatedforC18H26O6P+369.1).Melting point 83-84℃.1 HNMR(CDCl3 )δ: 7.70(dd, JHH ＝4.7Hz, JHH ＝8.6Hz, 1H), 6.87-6.85(m, 1H), 6.74(d, JHH ＝2.5 Hz,1H),4.83-4.80(m,2H),4.12-4.09(m,2H),2.96(d,JPH ＝1.1Hz,3H),1.45(d,JHH ＝5.5Hz,1H),1.41 -1.38(m,6H),1.33-1.30(m,6H).13 CNMR(CDCl3 )δ:163.4,162.6(d,JPC ＝17.1Hz),158.8(d,JPC ＝23.3Hz),155.6 ,127.2,113.5(d,JPC ＝25.8Hz),113.1,111.2,100.6,71.6(d,JPC ＝9.7Hz),64.3,24.0(d,JPC ＝7.2Hz),23.9(d,JPC ＝7.2Hz), 16.8(d, JPC ＝5.7Hz), 14.4.31 PNMR(CDCl3 )δ: 10.2.IR(KBr)ν(cm-1 ): 3096, 2967, 2855(-CH3 ,- CH2 ), 1735(C=O), 1562, 1480(Ar-), 1340(PC), 1178(P=O), 1025(PO).ESIMS369.2[M+H]+ (calculatedforC18 H26 O6 P+ 369.1).
实施例7.R＝-CH(CH3)2，R1＝-H，R2＝-OCH3时，6，7-二甲氧基香豆素-3-二异丙基膦酸酯衍生物的制备Example 7. Derivatization of 6,7-dimethoxycoumarin-3-diisopropylphosphonate when R=-CH(CH3 )2 , R1 =-H, R2 =-OCH3 preparation
在25mL反应瓶中加入6，7-二甲氧基香豆素(1.0mmol,204mg)和亚磷酸二异丙酯(2.0mmol,232mg)溶解在5.0mLCH3CN中，然后加入AgNO3(0.05mmol,8.4mg)和Mg(NO3)2·6H2O(0.5mmol,128mg)。在油浴中加热搅拌下反应，反应温度为90℃。通过TLC跟踪反应过程，反应时间为5h，反应结束后，减压蒸除溶剂，残液中加入10mL乙酸乙酯，用20mL饱和的NaHCO3洗涤二次，再用10mL饱和的食盐水洗涤一次，溶液浓缩后用硅胶柱层析提纯(洗脱剂：乙酸乙酯/石油醚＝2/1)，得到白色固体0.277g，产率75.0％。Add 6,7-dimethoxycoumarin (1.0mmol, 204mg) and diisopropyl phosphite (2.0mmol, 232mg) into 25mL reaction flask and dissolve in 5.0mL CH3 CN, then add AgNO3 (0.05 mmol, 8.4 mg) and Mg(NO3 )2 ·6H2 O (0.5 mmol, 128 mg). React under heating and stirring in an oil bath, and the reaction temperature is 90°C. The reaction process was tracked by TLC. The reaction time was 5 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 10 mL of ethyl acetate was added to the raffinate, and20 mL of saturated NaHCO was used. Washing twice, and then washing once with 10 mL of saturated brine, After the solution was concentrated, it was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=2/1) to obtain 0.277 g of white solid with a yield of 75.0%.
熔点196-198℃.1HNMR(CDCl3)δ:8.43(d,J＝16.9Hz),6.9(s,1H),6.84(s,1H),4.87-4.47(m,2H),3.98(s,3H,OCH3),3.93(s,3H,OCH3),1.41(d,J＝6.2Hz,6H),1.33(d,J＝6.2Hz,6H).13CNMR(CDCl3):δ158.70(d,J＝14.4Hz),154.96,152.78(d,J＝7.0Hz),152.03,146.71,114.67(d,J＝197.2Hz),110.79(d,J＝14.5Hz),108.69,99.69,72.02(d,J＝6.0Hz),56.59,56.41,24.10(d,J＝4.2Hz),23.89(d,J＝4.7Hz).31PNMR(CDCl3)δ:9.96.IR(KBr)ν(cm-1):2980,2934(-CH3),1740(C＝O),1615,1554(Ar-),1368(P-C),1250(P＝O),1138(P-O).ESIMS:m/z371.1([M+H]+,C17H24O7P+calcd.371.1).。Melting point 196-198℃.1 HNMR(CDCl3 )δ: 8.43(d, J=16.9Hz), 6.9(s, 1H), 6.84(s, 1H), 4.87-4.47(m, 2H), 3.98(s ,3H,OCH3 ),3.93(s,3H,OCH3 ),1.41(d,J=6.2Hz,6H),1.33(d,J=6.2Hz,6H).13 CNMR(CDCl3 ):δ158. 70(d, J=14.4Hz), 154.96, 152.78(d, J=7.0Hz), 152.03, 146.71, 114.67(d, J=197.2Hz), 110.79(d, J=14.5Hz), 108.69, 99.69, 72.02(d, J=6.0Hz), 56.59, 56.41, 24.10(d, J=4.2Hz), 23.89(d, J=4.7Hz).31 PNMR(CDCl3 )δ:9.96.IR(KBr)ν( cm-1 ):2980, 2934(-CH3 ), 1740(C=O), 1615, 1554(Ar-), 1368(PC), 1250(P=O), 1138(PO).ESIMS: m/ z371.1([M+H]+ ,C17 H24 O7 P+ calcd.371.1).
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| CN105566384A (en)* | 2016-01-15 | 2016-05-11 | 河南工程学院 | Method for preparing (E)-2-aryl-alpha, beta-unsaturated carbonyl phosphonate derivative |
| CN107955037A (en)* | 2017-11-21 | 2018-04-24 | 哈尔滨工业大学 | A kind of preparation method of benzenephosphonic acid ester derivant |
| Publication number | Publication date |
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| CN105037428B (en) | 2017-01-25 |
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