CN110078697A - 3-取代黄烷酮化合物的制备方法 - Google Patents
3-取代黄烷酮化合物的制备方法 Download PDFInfo
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- 235000011981 flavanones Nutrition 0.000 title claims abstract description 23
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 5
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- 238000002360 preparation method Methods 0.000 title claims description 12
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- 235000005513 chalcones Nutrition 0.000 claims abstract description 32
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 claims abstract description 31
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- 239000000047 product Substances 0.000 claims abstract description 7
- 238000010523 cascade reaction Methods 0.000 claims abstract description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公布了一种利用邻羟基查尔酮与查尔酮发生oxa‑Michael‑Michael串联反应一步直接得到3‑取代黄烷酮的方法。该过程操作简单，反应转化率高，原子利用率高，副产物少，产物容易分离提纯。所得产物利用价值高。
Description
技术领域
本发明属于有机合成化学技术领域，涉及一种3-取代黄烷酮化合物的制备方法。
背景技术
黄烷酮类化合物是植物代谢产物，在植物生长和发育中具有多种不同的重要功能，包括繁殖、信号传导和免受昆虫和哺乳动物的侵害等。除了它们在植物中的生物学作用外，这些植物化学物质还被用于研究对人类健康的潜在益处。因为它们能够与体内许多不同的受体相互作用，从而促成广泛的生物反应，黄烷酮被称为药物领域的“优势结构”。研究表明，黄烷酮的特殊结构及多变的取代基使其拥有多种生物活性，如苦参酮是从苦参中提取的一种活性成分，具有抗感染、抗真菌的作用；阿比松酮、松柏醇是一种芳香酶抑制剂，可用做抗肿瘤类药物；水飞蓟中的异水飞蓟素是一种“天然的保肝药”，可以保护肝细胞免受毒性物质侵害，其抗氧化性可以使肝脏免受自由基的破坏。
在自然界中，查尔酮异构酶将2，-羟基查尔酮环化成黄烷酮，并且许多不同的酶将黄烷酮转化为其他植物代谢物。所以2，-羟基查耳酮的分子内oxa-Michael反应成为合成黄烷酮最有效的方法。有很多基于此的研究报道，然而，关于3-取代黄烷酮的合成方法却鲜有报道。
为了克服上述缺陷，本发明的目的在于公开一种利用oxa-Michael-Michael串联反应合成3-取代黄烷酮化合物的方法。该方法原料廉价易得，原子经济性高，操作简单。
发明内容
本发以邻羟基查尔酮和查尔酮为底物，在碱和季铵盐的催化作用下，发生oxa-Michael-Michael串联反应，制备得到如式（Ⅰ）所示的3-取代黄烷酮。其中，R、R1、R2、R3为氢、烷基、甲氧基、三氟甲基或氟。
式（Ⅰ）
所述制备方法，其反应过程式如（Ⅱ）所示：
过程式（Ⅱ）
所述制备方法，其具体步骤如下：
将邻羟基查尔酮和查尔酮按摩尔比为1:1.5、10 mol%季铵盐、30 mol%碱称入反应瓶中，加入溶剂后在45℃下搅拌加热40小时；降温，反应体系中加水，以乙酸乙酯萃取，干燥，浓缩得到粗产品，将所得粗产品用柱层析提纯，得到产品。
其中，所述查尔酮可由相应的芳香甲醛和取代苯乙酮在碱作用下缩合制备。
其中，上述醛是苯甲醛、对甲氧基苯甲醛、对氟苯甲醛、对三氟甲基苯甲醛、间甲基苯甲醛、2-萘甲醛。上述化合物均由市面购得。
其中，R、R1、R2为氢， R3为氢、甲基、氟、三氟甲基、甲氧基等。
其中，所述季铵盐一般为四丁基氟化铵、四丁基溴化铵、四丁基乙酸铵、四丁基氢氧化铵、三乙基苄基氯化铵、甲基三辛基氯化铵，用量为10 mol%。
其中，所述碱一般为NaH、NaOH、KOH、K2CO3、Cs2CO3、K3PO4，用量为30 mol%。
其中，邻羟基查尔酮和查尔酮的摩尔比为1:1.5。
其中，所述溶剂是甲苯，用量为10 L/mol。
本发明所用芳香甲醛、取代苯乙酮、碱、季铵盐、硅胶均可由市面购得。
本发明的目的是在于提供一种原料廉价易得，原子经济性高，操作简单的3-取代黄烷酮化合物的合成方法。为了达到上述目的，本发明采用邻羟基查尔酮与查尔酮发生oxa-Michael-Michael串联反应一步直接得到3-取代黄烷酮。该过程操作简单，反应转化率高，原子利用率高，副产物少，产物容易分离提纯。所得产物利用价值高。
具体实施方法
结合以下具体实施例，对本发明作进一步的详细说明，本发明的保护内容不局限于以下实施例。 在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。 实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。
本发明制备方法的具体步骤包括：将邻羟基查尔酮和查尔酮按摩尔比为1:1.5、10mol%季铵盐、30 mol%碱称入反应瓶中，加入溶剂后在45℃下搅拌加热40小时；降温，反应体系中加水，以乙酸乙酯萃取，干燥，浓缩得到粗产品，将所得粗产品用柱层析提纯，得到产品。
实例1 制备3-(3-氧代-1,3-二苯基丙基)-黄烷酮（A）
称取邻羟基查尔酮（0.10 mmol）、查尔酮（0.15 mmol）、氢氧化钾（0.03 mmol）、四丁基溴化铵（0.01 mmol）加入反应瓶中，加入1 mL 甲苯，45℃下搅拌反应，用薄层层析检测反应至原料消耗完全。冷却至室温，加入5 mL水溶解固体，然后加入乙酸乙酯萃取混合物，用无水硫酸钠干燥有机相，过滤后旋转蒸发除去溶剂得到粗品。将所得粗品用硅胶柱层析，得到所述3-取代黄烷酮化合物A纯品，收率93%。
1H NMR (600 MHz, CDCl3) δ 7.97 – 7.60 (m, 3H), 7.50 (ddd, J = 22.5,11.5, 4.2 Hz, 2H), 7.45 – 7.27 (m, 5H), 7.27 – 7.12 (m, 5H), 7.12 – 7.03 (m,1H), 6.97 (dd, J = 13.2, 6.1 Hz, 1H), 5.29 (s, 1H), 4.00 (td, J = 10.0, 4.4Hz, 1H), 3.68 – 3.49 (m, 1H), 3.41 (dd, J = 17.7, 4.4 Hz, 1H), 3.31 (dd, J =10.8, 2.3 Hz, 1H)；13C NMR (151 MHz, CDCl3) δ 197.54, 193.57, 159.48, 141.67,138.00, 136.98, 136.65, 132.94, 128.99, 128.59, 128.46, 128.33, 127.94,127.29, 127.11, 126.34, 121.44, 120.77, 118.08, 79.10, 77.25, 77.04, 76.82,56.00, 42.54, 39.88。
制备3-(3-氧代-1-(4-氟苯基)-3-苯基丙基)-黄烷酮（B）
称取邻羟基查尔酮（0.10 mmol）、3-(4-氟苯基)查尔酮（0.15 mmol）、氢氧化钾（0.03mmol）、四丁基溴化铵（0.01 mmol）加入反应瓶中，加入1 mL 甲苯，45℃下搅拌反应，用薄层层析检测反应至原料消耗完全。冷却至室温，加入5 mL水溶解固体，然后加入乙酸乙酯萃取混合物，用无水硫酸钠干燥有机相，过滤后旋转蒸发除去溶剂得到粗品。将所得粗品用硅胶柱层析，得到所述3-取代黄烷酮化合物B纯品，收率80%。
1H NMR (600 MHz, CDCl3) δ 7.77 (dd, J = 17.9, 7.6 Hz, 3H), 7.56 –7.44 (m, 2H), 7.45 – 7.32 (m, 4H), 7.27 – 7.13 (m, 6H), 7.12 – 6.93 (m, 4H),5.28 (s, 1H), 3.98 (dd, J = 11.4, 7.0 Hz, 1H), 3.62 – 3.49 (m, 1H), 3.39 (dd,J = 17.6, 2.6 Hz, 1H), 3.29 (dd, J = 10.4, 2.2 Hz, 1H)；13C NMR (151 MHz,CDCl3) δ 197.45 (s), 193.37 (s), 162.70 (s), 161.07 (s), 159.47 (s), 137.82(s), 137.40 (d, J = 2.9 Hz), 136.87 (s), 136.73 (s), 133.08 (s), 129.89 (d, J= 7.9 Hz), 128.68 (s), 128.53 (s), 128.12 (s), 127.94 (s), 127.15 (s), 126.42(s), 121.56 (s), 120.73 (s), 118.09 (s), 115.93 (s), 115.78 (s), 79.20 (s),77.29 (s), 77.08 (s), 76.86 (s), 55.99 (s), 42.48 (s), 39.16 (s)。
制备3-(3-氧代-1-(2-萘)-3-苯基丙基)-黄烷酮（C）
称取邻羟基查尔酮（0.10 mmol）、3-(2-萘)查尔酮（0.15 mmol）、氢氧化钾（0.03mmol）、四丁基溴化铵（0.01 mmol）加入反应瓶中，加入1 mL 甲苯，45℃下搅拌反应，用薄层层析检测反应至原料消耗完全。冷却至室温，加入5 mL水溶解固体，然后加入乙酸乙酯萃取混合物，用无水硫酸钠干燥有机相，过滤后旋转蒸发除去溶剂得到粗品。将所得粗品用硅胶柱层析，得到所述3-取代黄烷酮化合物C纯品，收率90%。
1H NMR (600 MHz, CDCl3) δ 7.89 – 7.81 (m, 3H), 7.78 (dd, J = 12.1,4.4 Hz, 4H), 7.57 (dd, J = 8.4, 1.3 Hz, 1H), 7.55 – 7.49 (m, 1H), 7.49 – 7.40(m, 3H), 7.34 (t, J = 7.7 Hz, 2H), 7.17 (dd, J = 15.7, 6.8 Hz, 5H), 7.11 (d,J = 8.3 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 5.31 (d, J = 1.4 Hz, 1H), 4.19(td, J = 10.1, 4.4 Hz, 1H), 3.68 (dd, J = 17.7, 9.3 Hz, 1H), 3.50 (dd, J =17.7, 4.4 Hz, 1H), 3.42 (dd, J = 10.7, 2.3 Hz, 1H)；13C NMR (151 MHz, CDCl3) δ197.48 (s), 193.57 (s), 159.54 (s), 139.03 (s), 137.93 (s), 136.94 (s),136.69 (s), 133.57 (s), 132.96 (s), 132.69 (s), 128.90 (s), 128.52 (d, J =16.2 Hz), 127.93 (d, J = 6.6 Hz), 127.67 (d, J = 3.0 Hz), 127.15 (s), 126.34(d, J = 15.0 Hz), 125.93 (s), 125.78 (s), 121.48 (s), 120.80 (s), 118.13 (s),79.19 (s), 77.25 (s), 77.04 (s), 76.83 (s), 55.91 (s), 42.54 (s), 39.97 (s)。
制备3-(3-氧代-1-(3-甲基苯基)-3-苯基丙基)-黄烷酮（D）
称取邻羟基查尔酮（0.10 mmol）、3-(3甲基苯基)查尔酮（0.15 mmol）、氢氧化钾（0.03mmol）、四丁基溴化铵（0.01 mmol）加入反应瓶中，加入1 mL 甲苯，45℃下搅拌反应，用薄层层析检测反应至原料消耗完全。冷却至室温，加入5 mL水溶解固体，然后加入乙酸乙酯萃取混合物，用无水硫酸钠干燥有机相，过滤后旋转蒸发除去溶剂得到粗品。将所得粗品用硅胶柱层析，得到所述3-取代黄烷酮化合物D纯品，收率95%。
1H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 7.7Hz, 1H), 7.51 (ddd, J = 19.7, 11.6, 4.3 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H),7.21 (t, J = 7.6 Hz, 5H), 7.18 (d, J = 6.8 Hz, 3H), 7.10 (d, J = 8.4 Hz, 1H),7.03 (d, J = 6.3 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 5.31 (s, 1H), 3.96 (td, J= 9.9, 4.5 Hz, 1H), 3.55 (dd, J = 17.6, 9.1 Hz, 1H), 3.41 (dd, J = 17.6, 4.4Hz, 1H), 3.33 – 3.25 (m, 1H), 2.34 (s, 3H)；13C NMR (151 MHz, CDCl3) δ 197.59(s), 193.67 (s), 159.48 (s), 141.59 (s), 138.54 (s), 138.08 (s), 137.03 (s),136.60 (s), 132.88 (s), 129.13 (s), 128.83 (s), 128.49 (d, J = 19.6 Hz),127.97 (t, J = 13.0 Hz), 127.09 (s), 126.36 (s), 125.21 (s), 121.39 (s),120.79 (s), 118.06 (s), 79.08 (s), 77.23 (s), 77.01 (s), 76.80 (s), 56.01(s), 42.60 (s), 39.76 (s), 21.53 (s)。
制备3-(3-氧代-1-(4-甲氧基苯基)-3-苯基丙基)-黄烷酮（E）
称取邻羟基查尔酮（0.10 mmol）、3-(4-甲氧基苯基)查尔酮（0.15 mmol）、氢氧化钾（0.03 mmol）、四丁基溴化铵（0.01 mmol）加入反应瓶中，加入1 mL 甲苯，45℃下搅拌反应，用薄层层析检测反应至原料消耗完全。冷却至室温，加入5 mL水溶解固体，然后加入乙酸乙酯萃取混合物，用无水硫酸钠干燥有机相，过滤后旋转蒸发除去溶剂得到粗品。将所得粗品用硅胶柱层析，得到所述3-取代黄烷酮化合物E纯品，收率85%。
1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 2H), 7.75 (dd, J = 7.8,1.3 Hz, 1H), 7.51 (ddd, J = 19.7, 11.6, 4.5 Hz, 2H), 7.40 – 7.30 (m, 4H),7.24 – 7.19 (m, 2H), 7.18 (t, J = 6.3 Hz, 3H), 7.09 (d, J = 8.3 Hz, 1H), 6.98(t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 5.31 (s, 1H), 3.94 (td, J =10.2, 4.2 Hz, 1H), 3.77 (s, 3H), 3.54 (dd, J = 17.5, 9.5 Hz, 1H), 3.36 (dd, J= 17.5, 4.2 Hz, 1H), 3.26 (dd, J = 10.8, 2.1 Hz, 1H)；13C NMR (151 MHz, CDCl3)δ 197.71 (s), 193.71 (s), 159.46 (s), 158.68 (s), 138.05 (s), 136.98 (s),136.62 (s), 133.43 (s), 132.91 (s), 129.29 (s), 128.51 (d, J = 19.4 Hz),127.92 (d, J = 5.9 Hz), 127.08 (s), 126.31 (s), 121.40 (s), 120.72 (s),118.05 (s), 114.40 (s), 79.08 (s), 77.22 (s), 77.01 (s), 76.80 (s), 56.20(s), 55.23 (s), 42.63 (s), 39.20 (s)。
制备3-(3-氧代-1-(4-三氟甲基苯基)-3-苯基丙基)-黄烷酮（F）
称取邻羟基查尔酮（0.10 mmol）、3-(4-三氟甲基苯基)查尔酮（0.15 mmol）、氢氧化钾（0.03 mmol）、四丁基溴化铵（0.01 mmol）加入反应瓶中，加入1 mL 甲苯，45℃下搅拌反应，用薄层层析检测反应至原料消耗完全。冷却至室温，加入5 mL水溶解固体，然后加入乙酸乙酯萃取混合物，用无水硫酸钠干燥有机相，过滤后旋转蒸发除去溶剂得到粗品。将所得粗品用硅胶柱层析，得到所述3-取代黄烷酮化合物F纯品，收率98%。
1H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 7.7 Hz, 2H), 7.78 – 7.73 (m,1H), 7.60 (d, J = 8.1 Hz, 2H), 7.53 (dd, J = 18.0, 9.5 Hz, 4H), 7.38 (t, J =7.7 Hz, 2H), 7.24 (d, J = 8.9 Hz, 2H), 7.21 (t, J = 7.6 Hz, 3H), 7.09 (d, J =8.3 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 5.24 (d, J = 2.6 Hz, 1H), 4.05 (td, J= 9.8, 4.2 Hz, 1H), 3.62 (dd, J = 17.9, 9.5 Hz, 1H), 3.44 (dd, J = 17.9, 4.2Hz, 1H), 3.35 (dd, J = 10.2, 3.0 Hz, 1H)；13C NMR (151 MHz, CDCl3) δ 197.11(s), 193.02 (s), 159.46 (s), 146.04 (s), 137.53 (s), 136.80 (s), 136.66 (s),133.21 (s), 128.68 (dd, J = 19.5, 13.4 Hz), 128.26 (s), 127.92 (s), 127.17(s), 126.47 (s), 126.18 – 125.71 (m), 121.65 (s), 120.67 (s), 118.11 (s),79.27 (s), 77.23 (s), 77.02 (s), 76.81 (s), 55.51 (s), 42.03 (s), 39.44 (s)。
最后说明的是，以上优选实施例仅用以说明本发明的技术方案而非限制，尽管通过上述优选实施例已经对本发明进行了详细的描述，但本领域技术人员应当理解，可以在形式上和细节上对其做出各种各样的改变，而不偏离本发明权利要求书所限定的范围。
Claims (5)
1.3-取代黄烷酮化合物的制备方法，其特征在于，利用oxa-Michael-Michael串联反应合成3-取代黄烷酮化合物；在碱和季铵盐的催化作用下，邻羟基查尔酮与查尔酮发生oxa-Michael-Michael串联反应，制备得到如式（Ⅰ）所示的3-取代黄烷酮；
式（Ⅰ）
其中，其中，R、R1、R2、R3为氢、烷基、甲氧基或氟；
所述制备方法如式（Ⅱ）所示，
式（Ⅱ）
其中，其中，其中，R、R1、R2、R3为氢、烷基、甲氧基或氟；
包括以下步骤：
步骤（1），称取原料，按邻羟基查尔酮：查尔酮的摩尔比为1:1.5，季铵盐用量为10mol%，碱30 mol%；
步骤（2），加入溶剂用量为10 L/mol，45℃下搅拌加热40小时；
步骤（3），反应完全后，反应体系中加水，以乙酸乙酯萃取，干燥，浓缩得到粗产品，将所得粗产品用柱层析提纯，得到产品；其中，所述溶剂为甲苯。
2.如权利要求1所述的制备方法，其特征在于，所述邻羟基查尔酮：查尔酮的摩尔比为1:1.5，季铵盐用量为10 mol%，碱的用量为30 mol%。
3.如权利要求1所述的制备方法，其特征在于，所述查尔酮化物中，R、R1、R2、R3为氢、烷基、甲氧基或氟。
4.如权利要求1所述的制备方法，其特征在于，所用碱一般为NaH、NaOH、KOH、K2CO3、Cs2CO3、K3PO4。
5.如权利要求1所述的制备方法，其特征在于，所用季铵盐一般为四丁基氟化铵、四丁基溴化铵、四丁基乙酸铵、四丁基氢氧化铵、三乙基苄基氯化铵、甲基三辛基氯化铵。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114853708A (zh) * | 2022-05-25 | 2022-08-05 | 苏州大学 | 由羟基查尔酮化合物和黄原酸盐制备4-硫代黄酮化合物的方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107032972A (zh) * | 2017-05-23 | 2017-08-11 | 中国人民武装警察部队后勤学院 | 具有2’‑羟基查尔酮结构Diels‑Alder产物的制备方法 |
| CN107628960A (zh) * | 2017-09-30 | 2018-01-26 | 华南理工大学 | 一种利用烯烃一步合成烯酮缩胺的方法 |
-
2019
- 2019-06-21 CN CN201910540714.4A patent/CN110078697A/zh active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107032972A (zh) * | 2017-05-23 | 2017-08-11 | 中国人民武装警察部队后勤学院 | 具有2’‑羟基查尔酮结构Diels‑Alder产物的制备方法 |
| CN107628960A (zh) * | 2017-09-30 | 2018-01-26 | 华南理工大学 | 一种利用烯烃一步合成烯酮缩胺的方法 |
Non-Patent Citations (2)
| Title |
|---|
| TAMA´S PATONAY等: "Highly diastereoselective Michael reaction under solvent-free conditions using microwaves：conjugate addition of flavanone to its chalcone precursor", 《TETRAHEDRON LETTERS》 * |
| 宋艳春: "催化不对称oxa-Micheal/ Micheal串联反应合成手性3-取代黄烷酮类化合物", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114853708A (zh) * | 2022-05-25 | 2022-08-05 | 苏州大学 | 由羟基查尔酮化合物和黄原酸盐制备4-硫代黄酮化合物的方法 |
| CN114853708B (zh) * | 2022-05-25 | 2024-03-19 | 苏州大学 | 由羟基查尔酮化合物和黄原酸盐制备4-硫代黄酮化合物的方法 |
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