CN111247132B - 四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物及其制备与在制药中的应用 - Google Patents

四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物及其制备与在制药中的应用 Download PDF

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CN111247132B
CN111247132B CN201880046977.3A CN201880046977A CN111247132B CN 111247132 B CN111247132 B CN 111247132B CN 201880046977 A CN201880046977 A CN 201880046977A CN 111247132 B CN111247132 B CN 111247132B
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孙青�
张卫东
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Abstract

一种四氢萘并[1,2‑b]呋喃‑2(3H)‑酮衍生物，其化学结构以式Ⅰ所示：(I)，及其制备方法。所述四氢萘并[1,2‑b]呋喃‑2(3H)‑酮衍生物可用于制备预防/治疗类风湿性关节炎疾病药物。
Figure DDA0002454729300000011

Description

四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物及其制备与在制药中 的应用
技术领域
本发明涉及药物，具体涉及药物及其制备，尤其涉及一种四氢萘并[1,2-b]呋喃-2(3H)- 酮衍生物及其制备与在制备预防/治疗类风湿性关节炎药物中的应用。
背景技术
类风湿性关节炎(Rheumatoid Arthritis，RA)是一种病因尚未明了的慢性全身性炎症性疾病，以慢性、对称性、多滑膜关节炎和关节外病变为主要临床表现，属于自身免疫炎性疾病。该病好发于手、腕、足等小关节，易反复发作，并呈对称性分布。患病早期有关节红肿热痛和功能障碍表现，到达晚期时，关节可出现不同程度的僵硬畸形，并伴有骨和骨骼肌的萎缩，极易致残。从病理改变的角度来看，类风湿性关节炎是一种主要累及关节滑膜(以后可波及到关节软骨、骨组织、关节韧带和肌键)，其次为浆膜、心、肺及眼等结缔组织的广泛性炎症性疾病。类风湿性关节炎的全身性表现除关节病变外，还有发热、疲乏无力、心包炎、皮下结节、胸膜炎、动脉炎、周围神经病变等。但是，类风湿性关节炎至今尚无特效疗法，仍处于对炎症及后遗症的治疗阶段。目前临床上主要治疗药物包括非甾体抗炎药、肾上腺皮质激素等。由于药物的副作用严重，引起的肝肾损害、肺纤维化等使病人难以坚持长期服药。因此，寻求一种安全、有效的类风湿性关节炎治疗药物有重要意义。
发明内容
本发明所要解决的技术问题在于克服上述不足之处，研究设计安全、有效的类风湿性关节炎治疗药物。
本发明提供了一种四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物，其化学结构以式Ⅰ所示：
Figure BDA0002366188670000011
其中，R选自氢、烷基、环烷基、羟基取代烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基、杂环基、三氟甲基、多氟取代烷基、腈基、腈基甲基、酰基、氨基甲酰基、磺酰基、磺酰胺基或芳氧烷基；
R1和R2共同构成末端双键；
或R1选自氢或氘，R2为
Figure BDA0002366188670000021
及其与酸形成的在药学上可接受的盐，包括其与R5Z反应形成的季铵盐，所述Z选自氟、氯、溴、碘、对甲苯磺酸酯基、甲磺酸酯基、苯磺酸酯基或三氟甲基磺酸酯基；Q选自N，O或S；R3和R4可以相同或不同；
R3和R4分别选自氢、烷基、环烷基、羟基取代烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基、杂环基、三氟甲基、多氟取代烷基、腈基、腈基甲基、酰基、氨基甲酰基、磺酰基、磺酰胺基或芳氧烷基；R3、R4可与N原子形成环状结构，所述环状结构选自3-9个原子的环，环状结构中还可以包含杂原子或包含一个或多个取代基，所述取代基选自氢、烷基、环烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基或杂环基；R5选自烃基、环烷基、羟基取代烷基、烯基、炔基、芳基、杂环基、芳基取代烷基、芳基烯基、芳基炔基、氰基取代甲基、烷氧基取代烷基或芳氧取代烷基；Z为氟、氯、溴、碘、对甲苯磺酸酯基、甲磺酸酯基、苯磺酸酯基或三氟甲基磺酸酯基；酸L选自无机酸、有机酸或磺酸，所述的无机酸选自氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、亚硫酸、硝酸、磷酸、亚磷酸、碳酸、硼酸、亚硒酸或磷钼酸；所述的有机酸选自脂肪族或芳香族有机酸，所述脂肪族有机酸选自乙酸、丙酸、己酸、草酸、三氟乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、马来酸、富马酸、羟基马来酸、苹果酸、酒石酸、柠檬酸、扁桃酸、肉桂酸或氨基酸，所述氨基酸选自甘氨酸、谷氨酸、脯氨酸、精氨酸或赖氨酸；所述芳香族有机酸选自苯甲酸、水杨酸、4-氨基水杨酸、盐酸或异烟酸；所述的磺酸为甲烷磺酸、乙烷磺酸、 2-羟基乙烷磺酸、1,2-乙二磺酸、苯磺酸、对甲基苯磺酸、萘-2-磺酸或樟脑磺酸。
本发明所述的四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物，优选化合物以表1所示：
表1优选四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物
Figure BDA0002366188670000022
Figure BDA0002366188670000031
Figure BDA0002366188670000041
注：表1中的化合物序号对应实施例中的化合物序号。
本发明的另一目的是提供了所述四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物的制备方法，该方法包括下列步骤：
(1)重排反应：(3aS,5aS,9bS)-5a,9-二甲基-3-亚甲基-3a,5,5a,9b-四氢萘并[1,2-b]呋喃 -2,8(3H,4H)-二酮(化合物②)在酸性条件下发生重排反应生成中间体(3aS,9bR)-6,9-二甲基 -3-亚甲基-2-氧代-2,3,3a,4,5,9b-六氢萘并[1,2-b]呋喃-8-基乙酸酯(化合物③)；
(2)水解反应：中间体STN-3在碱性条件下发生酚酯键的水解生成中间体(3aS,9bR)-8- 羟基-6,9-二甲基-3-亚甲基-3a,4,5,9b-四氢萘并[1,2-b]呋喃-2(3H)-酮(化合物④)；
(3)亲核取代反应：中间体STN-4中的游离酚羟基作为亲核试剂与各种卤代烷烃(如卤代苄基或卤代烷基等)发生亲核取代反应生成(3aS,9bR)-8-烷氧基-6,9-二甲基-3-亚甲基 -3a,4,5,9b-四氢萘并[1,2-b]呋喃-2(3H)-酮(Ⅰ)；
(4)迈克尔加成反应：中间体Ⅰ中α亚甲基内酯环与含氧(如醇或酚)、含氮(脂肪族胺或芳香胺)及含硫(苯硫酚或硫醇)的亲核试剂发生迈克尔加成反应生成(3R或3S,3aS,9bR)-8- 取代烷氧基-3-(取代)胺甲基/烷氧基/烷硫基-6,9-二甲基-3a,4,5,9b-四氢萘并[1,2-b]呋喃2(3H)- 酮(Ⅱ)；
(5)成盐反应：中间体Ⅱ与酸发生成盐反应生成目标化合物(3R或3S,3aS,9bR)-8-取代烷氧基-3-二取代胺甲基-6,9-二甲基-3a,4,5,9b-四氢萘并[1,2-b]呋喃-2(3H)-酮可药用盐(Ⅲ)；
所述制备方法以下列反应式一所示：
Figure RE-GDA0003310360220000011
反应式一
反应式中，R选自氢、烷基、环烷基、羟基取代烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基、杂环基、三氟甲基、多氟取代烷基、腈基、腈基甲基、酰基、氨基甲酰基、磺酰基、磺酰胺基或芳氧烷基；
Q选自N，O或S；R3和R4可以相同或不同；R3和R4分别选自氢、烷基、环烷基、羟基取代烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基、杂环基、三氟甲基、多氟取代烷基、腈基、腈基甲基、酰基、氨基甲酰基、磺酰基、磺酰胺基或芳氧烷基； R3、R4可与N原子形成环状结构，所述环状结构选自3-9个原子的环，所述环可以包含杂原子或包含一个或多个取代基，所述取代基选自氢、烷基、环烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基或杂环基；R5选自烃基、环烷基、羟基取代烷基、烯基、炔基、芳基、杂环基、芳基取代烷基、芳基烯基、芳基炔基、氰基取代甲基、烷氧基取代烷基或芳氧取代烷基；Z选自氟、氯、溴、碘、对甲苯磺酸酯基、甲磺酸酯基、苯磺酸酯基或三氟甲基磺酸酯基；酸选自无机酸、有机酸或磺酸，所述的无机酸选自氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、亚硫酸、硝酸、磷酸、亚磷酸、碳酸、硼酸、亚硒酸或磷钼酸；所述的有机酸选自脂肪族或芳香族有机酸，所述脂肪族有机酸选自乙酸、丙酸、己酸、草酸、三氟乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、马来酸、富马酸、羟基马来酸、苹果酸、酒石酸、柠檬酸、扁桃酸、肉桂酸或氨基酸，所述氨基酸选自甘氨酸、谷氨酸、脯氨酸、精氨酸或赖氨酸；芳香族有机酸选自苯甲酸、水杨酸、4-氨基水杨酸、盐酸或异烟酸；所述的磺酸选自甲烷磺酸、乙烷磺酸、2-羟基乙烷磺酸、1,2-乙二磺酸、苯磺酸、对甲基苯磺酸、萘-2-磺酸或樟脑磺酸。
本发明制备方法步骤(1)重排反应，指在无溶剂条件下或适当溶剂中，一定温度条件下，催化剂存在下起始原料化合物②经重排反应生成化合物③。
步骤(1)所述溶剂为非质子溶剂选自甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、二氧六环、二氯甲烷或二氯乙烷，优选甲苯或四氢呋喃；所述催化剂选自乙酸酐或乙酸/硫酸；所述反应温度选自-20℃-25℃，优选-5℃-15℃，特别优选0℃-5℃。催化剂与化合物②的摩尔比为1:20-1:1，优选1:10-1:1，特别优选1:3-1:1。
本发明制备方法步骤(2)水解反应，指在适当溶剂中，一定温度条件下，催化剂存在下化合物③中的酚酯键断裂生成中间体④的反应。
步骤(2)所述溶剂选自甲醇、乙醇、异丙醇、甲苯、四氢呋喃、2-甲基四氢呋喃、二氧六环、二氯甲烷、二氯乙烷、丙酮或丁酮，优选甲醇或四氢呋喃；所述催化剂选自氨水、三乙胺、二乙胺、乙醇胺、甲酸或三氟乙酸，优选氨水；所述反应温度选自-20℃-25℃，优选-5℃-15℃，特别优选0℃-5℃。催化剂与化合物③的摩尔比为30:1-1:1，优选20:1-1:1，特别优选5:1-1:1。
本发明制备方法步骤(3)亲核取代反应，指在适当溶剂中，一定温度条件下，碱及催化剂存在条件下，中间体化合物④发生反应生成化合物Ⅰ的反应。
步骤(3)所述溶剂选自质子或非质子溶剂，选自甲醇、乙醇、异丙醇、二甲基亚砜、N,N-二甲基甲酰胺、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、二氯甲烷、二氯乙烷、氯仿、丙酮或丁酮，优选丙酮、乙醇或四氢呋喃。所述碱选自有机碱或者无机碱，所述有机碱选自二乙胺、三乙胺、吡啶、哌啶、4-二甲氨基吡啶、N,N-二异丙基乙胺、1,8- 二氮杂二环十一碳-7-烯或1,4-二氮杂二环[2.2.2]辛烷，优选三乙胺；无机碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸铯、碳酸氢钾、碳酸氢钠、醋酸钠、醋酸钾、磷酸钠或磷酸钾，优选醋酸钠或醋酸钾；所述催化剂选自四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丁基硫酸氢铵、苄基三乙基氯化铵或十二烷基三乙基氯化铵，优选四丁基碘化铵；所述反应温度-30℃-60℃，优选-10℃-35℃，特别优选0℃-25℃。碱与化合物④的摩尔比为6:1-1:1，优选3:1-1:1，特别优选2:1-1:1。催化剂与化合物④的摩尔比为1:20-1:1，优选1:10-1:1，特别优选1:3-1:1。
本发明制备方法步骤(4)迈克尔加成反应，指在适当溶剂中，一定温度及有机碱存在条件下，中间体Ⅰ中α亚甲基内酯环上的亚甲基发生加成反应生成中间体Ⅱ的反应；
步骤(4)所述溶剂为质子或非质子溶剂，选自甲醇、乙醇、丙醇、异丙醇、二甲基亚砜、N,N-二甲基甲酰胺、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、二氯甲烷、二氯乙烷、氯仿、丙酮或丁酮，优选甲醇、乙醇或四氢呋喃。所述碱为有机碱或者无机碱，所述有机碱选自二乙胺、三乙胺、吡啶、哌啶、4-二甲氨基吡啶、N，N-二异丙基乙胺、1,8- 二氮杂二环十一碳-7-烯或1,4-二氮杂二环[2.2.2]辛烷，优选三乙胺；无机碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸铯、碳酸氢钾、碳酸氢钠、醋酸钠、醋酸钾、磷酸钠或磷酸钾，优选醋酸钠或醋酸钾；所述反应温度-30℃-60℃，优选-10℃-35℃，特别优选0℃-25℃。
碱与中间体Ⅰ的摩尔比8:1-1:1，优选5:1-1:1，特别优选3:1-1:1。
本发明制备方法步骤(5)成盐反应，指在适当溶剂中，一定温度条件下，中间体Ⅱ与药学中可接受的酸发生反应生成目标化合物Ⅲ的反应；
步骤(5)所述的溶剂为质子或非质子溶剂，选自甲醇、乙醇、异丙醇、二甲基亚砜、N,N-二甲基甲酰胺、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、二氯甲烷、二氯乙烷、氯仿、丙酮或丁酮，优选乙醇或二氯甲烷。所述反应温度选自0℃-60℃，优选5℃ -35℃，特别优选15℃-25℃。所述的药学中可接受的酸选自无机酸、有机酸或磺酸；所述无机酸选自盐酸、氢溴酸、硫酸、硝酸或磷酸；所述的有机酸选自脂肪族或芳香族有机酸，所述脂肪族有机酸选自乙酸、丙酸、己酸、草酸、三氟乙酸、乙醇酸、丙酮酸、丙二酸、琥珀酸、马来酸、富马酸、羟基马来酸、苹果酸、酒石酸、柠檬酸、扁桃酸、肉桂酸或氨基酸，所述氨基酸选自甘氨酸、谷氨酸、精氨酸或赖氨酸；所述芳香族有机酸选自苯甲酸、水杨酸， 4-氨基水杨酸，盐酸或异烟酸；所述的磺酸选自甲烷磺酸、乙烷磺酸、2-羟基乙烷磺酸、1,2- 乙二磺酸、苯磺酸、对甲基苯磺酸、萘-2-磺酸或樟脑磺酸。
酸与中间体Ⅱ的摩尔比为3:1-1:8，优选1:1-1:5，特别优选1:1-1:3。
本发明又一目的是提供了所述四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物在制药中的应用。
本发明提供了四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物在制备制备预防/治疗类风湿性关节炎药物中的应用。
本发明所述四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物经动物实验表明：四氢萘并[1,2-b]呋喃 -2(3H)-酮衍生物经佐剂诱导的Wistar雄性大鼠类风湿性关节炎动物模型活性治疗效果评价显示该类衍生物对佐剂诱导的Wistar雄性大鼠关节炎具有明显抑制作用，能够使原发和继发性病变减轻，具有不同程度的预防作用。因此，本发明所述四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物可用于制备预防/治疗类风湿性关节炎疾病药物。目前尚未见关于式(I)所示化合物或其药物组合物在制备预防/治疗类风湿性关节炎药物中的应用报道。
本发明所述药物为由四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物作为活性成分与药用辅料组成的药物组合物。所述的药物组合物选自片剂、分散片、含片、口崩片、缓释片、胶囊剂、软胶囊剂、滴丸、颗粒剂、注射剂、粉针剂或气雾剂。
附图说明
图1化合物59每天治疗性给药对佐剂诱导大鼠关节炎体重的影响
横坐标：日期(天)；纵坐标：大鼠体重(克)
图2化合物59每天治疗性给药对佐剂性大鼠关节炎发病指数的影响
横坐标：日期(天)；纵坐标：类风湿关节炎临床发病指数
图3化合物59每天治疗性给药对大鼠佐剂性关节炎继发足病变的抑制作用
横坐标：日期(天)；纵坐标：大鼠足部直径
图4化合物59每天治疗性给药对大鼠佐剂性关节炎原发足病变的抑制作用
横坐标：日期(天)；纵坐标：大鼠足部直径
具体实施方式
现结合实施例对本发明作详细描述，但本发明的实施不仅限于此。
本发明所用试剂和原料均市售可得或可按文献方法制备。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件进行。
实施例1：(3aS,9bR)-6,9-二甲基-3-亚甲基-2-氧代-2,3,3a,4,5,9b-六氢萘并[1,2-b]呋喃-8-基乙酸酯的制备(表中化合物1)
250mL圆底烧瓶中加入化合物②(4.0g,16.4mmol)和醋酸酐(30mL)，0℃搅拌下向反应液逐滴滴加浓硫酸(1.0mL)，0℃搅拌至反应结束。将反应液倒入100mL冰水中，二氯甲烷(50mL×3)萃取，饱和碳酸氢钠(100mL×3)洗涤，饱和食盐水(50mL×3)洗涤，无水Na2SO4干燥，40℃下，真空度0.1MPa旋转蒸发仪减压浓缩，得到粗产品，粗品经硅胶柱层析(洗脱条件：石油醚/乙酸乙酯，3:1)，得到目标化合物③3.7克(收率：78.9％)。1H NMR(500MHz,Chloroform-d)δ6.87(s,1H),6.31(d,J＝2.0Hz,1H),5.72(d,J＝1.8Hz, 1H),5.57(d,J＝6.7Hz,1H),3.31(dddt,J＝8.7,6.8,4.8,1.9Hz,1H),2.75(ddd,J＝16.7,6.0, 4.6Hz,1H),2.54(ddd,J＝16.7,9.6,4.5Hz,1H),2.33(s,3H),2.23(d,J＝3.9Hz,6H),1.99(ddd, J＝13.6,10.9,4.8Hz,1H),1.83(ddt,J＝13.7,9.5,4.8Hz,1H)；13C NMR(125MHz, Chloroform-d)δ170.2,169.8,147.6,139.8,134.9,134.6,131.1,129.2,124.2,121.8,74.9,39.4,29.9,26.0,21.0,19.7,12.2.
实施例2：(3aS,9bR)-8-羟基-6,9-二甲基-3-亚甲基-3a,4,5,9b-四氢萘并[1,2-b]呋喃-2(3H)-酮的制备(表中化合物2)
25mL的烧瓶中加入化合物③(500mg,1.75mmol)，用25mL甲醇溶解，0℃搅拌下向反应液中滴加NH3·H2O(25mL)，待反应完全，减压蒸干有机溶剂，二氯甲烷(30mL×3) 萃取，饱和食盐水(30mL)洗涤，无水Na2SO4干燥，40℃下，真空度0.1MPa旋转蒸发仪减压浓缩，得到粗产品，粗品经硅胶柱层析(洗脱条件：二氯甲烷/甲醇，20:1)得到目标化合物④315毫克(收率：73.7％)。1H NMR(500MHz,Chloroform-d)δ6.68(s,1H),6.30(d, J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.59(d,J＝6.7Hz,1H),4.66(s,1H),3.30(dtt,J＝8.6, 4.7,1.9Hz,1H),2.70(ddd,J＝16.4,6.0,4.5Hz,1H),2.49(ddd,J＝16.4,9.6,4.5Hz,1H),2.31 (s,3H),2.19(s,3H),1.96(ddd,J＝13.5,10.8,4.7Hz,1H),1.86–1.75(m,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,152.0,140.1,134.6,130.8,128.8,122.5,121.6,117.9,75.3,39.6, 26.2,23.8,19.7,11.4.
实施例3：(3aS,9bR)-8-(2-氟苄氧基)-6,9-二甲基-3-亚甲基-3a,4,5,9b-四氢萘并[1,2-b]呋喃 -2(3H)-酮的制备(表中化合物3)
50mL的烧瓶中加入化合物④(30mg，0.12mmol)、邻氟氯苄(0.027mL，0.25mmol)、K2CO3(34mg，0.25mmol)、TBAI(90mg，0.25mmol)，用5mL丙酮溶解，室温搅拌至反应结束。反应结束后减压过滤反应液，减压蒸除有机溶剂，无水Na2SO4干燥得到粗品，粗品经硅胶柱层析(洗脱条件：石油醚/乙酸乙酯，5:1)，得到目标化合物(3aS,9bR)-8-(2-氟苄氧基)-6,9-二甲基-3-亚甲基-3a,4,5,9b-四氢萘并[1,2-b]呋喃-2(3H)-酮41毫克(收率：96.3％)。1HNMR(500MHz,Chloroform-d)δ7.57–7.52(m,1H),7.34–7.29(m,1H),7.18(t,J＝7.5Hz,1H),7.12–7.06(m,1H),6.84(s,1H),6.30(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.63(t,J ＝6.6Hz,1H),5.16–5.09(m,2H),3.31(ddd,J＝9.6,6.8,4.9Hz,1H),2.72(ddd,J＝16.4,6.0, 4.5Hz,1H),2.52(ddd,J＝16.4,9.6,4.5Hz,1H),2.36(s,3H),2.24(s,3H),1.97(ddd,J＝13.5, 10.9,4.7Hz,1H),1.82(dtd,J＝13.9,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ 170.4,154.9,140.2,134.2,130.7,129.5,129.5,129.0,126.4,124.4,124.4,121.5,115.4,115.2, 75.2,64.5,64.5,39.6,26.3,23.8,20.1,11.7.
表1中化合物4-58的合成参照实施例3的方法实施。
化合物4：收率：65.0％。1H NMR(500MHz,Chloroform-d)δ7.55(dd,J＝8.1,7.1Hz,1H), 7.22(dd,J＝9.3,1.8Hz,1H),7.12–7.08(m,1H),6.73(s,1H),6.31(d,J＝2.0Hz,1H),5.71(d, J＝1.8Hz,1H),5.62(d,J＝6.7Hz,1H),5.01(s,2H),3.32(ddd,J＝9.5,6.9,4.9Hz,1H),2.71 (ddd,J＝16.4,6.2,4.5Hz,1H),2.52(ddd,J＝16.3,9.4,4.4Hz,1H),2.36(s,3H),2.22(s,3H), 1.97(ddd,J＝13.5,11.0,4.7Hz,1H),1.82(dtd,J＝13.8,9.5,4.4Hz,1H)；13C NMR(125MHz, Chloroform-d)δ170.3,154.6,140.1,139.5,139.5,134.2,133.7,130.9,129.2,126.3,123.7,123.7, 121.6,115.3,115.0,75.2,69.3,39.6,26.3,23.7,20.1,11.8.
化合物5：收率：60.6％。1H NMR(500MHz,Chloroform-d)δ7.66(d,J＝8.1Hz,2H),7.56 (d,J＝8.0Hz,2H),6.77(s,1H),6.31(d,J＝2.0Hz,1H),5.72(d,J＝1.8Hz,1H),5.63(d,J＝ 6.7Hz,1H),5.12(s,2H),3.32(dtd,J＝9.5,4.9,2.9Hz,1H),2.72(ddd,J＝16.4,6.2,4.5Hz,1H), 2.52(ddd,J＝16.4,9.4,4.4Hz,1H),2.38(s,3H),2.23(s,3H),2.01–1.94(m,1H),1.83(dtd,J＝ 13.8,9.5,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.3,154.7,141.7,140.1,134.2, 130.9,129.1,127.2(4C),126.3,125.7,125.7,121.6,115.0,75.2,69.8,39.6,26.3,23.8,20.1,11.8.
化合物6：收率：99.7％。1H NMR(500MHz,Chloroform-d)δ6.94(d,J＝15.0Hz,2H),6.83 (s,1H),6.31(d,J＝2.0Hz,1H),5.72(d,J＝1.3Hz,1H),5.61(dd,J＝14.2,6.7Hz,1H),5.04– 4.92(m,2H),3.35–3.27(m,1H),2.78–2.66(m,1H),2.54(ddq,J＝19.0,9.5,4.4Hz,1H),2.39 –2.24(m,15H),1.97(ddd,J＝9.0,4.5,1.6Hz,1H),1.85–1.82(m,1H)；13CNMR(125MHz, Chloroform-d)δ170.5,155.6,152.1,140.2,138.2(2C),134.1,130.6,130.4,129.1(2C),129.0, 128.5,126.4,121.5,117.9,114.8,75.3,65.3,39.6,29.8,26.4,23.8,19.6,11.6.
化合物7：收率：87.0％。1H NMR(500MHz,Chloroform-d)δ7.30(t,J＝7.9Hz,1H),7.02 (d,J＝7.2Hz,2H),6.89–6.84(m,1H),6.80(s,1H),6.30(d,J＝2.0Hz,1H),5.71(d,J＝1.7Hz, 1H),5.63(d,J＝6.7Hz,1H),5.04(s,2H),3.83(s,3H),3.31(ddd,J＝9.5,6.8,4.9Hz,1H),2.71 (dt,J＝16.4,5.3Hz,1H),2.56–2.47(m,1H),2.37(s,3H),2.23(s,3H),1.96(ddd,J＝13.5,10.9, 4.7Hz,1H),1.82(dtd,J＝13.8,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4, 159.9,155.1,140.2,139.2,134.1,130.7,129.7,128.7,126.3,121.5,119.4,115.2,113.4,112.8, 75.3,70.5,55.4,39.6,26.3,23.8,20.1,11.8.
化合物8：收率：39.3％。1H NMR(500MHz,Chloroform-d)δ8.08–8.04(m,1H),7.92–7.88(m,1H),7.86(d,J＝8.3Hz,1H),7.62(d,J＝6.9Hz,1H),7.56–7.51(m,2H),7.51–7.46(m,1H),6.96(s,1H),6.31(d,J＝1.6Hz,1H),5.71(s,1H),5.63(d,J＝6.6Hz,1H),5.48(s,2H), 3.31(dd,J＝4.7,2.6Hz,1H),2.74(dt,J＝16.4,5.2Hz,1H),2.54(ddd,J＝16.1,9.4,4.4Hz,1H), 2.31(s,3H),2.27(s,3H),1.98(dq,J＝15.5,4.9Hz,1H),1.84(dtd,J＝13.8,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,155.2,140.2,134.2,133.9,132.9,131.6,130.8, 129.0,128.8,126.5,126.5,126.3,126.0,125.5,123.8,121.5,115.1,75.3,69.3,39.6,29.8,26.4, 23.8,20.2,11.7.
化合物9：收率：85.3％。1H NMR(500MHz,Chloroform-d)δ7.40(d,J＝8.0Hz,2H),7.28 (dd,J＝7.5,0.9Hz,1H),7.00(s,1H),6.33(d,J＝2.0Hz,1H),5.74(d,J＝1.7Hz,1H),5.63(d,J ＝6.7Hz,1H),5.27(s,2H),3.33(ddd,J＝9.5,6.8,4.9Hz,1H),2.79–2.73(m,1H),2.56(ddd,J ＝16.3,9.5,4.5Hz,1H),2.32(s,3H),2.31(s,3H),2.00(ddd,J＝13.4,10.8,4.8Hz,1H),1.85 (dtd,J＝13.9,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,155.1,140.2,137.1, 134.2,132.6,130.7,130.4,129.3,128.6(3C),127.0,121.4,116.0,75.3,66.3,39.6,26.3,23.8,20.1, 11.6.
化合物10：收率：85.5％。1H NMR(500MHz,Chloroform-d)δ7.77–7.62(m,3H),7.44(t, J＝7.6Hz,1H),6.84(s,1H),6.31(d,J＝2.0Hz,1H),5.72(d,J＝1.8Hz,1H),5.63(d,J＝6.7 Hz,1H),5.25(d,J＝5.0Hz,2H),3.32(ddd,J＝9.6,6.9,4.9Hz,1H),2.72(dt,J＝16.3,5.2Hz, 1H),2.57–2.47(m,1H),2.38(s,3H),2.25(s,3H),1.97(ddd,J＝13.5,11.0,4.7Hz,1H),1.82 (dtd,J＝13.9,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,154.4,141.2,140.1, 134.4,133.3,132.9,130.9,129.4,128.4,128.3,126.3,121.6,117.2,115.1,111.0,75.2,68.1,39.6, 26.3,23.8,20.1,11.8.
化合物11：收率：89.3％。1H NMR(500MHz,Chloroform-d)δ7.35(td,J＝7.9,5.9Hz,1H), 7.21(d,J＝7.6Hz,1H),7.16(d,J＝9.6Hz,1H),7.01(td,J＝8.4,2.2Hz,1H),6.77(s,1H),6.31 (d,J＝2.0Hz,1H),5.72(d,J＝1.8Hz,1H),5.63(d,J＝6.7Hz,1H),5.05(s,2H),3.31(dtd,J＝9.6,4.9,2.9Hz,1H),2.71(ddd,J＝16.4,6.1,4.5Hz,1H),2.51(ddd,J＝16.3,9.6,4.5Hz,1H), 2.37(s,3H),2.23(s,3H),2.01–1.93(m,1H),1.82(dtd,J＝13.9,9.6,4.4Hz,1H)；13C NMR (125MHz,Chloroform-d)δ170.4,164.1,154.8,140.2,140.1,134.2,130.8,130.3,130.2,129.0, 126.3,122.6,121.6,115.0,114.1,75.2,69.8,39.6,26.3,23.8,20.2,11.8.
化合物12：收率：96.8％。1H NMR(500MHz,Chloroform-d)δ7.45–7.42(m,1H),7.34– 7.28(m,3H),6.76(s,1H),6.31(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.63(d,J＝6.7Hz, 1H),5.03(s,2H),3.31(dtd,J＝9.5,4.9,2.9Hz,1H),2.71(ddd,J＝16.4,6.2,4.5Hz,1H),2.52 (ddd,J＝16.4,9.5,4.4Hz,1H),2.37(s,3H),2.23(s,3H),1.96(ddt,J＝9.5,6.1,4.8Hz,1H), 1.82(dtd,J＝13.8,9.5,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,154.8,140.1, 139.7,134.6,134.2,130.9,130.0,129.0,128.1,127.3,126.3,125.2,121.5,115.2,75.2,69.9,39.6, 26.3,23.8,20.1,11.8.
化合物13：收率：99.8％。1H NMR(500MHz,Chloroform-d)δ7.59(s,1H),7.46(d,J＝7.9 Hz,1H),7.37(d,J＝7.7Hz,1H),7.27(d,J＝7.4Hz,1H),6.76(s,1H),6.31(d,J＝2.0Hz,1H), 5.71(d,J＝1.8Hz,1H),5.63(d,J＝6.7Hz,1H),5.02(s,2H),3.32(ddd,J＝9.5,6.9,4.9Hz,1H), 2.72(ddd,J＝16.4,6.1,4.5Hz,1H),2.52(ddd,J＝16.3,9.4,4.4Hz,1H),2.37(s,3H),2.23(s, 3H),1.97(ddd,J＝13.5,11.0,4.7Hz,1H),1.82(dtd,J＝13.8,9.5,4.4Hz,1H)；13C NMR(125 MHz,Chloroform-d)δ170.4,154.8,140.1,139.9,134.2,131.0,130.9,130.3,130.2,129.1,126.3, 125.7,122.8,121.5,115.2,75.2,69.8,39.6,26.3,23.8,20.1,11.8.
化合物14：收率：84.5％。1H NMR(500MHz,Chloroform-d)δ7.70(s,1H),7.65(d,J＝7.6 Hz,1H),7.59(d,J＝7.8Hz,1H),7.52(t,J＝7.7Hz,1H),6.79(s,1H),6.31(d,J＝2.1Hz,1H), 5.71(d,J＝1.8Hz,1H),5.63(d,J＝6.7Hz,1H),5.10(s,2H),3.32(ddd,J＝9.6,6.9,4.9Hz,1H), 2.72(ddd,J＝16.4,6.2,4.5Hz,1H),2.52(ddd,J＝16.4,9.5,4.4Hz,1H),2.37(s,3H),2.23(s, 3H),2.02–1.93(m,1H),1.83(dtd,J＝13.8,9.5,4.5Hz,1H)；13CNMR(125MHz, Chloroform-d)δ170.4,154.8,140.1,138.6,134.3,130.9,130.5,129.2(2C),129.2,126.4,125.3, 124.8,124.0,121.5,115.2,75.2,70.0,39.6,26.3,23.8,20.1,11.7.
化合物15：收率：70.7％。1H NMR(500MHz,Chloroform-d)δ8.31(s,1H),8.19(d,J＝8.2 Hz,1H),7.80(d,J＝7.3Hz,1H),7.58(t,J＝7.9Hz,1H),6.77(s,1H),6.31(d,J＝2.0Hz,1H), 5.72(d,J＝1.8Hz,1H),5.64(dd,J＝6.4,2.7Hz,1H),5.15(s,2H),3.32(d,J＝4.6Hz,1H),2.71 (dd,J＝15.5,5.4Hz,1H),2.57–2.52(m,1H),2.37(d,J＝10.9Hz,3H),2.23(s,3H),1.98(dd,J ＝13.6,6.1Hz,1H),1.88–1.80(m,1H).
化合物16：收率：92.8％。1H NMR(500MHz,Chloroform-d)δ7.45–7.37(m,2H),7.10–7.06(m,2H),6.79(s,1H),6.31(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.62(d,J＝6.7Hz, 1H),5.01(s,2H),3.31(dtd,J＝9.5,4.9,2.9Hz,1H),2.72(ddd,J＝16.4,6.2,4.5Hz,1H),2.55– 2.48(m,1H),2.35(s,3H),2.23(s,3H),1.96(ddt,J＝9.6,6.2,4.8Hz,1H),1.82(dtd,J＝13.9, 9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,163.5,155.0,140.1,134.1,133.3, 130.8,129.1,129.1,128.9,126.3,121.5,115.7,115.5,115.3,75.2,70.1,39.6,26.3,23.8,20.1, 11.7.
化合物17：收率：85.0％。1H NMR(500MHz,Chloroform-d)δ7.46–7.43(m,2H),7.39(t, J＝7.5Hz,2H),7.33(t,J＝7.3Hz,1H),6.81(s,1H),6.31(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz, 1H),5.63(d,J＝6.7Hz,1H),5.06(s,2H),3.31(dtd,J＝9.6,4.9,2.9Hz,1H),2.72(ddd,J＝16.4, 6.1,4.5Hz,1H),2.52(ddd,J＝16.3,9.5,4.4Hz,1H),2.37(s,3H),2.23(s,3H),2.00–1.93(m, 1H),1.82(dtd,J＝13.8,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,155.1, 140.2,137.6,134.1,130.7,128.7,128.7(2C),127.9,127.3(2C),126.3,121.5,115.2,75.3,70.7, 39.6,26.4,23.8,20.1,11.7.
化合物18：收率：99.2％。1H NMR(500MHz,Chloroform-d)δ7.37(d,J＝1.2Hz,4H),6.76 (s,1H),6.31(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.62(d,J＝6.7Hz,1H),5.02(s,2H), 3.31(ddd,J＝9.6,6.9,4.9Hz,1H),2.71(ddd,J＝16.4,6.1,4.5Hz,1H),2.51(ddd,J＝16.4,9.5, 4.4Hz,1H),2.35(s,3H),2.22(s,3H),2.00–1.93(m,1H),1.82(dtd,J＝13.9,9.5,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,154.9,140.1,136.1,134.2,133.7,130.8,128.9, 128.9(2C),128.6(2C),126.3,121.5,115.2,75.2,69.9,39.6,26.3,23.8,20.1,11.7.
化合物19：收率：98.2％。1H NMR(500MHz,Chloroform-d)δ7.33(d,J＝8.0Hz,2H),7.20 (d,J＝7.8Hz,2H),6.81(s,1H),6.30(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.62(d,J＝ 6.7Hz,1H),5.01(s,2H),3.30(dtd,J＝9.6,4.9,2.9Hz,1H),2.71(ddd,J＝16.3,6.1,4.5Hz,1H), 2.51(ddd,J＝16.3,9.5,4.4Hz,1H),2.37(s,3H),2.35(s,3H),2.23(s,3H),1.96(ddt,J＝9.5,6.1, 4.8Hz,1H),1.82(dtd,J＝13.9,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.5, 155.2,140.2,137.7,134.5,134.1,130.6,129.3(2C),128.6,127.4(2C),126.3,121.4,115.3,75.3, 70.7,39.6,26.4,23.8,21.3,20.1,11.7.
化合物20：收率：96.7％。1H NMR(500MHz,Chloroform-d)δ7.67(s,1H),7.63–7.59(m, 2H),7.58–7.54(m,1H),7.49–7.42(m,4H),7.39–7.34(m,1H),6.84(s,1H),6.31(d,J＝2.0 Hz,1H),5.71(d,J＝1.8Hz,1H),5.63(d,J＝6.7Hz,1H),5.12(s,2H),3.31(ddd,J＝9.6,6.8, 4.9Hz,1H),2.72(ddd,J＝16.3,6.1,4.5Hz,1H),2.52(ddd,J＝16.3,9.5,4.5Hz,1H),2.39(s, 3H),2.24(s,3H),1.97(ddd,J＝13.5,11.0,4.7Hz,1H),1.83(dtd,J＝13.8,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,155.1,141.7,141.1,140.2,138.1,134.1,130.8,129.1, 129.0(2C),128.8,127.5,127.3(2C),126.8,126.4,126.2,126.1,121.5,115.3,75.3,70.8,39.6, 26.3,23.8,20.1,11.8.
化合物21：收率：81.0％。1H NMR(500MHz,Chloroform-d)δ7.32(tt,J＝8.4,6.5Hz,1H), 6.93(h,J＝4.0Hz,3H),6.30(d,J＝2.0Hz,1H),5.70(d,J＝1.8Hz,1H),5.59(d,J＝6.7Hz, 1H),5.09(s,2H),3.29(dddt,J＝8.6,6.7,4.8,1.8Hz,1H),2.72(ddd,J＝16.4,6.1,4.5Hz,1H), 2.56–2.48(m,1H),2.26(d,J＝6.5Hz,6H),2.01–1.90(m,1H),1.81(dtd,J＝13.9,9.6,4.4Hz, 1H)；13C NMR(125MHz,Chloroform-d)δ170.4,161.1,161.1,155.0,140.2,134.2,130.7,130.7, 130.6,129.4,127.0,121.4,116.1,111.6,111.4,75.2,59.2,39.6,26.3,23.8,20.1,11.5.
化合物22：收率：93.5％。1H NMR(500MHz,Chloroform-d)δ7.28(s,1H),7.07–6.96(m, 2H),6.80(s,1H),6.31(d,J＝1.9Hz,1H),5.71(d,J＝1.7Hz,1H),5.63(d,J＝6.7Hz,1H),5.09 (s,2H),3.35–3.28(m,1H),2.72(dt,J＝16.4,5.3Hz,1H),2.56–2.48(m,1H),2.37(s,3H), 2.24(s,3H),2.01–1.93(m,1H),1.82(dtd,J＝13.8,9.5,4.3Hz,1H)；13C NMR(125MHz, Chloroform-d)δ170.4,154.6,140.1,134.3,130.9,129.3,126.3,121.5,116.4,115.9,115.8,115.7, 115.7,115.6,115.1,75.2,63.9,39.6,26.3,23.8,20.1,11.7.
化合物23：收率：83.3％。1H NMR(500MHz,Chloroform-d)δ7.53–7.46(m,1H),6.95– 6.88(m,1H),6.85(ddd,J＝10.2,8.9,2.5Hz,1H),6.82(s,1H),6.31(d,J＝2.0Hz,1H),5.71(d, J＝1.8Hz,1H),5.62(d,J＝6.7Hz,1H),5.10–5.02(m,2H),3.31(dtd,J＝9.5,4.9,2.9Hz,1H), 2.72(ddd,J＝16.4,6.1,4.5Hz,1H),2.52(ddd,J＝16.3,9.5,4.4Hz,1H),2.34(s,3H),2.24(s, 3H),2.00–1.93(m,1H),1.82(dtd,J＝13.8,9.6,4.4Hz,1H)；13C NMR(125MHz, Chloroform-d)δ170.4,154.7,140.1,134.2,130.8,130.5,129.2,126.4,121.5,115.3,111.5,104.1, 103.9,103.7,75.2,64.1,64.1,39.6,26.3,23.8,20.1,11.7.
化合物24：收率：85.2％。1H NMR(500MHz,Chloroform-d)δ6.97(dd,J＝7.9,2.2Hz,2H), 6.78–6.71(m,2H),6.31(d,J＝2.1Hz,1H),5.71(d,J＝1.8Hz,1H),5.63(d,J＝6.7Hz,1H), 5.03(s,2H),3.32(ddd,J＝9.6,6.9,4.9Hz,1H),2.72(ddd,J＝16.3,6.2,4.5Hz,1H),2.52(ddd, J＝16.4,9.4,4.5Hz,1H),2.38(s,3H),2.23(s,3H),1.97(ddd,J＝13.5,11.0,4.7Hz,1H),1.83 (dtd,J＝13.9,9.6,4.5Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.3,164.4,154.5,140.1, 134.3,131.0,129.2,126.3,121.6,115.0,109.8,109.6,103.4,103.2,103.0,75.1,69.4,39.6,26.3, 23.8,20.1,11.8.
化合物25：收率：95.9％。1H NMR(500MHz,Chloroform-d)δ7.53(d,J＝8.3Hz,1H),7.29 (dd,J＝8.3,2.1Hz,1H),7.26–7.24(m,1H),6.77(s,1H),6.30(d,J＝2.0Hz,1H),5.72(d,J＝ 1.8Hz,1H),5.62(d,J＝6.7Hz,1H),5.09(s,2H),3.31(dddt,J＝8.7,6.7,4.7,1.8Hz,1H),2.71 (ddd,J＝16.4,6.1,4.5Hz,1H),2.51(ddd,J＝16.4,9.5,4.5Hz,1H),2.37(s,3H),2.23(s,3H), 1.96(ddt,J＝9.6,6.1,4.8Hz,1H),1.81(dtd,J＝13.9,9.6,4.4Hz,1H)；13C NMR(125MHz, Chloroform-d)δ170.4,154.5,140.0,137.0,134.3,133.9,133.1,130.8,129.5,129.2,129.2,127.4, 126.2,121.6,115.0,75.2,67.2,39.5,26.2,23.7,20.1,11.7.
化合物26：收率：92.9％。1H NMR(500MHz,Chloroform-d)δ7.53(d,J＝1.9Hz,1H),7.46 (d,J＝8.2Hz,1H),7.29–7.26(m,1H),6.74(s,1H),6.31(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz, 1H),5.62(d,J＝6.7Hz,1H),5.00(s,2H),3.32(ddd,J＝9.5,6.9,4.9Hz,1H),2.71(ddd,J＝16.4, 6.1,4.5Hz,1H),2.52(ddd,J＝16.4,9.5,4.5Hz,1H),2.36(s,3H),2.22(s,3H),1.97(ddd,J＝ 13.5,11.0,4.7Hz,1H),1.82(dtd,J＝13.8,9.5,4.4Hz,1H)；13CNMR(125MHz,Chloroform-d) δ170.4,154.6,140.0,137.9,134.3,132.8,131.9,130.9,130.7,129.2,129.1,126.4,126.3,121.6, 115.1,75.2,69.3,39.6,26.3,23.7,20.1,11.8.
化合物27：收率：90.7％。1H NMR(500MHz,Chloroform-d)δ7.92(s,2H),7.85(s,1H), 6.78(s,1H),6.32(d,J＝2.1Hz,1H),5.72(d,J＝1.8Hz,1H),5.63(d,J＝6.7Hz,1H),5.15(s, 2H),3.33(ddd,J＝9.5,7.0,5.0Hz,1H),2.73(ddd,J＝16.4,6.3,4.5Hz,1H),2.58–2.49(m, 1H),2.38(s,3H),2.24(s,3H),1.98(ddd,J＝13.6,11.1,4.7Hz,1H),1.84(dtd,J＝13.8,9.5,4.4 Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.3,154.5,140.3,140.0,134.4,132.2,131.9, 131.2,129.7,127.2,127.2,126.4,124.5,122.3,122.0,121.6,115.2,75.1,69.4,39.5,26.2,23.8, 20.1,11.7.
化合物28：收率：94.1％。1H NMR(500MHz,Chloroform-d)δ7.36(d,J＝8.7Hz,2H),6.93 (d,J＝8.7Hz,2H),6.82(s,1H),6.30(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.62(d,J＝ 6.7Hz,1H),4.98(s,2H),3.83(s,3H),3.30(dtd,J＝9.6,4.9,3.0Hz,1H),2.71(ddd,J＝16.4,6.1, 4.5Hz,1H),2.52(ddd,J＝16.3,9.5,4.4Hz,1H),2.34(s,3H),2.23(s,3H),2.00–1.93(m,1H), 1.82(dtd,J＝13.9,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,159.4,155.2, 140.2,134.0,130.6,129.6,129.5,129.0(2C),128.6,121.4,115.4,114.1(2C),113.9,75.3,70.5, 39.6,26.3,23.7,20.1,11.7.
化合物29：收率：94.8％。1H NMR(500MHz,Chloroform-d)δ7.39(t,J＝7.9Hz,1H),7.31 –7.27(m,1H),7.22(s,1H),7.08(dd,J＝8.1,1.9Hz,1H),6.78(s,1H),6.53(t,J＝73.9Hz,1H), 6.31(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.63(d,J＝6.7Hz,1H),5.05(s,2H),3.32(dtd, J＝9.6,4.9,2.9Hz,1H),2.72(ddd,J＝16.4,6.2,4.5Hz,1H),2.52(ddd,J＝16.3,9.5,4.4Hz, 1H),2.37(s,3H),2.23(s,3H),1.97(ddt,J＝13.5,6.1,4.7Hz,1H),1.82(dtd,J＝13.8,9.5,4.4 Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,154.8,151.6,140.1,139.9,134.2,130.9, 130.1,129.0,126.3,124.0,121.5,118.8,118.3,116.0,115.2,75.2,70.0,39.6,26.3,23.8,20.1, 11.7.
化合物30：收率：95.2％。1H NMR(500MHz,Chloroform-d)δ7.29(d,J＝7.3Hz,1H),7.14 (dt,J＝14.9,7.1Hz,2H),6.86(s,1H),6.30(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.62(d, J＝6.7Hz,1H),5.02(s,2H),3.31(ddd,J＝9.6,6.8,4.9Hz,1H),2.73(ddd,J＝16.4,6.1,4.5Hz, 1H),2.53(ddd,J＝16.3,9.5,4.4Hz,1H),2.38–2.12(m,12H),1.97(ddd,J＝13.5,10.9,4.7Hz, 1H),1.83(ddt,J＝13.6,9.5,4.8Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,155.2, 140.2,137.2,135.5,135.2,134.1,130.7,130.0,128.6,126.7,126.3,125.6,121.4,115.0,75.3, 69.9,39.6,26.4,23.8,20.5,20.2,15.0,11.7.
化合物31：收率：93.9％。1H NMR(500MHz,Chloroform-d)δ7.13–7.06(m,2H),6.92(dd, J＝7.2,2.5Hz,1H),6.87(s,1H),6.30(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.62(d,J＝ 6.7Hz,1H),5.10(s,2H),3.89(d,J＝5.5Hz,6H),3.30(ddd,J＝9.6,6.8,4.9Hz,1H),2.76– 2.68(m,1H),2.52(ddd,J＝16.3,9.6,4.4Hz,1H),2.35(s,3H),2.24(s,3H),1.97(ddd,J＝13.5, 10.9,4.7Hz,1H),1.82(dtd,J＝13.9,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ 170.4,155.2,152.7,146.9,140.2,134.1,131.5,130.6,128.6,126.2,124.3,121.4,120.9,115.1, 112.2,75.3,65.7,61.2,55.9,39.7,26.4,23.8,20.1,11.8.
化合物32：收率：69.1％。1H NMR(500MHz,Chloroform-d)δ7.10–7.03(m,2H),6.71(s, 1H),6.31(d,J＝2.0Hz,1H),5.72(d,J＝1.8Hz,1H),5.62(d,J＝6.7Hz,1H),4.98(s,2H),3.32 (dtd,J＝9.5,4.9,2.8Hz,1H),2.71(ddd,J＝16.4,6.2,4.5Hz,1H),2.52(ddd,J＝16.4,9.4,4.5 Hz,1H),2.36(s,3H),2.22(s,3H),2.00–1.94(m,1H),1.82(dtd,J＝13.8,9.5,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.3,154.4,140.0,134.3,131.0,129.4,126.3,121.6(2C), 115.0(2C),111.1,111.0,110.9,110.9,75.1,69.0,39.5,26.2,23.7,20.1,11.7.
化合物33：收率：82.9％。1H NMR(500MHz,Chloroform-d)δ6.92(s,1H),6.50–6.46(m, 2H),6.29(d,J＝2.0Hz,1H),5.70(d,J＝1.7Hz,1H),5.58(d,J＝6.7Hz,1H),5.01(s,2H),3.80 (s,3H),3.29(dtd,J＝9.6,4.9,3.0Hz,1H),2.71(ddd,J＝16.4,6.0,4.5Hz,1H),2.51(ddd,J＝ 16.4,9.5,4.4Hz,1H),2.26(d,J＝6.0Hz,6H),1.96(ddd,J＝13.5,10.9,4.7Hz,1H),1.81(dtd,J ＝13.9,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,163.8,161.8,161.7,155.0, 140.2,134.1,130.6,129.3,127.0,121.4,116.2,105.4,98.2,97.9,75.3,59.1,55.9,39.6,26.3,23.8, 20.0,11.5.
化合物34：收率：68.4％。1H NMR(500MHz,Chloroform-d)δ7.93(s,1H),7.56–7.51(m, 2H),6.82(s,1H),6.31(d,J＝2.0Hz,1H),5.72(d,J＝1.8Hz,1H),5.64(d,J＝6.7Hz,1H),5.14 (s,2H),3.33(ddd,J＝9.6,6.9,4.9Hz,1H),2.73(ddd,J＝16.4,6.2,4.5Hz,1H),2.53(ddd,J＝ 16.4,9.4,4.5Hz,1H),2.39(s,3H),2.25(s,3H),1.98(ddd,J＝13.5,11.0,4.7Hz,1H),1.83(dtd, J＝13.8,9.5,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.3,154.6,140.1,136.5,134.4, 131.0,130.0(2C),129.5,126.4,125.8,125.8,125.6,125.6,121.6,115.3,75.1,67.6,39.6,26.3, 23.8,20.1,11.7.
化合物35：收率：91.5％。1H NMR(500MHz,Chloroform-d)δ7.45–7.40(m,1H),7.14(dd, J＝8.9,2.3Hz,1H),6.87(d,J＝8.9Hz,1H),6.82(s,1H),6.31(d,J＝2.0Hz,1H),5.71(d,J＝ 1.8Hz,1H),5.64(d,J＝6.7Hz,1H),5.05(s,2H),3.88(s,3H),3.32(dtd,J＝9.6,4.9,2.9Hz, 1H),2.72(ddd,J＝16.4,6.1,4.5Hz,1H),2.52(ddd,J＝16.4,9.5,4.5Hz,1H),2.38(s,3H),2.24 (s,3H),2.01–1.93(m,1H),1.83(dtd,J＝13.8,9.6,4.4Hz,1H)；13C NMR(125MHz, Chloroform-d)δ170.4,155.0,155.0,142.9,140.2,134.2,130.7,128.9(2C),127.8,126.4,121.5, 121.2,121.1,115.3,110.7,75.2,65.3,55.9,39.6,26.3,23.8,20.1,11.7.
化合物36：收率：82.7％。收率：82.7％。1H NMR(500MHz,Chloroform-d)δ7.47–7.38 (m,4H),7.12–7.03(m,4H),6.79(s,1H),6.28(s,1H),5.71(d,J＝1.8Hz,1H),5.62(d,J＝6.7 Hz,1H),5.01(s,2H),3.31(dtd,J＝9.5,4.9,2.9Hz,1H),2.72(ddd,J＝16.4,6.2,4.5Hz,1H), 2.55–2.48(m,1H),2.35(s,3H),2.23(s,3H),1.96(ddt,J＝9.6,6.2,4.8Hz,1H),1.82(dtd,J＝ 13.9,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.6,163.6,155.2,140.1,134.1, 133.3,130.8,129.1,129.1,128.9,126.3,121.5,115.7,115.5,115.3,75.2,70.1,39.6,26.3,23.8, 20.1,11.7.
化合物37：收率：74.1％。1H NMR(500MHz,Chloroform-d)δ6.90(s,1H),6.83(dtd,J＝ 11.6,5.8,2.4Hz,1H),6.30(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.59(d,J＝6.7Hz,1H), 5.05(s,2H),3.30(dddt,J＝8.7,6.7,4.8,1.8Hz,1H),2.72(ddd,J＝16.4,6.2,4.5Hz,1H),2.52 (ddd,J＝16.4,9.5,4.5Hz,1H),2.26(s,6H),1.96(ddt,J＝9.5,6.1,4.8Hz,1H),1.82(dtd,J＝ 13.8,9.6,4.4Hz,1H).
化合物38：收率：92.3％。1H NMR(500MHz,Chloroform-d)δ6.88(s,1H),6.30(d,J＝2.0 Hz,1H),5.71(d,J＝1.8Hz,1H),5.59(d,J＝6.7Hz,1H),5.12–5.07(m,2H),3.31(ddd,J＝9.5, 6.9,4.9Hz,1H),2.72(ddd,J＝16.4,6.1,4.5Hz,1H),2.52(ddd,J＝16.5,9.4,4.4Hz,1H),2.26 (s,6H),1.97(ddd,J＝13.5,11.0,4.7Hz,1H),1.82(dtd,J＝13.8,9.5,4.4Hz,1H).
化合物39：收率：83.2％。1H NMR(500MHz,Chloroform-d)δ8.55(s,1H),7.80(dd,J＝8.2, 2.2Hz,1H),7.39(d,J＝8.2Hz,1H),6.77(s,1H),6.31(d,J＝2.0Hz,1H),5.71(d,J＝1.7Hz, 1H),5.61(d,J＝6.7Hz,1H),5.06(s,2H),3.32(ddd,J＝9.4,6.9,4.9Hz,1H),2.71(dt,J＝16.4, 5.3Hz,1H),2.57–2.47(m,1H),2.33(s,3H),2.23(s,3H),1.97(ddd,J＝13.4,11.0,4.7Hz,1H), 1.82(dtd,J＝13.8,9.5,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.3,154.4,151.1, 148.7,140.0,138.4,134.4,132.4,131.1,129.5,126.3,124.7,121.6,115.1,75.1,67.4,39.5,26.2, 23.7,20.1,11.7.
化合物40：收率：81.6％。1H NMR(500MHz,Chloroform-d)δ6.85(s,1H),6.31(d,J＝2.1 Hz,1H),5.72(d,J＝1.8Hz,1H),5.60(d,J＝6.7Hz,1H),5.32(d,J＝2.4Hz,2H),3.32(dddt,J ＝8.8,6.8,4.7,1.9Hz,1H),2.72(ddd,J＝16.5,6.2,4.5Hz,1H),2.52(ddd,J＝16.5,9.4,4.5Hz, 1H),2.32(s,3H),2.24(s,3H),1.97(ddt,J＝13.6,6.3,4.7Hz,1H),1.82(dtd,J＝13.8,9.5,4.4 Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.3,164.9(2C),153.7,139.8,134.7,131.4, 131.0,126.9,121.8(2C),115.7,75.0,60.8,39.4,26.1,23.8,20.1,11.6.
化合物41：收率：72.9％。1H NMR(500MHz,Chloroform-d)δ8.07–7.98(m,3H),7.68(dd, J＝8.5,2.2Hz,3H),6.83(s,1H),6.31(d,J＝2.0Hz,1H),5.72(d,J＝1.8Hz,1H),5.61(d,J＝ 6.7Hz,1H),5.18(d,J＝1.2Hz,2H),4.86(s,1H),3.32(ddd,J＝9.6,6.9,4.9Hz,1H),2.72(dt,J ＝16.4,5.3Hz,1H),2.58–2.53(m,1H),2.52(s,3H),2.33(s,3H),1.97(ddd,J＝13.5,11.0,4.7 Hz,1H),1.82(dtd,J＝13.9,9.5,4.5Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,164.8, 154.4,151.6,140.0,136.8,134.3,132.5,131.8,131.5,131.0,129.6,128.9,126.7(2C),126.1(2C), 121.7,115.5,75.2,63.2,57.1,39.5,26.2,20.2,15.6,11.7.
化合物42：收率：74.4％。1H NMR(500MHz,Chloroform-d)δ6.77–6.69(m,1H),6.68– 6.62(m,1H),6.58–6.47(m,1H),6.30(d,J＝1.9Hz,1H),5.72(d,J＝1.4Hz,1H),5.59(dd,J＝ 15.0,6.4Hz,1H),4.17–4.13(m,1H),4.11–4.01(m,1H),3.29(s,1H),2.75(dt,J＝16.3,5.0 Hz,1H),2.54(ddd,J＝16.2,9.6,4.3Hz,1H),2.37–2.26(m,3H),2.25–2.15(m,3H),2.00– 1.93(m,1H),1.79(ddt,J＝18.1,9.8,4.2Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4, 150.6,142.0,140.0,133.3,129.1,127.5,126.0,125.7,124.9,124.3,124.0,121.6,75.4,39.5,31.1, 29.8,26.2,24.7,12.0.
化合物43：收率：95.2％。1H NMR(500MHz,Chloroform-d)δ7.64(dd,J＝7.3,1.9Hz,1H), 7.34(qd,J＝7.5,1.8Hz,2H),7.31–7.27(m,1H),6.79(s,1H),6.31(d,J＝2.0Hz,1H),5.71(d, J＝1.8Hz,1H),5.63(d,J＝6.7Hz,1H),5.13(d,J＝1.4Hz,2H),3.31(ddd,J＝9.6,6.8,4.9Hz, 1H),2.72(ddd,J＝16.4,6.0,4.5Hz,1H),2.52(ddd,J＝16.3,9.5,4.4Hz,1H),2.37(s,3H),2.23 (s,3H),1.97(ddd,J＝13.5,10.9,4.7Hz,1H),1.82(dtd,J＝13.8,9.6,4.4Hz,1H)；13C NMR (125MHz,Chloroform-d)δ170.4,154.7,146.7,140.1,134.3,130.8,130.4,129.3,129.1,129.1, 127.2,126.3,121.5,120.5,120.5,115.1,75.2,65.0,39.6,26.3,23.8,20.1,11.7.
化合物44：收率：90.0％。1H NMR(500MHz,Chloroform-d)δ7.45(d,J＝7.5Hz,1H),7.27 –7.24(m,2H),7.23(s,1H),6.85(s,1H),6.31(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.63 (d,J＝6.7Hz,1H),5.01(s,2H),3.31(ddd,J＝9.6,6.8,4.9Hz,1H),2.77–2.69(m,1H),2.53 (ddd,J＝16.3,9.6,4.4Hz,1H),2.38(s,3H),2.34(s,3H),2.26(s,3H),1.97(ddd,J＝13.5,10.9, 4.7Hz,1H),1.82(dtd,J＝13.9,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.5, 155.2,140.2,136.6,135.4,134.1,130.7,130.4,128.6,128.4,128.2,126.3,126.1,121.5,114.9, 75.3,69.2,39.6,26.3,23.8,20.2,19.0,11.7.
化合物45：收率：64.9％。1H NMR(500MHz,Chloroform-d)δ7.71(d,J＝8.3Hz,2H),7.18 (d,J＝8.4Hz,2H),6.75(s,1H),6.30(d,J＝2.0Hz,1H),5.71(d,J＝1.8Hz,1H),5.62(d,J＝ 6.7Hz,1H),5.00(s,2H),3.31(ddd,J＝9.5,6.9,4.9Hz,1H),2.71(ddd,J＝16.4,6.1,4.5Hz, 1H),2.51(ddd,J＝16.3,9.4,4.4Hz,1H),2.35(s,3H),2.22(s,3H),1.96(ddd,J＝13.5,11.0,4.7 Hz,1H),1.82(dtd,J＝13.8,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,154.8, 140.1,137.8(2C),137.3,134.2,130.8,129.1(2C),128.9,126.3,121.5,115.1,93.4,75.2,70.0, 39.6,26.3,23.8,20.1,11.7.
化合物46：收率：79.5％。1H NMR(500MHz,Chloroform-d)δ7.51(d,J＝7.4Hz,1H),7.33 –7.27(m,1H),7.00(t,J＝7.5Hz,1H),6.91(d,J＝8.2Hz,1H),6.85(s,1H),6.30(d,J＝2.0Hz, 1H),5.71(d,J＝1.7Hz,1H),5.63(d,J＝6.7Hz,1H),5.09(s,2H),3.87(s,3H),3.30(ddd,J＝ 9.6,6.8,4.9Hz,1H),2.75–2.68(m,1H),2.56–2.48(m,1H),2.38(s,3H),2.23(s,3H),1.96 (ddd,J＝13.5,10.9,4.8Hz,1H),1.82(dt,J＝13.6,4.7Hz,1H)；13C NMR(125MHz, Chloroform-d)δ170.5,156.8,155.3,140.3,134.1,130.5,128.8,128.5,128.3,126.3,126.1,121.4, 120.8,115.3,110.2,75.3,65.8,55.5,39.6,29.8,26.4,20.1,11.7.
化合物47：收率：86.1％。1H NMR(500MHz,Chloroform-d)δ7.79(s,1H),7.66(d,J＝7.9 Hz,1H),7.41(d,J＝7.7Hz,1H),7.12(t,J＝7.8Hz,1H),6.76(s,1H),6.30(d,J＝2.0Hz,1H), 5.71(d,J＝1.8Hz,1H),5.62(d,J＝6.7Hz,1H),4.99(s,2H),3.31(dtd,J＝9.5,4.9,2.9Hz,1H), 2.71(ddd,J＝16.4,6.1,4.5Hz,1H),2.52(ddd,J＝16.2,9.4,4.4Hz,1H),2.36(s,3H),2.23(s, 3H),1.97(ddd,J＝13.5,11.0,4.7Hz,1H),1.82(dtd,J＝13.8,9.6,4.4Hz,1H)；13C NMR(125 MHz,Chloroform-d)δ170.4,154.8,140.1,140.0,137.0,136.1,134.2,130.8,130.4,129.0,126.4, 126.3,121.5,115.2,94.5,75.2,69.7,39.6,26.3,23.8,20.1,11.7.
化合物48：收率：77.3％。1H NMR(500MHz,Chloroform-d)δ8.75(s,1H),7.81(d,J＝7.0 Hz,1H),7.61(d,J＝7.5Hz,1H),7.27(d,J＝8.2Hz,1H),6.77(s,1H),6.30(s,1H),5.73(d,J＝ 15.6Hz,1H),5.60(d,J＝6.5Hz,1H),5.27(d,J＝12.2Hz,2H),3.33(s,1H),2.71(s,1H),2.52 (s,1H),2.32(s,3H),2.23(s,3H),1.97(s,1H),1.82(s,1H).
化合物49：收率：74.1％。1H NMR(500MHz,Chloroform-d)δ7.68(s,1H),7.60(s,1H), 7.46–7.43(m,2H),7.39(t,J＝7.5Hz,2H),7.33(t,J＝7.3Hz,1H),6.81(s,1H),6.31(d,J＝2.0 Hz,1H),5.71(d,J＝1.8Hz,1H),5.63(d,J＝6.7Hz,1H),5.06(s,2H),3.31(dtd,J＝9.6,4.9,2.9 Hz,1H),2.72(ddd,J＝16.4,6.1,4.5Hz,1H),2.52(ddd,J＝16.3,9.5,4.4Hz,1H),2.37(s,3H), 2.23(s,3H),2.00–1.93(m,1H),1.82(dtd,J＝13.8,9.6,4.4Hz,1H)；13C NMR(125MHz, Chloroform-d)δ170.4,155.1,140.2,139.9，137.6,134.1,130.7,128.7,128.7(2C),127.9, 127.3(2C),126.3,122.3，121.5,115.2,75.3,70.7,39.6,26.4,23.8,20.1,11.7.
化合物50：收率：93.0％。1H NMR(300MHz,Chloroform-d)δ7.59(2H,d,J＝7.9Hz),7.36 (1H,m),7.19(1H,m),6.80(1H,s),6.31(1H,s),5.72(1H,s),5.63(1H,d,J＝6.7Hz),5.10(2H, s),3.28–3.35(1H,m),2.66–2.81(1H,m),2.43–2.60(1H,m),2.39(3H,s),2.24(3H,s),1.91–2.09 (1H,m),1.70–1.91(1H,m)；13C NMR(125MHz,Chloroform-d)δ170.3,154.6,140.0,136.7, 134.1,132.5,130.6,129.1,128.8,128.7,126.1,122.1,121.3,114.9,75.1,69.8,53.4,39.4,26.1, 23.6,20.0,11.6；ESIMS:m/z 381.2[M+H]+.
化合物51：收率：93.2％。1H NMR(300MHz,Chloroform-d)δ7.87(1H,d,J＝7.6Hz),7.55 (1H,d,J＝7.6Hz),7.39(1H,m),7.03(1H,m),6.79(1H,s),6.31(1H,d,J＝1.7Hz),5.72(1H,d, J＝1.7Hz),5.63(1H,d,J＝6.7Hz),5.01(2H,s),3.28–3.35(1H,m),2.68–2.77(1H,m), 2.45–2.59(1H,m),2.39(3H,s),2.24(3H,s),1.92–2.02(1H,m),1.77–1.88(1H,m)；13C NMR (125MHz,Chloroform-d)δ170.3,154.5,140.0,139.5,139.2,134.1,130.6,129.4,128.8,128.5, 128.4,126.1,121.3,114.9,97.0,75.1,74.4,39.4,26.2,23.6,20.0,11.7；ESIMS:m/z 461.0 [M+H]+.
化合物52：收率：89.6％。1H NMR(300MHz,Chloroform-d)δ7.79(1H,d,J＝7.8Hz),7.70 (1H,d,J＝7.8Hz),7.59(1H,m),7.42(1H,m),6.75(1H,s),6.31(1H,s),5.72(1H,s),5.64(1H,d, J＝6.7Hz),5.25(2H,s),3.28–3.35(1H,m),2.67–2.76(1H,m),2.44–2.58(1H,m),2.39(3H,s), 2.22(3H,s),1.92–2.02(1H,m),1.77–1.88(1H,m)；13C NMR(125MHz,Chloroform-d)δ170.2, 154.5,140.0,136.1,134.1,132.2,130.7,128.9,128.4,127.5,127.2,126.0,125.7,125.5,121.4, 114.8,75.1,66.4,39.4,26.1,23.6,20.0,11.6；ESIMS:m/z 403.0[M+H]+.
化合物53：收率：81.5％。1H NMR(300MHz,Chloroform-d)δ7.73(1H,s),7.69(1H,d,J ＝7.6Hz),7.63(1H,d,J＝7.6Hz),7.51(1H,m),6.75(1H,s),6.31(1H,s),5.72(1H,s),5.63(1H, d,J＝6.8Hz),5.08(2H,s),3.29–3.36(1H,m),2.65–2.80(1H,m),2.42–2.59(1H,m),2.36(3H, s),2.23(3H,s),1.90–2.05(1H,m),1.79–1.88(1H,m)；13C NMR(125MHz,Chloroform-d)δ170.2,154.4,139.8,134.1,131.5,131.3,130.9,130.4,129.4,129.2,126.1,121.4,118.7,114.9, 112.7,75.0,69.3,53.4,39.4,26.1,23.6,20.0,11.6；ESIMS:m/z 382.1[M+Na]+.
化合物54：收率：67.6％。1H NMR(300MHz,Chloroform-d)δ7.19–7.35(3H,m),7.14(1H, d,J＝6.8Hz),6.81(1H,s),6.30(1H,s),5.71(1H,s),5.63(1H,d,J＝6.7Hz),5.02(2H,s), 3.27–3.34(1H,m),2.67–2.76(1H,m),2.43–2.61(1H,m),2.38(3H,s),2.37(3H,s),2.23(3H,s), 1.89–2.08(1H,m),1.77–1.83(1H,m)；13C NMR(125MHz,Chloroform-d)δ170.3,155.1,140.0, 138.2,137.4,133.9,130.5,128.5,128.4,127.9,126.2,124.2,121.3,115.1,75.1,70.6,53.4,39.4, 26.2,23.6,21.4,19.9,11.6；ESIMS:m/z 371.0[M+Na]+.
化合物55：收率：82.1％。1H NMR(300MHz,Chloroform-d)δ7.07–7.14(2H,m),6.91(1H, dd,J＝6.2,3.4Hz),6.87(1H,s),6.30(1H,d,J＝1.8Hz),5.71(1H,d,J＝1.8Hz),5.62(1H,d,J ＝6.7Hz),5.09(2H,s),3.89(3H,s),3.88(3H,s),3.22–3.37(1H,m),2.76–2.68(1H,m), 2.43–2.62(1H,m),2.35(3H,s),2.24(3H,s).1.87–1.99(1H,m),1.78–1.87(1H,m)；13C NMR (125MHz,Chloroform-d)δ170.3,155.0,152.5,146.8,140.1,134.0,130.4,128.4,126.0,124.1, 121.2,120.7,114.9,112.0,75.1,65.6,61.0,55.8,39.5,31.5,26.2,22.6,19.9,11.6；ESIMS:m/z 417.0[M+Na]+.
化合物56：收率：97.1％。1H NMR(300MHz,Chloroform-d)δ7.51(2H,d,J＝7.8Hz),7.31 (2H,d,J＝7.8Hz),6.76(1H,s),6.30(1H,s),5.71(1H,s),5.62(1H,d,J＝6.7Hz),5.01(2H,s), 3.28–3.34(1H,m),2.65–2.77(1H,m),2.44–2.57(1H,m),2.35(3H,s),2.22(3H,s),1.92–2.01 (1H,m),1.73–1.89(1H,m)；13C NMR(125MHz,Chloroform-d)δ170.2,154.6,139.9,136.5, 134.0,131.6(2C),130.7,128.79,128.75(2C),126.1,121.6,121.4,115.0,75.0,69.8,39.4,26.1, 23.6,20.0,11.6；ESIMS:m/z 847.2[2M+Na]+.
化合物57：收率：79.8％。1H NMR(300MHz,Chloroform-d)δ7.47(2H,d,J＝8.5Hz),7.24 (2H,d,J＝8.5Hz),6.78(1H,s),6.30(1H,s),5.71(1H,s),5.62(1H,d,J＝6.7Hz),5.05(2H,s), 3.28–3.35(1H,m),2.67–2.74(1H,m),2.52–2.56(1H,m),2.36(3H,s),2.23(3H,s),1.94–2.00 (1H,m),1.79–1.89(1H,m)；13C NMR(125MHz,Chloroform-d)δ170.2,154.7,148.7,139.9, 136.1,134.0,130.7,128.8,128.4(2C),126.1,121.3,121.0(2C),119.4,114.9,75.0,69.6,39.4, 26.1,23.6,19.9,11.5；ESIMS:m/z 419.0[M+H]+.
化合物58：收率：85.4％。1H NMR(500MHz,Chloroform-d)δ7.80–7.69(m,2H),7.46(t, J＝7.5Hz,2H),7.38(t,J＝7.3Hz,1H),6.81(s,1H),6.36(d,J＝2.0Hz,1H),5.81(d,J＝1.8Hz, 1H),5.63(d,J＝6.7Hz,1H),5.06(s,2H),3.31(dtd,J＝9.6,4.9,2.9Hz,1H),2.72(ddd,J＝16.4, 6.1,4.5Hz,1H),2.52(ddd,J＝16.3,9.5,4.4Hz,1H),2.37(s,3H),2.23(s,3H),2.00–1.93(m, 1H),1.82(dtd,J＝13.8,9.6,4.4Hz,1H)；13C NMR(125MHz,Chloroform-d)δ170.4,156.1, 146.2,137.6,134.1,130.7,129.7，128.7,128.7(2C),127.9,127.3(2C),126.3,121.5,115.2,75.3, 70.7,39.6,26.4,23.8,20.1,11.7.
实施例4：(3R/S,3aS,9bR)-8-(2-溴苄氧基)-3-二甲基胺基甲基-6,9-二甲基-3a,4,5,9b-四氢萘并 [1,2-b]呋喃-2(3H)-酮的制备(表中化合物59)
称取化合物(3aS,9bR)-8-(2-溴苄氧基)-6,9-二甲基-3-亚甲基-3a,4,5,9b-四氢萘并[1,2-b]呋喃-2(3H)-酮的制备(表中化合物51)(1.0g，2.43mmol，1.0eq)和二甲胺盐酸盐(0.3g， 3.64mmol，1.5eq)溶于20ml乙醇中，0℃时滴加三乙胺(0.37g，3.64mmol，0.51ml，1.5eq)，自然升至常温搅拌，TLC监测，待化合物51消耗完全后，低温减压蒸除乙醇，加二氯甲烷和水萃取，有机层用饱和食盐水洗涤，无水Na2SO4干燥，柱层析(PE/EA＝20:1-EA) 得白色固体即为化合物(3R/S,3aS,9bR)-8-(2-溴苄氧基)-3-二甲基胺基甲基-6,9-二甲基 -3a,4,5,9b-四氢萘并[1,2-b]呋喃-2(3H)-酮(1.1g，99％)。1H NMR(500MHz,Chloroform-d)δ 7.58(t,J＝7.1Hz,2H),7.35(t,J＝7.2Hz,1H),7.18(t,J＝7.2Hz,1H),6.81(s,1H),5.40(d,J＝ 3.4Hz,1H),5.09(s,2H),3.24–3.10(m,1H),2.84(d,J＝16.2Hz,1H),2.77–2.59(m,2H), 2.45(dd,J＝8.1,21.4Hz,1H),2.37(s,3H),2.34(s,6H),2.24(s,3H),2.05(d,J＝11.7Hz,1H), 1.40–1.25(m,1H)；13C NMR(125MHz,CDCl3)δ177.0,154.4,136.7,134.2,132.5,130.1, 129.2,129.1,128.7,127.6,125.8,122.1,115.0,75.9,69.8,54.6,45.6,44.3,38.3,25.1,20.0,19.3, 11.4.
表1中化合物60-69的合成参照实施例4的方法实施。
化合物60：收率：92.8％。1H NMR(500MHz,CDCl3)δ7.58–7.54(m,2H),7.33(t,J＝7.6 Hz,1H),7.21–7.18(m,1H),6.79(s,1H),5.38(d,J＝4.4Hz,1H),5.09(s,2H),3.15(q,J＝7.2 Hz,1H),3.04–2.98(m,1H),2.82(d,J＝15.9Hz,2H),2.72–2.63(m,2H),2.50(s,3H),2.35(s, 3H),2.23(s,3H),2.16(d,J＝7.8Hz,1H),1.93–1.86(m,1H),1.37(dd,J＝4.7,12.9Hz,1H)；13C NMR(125MHz,CDCl3)δ177.8,154.3,136.8,134.2,132.5,129.9,129.1,128.9,128.6, 127.6,125.8,122.1,115.0,75.9,69.8,47.5,45.7,38.4,36.6,25.1,19.9,19.6,11.4.
化合物61：收率：91.1％。1H NMR(500MHz,CDCl3)δ7.59–7.55(m,2H),7.34(t,J＝7.6 Hz,1H),7.20–7.16(m,1H),6.80(s,1H),5.39(d,J＝4.4Hz,1H),5.08(s,2H),3.14(q,J＝7.2 Hz,1H),3.06–2.99(m,1H),2.83(d,J＝15.9Hz,2H),2.71–2.62(m,2H),2.50(s,3H),2.35(s, 3H),2.23(s,3H),2.16(d,J＝7.8Hz,1H),1.93–1.86(m,1H),1.37(dd,J＝4.7,12.9Hz,1H)；13C NMR(125MHz,CDCl3)δ177.6,154.4,136.6,134.2,132.5,129.9,129.1,128.9,128.6, 127.6,125.8,122.1,115.0,75.9,69.8,47.5,45.7,38.4,36.6,25.1,19.9,19.6,11.4.
化合物62：收率：92.8％。1H NMR(500MHz,Chloroform-d)δ7.59(t,J＝7.1Hz,2H),7.36 (t,J＝7.2Hz,1H),7.19(t,J＝7.2Hz,1H),6.83(s,1H),5.38(d,J＝4.4Hz,1H),5.08(s,2H), 3.14(q,J＝7.2Hz,1H),3.06–2.99(m,1H),2.83(d,J＝15.9Hz,2H),2.71–2.62(m,2H), 2.51(s,3H),2.35(s,3H),2.23(s,3H),2.16(d,J＝7.8Hz,1H),1.93–1.86(m,1H),1.37(dd,J＝ 4.7,12.9Hz,1H)；13C NMR(125MHz,CDCl3)δ177.6,154.4,138.6,134.2,132.5,129.9,129.1, 128.9,128.6,127.6,125.8,122.1,115.0,75.9,69.8,47.5,45.7,38.5,36.6,25.1,19.9,19.6,11.4.
化合物63：收率：89.5％。1H NMR(500MHz,CDCl3)δ7.62–7.56(m,2H),7.36(td,J＝1.1,7.6Hz,1H),7.19(td,J＝1.6,7.9Hz,1H),6.81(s,1H),5.39(d,J＝4.5Hz,1H),5.11(s,2H), 3.17(ddd,J＝4.2,6.5,10.9Hz,1H),2.98–2.91(m,1H),2.85(ddd,J＝2.3,4.5,16.7Hz,1H), 2.79(dd,J＝4.2,12.7Hz,1H),2.76–2.70(m,1H),2.69–2.63(m,2H),2.59–2.53(m,2H), 2.51–2.42(m,1H),2.36(s,3H),2.24(s,3H),2.12–2.05(m,1H),1.83(t,J＝6.4Hz,4H),1.34 (qd,J＝4.6,13.1Hz,1H)；13C NMR(125MHz,CDCl3)δ177.0,154.4,136.7,134.2,132.5, 130.2,129.2,129.1,128.7,127.6,125.9,122.1,115.0,75.8,69.9,54.3,51.1,45.6,38.4,25.1,23.6, 19.9,19.4,11.4.
化合物64：收率：90.2％。1H NMR(500MHz,CDCl3)δ7.59(d,J＝8.0Hz,2H),7.39–7.32 (m,1H),7.20(td,J＝1.5,7.9Hz,1H),6.82(s,1H),5.39(d,J＝4.5Hz,1H),5.11(s,2H),3.81– 3.69(m,4H),3.21(ddd,J＝4.5,6.5,10.9Hz,1H),2.86(ddd,J＝2.2,4.3,16.7Hz,1H),2.81(dd, J＝4.4,13.1Hz,1H),2.73–2.58(m,4H),2.52–2.42(m,3H),2.36(s,3H),2.25(s,3H),2.06 (dd,J＝3.5,9.3Hz,1H),1.34(qd,J＝4.6,13.1Hz,1H)；13C NMR(125MHz,CDCl3)δ177.0, 154.4,136.7,134.2,132.5,130.0,129.1,128.7,127.6,125.8,122.1,115.0,75.8,69.9,66.9,53.7, 53.7,43.6,38.6,25.2,19.9,19.3,11.4.
化合物65：收率：96.3％。1H NMR(500MHz,CDCl3)δ7.62–7.56(m,2H),7.35(td,J＝1.1,7.6Hz,1H),7.19(td,J＝1.6,7.9Hz,1H),6.81(s,1H),5.38(d,J＝4.5Hz,1H),5.10(s,2H), 3.72(q,J＝7.0Hz,1H),3.20(ddd,J＝4.4,6.5,10.8Hz,1H),3.00(d,J＝10.3Hz,1H),2.88– 2.80(m,2H),2.76(dd,J＝4.3,13.2Hz,1H),2.71–2.64(m,2H),2.45(ddd,J＝4.7,13.1,17.1 Hz,1H),2.36(s,3H),2.24(s,3H),2.16(td,J＝2.5,11.6Hz,1H),2.10–2.03(m,1H),1.96(td,J ＝2.4,11.6Hz,1H),1.68–1.60(m,2H),1.43–1.35(m,1H),1.34–1.28(m,1H),1.24–1.17(m, 1H),0.94(d,J＝6.5Hz,3H)；13C NMR(125MHz,CDCl3)δ177.4,154.4,136.7,134.2,132.5, 130.2,129.2,129.0,128.7,127.6,125.8,122.1,115.0,75.8,69.9,55.4,53.5,52.8,44.1,38.7,34.4, 34.2,30.7,25.2,21.9,19.9,19.3,11.4.
化合物66：收率：93.1％。1H NMR(500MHz,CDCl3)δ7.59–7.53(m,1H),7.33–7.28(m,1H),7.18(t,J＝7.5Hz,1H),7.12–7.06(m,1H),6.82(s,1H),5.38(d,J＝4.5Hz,1H),5.11(s, 2H),3.81–3.69(m,4H),3.21(ddd,J＝4.5,6.5,10.9Hz,1H),2.86(ddd,J＝2.2,4.3,16.7Hz, 1H),2.81(dd,J＝4.4,13.1Hz,1H),2.73–2.58(m,4H),2.52–2.42(m,3H),2.36(s,3H),2.25 (s,3H),2.06(dd,J＝3.5,9.3Hz,1H),1.34(qd,J＝4.6,13.1Hz,1H)；13C NMR(125MHz, CDCl3)δ177.1,154.4,136.7,134.2,132.5,130.0,129.1,128.7,127.6,125.8,122.1,115.0,75.8, 69.9,66.9,53.7,53.7,43.6,38.6,25.2,19.9,19.5,11.6.
化合物67：收率：91.0％。1H NMR(500MHz,CDCl3)δ7.61–7.58(m,2H),7.36(td,J＝1.1,7.6Hz,1H),7.18(td,J＝1.6,7.9Hz,1H),6.80(s,1H),5.39(d,J＝4.5Hz,1H),5.10(s,2H), 3.72(q,J＝7.0Hz,1H),3.20(ddd,J＝4.4,6.5,10.8Hz,1H),3.00(d,J＝10.3Hz,1H),2.88– 2.80(m,2H),2.74(dd,J＝4.3,13.2Hz,1H),2.71–2.64(m,2H),2.45(ddd,J＝4.7,13.1,17.1 Hz,1H),2.36(s,3H),2.24(s,3H),2.16(td,J＝2.5,11.6Hz,1H),2.10–2.03(m,1H),1.96(td,J ＝2.4,11.6Hz,1H),1.68–1.60(m,2H),1.43–1.35(m,1H),1.34–1.28(m,1H),1.24–1.17(m, 1H)；13C NMR(125MHz,CDCl3)δ177.5,154.5,136.7,134.3,132.5,130.2,129.2,129.0,128.7, 127.6,125.8,122.1,115.0,75.8,69.9,56.4,53.5,52.8,44.1,38.7,34.4,34.2,30.7,25.2,21.9, 19.3,11.4.
化合物68：收率：95.2％。1H NMR(500MHz,CDCl3)δ7.59–7.55(m,2H),7.37-7.29(m,5H),7.34(t,J＝7.6Hz,1H),7.20–7.16(m,1H),6.80(s,1H),5.39(d,J＝4.4Hz,1H),5.08(s, 2H),3.25(s,2H),3.14(q,J＝7.2Hz,1H),3.06–2.99(m,1H),2.83(d,J＝15.9Hz,2H),2.71– 2.62(m,2H),2.35(s,3H),2.23(s,3H),2.16(d,J＝7.8Hz,1H),1.93–1.86(m,1H),1.37(dd,J ＝4.7,12.9Hz,1H)；13C NMR(125MHz,CDCl3)δ177.6,154.4,136.6,134.2,132.5,129.9, 129.1,128.9,128.6,128.5(2C),127.6,127.3(2C),126.8,125.8,122.1,115.0,75.9,69.8,52.6, 47.5,38.4,36.6,25.1,19.9,19.6,11.4.
化合物69：收率：93.6％。1H NMR(500MHz,CDCl3)δ7.58–7.52(m,1H),7.35–7.29(m,1H),7.19(t,J＝7.5Hz,1H),7.11–7.08(m,1H),6.81(s,1H),5.39(d,J＝4.5Hz,1H),5.11(s, 2H),4.13(m,2H),3.17(ddd,J＝4.2,6.5,10.9Hz,1H),2.98–2.91(m,1H),2.85(ddd,J＝2.3,4.5, 16.7Hz,1H),2.79(dd,J＝4.2,12.7Hz,1H),2.78–2.73(m,1H),2.76–2.70(m,1H),2.59– 2.53(m,2H),2.51–2.42(m,1H),2.36(s,3H),2.24(s,3H),2.12–2.05(m,1H),1.83(t,J＝6.4 Hz,4H),1.34(qd,J＝4.6,13.1Hz,1H),1.21(t,3H)；13C NMR(125MHz,CDCl3)δ177.0,173.5, 154.4,136.7,134.2,132.5,130.2,129.2,129.1,128.7,127.6,125.9,122.1,115.0,75.8,71.9,69.9, 61.3,51.1,45.6,38.4,25.1,23.6,19.9,19.4,14.1,11.6.
实施例5：(3R/S,3aS,9bR)-8-(2-溴苄氧基)-3-二甲基胺基甲基-6,9-二甲基-3a,4,5,9b-四氢萘并 [1,2-b]呋喃-2(3H)-酮盐酸盐的制备(表中化合物70)
称取表中化合物59(1.0g，2.18mmol，1.0eq)溶于20ml二氯甲烷中，室温条件下向二氯甲烷液中滴加等当量盐酸，常温搅拌反应，当水溶液pH值为4-5时，停止滴加盐酸水溶液。收集水相，冻干，得到0.99g化合物70，收率92％。1H NMR(500MHz,Chloroform-d)δ7.58(t,J＝7.1Hz,2H),7.35(t,J＝7.2Hz,1H),7.18(t,J＝7.2Hz,1H),6.81(s,1H),5.40(d,J＝3.4 Hz,1H),5.09(s,2H),3.74(d,J＝16.2Hz,1H),3.46(dd,J＝8.1,21.4Hz,1H),3.24–3.10(m, 1H),2.78–2.62(m,2H),2.74(s,6H),2.37(s,3H),2.24(s,3H),2.05(d,J＝11.7Hz,1H),1.40– 1.25(m,1H)；13C NMR(125MHz,CDCl3)δ177.0,154.4,136.7,134.2,132.5,130.1,129.2, 129.1,128.7,127.6,125.8,122.1,115.0,75.9,69.8,52.8,44.3,43.6,38.3,25.1,20.0,19.3,11.5.
表1中化合物71,72的合成参照实施例5的方法实施。
化合物71：收率：95.0％。1H NMR(500MHz,Chloroform-d)δ16.32(s,1H),7.58(t,J＝7.1Hz, 2H),7.35(t,J＝7.2Hz,1H),7.31(s,1H),7.18(t,J＝7.2Hz,1H),6.81(s,1H),6.28(s,1H),5.40 (d,J＝3.4Hz,1H),5.09(s,2H),3.74(d,J＝16.2Hz,1H),3.46(dd,J＝8.1,21.4Hz,1H),3.24– 3.10(m,1H),2.78–2.62(m,2H),2.74(s,6H),2.37(s,3H),2.24(s,3H),2.05(d,J＝11.7Hz, 1H),1.40–1.25(m,1H)；13C NMR(125MHz,CDCl3)δ177.0,170.4,167.4,154.4,138.9,136.7, 134.5,134.2,132.5,130.1,129.2,129.1,128.7,127.6,125.8,122.1,115.0,75.9,69.8,52.8,44.3, 43.6,38.3,25.1,20.0,19.3,11.5.
化合物72：收率：95.0％。1H NMR(500MHz,Chloroform-d)δ9.93(s,1H),7.58(t,J＝7.1Hz, 2H),7.35(t,J＝7.2Hz,1H),7.18(t,J＝7.2Hz,1H),6.81(s,1H),5.40(d,J＝3.4Hz,1H),5.09 (s,2H),3.74(d,J＝16.2Hz,1H),3.46(dd,J＝8.1,21.4Hz,1H),3.32(s,3H),3.24–3.10(m,1H), 2.78–2.62(m,2H),2.74(s,6H),2.37(s,3H),2.24(s,3H),2.05(d,J＝11.7Hz,1H),1.40–1.25 (m,1H)；13C NMR(125MHz,CDCl3)δ177.0,154.4,136.7,134.2,132.5,130.1,129.2,129.1, 128.7,127.6,125.8,122.1,115.0,75.9,69.8,52.8,44.3,43.6,39.8,38.3,25.1,20.0,19.3,11.5.
表1中化合物73-75的合成参照实施例4的方法实施。
化合物73：收率：95.0％。1H NMR(500MHz,CDCl3)δ7.59–7.55(m,2H),7.34(t,J＝7.6Hz, 1H),7.20–7.16(m,1H),6.80(s,1H),5.39(d,J＝4.4Hz,1H),5.08(s,2H),3.93(s,3H),3.14(q, J＝7.2Hz,1H),3.06–2.99(m,1H),2.83(d,J＝15.9Hz,2H),2.78–2.66(m,2H),2.50(s,3H), 2.35(s,3H),2.16(d,J＝7.8Hz,1H),1.93–1.86(m,1H),1.37(dd,J＝4.7,12.9Hz,1H)；13C NMR(125MHz,CDCl3)δ177.6,154.4,136.6,134.2,132.5,129.9,129.1,128.9,128.6,127.6, 125.8,122.1,115.0,75.9,69.8,47.5,45.7,38.4,36.6,25.1,19.9,19.6,11.4.
化合物74：收率：95.0％。1H NMR(500MHz,CDCl3)δ7.59–7.55(m,2H),7.34(t,J＝7.6Hz, 1H),7.29(m，4H),7.20–7.16(m,1H),7.18(m,1H),6.80(s,1H),5.39(d,J＝4.4Hz,1H),5.08(s, 2H),3.14(q,J＝7.2Hz,1H),3.06–2.99(m,1H),2.83(d,J＝15.9Hz,2H),2.78–2.66(m,2H), 2.50(s,3H),2.35(s,3H),2.16(d,J＝7.8Hz,1H),1.93–1.86(m,1H),1.37(dd,J＝4.7,12.9Hz, 1H)；13C NMR(125MHz,CDCl3)δ177.6,154.4,136.6,134.2,132.5,129.9,129.6,129.1,128.9, 128.6,128.3,127.6,125.8,125.2,122.1,115.0,75.9,69.8,47.5,45.7,38.4,36.6,25.1,19.9,11.4. 化合物75：收率：95.0％。1H NMR(500MHz,CDCl3)δ7.58–7.53(m,2H),7.35-7.29(m, 5H),7.33(t,J＝7.6Hz,1H),7.22–7.18(m,1H),6.80(s,1H),5.33(d,J＝4.4Hz,1H),5.03(s, 2H),3.25(s,2H),3.14(q,J＝7.2Hz,1H),3.06–2.99(m,1H),2.83(d,J＝15.9Hz,2H),2.71– 2.62(m,2H),2.35(s,3H),2.23(s,3H),2.16(d,J＝7.8Hz,1H),1.93–1.86(m,1H),1.37(dd,J ＝4.7,12.9Hz,1H)；13C NMR(125MHz,CDCl3)δ177.6,154.4,136.6,134.2,132.5,129.9, 129.1,128.9,128.8,128.3(2C),127.6,127.3(2C),126.8,125.8,122.1,115.0,75.9,69.8,52.6, 47.5,38.4,36.8,26.1,19.9,19.6,11.8.
实施例6：四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物(表1中化合物59)对佐剂诱导的大鼠关节炎的治疗作用研究
(1)试验动物及材料：Wistar大鼠，雄性，体重160～180克。动物饲养于上海中医药大学 SPF级动物房，至少饲养一周后使用。温度22±1℃，湿度55±5％，12h光暗循环。饲料和水均在消毒后由动物自由摄取。所有实验均严格按照实验动物有关条例进行。
卡介苗：H37Ra(购自美国Difco公司)；YSL-7A型足趾容积测量仪，山东省医学科学院设备站生产。
(2)试验方法及评价：
佐剂性关节炎大鼠模型的建立与给药方法：高温高压灭菌的液体石蜡，加卡介苗(10mg/ml水溶液)反复抽吸乳化制成弗氏完全佐剂(CFA)乳液。实验中每只大鼠左后足跖皮内注射CFA乳液0.1ml致敏，诱导大鼠产生四肢的佐剂性关节炎。
分组及给药情况：雄性wistar大鼠，按体重随机分成四组，每组10只。
空白对照组：每天灌胃0.3％CMC的溶液；
关节炎模型组(溶剂对照)：每天灌胃0.3％CMC的溶液；
化合物59不同剂量给药组(2个组)：5mg/kg、20mg/kg，各组每天灌胃口服给药1次
以上4组实验动物除空白对照组外，其余各组大鼠于左后足垫皮内注射含10mg/ml结合杆菌灭活菌株的佐剂0.1ml/只致敏，于试验组大鼠产生关节炎发病的第10天开始口服给药，进行治疗性药效学观察。
疗效观察：每天观察关节炎症状发展情况，2-3天称一次体重；按0-4分五级标准评分 (临床发病指数)来评价炎症严重程度(0分：无红肿；1分：小趾关节红肿；2分：趾关节和足趾肿胀；3分：踝关节以下的足爪肿胀；4分：包括踝关节在内的全部足爪肿胀)；测双后足体积(肿胀度)。
(3)试验结果：
模型组大鼠足垫皮内注射完全佐剂后，10天左右四肢关节开始肿胀发病，发病率达 100％，致敏侧踝关节系炎性肿胀，而致敏对侧则为继发性自身免疫性肿胀，说明大鼠佐剂性关节炎模型建立成功。此时开始测量双后足肿胀度并开始评分，同时测体重。
实验期间监测动物体重，结果见附图1(化合物59每天治疗性给药对佐剂诱导大鼠关节炎体重的影响)。结果发现大鼠佐剂性关节炎模型组的体重在观察期内明显降低，化合物 59各给药组(不同剂量—5mg/kg、20mg/kg每天给药1次)对关节炎大鼠的体重没有影响。
实验期间，通过记录各组动物标准评分(临床发病指数)来反映关节炎症严重程度。结果见附图2(化合物59每天治疗性给药对佐剂性大鼠关节炎发病指数的影响)。结果可见，模型组大鼠关节炎病情呈进行性加重，而化合物59给药组(不同剂量—5mg/kg、20mg/kg每天给药1次)使关节炎大鼠的发病指数明显降低，与模型组比较，有显著差异(P<0.05)。
模型组大鼠足垫皮内注射完全佐剂后，致敏侧踝关节系炎性肿胀，而致敏对侧则为继发性自身免疫性肿胀。本试验观察了化合物59对继发性免疫性病变的影响，结果如附图3 (化合物59每天治疗性给药对大鼠佐剂性关节炎继发足病变的抑制作用)。结果发现大鼠佐剂性关节炎模型组的继发足在观察期内显著肿胀，而化合物59各给药组(不同剂量—5mg/kg、20mg/kg每天给药1次)使关节炎大鼠的继发病变得到抑制，足肿胀程度明显减轻，与模型组比较，有显著差异(P<0.05)。
模型组大鼠足垫皮内注射完全佐剂后，致敏侧踝关节系炎性肿胀。本试验观察了TMX 对致敏原发足炎性病变的影响，结果如附图4(化合物59每天治疗性给药对大鼠佐剂性关节炎原发足病变的抑制作用)。结果发现大鼠佐剂性关节炎模型组的原发足在观察期内显著肿胀，而化合物59各给药组(不同剂量—20mg/kg、5mg/kg，每天给药1次)使关节炎大鼠的原发病变得到抑制，足肿胀程度明显减轻，与模型组比较，有显著差异(P<0.05)。
(4)结论：
本试验建立了佐剂诱导的Wistar雄性大鼠关节炎疾病动物模型，观察化合物59对大鼠佐剂关节炎的预防作用。结果证实，在关节炎病变达到发病高峰时，化合物59每天口服给药1次的5个剂量组(5mg/kg、20mg/kg)对关节炎大鼠的体重减轻没有明显影响，使关节炎大鼠的发病指数明显降低，使大鼠关节炎的原发和继发病变减轻，具有明显的治疗作用。
本试验结果证实，以化合物59为代表的四氢萘并[1,2-b]呋喃-2(3H)-酮类衍生物口服每天给药对佐剂诱导的大鼠关节炎具有不同程度的治疗作用。综上所述，本发明提供的一类四氢萘并[1,2-b]呋喃-2(3H)-酮类衍生物克用于制备治疗类风湿性关节炎药物，具有较好的应用前景。

Claims (10)

1.如通式Ⅰ所示的四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物，其特征在于，
Figure FDA0003264574530000011
所述衍生物为化合物59、化合物70或化合物71；
Figure FDA0003264574530000012
2.一种如权利要求1所述的四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物的制备方法，其特征在于，该方法包括下列步骤：
(1)重排反应：(3aS,5aS,9bS)-5a,9-二甲基-3-亚甲基-3a,5,5a,9b-四氢萘并[1,2-b]呋喃-2,8(3H,4H)-二酮，化合物②在酸性条件下发生重排反应生成中间体(3aS,9bR)-6,9-二甲基-3-亚甲基-2-氧代-2,3,3a,4,5,9b-六氢萘并[1,2-b]呋喃-8-基乙酸酯，化合物③；
(2)水解反应：中间体化合物③在碱性条件下发生酚酯键的水解生成中间体(3aS,9bR)-8-羟基-6,9-二甲基-3-亚甲基-3a,4,5,9b-四氢萘并[1,2-b]呋喃-2(3H)-酮，化合物④；
(3)亲核取代反应：中间体化合物④中的游离酚羟基作为亲核试剂与卤代烷烃，所述卤代烷烃为邻溴氯苄，发生亲核取代反应生成(3aS,9bR)-8-(2-溴苄氧基)-6,9-二甲基-3-亚甲基-3a,4,5,9b-四氢萘并[1,2-b]呋喃-2(3H)-酮Ⅰ；
(4)迈克尔加成反应：中间体Ⅰ中α亚甲基内酯环与二甲胺盐酸盐发生迈克尔加成反应生成(3R/S,3aS,9bR)-8-(2-溴苄氧基)-3-二甲基胺基甲基-6,9-二甲基-3a,4,5,9b-四氢萘并[1,2-b]呋喃-2(3H)-酮Ⅱ；
(5)成盐反应：中间体Ⅱ与盐酸或富马酸发生成盐反应生成所述化合物70或化合物71。
3.根据权利要求2所述四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物的制备方法，其特征在于，步骤(1)重排反应，溶剂选自甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、二氧六环、二氯甲烷或二氯乙烷；催化剂选自乙酸酐或乙酸/硫酸；反应温度选自-20℃-25℃；催化剂与化合物②的摩尔比为1:20-1:1。
4.根据权利要求2所述四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物的制备方法，其特征在于，步骤(2)水解反应，溶剂选自甲醇、乙醇、异丙醇、甲苯、四氢呋喃、2-甲基四氢呋喃、二氧六环、二氯甲烷、二氯乙烷、丙酮或丁酮；催化剂选自氨水、三乙胺、二乙胺、乙醇胺、甲酸或三氟乙酸；反应温度选自-20℃-25℃；催化剂与化合物③的摩尔比为30:1-1:1。
5.根据权利要求2所述四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物的制备方法，其特征在于，所述步骤(3)亲核取代反应，溶剂选自质子或非质子溶剂，选自甲醇、乙醇、异丙醇、二甲基亚砜、N,N-二甲基甲酰胺、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、二氯甲烷、二氯乙烷、氯仿、丙酮或丁酮；碱选自有机碱或者无机碱，所述有机碱选自二乙胺、三乙胺、吡啶、哌啶、4-二甲氨基吡啶、N,N-二异丙基乙胺、1,8-二氮杂二环十一碳-7-烯或1,4-二氮杂二环[2.2.2]辛烷；无机碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸铯、碳酸氢钾、碳酸氢钠、醋酸钠、醋酸钾、磷酸钠或磷酸钾；催化剂选自四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丁基硫酸氢铵、苄基三乙基氯化铵或十二烷基三乙基氯化铵；反应温度-30℃-60℃；碱与化合物④的摩尔比为6:1-1:1；催化剂与化合物④的摩尔比为1:20-1:1。
6.根据权利要求2所述四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物的制备方法，其特征在于，所述步骤(4)迈克尔加成反应，溶剂为质子或非质子溶剂，选自甲醇、乙醇、丙醇、异丙醇、二甲基亚砜、N,N-二甲基甲酰胺、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、二氯甲烷、二氯乙烷、氯仿、丙酮或丁酮；碱为有机碱或者无机碱，所述有机碱选自二乙胺、三乙胺、吡啶、哌啶、4-二甲氨基吡啶、N，N-二异丙基乙胺、1,8-二氮杂二环十一碳-7-烯或1,4-二氮杂二环[2.2.2]辛烷；无机碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸铯、碳酸氢钾、碳酸氢钠、醋酸钠、醋酸钾、磷酸钠或磷酸钾；所述反应温度-30℃-60℃；碱与中间体Ⅰ的摩尔比8:1-1:1。
7.根据权利要求2所述四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物的制备方法，其特征在于，所述步骤(5)成盐反应，溶剂为质子或非质子溶剂，选自甲醇、乙醇、异丙醇、二甲基亚砜、N,N-二甲基甲酰胺、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、二氯甲烷、二氯乙烷、氯仿、丙酮或丁酮；反应温度选自0℃-60℃；药学中可接受的酸选自无机酸、有机酸或磺酸；所述无机酸选自盐酸、氢溴酸、硫酸、硝酸或磷酸；所述的有机酸选自脂肪族或芳香族有机酸，所述脂肪族有机酸选自乙酸、丙酸、己酸、草酸、三氟乙酸、乙醇酸、丙酮酸、丙二酸、琥珀酸、马来酸、富马酸、羟基马来酸、苹果酸、酒石酸、柠檬酸、扁桃酸、肉桂酸或氨基酸，所述氨基酸选自甘氨酸、谷氨酸、精氨酸或赖氨酸；所述芳香族有机酸选自苯甲酸、水杨酸，4-氨基水杨酸，盐酸或异烟酸；所述的磺酸选自甲烷磺酸、乙烷磺酸、2-羟基乙烷磺酸、1,2-乙二磺酸、苯磺酸、对甲基苯磺酸、萘-2-磺酸或樟脑磺酸；酸与中间体Ⅱ的摩尔比为3:1-1:8。
8.如权利要求1所述四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物在制药中的应用，其特征在于，四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物在制备预防/治疗类风湿性关节炎药物中的应用。
9.根据权利要求8所述四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物在制药中的应用，其特征在于，所述药物为由四氢萘并[1,2-b]呋喃-2(3H)-酮衍生物作为活性成分与药用辅料组成的药物组合物；所述的药物组合物选自片剂、胶囊剂、滴丸、颗粒剂、注射剂或气雾剂。
10.根据权利要求9所述的应用，其特征在于，所述片剂选自分散片、含片、口崩片、和缓释片，所述胶囊剂为软胶囊剂，所述注射剂为粉针剂。
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