CN101235046A - 新的长春碱衍生物、其制备方法和用途、以及包含该衍生物的药物组合物 - Google Patents
新的长春碱衍生物、其制备方法和用途、以及包含该衍生物的药物组合物 Download PDFInfo
- Publication number
- CN101235046A CN101235046A CNA2007100369232A CN200710036923A CN101235046A CN 101235046 A CN101235046 A CN 101235046A CN A2007100369232 A CNA2007100369232 A CN A2007100369232A CN 200710036923 A CN200710036923 A CN 200710036923A CN 101235046 A CN101235046 A CN 101235046A
- Authority
- CN
- China
- Prior art keywords
- preparation
- nmr
- cdcl
- compd
- och
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明提供了一类具有右式1所示结构的长春碱衍生物或其生理上可接受的盐、其制备方法和用途,以及包括该衍生物的药物组合物。所述长春碱衍生物对肿瘤细胞株具有抑制活性,可用作治疗恶性肿瘤的药物。
Description
技术领域
本发明涉及药物化学领域,具体地,本发明涉及一类新的长春碱衍生物、其制备方法和用途,以及包括该衍生物的药物组合物。所述长春碱衍生物对肿瘤细胞株具有抑制活性,可用作治疗恶性肿瘤的药物。
背景技术
肿瘤是威胁人类生命的恶性疾病之一,全世界因患肿瘤死亡人数每年在500万以上,在中国每年新发现肿瘤患者有160多万,死亡130多万,因而世界各国都特别关注抗肿瘤药物的研究。
长春碱类(Vinca alkaloids)抗肿瘤药是从夹竹桃科长春花属植物长春花(Catharanthus roseus(L.)G.Don)和黄长春花(Catharanthusroseus(L.)G.Don cv.Flavus)中分离得到的一类具有抗癌活性的双吲哚生物碱。在植物体内,含量丰富的单吲哚生物碱长春质碱(catharanthine)和文朵灵(vindoline)通过生物偶合,并修饰可生成系列长春碱类生物碱。
目前应用于临床的长春花生物碱及其衍生物有四种:长春碱(Vinblastine,VLB)、长春新碱(Vincristine,VCR)、长春地辛(Vindesine,VDS)和长春瑞宾(Vinorelbine,NVB)。
长春碱类抗肿瘤药物属细胞周期特异性药物,主要作用于肿瘤细胞G2期(DNA合成后期),其作用机理据报道是与微管蛋白结合,阻止微管蛋白双微体聚合成为微管;又可诱导微管的解聚,使纺锤体不能形成,使肿瘤细胞的分裂增殖停止于有丝分裂中期,从而产生抗肿瘤作用(R.J.Owellen and C.A.Hartke,Cancer Res.,1976,36,1499-1504;R.N.Kersey,Cancer Res.,1976,36,3798-3806;R.S.Camplrjohn,CellTissue Kinet.,1980,13,327-332)。长春碱类抗肿瘤药物与微管的结合活性与其抑制细胞生长活性的线性相关性不好。一般认为,长春碱抗肿瘤药物之间的活性和副作用差异主要由药物在体内器官、组织的吸收程度以及半衰期长短的不同所造成的。
长春碱类似物结构上的微小变化,会引起在抗肿瘤谱和毒副作用谱上产生非常大的变化。例如长春碱和长春新碱的唯一差别是N-甲基被N-醛基取代,长春新碱在体内对棒瘤有很好的抑制活性,而长春碱却无效;它们的毒性谱也完全不同,长春新碱主要有外周神经毒性,而长春碱的主要毒性是贫血和减少白血球(N.Bruchovsky et al.,Cancer Res.1965,25,1232-1238)。长春瑞宾对P388和L1210细胞株的抑制活性弱于长春碱和长春新碱,但对肺癌的活性要强于其它长春碱类似物,现已是临床上用于治疗非小细胞肺癌的一线药物(S.Cros,el al.,Seminars in Oncology,1989,16,15-20)。
鉴于长春碱药物抗肿瘤作用的新机制的发现和长春碱类似物的体外与体内抗肿瘤活性缺乏直接的相关性,且结构上的微小变化,在抗肿瘤谱和毒性谱上产生非常大的差异,结合已有的构效关系研究结果,设计、合成系列新衍生物,然后在体内、外进行广泛的生物学评价,来发现活性更强,毒副作用更低的长春碱新衍生物。我们用修饰后的文朵灵与长春质碱偶合,合成一系列长春碱类似物,经体内外试验,发现了活性很强的抗肿瘤长春碱新衍生物。
发明内容
本发明的发明人是为了解决上述问题提出并完成本发明的。
本发明的目的为提供一类具有抗肿瘤作用的新的长春碱衍生物。
本发明的再一目的为提供制备上述长春碱衍生物的方法。
本发明的再一目的为提供包含上述长春碱衍生物的药物组合物。
本发明的再一目的为提供上述长春碱衍生物、和包含该衍生物的药物组合物的用途。
根据本发明的技术方案,本发明提供了一类长春碱衍生物或其生理上可接受的盐,其具有以下式1所示的结构,
其中,
R2为-OR7;
R4为氢或氟原子。
所述R5、R6、R7、和R8独立地为氢、C1-C5的烷酰基、C3-C8的环烷酰基、C2-C4不饱和烃酰基、C6-C12芳酰基、C1-C5的烷基、C3-C8的环烷基、C2-C4不饱和烃基或C6-C12芳基。
本发明中所述的生理上可接受的盐指本发明衍生物与各种酸所形成的生理上可接受的盐,其中酸包括有机或无机酸,例如盐酸、硫酸、磷酸、乙酸、酒石酸、苯甲酸、马来酸、琥珀酸、柠檬酸等。
优选地,根据本发明的长春碱衍生物具有以下式2~81中之一所示的结构,
本发明还提供了一种制备上述长春碱衍生物的方法,所述方法包括以下步骤:
4)中间产物化合物C~F再与长春质碱偶合,进一步还原、烷基化或酰基化、氟化制得本发明的长春碱衍生物,
其中,所述取代基R5、R6、和R7的限定与上述相同。
优选地,在根据本发明的方法中,烷基化反应所采用的溶剂为二氯甲烷、氯仿或四氢呋喃;烷基化反应中相转移催化剂为四正丁基碘化铵或四正丁基溴化铵;并且,根据具体化合物的反应情况,烷基化反应温度为0℃~室温或加热温度从50℃至100℃。
优选地,在根据本发明的方法中,酰化反应采用三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶(DMAP)作为催化剂;并且酰化剂为酸酐、酰氯、酸酐与噻唑烷-2-硫酮生成的配体或者酰氯与噻唑烷-2-硫酮生成的配体。
优选地,在根据本发明的方法中,中间产物化合物D的合成采用氢化钠、三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶(DMAP)作为催化剂;并且异氰酸酯或由胺和羰基二咪唑(CDI)合成的配体为原料。
优选地,在根据本发明的方法中,中间产物化合物F的合成采用三乙胺、二异丙基乙基胺(DIPEA)、吡啶或4-(N,N-二甲基)氨基吡啶(DMAP)作为催化剂;并且以氯甲酸酯或由醇和固体光气合成的氯甲酸酯为原料。
具体地,根据本发明的方法,以文朵灵为原料,经过还原得到中间产物化合物A,化合物A经过环氧化、叠氮取代、还原后得到中间产物化合物B。化合物A、B经过烷基化或酰基化等一系列反应,对其结构进行修饰得到中间产物化合物C~F,中间产物化合物C~F再与长春质碱偶合,进一步还原、烷基化或酰基化、氟化得到本发明所述的长春碱衍生物。通常用TLC来测定反应完成程度,反应完毕后一般用乙酸乙酯、二氯甲烷(DCM)、氯仿等溶剂来提取,依次用饱和碳酸氢钠、水、饱和食盐水洗,经无水硫酸镁或无水硫酸钠干燥后,低温减压除去溶剂。中间产物及最终产物用核磁共振或质谱来检测证明。
中间产物化合物A-B的合成路线如下所示:
文朵灵经四氢铝锂在四氢呋喃中还原得A;A用对甲基苯磺酰氯在碱性条件下处理得到环氧,经叠氮化钠开环、四氢铝锂在四氢呋喃中还原得B。
以化合物A或化合物B为原料合成中间产物化合物C~F的线路如下:
1、化合物C的合成路线
将化合物A溶于二氯甲烷、氯仿或四氢呋喃中,加入50%氢氧化钠的水溶液,在相转移催化剂四正丁基碘化铵或四正丁基溴化铵存在下,用卤代烃,环氧等一些烷化剂处理得到双烷基取代的产物C,反应温度为0℃~室温或加热温度从50℃至100℃;或单烷基取代产物在碱(三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶)存在下用酸酐、酰氯处理得到C;或化合物A直接在碱存在下用酸酐、酰氯处理得到双酰化产物C。
2、化合物D的合成路线
方法一:在氩气保护下,将胺溶于二氯甲烷或四氢呋喃溶液中,加入适量的碱(三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶),在冰浴条件下慢慢滴入固体光气的二氯甲烷或四氢呋喃溶液,冰浴下反应半个小时,室温下反应数小时得到异氰酸酯。在冰浴下加入适量的碱(三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶),慢慢滴入化合物B的二氯甲烷或四氢呋喃溶液,冰浴下反应半个小时,室温下反应3小时。反应完毕后加入饱和碳酸氢钠,用二氯甲烷萃取,无水硫酸钠干燥有机相,减压浓缩,在碱(三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶)存在下用酸酐、酰氯处理得到氨基甲酸酯类衍生物D。
方法二:在氩气保护下,将胺溶于二氯甲烷或四氢呋喃溶液中,加入适量的碱(三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶),加入羰基二咪唑,室温反应24小时后蒸干得到中间体,然后加入到在氢化钠和化合物A的四氢呋喃溶液中,室温反应8小时。反应完毕后加入饱和碳酸氢钠,用乙酸乙酯萃取,无水硫酸钠干燥有机相,减压浓缩,在碱(三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶)存在下用酸酐、酰氯处理得到氨基甲酸酯类衍生物D。
3、化合物E的合成路线
将化合物B溶于二氯甲烷、氯仿中,在碱(三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶)存在下用酸酐、酰氯处理得到双酰化产物E;或者直接在碱存在下用卤代烃、环氧等一些烷化剂直接烷化成单或双烷化产物E;或将化合物B溶于四氢呋喃中,在氩气保护下加入氢化钠和配体III(N-酰基噻唑烷-2-硫酮),反应得到单酰化产物后再用酸酐、酰氯处理得到双异酰化产物E。
4、配体III(N-酰基噻唑烷-2-硫酮)的合成路线
杂环噻唑烷-2-硫酮II溶于二氯甲烷、氯仿中,在碱(三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶)存在下用酸酐、酰氯处理得配体III(N-酰基噻唑烷-2-硫酮)。
5、化合物F的合成路线
在氩气保护下,将醇溶于二氯甲烷或四氢呋喃溶液中,加入适量的碱(三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶),在冰浴条件下滴入固体光气的二氯甲烷或四氢呋喃溶液,冰浴下反应半个小时,室温下反应数小时得到氯甲酸酯。在冰浴下加入适量的碱(三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶),慢慢滴入化合物B的二氯甲烷或四氢呋喃溶液,冰浴下反应半个小时,室温下反应3小时。反应完毕后加入饱和碳酸氢钠,用二氯甲烷萃取,无水硫酸钠干燥有机相,减压浓缩,在碱(三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶)存在下用酸酐、酰氯处理得到氨基甲酸酯类衍生物F。
然后,化合物C~F和长春质碱偶合,得到本发明化合物(化合物BM和BM′)。偶合反应在PH=2左右的缓冲溶液(由甘氨酸、氯化钠、0.1N盐酸和水配制)中进行,采用三氯化铁为催化剂,其操作方法参考文献(J.Vukovic等,Tetrahedron,1988,44,325-331)。偶合反应得到的化合物BM的产率一般在50%-80%左右。氟化在无水氢氟酸溶剂中,以五氟化锑为催化剂,-40度反应1小时得到BM’,得率为40%左右。(J.Fahy等,J.Am.Chem.Soc.1997,119,8567)
本发明还提供了一种包含有效治疗剂量的上述长春碱衍生物或其生理上可接受的盐。
本发明还提供了上述长春碱衍生物或其生理上可接受的盐在制备用于治疗肿瘤的药物中的应用。
本发明还提供了包含上述长春碱衍生物或其生理上可接受的盐作为活性成分的用于治疗肿瘤的药物组合物。
本发明设计与合成了一类新型的长春碱衍生物,其对A-549人肺腺癌、Hela宫颈癌等肿瘤细胞株具有良好的抑制活性,可用于制备治疗恶性肿瘤的药物。本发明化合物合成简单,易于制备,且合成原料丰富。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但不限制本发明。
下述制备例中,1H-NMR用Varian Mercury AMX300型仪测定。MS用VG ZAB-HS或VG-7070型以及Esquire 3000 plus-01005测定。所有溶剂在使用前均经过重新蒸馏,所使用的无水溶剂均是按标准方法干燥处理获得。除说明外,所有反应均是在氩气保护下进行并用TLC跟踪,后处理时均经饱和食盐水洗和无水硫酸镁干燥过程。产品的纯化除说明外均使用硅胶(200-300目)的柱色谱法,所使用的硅胶包括200-300目,GF254为青岛海洋化工厂或烟台缘博硅胶公司生产。
制备实施例1化合物A的制备
在氩气保护下,取456mg(1mmol)文朵灵溶于20mL无水四氢呋喃中,在0℃冰浴下缓慢加入230mg(6mmol)四氢铝锂,室温下搅拌4h后,加入0.23mL水淬灭反应;然后依次加入0.23mL 15%氢氧化钠和0.69mL水,搅拌5分钟后用砂星漏斗抽滤,无水硫酸镁干燥,减压浓缩,用丙酮重结晶得白色固体化合物A,产率85%-90%。
1H NMR(CDCl3,300MHz):δ:8.73(brs,1H),6.82(d,J=8.1Hz,1H),6.24(d,J=8.1Hz,1H),6.06(s,1H),5.80(dd,J=10.2,4.8Hz,1H),5.60(d,J=10.2Hz,1H),3.93(d,J=14.1Hz,1H),3.71(s,3H),3.54(s,1H),2.95(s,3H),2.51(s,1H),2.43(m,1H),2.16(m,1H),1.77(m,1H),1.30(m,1H),0.86(m,1H),0.56(t,J=8.4Hz,3H);
13C NMR(CDCl3,75MHz):δ:160.8(C),154.5(C),130.8(CH),126.4(C),124.1(CH),122.7(CH),104.4(CH),96.2(CH),80.7(CH),77.4(C),75.1(CH),68.3(CH),65.2(CH2),55.2(OCH3),51.6(CH2),51.6(C),51.2(CH2),44.7(CH2),43.6(C),40.2(CH3),32.3(CH2),7.7(CH3);
ESIMS(m/e)387.3[M+1]+。
制备实施例2化合物B的制备
在一个100mL的两颈圆底烧瓶中,将3.86g(10.00mmol)化合物A溶于25mL THF中,加入50%NaOH(1g NaOH∶1g H2O)在50℃下搅拌半小时,然后加入2.10g(1.1eq,11.00mmol)甲苯-4-磺酰氯,将温度提高到80℃,并搅拌反应1h。反应完毕后用乙酸乙酯萃取、无水硫酸钠干燥、减压浓缩得到环氧油状中间体,不必纯化,接着进行下步反应。在250mL圆底烧瓶中,将油状中间体溶于80mL甲醇和10mL水中,依次加入3.25g(5eq)叠氮化钠、1.4g(3eq)氯化铵,90℃下回流24h。反应完毕后用乙酸乙酯萃取、无水硫酸钠干燥,减压浓缩,经硅胶柱层析(石油醚∶丙酮=8∶1v/v洗脱)得到2.87g白色粉末化合物B’,然后在氩气保护下用四氢铝锂还原得到白色粉末化合物B。产率70%左右。
1H NMR(CDCl3,300MHz):δ:8.75(brs,1H),6.87(d,J=8.1Hz,1H),6.30(d,J=8.1Hz,1H),6.10(s,1H),5.88(dd,J=9.3,4.8Hz,1H),5.61(d,J=9.3Hz,1H),3.87(d,J=13.2Hz,1H),3.78(s,3H),3.61(s,1H),2.93(s,3H),2.54(s,1H),2.43(m,1H),2.16(m,1H),1.77(m,1H),1.30(m,1H),0.86(m,1H),0.58(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:160.8(C),154.5(C),132.1(CH),126.4(C),122.9(CH),122.9(CH),104.3(CH),96.2(CH),84.6(CH),78.4(CH),75.9(C),68.3(CH),55.5(OCH3),52.6(C),51.6(CH2),51.4(CH2),49.8(CH2),45.3(CH2),43.8(C),41.5(CH3),32.6(CH2),7.9(CH3)。
制备实施例3化合物C1的制备
在氩气保护下,取386mg(1mmol)化合物A溶于0mL四氢呋喃中,加入50%氢氧化钠水溶液(1g氢氧化钠溶于1g水中),在60℃下搅拌反应0.5h,然后加入0.15mL溴乙烷和50mg四正丁基碘化铵,继续反应6h后冷却至室温,将反应液转移到分液漏斗中,加入50mL水,然后用二氯甲烷萃取(10mL×3),经无水硫酸镁干燥,减压浓缩得到浓缩液。在氩气保护下,将浓缩液溶于1mL吡啶中,加入1mL醋酐,室温下搅拌反应8h,然后注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析(石油醚∶丙酮=6∶1v/v洗脱)得到263mg化合物C1(白色粉末),产率58%。
1H NMR(CDCl3,300MHz):δ:8.80(brs,1H),6.84(d,J=8.1Hz,1H),6.24(dd,J=8.1,2.1Hz,1H),6.08(d,J=2.1Hz,1H),5.84(dd,J=10.2,4.8Hz,1H),5.37(d,J=10.2Hz,1H),4.97(s,1H),3.76(s,3H),3.71(s,1H),2.93(s,3H),2.76(d,J=15.9Hz,1H),2.58(s,1H),2.40(m,1H),2.11(s,3H),1.22(m,1H),1.20(t,J=7.2Hz,3H),0.96(m,1H),0.50(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:171.0(C),161.1(C),154.8(C),130.4(CH),126.2(C),124.2(CH),122.7(CH),104.3(CH),96.0(CH),80.9(CH),77.6(C),77.6(CH),72.7(CH2),68.0(CH),66.8(CH2),55.4(OCH3),52.0(C),52.0(CH2),50.9(CH2),44.8(CH2),42.6(C),39.1(CH3),31.7(CH2),21.1(CH3),15.1(CH3),7.6(CH3)。
制备实施例4化合物C2的制备
在氩气保护下,取386mg(1mmol)化合物A溶于10mL四氢呋喃中,加入50%氢氧化钠水溶液(1g氢氧化钠溶于1g水中),在60℃下搅拌反应0.5h,然后加入0.17mL烯丙基溴和50mg四正丁基碘化铵,继续反应4h后冷却至室温,将其转移到分液漏斗中,加入50mL水,然后用二氯甲烷萃取(10mL×3),经无水硫酸镁干燥,减压浓缩得到浓缩液。在氩气保护下,将浓缩液溶于1mL吡啶中,加入1mL醋酐,室温下搅拌反应8h,然后注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液,继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析(石油醚∶丙酮=6∶1v/v洗脱)得286mg化合物C2(白色粉末),产率61%。
1H NMR(CDCl3,300MHz):δ:8.80(brs,1H),6.79(d,J=8.1Hz,1H),6.19(dd,J=8.1,2.1Hz,1H),6.03(d,J=2.1Hz,1H),5.85(m,1H),5.79(dd,J=10.2,4.5Hz,1H),5.31(d,J=10.2Hz,1H),5.17(d,J=17.1Hz,1H),5.07(d,J=10.2Hz,1H),4.92(s,1H),3.96(m,2H),3.70(s,3H),3.64(s,1H),2.89(s,3H),2.72(d,J=15.0Hz,1H),2.52(s,1H),2.40(m,1H),2.04(s,3H),1.15(m,1H),0.91(m,1H),0.45(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:171.0(C),161.1(C),154.8(C),135.0(CH),130.4(CH),126.2(C),124.3(CH),122.8(CH),117.3(CH2),104.5(CH),96.1(CH),81.0(CH),78.0(C),77.6(CH),72.8(CH2),72.5(CH2),68.1(CH),55.4(OCH3),52.0(C),52.0(CH2),51.0(CH2),44.8(CH2),42.7(C),39.4(CH3),31.7(CH2),21.1(CH3),7.7(CH3)。
制备实施例5化合物C3的制备
制备步骤参见化合物C1的制备(制备实施例3)。
1H NMR(CDCl3,300MHz):δ:8.80(brs,1H),6.86(d,J=8.1Hz,1H),6.26(dd,J=8.1,2.1Hz,1H),6.10(d,J=2.1Hz,1H),5.87(dd,J=10.5,4.8Hz,1H),5.38(d,J=10.5Hz,1H),5.00(s,1H),3.79(s,3H),3.72(s,1H),3.52-3.26(m,6H),2.95(s,3H),2.77(d,J=15.9Hz,1H),2.58(s,1H),2.50-2.40(m,1H),2.31-2.19(m,2H),2.12(s,3H),1.73-1.55(m,2H),1.32-1.20(m,1H),1.05-0.95(m,1H),0.89(t,J=7.2Hz,3H),0.51(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),160.7(C),154.3(C),130.0(CH),125.9(C),123.7(CH),122.3(CH),103.9(CH),95.6(CH),80.5(CH),77.1(CH),76.9(C),73.1(CH2),72.7(CH2),67.7(CH),54.9(OCH3),51.6(CH2),51.5(C),50.5(CH2),44.4(CH2),42.2(C),38.7(CH3),31.3(CH2),22.4(CH2),20.7(CH3),10.5(CH3),7.2(CH3)。
制备实施例6化合物C4的制备
在氩气保护下,取386mg(1mmol)化合物A溶于10mL四氢呋喃中,加入50%氢氧化钠水溶液(1g氢氧化钠溶于1g水中),在60℃下搅拌反应0.5h,然后加入0.21mL溴正丁烷和50mg四正丁基碘化铵,继续反应6h后冷却至室温,将反应液转移到分液漏斗中,加入50mL水,然后用二氯甲烷萃取(10mL×3),经无水硫酸镁干燥,减压浓缩得到浓缩液。在氩气保护下,将浓缩液溶于1mL吡啶中,加入1mL醋酐,室温下搅拌反应8h,然后注入30mL氯仿和10mL饱和碳酸氢钠溶液继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析(石油醚∶丙酮=6∶1v/v洗脱)得到262mg化合物C4(白色粉末),产率56%。
1H NMR(CDCl3,300M[Hz):δ:8.80(brs,1H),6.83(d,J=8.1Hz,1H),6.22(dd,J=8.1,2.4Hz,1H),6.06(d,J=2.4Hz,1H),5.81(dd,J=10.2,4.8Hz,1H),5.37(d,J=10.2Hz,1H),4.96(s,1H),3.74(s,3H),3.68(s,1H),2.90(s,3H),2.74(d,J=16.2Hz,1H),2.54(s,1H),2.40(m,1H),2.09(s,3H),1.54(m,1H),0.92(m,1H),0.85(t,J=7.2Hz,3H),0.48(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.9(C),161.0(C),154.6(C),130.3(CH),126.2(C),124.1(CH),122.6(CH),104.2(CH),95.9(CH),80.8(CH),77.5(C),77.3(CH),73.0(CH2),71.6(CH2),68.1(CH),53.3(OCH3),52.0(CH2),52.9(C),50.8(CH2),44.7(CH2),42.5(C),39.0(CH3),31.6(CH2),21.0(CH3),19.5(CH2),14.0(CH2),15.1(CH3),7.6(CH3)。
制备实施例7化合物C5的制备
在氩气保护下,取386mg(1mmol)化合物A溶于10mL四氢呋喃中,加入50%氢氧化钠水溶液(1g氢氧化钠溶于1g水中),在60℃下搅拌反应0.5h,然后加入0.25mL对甲氧基苄氯和50mg四正丁基碘化铵,继续反应6h后冷却至室温,将反应液转移到分液漏斗中,加入50mL水,然后用二氯甲烷萃取(10mL×3),经无水硫酸镁干燥,减压浓缩得到浓缩液。在氩气保护下,将浓缩液溶于1mL吡啶中,加入1mL醋酐,室温下搅拌反应8h,然后注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液继续搅拌10分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析(石油醚∶丙酮=6∶1v/v洗脱)得到356mg化合物C5(白色粉末),产率65%。
1H NMR(CDCl3,300MHz):δ:7.08(d,J=8.1Hz,2H),6.85(d,J=8.1Hz,1H),6.70(d,J=8.1Hz,2H),6.25(d,J=8.1Hz,1H),6.09(s,1H),5.51(dd,J=10.2,4.2Hz,1H),5.36(d,J=10.2Hz,1H),4.98(s,1H),4.58(q,J=11.7Hz,2H),3.74(s,6H),3.54(s,1H),3.51-3.32(m,4H),2.93(s,3H),2.77(d,J=16.2Hz,1H),2.58(s,1H),2.44(m,1H),2.26(m,2H),2.04(s,3H),1.25(m,1H),0.93(m,1H),0.50(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.9(C),161.1(C),160.0(C),154.6(C),130.7(CH),130.1(C),128.5(2CH),125.9(C),124.5(CH),123.1(CH),114.2(2CH),105.8(CH),97.2(CH),81.0(CH),78.0(C),77.6(CH),72.8(CH2),72.5(CH2),67.5(CH),55.7(2OCH3),52.0(C),51.8(CH2),45.2(CH2),44.3(CH2),43.2(C),40.3(CH3),31.6(CH2),21.3(CH3),7.8(CH3)。
制备实施例8化合物C6的制备
在氩气保护下,取386mg(1mmol)化合物A溶于1mL吡啶,加入1mL醋酐,室温下搅拌反应8h后,注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析(石油醚∶丙酮=6∶1v/v洗脱)得361mg化合物C6(白色粉末),产率77%。
1H NMR(CDCl3,300MHz):δ:9.02(brs,1H),6.86(d,J=8.1Hz,1H),6.28(d,J=8.1Hz,1H),6.11(s,1H),5.87(dd,J=9.9,3.3Hz,1H),5.35(d,J=9.9Hz,1H),5.00(s,1H),4.08(d,J=10.8Hz,2H),3.76(s,3H),3.62(s,1H),3.40(m,2H),2.84(s,3H),2.81(m,1H),2.61(s,1H),2.47(m,1H),2.25(m,1H),2.16(m,1H),2.11(s,6H),1.27(m,1H),0.96(m,1H),0.49(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.9(C),170.8(C),161.1(C),154.4(C),130.2(CH),125.9(C),124.3(CH),122.8(CH),104.9(CH),96.4(CH),81.6(CH),76.8(CH),76.2(C),67.8(CH),66.9(CH2),55.4(OCH3),52.2(C),51.8(CH2),50.9(CH2),44.7(CH2),42.7(C),40.1(CH3),31.5(CH2),21.2(CH3),21.1(CH3),7.6(CH3)。
制备实施例9配体III(N-酰基噻唑烷-2-硫酮)的制备
噻唑烷-2-硫酮(0.1mol)溶于干燥二氯甲烷(50mL)中,加入三乙胺(0.13mmol),在冰浴下慢慢滴入含酰氯或酸酐(0.11mol)的二氯甲烷溶液(20ml)(酰氯由相应的酸在二氯亚砜中回流制得或者在干燥二氯甲烷溶液(经过氢化钙回流处理)里和草酰氯室温反应制得)。然后在室温下反应数小时,反应进程由TLC检测,原料反应完时中止反应。反应完毕后用水洗,有机层用无水硫酸镁干燥,减压浓缩,用乙醚-正己烷重结晶得配体III(N-酰基噻唑烷-2-硫酮)。
1:3-苯甲酰基-噻唑烷-2-硫酮
1H NMR(CDCl3,300MHz):δ:7.71(d,J=6.9,2H),7.51-7.38(m,3H),4.51(t,J=7.25Hz,2H),3.44(t,J=7.25Hz,2H);
2:3-特戊酰基-噻唑烷-2-硫酮
1H NMR(CDCl3,300MHz):δ:1.41(s,9H),3.48(t,J=7.2Hz,2H),4.19(t,J=7.2Hz,2H);13C NMR(CDCl3,75MHz):δ:200.6(C),187.8(C),57.3(CH2),44.5(CH2),31.6(C),27.7(CH3).
3:3-(4-氟-苯甲酰基)-噻唑烷-2-硫酮
1H NMR(CDCl3,300MHz):δ:7.74(d,J=6.9,2H),7.08(d,J=6.9,2H),4.51(t,J=7.2Hz,2H),3.44(t,J=7.25Hz,2H);
4:3-异丁基酰基-噻唑烷-2-硫酮
1H NMR(CDCl3,300MHz):δ:4.54(t,J=7.2Hz,2H),4.46(m,1H),3.27(t,J=7.2Hz,2H),1.20(d,J=6.6Hz,6H)。
制备实施例10化合物C7的制备
将底物A(1.0mmol)和3-丙酰基-噻唑烷-2-硫酮(1.1mmol)溶于10mL无水四氢呋喃中,在氩气保护下,加入氢化钠(60%,1mmol),室温下搅拌反应1-4h。反应完毕后加入饱和氯化铵溶液1mL,用氯仿萃取,硫酸镁干燥,减压浓缩,接着在氩气保护下,将浓缩液溶于1mL吡啶中,加入1mL醋酐,室温下搅拌反应8h,然后注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析得化合物C7。
1H NMR(CDCl3,300MHz):δ:8.96(brs,1H),6.89(d,J=8.1Hz,1H),6.31(d,J=8.1Hz,1H),6.14(s,1H),5.87(dd,J=10.2,3.6Hz,1H),5.37(d,J=10.2Hz,1H),5.04(s,1H),4.23(d,J=11.4Hz,1H),4.03(d,J=11.4Hz,1H),3.80(s,3H),3.64(s,1H),3.46(m,2H),2.87(s,3H),2.81(d,J=15.9Hz,1H),2.64(s,1H),2.51(m,1H),2.44(q,J=7.2Hz,2H),2.29(m,2H),2.15(s,3H),1.32(m,1H),1.16(t,J=7.2Hz,3H),1.03(m,1H),0.53(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:173.9(C),170.5(C),160.8(C),154.2(C),129.9(CH),125.7(C),124.0(CH),122.5(CH),104.6(CH),96.1(CH),81.4(CH),76.6(CH),76.0(C),67.6(CH),66.3(CH2),55.1(OCH3),51.9(C),51.6(CH2),50.6(CH2),44.4(CH2),42.4(C),39.7(CH3),31.3(CH2),27.3(CH2),20.7(CH3),9.0(CH3),7.4(CH3)。
制备实施例11化合物C8的制备
制备步骤参见化合物C7的制备。
1H NMR(CDC13,300MHz):δ:8.83(brs,1H),6.89(d,J=8.1Hz,1H),6.31(dd,J=8.1,2.4Hz,1H),6.13(d,J=2.4Hz,1H),5.87(dd,J=10.2,3.6Hz,1H),5.36(d,J=10.2Hz,1H),5.03(s,1H),4.25(d,J=11.7Hz,1H),4.01(d,J=11.7Hz,1H),3.79(s,3H),3.62(s,1H),3.45(m,2H),2.88(s,3H),2.80(d,J=15.9Hz,1H),2.69(m,1H),2.62(s,1H),2.51(m,1H),2.29(m,2H),2.13(s,3H),1.32(m,1H),1.19(dd,J=6.6,1.2Hz,6H),1.03(m,1H),0.52(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:176.3(C),170.4(C),160.8(C),154.1(C),129.9(CH),125.7(C),123.9(CH),122.5(CH),104.5(CH),96.0(CH),81.4(CH),76.4(CH),76.0(C),67.6(CH),65.9(CH2),55.0(OCH3),51.8(C),51.6(CH2),50.6(CH2),44.4(CH2),42.4(C),39.6(CH3),33.6(CH),31.2(CH2),20.6(CH3),18.9(CH3),18.7(CH3),7.3(CH3)。
制备实施例12化合物C9的制备
制备步骤参见化合物C7的制备。
1H NMR(CDCl3,300MHz):δ:9.02(brs,1H),6.89(d,J=8.1Hz,1H),6.30(d,J=8.1Hz,1H),6.12(s,1H),5.84(dd,J=9.3,3.3Hz,1H),5.33(d,J=9.3Hz,1H),5.01(s,1H),4.32(d,J=11.4Hz,1H),3.94(d,J=11.4Hz,1H),3.79(s,3H),3.60(s,1H),3.48(m,2H),2.89(s,3H),2.81(m,1H),2.63(s,1H),2.50(m,1H),2.25(m,1H),2.16(m,1H),2.06(s,3H),1.27(m,1H),1.24(s,9H),0.96(m,1H),0.50(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:171.0(C),170.8(C),161.0(C),154.4(C),130.2(CH),125.9(C),124.3(CH),122.8(CH),104.9(CH),96.4(CH),81.6(CH),76.8(CH),76.2(C),67.8(CH),66.9(CH2),55.4(OCH3),52.2(C),51.8(CH2),50.9(CH2),44.9(CH2),42.7(C),40.1(CH3),38.9(C),31.5(CH2),27.7(3CH3),21.2(CH3),7.6(CH3)。
制备实施例13化合物C10的制备
制备步骤参见化合物C7的制备。
1H NMR(CDCl3,300MHz):δ:8.83(brs,1H),6.89(d,J=8.1Hz,1H),6.31(dd,J=8.1,2.4Hz,1H),6.13(d,J=2.1Hz,1H),5.88(dd,J=10.5,3.6Hz,1H),5.37(d,J=10.5Hz,1H),5.03(s,1H),4.26(d,J=11.4Hz,1H),4.00(d,J=11.4Hz,1H),3.80(s,3H),3.64(s,1H),3.48(m,2H),2.89(s,3H),2.81(d,J=15.9Hz,1H),2.64(s,1H),2.51(m,1H),2.29(m,4H),2.15(s,3H),1.32(m,1H),1.03(m,1H),0.97(d,J=6.6Hz,6H),0.89(m,1H),0.52(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:172.4(C),170.5(C),160.8(C),154.1(C),129.9(CH),125.7(C),123.9(CH),122.5(CH),104.6(CH),96.1(CH),81.2(CH),76.5(CH),76.0(C),67.6(CH),66.0(CH2),55.0(OCH3),51.8(C),51.5(CH2),50.6(CH2),44.4(CH2),43.1(CH2),42.4(C),39.7(CH3),31.3(CH2),25.3(CH),22.2(2CH3),20.7(CH3),7.3(CH3)。
制备实施例14化合物C11的制备
制备步骤参见化合物C7的制备。
1H NMR(CDCl3,300MHz):δ:8.95(brs,1H),6.90(d,J=8.1Hz,1H),6.32(dd,J=8.1,2.4Hz,1H),6.14(d,J=2.4Hz,1H),5.89(dd,J=10.2,3.6Hz,1H),5.38(d,J=10.2Hz,1H),5.04(s,1H),4.24(d,J=11.7Hz,1H),4.03(d,J=11.7Hz,1H),3.80(s,3H),3.68(s,1H),3.45(m,2H),2.90(s,3H),2.81(d,J=14.1Hz,1H),2.65(s,1H),2.50(m,1H),2.51(m,1H),2.30(m,2H),2.14(s,3H),1.74(m,1H),1.32(m,2H),1.01(m,2H),0.86(m,2H),0.53(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.5(C),170.6(C),160.9(C),154.3(C),130.0(CH),125.7(C),124.1(CH),122.6(CH),104.7(CH),96.2(CH),81.5(CH),76.7(CH),76.1(C),67.6(CH),66.6(CH2),55.2(OCH3),52.0(C),51.7(CH2),50.7(CH2),44.6(CH2),42.5(C),39.9(CH3),31.3(CH2),20.8(CH3),12.7(CH),8.5(2CH2),7.4(CH3)。
制备实施例15化合物C12的制备
将底物A(1.0mmol)和3-苯乙酰基-噻唑烷-2-硫酮(1.1mmol)溶于10mL无水四氢呋喃中,在氩气保护下,加入氢化钠(60%,1mmol),室温下搅拌反应1-4h。反应完毕后加入饱和氯化铵溶液1mL,用氯仿萃取,硫酸镁干燥,减压浓缩,接着在氩气保护下,将浓缩液溶于1mL吡啶中,加入1mL醋酐,室温下搅拌反应8h,然后注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析得化合物C12。
1H NMR(CDCl3,300MHz):δ:9.02(brs,1H),7.22(m,5H),6.86(d,J=8.4Hz,1H),6.29(d,J=8.4Hz,1H),6.05(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.37(d,J=10.2Hz,1H),4.99(s,1H),4.30(d,J=11.1Hz,1H),3.95(d,J=11.1Hz,1H),3.78(s,3H),3.72(s,2H),3.48(m,2H),2.81(m,1H),2.63(s,1H),2.56(s,3H),2.47(m,1H),2.25(m,1H),2.16(m,2H),2.12(s,3H),1.27(m,1H),0.96(m,1H),0.48(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:171.0(C),170.8(C),161.0(C),154.3(C),135.4(C),130.4(CH),129.6(2CH),129.0(2CH),127.2(CH),125.9(C),124.3(CH),122.8(CH),105.5(CH),97.4(CH),82.9(CH),76.5(C),75.8(CH),67.1(CH),66.9(CH2),55.5(OCH3),52.3(C),51.5(CH2),50.9(CH2),45.0(CH2),43.6(CH2),42.9(C),41.0(CH3),31.3(CH2),21.1(CH3),7.6(CH3)。
制备实施例16化合物C13的制备
制备步骤参见化合物C7的制备。
1H NMR(CDCl3,300MHz):δ:8.94(brs,1H),8.08(d,J=7.5Hz,2H),7.56(t,J=7.5Hz,1H),7.44(t,J=7.5Hz,2H),6.91(d,J=8.4Hz,1H),6.32(d,J=8.4Hz,1H),6.11(s,1H),5.89(dd,J=10.2,3.9Hz,1H),5.39(d,J=10.2Hz,1H),5.13(s,1H),4.57(d,J=11.4Hz,1H),4.20(d,J=11.4Hz,1H),3.79(s,3H),3.74(s,1H),3.51-3.38(m,2H),2.92(s,3H),2.82(d,J=15.6Hz,1H),2.67(s,1H),2.51(m,1H),2.31(m,2H),2.14(s,3H),1.32(m,1H),0.79(m,1H),0.54(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:171.3(C),165.7(C),160.8(C),154.0(C),132.7(CH),129.9(CH),129.9(C),129.4(2CH),128.1(2CH),125.5(C),123.9(CH),122.5(CH),104.5(CH),96.0(CH),82.8(CH),76.4(CH),76.1(C),67.4(CH),66.5(CH2),54.9(OCH3),52.3(C),51.4(CH2),50.5(CH2),44.5(CH2),42.4(C),39.7(CH3),31.2(CH2),20.6(CH3),7.3(CH3)。
制备实施例17化合物C14的制备
制备步骤参见化合物C7的制备。
1H NMR(CDCl3,300MHz):δ:8.86(brs,1H),7.86(d,J=7.5Hz,1H),7.47(t,J=7.5Hz,1H),6.97(t,J=7.5Hz,1H),6.97(d,J=7.5Hz,1H),6.90(d,J=8.4Hz,1H),6.31(d,J=8.4Hz,1H),6.12(s,1H),5.88(dd,J=10.5,3.6Hz,1H),5.38(d,J=10.5Hz,1H),5.12(s,1H),4.49(d,J=11.4Hz,1H),4.19(d,J=11.4Hz,1H),3.87(s,3H),3.79(s,3H),3.74(s,1H),3.50-3.36(m,2H),2.95(s,3H),2.80(d,J=15.6Hz,1H),2.66(s,1H),2.54(m,1H),2.31(m,2H),2.14(s,3H),1.36(m,1H),1.03(m,1H),0.53(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.2(C),165.5(C),160.6(C),158.7(C),154.0(C),133.1(CH),131.4(CH),129.6(CH),125.5(C),123.7(CH),122.3(CH),119.6(CH),119.5(C),111.5(CH),104.2(CH),95.7(CH),81.0(CH),76.3(CH),75.9(C),67.4(CH),66.3(CH2),55.2(OCH3),54.8(OCH3),51.6(C),51.3(CH2),50.3(CH2),44.2(CH2),42.2(C),39.1(CH3),31.1(CH2),20.4(CH3),7.1(CH3)。
制备实施例18化合物C15的制备
制备步骤参见化合物C7的制备。
1H NMR(CDCl3,300MHz):δ:8.86(brs,1H),7.97(d,J=8.7Hz,1H),6.84(d,J=8.7Hz,3H),6.24(d,J=8.7Hz,1H),6.04(s,1H),5.81(dd,J=10.5,4.5Hz,1H),5.32(d,J=10.5Hz,1H),5.07(s,1H),4.46(d,J=11.7Hz,1H),4.11(d,J=11.7Hz,1H),3.74(s,3H),3.69(s,3H),3.66(s,1H),3.42-3.30(m,2H),2.84(s,3H),2.73(d,J=16.2Hz,1H),2.60(s,1H),2.43(m,1H),2.24(m,2H),2.05(s,3H),1.28(m,1H),1.00(m,1H),0.48(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.6(C),165.7(C),163.2(C),160.9(C),154.2(C),131.5(2CH),130.5(CH),125.7(C),124.0(CH),122.6(CH),122.3(C),113.5(2CH),104.5(CH),96.0(CH),82.0(CH),76.5(CH),76.2(C),67.5(CH),66.4(CH2),55.1(2OCH3),52.0(C),51.5(CH2),50.5(CH2),44.6(CH2),42.6(C),39.7(CH3),31.3(CH2),20.7(CH3),7.4(CH3)。
制备实施例19化合物C16的制备
制备步骤参见化合物C7的制备。
1H NMR(CDCl3,300MHz):δ:8.79(brs,1H),7.79(d,J=7.2Hz,1H),7.29(m,2H),7.20(m,1H),6.79(t,J=8.1Hz,1H),6.20(d,J=8.1Hz,1H),6.02(s,1H),5.78(dd,J=10.5,3.6Hz,1H),5.29(d,J=10.5Hz,1H),5.01(s,1H),4.44(d,J=11.4Hz,1H),4.16(d,J=11.4Hz,1H),3.63(s,3H),3.61(s,1H),3.37-3.24(m,2H),2.89(s,3H),2.69(d,J=15.9Hz,1H),2.54(s,1H),2.39(m,1H),2.16(m,2H),2.01(s,3H),1.25(m,1H),0.95(m,1H),0.43(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),164.8(C),160.8(C),154.0(C),133.3(C),132.3(CH),131.3(CH),130.7(CH),129.8(CH),129.7(C),126.4(CH),125.6(C),123.9(CH),122.5(CH),104.6(CH),96.0(CH),81.4(CH),76.3(CH),76.0(C),67.5(CH),67.0(CH2),54.9(OCH3),51.8(C),51.5(CH2),50.6(CH2),44.4(CH2),42.4(C),39.8(CH3),31.2(CH2),20.6(CH3),7.3(CH3)。
制备实施例20化合物C17的制备
制备步骤参见化合物C7的制备。
1H NMR(CDCl3,300MHz):δ:8.85(brs,1H),7.92(d,J=7.2Hz,2H),7.29(d,J=7.2Hz,2H),6.82(d,J=8.4Hz,1H),6.22(d,J=8.4Hz,1H),6.02(s,1H),5.78(dd,J=10.5,3.6Hz,1H),5.30(d,J=10.5Hz,1H),5.04(s,1H),4.47(d,J=11.4Hz,1H),4.13(d,J=11.4Hz,1H),3.65(s,3H),3.61(s,1H),3.38-3.27(m,2H),2.82(s,3H),2.71(d,J=15.9Hz,1H),2.59(s,1H),2.43(m,1H),2.19(m,2H),2.02(s,3H),1.26(m,1H),0.97(m,1H),0.46(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),164.9(C),160.8(C),154.0(C),139.0(C),130.8(2CH),129.9(CH),128.4(2CH),128.4(C),125.5(C),124.0(CH),122.5(CH),104.5(CH),96.0(CH),82.0(CH),76.3(CH),76.0(C),67.4(CH),67.0(CH2),55.0(OCH3),52.0(C),51.4(CH2),50.7(CH2),44.5(CH2),42.4(C),39.8(CH3),31.2(CH2),20.6(CH3),7.3(CH3)。
制备实施例21化合物C18的制备
制备步骤参见化合物C7的制备。
1H NMR(CDCl3,300MHz):δ:8.88(brs,1H),8.14(s,4H),6.83(d,J=8.1Hz,1H),6.22(d,J=8.4Hz,1H),6.02(s,1H),5.80(dd,J=9.9,3.6Hz,1H),5.31(d,J=9.9Hz,1H),5.03(s,1H),4.51(d,J=11.1Hz,1H),4.18(d,J=11.1Hz,1H),3.65(s,3H),3.61(s,1H),3.41-3.28(m,2H),2.84(s,3H),2.74(d,J=16.2Hz,1H),2.61(s,1H),2.43(m,1H),2.20(m,2H),2.02(s,3H),1.23(m,1H),0.95(m,1H),0.45(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),164.0(C),160.8(C),154.0(C),150.2(C),135.2(C),130.5(2CH),129.8(CH),125.4(C),124.0(CH),123.3(2CH),122.5(CH),104.6(CH),96.1(CH),82.0(CH),76.2(CH),76.0(C),67.3(CH),67.2(CH2),55.0(OCH3),52.0(C),51.3(CH2),50.5(CH2),44.4(CH2),42.4(C),39.9(CH3),31.2(CH2),20.6(CH3),7.2(CH3)。
制备实施例22化合物D1的制备
在冰浴条件下将2.4mmol(0.24mL)异丁胺慢慢滴加到羰基二咪唑(CDI,1.1eq,428mg)的二氯甲烷溶液(10mL)中,反应半个小时后移去冰浴,室温下反应24h。反应完毕后加入20mL水,用二氯甲烷萃取(10mL×3),合并有机相,无水硫酸镁干燥,过滤减压浓缩得到中间体粗品。在氩气保护下,1mmol A和中间体粗品溶于20mL无水四氢呋喃溶液中,加入88mg(2.2mmol)60%氢化钠,室温下反应6小时。反应完毕后加入10mL饱和氯化氨溶液和10mL水,用乙酸乙酯萃取(10mL×3),无水硫酸钠干燥有机相,减压浓缩,将浓缩物溶于1mL吡啶,加入1mL醋酐,室温下搅拌反应8h后,注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析(石油醚∶丙酮=4∶1v/v洗脱)得212mg化合物D1(白色粉末),产率40%。
1H NMR(CDCl3,300MHz):δ:9.10(s),6.88(d,J=8.4Hz,1H),6.30(d,J=8.4Hz,1H),6.12(s,1H),5.88(dd,J=10.2,4.5Hz,1H),5.36(d,J=10.2Hz,1H),5.04(s,1H),4.98(m,1H),4.08(d,J=11.1Hz,2H),3.79(s,3H),3.63(s,1H),3.55-3.37(m,2H),3.01(t,J=6.6Hz,1H),2.88(s,3H),2.82(d,J=15.9Hz,1H),2.63(s,1H),2.50(q,J=9.3Hz,1H),2.31(m,2H),2.13(s,3H),1.76-1.70(m,2H),1.31(m,1H),1.02(m,1H),0.90(d,J=6.9Hz,6H),0.52(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),160.7(C),156.1(C),154.1(C),129.9(CH),125.5(C),123.9(CH),122.4(CH),104.4(CH),95.9(CH),81.1(CH),76.5(CH),76.0(C),67.5(CH),66.9(CH2),55.0(OCH3),51.7(C),51.5(CH2),50.5(CH2),48.1(CH2),44.3(CH2),42.4(C),39.4(CH3),31.1(CH2),28.4(CH),20.6(CH3),19.6(2CH3),7.3(CH3)。
制备实施例23化合物D2的制备
制备步骤参见化合物D1的制备。
1H NMR(CDCl3,300MHz):δ:9.10(s),6.86(d,J=8.4Hz,1H),6.30(d,J=8.4Hz,1H),6.12(s,1H),5.89(dd,J=10.2,2.4Hz,1H),5.36(d,J=10.2Hz,1H),5.04(s,1H),4.89(m,1H),4.10(s,2H),3.79(s,3H),3.63(s,1H),3.52-3.37(m,2H),3.18(q,J=6.9Hz,1H),2.88(s,3H),2.82(d,J=15.9Hz,1H),2.63(s,1H),2.50(q,J=9.3Hz,1H),2.31-2.26(m,2H),2.14(s,3H),1.52-1.41(m,2H),1.38-1.22(m,3H),1.05-0.98(m,1H),1.02(m,1H),0.91(t,J=7.2Hz,3H),0.52(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),160.7(C),156.0(C),154.1(C),129.9(CH),125.6(C),123.9(CH),122.4(CH),104.4(CH),95.9(CH),81.1(CH),76.4(CH),75.9(C),67.5(CH),66.7(CH2),54.9(OCH3),51.6(C),51.5(CH2),50.5(CH2),44.3(CH2),42.4(C),39.4(CH3),31.6(CH2),31.1(CH2),20.6(CH3),19.5(CH2),13.4(CH3),7.3(CH3)。
制备实施例24化合物D3的制备
制备步骤参见化合物D1的制备。
1H NMR(CDCl3,300MHz):δ:9.10(s),6.88(d,J=8.4Hz,1H),6.30(d,J=8.4Hz,1H),6.13(s,1H),5.89(dd,J=10.2,2.4Hz,1H),5.36(d,J=10.2Hz,1H),5.04(s,1H),4.88(m,1H),4.10(s,2H),3.79(s,3H),3.63(s,1H),3.55-3.37(m,2H),3.19(q,J=8.1Hz,1H),2.88(s,3H),2.81(d,J=15.9Hz,1H),2.63(s,1H),2.50(q,J=9.3Hz,1H),2.34-2.28(m,2H),2.14(s,3H),1.68-1.56(m,1H),1.34-1.26(m,2H),1.04-0.98(m,1H),1.02(m,1H),0.90(d,J=2.4Hz,6H),0.52(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),160.7(C),155.9(C),154.0(C),129.8(CH),125.5(C),123.8(CH),122.4(CH),104.4(CH),95.9(CH),81.1(CH),76.4(CH),75.9(C),67.5(CH),66.7(CH2),54.9(OCH3),51.6(C),51.5(CH2),50.5(CH2),44.2(CH2),42.4(C),39.4(CH3),38.9(CH2),38.4(CH2),31.1(CH2),25.2(CH),22.1(2CH3),20.6(CH3),7.3(CH3)。
制备实施例25化合物E1的制备
在氩气保护下,取385mg(1mmol)化合物B溶于1mL吡啶中,加入1mL醋酐,室温下搅拌反应8h后,注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析(石油醚∶丙酮=2∶1v/v洗脱)得417mg化合物E1(白色粉末),产率89%。
1H NMR(CDCl3,300MHz):δ:6.81(d,J=8.1Hz,1H),6.24(d,J=8.1Hz,1H),6.17(d,J=7.2Hz,1H),6.08(s,1H),5.82(dd,J=10.2,4.5Hz,1H),5.35(d,J=10.2Hz,1H),4.92(s,1H),3.78(s,3H),3.65(m,2H),3.41(m,2H),3.33(s,1H),3.28(m,1H),2.98(d,J=13.2Hz,1H),2.79(s,3H),2.73(d,J=4.8Hz,1H),2.59(s,1H),2.47(m,1H),2.16(m,2H),2.09(s,1H),2.03(s,3H),1.92(s,3H),1.22(m,1H),0.94(m,1H),0.45(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),170.3(C),161.0(C),154.3(C),130.3(CH),125.5(C),124.1(CH),122.6(CH),105.1(CH),96.6(CH),82.1(CH),77.0(CH),75.8(C),67.3(CH),55.3(OCH3),52.2(C),51.5(CH2),50.8(CH2),44.6(CH2),43.7(CH2),42.8(C),40.6(CH3),31.2(CH2),23.3(CH3),20.9(CH3),7.5(CH3)。
制备实施例26化合物E2的制备
1H NMR(CDCl3,300MHz):δ:9.44(brs,1H),7.18(d,J=7.2Hz,1H),6.88(d,J=8.1Hz,1H),6.35(d,J=8.1Hz,1H),6.17(s,1H),6.08(s,1H),5.91(dd,J=10.2,4.5Hz,1H),5.38(d,J=10.2Hz,1H),4.99(s,1H),3.79(s,3H),3.79-3.74(m,1H),3.49(dd,J=15.9,4.8Hz,1H),3.43-3.37(m,1H),3.33(s,1H),3.18(d,J=13.5Hz,1H),2.87(s,3H),2.85(d,J=15.9Hz,1H),2.70(s,1H),2.61-2.52(m,1H),2.34-2.16(m,2H),2.11(s,3H),1.33-1.23(m,1H),1.06-0.97(m,1H),0.54(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),161.1(C),157.1(C),156.6(C),154.0(C),130.0(CH),125.2(C),124.3(CH),122.8(CH),105.7(CH),97.1(CH),83.0(CH),76.7(CH),75.4(C),66.9(CH),55.2(OCH3),52.5(C),51.1(CH2),50.7(CH2),44.5(CH2),44.1(CH2),42.8(C),41.3(CH3),31.2(CH2),20.7(CH3),7.4(CH3)。
制备实施例27化合物E3的制备
将底物B(1.0mmol)和配体III(3-丙酰基-噻唑烷-2-硫酮)(1.1mmol)溶于10mL无水四氢呋喃中,在氩气保护下,加入氢化钠(60%,1mmol),室温下搅拌反应1~4h。反应完毕后加入饱和氯化铵溶液1mL,用氯仿萃取,硫酸镁干燥,减压浓缩,接着在氩气保护下,将浓缩液溶于1mL吡啶中,加入1mL醋酐,室温下搅拌反应8h,然后注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析得化合物E3。
1H NMR(CDCl3,300MHz):δ:9.20(s,1H),6.88(d,J=8.1Hz,1H),6.32(dd,J=8.1,2.1Hz,1H),6.16(d,J=5.7Hz,1H),6.15(d,J=2.1Hz,1H),5.89(dd,J=10.2,4.2Hz,1H),5.36(d,J=10.2Hz,1H),4.99(s,1H),3.79(s,3H),3.74(m,1H),3.50(dd,J=15.9,4.5Hz,1H),3.39(m,1H),3.39(s,1H),3.03(d,J=13.2Hz,1H),2.86(s,3H),2.83(d,J=15.9Hz,1H),2.66(s,1H),2.53(dd,J=18.0,9.6Hz,1H),2.33-2.19(m,2H),2.22(q,J=7.5Hz,2H),2.11(s,3H),1.36-1.29(m,1H),1.15(t,J=7.5Hz,3H),1.04-0.98(m,1H),0.52(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:173.9(C),170.5(C),161.0(C),154.3(C),130.4(CH),125.6(C),124.1(CH),122.7(CH),105.2(CH),96.7(CH),82.2(CH),76.9(CH),75.9(C),67.2(CH),55.4(OCH3),52.2(C),51.5(CH2),50.8(CH2),44.8(CH2),43.4(CH2),42.8(C),40.7(CH3),31.3(CH2),29.8(CH2),21.0(CH3),10.0(CH3),7.5(CH3)。
制备实施例28化合物E4的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.20(brs,1H),6.88(d,J=8.4Hz,1H),6.32(dd,J=8.4,2.1Hz,1H),6.19(d,J=8.1Hz,1H),6.15(d,J=2.1Hz,1H),5.89(dd,J=10.2,3.6Hz,1H),5.36(d,J=10.2Hz,1H),4.98(s,1H),3.79(s,3H),3.74(m,1H),3.48(dd,J=15.9,5.4Hz,1H),3.38(m,1H),3.38(s,1H),2.99(d,J=13.2Hz,1H),2.84(s,3H),2.83(d,J=15.9Hz,1H),2.66(s,1H),2.54-2.48(m,1H),2.42-2.33(m,1H),2.29-2.18(m,2H),2.11(s,3H),1.37-1.27(m,1H),1.15(d,J=2.1Hz,3H)1.13(d,J=2.1Hz,3H),1.07-0.98(m,1H),0.52(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:171.2(C),170.7(C),161.2(C),154.5(C),130.5(CH),125.8(C),124.2(CH),122.8(CH),105.4(CH),96.9(CH),82.2(CH),77.0(C),76.1(CH),67.4(CH),55.5(OCH3),52.4(C),51.7(CH2),51.0(CH2),45.0(CH2),43.2(CH2),43.0(C),40.7(CH3),35.9(CH),31.4(CH2),21.1(CH3),19.9(CH3),19.7(CH3),7.7(CH3)。
制备实施例29化合物E5的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.23(brs,1H),6.88(d,J=8.4Hz,1H),6.32(d,J=8.4Hz,1H),6.16(d,J=8.1Hz,1H),6.15(s,1H),5.89(dd,J=10.2,4.8Hz,1H),5.37(d,J=10.2Hz,1H),5.01(s,1H),3.79(s,3H),3.74(m,1H),3.48(dd,J=15.9,5.4Hz,1H),3.38(m,1H),3.41(s,1H),3.04(d,J=14.4Hz,1H),2.86(s,3H),2.83(d,J=15.9Hz,1H),2.67(s,1H),2.61-2.52(m,1H),2.34-2.16(m,2H),2.19(t,J=7.2Hz,2H),2.11(s,3H),1.70-1.63(m,2H),1.37-1.27(m,1H),0.91(t,J=7.2Hz,3H),1.03-0.85(m,1H),0.51(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:173.2(C),170.5(C),161.0(C),154.3(C),130.4(CH),125.6(C),124.1(CH),122.7(CH),105.2(CH),96.7(CH),82.0(CH),77.0(C),75.9(CH),67.4(CH),55.3(OCH3),52.2(C),51.6(CH2),50.8(CH2),44.8(CH2),43.3(CH2),42.9(C),40.6(CH3),38.8(CH2),31.3(CH2),20.9(CH3),19.2(CH2),13.9(CH3),7.5(CH3)。
制备实施例30化合物E6的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.25(brs,1H),6.87(d,J=8.1Hz,1H),6.31(dd,J=8.1,2.1Hz,1H),6.15(d,J=2.1Hz,1H),6.10(d,J=8.1Hz,1H),5.89(dd,J=10.5,3.6Hz,1H),5.36(d,J=10.5Hz,1H),5.00(s,1H),3.79(s,3H),3.79-3.72(m,1H),3.48(dd,J=15.9,5.1Hz,1H),3.42-3.34(m,1H),3.39(s,1H),3.03(d,J=13.2Hz,1H),2.86(s,3H),2.83(d,J=15.9Hz,1H),2.63(s,1H),2.57-2.48(m,1H),2.35-2.16(m,3H),2.11(s,3H),2.10(d,J=9.9Hz,2H),1.37-1.27(m,1H),0.94(d,J=6.3Hz,6H),1.03-0.85(m,1H),0.51(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:172.7(C),170.4(C),160.9(C),154.2(C),130.2(CH),125.5(C),124.0(CH),122.6(CH),105.1(CH),96.5(CH),81.8(CH),76.8(C),75.8(CH),67.4(CH),55.2(OCH3),52.1(C),51.6(CH2),50.7(CH2),46.1(CH2),44.7(CH2),43.2(CH2),42.8(C),40.4(CH3),31.2(CH2),26.0(CH),22.5(CH3),22.4(CH3),20.9(CH3),7.5(CH3)。
制备实施例31化合物E7的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.25(brs,1H),6.88(d,J=8.1Hz,1H),6.32(dd,J=8.1,2.1Hz,1H),6.15(d,J=2.1Hz,1H),6.10(d,J=8.1Hz,1H),5.89(dd,J=9.9,3.3Hz,1H),5.36(d,J=9.9Hz,1H),5.02(s,1H),3.79(s,3H),3.79-3.72(m,1H),3.48(dd,J=15.9,5.1Hz,1H),3.42-3.34(m,1H),3.42(s,1H),3.03(d,J=13.2Hz,1H),2.87(s,3H),2.83(d,J=15.9Hz,1H),2.64(s,1H),2.57-2.48(m,1H),2.35-2.16(m,2H),2.12(s,3H),2.10(s,2H),1.37-1.27(m,1H),0.94(d,J=6.3Hz,6H),1.03(s,9H),0.87-0.80(m,1H),0.50(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:171.9(C),170.3(C),160.9(C),154.2(C),130.2(CH),125.6(C),124.0(CH),122.5(CH),105.0(CH),96.5(CH),81.7(CH),76.9(C),75.7(CH),67.4(CH),55.2(OCH3),52.0(C),51.6(CH2),50.7(CH2),50.5(CH2),44.7(CH2),43.1(CH2),42.7(C),40.4(CH3),31.2(CH2),30.8(C),29.7(3CH3),20.8(CH3),7.4(CH3)。
制备实施例32化合物E8的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.15(s,1H),6.88(d,J=8.4Hz,1H),6.59(d,J=7.2Hz,1H),6.32(dd,J=8.4,2.1Hz,1H),6.15(d,J=2.1Hz,1H),5.89(dd,J=10.2,3.6Hz,1H),5.70(s,1H),5.37(d,J=10.5Hz,1H),5.31(s,1H),5.00(s,1H),3.86-3.79(m,1H),3.79(s,3H),3.48(dd,J=15.9,4.8Hz,1H),3.42-3.36(m,1H),3.39(s,1H),3.09(d,J=13.8Hz,1H),2.88(s,3H),2.81(d,J=16.2Hz,1H),2.68(s,1H),2.58-2.49(m,1H),2.32-2.15(m,2H),2.10(s,3H),1.96(s,3H),1.37-1.30(m,1H),1.09-0.99(m,1H),0.54(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.7(C),168.5(C),161.2(C),154.4(C),140.2(C),130.5(CH),125.7(C),124.2(CH),122.9(CH),119.5(CH2),105.5(CH),97.0(CH),82.8(CH),76.9(CH),76.1(C),67.3(CH),55.5(OCH3),52.5(C),51.6(CH2),51.0(CH2),45.0(CH2),43.7(CH2),43.0(C),41.0(CH3),31.4(CH2),21.1(CH3),18.8(CH3),7.6(CH3)。
制备实施例33化合物E9的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.02(s,1H),6.87(d,J=8.1Hz,1H),6.31(dd,J=8.1,2.4Hz,2H),6.14(d,J=2.4Hz,1H),5.89(d,J=10.2,3.6Hz,1H),5.37(d,J=10.2Hz,1H),5.01(s,1H),3.75(s,3H),3.75-3.70(m,1H),3.51(dd,J=15.9,4.5Hz,1H),3.43(s,1H),3.43-3.35(m,1H),3.09(d,J=13.5Hz,1H),2.86(s,3H),2.82(d,J=15.9Hz,1H),2.65(s,1H),2.58-2.49(m,1H),2.34-2.20(m,2H),2.10(s,3H),1.44-1.29(m,2H),1.18-1.07(m,1H),1.00-0.91(m,2H),0.76-0.67(m,2H),0.52(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:173.6(C),170.5(C),161.1(C),154.5(C),130.5(CH),125.7(C),124.2(CH),122.7(CH),105.2(CH),96.7(CH),82.3(CH),77.2(CH),76.0(C),67.5(CH),55.4(OCH3),52.3(C),51.7(CH2),51.0(CH2),44.8(CH2),44.0(CH2),43.0(C),40.7(CH3),31.4(CH2),21.0(CH3),14.8(CH),7.6(CH3),7.0(CH2)6.9(CH2)。
制备实施例34化合物E10的制备
将底物B(1.0mmol)和配体III(3-特戊酰基-噻唑烷-2-硫酮)(1.1mmol)溶于10mL无水四氢呋喃中,在氩气保护下,加入氢化钠(60%,1mmol),室温下搅拌反应1~4h。反应完毕后加入饱和氯化铵溶液1mL,用氯仿萃取,硫酸镁干燥,减压浓缩,接着在氩气保护下,将浓缩液溶于1mL吡啶中,加入1mL醋酐,室温下搅拌反应8h,然后注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析得化合物E10。
1H NMR(CDCl3,300MHz):δ:6.85(d,J=8.4Hz,1H),6.44(d,J=8.1Hz,1H),6.29(d,J=8.1Hz,1H),6.08(s,1H),5.84(dd,J=9.9,4.2Hz,1H),5.61(d,J=9.9Hz,1H),4.97(s,1H),3.74(s,3H),3.65(m,2H),3.41(m,2H),3.33(s,1H),3.28(m,1H),2.98(d,J=13.2Hz,1H),2.84(s,3H),2.73(d,J=4.8Hz,1H),2.59(s,1H),2.47(m,1H),2.16(m,2H),2.09(s,1H),2.05(s,3H),1.92(s,3H),1.30(m,1H),1.17(s,9H),0.90(m,1H),0.57(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:178.7(C),170.3(C),161.0(C),154.6(C),130.8(CH),126.6(C),124.5(CH),123.0(CH),105.1(CH),96.9(CH),82.4(CH),76.6(CH),75.3(C),68.5(CH),55.5(OCH3),52.1(C),52.0(CH2),51.3(CH2),44.9(CH2),44.0(CH2),43.6(C),41.2(CH3),38.9(C),32.6(CH2),27.7(3CH3),20.9(CH3),7.8(CH3)。
制备实施例35化合物E11的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.17(s,1H),6.87(d,J=8.1Hz,1H),6.32(dd,J=8.1,2.1Hz,1H),6.14(d,J=2.1Hz,1H),6.07(d,J=7.8Hz,1H),5.89(dd,J=10.5,3.6Hz,1H),5.36(d,J=10.5Hz,1H),4.98(s,1H),3.80-3.73(m,1H),3.79(s,3H),3.47(dd,J=15.9,4.8Hz,1H),3.42-3.34(m,1H),3.37(s,1H),3.05-3.00(m,2H),2.85(s,3H),2.81(d,J=15.9Hz,1H),2.66(s,1H),2.54-2.48(m,1H),2.32-2.12(m,6H),2.10(s,3H),1.98-1.87(m,2H),1.36-1.25(m,1H),1.05-0.98(m,1H),.0.52(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:175.1(C),170.6(C),161.1(C),154.4(C),130.4(CH),125.7(C),124.2(CH),122.8(CH),105.3(CH),96.8(CH),82.3(CH),77.0(CH),76.0(C),67.3(CH),55.4(OCH3),52.3(C),51.6(CH2),50.9(CH2),44.9(CH2),43.3(CH2),42.9(C),40.8(CH),40.1(CH),31.3(CH2),25.4(CH2),25.4(CH2),21.0(CH3),7.6(CH3)。
制备实施例36化合物E12的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.28(brs,1H),7.79(d,J=6.9Hz,2H),7.44(m,3H),6.91(s,1H),6.89(d,J=8.1Hz,1H),6.33(d,J=8.1Hz,1H),6.17(s,1H),5.91(m,1H),5.40(d,J=10.5Hz,1H),5.06(s,1H),3.93(m,1H),3.79(s,3H),3.55-3.41(m,3H),3.25(d,J=12.9Hz,1H),2.91(s,3H),2.83(m,1H),2.55(m,1H),2.70(s,1H),2.25(m,1H),2.10(m,3H),2.09(s,3H),1.05(m,1H),0.87(m,1H),0.54(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.3(C),167.6(C),161.5(C),154.6(C),135.4(C),132.2(CH),130.7(CH),128.6(2CH),127.5(2CH),125.9(C),124.5(CH),123.1(CH),105.8(CH),97.2(CH),83.1(CH),77.1(C),76.4(CH),67.5(CH),55.7(OCH3),52.4(C),51.5(CH2),51.0(CH2),45.2(CH2),44.2(CH2),43.2(C),41.3(CH3),31.6(CH2),21.1(CH3),7.8(CH3)。
制备实施例37化合物E13的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.23(brs,1H),7.69(d,J=8.1Hz,2H),7.23(d,J=8.1Hz,2H),6.89(d,J=8.1Hz,2H),6.33(dd,J=8.1,2.1Hz,1H),6.16(d,J=2.1Hz,1H),5.91(dd,J=10.2,3.9Hz,1H),5.39(d,J=10.2Hz,1H),5.06(s,1H),3.94(ddJ=13.5,8.1Hz,1H),3.79(s,3H),3.53-3.38(m,2H),3.46(s,1H),3.24(d,J=13.5Hz,1H),2.90(s,3H),2.83(d,J=15.9Hz,1H),2.69(s,1H),2.60-2.50(m,1H),2.39(s,3H),2.34-2.20(m,2H),2.17(s,1H),2.09(s,3H),1.38-1.31(m,1H),1.08-1.01(m,1H),0.54(t,J=7.5Hz,3H)。
13C NMR(CDCl3,75MHz):δ:170.7(C),167.4(C),161.2(C),154.4(C),141.8(C),132.0(C),130.5(CH),129.3(2CH),127.0(2CH),125.7(C),124.2(CH),122.8(CH),105.4(CH),96.9(CH),82.7(CH),76.8(CH),76.2(C),67.4(CH),55.5(OCH3),52.4(C),51.6(CH2),50.9(CH2),45.0(CH2),44.0(CH2),43.0(C),40.9(CH3),31.4(CH2),21.5(CH3),21.1(CH3),7.6(CH3)。
制备实施例38化合物E14的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.28(s,1H),7.79(t,J=8.1Hz,2H),7.11(t,J=8.1Hz,2H),6.89(d,J=8.4Hz,1H),6.34(d,J=8.4Hz,1H),6.17(s,1H),5.91(dd,J=10.2,2.4Hz,1H),5.40(d,J=10.2Hz,1H),5.05(s,1H),3.97-3.90(m,1H),3.79(s,3H),3.53-3.41(m,2H),3.45(s,1H),3.24(d,J=13.2Hz,1H),2.90(s,3H),2.85(d,J=15.9Hz,1H),2.70(s,1H),2.60-2.51(m,1H),2.30-2.17(m,2H),2.09(s,3H),1.37-1.30(m,1H),1.08-1.01(m,1H),0.55(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.7(C),166.4(2C),161.1(C),154.4(C),131.0(C),130.5(CH),129.3(CH),129.2(CH),125.6(C),124.3(CH),122.8(CH),115.8(CH),115.5(CH),105.5(CH),97.0(CH),82.8(CH),77.0(CH),76.1(C),67.2(CH),55.5(OCH3),52.5(C),51.5(CH2),50.9(CH2),44.9(CH2),44.1(CH2),43.0(C),41.1(CH3),31.4(CH2),21.0(CH3),7.6(CH3)。
制备实施例39化合物E15的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.16(s,1H),7.51(d,J=6.6Hz,1H),7.30-7.17(m,3H),6.83(d,J=9.0Hz,1H),6.80(d,J=9.9Hz,1H),6.23(d,J=9.9Hz,1H),6.07(s,1H),5.79(dd,J=10.2,4.8Hz,1H),5.30(d,J=10.2Hz,1H),4.98(s,1H),3.94-3.87(m,1H),3.67(s,3H),3.42(s,1H),3.37(dd,J=15.9,4.8Hz,1H),3.27-3.23(m,1H),3.15(d,J=13.5Hz,1H),2.88(s,3H),2.74(d,J=16.5Hz,1H),2.57(s,1H),2.47-2.38(m,1H),2.24-2.07(m,2H),2.02(s,3H),1.31-1.19(m,1H),1.02-0.89(m,1H),0.44(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.3(C),166.4(C),160.9(C),154.2(C),135.4(C),131.0(CH),130.5(C),130.2(CH),130.0(CH),129.8(CH),126.9(CH),125.5(C),124.3(CH),122.5(CH),105.1(CH),96.6(CH),81.8(CH),76.8(CH),75.8(C),67.3(CH),55.1(OCH3),52.1(C),51.4(CH2),50.7(CH2),44.6(CH2),43.8(CH2),42.7(C),40.7(CH3),31.2(CH2),20.8(CH3),7.4(CH3)。
制备实施例40化合物E16的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.29(brs,1H),7.77(s,1H),7.65(d,J=7.5Hz,1H),7.47(d,J=7.5Hz,1H),7.37(t,J=7.5Hz,1H),6.95(d,J=6.6Hz,1H),6.89(d,J=8.1Hz,1H),6.34(d,J=8.1Hz,1H),6.18(s,1H),5.92(dd,J=10.5,4.5Hz,1H),5.40(d,J=10.5Hz,1H),5.05(s,1H),3.95(dd,J=13.2,7.5Hz,1H),3.80(s,3H),3.54-3.42(m,2H),3.44(s,1H),3.24(d,J=13.5Hz,1H),2.91(s,3H),2.84(d,J=16.5Hz,1H),2.71(s,1H),2.58-2.53(m,1H),2.29-2.23(m,2H),2.10(s,3H),1.37-1.30(m,1H),1.08-1.01(m,1H),0.55(t,J=7.5Hz,3H)。
13C NMR(CDCl3,75MHz):δ:170.7(C),166.1(C),161.2(C),154.4(C),136.6(C),134.8(C),131.5(CH),130.5(CH),130.0(CH),127.4(CH),125.6(C),125.1(CH),124.3(CH),122.9(CH),105.7(CH),97.0(CH),82.9(CH),76.9(CH),76.1(C),67.2(CH),55.5(OCH3),52.5(C),51.4(CH2),51.0(CH2),44.9(CH2),44.1(CH2),43.0(C),41.2(CH3),31.4(CH2),21.1(CH3),7.6(CH3)。
制备实施例41化合物E17的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.21(brs,1H),7.64(d,J=8.7Hz,2H),7.28(d,J=8.7Hz,1H),6.89(d,J=7.2Hz,1H),6.81(d,J=8.1Hz,1H),6.25(d,J=8.1Hz,1H),6.08(s,1H),5.83(dd,J=9.9,4.5Hz,1H),5.31(d,J=9.9Hz,1H),4.97(s,1H),3.88-3.80(m,1H),3.68(s,3H),3.43-3.31(m,2H),3.37(s,1H),3.18(d,J=13.5Hz,1H),2.81(s,3H),2.76(d,J=16.5Hz,1H),2.62(s,1H),2.47(q,J=9.3Hz,1H),2.24-2.13(m,2H),1.97(s,3H),1.28-1.19(m,1H),1.02-0.93(m,1H),0.46(t,J=7.2Hz,3H)。
13C NMR(CDCl3,75MHz):δ:170.5(C),166.1(C),161.1(C),154.2(C),137.4(C),133.1(C),130.3(CH),128.7(2CH),128.3(2CH),125.5(C),124.1(CH),122.7(CH),105.4(CH),96.9(CH),82.9(CH),76.9(CH),75.9(C),67.1(CH),55.2(OCH3),52.4(C),51.4(CH2),50.8(CH2),44.7(CH2),44.1(CH2),42.8(C),41.0(CH3),31.2(CH2),20.9(CH3),7.5(CH3)。
制备实施例42化合物E18的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.37(brs,1H),8.74(d,J=3.9Hz,2H),7.62(d,J=3.9Hz,2H),7.10(d,J=5.4Hz,1H),6.90(d,J=8.4Hz,1H),6.35(d,J=8.4Hz,1H),6.18(s,1H),5.91(dd,J=10.2,4.5Hz,1H),5.40(d,J=10.2Hz,1H),5.05(s,1H),3.99-3.92(m,1H),3.80(s,3H),3.52-3.42(m,2H),3.42(s,1H),3.26(d,J=13.5Hz,1H),2.90(s,3H),2.86(d,J=16.5Hz,1H),2.72(s,1H),2.57(q,J=9.6Hz,1H),2.26-2.17(m,2H),2.09(s,3H),1.31-1.25(m,1H),1.08-1.03(m,1H),0.56(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.7(C),165.4(C),161.2(C),154.3(C),150.7(2CH),141.9(C),130.4(CH),125.5(C),124.4(CH),122.9(CH),120.9(2CH),105.8(CH),97.2(CH),83.1(CH),76.8(CH),76.0(C),67.1(CH),55.5(OCH3),52.6(C),51.4(CH2),50.9(CH2),44.9(CH2),44.2(CH2),43.0(C),41.4(CH3),31.4(CH2),21.1(CH3),7.6(CH3)。
制备实施例43化合物E19的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.37(s,1H),8.29(d,J=8.7Hz,2H),7.93(d,J=8.7Hz,2H),7.11(d,J=5.4Hz,1H),6.90(d,J=7.8Hz,1H),6.36(d,J=7.8Hz,1H),6.18(s,1H),5.91(dd,J=10.2,4.5Hz,1H),5.40(d,J=10.2Hz,1H),5.05(s,1H),4.01-3.94(m,1H),3.80(s,3H),3.53-3.42(m,2H),3.43(s,1H),3.27(d,J=13.5Hz,1H),2.91(s,3H),2.86(d,J=16.5Hz,1H),2.73(s,1H),2.62-2.53(m,1H),2.33-2.17(m,2H),2.09(s,3H),1.36-1.25(m,1H),1.08-1.01(m,1H),0.56(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.3(C),164.9(C),160.9(C),153.9(C),149.2(C),140.1(C),130.0(CH),127.9(2CH),125.3(C),124.0(CH),123.4(2CH),120.6(CH),105.3(CH),96.8(CH),82.8(CH),76.5(CH),75.6(C),66.8(CH),55.0(OCH3),52.3(C),51.0(CH2),50.5(CH2),44.5(CH2),44.1(CH2),42.6(C),41.0(CH3),31.0(CH2),20.6(CH3),7.2(CH3)。
制备实施例44化合物E20的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.09(s,1H),8.45(d,J=7.8Hz,1H),8.15(d,J=7.5Hz,1H),7.43(t,J=7.8Hz,1H),7.06(t,J=7.8Hz,1H),6.97(d,J=7.8Hz,1H),6.88(d,J=8.4Hz,1H),6.30(d,J=8.4Hz,1H),6.14(s,1H),5.88(dd,J=10.2,4.8Hz,1H),5.37(d,J=10.2Hz,1H),5.07(s,1H),4.01-3.93(m,1H),3.94(s,3H),3.79(s,3H),3.54-3.30(m,2H),3.49(s,1H),3.26(d,J=13.5Hz,1H),2.88(s,3H),2.83(d,J=16.5Hz,1H),2.65(s,1H),2.58-2.49(m,1H),2.35-2.16(m,2H),2.01(s,3H),1.42-135(m,1H),1.08-1.01(m,1H),0.52(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.1(C),164.8(C),160.6(C),157.3(C),154.1(C),132.2(CH),131.4(CH),130.0(CH),125.5(C),123.7(CH),122.3(CH),121.6(C),120.6(CH),111.2(CH),104.5(CH),96.2(CH),81.8(CH),76.8(CH),75.6(C),67.2(CH),55.7(OCH3),54.8(OCH3),51.8(C),51.3(CH2),50.4(CH2),44.5(CH2),43.7(CH2),42.5(C),40.1(CH3),31.1(CH2),20.4(CH3),7.2(CH3)。
制备实施例45化合物E21的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.04(brs,1H),7.19(d,J=8.4Hz,2H),6.87(d,J=8.4Hz,2H),6.85(d,J=8.1Hz,1H),6.32(dd,J=8.1,2.1Hz,1H),6.16(d,J=8.1Hz,1H),6.02(s,1H),5.87(dd,J=10.2,3.6Hz,1H),5.32(d,J=10.2Hz,1H),4.89(s,1H),3.86-3.82(m,1H),3.81(s,3H),3.79(s,3H),3.48(s,1H),3.48-3.41(m,1H),3.35-3.27(m,1H),3.16(s,1H),2.92(d,J=13.5Hz,1H),2.80(d,J=15.9Hz,1H),2.64(s,3H),2.53-2.44(m,1H),2.26-2.00(m,2H),2.09(s,3H),1.39-1.27(m,1H),1.03-0.91(m,1H),0.51(t,J=7.2Hz,3H)。
13C NMR(CDCl3,75MHz):δ:171.5(C),170.9(C),161.0(C),158.8(C),154.3(C),130.7(CH),130.4(CH),127.3(C),125.8(C),124.2(CH),122.7(CH),114.4(CH),105.4(CH),97.5(CH),82.9(CH),76.4(CH),75.7(C),67.1(CH),55.5(OCH3),55.3(OCH3),52.3(C),51.5(CH2),50.8(CH2),45.0(CH2),43.5(CH2),43.2(C),41.1(CH3),31.2(CH2),21.1(CH3),7.6(CH3)。
制备实施例46化合物E22的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:7.26-7.20(m,5H),6.79(d,J=8.4Hz,1H),6.25(d,J=8.4Hz,1H),6.10(d,J=9.0Hz,1H),5.95(s,1H),5.81(dd,J=10.2,4.2Hz,1H),5.26(d,J=10.2Hz,1H),4.83(s,1H),3.79-3.73(m,1H),3.73(s,3H),3.48(s,2H),3.38(dd,J=15.9,5.1Hz,1H),3.30-3.20(m,1H),3.08(s,1H),2.86(d,J=13.8Hz,1H),2.74(d,J=15.9Hz,1H),2.55(s,3H),2.47-2.38(m,1H),2.20-1.93(m,2H),2.02(s,1H),1.30-1.19(m,1H),0.94-0.89(m,1H),0.45(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:171.0(C),170.8(C),161.0(C),154.3(C),135.4(C),130.4(CH),129.6(2CH),129.0(2CH),127.2(CH),125.8(C),124.2(CH),122.8(CH),105.5(CH),97.4(CH),82.9(CH),76.4(CH),75.8(C),67.1(CH),55.5(OCH3),52.3(C),51.4(CH2),50.8(CH2),45.0(CH2),44.1(CH2),43.6(CH2),42.9(C),41.0(CH3),31.3(CH2),21.1(CH3),7.6(CH3)。
制备实施例47化合物E23的制备
制备步骤参见化合物E3的制备。
1H NMR(CDCl3,300MHz):δ:9.26(brs,1H),7.32(d,J=8.1Hz,1H),7.28(s,1H),6.88(d,J=8.4Hz,1H),6.83(d,J=8.1Hz,1H),6.82(s,1H),6.33(d,J=8.4Hz,1H),6.16(d,J=2.1Hz,1H),6.02(s,2H),5.91(dd,J=10.2,3.6Hz,1H),5.39(d,J=10.2Hz,1H),5.04(s,1H),3.89(dd J=13.5,8.1Hz,1H),3.79(s,3H),3.54-3.42(m,2H),3.45(s,1H),3.22(d,J=13.5Hz,1H),2.89(s,3H),2.83(d,J=15.9Hz,1H),2.69(s,1H),2.60-2.51(m,1H),2.33-2.10(m,2H),2.09(s,3H),1.37-1.25(m,1H),1.07-1.00(m,1H),0.54(t,J=7.5Hz,3H)。
13C NMR(CDCl3,75MHz):δ:170.2(C),166.3(C),160.7(C),153.9(C),149.9(C),147.6(C),130.0(CH),128.5(C),125.3(C),123.9(CH),122.5(CH),121.1(CH),107.7(CH),107.2(CH),105.0(CH),101.4(CH2),96.4(CH),82.3(CH),76.6(CH),75.7(C),66.8(CH),55.0(OCH3),52.0(C),51.1(CH2),50.5(CH2),44.5(CH2),43.7(CH2),42.5(C),40.6(CH3),30.9(CH2),20.6(CH3),7.3(CH3)。
制备实施例48化合物F1的制备
取底物B(1.0mmol)溶于10mL二氯甲烷中,加入二异丙基乙胺0.21mL(1.2mmol),冰浴下慢慢滴入氯甲酸甲酯93μL(1.2mmol),反应半小时后移去冰浴,室温继续反应3小时。反应结束后加入饱和碳酸氢钠10mL,用二氯甲烷萃取三次(10mL×3),无水硫酸钠干燥有机相,减压浓缩,将浓缩物溶于1mL吡啶,加入1mL醋酐,室温下搅拌反应8h后,注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析(石油醚∶丙酮=6∶1v/v洗脱)得300mg化合物F1(白色粉末),产率62%。
1H NMR(CDCl3,300MHz):δ:9.04(s),6.84(d,J=8.1Hz,1H),6.28(dd,J=8.1,2.1Hz,1H),6.12(d,J=2.1Hz,1H),5.85(dd,J=10.2,4.5Hz,1H),5.34(d,J=10.2Hz,1H),5.29(s,1H),4.98(s,1H),3.82(s,3H),3.75(s,3H),3.47(m,1H),3.40(s,1H),3.32(m,3H),3.09(d,J=12.6Hz,1H),2.87(s,3H),2.82(d,J=15.6Hz,1H),2.59(s,1H),2.49(m,1H),2.30-2.12(m,2H),2.08(s,3H),1.27(m,1H),0.98(m,1H),0.49(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.7(C),161.1(C),157.3(C),154.5(C),130.5(CH),125.8(C),124.2(CH),122.7(CH),105.2(CH),96.8(CH),82.0(CH),77.2(CH),76.0(C),67.5(CH),55.4(OCH3),52.3(C),52.2(OCH3),51.7(CH2),50.9(CH2),45.2(CH2),44.8(CH2),42.9(C),40.7(CH3),31.5(CH2),21.0(CH3),7.6(CH3)。
制备实施例49化合物F2的制备
制备步骤参见化合物F1的制备。
1H NMR(CDCl3,300MHz):δ:9.05(s),6.86(d,J=8.1Hz,1H),6.30(dd,J=8.1,2.4Hz,1H),6.14(d,J=2.4Hz,1H),5.87(dd,J=10.2,4.5Hz,1H),5.34(d,J=10.2Hz,1H),5.26(s,1H),5.00(s,1H),4.09(q,J=6.9Hz,1H),3.78(s,3H),3.51(m,1H),3.43(s,1H),3.35(m,2H),3.11(d,J=12.3Hz,1H),2.90(s,3H),2.81(d,J=15.9Hz,1H),2.62(s,1H),2.50(m,1H),2.26-2.17(m,2H),2.10(s,3H),1.27(m,1H),1.22(t,J=6.9Hz,3H),1.00(m,1H),0.51(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.2(C),160.8(C),156.5(C),154.1(C),130.1(CH),125.5(C),123.8(CH),122.4(CH),104.8(CH),96.4(CH),81.6(CH),76.9(CH),75.6(C),67.2(CH),60.3(CH2),55.0(0CH3),51.9(C),51.3(CH2),50.6(CH2),44.8(CH2),44.4(CH2),42.6(C),40.3(CH3),31.1(CH2),20.6(CH3),14.4(CH3),7.3(CH3)。
制备实施例50化合物F3的制备
在氩气保护下,将2.4mmol(0.18mL)异丙醇溶于10mL二氯甲烷溶液中,加入二异丙基乙基胺2.4mmol(0.42mL),在冰浴条件下滴入固体光气(0.9mmol,270mg)的二氯甲烷溶液(5mL),冰浴下反应半个小时,室温下反应1h。在冰浴下再加入二异丙基乙基胺(1.2mmol,0.21mL),慢慢滴入到B(1mmol)的二氯甲烷溶液(3mL)中,冰浴下反应半个小时,室温下反应3小时。反应完毕后加入10mL饱和碳酸氢钠,用二氯甲烷萃取(10mL×3),无水硫酸钠干燥有机相,减压浓缩,将浓缩物溶于1mL吡啶,加入1mL醋酐,室温下搅拌反应8h后,注入30mL乙酸乙酯和10mL饱和碳酸氢钠溶液继续搅拌2分钟,移去水层,用水洗去吡啶(20mL×3),将乙酸乙酯层干燥浓缩,经硅胶柱层析(石油醚∶丙酮=6∶1v/v洗脱)得222mg化合物F3(白色粉末),产率43%。
1H NMR(CDCl3,300MHz):δ:9.01(s),6.78(d,J=8.1Hz,1H),6.21(dd,J=8.1,1.8Hz,1H),6.04(d,J=1.8Hz,1H),5.78(dd,J=10.2,3.9Hz,1H),5.27(d,J=10.2Hz,1H),5.17(d,J=6.6Hz,1H),4.92(s,1H),4.79(m,1H),3.67(s,3H),3.40(m,2H),3.35(s,1H),3.24(m,1H),3.02(d,J=12.6Hz,1H),2.80(s,3H),2.73(d,J=16.2Hz,1H),2.54(s,1H),2.42(m,1H),2.22-2.11(m,2H),2.00(s,3H),1.20(m,1H),1.11(d,J=6.0Hz,6H),0.95(m,1H),0.42(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.3(C),160.8(C),156.2(C),154.2(C),130.2(CH),125.5(C),123.9(CH),122.4(CH),104.9(CH),96.4(CH),81.7(CH),77.0(CH),75.8(C),67.5(CH),67.3(CH),55.1(OCH3),52.0(C),51.4(CH2),50.7(CH2),44.9(CH2),44.5(CH2),42.7(C),40.3(CH3),31.2(CH2),22.0(2CH3),20.7(CH3),7.4(CH3)。
制备实施例51化合物F4的制备
制备步骤参见化合物F1的制备。
1H NMR(CDCl3,300MHz):δ:9.01(s),6.79(d,J=8.1Hz,1H),6.21(dd,J=8.1,1.8Hz,1H),6.04(d,J=1.8Hz,1H),5.80(dd,J=10.2,4.5Hz,1H),5.28(d,J=10.2Hz,1H),5.22(s,1H),4.92(s,1H),3.67(s,3H),3.40(m,2H),3.35(s,1H),3.25(m,1H),3.03(d,J=12.3Hz,1H),2.80(s,3H),2.73(d,J=15.9Hz,1H),2.54(s,1H),2.43(m,1H),2.22-2.06(m,2H),2.00(s,3H),1.36(s,9H),1.20(m,1H),0.90(m,1H),0.50(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.3(C),160.9(C),156.4(C),154.6(C),130.8(CH),126.5(C),124.3(CH),122.7(CH),104.6(CH),96.4(CH),81.6(CH),79.0(C),76.6(CH),75.7(C),68.5(CH),55.2(OCH3),51.9(C),51.4(CH2),50.6(CH2),44.9(CH2),44.5(CH2),43.6(C),40.5(CH3),31.5(CH2),28.4(3CH3),21.1(CH3),7.7(CH3)。
制备实施例52化合物F5的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:8.95(s),6.76(d,J=8.4Hz,1H),6.19(dd,J=8.4,1.8Hz,1H),6.02(d,J=1.8Hz,1H),5.77(dd,J=10.2,4.2Hz,1H),5.25(d,J=10.2Hz,1H),5.20(s,1H),4.89(s,1H),3.88(t,J=6.3Hz,2H),3.63(s,3H),3.40-3.36(m,1H),3.33(s,1H),3.23(m,1H),3.10(m,1H),3.01(d,J=12.6Hz,1H),2.78(s,3H),2.71(d,J=16.2Hz,1H),2.52(s,1H),2.40(q,J=9.0Hz,1H),2.16-2.11(m,2H),1.90(s,3H),1.53-1.46(m.2H),1.22-1.14(m,1H),0.92-0.83(m,1H),0.80(t,J=7.2Hz,3H),0.40(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.2(C),160.8(C),156.7(C),154.2(C),130.2(CH),125.5(C),123.9(CH),122.4(CH),104.9(CH),96.4(CH),81.7(CH),77.0(CH),75.7(C),67.3(CH),66.1(CH2),55.0(OCH3),51.9(C),51.4(CH2),50.6(CH2),44.9(CH2),44.4(CH2),42.6(C),40.3(CH3),31.2(CH2),22.2(CH2),20.6(CH3),10.1(CH3),7.3(CH3)。
制备实施例53化合物F6的制备
制备步骤参见化合物F1的制备。
1H NMR(CDCl3,300MHz):δ:9.01(s),6.79(d,J=8.1Hz,1H),6.21(dd,J=8.1,1.8Hz,1H),6.04(d,J=1.8Hz,1H),5.80(dd,J=10.2,4.5Hz,1H),5.28(d,J=10.2Hz,1H),5.22(s,1H),4.92(s,1H),3.73(d,J=6.3Hz,2H),3.67(s,3H),3.40(m,2H),3.35(s,1H),3.25(m,1H),3.03(d,J=12.3Hz,1H),2.80(s,3H),2.73(d,J=15.9Hz,1H),2.54(s,1H),2.43(m,1H),2.22-2.06(m,2H),2.00(s,3H),1.78(m,1H),1.20(m,1H),0.90(m,1H),0.80(d,J=6.6Hz,6H),0.42(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.3(C),160.8(C),156.7(C),154.2(C),130.2(CH),125.5(C),123.9(CH),122.4(CH),104.8(CH),96.4(CH),81.6(CH),77.0(CH),75.7(C),70.6(CH2),67.3(CH),55.1(OCH3),51.9(C),51.4(CH2),50.6(CH2),44.9(CH2),44.5(CH2),42.6(C),40.3(CH3),31.2(CH2),27.8(CH),20.7(CH3),18.8(2CH3),7.3(CH3)。
制备实施例54化合物F7的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:8.98(s),6.81(d,J=8.4Hz,1H),6.24(d,J=8.4Hz,1H),6.07(s,1H),5.80(dd,J=10.2,4.2Hz,1H),5.39(d,J=7.2Hz,1H),5.30(d,J=10.2Hz,1H),4.94(s,1H),4.14(t,J=6.3Hz,2H),3.71(s,3H),3.50(t,J=6.3Hz,2H),3.50-3.18(m,3H),3.38(s,1H),3.30(s,3H),3.05(d,J=12.6Hz,1H),2.83(s,3H),2.75(d,J=15.3Hz,1H),2.56(s,1H),2.45(q,J=9.0Hz,1H),2.24-2.08(m,2H),2.04(s,3H),1.26-1.18(m,1H),0.99-0.87(m,1H),0.45(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.5(C),161.0(C),156.5(C),154.4(C),130.3(CH),125.7(C),124.0(CH),122.6(CH),105.1(CH),96.6(CH),81.7(CH),77.1(CH),75.9(C),70.9(CH2),67.5(CH),63.7(CH2),58.8(OCH3),55.2(OCH3),52.1(C),51.5(CH2),50.8(CH2),45.0(CH2),44.6(CH2),42.8(C),40.5(CH3),31.4(CH2),20.8(CH3),7.5(CH3)。
制备实施例55化合物F8的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.12(s),6.87(d,J=8.4Hz,1H),6.32(dd,J=8.4,2.4Hz,1H),6.15(d,J=2.4Hz,1H),5.89(dd,J=10.5,3.6Hz,1H),5.43(m,1H),5.38(d,J=10.5Hz,1H),5.01(s,1H),4.35(t,J=6.3Hz,2H),3.79(s,3H),3.49(t,J=6.3Hz,2H),3.52-3.30(m,3H),3.43(s,1H),3.14(d,J=13.2Hz,1H),2.91(s,3H),2.83(d,J=14.7Hz,1H),2.64(s,1H),2.53(q,J=9.0Hz,1H),2.25-2.10(m,2H),2.12(s,3H),1.26-1.18(m,1H),1.10-0.87(m,1H),0.52(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),161.0(C),155.8(C),154.3(C),130.3(CH),125.6(C),124.0(CH),122.6(CH),105.1(CH),96.6(CH),82.0(CH),77.0(CH),75.8(C),67.4(CH),64.1(CH2),55.2(OCH3),52.2(C),51.5(CH2),50.8(CH2),45.2(CH2),44.6(CH2),42.8(C),40.7(CH3),31.3(CH2),29.5(CH2),20.9(CH3),7.4(CH3)。
制备实施例56化合物F9的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.05(s),6.82(d,J=8.1Hz,1H),6.25(dd,J=8.1,2.1Hz,1H),6.04(d,J=2.1Hz,1H),5.82(dd,J=10.2,3.3Hz,1H),5.31(d,J=10.2Hz,1H),5.25(d,J=10.2Hz,1H),4.96(s,1H),3.97(t,J=6.3Hz,2H),3.71(s,3H),3.45(m,2H),3.39(s,1H),3.29(m,1H),3.07(d,J=12.3Hz,1H),2.84(s,3H),2.77(d,J=15.9Hz,1H),2.58(s,1H),2.46(m,1H),2.26-2.10(m,2H),2.05(s,3H),1.53(m,2H),1.26(m,5H),0.93(m,1H),0.74(m,5H),0.46(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),160.9(C),156.9(C),154.4(C),130.3(CH),125.6(C),124.0(CH),122.6(CH),105.0(CH),96.5(CH),81.8(CH),77.1(CH),75.9(C),67.4(CH),64.8(CH2),55.2(OCH3),52.1(C),51.6(CH2),50.8(CH2),45.0(CH2),44.6(CH2),42.8(C),40.5(CH3),31.3(CH2),28.7(CH2),27.9(CH2),22.3(CH2),20.9(CH3),14.0(CH3),7.5(CH3)。
制备实施例57化合物F10的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.07(s),6.86(d,J=8.4Hz,1H),6.30(dd,J=8.4,2.4Hz,1H),6.14(d,J=2.4Hz,1H),5.87(dd,J=10.2,4.5Hz,1H),5.36(d,J=10.2Hz,2H),5.00(s,1H),3.86(d,J=7.2Hz,2H),3.78(s,3H),3.50(m,2H),3.45(s,1H),3.34(m,1H),3.12(d,J=12.6Hz,1H),2.90(s,3H),2.81(d,J=15.9Hz,1H),2.62(s,1H),2.51(m,1H),2.28-2.18(m,2H),2.11(s,3H),1.30(m,1H),1.10(m,1H),0.96(m,1H),0.51(t,J=7.2Hz,3H),0.51(d,J=4.8Hz,2H),0.25(d,J=4.8Hz,2H);
13C NMR(CDCl3,75MHz):δ:170.4(C),160.9(C),156.8(C),154.4(C),130.3(CH),125.6(C),124.0(CH),122.6(CH),105.0(CH),96.5(CH),81.7(CH),77.1(CH),75.9(C),69.4(CH2),67.4(CH),55.2(OCH3),52.1(C),51.5(CH2),50.8(CH2),45.0(CH2),44.6(CH2),42.8(C),40.4(CH3),31.3(CH2),20.8(CH3),10.1(CH),7.4(CH3),3.0(2CH2)。
制备实施例58化合物F11的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.06(s),6.86(d,J=8.4Hz,1H),6.30(dd,J=8.4,2.4Hz,1H),6.14(d,J=2.4Hz,1H),5.87(dd,J=10.2,4.8Hz,1H),5.36(d,J=10.2Hz,1H),5.27(d,J=7.5Hz,1H),4.99(s,1H),4.90(m,1H),3.78(s,3H),3.48(m,2H),3.43(s,1H),3.35(m,1H),3.09(d,J=12.3Hz,1H),2.89(s,3H),2.80(d,J=15.9Hz,1H),2.62(s,1H),2.49(m,1H),2.32-2.14(m,4H),2.10(s,3H),2.01(m,2H),1.73(m,1H),1.57(m,1H),1.28(m,1H),0.98(m,1H),0.51(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.1(C),160.7(C),155.7(C),154.1(C),130.1(CH),125.4(C),123.8(CH),122.4(CH),104.8(CH),96.4(CH),81.6(CH),76.8(CH),75.6(C),68.3(CH),67.1(CH),54.9(OCH3),51.9(C),51.2(CH2),50.5(CH2),44.7(CH2),44.4(CH2),42.5(C),40.3(CH3),31.1(CH2),30.3(CH2),30.1(CH2),20.6(CH3),12.9(CH2),7.2(CH3)。
制备实施例59化合物F12的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:8.97(s),6.78(d,J=8.4Hz,1H),6.48(dd,J=8.4,2.4Hz,1H),6.04(d,J=2.4Hz,1H),5.79(dd,J=10.2,4.8Hz,1H),5.27(d,J=10.2Hz,1H),5.14(d,J=7.5Hz,1H),4.97(m,1H),4.91(s,1H),3.67(s,3H),3.38(m,2H),3.34(s,1H),3.25(m,1H),3.20(d,J=12.3Hz,1H),2.80(s,3H),2.73(d,J=15.6Hz,1H),2.54(s,1H),2.40(m,1H),2.21-2.13(m,2H),2.00(s,3H),1.72(m,2H),1.58(m,4H),1.44(m,2H),1.24(m,1H),0.92(m,1H),0.42(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.2(C),160.8(C),156.4(C),154.2(C),130.2(CH),125.5(C),123.9(CH),122.4(CH),104.8(CH),96.4(CH),81.7(CH),77.0(2CH),75.7(C),67.3(CH),55.0(OCH3),51.9(C),51.4(CH2),50.7(CH2),44.9(CH2),44.4(CH2),42.6(C),40.2(CH3),32.6(2CH2),31.2(CH2),23.4(2CH2),20.7(CH3),7.3(CH3)。
制备实施例60化合物F13的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:8.97(s),6.79(d,J=8.4Hz,1H),6.22(dd,J=8.4,2.4Hz,1H),6.06(d,J=2.4Hz,1H),5.79(dd,J=10.2,4.8Hz,1H),5,29(d,J=10.2Hz,1H),5.19(d,J=5.7Hz,1H),4.93(s,1H),4.53(m,1H),3.69(s,3H),3.40(m,2H),3.37(s,1H),3.27(m,1H),3.04(d,J=12.3Hz,1H),2.82(s,3H),2.74(d,J=15.6Hz,1H),2.55(s,1H),2.42(m,1H),2.25-2.15(m,2H),2.02(s,3H),1.75(m,2H),1.62(m,2H),1.42(m,1H),1.26(m,6H),0.88(m,1H),0.44(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.3(C),160.9(C),156.3(C),154.3(C),130.3(CH),125.6(C),124.0(CH),122.5(CH),104.9(CH),96.4(CH),81.7(CH),77.1(CH),75.8(C),72.6(CH),67.4(CH),55.1(OCH3),52.0(C),51.5(CH2),50.7(CH2),45.0(CH2),44.5(CH2),42.7(C),40.3(CH3),31.9(CH2),31.3(2CH2),25.5(CH2),23.7(2CH2),20.8(CH3),7.4(CH3)。
制备实施例61化合物F14的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.18(s),7.30(t,J=7.2Hz,2H),7.01(m,3H),6.86(dd,J=8.4,1.8Hz,1H),6.30(dd,J=8.4,1.8Hz,1H),6.14(s,1H),5.87(dd,J=10.2,4.5Hz,1H),5.76(d,J=7.5Hz,1H),5.37(d,J=9.9Hz,1H),5.01(s,1H),3.74(s,3H),3.60(m,1H),3.47(s,1H),3.42(m,1H),3.34(m,1H),3.22(d,J=12.6Hz,1H),2.88(s,3H),2.80(d,J=15.9Hz,1H),2.65(s,1H),2.49(m,1H),2.26-2.16(m,2H),2.10(s,3H),1.28(m,1H),1.00(m,1H),0.52(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.5(C),160.9(C),154.6(C),154.2(C),151.0(C),130.2(CH),129.1(2CH),125.5(C),125.0(CH),124.0(CH),122.6(CH),121.5(2CH),105.3(CH),96.7(CH),82.3(CH),76.8(CH),75.8(C),67.2(CH),55.2(OCH3),52.2(C),51.3(CH2),50.7(CH2),45.2(CH2),44.5(CH2),42.7(C),40.9(CH3),31.2(CH2),20.8(CH3),7.4(CH3)。
制备实施例62化合物F15的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.19(s),7.03(m,4H),6.86(dd,J=8.4,1.8Hz,1H),6.30(dd,J=8.4,1.8Hz,1H),6.15(s,1H),5.87(dd,J=10.2,4.5Hz,1H),5.77(d,J=7.5Hz,1H),5.37(d,J=10.2Hz,1H),5.01(s,1H),3.74(s,3H),3.60(m,1H),3.47(s,1H),3.42(m,1H),3.34(m,1H),3.22(d,J=12.6Hz,1H),2.92(s,3H),2.80(d,J=15.9Hz,1H),2.65(s,1H),2.49(m,1H),2.30-2.16(m,2H),2.08(s,3H),1.28(m,1H),1.00(m,1H),0.51(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.5(C),161.0(C),154.6(C),154.2(C),146.9(C),130.2(CH),125.5(C),124.1(CH),123.0(d,2CH),122.7(CH),115.8(d,2CH),105.4(CH),96.9(CH),82.4(CH),76.8(CH),75.8(C),67.0(CH),55.2(OCH3),52.2(C),51.3(CH2),50.7(CH2),45.3(CH2),44.6(CH2),42.7(C),41.0(CH3),31.2(CH2),20.9(CH3),7.4(CH3)。
制备实施例63化合物F16的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.19(s),7.04(m,2H),6.96(m,2H),6.29(dd,J=8.4,1.8Hz,1H),6.14(s,1H),5.83(dd,J=10.2,4.5Hz,1H),5.79(d,J=7.5Hz,1H),5.35(d,J=10.2Hz,1H),4.99(s,1H),3.72(s,3H),3.61(m,1H),3.45(s,1H),3.42(m,1H),3.34(m,1H),3.22(d,J=12.6Hz,1H),2.92(s,3H),2.80(d,J=15.9Hz,1H),2.65(s,1H),2.49(m,1H),2.30-2.16(m,2H),2.08(s,3H),1.28(m,1H),1.00(m,1H),0.51(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.5(C),161.0(C),154.1(C),153.9(C),149.9(C),146.3(C),130.2(CH),125.4(C),124.1(CH),122.6(CH),117.5(CH),116.7(d,CH),111.5(d,CH),105.4(CH),96.9(CH),82.5(CH),76.7(CH),75.7(C),67.0(CH),55.1(OCH3),52.2(C),51.2(CH2),50.7(CH2),45.3(CH2),44.5(CH2),42.7(C),41.1(CH3),31.2(CH2),20.8(CH3),7.4(CH3)。
制备实施例64化合物F17的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.16(s),7.15(t,J=7.2Hz,1H),7.07(d,J=7.2Hz,1H),7.01(m,3H),6.94-6.87(m,3H),6.31(dd,J=8.4,1.8Hz,1H),6.15(s,1H),5.89(dd,J=10.2,4.5Hz,1H),5.78(d,J=8.1Hz,1H),5.38(d,J=10.5Hz,1H),5.03(s,1H),3.78(s,6H),3.60(m,1H),3.53(s,1H),3.47(m,1H),3.35(m,1H),3.22(d,J=12.6Hz,1H),2.88(s,3H),2.82(d,J=15.9Hz,1H),2.66(s,1H),2.52(m,1H),2.26-2.16(m,2H),2.12(s,3H),1.28(m,1H),1.00(m,1H),0.53(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.6(C),161.9(C),154.5(2C),151.8(C),140.1(C),130.4(CH),126.5(CH),125.7(C),124.2(CH),123.4(CH),122.7(CH),120.7(CH),112.3(CH),105.3(CH),96.7(CH),82.0(CH),77.0(CH),76.1(C),67.4(CH),55.8(OCH3),55.4(OCH3),52.3(C),51.6(CH2),50.9(CH2),45.3(CH2),44.7(CH2),42.9(C),40.7(CH3),31.4(CH2),21.0(CH3),7.6(CH3)。
制备实施例65化合物F18的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.19(s),7.04(d,J=7.2Hz,2H),6.87(m,3H),6.33(dd,J=8.4,1.8Hz,1H),6.16(s,1H),5.89(dd,J=10.2,4.5Hz,1H),5.70(d,J=7.8Hz,1H),5.38(d,J=10.2Hz,1H),5.03(s,1H),3.78(s,6H),3.61(m,1H),3.48(m,1H),3.47(s,1H),3.37(m,1H),3.22(d,J=12.6Hz,1H),2.95(s,3H),2.84(d,J=15.9Hz,1H),2.67(s,1H),2.52(m,1H),2.26-2.16(m,2H),2.12(s,3H),1.28(m,1H),1.00(m,1H),0.53(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.6(C),161.0(C),156.8(C),155.1(C),154.3(C),144.6(C),130.3(CH),125.6(C),124.2(CH),122.7(CH),122.4(2CH),114.2(2CH),105.3(CH),96.8(CH),82.3(CH),76.8(CH),75.8(C),67.2(CH),55.5(OCH3),55.3(OCH3),52.3(C),51.4(CH2),50.8(CH2),45.3(CH2),44.7(CH2),42.8(C),41.0(CH3),31.3(CH2),21.0(CH3),7.5(CH3)。
制备实施例66化合物F19的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.10(s),7.30(m,5H),6.86(d,J=8.4Hz,1H),6.30(dd,J=8.4,2.4Hz,1H),6.13(d,J=2.4Hz,1H),5.87(dd,J=10.2,4.5Hz,1H),5.43(d,J=7.5Hz,1H),5.36(d,J=10.2Hz,1H),5.09(s,2H),5.01(s,1H),3.77(s,3H),3.50(m,2H),3.42(s,1H),3.34(m,1H),3.14(d,J=12.6Hz,1H),2.88(s,3H),2.81(d,J=15.9Hz,1H),2.62(s,1H),2.49(m,1H),2.26-2.16(m,2H),2.08(s,3H),1.28(m,1H),1.00(m,1H),0.51(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.6(C),161.1(C),156.6(C),154.5(C),136.8(C),130.4(CH),128.5(2CH),128.1(2CH),125.7(C),124.2(CH),122.7(CH),105.2(CH),96.7(CH),81.9(CH),77.2(CH),76.0(C),67.5(CH),66.6(CH2),55.4(OCH3),52.2(C),51.6(CH2),50.9(CH2),45.2(CH2),44.7(CH2),42.9(C),40.6(CH3),31.4(CH2),21.0(CH3),7.6(CH3)。
制备实施例67化合物F20的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.10(s),7.23(d,J=7.2Hz,1H),7.16(t,J=7.2Hz,1H),6.82(t,J=7.2Hz,1H),6.77(d,J=8.4Hz,1H),6.76(d,J=7.2Hz,1H),6.21(dd,J=8.4,2.4Hz,1H),6.04(s,1H),5.77(dd,J=10.2,3.9Hz,1H),5.35(d,J=6.3Hz,1H),5.27(d,J=10.2Hz,1H),5.07(s,2H),4.93(s,1H),3.70(s,3H),3.66(s,3H),3.47-3.32(m,2H),3.35(s,1H),3.27-3.19(m,1H),3.07(d,J=12.9Hz,1H),2.79(s,3H),2.71(d,J=15.9Hz,1H),2.52(s,1H),2.42-2.36(m,1H),2.20-2.08(m,2H),1.908(s,3H),1.33-1.22(m,1H),0.95-0.86(m,1H),0.42(t,J=7.5Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),160.9(C),157.2(C),156.6(C),154.4(C),130.3(CH),129.3(CH),129.2(CH),125.6(C),124.9(C),124.0(CH),122.5(CH),120.3(CH),110.2(CH),105.0(CH),96.5(CH),81.7(CH),77.1(CH),75.9(C),67.5(CH),61.8(CH2),55.2(2OCH3),52.0(C),51.5(CH2),50.7(CH2),45.2(CH2),44.5(CH2),42.8(C),40.4(CH3),31.3(CH2),20.7(CH3),7.4(CH3)。
制备实施例68化合物F21的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:8.95(s),7.19(d,J=8.4Hz,2H),6.78(d,J=8.4Hz,2H),6.76(d,J=8.1Hz,1H),6.21(dd,J=8.1,1.8Hz,1H),6.04(s,1H),5.77(dd,J=10.2,4.5Hz,1H),5.32(d,J=6.3Hz,1H),5.27(d,J=10.2Hz,1H),4.93(s,3H),3.67(s,6H),3.43-3.38(m,2H),3.33(s,1H),3.26-3.20(m,1H),3.06(d,J=12.3Hz,1H),2.78(s,3H),2.71(d,J=16.2Hz,1H),2.53(s,1H),2.40(q,J=8.7Hz,1H),2.16-2.06(m,2H),1.98(s,3H),1.25-1.17(m,1H),0.94-0.87(m,1H),0.43(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),160.9(C),159.4(C),156.4(C),154.3(C),130.3(CH),129.8(2CH),128.7(C),125.6(C),124.0(CH),122.5(CH),113.7(2CH),105.0(CH),96.5(CH),81.7(CH),77.0(CH),75.8(C),67.5(CH),66.2(CH2),55.2(OCH3),55.1(OCH3),52.1(C),51.5(CH2),50.7(CH2),45.1(CH2),44.5(CH2),42.8(C),40.4(CH3),31.3(CH2),20.8(CH3),7.4(CH3)。
制备实施例69化合物F22的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.00(s),6.83-6.67(m.4H),6.25(dd,J=8.1,1.8Hz,1H),6.08(s,1H),5.84(s,2H),5.80(dd,J=10.2,4.5Hz,1H),5.39(d,J=6.0Hz,1H),5.31(d,J=10.2Hz,1H),4.96(s,1H),4.92(s,2H),3.70(s,6H),3.50-3.42(m,2H),3.37(s,1H),3.31-3.25(m,1H),3.10(d,J=12.3Hz,1H),2.82(s,3H),2.76(d,J=16.2Hz,1H),2.57(s,1H),2.45(q,J=9.6Hz,1H),2.24-2.09(m,2H),2.02(s,3H),1.28-1.20(m,1H),0.98-0.89(m,1H),0.46(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.3(C),160.9(C),156.3(C),154.3(C),147.6(C),147.3(C),130.4(C),130.2(CH),125.6(C),123.9(CH),122.5(CH),121.8(CH),108.7(CH),108.0(CH),104.9(CH),100.9(CH2),96.5(CH),81.7(CH),77.0(CH),75.8(C),67.4(CH),66.3(CH2),55.1(OCH3),52.0(C),51.4(CH2),50.7(CH2),45.1(CH2),44.4(CH2),42.7(C),40.4(CH3),31.3(CH2),20.7(CH3),7.4(CH3)。
制备实施例70化合物F23的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.11(s),7.34(s,1H),7.27-7.20(m.2H),6.86(d,J=8.4Hz,1H),6.31(d,J=8.4Hz,1H),6.14(s,1H),5.88(dd,J=10.2,4.5Hz,1H),5.44(d,J=6.0Hz,1H),5.37(d,J=10.2Hz,1H),5.06(s,2H),5.01(s,1H),3.79(s,3H),3.56-3.34(m,3H),3.42(s,1H),3.15(d,J=12.9Hz,1H),2.88(s,3H),2.82(d,J=16.2Hz,1H),2.64(s,1H),2.56-2.47(m,1H),2.33-2.17(m,2H),2.09(s,3H),1.37-1.28(m,1H),1.06-0.94(m,1H),0.52(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),161.0(C),156.1(C),154.3(C),138.8(C),134.2(C),130.3(CH),129.7(CH),128.0(CH),127.7(CH),125.7(CH),125.5(C),124.0(CH),122.6(CH),105.1(CH),96.6(CH),81.9(CH),77.0(CH),75.9(C),67.4(CH),65.4(CH2),55.2(OCH3),52.1(C),51.4(CH2),50.8(CH2),45.2(CH2),44.6(CH2),42.8(C),40.5(CH3),31.3(CH2),20.8(CH3),7.4(CH3)。
制备实施例71化合物F24的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.01(s),7.29(m.4H),6.87(d,J=8.4Hz,1H),6.31(d,J=8.4Hz,1H),6.14(s,1H),5.87(dd,J=10.2,4.5Hz,1H),5.42(d,J=6.6Hz,1H),5.36(d,J=10.2Hz,1H),5.05(s,2H),5.00(s,1H),3.79(s,3H),3.60-3.25(m,3H),3.41(s,1H),3.14(d,J=12.6Hz,1H),2.88(s,3H),2.84(d,J=16.2Hz,1H),2.63(s,1H),2.56-2.42(m,1H),2.31-2.14(m,2H),2.09(s,3H),1.40-1.20(m,1H),1.04-0.96(m,1H),0.52(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.2(C),160.9(C),156.1(C),154.2(C),135.2(C),133.5(C),130.2(CH),129.2(2CH),128.4(2CH),125.5(C),123.9(CH),122.5(CH),105.0(CH),96.5(CH),81.8(CH),76.9(CH),75.7(C),67.3(CH),65.4(CH2),55.0(OCH3),52.0(C),51.4(CH2),50.6(CH2),45.1(CH2),44.4(CH2),42.7(C),40.4(CH3),31.2(CH2),20.6(CH3),7.3(CH3)。
制备实施例72化合物F25的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.11(s),7.97(d,J=8.1Hz,1H),7.52(m,2H),7.36(m.1H),6.80(d,J=8.4Hz,1H),6.23(d,J=8.4Hz,1H),6.06(s,1H),5.81(dd,J=10.2,4.5Hz,1H),5.50(d,J=7.5Hz,1H),5.42(s,2H),5.30(d,J=10.2Hz,1H),4.94(s,1H),3.68(s,3H),3.49-3.25(m,3H),3.37(s,1H),3.08(d,J=12.9Hz,1H),2.81(s,3H),2.76(d,J=16.2Hz,1H),2.58(s,1H),2.50-2.41(m,1H),2.24-2.12(m,2H),2.01(s,3H),1.25-1.17(m,1H),0.98-0.84(m,1H),0.44(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.5(C),161.0(C),155.9(C),154.3(C),147.3(C),133.7(CH),133.4(C),130.3(CH),128.6(CH),128.4(CH),125.6(C),124.9(CH),124.1(CH),122.7(CH),105.2(CH),96.7(CH),82.1(CH),77.0(CH),75.9(C),67.4(CH),63.1(CH2),55.3(OCH3),52.2(C),51.5(CH2),50.8(CH2),45.2(CH2),44.6(CH2),42.8(C),40.7(CH3),31.4(CH2),20.9(CH3),7.5(CH3)。
制备实施例73化合物F26的制备
制备步骤参见化合物F3的制备。
1H NMR(CDCl3,300MHz):δ:9.20(s),8.21(d,J=8.7Hz,2H),8.50(d,J=8.7Hz,2H),6.88(d,J=8.4Hz,1H),6.32(dd,J=8.4,2.4Hz,1H),6.15(s,1H),5.90(dd,J=10.2,3.6Hz,1H),5.52(d,J=7.5Hz,1H),5.38(d,J=10.2Hz,1H),5.19(s,2H),5.01(s,1H),3.79(s,3H),3.58-3.33(m,3H),3.42(s,1H),3.16(d,J=12.9Hz,1H),2.89(s,3H),2.87(d,J=16.2Hz,1H),2.65(s,1H),2.58-2.49(m,1H),2.33-2.23(m,2H),2.09(s,3H),1.34-1.25(m,1H),1.03-0.96(m,1H),0.53(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.4(C),160.9(C),155.8(C),154.1(C),147.3(C),144.2(C),130.2(CH),127.9(2CH),125.5(C),124.0(CH),123.5(2CH),122.6(CH),105.1(CH),96.6(CH),82.0(CH),76.9(CH),75.7(C),67.3(CH),64.9(CH2),55.1(OCH3),52.1(C),51.3(CH2),50.7(CH2),45.2(CH2),44.5(CH2),42.7(C),40.6(CH3),31.2(CH2),20.7(CH3),7.4(CH3)。
制备实施例74化合物F27的制备
在氩气保护下,将1mmol(547mg)F14溶于10mL四氢呋喃溶液中,加入氢化钠48mg(1.2eq),室温下反应2h。反应完毕后加入10mL饱和氯化铵,用乙酸乙酯萃取(10mL×3),无水硫酸钠干燥有机相,减压浓缩,经硅胶柱层析(石油醚∶丙酮=2∶1v/v洗脱)得180mg化合物F15(白色粉末),产率40%
1H NMR(CDCl3,300MHz):δ:6.83(d,J=7.8Hz,1H),6.12(d,J=7.8Hz,1H),5.96(s,1H),5.87(dd,J=9.9,4.8Hz,1H),5.30(d,J=9.9Hz,1H),5.17(s,1H),4.90(s,1H),3.81(s,1H),3.78(s,3H),3.40(dd,J=16.5,4.8Hz,1H),3.18(s,2H),3.21-3.12(m,2H),3.10(s,3H),2.69(d,J=16.5Hz,1H),2.65(s,1H),2.39-2.29(m,1H),2.19-2.10(m,1H),2.04(s,3H),1.62-1.52(m,1H),130-1.18(m,1H),0.88(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:170.3(C),160.9(C),158.4(C),151.1(C),128.2(CH),127.9(C),126.4(CH),120.4(CH),100.9(CH),92.5(CH),87.1(C),75.2(CH),74.8(CH),62.5(CH),55.0(OCH3),52.9(C),52.3(CH2),51.6(CH2),45.2(CH2),44.4(C),43.4(CH2),33.5(CH3),28.5(CH2),20.9(CH3),8.5(CH3)。
实施例1化合物BM1的制备
在氩气保护下,将280mg(0.58mmol)长春质碱的酒石酸盐和280mg(1.74mmol)无水三氯化铁加入到缓冲溶液中(由185mg甘氨酸、145mg氯化钠、水24mL和24mL 0.1N盐酸配制),室温下搅拌10分钟,然后加入263mg(0.58mmol)化合物C1。室温下搅拌8h后,在冰浴(0℃)下滴加入含48mg硼氢化纳的氨水溶液(5mL),冰浴下反应15-20分钟。完毕后用二氯甲烷萃取(20mL×4),二氯甲烷层依次经饱和食盐水洗涤(20mL×3)、硅藻土过滤和低温减压浓缩。将浓缩物溶于2mL甲醇,放置2分钟,有白色晶体析出,过滤干燥得257mg化合物BM1,产率56%。
1H NMR(CDCl3,300MHz):δ:9.03(s,1H),8.02(s,1H),7.51(d,J=7.8Hz,1H),7.10(m,3H),6.60(s,1H),6.16(s,1H),5.86(dd,J=10.5,4.2Hz,1H),5.46(d,J=6.0Hz,1H),5.45(d,J=10.5Hz,1H),5.01(s,1H),3.82(s,3H),3.70(s,1H),3.60(s,3H),3.00(s,3H),2.58(s,1H),2.17(s,3H),1.43(m,1H),1.22(t,J=6.9Hz,3H),0.99(t,J=7.8Hz,3H),0.81(t,J=7.2Hz,3H);
13C NMR(CDCl3,75NMHz):δ:175.1(C),171.3(C),158.0(C),153.9(C),140.1(C),135.1(C),131.3(C),129.9(CH),129.6(C),124.7(CH),124.1(CH),123.8(CH),123.8(C),122.4(CH),121.3(C),119.0(CH),118.5(CH),117.2(C),110.6(CH),94.5(CH),81.0(CH),77.7(C),76.8(CH),72.4(CH2),66.9(CH2),66.5(CH),56.0(OCH3),55.6(C),54.6(CH2),52.5(OCH3),52.4(CH2),52.3(C),50.5(CH2),50.2(CH2),46.1(CH2),45.2(CH2),42.3(C),39.1(CH3),34.6(CH2),33.1(CH),31.8(CH2),28.0(CH2),25.8(CH2),21.2(CH3),15.1(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)793.5[M+1]+。
实施例2化合物BM2的制备
制备步骤参见化合物BM1的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.01(s,1H),8.01(s,1H),7.52(d,J=7.8Hz,1H),7.10(m,3H),6.60(s,1H),6.16(s,1H),5.97(m,1H),5.86(dd,J=10.2,4.5Hz,1H),5.46(d,J=6.0Hz,1H),5.45(d,J=10.2Hz,1H),5.24(d,J=17.1Hz,1H),5.14(d,J=10.2Hz,1H),5.02(s,1H),4.04(m,2H),3.84(s,3H),3.61(s,3H),3.00(s,3H),2.59(s,1H),2.15(s,3H),1.43(m,1H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.82(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:175.1(C),171.3(C),158.0(C),154.0(C),140.1(C),135.2(C),135.0(CH),131.4(C),130.0(CH),129.6(C),124.8(CH),124.2(CH),123.9(CH),123.9(C),122.5(CH),121.1(C),119.0(CH),118.6(CH),117.2(CH2),117.2(C),110.7(CH),94.6(CH),81.2(CH),77.4(CH),77.4(C),72.9(CH2),72.2(CH2),66.7(CH),56.1(OCH3),55.7(C),54.7(CH2),52.5(OCH3),52.5(CH2),52.5(C),50.6(CH2),50.3(CH2),46.2(CH2),45.3(CH2),42.6(C),39.4(CH3),34.7(CH2),33.2(CH),31.9(CH2),28.0(CH2),26.1(CH2),21.2(CH3),12.6(CH3),8.5(CH3);
ESIMS(m/e)805.4[M+1]+。
实施例3化合物BM3的制备
制备步骤参见化合物BM1的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.00(s,1H),8.02(s,1H),7.52(d,J=7.5Hz,1H),7.14(m,3H),6.58(s,1H),6.16(s,1H),5.88(m,1H),5.86(dd,J=9.6,4.5Hz,1H),5.51(d,J=6.0Hz,1H),5.45(d,J=9.6Hz,1H),5.03(s,1H),3.83(s,3H),3.62(s,3H),3.01(s,3H),2.57(s,1H),2.18(s,3H),1.96(q,J=7.5Hz,2H),1.43(m,1H),1.21(m,1H),1.01(t,J=7.5Hz,3H),0.91(t,J=7.2Hz,3H),0.82(t,J=7.2Hz,3H);
实施例4化合物BM4的制备
制备步骤参见化合物BM1的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.04(s,1H),8.01(s,1H),7.51(d,J=7.8Hz,1H),7.10(m,3H),6.60(s,1H),6.16(s,1H),5.86(dd,J=10.5,4.2Hz,1H),5.46(d,J=6Hz,1H),5.45(d,J=10.5Hz,1H),5.02(s,1H),3.82(s,3H),3.74(s,1H),3.60(s,3H),3.00(s,3H),2.58(s,1H),2.17(s,3H),1.00(t,J=7.5Hz,3H),0.89(t,J=7.2Hz,3H),0.82(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:175.0(C),171.2(C),157.8(C),153.8(C),140.0(C),135.0(C),131.2(C),129.8(CH),129.5(C),124.7(CH),124.1(C),124.0(CH),123.7(CH),122.3(CH),120.8(C),118.9(CH),118.5(CH),117.4(C),110.5(CH),94.3(CH),80.9(CH),77.7(CH),77.2(C),72.6(CH2),71.6(CH2),66.4(CH),55.9(OCH3),55.5(C),54.5(CH2),52.4(OCH3),52.3(C),52.2(CH2),50.5(CH2),50.1(CH2),46.0(CH2),45.2(CH2),42.4(C),39.0(CH3),34.5(CH2),33.1(CH),31.7(2×CH2),27.9(CH2),25.8(CH2),21.2(CH3),19.5(CH2),14.0(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)821.5[M+1]+。
实施例5化合物BM5的制备
制备步骤参见化合物BM1的制备。
白色粉末,产率63%。1H NMR(DMSO-d6,300MHz):δ9.76(s,1H),8.08(s,1H),7.43(d,J=7.2Hz,1H),7.24(d,J=7.8Hz,2H),7.00(m,3H),6.91(d,J=7.8Hz,2H),6.56(s,1H),6.42(s,1H),5.78(dd,J=10.2,4.5Hz,1H),5.44(m,2H),4.77(s,1H),4.41(q,J=11.7Hz,2H),4.23(s,4H),3.79(s,3H),3.74(s,3H),3.58(s,3H),2.96(s,3H),2.06(s,3H),1.43(m,1H),1.21(m,1H),0.95(t,J=7.5Hz,3H),0.65(t,J=6.9Hz,3H);
13C NMR(DMSO-d6,75MHz):δ:173.9(2C),170.7(C),158.8(C),157.3(C),153.7(C),137.1(C),135.7(C),131.4(C),130.7(C),130.4(CH),129.5(2CH),128.5(C),124.4(CH),123.9(CH),123.9(CH),123.9(C),121.7(CH),120.0(C),118.6(CH),117.8(CH),113.7(2CH),113.2(C),112.0(CH),94.3(CH),80.7(CH),77.2(CH),76.9(CH2),72.6(CH2),72.3(4CH),71.4(C),64.4(CH),56.2(OCH3),55.1(OCH3),55.1(2C),53.7(CH2),52.3(OCH3),52.2(CH2),49.6(CH2),48.9(CH2),45.6(CH2),45.2(CH2),42.0(C),39.9(CH3),34.7(CH2),31.6(CH),30.8(CH2),30.5(CH2),27.2(CH2),20.8(CH3),11.6(CH3),7.9(CH3);
ESIMS(m/e)885.5[M+1]+。
实施例6化合物BM6的制备
在氩气保护下,将486mg(1mmol)长春质碱的酒石酸盐和486mg(3mmol)无水三氯化铁加入到缓冲溶液中(由320mg甘氨酸、250mg氯化钠、40mL水和40mL 0.1N盐酸配制),室温下搅拌10分钟,然后加入470mg(1mmol)化合物C6。室温下搅拌8h后,在冰浴(0℃)下滴加入含80mg硼氢化纳的氨水溶液(8mL),冰浴下反应15-20分钟。完毕后用二氯甲烷萃取(40mL×4),二氯甲烷层依次经过饱和食盐水洗涤(20mL×3)、硅藻土过滤和低温减压浓缩。将浓缩物溶于2mL甲醇,放置2分钟,有白色晶体析出,过滤干燥得到475mg化合物BM6,产率60%。
1H NMR(CDCl3,300MHz):δ:9.25(s,1H),8.06(s,1H),7.48(d,J=7.2Hz,1H),7.10(m,3H),6.59(s,1H),6.17(s,1H),5.86(dd,J=10.2,4.5Hz,1H),5.41(d,J=10.2Hz,1H),5.40(s,1H),5.02(s,1H),4.16(d,J=11.7Hz,1H),4.12(d,J=11.7Hz,1H),3.79(s,3H),3.58(s,3H),2.89(s,3H),2.59(s,1H),2.15(s,3H),2.10(s,3H),1.43(m,1H),1.21(m,1H),0.96(t,J=7.5Hz,3H),0.79(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.7(C),170.9(C),170.7(C),157.7(C),153.3(C),139.7(C),134.9(C),130.8(C),129.5(CH),129.3(C),124.6(CH),123.8(CH),123.5(CH),123.5(C),122.2(CH),121.3(C),118.8(CH),118.3(CH),117.2(C),110.4(CH),94.6(CH),81.5(CH),76.6(CH),76.0(C),66.3(CH2),66.0(CH),55.7(OCH3),55.3(C),54.4(CH2),52.4(OCH3),52.3(CH2),51.9(C),50.1(CH2),49.9(CH2),45.7(CH2),44.9(CH2),42.3(C),39.9(CH3),34.2(CH2),32.8(CH),31.4(CH2),27.7(CH2),25.4(CH2),21.0(CH3),20.9(CH3),12.2(CH3),8.2(CH3);
ESIMS(m/e)807.5[M+1]+。
实施例7化合物BM7的制备
取60mg(0.07mmol)化合物BM6溶于20mL甲醇中,加入1g 50%碳酸钾水溶液,在氩气保护下室温搅拌8h,反应完毕后浓缩,CH2C12萃取(10mL×3),减压浓缩得52mg化合物BM7(白色粉末),产率98%。
1H NMR(CDCl3,300MHz):δ:8.94(s,1H),8.03(s,1H),7.53(d,J=7.2Hz,1H),7.13(m,3H),6.59(s,1H),6.17(s,1H),5.86(dd,J=10.2,4.5Hz,1H),5.70(d,J=10.2Hz,1H),5.51(d,J=5.7Hz,1H),3.82(s,3H),3.59(s,3H),3.01(s,3H),2.53(s,1H),1.01(t,J=7.5Hz,3H),0.91(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:175.0(C),157.9(C),153.8(C),139.7(C),135.1(C),131.2(C),130.3(CH),129.4(C),125.1(CH),124.4(C),124.1(CH),123.9(CH),122.5(CH),121.2(C),119.0(CH),118.4(CH),117.1(C),110.7(CH),94.7(CH),81.0(CH),77.4(C),75.4(CH),66.7(CH2),65.5(CH),56.0(OCH3),55.6(C),54.5(CH2),52.6(OCH3),52.2(CH2),52.0(C),50.7(CH2),50.3(CH2),45.9(CH2),45.2(CH2),43.5(C),40.4(CH3),34.4(CH2),32.8(CH),29.8(CH2),28.0(CH2),25.4(CH2),12.4(CH3),8.7(CH3);
ESIMS(m/e)721.4[M-1]+。
实施例8化合物BM8的制备
在氩气保护下,取403mg(0.5mmol)BM6溶于20mL无水四氢呋喃中,在0℃冰浴下缓慢加入115mg(3mmol)四氢铝锂,室温下搅拌4h后,加入0.16mL水淬灭反应。然后依次加入0.16mL 15%氢氧化钠和0.48mL水,搅拌5分钟后用砂星漏斗抽滤,无水硫酸镁干燥,减压浓缩,得348mg白色固体化合物BM8,产率98%。
1H NMR(CDCl3,300MHz):8.99(s,1H),7.54(d,J=7.5Hz,1H),7.20(m,4H),6.15(s,1H),5.84(dd,J=10.2,3.9Hz,1H),5.51(d,J=10.2Hz,1H),5.46(s,1H),3.58(s,3H),3.06(s,3H),2.15(s,6H),0.99(t,J=7.5Hz,3H),0.66(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:158.9(C),153.6(C),139.8(C),134.6(C),130.5(C),130.5(CH),129.4(C),124.3(3CH),124.3(C),120.9(2CH),120.9(C),118.5(CH),117.8(C),110.2(CH),95.0(CH),80.8(CH),77.4(C),75.4(CH),67.2(2CH2OH),65.6(CH),55.2(OCH3),55.2(CH2),53.0(C),52.0(C),51.2(2CH2),50.8(CH2),48.3(CH2),44.2(CH2),43.6(C),40.5(NCH3),34.0(CH2),32.5(CH),29.7(CH2),27.7(CH2),25.5(CH2),12.4(CH3),8.2(CH3);
ESIMS(m/e)693.4[M-1]+。
实施例9化合物BM9的制备
将480mg(0.60mmol)化合物BM6溶于20mL甲醇中,加入Pa/C(5%,40mg),在室温、常压下氢化反应6h,用乙酸乙酯/甲醇系统检测反应完毕后,经硅藻土过滤、低温减压浓缩。将浓缩物用甲醇重结晶得430mg化合物BM9(白色粉末),产率90%。
1H NMR(CDCl3,300MHz):δ:9.25(brs,1H),7.9(s,1H),7.48(d,J=7.5Hz,1H),7.10(m,3H),6.52(s,1H),6.16(s,1H),5.89(dd,J=10.2,4.5Hz,1H),5.43(d,J=10.2Hz,1H),5.04(s,1H),4.16(d,J=11.7Hz,1H),4.12(d,J=11.7Hz,1H),3.81(s,3H),3.61(s,3H),2.92(s,3H),2.58(s,1H),2.18(s,3H),2.13(s,3H),1.46(m,1H),1.31(m,1H),0.88(t,J=7.2Hz,3H),0.82(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.5(C),171.0(C),170.7(C),157.8(C),153.4(C),135.0(C),130.4(C),129.6(CH),129.3(C),124.6(CH),123.7(CH),123.7(C),122.3(CH),121.2(C),118.9(CH),118.2(CH),117.4(C),110.4(CH),94.7(CH),81.6(CH),76.8(CH),76.0(C),66.4(CH2),66.4(CH),55.8(OCH3),55.7(C),54.1(CH2),52.5(CH2),52.5(C),52.3(OCH3),50.3(CH2),50.0(CH2),45.0(CH2),44.3(CH2),42.4(C),40.1(CH2),39.8(CH3),35.6(CH2),35.2(CH),31.6(CH2),30.4(CH),28.2(CH2),22.6(CH2),21.0(2CH3),20.0(CH3),11.4(CH3),8.3(CH3);
ESIMS(m/e)809.5[M+1]+。
实施例10化合物BM10的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.13(s,1H),8.03(s,1H),7.53(d,J=7.5Hz,1H),7.14(m,3H),6.61(s,1H),6.18(s,1H),5.89(dd,J=10.5,4.5Hz,1H),5.51(d,J=6.0Hz,1H),5.43(d,J=10.5Hz,1H),5.06(s,1H),4.23(d,J=11.4Hz,1H),4.02(d,J=11.4Hz,1H),3.83(s,3H),3.65(s,3H),2.92(s,3H),2.64(s,1H),2.42(q,J=7.8Hz,2H),2.19(s,3H),1.95(q,J=7.5Hz,2H),1.43(m,1H),1.21(m,1H),1.16(t,J=7.8Hz,3H),1.01(t,J=7.5Hz,3H),0.82(t,J=7.2Hz,3H);
实施例11化合物BM11的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.00(s,1H),8.02(s,1H),7.52(d,J=7.5Hz,1H),7.13(m,3H),6.61(s,1H),6.17(s,1H),5.85(dd,J=10.2,6.3Hz,1H),5.49(d,J=6.0Hz,1H),5.41(d,J=10.2Hz,1H),5.05(s,1H),4.24(d,J=11.4Hz,1H),3.99(d,J=11.4Hz,1H),3.82(s,3H),3.64(s,3H),2.92(s,3H),2.59(s,1H),2.17(s,3H),1.94(q,J=7.5Hz,2H),1.47(m,1H),1.21(m,1H),1.19(d,J=5.1Hz,6H),1.00(t,J=7.5Hz,3H),0.81(t,J=7.2Hz,3H);
ESIMS(m/e)835.3[M+1]+。
实施例12化合物BM12的制备
在氩气保护下,将190mg(0.39mmol)长春质碱的酒石酸盐和190mg(3mmol)无水三氯化铁加入到缓冲溶液中(由125mg甘氨酸、96mg氯化钠、16mL水和16mL 0.1N盐酸配制),室温下搅拌10分钟,然后加入200mg(0.39mmol)化合物C6。室温下搅拌8h后,在冰浴(0℃)下滴加入含32mg硼氢化纳的氨水溶液(4mL),冰浴下反应15~20分钟。完毕后用二氯甲烷萃取(40mL×4),二氯甲烷层依次经过饱和食盐水洗涤(20mL×3)、硅藻土过滤和低温减压浓缩。将浓缩物溶于2mL甲醇,放置2分钟,有白色晶体析出,过滤干燥得到158mg化合物BM12,产率48%。
1H NMR(DMSO-d6,300MHz):δ:9.86(s,1H),8.21(s,1H),7.44(d,J=7.8Hz,1H),7.28(d,J=7.8Hz,1H),6.99(m,3H),6.47(s,1H),6.30(s,1H),5.73(dd,J=10.2,4.5Hz,1H),5.45(m,2H),4.82(s,1H),4.32(s,4H),4.11(d,J=11.4Hz,1H),3.78(s,3H),3.70(d,J=11.4Hz,1H),3.57(s,3H),2.93(s,3H),2.70(s,1H),2.08(s,3H),1.15(s,9H),0.96(t,J=7.5Hz,3H),0.66(t,J=6.9Hz,3H);
13C NMR(DMSO-d6,75MHz):δ:177.1(C),173.9(2C),170.7(C),157.4(C),153.5(C),137.1(C),135.7(C),131.3(C),130.5(CH),128.4(C),124.5(CH),123.7(CH),123.7(CH),123.7(C),121.2(CH),120.3(C),118.5(CH),117.7(CH),113.2(C),112.0(CH),94.6(CH),81.5(CH),76.2(CH),75.9(C),72.3(4CH),64.5(CH2),64.0(CH),56.2(OCH3),55.0(C),53.7(CH2),52.4(OCH3),52.3(CH2),52.3(C),49.6(CH2),48.9(CH2),45.5(CH2),45.2(CH2),42.0(C),39.9(CH3),38.5(C),34.7(CH2),31.5(CH),30.5(CH2),27.2(CH2),27.0(3CH3),21.1(CH2),20.8(CH3),11.6(CH3),7.9(CH3);
ESIMS(m/e)849.5[M+1]+。
实施例13化合物BM13的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.05(s,1H),8.02(s,1H),7.53(d,J=7.5Hz,1H),7.14(m,3H),6.62(s,1H),6.18(s,1H),5.88(dd,J=10.2,6.3Hz,1H),5.48(d,J=6.0Hz,1H),5.43(d,J=10.2Hz,1H),5.06(s,1H),4.25(d,J=11.7Hz,1H),4.00(d,J=11.7Hz,1H),3.83(s,3H),3.62(s,3H),2.92(s,3H),2.60(s,1H),2.19(s,3H),1.94(q,J=7.5Hz,2H),1.47(m,1H),1.21(m,1H),1.01(t,J=7.5Hz,3H),0.97(d,J=6.6Hz,6H),0.82(t,J=7.2Hz,3H);
ESIMS(m/e)849.5[M+1]+。
实施例14化合物BM14的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.14(s,1H),8.03(s,1H),7.53(d,J=7.8Hz,1H),7.14(m,3H),6.62(s,1H),6.19(s,1H),5.89(dd,J=10.2,3.9Hz,1H),5.51(d,J=6.0Hz,1H),5.44(d,J=10.2Hz,1H),5.06(s,1H),4.24(d,J=11.4Hz,1H),4.02(d,J=11.4Hz,1H),3.84(s,3H),3.65(s,1H),3.63(s,3H),2.94(s,3H),2.62(s,1H),2.18(s,3H),1.94(q,J=7.5Hz,2H),1.47(m,1H),1.21(m,1H),1.01(t,J=7.5Hz,5H),0.86(t,J=7.5Hz,2H),0.82(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),174.8(C),171.8(C),157.9(C),153.5(C),139.8(C),135.0(C),130.9(C),129.7(CH),129.4(C),124.6(CH),123.9(CH),123.7(CH),123.6(C),122.3(CH),121.3(C),118.9(CH),118.4(CH),117.3(C),110.5(CH),94.7(CH),81.7(CH),76.8(CH),76.0(C),66.4(CH2),66.3(CH),55.8(OCH3),55.5(C),54.5(CH2),52.5(C),52.4(OCH3),52.0(CH2),50.3(CH2),50.1(CH2),45.8(CH2),45.1(CH2),42.5(C),40.0(CH3),34.4(CH2),32.9(CH),31.5(CH2),27.9(CH2),25.4(CH2),20.9(CH3),12.8(CH),12.3(CH3),8.7(CH2),8.6(CH2),8.3(CH3);
ESIMS(m/e)833.5[M+1]+。
实施例15化合物BM15的制备
制备步骤参见化合物BM6的制备。
白色粉末,产率60%。1H NMR(CDCl3,300MHz):δ:9.11(s,1H),8.03(s,1H),7.53(d,J=7.5Hz,1H),7.29(m,5H),7.14(m,3H),6.62(s,1H),6.11(s,1H),5.88(dd,J=10.2,4.5Hz,1H),5.46(m,2H),5.04(s,1H),4.32(d,J=11.4Hz,1H),3.96(d,J=11.4Hz,1H),3.82(s,3H),3.72(s,2H),3.61(s,3H),3.44(s,1H),2.60(s,3H),2.59(s,1H),2.17(s,3H),1.94(q,J=7.5Hz,2H),1.43(m,1H),1.21(m,1H),1.01(t,J=7.5Hz,3H),0.83(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.8(C),171.1(C),171.0(C),157.9(C),153.5(C),140.1(C),135.0(C),134.0(C),131.0(C),129.7(CH),129.5(2CH),128.5(2CH),127.0(CH),127.0(C),124.7(CH),123.9(CH),123.6(CH),123.6(C),122.3(CH),121.4(C),118.9(CH),118.4(CH),117.4(C),110.5(CH),94.7(CH),81.6(CH),76.7(CH),76.2(C),66.4(CH2),66.2(CH),55.8(OCH3),55.5(C),54.5(CH2),52.5(OCH3),52.4(CH2),52.3(C),50.2(CH2),50.1(CH2),46.0(CH2),45.1(CH2),42.5(C),41.4(CH2),39.7(CH3),34.4(CH2),33.0(CH),31.6(CH2),27.8(CH2),25.9(CH2),21.0(CH3),12.4(CH3),8.3(CH3);
ESIMS(m/e)883.5[M+1]+。
实施例16化合物BM16的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.12(s,1H),8.09(d,J=6.9Hz,2H),8.06(s,1H),7.55(m,2H),7.45(d,J=7.2Hz,1H),7.44(t,J=7.2Hz,1H),7.15(m,3H),6.65(s,1H),6.17(s,1H),5.90(dd,J=10.2,4.5Hz,1H),5.48(d,J=9.6Hz,1H),5.45(d,J=10.2Hz,1H),5.18(s,1H),4.56(d,J=11.4Hz,1H),4.20(d,J=11.4Hz,1H),3.88(s,3H),3.73(s,1H),3.65(s,3H),2.96(s,3H),2.65(s,1H),2.18(s,3H),1.94(q,J=7.5Hz,2H),1.43(m,1H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.84(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.2(C),166.3(C),158.0(C),153.6(C),140.0(C),135.2(C),133.2(CH),131.1(C),131.0(C),130.2(C),129.9(3CH),129.6(C),128.5(2CH),124.8(CH),124.0(CH),123.9(CH),122.4(CH),121.5(C),119.0(CH),118.5(CH),117.5(C),110.6(CH),94.6(CH),82.4(CH),76.9(CH),76.4(C),66.7(CH2),66.4(CH),56.0(OCH3),55.6(C),54.6(CH2),52.5(OCH3),52.2(CH2),52.2(C),50.4(CH2),50.3(CH2),46.0(CH2),45.4(CH2),42.7(C),40.1(CH3),34.5(CH2),33.0(CH),31.7(CH2),28.0(CH2),25.7(CH2),21.2(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)869.4[M+1]+。
实施例17化合物BM17的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.07(s,1H),8.05(s,1H),7.87(d,J=7.8Hz,1H),7.53(d,J=7.2Hz,1H),7.46(t,J=7.8Hz,1H),7.14(m,3H),7.00(t,J=7.8Hz,1H),6.95(d,J=7.8Hz,1H),6.63(s,1H),6.17(s,1H),5.88(dd,J=10.2,4.5Hz,1H),5.48(d,J=9.3Hz,1H),5.44(d,J=10.2Hz,1H),5.14(s,1H),4.50(d,J=11.4Hz,1H),4.18(d,J=11.4Hz,1H),3.85(s,3H),3.82(s,3H),3.71(s,1H),3.62(s,3H),2.99(s,3H),2.62(s,1H),2.18(s,3H),1.95(q,J=7.5Hz,2H),1.43(m,1H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.83(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.2(C),166.0(C),159.3(C),158.0(C),153.7(C),140.1(C),135.1(C),133.7(CH),132.1(CH),131.1(2C),129.8(CH),129.6(C),124.7(CH),124.0(CH),123.8(CH),122.4(CH),121.3(C),120.2(CH),120.0(C),119.0(CH),118.5(CH),117.4(C),112.0(CH),110.6(CH),94.6(CH),82.0(CH),76.9(CH),76.4(C),66.5(CH2),66.5(CH),56.0(OCH3),55.9(OCH3),55.6(C),54.6(CH2),52.6(C),52.5(OCH3),52.3(CH2),50.4(CH2),50.2(CH2),46.0(CH2),45.3(CH2),42.7(C),39.7(CH3),34.5(CH2),33.0(CH),31.7(CH2),28.0(CH2),25.8(CH2),21.2(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)899.4[M+1]+。
实施例18化合物BM18的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.10(s,1H),8.06(s,1H),8.04(d,J=8.7Hz,2H),7.53(d,J=7.8Hz,1H),7.14(m,3H),6.92(d,J=8.7Hz,2H),6.64(s,1H),6.15(s,1H),5.89(dd,J=10.5,4.5Hz,1H),5.47(d,J=9.6Hz,1H),5.44(d,J=10.5Hz,1H),5.18(s,1H),4.51(d,J=11.4Hz,1H),4.16(d,J=11.4Hz,1H),3.85(s,3H),3.82(s,3H),3.69(s,1H),3.63(s,3H),2.93(s,3H),2.64(s,1H),2.17(s,3H),1.94(q,J=7.5Hz,2H),1.43(m,1H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.83(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.2(C),166.0(C),163.6(C),158.0(C),153.6(C),140.0(C),135.1(C),132.0(2CH),132.0(C),131.4(C),129.9(CH),129.6(C),124.8(CH),124.0(CH),123.9(CH),122.6(C),122.4(CH),121.4(C),119.0(CH),118.5(CH),117.4(C),113.8(2CH),110.6(CH),94.6(CH),82.5(CH),76.9(CH),76.4(C),66.5(CH2),66.4(CH),56.0(OCH3),55.6(C),55.5(OCH3),54.6(CH2),52.8(C),52.5(OCH3),52.3(CH2),50.5(CH2),50.3(CH2),46.0(CH2),45.4(CH2),42.8(C),40.0(CH3),34.5(CH2),33.0(CH),31.7(CH2),28.0(CH2),25.8(CH2),21.2(CH3),12.4(CH3),8.5(CH3);
ESIMS(m/e)899.4[M+1]+。
实施例19化合物BM19的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.10(s,1H),8.05(s,1H),7.89(d,J=6.6Hz,1H),7.53(d,J=7.2Hz,1H),7.42(d,J=7.8Hz,2H),7.31(t,J=7.8Hz,1H),7.14(m,3H),6.63(s,1H),6.18(s,1H),5.89(dd,J=10.2,4.5Hz,1H),5.48(d,J=9.3Hz,1H),5.45(d,J=10.2Hz,1H),5.14(s,1H),4.52(d,J=11.4Hz,1H),4.26(d,J=11.4Hz,1H),3.82(s,3H),3.68(s,1H),3.62(s,3H),3.00(s,3H),2.62(s,1H),2.19(s,3H),1.94(q,J=7.5Hz,2H),1.50(m,1H),1.29(m,1H),1.00(t,J=7.5Hz,3H),0.83(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.2(C),165.3(C),158.0(C),153.6(C),140.1(C),135.1(C),133.9(C),132.7(CH),131.7(CH),131.2(CH),131.1(C),130.1(C),129.8(CH),129.6(C),126.7(CH),124.8(CH),124.0(CH),123.8(CH),122.4(CH),121.5(2C),119.0(CH),118.5(CH),117.4(C),110.6(CH),94.7(CH),82.0(CH),76.8(CH),76.3(C),67.2(CH2),66.4(CH),56.0(OCH3),55.6(C),54.6(CH2),52.7(C),52.5(OCH3),52.2(CH2),50.4(CH2),50.2(CH2),46.0(CH2),45.3(CH2),42.7(C),40.2(CH3),34.5(CH2),33.0(CH),31.7(CH2),28.0(CH2),25.7(CH2),21.2(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)903.5[M+1]+。
实施例20化合物BM20的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.15(s,1H),8.06(s,1H),8.02(d,J=8.4Hz,2H),7.53(d,J=7.5Hz,1H),7.41(d,J=8.4Hz,2H),7.14(m,3H),6.65(s,1H),6.16(s,1H),5.89(dd,J=10.2,4.5Hz,1H),5.48(d,J=8.4Hz,1H),5.44(d,J=10.2Hz,1H),5.17(s,1H),4.54(d,J=11.7Hz,1H),4.20(d,J=11.7Hz,1H),3.82(s,3H),3.66(s,1H),3.64(s,3H),2.93(s,3H),2.65(s,1H),2.17(s,3H),1.94(q,J=7.5Hz,2H),1.53(m,1H),1.29(m,1H),0.98(t,J=7.5Hz,3H),0.84(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.2(C),165.5(C),158.1(C),153.5(C),140.1(C),139.6(C),135.2(C),131.3(2CH),131.3(C),131.1(C),129.8(CH),129.6(C),128.9(2CH),128.6(C),124.8(CH),124.0(CH),123.9(CH),122.4(CH),121.6(C),119.0(CH),118.5(CH),117.5(C),110.6(CH),94.6(CH),82.6(CH),76.8(CH),76.4(C),67.8(CH2),66.3(CH),56.0(OCH3),55.6(C),54.6(CH2),52.8(C),52.5(OCH3),52.2(CH2),50.4(CH2),50.2(CH2),46.0(CH2),45.4(CH2),42.7(C),40.2(CH3),34.5(CH2),33.0(CH),31.7(CH2),28.0(CH2),25.8(CH2),21.2(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)903.5[M+1]+。
实施例21化合物BM21的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.18(s,1H),8.28(d,J=6.0Hz,4H),8.04(s,1H),7.52(d,J=7.5Hz,1H),7.14(m,3H),6.61(s,1H),6.17(s,1H),5.89(dd,J=10.2,4.5Hz,1H),5.53(s,1H),5.44(d,J=10.2Hz,1H),5.17(s,1H),4.59(d,J=11.4Hz,1H),4.26(d,J=11.4Hz,1H),3.83(s,3H),3.71(s,1H),3.65(s,3H),2.95(s,3H),2.65(s,1H),2.18(s,3H),1.96(q,J=7.5Hz,2H),1.53(m,1H),1.29(m,1H),1.01(t,J=7.5Hz,3H),0.83(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.8(C),171.3(C),164.5(C),158.1(C),153.6(C),150.7(C),135.6(C),135.2(C),131.0(2CH),131.0(C),130.4(C),129.7(CH),129.7(C),129.5(C),125.0(CH),123.9(2CH),123.8(2CH),122.7(CH),121.6(C),119.3(CH),118.5(CH),117.5(C),110.7(CH),94.8(CH),82.6(CH),76.7(CH),76.4(C),67.3(CH2),66.3(CH),56.1(OCH3),55.6(C),54.6(CH2),54.3(C),52.7(OCH3),51.8(CH2),50.4(CH2),50.4(CH2),45.7(CH2),45.4(CH2),42.8(C),40.3(CH3),34.4(CH2),32.5(CH),31.7(CH2),28.0(CH2),25.8(CH2),21.2(CH3),12.3(CH3),8.5(CH3);
ESIMS(m/e)914.5[M+1]+。
实施例22化合物BM22的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.29(s,1H),8.02(s,1H),7.53(d,J=7.5Hz,1H),7.14(m,3H),6.60(s,1H),6.18(s,1H),5.88(dd,J=10.2,3.9Hz,1H),5.50(s,1H),5.42(d,J=10.2Hz,1H),5.07(s,1H),4.96(m,1H),4.10(q,J=4.8Hz,2H),3.83(s,3H),3.64(s,3H),3.62(s,1H),2.92(s,3H),2.81(d,J=16.5Hz,1H),2.61(s,1H),2.18(s,3H),1.94(q,J=7.5Hz,2H),1.46(m,1H),1.23(m,1H),1.01(t,J=7.2Hz,3H),0.90(d,J=6.9Hz,6H),0.82(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:175.0(C),171.2(C),158.1(C),156.5(C),153.7(C),140.1(C),135.2(C),131.2(C),129.9(CH),129.6(C),124.8(CH),124.1(C),123.9(CH),123.8(CH),122.5(CH),121.5(C),119.1(CH),118.5(CH),117.5(C),110.6(CH),94.8(CH),81.8(CH),77.0(CH),76.4(C),67.1(CH2),66.5(CH),56.0(OCH3),55.7(C),54.7(CH2),52.7(C),52.6(OCH3),52.3(CH2),50.5(CH2),50.3(CH2),48.7(CH2),46.1(CH2),45.2(CH2),42.7(C),40.0(CH3),34.6(CH2),33.1(CH),31.7(CH2),28.9(CH2),28.0(CH2),25.8(CH),21.2(CH3),20.1(2CH3),12.1(CH3),8.4(CH3);
ESIMS(m/e)864.4[M+1]+。
实施例23化合物BM23的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.29(s,1H),8.03(s,1H),7.53(d,J=7.5Hz,1H),7.14(m,3H),6.60(s,1H),6.18(s,1H),5.88(dd,J=10.2,3.9Hz,1H),5.51(s,1H),5.42(d,J=10.2Hz,1H),5.06(s,1H),4.90(m,1H),4.10(s,2H),3.84(s,3H),3.63(s,3H),3.54(s,1H),2.92(s,3H),2.81(d,J=15.6Hz,1H),2.61(s,1H),2.19(s,3H),1.94(q,J=7.5Hz,2H),1.46(m,1H),1.23(m,1H),1.03(t,J=7.5Hz,3H),0.92(d,J=7.2Hz,3H),0.82(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.0(C),158.1(C),156.3(C),153.6(C),140.2(C),135.1(C),131.2(C),129.9(CH),129.6(C),124.8(CH),124.0(CH),123.9(C),123.8(CH),122.4(CH),121.5(C),119.0(CH),118.5(CH),117.5(C),110.6(CH),94.8(CH),81.8(CH),76.9(CH),76.3(C),67.0(CH2),66.4(CH),56.0(OCH3),55.6(C),54.6(CH2),52.6(C),52.5(OCH3),52.4(CH2),50.5(CH2),50.2(CH2),46.1(CH2),45.2(CH2),42.7(C),40.9(CH2),40.0(CH3),34.5(CH2),33.0(CH),32.1(CH2),31.6(CH2),27.9(CH2),25.9(CH2),21.1(CH3),20.0(CH2),13.8(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)864.3[M+1]+。
实施例24化合物BM24的制备
制备步骤参见化合物BM6的制备。
白色粉末。1H NMR(CDCl3,300MHz):δ:9.26(s,1H),8.02(s,1H),7.53(d,J=7.5Hz,1H),7.14(m,3H),6.60(s,1H),6.18(s,1H),5.88(dd,J=10.2,3.9Hz,1H),5.51(s,1H),5.42(d,J=10.2Hz,1H),5.06(s,1H),4.85(m,1H),4.10(s,2H),3.84(s,3H),3.63(s,3H),3.59(s,1H),2.92(s,3H),2.81(d,J=16.2Hz,1H),2.61(s,1H),2.18(s,3H),1.94(q,J=7.5Hz,2H),1.46(m,1H),1.38(q,J=6.9Hz,2H),1.23(m,1H),1.01(t,J=7.5Hz,3H),0.91(d,J=6.6Hz,6H),0.82(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.7(C),171.1(C),158.0(C),156.3(C),153.8(C),138.4(C),135.1(C),131,0(C),129.8(CH),129.3(C),124.9(CH),124.2(C),123.9(CH),123.6(CH),122.8(CH),120.8(C),119.4(CH),118.4(CH),116.1(C),110.6(CH),94.7(CH),81.7(CH),76.9(CH),76.3(C),67.0(CH2),66.4(CH),56.0(OCH3),55.5(C),54.3(CH2),52.6(C),52.6(OCH3),51.0(CH2),50.5(CH2),50.3(CH2),45.4(CH2),45.2(CH2),42.7(C),40.0(CH3),39.5(CH2),39.0(CH2),34.4(CH2),31.9(CH),31.6(CH2),29.8(CH2),28.0(CH2),25.7(CH),22.5(2CH3),21.1(CH3),12.1(CH3),8.4(CH3);
ESIMS(m/e)878.4[M+1]+。
实施例25化合物BM25的制备
在氩气保护下,将280mg(0.58mmol)长春质碱的酒石酸盐和280mg(1.74mmol)无水三氯化铁加入到缓冲溶液中(由185mg甘氨酸、145mg氯化钠、水24mL和24mL 0.1N盐酸配制),室温下搅拌10分钟,然后加入272mg(0.58mmol)化合物E1。室温下搅拌8h后,在冰浴(0℃)下滴加入含48mg硼氢化纳的氨水溶液(5mL),冰浴下反应15~20分钟。完毕后用二氯甲烷萃取(20mL×4),二氯甲烷层依次经饱和食盐水洗涤(20mL×3)、硅藻土过滤和低温减压浓缩。将浓缩物溶于2mL甲醇,放置2分钟,有白色晶体析出,过滤干燥得233mg化合物BM25,产率50%。
1H NMR(CDCl3,300MHz):δ:9.33(s,1H),7.95(s,1H),7.45(d,J=7.2Hz,1H),7.06(m,3H),6.52(s,1H),6.13(s,1H),6.10(d,J=8.7Hz,1H),5.81(dd,J=10.2,4.5Hz,1H),5.42(d,J=4.8Hz,1H),5.35(d,J=10.2Hz,1H),4.96(s,1H),3.76(s,3H),3.55(s,3H),2.82(s,3H),2.55(s,1H),2.07(s,3H),1.93(s,3H),1.43(m,1H),0.93(t,J=7.2Hz,3H),0.73(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),170.9(C),170.5(C),158.1(C),153.7(C),139.9(C),135.2(C),131.1(C),130.1(CH),129.6(C),124.7(CH),124.0(CH),123.7(CH),123.7(C),122.5(CH),121.8(C),119.1(CH),118.5(CH),117.4(C),110.7(CH),95.3(CH),82.4(CH),76.8(CH),76.0(C),66.2(CH),56.0(OCH3),55.6(C),54.7(CH2),52.8(C),52.6(OCH3),52.2(CH2),50.3(2CH2),46.0(CH2),45.3(CH2),43.5(CH2),42.9(C),40.9(CH3),34.5(CH2),32.9(CH),31.6(CH2),28.0(CH2),25.6(CH2),23.5(CH3),21.1(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)806.5[M+1]+。
实施例26化合物BM26的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.64(s,1H),8.01(s,1H),7.53(d,J=7.8Hz,1H),7.20-7.12(m,3H),6.62(s,1H),6.22(s,1H),5.90(dd,J=10.2,4.2Hz,1H),5.49-5.42(m,2H),5.03(s,1H),3.83(s,3H),3.79-3.74(m,1H),3.63(s,3H),3.53(d,J=16.5Hz,1H),3.29(s,1H),2.88(s,3H),2.66(s,1H),2.58(d,J=12.9Hz,1H),2.50-2.40(m,2H),2.15(s,3H),1.93(q,J=7.2Hz,2H),1.50-1.43(m,1H),1.00(t,J=7.5Hz,3H),0.81(t,J=7.2Hz,3H)。
ESIMS(m/e)860.4[M+1]+。
实施例27化合物BM27的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.40(s,1H),8.00(s,1H),7.45(d,J=7.5Hz,1H),7.13(m,3H),6.53(s,1H),6.18(d,J=7.8Hz,1H),6.14(s,1H),5.81(dd,J=10.2,3.9Hz,1H),5.43(d,J=6.3Hz,1H),5.35(d,J=10.2Hz,1H),4.95(s,1H),3.76(s,3H),3.55(s,3H),3.28(s,1H),2.81(s,3H),2.56(s,1H),2.16(q,J=7.8Hz,2H),2.08(s,3H),1.87(q,J=7.8Hz,2H),1.41(m,1H),1.08(t,J=7.8Hz,3H),0.93(t,J=7.8Hz,3H),0.74(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),174.3(C),170.9(C),158.0(C),153.6(C),139.8(C),135.0(C),130.9(C),130.0(CH),129.5(C),124.6(CH),123.8(CH),123.6(CH),123.6(C),122.4(CH),121.7(C),120.0(CH),118.4(CH),117.4(C),110.7(CH),95.2(CH),82.2(CH),77.0(CH),76.0(C),65.9(CH),56.0(OCH3),55.5(C),54.6(CH2),52.7(C),52.5(OCH3),51.9(CH2),50.1(2CH2),45.8(CH2),45.3(CH2),43.1(CH2),42.8(C),40.7(CH3),34.3(CH2),32.8(CH),31.5(CH2),29.9(CH2),28.0(CH2),25.3(CH2),21.0(CH3),12.3(CH3),10.1(CH3),8.4(CH3);
ESIMS(m/e)820.5[M+1]+。
实施例28化合物BM28的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.43(s,1H),8.01(s,1H),7.52(d,J=7.5Hz,1H),7.16(m,3H),6.61(s,1H),6.21(s,1H),6.19(s,1H),5.88(dd,J=10.2,3.6Hz,1H),5.47(d,J=6.0Hz,1H),5.42(d,J=10.2Hz,1H),5.02(s,1H),3.82(s,3H),3.62(s,3H),3.34(s,1H),2.86(s,3H),2.62(s,1H),2.15(s,3H),1.96(q,J=7.5Hz,2H),1.49(m,1H),1.15(d,J=1.8Hz,3H),1.14(d,J=1.8Hz,3H),0.99(t,J=7.5Hz,3H),0.80(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:177.3(C),174.3(C),170.9(C),158.0(C),153.6(C),139.8(C),135.1(C),131.0(C),130.0(CH),129.5(C),124.7(CH),123.9(CH),123.7(CH),123.7(C),122.5(CH),121.7(C),119.1(CH),118.5(CH),117.2(C),110.7(CH),95.2(CH),82.1(CH),77.0(CH),76.0(C),66.0(CH),56.0(OCH3),55.5(C),54.6(CH2),52.7(C),52.6(OCH3),51.9(CH2),50.8(CH2),50.2(CH2),45.8(CH2),45.4(CH2),42.8(CH2),42.8(C),40.6(CH3),35.8(CH),34.4(CH2),32.7(CH),31.5(CH2),28.0(CH2),25.3(CH2),21.0(CH3),19.8(CH3),19.7(CH3),12.3(CH3),8.4(CH3);
ESIMS(m/e)834.5[M+1]+。
实施例29化合物BM29的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.41(s,1H),8.02(s,1H),7.52(d,J=7.8Hz,1H),7.19-7.09(m,3H),6.59(s,1H),6.19(s,1H),6.15(d,J=7.8Hz,1H),5.89(dd,J=10.2,6.0Hz,1H),5.49(d,J=5.7Hz,1H),5.41(d,J=10.2Hz,1H),5.02(s,1H),3.83(s,3H),3.79-3.70(m,1H),3.62(s,3H),3.55(d,J=16.5Hz,1H),3.35(s,1H),2.88(s,3H),2.62(s,1H),2.18(t,J=7.5Hz,2H),2.15(s,3H),1.94(q,J=7.2Hz,2H),1.70-1.60(m,2H),1.53-1.45(m,1H),1.30-1.20(m,1H),1.00(t,J=7.5Hz,3H),0.94(t,J=7.5Hz,3H),0.80(t,J=7.2Hz,3H);
ESIMS(m/e)834.5[M+1]+。
实施例30化合物BM30的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.40(s,1H),8.03(s,1H),7.53(d,J=7.8Hz,1H),7.19-7.09(m,3H),6.58(s,1H),6.19(s,1H),6.15(d,J=7.8Hz,1H),5.89(dd,J=10.2,6.0Hz,1H),5.49(d,J=5.7Hz,1H),5.41(d,J=10.2Hz,1H),5.02(s,1H),3.83(s,3H),3.79-3.72(m,1H),3.62(s,3H),3.55(d,J=16.5Hz,1H),3.35(s,1H),2.88(s,3H),2.62(s,1H),2.15(s,3H),2.10(d,J=9.9Hz,2H),1.95(q,J=7.2Hz,2H),1.69-1.59(m,2H),1.53-1.45(m,1H),1.31-1.21(m,1H),0.99(t,J=7.5Hz,3H),0.94(d,J=6.3Hz,6H),0.80(t,J=7.2Hz,3H);
ESIMS(m/e)848.5[M+1]+。
实施例31化合物BM31的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.42(s,1H),8.01(s,1H),7.52(d,J=7.8Hz,1H),7.17-7.09(m,3H),6.58(s,1H),6.19(s,1H),6.07(d,J=7.8Hz,1H),5.88(dd,J=10.2,3.6Hz,1H),5.49(d,J=6.0Hz,1H),5.41(d,J=10.2Hz,1H),5.02(s,1H),3.83(s,3H),3.79-3.69(m,1H),3.62(s,3H),3.32(s,1H),2.89(s,3H),2.81(d,J=14.1Hz,1H),2.59(s,1H),2.15(s,3H),2.10(s,2H),1.94(q,J=7.2Hz,2H),1.53-1.46(m,1H),1.49(m,1H),1.30-1.19(m,1H),1.02(s,9H),0.99(t,J=7.5Hz,3H),0.80(t,J=7.2Hz,3H);
ESIMS(m/e)862.5[M+1]+。
实施例32化合物BM32的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.38(s,1H),8.01(s,1H),7.53(d,J=7.8Hz,1H),7.19-7.09(m,3H),6.62(s,1H),6.58(d,J=7.2Hz,1H),6.19(s,1H),5.88(dd,J=10.2,3.9Hz,1H),5.71(s,1H),5.48(d,J=6.0Hz,1H),5.42(d,J=10.2Hz,1H),5.32(s,1H),5.03(s,1H),3.83(s,3H),3.79-3.76(m,1H),3.62(s,3H),3.53(d,J=16.5Hz,1H),3.35(s,1H),2.89(s,3H),2.64(s,1H),2.15(s,3H),1.97(s,3H),1.49(m,1H),1.00(t,J=7.5Hz,3H),0.81(t,J=7.2Hz,3H);
ESIMS(m/e)832.5[M+1]+。
实施例33化合物BM33的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.38(s,1H),8.01(s,1H),7.52(d,J=7.5Hz,1H),7.19-7.09(m,3H),6.61(s,1H),6.31(d,J=7.2Hz,1H),6.19(s,1H),5.88(dd,J=10.2,3.6Hz,1H),5.48(d,J=6.0Hz,1H),5.42(d,J=10.2Hz,1H),5.04(s,1H),3.83(s,3H),3.77-3.70(m,1H),3.62(s,3H),3.54(d,J=16.5Hz,1H),3.40(s,1H),2.89(s,3H),2.62(s,1H),2.15(s,3H),1.93(q,J=7.5Hz,2H),1.49(m,1H),1.00(t,J=7.5Hz,3H),0.93(m,2H),0.81(t,J=7.2Hz,3H),0.71(m,2H);
ESIMS(m/e)832.5[M+1]+。
实施例34化合物BM34的制备
制备步骤参见化合物BM25的制备。
1H NMR(DMSO-d6,300MHz):δ:9.93(s,1H),8.56(s,1H),7.44(d,J=8.1Hz,1H),7.29(d,J=8.1Hz,1H),6.98(m,2H),6.62(s,2H),6.55(s,1H),5.79(m,1H),5.50(d,J=5.7Hz,1H),5.43(d,J=10.2Hz,1H),4.78(s,1H),4.24(s,4H),3.78(s,3H),3.58(s,3H),2.86(s,3H),2.08(s,3H),1.43(m,1H),1.10(s,9H),0.96(t,J=7.2Hz,3H),0.65(t,J=6.9Hz,3H);
13C NMR(DMSO-d6,75MHz):δ:177.2(C),173.9(C),174.9(C),170.5(C),158.1(C),153.7(C),139.9(C),135.2(C),131.1(C),130.1(CH),129.6(C),124.7(CH),124.0(CH),123.7(CH),123.7(C),122.5(CH),121.8(C),119.1(CH),118.5(CH),117.4(C),110.7(CH),95.3(CH),82.4(CH),76.8(CH),76.0(C),72.3(4CH),66.2(CH),56.0(OCH3),55.6(C),54.7(CH2),52.8(C),52.6(OCH3),52.2(CH2),50.3(2CH2),46.0(CH2),45.3(CH2),43.5(CH2),42.9(C),40.9(CH3),38.9(C),34.5(CH2),32.9(CH),31.6(CH2),28.0(CH2),27.0(3CH3),25.6(CH2),21.1(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)848.5[M+1]+。
实施例35化合物BM35的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.38(s,1H),8.01(s,1H),7.52(d,J=7.8Hz,1H),7.16-7.08(m,3H),6.60(s,1H),6.19(s,1H),6.08(d,J=7.8Hz,1H),5.87(dd,J=10.2,3.6Hz,1H),5.47(d,J=6.0Hz,1H),5.41(d,J=10.2Hz,1H),5.01(s,1H),3.82(s,3H),3.62(s,3H),3.31(s,1H),2.87(s,3H),2.62(s,1H),2.14(s,3H),1.98-1.87(m,2H),1.48(m,1H),0.99(t,J=7.5Hz,3H),0.80(t,J=7.5Hz,3H);
ESIMS(m/e)846.5[M+1]+。
实施例36化合物BM36的制备
制备步骤参见化合物BM25的制备。
1H NMR(DMSO-d6,300MHz):δ:9.90(s,1H),8.64(s,1H),7.78(d,J=7.8Hz,2H),7.49(m,3H),7.29(d,J=7.8Hz,1H),6.98(m,3H),6.62(s,1H),6.56(s,1H),5.75(dd,J=10.2,4.5Hz,1H),5.47(m,2H),4.86(s,1H),4.23(s,4H),3.80(s,3H),3.58(s,3H),2.90(s,3H),2.09(s,3H),0.95(t,J=7.2Hz,3H),0.66(t,J=6.9Hz,3H);
13C NMR(DMSO-d6,75MHz):δ:173.9(C),173.6(C),170.6(C),166.38(C),157.3(C),153.6(C),137.6(C),137.0(C),135.6(C),134.6(CH),131.3(2CH),130.6(C),128.5(2CH),127.0(2CH),124.4(CH),123.8(2CH),121.4(CH),121.0(C),118.4(CH),117.7(C),113.2(C),112.7(C),111.9(CH),95.3(CH),81.2(CH),76.6(CH),75.8(C),77.11(4CH),63.8(CH),56.3(OCH3),55.0(C),53.8(CH2),52.6(C),52.2(OCH3),49.5(2CH2),48.7(CH2),45.2(2CH2),43.1(CH2),42.1(C),38.7(CH3),34.8(CH2),31.4(CH),31.4(CH2),30.7(CH2),27.2(CH2),20.8(CH3),11.8(CH3),7.9(CH3);
ESIMS(m/e)868.5[M+1]+。
实施例37化合物BM37的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.44(s,1H),8.02(s,1H),7.69(d,J=8.4Hz,2H),7.53(d,J=8.1Hz,1H),7.23(d,J=8.4Hz,2H),7.18-7.09(m,3H),6.90(d,J=7.5Hz,1H),6.62(s,1H),6.20(s,1H),5.90(dd,J=10.2,3.9Hz,1H),5.45(m,2H),5.09(s,1H),3.92(dd,J=13.5,8.1Hz,1H),3.83(s,3H),3.63(s,3H),3.53(d,J=16.5Hz,1H),3.42(s,1H),2.91(s,3H),2.65(s,1H),2.39(s,3H),2.14(s,3H),1.85(m,2H),1.51(m,1H),0.99(t,J=7.5Hz,3H),0.82(t,J=7.2Hz,3H)。
ESIMS(m/e)882.5[M+1]+。
实施例38化合物BM38的制备
制备步骤参见化合物BM25的制备。
1HNMR(CDCl3,300MHz):δ:9.51(s,1H),8.03(s,1H),7.80(dd,J=8.4,5.4Hz,2H),7.53(d,J=7.5Hz,1H),7.19-7.08(m,5H),6.90(d,J=7.5Hz,1H),6.63(s,1H),6.21(s,1H),5.90(dd,J=10.2,3.9Hz,1H),5.46(s,1H),5.44(d,J=10.2Hz,1H),5.09(s,1H),3.95-3.88(m,1H),3.83(s,3H),3.63(s,3H),3.53(d,J=16.8Hz,1H),3.41(s,1H),2.91(s,3H),2.85(d,J=16.2Hz,1H),2.66(s,1H),2.14(s,3H),1.93(q,J=7.5Hz,2H),1.54-1.49(m,1H),0.99(t,J=7.5Hz,3H),0.82(t,J=7.2Hz,3H);
ESIMS(m/e)886.5[M+1]+。
实施例39化合物BM39的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.44(s,1H),8.04(s,1H),7.60(dd,J=6.6,2.2Hz,1H),7.52(d,J=7.8Hz,1H),7.32(m,3H),7.13(m,3H),6.90(d,J=7.5Hz,1H),6.61(s,1H),6.23(s,1H),5.88(dd,J=10.2,4.2Hz,1H),5.47(s,1H),5.44(d,J=10.2Hz,1H),5.09(s,1H),3.98(m,1H),3.83(s,3H),3.62(s,3H),3.46(s,1H),3.00(s,3H),2.81(d,J=15.6Hz,2H),2.62(s,1H),2.18(s,3H),1.93(q,J=7.5Hz,2H),1.51(m,1H),1.26(m,1H),0.99(t,J=7.5Hz,3H),0.82(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),170.9(C),166.9(C),158.1(C),153.7(C),140.0(C),135.6(C),135.1(C),131.3(CH),130.8(C),130.3(CH),130.0(2CH),130.0(C),129.61(C),127.2(CH),124.6(CH),124.0(CH),123.7(CH),123.7(C),122.4(CH),121.8(C),119.0(CH),118.5(CH),117.5(C),110.6(CH),94.7(CH),82.1(CH),77.0(CH),76.1(C),66.2(CH),56.0(OCH3),55.6(C),54.7(CH2),52.7(C),52.5(OCH3),52.2(CH2),50.3(CH2),50.2(CH2),46.0(CH2),45.4(CH2),43.8(CH2),42.9(C),41.0(CH3),34.5(CH2),33.0(CH),31.6(CH2),28.0(CH2),25.8(CH2),21.2(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)902.5[M+1]+。
实施例40化合物BM40的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.48(s,1H),8.03(s,1H),7.77(s,1H),7.66(d,J=7.8Hz,1H),7.53(d,J=7.8Hz,1H),7.47(d,J=7.8Hz,1H),7.36(t,J=7.8Hz,1H),7.19-7.09(m,3H),6.95(d,J=7.8Hz,1H),6.63(s,1H),6.22(s,1H),5.90(dd,J=9.6,4.5Hz,1H),5.47-5.43(m,2H),5.08(s,1H),3.93(dd,J=13.5,7.5Hz,1H),3.83(s,3H),3.63(s,3H),3.53(d,J=16.5Hz,1H),3.40(s,1H),2.92(s,3H),2.85(d,J=15.9Hz,1H),2.66(s,1H),2.14(s,3H),1.93(q,J=7.2Hz,2H),1.54-1.47(m,1H),1.31-1.25(m,1H),0.99(t,J=7.5Hz,3H),0.82(t,J=7.2Hz,3H)。
ESIMS(m/e)902.5[M+1]+。
实施例41化合物BM41的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.48(s,1H),8.04(s,1H),7.73(d,J=8.7Hz,2H),7.52(d,J=7.5Hz,1H),7.39(d,J=8.7Hz,1H),7.13(m,3H),6.93(d,J=6.9Hz,1H),6.63(s,1H),6.21(s,1H),5.89(dd,J=10.2,4.2Hz,1H),5.46(s,1H),5.46(d,J=10.2Hz,1H),5.09(s,1H),3.91(m,1H),3.83(s,3H),3.62(s,3H),3.40(s,1H),2.91(s,3H),2.84(d,J=16.5Hz,2H),2.65(s,1H),2.12(s,3H),1.93(q,J=7.2Hz,2H),1.51(m,1H),1.28(m,1H),0.99(t,J=7.5Hz,3H),0.82(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.0(C),166.5(C),158.1(C),153.6(C),140.0(C),137.8(C),135.2(C),131.2(C),130.1(C),130.1(CH),129.6(C),129.0(2CH),128.5(2CH),124.7(CH),124.0(CH),123.8(CH),123.7(C),122.5(CH),122.1(C),119.1(CH),118.6(CH),117.5(C),110.7(CH),95.4(CH),82.9(CH),77.0(CH),76.1(C),66.0(CH),56.0(OCH3),55.7(C),54.7(CH2),52.9(C),52.6(OCH3),52.3(CH2),50.3(2CH2),46.0(CH2),45.4(CH2),43.9(CH2),42.9(C),41.1(CH3),34.5(CH2),33.0(CH),31.6(CH2),28.0(CH2),25.8(CH2),21.1(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)902.5[M+1]+。
实施例42化合物BM42的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.57(s,1H),8.73(d,J=6.0Hz,2H),8.03(s,1H),7.62(d,J=6.0Hz,2H),7.52(d,J=7.5Hz,1H),7.20-7.09(m,3H),6.63(s,1H),6.22(s,1H),5.90(dd,J=10.2,3.9Hz,1H),5.46(d,J=10.2Hz,1H),5.43(s,1H),5.09(s,1H),3.97-3.90(m,1H),3.83(s,3H),3.63(s,3H),3.52(d,J=16.5Hz,1H),3.38(s,1H),2.91(s,3H),2.67(s,1H),2.13(s,3H),1.92(q,J=7.5Hz,2H),1.53-1.48(m,1H),0.99(t,J=7.5Hz,3H),0.82(t,J=7.2Hz,3H);
ESIMS(m/e)869.5[M+1]+。
实施例43化合物BM43的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.58(s,1H),8.28(d,J=8.7Hz,2H),8.04(s,1H),7.94(d,J=8.7Hz,2H),7.53(d,J=7.5Hz,1H),7.13(m,4H),6.64(s,1H),6.23(s,1H),5.91(dd,J=10.2,4.2Hz,1H),5.47(s,1H),5.45(d,J=10.2Hz,1H),5.09(s,1H),3.91(m,1H),3.84(s,3H),3.63(s,3H),3.43(s,1H),2.93(s,3H),2.84(d,J=16.5Hz,2H),2.68(s,1H),2.13(s,3H),1.93(q,J=7.2Hz,2H),1.51(m,1H),1.28(m,1H),0.99(t,J=7.5Hz,3H),0.82(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.8(C),171.0(C),165.4(C),158.1(C),153.4(C),149.6(C),140.3(C),140.0(C),135.1(C),130.9(C),130.0(CH),129.6(C),128.2(2CH),124.8(2CH),124.0(2CH),123.8(2CH),123.5(C),122.5(CH),122.3(C),119.1(CH),118.5(CH),117.6(C),110.7(CH),95.4(CH),83.0(CH),76.8(CH),76.0(C),65.8(CH),56.0(OCH3),55.6(C),54.5(CH2),53.0(C),52.6(OCH3),52.2(CH2),50.2(CH2),50.1(CH2),45.9(CH2),45.4(CH2),44.0(CH2),42.9(C),41.4(CH3),34.4(CH2),33.0(CH),31.6(CH2),28.0(CH2),25.7(CH2),21.2(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)913.5[M+1]+。
实施例44化合物BM44的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.27(s,1H),8.47(d,J=7.2Hz,1H),8.14(d,J=7.5Hz,1H),8.05(s,1H),7.52(d,J=7.5Hz,1H),7.42(t,J=7.5Hz,1H),7.14(m,3H),7.08(t,J=7.5Hz,1H),6.96(d,J=7.5Hz,1H),6.61(s,1H),6.20(s,1H),5.88(dd,J=10.2,4.2Hz,1H),5.49(s,1H),5.45(d,J=10.2Hz,1H),5.09(s,1H),3.93(m,1H),3.90(s,3H),3.82(s,3H),3.61(s,3H),3.44(s,1H),2.91(s,3H),2.83(d,J=15.6Hz,2H),2.63(s,1H),2.13(s,3H),1.93(q,J=7.5Hz,2H),1.51(m,1H),1.26(m,1H),0.99(t,J=7.5Hz,3H),0.82(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),170.9(C),165.5(C),158.1(C),157.7(C),153.8(C),140.0(C),135.1(C),132.6(CH),132.0(CH),131.3(C),130.2(CH),129.6(C),124.6(CH),124.0(CH),123.8(C),123.7(C),122.4(CH),122.3(CH),121.5(C),121.2(CH),119.0(CH),118.5(CH),117.5(C),111.6(CH),110.6(CH),95.1(CH),82.2(CH),77.3(CH),76.1(C),66.3(CH),56.1(OCH3),56.0(OCH3),55.6(C),54.7(CH2),52.7(C),52.5(OCH3),52.3(CH2),50.4(CH2),50.3(CH2),46.0(CH2),45.4(CH2),43.8(CH2),42.9(C),40.6(CH3),34.5(CH2),33.0(CH),31.6(CH2),28.0(CH2),25.8(CH2),21.1(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)898.4[M+1]+。
实施例45化合物BM45的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.24(s,1H),8.00(s,1H),7.52(d,J=7.8Hz,1H),7.20(d,J=8.7Hz,2H),7.14-7.08(m,3H),6.87(d,J=8.7Hz,2H),6.58(s,1H),6.17(d,J=8.4Hz,1H),6.10(s,1H),5.85(dd,J=10.2,4.2Hz,1H),5.46(s,1H),5.38(d,J=10.2Hz,1H),4.95(s,1H),3.84(s,3H),3.79(s,3H),3.63(s,1H),3.12(s,1H),2.91(d,J=13.5Hz,1H),2.80(d,J=15.9Hz,1H),2.68(s,3H),2.59(s,1H),2.13(s,3H),1.93(q,J=7.2Hz,2H),1.45(m,1H),1.00(t,J=7.5Hz,3H),0.79(t,J=7.2Hz,3H)。
ESIMS(m/e)898.5[M+1]+。
实施例46化合物BM46的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.25(s,1H),7.99(s,1H),7.52(d,J=7.5Hz,1H),7.37-7.27(m,5H),7.19-7.11(m,3H),6.59(s,1H),6.18(d,J=8.7Hz,1H),6.09(s,1H),5.84(dd,J=10.2,4.2Hz,1H),5.45(s,1H),5.38(d,J=10.2Hz,1H),4.95(s,1H),3.84(s,3H),3.79-3.77(m,1H),3.63(s,3H),3.56(s,2H),3.10(s,1H),2.91(d,J=13.8Hz,1H),2.80(d,J=15.9Hz,1H),2.65(s,3H),2.59(s,1H),2.13(s,3H),1.92(q,J=7.5Hz,2H),1.51-1.44(m,1H),1.25-1.20(m,1H),1.00(t,J=7.5Hz,3H),0.79(t,J=7.2Hz,3H);
ESIMS(m/e)882.5[M+1]+。
实施例47化合物BM47的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.45(s,1H),8.03(s,1H),7.53(d,J=8.1Hz,1H),7.32(d,J=8.1Hz,1H),7.29(s,1H),7.18-7.09(m,3H),6.83(m,2H),6.62(s,1H),6.20(s,1H),6.02(s,2H),5.90(dd,J=10.2,3.9Hz,1H),5.46(m,2H),5.08(s,1H),3.93-3.86(m,1H),3.83(s,3H),3.63(s,3H),3.52(d,J=16.5Hz,1H),3.40(s,1H),2.91(s,3H),2.65(s,1H),2.58(d,J=12.9Hz,1H),2.14(s,3H),1.97-1.89(m,2H),1.54-1.47(m,1H),1.31-1.25(m,1H),0.99(t,J=7.5Hz,3H),0.82(t,J=7.2Hz,3H)。
ESIMS(m/e)912.4[M+1]+。
实施例48化合物BM48的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.26(s,1H),8.04(s,1H),7.51(d,J=7.5Hz,1H),7.12(m,3H),6.59(s,1H),6.20(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.48(d,J=5.7Hz,1H),5.42(d,J=10.2Hz,1H),5.36(d,J=6.6Hz,1H),5.02(s,1H),3.82(s,3H),3.65(s,3H),3.61(s,3H),3.38(s,1H),2.92(s,3H),2.80(d,J=16.2Hz,1H),2.60(s,1H),2.14(s,3H),1.93(q,J=7.5Hz,2H),1.46(m,1H),1.23(m,1H),0.99(t,J=7.5Hz,3H),0.80(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.0(C),158.0(C),157.4(C),153.7(C),140.0(C),135.1(C),131.0(C),130.0(CH),129.6(C),124.7(CH),124.0(CH),123.7(CH),123.7(C),122.4(CH),121.8(C),119.0(CH),118.5(CH),117.5(C),110.6(CH),95.3(CH),82.2(CH),76.8(CH),76.1(C),66.1(CH),56.0(OCH3),55.6(C),54.7(CH2),52.8(C),52.5(OCH3),52.2(CH2),50.7(OCH3),50.2(2CH2),45.9(CH2),45.2(CH2),44.9(CH2),42.8(C),40.8(CH3),34.5(CH2),33.0(CH),31.6(CH2),28.0(CH2),25.7(CH2),21.1(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)822.3[M+1]+。
实施例49化合物BM49的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.25(s,1H),8.00(s,1H),7.53(d,J=7.5Hz,1H),7.13(m,3H),6.61(s,1H),6.20(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.48(d,J=6.3Hz,1H),5.42(d,J=10.2Hz,1H),5.30(d,J=3.9Hz,1H),5.03(s,1H),4.09(q,J=7.2Hz,2H),3.83(s,3H),3.62(s,3H),3.40(s,1H),2.94(s,3H),2.82(d,J=15.9Hz,1H),2.61(s,1H),2.16(s,3H),1.43(m,1H),1.23(t,J=7.2Hz,3H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.81(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.4(C),170.8(C),157.8(C),156.9(C),153.8(C),137.7(C),134.9(C),130.8(C),129.8(CH),129.0(C),124.7(CH),123.9(C),123.8(CH),123.3(CH),122.8(CH),120.7(C),119.4(CH),118.2(CH),115.6(C),110.6(CH),95.0(CH),81.8(CH),77.0(CH),75.9(C),65.9(CH),60.7(CH2),55.9(OCH3),55.3(C),54.4(CH2),52.5(C),52.5(OCH3),50.9(CH2),50.1(CH2),50.0(CH2),45.4(CH2),45.2(CH2),44.6(CH2),42.7(C),40.4(CH3),34.2(CH2),31.5(CH),31.5(CH2),27.8(CH2),23.2(CH2),21.0(CH3),14.7(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)836.4[M+1]+。
实施例50化合物BM50的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.24(s,1H),8.00(s,1H),7.53(d,J=7.5Hz,1H),7.18(m,3H),6.60(s,1H),6.20(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.47(d,J=6.0Hz,1H),5.42(d,J=10.2Hz,1H),5.25(d,J=3.9Hz,1H),5.03(s,1H),4.89(m,1H),3.83(s,3H),3.64(s,3H),3.38(s,1H),2.93(s,3H),2.82(d,J=15.9Hz,1H),2.61(s,1H),2.16(s,3H),1.93(q,J=7.5Hz,2H),1.43(m,1H),1.25(m,1H),1.23(d,J=7.2Hz,6H),1.00(t,J=7.5Hz,3H),0.81(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.0(C),158.1(C),156.7(C),153.8(C),139.9(C),135.1(C),131.0(C),130.1(CH),129.6(C),124.7(CH),124.0(CH),123.9(C),123.7(CH),122.5(CH),121.7(C),119.0(CH),118.5(CH),117.3(C),110.6(CH),95.2(CH),82.2(CH),77.3(CH),76.1(C),68.0(CH),66.2(CH),56.0(OCH3),55.6(C),54.6(CH2),52.7(C),52.5(OCH3),52.2(CH2),50.3(2CH2),46.0(CH2),45.3(CH2),44.9(CH2),42.9(C),40.7(CH3),34.5(CH2),32.9(CH),31.7(CH2),28.0(CH2),25.7(CH2),22.3(2CH3),21.1(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)850.3[M+1]+。
实施例51化合物BM51的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.25(s,1H),8.00(s,1H),7.53(d,J=7.5Hz,1H),7.13(m,3H),6.59(s,1H),6.20(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.48(d,J=6.0Hz,1H),5.42(d,J=10.2Hz,1H),5.25(d,J=3.9Hz,1H),5.03(s,1H),3.83(s,3H),3.64(s,3H),3.38(s,1H),2.93(s,3H),2.82(d,J=15.9Hz,1H),2.61(s,1H),2.16(s,3H),1.43(m,1H),1.36(s,9H),1.21(m,1H),0.99(t,J=7.5Hz,3H),0.81(t,J=6.9Hz,3H);
ESIMS(m/e)864.4[M+1]+。
实施例52化合物BM52的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.26(s,1H),8.01(s,1H),7.52(d,J=8.1Hz,1H),7.12(m,3H),6.60(s,1H),6.20(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.48(d,J=5.7Hz,1H),5.42(d,J=10.2Hz,1H),5.25(d,J=6.6Hz,1H),5.03(s,1H),4.01(t,J=6.3Hz,2H),3.82(s,3H),3.61(s,3H),3.37(s,1H),2.93(s,3H),2.81(d,J=16.2Hz,1H),2.61(s,1H),2.15(s,3H),1.93(q,J=7.5Hz,2H),1.46(m,1H),1.23(m,1H),0.99(t,J=7.2Hz,3H),0.92(t,J=7.2Hz,3H),0.81(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.0(C),158.1(C),157.2(C),153.7(C),140.1(C),135.1(C),131.0(C),130.1(CH),129.6(C),124.7(CH),124.0(CH),123.7(CH),123.7(C),122.4(CH),121.8(C),119.0(CH),118.5(CH),117.5(C),110.6(CH),95.2(CH),82.1(CH),77.2(CH),76.1(C),66.5(CH2),66.1(CH),56.0(OCH3),55.6(C),54.7(CH2),52.7(C),52.5(OCH3),52.3(CH2),50.2(2CH2),46.0(CH2),45.3(CH2),44.9(CH2),42.9(C),40.7(CH3),34.5(CH2),33.0(CH),31.7(CH2),28.0(CH2),25.9(CH2),22.5(CH2),21.1(CH3),12.4(CH3),10.5(CH3),8.4(CH3);
ESIMS(m/e)850.3[M+1]+。
实施例53化合物BM53的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.30(s,1H),8.00(s,1H),7.53(d,J=7.5Hz,1H),7.12(m,3H),6.60(s,1H),6.20(s,1H),5.88(dd,J=10.2,3.9Hz,1H),5.47(d,J=5.4Hz,1H),5.42(d,J=10.2Hz,1H),5.30(d,J=3.9Hz,1H),5.04(s,1H),3.84(d,J=6.0Hz,2H),3.83(s,3H),3.62(s,3H),3.40(s,1H),2.93(s,3H),2.82(d,J=15.9Hz,1H),2.61(s,1H),2.15(s,3H),1.46(m,1H),1.23(m,1H),1.00(t,J=7.2Hz,3H),0.91(d,J=6.0Hz,6H),0.81(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:173.6(C),170.6(C),157.5(C),156.8(C),153.9(C),134.6(2C),130.4(C),129.4(CH),128.2(C),124.6(CH),123.9(C),123.8(CH),123.3(CH),122.6(CH),119.9(CH),119.1(C),117.7(CH),112.9(C),110.5(CH),94.7(CH),81.2(CH),76.8(CH),75.7(C),70.7(CH2),65.8(CH),55.7(OCH3),54.9(C),54.0(CH2),52.5(OCH3),52.3(C),49.9(2CH2),48.9(CH2),45.1(CH2),44.6(CH2),44.4(CH2),42.4(C),39.9(CH3),33.7(CH2),31.2(CH2),29.4(CH),27.8(CH),27.5(CH2),20.8(CH3),19.6(CH2),18.8(2CH3),11.2(CH3),8.1(CH3);
ESIMS(m/e)864.5[M+1]+。
实施例54化合物BM54的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.26(s,1H),8.04(s,1H),7.48(d,J=7.2Hz,1H),7.11(m,3H),6.49(s,1H),6.19(s,1H),5.87(dd,J=10.2,4.5Hz,1H),5.61(d,J=5.4Hz,1H),5.50(d,J=6.6Hz,1H),5.41(d,J=10.2Hz,1H),4.99(s,1H),4.21(s,2H),3.82(s,3H),3.62(s,3H),3.41(s,1H),3.37(s,3H),2.93(s,3H),2.81(d,J=16.2Hz,1H),2.59(s,1H),2.14(s,3H),1.99(q,J=7.5Hz,2H),1.46(m,1H),1.23(m,1H),1.01(t,J=7.2Hz,3H),0.77(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.4(C),171.0(C),158.0(C),156.7(C),154.0(C),137.2(C),135.1(C),130.8(C),130.0(CH),129.1(C),124.9(CH),124.2(C),123.9(CH),123.5(CH),123.1(CH),120.6(C),119.7(CH),118.4(CH),115.2(C),110.7(CH),95.1(CH),81.8(CH),77.2(CH),76.1(C),71.1(CH2),66.1(CH),64.0(CH2),59.0(OCH3),56.0(OCH3),55.5(C),54.1(CH2),52.7(C),52.7(OCH3),50.2(3CH2),45.3(CH2),45.1(CH2),44.8(CH2),42.9(C),40.5(CH3),34.3(CH2),31.6(CH2),31.0(CH),27.9(CH2),22.2(CH2),21.1(CH3),11.9(CH3),8.4(CH3);
ESIMS(m/e)866.4[M+1]+。
实施例55化合物BM55的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.32(s,1H),8.02(s,1H),7.51(d,J=7.8Hz,1H),7.12(m,3H),6.60(s,1H),6.20(s,1H),5.87(dd,J=10.2,4.5Hz,1H),5.47(m,2H),5.42(d,J=10.2Hz,1H),5.02(s,1H),4.34(m,2H),3.82(s,3H),3.60(s,3H),3.38(s,1H),2.92(s,3H),2.81(d,J=16.2Hz,1H),2.61(s,1H),2.15(s,3H),1.92(q,J=7.5Hz,2H),1.46(m,1H),1.23(m,1H),0.98(t,J=7.5Hz,3H),0.80(t,J=6.6Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.8(C),171.8(C),158.0(C),156.0(C),153.5(C),139.9(C),135.0(C),130.9(C),129.9(CH),129.5(C),124.6(CH),123.8(CH),123.6(CH),123.5(C),122.3(CH),121.7(C),118.9(CH),118.4(CH),117.4(C),110.5(CH),95.2(CH),82.1(CH),77.0(CH),75.9(C),65.9(CH),64.2(CH2),56.0(OCH3),55.5(C),54.6(CH2),52.7(C),52.4(OCH3),52.1(CH2),50.1(CH2),50.0(CH2),45.9(CH2),45.1(CH2),44.8(CH2),42.6(C),40.8(CH3),34.3(CH2),32.8(CH),31.5(CH2),29.7(CH2),27.9(CH2),25.6(CH2),21.1(CH3),12.3(CH3),8.3(CH3);
ESIMS(m/e)916.2[M+1]+。
实施例56化合物BM56的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.27(s,1H),8.00(s,1H),7.54(d,J=7.5Hz,1H),7.13(m,3H),6.60(s,1H),6.20(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.48(d,J=6.0Hz,1H),5.42(d,J=10.2Hz,1H),5.30(d,J=3.9Hz,1H),5.03(s,1H),4.04(t,J=6.0Hz,2H),3.83(s,3H),3.64(s,3H),3.38(s,1H),2.93(s,3H),2.82(d,J=15.9Hz,1H),2.61(s,1H),2.16(s,3H),1.60(m,2H),1.46(m,1H),1.26(m,4H),1.23(m,1H),1.00(t,J=7.2Hz,3H),0.89(d,J=6.6Hz,3H),0.81(t,J=7.2Hz,3H);
ESIMS(m/e)878.4[M+1]+。
实施例57化合物BM57的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.27(s,1H),8.00(s,1H),7.53(d,J=7.5Hz,1H),7.13(m,3H),6.60(s,1H),6.20(s,1H),5.87(dd,J=10.2,4.2Hz,1H),5.47(d,J=6.0Hz,1H),5.42(d,J=10.2Hz,1H),5.36(d,J=4.5Hz,1H),5.03(s,1H),3.89(d,J=7.2Hz,2H),3.83(s,3H),3.62(s,3H),3.41(s,1H),2.94(s,3H),2.82(d,J=15.9Hz,1H),2.61(s,1H),2.15(s,3H),1.46(m,1H),1.25(m,1H),1.00(t,J=7.2Hz,3H),0.81(t,J=7.2Hz,3H),0.51(d,J=4.8Hz,2H),0.25(d,J=4.8Hz,2H);
13C NMR(CDCl3,75MHz):δ:175.0(C),171.0(C),158.1(C),157.1(C),153.8(C),140.1(C),135.2(C),131.2(C),130.1(CH),129.7(C),124.7(CH),124.1(CH),123.8(CH),123.8(C),122.5(CH),121.8(C),119.0(CH),118.6(CH),117.6(C),110.7(CH),95.3(CH),82.2(CH),77.3(CH),76.1(C),69.7(CH2),66.3(CH),56.0(OCH3),55.7(C),54.7(CH2),52.8(C),52.5(OCH3),52.4(CH2),50.3(2CH2),46.1(CH2),45.3(CH2),45.0(CH2),43.0(C),40.8(CH3),34.5(CH2),33.1(CH),31.7(CH2),28.0(CH2),25.9(CH2),21.2(CH3),12.5(CH3),10.3(CH),8.3(CH3),3.2(2CH2);
ESIMS(m/e)862.3[M+1]+。
实施例58化合物BM58的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.25(s,1H),8.00(s,1H),7.53(d,J=7.5Hz,1H),7.13(m,3H),6.60(s,1H),6.20(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.47(d,J=5.4Hz,1H),5.42(d,J=10.2Hz,1H),5.30(d,J=3.9Hz,1H),5.02(s,1H),4.92(m,1H),3.83(s,3H),3.64(s,3H),3.39(s,1H),2.93(s,3H),2.82(d,J=15.9Hz,1H),2.62(s,1H),2.30(m,2H),2.15(s,3H),2.02(m,2H),1.92(q,J=7.5Hz,2H),1.73(m,1H),1.57(m,1H),1.25(m,1H),1.00(t,J=7.5Hz,3H),0.81(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),170.9(C),158.0(C),156.3(C),153.7(C),140.2(C),135.1(C),131.1(C),130.1(CH),129.6(C),124.7(CH),124.0(CH),123.7(CH),123.7(C),122.4(CH),121.8(C),119.0(CH),118.5(CH),117.6(C),110.6(CH),95.3(CH),82.2(CH),77.1(CH),76.0(C),68.9(CH),66.0(CH),56.0(OCH3),55.6(C),54.7(CH2),52.7(C),52.5(OCH3),52.3(CH2),50.2(2CH2),46.0(CH2),45.3(CH2),44.7(CH2),42.8(C),40.9(CH3),34.4(CH2),33.0(CH),31.6(CH2),30.7(CH2),30.5(CH2),28.0(CH2),25.9(CH2),21.2(CH3),13.3(CH2),12.4(CH3),8.5(CH3);
ESIMS(m/e)862.3[M+1]+。
实施例59化合物BM59的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.25(s,1H),8.00(s,1H),7.53(d,J=7.5Hz,1H),7.13(m,3H),6.60(s,1H),6.20(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.47(d,J=5.1Hz,1H),5.42(d,J=10.2Hz,1H),5.21(d,J=3.9Hz,1H),5.08(m,1H),5.03(s,1H),3.83(s,3H),3.64(s,3H),3.40(s,1H),2.93(s,3H),2.82(d,J=15.9Hz,1H),2.60(s,1H),2.40(m,2H),2.16(s,3H),1.92(q,J=7.5Hz,2H),1.72(m,2H),1.58(m,4H),1.44(m,2H),1.25(m,1H),1.00(t,J=7.5Hz,3H),0.81(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),170.9(C),158.1(C),156.9(C),153.8(C),140.1(C),135.2(C),131.2(C),130.1(CH),129.6(C),124.7(CH),124.1(CH),123.8(CH),123.8(C),122.4(CH),121.8(C),119.0(CH),118.6(CH),117.5(C),110.6(CH),95.3(CH),82.2(CH),77.7(CH),77.4(CH),76.1(C),66.3(CH),56.0(OCH3),55.7(C),54.7(CH2),53.6(C),52.7(CH2),52.5(OCH3),52.4(CH2),50.3(CH2),46.1(CH2),45.3(CH2),45.0(CH2),42.9(C),40.7(CH3),34.5(CH2),33.1(CH),31.7(CH2),33.0(2CH2),28.0(CH2),26.0(CH2),24.0(2CH2),21.1(CH3),12.5(CH3),8.5(CH3);
ESIMS(m/e)876.3[M+1]+。
实施例60化合物BM60的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.25(s,1H),8.00(s,1H),7.52(d,J=7.5Hz,1H),7.13(m,3H),6.60(s,1H),6.20(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.47(d,J=5.1Hz,1H),5.42(d,J=10.2Hz,1H),5.26(d,J=6.0Hz,1H),5.03(s,1H),4.62(m,1H),3.83(s,3H),3.63(s,3H),3.40(s,1H),2.93(s,3H),2.82(d,J=15.9Hz,1H),2.61(s,1H),2.40(m,2H),2.16(s,3H),1.72(m,2H),1.62(m,2H),1.42(m,1H),1.26(m,6H),1.00(t,J=7.5Hz,3H),0.81(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:175.0(C),171.0(C),158.1(C),156.7(C),153.8(C),140.1(C),135.2(C),131.2(C),130.2(CH),129.7(C),124.7(CH),124.1(CH),123.9(C),123.8(CH),122.5(CH),121.8(C),119.1(CH),118.6(CH),117.6(C),110.6(CH),95.3(CH),82.2(CH),77.4(CH),76.1(C),73.0(CH),66.3(CH),56.0(OCH3),55.7(C),54.7(CH2),52.8(C),52.5(OCH3),52.4(CH2),50.4(2CH2),46.1(CH2),45.3(CH2),45.0(CH2),42.9(C),40.7(CH3),34.5(CH2),33.1(CH),31.7(2CH2),31.7(CH2),28.0(CH2),25.9(CH2),26.0(CH2),24.0(2CH2),21.2(CH3),12.5(CH3),8.5(CH3);
ESIMS(m/e)890.3[M+1]+。
实施例61化合物BM61的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.38(s,1H),8.01(s,1H),7.53(d,J=7.8Hz,1H),7.35(t,J=7.8Hz,2H),7.14(m,6H),6.63(s,1H),6.23(s,1H),5.89(dd,J=10.2,3.9Hz,1H),5.76(d,J=7.8Hz,1H),5.46(m,2H),5.07(s,1H),3.83(s,3H),3.63(s,3H),3.45(s,1H),2.99(s,3H),2.85(d,J=15.9Hz,1H),2.65(s,1H),2.18(s,3H),1.43(m,1H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.82(t,J=6.9Hz,3H);
ESIMS(m/e)884.4[M+1]+。
实施例62化合物BM62的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.38(s,1H),8.01(s,1H),7.53(d,J=7.8Hz,1H),7.11(m,7H),6.63(s,1H),6.23(s,1H),5.90(dd,J=10.2,3.9Hz,1H),5.77(d,J=7.8Hz,1H),5.46(m,2H),5.07(s,1H),3.84(s,3H),3.64(s,3H),3.44(s,1H),2.98(s,3H),2.85(d,J=15.9Hz,1H),2.66(s,1H),2.18(s,3H),1.43(m,1H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.82(t,J=6.9Hz,3H);
ESIMS(m/e)902.3[M+1]+。
实施例63化合物BM63的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.40(s,1H),8.02(s,1H),7.53(d,J=7.5Hz,1H),7.14(m,5H),7.02(m,1H),6.63(s,1H),6.24(s,1H),5.89(dd,J=10.2,3.9Hz,1H),5.80(d,J=7.8Hz,1H),5.46(m,2H),5.07(s,1H),3.84(s,3H),3.63(s,3H),3.45(s,1H),2.99(s,3H),2.85(d,J=15.9Hz,1H),2.65(s,1H),2.18(s,3H),1.43(m,1H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.82(t,J=6.9Hz,3H);
ESIMS(m/e)920.4[M+1]+。
实施例64化合物BM64的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.35(s,1H),8.02(s,1H),7.53(d,J=7.8Hz,1H),7.14(m,5H),6.94(d,J=8.4Hz,2H),6.63(s,1H),6.23(s,1H),5.89(dd,J=10.2,3.9Hz,1H),5.81(d,J=8.1Hz,1H),5.47(m,2H),5.06(s,1H),3.83(s,3H),3.81(s,3H),3.64(s,3H),3.49(s,1H),3.00(s,3H),2.85(d,J=15.9Hz,1H),2.65(s,1H),2.18(s,3H),1.92(q,J=7.5Hz,2H),1.43(m,1H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.83(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.0(C),158.1(C),154.7(C),153.8(C),151.9(C),140.2(C),140.1(C),135.2(C),131.2(C),130.1(CH),129.6(C),126.6(CH),124.8(CH),124.0(CH),123.8(CH),123.8(C),123.5(CH),122.5(CH),121.9(C),120.9(CH),119.1(CH),118.6(CH),117.5(C),112.5(CH),110.7(CH),95.4(CH),82.2(CH),77.1(CH),76.2(C),66.2(CH),56.0(OCH3),55.9(OCH3),55.7(C),54.7(CH2),52.9(C),52.6(OCH3),52.4(CH2),50.3(2CH2),46.0(CH2),45.3(CH2),45.1(CH2),42.9(C),40.9(CH3),34.5(CH2),33.1(CH),31.7(CH2),28.0(CH2),25.9(CH2),21.2(CH3),12.5(CH3),8.5(CH3);
ESIMS(m/e)914.4[M+1]+。
实施例65化合物BM65的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.36(s,1H),8.02(s,1H),7.53(d,J=7.5Hz,1H),7.14(m,5H),7.02(d,J=8.4Hz,2H),6.94(d,J=8.4Hz,2H),6.63(s,1H),6.23(s,1H),5.89(dd,J=10.2,3.9Hz,1H),5.81(d,J=8.1Hz,1H),5.47(m,2H),5.07(s,1H),3.83(s,3H),3.79(s,3H),3.64(s,3H),3.46(s,1H),2.98(s,3H),2.85(d,J=15.9Hz,1H),2.65(s,1H),2.17(s,3H),1.92(q,J=7.5Hz,2H),1.43(m,1H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.82(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.0(C),158.1(C),157.0(C),155.4(C),153.7(C),144.8(C),140.2(C),135.2(C),131.1(C),130.1(CH),129.7(C),124.7(CH),124.0(CH),123.8(CH),123.8(C),122.6(2CH),122.5(CH),122.1(C),119.1(CH),118.6(CH),117.5(C),114.5(2CH),110.7(CH),95.5(CH),82.7(CH),77.0(CH),76.0(C),66.1(CH),56.0(OCH3),55.7(OCH3),54.7(CH2),52.9(C),52.7(C),52.5(OCH3),52.4(CH2),50.3(2CH2),46.0(CH2),45.3(2CH2),42.9(C),41.2(CH3),34.5(CH2),33.1(CH),31.7(CH2),28.0(CH2),26.0(CH2),21.2(CH3),12.4(CH3),8.5(CH3);
ESIMS(m/e)914.4[M+1]+。
实施例66化合物BM66的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.30(s,1H),8.04(s,1H),7.54(d,J=7.5Hz,1H),7.35(m,5H),7.15(m,3H),6.63(s,1H),6.22(s,1H),5.88(dd,J=10.2,4.5Hz,1H),5.48(m,2H),5.42(d,J=10.2Hz,1H),5.12(s,2H),5.05(s,1H),3.84(s,3H),3.63(s,3H),3.40(s,1H),2.93(s,3H),2.82(d,J=15.9Hz,1H),2.63(s,1H),2.14(s,3H),1.95(q,J=7.5Hz,2H),1.46(m,1H),1.28(m,1H),1.01(t,J=7.5Hz,3H),0.83(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.8(C),170.8(C),157.9(C),156.6(C),153.5(C),140.0(C),136.7(C),135.0(C),131.0(C),130.0(CH),129.5(C),128.5(2CH),128.0(CH),128.0(2CH),124.6(CH),123.9(CH),123.6(CH),123.6(C),122.3(CH),121.7(C),118.9(CH),118.4(CH),117.5(C),110.6(CH),95.2(CH),82.0(CH),77.0(CH),76.0(C),66.6(CH2),65.9(CH),55.9(OCH3),55.5(C),54.6(CH2),52.6(C),52.4(OCH3),52.3(CH2),50.0(2CH2),45.9(CH2),45.1(CH2),44.8(CH2),42.7(C),40.7(CH3),34.4(CH2),33.0(CH),31.5(CH2),27.8(CH2),25.9(CH2),21.0(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)898.4[M+1]+。
实施例67化合物BM67的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.26(s,1H),8.03(s,1H),7.53(d,J=7.5Hz,1H),7.34(d,J=7.5Hz,1H),7.27(d,J=7.5Hz,1H),7.13(m,3H),6.93(d,J=7.5Hz,1H),6.89(d,J=7.5Hz,1H),6.60(s,1H),6.21(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.44(m,3H),5.17(s,2H),5.04(s,1H),3.83(s,6H),3.62(s,3H),3.38(s,1H),2.93(s,3H),2.81(d,J=15.3Hz,1H),2.61(s,1H),2.14(s,3H),1.94(q,J=7.5Hz,2H),1.47(m,1H),1.26(m,1H),1.00(t,J=7.5Hz,3H),0.82(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),170.9(C),158.0(C),157.7(C),156.9(C),153.7(C),140.1(C),135.1(C),131.1(C),130.1(CH),129.6(CH),129.6(C),129.4(CH),125.1(C),124.6(CH),124.0(CH),123.7(CH),123.7(C),122.4(CH),121.7(C),120.5(CH),119.0(CH),118.5(CH),117.5(C),110.6(CH),110.5(CH),95.2(CH),82.0(CH),77.2(CH),76.1(C),66.1(CH),62.1(CH2),56.0(OCH3),55.6(OCH3),55.5(C),54.7(CH2),52.7(C),52.5(OCH3),52.3(CH2),50.2(2CH2),46.0(CH2),45.2(CH2),45.0(CH2),42.8(C),40.7(CH3),34.5(CH2),33.0(CH),31.6(CH2),28.0(CH2),25.9(CH2),21.1(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)928.4[M+1]+。
实施例68化合物BM68的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.24(s,1H),8.03(s,1H),7.53(d,J=7.5Hz,1H),7.26(d,J=7.5Hz,2H),7.13(m,3H),6.87(d,J=7.5Hz,2H),6.61(s,1H),6.20(s,1H),5.87(dd,J=10.5,4.5Hz,1H),5.49(d,J=5.4Hz,1H),5.42(m,2H),5.03(s,3H),3.83(s,3H),3.79(s,3H),3.62(s,3H),3.38(s,1H),2.91(s,3H),2.80(d,J=16.2Hz,1H),2.61(s,1H),2.13(s,3H),1.94(q,J=7.5Hz,2H),1.43(m,1H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.81(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.0(C),159.6(C),158.1(C),156.8(C),153.7(C),140.2(C),135.2(C),131.2(C),130.1(CH),130.0(2CH),129.6(C),129.0(C),124.7(CH),124.1(CH),123.8(CH),123.8(C),122.4(CH),122.8(C),119.0(CH),118.6(CH),117.6(C),114.0(2CH),110.6(CH),95.3(CH),82.1(CH),77.2(CH),76.1(C),66.5(CH2),66.1(CH),56.0(OCH3),55.7(C),55.4(OCH3),54.7(CH2),52.8(C),52.5(OCH3),52.4(CH2),50.2(2CH2),46.0(CH2),45.2(CH2),45.0(CH2),42.9(C),40.8(CH3),34.5(CH2),33.1(CH),31.7(CH2),28.0(CH2),26.0(CH2),21.1(CH3),12.5(CH3),8.5(CH3);
ESIMS(m/e)928.4[M+1]+。
实施例69化合物BM69的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.26(s,1H),8.03(s,1H),7.52(d,J=7.5Hz,1H),7.13(m,3H),6.80(m,3H),6.60(s,1H),6.21(s,1H),5.94(s,2H),5.87(dd,J=10.5,4.5Hz,1H),5.49(d,J=6.0Hz,1H),5.42(d,J=10.5Hz),5.03(s,3H),5.00(s,2H),3.83(s,3H),3.62(s,3H),3.35(s,1H),2.91(s,3H),2.81(d,J=15.9Hz,1H),2.61(s,1H),2.13(s,3H),1.94(q,J=7.5Hz,2H),1.43(m,1H),1.21(m,1H),1.00(t,J=7.5Hz,3H),0.81(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.0(C),158.0(C),156.7(C),153.7(C),147.8(C),147.6(C),140.0(C),135.1(C),131.1(C),130.6(C),130.0(CH),129.6(C),124.7(CH),124.0(CH),123.7(CH),123.7(C),122.4(CH),122.1(CH),121.8(C),119.0(CH),118.5(CH),117.4(C),110.6(CH),109.0(CH),108.3(CH),101.2(CH2),95.3(CH),82.1(CH),77.2(CH),76.1(C),66.7(CH2),66.1(CH),56.0(OCH3),55.6(C),54.7(CH2),52.7(C),52.5(OCH3),52.3(CH2),50.2(2CH2),46.0(CH2),45.2(CH2),44.9(CH2),42.8(C),40.8(CH3),34.5(CH2),33.0(CH),31.7(CH2),27.9(CH2),25.8(CH2),21.1(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)942.4[M+1]+。
实施例70化合物BM70的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.21(s,1H),7.94(s,1H),7.45(d,J=7.5Hz,1H),7.16(m,4H),7.04(m,3H),6.53(s,1H),6.13(s,1H),5.80(dd,J=10.2,3.9Hz,1H),5.38(m,3H),5.05(s,2H),4.96(s,1H),3.76(s,3H),3.57(s,3H),3.31(s,1H),2.84(s,3H),2.75(d,J=15.9Hz,1H),2.54(s,1H),2.06(s,3H),1.87(q,J=7.5Hz,2H),1.39(m,1H),1.18(m,1H),0.93(t,J=7.5Hz,3H),0.74(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.0(C),158.1(C),156.5(C),153.7(C),140.0(C),139.0(C),135.2(C),134.5(C),131.1(C),130.1(CH),129.9(CH),129.6(C),128.3(CH),128.0(CH),126.0(CH),124.7(CH),124.0(CH),123.7(CH),123.7(C),122.5(CH),121.9(C),119.1(CH),118.6(CH),117.4(C),110.7(CH),95.4(CH),82.0(CH),77.2(CH),76.1(C),66.1(CH),65.8(CH2),56.0(OCH3),55.7(C),54.7(CH2),52.8(C),52.6(OCH3),52.3(CH2),50.2(2CH2),46.0(CH2),45.3(CH2),45.0(CH2),42.9(C),40.9(CH3),34.5(CH2),33.0(CH),31.7(CH2),28.0(CH2),25.7(CH2),21.1(CH3),12.4(CH3),8.5(CH3);
ESIMS(m/e)932.4[M+1]+。
实施例71化合物BM71的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.29(s,1H),8.02(s,1H),7.53(d,J=7.8Hz,1H),7.30(m,4H),7.13(m,3H),6.61(s,1H),6.20(s,1H),5.87(dd,J=10.2,3.9Hz,1H),5.45(m,3H),5.06(s,2H),5.03(s,1H),3.83(s,3H),3.62(s,3H),3.37(s,1H),2.90(s,3H),2.81(d,J=15.9Hz,1H),2.61(s,1H),2.12(s,3H),1.93(q,J=7.5Hz,2H),1.47(m,1H),1.24(m,1H),1.00(t,J=7.5Hz,3H),0.81(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),171.0(C),158.1(C),156.5(C),153.7(C),140.2(C),135.5(C),135.2(C),134.0(C),131.2(C),130.1(CH),129.7(C),129.6(2CH),128.8(2CH),124.7(CH),124.0(CH),123.8(CH),123.7(C),122.5(CH),122.0(C),119.1(CH),118.6(CH),117.6(C),110.7(CH),95.4(CH),82.3(CH),77.2(CH),76.1(C),66.1(CH),65.9(CH2),56.1(OCH3),55.7(C),54.7(CH2),52.8(C),52.6(OCH3),52.4(CH2),50.3(2CH2),46.1(CH2),45.3(CH2),45.0(CH2),42.9(C),40.9(CH3),34.5(CH2),33.1(CH),31.7(CH2),28.0(CH2),26.0(CH2),21.2(CH3),12.5(CH3),8.5(CH3);
ESIMS(m/e)932.4[M+1]+。
实施例72化合物BM72的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.35(s,1H),8.03(s,1H),8.07(d,J=8.1Hz,1H),7.60(m,2H),7.52(d,J=7.5Hz,1H),7.46(m,1H),7.13(m,3H),6.62(s,1H),6.22(s,1H),5.88(dd,J=10.2,3.9Hz,1H),5.51(m,3H),5.51(s,2H),5.05(s,1H),3.83(s,3H),3.64(s,3H),3.41(s,1H),2.93(s,3H),2.83(d,J=16.2Hz,1H),2.63(s,1H),2.14(s,3H),1.93(q,J=7.5Hz,2H),1.47(m,1H),1.24(m,1H),1.00(t,J=7.5Hz,3H),0.82(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),170.9(C),158.1(C),156.0(C),153.6(C),147.2(C),140.1(C),135.1(C),133.7(CH),133.7(C),131.1(C),130.0(CH),129.6(C),128.8(CH),128.6(CH),125.0(CH),124.7(CH),124.0(CH),123.7(CH),123.7(C),122.4(CH),122.0(C),119.0(CH),118.6(CH),117.5(C),110.6(CH),95.3(CH),82.3(CH),77.1(CH),76.0(C),66.1(CH),63.3(CH2),56.1(OCH3),55.6(C),54.7(CH2),52.8(C),52.5(OCH3),52.4(CH2),50.2(2CH2),46.0(CH2),45.3(CH2),45.0(CH2),42.8(C),40.9(CH3),34.5(CH2),33.1(CH),31.6(CH2),28.0(CH2),26.0(CH2),21.1(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)943.3[M+1]+。
实施例73化合物BM73的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:9.36(s,1H),8.19(d,J=8.7Hz,2H),8.03(s,1H),7.52(d,J=7.5Hz,1H),7.52(d,J=8.7Hz,2H),7.13(m,3H),6.61(s,1H),6.21(s,1H),5.88(dd,J=10.2,3.9Hz,1H),5.49(m,3H),5.19(s,2H),5.03(s,1H),3.83(s,3H),3.62(s,3H),3.38(s,1H),2.90(s,3H),2.83(d,J=16.2Hz,1H),2.63(s,1H),2.13(s,3H),1.93(q,J=7.5Hz,2H),1.47(m,1H),1.24(m,1H),1.00(t,J=7.5Hz,3H),0.81(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),170.9(C),158.1(C),156.2(C),153.6(C),147.7(C),144.4(C),140.1(C),135.2(C),131.0(C),130.0(CH),129.6(C),128.2(2CH),124.7(CH),123.9(CH),123.8(3CH),123.7(C),122.5(CH),122.1(C),119.0(CH),118.5(CH),117.6(C),110.6(CH),95.4(CH),82.4(CH),77.1(CH),76.0(C),66.1(CH),65.2(CH2),56.1(OCH3),55.7(C),54.7(CH2),52.8(C),52.5(OCH3),52.3(CH2),50.2(2CH2),46.0(CH2),45.3(CH2),45.1(CH2),42.8(C),41.0(CH3),34.5(CH2),33.1(CH),31.7(CH2),28.0(CH2),25.9(CH2),21.1(CH3),12.4(CH3),8.4(CH3);
ESIMS(m/e)943.3[M+1]+。
实施例74化合物BM74的制备
制备步骤参见化合物BM25的制备。
1H NMR(CDCl3,300MHz):δ:8.43(s,1H),7.51(d,J=7.2Hz,1H),7.12(m,3H),6.63(s,1H),6.03(s,1H),5.80(s,1H),5.75(dd,J=10.2,3.9Hz,1H),5.46(d,J=5.7Hz,1H),5.27(d,J=10.2Hz,1H),5.23(s,1H),3.82(s,3H),3.79(s,1H),3.63(s,3H),3.12(s,3H),2.39(s,1H),2.03(s,3H),0.99(t,J=7.5Hz,3H),0.90(t,J=6.9Hz,3H);
13C NMR(CDCl3,75MHz):δ:175.4(C),171.3(C),158.4(C),158.0(C),150.4(C),140.2(C),135.3(C),131.4(C),129.2(C),127.9(CH),126.8(CH),126.8(C),124.3(CH),122.5(CH),122.1(CH),118.9(C),118.8(CH),118.3(CH),116.9(C),110.7(CH),90.9(CH),87.2(C),74.8(2CH),62.7(CH),56.2(OCH3),55.9(C),54.3(CH2),53.5(C),52.5(OCH3),52.4(CH2),52.2(CH2),51.5(CH2),46.2(CH2),45.5(CH2),44.9(CH2),44.4(C),34.8(CH2),34.0(CH3),33.6(CH),28.9(CH2),27.9(CH2),25.9(CH2),21.3(CH3),12.4(CH3),9.2(CH3);
ESIMS(m/e)790.3[M+1]+。
实施例75化合物BM75的制备
在100mL的四氟乙烯圆底烧瓶中,注入12mL(0.6mmol)无水氢氟酸,用丙酮/干冰冷却至-35度。然后加入12克(55mmol)无水五氟化锑,冷却至-35度。将BM6(1g,1.2mmol)溶于2mL氯仿中,在剧烈搅拌下慢慢滴入反应器,温度不高于-30度。反应1小时后,将反应液仔细慢慢倒入包含200mL水、碎冰、63.6g(0.6mol)碳酸钠和30mL二氯甲烷的混合液中。然后用(2×50mL)的二氯甲烷萃取,饱和食盐水洗涤,无水硫酸镁干燥,过滤得到粗品。用硅胶柱层析(CHCl3∶CH3OH=400∶1)得到312mg白色粉末BM75,产率31%。
1H NMR(CDCl3,300MHz):δ:9.18(s,1H),8.03(s,1H),7.50(d,J=7.5Hz,1H),7.14(m,3H),6.63(s,1H),6.18(s,1H),5.89(dd,J=9.9,4.2Hz,1H),5.44(d,J=9.9Hz,1H),5.07(s,1H),4.21(d,J=11.7Hz,1H),4.03(d,J=11.7Hz,1H),3.83(s,3H),3.63(s,3H),2.93(s,3H),2.62(s,1H),2.19(s,3H),2.13(s,3H),1.87-1.67(m,4H),1.53(t,J=19.2Hz,3H),1.42-1.21(m,1H),0.86(m,1H),0.83(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.7(C),170.9(C),170.5(C),157.8(C),153.3(C),134.9(C),130.4(C),129.5(CH),129.1(C),125.1(C),124.5(CH),123.5(C),123.3(CH),122.3(CH),121.1(C),118.8(CH),118.2(CH),116.8(C),110.3(CH),94.5(CH),81.5(CH),76.7(CH),76.0(C),66.4(CH2),66.1(CH),56.5(CH2),55.7(OCH3),55.3(C),53.1(CH2),52.4(C),52.3(OCH3),50.2(CH2),50.0(CH2),47.3(CH2),44.9(CH2),42.3(C),39.8(CH3),38.7(CH),33.2(CH2),31.8(CH2),31.4(CH2),29.1(CH),29.0(CH2),20.9(2CH3),20.9(CH3),8.2(CH3);
ESIMS(m/e)845.4[M+1]+。
实施例76化合物BM76的制备
制备步骤参见化合物BM75的制备。
1H NMR(CDCl3,300MHz):δ:9.14(s,1H),8.01(s,1H),7.50(d,J=7.8Hz,1H),7.13(m,3H),6.62(s,1H),6.17(s,1H),5.88(dd,J=9.9,3.9Hz,1H),5.43(d,J=9.9Hz,1H),5.06(s,1H),4.23(d,J=11.4Hz,1H),4.02(d,J=11.4Hz,1H),3.82(s,3H),3.66(s,1H),3.63(s,3H),2.94(s,3H),2.62(s,1H),2.20(s,3H),1.87-1.66(m,4H),1.53(t,J=19.2Hz,3H),1.42-1.21(m,1H),1.01(m,2H),0.86(m,3H),0.83(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:175.0(C),174.9(C),171.2(C),158.1(C),153.7(C),135.3(C),130.8(C),129.8(CH),129.4(C),125.2(C),124.9(CH),123.9(C),123.6(CH),122.6(CH),121.3(C),119.1(CH),118.5(CH),117.2(C),110.7(CH),94.7(CH),81.9(CH),77.0(CH),76.3(C),66..(CH2),66.5(CH),56.9(CH2),56.0(OCH3),55.6(C),53.4(CH2),52.7(C),52.6(OCH3),50.5(CH2),50.3(CH2),47.6(CH2),45.3(CH2),42.7(C),40.1(CH3),39.3(CH),33.5(CH2),32.1(CH2),31.7(CH2),29.5(CH),29.3(CH2),21.3(CH3),21.2(CH3),13.0(CH),8.9(CH2),8.8(CH2),8.5(CH3);
ESIMS(m/e)871.4[M+1]+。
实施例77化合物BM77的制备
制备步骤参见化合物BM75的制备。
1H NMR(CDCl3,300MHz):δ:9.42(s,1H),8.00(s,1H),7.49(d,J=7.5Hz,1H),7.13(m,3H),6.59(s,1H),6.18(s,1H),6.15(s,1H),5.88(dd,J=10.5,4.2Hz,1H),5.41(d,J=10.5Hz,1H),5.02(s,1H),3.81(s,3H),3.63(s,3H),3.37(s,1H),2.90(s,3H),2.82(d,J=14.1Hz,2H),2.62(s,1H),2.14(s,3H),2.00(s,3H),1.85-1.66(m,4H),1.53(t,J=18.9Hz,3H),1.42-1.21(m,1H),0.86(m,1H),0.81(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),170.9(C),170.5(C),157.1(C),153.7(C),135.2(C),130.6(C),130.1(CH),129.3(C),125.2(C),124.8(CH),123.6(C),123.5(CH),122.7(CH),121.5(C),119.2(CH),118.5(CH),117.0(C),110.7(CH),95.2(CH),82.3(CH),77.2(CH),76.0(C),66.0(CH),56.9(CH2),56.0(OCH3),55.5(C),53.3(CH2),52.8(C),52.7(OCH3),50.3(2CH2),47.3(CH2),45.4(CH2),43.4(CH2),42.9(C),40.8(CH3),38.7(CH),33.5(CH2),31.9(CH2),31.5(CH2),29.2(CH),28.8(CH2),23.5(CH3),21.2(CH3),21.3(CH3),8.5(CH3);
ESIMS(m/e)844.4[M+1]+。
实施例78化合物BM78的制备
制备步骤参见化合物BM75的制备。
1H NMR(CDCl3,300MHz):δ:9.41(s,1H),8.00(s,1H),7.49(d,J=7.5Hz,1H),7.13(m,3H),6.60(s,1H),6.18(s,1H),6.15(s,1H),5.88(dd,J=10.5,4.2Hz,1H),5.41(d,J=10.5Hz,1H),5.02(s,1H),3.81(s,3H),3.63(s,3H),3.33(s,1H),2.85(s,3H),2.82(d,J=14.1Hz,2H),2.62(s,1H),2.23(q,J=7.2Hz,2H),2.14(s,3H),1.84-1.66(m,4H),1.53(t,J=18.9Hz,3H),1.42-1.20(m,1H),1.15(t,J=7.2Hz,3H),0.84(m,1H),0.81(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),174.2(C),170.9(C),158.1(C),153.7(C),135.2(C),130.6(C),130.1(CH),129.4(C),125.2(C),124.7(CH),123.7(C),123.5(CH),122.6(CH),121.5(C),119.1(CH),118.5(CH),117.1(C),110.7(CH),95.2(CH),82.3(CH),77.1(CH),76.0(C),66.0(CH),56.9(CH2),56.0(OCH3),55.5(C),53.3(CH2),52.8(C),52.7(OCH3),50.3(2CH2),47.4(CH2),45.4(CH2),43.2(CH2),42.9(C),40.8(CH3),38.7(CH),33.4(CH2),32.0(CH2),31.5(CH2),30.5(CH2),29.3(CH2),29.2(CH),21.3(CH3),21.2(CH3),10.2(CH3),8.5(CH3);
ESIMS(m/e)858.4[M+1]+。
实施例79化合物BM79的制备
制备步骤参见化合物BM75的制备。
1H NMR(CDCl3,300MHz):δ:9.23(s,1H),8.02(s,1H),7.50(d,J=7.5Hz,1H),7.13(m,3H),6.62(s,1H),6.19(s,1H),5.88(dd,J=10.2,4.2Hz,1H),5.43(d,J=10.2Hz,1H),5.34(bs,1H),5.03(s,1H),3.81(s,3H),3.66(s,3H),3.63(s,3H),3.41(s,1H),2.95(s,3H),2.82(d,J=13.8Hz,2H),2.62(s,1H),2.16(s,3H),2.12-2.02(m,2H),1.84-1.66(m,2H),1.53(t,J=18.9Hz,3H),1.42-1.20(m,1H),0.84(m,1H),0.81(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),170.9(C),158.1(C),157.4(C),153.7(C),135.2(C),130.7(C),130.1(CH),129.4(C),125.2(C),124.7(CH),123.7(C),123.5(CH),122.5(CH),121.6(C),119.1(CH),118.5(CH),117.1(C),110.7(CH),95.2(CH),82.2(CH),77.1(CH),76.0(C),66.1(CH),56.8(CH2),55.9(OCH3),55.6(C),53.3(CH2),52.8(C),52.6(OCH3),52.2(OCH3),50.2(2CH2),47.5(CH2),45.3(CH2),44.9(CH2),42.8(C),40.8(CH3),38.9(CH),33.4(CH2),32.1(CH2),31.6(CH2),29.4(CH),29.2(CH2),21.2(CH3),21.1(CH3),8.4(CH3);
ESIMS(m/e)860.4[M+1]+。
实施例80化合物BM80的制备
制备步骤参见化合物BM75的制备。
1H NMR(CDCl3,300MHz):δ:9.26(s,1H),8.00(s,1H),7.49(d,J=7.5Hz,1H),7.13(m,3H),6.60(s,1H),6.18(s,1H),5.88(dd,J=10.2,4.2Hz,1H),5.42(d,J=10.2Hz,1H),5.29(bs,1H),5.04(s,1H),3.87(d,J=9.0Hz,1H),3.82(s,3H),3.63(s,3H),3.42(s,1H),2.94(s,3H),2.82(d,J=13.8Hz,2H),2.61(s,1H),2.15(s,3H),2.10-2.03(m,1H),1.94-1.70(m,3H),1.53(t,J=19.2Hz,3H),1.45-1.20(m,1H),0.91(d,J=6.6Hz,6H),0.81(t,J=7.2Hz,3H);
13C NMR(CDCl3,75MHz):δ:174.9(C),170.9(C),158.1(C),157.1(C),153.7(C),135.2(C),130.7(C),130.0(CH),129.3(C),125.2(C),124.7(CH),123.7(C),123.5(CH),122.5(CH),121.4(C),119.0(CH),118.4(CH),117.1(C),110.6(CH),95.0(CH),82.1(CH),77.3(CH),76.1(C),71.1(CH2),66.2(CH),56.8(CH2),55.9(OCH3),55.5(C),53.3(CH2),52.7(C),52.5(OCH3),50.2(2CH2),47.5(CH2),45.2(CH2),44.9(CH2),42.8(C),40.6(CH3),38.9(CH),33.4(CH2),32.1(CH2),31.6(CH2),29.3(CH),29.2(CH2),28.1(CH),21.2(CH3),21.1(CH3),19.1(2CH3),8.4(CH3);
ESIMS(m/e)902.4[M+1]+。
试验实施例
试验实施例1发明化合物的体外抗肿瘤活性实验
1、试剂材料
A-549人非小细胞性肺癌细胞株(American Type CultureCollection)、Hela人宫颈癌细胞株(中国科学院上海生化细胞所细胞库)
阳性对照为长春碱硫酸盐(VLB)(由长春花植物中分离得到)、脱水长春碱酒石酸盐(AVLB)和长春瑞宾酒石酸盐(NVB)(按常规方法配制);纯度由HPLC-UV检测98%以上,结构由NMR确证。
待测化合物和阳性对照物以生理盐水稀释,浓度梯度为10-4M、10-5M、10-6M、10-7M、10-8M。
2、实验方法
SRB法:A549人非小细胞性肺癌细胞株和Hela人宫颈癌细胞株
根据细胞生长速率,将处于对数生长期的肿瘤细胞以100μL/孔接种于96孔培养板,贴壁生长24小时再加待测化合物或阳性对照物10μL/孔。每个浓度设三复孔。并设相应浓度的生理盐水溶媒对照及无细胞调零孔。肿瘤细胞在37℃、5%CO2条件下培养72小时,然后倾去培养液(RPMI-1640),用10%冷TCA固定细胞,4℃放置1小时后用蒸馏水洗涤5次,空气中自然干燥。然后加入由1%冰醋酸配制的SRB(Sigma)4mg/mL溶液100μL/孔,室温中染色15分钟,去上清液,用1%醋酸洗涤5次,空气干燥。最后加入150μL/孔的Tris溶液,酶标仪515nm波长下测定A值。按以下列公式计算肿瘤细胞生长的抑制率IC50:
抑制率%=[(阴性对照吸光值-空白吸光值)-(样品吸光值-空白吸光值)]/(阴性对照吸光值-空白吸光值)×100%
药物作用浓度:10μM、1μM、0.1μM、10nM、1nM、0.1nM
用GraphPad Prism 4拟合出IC50。
表1、对人源A-549肺癌细胞株和Hela人宫颈癌细胞株的抑制活性(用于评价的样品全是酒石酸盐)
化合物 | A549(IC50,nM) | Hela(IC50,nM) |
长春碱硫酸盐 | 3.4 | 2.5 |
长春瑞宾酒石酸盐 | 23.1 | 9.1 |
长春新碱硫酸盐 | 25.1 | 11.3 |
脱水长春碱酒石酸盐 | 60.2 | 40.2 |
BM1 | 348.3 | 154.0 |
BM2 | 440.7 | 113.4 |
BM3 | >1000 | >1000 |
BM4 | >1000 | 295.4 |
BM5 | >1000 | 286.3 |
BM6 | 124.0 | 47.6 |
BM10 | 709.8 | 637 |
BM11 | >1000 | >1000 |
BM12 | 575.7 | 95.9 |
BM13 | >1000 | >1000 |
BM14 | >1000 | >1000 |
BM15 | >1000 | 227.5 |
BM22 | >1000 | >1000 |
BM23 | >1000 | >1000 |
BM24 | >1000 | >1000 |
BM25 | >1000 | 476.7 |
BM26 | 56.3 | 61.6 |
BM27 | 42.9 | 13.4 |
BM28 | 101.3 | 75.8 |
BM29 | 348.2 | 126 |
BM30 | >1000 | >1000 |
BM31 | 395.3 | 245 |
BM32 | 17.9 | 12.5 |
BM33 | 26.4 | 17.0 |
BM34 | 337.6 | 73.5 |
BM35 | 116.9 | 45.2 |
BM36 | 87.4 | 16.4 |
BM37 | 20.7 | 16.0 |
BM38 | 46.5 | 20.4 |
BM40 | 102.8 | 42.0 |
BM42 | 78.3 | 22.4 |
BM45 | 578.3 | 135.2 |
BM46 | 173.7 | 22.9 |
BM47 | 14.4 | 19.0 |
BM48 | 75.3 | 34.8 |
BM49 | 23.7 | 34.8 |
BM50 | 162.4 | 26.2 |
BM51 | 504.6 | 171.5 |
BM53 | 13.7 | 7.1 |
BM54 | 632.1 | 425 |
BM56 | 332.3 | 78.4 |
BM57 | 60.6 | 13.2 |
BM58 | 97.3 | 62.9 |
BM59 | 169.5 | 79.8 |
BM60 | 226.2 | 75.9 |
BM61 | 977.6 | 683.3 |
BM62 | >1000 | 377.0 |
BM63 | >1000 | 263.9 |
BM64 | 950.6 | 226.8 |
BM65 | 344.4 | 158.9 |
BM66 | 261.2 | 87.5 |
BM67 | 480 | 176 |
BM68 | 150 | 87.6 |
BM69 | 230 | 127 |
BM70 | >1000 | >1000 |
BM71 | 510 | 347 |
BM72 | 830 | 561 |
BM73 | 780 | 432 |
BM74 | 710 | 342 |
BM75 | >1000 | >1000 |
BM76 | >1000 | >1000 |
BM77 | >1000 | >1000 |
BM78 | >1000 | >1000 |
BM79 | >1000 | >1000 |
BM80 | >1000 | >1000 |
试验实施例2体内抗肿瘤活性
1、肉瘤S180模型上的评价
实验方法:
实验动物KM小鼠,雌性,6-8周龄,体重18-22g,由中国科学院上海实验动物中心提供。合格证编号:SCXK(沪)(2003-0003)。饲养环境:SPF级。取生长良好的7-11天的S180瘤种,将瘤组织制成约2-5×106/ml的悬浮液,接种于小鼠右侧腋部皮下。将动物随机分组(d0)。静脉注射化合物的给药时间为d1或d1、d4。长春瑞滨酒石酸盐、脱水长春碱酒石酸盐、长春氟宁酒石酸盐作为阳性对照药,静脉注射给药时间均为d1、d4。每周测2-3次瘤体积,称鼠重,记录数据。表2、部分发明化合物(长春瑞滨、长春氟宁、脱水长春碱为阳性对照)对小鼠S180肉瘤的疗效
*P<0.01与对照组相比较
2、人非小细胞肺癌A549裸小鼠移植瘤模型上的评价
实验方法:
BALB/cA-nude裸小鼠,购自上海斯莱克实验动物有限责任公司。合格证号:SCXK(沪)2004-0005。饲养环境:SPF级。裸小鼠皮下接种人非小细胞肺癌A549细胞,待肿瘤生长至100-300mm3后,将动物随机分组(d0)。BM48酒石酸盐的给药剂量为1.5mg/kg、3.0mg/kg、6.0mg/kg。长春瑞滨酒石酸盐为10mg/kg。BM48酒石酸盐、长春瑞滨酒石酸盐均静脉注射。BM48酒石酸盐的给药时间均为d0,共1次。长春瑞滨酒石酸盐在d0、d4给药共2次。每周测2-3次瘤体积,称鼠重,记录数据。肿瘤体积(V)计算公式为:
V=1/2×a×b2 其中a、b分别表示长、宽。
BM48单次静脉注射明显抑制人肺癌A549的生长,抑制作用具有明显的剂量依赖性。BM48给药后,小鼠出现毒性反应,但能够较好地恢复。长春瑞滨酒石酸盐静脉给药2次,疗效较BM48酒石酸盐略好,但毒性比BM48酒石酸盐大。总体上BM48酒石酸盐与长春瑞滨酒石酸盐疗效相当或略优于长春瑞滨酒石酸盐。
表3、静脉注射BM48对人非小细胞肺癌A549裸小鼠移植瘤的疗效
d0:分笼给药时间;dn:第1次给药后12天;TV:肿瘤体积;RTV:相对肿瘤体积;*P<0.01vs对照
Claims (10)
4. 如权利要求3所述的方法,其特征在于,烷基化反应所采用的
溶剂为二氯甲烷、氯仿或四氢呋喃;烷基化反应中相转移催化剂为四正丁基碘化铵或四正丁基溴化铵;并且,烷基化反应温度为0℃~室温或50℃至100℃。
5. 如权利要求3所述的方法,其特征在于,酰化反应采用三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶(DMAP)碱作为催化剂;并且酰化剂为酸酐、酰氯、酸酐与噻唑烷-2-硫酮生成的配体或者酰氯与噻唑烷-2-硫酮生成的配体。
6. 如权利要求3所述的方法,其特征在于,中间产物化合物D的合成采用氢化钠、三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶(DMAP)作为催化剂;并且异氰酸酯或由胺和羰基二咪唑(CDI)合成的配体为原料。
7. 如权利要求3所述的方法,其特征在于,中间产物化合物F的合成采用三乙胺、二异丙基乙基胺、吡啶或4-(N,N-二甲基)氨基吡啶(DMAP)碱作为催化剂;并且以氯甲酸酯或由醇和固体光气合成的氯甲酸酯为原料。
8. 如权利要求3所述的方法,其特征在于,氟化是以无水氢氟酸为溶剂,无水五氟化锑为催化剂,在-40度下进行。
9. 权利要求1所述长春碱衍生物或其生理上可接受的盐在制备用于治疗肿瘤的药物中的应用。
10. 一种药物组合物,其特征在于,包含有效治疗剂量的权利要求1所述的长春碱衍生物或其生理上可接受的盐。
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2007100369232A CN101235046B (zh) | 2007-01-29 | 2007-01-29 | 长春碱衍生物、其制备方法和用途、以及包含该衍生物的药物组合物 |
US12/449,180 US8168647B2 (en) | 2007-01-29 | 2007-12-17 | Vinblastine derivatives, their preparation, use and pharmaceutical compositions comprising the said derivatives |
JP2009547511A JP2010516790A (ja) | 2007-01-29 | 2007-12-17 | 新規なビンブラスチン誘導体、その調製方法と用途、及び該誘導体を含む医薬組成物 |
PCT/CN2007/003624 WO2008092335A1 (fr) | 2007-01-29 | 2007-12-17 | Nouveaux dérivées de la vinblastine, leur préparation, et compositions pharmaceutiques les comprenant. |
EP07866193A EP2119720A4 (en) | 2007-01-29 | 2007-12-17 | NEW VINBLASTINE DERIVATIVES, THEIR PREPARATION, APPLICATION AND PHARMACEUTICAL COMPOSITION CONTAINING SUCH DERIVATIVES |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2007100369232A CN101235046B (zh) | 2007-01-29 | 2007-01-29 | 长春碱衍生物、其制备方法和用途、以及包含该衍生物的药物组合物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101235046A true CN101235046A (zh) | 2008-08-06 |
CN101235046B CN101235046B (zh) | 2010-09-08 |
Family
ID=39673642
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2007100369232A Expired - Fee Related CN101235046B (zh) | 2007-01-29 | 2007-01-29 | 长春碱衍生物、其制备方法和用途、以及包含该衍生物的药物组合物 |
Country Status (5)
Country | Link |
---|---|
US (1) | US8168647B2 (zh) |
EP (1) | EP2119720A4 (zh) |
JP (1) | JP2010516790A (zh) |
CN (1) | CN101235046B (zh) |
WO (1) | WO2008092335A1 (zh) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103304565A (zh) * | 2012-03-15 | 2013-09-18 | 中国科学院上海药物研究所 | 文朵灵衍生物的医药用途 |
CN103421028A (zh) * | 2012-05-16 | 2013-12-04 | 石家庄以岭药业股份有限公司 | 长春瑞滨衍生物、其药物组合物及其制备方法和用途 |
CN108794335A (zh) * | 2018-07-17 | 2018-11-13 | 常州大学 | 一种采用相转移催化法合成二碳酸二叔丁酯的方法 |
CN113603711A (zh) * | 2021-08-25 | 2021-11-05 | 山东省分析测试中心 | 一种双吲哚生物碱化合物及其制备方法和应用 |
CN114805162A (zh) * | 2022-04-26 | 2022-07-29 | 湖北华洲药业有限公司 | 一种美罗培南侧链关键中间体o粉的连续化生产方法及装置 |
CN114805162B (zh) * | 2022-04-26 | 2024-05-31 | 湖北华洲药业有限公司 | 一种美罗培南侧链关键中间体o粉的连续化生产方法及装置 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102464622B (zh) | 2010-11-19 | 2014-04-09 | 中国中化股份有限公司 | 取代嘧啶氨类化合物及其应用 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2434172A1 (fr) * | 1978-08-24 | 1980-03-21 | Anvar | Nouveaux composes intermediaires utiles dans la synthese de derives bis-indoliques et procede pour leur preparation |
FR2434171A1 (fr) | 1978-08-24 | 1980-03-21 | Anvar | Nouveaux composes bis-indoliques utiles comme medicaments et procede pour leur preparation |
WO1986005491A1 (en) * | 1985-03-12 | 1986-09-25 | The University Of Vermont And State Agricultural C | Synthesis of vinblastine and vincristine type compounds |
JPH04169587A (ja) * | 1990-11-01 | 1992-06-17 | Mitsui Petrochem Ind Ltd | 二量体アルカロイド類の還元方法 |
FR2707988B1 (fr) * | 1993-07-21 | 1995-10-13 | Pf Medicament | Nouveaux dérivés antimitotiques des alcaloïdes binaires du catharantus rosesus, leur procédé de préparation et les compositions pharmaceutiques les comprenant. |
US20030162803A1 (en) * | 1997-03-04 | 2003-08-28 | Bruce Schmidt | Anhydrovinblastine for the treatment of cancer |
FR2779146B1 (fr) | 1998-06-02 | 2002-01-18 | Roowin | Nouveaux derives de vinca-alcaloides et procedes de preparation |
CN1854143A (zh) | 2005-04-19 | 2006-11-01 | 江苏豪森药业股份有限公司 | 长春碱类化合物及其可药用盐的制备方法 |
-
2007
- 2007-01-29 CN CN2007100369232A patent/CN101235046B/zh not_active Expired - Fee Related
- 2007-12-17 WO PCT/CN2007/003624 patent/WO2008092335A1/zh active Application Filing
- 2007-12-17 JP JP2009547511A patent/JP2010516790A/ja active Pending
- 2007-12-17 US US12/449,180 patent/US8168647B2/en not_active Expired - Fee Related
- 2007-12-17 EP EP07866193A patent/EP2119720A4/en not_active Withdrawn
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103304565A (zh) * | 2012-03-15 | 2013-09-18 | 中国科学院上海药物研究所 | 文朵灵衍生物的医药用途 |
CN103304565B (zh) * | 2012-03-15 | 2016-05-11 | 中国科学院上海药物研究所 | 文朵灵衍生物的医药用途 |
CN103421028A (zh) * | 2012-05-16 | 2013-12-04 | 石家庄以岭药业股份有限公司 | 长春瑞滨衍生物、其药物组合物及其制备方法和用途 |
CN103421028B (zh) * | 2012-05-16 | 2016-03-02 | 石家庄以岭药业股份有限公司 | 长春瑞滨衍生物、其药物组合物及其制备方法和用途 |
CN108794335A (zh) * | 2018-07-17 | 2018-11-13 | 常州大学 | 一种采用相转移催化法合成二碳酸二叔丁酯的方法 |
CN113603711A (zh) * | 2021-08-25 | 2021-11-05 | 山东省分析测试中心 | 一种双吲哚生物碱化合物及其制备方法和应用 |
CN114805162A (zh) * | 2022-04-26 | 2022-07-29 | 湖北华洲药业有限公司 | 一种美罗培南侧链关键中间体o粉的连续化生产方法及装置 |
CN114805162B (zh) * | 2022-04-26 | 2024-05-31 | 湖北华洲药业有限公司 | 一种美罗培南侧链关键中间体o粉的连续化生产方法及装置 |
Also Published As
Publication number | Publication date |
---|---|
US8168647B2 (en) | 2012-05-01 |
WO2008092335A1 (fr) | 2008-08-07 |
US20100113498A1 (en) | 2010-05-06 |
CN101235046B (zh) | 2010-09-08 |
EP2119720A4 (en) | 2010-12-15 |
JP2010516790A (ja) | 2010-05-20 |
EP2119720A1 (en) | 2009-11-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11046697B2 (en) | Compounds and compositions useful for treating disorders related to NTRK | |
CN113651814A (zh) | Kras突变蛋白抑制剂 | |
RU2679805C2 (ru) | Модуляторы ship1 и относящиеся к ним способы | |
CN101235046B (zh) | 长春碱衍生物、其制备方法和用途、以及包含该衍生物的药物组合物 | |
EP2049543A1 (en) | Acyclic amine inhibitors of 5'-methylthioadenosine phosphorylase and nucleosidase | |
CN110156813A (zh) | 作为trk抑制剂的杂环化合物 | |
EP4361142A1 (en) | Compound as kif18a inhibitor | |
CN110627812A (zh) | 作为trk抑制剂的杂环化合物 | |
CN103582638A (zh) | 杂芳基并嘧啶类衍生物、其制备方法和用途 | |
US20090118220A1 (en) | Substituted adenines and the uses thereof | |
Lei et al. | Synthesis and anti-tumor activity of 14-O-derivatives of natural oridonin | |
CN102675323A (zh) | 吡咯并[2,1-f][1,2,4]三嗪衍生物及其抗肿瘤用途 | |
EP4289852A1 (en) | 5,6-dihydrothieno[3,4-h]quinazoline compound | |
EP3929185A1 (en) | Nitrogen-containing fused cyclic compound, preparation method therefor and use thereof | |
CN110143974B (zh) | 一类新型青蒿素衍生物、合成方法及其用途 | |
EP2233467B1 (en) | Alpha-amino-n-substituted amides, pharmaceutical composition containing them and uses thereof | |
KR102473019B1 (ko) | 트립톨라이드 유도체 및 이의 제조방법과 응용 | |
WO2023196517A1 (en) | Cdk9 inhibitors | |
CN115785088A (zh) | 作为sos1抑制剂的化合物及其应用 | |
CN104211712B (zh) | 含杂芳基哌啶的青蒿素衍生物、其制备方法及应用 | |
CN110016026A (zh) | 一类具有抗肿瘤活性的嘧啶并吡啶酮类化合物、制备方法和用途 | |
KR20240062104A (ko) | 교모세포종 약물내성 극복을 위한 테모졸로마이드 유사 항암제 | |
CN116041362A (zh) | Aurovertin B衍生物及其制备方法与应用 | |
EP3985007A1 (en) | Triazolopyrimidine compound and salt, composition and use thereof | |
CN116354932A (zh) | 嘧啶衍生物及其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100908 Termination date: 20130129 |