CN117186045A - 异苯并呋喃-1(3h)-酮类trek-1抑制剂及其制备方法、药物组合物和用途 - Google Patents
异苯并呋喃-1(3h)-酮类trek-1抑制剂及其制备方法、药物组合物和用途 Download PDFInfo
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- CN117186045A CN117186045A CN202210615903.5A CN202210615903A CN117186045A CN 117186045 A CN117186045 A CN 117186045A CN 202210615903 A CN202210615903 A CN 202210615903A CN 117186045 A CN117186045 A CN 117186045A
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Abstract
本发明属于药物化学领域,公开了一类新的异苯并呋喃‑1(3H)‑酮类TREK‑1抑制剂,及其制法和药物组合物与用途。
Description
技术领域
本发明属于药物化学领域,涉及式I所示的新结构的异苯并呋喃-1(3H)-酮类TREK-1抑制剂,其可药用盐,及其制备方法,含有一个或多个该类化合物的组合物,和该类化合物在抑制TREK-1与治疗TREK-1有关的疾病,及在制备、预防和/或治疗精神神经系统疾病和心脑血管疾病药物中的用途。
背景技术
TREK-1(又名K2P2.1/KCNK2)属于双孔钾通道(K2P)家族,主要功能是介导细胞的背景钾电流和调节细胞的兴奋性,当双孔钾通道开放时,允许细胞内的钾离子向细胞外流出,使细胞膜内带过量负电荷,膜外带正电荷,形成静息电位,从而维持细胞的静息状态;另外,这种强有力的外向整流作用还可以抵制去极化,调节细胞的兴奋性[Nature reviewsneuroscience,2007.8(4):p.251-261]。双孔钾离子通道家族包括15个亚型,根据氨基酸序列的相似性分为6个亚家族,如TWIK、TREK、TASK等,每个亚族根据不同功能又分为若干个亚型,其中TREK亚家族包括TREK-1、TREK-2、TRAAK三个亚型。人源TREK-1在中枢神经系统中高度而广泛地表达,特别是在杏仁核、基底神经节、皮质、背根神经节和海马区;在大脑,脊髓,心脏,肾脏,卵巢和小肠等组织中也表达丰富[Pflügers Archiv,2000.439(6):p.714-722]。TREK-1参与调节广泛的神经元功能,包括调节神经元兴奋性和细胞体积大小、感觉转导、离子转运、细胞的代谢和凋亡,在多种生理、病理过程中发挥着重要作用[Cellbiochemistry and biophysics,2007.47(2):p.209-256]。因此,对于该靶点的调控有助于阿尔茨海默症、癫痫、抑郁症、脑缺血、疼痛和心律失常等多种疾病的研究和治疗。[Journalof medicinal chemistry,2016.59(11):p.5149-5157]。
文献报道的TREK-1小分子抑制剂多数是通过随机筛选已知药物的方法获得,抑制活性弱,选择性差,如:神经保护药物西帕曲近[The EMBO journal,2011.30(17):p.3594-3606],抗抑郁药物氟西汀[Nature neuroscience,1999.2(5):p.422-426],抗精神病药物氯丙嗪[Douleur et Analgésie,2008.21(4):p.215-220]等,二氢吡啶类降压药氨氯地平[Pflügers Archiv-European Journal of Physiology,2015.467(5):p.959-972]等,抗心律失常药物普罗帕酮[ACS chemical neuroscience,2014.5(12):p.1246-1252]等。2010年,Catherine Heurteaux等报道了一个从神经降压素受体-3中截取的多肽片段Spadin,对TREK-1具有较强的抑制活性和较高的选择性[PLoS Biol,2010.8(4):p.e1000355]。因此,寻找新结构的TREK-1小分子抑制剂具有重要意义,为发现以TREK-1为靶点的药物奠定基础。
本专利设计合成了新结构的异苯并呋喃-1(3H)-酮类TREK-1抑制剂,旨在为治疗与TREK-1相关的疾病提供全新的物质基础。
发明内容
本发明解决的技术问题在于提供式I所示的含有异苯并呋喃-1(3H)-酮类衍生物和生理上可接受的盐、其制备方法、药物组合物、及其在制备TREK-1抑制剂及其潜在的药物中的用途、在制备治疗精神神经系统疾病药物和心脑血管疾病药物中的用途。
为解决本发明的技术问题,本发明提供了如下技术方案:
本发明技术方案的第一方面是提供了如通式I所示的异苯并呋喃-1(3H)-酮类衍生物或生理上可接受的盐:
在式I中,
R1、R2、R4独立地选自:
H、F、Cl、Br、CN、甲基、乙基、三氟甲基、三氟乙基、CHF2、OH、OCH3或OC2H5;
R5、R6、R7、R8独立地选自:
H、F、Cl、Br、CN、甲基、乙基、丙基、异丙基、环丙基、环丙甲基、三氟甲基、三氟乙基、CHF2、乙炔基、三氟甲氧基、CONH2、OH、OCH3、OC2H5、亚甲二氧基、NH2、NHCH3、N(CH3)2、NHCOCH3;
R9独立地选自:
(1)H、F、Cl、Br、CN、甲基、乙基、丙基、异丙基、环丙基、环丙甲基、三氟甲基、三氟乙基、CHF2、乙炔基、三氟甲氧基、CONH2、OH、OCH3、OC2H5、亚甲二氧基、NH2、NHCH3、N(CH3)2、NHCOCH3;
(2)苯基、取代的苯基,其中取代基选自:F、Cl、Br、CN、甲基、乙基、丙基、异丙基、环丙基、环丙甲基、三氟甲基、三氟乙基、CHF2、乙炔基、三氟甲氧基、CONH2、OH、OCH3、OC2H5、亚甲二氧基、NH2、NHCH3、N(CH3)2、NHCOCH3;R3独立地选自:
其中,R11选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2;
R12、R13、R14、R15独立地选自:
甲基、乙基、丙基;
R16选自:
H、甲基、乙基、丙基、异丙基;
R17选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2;
R18选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2;
R19选自:
H、甲基、乙基、丙基、异丙基;
R20选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2;
n选自1、2或3;
其中手性碳原子可为R构型或S构型。
本发明技术方案的第二方面是提供了如通式IA所示的异苯并呋喃-1(3H)-酮类衍生物或生理上可接受的盐:
在式IA中,
R1、R2、R4、R5、R6、R7、R8和R9同本发明技术方案的第一方面所示通式I;
R21选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2。
本发明技术方案的第三方面是提供了如通式IB所示的异苯并呋喃-1(3H)-酮类衍生物或生理上可接受的盐:
在式IB中,
R1、R2、R4、R5、R6、R7、R8和R9同本发明技术方案的第一方面所示通式I;
R22选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2。
本发明技术方案的第四方面是提供了如通式IC所示的异苯并呋喃-1(3H)-酮类衍生物或生理上可接受的盐:
在式IC中,
R1、R2、R4、R5、R6、R7、R8和R9同本发明技术方案的第一方面所示通式I;
n选自1、2、3。
本发明技术方案的第五方面是提供了如通式ID所示的异苯并呋喃-1(3H)-酮类衍生物或生理上可接受的盐:
在式ID中,
R1、R2、R4、R5、R6、R7、R8和R9同本发明技术方案的第一方面所示通式I;
R23选自:
H、甲基、乙基、丙基、异丙基;
R24选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2。
本发明技术方案的第六方面是提供了如通式IE所示的异苯并呋喃-1(3H)-酮类衍生物或生理上可接受的盐:
在式IE中,
R1、R2、R4、R5、R6、R7、R8和R9同本发明技术方案的第一方面所示通式I;
R25选自:
H、甲基、乙基、丙基、异丙基;
R26选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2。
本发明技术方案的第七方面,为完成本发明的目的,优选的化合物包括但不限定于:
本发明技术方案的第八方面是提供了第一方面至第七方面所述化合物的制备方法,采用的技术方案包括以下步骤:
以3-氧代-1,3-二氢异苯并呋喃-1-膦酸二甲酯1为起始原料,通过硝化反应(如:硝酸钾,浓硫酸,0℃),在异苯并呋喃-1(3H)-酮6-位引入硝基,得到中间体2;
中间体2与取代的芳醛发生Wittig-Horner反应(如:取代的苯甲醛,三乙胺,四氢呋喃,0℃,氩气),制备中间体3;
中间体3发生催化氢化反应,硝基和碳碳双键同时被还原(如:钯碳,氢气,甲醇,室温),制备中间体4;
中间体4通过Sandermayer反应引入卤素(如:三甲基溴硅烷,亚硝酸钠,三乙基苄基氯化铵,乙腈,0℃),制备关键中间体5;
中间体5与脂杂环发生偶联反应(如:Pd2(dba)3或醋酸钯,含氮脂杂环,BINAP或Xantphos或Xphos或Davephos或Sphos,碳酸铯,1,4-二氧六环,80-100℃,氩气;频哪醇酯,[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物,碳酸钾,N,N-二甲基乙酰胺,100℃,氩气),得到通式I所示化合物;如果脂杂环含有Boc保护基团,采用三氟乙酸或氯化氢的1,4-二氧六环溶液,脱除Boc,得到N上无取代化合物;在此基础上,采用烷基化或还原胺化反应,引入取代基,得到通式I所示化合物;
中间体5与N-取代哌嗪进行偶联反应(如:N-取代哌嗪,Pd(OAc)2或Pd2(dba)3,Xantphos或BINAP,碳酸铯,1,4-二氧六环,100℃,氩气),得到通式IA所示化合物;如果含氮脂杂环含有Boc保护基团,采用三氟乙酸或氯化氢的1,4-二氧六环溶液,脱除Boc,得到N上无取代化合物;在此基础上,采用烷基化或还原胺化反应,引入取代基,得到通式IA所示化合物;
中间体5与N-取代1,2,5,6-四氢吡啶-4-硼酸频哪醇酯进行偶联反应(如:N-取代-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯,[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物,碳酸钾,N,N-二甲基乙酰胺,100℃,氩气),制备中间体6;
中间体6发生氢化还原反应(如:钯碳,氢气,甲醇,室温),得到通式IB所示化合物;如果含氮脂杂环含有Boc保护基团,采用三氟乙酸或氯化氢的1,4-二氧六环溶液,脱除Boc,得到N上无取代化合物;在此基础上,采用烷基化或还原胺化反应,引入取代基,得到通式IB所示化合物;
中间体5与稠杂环进行偶联反应(如:稠杂环,Pd(OAc)2,Xphos,碳酸铯,1,4-二氧六环,90℃,氩气),得到通式IC所示化合物;
中间体5与取代的吡咯烷进行偶联反应(如:取代的氨基吡咯烷,Pd(OAc)2,Xantphos,碳酸铯,1,4-二氧六环,90℃,氩气;或取代的氨基吡咯烷,Pd(OAc)2,Davephos,碳酸铯,1,4-二氧六环,100℃,氩气),得到如通式ID或IE所示化合物;如果吡咯烷含有Boc保护基团,采用三氟乙酸或氯化氢的1,4-二氧六环溶液,脱除Boc,得到N上无取代化合物;在此基础上,采用烷基化或还原胺化反应,引入取代基,得到通式ID或IE所示化合物;
中间体5与取代的哌嗪进行偶联反应(如:取代的哌嗪,Pd2(dba)3,BINAP,碳酸铯,1,4-二氧六环,90℃,氩气),得到化合物7;如果取代的哌嗪环N原子上为Boc基团,采用三氟乙酸或氯化氢的1,4-二氧六环溶液,脱除Boc,得到N上无取代化合物;在此基础上,采用烷基化或还原胺化反应,引入取代基,得到如7所示化合物。
试剂及反应条件:(a)硝酸钾,浓硫酸,0℃;(b)取代的苯甲醛,三乙胺,四氢呋喃,0℃,氩气;(c)钯碳,氢气,甲醇,室温;(d)三甲基溴硅烷,亚硝酸钠,三乙基苄基氯化铵,乙腈,0℃;(e)(1)Pd2(dba)3或醋酸钯,含氮脂杂环,BINAP或Xantphos或Xphos或Davephos或Sphos,碳酸铯,1,4-二氧六环,80-100℃,氩气;频哪醇酯,[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物,碳酸钾,N,N-二甲基乙酰胺,100℃,氩气;钯碳,氢气,甲醇,室温;(2)三氟乙酸或氯化氢的1,4-二氧六环溶液,室温。
试剂及反应条件:(g)N-取代哌嗪,Pd(OAc)2或Pd2(dba)3,Xantphos或BINAP,碳酸铯,1,4-二氧六环,100℃,氩气。
试剂及反应条件:(k)N-取代-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯,[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物,碳酸钾,N,N-二甲基乙酰胺,100℃,氩气;(l)钯碳,氢气,甲醇,室温。
试剂及反应条件:(j)稠杂环,Pd(OAc)2,Xphos,碳酸铯,1,4-二氧六环,90℃,氩气。
试剂及反应条件:(n)取代的氨基吡咯烷,Pd(OAc)2,Xantphos,碳酸铯,1,4-二氧六环,90℃,氩气。
试剂及反应条件:(p)取代的氨基吡咯烷,Pd(OAc)2,Davephos,碳酸铯,1,4-二氧六环,100℃,氩气。
试剂及反应条件:(h)取代的哌嗪,Pd2(dba)3,BINAP,碳酸铯,1,4-二氧六环,90℃,氩气。其中所述的R1、R2、R3、R4、R5、R6、R7、R8、R9、R11、R12、R13、R14、R15、R21、R22、R23、R24、R25、R26的定义如本发明技术方案第一方面至第七方面所述,n选自1、2、3。
上述反应中的起始原料及中间体容易得到,各步反应可依据已报道的文献或对本领域熟练技术人员来说可以用有机合成中的常规方法很容易合成。通式I所述化合物可以溶剂化物或非溶剂化物的形式存在,利用不同的溶剂进行结晶可能得到不同的溶剂化物。通式I所述药学上可接受的盐包括不同酸的盐,如下列无机酸或有机酸的盐:盐酸,氢溴酸,磷酸,硫酸,甲磺酸,对甲苯磺酸,三氟乙酸,枸杞酸,马来酸,酒石酸,富马酸,柠檬酸,乳酸。通式I所述药学上可接受的盐还包括不同碱金属盐(锂,钠,钾盐),碱土金属盐(钙,镁盐)及铵盐,和能提供生理上可接受的阳离子的有机碱的盐,如甲胺,二甲胺,三甲胺,哌啶,吗啉及三(2-羟乙基)胺的盐。在本发明范围内的所有这些盐都可采用常规方法制备。
本发明技术方案的第九方面是提供了一种药物组合物,所述药物组合物包括作为本发明技术方案第一方面至第七方面所述的化合物或其可药用盐和药学上的常用载体。
该组合物包括本发明中至少一种化合物和在药学上可接受的载体。所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量%。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
这些制剂是按照本领域的技术人员所熟知的方法制备的。为制造片剂、胶囊剂、包衣剂所用的辅料是常规用的助剂,例如淀粉,明胶,阿拉伯胶,硅石,聚乙二醇,液体剂型所用的溶剂例如有水,乙醇,丙二醇,植物油类如玉米油,花生油,橄榄油等。含有本发明化合物的制剂中还可有其他助剂,例如表面活性剂,润滑剂,崩解剂,防腐剂,矫味剂,色素等。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本发明化合物的每天的合适剂量范围为0.1-1000mg/Kg体重,优选为1-500mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明技术方案的第十方面是提供了本发明第一方面至第七方面所述的化合物及其药用盐在制备TREK-1抑制剂中的应用、在制备预防和/或治疗与TREK-1有关的疾病的药物中的应用、在制备与TREK-1有关的疾病选自精神神经系统疾病、代谢性疾病和心脑血管疾病治疗药物中的应用、在制备与阿尔茨海默症、帕金森病、抑郁症、癫痫、疼痛、脑缺血、心律失常等疾病有关药物中的作用。
有益技术效果:
本专利申请的新结构异苯并呋喃-1(3H)-酮类化合物对TREK-1具有抑制活性,为治疗与TREK-1相关疾病提供了新的物质基础。
具体实施方式
以下将结合实施例对发明做进一步说明,但并不限制本发明的范围。
化合物的结构是通过核磁共振(NMR)或高分辨质谱(HRMS)来确定的。NMR的测定是用Varian mercury 400或者Varian mercury 500,测定溶剂为CDCl3、DMSO-d6、Acetone-d6、MeOD,内标为TMS,化学位移是以ppm作为单位给出。m.p.是以℃给出的熔点,温度未加校正。硅胶柱层析一般使用200-300目硅胶为载体。
缩写列表:
KNO3:硝酸钾;Na2CO3:碳酸钠;Cs2CO3:碳酸铯
H2SO4:硫酸;HCl:盐酸;TFA:三氟乙酸
NaCl:氯化钠;TEA:三乙胺
DMF:N,N-二甲基甲酰胺;DME:N,N-二甲基乙酰胺;
THF:四氢呋喃;PE:石油醚;EA:乙酸乙酯;Acetone:丙酮
DCM:二氯甲烷;MeOH:甲醇
min:分钟;r.t.:室温;h:小时;Ar:氩气
Pd2(dba)3:三(二亚苄基丙酮)二钯;
BINAP:1,1’-联萘-2,2’-双二苯膦
Xantphos:4,5-双二苯基膦-9,9-二甲基氧杂蒽
Xphos:2-二环己基磷-2,4,6-三异丙基联苯
Davephos:2-二环己膦基-2’-(N,N-二甲胺)-联苯
CDCl3:氘代氯仿;DMSO-d6:氘代二甲基亚砜;Acetone-d6:氘代丙酮
实施例1:
3-(2-甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物1)的合成
(1)(5-硝基-3-氧代-1,3-二氢异苯并呋喃-1-基)膦酸二甲酯(中间体1)的合成
将KNO3(835mg,8.26mmol)溶于浓H2SO4(7mL)中,冰浴搅拌20min,缓慢加入(3-氧代-1,3-二氢异苯并呋喃-1-基)膦酸二甲酯(2g,8.26mmol),冰浴搅拌4h,原料消失。将反应液倾倒入冰水中,搅拌30min,析出白色固体,过滤,将滤液溶剂旋干,乙醇热重结晶,得白色固体,与滤饼合并,干燥,共得白色固体2.09g,产率88%,熔点:138-139℃。
1H NMR(400MHz,CDCl3)δ(ppm):8.78(s,1H),8.61(dd,J1=8.4Hz,J2=2.0Hz,1H),7.98–7.95(m,1H),5.81(d,J=12.8Hz,1H),3.97(d,J=11.2Hz,3H),3.71(d,J=10.4Hz,3H).
(2)(Z)-3-(2-甲基亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体2)的合成
将中间体1(2.76g,9.6mmol)和邻甲基苯甲醛(1.15g,9.6mmol)溶于无水THF(40mL)中,缓慢滴加TEA(1.07g,10.56mmol)的THF溶液(10mL),Ar保护下室温反应5h。将反应液倾倒入冰水中,搅拌20min,析出亮黄色固体,过滤,水洗,干燥,得黄色固体2.5g,产率92.6%,熔点:>250℃。
1H NMR(400MHz,CDCl3)δ(ppm):8.80(d,J=2.0Hz,1H),8.59(dd,J1=8.8Hz,J2=2.0Hz,1H),8.19(dd,J1=6.8Hz,J2=2.0Hz,1H),7.98(d,J=8.8Hz,1H),7.35–7.25(m,3H),6.86(s,1H),2.51(s,3H).
(3)6-氨基-3-(2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体3)的合成
将中间体2(2.5g,8.9mmol)溶于三氟乙醇(50mL)中,加入钯碳(500mg),室温催化氢化2h,原料消失。过滤,滤液浓缩,EA/THF(1/1)(90mL×3)萃取,合并有机层,有机相浓缩,柱层析(PE/EA=5/1-3/1)得白色固体1.58g,产率70.4%,熔点:161-162℃。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.20–7.09(m,5H),6.92(dd,J1=8.0Hz,J2=2.4Hz,1H),6.85(d,J=2.0Hz,1H),5.66(dd,J1=8.0Hz,J2=4.8Hz,1H),5.56(brs,2H),3.23(dd,J1=14.4Hz,J2=4.8Hz,1H),2.93(dd,J1=14.4Hz,J2=8.0Hz,1H),2.27(s,3H).
(4)6-溴-3-(2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体4)的合成
取亚硝酸钠(1.01g,14.7mmol)、三乙基苄基氯化铵(223mg,0.98mmol)和三甲基溴硅烷(2.25g,14.7mmol)溶于乙腈8mL,冰水浴中搅拌30min。将中间体3(1.24g,4.9mmol)溶于8mL乙腈,在冰浴下滴加入反应瓶中,继续冰水浴搅拌8h。加入30mL乙酸乙酯,用饱和NaCl(50mL×2)洗,无水硫酸镁干燥,浓缩,柱层析(0-1%Acetone/PE),得白色固体632mg,产率41%,熔点160-161℃。1H NMR(400MHz,CDCl3)δ(ppm):8.01(d,J=2.0Hz,1H),7.68(dd,J1=8.4Hz,J2=2.0Hz,1H),7.22–7.13(m,4H),6.89(dd,J1=8.0Hz,J2=0.8Hz,1H),5.63(t,J=7.2Hz,1H),3.34(dd,J1=14.0Hz,J2=6.8Hz,1H),3.07(dd,J1=14.0Hz,J2=7.2Hz,1H),2.30(s,3H);HRMS(ESI):m/z,Calcd for C16H14O2Br[M+H]+:317.0171,Found317.0166.
(5)3-(2-甲基苄基)-6-(4-Boc-哌嗪-1-基)异苯并呋喃-1(3H)-酮(中间体5)的合成
将中间体4(150mg,0.48mmol)、N-Boc-哌嗪(180mg,0.97mmol)、Pd2(dba)3(120mg,0.098mmol)、BINAP(1.9g,0.193mmol)和碳酸铯(315mg,0.97mmol)置于微波管中,加入1,4-二氧六环(1mL),氩气保护,80℃微波加热1.5h。过滤,滤液浓缩,柱层析(DCM-DCM/Acetone=20/1),得浅黄色油状物80mg,产率40%。1H-NMR(400MHz,CDCl3)δ(ppm):7.38(d,J=2.4Hz,1H),7.34(d,J=8.4Hz,1H),7.21–7.16(m,4H),6.94(d,J=8.4Hz,1H),3.67(t,J=5.2Hz,4H),3.29(dd,J1=14.0Hz,J2=6.8Hz,1H),3.23(t,J=5.2Hz,4H),3.00(dd,J1=14.4Hz,J2=7.2Hz,1H),2.31(s,3H),1.49(s,9H).
(6)3-(2-甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物1)的合成
冰浴下,将中间体5(156mg,0.36mmol)溶于HCl的EA溶液(4M)2.0mL中,冰浴搅拌2h,析出固体,过滤,无水乙醚洗。乙醇热重结晶,析出固体,过滤,无水乙醚洗,得类白色固体192mg,收率81%,熔点:218-219℃。
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.28(brs,1H),7.46–7.40(m,2H),7.27(d,J=2.0Hz,1H),7.22–7.10(m,4H),5.79(dd,J1=8.0Hz,J2=4.8Hz,1H),3.48(t,J=4.4Hz,4H),3.33–3.28(m,1H),3.21(t,J=5.2Hz,4H),3.00(dd,J1=14.4Hz,J2=8.0Hz,1H),2.28(s,3H);13C-NMR(150MHz,DMSO-d6)δ(ppm):169.92,151.16,140.95,136.68,134.71,130.17,126.85,126.57,125.76,123.58,122.75,110.01,80.63,45.34,42.38,37.51,19.47;HRMS(ESI):m/z,Calcd for C20H23O2N2[M+H]+:323.1754,Found 323.1754.
实施例2:
3-(2,4-二甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物2)的合成
(1)(Z)-3-(2,4-二甲基亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体6)的合成
将中间体1(8g,27.8mmol)溶于无水THF(160mL)中,依次加入2,4-二甲基苯甲醛(3.74g,27.8mmol)和TEA(3.38g,33.4mmol),Ar保护下室温反应5h,将反应液倾倒入冰水中,搅拌60min,析出大量亮黄色固体,过滤,水洗,正己烷洗,干燥,得亮黄色固体7.21g,产率88%。
1H-NMR(400MHz,CDCl3)δ(ppm):8.79(dd,J1=2.0Hz,J2=0.8Hz,1H),8.57(dd,J1=8.4Hz,2.0Hz,1H),8.11(d,J=8.0Hz,1H),7.95(dd,J1=8.4Hz,J2=0.8Hz,1H),7.13(d,J=8.0Hz,1H),7.08(s,1H),6.84(s,1H),2.48(s,3H),2.37(s,3H).
(2)6-氨基-3-(2,4-二甲基苄基)异苯并呋喃-1(3H)-酮(中间体7)的合成
将中间体6(4g,13.6mmol)加入到EA(20mL)、MeOH(10mL)与THF(20mL)的混合溶液中,加入钯碳(800mg),室温催化氢化反应2h,原料消失。过滤,滤液浓缩,柱层析(P/E=3/1-1/1)得白色固体2.9g,产率81%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.08–6.95(m,4H),6.88–6.80(m,2H),5.54(t,J=7.2Hz,1H),3.91(brs,2H),3.20(dd,J1=14.0Hz,J2=6.8Hz,1H),3.00(dd,J1=14.0Hz,J2=6.8Hz,1H),2.31(s,3H),2.26(s,3H).
(3)6-溴-3-(2,4-二甲基苄基)异苯并呋喃-1(3H)-酮(中间体8)的合成
取亚硝酸钠(2.33g,8.7mmol)、三乙基苄基氯化铵(596mg,1.74mmol)和三甲基溴硅烷(4.0g,26.2mmol)溶于乙腈50mL,在冰水浴下搅拌30min后将中间体7(2.33g,8.7mmol)溶于50mL乙腈,在冰浴下滴加入反应瓶中,继续冰水浴搅拌12h。加入水200mL,EA萃取(50mL×3)洗,柱层析(PE-P/A=100:1-60/1),得白色固体2.05g,产率83%。
1H-NMR(400MHz,CDCl3)δ(ppm):8.01(d,J=2.0Hz,1H),7.67(dd,J1=8.0Hz,J2=1.6Hz,1H),7.03–6.96(m,3H),6.89(d,J=8.0Hz,1H),5.60(t,J=7.6Hz,1H),3.30(dd,J1=14.4Hz,J2=6.8Hz,1H),3.00(dd,J1=14.4Hz,J2=6.8Hz,1H),2.32(s,3H),2.26(s,3H).
(4)4-(2,4-二甲基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-甲酸叔丁酯(中间体9)的合成
将中间体8(750mg,2.27mmol)、N-Boc-哌嗪(635mg,3.41mmol)、Pd2(dba)3(211mg,0.23mmol)、BINAP(286mg,0.46mmol)和碳酸铯(1480mg,4.54mmol)加入100mL三颈瓶中,加入1,4-二氧六环30mL,氩气保护,90℃加热11h,原料消失。硅藻土助滤,滤掉不溶物,EA洗。柱层析第一次(P/A=10/1),第二次(DCM/Acetone=40/1),得浅黄色油状物595mg,产率60%。
(5)3-(2,4-二甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物2)的合成
冰浴下,将中间体9(123mg,0.28mmol)溶于DCM(2mL)中,逐滴滴加TFA(640mg,5.60mmol)的DCM溶液(1mL),冰浴搅拌30min,室温搅拌2h,原料消失。加入饱和Na2CO3溶液至不再产生气泡,D/M=10/1(50mL×3)萃取,柱层析D/M=20/1-10/1,得白色油状物100mg,加入0.5mL HCl的1,4-二氧六环溶液(4M),室温搅拌过夜,析出白色固体,过滤,正己烷、无水乙醚洗,干燥,得白色固体78mg,产率75%,熔点:133-134℃。
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.26(brs,2H),7.44(dd,J1=8.4Hz,J2=2.4Hz,1H),7.39(d,J=8.8Hz,1H),7.26(d,J=2.0Hz,1H),7.06(d,J=7.6Hz,1H),6.98(s,1H),6.92(d,J=8.0Hz,1H),5.75(dd,J1=8.0Hz,J2=4.8Hz,1H),3.47(t,J=5.2Hz,4H),3.27–3.21(m,5H),2.97(dd,J1=14.4Hz,J2=8.0Hz,1H),2.24(s,6H);HRMS(ESI):m/z,Calcd forC21H25O2N2[M+H]+:337.1910,Found 337.1913.
实施例3:
3-(2-甲基-4-(三氟甲氧基)苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物3)的合成
(1)2-甲基-4-(三氟甲氧基)苯甲醛(中间体10)的合成
氩气保护下,将N,N,N'-三甲基乙二胺(8.00g,78.9mmol)溶于100mL超干THF,0℃下加入32mL的正丁基锂的环己烷溶液,搅拌30min,冷却至-40℃,加入对三氟甲氧基苯甲醛(5g,26.3mmol)的超干THF溶液20mL,搅拌30min,加入32mL的正丁基锂的环己烷溶液(2.5M),搅拌3h,加入碘甲烷(30g,210mmol)的超干THF溶液20mL,升温至室温,搅拌1h,倾倒入1N盐酸中。DCM萃取(200mL×3),柱层析P-P/A=100/1-50/1,得浅无色油状物2.8g,产率52%。
(2)(Z/E)-3-(2-甲基-4-(三氟甲氧基)亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体11)的合成
将中间体1(6.77g,23.6mmol)溶于无水THF(60mL)中,加入中间体10(5.79g,28.4mmol),冰浴下,滴入TEA(3.13g,31.0mmol)的无水THF(40mL),Ar保护下,冰浴搅拌30min,转移至室温反应8h,将反应液倾倒入冰水中,搅拌60min,析出固体,过滤,水洗,无水乙醚洗,干燥,得黄色固体6.0g,产率70%。核磁显示反式:顺式比例约为0.7/0.3
1H-NMR(400MHz,CDCl3)δ(ppm):8.81(d,J=2.0Hz,0.7H),8.76(d,J=2.0Hz,0.3H),8.61(dd,J1=8.4Hz,J2=2.0Hz,0.7H),8.36(dd,J1=8.8Hz,J2=2.0Hz,0.3H),8.21(d,J=8.8Hz,0.7H),7.99(d,J=8.8Hz,0.7H),7.43(d,J=8.4Hz,0.3H),7.33(d,J=8.4Hz,0.3H),7.26(s,0.3H),7.18(d,J=8.8Hz,1H),7.11(s,0.7H),7.03(s,0.3H),6.78(s,0.7H),2.53(s,2.1H),2.36(s,0.9H).
(3)6-氨基-3-(2-甲基-4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮(中间体12)的合成
将中间体11(1.53g,4.2mmol)加入到EA(5mL)、MeOH(5mL)与THF(10mL)的混合溶液中,加入20%钯碳(300mg),室温催化氢化8h。过滤,滤液浓缩,柱层析(P/E=3/1-2/1),得白色固体940mg,产率77%。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.32(d,J=8.4Hz,1H),7.23(d,J=8.4Hz,1H),7.19–7.18(m,1H),7.12(d,J=8.4Hz,1H),6.94(dd,J1=8.0Hz,J2=2.0Hz,1H),6.85(d,J=2.0Hz,1H),6.57(dd,J1=8.4Hz,J2=4.0Hz,1H),5.59(brs,2H),3.30(dd,J1=14.4Hz,J2=4.0Hz,1H),2.91(dd,J1=14.4Hz,J2=8.4Hz,1H),2.32(s,3H).
(4)6-溴-3-(2-甲基-4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮(中间体13)的合成
取亚硝酸钠(556mg,8.06mmol)、TEBAC(228mg,0.54mmol)和三甲基溴硅烷(1.23g,8.06mmol)溶于乙腈30mL,冰浴下搅拌15min,将中间体12(900mg,2.69mmol)溶于20mL乙腈,滴入反应瓶中,继续冰水浴搅拌8h。加入80mL水,EA萃取(50mL×3),无水硫酸镁干燥,浓缩,Flash柱层析(30g柱,0-6%EA/PE),得类白色固体846mg,产率79%。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.01(s,1H),8.00(dd,J1=6.4Hz,J2=1.6Hz,1H),7.67(d,J=8.8Hz,1H),7.34(d,J=8.4Hz,1H),7.20(s,1H),7.15–7.13(m,1H),5.90(dd,J1=8.8Hz,J2=4.4Hz,1H),3.44(dd,J1=14.8Hz,J2=4.4Hz,1H),3.03(dd,J1=14.8Hz,J2=8.8Hz,1H),2.34(s,3H).
(5)4-(1-(2-甲基-4-(三氟甲氧基)苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-羧酸叔丁酯(中间体14)的合成
将中间体13(236mg,0.59mmol)、N-Boc-哌嗪(166mg,0.89mmol)、Pd(OAc)2(13mg,0.059mmol)、Xantphos(68mg,0.12mmol)和碳酸銫(384mg,1.2mmol)加入1,4-二氧六环(8mL)中,氩气保护,100℃加热12h。过滤,EA洗,Flash柱层析(30g柱,3-22%EA/PE),正己烷洗,得白色固体230mg,产率77%。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.37(d,J=8.4Hz,1H),7.34(d,J=8.4Hz,1H),7.22–7.19(m,1H),7.13(d,J=8.4Hz,1H),6.94(dd,J1=8.4Hz,J2=2.4Hz,1H),6.71(d,J=2.4Hz,1H),5.74(dd,J1=8.4Hz,J2=4.4Hz,1H),4.17–4.13(m,1H),3.51(dd,J1=9.6Hz,J2=6.4Hz,1H),3.43–3.39(m,1H),3.32–3.25(m,2H),3.09(dd,J1=9.6Hz,J2=4.8Hz,1H),2.94(dd,J1=14.4Hz,J2=8.4Hz,1H),2.33(s,3H),2.20–2.12(m,1H),1.95–1.87(m,1H),1.40(s,9H).
(6)3-(2-甲基-4-(三氟甲氧基)苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物3)的合成
冰浴下,将中间体14(450mg,0.92mmol)溶于DCM(4mL)中,逐滴滴加TFA(1.05g,9.20mmol)的DCM溶液(5mL),冰浴搅拌30min,室温搅拌2h。加入饱和Na2CO3溶液至不再产生气泡,D/M=10/1(50mL×3)萃取,柱层析D/M=20/1-10/1,得浅黄色油状物350mg,加入2mLHCl的1,4-二氧六环溶液(4M),室温搅拌过夜,析出白色固体,过滤,无水乙醚洗,干燥,得白色固体331mg,产率81%,熔点:184-185℃。
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.46(brs,1H),7.53–7.46(m,2H),7.35(d,J=8.4Hz,1H),7.28(d,J=2.4Hz,1H),7.20(s,1H),7.14(d,J=7.6Hz,1H),6.47(brs,1H),5.80(dd,J1=8.4Hz,J2=4.4Hz,1H),3.50(t,J=4.8Hz,4H),3.37(dd,J1=14.8Hz,J2=4.4Hz,1H),3.20(m,4H),2.96(dd,J1=14.8Hz,J2=4.4Hz,1H),2.34(s,3H);HRMS(ESI):m/z,Calcd for C21H22O3N2F3[M+H]+:407.1577,Found 407.1571.
实施例4和实施例5:
(-)-3-(2-甲基-4-(三氟甲氧基)苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物4)和(+)-3-(2-甲基-4-(三氟甲氧基)苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物5)的合成
将实施例3用IG手性半制备柱(10mm I.D.×250mmL)进行手性拆分:
拆分条件:45%乙醇–55%正己烷(加入0.1%二乙胺),流速:4mL/min;
得到两个对映异构体,分别记为化合物4(实施例4)、化合物5(实施例5):
化合物4(实施例4):Rf1=17min;[α]589 21.8(MeOH)=-70.48
化合物5(实施例5):Rf2=33min;[α]589 22.0(MeOH)=+63.35
实施例6:
3-(2-甲基-4-(三氟甲基)苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物6)的合成
(1)2-甲基-4-(三氟甲基)苯甲醛(中间体15)的合成
氩气保护下,将N,N,N'-三甲基乙二胺(323mg,3.16mmol)溶于10mL超干THF,0℃下,加入2mL的正丁基锂的环己烷溶液(2.5M),搅拌30min,冷却至-40℃,加入对三氟甲基苯甲醛(500mg,2.87mmol)的超干THF溶液2mL,搅拌30min,加入3.44mL的正丁基锂的环己烷溶液(2.5M),搅拌3h,加入碘甲烷(3.26g,23.0mmol)的超干THF溶液6mL,升温至室温,搅拌1h,倾倒入1N盐酸中。DCM萃取(80mL×3),柱层析石油醚-P/A=100/1-50/1,得浅无色油状物322mg,产率60%。
1H-NMR(400MHz,CDCl3)δ(ppm):10.32(s,1H),7.89(d,J=8.0Hz,1H),7.51(d,J=8.4Hz,1H),7.51(s,1H),2.71(s,3H).
(2)(Z)-3-(2-甲基-4-(三氟甲基)亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体16)的合成
将中间体1(5.25g,18.3mmol)溶于无水THF(100mL)中,依次加入中间体15(3.44g,18.3mmol)和TEA(2.2g,21.9mmol),Ar保护下冰浴搅拌30min,转移至室温反应8h,将反应液倾倒入冰水中,搅拌60min,析出大量褐色固体,过滤,水洗,无水乙醚洗,干燥,得黄色固体5.85g,产率93%。
(3)6-氨基-3-(2-甲基-4-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮(中间体17)的合成
将中间体16(3.95g,11.2mmol)加入到EA(20mL)、MeOH(10mL)与THF(20mL)的混合溶液中,加入20%钯碳(800mg),室温催化氢化反应2h,原料消失。过滤,滤液浓缩,柱层析(P/E=3/1-1/1)得白色固体2.8g,产率77%。
(4)6-溴-3-(2-甲基-4-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮(中间体18)的合成
取亚硝酸钠(106mg,1.53mmol)、TEBAC(23mg,0.10mmol)和三甲基溴硅烷(234mg,1.53mmol)溶于乙腈5mL,冰浴下搅拌15min后将中间体17(164mg,0.51mmol)溶于5mL乙腈,滴入反应瓶中,继续冰浴搅拌12h。加入20mL水,EA萃取(30mL×3),无水硫酸镁干燥,浓缩,Flash柱层析(30g柱,6-17%EA/PE),得白色固体117mg,产率60%。
1H-NMR(400MHz,CDCl3)δ(ppm):8.03(d,J=1.6Hz,1H),7.76(dd,J1=8.0Hz,J2=1.6Hz,1H),7.46(s,1H),7.42(d,J=8.0Hz,1H),7.28(d,J=8.0Hz,1H),7.06(dt,J1=8.4Hz,J2=0.08Hz,1H),5.64(t,J=6.4Hz,1H),3.24(m,2H),2.39(s,3H).
(5)4-(1-(2-甲基-4-(三氟甲基)苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-甲酸叔丁酯(中间体19)的合成
将中间体18(737mg,1.92mmol)、N-Boc-哌嗪(536mg,2.88mmol)、Pd2(dba)3(176mg,0.19mmol)、BINAP(240mg,0.38mmol)和碳酸铯(1250mg,3.84mmol)加入1,4-二氧六环30mL中,氩气保护,90℃加热11h。硅藻土助滤,滤掉不溶物,EA洗。柱层析第一次(P/E=3/1-P/A=10/1),第二次(D/M=80/1),得浅黄色油状物444mg,产率50%。
(6)3-(2-甲基-4-(三氟甲基)苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物6)的合成
冰浴下,将中间体18(100mg,0.25mmol)溶于DCM(2mL)中,逐滴滴加TFA(570mg,5.00mmol)的DCM溶液(1mL),冰浴搅拌30min,室温搅拌2h。加入饱和Na2CO3溶液至不再产生气泡,D/M=10/1(50mL×3)萃取,柱层析D/M=20/1-10/1,得浅黄色油状物100mg,加入0.5mL HCl的EA溶液(4M),室温搅拌过夜,析出白色固体,过滤,无水乙醚洗,干燥,得白色固体78mg,产率90%,熔点:205-206℃。
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.26(brs,1H),7.55–7.45(m,5H),7.28(d,J=2.4Hz,1H),5.84(dd,J1=8.4Hz,J2=4.0Hz,1H),3.77(brs,1H),3.50–3.44(m,5H),3.21(s,4H),3.04(dd,J1=14.4Hz,J2=8.4Hz,1H),2.39(s,3H);HRMS(ESI):m/z,Calcd forC21H22O2N2F3[M+H]+:391.1627,Found 391.1623.
实施例7:
3-(4-甲氧基-2-甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物7)的合成
(1)(Z)-3-(4-甲氧基-2-甲基亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体20)的合成
Ar保护下,将中间体1(5g,17.4mmol)、2-甲基-4-甲氧基苯甲醛(2.60g,17.4mmol)加入到无水THF(50mL)中,冰浴,向上述溶液中滴加TEA(1.94g,19.1mmol)的无水THF(20mL)溶液,继续搅拌6h,浓缩,加入冰水60mL,搅拌60min,析出黄色固体,过滤,水洗,干燥,得桔红色固体5.3g,产率98%。
(核磁显示Z/E=0.6/0.4)
1H NMR(400MHz,CDCl3)δ(ppm):8.78(d,J=2.0Hz,0.4H),8.75(d,J=2.4Hz,0.6H),8.56(dd,J1=8.8Hz,J2=2.0Hz,0.4H),8.32(dd,J1=8.8Hz,J2=2.4Hz,0.6H),8.23(d,J=8.8Hz,0.4H),7.93(d,J=8.8Hz,0.4H),7.47(d,J=8.8Hz,0.6H),7.32(d,J=8.4Hz,0.6H),7.07(s,0.6H),6.89(d,J=2.4Hz,0.6H),6.86(dd,J1=8.8Hz,J2=2.4Hz,0.4H),6.82(dd,J1=8.0Hz,J2=2.4Hz,0.6H),6.81(s,0.4H),6.79(d,J=2.8Hz,0.4H),3.88(s,1.8H),3.86(s,1.2H),2.50(s,1.2H),2.32(s,1.8H).
(2)6-氨基-3-(4-甲氧基-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体21)的合成
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将中间体20(5.3g,17.0mmol)溶于MeOH(60mL)和DCM(80mL)的溶液中,加入钯碳(1g),室温催化氢化反应24h,原料消失。过滤,滤液浓缩,柱层析(0-5%EA/DCM),过滤,正己烷洗,得白色固体2.10g,产率44%。
1H NMR(400MHz,CDCl3)δ7.08–7.06(m,2H),6.86(dd,J1=8.4Hz,J2=2.0Hz,1H),6.80(d,J=4.0Hz,1H),6.73(d,J=2.4Hz,1H),6.69(dd,J1=8.0Hz,J2=2.8Hz,1H),5.52(t,J=6.8Hz,1H),3.80(s,3H),3.20(dd,J1=14.4Hz,J2=6.8Hz,1H),2.97(dd,J1=14.4Hz,J2=7.2Hz,1H),2.27(s,3H).
(3)6-溴-3-(4-甲氧基-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体22)的合成
取亚硝酸钠(919mg,13.3mmol)、三乙基苄基氯化铵(2.04g,13.3mmol)和三甲基溴硅烷(2.04g,13.3mmol)溶于乙腈30mL,冰浴下搅拌15min,将中间体21(1.26g,4.44mmol)溶于20mL乙腈,滴入反应瓶中,继续冰水浴搅拌18h。加入40mL水,EA萃取(40mL×3),无水硫酸镁干燥,浓缩,柱层析(4-10%EA/PE),得类白色固体1.11g,产率72%。
1H NMR(400MHz,CDCl3)δ(ppm):8.00(s,1H),7.67(dd,J1=8.4Hz,J2=1.6Hz,1H),7.02(d,J=8.4Hz,1H),6.89(d,J=8.0Hz,1H),6.75(t,J=2.8Hz,1H),6.70(dd,J1=8.4Hz,J2=2.8Hz,1H),5.58(t,J=7.2Hz,1H),3.80(s,3H),3.29(dd,J1=14.0Hz,J2=6.4Hz,1H),3.00(dd,J1=14.4Hz,J2=7.6Hz,1H),2.27(s,3H).
(4)4-(4-甲氧基-2-甲基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-甲酸叔丁酯(中间体23)的合成
将中间体22(200mg,0.58mmol)、N-Boc-哌嗪(215mg,1.16mmol)、Pd2(dba)3(53mg,0.058mmol)、BINAP(72mg,0.116mmol)和碳酸銫(378mg,1.16mmol)加入到6mL 1,4-二氧六环中,氩气保护,90℃加热12h,原料消失。硅藻土助滤,滤掉不溶物,EA洗。柱层析(30g柱,0-6%Acetone/PE),得黄色油状物172mg,产率66%。
1H-NMR(500MHz,CDCl3)δ(ppm):7.32(d,J=2.5Hz,1H),7.21(d,J=8.5Hz,1H),7.06(d,J=8.5Hz,1H),6.92(d,J=8.5Hz,1H),6.74(d,J=3.0Hz,1H),6.70(dd,J1=8.5Hz,J2=3.0Hz,1H),5.55(t,J=2.0Hz,1H),3.80(s,3H),3.62(t,J=5.0Hz,1H),3.23(dd,J1=14.0Hz,J2=6.5Hz,1H),3.20(d,J=6.0Hz,4H),2.98(dd,J1=14.0Hz,J2=7.0Hz,1H),2.28(s,3H),1.49(s,9H).
(5)3-(4-甲氧基-2-甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸(化合物7)的合成
将中间体23(140mg,0.31mmol)溶于HCl的EA溶液4mL中(1M),室温搅拌2h,析出固体,过滤,无水乙醚洗,得白色固体124mg,收率91%,熔点:128-129℃。
1H-NMR(500MHz,MeOD)δ(ppm):7.41(d,J=8.5Hz,1H),7.34(s,1H),7.25(d,J=8.5Hz,1H),7.00(d,J=8.5Hz,1H),6.72(s,1H),6.63(d,J=8.0Hz,1H),5.71(t,J=5.0Hz,4H),3.39(t,J=5.0Hz,4H),3.18(dd,J1=14.0Hz,J2=6.5Hz,1H),3.14(dd,J1=14.5Hz,J2=7.0Hz,1H),2.27(s,3H);13C-NMR(150MHz,DMSO-d6)δ(ppm):169.95,158.00,151.09,140.97,138.05,131.30,126.61,126.48,123.62,122.72,115.56,111.09,110.02,80.84,55.00,45.34,42.35,36.70,19.75;HRMS(ESI):m/z,Calcd for C21H25O3N2[M+H]+:353.1859,Found 353.1854.
实施例8:
6-(哌嗪-1-基)-3-((5-(三氟甲基)-[1,1'-联苯]-2-基)甲基)异苯并呋喃-1(3H)-酮盐酸盐(化合物8)的合成
(1)5-(三氟甲基)-[1,1'-联苯]-2-甲醛(中间体24)的合成
将2-溴-4-三氟甲基苯甲醛(200mg,0.79mmol)、苯硼酸(116mg,0.95mmol)、四三苯基膦钯(9mg,0.079mmol)和碳酸钾(218mg,1.58mmol)加入到1,4-二氧六环5mL中,氩气保护,80℃加热12h。过滤,硅藻土助滤,滤掉不溶物,EA洗。滤液浓缩,Flash柱层析(30g柱,PE),得无色油状物178mg,产率90%。1H NMR(500MHz,CDCl3)δ10.01(s,1H),8.13(d,J=8.0Hz,1H),7.74(d,J=10.0Hz,2H),7.53–7.48(m,3H),7.41–7.39(m,2H).
(2)(Z)-6-硝基-3-((5-(三氟甲基)-[1,1'-联苯]-2-基)亚甲基)异苯并呋喃-1(3H)-酮(中间体25)的合成
将中间体1(3.05g,10.6mmol)、中间体24(2.66g,10.6mmol)加入到无水THF(30mL)中,冰浴,缓慢滴加TEA(1.29g,12.72mmol)的无水THF(15mL),Ar保护继续反应8h,反应完毕,旋干溶剂,加入冰水搅拌60min,析出黄色固体,过滤,水洗,干燥,得黄色固体3.75g,产率86%。
1H NMR(400MHz,CDCl3)δ8.80(d,J=2.0Hz,1H),8.51(dd,J1=8.8Hz,J2=2.0Hz,1H),8.47(d,J=8.4Hz,1H),7.73(dd,J1=8.4Hz,J2=2.0Hz,1H),7.66(s,1H),7.65(d,J=6.4Hz,0.2H),7.54–7.47(m,3H),7.41–7.39(m,2H),6.62(s,1H).
(3)6-氨基-3-((5-(三氟甲基)-[1,1'-联苯]-2-基)甲基)异苯并呋喃-1(3H)-酮(中间体26)的合成
将中间体25(2.5g,6.08mmol)溶于MeOH(40mL)中,加入钯碳(500mg),室温催化氢化反应12h,原料消失。过滤,滤液浓缩,Flash柱层析(45g柱,12-100%EA/PE),过滤,正己烷洗,得白色固体2.10g,收率90%。
1H NMR(400MHz,MeOD)δ7.62–7.58(m,2H),7.48–7.45(m,2H),7.44–7.37(m,2H),7.31–7.28(m,2H),6.75(dt,J1=8.0Hz,J2=0.8Hz,1H),5.45(dd,J1=8.0Hz,J2=4.8Hz,1H),3.34(dd,J1=14.8Hz,J2=4.8Hz,1H),3.06(d,J1=14.8Hz,J2=8.0Hz,1H).
(4)6-溴-3-((5-(三氟甲基)-[1,1'-联苯]-2-基)甲基)异苯并呋喃-1(3H)-酮(中间体27)的合成
取亚硝酸钠(1.03g,14.9mmol)、三乙基苄基氯化铵(226mg,0.992mmol)和三甲基溴硅烷(2.28g,14.9mmol)溶于乙腈20mL,冰浴下搅拌15min后将中间体26(1.9g,4.96mmol)加入,继续冰浴搅拌12h。加入40mL水,EA萃取(30mL×3),无水硫酸镁干燥,浓缩,Flash柱层析(30g柱,4-9%EA/PE),再次Flash柱层析(20g柱,0-5%EA/PE),得白色固体1.69g,产率76.5%。
1H NMR(500MHz,CDCl3)δ7.95(s,1H),7.62(d,J=8.5Hz,1H),7.60(d,J=8.0Hz,1H),7.53(s,1H),7.51(d,J=8.0Hz,1H),7.47–7.41(m,3H),7.27(d,J=7.5Hz,2H),6.70(d,J=8.0Hz,1H),5.36(dd,J1=8.0Hz,J2=5.5Hz,1H),3.29(dd,J1=14.5Hz,J2=5.0Hz,1H),3.18(dd,J1=14.5Hz,J2=8.0Hz,1H).
(5)叔丁基4-(3-氧代-1-((5-(三氟甲基)-[1,1'-联苯]-2-基)甲基)-1,3-二氢异苯并呋喃-5-基)哌嗪-1-羧酸盐(中间体28)的合成
将中间体27(300mg,0.67mmol)、N-Boc-哌嗪(250mg,1.34mmol)、Pd2(dba)3(61mg,0.067mmol)、BINAP(83mg,0.134mmol)和碳酸銫(437mg,1.34mmol)加入到10mL 1,4-二氧六环,氩气保护,90℃加热5h。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(45g柱,4-38%Acetone/PE),得浅黄色固体213mg,产率57.4%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.59(dd,J1=8.0Hz,J2=1.6Hz,1H),7.52(dd,J1=2.0Hz,J2=0.8Hz,1H),7.51(d,J=4.0Hz,1H),7.45–7.41(m,3H),7.30–7.27(m,3H),7.16(dd,J1=8.4Hz,J2=2.4Hz,1H),6.74(d,J=8.4Hz,1H),5.35(dd,J1=8.4Hz,J2=5.2Hz,1H),3.60(t,J=5.2Hz,4H),3.25(dd,J1=14.4Hz,J2=4.8Hz,1H),3.18(t,J=5.2Hz,4H),3.12(dd,J1=14.4Hz,J2=8.0Hz,1H),1.48(s,9H).
(6)6-(哌嗪-1-基)-3-((5-(三氟甲基)-[1,1'-联苯]-2-基)甲基)异苯并呋喃-1(3H)-酮盐酸盐(化合物8)的合成
将中间体28(105mg,0.19mmol)溶于HCl的EA溶液(1M)5mL中,室温搅拌2h,析出固体,过滤,无水乙醚洗,得棕色固体80mg,收率86.1%,熔点:141-142℃。
1H-NMR(400MHz,MeOD)δ(ppm):7.61(dd,J1=9.6Hz,J2=8.0Hz,2H),7.49–7.39(m,4H),7.36(dd,J1=8.4Hz,J2=2.4Hz,1H),7.30–7.27(m,3H),7.00(d,J=8.4Hz,1H),5.56(dd,J1=8.0Hz,J2=4.8Hz,1H),3.50–3.48(m,4H),3.41–3.36(m,5H),3.11(dd,J1=14.4Hz,J2=8.0Hz,1H);HRMS(ESI):m/z,Calcd for C26H24O2N2F3[M+H]+:453.1784,Found453.1781.
实施例9:
3-(4-氟-2-甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物9)的合成
(1)(Z/E)-3-(4-氟-2-甲基亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体29)的合成
将中间体1(2.00g,10.4mmol)、2-甲基-4-氟苯甲醛(1.44g,10.4mmol)加入到无水THF(30mL)中,冰浴,缓慢滴加TEA(1.16g,11.4mmol)的无水THF(20mL),Ar保护继续反应8h,反应完毕。旋干溶剂,加入冰水搅拌60min,析出黄色固体,过滤,水洗,干燥,得黄色固体2.49g,产率80%。
(核磁显示Z/E=0.6/0.4)
1H-NMR(400MHz,CDCl3)δ(ppm):8.80(d,J=2.0Hz,0.4H),8.76(d,J=2.4Hz,0.6H),8.59(dd,J1=8.4Hz,J2=2.0Hz,0.4H),8.34(dd,J1=8.8Hz,J2=2.0Hz,0.6H),8.20(dd,J1=8.8Hz,J2=6.0Hz,0.4H),7.97(d,J=8.8Hz,0.4H),7.36(dd,J1=8.4Hz,J2=5.6Hz,0.6H),7.33(d,J=8.8Hz,0.6H),7.09–7.07(m,0.6H),7.03(s,0.6H),7.01–6.96(m,1.4H),6.78(s,0.4H),2.51(s,1.2H),2.34(s,1.8H).
(2)6-氨基-3-(4-氟-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体30)的合成
将中间体29(1.6g,5.35mmol)溶于DCM(20mL)与MeOH(20mL)的溶液中,加入钯碳(300mg),室温催化氢化反应16h,原料消失。过滤,滤液浓缩,Flash柱层析(45g柱,6-100%EA/PE),过滤,正己烷洗,得白色固体1.13g,收率78%。
1H-NMR(500MHz,MeOH-d4)δ(ppm):8.28(d,J=5.0Hz,1H),7.94(s,1H),7.91(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.57(d,J=8.5Hz,1H),7.17(dd,J1=8.0Hz,J2=5.0Hz,1H),5.86(dd,J1=7.5Hz,J2=4.5Hz,1H),3.51(dd,J1=15.0Hz,J2=4.5Hz,1H),3.16(dd,J1=15.0Hz,J2=7.5Hz,1H),2.57(s,3H).
(3)6-溴-3-(4-氟-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体31)的合成
取亚硝酸钠(1.50g,9.79mmol)、三乙基苄基氯化铵(149mg,0.65mmol)和三甲基溴硅烷(1.50g,9.79mmol)溶于乙腈50mL,冰浴下搅拌15min后将中间体30(885mg,3.26mmol)溶于20mL乙腈,滴入反应瓶中,继续冰浴搅拌12h。加入50mL水,EA萃取(30mL×3),无水硫酸镁干燥,浓缩,Flash柱层析(30g柱,4-13%EA/PE),得白色固体927mg,产率85%。
1H-NMR(400MHz,MeOH-d4)δ(ppm):7.94(d,J=1.6Hz,1H),7.87(dd,J1=8.0Hz,J2=1.6Hz,1H),7.39(dt,J1=8.0Hz,J2=0.8Hz,1H),7.11(dd,J1=8.8Hz,J2=6.0Hz,1H),6.91(dd,J1=9.6Hz,J2=2.8Hz,1H),6.80(td,J1=8.4Hz,J2=2.8Hz,1H),5.79(ddd,J1=7.6Hz,J2=5.6Hz,J3=0.8Hz,1H),3.34(dd,J1=14.4Hz,J2=5.2Hz,1H),3.17(dd,J1=14.8Hz,J2=7.2Hz,1H),2.33(s,3H).
(4)3-(4-氟-2-甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物9)的合成
将中间体31(311mg,0.93mmol)、N-Boc-哌嗪(346mg,1.86mmol)、Pd2(dba)3(85mg,0.093mmol)、BINAP(116mg,0.19mmo)和碳酸铯(606mg,1.86mmol)加入1,4-二氧六环9mL中,氩气保护,90℃加热6h。过滤,滤液浓缩,Flash柱层析(30g柱,6-16%EA/PE),得白色固体258mg。加入4mL氯化氢的1,4-二氧六环溶液(4M),30℃搅拌12h。加入少量乙醚,析出固体,过滤,得类白色固体197mg,两步产率56.1%,熔点190-191℃。
1H-NMR(400MHz,MeOH-d4)δ(ppm):7.41(dd,J1=8.4Hz,J2=2.4Hz,1H),7.33(d,J=8.4Hz,1H),7.31(d,J=2.4Hz,1H),7.08(dd,J1=8.8Hz,J2=6.0Hz,1H),6.87(dd,J1=10.0Hz,J2=6.8Hz,1H),6.75(td,J1=8.4Hz,J2=2.8Hz,1H),5.71(dd,J1=6.8Hz,J2=6.0Hz,1H),3.49–3.46(m,4H),3.38–3.35(m,4H),3.28(dd,J1=14.4Hz,J2=5.6Hz,1H),3.10(dd,J1=14.4Hz,J2=7.2Hz,1H),2.29(s,3H);HRMS(ESI):m/z,Calcd for C20H22O2N2F[M+H]+:341.1660,Found 341.1668.
实施例10:
3-(5-氟-2-甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物10)的合成
(1)(Z/E)-3-(5-氟-2-甲基亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体32)的合成
将中间体1(1.5g,5.22mmol)和2-甲基-5-氟苯甲醛(722mg,5.22mmol)溶于无水THF(16mL)中,冰浴下,缓慢滴加TEA(630mg,6.26mmol)的THF溶液(4mL),Ar保护下室温反应5h。将反应液倾倒入冰水中,搅拌20min,析出黄色固体,过滤,水洗,干燥,得黄色固体1.45g,产率92.9%。
(核磁显示Z/E=0.8/0.2)
1H-NMR(400MHz,CDCl3)δ(ppm):8.81(d,J=2.0Hz,0.8H),8.76(d,J=2.4Hz,0.2H),8.60(dd,J1=8.4Hz,J2=2.0Hz,0.8H),8.36(dd,J1=8.4Hz,J2=2.4Hz,0.2H),7.98(d,J=8.4Hz,0.8H),7.91(dd,J1=10.4Hz,J2=3.2Hz,0.8H),7.35(d,J=8.4Hz,0.2H),7.33–7.28(m,0.2H),7.21(dd,J1=8.8Hz,J2=6.0Hz,0.8H),7.12–7.08(m,0.4H),7.03(s,0.2H),6.99(td,J1=8.4Hz,J2=2.8Hz,0.8H),6.78(s,0.8H),2.47(s,2.4H),2.29(s,0.6H).
(2)6-氨基-3-(5-氟-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体33)的合成
将中间体32(1.44g,4.82mmol)溶于三氟乙醇(20mL),加入钯碳(300mg),50℃催化氢化12h,原料消失。过滤,除去钯碳,滤液浓缩,正己烷洗,得白色固体1.17g,产率90.3%。
1H NMR(400MHz,MeOH-d4)δ(ppm):7.14(dd,J1=8.4Hz,J2=6.0Hz,1H),7.13(d,J=8.0Hz,1H),7.02(dd,J1=8.0Hz,J2=2.4Hz,1H),7.00(d,J=2.0Hz,1H),6.92(dd,J1=10.0Hz,J2=2.8Hz,1H),6.85(td,J1=8.4Hz,J2=2.4Hz,1H),5.67(dd,J1=7.6Hz,J2=5.2Hz,1H),3.27(dd,J1=14.4Hz,J2=5.2Hz,1H),3.06(dd,J1=14.4Hz,J2=7.6Hz,1H),2.27(s,3H).
(3)6-溴-3-(5-氟-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体34)的合成
取亚硝酸钠(457mg,6.63mmol)、三乙基苄基氯化铵(101mg,0.44mmol)和三甲基溴硅烷(1.01g,6.63mmol)溶于乙腈10mL,冰水浴中搅拌20min。将中间体33(600mg,2.21mmol)溶于3mL乙腈,在冰浴下滴加入反应瓶中,继续冰水浴搅拌12h。加入30mL乙酸乙酯,用饱和NaCl(30mL×2)洗,无水硫酸镁干燥,浓缩,Flash柱层析(45g柱,2-12%EA/PE),得白色固体632mg,产率85.5%。
1H-NMR(400MHz,CDCl3)δ(ppm):8.03(d,J=1.6Hz,1H),7.73(dd,J1=8.4Hz,J2=2.0Hz,1H),7.15(dd,J1=8.4Hz,J2=6.0Hz,1H),7.00(d,J=8.4Hz,1H),6.93–6.88(m,2H),5.62(t,J=7.2Hz,1H),3.24(dd,J1=14.4Hz,J2=7.6Hz,1H),3.09(dd,J1=14.4Hz,J2=6.8Hz,1H),2.26(s,3H).
(4)4-(5-氟-2-甲基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-甲酸叔丁酯(中间体35)的合成
将中间体34(150mg,0.45mmol)、N-Boc-哌嗪(167mg,0.90mmol)、Pd2(dba)3(41mg,0.045mmol)、BINAP(56mg,0.09mmo)和碳酸铯(293mg,0.90mmol)加入1,4-二氧六环5mL中,氩气保护,90℃加热12h。过滤,滤液浓缩,Flash柱层析(30g柱,6-25%EA/PE),得浅黄色固体156mg,产率79.2%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.34(d,J=2.4Hz,1H),7.25(dd,J1=8.4Hz,J2=2.4Hz,1H),7.14(dd,J1=8.0Hz,J2=6.0Hz,1H),7.01(d,J=8.4Hz,1H),6.92–6.86(m,2H),5.59(t,J=6.8Hz,1H),3.62(t,J=4.8Hz,4H),3.22(t,J=4.4Hz,4H),3.19(dd,J1=14.4Hz,J2=7.2Hz,1H),3.07(dd,J1=14.4Hz,J2=6.4Hz,1H),2.27(s,3H),1.49(s,9H).
(5)3-(5-氟-2-甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物10)的合成
中间体35(140mg,0.32mmol)加入3mL氯化氢的1,4-二氧六环溶液(4M),30℃搅拌5h。加入少量乙醚,析出固体,过滤,得浅粉色固体102mg,产率85%,熔点251-252℃。
1H-NMR(400MHz,MeOH-d4)δ(ppm):7.47(dd,J1=8.4Hz,J2=2.4Hz,1H),7.39(d,J=8.4Hz,1H),7.35(d,J=2.0Hz,1H),7.14(dd,J1=8.4Hz,J2=6.0Hz,1H),6.90(dd,J1=10.0Hz,J2=2.8Hz,1H),6.85(td,J1=8.4Hz,J2=2.8Hz,1H),5.77(dd,J1=7.2Hz,J2=5.2Hz,1H),3.53–3.50(m,4H),3.41–3.39(m,4H),3.35–3.31(m,1H),3.12(dd,J1=14.4Hz,J2=7.2Hz,1H),2.28(s,3H);HRMS(ESI):m/z,Calcd for C20H22O2N2F[M+H]+:341.1660,Found 341.1668.
实施例11:
3-(3-氟-4-甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物11)的合成
(1)(Z/E)-3-(3-氟-4-甲基亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体36)的合成
将中间体1(3.50g,12.2mmol)、3-氟-4-甲基苯甲醛(1.68g,12.2mmol)加入到无水THF(40mL)中,冰浴,缓慢滴加TEA(1.36g,13.4mmol)的无水THF(20mL),Ar保护继续反应6h,反应完毕,旋干溶剂,加入冰水搅拌60min,析出浅黄色固体,过滤,水洗,干燥,得浅黄色固体3.50g,产率95%。
(核磁显示Z/E=0.7/0.3)
1H-NMR(400MHz,CDCl3)δ(ppm):8.80–8.78(m,0.7H),8.76–8.75(m,0.3H),8.59(dd,J1=8.4Hz,J2=2.0Hz,0.7H),8.39(dd,J1=8.8Hz,J2=2.0Hz,0.3H),7.92(dd,J1=8.8Hz,J2=0.8Hz,0.7H),7.70(d,J=8.8Hz,0.3H),7.60(dd,J1=10.8Hz,J2=1.6Hz,0.7H),7.50(dd,J1=7.6Hz,J2=1.6Hz,0.7H),7.31(t,J=7.6Hz,0.3H),7.25(t,J=8.0Hz,0.7H),7.16(d,J=7.6Hz,0.3H),7.12(t,J=10.0Hz,0.3H),7.06(s,0.3H),6.56(s,0.7H),2.37(d,J=2.0Hz,0.9H),2.33(d,J=2.0Hz,2.1H).
(2)6-氨基-3-(3-氟-4-甲基苄基)异苯并呋喃-1(3H)-酮(中间体37)的合成
将中间体36(3.00g,9.96mmol)溶于THF(40mL)与MeOH(40mL)的溶液中,加入钯碳(600mg),室温催化氢化反应6h,原料消失。过滤,滤液浓缩,Flash柱层析(40g柱,20-80%EA/PE),过滤,正己烷洗,得白色固体2.3g,收率85%。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.16(d,J=8.4Hz,1H),7.09(t,J=8.0Hz,1H),6.91(d,J=10.8Hz,1H),6.88(dd,J1=6.0Hz,J2=2.0Hz,1H),6.85(d,J=3.6Hz,1H),6.75(d,J=2.0Hz,1H),5.62(dd,J1=6.8Hz,J2=4.4Hz,1H),5.50(brs,2H),3.20(dd,J1=14.0Hz,J2=4.4Hz,1H),2.92(dd,J1=14.4Hz,J2=7.2Hz,1H),2.12(s,3H).
(3)6-溴-3-(3-氟-4-甲基苄基)异苯并呋喃-1(3H)-酮(中间体38)的合成
取亚硝酸钠(1.63g,23.7mmol)、三乙基苄基氯化铵(359mg,1.58mmol)和三甲基溴硅烷(3.63g,23.7mmol)溶于乙腈60mL,冰浴下搅拌15min后将中间体37(2.14g,7.90mmol)溶于20mL乙腈,滴入反应瓶中,继续冰浴搅拌12h。加入60mL水,EA萃取(40mL×3),无水硫酸镁干燥,浓缩,Flash柱层析(40g柱,10-30%EA/PE,20%出柱),得白色固体1.20g,产率45%。
1H NMR(400MHz,Acetone-d6)δ(ppm):7.91(dd,J1=8.4Hz,J2=2.0Hz,1H),7.89(d,J=1.6Hz,1H),7.59(d,J=8.0Hz,1H),7.14(t,J=8.0Hz,1H),6.98(dd,J1=8.4Hz,J2=1.6Hz,1H),6.96(dd,J1=4.8Hz,J2=1.6Hz,1H),5.86(dd,J1=6.8Hz,J2=4.8Hz,1H),3.42(dd,J1=14.4Hz,J2=4.8Hz,1H),3.21(dd,J1=14.4Hz,J2=6.8Hz,1H),3.19(d,J=2.0Hz,3H).
(4)4-(3-氟-4-甲基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-甲酸叔丁酯(中间体39)的合成
将中间体38(200mg,0.60mmol)、N-Boc-哌嗪(223mg,1.20mmol)、Pd2(dba)3(55mg,0.06mmol)、BINAP(75mg,0.20mmo)和碳酸铯(391mg,1.20mmol)加入1,4-二氧六环6mL中,氩气保护,90℃加热12h。过滤,滤液浓缩,Flash柱层析(30g柱,6-17%EA/PE),得浅黄色固体176mg,产率66.8%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.32–7.26(m,2H),7.11–7.06(m,2H),6.89(dd,J1=7.6Hz,J2=2.0Hz,1H),6.86(dd,J1=8.0Hz,J2=1.6Hz,1H),5.59(t,J=6.0Hz,1H),3.63(t,J=5.2Hz,4H),3.21(t,J=4.8Hz,4H),3.19(dd,J1=14.0Hz,J2=6.8Hz,1H),3.01(dd,J1=14.4Hz,J2=6.0Hz,1H),2.27(d,J=2.0Hz,3H),1.49(s,9H).
(5)3-(3-氟-4-甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物11)的合成
中间体39(140mg,0.32mmol)加入3mL氯化氢的1,4-二氧六环溶液(4M),30℃搅拌5h。加入少量乙醚,析出固体,过滤,得浅粉色固体89mg,产率74%,熔点201-202℃。
1H-NMR(400MHz,MeOH-d4)δ(ppm):7.42(dd,J1=8.4Hz,J2=2.4Hz,1H),7.39(dt,J1=8.4Hz,J2=0.8Hz,1H),7.27(d,J=2.0Hz,1H),7.04(t,J=8.0Hz,1H),6.84(dd,J1=8.0Hz,J2=2.0Hz,1H),6.81(dd,J1=10.8Hz,J2=2.0Hz,1H),5.74(t,J=5.6Hz,1H),3.47–3.44(m,4H),3.37–3.35(m,4H),3.28–3.25(m,1H),3.11(dd,J1=14.4Hz,J2=6.0Hz,1H),2.15(d,J=2.0Hz,1H);HRMS(ESI):m/z,Calcd for C20H21O2N2FNa[M+Na]+:363.1479,Found363.1497.
实施例12:
6-(哌嗪-1-基)-3-(2-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮盐酸盐(化合物12)的合成
(1)(Z)-6-硝基-3-(2-(三氟甲基)亚苄基)异苯并呋喃-1(3H)-酮(中间体40)的合成
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将中间体1(1.00g,3.48mmol)、2-三氟甲基苯甲醛(667mg,3.83mmol)加入到无水THF(6mL)中,冰浴,缓慢滴加TEA(423mg,4.18mmol)的无水THF(2mL),Ar保护继续反应2h,反应完毕,旋干溶剂,加入冰水搅拌60min,析出浅黄色固体,过滤,水洗,干燥,得浅黄色固体1.08g,产率92.3%。
1H-NMR(400MHz,CDCl3)δ(ppm):8.81(d,J=2.0Hz,1H),8.63(dd,J1=8.4Hz,J2=2.0Hz,1H),8.35(d,J=8.0Hz,1H),8.01(d,J=8.4Hz,1H),7.76(dt,J1=7.6Hz,J2=0.8Hz,1H),7.67(t,J=7.6Hz,1H),7.49(tt,J1=8.0Hz,J2=0.8Hz,1H),6.96(dd,J1=7.6Hz,J2=2.0Hz,1H).
(2)6-氨基-3-(2-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮(中间体41)的合成
将中间体40(1.00g,2.98mmol)溶于三氟乙醇(10mL)的溶液中,加入钯碳(200mg),室温催化氢化反应2h,原料消失。过滤,滤液浓缩得白色固体743mg,收率81%。
1H-NMR(500MHz,CDCl3)δ(ppm):7.72–7.69(m,1H),7.57–7.52(m,2H),7.42–7.39(m,1H),7.14–7.11(m,2H),6.99–6.95(m,1H),5.55–5.51(m,1H),4.02(brs,2H),3.49–3.47(m,1H),3.07–3.03(m,1H).
(3)6-溴-3-(2-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮(中间体42)的合成
取亚硝酸钠(270mg,3.91mmol)、三乙基苄基氯化铵(59mg,0.26mmol)和三甲基溴硅烷(599mg,3.91mmol)溶于乙腈10mL,冰浴下搅拌20min后将中间体41(400mg,1.30mmol)溶于3mL乙腈,滴入反应瓶中,继续冰浴搅拌12h。加入20mL水,EA萃取(20mL×3),无水硫酸镁干燥,浓缩,柱层析(30g柱,0-4%EA/PE),得白色固体353mg,产率73.2%。
1H-NMR(500MHz,CDCl3)δ(ppm):8.05(d,J=1.5Hz,1H),7.78(dd,J1=8.0Hz,J2=2.0Hz,1H),7.71(d,J=8.0Hz,1H),7.56–7.52(m,2H),7.44(t,J=5.6Hz,1H),7.23(d,J=3.0Hz,1H),5.59(dd,J1=9.5Hz,J2=3.5Hz,1H),3.53–3.49(m,1H),3.10(dd,J1=14.5Hz,J2=9.5Hz,1H).
(4)4-(2-三氟甲基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-甲酸叔丁酯(中间体43)的合成
将中间体42(200mg,0.54mmol)、N-Boc-哌嗪(201mg,1.08mmol)、Pd2(dba)3(49mg,0.054mmol)、BINAP(67mg,0.11mmol)和碳酸銫(352mg,1.08mmol)加入到5mL 1,4-二氧六环,氩气保护,90℃加热8h。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(30g柱,6-22%EA/PE),得白色固体155mg,产率60.3%。1H-NMR(500MHz,CDCl3)δ(ppm):7.71(d,J=7.5Hz,1H),7.58–7.55(m,2H),7.50–7.39(m,3H),7.30–7.28(m,1H),5.59(dd,J1=9.0Hz,J2=4.0Hz,1H),3.71–3.69(m,4H),3.51–3.48(m,1H),3.30–3.23(m,4H),3.07(dd,J1=14.5Hz,J2=9.5Hz,1H),1.50(s,9H).
(5)6-(哌嗪-1-基)-3-(2-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮盐酸盐(化合物12)的合成
将中间体43(143mg,0.30mmol)溶于HCl的EA溶液(1M)5mL中,室温搅拌5h,析出固体,过滤,无水乙醚洗,得白色固体106mg,收率85%,熔点:244-245℃。
1H-NMR(500MHz,MeOH-d4)δ(ppm):7.23(d,J=7.5Hz,1H),7.62–7.59(m,2H),7.49–7.48(m,1H),7.46(dd,J1=8.5Hz,J2=2.5Hz,1H),7.41(d,J=2.0Hz,1H),7.34(d,J=8.5Hz,1H),5.74(dd,J1=9.0Hz,J2=4.5Hz,1H),3.55–3.49(m,1H),3.53–3.52(m,4H),3.42–3.40(m,4H),3.14(dd,J1=15.0Hz,J2=9.0Hz,1H);HRMS(ESI):m/z,Calcd forC20H20O2N2F3[M+H]+:377.1471,Found 377.1481.
实施例13:
3-(2-环丙基-4-(三氟甲基)苄基)-6-(哌嗪-1-基)异苯并呋喃-(3H)-酮盐酸盐(化合物13)的合成
(1)2-环丙基-4-(三氟甲基)苯甲醛(中间体44)的合成
将2-溴-4-三氟甲基苯甲醛(2.53g,10mmol)、环丙基苯硼酸(1.03g,12mmol)、醋酸钯(224mg,1mmol)、三环己基膦(560mg,2mmol)和碳酸銫(6.37g,30mmol)加入到20mL甲苯和5mL水,氩气保护,100℃加热8h。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(45g柱,纯PE),得浅黄色油状物1.79g,产率83.6%。
(2)(Z)-3-(2-环丙基-4-(三氟甲基)亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体45)的合成
将中间体1(1.79g,6.24mmol)、中间体44(1.47g,6.86mmol)加入到无水THF(16mL)中,冰浴,缓慢滴加TEA(833mg,8.23mmol)的无水THF(4mL),Ar保护继续反应2h,反应完毕,旋干溶剂,加入冰水搅拌60min,析出浅黄色固体,过滤,水洗,干燥,得浅黄色固体2.28g,产率97.4%。
核磁显示反式/顺式=0.8/0.2
1H-NMR(500MHz,CDCl3)δ(ppm):8.82(d,J=1.5Hz,0.8H),8.78(d,J=1.5Hz,0.2H),8.63(dd,J1=8.5Hz,J2=2.0Hz,0.8H),8.37(d,J=8.5Hz,0.2H),8.28(d,J=8.0Hz,0.8H),8.01(d,J=8.5Hz,0.8H),7.56(d,J=9.0Hz,0.8H),7.53–7.51(m,0.4H),7.43(s,0.8H),7.35–7.33(m,0.4H),7.29(s,0.8H),7.26(s,0.2H),2.13–2.07(m,0.8H),1.87–1.84(m,0.2H),1.15–1.03(m,1.6H),1.07–1.03(m,0.4H),0.84–0.81(m,1.6H),0.78–0.76(m,0.4H).
(3)6-氨基-3-(2-环丙基-4-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮(中间体46)的合成
将中间体45(2.2g,5.87mmol)溶于三氟乙醇(20mL)的溶液中,加入钯碳(440mg),室温催化氢化反应12h,原料消失。过滤,Flash柱层析(30g柱,6-27-50%EA/PE),得白色固体1.47g,收率72.1%。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.50(dd,J1=8.4Hz,J2=2.0Hz,1H),7.47(d,J=8.0Hz,1H),7.26(s,1H),7.25(d,J=5.6Hz,1H),6.95(dd,J1=8.4Hz,J2=2.4Hz,1H),6.87(d,J=2.0Hz,1H),5.77(dd,J1=8.4Hz,J2=4.0Hz,1H),5.59(brs,2H),3.58(dd,J1=14.8Hz,J2=4.4Hz,1H,3.14(dd,J1=14.4Hz,J2=8.4Hz,1H),2.11(tt,J1=8.4Hz,J2=5.6Hz,1H),1.02–0.89(m,2H),0.74–0.66(m,2H).
(4)6-溴-3-(2-环丙基-4-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮(中间体47)的合成
取亚硝酸钠(328mg,4.75mmol)、三乙基苄基氯化铵(26mg,0.12mmol)和三甲基溴硅烷(728mg,4.75mmol)溶于乙腈8mL,冰浴下搅拌20min后将中间体46(550mg,1.58mmol)溶于2mL乙腈,滴入反应瓶中,继续冰浴搅拌12h。加入30mL水,EA萃取(20mL×3),无水硫酸镁干燥,浓缩,柱层析(30g柱,0-9%EA/PE),得白色固体462mg,产率71%。
1H-NMR(500MHz,CDCl3)δ(ppm):8.04(s,1H),7.74(dd,J1=8.0Hz,J2=2.0Hz,1H),7.41(d,J=8.0Hz,1H),7.30(d,J=9.0Hz,1H),7.29(s,1H),7.02(d,J=8.5Hz,1H),5.74(t,J=7.5Hz,1H),3.46(dd,J1=14.5Hz,J2=7.5Hz,1H),3.41(dd,J1=14.5Hz,J2=6.5Hz,1H),1.98–1.93(m,1H),1.07–0.99(m,2H),0.76–0.69(m,2H).
(5)4-(1-(2-环丙基-4-(三氟甲基)苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-羧酸叔丁酯(中间体48)的合成
将中间体47(350mg,0.85mmol)、N-Boc-哌嗪(317mg,1.7mmol)、Pd2(dba)3(78mg,0.085mmol)、BINAP(106mg,0.17mmol)和碳酸銫(554mg,1.7mmol)加入到5mL 1,4-二氧六环,氩气保护,90℃加热8h。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(20g柱,6-28%EA/PE),得浅黄色油状物146mg,产率33.3%。
1H-NMR(500MHz,CDCl3)δ(ppm):7.42–7.38(m,2H),7.35–7.29(m,3H),7.04(d,J=8.5Hz,1H),5.72(t,J=6.5Hz,1H),3.67–3.65(m,4H),3.46–3.37(m,2H),3.25–3.23(m,4H),2.01–1.95(m,1H),1.49(s,9H),1.04–1.00(m,2H),0.74–0.70(m,2H).
(6)3-(2-环丙基-4-(三氟甲基)苄基)-6-(哌嗪-1-基)异苯并呋喃-(3H)-酮盐酸盐(化合物13)的合成
将中间体48(100mg,0.19mmol)溶于HCl的EA溶液(1M)3mL中,室温搅拌5h,析出固体,过滤,无水乙醚洗,得白色固体76mg,收率87%,熔点:137-138℃。
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.23(brs,2H),7.53–7.46(m,4H),7.30(d,J=2.4Hz,1H),7.26(s,1H),5.89(dd,J1=8.8Hz,J2=4.4Hz,1H),3.65(dd,J1=14.8Hz,J2=4.4Hz,1H),3.50–3.47(m,4H),3.24–3.18(m,5H),2.16–2.09(m,1H),1.02–0.93(m,2H),0.75–0.66(m,2H);HRMS(ESI):m/z,Calcd for C23H23O2N2F3Na[M+Na]+:439.1622,Found439.1604.
实施例14:
3-(2-乙基苄基)-6-(哌嗪-1-基)异苯并呋喃-1-(3H)-酮盐酸盐(化合物14)的合成
(1)(Z/E)-3-(2-乙基亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体49)的合成
将中间体1(500mg,1.74mmol)、2-乙基苯甲醛(234mg,1.74mmol)加入到无水THF(4mL)中,冰浴,缓慢滴加TEA(211mg,2.10mmol)的无水THF(2mL),Ar保护继续反应2h,反应完毕,旋干溶剂,加入冰水搅拌60min,析出浅黄色固体,过滤,水洗,干燥,得浅黄色固体467mg,产率94.0%。
核磁显示反式/顺式=0.8/0.2
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.70(dd,J1=8.4Hz,J2=2.0Hz,0.8H),8.65(dd,J1=2.4Hz,J2=0.8Hz,0.8H),8.62(dd,J1=8.4Hz,J2=0.8Hz,0.8H),8.61(dd,J1=2.4Hz,J2=0.8Hz,0.2H),8.47(dd,J1=8.8Hz,J2=2.4Hz,0.2H),7.99–7.96(m,0.6H),7.49–7.45(m,0.2H),7.44–7.41(m,0.2H),7.39–7.33(m,4H),7.26(d,J=8.4Hz,0.2H),2.89(q,J=7.6Hz,1.6H),2.66(q,J=7.6Hz,0.4H),1.19(t,J=7.6Hz,2.4H),1.09(t,J=7.6Hz,0.6H).
(2)6-氨基-3-(2-乙基苄基)异苯并呋喃-1(3H)-酮(中间体50)的合成
将中间体49(400mg,1.36mmol)溶于三氟乙醇(10mL)的溶液中,加入钯碳(80mg),室温催化氢化反应2h,原料消失。过滤,滤液浓缩得白色固体267mg,收率73.8%。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.23(d,J=7.2Hz,1H),7.20–7.18(m,2H),7.15–7.10(m,2H),6.91(dd,J1=8.4Hz,J2=2.0Hz,1H),6.85(d,J=2.0Hz,1H),5.66(dd,J1=8.0Hz,J2=4.8Hz,1H),5.54(brs,2H),3.24(dd,J1=14.4Hz,J2=4.8Hz,1H),2.95(dd,J1=14.4Hz,J2=8.4Hz,1H),2.61(q,J=7.6Hz,2H),1.12(t,J=7.6Hz,3H).
(3)6-溴-3-(2-乙基苄基)异苯并呋喃-1(3H)-酮(中间体51)的合成
取亚硝酸钠(100mg,1.46mmol)、三乙基苄基氯化铵(22mg,0.098mmol)和三甲基溴硅烷(223mg,1.46mmol)溶于乙腈2mL,冰浴下搅拌20min后将中间体50(130mg,0.49mmol)溶于2mL乙腈,滴入反应瓶中,继续冰浴搅拌12h。加入20mL水,EA萃取(10mL×3),无水硫酸镁干燥,浓缩,柱层析(20g柱,0-9%EA/PE),得白色固体135mg,产率83.3%。
1H-NMR(500MHz,CDCl3)δ(ppm):8.01(d,J=2.0Hz,1H),7.66(dd,J1=8.0Hz,J2=2.0Hz,1H),7.28–7.23(m,2H),7.19–7.17(m,2H),6.84(d,J=8.0Hz,1H),5.63(t,J=7.5Hz,1H),3.37(dd,J1=14.5Hz,J2=5.6Hz,1H),3.06(dd,J1=14.5Hz,J2=7.5Hz,1H),2.64–2.59(m,2H),1.19(t,J=7.5Hz,3H).
(4)4-(1-(2-乙基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-羧酸叔丁酯(中间体52)的合成
将中间体51(200mg,0.60mmol)、N-Boc-哌嗪(224mg,1.2mmol)、Pd2(dba)3(55mg,0.06mmol)、BINAP(75mg,0.12mmol)和碳酸銫(391mg,1.2mmol)加入到5mL 1,4-二氧六环,氩气保护,90℃加热8h。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(20g柱,3-19%EA/PE),得浅黄色油状物166mg,产率62.9%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.33(d,J=6.4Hz,1H),7.26–7.24(m,2H),7.22–7.15(m,3H),6.87(dd,J1=8.4Hz,J2=0.8Hz,1H),5.60(t,J=7.2Hz,1H),3.61(t,J=5.2Hz,4H),3.31(dd,J1=14.4Hz,J2=3.2Hz,1H),3.20(t,J=5.2Hz,4H),3.05(dd,J1=14.0Hz,J2=3.2Hz,1H),3.63(qd,J1=7.6Hz,J2=1.6Hz,2H),1.49(s,9H),1.19(t,J=7.6Hz,3H).
(5)3-(2-乙基苄基)-6-(哌嗪-1-基)异苯并呋喃-1-(3H)-酮盐酸盐(化合物14)的合成
将中间体52(160mg,0.37mmol)溶于HCl的EA溶液(1M)5mL中,室温搅拌5h,析出固体,过滤,无水乙醚洗,得白色固体127mg,收率92.7%,熔点:157-158℃。
1H-NMR(500MHz,MeOH-d4)δ(ppm):7.41(dd,J1=8.5Hz,J2=2.5Hz,1H),7.35(d,J=2.5Hz,1H),7.22(d,J=8.5Hz,1H),7.20–7.16(m,3H),7.09(td,J1=6.5Hz,J2=2.5Hz,1H),5.75(t,J=6.5Hz,1H),3.51–3.49(m,4H),3.41–3.39(m,4H),3.26(dd,J1=14.5Hz,J2=6.0Hz,1H),3.21(dd,J1=14.5Hz,J2=7.0Hz,1H),2.66(q,J=7.5Hz,2H),1.17(t,J=7.5Hz,3H);13C-NMR(100MHz,DMSO-d6)δ(ppm):169.93,151.16,142.53,140.98,133.96,130.24,128.43,127.06,126.59,125.71,123.64,122.78,110.07,80.93,45.36,42.35,36.82,25.12,15.26;HRMS(ESI):m/z,Calcd for C21H25O2N2[M+H]+:337.1911,Found337.1918.
实施例15:
3-(2-氯苄基)-6-(哌嗪-1-基)异苯并呋喃-1-(3H)-酮盐酸盐(化合物15)的合成
(1)(Z)-叔丁基-(2-((5-硝基-3-氧代异苯并呋喃-1(3H)-亚叉基)甲基)苯基)氨基甲酸酯(中间体53)的合成
将中间体1(1.0g,3.6mmol)、2-Boc氨基苯甲醛(785mg,3.6mmol)加入到无水THF(10mL)中,冰浴,缓慢滴加TEA(431mg,4.3mmol)的无水THF(2mL),Ar保护继续反应4h,反应完毕,旋干溶剂,加入冰水搅拌60min,析出桔黄色固体,过滤,水洗,干燥,得桔黄色固体1.3g,产率93%。
(核磁显示Z/E=0.8/0.2)
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.14(s,0.2H),8.84(s,0.8H),8.71(dd,J1=8.5Hz,J2=2.0Hz,0.2H),8.66(s,0.2H),8.62(s,0.8H),8.48(d,J=8.5Hz,0.8H),8.36(d,J=9.0Hz,0.2H),8.01(d,J=8.0Hz,0.2H),7.67(d,J=8.0Hz,0.8H),7.58(d,J=8.0Hz,0.2H),7.50–7.46(m,1.6H),7.41(d,J=8.5Hz,0.8H),7.37(t,J=8.0Hz,0.2H),7.28–7.26(m,0.2H),7.25(t,J=7.5Hz,0.8H),7.21(s,0.2H),7.18(s,0.8H),1.48(s,1.8H),1.39(s,7.2H).
(2)(2-((5-氨基-3-氧代-1,3-二氢异苯并呋喃-1-基)甲基)苯基)氨基甲酸叔丁酯(中间体54)的合成
将中间体53(1.6g,4.1mmol)溶于MeOH(20mL)的溶液中,加入钯碳(310mg),70℃催化氢化反应3h。过滤,滤液浓缩,Flash柱层析(45g柱,12-50%EA/PE),过滤,正己烷洗,得白色固体1.12g,收率78%。
1H-NMR(500MHz,CDCl3)δ(ppm):7.61(d,J=8.0Hz,1H),7.22(t,J=7.5Hz,1H),7.08–6.97(m,5H),6.71(s,1H),5.63(t,J=6.0Hz,1H),3.23(dd,J1=14.5Hz,J2=5.5Hz,1H),3.13(dd,J1=14.5Hz,J2=6.0Hz,1H),1.51(s,9H).
(3)(2-((5-溴-3-氧代-1,3-二氢异苯并呋喃-1-基)甲基)苯基)氨基甲酸叔丁酯(中间体55)的合成
取亚硝酸钠(292mg,4.2mmol)、三乙基苄基氯化铵(64mg,0.28mmol)和三甲基溴硅烷(648mg,4.2mmol)溶于乙腈8mL,冰浴下搅拌15min后将中间体54(1.5g,4.2mmol)溶于2mL乙腈,滴入反应瓶中,继续冰浴搅拌12h。加入40mL水,EA萃取(30mL×3),无水硫酸镁干燥,浓缩,Flash柱层析(30g柱,3-15%EA/PE),得白色固体480mg,产率54%。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.66(s,1H),7.99(d,J=1.6Hz,1H),7.93(dd,J1=8.0Hz,J2=1.6Hz,1H),7.40–7.36(m,2H),7.29(dd,J1=7.6Hz,J2=1.6Hz,1H),7.23(td,J1=8.0Hz,J2=1.6Hz,1H),7.10(td,J1=7.6Hz,J2=1.6Hz,1H),5.83(dd,J1=8.4Hz,J2=4.8Hz,1H),3.33(dd,J1=14.8Hz,J2=5.2Hz,1H),3.12(dd,J1=14.8Hz,J2=8.4Hz,1H),1.44(s,9H).
(4)3-(2-氨基苄基)-6-溴异苯并呋喃-1(3H)-酮(中间体56)的合成
将中间体55(940mg,2.25mmol)溶于HCl的1M EA溶液6mL中,室温搅拌10h,加入饱和碳酸氢钠溶液至不再产生气泡,DCM萃取(30mL×3),无水硫酸镁干燥,浓缩,Flash柱层析(45g柱,6-32%EA/PE),得浅棕色固体659mg,产率92%。
1H-NMR(500MHz,CDCl3)δ(ppm):7.97(d,J=1.5Hz,1H),7.71(dd,J1=8.0Hz,J2=1.5Hz,1H),7.11–7.06(m,2H),6.89(dd,J1=7.5Hz,J2=1.5Hz,1H),6.73(dd,J1=7.5Hz,J2=1.0Hz,1H),6.70(td,J1=7.5Hz,J2=1.0Hz,1H),5.76(t,J=6.5Hz,1H),3.85(brs,2H),3.23(dd,J1=14.5Hz,J2=5.5Hz,1H),3.09(dd,J1=14.5Hz,J2=6.5Hz,1H).
(5)6-溴-3-(2-氯苄基)异苯并呋喃-1(3H)-酮(中间体57)的合成
取氯化铜(229mg,1.7mmol)和亚硝酸叔丁酯(204mg,2.5mmol)溶于乙腈8mL,冰浴下搅拌15min后,将中间体56(450mg,1.4mmol)溶于4mL乙腈,滴入反应瓶中,继续冰浴搅拌12h。倾倒入1N盐酸20mL,搅拌30min,EA萃取(20mL×3),无水硫酸镁干燥,浓缩,Flash柱层析(30g柱,0-26%EA/PE),得白色固体263mg,产率55%。
1H-NMR(500MHz,CDCl3)δ(ppm):8.01(d,J=2.0Hz,1H),7.73(dd,J1=8.0Hz,J2=2.0Hz,1H),7.41(dd,J1=7.0Hz,J2=2.0Hz,1H),7.31–7.24(m,3H),7.11(d,J=8.0Hz,1H),5.63(dd,J1=7.0Hz,J2=6.5Hz,1H),3.35(dd,J1=14.0Hz,J2=5.5Hz,1H),3.28(dd,J1=14.5Hz,J2=6.4Hz,1H).
(6)4-(1-(2-氯苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-羧酸叔丁酯(中间体58)的合成
将中间体57(250mg,0.74mmol)、N-Boc-哌嗪(166mg,0.89mmol)、Pd2(dba)3(68mg,0.074mmol)、BINAP(92mg,0.15mmol)和碳酸銫(482mg,1.5mmol)加入到6mL 1,4-二氧六环,氩气保护,90℃加热6h。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(30g柱,6-13%EA/PE),得浅黄色油状物127mg,产率39%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.40–7.38(m,1H),7.33(d,J=2.4Hz,1H),7.31–7.27(m,2H),7.24–7.21(m,2H),7.11(d,J=8.4Hz,1H),5.69(dd,J1=8.0Hz,J2=6.4Hz,1H),3.61(t,J=4.8Hz,4H),3.32(dd,J1=14.4Hz,J2=5.6Hz,1H),3.24–3.18(m,5H),1.48(s,9H).
(7)3-(2-氯苄基)-6-(哌嗪-1-基)异苯并呋喃-1-(3H)-酮盐酸盐(化合物15)的合成
将中间体58(120mg,0.27mmol)溶于HCl的EA溶液(1M)3mL中,室温搅拌3h,析出固体,过滤,无水乙醚洗,得浅桔色固体96mg,收率93%,熔点:194-195℃。
1H-NMR(400MHz,MeOH-d4)δ(ppm):7.44(dd,J1=8.4Hz,J2=2.4Hz,1H),7.41–7.38(m,1H),7.37–7.33(m,3H),7.27–7.24(m,2H),5.80(dd,J1=7.2Hz,J2=5.2Hz,1H),3.52–3.49(m,4H),3.44(dd,J1=14.0Hz,J2=5.2Hz,1H),3.41–3.38(m,4H),3.27(dd,J1=14.4Hz,J2=7.6Hz,1H);HRMS(ESI):m/z,Calcd for C19H20O2N2Cl[M+H]+:343.1208,Found343.1220.
实施例16:
3-(2-甲基苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物16)的合成
将中间体4(300mg,0.95mmol)、N-甲基哌嗪(190mg,1.9mmol)、醋酸钯(22mg,0.095mmol)、Xantphos(110mg,0.19mmol)和碳酸铯(619mg,1.90mmol)加入1,4-二氧六环15mL,氩气保护,100℃加热11h。硅藻土助滤,滤掉不溶物,EA洗。柱层析(D/M=40/1),得浅黄色油状物310mg,加入2mL HCl的4M 1,4-二氧六环溶液,室温搅拌4h,析出白色固体,过滤,无水乙醚洗,干燥,得白色固体300mg,产率85%,熔点:131-132℃。
1H-NMR(400MHz,DMSO-d6)δ(ppm):10.73(brs,1H)),7.48–7.41(m,2H),7.29(d,J=2.4Hz,1H),7.22–7.10(m,4H),5.79(dd,J1=8.0Hz,J2=4.8Hz,1H),4.31(brs,1H)),3.95(d,J=14.8Hz,2H),3.48(d,J=8.4Hz,2H),3.31(dd,J1=14.8Hz,J2=4.8Hz,1H),3.19–3.12(m,4H),2.99(dd,J1=14.8Hz,J2=8.4Hz,1H),2.81(d,J=4.8Hz,3H),2.28(s,3H);HRMS(ESI):m/z,Calcd for C21H25O2N2[M+H]+:337.1910,Found 337.1911.
实施例17:
3-(2-甲基苄基)-6-((R)-2-甲基哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物17)的合成
将中间体4(700mg,2.12mmol)、R-N-Boc-3-甲基哌嗪(637mg,3.18mmol)、醋酸钯(48mg,0.212mmol)、Xphos(202mg,0.424mmol)和碳酸铯(1.38g,4.24mmol)加入到100mL三颈瓶中,加入1,4-二氧六环30mL,氩气保护,90℃加热10h,原料消失。硅藻土助滤,滤掉不溶物,EA洗。柱层析P/A=10/1,得浅黄色油状物274mg。冰浴下,将该浅黄色油状物溶于DCM3mL,滴加TFA(1.47g,0.93mmol)的DCM溶液3mL,冰浴搅拌2h,原料消失。加入饱和Na2CO3溶液至不再产生气泡,D/M=10/1(20mL×3)萃取,柱层析D/M=20/1,得无色油状物186mg。加入4.0mLHCl的1,4-二氧六环溶液(4M),室温搅拌2h,析出固体,过滤,无水乙醚洗,干燥,得白色固体299mg,产率38%,熔点:187-188℃。1H-NMR(400MHz,DMSO-d6)δ(ppm):9.57(brs,1H),9.07(brs,1H),7.45–7.39(m,2H),7.24–7.23(m,1H),7.21–7.09(m,4H),5.79(dd,J1=8.0Hz,J2=4.8Hz,1H),5.42(brs,2H),4.31–4.24(m,1H),3.57(dd,J1=13.2Hz,J2=3.6Hz,1H),3.31(dd,J1=14.4Hz,J2=4.8Hz,1H),3.27–3.16(m,4H),3.09–3.03(m,1H),3.00(ddd,J1=14.4Hz,J2=8.0Hz,J3=1.2Hz,1H),2.28(s,3H),1.08(dd,J1=6.8Hz,J2=2.7Hz,3H);HRMS(ESI):m/z,Calcd for C21H25O2N2[M+H]+:337.1910,Found 337.1909.
实施例18:
3-(2-甲基苄基)-6-(哌啶-4-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物18)的合成
(1)4-(1-(2-甲基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(中间体59)的合成
将中间体4(300mg,0.95mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(280mg,1.4mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(160mg,0.19mmol)和碳酸钾(250mg,1.9mmol)加入到DME 15mL和水0.5mL中,氩气保护,100℃加热10h。硅藻土助滤,滤掉不溶物,EA洗。柱层析5%EA in PE,得浅黄色油状物276mg,产率70%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.86(s,1H),7.60(dd,J1=8.0Hz,J2=2.0Hz,1H),7.19(m,4H),7.00(d,J=8.0Hz,1H),6.13(s,1H),5.66(t,J=7.2Hz,1H),4.10(d,J=2.8Hz,2H),3.65(t,J=5.6Hz,2H),3.31(dd,J1=14.0Hz,J2=7.2Hz,1H),3.10(dd,J1=14.0Hz,J2=6.8Hz,1H),2.57–2.50(m,2H),2.32(s,3H),1.49(s,9H);HRMS(ESI):m/z,Calcd for C21H22O2N[M+H]+:320.1645,Found 320.1660.
(2)叔丁基4-(1-(2-甲基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌啶-1-羧酸盐(中间体60)的合成
将中间体59(276mg,0.65mmol)溶于MeOH(6mL)中,加入钯碳(55mg),室温催化氢化反应2h。过滤,滤液浓缩,柱层析3%-25%EA/PE,得无色油状物226mg,产率82%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.72(d,J=1.6Hz,1H),7.43(dd,J1=8.0Hz,J2=1.6Hz,1H),7.20(m,4H),7.01(d,J=8.0Hz,1H),5.63(t,J=7.2Hz,1H),4.28(d,J=13.2Hz,2H),3.28(dd,J1=14.4Hz,J2=7.2Hz,1H),3.10(dd,J1=14.4Hz,J2=6.8Hz,1H),2.82(td,J1=13.2Hz,J2=2.4Hz,2H),2.76(tt,J1=12.4Hz,J2=3.6Hz,1H),2.32(s,3H),1.83(d,J=13.2Hz,2H),1.65(td,J1=12.4Hz,J2=4.4Hz,3H),1.49(s,9H).
(3)3-(2-甲基苄基)-6-(哌啶-4-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物18)的合成
将中间体60(150mg,0.36mmol)溶于2mL HCl的1,4-二氧六环溶液(4M),室温搅拌2h,析出固体,过滤,无水乙醚洗,干燥,得白色固体125mg,产率98%,熔点:220-221℃。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.93–8.80(m,1H),7.66(dd,J1=8.0Hz,J2=1.6Hz,1H),7.63(s,1H),7.57(d,J=8.0Hz,1H),7.25(m,1H),7.20(m,3H),5.87(dd,J1=8.4Hz,J2=4.4Hz,1H),3.39–3.35(m,2H),3.36(dd,J1=14.4Hz,J2=5.2Hz,1H),3.05–2.95(m,3H),3.00(dd,J1=14.8Hz,J2=8.8Hz,1H),2.29(s,3H),1.98–1.83(m,4H);HRMS(ESI):m/z,Calcd for C21H24O2N[M+H]+:322.1801,Found322.1810.
实施例19:
3-(2,4-二甲基苄基)-6-(哌啶-4-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物19)的合成
(1)4-(1-(2,4-二甲基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(中间体61)的合成
将中间体8(500mg,1.52mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(702mg,2.27mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(248mg,0.30mmol)和碳酸钾(414mg,3.0mmol)加入到100mL三颈瓶中,加入DME 10mL,水0.2mL,氩气保护,100℃加热17h,原料消失。硅藻土助滤,滤掉不溶物,EA洗。柱层析(45g柱,4-13%EA/PE),得深黄色油状物598mg,产率86%。
(2)4-(1-(2,4-二甲基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌啶-1-甲酸叔丁酯(中间体62)的合成
将中间体61(498mg,1.15mmol)溶于MeOH(10mL)中,加入钯碳(50mg),室温催化氢化反应12h,原料消失。过滤,滤液浓缩,柱层析(30g柱,4-18%EA/PE),得无色油状物370mg,产率91%。
1H-NMR(400MHz,MeOD)δ(ppm):7.67(d,J=1.6Hz,1H),7.60(dd,J1=8.0Hz,J2=1.6Hz,1H),7.27(dt,J1=8.0Hz,J2=0.8Hz,1H),7.01(d,J=7.6Hz,1H),6.98(s,1H),6.91–6.89(m,1H),5.75(t,J=6.8Hz,1H),4.24–4.21(m,2H),3.21(dd,J1=14.4Hz,J2=6.0Hz,1H),3.15(dd,J1=14.4Hz,J2=6.8Hz,1H),2.90–2.83(m,3H),2.26(s,6H),1.86–1.83(m,2H),1.63(td,J1=12.4Hz,J2=4.0Hz,2H),1.48(s,9H).
(3)3-(2,4-二甲基苄基)-6-(哌啶-4-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物19)的合成
将中间体62(343mg,0.79mmol)溶于HCl的1M EA溶液4mL中,室温搅拌2h,析出固体,过滤,无水乙醚洗,得白色固体147mg,收率60%,熔点:258-259℃。1H-NMR(400MHz,MeOD)δ(ppm):7.72(d,J=1.6Hz,1H),7.63(dd,J1=8.4Hz,J2=2.0Hz,1H),7.33(d,J=8.0Hz,1H),7.01–6.98(m,2H),6.88(dd,J1=7.6Hz,J2=2.0Hz,1H),5.79(t,J=6.4Hz,1H),3.54–3.49(m,2H),3.27–3.13(m,4H),3.07(tt,J1=12.0Hz,J2=3.6Hz,1H),3.27(s,3H),2.26(s,3H),2.13–2.09(m,2H),1.96(dd,J1=13.2Hz,J2=4.0Hz,1H),1.92–1.88(m,1H);13C-NMR(150MHz,DMSO-d6)δ(ppm):169.67,148.31,146.45,136.43,135.78,133.06,131.55,130.88,130.06,126.37,125.84,123.28,122.41,80.98,43.40,38.64,36.94,29.26,20.66,19.39;HRMS(ESI):m/z,Calcd for C22H26O2N[M+H]+:336.1958,Found336.1956.
实施例20:
3-(2-甲基-4-(三氟甲氧基)苄基)-6-(哌啶-4-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物20)的合成
(1)4-(1-(2-甲基-4-(三氟甲氧基)苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(中间体63)的合成
将中间体13(300mg,0.75mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(348mg,1.5mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(122mg,0.15mmol)和碳酸钾(207mg,1.5mmol)加入到50mL圆底烧瓶中,加入DME 8mL和水0.1mL,氩气保护,100℃加热11h,原料消失。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(30g柱,6-21%EA/PE),得无色油状物242mg,产率64%。
(2)4-(1-(2-甲基-4-(三氟甲氧基)苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(中间体64)的合成
将中间体63(140mg,0.28mmol)溶于MeOH(10mL)中,加入钯碳(30mg),室温催化氢化反应12h,原料消失。过滤,滤液浓缩,Flash柱层析(30g柱,6-18%EA/PE),得无色油状物127mg,产率90%。
(3)3-(2-甲基-4-(三氟甲氧基)苄基)-6-(哌啶-4-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物20)的合成
将中间体64(78mg,0.15mmol)溶于HCl的1M EA溶液5.0mL中,室温搅拌2h,析出固体,过滤,无水乙醚洗,得白色固体62mg,收率91%,熔点:221-222℃。1H-NMR(400MHz,MeOD)δ(ppm):7.73(s,1H),7.68(dd,J1=8.0Hz,J2=1.6Hz,1H),7.50(d,J=8.0Hz,1H),7.23(d,J=8.4Hz,1H),7.08(s,1H),6.97(d,J=8.8Hz,1H),5.83(dd,J1=7.2Hz,J2=4.8Hz,1H),3.54–3.50(m,2H),3.41(dd,J1=14.4Hz,J2=4.8Hz,1H),3.20–3.13(m,3H),3.08(tt,J1=12.4Hz,J2=3.6Hz,1H),2.37(s,3H),2.12(d,J=14.0Hz,2H),1.96(dd,J1=13.2Hz,J2=4.0Hz,1H),1.89(dd,J1=13.2Hz,J2=4.0Hz,1H);HRMS(ESI):m/z,Calcd for C22H23O3NF3[M+H]+:406.1624,Found 406.1620.
实施例21:
6-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)-3-(2-甲基苄基)异苯并呋喃-1(3H)-酮(化合物21)的合成
将中间体4(300mg,0.95mmol)、1,4-氮杂双环[4.3.0]壬烷(180mg,1.40mmol)、醋酸钯(20mg,0.095mmol)、Xphos(90mg,0.14mmol)和碳酸铯(593mg,1.80mmol)加入到1,4-二氧六环15mL中,氩气保护,100℃加热11h。硅藻土助滤,滤掉不溶物,EA洗。柱层析(D/M=50/1),无水乙醚洗,干燥,得类白色固体218mg,产率63%。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.41(dd,J1=8.4Hz,J2=2.0Hz,1H),7.33(d,J=8.4Hz,1H),7.22–7.09(m,5H),5.75(dd,J1=8.0Hz,J2=4.8Hz,1H),3.88(d,J=11.2Hz,1H),3.72(d,J=11.2Hz,1H),3.28(dd,J1=14.4Hz,J2=4.8Hz,1H),3.08–2.95(m,3H),2.82(td,J1=11.6Hz,J2=3.2Hz,1H),2.45(t,J=10.8Hz,1H),2.29(s,3H),2.28–2.19(m,1H),2.10–2.03(m,2H),1.87–1.78(m,1H),1.75–1.66(m,2H),1.42–1.32(m,1H);HRMS(ESI):m/z,Calcd for C23H27O2N2[M+H]+:363.2067,Found 363.2074.
实施例22:
6-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)-3-(2-甲基-4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮(化合物22)的合成
将中间体13(150mg,0.47mmol)、1,4-氮杂双环[4.3.0]壬烷(120mg,0.95mmol)、醋酸钯(11mg,0.047mmol)、Xphos(45mg,0.094mmo)和碳酸铯(306mg,0.94mmol)加入1,4-二氧六环5mL中,氩气保护,90℃加热6h。过滤,滤液浓缩,Flash柱层析(30g柱,3-12%MeOH/DCM),得浅褐色固体87mg,产率41.2%,熔点104-105℃。
1H-NMR(500MHz,MeOH-d4)δ(ppm):7.44(d,J=9.0Hz,1H),7.36(d,J=9.0Hz,1H),7.31(s,1H),7.28(d,J=8.5Hz,1H),7.12(s,1H),7.03(d,J=8.5Hz,1H),5.77(t,J=6.0Hz,1H),3.93(d,J=11.5Hz,1H),3.78(d,J=12.0Hz,1H),3.38(dd,J1=14.5Hz,J2=5.0Hz,1H),3.27(d,J=11.0Hz,1H),3.24–3.20(m,1H),3.15(dd,J1=15.0Hz,J2=7.0Hz,1H),3.01(t,J=12.0Hz,1H),2.69(t,J=11.0Hz,1H),2.57(t,J=11.0Hz,1H),2.46–2.43(m,2H),2.39(s,3H),2.08–2.02(m,1H),1.98–1.90(m,2H),1,.64–1.56(m,1H),HRMS(ESI):m/z,Calcd.for C24H26O3N2F3[M+H]+:447.1890,Found 447.1891.
实施例23:
3-(2-环丙基-4-(三氟甲基)苄基)-6-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)异苯并呋喃-1(3H)-酮(化合物23)的合成
将中间体47(170mg,0.41mmol)、1,4-氮杂双环[4.3.0]壬烷(104mg,0.83mmol)、醋酸钯(9mg,0.041mmol)、Xphos(40mg,0.083mmol)和碳酸铯(270mg,0.83mmol)加入到1,4-二氧六环6mL中,氩气保护,100℃加热11h。硅藻土助滤,滤掉不溶物,EA洗。滤液浓缩,Flash柱层析(20g柱,1-20%MeOH/DCM),得类白色固体96mg,产率51%,熔点:113-114℃。
1H-NMR(500MHz,MeOH-d4)δ(ppm):7.39–7.38(m,3H),7.30–7.27(m,3H),5.83(dd,J1=8.0Hz,J2=5.5Hz,1H),3.87(d,J=12.0Hz,1H),3.73(d,J=12.0Hz,1H),3.60(dd,J1=14.5Hz,J2=5.0Hz,1H),3.35(dd,J1=14.5Hz,J2=8.0Hz,1H),3.20(dd,J1=11.0Hz,J2=3.0Hz,1H),3.16(td,J1=9.0Hz,J2=3.0Hz,1H),2.96(td,J1=12.0Hz,J2=3.5Hz,1H),2.64(t,J=11.0Hz,1H),2.49(t,J=11.0Hz,1H),2.39–2.29(m,2H),2.12–2.07(m,1H),2.02–1.96(m,1H),1.93–1.84(m,2H),1.59–1.51(m,1H),1.06–0.99(m,2H),0.69–0.66(m,2H);HRMS(ESI):m/z,Calcd for C26H28O2N2F3[M+H]+:457.2097,Found 457.2105.
实施例24:
6-((R)-3-氨基吡咯烷-1-基)-3-(2-甲基苄基)异苯并呋喃-1(3H)-酮盐酸盐(化合物24)的合成
(1)((3R)-1-(1-(2-甲基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)吡咯烷-3-基氨基甲酸叔丁酯(中间体65)的合成
将中间体4(700mg,2.22mmol)、(R)-3-叔丁氧羰基氨基吡咯烷(618mg,3.32mmol)、醋酸钯(64mg,0.29mmol)、Xantphos(255mg,0.44mmol)和碳酸铯(1.45g,4.44mmol)加入到1,4-二氧六环30mL中,氩气保护,100℃加热10h。硅藻土助滤,滤掉不溶物,EA洗。柱层析(P/A=10/1),正己烷洗,得白色固体700mg,产率80%。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.27(d,J=8.4Hz,1H),7.21–7.09(m,5H),6.91(dd,J1=8.4Hz,J2=2.4Hz,1H),6.70(d,J=2.0Hz,1H),5.73(dd,J1=8.0Hz,J2=4.8Hz,1H),4.17–4.13(m,1H),3.50(dd,J1=9.6Hz,J2=6.4Hz,1H),3.42–3.36(m,1H),3.33–3.23(m,2H),3.08(dd,J1=9.6Hz,J2=4.8Hz,1H),2.97(dd,J1=14.4Hz,J2=8.0Hz,1H),2.28(s,3H),2.20–2.12(m,1H),1.94–1.86(m,1H),1.39(s,9H).
(2)6-((R)-3-氨基吡咯烷-1-基)-3-(2-甲基苄基)异苯并呋喃-1(3H)-酮盐酸盐(化合物24)的合成
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冰浴下,将中间体65(300mg,0.72mmol)溶于HCl的1,4-二氧六环溶液(4M)2mL中,冰浴搅拌2h。加入饱和Na2CO3溶液至不再产生气泡,D/M=10/1(50mL×3)萃取,柱层析D/M=30/1–20/1,得浅黄色油状物205mg,产率90%,取出74mg加入2mL氯化氢的1,4-二氧六环溶液(4M),室温搅拌2h,析出固体,过滤,无水乙醚洗,干燥,得深棕色固体50mg,产率68%,熔点:216-217℃。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.32(brs,2H),7.32(d,J=8.4Hz,1H),7.20–7.09(m,4H),6.98(dd,J1=8.4Hz,J2=2.0Hz,1H),6.77(d,J=2.0Hz,1H),5.76(dd,J1=7.6Hz,J2=4.8Hz,1H),3.99–3.93(m,1H),3.61–3.49(m,2H),3.39–3.36(m,2H),3.28(dd,J1=14.4Hz,J2=4.8Hz,1H),3.00(dd,J1=14.4Hz,J2=7.6Hz,1H),2.38–2.31(m,1H),2.28(s,3H),2.18–2.08(m,1H);HRMS(ESI):m/z,Calcd for C20H23O2N2[M+H]+:323.1754,Found323.1752.
实施例25:
6-((R)-3-氨基吡咯烷-1-基)-3-(2-甲基-4-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮盐酸盐(化合物25)的合成
(1)((3R)-1-(1-(2-甲基-2-(三氟甲基)苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)吡咯烷-3-基氨基甲酸叔丁酯(中间体66)的合成
将中间体18(117mg,0.30mmol)、(R)-3-叔丁氧羰基氨基吡咯烷(113mg,0.61mmol)、醋酸钯(6.7mg,0.03mmol)、Xantphos(35mg,0.06mmol)和碳酸铯(195mg,0.6mmol)加入到50mL三颈瓶中,加入1,4-二氧六环3mL,氩气保护,100℃加热14h,原料消失。过滤,滤液浓缩,Flash柱层析(30g柱,6-28%EA/PE),得类白色固体119mg,产率80%。
1H-NMR(400MHz,MeOD)δ(ppm):7.45(s,1H),7.37(dd,J1=8.0Hz,J2=2.0Hz,1H),7.33(d,J=8.0Hz,1H),7.27(d,J=8.4Hz,1H),6.95(dd,J1=8.8Hz,J2=2.4Hz,2H),6.83(d,J=2.0Hz,1H),5.74(dd,J1=7.2Hz,J2=5.2Hz,1H),4.28–4.22(m,1H),3.59(dd,J1=9.6Hz,J2=6.4Hz,1H),3.49–3.34(m,3H),3.19–3.13(m,2H),2.40(s,3H),2.33–2.24(m,1H),2.03–1.94(m,1H),1.45(s,9H).
(2)6-((R)-3-氨基吡咯烷-1-基)-3-(2-甲基-4-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮盐酸盐(化合物25)的合成
将中间体66(94mg,0.19mmol)溶于HCl的1M EA溶液1.5mL中,室温搅拌2h,析出固体,过滤,无水乙醚洗,得白色固体100mg,收率100%。
1H-NMR(400MHz,MeOD)δ(ppm):7.41(s,1H),7.33(d,J=8.4Hz,1H),7.31(dd,J1=8.0Hz,J2=1.6Hz,1H),7.28(d,J=8.0Hz,1H),7.03(dd,J1=8.4Hz,J2=2.4Hz,1H),6.89(d,J=2.4Hz,1H),5.76(dd,J1=6.8Hz,J2=5.2Hz,1H),4.04(m,1H),3.66–3.57(m,2H),3.47–3.42(m,2H),3.41–3.39(m,1H),3.16(dd,J1=14.4Hz,J2=6.8Hz,1H),2.53–2.44(m,1H),2.37(s,3H),2.21–2.15(m,1H).
实施例26:
(R)-3-(2-甲基苄基)-6-(吡咯烷-3-基氨基)-3-异苯并呋喃-1(3H)-酮(化合物26)的合成
(1)(R)-叔丁基3-(((1-(2-甲基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)氨基)吡咯烷-1-羧酸酯(中间体67)的合成
将中间体4(700mg,2.22mmol)、(R)-1-Boc-3-氨基吡咯烷(618mg,3.32mmol)、醋酸钯(49mg,0.22mmol)、Davephos(173mg,0.44mmol)和碳酸铯(1.45g,4.44mmol)加入到1,4-二氧六环35mL中,氩气保护,100℃加热11h。硅藻土助滤,滤掉不溶物,EA洗。柱层析(P/E=1/1),正己烷洗,得棕色油状物197mg,产率21%。
1H-NMR(500MHz,CDCl3)δ(ppm):7.20–7.17(m,4H),7.04–7.00(m,1H),6.84–6.82(m,2H),5.57(t,J=7.0Hz,1H),4.07–4.03(m,1H),3.71(dd,J1=11.5Hz,J2=7.5Hz,1H),3.52–3.42(m,2H),3.37–3.28(m,1H),3.26(dd,J1=14.0Hz,J2=7.5Hz,1H),3.04(dd,J1=14.0Hz,J2=6.5Hz,1H),2.31(s,3H),2.25–2.18(m,1H),1.94–1.87(m,1H),1.47(s,9H).
(2)(R)-3-(2-甲基苄基)-6-(吡咯烷-3-基氨基)-3-异苯并呋喃-1(3H)-酮(化合物26)的合成
冰浴下,将中间体67(150mg,0.36mmol)溶于HCl的1,4-二氧六环溶液(4M)2mL中,冰浴搅拌2h。加入饱和Na2CO3溶液至不再产生气泡,D/M=10/1(50mL×3)萃取,柱层析D/M=30/1–5/1,得浅黄色油状物,抽干,无水乙醚洗,干燥,得浅棕色固体21mg,产率18%,熔点:178-179℃。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.25(d,J=8.4Hz,1H),7.21–7.09(m,4H),7.01(d,J=7.6Hz,1H),6.83(d,J=2.0Hz,1H),6.56–6.48(m,1H),5.71(dd,J1=8.0Hz,J2=4.4Hz,1H),4.17–4.09(m,1H),3.42–3.32(m,3H),3.26(dd,J1=14.4Hz,J2=4.8Hz,1H),3.04–2.99(m,1H),2.95(dd,J1=14.4Hz,J2=8.4Hz,1H),2.33–2.15(m,1H),2.28(s,3H),1.88–1.78(m,1H);HRMS(ESI):m/z,Calcd for C20H23O2N2[M+H]+:323.1754,Found323.1753.
实施例27:
2-((3-氧代-5-(哌嗪-1-基)-1,3-二氢异苯并呋喃-1-基)甲基)苯甲腈盐酸盐(化合物27)的合成
(1)(Z/E)-2-((5-硝基-3-氧代异苯并呋喃-1(3H)-亚叉基)甲基)苄腈(中间体68)的合成
将中间体1(400mg,1.39mmol)和2-氰基苯甲醛(184mg,1.39mmol)溶于无水THF(10mL)中,缓慢滴加TEA(169mg,1.67mmol)的THF溶液(3mL),Ar保护下室温反应2h。将反应液倾倒入冰水中,搅拌20min,析出黄色固体,过滤,水洗,干燥,得黄色固体293mg,产率71%。
核磁显示反式:顺式比例约为0.8/0.2.
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.71–8.69(m,2H),8.54(dd,J1=7.6Hz,J2=1.6Hz,0.8H),8.49(dd,J2=8.8Hz,J1=2.4Hz,0.2H),8.23(d,J=8.0Hz,0.8H),8.07(dd,J1=8.0Hz,J2=1.6Hz,0.2H),7.98(dd,J1=8.0Hz,J2=1.6Hz,0.8H),7.88(td,J1=7.6Hz,J2=1.6Hz,0.8H),7.83(d,J=7.6Hz,0.2H),7.73(t,J=7.2Hz,0.2H),7.60(td,J1=7.6Hz,J2=1.2Hz,0.8H),7.39(d,J=8.4Hz,0.2H),7.38(s,0.2H),7.23(s,0.8H).
(2)2-((5-氨基-3-氧代-1,3-二氢异苯并呋喃-1-基)甲基)苄腈(中间体69)的合成
将中间体68(240mg,0.21mmol)加入到甲醇(5mL)中,加入钯碳(48mg),室温催化氢化反应3h,原料消失。过滤,滤液浓缩,柱层析(12%-49%EA/PE)得白色固体100mg,产率46%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.61(d,J=7.6Hz,1H),7.56–7.52(m,1H),7.49(d,J=7.6Hz,1H),7.34(td,J1=7.6Hz,J2=1.2Hz,1H),7.29(s,1H),7.03(d,J=2.0Hz,1H),6.97(dd,J1=8.0Hz,J2=2.0Hz,1H),5.66(dd,J1=7.6Hz,J2=3.6Hz,1H),3.57(dd,J1=14.4Hz,J2=4.0Hz,1H),3.23(dd,J1=14.4Hz,J2=8.0Hz,1H).
(3)2-((5-溴-3-氧代-1,3-二氢异苯并呋喃-1-基)甲基)苄腈(中间体70)的合成
将亚硝酸叔丁酯(78mg,0.76mmol)和溴化铜(101mg,0.45mmol)溶于乙腈4mL,冰浴下搅拌15min后将中间体69(100mg,0.38mmol)溶于4mL乙腈,缓慢滴入反应瓶中,继续冰浴搅拌3h。加入40mL水,EA萃取(20mL×3),无水硫酸镁干燥,浓缩,Flash柱层析(10g柱,0-14%EA/PE),得白色固体70mg,产率56.5%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.97(d,J=2.0Hz,1H),7.81(dd,J1=8.4Hz,J2=2.0Hz,1H),7.63(dd,J1=8.0Hz,J2=1.6Hz,1H),7.56(td,J1=8.0Hz,J2=1.6Hz,1H),7.48(dd,J1=8.0Hz,J2=1.6Hz,1H),7.44–7.41(m,1H),7.38(td,J1=7.6Hz,J2=1.2Hz,1H),5.74(dd,J1=7.6Hz,J2=4.0Hz,1H),3.62(dd,J1=14.8Hz,J2=4.0Hz,1H),3.30(dd,J1=14.8Hz,J2=7.6Hz,1H).
(4)4-(1-(2-氰基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-羧酸叔丁酯(中间体71)的合成
将中间体70(60mg,0.031mmol)、N-Boc-哌嗪(68mg,0.061mmol)、醋酸钯(4.2mg,0.0031mmol)、Xphos(18mg,0.0062mmol)和碳酸銫(120mg,0.061mmol)加入到5mL 1,4-二氧六环,氩气保护,100℃加热4h。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(10g柱,6-20%EA/PE),得白色固体73mg,产率91.8%。
(5)2-((3-氧代-5-(哌嗪-1-基)-1,3-二氢异苯并呋喃-1-基)甲基)苯甲腈盐酸盐(化合物27)的合成
中间体71(70mg,0.16mmol)加入1.5mL氯化氢的1,4-二氧六环溶液(4M),室温搅拌2h。加入少量乙醚,析出固体,过滤,得白色固体51mg,产率86%。1H-NMR(400MHz,MeOH-d4)δ(ppm):7.66(dd,J1=8.0Hz,J2=1.2Hz,1H),7.58(td,J1=7.6Hz,J2=1.2Hz,1H),7.53–7.49(m,3H),7.41(td,J1=7.6Hz,J2=1.2Hz,1H),7.32(d,J=2.0Hz,1H),5.83(dd,J1=7.2Hz,J2=4.8Hz,1H),3.62(dd,J1=14.4Hz,J2=4.4Hz,1H),3.52–3.49(m,4H),3.41–3.38(m,4H),3.37(dd,J1=14.8Hz,J2=6.8Hz,1H);HRMS(ESI):m/z,Calcd for C20H20O2N3[M+H]+:341.1550,Found334.1542.
实施例28:
3-(2-氯-4-(三氟甲氧基)苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物28)的合成
(1)(Z)-3-(2-氯-4-(三氟甲氧基)亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体72)的合成
将中间体1(569mg,1.98mmol)和2-氯4-三氟甲氧基苯甲醛(493mg,2.2mmol)溶于无水THF(20mL)中,缓慢滴加TEA(222mg,2.2mmol)的THF溶液(4mL),Ar保护下室温反应2h。将反应液倾倒入冰水中,搅拌20min,析出黄色固体,过滤,水洗,干燥,得黄色固体742mg,产率97.4%。
1H-NMR(400MHz,CDCl3)δ(ppm):8.81(d,J=1.6Hz,1H),8.63(dd,J2=8.8Hz,J1=2.0Hz,1H),8.38(d,J=8.8Hz,1H),8.04(d,J=8.4Hz,1H),7.36(d,J=2.4Hz,1H),7.27–7.25(m,1H),7.05(s,1H).
(2)6-氨基-3-(2-氯-4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮(中间体73)的合成
将中间体72(900mg,2.34mmol)加入到甲醇(16mL)中,加入钯碳(180mg),室温催化氢化反应2h,原料消失。过滤,滤液浓缩,柱层析(12%-49%EA/PE)得白色固体785mg,产率94%。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.58–7.57(m,1H),7.56(d,J=8.4Hz,1H),7.38(ddd,J1=8.8Hz,J2=6.4Hz,J3=1.2Hz,1H),7.24(d,J=8.4Hz,1H),6.96(dd,J1=8.4Hz,J2=2.0Hz,1H),6.86(d,J=2.0Hz,1H),5.70(dd,J1=8.4Hz,J2=4.0Hz,1H),5.61(brs,2H),3.44(dd,J1=14.8Hz,J2=4.4Hz,1H),3.05(dd,J1=14.8Hz,J2=8.8Hz,1H).
(3)6-溴-3-(2-氯-4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮(中间体74)的合成
取亚硝酸钠(203mg,2.94mmol)、三乙基苄基氯化铵(45mg,0.20mmol)和三甲基溴硅烷(450mg,2.94mmol)溶于乙腈10mL,冰水浴中搅拌20min,将中间体73(350mg,0.98mmol)溶于5mL乙腈,在冰浴下滴加入反应瓶中,继续冰水浴搅拌4h。加入20mL乙酸乙酯,用饱和NaCl(30mL×2)洗,无水硫酸镁干燥,浓缩,Flash柱层析(30g柱,0-11%EA/PE),得白色固体276mg,产率70.4%。
1H-NMR(400MHz,CDCl3)δ(ppm):8.03(d,J=2.0Hz,1H),7.78(dd,J1=8.0Hz,J2=2.0Hz,1H),7.37(d,J=8.4Hz,1H),7.31–7.30(m,1H),7.24(d,J=8.0Hz,1H),7.13(ddd,J1=8.4Hz,J2=2.4Hz,J3=1.2Hz,1H),5.70(dd,J1=8.4Hz,J2=0.8Hz,1H),3.43(dd,J1=14.4Hz,J2=4.8Hz,1H),3.18(dd,J1=14.4Hz,J2=8.4Hz,1H).
(4)4-(1-(2-氯-4-(三氟甲氧基)苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-羧酸叔丁酯(中间体75)的合成
将中间体74(242mg,0.58mmol)、N-Boc-哌嗪(216mg,1.16mmol)、醋酸钯(13mg,0.058mmol)、Xphos(57mg,0.12mmol)和碳酸銫(377mg,1.16mmol)加入到8mL 1,4-二氧六环,氩气保护,90℃加热6h。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(30g柱,6-12%EA/PE),得无色油状物200mg,产率64.9%,另分离得到30mg无色油状物(脱氯产物)记为中间体76。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.59(d,J=2.0Hz,1H),7.58(d,J=5.6Hz,1H),7.47(d,J=8.8Hz,1H),7.44(dd,J1=8.4Hz,J2=2.0Hz,1H),7.39(dq,J1=8.4Hz,J2=1.2Hz,1H),7.21(d,J=1.6Hz,1H),5.81(dd,J1=8.4Hz,J2=4.0Hz,1H),3.51(dd,J1=14.4Hz,J2=4.0Hz,1H),3.48–3.45(m,4H),3.22–3.19(m,4H),3.10(dd,J1=14.4Hz,J2=8.8Hz,1H),1.43(s,9H).
(5)3-(2-氯-4-(三氟甲氧基)苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物28)的合成
将中间体75(120mg,0.37mmol)溶于HCl的1,4-二氧六环溶液(1M)2mL中,室温搅拌2h,析出固体,过滤,无水乙醚洗,得白色固体123mg,收率71.9%。1H-NMR(400MHz,MeOH-d4)δ(ppm):7.50–7.44(m,3H),7.50–7.44(m,3H),7.22–7.19(m,1H),5.81(dd,J1=7.6Hz,J2=4.4Hz,1H),3.55–3.50(m,5H),3.42–3.39(m,4H),3.24(dd,J1=14.4Hz,J2=8.0Hz,1H);HRMS(ESI):m/z,Calcd for C20H19O3N2ClF3[M+H]+:427.1031,Found 427.1025.
实施例29:
6-(哌嗪-1-基)-3-(4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮盐酸盐(化合物29)的合成
将中间体76(25mg,0.051mmol)溶于HCl的1,4-二氧六环溶液(1M)1mL中,室温搅拌1h,析出固体,过滤,无水乙醚洗,得白色固体17mg,收率85%。
1H-NMR(400MHz,MeOH-d4)δ(ppm):7.46(d,J=1.2Hz,2H),7.30(t,J=1.2Hz,1H),7.29–7.27(m,2H),7.14–7.11(m,2H),5.79(dd,J1=6.4Hz,J2=4.8Hz,1H),3.50–3.47(m,4H),3.43–3.37(m,5H),3.17(dd,J1=14.4Hz,J2=6.4Hz,1H);HRMS(ESI):m/z,Calcd forC20H20O3N2F3[M+H]+:393.1420,Found 393.1420.
实施例30:
N-(2-((3-氧代-5-(哌嗪-1-基)-1,3-二氢异苯并呋喃-1-基)甲基)苯基)乙酰胺盐酸盐(化合物30)的合成
(1)(Z/E)-N-(2-((5-硝基-3-氧代异苯并呋喃-1(3H)-亚叉基)甲基)苯基)乙酰胺(中间体77)的合成
将中间体1(400mg,1.39mmol)、2-乙酰氨基苯甲醛(250mg,1.53mmol)加入到无水THF(8mL)中,冰浴,缓慢滴加TEA(169mg,1.67mmol)的无水THF(2mL),Ar保护继续反应2h,反应完毕,旋干溶剂,加入冰水搅拌,析出浅黄色固体,过滤,水洗,干燥,得黄色固体447mg,产率99.1%。
(核磁显示Z/E=0.7/0.3)
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.77(brs,0.3H),9.51(brs,0.7H),8.70(dd,J1=8.8Hz,J2=2.0Hz,0.3H),8.67(dd,J1=2.0Hz,J2=0.4Hz,0.3H),8.63(dd,J1=2.4Hz,J2=0.4Hz,0.7H),8.49(dd,J1=8.8Hz,J2=2.0Hz,0.7H),8.42(dd,J1=8.4Hz,J2=0.4Hz,0.3H),8.06(dd,J1=8.0Hz,J2=1.6Hz,0.3H),7.79(d,J=8.4Hz,0.7H),7.59(d,J=8.0Hz,0.3H),7.54(dt,J1=7.6Hz,J2=1.2Hz,0.7H),7.50(td,J1=7.2Hz,J2=1.6Hz,0.7H),7.44(d,J=8.4Hz,0.7H),7.39(td,J1=7.2Hz,J2=1.6Hz,0.3H),7.32(dd,J1=8.0Hz,J2=1.6Hz,0.3H),7.28(td,J1=7.6Hz,J2=1.2Hz,0.7H),7.18(s,0.3H),7.17(s,0.7H),2.15(s,0.9H),1.99(s,2.1H).
(2)N-(2-((5-氨基-3-氧代-1,3-二氢异苯并呋喃-1-基)甲基)苯基)乙酰胺(中间体78)的合成
将中间体77(420mg,1.30mmol)溶于甲醇(13mL)的溶液中,加入钯碳(80mg),室温催化氢化反应2h,原料消失。过滤,滤液浓缩得白色固体370mg,收率96.7%。1H-NMR(400MHz,DMSO-d6)δ(ppm):9.37(s,1H),7.42(d,J=8.0Hz,1H),7.31(dd,J1=7.6Hz,J2=1.6Hz,1H),7.24(td,J1=7.6Hz,J2=1.6Hz,1H),7.14(td,J1=7.6Hz,J2=1.6Hz,1H),7.08(d,J=8.4Hz,1H),6.92(dd,J1=8.4Hz,J2=2.0Hz,1H),6.86(d,J=2.0Hz,1H),5.61(dd,J1=8.8Hz,J2=4.4Hz,1H),5.56(brs,2H),3.22(dd,J1=14.8Hz,J2=4.4Hz,1H),2.94(dd,J1=14.4Hz,J2=8.4Hz,1H),2.05(s,3H).
(3)N-(2-((5-溴-3-氧代-1,3-二氢异苯并呋喃-1-基)甲基)苯基)乙酰胺(中间体79)的合成
将亚硝酸叔丁酯(116mg,1.13mmol)和溴化铜(150mg,0.67mmol)加入到乙腈5mL中,冰浴下搅拌5min,将中间体78(223mg,0.56mmol)溶于3mL乙腈,滴入反应瓶中,继续冰水浴搅拌5h。倾倒入1N稀盐酸溶液中,EA萃取(15mL×3),无水硫酸镁干燥,浓缩,柱层析(12-60%EA/PE),得类白色固体120mg,产率56%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.97(d,J=1.6Hz,1H),7.81(dd,J1=8.0Hz,J2=1.6Hz,1H),7.72(s,1H),7.61(d,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),7.29–7.25(m,1H),7.11–7.06(m,2H),5.71(t,J=4.8Hz,1H),3.33(dd,J1=14.4Hz,J2=4.0Hz,1H),3.11(dd,J1=14.4Hz,J2=4.0Hz,1H),2.22(s,3H).
(4)4-(1-(2-乙酰氨基苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-羧酸叔丁酯(中间体80)的合成
将中间体79(280mg,0.7mmol)、N-Boc-哌嗪(260mg,1.4mmol)、醋酸钯(16mg,0.07mmol)、Xphos(67mg,0.14mmol)和碳酸銫(456mg,1.4mmol)加入到7mL 1,4-二氧六环,氩气保护,90℃加热6h。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(30g柱,12-80%EA/PE),得浅黄色油状物246mg,产率76%。
(5)N-(2-((3-氧代-5-(哌嗪-1-基)-1,3-二氢异苯并呋喃-1-基)甲基)苯基)乙酰胺盐酸盐(化合物30)的合成
将中间体80(100mg,0.21mmol)溶于HCl的EA溶液(1M)1.5mL中,室温搅拌2h,析出固体,过滤,无水乙醚洗,得浅桔色固体71mg,收率83%。
1H-NMR(500MHz,MeOH-d4)δ(ppm):7.41(dd,J1=8.5Hz,J2=2.5Hz,1H),7.37–7.25(m,5H),7.17(t,J=7.5Hz,1H),5.77(t,J=6.0Hz,1H),3.50–3.48(m,4H),3.39–3.38(m,4H),3.27(dd,J1=14.5Hz,J2=5.5Hz,1H),3.18(dd,J1=14.5Hz,J2=7.0Hz,1H),2.15(s,3H);HRMS(ESI):m/z,Calcd for C21H24O3N3[M+H]+:366.1812,Found 366.1812.
实施例31:
3-(2-乙基-4-(三氟甲基)苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物31)的合成
(1)4-(三氟甲基)-2-乙烯基苯甲醛(中间体81)的合成
将2-溴-4-三氟甲基苯甲醛(2g,7.9mmol)、乙烯三氟硼酸钾(2.1g,15.8mmol)、醋酸钯(177mg,0.79mmol)、三苯基膦(414mg,1.6mmol)和碳酸銫(772mg,24mmol)加入到45mL四氢呋喃和5mL水,氩气保护,70℃加热8h。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(30g柱,纯PE),得无色油状物1.58g,产率100%。
(2)(Z)-6-硝基-3-(4-(三氟甲基)-2-乙烯基亚苄基)异苯并呋喃-1(3H)-酮(中间体82)的合成
将中间体1(500mg,1.74mmol)、中间体81(349mg,1.74mmol)加入到无水THF(4mL)中,冰浴,恒压滴液漏斗缓慢滴加TEA(354mg,0.35mmol)的无水THF(2mL),Ar保护继续反应4h,反应完毕,旋干溶剂,加水,DCM萃取,Flash柱层析(10g柱,1-20%EA/PE),得黄色固体525mg,产率83.5%。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.71(dd,J1=8.8Hz,J2=2.4Hz,1H),8.66(dd,J1=6.4Hz,J2=0.8Hz,1H),8.61(dd,J1=8.8Hz,J2=0.4Hz,1H),8.26(d,J=2.0Hz,1H),7.91(d,J=8.4Hz,1H),7.74(dd,J1=8.4Hz,J2=2.0Hz,1H),7.46(s,1H),7.40(dd,J1=17.2Hz,J2=11.2Hz,1H),6.00(dd,J1=17.2Hz,J2=1.2Hz,1H),5.61(dd,J1=11.2Hz,J2=1.2Hz,1H).
(3)6-氨基-3-(2-乙基-4-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮(中间体83)的合成
将中间体82(450mg,1.25mmol)溶于三氟乙醇(10mL)的溶液中,加入钯碳(100mg),70℃催化氢化反应6h,原料消失。过滤,得白色固体390mg,收率93.3%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.48(dd,J1=8.0Hz,J2=0.8Hz,1H),7.41(d,J=0.8Hz,1H),7.33(d,J=8.0Hz,1H),7.12(s,1H),6.94–6.92(m,1H),6.88(d,J=7.6Hz,1H),5.58(t,J=6.8Hz,1H),3.26(dd,J1=14.4Hz,J2=7.2Hz,1H),3.15(dd,J1=14.4Hz,J2=6.4Hz,1H),2.71(q,J=7.6Hz,2H),1.22(t,J=7.6Hz,3H).
(4)6-溴-3-(2-乙基-4-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮(中间体84)的合成
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取亚硝酸钠(124mg,1.79mmol)、三乙基苄基氯化铵(27mg,0.12mmol)和三甲基溴硅烷(274mg,0.60mmol)溶于乙腈3mL,冰浴下搅拌20min后将中间体83(200mg,0.60mmol)溶于2mL乙腈,滴入反应瓶中,继续冰浴搅拌12h。加入30mL水,EA萃取(10mL×3),无水硫酸镁干燥,浓缩,柱层析(30g柱,0-10%EA/PE),得白色固体202mg,产率85%。
1H-NMR(500MHz,CDCl3)δ(ppm):8.02–8.01(m,1H),7.73(dd,J1=8.5Hz,J2=2.0Hz,1H),7.36(d,J=8.0Hz,1H),7.39(s,1H),7.36(d,J=8.0Hz,1H),7.00(d,J=8.0Hz,1H),5.64(t,J=7.0Hz,1H),3.31(dd,J1=14.5Hz,J2=7.0Hz,1H),3.20(dd,J1=14.5Hz,J2=6.5Hz,1H),2.70(q,J=7.5Hz,2H),1.22(t,J=7.5Hz,3H).
(5)4-(1-(2-乙基-4-(三氟甲基)苄基)-3-氧代-1,3-二氢异苯并呋喃-5-基)哌嗪-1-羧酸叔丁酯(中间体85)的合成
将中间体84(350mg,0.88mmol)、N-Boc-哌嗪(327mg,1.75mmol)、Pd2(dba)3(81mg,0.088mmol)、BINAP(110mg,0.18mmol)和碳酸銫(573mg,1.8mmol)加入到8mL 1,4-二氧六环,氩气保护,90℃加热6h。硅藻土助滤,滤掉不溶物,EA洗。Flash柱层析(20g柱,6-17%EA/PE),得浅黄色油状物310mg,产率70%。
1H-NMR(400MHz,CDCl3)δ(ppm):7.48(dd,J1=8.0Hz,J2=1.2Hz,1H),7.37(d,J=1.6Hz,1H),7.34(d,J=8.0Hz,1H),7.32(d,J=2.4Hz,1H),7.24(dd,J1=8.4Hz,J2=2.4Hz,1H),7.01(d,J=8.4Hz,1H),5.62(t,J=6.4Hz,1H),3.62(t,J=5.2Hz,4H),3.27(dd,J1=14.4Hz,J2=7.2Hz,1H),3.21(t,J=5.2Hz,4H),3.19(dd,J1=14.4Hz,J2=6.4Hz,1H),2.72(q,J=7.6Hz,2H),1.49(s,9H),1.22(t,J=7.6Hz,3H).
(6)3-(2-乙基-4-(三氟甲基)苄基)-6-(哌嗪-1-基)异苯并呋喃-1(3H)-酮盐酸盐(化合物31)的合成
将中间体86(300mg,0.59mmol)溶于HCl的EA溶液(1M)5mL中,室温搅拌5h,析出固体,过滤,无水乙醚洗,得白色固体228mg,收率87%,熔点:131-132℃。
1H-NMR(500MHz,MeOH-d4)δ(ppm):7.49–7.43(m,3H),7.38–7.37(m,2H),7.32(s,1H),5.81(t,J=6.0Hz,1H),3.51–3.48(m,5H),3.41–3.39(m,4H),3.21(dd,J1=14.5Hz,J2=7.0Hz,1H),2.82–2.74(m,2H),1.22(t,J=7.5Hz,3H);HRMS(ESI):m/z,Calcd forC22H24O2N2F3[M+H]+:405.1784,Found 405.1796.
药理实验:
1.化合物抑制TREK-1钾电流的IC50
1.1实验方法:
1.1.1 HEK293/TREK-1细胞培养与转染
HEK-293细胞完全培养基:DMEM培养基88%,10%Sigma FBS,HEPES储备液1%,青霉素-链霉素1%,混匀,使用0.22μm滤膜过滤除菌,于水浴锅中预热后备用。
转染:HEK293细胞消化分至10μg/mL PDL预先包被1小时的35mm直径小皿中,细胞传代后在37℃培养一晚使汇合度在30~40%,要求细胞单个散在。吸弃完全培养液,PBS润洗3遍,换用Opti-MEM培养基饥饿培养,每个小皿加入2~4ul lipo 2000、2~4ng的TREK-1基因质粒、1ng GFP质粒共转,饥饿6-10h后换用完全培养基培养过夜(12h)。转染后48~72h用全细胞膜片钳技术记录TREK-1钾电流。
1.1.2 HEK293/TREK-1全细胞膜片钳电压钳方法
1.1.2.1电生理内液(mM):KF,160;EGTA,10;MgCl2,2;HEPES,10;pH 7.2(KOH滴定);外液(mM):NaCl,160;KCl,4.5;CaCl2,2;MgCl2,1;HEPES,10;pH 7.4(NaOH滴定).
1.1.2.2(1)使用预热的对应细胞外液将35mm小皿的细胞清洗2次,加入1.5mL对应实验细胞外液,置于显微镜下。
(2)玻璃电极内加入约1/3体积的电极内液,将玻璃电极安装在微距操作器上,使用微距控制系统控制电极接近细胞,在入水前,微距控制器可使用高速模式接近细胞,如0-3量程,入水后,使用中速模式接近细胞,如4-6量程,在靠近细胞后,使用低速模式接近细胞,如7-9量程。入水电阻在3-5MΩ。
(3)电极靠近细胞后,下压0.2MΩ并给予负压,待封接显示阻值为1GΩ左右,再次给予短促强力的负压,待封接峰形变化为破膜峰形,等待阻值稳定在GΩ3-5分钟后进行后续电生理数据记录。
(4)去极化单刺激:将细胞钳制在-80mV 100ms,去极化至+20mV 300ms,再钳制至-80mV,记录去极化至+20mV时产生的最大外向电流。
(5)给药方式:室温下给药,以细胞自身做空白对照。初筛终浓度为10μM,选取抑制率大于50%的化合物进行复筛,浓度分别为0.1、0.3、1、3、10、30μM。
1.1.3数据处理
采集和记录电生理数据使用Patchmaster软件,数据处理和分析使用Origin 8和GraphPad(Version 6.0)软件。所有数据均以Mean±SEM的形式表示,n表示单独用于实验的细胞数
实验结果见表1
表1.部分化合物抑制TREK-1的IC50
ND:未测定。
Claims (15)
1.如通式I所示化合物或其药用盐
在式I中,
R1、R2、R4独立地选自:
H、F、Cl、Br、CN、甲基、乙基、三氟甲基、三氟乙基、CHF2、OH、OCH3或OC2H5;
R5、R6、R7、R8独立地选自:
H、F、Cl、Br、CN、甲基、乙基、丙基、异丙基、环丙基、环丙甲基、三氟甲基、三氟乙基、CHF2、乙炔基、三氟甲氧基、CONH2、OH、OCH3、OC2H5、亚甲二氧基、NH2、NHCH3、N(CH3)2、NHCOCH3;
R9独立地选自:
(1)H、F、Cl、Br、CN、甲基、乙基、丙基、异丙基、环丙基、环丙甲基、三氟甲基、三氟乙基、CHF2、乙炔基、三氟甲氧基、CONH2、OH、OCH3、OC2H5、亚甲二氧基、NH2、NHCH3、N(CH3)2、NHCOCH3;
(2)苯基、取代的苯基,其中取代基选自:F、Cl、Br、CN、甲基、乙基、丙基、异丙基、环丙基、环丙甲基、三氟甲基、三氟乙基、CHF2、乙炔基、三氟甲氧基、CONH2、OH、OCH3、OC2H5、亚甲二氧基、NH2、NHCH3、N(CH3)2、NHCOCH3;
R3独立地选自:
其中,R11选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2;
R12、R13、R14、R15独立地选自:
甲基、乙基、丙基;
R16选自:
H、甲基、乙基、丙基、异丙基;
R17选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2;
R18选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2;
R19选自:
H、甲基、乙基、丙基、异丙基;
R20选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2;
n选自1、2或3;
其中手性碳原子可为R构型或S构型。
2.根据权利要求1的化合物或其药用盐,其特征在于,所述的化合物如通式IA所示
在式IA中,
R1、R2、R4、R5、R6、R7、R8和R9同权利要求1;
R21选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2。
3.根据权利要求1的化合物或其药用盐,其特征在于,所述的化合物如通式IB所示
在式IB中,
R1、R2、R4、R5、R6、R7、R8和R9同权利要求1;
R22选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2。
4.根据权利要求1的化合物或其药用盐,其特征在于,所述的化合物如通式IC所示
在式IC中,
R1、R2、R4、R5、R6、R7、R8和R9同权利要求1;
n选自1、2或3。
5.根据权利要求1的化合物或其药用盐,其特征在于,所述的化合物如通式ID所示
在式ID中,
R1、R2、R4、R5、R6、R7、R8和R9同权利要求1;
R23选自:
H、甲基、乙基、丙基、异丙基;
R24选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2。
6.根据权利要求1的化合物或其药用盐,其特征在于,所述的化合物如通式IE所示
在式IE中,
R1、R2、R4、R5、R6、R7、R8和R9同权利要求1;
R25选自:
H、甲基、乙基、丙基、异丙基;
R26选自:
H、甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、环丙基、环丁基、环戊基、环丙甲基、三氟甲基、三氟乙基、CHF2。
7.根据权利要求1-6化合物或其药用盐,其特征在于,所述的化合物选自如下群组:
8.根据权利要求1-7任一项的化合物或其药用盐,其特征在于,所述化合物的药用盐选自与无机酸、有机酸、碱金属离子、碱土金属离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐。
9.根据权利要求8的化合物或其药用盐,其特征在于,所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸;所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、枸杞酸、马来酸、酒石酸、富马酸、柠檬酸或乳酸;所述的碱金属离子选自锂离子,钠离子,钾离子;所述的碱土金属离子选自钙离子,镁离子;所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2-羟乙基)胺。
10.制备权利要求1-9中任一项化合物的方法,其特征在于,包括如下步骤:
以3-氧代-1,3-二氢异苯并呋喃-1-膦酸二甲酯1为起始原料,通过硝化反应,在异苯并呋喃-1(3H)-酮6-位引入硝基,得到中间体2;
中间体2与取代的芳醛发生Wittig-Horner反应,制备中间体3;
中间体3发生催化氢化反应,硝基和碳碳双键同时被还原,制备中间体4;
中间体4通过Sandermayer反应引入卤素,制备关键中间体5;
中间体5与脂杂环发生偶联反应,得到通式I所示化合物;如果脂杂环含有Boc保护基团,采用三氟乙酸或氯化氢的1,4-二氧六环溶液,脱除Boc,得到N上无取代化合物;在此基础上,采用烷基化或还原胺化反应,引入取代基,得到通式I所示化合物;
中间体5与N-取代哌嗪进行偶联反应,得到通式IA所示化合物;如果含氮脂杂环含有Boc保护基团,采用三氟乙酸或氯化氢的1,4-二氧六环溶液,脱除Boc,得到N上无取代化合物;在此基础上,采用烷基化或还原胺化反应,引入取代基,得到通式IA所示化合物;
中间体5与N-取代1,2,5,6-四氢吡啶-4-硼酸频哪醇酯进行偶联反应,制备中间体6;
中间体6发生氢化还原反应,得到通式IB所示化合物;如果含氮脂杂环含有Boc保护基团,采用三氟乙酸或氯化氢的1,4-二氧六环溶液,脱除Boc,得到N上无取代化合物;在此基础上,采用烷基化或还原胺化反应,引入取代基,得到通式IB所示化合物;
中间体5与稠杂环进行偶联反应,得到通式IC所示化合物;
中间体5与取代的吡咯烷进行偶联反应,得到如通式ID或IE所示化合物;如果吡咯烷含有Boc保护基团,采用三氟乙酸或氯化氢的1,4-二氧六环溶液,脱除Boc,得到N上无取代化合物;在此基础上,采用烷基化或还原胺化反应,引入取代基,得到通式ID或IE所示化合物;
中间体5与取代的哌嗪进行偶联反应,得到化合物7;如果取代的哌嗪环N原子上为Boc基团,采用三氟乙酸或氯化氢的1,4-二氧六环溶液,脱除Boc,得到N上无取代化合物;在此基础上,采用烷基化或还原胺化反应,引入取代基,得到如7所示化合物;
其中所述的R1、R2、R3、R4、R5、R6、R7、R8、R9、R11、R12、R13、R14、R15、R21、R22、R23、R24、R25、R26的定义同权利要求1-7,n选自1、2、3。
11.一种药物组合物,其特征在于,包括有效剂量的权利要求1-9中任一项的化合物或其药用盐和药效学上可接受的载体。
12.权利要求1-9中任一项的化合物或其药用盐在制备TREK-1抑制剂中的应用。
13.权利要求1-9中任一项的化合物或其药用盐在制备预防和\或治疗与TREK-1有关的疾病的药物中的应用。
14.根据权利要求13中的应用,其特征在于,所述与TREK-1有关的疾病选自精神神经系统疾病或心脑血管疾病。
15.根据权利要14的应用,其特征在于,所述精神神经系统疾病选自阿尔茨海默症、帕金森病、癫痫、抑郁症或疼痛,所述心脑血管疾病选自脑缺血或心律失常。
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