CN107001387A - 抑制mcl‑1蛋白的化合物 - Google Patents
抑制mcl‑1蛋白的化合物 Download PDFInfo
- Publication number
- CN107001387A CN107001387A CN201580054328.4A CN201580054328A CN107001387A CN 107001387 A CN107001387 A CN 107001387A CN 201580054328 A CN201580054328 A CN 201580054328A CN 107001387 A CN107001387 A CN 107001387A
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- compound
- chloro
- methyl
- alkene
- mixture
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Abstract
Description
本申请要求2014年8月29日提交的美国临时申请No.62/043,929的权益,该临时申请据此以引用的方式并入。
发明领域
本发明涉及抑制髓细胞白血病1蛋白(Mcl-1,也简称为MCL-1或MCL1)的化合物;使用该化合物治疗疾病或病症(诸如癌症)的方法;和含有该化合物的药物组合物。
发明背景
人类癌症的一个常见特征为Mcl-1过表达。Mcl-1过表达使癌细胞避免发生程序性细胞死亡(细胞凋亡),尽管有广泛的基因损伤,仍能让这些细胞存活。
Mcl-1为Bcl-2蛋白家族的成员。Bcl-2家族包括促细胞凋亡成员(诸如BAX和BAK),这些成员在活化后在粒线体外膜中形成均低聚物,其导致孔隙形成和粒线体内容物流失,这是一个触发细胞凋亡的步骤。Bcl-2家族的抗细胞凋亡成员(诸如Bcl-2、Bcl-XL和Mcl-1)阻断BAX和BAK的活性。其他蛋白质(诸如BID、BIM、BIK和BAD)表现出另外的调节功能。
研究已表明Mcl-1抑制剂可用于治疗癌症。MCl-1在许多癌症中过表达。参见Beroukhim等人(2010)Nature 463,899-90。在Mcl-1和Bcl-2-l-1抗细胞凋亡基因周围含有扩增的癌细胞的存活取决于这些基因的表达。Beroukhim等人。Mcl-1是在许多癌细胞中再引发(re-iniation)细胞凋亡的相关靶标。参见G.Lessene,P.Czabotar和P.Colman,Nat.Rev.Drug.Discov.,2008,7,989-1000;C.Akgul Cell.Mol.Life Sci.第66卷,2009;和Arthur M.Mandelin II,Richard M.Pope,Expert Opin.Ther.Targets(2007)11(3):363-373。
用于制备和配制Mcl-1抑制剂的新组合物和方法将是有用的。
附图简述
图1示出实施例4的化合物的Mcl-1抑制剂体内功效。
图2示出实施例17的化合物的Mcl-1抑制剂体内功效。
图3示出实施例20的化合物的Mcl-1抑制剂体内功效。
发明内容
在一个实施方案中,本发明提供式I的化合物,
其中以符号表示的b为单化学键或双化学键,其可为顺式或反式的;R为卤基;R1为H、C1-6烷基和(CH2CH2O)nCH3,其中n为1至4的整数;R2为H或C1-6烷基;R2A为H或C1-6烷基;R3为H或C1-6烷基;且R3A为H、C1-6烷基、C3-6环烷基或(CH2)m-C3-6环烷基,其中m为1至4的整数。在一个实施方案中,R为Cl。在一个实施方案中,R1为C1-6烷基。在另一个实施方案中,R1为CH3。在一个实施方案中,R2为H且R2A为C1-6烷基。在一个实施方案中,R3为H且R3A为C1-6烷基。在另一个实施方案中,b指示双键。
在本发明的一些实施方案中,式I的化合物为式II的化合物,
其中R1、R2、R2A、R3和R3A如上文所定义。
在本发明的一些实施方案中,本发明提供具有以下结构的化合物:
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的一个实施方案涉及一种化合物,其中该化合物具有选自以下的结构:
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的一个实施方案涉及一种具有以下结构的化合物
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的另一个实施方案涉及一种具有以下结构的化合物
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的另一个实施方案涉及一种具有以下结构的化合物
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的另一个实施方案涉及一种具有以下结构的化合物
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的另一个实施方案涉及一种具有以下结构的化合物
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的另一个实施方案涉及一种具有以下结构的化合物
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的另一个实施方案涉及一种具有以下结构的化合物
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的另一个实施方案涉及一种具有以下结构的化合物
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的另一个实施方案涉及一种具有以下结构的化合物
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的另一个实施方案涉及一种具有以下结构的化合物
或其药学上可接受的盐,和药学上可接受的赋形剂,结合上文或下文实施方案中的任一者。
本发明的一个实施方案涉及一种包含式I的化合物或其药学上可接受的盐和药学上可接受的赋形剂的药物组合物。
本发明的另一个实施方案涉及一种抑制细胞的髓细胞白血病1蛋白(Mcl-1)的方法,其包括将使细胞与有效抑制Mcl-1的量的式I的化合物接触,结合上文或下文实施方案中的任一者。在一个实施方案中,该接触在体外。在另一个实施方案中,该接触在体内。在一个实施方案中,该接触包括向受试者施用该化合物。在一个实施方案中,施用经口、经肠胃外、经由注射、经由吸入、经皮或经粘膜进行。在一个实施方案中,受试者罹患癌症。
本发明的一个实施方案涉及一种治疗癌症的方法,其包括向对其有需要的患者施用治疗有效量的式I的化合物或包含式I的化合物或其药学上可接受的盐,和药学上可接受的赋形剂的药物组合物,结合上文或下文实施方案中的任一者。在一个实施方案中,癌症为恶性血液病。在一个实施方案中,癌症选自:乳腺癌、结直肠癌、皮肤癌、黑素瘤、卵巢癌、肾癌、肺癌、非小细胞肺癌、淋巴瘤、非霍奇金氏淋巴瘤(non-Hodgkin’s lymphoma)、骨髓瘤、多发性骨髓瘤、白血病和急性骨髓性白血病。在一个实施方案中,癌症为多发性骨髓瘤。在另一个实施方案中,该方法还包括向对其有需要的患者施用治疗有效量的至少一种另外的药物活性化合物的步骤。在一个实施方案中,该另外的药物活性化合物为卡非佐米(carfilzomib),结合上文实施方案中的任一者。
除非另外定义,否则本文所用的所有技术和科学术语均具有与本公开所属领域的普通技术人员通常所理解的相同含义。本文描述适用于本公开的方法和物质;也可使用本领域已知的其他适合方法和物质。这些物质、方法和例子仅为说明性的而无意为限制性的。本文所提及的所有公开、专利申请、专利、序列、数据库条目和其他参考文献均以全文引用的方式并入。在有矛盾的情况下,将以本说明书(包括定义)为准。
本公开的其他特征和优点将从以下详细说明和附图以及权利要求中显而易见。
详细说明
符号“–”表示共价键,且也可用于自由基中以指示连接至另一基团的点。在化学结构中,符号-常用于表示分子中的甲基基团。
如本文所用,含有一个或多个用虚线和粗体键(即,和)描绘的立体中心的化学结构意在指示存在于化学结构中的立体中心的绝对立体化学。如本文所用,由简单线表示的键不指示立体偏好。除非另外相反指示,否则包括本文说明的不指示绝对或相对立体化学的一个或多个立体中心的化学结构涵盖化合物的所有可能的立体异构体形式(例如,非对映异构体、对映异构体)及其混合物。具有单一粗线或虚线和至少一条另外简单线的结构涵盖所有可能的非对映异构体的单一对映异构体系列。
如本文所用,术语“约”意在考虑因实验误差所致的变化。除非另外明确陈述,否则本文所报告的所有测量值均应理解为由术语“约”来修饰,无论是否明确使用该术语。除非本文另外明确规定,否则如本文所用,单数形式“a”、“an”和“the”包括多个指示物。
术语“烷基”意指直链或支链烃。烷基基团的代表性例子包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基和己基。典型的烷基基团为具有1至8个碳原子的烷基基团,这些基团通常表示为C1-8烷基。
如本文所用的术语“化合物”意在包括所描绘结构的所有立体异构体、几何异构体、互变异构体和同位素。除非另外规定,否则在本文中通过名称或结构来标识为一种特定互变异构体形式的化合物旨在包括其他互变异构体形式。
发现所有化合物及其药学上可接受的盐可与其他物质(诸如水和溶剂)一起存在(例如,水合物和溶剂化物)。
术语“环烷基”意指环状非芳族烃。环烷基基团的代表性例子包括环丙基、环丁基、环戊基、环己基和环庚基。环烷基基团可含有一个或多个双键。含有双键的环烷基基团的代表性例子包括环戊烯基、环己烯基、环己二烯基和环丁二烯基。常见的环烷基基团为C3-8环烷基基团。
如本文所用的术语“赋形剂”意指除活性药物成分(API)以外的任何药学上可接受的添加剂、载剂、稀释剂、佐剂或其他成分,其通常被包括在内以进行配制和/或施用给患者。Handbook ofPharmaceutical Excipients,第5版,编者为R.C.Rowe、P.J.Sheskey和S.C.Owen,Pharmaceutical Press,2005,Hardback,928,0853696187。
对于术语“例如”和“诸如”及其语法等同物而言,除非另外明确陈述,否则短语“但不限于”应理解为跟随其后。
术语“卤素”或“卤基”意指F、Cl、Br或I。
术语“患者”意指受试者,包括诸如狗、猫、牛、马、羊和人的动物。特定的患者为哺乳动物。术语患者包括男(雄)性和女(雌)性。
术语“有需要的患者”意指患有一种或多种牵涉Mcl-1蛋白的疾病或病症(诸如癌症)或处于患有所述疾病或病症的风险中的患者。鉴别有需要的患者可由受试者或健康护理专业人员判断,且可为主观的(例如,意见)或客观的(例如,可通过测试或诊断方法测量)。
如本文所用的短语“肠胃外施用”和“经肠胃外施用”意指除经肠和局部施用以外的施用模式,通常通过注射,且包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内和脑干内注射和输注。
适合于肠胃外注射的组合物可包括生理上可接受的无菌水性或非水性溶液、分散体、悬浮液或乳液,和用于复水成无菌可注射溶液或分散体的无菌粉末。适合的水性和非水性载剂、稀释剂、溶剂或媒介物的例子包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、其适合的混合物、植物油(诸如橄榄油)和可注射有机酯(诸如油酸乙酯)。例如,可通过使用包衣(诸如卵磷脂)、维持所需粒度(在分散体的情况下)和使用表面活性剂来维持适当的流动性。
术语“药学上可接受的”在本文中用于指在合理医学判断的范围内、适合于向患者施用、与合理的效益/风险比相称的那些配体、物质、组合物和/或剂型。
如本文所用的短语“药学上可接受的载剂”意指药学上可接受的物质、组合物或媒介物,诸如液体或固体填充剂、稀释剂、赋形剂、溶剂或囊化物质。如本文所用,用语“药学上可接受的载剂”包括与药物施用相容的缓冲剂、无菌注射用水、溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。各载剂在与制剂的其他成分相容且对患者无害的意义上必须为“可接受的”。可充当药学上可接受的载剂的物质的一些例子包括:(1)糖,诸如乳糖、葡萄糖和蔗糖;(2)淀粉,诸如玉米淀粉、马铃薯淀粉和经取代或未经取代的β-环糊精;(3)纤维素及其衍生物,诸如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;(4)粉末状黄蓍胶;(5)麦芽;(6)明胶;(7)滑石粉;(8)赋形剂,诸如可可脂和栓剂蜡;(9)油,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇,诸如丙二醇;(11)多元醇,诸如甘油、山梨糖醇、甘露糖醇和聚乙二醇;(12)酯,诸如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,诸如氢氧化镁和氢氧化铝;(15)褐藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液(Ringer’s solution);(19)乙醇;(20)磷酸盐缓冲溶液;和(21)药物制剂中采用的其他无毒相容性物质。在某些实施方案中,本文所提供的药物组合物为无热原的,即,在施用给患者时不引起显著的体温升高。
术语“药学上可接受的盐”是指本文所提供的化合物的相对无毒的无机酸和有机酸加成盐。这些盐可在本文所提供的化合物的最终分离和纯化期间原位制备,或通过分别使其游离碱形式的化合物与适合的有机酸或无机酸反应并分离由此形成的盐来制备。代表性盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、乙酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘二甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐、月桂基磺酸盐和氨基酸盐等。(参见例如Berge等人(1977)"Pharmaceutical Salts”,J.Pharm.Sci.66:1-19。)
如本文所用的短语“全身施用”、“经全身施用”、“外周施用”和“经外周施用”意指经由除直接进入中枢神经系统以外的途径(例如,皮下施用)施用配体、药物或其他物质以使得其进入患者的系统,且因此经受代谢和其他类似过程。
术语“治疗有效量”意指改善、减轻或消除特定疾病或病症的一种或多种症状,或防止或延迟特定疾病或病症的一种或多种症状发作的化合物的量。
术语“治疗(treating/treat/treatment)”等包括预防性(例如,防治性)和治标性治疗(palliative treatment)。
本文所提供的方法包括制造和使用药物组合物,该药物组合物包含一种或多种本文所提供的化合物。也包括药物组合物本身。
在一些实施方案中,本文所提供的化合物可含有一个或多个酸性官能团,且因此能够与药学上可接受的碱形成药学上可接受的盐。术语“药学上可接受的盐”在这些情况下是指本文所提供的化合物的相对无毒的无机碱和有机碱加成盐。这些盐同样可在化合物的最终分离和纯化期间原位制备,或通过分别使游离酸形式的纯化化合物与适合的碱(诸如药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐)、氨或药学上可接受的有机伯胺、仲胺或叔胺反应来制备。代表性碱金属盐或碱土金属盐包括锂盐、钠盐、钾盐、钙盐、镁盐和铝盐等。适用于形成碱加成盐的代表性有机胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等(参见例如Berge等人,见上文)。
润湿剂、乳化剂和润滑剂(诸如月桂基硫酸钠和硬脂酸镁)以及着色剂、脱模剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂(antioxida)。
药学上可接受的抗氧化剂的例子包括:(1)水溶性抗氧化剂,诸如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠(sodium metabisulfite)、亚硫酸钠等;(2)油溶性抗氧化剂,诸如棕榈酸抗坏血酸酯、丁基化羟基茴香醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等;和(3)金属螯合剂,诸如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸等。
药物组合物也可含有辅料,诸如防腐剂、润湿剂、乳化剂和分散剂。可通过包含各种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚山梨酸等来确保对微生物作用的预防。还可能希望将诸如糖等的等渗调节剂包含在组合物中。另外,可注射药物形式的延长吸收可通过包含延迟吸收的试剂(诸如单硬脂酸铝和明胶)来实现。
在一些情况下,为延长本文所提供的一种或多种化合物的效果,希望通过皮下或肌内注射而减缓化合物的吸收。例如,经肠胃外施用的化合物的延迟吸收可通过将化合物溶解或悬浮于油性媒介物中来实现。
本发明的化合物以治疗有效量施用给患者。这些化合物可单独施用或作为药学上可接受的组合物或制剂的一部分施用。另外,化合物或组合物可同时一起施用,例如通过多次推注,诸如通过一系列片剂,或在一段时间内基本上均匀地递送,例如使用经皮递送。化合物或组合物的剂量可随时间推移而变化。涵盖所有组合、递送方法和施用顺序。
本发明的化合物以及在一些实施方案中其他另外的药物活性化合物可经口、经直肠、经肠胃外(例如,静脉内、肌内或皮下)、脑池内、阴道内、腹膜内、膀胱内、局部(例如,粉末、药膏或滴剂)或以口腔或鼻腔喷雾形式施用给患者。涵盖本领域的技术人员使用的施用药物活性剂的所有方法。
如本文所描述而制备的组合物可取决于患者的待治疗病状和年龄、病症和体重而以各种形式施用,如本领域熟知的那样。例如,当组合物经口施用时,其可配制为片剂、胶囊、颗粒、粉末或糖浆;或对于肠胃外施用,其可配制为注射剂(静脉内、肌内或皮下)、滴注制剂或栓剂。对于通过眼粘膜途径施用,其可配制为滴眼剂或眼药膏。这些制剂可通过常规手段结合本文所描述的方法制备,且若需要,活性成分可与任何常规添加剂或赋形剂混合,这些添加剂或赋形剂诸如为粘合剂、崩解剂、润滑剂、矫味剂、增溶剂、助悬剂、乳化剂或包衣剂。
适合于经口施用的制剂可呈以下形式:胶囊(例如,明胶胶囊)、扁囊剂、丸剂、片剂、锭剂(使用调味基质,通常为蔗糖和阿拉伯胶或黄蓍胶)、粉末、糖锭、颗粒;或呈水性或非水性液体中的溶液或悬浮液形式;或呈水包油或油包水液体乳液形式;或呈酏剂或糖浆形式;或呈糖果锭剂(使用惰性基质,诸如明胶和甘油,或蔗糖和阿拉伯胶)和/或漱口剂形式;等等,它们各含有预定量的本文所提供的化合物作为活性成分。组合物也可以作大丸剂、药糖剂或糊剂施用。口服组合物一般包含惰性稀释剂或可食用载剂。
可包括药学上相容的粘结剂和/或辅助物质作为口服组合物的一部分。在经口施用的固体剂型(胶囊、片剂、丸剂、糖衣药丸、粉末、颗粒等)中,活性成分可与一种或多种药学上可接受的载剂混合,这些载剂诸如为柠檬酸钠或磷酸二钙和/或以下中的任一者:(1)填充剂或增量剂,诸如淀粉、环糊精、乳糖、蔗糖、糖精、葡萄糖、甘露糖醇和/或硅酸;(2)粘合剂,诸如羧甲基纤维素、微晶纤维素、黄蓍胶、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;(3)保湿剂,诸如甘油;(4)崩解剂,诸如琼脂、碳酸钙、马铃薯淀粉、玉米淀粉或木薯淀粉、褐藻酸、Primogel、某些硅酸盐和碳酸钠;(5)溶解阻滞剂,诸如石蜡;(6)吸收促进剂,诸如季铵化合物;(7)润湿剂,诸如乙酰基醇和单硬脂酸甘油酯;(8)吸附剂,诸如高岭土和膨润土;(9)润滑剂,诸如滑石粉、硬脂酸钙、硬脂酸镁、Sterotes、固体聚乙二醇、月桂基硫酸钠及其混合物;(10)助滑剂,诸如胶态二氧化硅;(11)着色剂;和(12)调味剂,诸如胡椒薄荷、水杨酸甲酯或橙味剂。在胶囊、片剂和丸剂的情况下,药物组合物也可包含缓冲剂。也可使用诸如乳糖(lactose/milk sugar)以及高分子量聚乙二醇等赋形剂将类似类型的固体组合物用作软填充和硬填充明胶胶囊中的填充物。
可通过任选地与一种或多种辅助成分一起压制或模制来制备片剂。可使用粘合剂(例如,明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如,羟基乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备压制片剂。可通过在适合的机器中模制经惰性液体稀释剂湿润的粉末状化合物的混合物来制备模制片剂。
片剂和其他固体剂型,诸如糖衣丸、胶囊、丸剂和颗粒可任选地刻痕或制备有包衣和外壳,诸如药物配制领域中熟知的肠溶衣和其他包衣。它们也可使用例如不同比例以提供所需释放特征的羟丙基甲基纤维素、其他聚合物基质、脂质体、微球体和/或纳米粒子来配制,以便提供其中的活性成分的缓慢或控制释放。它们可通过例如经由细菌截留过滤器过滤或通过掺入以无菌固体组合物形式的灭菌剂来灭菌,所述以无菌固体组合物形式的灭菌剂在临用前可溶于无菌水或一些其他无菌可注射介质中。这些组合物也可任选地含有遮光剂且可以为任选地以延迟方式仅仅或优先在胃肠道的某一部分中释放活性成分的组合物。可使用的包埋组合物的例子包括聚合物物质和蜡。活性成分也可在适当时与一种或多种上文所述的赋形剂一起呈微囊化形式。
用于经口施用的液体剂型包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除活性成分之外,液体剂型还可含有本领域常用的惰性稀释剂(诸如,水或其他溶剂)、增溶剂和乳化剂,诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(尤其是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯及其混合物。
除惰性稀释剂外,口服组合物也可包含辅料,诸如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂、着色剂、芳香剂和防腐剂。
除活性化合物之外,悬浮液还可含有悬浮剂,例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝(aluminum metahydroxide)、膨润土、琼脂和黄蓍胶及其混合物。
适合于肠胃外施用的药物组合物可包含一种或多种本文所提供的化合物,以及一种或多种药学上可接受的无菌水性或非水性溶液、分散体、悬浮液或乳液,或可在临用前复水成无菌可注射溶液或分散体的无菌粉末,其可含有抗氧化剂、缓冲剂、抑菌剂、溶质(其使得制剂与预期接受者的血液等渗)或悬浮剂或增稠剂。
在一个实施方案中,静脉内(IV)制剂由含有在8与10之间pH范围内的羟丙基β环糊精作为缓冲或无缓冲溶液的组合物组成。IV制剂可配制为即用于注射的无菌溶液、即用于稀释成IV混合物的无菌溶液或复水用无菌固体。IV制剂中的API可以游离酸/碱或原位盐的形式存在。
可用于本文所提供的药物组合物中的适合的水性和非水性载剂的例子包括注射用水(例如,无菌注射用水)、抑菌水、乙醇、多元醇(诸如甘油、丙二醇、诸如液体聚乙二醇的聚乙二醇等)、无菌缓冲剂(诸如柠檬酸盐缓冲剂)及其适合的混合物、植物油(诸如橄榄油)、可注射有机酯(诸如油酸乙酯)和Cremophor ELTM(BASF,Parsippany,NJ)。在所有情况下,该组合物必须为无菌的且流动性应达到易于注射(syringability)的程度。可例如通过使用包衣物质(诸如卵磷脂)、维持所需粒度(在分散体的情况下)和使用表面活性剂来维持适当的流动性。
组合物在制造和储存条件下应为稳定的,且必须防微生物(诸如细菌和真菌)的污染作用。微生物作用的预防可通过各种抗细菌剂和抗真菌剂实现,例如对羟基苯甲酸酯、氯丁醇、酚、抗坏血酸、硫柳汞(thimerosal)等。在许多情况下,组合物中将优选包含等渗剂(例如糖)、多元醇(诸如甘露醇、山梨醇)和氯化钠。可注射组合物的延长吸收可通过在组合物中包含延迟吸收的试剂(例如,单硬脂酸铝和明胶)来实现。
无菌可注射溶液可通过如下方式制备:将所需量的活性化合物与上文所列举的成分中的一者或组合一起掺入适当溶剂中,视需要随后进行过滤灭菌。一般而言,通过将活性化合物掺入无菌媒介物中来制备分散体,所述无菌媒介物含有碱性分散介质和上文所列举的那些成分中的所需其他成分。在用于制备无菌可注射溶液的无菌粉末的情况下,制备方法为冷冻干燥(冻干),其产生活性成分加上来自其先前无菌过滤溶液的任何另外所需成分的粉末。
可通过在可生物降解的聚合物(诸如聚交酯-聚乙交酯)中形成本文所提供的化合物的微胶囊或纳米胶囊基质来制备可注射贮库(Injectable depot)形式。取决于药物与聚合物的比率和所用特定聚合物的性质,可控制药物释放的速率。其他可生物降解的聚合物的例子包括聚(原酸酯)和聚(酸酐)。也通过将药物包埋在与身体组织相容的脂质体、微乳液或纳米乳液中来制备可注射贮库制剂。
对于通过吸入来施用,化合物可以气溶胶喷雾形式从含有适合的推进剂(例如气体,诸如二氧化碳)的加压容器或分配器或喷雾器递送。此类方法包括美国专利No.6,468,798中所描述的那些方法。另外,可实现鼻内递送,如尤其描述于Hamajima等人,Clin.Immunol.Immunopathol.,88(2),205-10(1998)中的那样。也可使用脂质体(例如,如描述于美国专利No.6,472,375中,该专利以全文引用的方式并入本文)、微胶囊和纳米胶囊。也可使用可生物降解的可靶向微粒递送系统或可生物降解的可靶向纳米粒子递送系统(例如,如描述于美国专利No.6,471,996中,该专利以全文引用的方式并入本文)。
如本文所述的治疗性化合物也可通过经粘膜或经皮方式来全身施用。用于局部或经皮施用本文所提供的化合物的剂型包括粉末、喷雾、药膏、糊剂、乳膏、洗剂、凝胶、溶液、贴片和吸入剂。活性组分可在无菌条件下与药学上可接受的载剂和与可能需要的任何防腐剂、缓冲剂或推进剂混合。对于经粘膜或经皮施用,在制剂中使用适于待渗透的屏障的渗透剂。此类渗透剂一般为本领域已知的,且对于经粘膜施用,包括例如清洁剂、胆汁盐和梭链孢酸衍生物。经粘膜施用可通过使用鼻喷雾或栓剂实现。对于经皮施用,如本领域一般已知的那样,将活性化合物配制成药膏、油膏、凝胶或乳膏。
除一种或多种本文所提供的化合物之外,药膏、糊剂、乳膏和凝胶还可含有赋形剂,诸如动物和植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石粉和氧化锌或其混合物。
除本文所提供的化合物之外,粉末和喷雾还可含有赋形剂,诸如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物。喷雾可另外含有常规推进剂,诸如氯氟烃和挥发性未经取代的烃,诸如丁烷和丙烷。
本文所提供的化合物可通过气溶胶施用。这通过制备含有本文所提供的化合物或组合物的水性气溶胶、脂质体制剂或固体粒子来实现。可使用非水性(例如,碳氟化合物推进剂)悬浮液。在一些实施方案中,使用声波喷雾器,因为它们使药剂暴露于剪切(可导致化合物降解)降至最低。
通常,水性气溶胶可通过将药剂的水性溶液或悬浮液与常规药学上可接受的载剂和稳定剂配制在一起来制备。载剂和稳定剂随特定组合物的要求而变化,但通常包括非离子表面活性剂((聚山梨醇酯)、(泊洛沙姆)、脱水山梨糖醇酯、卵磷脂、(聚乙氧基化物))、药学上可接受的共溶剂(诸如聚乙二醇)、无害蛋白(如血清白蛋白)、脱水山梨糖醇酯、油酸、卵磷脂、氨基酸(诸如甘氨酸)、缓冲剂、盐、糖或糖醇。气溶胶一般由等渗溶液制备。
经皮贴片具有提供本文所提供的化合物受控递送至身体的额外优点。可通过将药剂溶解或分散于适当介质中来制备此类剂型。也可使用吸收增强剂来增加化合物跨过皮肤的流通。该流通的速率可通过提供速率控制膜或使化合物分散于聚合物基质或凝胶中来控制。
药物组合物也可以栓剂或保留灌肠剂形式制备以用于直肠和/或阴道递送。以栓剂形式呈现的制剂可通过混合一种或多种本文所提供的化合物与一种或多种适合的无刺激性赋形剂或载剂来制备,这些赋形剂或载剂包括例如可可脂、甘油酯、聚乙二醇、栓剂蜡或水杨酸酯,其在室温下为固体,但在体温下为液体,且因此将在直肠或阴道腔中融化且释放活性剂。适合于阴道施用的制剂也包括含有如本领域已知为适合的载剂的子宫帽、棉塞、乳膏、凝胶、糊剂、泡沫或喷雾制剂。
在一个实施方案中,治疗性化合物用载剂来制备,所述载剂将保护治疗性化合物以免从身体快速消除,这些载剂诸如为控释制剂,包括植入物和微胶囊化递送系统。可使用可生物降解的生物相容性聚合物,诸如乙烯乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯和聚乳酸。此类制剂可使用标准技术制备,或从商业渠道得到(例如,获自AlzaCorporation和Nova Pharmaceuticals,Inc)。脂质体悬浮液(包括用针对细胞抗原的单克隆抗体靶向所选细胞的脂质体)也可用作药学上可接受的载剂。它们可根据本领域的技术人员已知的方法制备,例如如描述于美国专利No.4,522,811中,出于所有目的其以全文引用的方式并入本文。
本发明的化合物用于治疗通过Mcl-1抑制而介导的疾病、病状或症状。通过Mcl-1抑制而介导的疾病、障碍或症状的例子包括但不限于癌症。癌症的非限制性例子包括乳腺癌、结直肠癌、皮肤癌、黑素瘤、卵巢癌、肾癌、肺癌、非小细胞肺癌、淋巴瘤、非霍奇金氏淋巴瘤、骨髓瘤、多发性骨髓瘤、白血病和急性骨髓性白血病。
癌症可包括癌瘤(起源于皮肤和内部膜的外层细胞,例如乳腺、肾、肺、皮肤);肉瘤(源自结缔组织,诸如骨骼、肌肉、软骨和血管)和恶性血液病(例如,淋巴瘤和白血病,其产生于血液或诸如脾、淋巴结和骨髓的血液形成器官中)。癌细胞可包括例如肿瘤细胞、赘生性细胞、恶性细胞、转移性细胞和增生性细胞。
在一个实施方案中,疾病、病状或症状为过度增生性病状,例如淋巴瘤、白血病、癌瘤(例如,肾、乳腺、肺、皮肤)、多发性骨髓瘤或肉瘤。在一个实施方案中,白血病为急性髓性白血病。在一个实施方案中,过度增生性病状为复发性或难治性癌症。
本文所提供的药物组合物中活性成分的实际剂量水平可以变化,以便得到有效实现特定患者、组合物和施用模式的所需治疗反应而对患者无毒性的活性成分的量。
特定剂量和剂量范围取决于多种因素,包括患者需求、所治疗的病症或疾病的严重程度、所用的化合物的药代动力学特征和施用途径。在一些实施方案中,本文所提供的组合物可以除其他物质外还含有约0.1-10%w/v本文所公开的化合物的水溶液形式提供以供肠胃外施用。典型的剂量范围可包括每日每千克体重约0.01mg至约50mg,以1-4个分次剂量给予。各分次剂量可包含相同或不同的化合物。该剂量将为取决于若干因素的治疗有效量,所述因素包括患者的整体健康状况和所选化合物的制剂和施用途径。
可制备含有在0.005%至100%范围内的如本文所述的化合物而其余部分由无毒载剂构成的剂型或组合物。本领域的技术人员已知制备这些组合物的方法。所涵盖的组合物可含有约0.001%-100%的活性成分,在一个实施方案中约0.1至约95%,在另一个实施方案中约75至约85%。尽管剂量将取决于患者的症状、年龄和体重、待治疗或预防的病状的性质和严重程度、施用途径和药物形式而变化,但是一般而言,建议成人患者的日剂量为约0.01mg至约3,000mg的化合物,且此剂量可以按单次剂量或分次剂量施用。可与载剂物质组合以产生单一剂型的活性成分的量一般将为该化合物产生治疗效果的量。
药物组合物可一次性施用,或可分成多个较小剂量以时间间隔施用。应当理解,治疗的精确剂量和持续时间随所治疗的疾病而变化,且可使用已知的测试方案或通过从体内或体外实验数据推断而凭经验确定。应当指出,浓度和剂量值也可随待缓解的病症的严重程度变化。应进一步理解,对于任何特定患者,具体的给药方案应根据个体需要和管理或监督组合物施用的人员的专业判断而随时间调整,且本文所阐述的浓度范围仅为示例性的且无意限制受权利要求书保护的组合物的范围或实践。
在给定患者中将在疗效方面产生最有效结果的组合物的精确施用时间和/或量将取决于特定化合物的活性、药代动力学和生物利用度、患者生理状况(包括年龄、性别、疾病类型和阶段、一般身体状况、对所给予的剂量的反应以及药物类型)、施用途径等。然而,以上指导原则可用作微调治疗(例如确定施用的最佳时间和/或量)的基础,这将仅需要由监测患者和调节剂量和/或时间选择组成的常规实验
本发明的化合物可单独施用、与本发明的其他化合物或与其他药物活性化合物或药剂组合施用。其他药物活性化合物/药剂可旨在与本发明的化合物一样治疗相同的疾病或病症,或治疗不同疾病或病症。如果患者将接受或正在接受多种药物活性化合物或药剂,则这些化合物可同时或依序施用。
本发明的化合物或其药学上可接受的盐可与一种或多种另外的药物活性化合物/药剂组合使用。
一种或多种另外的药物活性化合物或药剂可作为多剂量方案的一部分与式I的化合物分开施用(例如依序,例如以不同的重叠进度,其中施用一种或多种式I的化合物(包括其任何亚类或特定化合物))。在其他实施方案中,所述一种或多种另外的化合物/药剂可为单一剂型的一部分,与式I的化合物一起混合于单一组合物中。在再一实施方案中,所述一种或多种另外的化合物/药剂可以按单独剂量给予,所述单独剂量在大约与施用一种或多种式I的化合物相同的时间施用(例如,与一种或多种式I的化合物(包括其任何亚类或特定化合物)同时施用)。式I的化合物和一种或多种另外的化合物/药剂均可以按单药疗法方案中通常施用的剂量的约1至100%之间且更优选地约5至95%之间的剂量水平存在。
在特定实施方案中,所述另外的药物活性化合物/药剂为可用于治疗癌症的化合物或药剂。例如,所述另外的药物活性化合物/药剂可选自抗肿瘤剂、抗血管生成剂、化疗剂和肽类(peptidal)癌症治疗剂。在另一个实施方案中,抗肿瘤剂选自抗生素类药剂、烷基化剂、抗代谢物剂、激素剂、免疫剂、干扰素类试剂、激酶抑制剂、蛋白酶体抑制剂及其组合。应当指出,所述另外的药物活性化合物/药剂可为传统的小有机化学分子,或可以为大分子,诸如蛋白质、抗体、肽体(peptibody)、DNA、RNA或此类大分子的片段。
可用于治疗癌症且可与一种或多种本发明化合物组合使用的另外的药物活性化合物/药剂的例子包括:醋孟南(acemannan);阿柔比星(aclarubicin);阿地白介素(aldesleukin);阿利维甲酸(alitretinoin);氨磷汀(amifostine);氨柔比星(amrubicin);安吖啶(amsacrine);阿那格雷(anagrelide);阿格拉滨(arglabin);三氧化二砷;BAM 002(Novelos);比卡鲁胺(bicalutamide);溴尿苷(broxuridine);西莫白介素(celmoleukin);西曲瑞克(cetrorelix);克拉屈滨(cladribine);克霉唑;DA3030(Dong-A);达利珠单抗(daclizumab);地尼白介素(denileukin diftitox);德舍瑞林(deslorelin);地拉齐普(dilazep);二十二醇(docosanol);度骨化醇(doxercalciferol);脱氧氟尿苷(doxifluridine);溴麦角环肽(bromocriptine);阿糖胞苷(cytarabine);HIT双氯芬酸(HIT diclofenac);干扰素α;维甲酸;依地福新(edelfosine);依决洛单抗(edrecolomab);依洛尼塞(eflornithine);乙嘧替氟(emitefur);表柔比星(epirubicin);倍他依泊汀(epoetin beta);磷酸依托泊苷(etoposide phosphate);依昔舒林(exisulind);法屈唑(fadrozole);非那雄安(finasteride);磷酸氟达拉滨(fludarabinephosphate);福美司坦(formestane);福莫司汀(fotemustine);硝酸镓;吉妥珠单抗奥唑米星(gemtuzumab zogamicin);吉美拉西(gimeracil)/奥特拉西(oteracil)/喃氟啶(tegafur)组合;甘氨酸;戈舍瑞林(goserelin);庚铂(heptaplatin);人绒毛膜促性腺激素;人甲胎蛋白;伊班膦酸(ibandronic acid);干扰素α;天然干扰素α;干扰素α-2;干扰素α-2a;干扰素α-2b;干扰素α-N1;干扰素α-n3;干扰素α-1;天然干扰素α;干扰素β;干扰素β-1a;干扰素β-1b;天然干扰素γ;干扰素γ-1a;干扰素γ-1b;白介素-1β;碘苄胍(iobenguane);伊索拉啶(irsogladine);兰瑞肽(lanreotide);LC 9018(Yakult);来氟米特(leflunomide);来格司亭(lenograstim);香菇多糖硫酸酯(lentinan sulfate);来曲唑(letrozole);白细胞α干扰素;亮丙瑞林(leuprorelin);左旋咪唑(levamisole)+氟尿嘧啶(fluorouracil);利阿唑(liarozole);洛铂(lobaplatin);氯尼达明(lonidamine);洛伐他汀(lovastatin);马索罗酚(masoprocol);美拉胂醇(melarsoprol);甲氧氯普胺(metoclopramide);米非司酮(mifepristone);米替福新(miltefosine);米立司亭(mirimostim);错配双链RNA;丙脒腙(mitoguazone);二溴卫矛醇(mitolactol);米托蒽醌(mitoxantrone);莫拉司亭(molgramostim);那法瑞林(nafarelin);纳洛酮(naloxone)+戊唑辛(pentazocine);那托司亭(nartograstim);奈达铂(nedaplatin);尼鲁米特(nilutamide);诺斯卡品(noscapine);新红细胞生成刺激蛋白;NSC631570奥曲肽(octreotide);奥普瑞白介素(oprelvekin);奥沙特隆(osaterone);紫杉醇(paclitaxel);帕米膦酸(pamidronic acid);聚乙二醇化干扰素α-2b;戊聚糖聚硫酸钠(pentosanpolysulfate sodium);喷司他汀(pentostatin);毕西巴尼(picibanil);吡柔比星(pirarubicin);兔抗胸腺细胞多克隆抗体;聚乙二醇干扰素α-2a;卟吩姆钠(porfimersodium);雷替曲塞(raltitrexed);拉布立酶(rasburicase);Re 186依替膦酸铼(rheniumRe 186etidronate);RII维甲酰胺(RII retinamide);罗莫肽(romurtide);钐(153Sm);沙格司亭(sargramostim);西佐喃(sizofuran);索布佐生(sobuzoxane);索纳明(sonermin);氯化锶-89;苏拉明(suramin);他索那明(tasonermin);他扎罗汀(tazarotene);喃氟啶;替莫泊芬(temoporfin);替尼泊苷(teniposide);四氯十氧化物(tetrachlorodecaoxide);胸腺法新(thymalfasin);促甲状腺激素α;托瑞米芬(toremifene);托西莫单抗(tositumomab)-碘131;曲奥舒凡(treosulfan);维甲酸;曲洛司坦(trilostane);曲美沙特(trimetrexate);曲普瑞林(triptorelin);天然肿瘤坏死因子α;乌苯美司(ubenimex);膀胱癌疫苗;丸山(Maruyama)疫苗;黑素瘤溶解物疫苗;戊柔比星(valrubicin);维替泊芬(verteporfin);维力金(virulizin);净司他丁(zinostatin);司他美(stimalamer);阿巴瑞克(abarelix);AE 941(Aeterna);氨莫司汀(ambamustine);反义寡核苷酸;bcl-2(Genta);APC 8015(Dendreon);右旋胺鲁米特;地吖醌(diaziquone);EL 532(Elan);EM800(Endorecherche);恩尿嘧啶(eniluracil);依他哒唑(etanidazole);非瑞替尼(fenretinide);加洛他滨(galocitabine);胃泌素17免疫原;HLA-B7基因疗法(Vical);粒细胞巨噬细胞集落刺激因子;组胺二盐酸盐;替伊莫单抗(ibritumomab tiuxetan);伊洛马司他(ilomastat);IM 862(Cytran);白介素-2;普洛昔芬(iproxifene);LDI 200(Milkhaus);来立司亭(leridistim);林妥珠单抗(lintuzumab);CA 125单克隆抗体(MAb)(Biomira);癌单抗(Japan Pharmaceutical Development);HER-2和Fc MAb(Medarex);个体基因型105AD7 MAb(CRC Technology);个体基因型CEA MAb(Trilex);LYM-1-碘131 MAb(Techniclone);多晶型上皮粘蛋白-钇90MAb(Antisoma);马立马司他(marimastat);美诺立尔(menogaril);米妥莫单抗(mitumomab);莫特沙芬钆(motexafin gadolinium);MX 6(Galderma);诺拉曲特(nolatrexed);P 30蛋白;派格索曼(pegvisomant);泊非罗霉素(porfiromycin);普啉司他(prinomastat);RL 0903(Shire);鲁比替康(rubitecan);沙铂(satraplatin);苯基乙酸钠;斯帕磷酸(sparfosic acid);SRL 172(SRPharma);SU 5416(SUGEN);TA 077(Tanabe);四硫钼酸盐;噻立拉斯汀(thaliblastine);血小板生成素;锡乙基初紫红素(tin ethyl etiopurpurin);替拉扎明(tirapazamine);癌症疫苗(Biomira);黑素瘤疫苗;黑素瘤肿瘤溶解物疫苗;病毒黑素瘤细胞溶解物疫苗;伐司朴达(valspodarl);氟尿嘧啶;5-氟尿嘧啶;紫杉醇;伊马替尼(imatinib);六甲蜜胺(altretamine);克拉屈滨;环磷酰胺;达卡巴嗪(decarazine);伊立替康(irinotecan);丝裂霉素(mitosmycin);米托坦(mitoxane);拓朴替康(topotecan);长春瑞滨(vinorelbine);阿霉素(adriamycin);密特拉(mithram);咪喹莫特(imiquimod);雷妥珠单抗(alemtuzmab);依西美坦(exemestane);贝伐单抗(bevacizumab);西妥昔单抗(cetuximab);阿扎胞苷(azacitidine);氯法拉滨(clofarabine);地西他滨(decitabine);德莎替尼(desatinib);右雷佐生(dexrazoxane);多烯紫杉醇(docetaxel);表柔比星(epirubicin);奥沙利铂(oxaliplatin);埃罗替尼(erlotinib);雷洛昔芬(raloxifene);氟维司群(fulvestrant);来曲唑;吉非替尼(gefitinib);吉妥珠单抗;曲妥珠单抗(trastuzumab);吉非替尼(gefitinib);伊沙匹隆(ixabepilone);拉帕替尼(lapatinib);来那度胺(lenalidomide);氨基乙酰丙酸;替莫唑胺(temozolomide);奈拉滨(nelarabine);索拉非尼(sorafenib);尼罗替尼(nilotinib);培门冬酶(pegaspargase);培美曲塞(pemetrexed);利妥昔单抗;达沙替尼(dasatinib);撒力多胺(thalidomide);贝瑟罗汀(bexarotene);替西罗莫司(temsirolimus);硼替佐米(bortezomib);卡非佐米(carfilozmib);奥普洛佐米(oprozomib);伏立诺他(vorinostat);卡培他滨(capecitabine);唑来膦酸(zoledronic acid);阿那曲唑(anastrozole);舒尼替尼(sunitinib);阿瑞匹坦(aprepitant)和奈拉滨(nelarabine);或其药学上可接受的盐。
可用于治疗癌症且可与一种或多种本发明化合物组合使用的另外药物活性化合物/药剂包括:阿法依泊汀(epoetin alfa);阿法达贝泊汀(darbepoetin alfa);帕尼单抗(panitumumab);派非格司亭(pegfilgrastim);帕利夫明(palifermin);非格司亭(filgrastim);德诺单抗(denosumab);安西司亭(ancestim);AMG 102;AMG 386;AMG 479;AMG 655;AMG 745;AMG 951;和AMG 706,或其药学上可接受的盐。
在某些实施方案中,本文所提供的组合物与化学治疗剂结合施用。适合的化学治疗剂可包括:天然产物,诸如长春花生物碱(vinca alkaloid)(例如,长春碱(vinblastine)、长春新碱(vincristine)和长春瑞滨);紫杉醇;表鬼臼毒素(epidipodophyllotoxin)(例如,依托泊苷和替尼泊苷);抗生素(例如,更生霉素(dactinomycin)(放线菌素D(actinomycin D))、道诺霉素(daunorubicin)、阿霉素(doxorubicin)和伊达比星(idarubicin));蒽环霉素(anthracycline);米托蒽醌;博来霉素(bleomycin);普卡霉素(plicamycin)(光神霉素(mithramycin));丝裂霉素(mitomycin);酶(例如,L-天冬酰胺酶,其全身性地代谢L-天冬酰胺且剥夺不能够合成其自身天冬酰胺的细胞);抗血小板剂;抗增殖/抗有丝分裂烷基化剂,诸如氮芥(nitrogenmustard)(例如,二氯甲基二乙胺(mechlorethamine)、环磷酰胺和类似物、美法仑(melphalan)和苯丁酸氮芥);乙烯亚胺和甲基三聚氰胺(例如,六甲基三聚氰胺和噻替派(thiotepa));CDK抑制剂(例如,塞利希布(seliciclib)、UCN-01、P1446A-05、PD-0332991、戴那西里(dinaciclib)、P27-00、AT-7519、RGB286638和SCH727965);磺酸烷基酯(例如,白消安(busulfan));亚硝基脲(例如,卡莫司汀(carmustine,BCNU)和类似物,和链脲菌素);达卡巴嗪(trazenes-dacarbazinine,DTIC);抗增殖/抗有丝分裂抗代谢物,诸如叶酸类似物(例如,甲氨蝶呤(methotrexate));嘧啶类似物(例如,氟尿嘧啶、氟尿苷和阿糖胞苷);嘌呤类似物和相关抑制剂(例如,巯嘌呤(mercaptopurine)、硫鸟嘌呤(thioguanine)、喷司他汀和2-氯脱氧腺苷);芳香酶抑制剂(例如,阿那曲唑、依西美坦和来曲唑);和铂配位复合物(例如,顺铂和卡铂);丙卡巴肼(procarbazine);羟基脲;米托坦(mitotane);胺鲁米特(aminoglutethimide);组蛋白脱乙酰基酶(HDAC)抑制剂(例如,曲古霉素(trichostatin)、丁酸钠、阿匹西坦(apicidan)、辛二酰苯胺异羟肟酸(suberoyl anilide hydroamicacid)、伏立诺他(vorinostat)、LBH 589、罗米地辛(romidepsin)、ACY-1215和帕比司他(panobinostat));mTor抑制剂(例如,替西罗莫司、依维莫司(everolimus)、地磷莫司(ridaforolimus)和西罗莫司(sirolimus));KSP(Eg5)抑制剂(例如,Array 520);DNA结合剂(例如,Zalypsis);PI3Kδ抑制剂(例如,GS-1101和TGR-1202);PI3Kδ和γ抑制剂(例如,CAL-130);多激酶抑制剂(例如,TG02和索拉非尼);激素(例如,雌激素)和激素激动剂,诸如黄体生成激素释放激素(leutinizing hormone releasing hormone,LHRH)激动剂(例如,戈舍瑞林、亮丙立德(leuprolide)和曲普瑞林);BAFF中和抗体(例如,LY2127399);IKK抑制剂;p38MAPK抑制剂;抗IL-6(例如,CNTO328);端粒酶抑制剂(例如,GRN 163L);极光激酶抑制剂(例如,MLN8237);细胞表面单克隆抗体(例如,抗CD38(HUMAX-CD38)、抗CS1(例如,埃罗妥珠单抗(elotuzumab)));HSP90抑制剂(例如,17AAG和KOS 953);P13K/Akt抑制剂(例如,哌立福新(perifosine));Akt抑制剂(例如,GSK-2141795);PKC抑制剂(例如,恩扎妥林(enzastaurin));FTI(例如,ZarnestraTM);抗CD138(例如,BT062);Torc1/2特异性激酶抑制剂(例如,INK128);激酶抑制剂(例如,GS-1101);ER/UPR靶向剂(例如,MKC-3946);cFMS抑制剂(例如,ARRY-382);JAK1/2抑制剂(例如,CYT387);PARP抑制剂(例如,奥拉帕尼(olaparib)和维利帕尼(veliparib)(ABT-888));BCL-2拮抗剂。其他化学治疗剂可包括氮芥、喜树碱(camptothecin)、异环磷酰胺、他莫昔芬(tamoxifen)、雷洛昔芬、吉西他滨(gemcitabine)、温诺平(navelbine)、索拉非尼或前述治疗剂的任何类似物或衍生物变体。
本发明的化合物也可与放疗、激素疗法、手术和免疫疗法组合使用,这些疗法为本领域的技术人员所熟知的。
在某些实施方案中,本文所提供的药物组合物与类固醇结合施用。适合的类固醇可包括但不限于21-乙酰氧基妊烯醇酮、阿氯米松(alclometasone)、阿尔孕酮(algestone)、安西奈德(amcinonide)、倍氯米松(beclomethasone)、倍他米松(betamethasone)、布地奈德(budesonide)、氯泼尼松(chloroprednisone)、氯倍他索(clobetasol)、氯可托龙(clocortolone)、氯泼尼醇(cloprednol)、皮质酮、可的松(cortisone)、可的伐唑(cortivazol)、地夫可特(deflazacort)、地奈德(desonide)、去羟米松(desoximetasone)、地塞米松(dexamethasone)、二氟拉松(diflorasone)、二氟可龙(diflucortolone)、二氟孕甾丁酯(difuprednate)、甘草次酸(enoxolone)、氟扎可特(fluazacort)、氟氯奈德(flucloronide)、氟米松(flumethasone)、氟尼缩松(flunisolide)、丙酮化氟新龙(fluocinolone acetonide)、醋酸氟轻松(fluocinonide)、氟考丁酯(fluocortinbutyl)、氟可龙(fluocortolone)、氟米龙(fluorometholone)、乙酸氟培龙(fluperolone acetate)、乙酸氟泼尼定(fluprednidene acetate)、氟泼尼龙(fluprednisolone)、氟氢缩松(flurandrenolide)、丙酸氟替卡松(fluticasonepropionate)、氟甲酰龙(formocortal)、哈西奈德(halcinonide)、丙酸卤贝他索(halobetasol propionate)、卤米松(halometasone)、氢化可的松(hydrocortisone)、氯替泼诺(loteprednol etabonate)、马泼尼酮(mazipredone)、甲羟松(medrysone)、甲泼尼松(meprednisone)、甲泼尼龙(methylprednisolone)、糠酸莫米松(mometasone furoate)、帕拉米松(paramethasone)、泼尼卡酯(prednicarbate)、泼尼松龙(prednisolone)、泼尼松龙25-二乙氨基乙酸盐(prednisolone 25-diethylaminoacetate)、泼尼松龙磷酸钠、泼尼松(prednisone)、泼尼松龙戊酸酯(prednival)、泼尼立定(prednylidene)、利美索龙(rimexolone)、替可的松(tixocortol)、曲安西龙(triamcinolone)、曲安奈德(triamcinolone acetonide)、苯曲安奈德(triamcinolone benetonide)、己曲安奈德(triamcinolone hexacetonide),和其盐和/或衍生物。在特定实施方案中,本发明的化合物也可与治疗恶心的另外的药物活性剂组合使用。可用于治疗恶心的药剂的例子包括:屈大麻酚(dronabinol);格拉司琼(granisetron);甲氧氯普胺;昂丹司琼(ondansetron);和丙氯拉嗪(prochlorperazine);或其药学上可接受的盐。
由于本发明的一个方面涵盖用可单独施用的药物活性化合物的组合来治疗疾病/病症,因此本发明进一步涉及以试剂盒形式组合单独的药物组合物。试剂盒包括两种单独的药物组合物:本发明的化合物和第二药物化合物。试剂盒包括用于容纳单独组合物的容器,诸如分开的瓶或分开的箔包装。容器的另外例子包括注射器、盒子和袋子。在一些实施方案中,试剂盒包括用于使用单独组分的说明。当单独组分优选以不同的剂型(例如,经口和肠胃外)施用时,以不同的给药间隔施用时或当处方健康护理专业人员希望上下调整组合的各个组分时,该试剂盒形式尤其有利。
本发明的化合物可以药学上可接受的盐、酯、酰胺或前药形式施用。术语“盐”是指本发明化合物的无机盐和有机盐。盐可在化合物的最终分离和纯化期间原位制备,或通过分别使游离碱或游离酸形式的纯化化合物与适合的有机或无机碱或酸反应且分离由此形成的盐来制备。代表性盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘二甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐和月桂基磺酸盐等。这些盐可包括基于碱金属和碱土金属(诸如钠、锂、钾、钙、镁等)的阳离子,以及无毒铵、季铵和胺阳离子,包括但不限于铵、四甲铵、四乙铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。参见例如S.M.Berge等人,“Pharmaceutical Salts,”JPharm Sci,66:1-19(1977)。
术语“前药”意指在体内转化以产生本发明化合物的化合物。转化可通过各种机制发生,诸如通过在血液中水解。T.Higuchi和W.Stella,“Pro-drugs as Novel DeliverySystems,”A.C.S.Symposium Series第14卷以及在Bioreversible Carriers in DrugDesign,Edward B.Roche编,American Pharmaceutical Association and PergamonPress,1987中提供了前药用途的论述。
举例而言,如果本发明的化合物含有羧酸官能团,则前药可包含通过用诸如以下的基团置换酸基团中的氢原子而形成的酯:(C1-C8烷基、(C2-C12)烷酰氧基甲基、具有4至9个碳原子的1-(烷酰氧基)乙基、具有5至10个碳原子的1-甲基-1-(烷酰氧基)乙基、具有3至6个碳原子的烷氧基羰氧基甲基、具有4至7个碳原子的1-(烷氧基羰氧基)乙基、具有5至8个碳原子的1-甲基-1-(烷氧基羰氧基)乙基、具有3至9个碳原子的N-(烷氧羰基)氨基甲基、具有4至10个碳原子的1-(N-(烷氧羰基)氨基甲基、3-酞基、4-巴豆酸内酯基、γ-丁内酯-4-基、二-N,N-(C1-C2)烷基氨基(C2-C3)烷基(诸如β-二甲基氨基乙基)、氨甲酰基-(C1-C2)烷基、N,N-二(C1-C2)烷基氨甲酰基-(C1-C2)烷基和哌啶子基(C2-3)烷基、吡咯烷子基(C2-3)烷基或吗啉代基(C2-3)烷基。
类似地,如果本发明化合物包含醇官能团,则前药可通过用诸如以下的基团置换醇基团中的氢原子而形成:(C1-C6)烷酰基氧基甲基、1-((C1-C6)烷酰氧基)乙基、1-甲基-1-((C1-C6)烷酰氧基)乙基、(C1-C6)烷氧基羰氧基甲基、N-(C1-C6)烷氧羰基氨基甲基、丁二酰基、(C1-C6)烷酰基、α-氨基(C1-C4)烷酰基、芳酰基和α-氨酰基或α-氨酰基-α-氨酰基,其中各α-氨酰基独立地选自天然存在的L-氨基酸、-P(O)(OH)2、-P(O)(O(C1-C6)烷基)2或糖基(该基团通过移除半缩醛形式碳水化合物中的羟基而产生)。
本发明的化合物可含有不对称或手性中心,且因此以不同的立体异构体形式存在。设想这些化合物的所有立体异构体形式及其混合物(包括外消旋混合物)形成本发明的一部分。另外,本发明涵盖所有几何和位置异构体。例如,如果化合物含有双键,则涵盖顺式和反式形式(分别称为Z和E)以及混合物。
可基于其物理化学差异通过诸如色谱和/或分离结晶的已知方法,将立体异构体的混合物(诸如非对映异构体混合物)分离成其各个立体化学组分。对映异构体也可通过以下方式分离:通过与适当光学活性化合物(例如,醇)反应将对映异构体混合物转化为非对映异构体混合物,分离非对映异构体且将各个非对映异构体转化(例如,水解)成相应的纯对映异构体。
本发明的化合物可以非溶剂化形式以及与诸如水(水合物)、乙醇等药学上可接受的溶剂的溶剂化形式存在。本发明设想并涵盖溶剂化形式和非溶剂化形式。
也有可能的是,本发明的化合物可以不同的互变异构体形式存在。涵盖本发明化合物的所有互变异构体。本领域的技术人员将认识到,本文所含的化合物名称和结构可基于化合物的特定互变异构体。虽然可使用仅特定互变异构体的名称或结构,但是除非另外说明,否则本发明旨在涵盖所有互变异构体。
本发明也旨在涵盖使用诸如合成化学家熟知的那些实验室技术的实验室技术体外合成的或使用诸如经由代谢、发酵、消化等体内技术合成的化合物。还设想,本发明的化合物可使用体外技术与体内技术的组合合成。
本发明的化合物可以各种固体状态存在,包括结晶状态和无定形状态。涵盖本发明化合物的不同结晶状态(也称为多晶型物)和无定形状态作为本发明的一部分。
实施例
下文提供的实施例说明本发明的具体实施方案。这些实施例旨在为代表性的而无意以任何方式限制权利要求书的范围。
可在本文中使用以下缩写:
应当指出,当关于液体使用百分比(%)时,其为相对于溶液的体积百分比。当关于固体使用时,其为相对于固体组合物的百分比。
生物学分析
无Mcl-1的细胞:Bim亲和力分析(Mcl-1HTRF)
使用时间分辨荧光共振能量转移(TR-FRET)分析来测量Mcl-1/Bim相互作用的抑制。在Amgen Inc(Thousand Oaks,CA)产生重组人Mcl-1(C-末端6xHis标记的含有残基171-327的Mcl-1)。来源于人Bim(残基51-76)的生物素化肽购自CPC Scientific(San Jose,CA)。TR-FRET分析以40μL总体积在384孔白色OptiPlateTM(PerkinElmer,Waltham,MA)中进行。反应混合物含有0.1nM Mcl-1(171-327)、0.05nM生物素-Bim(51-76)、0.05nMEu-W1024抗6xHis(PerkinElmer)、0.072nM链霉亲和素-XLent(Cisbio,Bedford,MA),且在20mM Hepes(pH 7.5)、150mM NaCl、0.016mM35和1mM二硫苏糖醇的结合缓冲剂中连续稀释测试化合物。测试化合物与Mcl-1(171-327)和生物素-Bim(51-76)一起预温育60min,随后添加检测混合物(Eu-W1024抗6xHis和链霉亲和素-XLent)。反应板进一步温育过夜,随后在多模式读取器(PerkinElmer)上读取。在320nm(75nm带宽)下激发之后在60μs延迟的情况下测量620nm(40nm带宽)和665nm(7.5nm带宽)下的荧光信号。665/620nm下的信号比率对应于Mcl-1/Bim相互作用且用于所有数据分析。通过使用GraphPad Prism(GraphPad Software,San Diego,CA)或Genedata (Genedata,Basel,Switzerland)中的四参数反曲模型(sigmoidal model)分析竞争曲线以由重复数据确定测试化合物的IC50值。
基于细胞的分析(分裂荧光素酶(SplitLuciferase))
开发了分裂荧光素酶补充分析来确定细胞中Mcl-1/Bak蛋白间相互作用的抑制。编码与人Bak基因融合的萤火虫荧光素酶的氨基酸(1-298)的pcDNA-Luc(1-298)-BAK表达载体连同编码与人Mcl-1基因融合的萤火虫荧光素酶的氨基酸(395-550)的pcDNA-Luc(395-550)-Mcl-1表达载体一起生成。人胚肾(HEK)293M细胞经3:1DNA混合比率的pcDNA-Luc(1-298)-BAK和pcDNA-Luc(395-550)-Mcl-1瞬时转染。使用LTX/PlusTM试剂(Life Technologies,Grand Island,NY)进行瞬时转染。转染后24h,使用非基于酶的细胞解离缓冲剂(Life Technologies)收集细胞,并重悬于无血清的Opti-(Life Technologies)中。随后将细胞以5000个细胞/孔的密度接种至分析板,该板具有在0.3%DMSO中连续稀释的测试化合物。细胞随后在37℃下在补充有5%CO2的细胞培养箱中温育4h。将测试板平衡至室温持续30min,随后向各测试孔中添加30μLSteady-荧光素酶分析试剂(Promega,Madison,WI)。在添加检测试剂之后25min使用多标记酶标仪(Multilabel plate reader)测定荧光。随后使用GraphPadPrism(GraphPad Software,San Diego,CA)或Genedata(Genedata,Basel,Switzerland)中的逻辑4参数拟合模型通过Xlfit计算IC50值。
细胞活力分析(OPM-210FBS)
将人多发性骨髓瘤细胞系OPM-2在含有RPMI 1640和10%胎牛血清(FBS)的完全生长培养基中培养。细胞以3000个细胞/孔的密度接种至384孔板中的含有10%FBS的完全生长培养基中,且在具有5%CO2的37℃培养箱中与连续稀释的测试化合物温育16h。使用CellTiter-分析(Promega,Madison,WI)根据制造商建议测试细胞活力。在添加检测试剂之后25min使用多标记酶标仪测定荧光。随后使用GraphPad Prism(GraphPad Software,San Diego,CA)或Genedata(Genedata,Basel,Switzerland)中的逻辑4参数拟合模型通过Xlfit计算IC50值。
这些生物学分析中所测试的化合物的结果在下文示出。
OPM2多发性骨髓瘤异种移植模型
对雌性无胸腺裸小鼠(Harlan,Inc.,Indianapolis,IN)皮下接种五百万个OPM-2细胞。图1、图2和图3说明用各种浓度的测试化合物治疗相比于媒介物(定义为无活性化合物的赋形剂)的结果,且在图2中还与bortezomibTM进行比较,bortezomibTM是可购自Millennium Pharmaceuticals,Inc.(Cambride,MA)的化合物。在14天后在肿瘤已达到100-200mm3的平均体积时开始治疗且再持续10天。每周两次分别使用电子卡尺和分析天平(analytical scale)记录肿瘤体积和体重。使用重复测量方差分析(RepeatedMeasuresANOVA,RMANOVA)进行统计分析,随后进行Dunnett事后分析(Dunnett’s post-hocanalysis)。
以下合成方案一般性展示如何制备中间体和本发明的化合物。
一般合成方案
一般程序1
可使用标准化学技术制备中间体III。例如,将环丁烷甲醛II与氧氮杂(oxazepine)I在适当溶剂中在低于RT的温度(优选约0℃)下组合。添加氰基硼氢化钠,且将混合物添加至NaOH溶液中,以提供化合物III。
一般程序2
可使用标准肽样化学制备中间体IV。例如,在适当溶剂中在低于RT的温度(优选约0℃)下将DMAP添加至羧酸中间体AA和中间体EE中,随后添加EDC盐酸盐。将混合物升至环境温度,以提供甲酰胺IV。
一般程序3
可使用标准化学技术制备实施例A中间体。例如,将甲酰胺IV与DCM组合,随后添加Hoveyda-Grubbs II。将混合物冷却至环境温度,以提供实施例A。
一般程序4
可使用标准化学技术制备中间体V。例如,将中间体AA与中间体EE在适当溶剂中组合,随后添加Hoveyda-Grubbs II,以提供化合物V。
一般程序5
可使用标准化学技术制备实施例A中间体。例如,将N,N-二甲基吡啶-4-胺与化合物VI在适当溶剂中在低于RT的温度(优选约0℃)下组合,随后添加N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐。将所得混合物升至环境温度,以提供实施例A。
一般程序6
可使用标准化学技术制备实施例B中间体。例如,在低于RT的温度(优选约0℃)下将氢化钠添加至实施例A的溶液中,随后添加MeI。将所得混合物升至环境温度,以提供实施例B。
一般程序7
可使用标准化学技术制备诸如实施例C的中间体。例如,将实施例A和/或B和/或VII和氧化铂(IV)在适当溶剂中在环境温度下组合,以提供实施例C。
本发明的化合物一般可将由市售原料产生的合成中间体组合且进一步加工来制备。这些中间体的合成概述于下文中,且在所提供的具体实施例中存在进一步的例证说明。
中间体AA11A
(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
步骤1:(R)-6-氯-3,4-二氢-2H-螺[萘-1,2'-环氧乙烷]和(R)-6-氯-3,4-二氢-2H-螺[萘-1,2'-环氧乙烷]
向2L4颈RBF中装入6-氯-3,4-二氢-1(2H)-萘酮(123g,681mmol)、三甲基碘化锍(143g,701mmol)和DMSO(1100mL)。添加KOH(76g,1362mmol)(粒料)。将悬浮液在环境温度下搅拌2天,在该时间之后粗1H NMR显示出无剩余原料。将溶液倾入800g碎冰中,用MTBE(200mL)冲洗,且添加另外一部分MTBE(700mL)。将所得混合物搅拌5min,且在分开之后用MTBE萃取底部水层两次(500mL,300mL),并与主要MTBE萃取物合并。合并的有机料流用盐水(2X600mL)洗涤,且添加330g Al2O3(中性)。所得悬浮液在22℃下搅拌5min、过滤且用MTBE(400mL)洗涤。浓缩滤液得到为红色粘性油状物的产物(125g,94%)。
步骤2:(S)-6-氯-1,2,3,4-四氢萘-1-甲醛和(R)-6-氯-1,2,3,4-四氢萘-1-甲醛
向3L 3颈RBF中装入外消旋6-氯-3,4-二氢-2H-螺[萘-1,2'-环氧乙烷](160g,822mmol)和THF(1760mL)。在用干冰/IPA浴将批料冷却至-8℃之后,历经3min添加三氟化硼乙醚(5.07mL,41.1mmol)。放热使批料温度即刻升至10℃。批料在-5℃至0℃下搅拌5min,并且样品(在冷NaHCO3溶液中淬灭)的LC/MS分析表明完全转化。通过在-5℃下添加饱和NaHCO3(300mL)随后添加MTBE(400mL)来淬灭反应,并将混合物转移至分液漏斗且用MTBE(240mL)冲洗。在分开之后,将水层连同一些白色固体(可能为硼酸或硼砂)一起丢弃。有机层用盐水(350mL)洗涤且在减压下浓缩,得到红色油状物。粗物质直接用于步骤4。
步骤3:(6-氯-1,2,3,4-四氢萘-1,1-二基)二甲醇
将外消旋6-氯-1,2,3,4-四氢-1-萘甲醛装入3L 3颈RBF中,且用二乙二醇(1000mL)冲洗。添加甲醛(37%的H2O溶液;652mL,8757mmol),且用干冰/IPA浴将所得两相乳液冷却至5℃。历时约30min添加KOH(45%水溶液,652mL,11.9mol),维持温度低于20℃。完全添加后,将批料(20℃)缓慢加热至45℃(注意:放热反应)且老化1h。HPLC显示完全转化。形成一些粘性不溶性焦油,在水溶液后处理(aqueous workup)之前将其移除。向批料中添加盐水(500mL),且用DCM萃取混合物直至水相中的产物含量低于5%。将合并的DCM萃取物浓缩至750mL红色油状物,用H2O(500mL)洗涤,且产物开始结晶出来。分离之后,丢弃澄清顶部水层,并将底层在冰/H2O浴中搅拌30min,过滤且用DCM(约100mL)和H2O(100mL)洗涤。将产物在干燥空气/真空下干燥,得到第一批产物(113g,498mmol,57%产率)。将来自所得母液的DCM层分离且浓缩至200-300g(KF=0.5%),接种且在冰/H2O浴中搅拌30min。过滤产物,用DCM(50mL)洗涤,且在干燥空气/真空中干燥,得到第二批产物(14.3g,63.1mmol,7%产率),合并的总产量为127g(64%)的6-氯-1,2,3,4-四氢萘-1,1-二基)二甲醇。
步骤4:4-溴苯甲酸(S)-(6-氯-1-(羟甲基)-1,2,3,4-四氢萘-1-基)甲酯
向2,6-双((R)-5,5-二丁基-4-苯基-4,5-二氢噁唑-2-基)吡啶(R,R-Kang催化剂)(1.57g,2.64mmol)于无水DCM(450mL)中的溶液添加氯化铜(II)(0.355g,2.64mmol),且将所得绿色溶液在rt下搅拌1h。将此溶液经由套管添加至(6-氯-1,2,3,4-四氢萘-1,1-二基)二甲醇(30g,132.73mmol)于无水DCM(800mL)中的溶液。将所得混合物冷却至-78℃,且观测到淡绿色沉淀。随后缓慢添加4-溴苯甲酰氯(34.77g,158.79mmol)于DCM(500mL)中的溶液,再逐滴添加N-乙基-N-异丙基丙-2-胺(20g,154mmol)。所得反应混合物在-78℃下搅拌3h,随后用pH 3磷酸盐缓冲液(1L)淬灭且在剧烈搅拌下升至环境温度。混合物随后用DCM(2L)稀释,且分离各层。有机相用pH 3缓冲液(1L)、饱和NaHCO3(1L)和盐水(2L)洗涤,随后经Na2SO4干燥,过滤且浓缩。通过柱色谱经由SiO2凝胶(100-200目,80%DCM/Hex)纯化粗物质,得到纯4-溴苯甲酸(S)-(6-氯-1-(羟甲基)-1,2,3,4-四氢萘-1-基)甲酯(45g,84%;e.r=91.4:8.6)。OD-H(250mm×4.6mm);流动相:正己烷:IPA:90:10;运行时间:20min;流动速率:1mL/min;样品制备:IPA。保留时间(主峰)-9.32min;保留时间(次峰)-11.46min)。
步骤5:4-溴苯甲酸(R)-(6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲酯
在10℃下向4-溴苯甲酸(S)-(6-氯-1-(羟甲基)-1,2,3,4-四氢萘-1-基)甲酯(100g,244.5mmol)于DCM(2.5L)中的搅拌溶液中添加戴斯-马丁高碘烷(121.4g,293.3mmol)。在添加之后移除冷却浴,且将反应混合物在环境温度下搅拌30min。随后添加H2O(9mL),且将所得两相混合物在环境温度下搅拌30min。反应混合物冷却至0℃且用2L10%Na2S2O3/NaHCO3饱和溶液的1:1混合物淬灭。反应混合物在环境温度下进一步搅拌10min,随后分离各层且用EtOAc(2×1.5L)萃取水层。合并的有机层用1L 10%Na2S2O3/NaHCO3饱和溶液和1L盐水洗涤,随后经Na2SO4干燥,过滤且浓缩。通过柱色谱经由SiO2凝胶(100-200目,5%EtOAc/Hex)纯化残余物,得到4-溴苯甲酸(R)-(6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲酯(80g,81%)。
标题化合物的对映异构体纯度可通过以下程序提高:将4-溴苯甲酸(R)-(6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲酯(190g)添加至甲苯(950mL)中,且加热至50℃以完全溶解。将均质溶液冷却至环境温度且接种外消旋化合物。将溶液冷却至-25℃且老化过夜。随后将母液滗析且浓缩,得到160g对映异构体富集的4-溴苯甲酸(R)-(6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲酯(94%ee,如通过手性HPLC测定)。手性HPLC条件:柱:OD-H(250mm×4.6mm);流动相:正己烷:IPA:90:10。运行时间:20min。流动速率:1mL/min。样品制备:乙醇。保留时间(主峰):8.488min(96.97%);保留时间(次峰):9.592min(3.03%)。
步骤6:(R)-(6-氯-1-(二甲氧基甲基)-1,2,3,4-四氢萘-1-基)甲醇
向4-溴苯甲酸(R)-(6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲酯(75g,183.8mmol)于无水MeOH(1L)中的溶液添加对甲苯磺酸(p-TsOH)(1g,9.2mmol)和原甲酸三甲酯(58.4mL,551mmol),且将反应混合物回流直至完全消耗掉原料(约4h)。将反应物料浓缩至50%体积且用THF(1L)和1N NaOH(1L,1mol)稀释。所得反应混合物在40℃下搅拌过夜,且随后减压浓缩。将残余物用EtOAc(1.5L)稀释。分离水层且用EtOAc(2×500mL)萃取,并且合并的有机层用1N NaOH(1L)和盐水(1L)洗涤,经Na2SO4干燥且减压浓缩。通过柱色谱经由100-200网目尺寸的SiO2凝胶(10%EtOAc/Hex)纯化粗物质,得到为浅棕色浓稠油状物的纯(R)-(6-氯-1-(二甲氧基甲基)-1,2,3,4-四氢萘-1-基)甲醇(44g,89%)。
步骤7:4-氟-3-硝基苯甲酸叔丁酯
向4-氟-3-硝基苯甲酸(100g,540.2mmol)于叔丁醇(2.5L)中的溶液添加DMAP(13.18g,108.04mmol)和二碳酸二叔丁酯(248mL,1080.4mmol),且将反应混合物在40℃下加热过夜。完成后,反应混合物用H2O稀释,且水相用EtOAc(3×1.5L)萃取。合并的有机层进一步用H2O(1×1L)、盐水(1×1L)洗涤,且经Na2SO4干燥。减压移除溶剂,并将由此得到的粗物质通过柱色谱(100-200网目尺寸的SiO2凝胶,用100%Hex至5%EtOAc/Hex的梯度洗脱)纯化,得到为淡黄色固体的纯4-氟-3-硝基苯甲酸叔丁酯(70g,54%)。
步骤8:(R)-4-((6-氯-1-(二甲氧基甲基)-1,2,3,4-四氢萘-1-基)甲氧基)-3-硝基苯甲酸叔丁酯
将(R)-(6-氯-1-(二甲氧基甲基)-1,2,3,4-四氢萘-1-基)甲醇(70g,259.2mmol)于无水THF(3.5L)中的溶液冷却至0℃,且逐滴添加LiHMDS(1M于THF中;363mL,363mmol)。5min之后,经由滴液漏斗逐滴添加4-氟-3-硝基苯甲酸叔丁酯(74.9g,311mmol)于THF(500mL)中的溶液,且将所得混合物升至环境温度。完成后(约1h),将混合物冷却至0℃,用NH4Cl饱和溶液(1L)淬灭且用EtOAc(3×1L)萃取。合并的有机层用NH4Cl(1L)和盐水(1L)洗涤,经Na2SO4干燥且减压浓缩。将由此得到的粗物质通过柱色谱使用100-200网目尺寸的SiO2凝胶(5%EtOAc/己烷)纯化,得到为黄色浓稠油状物的(R)-4-((6-氯-1-(二甲氧基甲基)-1,2,3,4-四氢萘-1-基)甲氧基)-3-硝基苯甲酸叔丁酯(110g,87%产率)。
步骤9A:(R)-4-((6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲氧基)-3-硝基苯甲酸
向(R)-4-((6-氯-1-(二甲氧基甲基)-1,2,3,4-四氢萘-1-基)甲氧基)-3-硝基苯甲酸叔丁酯(35g,71.25mmol)于MeCN(1L)中的溶液添加三氟甲磺酸铒(4.3g,7.1mmol)和H2O(13mL)。将所得混合物加热至80℃过夜。随后减压移除溶剂,且将残余物溶于Et2O(1.5L)中且用1N HCl(500mL)和盐水(500mL)洗涤。有机层经Na2SO4干燥,过滤且浓缩,得到(R)-4-((6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲氧基)-3-硝基苯甲酸(30g),其不经进一步纯化即使用。
或者,(R)-4-((6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲氧基)-3-硝基苯甲酸可如下由(6-氯-1,2,3,4-四氢萘-1,1-二基)二甲醇(步骤4)制备:
向250mL 3颈RBF中装入氯化铜(II)(0.095g,0.02当量)、2,6-双((R)-5,5-二丁基-4-苯基-4,5-二氢噁唑-2-基)吡啶(0.42g,0.02当量)和THF(28.5g,4V)。在用N2惰化之后,将批料在20℃下搅拌0.5h。向均质绿色溶液中添加(6-氯-1,2,3,4-四氢萘-1,1-二基)二甲醇(8.0g,1.00当量)随后添加THF(14.2g,2V)和4-甲基吗啉(3.75g,1.05当量)。将反应混合物冷却至-20℃,并且历经0.5h将1-萘甲酰氯(7.06g,1.05当量)于THF(21.3g,3V)中的溶液添加至批料中,维持温度低于-15℃。在-20℃下老化20h之后,取反应浆液的等分试样且通过HPLC分析。在将温度维持在-20℃的同时经由玻璃烧结漏斗直接过滤浆液。用穿过反应容器冲洗的两份冷(<-10℃)THF(2×14.2g,2V)洗涤滤饼。将滤饼(4-甲基吗啉·HCl)转移至带标签的容器中。将母液和洗涤液浓缩至最小体积,且通过装入甲苯使蒸馏溶剂交换,直至批料体积为6V,并且如通过QNMR所测量,甲苯/THF比率>98:2(v/v)。在20℃下向批料中添加庚烷(11g,2V),且将浆液加热至85℃(观察到溶解)。将溶液冷却至75℃且装入晶种(0.27g,0.02当量)。浆液历经3h冷却至20℃,且老化>1h。经由玻璃烧结过滤器过滤批料,并将滤饼用甲苯/庚烷(3:1v/v)(11g,2V)随后用甲苯/庚烷(1:1v/v)(11g,2V)洗涤。将滤饼在N2下在环境温度下干燥12h,且通过QNMR(<1wt%甲苯和庚烷)干法分析滤饼。得到为灰白色固体的产物(8.75g,重量调整后为63%)。
向装有漂白洗涤器(bleach scrubber)的60L夹套反应器中装入1-萘甲酸(S)-(6-氯-1-(羟甲基)-1,2,3,4-四氢萘-1-基)甲酯(2.693Kg,88.6wt%,6.3mol)随后装入DCM(17.9Kg,5倍体积)和EtNiPr2(2.84Kg,3.5当量)。在N2惰化之后,搅拌批料且冷却至0℃。在维持批料温度低于15℃的同时历经30min向反应器中的醇浆液混合物添加新制备的三氧化硫吡啶溶液(2.10Kg,2.5当量三氧化硫吡啶于7.43Kg,3倍体积DMSO)。添加之后,HPLC分析表明>99%转化。通过历经约20min添加H2O(14L,5倍体积)淬灭批料,维持批料温度低于15℃且随后添加甲苯(16.8L,6倍体积)。在分开之后,将有机层用H2O(14L,5倍体积)和甲苯(16.8L,6倍体积)处理。顶部有机层用2N HCl洗涤两次(每次14L,5倍体积)且用盐水(14L,5倍体积)洗涤。将有机层排出至清洁容器,通过HPLC分析,且随后经由管线过滤器(inlinefilter)转移回至清洁的60L反应器。将批料浓缩至最小体积且溶剂转换为MeOH,直至批料体积为28L(10倍体积)且如通过QNMR所测量MeOH/甲苯比率为3:1(v/v)。随后经由管线过滤器将批料转移至30L夹套反应器中。在将批料温度调整至30℃之后,将批料用醛(51g,0.02当量)在MeOH(400mL)中接种作为浆液。浆液在30℃下老化30min之后,通过蒸馏使批料与MeOH进行溶剂转换直至批料体积为11L(4倍体积)且MeOH/甲苯比率≥99:1(v/v)。随后将批料冷却至5℃,且历经1.5h添加MeOH/H2O混合物(3.70Kg MeOH+1.34Kg H2O),使总溶剂体积为约5.5倍体积且最终MeOH/H2O为90/10(v/v)。历经30min将批料加热至65℃,然后历经2h冷却至20℃且老化约2h。批料经由装有≤25μm滤布的过滤器过滤。滤饼用MeOH/H2O(10:1)(1×2倍体积)随后用MeOH/H2O(2:1)(1×2倍体积)洗涤。将滤饼在N2下在环境温度下干燥≥4h直至干燥,得到作为灰白色固体的产物(1.99Kg,wt%调整后为72%)。
向3颈250mL RBF中装入1-萘甲酸(R)-(6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲酯(10g,94.4wt%,95.3%LCAP,>99%ee)、甲醇(100mL)、原甲酸三甲酯(7mL)和TsOH·H2O(0.24g)。将RBF用N2惰化,且开始搅拌。将批料加热至60℃且老化2h。HPLC分析表明≥98%转化。
使用旋转蒸发仪将批料在真空(约150-190托,外部温度为约40℃)下浓缩至最小体积。通过三次装入THF(每次50mL)且在真空(约165托,外部温度为约40℃)下蒸馏,将批料移至THF中。在前两次THF装入的每一次之后,将批料浓缩至最小体积,且在最后THF装入和蒸馏之后,样品的QNMR分析表明THF/MeOH(v/v)的目标比率>20/1。将LiOH·H2O(10.46g,10当量)和H2O(50mL)装入3颈250mL RBF中。将反应混合物加热至65℃且老化18h。HPLC分析表明>99%转化。将批料冷却至20℃且转移至500-mL分液漏斗中。将MTBE(106mL)装入分液漏斗且使漏斗充分震荡。沉降5min之后,排出底部水层。顶部有机层用20%K2CO3洗涤两次(32mL和11mL)。将批料转移至250mL RBF中。通过HPLC的分析表明<2%的萘甲酸副产物。在减压下在旋转蒸发仪(300毫巴,外部温度为约40℃)上将批料浓缩至最小体积。通过添加和蒸馏THF(约50mL,约50mL)使用旋转蒸发仪(约250毫巴,外部温度为约40℃)将批料转至THF中。在每次THF装入之后,将批料蒸馏至最小体积。将THF(50mL)装入250mL RBF中。样品的KF显示0%H2O(≤0.1%可接受)。批料经过滤处理(60mL中等玻璃料漏斗)至清洁且干燥的250mL 3颈RBF中,使用THF(50mL)进行冲洗和体积调整。向批料中添加4-氟-3-硝基苯甲酸(4.61g,1.0当量),将混合物冷却至-20℃,且历经1.5h添加20%叔丁醇钾THF溶液(40mL),维持批料温度在-20±10℃下(放热)。完成添加之后,将批料在-20℃下老化,且在1.5h之后通过HPLC分析的等分试样显示出98%转化。向烧瓶中的批料中添加NH4Cl饱和溶液(10mL),维持温度在-20±10℃下,随后在-20±20℃下添加H2O(20mL)和MeTHF(34mL)。将混合物升至20℃且搅拌13h。将批料转移至分液漏斗中,使其沉淀约5min,且移除底部水层,保留残余有机料流。在20℃下用NH4Cl饱和溶液(10mL)和H2O(20mL)洗涤顶部有机料流。在沉降约5min之后,分离水层。在250mL 3颈RBF中向总粗有机料流(KF=14%)中添加MSA(4mL)。将批料加热至回流(65℃)后保持25h,并且LC分析表明完全转化(≥97%)。
将批料冷却至<20℃,且添加K3PO4·H2O(4.5g)和H2O(7mL)。将批料转移至分液漏斗中且排出底部水层,得到醛产物粗溶液。使用旋转蒸发仪将合并的有机粗料流浓缩至最小体积。向500mL RBF中的批料中装入AcOH(约50mL,约50mL)且在减压(30毫巴,外部温度为约40℃)下使用旋转蒸发仪蒸馏。通过QNMR测量THF水平,未观测到任何THF。将混合物转移至250mL 3颈RBF中,且在发生结晶时添加AcOH以将总体积调整至约40mL。历经约1h向批料中添加H2O(12mL)。在老化>1h之后,LC分析的上清液浓度为9mg/mL。若浓度>10mg/mL,则可添加一小部分H2O(0.2倍体积);在通过LC检查之后,在必要时重复。将批料过滤,用20%H2O/AcOH(23mL)洗涤,且在N2/真空下干燥3.25h,得到为灰白色固体的标题化合物(8.22g)(纯度校正后的产率为82%)。
步骤9B:(R)-4-((6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲氧基)-3-硝基苯甲酸叔丁酯
向(R)-4-((6-氯-1-(二甲氧基甲基)-1,2,3,4-四氢萘-1-基)甲氧基)-3-硝基苯甲酸叔丁酯(1g,2.033mmol)于无水丙酮(41mL)中的溶液添加-15(1g,2.033mmol;用2×10mL无水丙酮预洗涤)。将混合物加热至50℃保持3.5h,随后过滤且用DCM冲洗。浓缩滤液且在高真空下干燥过夜(其变为深红色)。LC/MS和NMR分析表明存在约10%的相应羧酸以及0.5当量的异丙叉丙酮(mesityl oxide)。混合物不经进一步纯化即转至步骤11。
步骤10:(S)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
将粗(R)-4-((6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲氧基)-3-硝基苯甲酸(30g,77.10mmol)于AcOH(1L)中的溶液加热至70℃,然后添加铁粉(28g,500mmol)。将所得混合物在70℃下加热约4h。随后减压移除AcOH,且将残余物溶于DCE(1L)中。逐份添加三乙酰氧基硼氢化钠(46.5g,740mmol),且将反应混合物在环境温度下搅拌1h。随后用H2O再用10%柠檬酸水溶液(500mL)淬灭反应。用DCM(2×1L)萃取水相,且将合并的有机层用盐水(500mL)洗涤,经Na2SO4干燥且减压浓缩。通过柱色谱使用100-200网目尺寸的SiO2凝胶(40%EtOAc/Hex)纯化残余物,得到为白色固体的纯(S)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(24g,两个步骤后为99%)。
或者,(S)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸与((1S,4R)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)甲磺酸(1:1)可如下制备:
向压力反应器中装入(R)-4-((6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲氧基)-3-硝基苯甲酸(20g,94wt%)、5%湿Pt/S/C(2.2g)、THF(400mL)和异丙醇钛(0.5mL)。将反应器密封,用惰性气体吹扫(3次循环,至少一次在搅拌下进行),随后用H2吹扫(1次循环)。反应器用H2加压至70psig,开始搅拌(950rpm),将温度升至90℃,维持反应器中的H2压力(在22-30℃下为70psig,在50-60℃下为80psig且在88-91℃下为90psig)。16h后,将反应器冷却至环境温度且用惰性气体吹扫(3次循环)。反应的HPLC分析证实>98%转化。
使用另外的THF进行冲洗将反应混合物经垫(2英寸)过滤,且在40℃下减压浓缩滤液。向残余物中添加IPA(60mL)和2-4%MeOH水溶液(10mL)。将混合物搅拌10min,随后经由垫(2英寸)过滤。将MeOH在40℃下减压蒸发,且历经2h向冷却至环境温度的浓缩IPA溶液中逐滴添加+CSA(56.0g)于IPA(200mL)中的溶液。在添加10%CSA溶液之后,将混合物接种标题化合物的晶体(10-15mg),随后添加剩余的CSA溶液。在环境温度下搅拌过夜后,过滤混合物,且用100mL IPA洗涤滤饼且在真空/N2下在环境温度下干燥。产物经分离为白色固体:(S)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸与((1S,4R)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)甲磺酸(1:1)(85-88%产率,>99.5%ee)。
步骤11A:(S)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸甲酯
向(S)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(130g,379mmol)于甲醇(6L)中的溶液添加-15(130g,用无水甲醇预洗涤),且加热至回流保持10h。随后通过过滤移除且用甲醇(3×300mL)冲洗。浓缩合并的滤液且通过柱色谱纯化残余物,得到为白色固体的纯(S)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸甲酯(105g,77%)。手性HPLC条件:柱:OD-H(250mm×4.6mm,5μm);流动相:正己烷:EtOH:95:05。运行时间:25min。流动速率:1mL/min。保留时间(次峰):10.162min(1.98%);保留时间(主峰):12.292min(98.02%)。
步骤11B:(S)-6’-氯-3’,4,4’,5-四氢-2H,2’H-螺[苯并[B][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯
在70℃下向(R)-4-((6-氯-1-甲酰基-1,2,3,4-四氢萘-1-基)甲氧基)-3-硝基苯甲酸叔丁酯(0.9g,2.018mmol)于AcOH(20.22mL,353mmol)中的溶液添加铁(0.676g,12.11mmol)。将混合物剧烈搅拌4h,随后浓缩,且用20mL 1,2-DCE稀释残余物。添加三乙酰氧基氢硼化钠(1.711g,8.07mmol),且将混合物在环境温度下搅拌20min。在通过添加20mLH2O淬灭后,形成粘稠浆液。添加20mL 10%柠檬酸溶液,且混合物的颜色变得较淡。分离各层,且用2×20mL DCM萃取水层。合并的有机物用10mL 10%柠檬酸和10mL盐水洗涤,经MgSO4干燥,过滤且浓缩。将残余物沉积于3g SiO2凝胶上且使用Hex中的5-10%EtOAc纯化,得到(S)-6’-氯-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯(557mg,1.393mmol,69.0%产率)。进一步用Hex中的30%EtOAc洗脱,得到(S)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(132mg,0.384mmol,19.02%产率)。
步骤12:(1R,2S)-1,2-环丁烷二基二甲醇
在3000mL 3颈RBF中在氩气流下向在环境温度下快速搅拌的LAH溶液(THF中的1.0M溶液,1000mL,1000mmol)中历经2h逐渐添加固体(1R,5S)-3-氧杂双环[3.2.0]庚烷-2,4-二酮(40g,317mmol),维持反应混合物的内部温度低于50℃。在环境温度下在氩气下搅拌反应物过夜。16h后,反应混合物通过冰浴冷却至10℃,然后在快速氩气流下,在剧烈搅拌(500rpm)下通过加料漏斗以将温度维持在12℃-15℃之间的约1mL/min速率逐滴添加36mLH2O溶液。混合物随后在冰浴中剧烈搅拌(500rpm)1h,随后从该浴移除且搅拌至rt后保持1h,随后再次用冰浴冷却至5-10℃。历经45min的时间向混合物中添加36mL 15%NaOH水溶液,维持温度在10-20℃之间。历经约1h通过加料漏斗向混合物中逐滴添加108mL H2O,维持温度在10-20℃之间。在完成添加H2O之后,从冰浴移除烧瓶,平衡至rt且保持在氩气下剧烈搅拌过夜。搅拌16h后,过滤混合物且减压浓缩滤液,得到无色不太透明的油状物。将油状物溶于Et2O,经无水MgSO4搅拌且经由垫过滤。减压浓缩滤液,得到32.8g无色油状物(89%产率),其不经进一步纯化即用于下一步骤。
步骤13:顺-环丁烷-1,2-二基双(亚甲基)二乙酸酯
将Ac2O(2.59mL;3.0当量)添加至顺-1,2-环丁烷二基二甲醇(1.06g,9.15mmol)中,且将所得溶液加热至50℃。在搅拌过夜之后,通过GC分析混合物且显示完全转化。混合物随后用15mL庚烷稀释且在真空下浓缩,得到澄清油状物。将油状物溶于15mL庚烷且浓缩回油状物(共沸移除Ac2O),得到为油状物的标题化合物(1.827g,88%产率,使用苯甲酸苄酯作为内标通过QNMR表明纯度为88.3%)。
步骤14:乙酸((1R,2S)-2-(羟甲基)环丁基)甲酯
向装有机械搅拌器的12L 3颈RBF中装入1M柠檬酸钠溶液(通过混合柠檬酸三钠二水合物;682g,2320mmol)与H2O来制备,以达到约2.3L的总体积)和3.48L H2O(约25℃)。使用冰/H2O浴将混合物冷却至约20.2℃。pH为约8.46(用pH探头测量)。随后一次性添加来自荧光假单胞菌(Pseudomonas fluorescens)的天野脂肪酶(Amano Lipase)(41.8g,1547mmol)(pH为约8.12),且将混合物在环境温度下剧烈搅拌约5min。一次性添加(1R,2S)-环丁烷-1,2-二基双(亚甲基)二乙酸酯(348g,1547mmol),且在监测内部温度和pH的环境温度下剧烈搅拌所得混合物。在搅拌混合物过夜(约20.9℃且pH为约5.45)之后,采集等分试样,用IPAc萃取,用MeCN稀释且通过GC分析,认为反应完成(1.21%SM残余,0.17%对映异构体,1.8%二醇)。将(70g)添加至反应混合物中,且将浆液在中等孔隙率玻璃过滤器上经由垫过滤(快速过滤,15-20min),用2.5LIPA冲洗。将两相混合物转移至12L萃取器中且搅拌1min。分离水层且用IPAc(1×4L)萃取,且在真空中浓缩经合并的有机萃取物,得到337.28g(99.6%ee;通过1H NMR表明存在约50-60mol%的残余IPA;QNMR:37.63mg+苯甲酸苄酯(Aldrich目录号B6630,批号MKBG9990V,61.27mg;结果:约65wt%;校正产率89%)。粗产物按原样用于下一步骤。
步骤15:乙酸((1R,2R)-2-甲酰基环丁基)甲酯
向2-L阿特拉斯(Atlas)反应器中装入乙酸((1R,2S)-2-(羟甲基)环丁基)甲酯(126.39g,通过QNMR表明为79.6wt%;636mmol)和1L DCM,且夹套温度设为20℃。添加为固体的二乙酸碘苯(225g,700mmol)(吸热加成:温度降至15℃)。一次性添加为固体的TEMPO(3.97g,25.4mmol),产生混浊橙色溶液,其历经20min的时间变澄清。在20℃下搅拌过夜之后,采集等分试样,用MeOH稀释且通过GC分析。在必要时可另外喷射添加(kicker charge)二乙酸碘苯和TEMPO以用于推进反应完成。随后将反应混合物冷却至1.8℃(内部温度,冰/干冰/H2O浴),并且历经65min经由加料漏斗逐滴添加DIPEA(194mL,1113mol),保持内部温度<5℃。移除冷却浴,并在搅拌下使混合物升至环境温度。48h后,采集等分试样,用甲醇稀释,且通过GC分析,显示12:1的反式异构体:顺式异构体比率。反应混合物随后冷却至<5℃(冰/H2O浴),历经约10min添加H2O(230mL)(内部温度达到14℃)。分离有机层,用H2O(125mL)和1M NaH2PO4水溶液(90mL)洗涤且在真空中浓缩,得到273.4g乙酸((1R,2R)-2-甲酰基环丁基)甲酯(QNMR:68.85mg+苯甲酸苄酯(Aldrich目录号B6630,批号MKBG9990V,72.36mg)。粗产物按原样用于下一步骤。
步骤16:乙酸((1R,2R)-2-((R)-(1H-苯并[D][1,2,3]三唑-1-基)(羟基)甲基)环丁基)甲酯
向粗乙酸((1R,2R)-2-甲酰基环丁基)甲酯(5g,10.27mmol)于8mL MTBE中的溶液添加为固体的苯并三唑(1.296g,10.00mmol)(轻微放热)。澄清溶液变得越来越混浊且形成沉淀。使混合物在环境温度下平衡过夜,随后添加庚烷(6mL)。在老化6h之后,在环境温度下过滤混合物且用10mL的1:1MTBE/庚烷洗涤。将白色固体在玻璃料上在真空下风干,得到2.48g乙酸((1R,2R)-2-((R)-(1H-苯并[d][1,2,3]三唑-1-基)(羟基)甲基)环丁基)甲酯。
步骤17:(S)-5-(((1S,2R)-2-乙酰氧基环丁基)甲基)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸甲酯
将乙酸((1R,2R)-2-甲酰基环丁基)甲酯(来自步骤16;4.36g,27.9mmol)添加至(S)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸甲酯(5.0g,13.97mmol)(步骤12)于DCM(78mL)和AcOH(38.8mL)中的溶液。将溶液在环境温度下搅拌10min,随后冷却至0℃,历经1h缓慢添加氰基硼氢化钠(1.463mL,27.9mmol)。将混合物在0℃下搅拌10min,随后缓慢倾入冷NaOH溶液中,且用EtOAc(120mL)萃取。有机相用盐水洗涤、经无水Na2SO4干燥且浓缩。将残余物上样至220g ISCO gold柱,且用0%至10%EtOAc/Hex洗脱,得到为白色固体的6.0g标题化合物。m/z(ESI+ve离子)498.1(M+H)+。
步骤18A:(S)-6’-氯-5-(((1R,2R)-2-(羟甲基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[B][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯
将KOH(0.278mL,10.14mmol)添加至(S)-5-(((1R,2S)-2-(乙酰氧基甲基)环丁基)甲基)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸甲酯(来自步骤18;1.530g,3.07mmol)于MeOH(99mL)中的溶液。将混合物在环境温度下搅拌4h,随后用1N HCl中和至pH=7,且减压浓缩。将水性残余物用EtOAc(400mL)萃取,且将有机萃取物用盐水洗涤,经无水Na2SO4干燥,且通过SiO2凝胶短塞过滤,得到为白色固体的标题化合物。(得到1.354g。m/z(ESI,+ve离子)456.2(M+H)+)
或者,(S)-6’-氯-5-(((1R,2R)-2-(羟甲基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯可如下制备:
向(S)-6'-氯-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸与((1S,4R)-7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)甲磺酸(1:1)(步骤11)(32.22g,52.5mmol)和乙酸((1R,2R)-2-((R)-(1H-苯并[d][1,2,3]三唑-1-基)(羟基)甲基)环丁基)甲酯(步骤17)(15.89g,57.7mmol)于DCM(226mL,7mL/g)中的浆液历经30min分4部分添加三乙酰氧基硼氢化钠(13.90g,65.6mmol)。添加另外的乙酸((1R,2R)-2-((R)-(1H-苯并[d][1,2,3]三唑-1-基)(羟基)甲基)环丁基)甲酯(2.89g,10.50mmol)和三乙酰氧基硼氢化钠(2.78g,13.12mmol)以驱动反应完成(通过HPLC分析而确定)。随后添加80mLH2O,且将所得混合物搅拌5min。分离各层,有机相用60mL H2O和20mL盐水洗涤,随后减压浓缩为油状物。将残余物溶于50mL MeOH中,随后在环境温度下添加40mL的5N NaOH(放热)。在反应完成(通过HPLC分析而确定)后,将反应混合物分配于133mL MTBE与35mL 1.5M柠檬酸之间。将有机相转移至RBF,且溶剂经由常压蒸馏交换为MeCN。将此溶液在62℃下接种(形成浆液),使其达到环境温度,随后老化过夜。将浆液在20.5℃下经由粗玻璃料烧结漏斗过滤,并且滤饼用60mL MeCN洗涤,随后在真空烘箱中在40℃下干燥至恒重。最终质量:21.87g(通过HPLC表明为96.4wt%)。
向100mL 3颈RBF中装入(S)-6'-氯-5-(((1R,2R)-2-(羟甲基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(4.53g,1.0当量)、MeOH(45mL,10倍体积),随后添加配制的SOCl2溶液(11.28mL,1.0M MeCN,1.1当量)。在N2氛围下,将批料加热至55℃且搅拌18h(或直至通过HPLC测定表明>99%转化)。随后使反应混合物历经2h冷却至20℃。向所得白色浆液中添加Hunig’s碱(3.94mL,2.2当量),且在老化0.5h后,历经1h添加H2O(9.0mL,2V)作为反溶剂。将白色浆液老化>2h,并将批料经由玻璃烧结过滤器过滤,滤饼用MeOH/H2O(5:1v/v)(9.0mL,2V)随后用MeOH/H2O(2:1v/v)(9.0mL,2V)洗涤。在环境温度下将滤饼在N2下在真空下干燥12h。得到为白色固体的产物(4.36g,92%产率)。
步骤18B:(S)-6’-氯-5-(((1R,2R)-2-(羟甲基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[B][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯
按照针对中间体AA11A的步骤18-19A)所描述的程序由(S)-6’-氯-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯(中间体AA11A,步骤12B)合成标题化合物。
步骤19A:(S)-6’-氯-5-(((1R,2R)-2-甲酰基环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[B][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯
在用N2惰化的1L 3颈RBF中以维持温度低于-70℃的速率向DMSO(7.12mL,2.5当量)和DCM(183mL,10倍体积)的冷却(-70℃)溶液中添加草酰氯(26.1mL,1.0M于DCM中,1.3当量)。将批料在低于-70℃下老化30min,随后以维持反应温度<-70℃的速率添加(S)-6’-氯-5-(((1R,2R)-2-(羟甲基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯(来自步骤19A;18.3g,1.0当量)于DCM(183mL,10倍体积)中的配制溶液。将批料老化1.5h,随后以维持批料温度<-70℃的速率添加Et3N(22.4mL,4.0当量)。老化1h后,使批料升至-20℃且添加H2O(366mL,20倍体积)。将批料在20℃下搅拌且分离各相。有机层用2×1N HCl(183mL,10倍体积)和盐水(183mL,10倍体积)洗涤。有机层经过滤处理且在真空中浓缩,得到为褐色泡沫的(S)-6’-氯-5-(((1R,2R)-2-甲酰基环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯(19.91g,wt%校正的产率为94%)。
步骤19B:(S)-6’-氯-5-(((1R,2R)-2-甲酰基环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[B][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯
按照针对中间体AA11A的步骤20A所描述的程序由(S)-6’-氯-5-(((1R,2R)-2-(羟甲基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯(中间体AA11A,步骤19B)合成标题化合物。
步骤20:(S)-6’-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[B][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯
在氩气吹扫下将装有压力均衡加料漏斗、热电偶和磁力搅拌棒的烘箱干燥的3颈RBF冷却至环境温度。针对氩气正压,向烧瓶中装入(1R,2S)-2-吗啉基-1-苯基丙-1-醇(40.2g,182mmol;根据Brubaker,J.D.;Myers,A.G.Org.Lett.2007,9,3523-3525的文献程序制备)。向加料漏斗中装入甲苯(450mL),将其滴入反应器中。将溶液在乙二醇-CO2浴(约-12℃)中冷却且用丁基锂溶液(2.5M于Hex中,72.6mL,182mmol)处理,导致产生白色固体沉淀,在历经30min搅拌下其逐渐进入溶液。二乙烯基锌溶液(605mL,182mmol;根据Brubaker,J.D.;Myers,A.G.Org.Lett.2007,9,3523-3525制备。二乙烯基锌溶液的浓度通过对碘进行滴定来测定(Krasovskiy,A.;Knochel,P.Synthesis 2006,890-891;浓度一般为约0.25M),并将溶液在搅拌下在冷浴中老化1h;内部温度为-15℃。经由套管(16G)以甲苯溶液(200mL,150mL+2×25mL套管/小瓶冲洗)形式添加(S)-6’-氯-5-(((1R,2R)-2-甲酰基环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯(来自步骤20A;48.5g,107mmol)(用甲苯共沸三次),历经约20min。内部温度升至-10℃。在维持内部反应温度低于-5℃的同时搅拌混合物90min。向加料漏斗中装入30%w/w柠檬酸水溶液(450mL),随后通过添加溶液至反应混合物中来淬灭反应。从浴移除反应器且使之在环境温度下搅拌。将溶液转移至分液漏斗,并用甲苯和30%柠檬酸水溶液(每次50mL)冲洗烧瓶。混合各层,随后分离。将有机层用H2O(250mL)随后用盐水(250mL)洗涤,最后经MgSO4干燥。过滤且浓缩溶液,在真空下过夜之后得到约90g黄色油状物(20:1dr)。将该油状物分成3批且通过柱色谱(10至20%EtOAc/Hex 1.5kg SiO2)纯化,得到(S)-6’-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯(43.3g,84%)。将水层和洗涤液置于冰/H2O浴中,通过添加8N NaOH水溶液碱化至pH>13。随后用甲苯(3×250mL)萃取此溶液。将合并的有机萃取物用H2O(250mL)和盐水(250mL)洗涤,随后经MgSO4干燥。过滤且浓缩溶液,以>95%的产率回收到配体。
步骤21:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
向(S)-6’-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯(来自步骤21;4.59g,9.52mmol)于THF(18mL)、MeOH(6.00mL)和H2O(6.00mL)的混合物中的溶液添加LiOH·H2O(0.799g,19.05mmol),并将反应物在50℃下搅拌4h。将反应混合物浓缩至约15mL,冷却至0℃且用2N HCl酸化至pH=3。将所得粘性油状物用20mL H2O和50mL EtOAc稀释,且得到澄清双层混合物。添加更多的EtOAc(约200mL),将有机层分离,用盐水洗涤,经MgSO4干燥,过滤且减压浓缩。将粗物质上样至柱(220g)上,用EtOAc/Hex使用以下梯度纯化:0-2.5min 0%EtOAc、2.5m-6m 0-20%EtOAc、6m-35m20-60%EtOAc、35m-40m 70%EtOAc,得到为白色固体的(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(4.22g,9.02mmol,95%产率)。
中间体AA12A
(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
步骤1A:(S)-6’-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[B][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯
在氩气氛围下,将装有无水Hex(27mL)的干燥3颈RBF冷却至0℃。向此溶液中添加硼烷-二甲硫醚络合物(3.29mL,34.6mmol)和环己烯(7.01mL,69.3mmol),且将混合物在0℃下搅拌2h。向所得白色悬浮液中添加1-戊炔(3.41mL,34.6mmol),且将混合物在环境温度下搅拌0.5h。随后将混合物冷却至-78℃,并添加二乙基锌于Hex中的1.0M溶液(32.3mL,32.3mmol)。在添加之后,将混合物升至0℃,搅拌3min随后再冷却至-78℃。此溶液命名为溶液A。向独立烧瓶中装入((S)-6'-氯-5-(((1R,2R)-2-甲酰基环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸甲酯(中间体AA11A,步骤20A,5.24g,11.54mmol)和(2s)-3-外型-(吗啉)异冰片((2s)-3-exo-(morpholino)isoborneal)(0.486g,2.032mmol)于Hex(50.9mL)和甲苯(16.97mL)中的混合物。将混合物在环境温度下搅拌直至所有固体溶解,随后冷却至0℃。在氩气氛围下,在1.6h期间经由注射器缓慢添加54mL溶液A。在0℃下搅拌5min后,将混合物用NH4Cl饱和溶液(70mL)淬灭,用H2O(30mL)稀释且用EtOAc(3×270mL)萃取,用盐水洗涤,经无水Na2SO4干燥且浓缩。将残余物上样至330gISCO gold柱,且用0%至5%EtOAc/Hex洗脱,得到为白色固体的3.8g标题化合物。m/z(ESI,+ve离子)524.1(M+H)+。
步骤1B:(S)-6’-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[B][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯和(S)-6’-氯-5-(((1R,2R)-2-((R,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[B][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯
按照针对中间体AA12A的步骤1A所描述的程序由(S)-6’-氯-5-(((1R,2R)-2-甲酰基环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯(3.19g,中间体AA11A,步骤20B)合成标题化合物。将粗物质吸附至SiO2塞上且在330g ISCO gold柱上历经45min用0至15%EtOAc/庚烷洗脱而纯化,得到(S)-6’-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯(2.36g)。进一步洗脱得到(S)-6’-氯-5-(((1R,2R)-2-((R,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯(0.45g)。
步骤2:(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
将(S)-6’-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯(来自中间体AA12A,步骤A;4.6g,8.78mmol)和LiOH·H2O(3.68g,88mmol)于MeOH(98mL)和THF(98mL)中的混合物(具有几滴H2O)在50℃下搅拌过夜。移除溶剂,且用1N HCl将残余物酸化至pH 2-3。用EtOAc(80mL×3)萃取混合物,并将合并的有机层用盐水(10mL)洗涤,经无水MgSO4干燥且减压浓缩,得到(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(4.25g,8.34mmol,95%产率)。
或者,标题化合物可如下合成:
向(S)-6’-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯(中间体AA12A,步骤1B,第一洗脱异构体,4.50g,7.95mmol)与LiOH·H2O(1.66g,39.7mmol)的固体混合物中添加溶剂二噁烷/MeOH(1:1)(159mL)。将混合物加热至65℃,且搅拌过夜。混合物随后用H2O稀释且用1.0N HCl酸化至pH约4。减压蒸发有机溶剂,且向残余物中添加H2O。水溶液混合物随后用EtOAc萃取三次,且将合并的有机萃取物浓缩。在120g SiO2凝胶柱上用0-70%EtOAc/Hex梯度洗脱来纯化残余物,得到(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(3.80g,7.45mmol,94%产率)。
中间体AA13A
(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
步骤1A:(S)-6’-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[B][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯
将在氩气下装有(1R,2R)-N-甲基-1-苯基-1-(((1S,5S,10R)-10-(三甲基硅烷基)-9-硼双环[3.3.2]癸-9-基)氧基)丙-2-胺(5.40g,14.54mmol)于Et2O(73mL)中的悬浮液的烘箱干燥的200-mL烧瓶冷却至-78℃,且用烯丙基溴化镁(13.22mL,13.22mmol)溶液逐滴处理。使混合物升至环境温度且搅拌1h。随后将溶液(约0.17M;溶液A)再冷却至-78℃。
将在氩气下装有于Et2O(22.03mL)中的((S)-6'-氯-5-(((1R,2R)-2-甲酰基环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸甲酯(中间体AA11A,步骤20A,2.0g,4.41mmol)的独立200mL烧瓶冷却至-78℃。向此溶液中添加40mL上文提及的溶液A,且将所得混合物在-78℃下搅拌40min。随后添加4-甲基吗啉4-氧化物(3.10g,26.4mmol),且使混合物升至环境温度保持10min。添加甲醇(10mL),且将挥发性有机物在环境温度下减压蒸发。添加另外的甲醇(100mL),且在环境温度下搅拌1h之后浓缩混合物。残余物用EtOAc(450mL)稀释,用1N HCl(15mL)、Na2CO3溶液(10mL)和盐水(6mL)洗涤,经无水Na2SO4干燥且浓缩。将残余物上样至220g ISCO gold柱,且用0%至5%EtOAc/Hex洗脱,得到为白色固体的1.88g标题化合物。m/z(ESI,+ve离子)496.0(M+H)+。
步骤1B:(S)-6’-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[B][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯
按照针对中间体AA13A的步骤1A所描述的程序由(S)-6’-氯-5-(((1R,2R)-2-甲酰基环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯(中间体AA11A,步骤20B;3.0g)合成标题化合物。在220g SiO2凝胶柱上历经60min用5%EtOAc/Hex洗脱来纯化粗物质,得到(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸叔丁酯(2.19g)。
步骤2:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
将(S)-6’-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸甲酯(来自中间体AA13A,步骤1A;1.88g,3.79mmol)和LiOH溶液(1M)(34.1mL,34.1mmol)于MeOH(34mL)和THF(50mL)中的混合物在65℃下搅拌50min。在冷却至环境温度之后,将混合物用1N HCl酸化至pH 2至3,用EtOAc(350mL)萃取,经无水Na2SO4干燥且浓缩,得到为白色固体的1.82g标题化合物。m/z(ESI,+ve离子)482.0(M+H)+。
或者,标题化合物可如下合成:
在环境温度下向(S)-6’-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯(中间体AA13A,步骤1B,250mg,0.465mmol)于DCM(3.717mL)中的溶液添加TFA(0.929mL),且将反应混合物搅拌4h。随后浓缩粗反应混合物,将残余物溶于EtOAc,用饱和NaHCO3洗涤一次,经MgSO4干燥,过滤且浓缩,得到白色泡沫。粗物质不经进一步纯化即按原样使用。
中间体EE11
N,N-双(4-甲氧基苄基)胺
使用迪安-斯塔克(Dean-Stark)装置将4-甲氧基苯甲醛(Spectrochem;100g,734.5mmol)和4-甲氧基苄基胺(G.L.R.;100g,734.5mmol)于甲苯(0.8L)中的溶液在130℃下回流6h。通过TLC监测反应,并在完成后,减压移除过量的溶剂且将残余物溶于甲醇(0.8L)中。将所得溶液冷却至0℃,并逐份添加硼氢化钠(36.12g,954.8mmol)。完成添加后,将反应混合物在环境温度下搅拌3h。移除甲醇,并用H2O(1.0L)和EtOAc(2.0L)稀释残余物。分离各层,并用EtOAc(2×1.0L)萃取水层。将合并的有机层用H2O、盐水洗涤,并经Na2SO4干燥。减压移除溶剂,并将所得的粗物质通过柱色谱经由SiO2凝胶(100-200网目尺寸)用100%Hex至25%EtOAc/Hex梯度洗脱来纯化,得到为无色但不透明液体的标题化合物(160g,84.6%)。
中间体EE12
N,N-双(4-甲氧基苄基)甲磺酰胺
将甲磺酰胺(Sigma-Aldrich,5g,52.6mmol)、对甲氧基苄氯(14.98mL,110mmol)、无水K2CO3(36.3g,263mmol)和碘化钾(0.873g,5.26mmol)于无水2-丁酮(175mL)中的混合物回流(75℃)过夜。通过TLC和LC/MS监测反应,并在完成后,将混合物冷却至环境温度,过滤,用Et2O洗涤且浓缩。粗物质(17.54g,52.3mmol,99%产率)不经进一步纯化即使用。MS(ESI,正离子)m/z:358.1(M+Na)。
中间体EE13
N,N-双(4-甲氧基苄基)乙磺酰胺
向N,N-双(4-甲氧基苄基)胺(中间体EE11;200g,775.19mmol)于DCM(2.5L)中的溶液添加Et3N(336.17mL,2325.5mmol),且将反应混合物冷却至0℃。以逐滴方式添加乙磺酰氯(95mL,1007.75mmol)随后添加DMAP(19.0g,155.03mmol)。将所得反应混合物在环境温度下搅拌30min。通过TLC监测反应,并在完成后,用H2O稀释混合物,然后分离各层且用DCM(3×1.5L)萃取水相。将合并的有机层用H2O、盐水洗涤,并经Na2SO4干燥。减压移除溶剂,得到粗物质,通过柱色谱经由SiO2凝胶(100-200目)用0-12%EtOAc/Hex梯度洗脱来纯化,得到为白色蓬松固体的标题化合物(145g,53.4%)。
中间体EE14
N,N-双(4-甲氧基苄基)丙磺酰胺
向N,N-双(4-甲氧基苄基)胺(中间体EE11;405g,1569.7mmol)于DCM(4.0L)中的溶液添加Et3N(681.0mL,4709.3mmol),且将反应混合物冷却至0℃。以逐滴方式添加丙磺酰氯(231mL,2040.6mmol)随后添加DMAP(38.3g,313.9mmol)。将所得混合物在环境温度下搅拌30min。通过TLC监测反应,并在完成后,用2.0L H2O稀释混合物,分离各层且用DCM(3×2.0L)萃取水相。将合并的有机层用H2O、盐水洗涤,并经Na2SO4干燥。减压移除溶剂,得到粗物质,通过柱色谱经由SiO2凝胶(100-200目)用0-12%EtOAc/Hex梯度洗脱来纯化所述粗物质,得到为白色蓬松固体的标题化合物(300g,52.44%)。
中间体EE15
丁-3-烯-1-磺酰胺
步骤1:丁-3-烯-1-磺酸钠
将4-溴-1-丁烯(LLBChem,3.01mL,29.6mmol)和亚硫酸钠(4.11g,32.6mmol)于H2O(20mL)中的混合物在110℃下搅拌过夜。通过TLC监测反应,并在完成后,减压移除H2O且用丙酮磨碎残余物。过滤所得的固体,得到为白色固体的标题化合物(4.53g),其按原样用于下一步骤。
步骤2:丁-3-烯-1-磺酰胺
将丁-3-烯-1-磺酸钠(4.50g,28.5mmol)与氧氯化磷(70mL)的混合物在135℃下搅拌7h。随后减压移除氧氯化磷,得到含有深色残余物的白色固体。用MeCN(20mL)稀释残余物,随后过滤以移除沉淀。将滤液冷却至0℃且用氨溶液(30%水溶液)(30mL)逐滴处理。在完成添加之后,将反应物在0℃下搅拌30min。混合物用EtOAc(300mL)稀释,用盐水洗涤,并经无水Na2SO4干燥。减压移除溶剂,且通过柱色谱经由SiO2凝胶(100-200目;用1:1EtOAc/Hex洗脱)来纯化残余物,得到为白色固体的标题化合物(1.55g,产率:40%)。MS(ESI,正离子)m/z:117.1(M+1)。
中间体EE16
N,N-双(4-甲氧基苄基)丁-3-烯-1-磺酰胺
将丁-3-烯-1-磺酰胺(中间体EE15;1.5g,11.10mmol)、对甲氧基苄氯(3.76mL,27.7mmol)、无水K2CO3(7.67g,55.5mmol)和碘化钠(0.166g,1.110mmol)于无水2-丁酮(55.5mL)中的混合物回流(75℃)过夜。通过TLC和LC/MS监测反应,且在完成后,将混合物冷却至环境温度,过滤且浓缩。将粗物质吸附至SiO2凝胶塞上且通过色谱经由SiO2凝胶(100-200目)用0至30%EtOAc/Hex洗脱来纯化,得到为无色油状物的标题化合物(4.10g,10.92mmol,98%产率)。MS(ESI,正离子)m/z:376.2(M+1)。
中间体EE17
(R)-戊-4-烯-2-磺酰胺
步骤1:(S)-N,N-双(4-甲氧基苄基)戊-4-烯-2-磺酰胺和(R)-N,N-双(4-甲氧基苄基)戊-4-烯-2-磺酰胺
将N,N-双(4-甲氧基苄基)丁-3-烯-1-磺酰胺(中间体EE16;50.0g,133.2mmol)用甲苯共沸且在真空下干燥1h。添加THF(890mL)且将混合物冷却至-78℃。随后添加丁基锂(于Hex中2.5M,63.9mL,159.9mmol),将反应混合物在-78℃下搅拌1h。将此阴离子溶液缓慢添加至MeI(16.8mL,266.5mmol)于THF(300mL)中的溶液(冷却至-78℃)。所得反应混合物在-78℃下再搅拌15min。在反应完成(通过TLC监测)时,将混合物用NH4Cl饱和溶液淬灭且用EtOAc萃取。有机层经Na2SO4干燥且减压浓缩,得到粗物质,通过柱色谱经由SiO2凝胶用5-10%EtOAc/Hex洗脱来纯化所述粗物质,得到为具有半固体性质的外消旋混合物的标题化合物(22.0g)。通过SFC(柱:AD-H,50X250mm,5μm;流动相A:CO2;流动相B:乙醇;等度:40%B,CO2循环器打开;流动速率:200g/min;上样:2.0mL如上所述制备的样品(约100mg);检测:在230nm下的UV;循环时间:5min;总洗脱时间:10min;仪器:Thar 350(Lakers))分离对映异构体,得到为第一洗脱异构体的(S)-N,N-双(4-甲氧基苄基)戊-4-烯-2-磺酰胺(保留时间:2.22min)和为第二洗脱异构体的(R)-N,N-双(4-甲氧基苄基)戊-4-烯-2-磺酰胺(保留时间:2.57min)。
步骤2:(R)-戊-4-烯-2-磺酰胺
向(R)-N,N-双(4-甲氧基苄基)戊-4-烯-2-磺酰胺(中间体EE17,步骤1,第二洗脱异构体;221mg,0.567mmol)于DCM(2.8mL)中的溶液逐滴添加三氟乙酸(1.7mL,22.70mmol)(澄清溶液极快变成深色)。搅拌7h之后(TLC 30%EtOAc/Hex显示原料耗尽),将混合物用EtOAc稀释,用饱和NaHCO3洗涤,用EtOAc反萃取,经MgSO4干燥且浓缩。粗物质经由色谱(12gISCO gold柱;0-40%EtOAc Hex)纯化,得到(R)-戊-4-烯-2-磺酰胺(70mg,0.469mmol,83%产率)
中间体EE172
(S)-戊-4-烯-2-磺酰胺
使用针对中间体EE17的步骤2所描述的程序由(S)-N,N-双(4-甲氧基苄基)戊-4-烯-2-磺酰胺(中间体EE17,步骤1,第一洗脱异构体)合成此中间体。
中间体EE18
(R)-己-5-烯-3-磺酰胺
步骤1:(S)-N,N-双(4-甲氧基苄基)己-5-烯-3-磺酰胺和(R)-N,N-双(4-甲氧基苄基)己-5-烯-3-磺酰胺
使N,N-双(4-甲氧基苄基)丁-3-烯-1-磺酰胺(中间体EE16;40.0g,106.6mmol)在甲苯中在真空下共沸2h。在氩气氛围下添加THF(700mL),且将反应混合物冷却至-78℃。添加丁基锂(2.5M Hex;71.6mL,127.9mmol),且将反应混合物在-78℃下搅拌1h。将此阴离子溶液缓慢添加至碘乙烷(36.44mL,340.1mmol)于THF(40mL)中的溶液(冷却至-78℃)。所得反应混合物随后用NH4Cl饱和溶液淬灭,使其达到环境温度且用EtOAc萃取。有机层经Na2SO4干燥且减压浓缩,得到粗物质,所述粗物质通过柱色谱经由SiO2凝胶用5-10%EtOAc/Hex洗脱来纯化,得到为具有半固体性质的外消旋混合物的标题化合物(24g)。MS(ESI,正离子)m/z;404.03(M+1)。通过SFC(样品制备:在MeOH:DCM(3:1)中的14.4g/200mL(72mg/mL)的样品溶液;柱:AD-H,30X250mm,5μm;流动相A:CO2;流动相B:MeOH(20mM NH3);等度:50%B,流动速率:100mL/min;出口压力:100巴;上样:1.0mL如上所述制备的样品溶液(72mg);检测:在227nm下的UV;循环时间:8min;总洗脱时间:17min;仪器:Thar 350 SFC)分离对映异构体,得到为第一洗脱异构体的(S)-N,N-双(4-甲氧基苄基)己-5-烯-3-磺酰胺和为第二洗脱异构体的(R)-N,N-双(4-甲氧基苄基)己-5-烯-3-磺酰胺。
步骤2:(R)-己-5-烯-3-磺酰胺
使用针对中间体EE17的步骤2所描述的程序由(R)-N,N-双(4-甲氧基苄基)己-5-烯-3-磺酰胺(中间体EE18,步骤1,第二洗脱异构体)合成此中间体。
中间体EE182
(S)-己-5-烯-3-磺酰胺
使用针对中间体EE17的步骤2所描述的程序由(S)-N,N-双(4-甲氧基苄基)己-5-烯-3-磺酰胺(中间体EE18,步骤1,第一洗脱异构体)合成此中间体。
中间体EE19
N,N-双(4-甲氧基苄基)戊-4-烯-1-磺酰胺
步骤1:戊-4-烯-1-磺酸钠
向装有机械搅拌器、N2进气口、冷凝器和温度探头的3L3颈RBF中装入5-溴-1-戊烯(Sigma Aldrich,200g,1342mmol)、亚硫酸钠(Strem Chemicals;186g,1476mmol)和H2O(400mL)。将混合物加热至回流(设定在100℃下且在93-94℃下回流)保持4h;等分试样NMR显示>95%转化。将混合物浓缩且用丙酮共沸以移除H2O。粗固体用丙酮洗涤且过滤,得到戊-4-烯-1-磺酸钠(350g,2033mmol)。
步骤2:戊-4-烯-1-磺酰胺
向装有机械搅拌器、N2进气口、冷凝器和温度探头的3L3颈RBF中装入戊-4-烯-1-磺酸钠(100g,581mmol)(约150g来自步骤1的粗物质)和氧氯化磷(Sigma Aldrich;532mL,5808mmol)。将混合物加热至90℃后保持18h,之后过滤反应物且用MeCN洗涤固体。将有机溶液浓缩且用MeCN共沸以移除POCl3,得到85g戊-4-烯-1-磺酰氯中间体。将此物质(300mLMeCN中的溶液)装入装有机械搅拌器、N2进气口、冷凝器和温度探头的1L 3颈RBF中。将反应物冷却至0-5℃,且历经30min缓慢添加NH4OH(Sigma Aldrich;28%NH3;404mL,2904mmol)。将反应物在0-5℃下搅拌1h,之后添加EtOAc(300mL),且将混合物用EtOAc萃取并浓缩,得到为棕色油状物的戊-4-烯-1-磺酰胺(50g,335mmol,57.7%产率)。
步骤3:N,N-双(4-甲氧基苄基)戊-4-烯-1-磺酰胺
按照针对中间体EE16所描述的程序由戊-4-烯-1-磺酰胺(4.5g,30.2mmol)合成标题化合物。粗物质的纯化得到作为无色油状物的N,N-双(4-甲氧基苄基)戊-4-烯-1-磺酰胺(11.4g,29.3mmol,97%产率)。
中间体EE20
(R)-己-5-烯-2-磺酰胺
步骤1:(S)-N,N-双(4-甲氧基苄基)己-5-烯-2-磺酰胺和(R)-N,N-双(4-甲氧基苄基)己-5-烯-2-磺酰胺
将N,N-双(4-甲氧基苄基)乙磺酰胺(中间体EE13;140.0g,400.64mmol)于THF(1.4L,THF在使用前用氩气吹扫15min)中的溶液冷却至-78℃,且逐滴添加丁基锂溶液(2.6M Hex,200.0mL,520.83mmol)。所得溶液在-78℃下搅拌10min,且历经2min添加4-溴-1-丁烯(73.2mL,721.15mmol)。5min后,使反应物达到环境温度且搅拌1h。通过TLC监测反应,且在完成后,将混合物用饱和NH4Cl溶液(400mL)淬灭,并将所得水层用EtOAc(2×1.0L)萃取。将合并的有机层用盐水洗涤且经Na2SO4干燥。减压移除溶剂,得到粗物质,所述粗物质通过柱色谱(SiO2凝胶100-200目)用0-4%丙酮/Hex梯度洗脱来纯化,得到为无色浓稠油状物的标题化合物(外消旋混合物,80.0g,49.5%)。MS(ESI,正离子)m/z:404.25(M+1)。通过SFC(样品制备:75g/1.5L(50mg/mL)的样品的MeOH溶液;柱:IF,21X250mm,5μm;流动相A:CO2;流动相B:MeOH(0.2%DEA);等度:40%B,流动速率:80mL/min;出口压力:100巴;上样:3.0mL如上所述制备的样品溶液(150mg);检测:在225nm下的UV;循环时间:3.9min;总洗脱时间:6min;仪器:Thar 80 SFC)分离对映异构体,得到为第一洗脱异构体的(S)-N,N-双(4-甲氧基苄基)己-5-烯-2-磺酰胺和作为第二洗脱异构体的(R)-N,N-双(4-甲氧基苄基)己-5-烯-2-磺酰胺。
步骤2:(R)-己-5-烯-2-磺酰胺
使用针对中间体EE17的步骤2所描述的程序由(R)-N,N-双(4-甲氧基苄基)己-5-烯-2-磺酰胺(中间体EE20,步骤1,第二洗脱异构体)合成标题化合物。
中间体EE202
(S)-己-5-烯-2-磺酰胺
使用针对中间体EE17的步骤2所描述的程序由(S)-N,N-双(4-甲氧基苄基)己-5-烯-2-磺酰胺(中间体EE20,步骤1,第一洗脱异构体)合成标题化合物。
中间体EE21
(R)-庚-6-烯-3-磺酰胺
步骤1:(S)-N,N-双(4-甲氧基苄基)庚-6-烯-3-磺酰胺和(R)-N,N-双(4-甲氧基苄基)庚-6-烯-3-磺酰胺
使用针对中间体AA20的步骤1所描述的程序由N,N-双(4-甲氧基苄基)丙磺酰胺(中间体EE14)合成标题化合物。通过SFC(样品制备:40.55g/170mL(238.5mg/mL)的样品的MeOH溶液;柱:AD-H,50×150mm,5μm;流动相A:CO2;流动相B:MeOH(20mM NH3);等度:50%B,流动速率:190mL/min;出口压力:100巴;上样:1.5mL如上所述制备的样品溶液(357.8mg);检测:在227nm下的UV;循环时间:17.5min;总洗脱时间:21min;仪器:Thar350SFC)分离对映异构体,得到为第一洗脱异构体的(S)-N,N-双(4-甲氧基苄基)庚-6-烯-3-磺酰胺和为第二洗脱异构体的(R)-N,N-双(4-甲氧基苄基)庚-6-烯-3-磺酰胺。
步骤2:(R)-庚-6-烯-3-磺酰胺
使用针对中间体EE17的步骤2所描述的程序由(R)-N,N-双(4-甲氧基苄基)庚-6-烯-3-磺酰胺(中间体EE21,步骤1,第二洗脱异构体)合成标题化合物。
中间体EE212
(S)-庚-6-烯-3-磺酰胺
使用针对中间体EE17的步骤2所描述的程序由(S)-N,N-双(4-甲氧基苄基)庚-6-烯-3-磺酰胺(中间体EE21,步骤1,第一洗脱异构体)合成标题化合物。
中间体EE22
(2R,3S)-3-甲基己-5-烯-2-磺酰胺
步骤1:(4S,5S)-4,5-二甲基-1,3,2-二氧硫杂环戊烷2,2-二氧化物
向500mL 3颈RBF(装有H2O冷却的回流冷凝器和HCl分离器)中添加(2s,3s)-(+)-2,3-丁二醇(Aldrich;15.00mL,166mmol)和CCl4(120mL)。随后历经20min的时段经由注射器逐滴添加SOCl2(reagentplus)(14.57mL,200mmol),且将所得混合物加热至98℃保持45min,随后使其冷却至rt。随后在冰/H2O浴中冷却反应混合物,添加MeCN(120mL)和H2O(150mL)随后添加氯化钌(III)(0.035g,0.166mmol)。随后历经30min缓慢逐份添加高碘酸钠(53.4g,250mmol)。剧烈搅拌所得两相棕色混合物,同时使其达到rt保持1.5h的时间(内部温度不要升至rt以上)。TLC(50%EtOAc/庚烷)显示完全转化。随后将粗混合物倾入冰H2O中且用300mL Et2O萃取两次。将合并的有机层用200mL饱和碳酸氢钠洗涤一次,用200mL盐水洗涤一次,经Na2SO4干燥且通过旋转蒸发浓缩,得到为红色油状物的(4S,5S)-4,5-二甲基-1,3,2-二氧硫杂环戊烷2,2-二氧化物(21.2g,139mmol)。
步骤2:(2S,3S)-3-甲基己-5-烯-2-醇
向500mL烧瓶中添加(4S,5S)-4,5-二甲基-1,3,2-二氧硫杂环戊烷2,2-二氧化物(来自中间体EE22,步骤1;21.2g,139mmol)和THF(220mL),此时将溶液冷却至-78℃且进行3次排空/氩气回填循环。向溶液中添加四氯铜酸二锂(ii)(0.1M于THF中的溶液,69.7mL,6.97mmol)。将所得混合物在-78℃下搅拌30min,随后历经80min经由套管缓慢添加烯丙基溴化镁(1.0M于Et2O中的溶液,397mL,397mmol)。将所得混合物在0℃下搅拌4h。用200mL H2O淬灭混合物且使其达到rt,此时通过旋转蒸发移除挥发物。随后向水性残余物中添加50%H2SO4(150mL),将混合物搅拌5min,随后添加Et2O(400mL)且将混合物在rt下剧烈搅拌过夜。分离各层;水层用300mL Et2O萃取,并将合并的有机层用300mL饱和NaHCO3洗涤,经Na2SO4干燥,过滤且通过旋转蒸发浓缩,得到为澄清油状物的(2S,3S)-3-甲基己-5-烯-2-醇(6.7g,58.7mmol)。
步骤3:2-(((2R,3S)-3-甲基己-5-烯-2-基)硫基)嘧啶
在氩气氛围下向0℃下容纳三丁基膦(57.7mL,231mmol)于1000mL脱气THF(用氩气吹扫30min加5次抽吸/添加氩气循环)中的搅拌溶液的2000mL干燥RBF中逐滴添加偶氮二甲酸二乙酯(40wt.%于甲苯中的溶液;103mL,262mmol)。经由注射器式过滤器(0.45um)将(2S,3S)-3-甲基己-5-烯-2-醇(来自中间体EE22,步骤2;17.6g,154mmol;经Na2SO4干燥)溶液以50mLTHF溶液形式逐滴添加至膦/偶氮二甲酸二乙酯复合物的溶液中。将所得ROH/偶氮二甲酸二乙酯/三正丁基膦混合物在零度下老化15min(溶液变为浅橙色),此时在正氩气压力下将嘧啶-2-硫醇(49.3g,439mmol)逐渐添加至反应容器顶部(作为固体)。将反应物在0℃下搅拌1h,随后在rt下搅拌15h(通过LC/MS分析表明在12h时反应未完成)。随后过滤粗反应物以移除过量的嘧啶-2-硫醇,用1000mL EtOAc稀释,用500mL的1N K2CO3萃取两次且用500mL盐水萃取一次。水层用300mL EtOAc反萃取,并将合并的有机层经Na2SO4干燥。随后过滤有机溶液,通过旋转蒸发移除溶剂,且过滤粗物质以移除反应中产生的(E)-二氮烯-1,2-二甲酸二乙酯。使滤液(125g)通过SiO2塞(500g SiO2,用2LDCM洗脱),在移除溶剂之后得到75g粗产物。再次在(125g gold SiO2柱)上用10%EtOAc/庚烷洗脱来纯化粗产物,得到为淡黄色油状物的2-(((2R,3S)-3-甲基己-5-烯-2-基)硫基)嘧啶(20.37g,98mmol)。
步骤4:2-(((2R,3S)-3-甲基己-5-烯-2-基)磺酰基)嘧啶
向具有回流冷凝器的500mL 3颈RBF中添加苯膦酸(3.95g,24.96mmol)、钨酸钠氧化物二水合物(sodiumtungstate oxide dihydrate)(8.23g,24.96mmol)、四丁基硫酸铵(50wt.%于H2O中的溶液,28.7mL,24.96mmol)、催化量的过氧化氢(30%于H2O中的溶液,12.75mL,125mmol)、甲苯(200mL)和2-(((2R,3S)-3-甲基己-5-烯-2-基)硫基)嘧啶(来自中间体EE22,步骤3;52g,250mmol)。将反应物在45℃下搅拌5min,此时逐份(一次10mL)添加过氧化氢(30%于H2O中的溶液,58.6mL,574mmol)。在添加第一份过氧化氢之后5min,观测到放热(65℃),从油浴取出反应物,停止添加且将烧瓶置于H2O浴中直至温度稳定。从H2O浴取出烧瓶,且以内部温度保持在45℃与55℃之间的速率持续逐份添加过氧化氢(约40min)。若温度上升超过60℃,则利用冰浴,并且若温度下降到45℃以下,则使用油浴。反应物随后在45℃下搅拌1h。将反应物用1400mL EtOAc稀释,且用500mL H2O萃取两次并用500mL盐水萃取一次。有机层经Na2SO4干燥,过滤,浓缩,且在(每30克粗物质330g goldSiO2柱)上用0%-50%EtOAc/庚烷洗脱来纯化粗物质,得到为淡黄色油状物的2-(((2R,3S)-3-甲基己-5-烯-2-基)磺酰基)嘧啶(55.7g,232mmol)。
步骤5:(2R,3S)-3-甲基己-5-烯-2-亚磺酸钠
在rt下历经70min向2-(((2R,3S)-3-甲基己-5-烯-2-基)磺酰基)嘧啶(来自中间体EE22,步骤4;52g,216mmol)于MeOH(400mL)中的溶液添加甲醇钠溶液(51.0mL,223mmol)。逐份添加甲醇钠,监测内部温度,且使添加减缓或在H2O浴中冷却反应物,不要使内部温度超过30℃。通过旋转蒸发浓缩混合物,并将蜡质固体用MTBE(添加200mL MTBE,使用抹刀搅拌1h以使团块破碎)磨碎,过滤(在滤饼上方使用N2流)且用100mL冷MTBE洗涤,得到为灰白色固体的(2R,3S)-3-甲基己-5-烯-2-亚磺酸钠(46g,250mmol)。
步骤6:(2R,3S)-3-甲基己-5-烯-2-磺酰胺
在rt下向1000mL3颈RBF中添加(2R,3S)-3-甲基己-5-烯-2-亚磺酸钠(来自中间体EE22,步骤5;46g,225mmol)、500mL H2O和KOAc(44.1g,449mmol)。将烧瓶置于45℃油浴中,并且历经90min逐份添加羟胺-O-磺酸(21.09g,187mmol)。监测反应的内部温度,且从油浴移除反应物(若需要)以控制放热(Tmax=55℃)。每10min通过LC/MS监测反应,并且在添加0.83当量羟胺-O-磺酸之后完成反应。随后使混合物冷却至rt且用1000mL EtOAc萃取。有机相用500mL的1N HCl萃取三次,用300mL饱和碳酸氢钠萃取两次,用200mL盐水萃取一次,经Na2SO4干燥,过滤且通过旋转蒸发浓缩,得到为白色固体的(2R,3S)-3-甲基己-5-烯-2-磺酰胺(32g,181mmol)。
实施例1.(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羟基-11',11'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:2,2-二甲基戊-4-烯-1-醇
向100mL烧瓶中添加2,2-二甲基戊-4-烯酸甲酯(Sigma-Aldrich;8.40g,59.1mmol)、四氢硼酸锂(4.06mL,124mmol),随后缓慢添加(每5min 1mL)MeOH(5.26mL,130mmol)。将反应物在22℃下搅拌2h。反应随后用300mL H2O淬灭且用300mL Et2O萃取2次。有机层经Na2SO4干燥,过滤且通过旋转蒸发(用H2O浴在0℃下历经4h缓慢进行且缓慢降低压力,分离器中无微量产物)移除溶剂,得到为澄清油状物的2,2-二甲基戊-4-烯-1-醇(6.75g,59.1mmol,100%产率)。
步骤2:甲磺酸2,2-二甲基戊-4-烯-1-基酯
向2,2-二甲基戊-4-烯-1-醇(来自步骤1,6.5g,56.9mmol)于DCM(40mL)中的溶液(冷却至-78℃)添加MsCl(6.75mL,85mmol)。在添加之后,将混合物置于冰浴中且搅拌16h(16h后浴在rt下)。将反应物过滤且用400mL DCM稀释。有机层用200mL H2O萃取一次且再次用200mL的1N HCl萃取。有机层经Na2SO4干燥,过滤且浓缩,得到橙色油状物。在(80g gold SiO2柱)上用10%至50%EtOAc/庚烷洗脱来纯化粗产物,得到为澄清油状物的甲磺酸2,2-二甲基戊-4-烯-1-基酯(6.66g,34.6mmol,60.8%产率)。
步骤3:2-((2,2-二甲基戊-4-烯-1-基)硫基)嘧啶
将嘧啶-2-硫醇(962mg,8.58mmol)和甲醇钠(30wt%甲醇溶液,1.825mL,9.83mmol)于MeOH(8mL)中的溶液用甲磺酸2,2-二甲基戊-4-烯-1-基酯(1500mg,7.80mmol)于2mL MeOH中的溶液处理。向溶液中添加20mL DMF,随后通过将氩气吹扫通过反应混合物持续10min使溶液脱气。将反应物加热至130℃,同时通过两根18号针(18gauge needle)排出MeOH持续11h。将反应物用300mL EtOAc稀释且用200mL盐水萃取两次。有机层经Na2SO4干燥,过滤,浓缩,且在(24g gold SiO2柱)上用10%至50%EtOAc/庚烷洗脱来纯化粗物质,得到为澄清油状物的2-((2,2-二甲基戊-4-烯-1-基)硫基)嘧啶(1250mg,6.00mmol,77%产率)。
步骤4:2-((2,2-二甲基戊-4-烯-1-基)磺酰基)嘧啶
向25mL烧瓶中添加苯膦酸(0.056mL,0.504mmol)、钨酸钠氧化物二水合物(0.051mL,0.504mmol)、四丁基硫酸铵(50wt.%于H2O中的溶液,0.580mL,0.504mmol)和过氧化氢(30%于H2O中的溶液,1.287mL,12.60mmol)。将反应物在22℃下搅拌5min,此时以5mL甲苯溶液的形式添加2-((2,2-二甲基戊-4-烯-1-基)硫基)嘧啶(来自步骤3,1050mg,5.04mmol)。将反应物在22℃下搅拌30min,然后在50℃下搅拌1h。反应物用300mL EtOAc稀释,且用100mL H2O萃取一次随后用100mL盐水萃取一次。有机层经Na2SO4干燥,过滤,浓缩,且在(12g gold SiO2柱)上用10%至50%EtOAc/庚烷洗脱来纯化粗物质,得到为澄清油状物的2-((2,2-二甲基戊-4-烯-1-基)磺酰基)嘧啶(910mg,3.79mmol,75%产率)。
步骤5:2,2-二甲基戊-4-烯-1-亚磺酸钠
向100mL烧瓶中添加2-((2,2-二甲基戊-4-烯-1-基)磺酰基)嘧啶(来自步骤4,910mg,3.79mmol)和MeOH(20mL),此时在22℃下添加甲醇钠溶液(30wt%的甲醇溶液,0.710mL,3.79mmol),且将混合物搅拌45min。随后通过旋转蒸发浓缩反应混合物,且用Et2O磨碎残余物。收集固体且干燥,得到为亮橙色固体的2,2-二甲基戊-4-烯-1-亚磺酸钠(465mg,2.52mmol,66.7%产率)。
步骤6:2,2-二甲基戊-4-烯-1-磺酰胺
在rt下向2,2-二甲基戊-4-烯-1-亚磺酸钠(来自步骤5,465mg,2.52mmol)和乙酸钠(414mg,5.05mmol)于H2O(20mL)中的溶液添加羟胺-o-磺酸(571mg,5.05mmol)。将混合物加热至50℃且搅拌1h,随后在rt下搅拌4h。将混合物用EtOAc萃取,有机相经Na2SO4干燥,过滤且浓缩。在(12g gold SiO2柱)上用10%至50%EtOAc/庚烷洗脱来纯化粗物质,得到为白色固体的2,2-二甲基戊-4-烯-1-磺酰胺(246mg,1.388mmol,55.0%产率)。
步骤7:(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基-5,5-二甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
向100mL烧瓶中添加(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12A;100mg,0.196mmol)、2,2-二甲基戊-4-烯-1-磺酰胺(来自步骤6,104mg,0.588mmol)和DCE(2mL)。将溶液用氩气吹扫15min,此时在rt下以0.2mL DCE溶液的形式添加1,3-双(2,4,6-三甲基苯基)-2-咪唑烷亚基)二氯(邻异丙氧基苯亚甲基)合钌(VI)((1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI)chloride)(12.29mg,0.020mmol)。将混合物在rt下搅拌16h。随后将反应混合物用空气吹扫5min且过滤。从滤液移除溶剂,且在(12g gold SiO2柱)上用50%-90%EtOAc/庚烷+0.2%AcOH洗脱来直接纯化粗产物,得到为白色固体的(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基-5,5-二甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(98mg,0.159mmol,81%产率)。
步骤8:(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羟基-11',11'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.0~3,6~.0~19,24~]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向容纳(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基-5,5-二甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(来自步骤7,98mg,0.159mmol)的先前通过用5mL甲苯共沸两次而干燥的250mL烧瓶中添加N,N-二甲基吡啶-4-胺(33.0mg,0.270mmol)和100mL DCM。将反应混合物冷却至0℃,在0℃下添加N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(60.9mg,0.318mmol)。将反应物在rt下搅拌12h。混合物随后用100mL的1N盐酸淬灭且用300mL DCM萃取。有机层经无水Na2SO4干燥,过滤且通过旋转蒸发浓缩。首先在(12g gold SiO2柱)上用30%-70%EtOAc/庚烷+0.2%AcOH洗脱来纯化粗物质,随后通过制备型反相HPLC(GeminiTMPrep C18 5μm柱;Phenomenex,Torrance,CA;10%至90%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,45min方法)纯化,得到为白色固体的(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羟基-11',11'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(2.5mg,4.17μmol,2.63%产率)。1H NMR(400MHz,CDCl3)δ8.35(br.s.,1H),7.70(d,J=8.4Hz,1H),7.18(dd,J=2.2,8.5Hz,1H),7.09(d,J=2.2Hz,1H),6.93(s,2H),6.85-6.79(m,1H),5.98-5.82(m,1H),5.69(dd,J=8.1,15.4Hz,1H),4.27-4.17(m,1H),4.14-4.01(m,2H),4.15-3.94(m,1H),3.79-3.60(m,2H),3.25(d,J=13.3Hz,2H),3.14-2.95(m,1H),2.86-2.62(m,2H),2.49-2.21(m,3H),2.14-1.89(m,4H),1.86-1.80(m,3H),1.69-1.61(m,1H),1.48-1.36(m,1H),1.26(s,6H).m/z(ESI,+ve离子)599.0(M+H)+。
实施例2.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-N-(((2R,3S)-3-甲基己-5-烯-2-基)磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酰胺
将DMAP(3.42g,28.0mmol)添加至(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA11A;7.7g,16.45mmol)和(2R,3S)-3-甲基己-5-烯-2-磺酰胺(中间体EE22;5.83g,32.9mmol)于DCM(411mL)中的溶液(冷却至0℃)。随后缓慢逐份添加EDC盐酸盐(6.31g,32.9mmol)。搅拌混合物同时使其达到环境温度过夜。混合物用1N HCl和盐水洗涤,且水层用EtOAc反萃取。合并的有机物经MgSO4干燥,过滤且浓缩。将黄色油性残余物上样至220ISCO gold柱上,且用0%至20%EtOAc(含有0.3%AcOH)/庚烷洗脱来纯化,得到(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-N-(((2R,3S)-3-甲基己-5-烯-2-基)磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺(7.89g,12.58mmol,76%产率)。
步骤2:(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向氩气覆盖的20L反应器中装入14L 1,2-DCE。以400mL1,2-DCE中的溶液的形式添加(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-N-(((2R,3S)-3-甲基己-5-烯-2-基)磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺(18.75g,29.9mmol),随后添加400mL冲洗剂。将反应器密封且用氩气吹扫。以150mL 1,2-DCE中的溶液的形式添加Hoveyda-Grubbs II(1.873g,2.99mmol),随后添加50mL冲洗剂。历经1h将反应器加热至60℃,用氩气吹扫顶部空间且保持温度9h。反应通过添加2-(2-(乙烯基氧基)乙氧基)乙醇(1.501g,11.36mmol)淬灭,冷却至环境温度,通过旋转蒸发浓缩至约200mL体积。将反应物转移至1L RBF,且用1,2-DCE稀释至500mL体积。将反应物在40℃在搅拌下用52g Silicycle Si-Thiol(SiliCycle Inc.,Quebec City,QuebecCANADA目录号R51030B)处理9h,过滤且用2×65mLDCM冲洗。使溶液通过Whatman GF/F滤杯(GE Healthcare Bio-Sciences Pittsburgh,PA,USA),得到透明黄色溶液。浓缩反应物,得到质量为27.4g的粗产物。将残余物在250mL IPAc中制成浆液且蒸发至干三次。将反应物悬浮于270mL IPAc中,加热至溶解,使其冷却至环境温度,且搅拌18。过滤固体且用65mLIPAc洗涤。将固体风干30min,随后置于高真空下3h,得到12.56g(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,其按重量计为91.7%。1H NMR(500MHz,CD2Cl2)δ8.06(s,1H),7.71(d,J=8.56Hz,1H),7.17(dd,J=8.44,2.32Hz,1H),7.09(d,J=2.20Hz,1H),6.91(s,3H),5.81(ddd,J=14.92,7.82,4.16Hz,1H),5.71(dd,J=15.41,8.31Hz,1H),4.16-4.26(m,2H),3.83(d,J=14.43Hz,1H),3.69(d,J=14.43Hz,1H),3.25(d,J=14.43Hz,1H),3.04(dd,J=15.28,9.66Hz,1H),2.68-2.84(m,2H),2.41(app qd,J=9.80,3.70Hz,1H),2.25-2.34(m,1H),1.93-2.00(m,5H),1.74-2.11(m,9H),1.62-1.73(m,1H),1.43(d,J=7.09Hz,3H)1.35-1.42(m,1H)1.03(d,J=6.60Hz,3H).MS(ESI,+ve离子)m/z 599.2(M+H)+。
实施例3.(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向1000mL RBF中装入(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-N-(((2R,3S)-3-甲基己-5-烯-2-基)磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺(实施例2,步骤1,710mg,1.132mmol)和DCM(569.00mL)。将溶液用氩气吹扫15min,随后添加Hoveyda-Grubbs II(70.9mg,0.113mmol)。混合物在45℃下搅拌15h。反应混合物用空气吹扫20min同时冷却至环境温度,随后减压浓缩。将粗油吸附至SiO2凝胶塞上,且经由220g ISCO gold柱用10-20(15min)-50%EtOAc(含有0.3%AcOH)/庚烷历经36min洗脱而纯化,得到作为第一洗脱次要异构体的(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例3),随后是作为第二洗脱主要异构体的(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例2)。将由此得到的半纯物质上样至SiO2凝胶柱上且用5%丙酮/DCM洗脱来纯化,得到标题化合物。1H NMR(500MHz,CD2Cl2)δ8.83(br.s.,1H),7.71(d,J=8.3Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.11(dd,J=1.6,8.2Hz,1H),7.09(d,J=2.2Hz,1H),7.02(s,1H),6.93(d,J=8.1Hz,1H),5.82-5.75(m,1H),5.67(dd,J=6.5,11.4Hz,1H),4.43(s,1H),4.12-4.05(m,2H),3.85-3.76(m,2H),3.67(d,J=14.4Hz,1H),3.25(d,J=14.4Hz,1H),3.28-3.19(m,1H),2.83-2.65(m,3H),2.38-2.23(m,2H),2.19-2.11(m,2H),2.10-1.99(m,3H),1.97-1.87(m,2H),1.87-1.80(m,1H),1.79-1.70(m,2H),1.47(d,J=7.3Hz,3H),1.47-1.40(m,1H),1.06(d,J=6.6Hz,3H).MS(ESI,+ve离子)m/z599.1(M+H)+。
实施例4.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-甲氧基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮-13',13'-二氧化物
在N2下向(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例2;32.6g,49.1mmol)(含有9.8%甲苯,原料并非完全可溶于Me-THF)和MeI(15.2mL,245mmol)于Me-THF(820mL)中的浆液逐滴添加KHMDS(1.0M于THF中,167mL,167mmol)持续30min,同时维持反应温度在-44℃与-38℃之间。在-44℃下搅拌混合物30min之后,使反应物升至rt且搅拌1.5h(LC/MS证实反应完成)。将反应混合物冷却至5℃,淬灭(170mL NH4Cl饱和水溶液和170mL H2O),同时维持温度在5℃与14℃之间,然后酸化(340mL的10%柠檬酸水溶液)。分离有机层,并且水层用EtOAc(500mL)反萃取。合并的有机层用盐水(3×500mL)洗涤,干燥(MgSO4)且减压浓缩,得到为亮黄色固体的粗目标化合物(30.1g,49.1mmol,定量)(根据HPLC,纯度>98%,不具有超过1%的主要杂质)。在相同规模的反应重复四次之后,将所有粗产物(4×49.1mmol=196mmol)溶于EtOAc中,合并且减压浓缩。随后将合并的粗产物如下重结晶:将乙醇(800mL)添加至粗产物中,且震荡所得浆液溶液同时将溶液加热20min。在rt下逐滴添加H2O(250mL)持续30min,并将浆液冷却至0℃。在浆液在冰浴中保持4h之后,经由滤纸过滤固体产物。滤饼用冰冷30%H2O/EtOH(300mL)冲洗且风干2天。将产物在高真空下在40℃进一步干燥4天,得到为白色固体的纯目标化合物(115g,188mmol,96%产率)。1H NMR(600MHz,DMSO-d6)11.91(s,1H),7.65(d,J=8.6Hz,1H),7.27(dd,J=8.5,2.3Hz,1H),7.17(d,J=2.4Hz,1H),7.04(dd,J=8.2,2.0Hz,1H),6.90(d,J=8.2Hz,1H),6.76(d,J=1.8Hz,1H),5.71(ddd,J=15.1,9.7,3.5Hz,1H),5.50(ddd,J=15.2,9.2,1.1Hz,1H),4.08(qd,J=7.2,7.2,7.2,1.5Hz,1H),4.04(d,J=12.3Hz,1H),3.99(d,J=12.3Hz,1H),3.73(d,J=14.9Hz,1H),3.56(d,J=14.1Hz,1H),3.53(dd,J=9.1,3.3Hz,1H),3.19(d,J=14.1Hz,1H),3.09(s,3H),3.03(dd,J=15.4,10.4Hz,1H),2.79(dt,J=17.0,3.5,3.5Hz,1H),2.69(ddd,J=17.0,10.7,6.3Hz,1H),2.44-2.36(m,1H),2.24-2.12(m,2H),2.09(ddd,J=15.5,9.6,2.3Hz,1H),1.97(dt,J=13.6,3.6,3.6Hz,1H),1.91-1.80(m,4H),1.80-1.66(m,3H),1.38(td,J=12.3,12.3,3.5Hz,1H),1.33(d,J=7.2Hz,3H),0.95(d,J=6.8Hz,3H);[α]D(24℃,c=0.0103g/mL,DCM)=-86.07°;m.p.222.6-226.0℃;FT-IR(KBr):3230(b),2931(b),1688(s),1598(s),1570(s),1505(s),1435(s),1384(s),1335(s),1307(s),1259(s),1155(s),1113(s),877(s),736(s)cm-1;C33H41ClN2O5S的分析计算值:C,64.64;H,6.74;N,4.57;Cl,5.78;S,5.23.实测值:C,64.71;H,6.81;N,4.65;Cl,5.81;S,5.11;HRMS(ESI)m/z 613.2493[M+H]+(C33H41ClN2O5S需要613.2503)。
减压浓缩母液,并通过快速柱色谱(200g SiO2,10%和10%至45%和45%EtOA/Hexw/0.3%AcOH,梯度洗脱)进一步纯化残余物,得到为灰白色固体的另外纯产物(3.1g,5.1mmol,2.6%)。
实施例5.(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-氯-7'-甲氧基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例3;34mg;0.057mmol)于THF中的溶液(冷却至0℃)添加氢化钠(60%矿物油中的分散体;22.70mg,0.567mmol)。将反应混合物在0℃下搅拌20min,随后添加MeI(0.018mL,0.284mmol)。将反应混合物在环境温度下搅拌1h,随后用NH4Cl水溶液淬灭且用EtOAc稀释。有机层经MgSO4干燥且浓缩。经由柱色谱用10-40%EtOAc(含有0.3%AcOH)/庚烷洗脱来纯化粗物质,得到(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-氯-7'-甲氧基-11',12'-二甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(34mg,0.054mmol,95%产率)。1H NMR(400MHz,CD2Cl2)δ8.29(s,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.2,8.5Hz,1H),7.09(d,J=2.3Hz,1H),7.01(dd,J=1.6,7.8Hz,1H),6.92(d,J=8.2Hz,1H),6.88(s,1H),5.90-5.80(m,1H),5.54(t,J=10.2Hz,1H),4.14-4.04(m,3H),3.87-3.79(m,2H),3.73(d,J=14.7Hz,1H),3.32(d,J=14.5Hz,1H),3.23(s,3H),3.28-3.19(m,1H),2.82-2.73(m,2H),2.62(t,J=10.6Hz,1H),2.55-2.44(m,1H),2.29-2.21(m,1H),2.10-1.97(m,4H),1.97-1.80(m,4H),1.75(dd,J=8.9,18.7Hz,1H),1.48(d,J=7.4Hz,3H),1.43(br.s.,1H),1.08(d,J=6.5Hz,3H).MS(ESI,+ve离子)m/z613.3(M+H)+。
实施例6.(1S,3'R,6'R,7'S,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
将(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例2,7.5mg,0.013mmol)和氧化铂(IV)(2.84mg,0.013mmol)于EtOAc(1.536mL)中的混合物在H2(气球)氛围下在环境温度搅拌45min。随后经由注射器式过滤器过滤反应混合物。通过色谱经由Redi-预装填SiO2凝胶柱(4g)用15%至50%EtOAc(含有0.3%AcOH)/庚烷洗脱来纯化粗物质,得到标题产物。1H NMR(400MHz,CD2Cl2)δ8.24(br.s.,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.2Hz,1H),7.06(d,J=1.8Hz,1H),6.99(dd,J=2.0,8.0Hz,1H),6.93(d,J=8.2Hz,1H),4.10(s,2H),4.05(ddd,J=1.2,7.2,14.3Hz,1H),3.82(d,J=15.3Hz,1H),3.74-3.69(br.S.,1H),3.68(d,J=14.3Hz,1H),3.23(d,J=14.3Hz,1H),3.06(dd,J=7.3,15.4Hz,1H),2.84-2.68(m,2H),2.38(d,J=3.5Hz,2H),2.08-1.96(m,3H),1.96-1.88(m,1H),1.88-1.75(m,2H),1.74-1.56(m,4H),1.47(d,J=12.1Hz,2H),1.40(d,J=7.2Hz,3H),1.32-1.26(m,2H),1.23-1.15(m,2H),1.00(d,J=6.8Hz,3H)。MS(ESI,+ve离子)m/z 601.2(M+H)+。
实施例7.(1S,3'R,6'R,7'S,11'S,12'R)-6-氯-7'-甲氧基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照实施例6中所描述的程序由(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-甲氧基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮-13',13'-二氧化物(实施例4)的混合物合成标题化合物。1H NMR(500MHz,CD2Cl2)δ8.14(s,1H),7.72(d,J=8.6Hz,1H),7.17(dd,J=2.2,8.6Hz,1H),7.09(d,J=2.2Hz,1H),7.00(d,J=1.7Hz,1H),6.95(dd,J=2.0,8.1Hz,1H),6.92(d,J=8.1Hz,1H),4.10(s,2H),4.07(ddd,J=1.2,7.1,14.2Hz,1H),3.81(dd,J=2.0,15.2Hz,1H),3.68(d,J=14.2Hz,1H),3.25(s,3H),3.22(dd,J=9.0,14.4Hz,1H),3.03(dd,J=8.6,15.4Hz,1H),2.83-2.69(m,2H),2.60-2.51(m,1H),2.41-2.32(m,1H),2.07-2.01(m,1H),1.99-1.88(m,2H),1.88-1.77(m,1H),1.76-1.68(m,1H),1.68-1.58(m,2H),1.53-1.46(m,2H),1.45-1.42(m,1H),1.40(d,J=7.1Hz,3H),1.29(br.s.,1H),1.25-1.21(m,2H),1.20-1.10(m,2H),0.99(d,J=6.8Hz,3H).MS(ESI,+ve离子)m/z 615.1(M+H)+。
实施例8.(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
向100mL烧瓶中添加(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12A;500mg,0.980mmol)、戊-4-烯-1-磺酰胺(中间体EE19;878mg,5.88mmol)和DCE(14mL)。将溶液用氩气吹扫15min,此时在rt下以0.2mL DCE溶液的形式添加Hoveyda-Grubbs II(61.4mg,0.098mmol)。将混合物在rt下搅拌且用氩气吹扫(将小瓶排气)2h。反应混合物随后用空气鼓泡5min且过滤以分离不溶性磺酰胺同二聚体。在(24ggold SiO2柱)上用50%-90%EtOAc/庚烷+0.2%AcOH)洗脱来纯化粗产物,得到为白色固体的(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2h,2'h-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(439mg,0.745mmol,76%产率)。
步骤2:(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向容纳(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(来自步骤1,439mg,0.745mmol)的先前通过用10mL甲苯共沸两次干燥的1L烧瓶中添加N,N-二甲基吡啶-4-胺(155mg,1.267mmol)和400mL DCM。将反应混合物冷却至0℃,此时缓慢添加N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(286mg,1.490mmol)。将反应物随后在rt下搅拌18h。混合物用200mL的1N HCl淬灭且用600mL EtOAc萃取。有机层经无水Na2SO4干燥,过滤且通过旋转蒸发浓缩。在(24g gold SiO2柱)上用30%-70%EtOAc/庚烷洗脱来纯化粗产物,得到作为白色固体的标题化合物。1H NMR(500MHz,CD3OD)δ7.75(d,J=8.3Hz,1H),7.20(dd,J=2.9,7.6Hz,1H),7.12(d,J=3.7Hz,1H),7.00(dd,J=1.7,8.8Hz,1H),6.94(d,J=8.3Hz,1H),6.88(d,J=2.2Hz,1H),5.95-5.86(m,1H),5.70(dd,J=8.8,15.9Hz,1H),4.25-4.19(m,1H),4.22(dd,J=4.4,8.6Hz,1H),4.14-4.06(m,3H),4.14-4.05(m,3H),3.84(d,J=15.2Hz,1H),3.68(d,J=15.2Hz,1H),3.09(dd,J=8.3,15.9Hz,1H),2.87-2.74(m,2H),2.45-2.30(m,3H),2.14-1.88(m,5H),1.86-1.69(m,4H).m/z(ESI,+ve离子)571.2(M+H)+。
实施例9.(1S,3'R,6'R,7'S,8'E)-6-氯-7'-甲氧基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向100mL烧瓶中添加(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例8,138mg,0.242mmol)、THF(10mL)和氢化钠(29.0mg,1.208mmol)。将反应物在rt下搅拌15min,此时添加MeI(0.092mL,1.480mmol)。将反应物在rt下搅拌2h,此时添加另外的氢化钠(58.0mg,2.42mmol)和MeI(0.092mL,1.480mmol),且将反应物在rt下再搅拌16h。将反应物用100mL饱和NH4Cl淬灭且用400mLEtOAc萃取。有机层经Na2SO4干燥,过滤且通过旋转蒸发移除溶剂。在(12ggold SiO2柱)上用10%至50%EtOAc/庚烷洗脱来纯化粗产物,得到为灰白色固体的(1S,3'R,6'R,7'S,8'E)-6-氯-7'-甲氧基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(120mg,0.205mmol,85%产率)。1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.70(d,J=8.6Hz,1H),7.19(dd,J=2.2,8.5Hz,1H),7.10(d,J=2.2Hz,1H),6.97-6.87(m,2H),6.84(d,J=1.6Hz,1H),5.88(ddd,J=5.2,8.1,15.1Hz,1H),5.53(dd,J=8.7,15.4Hz,1H),4.30(ddd,J=4.8,9.8,15.0Hz,1H),4.15-3.98(m,2H),3.84-3.69(m,2H),3.67(dd,J=3.8,8.7Hz,1H),3.36-3.21(m,2H),3.25(s,3H),3.01(dd,J=10.3,15.2Hz,1H),2.87-2.64(m,2H),2.52-2.29(m,3H),2.25-1.91(m,5H),1.88-1.75(m,3H),1.71-1.60(m,2H),1.41(t,J=12.4Hz,1H).m/z(ESI,+ve离子)585.0(M+H)+。
实施例10.(1S,3'R,6'R,7'S)-6-氯-7'-羟基-3,4-二氢-2H,15'H螺[萘-1,22'[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步骤1:(1'S)-N-(丁-3-烯-1-基磺酰基)-6'-氯-5-(((1R,2R)-2-(1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酰胺
将DMAP(0.830g,6.80mmol)添加至(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA13A;1.82g,3.78mmol)和丁-3-烯-1-磺酰胺(EE15;1.873g,13.86mmol)于DCM(140mL)中的溶液(冷却至0℃)。逐份添加EDC(1.303g,6.80mmol),且将其在环境温度下搅拌16h。反应混合物用EtOAc(400mL)稀释,用1N HCl溶液(2×5mL)、盐水(3mL)洗涤,经无水Na2SO4干燥且浓缩。将残余物上样至80g ISCO gold柱,且用0%至15%EtOAc(含有0.3%AcOH)/Hex(含有0.3%AcOH)洗脱,得到为白色固体的标题化合物(2.09g)。m/z(ESI,+ve离子)599.0(M+H)+。
步骤2:(1S,3'R,6'R,7'S,9'E)-6-氯-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
向1L RBF中装入甲苯(587mL)中的含(1'S)-N-(丁-3-烯-1-基磺酰基)-6'-氯-5-(((1R,2R)-2-(1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺(来自步骤1,1.02g,1.70mmol)。将混合物在环境温度下搅拌10min以溶解固体原料,随后进行三次排空/N2回填循环。向均质溶液中添加Hoveyda-Grubbs II(0.213g,0.340mmol)于甲苯(20mL)中的溶液。在106℃在N2下搅拌混合物75min之后,用空气吹10min以使催化剂失活,随后浓缩。将残余物上样至330g ISCO gold柱,并用0%至25%EtOAc(含有0.3%AcOH)/Hex(含有0.3%AcOH)洗脱。第二峰是为白色固体的标题化合物(0.27g)。1H NMR(400MHz,CD2Cl2)δ9.96(br.s.,1H),7.78-7.65(m,1H),7.37(dd,J=1.96,8.22Hz,1H),7.16(dd,J=2.35,8.61Hz,1H),7.10(d,J=2.15Hz,1H),7.04(br.s.,1H),6.98(m,1H),5.66-5.47(m,2H),4.23-4.09(m,2H),3.98(ddd,J=5.18,10.56,15.55Hz,1H),3.86(dd,J=3.81,9.49Hz,1H),3.64-3.49(m,2H),3.38(td,J=4.74,15.36Hz,2H),2.92(br.s.,1H),2.81(br.s.,1H),2.79-2.73(m,2H),2.73-2.63(m,1H),2.52(d,J=12.72Hz,1H),2.40-2.25(m,2H),2.18(d,J=8.22Hz,1H),2.01-1.52(m,8H).m/z(ESI,+ve离子)571.0(M+H)+。
步骤3:(1S,3'R,6'R,7'S)-6-氯-7'-羟基-3,4-二氢-2H,15'H螺[萘-1,22'[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
在H2下在环境温度将(1S,3'R,6'R,7'S,9'E)-6-氯-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(来自步骤2,0.112g,0.196mmol)和氧化铂(IV)(0.045g,0.196mmol)于EtOAc(33mL)中的混合物搅拌3h。经由注射器式过滤器过滤混合物以移除固体催化剂,并浓缩溶液,得到为白色固体的标题化合物(112mg)。1H NMR(400MHz,CD2Cl2)δ8.93(m,1H),7.71(m,1H),7.15(m,3H),7.09(d,J=2.35Hz,1H),6.95(m,1H),4.10(m,2H),3.78-3.62(m,4H),3.46-3.34(m,1H),3.26(d,J=14.28Hz,1H),3.16(dd,J=9.00,15.26Hz,1H),2.82-2.71(m,2H),2.45-2.33(m,1H),2.26-2.16(m,1H),2.08-1.16(m,17H).m/z(ESI,+ve离子)573.2(M+H)+。
实施例11.(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物和
实施例12.(1S,3'R,6'R,7'S,8'E,12'S)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以类似于实施例2中所描述的方式的方式使用(R)-己-5-烯-磺酰胺(中间体EE20)与(S)-己-5-烯-磺酰胺(中间体EE202)的混合物制备标题化合物,且使所需产物(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(来自制备型反相HPLC的第一差向异构体,实施例11)与(1S,3'R,6'R,7'S,8'E,12'S)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(来自制备型反相HPLC的第二差向异构体,实施例12)分离。实施例11的共晶体结构证实位置12处的甲基具有R立体化学。(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物:1H NMR(400MHz,CD3OD)δ7.74(d,J=8.0Hz,1H),7.19(dd,J=3.5,11.5Hz,1H),7.12(d,J=1.8Hz,1H),7.01(d,J=9.2Hz,1H),7.01(d,J=7.6Hz,1H),6.94(d,J=8.0Hz,1H),6.88(s,1H),5.89-5.81(m,1H),5.73(dd,J=7.4,14.5Hz,1H),4.22(dd,J=3.5,7.6Hz,1H),4.18-4.12(m,1H),4.09(d,J=2.0Hz,2H),3.85(d,J=15.1Hz,1H),3.85(d,J=15.3Hz,1H),3.68(d,J=14.1Hz,1H),3.08(dd,J=10.2,15.1Hz,1H),2.87-2.73(m,2H),2.48-2.18(m,4H),2.11(d,J=13.7Hz,1H),2.05-1.65(m,8H),1.52(d,J=6.8Hz,3H),1.47-1.41(m,1H).m/z(ESI,+ve离子)585.2(M+H)+;(1S,3'R,6'R,7'S,8'E,12'S)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物:1H NMR(400MHz,CD3OD)δ7.73(d,J=9.2Hz,1H),7.19(dd,J=2.5,8.6Hz,1H),7.13(d,J=2.3Hz,1H),7.12-7.10(m,1H),7.05(dd,J=1.8,8.0Hz,1H),6.94(d,J=8.6Hz,1H),5.93-5.83(m,1H),5.65(dd,J=5.5,15.5Hz,1H),4.12(d,J=6.8Hz,2H),4.06(dd,J=4.1,10.2Hz,1H),3.91(dd,J=6.3,12.5Hz,1H),3.67-3.55(m,2H),3.53-3.46(m,1H),3.29-3.08(m,1H),2.88-2.70(m,2H),2.64-2.52(m,1H),2.49-2.31(m,2H),1.98-1.91(m,3H),1.99-1.89(m,4H),1.86-1.73(m,4H),1.49(d,J=7.4Hz,3H).m/z(ESI,+ve离子)585.2(M+H)+。
实施例13.(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-甲氧基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以类似于实施例4中所描述的方式的方式使用(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例11)制备标题化合物,且分离所需产物(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-甲氧基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物为白色固体。1H NMR(400MHz,CD3OD)δ7.75(d,J=8.4Hz,1H),7.19(dd,J=1.8,8.8Hz,1H),7.12(d,J=2.0Hz,1H),7.00(dd,J=2.2,7.8Hz,1H),6.95(d,J=8.4Hz,1H),6.86(d,J=1.6Hz,1H),5.92-5.84(m,1H),5.58(dd,J=9.0,15.1Hz,1H),4.85-4.85(m,1H),4.20(ddd,J=3.0,6.7,9.8Hz,1H),4.08(d,J=2.2Hz,2H),3.86(d,J=15.3Hz,1H),3.73(dd,J=2.9,8.6Hz,1H),3.67(d,J=14.1Hz,1H),3.26-3.23(m,3H),3.08(dd,J=10.3,15.2Hz,1H),2.88-2.72(m,2H),2.54-2.25(m,4H),2.12(d,J=13.1Hz,1H),1.99-1.71(m,7H),1.53(d,J=6.8Hz,3H),1.50-1.40(m,1H).m/z(ESI,+ve离子)599.2(M+H)+。
实施例14.(1S,3'R,6'R,7'S,12'R)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步骤1:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-((R)-戊-4-烯-2-基磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酰胺
按照针对实施例2的步骤1所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA13A;166mg,0.344mmol)和(R)-戊-4-烯-2-磺酰胺(中间体EE17;87mg,0.585mmol)合成标题化合物。粗物质的纯化得到(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-((R)-戊-4-烯-2-基磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺(134mg,0.219mmol,63.5%产率)。
步骤2.(1S,3'R,6'R,7'S,9'E,12'R)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物和(1S,3'R,6'R,7'S,9'Z,12'R)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
向500mL RBF中装入甲苯(146.00mL)中的(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-((R)-戊-4-烯-2-基磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺(134mg,0.219mmol)。将混合物在环境温度下搅拌10min以溶解固体原料,随后进行三次排空/N2回填循环。在环境温度下向均质溶液中添加Hoveyda-Grubbs II(27.4mg,0.044mmol)于甲苯(8mL)中的溶液。将混合物在106℃在N2下搅拌80min。吹动空气通过溶液持续10min以使催化剂失活,随后浓缩混合物。将粗深色油状物吸附至SiO2凝胶塞上,且通过色谱经由24g ISCO柱用10%至20%至40%EtOAc(含有0.3%AcOH)/Hex历经90min洗脱来纯化,得到标题化合物的混合物。
步骤3:(1S,3'R,6'R,7'S,12'R)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照针对实施例6所描述的程序由(1S,3'R,6'R,7'S,9'E,12'R)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物与(1S,3'R,6'R,7'S,9'Z,12'R)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物的混合物(来自步骤2,119mg,0.203mmol)合成标题化合物(94mg,0.160mmol,79%产率)。1H NMR(400MHz,CD2Cl2)δ9.03(br.s.,1H),7.71(d,J=8.4Hz,1H),7.16(dd,J=2.3,8.4Hz,1H),7.13(dd,J=2.2,8.2Hz,1H),7.10(br.s.,1H),7.09(d,J=2.3Hz,1H),6.93(d,J=8.2Hz,1H),4.09(s,2H),3.86(td,J=5.3,6.8Hz,1H),3.74(d,J=14.1Hz,1H),3.70(br.s.,1H),3.65(d,J=14.9Hz,1H),3.25(d,J=14.1Hz,1H),3.13(dd,J=8.2,15.5Hz,1H),2.85-2.68(m,2H),2.44(quin,J=8.8Hz,1H),2.25(ddd,J=5.5,9.6,17.8Hz,1H),2.04-1.94(m,2H),1.89(dt,J=5.0,9.5Hz,2H),1.85-1.77(m,2H),1.76-1.68(m,2H),1.68-1.60(m,4H),1.60-1.50(m,3H),1.48(d,J=7.0Hz,3H),1.46-1.35(m,2H).MS(ESI,+ve离子)m/z 587.1(M+H)+。
实施例15.(1S,3'R,6'R,7'S,12'S)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步骤1:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-((S)-戊-4-烯-2-基磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酰胺
按照针对实施例2的步骤1所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA13A;15mg,0.031mmol)和(S)-戊-4-烯-2-磺酰胺(中间体EE172;5.6mg,0.037mmol)合成标题化合物。粗物质的纯化得到(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-((S)-戊-4-烯-2-基磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺(19mg,0.031mmol)。
步骤2:(1S,3'R,6'R,7'S,9'Z,12'S)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物和(1S,3'R,6'R,7'S,9'E,12'S)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照针对实施例14的步骤2所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-((S)-戊-4-烯-2-基磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺(来自步骤1,42.5mg,0.067mmol)合成标题化合物。通过色谱经由24g ISCO柱用10%至20%至40%EtOAc(含有0.3%AcOH)/Hex历经90min洗脱来纯化,随后经由12g ISCO柱用0%至30%EtOAc(含有0.3%AcOH)/Hex洗脱进行第二次纯化,得到为第一洗脱异构体的(1S,3'R,6'R,7'S,9'Z,12'S)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(13.4mg,0.023mmol,34.3%产率),且得到为第二洗脱异构体的(1S,3'R,6'R,7'S,9'E,12'S)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(13.2mg,0.023mmol,34.3%产率)。
步骤3:(1S,3'R,6'R,7'S,12'S)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照针对实施例6所描述的程序由(1S,3'R,6'R,7'S,9'E,12'S)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物和(1S,3'R,6'R,7'S,9'Z,12'S)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(来自步骤2,10.8mg,0.018mmol)的混合物合成标题化合物(7.5mg,0.013mmol,71%产率)。1H NMR(400MHz,CD2Cl2)δ9.72(br.s.,1H),7.71(d,J=8.6Hz,1H),7.30(dd,J=2.0,8.4Hz,1H),7.28(s,1H),7.16(dd,J=2.4,8.5Hz,1H),7.09(d,J=2.3Hz,1H),6.94(d,J=8.4Hz,1H),4.10-4.05(m,2H),3.85-3.76(m,1H),3.70(d,J=15.1Hz,1H),3.60(br.s.,1H),3.60(d,J=13.9Hz,1H),3.26(d,J=14.3Hz,1H),3.23-3.14(m,1H),2.83-2.69(m,2H),2.33(quin,J=8.6Hz,1H),2.12(quin,J=8.2Hz,1H),2.04-1.94(m,2H),1.94-1.85(m,1H),1.84-1.71(m,5H),1.71-1.64(m,2H),1.64-1.52(m,3H),1.49(d,J=7.2Hz,3H),1.52-1.43(m,2H),1.38-1.28(m,2H).MS(ESI,+ve离子)m/z 587.2(M+H)+。
实施例16.(1S,3'R,6'R,7'S,12'R)-6-氯-7'-甲氧基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
将(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-甲氧基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例13;5mg,8.34μmol)和氧化铂(iv)(0.379mg,1.67μmol,Omega)于EtOAc(2.8mL)中的混合物在H2(气球)下在rt搅拌3h,随后经由过滤以移除固体催化剂,浓缩,通过制备型反相HPLC(GeminiTM Prep C18 5μm柱;40%至95%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)纯化,得到(1S,3'R,6'R,7'S,12'R)-6-氯-7'-甲氧基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物(4.4mg,7.32μmol)。1H NMR(400MHz,CD3OD)δ7.73(d,J=8.4Hz,1H),7.16(d,J=8.7Hz,1H),7.11-7.03(m,2H),6.93(d,J=9.1Hz,2H),4.14-4.03(m,3H),3.83(d,J=14.7Hz,1H),3.69(d,J=14.3Hz,1H),3.33-3.29(m,3H与溶剂重叠),3.23(d,J=14.5Hz,1H),3.06(dd,J=9.1,15.4Hz,1H),2.85-2.71(m,2H),2.62(d,J=8.2Hz,1H),2.36(t,J=8.5Hz,1H),2.10-1.84(m,5H),1.84-1.56(m,6H),1.55-1.40(m,6H),1.38-1.24(m,3H).m/z(ESI,+ve离子)601.2(M+H)+。
实施例17.(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物、
实施例18.(1S,3'R,6'R,7'S,8'Z,12'R)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物和
实施例19.(1S,3'R,6'R,7'S,8'E,12'S)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以类似于实施例2中所描述的方式的方式使用(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基烯丙基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA11A)和(R)-庚-6-烯-3-磺酰胺(中间体EE21)与(S)-庚-6-烯-3-磺酰胺(中间体EE212)的外消旋混合物来制备标题化合物,且分离以下所需产物:(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(实施例17),作为来自制备型反相HPLC的第一洗脱主要异构体;(1S,3'R,6'R,7'S,8'Z,12'R)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例18),作为来自制备型反相HPLC的第二洗脱次要异构体;和(1S,3'R,6'R,7'S,8'E,12'S)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例19),作为来自制备型反相HPLC的第三洗脱主要异构体。(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(实施例17):1H NMR(400MHz,CD3OD)δ7.75(d,J=8.4Hz,1H),7.19(dd,J=2.0,8.8Hz,1H),7.12(d,J=2.2Hz,1H),7.00(dd,J=1.8,8.0Hz,1H),6.93(d,J=8.2Hz,1H),6.87(d,J=1.6Hz,1H),5.90-5.82(m,1H),5.73(dd,J=7.8,15.1Hz,1H),4.21(dd,J=3.7,7.8Hz,1H),4.09(dd,J=12.1,14.7Hz,2H),4.02(dd,J=6.5,13.5Hz,1H),3.85(d,J=15.1Hz,1H),3.68(d,J=14.1Hz,1H),3.29(d,J=14.3Hz,1H),3.08(dd,J=10.0,15.3Hz,1H),2.88-2.73(m,2H),2.46-2.22(m,4H),2.16-2.05(m,2H),2.02-1.79(m,8H),1.73(dd,J=9.0,17.6Hz,1H),1.46(t,J=12.6Hz,1H),1.20(t,J=7.5Hz,3H).m/z(ESI,+ve离子)599.2(M+H)+;(1S,3'R,6'R,7'S,8'Z,12'R)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例18)。1H NMR(500MHz,CD3OD)δ7.75(d,J=8.6Hz,1H),7.19(dd,J=2.3,8.4Hz,1H),7.12(d,J=2.2Hz,1H),7.03(dd,J=2.0,8.1Hz,1H),6.97-6.92(m,2H),5.62-5.55(m,2H),4.49(dd,J=3.5,7.9Hz,1H),4.09(dd,J=12.5,21.8Hz,2H),3.88(d,J=15.7Hz,1H),3.71(d,J=14.4Hz,1H),3.62(br.s.,1H),2.87-2.74(m,2H),2.49-2.38(m,3H),2.26-2.10(m,3H),2.06-1.89(m,8H),1.84-1.73(m,3H),1.55-1.40(m,1H),1.16(t,J=7.5Hz,3H).m/z(ESI,+ve离子)599.2(M+H)+;和(1S,3'R,6'R,7'S,8'E,12'S)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例19):1H NMR(400MHz,CD3OD)δ7.74(d,J=8.6Hz,1H),7.19(dd,J=2.3,8.4Hz,1H),7.13(d,J=2.2Hz,1H),7.08-7.02(m,2H),6.95(d,J=9.0Hz,1H),5.92(ddd,J=5.9,14.7,21.5Hz,1H),5.66(dd,J=6.1,15.3Hz,1H),4.15-4.05(m,3H),3.74-3.62(m,3H),3.47(d,J=14.3Hz,1H),3.51-3.43(m,1H),2.88-2.74(m,2H),2.58-2.33(m,3H),2.24-2.03(m,4H),1.97-1.73(m,8H),1.63-1.45(m,1H),1.17(t,J=7.5Hz,3H).m/z(ESI,+ve离子)599.2(M+H)+。
实施例20.(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-甲氧基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以类似于实施例4中所描述的方式的方式使用(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(实施例17)制备标题化合物,且分离所需产物(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-甲氧基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物为白色固体。1H NMR(400MHz,CD3OD)δ7.75(d,J=8.6Hz,1H),7.18(dd,J=2.2,8.6Hz,1H),7.12(d,J=2.0Hz,1H),7.00(dd,J=1.8,8.2Hz,1H),6.94(d,J=8.0Hz,1H),6.86(d,J=1.6Hz,1H),5.94-5.85(m,1H),5.58(dd,J=8.9,15.2Hz,1H),4.13-4.02(m,3H),3.85(d,J=14.9Hz,1H),3.74(dd,J=3.9,9.0Hz,1H),3.68(d,J=14.3Hz,1H),3.26(s,3H),3.22-3.04(m,1H),2.88-2.73(m,2H),2.54-2.39(m,2H),2.33(t,J=7.4Hz,2H),2.12(qd,J=7.3,14.4Hz,2H),2.02-1.69(m,10H),1.45(t,J=12.0Hz,1H),1.21(t,J=7.5Hz,3H).m/z(ESI,+ve离子)613.2(M+H)+。
实施例21.(1S,3'R,6'R,7'S,12'R)-6-氯-12'-乙基-7'-甲氧基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
以类似于实施例6中所描述的方式的方式使用(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-甲氧基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例20)制备标题化合物,且分离所需产物(1S,3'R,6'R,7'S,12'R)-6-氯-12'-乙基-7'-甲氧基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物。1H NMR(500MHz,CD3OD)δ7.76(d,J=8.6Hz,1H),7.19(dd,J=2.3,8.4Hz,1H),7.13(d,J=2.2Hz,1H),7.06(dd,J=2.0,8.3Hz,1H),7.00(d,J=1.7Hz,1H),6.95(d,J=8.3Hz,1H),4.11(ddd,J=2.9,12.0,14.2Hz,2H),3.88-3.81(m,2H),3.69(d,J=14.2Hz,1H),3.30(s,3H),3.12(dd,J=8.1,14.9Hz,1H),2.86-2.74(m,2H),2.69-2.62(m,1H),2.35(t,J=7.7Hz,1H),2.15-2.05(m,2H),2.01-1.85(m,5H),1.82-1.63(m,4H),1.47(br.s.,5H),1.42-1.24(m,4H),1.18(t,J=7.6Hz,3H).m/z(ESI,+ve离子)615.2(M+H)++。
实施例22.(1S,3'R,6'R,7'S,12'R)-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
将(1S,3'R,6'R,7'S,8'Z,12'R)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例18;5.2mg,8.68μmol)和钯10wt.%(按干重计)/湿活性碳(4.6mg,4.34μmol)于1:1比率的EtOAc:EtOH(3.0mL)中的混合物在H2下在rt搅拌过夜,随后经由过滤以移除固体催化剂。将有机层浓缩,且通过制备型反相HPLC(GeminiTM Prep C18 5μm柱;40%至95%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)纯化,得到(1S,3'R,6'R,7'S,12'R)-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物(1.9mg,3.35μmol)。1H NMR(400MHz,CD3OD)δ7.77(d,J=7.0Hz,1H),7.21-7.02(m,4H),6.97(d,J=8.2Hz,1H),6.93(d,J=2.2Hz,1H),4.13(dd,J=12.1,22.7Hz,2H),3.92-3.80(m,2H),3.76-3.70(m,2H),3.13(dd,J=8.8,19.2Hz,1H),2.87-2.75(m,2H),2.44-2.29(m,2H),2.15-2.04(m,2H),1.99-1.37(m,17H),1.18(t,J=7.6Hz,3H).m/z(ESI,+ve离子)567.2(M+H)+。
实施例23.(1S,3'R,6'R,7'S,12'S)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步骤1:(S)-6'-氯-N-((R)-己-5-烯-3-基磺酰基)-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酰胺和(S)-6'-氯-N-((S)-己-5-烯-3-基磺酰基)-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酰胺
按照针对实施例2的步骤1所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA13A;224mg,0.465mmol)和(R)-己-5-烯-3-磺酰胺(中间体EE18)与(S)-己-5-烯-3-磺酰胺(中间体EE182;167mg,1.023mmol)的外消旋混合物合成标题化合物。粗物质的纯化得到(S)-6'-氯-N-((R)-己-5-烯-3-基磺酰基)-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺与(S)-6'-氯-N-((S)-己-5-烯-3-基磺酰基)-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺的混合物(235mg,0.375mmol,81%产率)。
步骤2.(1S,3'R,6'R,7'S,9'Z,12'S)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物和(1S,3'R,6'R,7'S,9'E,12'S)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照针对实施例14的步骤2所描述的程序由(S)-6'-氯-N-((R)-己-5-烯-3-基磺酰基)-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺与(S)-6'-氯-N-((R)-己-5-烯-3-基磺酰基)-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺的混合物(来自步骤1,235mg,0.375mmol)合成标题化合物。通过色谱经由24g ISCO柱用10%至20%至40%EtOAc(含有0.3%AcOH)/Hex历经60min洗脱对粗物质进行第一次纯化,得到标题化合物的混合物。
步骤3:(1S,3'R,6'R,7'S,12'S)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照针对实施例6所描述的程序由(1S,3'R,6'R,7'S,9'Z,12'S)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物与(1S,3'R,6'R,7'S,9'E,12'S)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物的混合物(来自步骤2,12mg,0.020mmol)合成标题化合物(6.3mg,0.010mmol,52.3%产率)。1H NMR(400MHz,CD2Cl2)δ10.11(br.s.,1H),7.70(d,J=8.6Hz,1H),7.36(dd,J=2.1,8.3Hz,1H),7.28(d,J=1.8Hz,1H),7.15(dd,J=2.3,8.4Hz,1H),7.08(d,J=2.3Hz,1H),6.93(d,J=8.2Hz,1H),4.06(d,J=11.5Hz,1H),3.99(d,J=12.1Hz,1H),3.76(d,J=15.5Hz,1H),3.65-3.61(m,1H),3.59(d,J=14.1Hz,1H),3.57-3.50(m,1H),3.16(d,J=14.3Hz,1H),3.09(dd,J=8.5,15.2Hz,1H),2.83-2.67(m,2H),2.25(quin,J=9.0Hz,1H),2.20-2.08(m,3H),2.03-1.88(m,3H),1.89-1.74(m,7H),1.72-1.57(m,3H),1.55-1.39(m,2H),1.36-1.19(m,2H),1.10(t,J=7.4Hz,3H).MS(ESI,+ve离子)m/z601.2(M+H)+。
实施例24.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(3R,4S)-N,N-双(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺酰胺和(3S,4S)-N,N-双(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺酰胺
按照针对实施例26的步骤1所描述的程序由N,N-双(4-甲氧基苄基)丙烷-1-磺酰胺(中间体EE14;1512mg,4.16mmol)和4-甲基苯磺酸(R)-戊-4-烯-2-基酯(根据Sigman,M.S.等人;J.Am.Chem.Soc.,2012,134(28),11408-11411的程序制备;1999mg,8.32mmol)合成标题化合物。得到为不可分离的混合物的(3R,4S)-N,N-双(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺酰胺和(3S,4S)-N,N-双(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺酰胺(335mg,0.776mmol,18.7%产率)。
步骤2:(3R,4S)-4-甲基庚-6-烯-3-磺酰胺和(3S,4S)-4-甲基庚-6-烯-3-磺酰胺
按照针对实施例26的步骤2所描述的程序由(3R,4S)-N,N-双(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺酰胺和(3S,4S)-N,N-双(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺酰胺(335mg,0.776mmol,步骤1)合成标题化合物。得到为不可分离的混合物的(3R,4S)-4-甲基庚-6-烯-3-磺酰胺和(3S,4S)-4-甲基庚-6-烯-3-磺酰胺(67.6mg,0.35mmol,45.5%产率)。
步骤3:(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羟基-5-甲基-6-氨磺酰基辛-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸和(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羟基-5-甲基-6-氨磺酰基辛-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
按照针对实施例26的步骤3所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12A;40mg,0.078mmol)和(3R,4S)-4-甲基庚-6-烯-3-磺酰胺与(3S,4S)-4-甲基庚-6-烯-3-磺酰胺的混合物(67.6mg,0.35mmol)合成标题化合物。将(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羟基-5-甲基-6-氨磺酰基辛-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸与(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羟基-5-甲基-6-氨磺酰基辛-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸的混合物(46mg,0.073mmol,92%产率)用于下一步骤。
步骤4.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照针对实施例26的步骤4所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羟基-5-甲基-6-氨磺酰基辛-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸和(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羟基-5-甲基-6-氨磺酰基辛-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(63mg,0.100mmol)合成标题化合物。通过色谱经由12g ISCO gold柱用10-40-50%EtOAc(含有0.3%AcOH)/Hex历经24min洗脱来纯化粗物质,得到为第二洗脱主要异构体的(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物。此物质通过色谱经由12g ISCO gold柱用0-10%丙酮/DCM洗脱而再纯化,得到标题化合物(20mg,0.033mmol,32.7%产率)。1H NMR(400MHz,CD2Cl2)δ8.33(br.s.,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.3Hz,1H),6.96-6.88(m,3H),5.86(ddd,J=3.9,9.0,15.1Hz,1H),5.71(dd,J=8.2,15.1Hz,1H),4.22(dd,J=3.9,8.2Hz,1H),4.09-4.08(m,2H),3.98(ddd,J=1.2,3.7,8.8Hz,1H),3.82(d,J=14.7Hz,1H),3.69(d,J=14.3Hz,1H),3.25(d,J=14.3Hz,1H),3.04(dd,J=9.5,15.4Hz,1H),2.85-2.69(m,2H),2.41(ddd,J=3.7,9.8,18.4Hz,1H),2.35-2.24(m,1H),2.21-2.11(m,1H),2.10-2.03(m,2H),1.99-1.90(m,3H),1.90-1.74(m,5H),1.67(quin,J=9.5Hz,2H),1.45-1.34(m,1H),1.27(t,J=7.4Hz,3H),1.02(d,J=6.8Hz,3H).MS(ESI,+ve离子)m/z 613.0(M+H)+。
实施例25.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照针对实施例4所描述的程序由(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例24;10mg,0.016mmol)合成标题化合物。粗物质经由柱色谱用10-40%EtOAc(含有0.3%AcOH)/庚烷洗脱来纯化,得到(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(7.3mg,0.012mmol,71.4%产率)。1H NMR(500MHz,CD2Cl2)δ8.13(s,1H),7.71(d,J=8.6Hz,1H),7.17(dd,J=2.2,8.6Hz,1H),7.09(d,J=2.0Hz,1H),6.91(s,2H),6.87(s,1H),5.84(ddd,J=3.4,9.6,15.1Hz,1H),5.51(dd,J=9.0,15.2Hz,1H),4.11-4.06(m,2H),4.04-4.00(m,1H),3.82(d,J=15.4Hz,1H),3.69(d,J=14.2Hz,1H),3.64(dd,J=3.3,9.2Hz,1H),3.25(d,J=14.2Hz,1H),3.18(s,3H),3.03(dd,J=10.1,15.3Hz,1H),2.84-2.69(m,2H),2.44(ddd,J=3.2,9.8,18.6Hz,1H),2.33(quin,J=8.8Hz,1H),2.28-2.21(m,1H),2.15-2.09(m,1H),2.09-2.02(m,2H),2.01-1.90(m,3H),1.90-1.73(m,4H),1.72-1.61(m,1H),1.39(t,J=12.6Hz,1H),1.28(t,J=7.3Hz,3H),1.02(d,J=6.8Hz,3H).MS(ESI,+ve离子)m/z627.1(M+H)+。
实施例26.(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(2R,3R)-N,N-双(4-甲氧基苄基)-3-甲基己-5-烯-2-磺酰胺和(2S,3R)-N,N-双(4-甲氧基苄基)-3-甲基己-5-烯-2-磺酰胺
将N,N-双(4-甲氧基苄基)乙磺酰胺(中间体EE13;1030mg,2.95mmol)在甲苯中在真空下共沸2h。在氩气下,添加THF,且将溶液冷却至-78℃。随后添加正丁基锂溶液(2.5MHex,1.533mL,3.83mmol),且将混合物在-78℃下搅拌60min。以3mL溶液的形式添加4-甲基苯磺酸(S)-戊-4-烯-2-基酯(根据Sigman,M.S.等人,J.Am.Chem.Soc.,2012,134(28),11408-11411的程序制备;1417mg,5.90mmol)。随后添加THF。5min后,使混合物升至环境温度且在氩气下搅拌过夜。将混合物用饱和NH4Cl淬灭且用EtOAc萃取,经MgSO4干燥且浓缩。将粗物质注入SiO2凝胶滤筒中,且通过色谱经由40g ISCO柱用5%至10%至20%至40%EtOAc/Hex洗脱来纯化,得到标题化合物的2.3:1混合物(420mg,1.00mmol,34.1%产率)。
步骤2:(2R,3R)-3-甲基己-5-烯-2-磺酰胺和(2S,3R)-3-甲基己-5-烯-2-磺酰胺
在环境温度下向(2R,3R)-N,N-双(4-甲氧基苄基)-3-甲基己-5-烯-2-磺酰胺和(2S,3R)-N,N-双(4-甲氧基苄基)-3-甲基己-5-烯-2-磺酰胺(2.3:1非对映异构体混合物;420mg,1.00mmol)和苯甲醚(1.093mL,10.06mmol)于DCM(5.029mL)中的溶液缓慢添加三氟乙酸(2.99mL,40.2mmol)。搅拌过夜后,浓缩混合物。残余物用EtOAc稀释,用饱和NaHCO3洗涤,用EtOAc反萃取,经MgSO4干燥且浓缩。经由色谱在24g ISCO gold柱上用0-50%EtOAc/Hex)梯度洗脱来纯化粗物质,得到标题化合物的2.3:1混合物(153mg,0.863mmol,86%产率)。
步骤3:(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,6R,E)-1-羟基-5-甲基-6-氨磺酰基庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸和(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,6S,E)-1-羟基-5-甲基-6-氨磺酰基庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
向小瓶中装入1,2-DCE(2.101mL)中的(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12A;75mg,0.147mmol)和(2R,3R)-3-甲基己-5-烯-2-磺酰胺与(2S,3R)-3-甲基己-5-烯-2-磺酰胺的2.3:1混合物(153mg,0.863mmol)。将溶液用氩气吹扫,随后在环境温度下以1mL 1,2-DCE中的溶液的形式添加Hoveyda-Grubbs II(9.21mg,0.015mmol)。在环境温度下搅拌所得混合物(用氩气吹扫且使小瓶排气)。2h后,反应混合物用空气吹扫5min且过滤以分离不溶性磺酰胺同二聚体。将滤液直接注入12g ISCO gold柱中,且用0-20-50-100%EtOAc/Hex洗脱历经16min来纯化,得到标题化合物的混合物(74mg,0.120mmol,82%产率)。
步骤4.(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
在0℃下将N,N-二甲基吡啶-4-胺(24.90mg,0.204mmol)添加至(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,6R,E)-1-羟基-5-甲基-6-氨磺酰基庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸和(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,6S,E)-1-羟基-5-甲基-6-氨磺酰基庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(74mg,0.120mmol)(先前用2.0mL PhMe共沸3h)于DCM(59.900mL)中的溶液。随后缓慢逐份添加N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(46.0mg,0.240mmol),且搅拌所得混合物同时使其升至环境温度后保持15h。将混合物用1N HCl和盐水洗涤,将水溶液用EtOAc反萃取,并将合并的有机物经无水硫酸镁干燥,随后浓缩。通过色谱经由12g ISCO gold柱用10-40-50%EtOAc(含有0.3%AcOH)/Hex历经24min洗脱来纯化粗物质,得到为第一洗脱主要异构体的(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(19.5mg,0.033mmol,27.1%产率,90%纯度)。1H NMR(400MHz,CD2Cl2)δ8.31(br.s.,1H),7.65(d,J=8.4Hz,1H),7.62(br.s.,1H),7.14(dd,J=2.4,8.5Hz,1H),7.10(d,J=2.3Hz,1H),6.93(dd,J=2.0,8.2Hz,1H),6.90(d,J=8.0Hz,1H),5.66(dd,J=3.7,15.8Hz,1H),5.58-5.45(m,1H),4.22(s,2H),4.15-4.08(m,2H),3.87(br.s.,1H),3.74(d,J=13.9Hz,1H),3.33(d,J=14.1Hz,1H),3.11(d,J=13.9Hz,1H),2.79-2.69(m,2H),2.57-2.39(m,2H),2.06-1.92(m,2H),1.91-1.81(m,4H),1.80-1.73(m,4H),1.71-1.55(m,2H),1.41(d,J=7.4Hz,3H),1.04(d,J=6.7Hz,3H).MS(ESI,+ve离子)m/z 599.1(M+H)+。
实施例27.(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
如针对实施例26的步骤4所描述合成标题化合物。分离(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(11.5mg,0.019mmol,16.0%产率,95%纯度)为第二洗脱次要异构体。1H NMR(400MHz,CD2Cl2)δ9.08-8.57(m,1H),7.72(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),7.06(d,J=8.6Hz,1H),6.93(d,J=8.0Hz,1H),6.83(s,1H),6.03(ddd,J=5.3,8.2,15.7Hz,1H),5.76(dd,J=7.8,15.7Hz,1H),4.20(dd,J=3.2,7.9Hz,1H),4.14-4.03(m,3H),3.78-3.63(m,2H),3.29(d,J=14.3Hz,1H),3.12(dd,J=9.9,15.4Hz,1H),2.85-2.68(m,2H),2.62(br.s.,1H),2.55-2.42(m,1H),2.36(dq,J=3.2,9.2Hz,1H),2.26-2.16(m,1H),2.14-2.07(m,1H),2.04-1.93(m,3H),1.90(dd,J=4.1,9.2Hz,1H),1.87-1.74(m,3H),1.73-1.63(m,1H),1.46(d,J=7.2Hz,3H),1.46-1.39(m,1H),1.07(d,J=7.0Hz,3H).MS(ESI,+ve离子)m/z 599.0(M+H)+。
实施例28.(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(2R,3S)-N,N-双(4-甲氧基苄基)-3-甲基己-5-烯-2-磺酰胺和(2S,3S)-N,N-双(4-甲氧基苄基)-3-甲基己-5-烯-2-磺酰胺
按照针对实施例26的步骤1所描述的程序由N,N-双(4-甲氧基苄基)乙磺酰胺(中间体EE13;1148mg,3.29mmol)和4-甲基苯磺酸(R)-戊-4-烯-2-基酯(根据Sigman,M.S.等人;J.Am.Chem.Soc.,2012,134(28),11408-11411的程序制备;1579mg,6.57mmol)合成标题化合物。得到为2.4:1混合物的步骤1(2R,3S)-N,N-双(4-甲氧基苄基)-3-甲基己-5-烯-2-磺酰胺和(2S,3S)-N,N-双(4-甲氧基苄基)-3-甲基己-5-烯-2-磺酰胺(539mg,1.29mmol,39.3%产率)。
步骤2:(2R,3S)-3-甲基己-5-烯-2-磺酰胺和(2S,3S)-3-甲基己-5-烯-2-磺酰胺
按照针对实施例26的步骤2所描述的程序由(2R,3S)-N,N-双(4-甲氧基苄基)-3-甲基己-5-烯-2-磺酰胺和(2S,3S)-N,N-双(4-甲氧基苄基)-3-甲基己-5-烯-2-磺酰胺(539mg;1.29mmol)合成标题化合物。得到为2.3:1混合物的(2R,3S)-3-甲基己-5-烯-2-磺酰胺和(2S,3S)-3-甲基己-5-烯-2-磺酰胺(203mg,1.15mmol,89%产率)。
步骤3:(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羟基-5-甲基-6-氨磺酰基庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸和(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羟基-5-甲基-6-氨磺酰基庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
按照针对实施例26的步骤3所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12A;75mg,0.147mmol)和(2R,3S)-3-甲基己-5-烯-2-磺酰胺与(2S,3S)-3-甲基己-5-烯-2-磺酰胺的2.3:1混合物(153mg,0.863mmol)合成标题化合物。将(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羟基-5-甲基-6-氨磺酰基庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸与(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羟基-5-甲基-6-氨磺酰基庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸的混合物(73mg,0.118mmol,80%产率)用于下一步骤。
步骤4.(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照针对实施例26的步骤4所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羟基-5-甲基-6-氨磺酰基庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸和(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羟基-5-甲基-6-氨磺酰基庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(73mg,0.118mmol)合成标题化合物。通过色谱经由12g ISCO gold柱用10-40-50%EtOAc(含有0.3%AcOH)/Hex洗脱历经24min来纯化粗物质,得到为第一洗脱次要异构体的(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物。此物质经由制备型反相HPLC用50-70%MeCN(含有0.1%TFA)/H2O(含有0.1%TFA)洗脱而再纯化,得到标题化合物(5.8mg,0.0097mmol,8.2%产率,90%纯度)。1H NMR(400MHz,CD2Cl2)δ8.21(s,1H),7.71(d,J=8.4Hz,1H),7.18(dd,J=2.3,8.4Hz,1H),7.14(dd,J=2.1,8.1Hz,1H),7.09(d,J=2.3Hz,1H),6.95(d,J=8.2Hz,1H),6.69(br.s.,1H),6.10-5.99(m,1H),5.67(dd,J=6.4,15.4Hz,1H),4.20-4.14(m,1H),4.11(d,J=12.1Hz,1H),4.06(d,J=11.9Hz,1H),3.84-3.74(m,1H),3.76(d,J=15.5Hz,1H),3.65(d,J=14.7Hz,1H),3.44(d,J=14.7Hz,1H),3.33-3.20(m,1H),2.86-2.70(m,2H),2.60-2.48(m,2H),2.31-2.20(m,2H),2.08-1.98(m,2H),1.97-1.80(m,4H),1.79-1.68(m,1H),1.67-1.49(m,2H),1.46(d,J=7.2Hz,3H),1.42(br.s.,1H),1.08(d,J=7.0Hz,3H).MS(ESI,+ve离子)m/z 599.1(M+H)+。
实施例29.(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(S)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(R)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺
将N,N-双(4-甲氧基苄基)甲磺酰胺(中间体EE12;1.05g,3.13mmol)在PhMe中在真空下共沸12h。在氩气下,添加THF(21mL)且将溶液冷却至-78℃。随后添加丁基锂溶液(2.5MHex;1.63mL,4.07mmol),且将混合物在-78℃下搅拌30min。以1.5mL THF中的溶液的形式添加4-甲基苯磺酸戊-4-烯-2-基酯(根据Sigman,M.S.等人;J.Am.Chem.Soc.,2012,134(28),11408-11411的程序制备;1.3g,5.41mmol)。完成添加后,使混合物升至环境温度且搅拌过夜。LC/MS分析表明50%转化为所需产物;另外24h的延长搅拌并未提高转化。混合物随后用饱和NH4Cl淬灭,用EtOAc萃取,经MgSO4干燥且浓缩。通过色谱经由24g ISCO柱用10%至20%至60%EtOAc/Hex洗脱来纯化粗物质,得到(S)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺与(R)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺的外消旋混合物(408mg,1.01mmol,32%产率)。
步骤2:(S)-2-甲基戊-4-烯-1-磺酰胺和(R)-2-甲基戊-4-烯-1-磺酰胺
按照针对实施例26的步骤2所描述的程序由(S)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(R)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺(506mg,1.25mmol)合成标题化合物。得到为外消旋混合物的步骤2.(S)-2-甲基戊-4-烯-1-磺酰胺和(R)-2-甲基戊-4-烯-1-磺酰胺(152mg,0.93mmol,74%产率)。
步骤3:(1'S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羟基-5-甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸叔丁酯和(1'S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羟基-5-甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸叔丁酯
向小瓶装入((S)-6’-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3’,4,4’,5-四氢-2H,2’H-螺[苯并[b][1,4]氧氮杂-3,1’-萘]-7-甲酸叔丁酯(中间体AA12A,步骤1B,第一洗脱异构体;120mg,0.212mmol)和(S)-2-甲基戊-4-烯-1-磺酰胺与(R)-2-甲基戊-4-烯-1-磺酰胺于1,2-DCE(3.028mL)中的外消旋混合物(156mg,0.954mmol)。将溶液用氩气吹扫,且在环境温度下以1.5mL 1,2-DCE中的溶液的形式添加Hoveyda-Grubbs II(13.28mg,0.021mmol)。将混合物在环境温度下搅拌(用氩气吹扫且使小瓶排气)1.5h(通过LC/MS分析表明转化了70%)。反应混合物随后用空气吹扫5min,浓缩,然后直接注入24g ISCO gold柱中,且用0-20-50-100%EtOAc/Hex历经16min洗脱来纯化,得到(1'S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羟基-5-甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸叔丁酯与(1'S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羟基-5-甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸叔丁酯的混合物(63mg,0.096mmol,45.1%产率)。
步骤4:(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羟基-5-甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸和(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羟基-5-甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
向(1'S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羟基-5-甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸叔丁酯与(1'S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羟基-5-甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸叔丁酯(63mg,0.096mmol)和LiOH单水合物(0.013mL,0.478mmol)的固体混合物添加二噁烷/MeOH的1:1混合物(1.911mL)。将反应加热至70℃。1.5h后几乎未观测到反应;添加H2O(约0.4mL),且将混合物搅拌40h。随后将混合物用1N HCl(1.0mL)淬灭,用盐水稀释,用EtOAc萃取,经MgSO4干燥且浓缩。所得的粗物质不经进一步纯化即用于下一步骤。
步骤5.(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照针对实施例26的步骤4所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羟基-5-甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸和(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羟基-5-甲基-6-氨磺酰基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(57mg,0.095mmol)合成标题化合物。通过色谱经由12g ISCO gold柱用10-40-50%EtOAc(含有0.3%AcOH)/Hex历经24min洗脱来纯化粗物质,得到为第一洗脱次要异构体的(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(11mg,0.019mmol,19.9%产率,90%纯度)。1H NMR(400MHz,CD2Cl2)δ8.41(s,1H),7.66(d,J=8.4Hz,1H),7.50(br.s.,1H),7.15(dd,J=2.3,8.4Hz,1H),7.10(d,J=2.3Hz,1H),6.95(dd,J=2.0,8.2Hz,1H),6.90(d,J=8.0Hz,1H),5.69(dd,J=4.3,15.8Hz,1H),5.63-5.54(m,1H),4.20(s,2H),4.04(d,J=15.3Hz,1H),3.94(dd,J=2.2,5.2Hz,1H),3.89-3.81(m,1H),3.74-3.63(m,1H),3.39(d,J=15.3Hz,1H),3.26-3.17(m,1H),3.09-2.96(m,1H),2.81-2.71(m,2H),2.57-2.41(m,2H),2.16(dd,J=6.5,11.7Hz,1H),1.92-1.76(m,6H),1.75-1.63(m,3H),1.62-1.41(m,2H),1.19(d,J=6.1Hz,3H).MS(ESI,+ve离子)m/z 585.1(M+H)+。
实施例30.(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
如针对实施例29的步骤5所描述合成标题化合物。分离(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物为第二洗脱主要异构体(11.6mg,0.020mmol,21.0%产率)。1HNMR(400MHz,CD2Cl2)δ8.44(br.s.,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),6.95-6.90(m,2H),6.89(s,1H),5.82(ddd,J=5.1,7.6,15.1Hz,1H),5.70(dd,J=8.2,15.3Hz,1H),4.24(dd,J=3.9,12.3Hz,1H),4.20(dd,J=4.7,8.8Hz,1H),4.10-4.05(m,2H),3.82(d,J=14.9Hz,1H),3.69(d,J=14.3Hz,1H),3.25(d,J=14.3Hz,1H),3.05(dd,J=9.6,15.1Hz,1H),2.98(dd,J=8.0,15.3Hz,1H),2.84-2.67(m,2H),2.41(ddd,J=4.3,9.8,18.0Hz,1H),2.36-2.28(m,1H),2.24(ddd,J=2.2,7.9,15.2Hz,1H),2.08-1.99(m,2H),1.98-1.87(m,3H),1.87-1.74(m,4H),1.68(dd,J=9.4,18.8Hz,1H),1.46-1.35(m,1H),1.15(d,J=6.5Hz,3H).MS(ESI,+ve离子)m/z585.1(M+H)+。
实施例31.(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照针对实施例4所描述的程序由(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例29;8.0mg,0.014mmol)合成标题化合物。粗物质的纯化得到(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(8.1mg,0.014mmol,99%产率,94%纯度)。1H NMR(400MHz,CD2Cl2)δ8.22(s,1H),7.69(d,J=8.4Hz,1H),7.16(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),6.97-6.88(m,3H),5.84(td,J=6.3,15.6Hz,1H),5.48(dd,J=7.3,15.4Hz,1H),4.15-4.03(m,2H),3.64(dd,J=6.5,15.3Hz,1H),3.61-3.56(m,2H),3.55-3.46(m,2H),3.38(d,J=14.1Hz,1H),3.29(s,3H),3.23(d,J=14.1Hz,1H),2.84-2.68(m,2H),2.48-2.31(m,2H),2.27-2.15(m,3H),2.02-1.93(m,1H),1.93-1.82(m,3H),1.77-1.63(m,3H),1.56-1.44(m,1H),1.16(d,J=6.5Hz,3H).MS(ESI,+ve离子)m/z 599.0(M+H)+。
实施例32.(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照针对实施例4所描述的程序由(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例30;8.0mg,0.014mmol)合成标题化合物。粗物质的纯化得到(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(8.1mg,0.014mmol,99%产率)。1H NMR(400MHz,CD2Cl2)δ8.18(s,1H),7.71(d,J=8.6Hz,1H),7.17(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),6.93-6.87(m,2H),6.82(s,1H),5.82(ddd,J=5.7,7.6,14.9Hz,1H),5.52(dd,J=9.2,15.3Hz,1H),4.32(dd,J=4.9,15.3Hz,1H),4.07(s,2H),3.81(d,J=14.9Hz,1H),3.70(d,J=14.3Hz,1H),3.64(dd,J=3.5,9.2Hz,1H),3.23(d,J=14.3Hz,1H),3.19(s,3H),3.02(dd,J=6.1,15.3Hz,1H),2.99(dd,J=3.2,15.2Hz,1H),2.85-2.67(m,2H),2.44(ddd,J=3.3,9.6,18.6Hz,1H),2.36-2.23(m,2H),2.15-2.02(m,1H),2.00-1.89(m,2H),1.88-1.82(m,1H),1.82-1.74(m,2H),1.71-1.62(m,1H),1.59-1.48(m,2H),1.44-1.34(m,1H),1.14(d,J=6.8Hz,3H).MS(ESI,+ve离子)m/z 599.0(M+H)+。
实施例33.(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-11'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(S)-2-乙基-N,N-双(4-甲氧基苄基戊-4-烯-1-磺酰胺和(R)-2-乙基-N,N-双(4-甲氧基苄基)戊-4-烯-1-磺酰胺
根据针对中间体26的步骤1所描述的程序由N,N-双(4-甲氧基苄基)甲磺酰胺(中间体EE12;1.10g,3.28mmol)和4-甲基苯磺酸己-5-烯-3-基酯(根据Sigman,M.S.等人;J.Am.Chem.Soc.,2012,134(28),11408-11411的程序制备;1.50g,5.90mmol)合成标题化合物。得到为外消旋混合物的(S)-2-乙基-N,N-双(4-甲氧基苄基)戊-4-烯-1-磺酰胺和(R)-2-乙基-N,N-双(4-甲氧基苄基)戊-4-烯-1-磺酰胺(435mg,1.04mmol,31.8%产率)。
步骤2:(S)-2-乙基戊-4-烯-1-磺酰胺和(R)-2-乙基戊-4-烯-1-磺酰胺
根据针对实施例26的步骤2所描述的程序由(S)-2-乙基-N,N-双(4-甲氧基苄基)戊-4-烯-1-磺酰胺与(R)-2-乙基-N,N-双(4-甲氧基苄基)戊-4-烯-1-磺酰胺的外消旋混合物(435mg,1.04mmol)合成标题化合物。得到为外消旋混合物的(S)-2-乙基戊-4-烯-1-磺酰胺和(R)-2-乙基戊-4-烯-1-磺酰胺(149mg,0.84mmol,81%产率)。
步骤3:(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羟基-5-(氨磺酰基甲基)庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸和(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羟基-5-(氨磺酰基甲基)庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酸
按照针对实施例26的步骤3所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12A;80mg,0.157mmol)和(S)-2-乙基戊-4-烯-1-磺酰胺与(R)-2-乙基戊-4-烯-1-磺酰胺的混合物(149mg,0.84mmol)合成标题化合物。粗物质用0-20-50-100%EtOAc/庚烷的梯度,随后用20-50%EtOAc(含有0.3%AcOH)/庚烷的梯度洗脱来纯化,得到(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羟基-5-(氨磺酰基甲基)庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸与(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羟基-5-(氨磺酰基甲基)庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸的不可分离混合物(75mg,0.122mmol,77%产率)。
步骤4.1S,3'R,6'R,7'S,8'E,11'R)-6-氯-11'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照针对实施例26的步骤4所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羟基-5-(氨磺酰基甲基)庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸和(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羟基-5-(氨磺酰基甲基)庚-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(75mg,0.122mmol)合成标题化合物。通过色谱经由12g ISCO gold柱用10-30-50%EtOAc(含有0.3%AcOH)/Hex历经24min洗脱来纯化粗物质,得到为第一洗脱异构体的(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-11'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(20.4mg,0.034mmol,28.0%产率)。1HNMR(400MHz,CD2Cl2)δ8.45(br.s.,1H),7.67(d,J=8.6Hz,1H),7.44(br.s.,1H),7.15(dd,J=2.3,8.4Hz,1H),7.10(d,J=2.3Hz,1H),6.96(dd,J=1.8,8.0Hz,1H),6.91(d,J=8.0Hz,1H),5.71(dd,J=4.7,15.7Hz,1H),5.66-5.55(m,1H),4.24-4.13(m,2H),3.96(br.s.,1H),3.92(d,J=15.7Hz,1H),3.79(br.s.,1H),3.64(d,J=13.3Hz,1H),3.42(d,J=14.5Hz,1H),3.30-3.11(m,2H),2.79-2.71(m,2H),2.56-2.41(m,2H),2.29(dd,J=5.5,13.9Hz,1H),1.91-1.75(m,7H),1.75-1.63(m,4H),1.45(dt,J=7.6,14.3Hz,2H),0.92(t,J=7.3Hz,3H).MS(ESI,+ve离子)m/z 599.0(M+H)+。
实施例34.(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-11'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
如针对实施例33的步骤4所描述的那样合成标题化合物。(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-11'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物作为第二洗脱异构体。此物质用60%EtOAc/庚烷洗脱而再纯化,得到纯标题化合物(15.7mg,0.026mmol,21.6%产率)。1H NMR(500MHz,CD2Cl2)δ8.59(br.s.,1H),7.69(d,J=8.6Hz,1H),7.15(dd,J=2.3,8.4Hz,1H),7.08(d,J=2.2Hz,1H),6.93(dd,J=2.0,8.1Hz,1H),6.90(d,J=8.1Hz,1H),6.85(d,J=1.5Hz,1H),5.81(td,J=6.6,15.2Hz,1H),5.68(dd,J=8.3,15.2Hz,1H),4.19(dd,J=3.9,8.1Hz,1H),4.12(dd,J=5.9,15.4Hz,1H),4.06(s,2H),3.78(d,J=14.9Hz,1H),3.68(d,J=14.4Hz,1H),3.23(d,J=14.2Hz,1H),3.13(dd,J=6.7,15.5Hz,1H),3.02(dd,J=9.7,15.3Hz,1H),2.82-2.68(m,2H),2.39(ddd,J=4.2,9.8,18.1Hz,1H),2.36-2.25(m,2H),2.06-1.96(m,3H),1.96-1.88(m,2H),1.87-1.70(m,4H),1.69-1.56(m,3H),1.42-1.35(m,1H),0.90(t,J=7.5Hz,3H).MS(ESI,+ve离子)m/z599.2(M+H)+。
实施例35.(1S,3'R,6'R,7'S,11'R,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'二氧化物或(1S,3'R,6'R,7'S,11'R,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
将(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例26;17mg,0.028mmol)和氧化铂(IV)(6.44mg,0.028mmol)于EtOAc(3.5mL)中的混合物在H2(气球)下在环境温度搅拌50min。随后经由注射器式过滤器过滤反应混合物。通过色谱经由Redi-预装填SiO2凝胶柱(4g)用20%至50%EtOAc(含有0.3%AcOH)/庚烷洗脱来纯化粗物质,得到(1S,3'R,6'R,7'S,11'R,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'二氧化物或(1S,3'R,6'R,7'S,11'R,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物(12.1mg,0.020mmol,70.9%产率)。1H NMR(500MHz,CD2Cl2)δ8.55(br.s.,1H),7.67(d,J=8.6Hz,1H),7.48(br.s.,1H),7.14(dd,J=2.4,8.6Hz,1H),7.09(d,J=2.2Hz,1H),7.03(dd,J=1.7,8.1Hz,1H),6.92(d,J=8.3Hz,1H),4.22-4.13(m,2H),4.05-3.96(m,1H),3.66(br.s.,1H),3.61(d,J=13.7Hz,1H),3.51-3.45(m,1H),3.43(d,J=14.4Hz,1H),3.28(d,J=12.2Hz,1H),2.81-2.69(m,2H),2.62-2.53(m,1H),2.48-2.41(m,1H),2.16-2.08(m,2H),1.91(q,J=9.0Hz,1H),1.87-1.78(m,3H),1.78-1.72(m,1H),1.68(q,J=8.6Hz,2H),1.59(dd,J=6.1,10.3Hz,2H),1.50-1.43(m,1H),1.41(d,J=7.1Hz,3H),1.37-1.25(m,4H),1.00(d,J=6.8Hz,3H).MS(ESI,+ve离子)m/z 601.0(M+H)+。
实施例36.(1S,3'R,6'R,7'S,11'R,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,11'R,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照针对实施例35所描述的程序由(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例27;9.4mg,0.016mmol)合成标题化合物。粗物质的纯化得到(1S,3'R,6'R,7'S,11'R,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,11'R,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物(5.2mg,0.0087mmol,55.1%产率)。1H NMR(500MHz,CD2Cl2)δ9.70(br.s.,1H),7.70(d,J=8.6Hz,1H),7.17(dd,J=2.2,8.3Hz,1H),7.16(d,J=8.3Hz,1H),7.10(d,J=2.2Hz,1H),6.97(d,J=8.1Hz,1H),4.18(d,J=11.7Hz,1H),4.12(d,J=12.0Hz,1H),3.69-3.57(m,3H),3.49(d,J=14.7Hz,1H),3.38(d,J=14.2Hz,1H),3.33(br.s.,1H),2.90(d,J=4.6Hz,2H),2.82-2.70(m,2H),2.46-2.36(m,1H),2.31-2.20(m,1H),2.11-2.01(m,1H),1.99-1.91(m,3H),1.90-1.78(m,3H),1.77-1.70(m,2H),1.70-1.62(m,4H),1.61-1.55(m,1H),1.45(m,1H),1.42(d,J=7.3Hz,3H),0.97(d,J=6.8Hz,3H).MS(ESI,+ve离子)m/z 601.1(M+H)+。
实施例37.(1S,3'R,6'R,7'S,11'S,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照针对实施例35所描述的程序由(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例28;3.9mg,0.0065mmol)合成标题化合物。粗物质的纯化得到(1S,3'R,6'R,7'S,11'S,12'S)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物(2.8mg,0.0047mmol,71.6%产率,90%纯度)。1H NMR(500MHz,CD2Cl2)δ10.44(s,1H),7.73(d,J=8.3Hz,1H),7.43(dd,J=2.2,8.3Hz,1H),7.32(d,J=2.2Hz,1H),7.17(dd,J=2.4,8.6Hz,1H),7.09(d,J=2.4Hz,1H),6.96(d,J=8.3Hz,1H),4.10-4.05(m,2H),3.87(d,J=15.4Hz,1H),3.66(d,J=13.9Hz,1H),3.61(q,J=8.8Hz,1H),3.55(ddd,J=1.2,7.1,14.4Hz,1H),3.16(d,J=14.2Hz,1H),3.09(dd,J=8.7,15.3Hz,1H),2.84-2.69(m,2H),2.46-2.37(m,1H),2.34(d,J=8.6Hz,1H),2.24(quin,J=8.8Hz,1H),2.17-2.08(m,2H),2.06(d,J=8.8Hz,1H),2.04-1.96(m,1H),1.96-1.87(m,1H),1.86-1.71(m,5H),1.71-1.61(m,2H),1.51-1.46(m,1H),1.45-1.41(m,1H),1.40(d,J=7.3Hz,3H),1.35-1.28(m,1H),1.03(d,J=6.8Hz,3H).MS(ESI,+ve离子)m/z601.1(M+H)+。
实施例38.(1S,3'R,6'R,7'S,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'二氧化物或(1S,3'R,6'R,7'S,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步骤1:(S)-苄基(2-甲基丁-3-烯-1-基)硫烷和(R)-苄基(2-甲基丁-3-烯-1-基)硫烷
将2-甲基丁-3-烯-1-醇(1.198mL,11.61mmol)、苯甲硫醇(2.044mL,17.42mmol)和2-(三丁基正膦亚基)MeCN(4.67mL,17.42mmol)的混合物在100℃下加热2h。将反应混合物冷却至rt,用EtOAc稀释,用NH4Cl饱和水溶液和盐水洗涤,经Na2SO4干燥且浓缩。将粗产物吸附至30g SiO2凝胶中且干燥,随后在SiO2凝胶上通过色谱用Hex洗脱来纯化,得到为无色油状物的标题产物(1.62g,72.4%)。1H NMR(400MHz,CDCl3)δ7.44-7.27(m,5H),5.84(ddd,J=17.17,10.32,6.75Hz,1H),5.16-5.03(m,2H),3.79(s,2H),2.58-2.39(m,3H),1.19-1.14(m,3H)。
步骤2:(S)-2-甲基丁-3-烯-1-磺酰胺和(R)-2-甲基丁-3-烯-1-磺酰胺
在剧烈搅拌下向(S)-苄基(2-甲基丁-3-烯-1-基)硫烷、(R)-苄基(2-甲基丁-3-烯-1-基)硫烷(0.650g,3.38mmol)和亚碘酰苯(2.454g,11.15mmol)于133mL醚中的混合物缓慢添加浓HCl(18.31mL,220mmol)。将所得混合物搅拌30min。使反应混合物沉降且分离各层。减压浓缩有机层。残余物在高真空下干燥1h。将残余物于8mLDCM中的溶液添加至氨的7.0M甲醇溶液(2.414mL,16.90mmol)、N,N-DIPEA(2.94mL,16.90mmol)和4-(二甲氨基)吡啶(8.26mg,0.068mmol)于10mLDCM中的混合物。将反应混合物在rt下搅拌16h之后浓缩。在SiO2凝胶上通过色谱用0%至60%EtOAc/己烷洗脱来纯化粗产物,得到标题化合物(0.076g,15.1%)。1H NMR(400MHz,CDCl3)δ5.82(ddd,J=17.36,10.03,7.63Hz,1H),5.21-5.05(m,4H),3.25-3.07(m,2H),2.92-2.78(m,1H),1.20(d,J=6.85Hz,3H)。
步骤3:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-(((S)-2-甲基丁-3-烯-1-基)磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酰胺和(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-(((R)-2-甲基丁-3-烯-1-基)磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酰胺
将(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA13A;0.010g,0.021mmol)、(S)-2-甲基丁-3-烯-1-磺酰胺与(R)-2-甲基丁-3-烯-1-磺酰胺(0.019g,0.124mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.012g,0.062mmol)和4-(二甲氨基)吡啶(7.60mg,0.062mmol)于DCM(0.5mL)中的混合物在rt下搅拌16h。将混合物直接上样至柱(5g SiO2凝胶)上以通过色谱用0%至50%EtOAc(含有0.2%AcOH)/己烷洗脱来纯化,得到标题化合物(0.011g,86%)。m/z(ESI,+ve离子)613.2(M+H)+。
步骤4:(1S,3'R,6'R,7'S,9'E,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(116762-34-3)和(1S,3'R,6'R,7'S,9'E,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物和(1S,3'R,6'R,7'S,9'Z,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物和(1S,3'R,6'R,7'S,9'Z,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
将(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-(((S)-2-甲基丁-3-烯-1-基)磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺和(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-(((R)-2-甲基丁-3-烯-1-基)磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺(21mg,0.034mmol)于甲苯(80mL)中的溶液进行三次排空/N2回填循环。在rt下向均质溶液中添加Hoveyda-Grubbs II(4.29mg,6.85μmol)于1mL甲苯中的溶液。将反应混合物在106℃在N2下搅拌2h。将空气吹至混合物中。将反应物冷却至rt且浓缩。通过制备型反相HPLC(GeminiTM Prep C18 5μm柱;40%至90%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)纯化残余物,得到标题化合物的混合物。
步骤5:(1S,3'R,6'R,7'S,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
将(1S,3'R,6'R,7'S,9'E,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(116762-34-3)和(1S,3'R,6'R,7'S,9'E,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物和(1S,3'R,6'R,7'S,9'Z,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物和(1S,3'R,6'R,7'S,9'Z,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(来自步骤4,1.6mg,2.73μmol)和氧化铂(iv)(0.621mg,2.73μmol)于EtOAc(2.0mL)中的混合物在H2(气球)下在rt搅拌2h。使用注射器式过滤器过滤出固体催化剂,且浓缩滤液得到粗产物。通过制备型反相HPLC(GeminiTM PrepC18 5μm柱;40%至90%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)纯化残余物,得到为白色固体的第二洗脱异构体的标题化合物。1H NMR(500MHz,CDCl3)δ9.02(br.s.,1H),7.73-7.69(m,1H),7.22-7.16(m,3H),7.09(d,J=2.20Hz,1H),6.96(d,J=8.07Hz,1H),4.16-4.09(m,2H),3.88-3.63(m,6H),3.28-3.22(m,1H),3.17(dd,J=15.16,5.87Hz,1H),3.13-3.07(m,1H),2.80-2.74(m,2H),2.36-2.29(m,2H),2.21-2.18(m,1H),2.03-1.98(m,2H),1.94-1.77(m,2H),1.75-1.27(m,9H),1.13(d,J=6.85Hz,3H).m/z(ESI,+ve离子)587.2(M+H)+。
实施例39.(1S,3'R,6'R,7'S,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
分离标题化合物为实施例38中来自制备型反相HPLC的第二洗脱异构体。1H NMR(400MHz,CDCl3)δ9.38(br.s.,1H),7.69(d,J=8.61Hz,1H),7.29(m,1H),7.25-7.15(m,2H),7.10(d,J=2.35Hz,1H),6.98(d,J=8.22Hz,1H),4.16(s,2H),3.89-3.83(m,1H),3.67(d,J=7.83Hz,1H),3.61-3.44(m,4H),3.41(d,J=12.52Hz,2H),2.81-2.68(m,3H),2.23-2.06(m,3H),2.02-1.72(m,5H),1.64-1.51(m,5H),1.49-1.38(m,2H),1.25-1.13(m,1H),1.06(d,J=6.85Hz,3H).m/z(ESI,+ve离子)587.1(M+H)+。
实施例40.(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物和
实施例41.(1S,3'R,6'R,7'S,8'Z)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:2-甲基己-5-烯-2-磺酰胺
以类似于中间体EE20中所描述的方式的方式使用5当量丁基锂溶液(2.5M于己烷(Aldrich)中)和5当量MeI(Aldrich)制备标题化合物,且分离为浅棕色油状物的所需产物1-(三氟甲氧基)庚-6-烯-3-磺酰胺。
步骤2:(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物和(1S,3'R,6'R,7'S,8'Z)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以类似于实施例2的步骤1和2中所描述的方式的方式使用中间体AA11A和来自步骤1的2-甲基己-5-烯-2-磺酰胺制备标题化合物,且分离以下所需产物:(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例40),作为来自制备型反相HPLC的第一洗脱主要异构体;和(1S,3'R,6'R,7'S,8'Z)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例41),作为来自制备型反相HPLC的第二洗脱主要异构体。(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例40):1H NMR(500MHz,CD3OD)δ7.75(d,J=8.6Hz,1H),7.20(dd,J=2.2,8.6Hz,1H),7.13(d,J=2.2Hz,1H),7.07(br.s.,1H),6.94(d,J=7.8Hz,2H),5.82(br.s.,1H),5.65(dd,J=7.5,15.5Hz,1H),4.17(br.s.,1H),4.10(dd,J=12.0,46.0Hz,2H),3.78(d,J=14.4Hz,1H),3.67(d,J=13.4Hz,1H),3.11-3.00(m,1H),2.87-2.75(m,2H),2.54(br.s.,1H),2.41-2.07(m,5H),2.01-1.88(m,3H),1.80(dd,J=8.1,14.2Hz,3H),1.70(dd,J=9.0,18.3Hz,1H),1.54-1.42(m,2H),1.45(d,J=8.1Hz,6H).m/z(ESI,+ve离子)599.2(M+H)+;(1S,3'R,6'R,7'S,8'Z)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例41):1H NMR(400MHz,CD3OD)δ7.76(d,J=8.6Hz,1H),7.29(d,J=7.8Hz,1H),7.20(dd,J=2.2,8.4Hz,1H),7.17(br.s.,1H),7.13(d,J=2.2Hz,1H),6.96(d,J=7.5Hz,1H),5.68-5.60(m,1H),5.53(dd,J=8.4,11.2Hz,1H),4.59(dd,J=1.8,8.6Hz,1H),4.11(s,2H),4.07(d,J=13.7Hz,1H),3.74(d,J=15.3Hz,1H),3.45(d,J=14.5Hz,1H),2.90-2.75(m,2H),2.72-2.53(m,1H),2.50-2.40(m,1H),2.40-2.23(m,2H),2.14(d,J=13.1Hz,1H),2.08-1.96(m,4H),1.96-1.78(m,5H),1.53(d,J=12.7Hz,6H)1.52–1.46(m,1H).m/z(ESI,+ve离子)599.2(M+H)+。
实施例42.(1S,3'R,6'R,7'S)-6-氯-7'-羟基-12',12'-乙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步骤1.N,N-双(4-甲氧基苄基)2-甲基戊-4-烯-2-磺酰胺
将N,N-双(4-甲氧基苄基)丁-3-烯-1-磺酰胺(中间体EE16;500mg,1.332mmol)在PhMe中在真空下共沸1h。在氩气下,添加THF且将溶液冷却至-78℃。随后添加丁基锂溶液(Sigma Aldrich,2.5M于己烷中的溶液;1.065mL,2.66mmol),且将混合物在-78℃下搅拌60min。添加MeI(Sigma Aldrich;0.166mL,2.66mmol),且将混合物在-78℃下再搅拌30min,(LC/MS分析表明完成转化为单甲基化产物与二甲基化产物的1:1混合物)。将混合物用饱和NH4Cl淬灭,使其达到环境温度,用EtOAc萃取,经MgSO4干燥且浓缩。经由24g ISCO gold柱用5-10%EtOAc/己烷的梯度洗脱来纯化粗物质,得到N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-2-磺酰胺(173mg,0.429mmol,32.2%产率)。
步骤2.2-甲基戊-4-烯-2-磺酰胺
向N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-2-磺酰胺(173mg,0.429mmol)于DCM中的溶液添加苯甲硫醚(0.503mL,4.29mmol),随后逐滴添加三氟乙酸(1.2mL,16.15mmol)。搅拌6h之后(30%EtOAc/己烷的TLC显示原料耗尽),将混合物用EtOAc稀释,用饱和NaHCO3洗涤,用EtOAc反萃取,经MgSO4干燥且浓缩。经由色谱经由12g ISCO gold柱用10-50%EtOAc/己烷的梯度洗脱来纯化粗物质,得到2-甲基戊-4-烯-2-磺酰胺(45mg,0.276mmol,64.3%产率)。
步骤3:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-((2-甲基戊-4-烯-2-基)磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[B][1,4]氧氮杂-3,1'-萘]-7-甲酰胺
按照针对实施例2的步骤1所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA13A;41mg,0.085mmol)和2-甲基戊-4-烯-2-磺酰胺(45mg,0.276mmol)合成标题化合物。粗物质的纯化得到(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-((2-甲基戊-4-烯-2-基)磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺(45.8mg,0.073mmol,86%产率)。
步骤4:(1S,3'R,6'R,7'S,9'Z)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物和(1S,3'R,6'R,7'S,9'E)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照针对实施例14的步骤2所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羟基丁-3-烯-1-基)环丁基)甲基)-N-((2-甲基戊-4-烯-2-基)磺酰基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酰胺(45.8mg,0.073mmol)合成标题化合物。通过色谱经由12g ISCO柱用10%至20%EtOAc(含有0.3%AcOH)/己烷历经90min来洗脱纯化粗物质,得到标题化合物的混合物。
步骤5:(1S,3'R,6'R,7'S)-6-氯-7'-羟基-12',12'-乙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照针对实施例14的步骤3所描述的程序由(1S,3'R,6'R,7'S,9'Z)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物和(1S,3'R,6'R,7'S,9'E)-6-氯-7'-羟基-12',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(来自步骤4,9mg,0.015mmol)的混合物合成标题化合物(6.4mg,0.011mmol,71%产率)。1H NMR(400MHz,CD2Cl2)δ10.50(br.s.,1H),7.70(d,J=8.6Hz,1H),7.47(dd,J=1.2,8.4Hz,1H),7.35(s,1H),7.14(dd,J=2.0,8.2Hz,1H),7.08(d,J=2.2Hz,1H),6.91(d,J=8.4Hz,1H),4.02(d,J=12.1Hz,1H),3.96(d,J=11.9Hz,1H),3.73(d,J=15.5Hz,1H),3.64-3.54(m,1H),3.13(d,J=14.3Hz,1H),3.05(dd,J=9.1,15.6Hz,1H),2.94(d,J=8.6Hz,1H),2.82-2.71(m,2H),2.33(quin,J=8.6Hz,1H),2.20-2.06(m,2H),2.05-1.96(m,2H),1.95-1.87(m,3H),1.86-1.74(m,4H),1.73-1.59(m,4H),1.49(s,3H),1.47(s,3H),1.44-1.34(m,3H).MS(ESI,+ve离子)m/z 601.2(M+H)+。
实施例43.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-11',12'-二甲基-7'-(1-甲基乙氧基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮-13',13'-二氧化物
向(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例2;20.4mg,0.034mmol)于THF(0.681mL)中的溶液(冷却至0℃)添加氢化钠(60%矿物油分散体;13.62mg,0.340mmol)。将反应混合物在0℃下搅拌15min,随后添加2-碘丙烷(3.40μl,0.034mmol)。将反应混合物在环境温度下搅拌4天,添加更多试剂以驱动反应。混合物随后用NH4Cl水溶液淬灭且用EtOAc稀释。有机层经MgSO4干燥且浓缩。通过色谱经由Redi-预装填SiO2凝胶柱(4g)用10-40%EtOAc(含有0.3%AcOH)/庚烷洗脱来纯化粗物质,得到标题化合物(0.6mg)。1H NMR(500MHz,CD2Cl2)δ8.03(br.s.,1H),7.71(d,J=8.3Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.4Hz,1H),6.91-6.89(m,2H),6.88(s,1H),5.72(ddd,J=3.4,9.3,15.2Hz,1H),5.53(dd,J=8.8,15.4Hz,1H),4.29-4.22(m,1H),4.08(s,2H),3.85-3.80(m,2H),3.69(d,J=14.2Hz,1H),3.59(td,J=6.1,12.2Hz,1H),3.28-3.22(m,2H),3.02(dd,J=9.7,15.3Hz,1H),2.83-2.70(m,2H),2.39-2.24(m,2H),2.20-2.02(m,3H),2.01-1.89(m,3H),1.83(dd,J=5.6,12.7Hz,1H),1.81-1.75(m,1H),1.70-1.59(m,1H),1.44(d,J=7.3Hz,3H),1.43-1.35(m,1H),1.09(d,J=5.9Hz,3H),1.04(d,J=6.1Hz,3H),1.02(d,J=6.8Hz,3H).MS(ESI,+ve离子)m/z 641.0(M+H)+。
实施例44.(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(2S)-甲基戊-4-烯醛和(2R)-甲基戊-4-烯醛
在N2下在-60℃向草酰氯(6.65mL,74.9mmol)于DCM(30mL)中的溶液添加无水DMSO(10.62mL,150mmol)于DCM(20mL)中的溶液,且搅拌2min。添加2-甲基戊-4-烯-1-醇(5.00g,49.9mmol)于DCM(20mL)中的溶液,且将所得混合物在-60℃下搅拌15min。随后添加Et3N(34.7mL,250mmol),且将反应混合物在环境温度下搅拌20min。混合物用DCM和H2O淬灭。有机层用盐水洗涤,干燥(MgSO4)且过滤。浓缩滤液,得到标题化合物(4.90g,100%),其不进一步纯化。
步骤2:(1S,2R)-1-环丙基-2-甲基-4-戊烯-1-醇和
(1R,2R)-1-环丙基-2-甲基-4-戊烯-1-醇和
(1S,2S)-1-环丙基-2-甲基-4-戊烯-1-醇和
(1R,2S)-1-环丙基-2-甲基-4-戊烯-1-醇
在-78℃下向(2S)-甲基戊-4-烯醛和(2R)-甲基戊-4-烯醛(9.80g,100mmol)于THF(30mL)中的溶液添加环丙基溴化镁的1.0M的于2-MeTHF中的溶液(300mL,150mmol)。将反应混合物在环境温度下搅拌3h。将混合物用NH4Cl饱和水溶液淬灭,且用醚萃取。有机层用盐水洗涤,干燥(Na2SO4)且浓缩。将所得残余物通过色谱(SiO2凝胶,0至40%EtOAc/己烷)分离,得到标题化合物(4.20g,30.0%)。
步骤3:(1R,2R)-1-环丙基-2-甲基-4-戊烯-1-磺酰胺和
(1R,2R)-1-环丙基-2-甲基-4-戊烯-1-磺酰胺和
(1R,2R)-1-环丙基-2-甲基-4-戊烯-1-磺酰胺和
(1R,2R)-1-环丙基-2-甲基-4-戊烯-1-磺酰胺
按照E22中步骤3至6所描述的类似程序由(1S,2R)-1-环丙基-2-甲基-4-戊烯-1-醇、(1R,2R)-1-环丙基-2-甲基-4-戊烯-1-醇、(1S,2S)-1-环丙基-2-甲基-4-戊烯-1-醇和(1R,2S)-1-环丙基-2-甲基-4-戊烯-1-醇(来自步骤2)的混合物作为起始醇来制备标题化合物。
步骤4:(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照实施例2的步骤1和2中所描述的类似程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12A)和(1R,2R)-1-环丙基-2-甲基-4-戊烯-1-磺酰胺、(1R,2R)-1-环丙基-2-甲基-4-戊烯-1-磺酰胺、(1R,2R)-1-环丙基-2-甲基-4-戊烯-1-磺酰胺和(1R,2R)-1-环丙基-2-甲基-4-戊烯-1-磺酰胺的混合物(来自步骤3)制备标题化合物。通过制备型反相HPLC(GeminiTM Prep C18 5μm柱;50%至90%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)纯化粗油状物,得到为第一洗脱异构体的标题化合物(12mg,6.7%)。1H NMR(400MHz,CD2Cl2)δ8.15(s,1H),7.71(d,J=8.6Hz,1H),7.17(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.2Hz,1H),6.93-6.88(m,3H),5.91-5.63(m,2H),4.22(dd,J=3.9,7.6Hz,1H),3.81(d,J=15.1Hz,1H),3.68(d,J=14.3Hz,1H),3.40(d,J=11.0Hz,1H),3.25(d,J=14.3Hz,1H),3.04(dd,J=9.8,15.3Hz,1H),2.82-2.67(m,2H),2.49-2.23(m,3H),2.14-1.84(m,11H),1.73-1.62(m,1H),1.45-1.34(m,1H),1.20(d,J=6.8Hz,3H),1.17-1.07(m,1H),0.93-0.76(m,3H),0.50-0.37(m,1H).m/z(ESI,+ve离子)625.2(M+H)+。
实施例45.(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根据实施例49中的制备型反相HPLC分离,得到为第二洗脱异构体的标题化合物(5mg,2.8%)。1H NMR(400MHz,CD2Cl2)δ9.04(br.s.,1H),7.83-7.61(m,1H),7.17(d,J=8.4Hz,1H),7.09(m,1H),6.97-6.88(m,1H),6.84(m,1H),6.15(br.s.,1H),5.92-5.69(m,1H),4.26-4.04(m,2H),3.68(d,J=14.1Hz,1H),3.36-2.94(m,3H),2.77(m,2H),2.38(d,J=7.6Hz,2H),2.24-1.87(m,6H),1.69(dd,J=9.8,19.4Hz,2H),1.53-1.41(m,1H),1.30-1.06(m,10H),0.83(d,J=3.1Hz,2H),0.44(br.s.,1H)m/z(ESI,+ve离子)625.2(M+H)+。
实施例46.(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根据实施例49中的制备型反相HPLC分离,得到为第三洗脱异构体的标题化合物(9mg,5.0%)。1H NMR(400MHz,CD2Cl2)δ8.21(br.s.,1H),7.66(d,J=8.6Hz,1H),7.44(br.s.,1H),7.14(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),6.94-6.86(m,2H),5.62(br.s.,2H),4.20(s,2H),3.92(d,J=7.4Hz,1H),3.85(d,J=13.9Hz,1H),3.66(d,J=14.1Hz,1H),3.39(d,J=14.3Hz,1H),3.33(d,J=11.0Hz,1H),3.17(d,J=13.7Hz,1H),2.74(t,J=5.3Hz,2H),2.57(d,J=7.6Hz,1H),2.40(td,J=8.7,17.1Hz,1H),2.29-2.16(m,1H),2.03-1.62(m,10H),1.60-1.45(m,1H),1.22(d,J=6.7Hz,3H),1.17-1.04(m,1H),0.91-0.78(m,3H),0.52-0.41(m,1H).m/z(ESI,+ve离子)625.2(M+H)+。
实施例47.(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根据实施例49中的制备型反相HPLC分离,得到为最慢洗脱异构体的标题化合物(3mg,1.9%)。1H NMR(400MHz,CD2Cl2)δ8.14(br.s.,1H),7.71(d,J=8.6Hz,1H),7.22-7.06(m,3H),6.98-6.91(m,1H),6.62(br.s.,1H),6.05(d,J=7.2Hz,1H),5.69(dd,J=5.8,15.2Hz,1H),4.19(br.s.,1H),4.15-3.99(m,2H),3.79(d,J=14.5Hz,1H),3.65(d,J=14.5Hz,1H),3.43(d,J=14.5Hz,1H),3.33-3.22(m,1H),2.99(d,J=11.0Hz,1H),2.86-2.66(m,3H),2.51(br.s.,2H),2.32-2.18(m,2H),2.09-1.87(m,5H),1.75(d,J=10.4Hz,2H),1.52-1.38(m,2H),1.19(d,J=7.0Hz,3H),1.11(br.s.,1H),0.93-0.73(m,3H),0.54-0.40(m,1H).m/z(ESI,+ve离子)625.2(M+H)+。
实施例48.(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-环丙基-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-环丙基-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-环丙基-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-环丙基-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用实施例46中所描述的类似程序由(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-环丙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例49)制备标题化合物(9.5mg,62%)。1H NMR(400MHz,CD2Cl2)δ8.15-7.94(m,1H),7.71(d,J=8.41Hz,1H),7.17(dd,J=2.35,8.41Hz,1H),7.09(d,J=2.15Hz,1H),6.91(d,J=0.98Hz,2H),6.86(s,1H),5.81-5.70(m,J=3.13,9.39Hz,1H),5.51(ddd,J=1.17,8.41,14.67Hz,1H),4.08(s,2H),3.80(d,J=15.06Hz,1H),3.69(d,J=14.28Hz,1H),3.62(dd,J=3.33,9.00Hz,1H),3.45(d,J=10.17Hz,1H),3.25(d,J=14.28Hz,1H),3.17(s,3H),3.03(dd,J=10.17,15.26Hz,1H),2.80-2.72(m,2H),2.59-2.39(m,2H),2.38-2.25(m,1H),2.17-1.73(m,8H),1.72-1.59(m,1H),1.21(d,J=6.85Hz,3H),1.17-1.08(m,1H),0.92-0.78(m,4H),0.47-0.37(m,1H).m/z(ESI,+ve离子)639.2(M+H)+。
实施例49.(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(3R,4R)-2,4-二甲基庚-6-烯-3-醇和(3R,4S)-2,4-二甲基庚-6-烯-3-醇和(3S,4R)-2,4-二甲基庚-6-烯-3-醇和(3S,4S)-2,4-二甲基庚-6-烯-3-醇
在0℃下向2-甲基戊-4-烯醛(2.40g,24.4mmol)于THF(10mL)中的溶液添加异丙基氯化镁(2.0M于THF中的溶液)(24.4mL,48.9mmol)。使反应混合物升至环境温度。在环境温度下搅拌12h后,将反应混合物淬灭(饱和NH4Cl),萃取(2×Et2O)且洗涤(盐水)。将合并的有机层干燥(Na2SO4)且减压浓缩。将残余物注入40g ISCO gold柱中,且通过Combi-用0%至20%EtOAc/己烷洗脱来纯化,得到标题化合物(550mg,3.85mmol)。
步骤2:(3S,4R)-N,N-双(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺酰胺和(3S,4S)-N,N-双(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺酰胺和(3R,4R)-N,N-双(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺酰胺和(3R,4S)-N,N-双(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺酰胺
按照中间体EE22的步骤3至6中所描述的类似程序由(3R,4R)-2,4-二甲基庚-6-烯-3-醇、(3R,4S)-2,4-二甲基庚-6-烯-3-醇、(3S,4R)-2,4-二甲基庚-6-烯-3-醇和(3S,4S)-2,4-二甲基庚-6-烯-3-醇的混合物(来自步骤1)制备标题化合物。
步骤3:(3S,4R)-2,4-二甲基庚-6-烯-3-磺酰胺和(3S,4S)-2,4-二甲基庚-6-烯-3-磺酰胺和(3R,4R)-2,4-二甲基庚-6-烯-3-磺酰胺和(3R,4S)-2,4-二甲基庚-6-烯-3-磺酰胺
按照针对实施例26的步骤2所描述的类似程序由(3S,4R)-N,N-双(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺酰胺、(3S,4S)-N,N-双(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺酰胺、(3R,4R)-N,N-双(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺酰胺和(3R,4S)-N,N-双(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺酰胺的混合物(来自步骤2)合成标题化合物。
步骤4:(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(异构体1)
按照实施例2的步骤1和2中所描述的类似程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12A)和(3S,4R)-2,4-二甲基庚-6-烯-3-磺酰胺、(3S,4S)-2,4-二甲基庚-6-烯-3-磺酰胺、(3R,4R)-2,4-二甲基庚-6-烯-3-磺酰胺和(3R,4S)-2,4-二甲基庚-6-烯-3-磺酰胺的混合物制备标题化合物。将残余物注入40g ISCO gold柱中,且通过Combi-用10%至100%EtOAc(含有0.5%AcOH)/己烷洗脱来纯化,得到为较快洗脱异构体的粗产物。通过制备型反相HPLC(GeminiTM Prep C18 5μm柱;50%至90%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)纯化此粗产物,得到为白色泡沫的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm8.30(s,1H),7.79-7.70(m,1H),7.66(d,J=8.4Hz,1H),7.14(m,1H),7.10(m,1H),6.95-6.87(m,2H),5.67(dd,J=4.1,15.8Hz,1H),5.44-5.34(m,1H),4.29-4.13(m,3H),4.04(m,1H),3.89-3.77(m,2H),3.29(d,J=14.3Hz,1H),3.05(dd,J=3.5,16.0Hz,1H),2.78-2.69(m,2H),2.62-2.53(m,1H),2.48(m,1H),2.31-2.19(m,1H),2.05-1.70(m,9H),1.61(m,1H),1.37(d,J=7.0Hz,3H),1.35-1.26(m,4H),1.17(d,J=6.7Hz,3H);m/z(ESI,+ve离子)627(M+H)+。
实施例50.(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如实施例54中所描述的Combi-分离,得到为第二(较慢)洗脱异构体的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm 8.13(s,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.3Hz,1H),6.91(m,3H),5.79-5.67(m,2H),4.22-4.13(m,2H),4.09(s,2H),3.90-3.78(m,1H),3.69(d,J=14.3Hz,1H),3.24(d,J=14.3Hz,1H),3.03(dd,J=9.3,15.4Hz,1H),2.83-2.70(m,2H),2.46-2.37(m,1H),2.35-2.23(m,2H),2.19-1.91(m,6H),1.88-1.75(m,3H),1.70-1.61(m,1H),1.44-1.30(m,7H),1.14(d,J=6.7Hz,3H);m/z(ESI,+ve离子)627(M+H)+。
实施例51.(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如实施例54中所描述的Combi-分离,得到为第三(较慢)洗脱异构体的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm 8.11(s,1H),7.77-7.69(m,1H),7.16(d,J=8.4Hz,1H),7.13-7.06(m,1H),7.00-6.88(m,3H),5.85-5.60(m,2H),4.24-4.06(m,4H),3.95-3.80(m,1H),3.69(d,J=14.1Hz,1H),3.51-3.34(m,2H),2.83-2.70(m,2H),2.46-2.24(m,3H),2.18-1.90(m,6H),1.87-1.70(m,4H),1.35(dd,J=7.0,14.3Hz,7H),1.22-1.07(m,3H);m/z(ESI,+ve离子)627(M+H)+。
实施例52.(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如实施例54中所描述的Combi-分离,得到作为第四(较慢)洗脱异构体的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm 8.11(br.s.,1H),7.71(t,J=6.9Hz,1H),7.25-6.87(m,5H),5.88-5.43(m,2H),4.20-4.02(m,3H),3.84(m,1H),3.74-3.55(m,2H),3.55-3.40(m,1H),3.40-3.12(m,1H),2.82-2.62(m,3H),2.53(d,J=5.3Hz,2H),2.32(m,3H),2.08-1.62(m,8H),1.37-1.12(m,10H);m/z(ESI,+ve离子)627(M+H)+。
实施例53.(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-甲氧基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-甲氧基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-甲氧基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-甲氧基-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向产物(来自实施例54;9mg,0.014mmol)于THF(1mL)中的溶液添加氢化钠(于矿物油中的60%分散体)(1.43mg,0.036mmol)随后添加MeI(3.1mg,0.022mmol)。在室温下搅拌溶液过夜。随后将反应用饱和NH4Cl和盐水淬灭,萃取(2×Et2O)且洗涤(1×盐水)。将合并的有机层干燥(Na2SO4)且减压浓缩。将残余物注入4g ISCO gold柱中,且通过Combi-用0%至100%EtOAc(含有0.5%AcOH)/己烷洗脱来纯化,得到为无色油状物的标题化合物中的一者(7mg,10.9μmol)。1H NMR(400MHz,CD2Cl2)δppm 8.15(br.s.,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.2Hz,1H),6.90(m,2H),6.84(m,1H),5.73(ddd,J=3.9,8.7,15.2Hz,1H),5.52(dd,J=8.8,15.5Hz,1H),4.23(m,1H),4.12-4.04(m,2H),3.82(d,J=15.1Hz,1H),3.72-3.62(m,2H),3.25-3.17(m,4H),3.02(dd,J=10.0,15.5Hz,1H),2.83-2.69(m,2H),2.47-2.38(m,1H),2.35-2.23(m,3H),2.21-2.02(m,3H),1.97-1.72(m,5H),1.68-1.60(m,1H),1.40-1.30(m,7H),1.13(d,J=6.7Hz,3H);m/z(ESI,+ve离子)641(M+H)+。
实施例54.(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-12'-(1-甲基乙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向来自实施例54的产物(10mg,0.016mmol)于THF(1mL)中的溶液添加氢化钠(于矿物油中的60%分散体)(1.6mg,0.040mmol)随后添加2-溴乙基甲醚(2.2mg,0.016mmol)。在室温下搅拌溶液约48h。随后将反应用饱和NH4Cl和盐水淬灭,萃取(2×Et2O)且洗涤(1×盐水)。将合并的有机层干燥(Na2SO4)且减压浓缩。通过制备型反相HPLC(GeminiTM Prep C18 5μm柱;50%至90%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)纯化此粗产物,得到为白色无定形固体的标题化合物中的一者(4mg,5.8μmol)。1H NMR(400MHz,CD2Cl2)δppm 8.09(s,1H),7.70(d,J=8.6Hz,1H),7.16(dd,J=2.2,8.5Hz,1H),7.09(d,J=2.2Hz,1H),6.94-6.87(m,2H),6.84(s,1H),5.71(ddd,J=4.0,8.5,15.3Hz,1H),5.60-5.48(m,1H),4.21(m,1H),4.08(s,2H),3.86-3.74(m,2H),3.68(d,J=13.9Hz,1H),3.53-3.36(m,4H),3.32(s,3H),3.23(d,J=14.3Hz,1H),3.01(dd,J=10.1,15.2Hz,1H),2.83-2.69(m,2H),2.48-2.39(m,1H),2.34-2.12(m,4H),2.12-2.01(m,2H),1.99-1.75(m,5H),1.72-1.63(m,1H),1.45-1.30(m,7H),1.13(d,J=6.8Hz,3H);m/z(ESI,+ve离子)685(M+H)+。
实施例55.(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(R)-2-甲基戊-4-烯醛和(S)-2-甲基戊-4-烯醛
在N2下在-60℃向草酰氯(6.65mL,74.9mmol)于DCM(30mL)中的溶液添加无水DMSO(10.6mL,150mmol)于DCM(20mL)中的溶液。搅拌2min后,添加2-甲基戊-4-烯-1-醇(5.00g,49.9mmol)于DCM(20mL)中的溶液,且将所得混合物在-60℃下搅拌15min。随后添加Et3N(34.7mL,250mmol)。在环境温度下搅拌20min后,将混合物用DCM和H2O淬灭,萃取(2×Et2O)且洗涤(1×盐水)。将合并的有机层干燥(Na2SO4)且减压浓缩,得到标题化合物。标题化合物不经进一步纯化即用于下一步骤。
步骤2:(1R,2R)-1-环丁基-2-甲基戊-4-烯-1-醇和(1R,2S)-1-环丁基-2-甲基戊-4-烯-1-醇和(1S,2R)-1-环丁基-2-甲基戊-4-烯-1-醇和(1S,2S)-1-环丁基-2-甲基戊-4-烯-1-醇
在-78℃下向(R)-2-甲基戊-4-烯醛和(S)-2-甲基戊-4-烯醛(5g,50.9mmol)(实施例183,步骤1)于THF(30mL)中的溶液添加环丁基溴化镁(17.8g,112mmol)。使反应物升至室温。在室温下搅拌3h后,将反应淬灭(饱和NH4Cl),萃取(2×Et2O)且洗涤(1×盐水)。将合并的有机层干燥(Na2SO4)且减压浓缩。将残余物注入40g ISCO gold柱中,且通过Combi-用0%至30%EtOAc/己烷洗脱来纯化,得到标题化合物(4.2g,27.2mmol)。
步骤2:(1S,2R)-1-环丁基-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(1R,2R)-1-环丁基-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(1S,2S)-1-环丁基-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(1R,2S)-1-环丁基-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺
按照中间体EE22的步骤3至6中所描述的类似程序由(1R,2R)-1-环丁基-2-甲基戊-4-烯-1-醇、(1R,2S)-1-环丁基-2-甲基戊-4-烯-1-醇、(1S,2R)-1-环丁基-2-甲基戊-4-烯-1-醇和(1S,2S)-1-环丁基-2-甲基戊-4-烯-1-醇的混合物(来自步骤2)制备标题化合物。
步骤3:(1S,2R)-1-环丁基-2-甲基戊-4-烯-1-磺酰胺和(1R,2R)-1-环丁基-2-甲基戊-4-烯-1-磺酰胺和(1S,2S)-1-环丁基-2-甲基戊-4-烯-1-磺酰胺和(1R,2S)-1-环丁基-2-甲基戊-4-烯-1-磺酰胺
按照实施例26的步骤2中所描述的类似程序由(1S,2R)-1-环丁基-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺、(1R,2R)-1-环丁基-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺、(1S,2S)-1-环丁基-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(1R,2S)-1-环丁基-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺的混合物(来自步骤2)合成标题化合物。
步骤4:(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照实施例2的步骤1和2中所描述的类似程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12)和(1S,2R)-1-环丁基-2-甲基戊-4-烯-1-磺酰胺、(1R,2R)-1-环丁基-2-甲基戊-4-烯-1-磺酰胺、(1S,2S)-1-环丁基-2-甲基戊-4-烯-1-磺酰胺和(1R,2S)-1-环丁基-2-甲基戊-4-烯-1-磺酰胺的混合物(来自步骤3)制备标题化合物。将残余物注入40g ISCO gold柱中,且通过Combi-用10%至100%EtOAc(含有0.5%AcOH)/己烷洗脱来纯化,得到作为较快洗脱异构体的粗产物。通过制备型反相HPLC(GeminiTM Prep C18 5μm柱;50%至90%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)纯化此粗产物,得到为白色泡沫的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm 8.26(br.s.,1H),7.71(d,J=8.4Hz,1H),7.16(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.3Hz,1H),6.95-6.89(m,3H),5.91(ddd,J=3.8,8.9,15.0Hz,1H),5.70(dd,J=8.1,15.2Hz,1H),4.25(dd,J=3.8,8.1Hz,1H),4.12-4.05(m,3H),3.84(m,1H),3.68(d,J=14.3Hz,1H),3.25(d,J=14.3Hz,1H),3.09–3.02(m,1H),3.00–2.89(m,1H),2.82-2.70(m,2H),2.47-2.38(m,1H),2.36-2.12(m,5H),2.06-1.94(m,6H),1.88-1.77(m,4H),1.73-1.62(m,1H),1.49-1.32(m,2H),1.08(d,J=6.8Hz,3H);m/z(ESI,+ve离子)639(M+H)+。
实施例56.(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如实施例55中所描述的Combi-分离,得到为第二(较慢)洗脱异构体的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm 8.10(br.s.,1H),7.73-7.67(m,1H),7.17(m,1H),7.11-7.05(m,2H),6.97-6.89(m,2H),6.01(m,1H),5.65(dd,J=6.1,15.5Hz,1H),4.18(m,1H),4.13-4.01(m,2H),3.75(m,2H),3.60(m,1H),3.40(m,1H),3.25(m,1H),2.92(m,1H),2.83-2.72(m,2H),2.53(m,2H),2.35-1.56(m,16H),1.44(m,1H),1.15-1.03(m,3H);m/z(ESI,+ve离子)639(M+H)+。
实施例57.(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-环丁基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如实施例55中所描述的Combi-分离,得到为第三(较慢)洗脱异构体的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm 8.22(br.s.,1H),7.67(d,J=8.4Hz,1H),7.58(m,1H),7.15(dd,J=2.3,8.4Hz,1H),7.10(d,J=2.2Hz,1H),6.94-6.88(m,2H),5.78-5.61(m,2H),4.26-4.18(m,2H),4.07(d,J=11.0Hz,1H),4.02-3.87(m,2H),3.72(m,1H),3.36(m,1H),3.14(m,1H),3.00-1.60(m,21H),1.55-1.40(m,1H),1.10(d,J=6.7Hz,3H);m/z(ESI,+ve离子)639(M+H)+。
实施例58.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(2S)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(2R)-N,N-双(4-甲氧基苄基)-2-甲基-4-戊烯-1-磺酰胺
按照实施例26的步骤1中所描述的类似程序由中间体EE12和4-甲基苯磺酸戊-4-烯-2-基酯制备标题化合物。
步骤2:(2S,3R)-1-环丙基-N,N-双(4-甲氧基苄基)-3-甲基-5-己烯-2-磺酰胺和(2R,3S)-1-环丙基-N,N-双(4-甲氧基苄基)-3-甲基-5-己烯-2-磺酰胺和(2R,3R)-1-环丙基-N,N-双(4-甲氧基苄基)-3-甲基-5-己烯-2-磺酰胺和(2S,3S)-1-环丙基-N,N-双(4-甲氧基苄基)-3-甲基-5-己烯-2-磺酰胺
在-78℃在N2下向(2S)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(2R)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺(600mg,1.49mmol)于THF中的溶液添加丁基锂溶液(2.5N于己烷中的溶液)(0.624mL,1.561mmol)。在-78℃下搅拌反应物15min后,添加(溴甲基)-环丙烷(0.288mL,2.97mmol)于THF(1mL)中的溶液。将反应混合物在-78℃下搅拌1h,随后使其升至环境温度。将混合物用H2O淬灭且用EtOAc萃取。有机层用H2O洗涤且干燥(Na2SO4)。蒸发溶剂,且通过色谱(SiO2凝胶,10至50%EtOAc/己烷)纯化所得残余物,得到作为无色液体的标题化合物。
步骤3:(120637-9):(2S,3S)-1-环丙基-3-甲基己5-烯-2-磺酰胺和(2S,3R)-1-环丙基-3-甲基己-5-烯-2-磺酰胺和(2R,3S)-1-环丙基-3-甲基己-5-烯-2-磺酰胺和(2R,3R)-1-环丙基-3-甲基己-5-烯-2-磺酰胺
将(2S,3R)-1-环丙基-N,N-双(4-甲氧基苄基)-3-甲基-5-己烯-2-磺酰胺、(2R,3S)-1-环丙基-N,N-双(4-甲氧基苄基)-3-甲基-5-己烯-2-磺酰胺、(2R,3R)-1-环丙基-N,N-双(4-甲氧基苄基)-3-甲基-5-己烯-2-磺酰胺和(2S,3S)-1-环丙基-N,N-双(4-甲氧基苄基)-3-甲基-5-己烯-2-磺酰胺的混合物(510mg,1.11mmol)用于TFA(3.81g,33.4mmol)中的苯甲醚(1.81g,16.7mmol)处理。将混合物在40℃下搅拌、加热18h,随后浓缩。通过色谱(SiO2凝胶,己烷/EtOAc,9:1至1:1)纯化所得残余物,得到作为浅棕色油的标题化合物。
步骤4:(3S)-6'-氯-N-(((2R,3S)-1-环丙基-3-甲基-5-己烯-2-基)磺酰基)-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺和(3S)-6'-氯-N-(((2R,3R)-1-环丙基-3-甲基-5-己烯-2-基)磺酰基)-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺和(3S)-6'-氯-N-(((2S,3S)-1-环丙基-3-甲基-5-己烯-2-基)磺酰基)-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺和(3S)-6'-氯-N-(((2S,3R)-1-环丙基-3-甲基-5-己烯-2-基)磺酰基)-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺
将(2S,3S)-1-环丙基-3-甲基己-5-烯-2-磺酰胺、(2S,3R)-1-环丙基-3-甲基己-5-烯-2-磺酰胺、(2R,3S)-1-环丙基-3-甲基己-5-烯-2-磺酰胺和(2R,3R)-1-环丙基-3-甲基己-5-烯-2-磺酰胺的混合物(160mg,0.74mmol)添加至于DCM(1mL)中的(S)-6'-氯-5-(((1R,2S)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12A;250mg,0.49mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(141mg,0,74mmol)、DMAP(90mg,0.74mmol)和Et3N(0.20mL,1.47mmol)。在环境温度下搅拌反应混合物3天。随后用DCM稀释混合物且添加H2O。将有机层干燥(MgSO4)且浓缩。将所得残余物通过色谱(SiO2凝胶,1:0至1:1,己烷/EtOAc+0.5%HOAc)分离,得到标题化合物。
步骤5:(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向RBF中装入以上(3S)-6'-氯-n-(((2R,3S)-1-环丙基-3-甲基-5-己烯-2-基)磺酰基)-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺、(3S)-6'-氯-n-(((2R,3R)-1-环丙基-3-甲基-5-己烯-2-基)磺酰基)-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺、(3S)-6'-氯-n-(((2S,3S)-1-环丙基-3-甲基-5-己烯-2-基)磺酰基)-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺和(3S)-6'-氯-n-(((2S,3R)-1-环丙基-3-甲基-5-己烯-2-基)磺酰基)-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺于DCE(100mL)中的混合物(210mg,0.30mmol)。在用氩气鼓入烧瓶中15min之后,向均质溶液中添加Hoveyda-Grubbs II(65mg,0.35mmol),且将烧瓶的内含物在50℃下搅拌18h。冷却反应混合物,且通过鼓吹将空气引入烧瓶中保持2min。蒸发溶剂,通过制备型反相HPLC(GeminiTM Prep C18 5μm柱;25%至75%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)纯化粗残余物,得到为第一洗脱异构体的标题化合物。1H NMR(500MHz,CDCl3)δppm 8.08(s,1H),7.70(d,J=8.3Hz,1H),7.19(dd,J=2.2,8.6Hz,1H),7.10(d,J=2.0Hz,1H),6.99(br s,1H),6.97-6.89(m,2H),5.97-5.88(m,1H),5.72(dd,J=8.1,15.2Hz,1H),4.30-4.22(m,2H),4.10(s,2H),3.82(d,J=14.9Hz,1H),3.69(d,J=14.2Hz,1H),3.26(d,J=14.2Hz,1H),3.06(br s,1H),2.85-2.71(m,2H),2.53-2.39(m,1H),2.33(quin,J=8.7Hz,1H),2.27-2.12(m,2H),2.09-1.86(m,5H),1.86-1.77(m,3H),1.75-1.61(m,1H),1.50-1.31(m,2H),1.23-1.12(m,1H),1.05(d,J=6.8Hz,3H),0.63(d,J=7.8Hz,2H),0.35-0.25(m,1H),0.13-0.06(m,1H).m/z(ESI,+ve离子)639.2(M+H)+。
实施例59.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根据实施例58中的制备型反相HPLC分离,得到为单一异构体(第二洗脱峰)的标题化合物。1H NMR(500MHz,CDCl3)δppm 8.17(br s,1H),7.79(d,J=8.6Hz,1H),7.24-7.15(m,2H),7.10(s,1H),6.98(d,J=8.3Hz,1H),6.67(br s,1H),6.03(m,1H),5.66(dd,J=6.4,15.2Hz,1H),4.32-4.02(m,3H),3.91-3.82(m,1H),3.80-3.72(m,1H),3.63(m,1H),3.42-3.38(m,1H),3.30-3.20(m,1H),2.85-2.73(m,2H),2.55-2.50(m,2H),2.29(br s,1H),2.20-2.15(m,1H),2.10-1.60(m,9H),1.55-1.43(m,2H),1.42-1.35(m,1H),1.13(d,J=7.1Hz,3H),0.61(d,J=8.6Hz,2H),0.30-0.25(m,1H),0.15-0.11(m,1H).m/z(ESI,+ve离子)639.2(M+H)+。
实施例60.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根据实施例58中的制备型反相HPLC分离,得到为单一异构体(第三洗脱峰)的标题化合物。1H NMR(500MHz,CDCl3)δppm 8.19(br s,1H),7.72(br s,1H),7.65(d,J=8.6Hz,1H),7.17(dd,J=2.2,8.6Hz,1H),7.11(s,1H),6.92(s,2H),5.72(dd,J=3.7,15.7Hz,1H),5.55(br s,1H),4.27-4.20(m,2H),4.20-4.14(m,1H),4.14-4.10(m,1H),4.00-3.88(m,1H),3.79(d,J=12.7Hz,1H),3.30(d,J=13.9Hz,1H),3.10(d,J=15.7Hz,1H),2.80-2.70(m,2H),2.58-2.39(m,2H),2.35-2.06(m,3H),2.05-1.93(m,3H),1.90-1.62(m,4H),1.70-1.64(m,1H),1.51-1.30(m,2H),1.24-1.15(m,1H),1.11(d,J=5.1Hz,3H),0.71-0.50(m,2H),0.31(qd,J=4.8,9.4Hz,1H),0.15(qd,J=4.6,9.3Hz,1H).m/z(ESI,+ve离子)639.2(M+H)+。
实施例61.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'Z,11'S,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'Z,11'R,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'Z,11'R,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根据实施例58中的制备型反相HPLC分离,得到为单一异构体(第四洗脱峰)的标题化合物。1H NMR(500MHz,CDCl3)δppm 7.72(d,J=11Hz,1H),7.50-7.44(m,1H),7.21-7.16(m,1H),7.15-7.05(m,2H),7.00(d,J=8.3Hz,1H),5.75(m,1H),5.54(m,1H),4.42(br s,1H),4.16-4.01(m,2H),3.90(d,J=15.2Hz,1H),3.80-3.60(m,2H),3.25-3.04(m,2H),2.87-2.70(m,2H),2.27-2.10(m,3H),2.09-1.52(m,9H),1.53-1.39(m,3H),1.21-1.14(m,1H),1.08(d,J=6.8Hz,3H),0.71-0.50(m,2H),0.31-0.20(m,1H),0.16-0.10(m,1H).m/z(ESI,+ve离子)639.2(M+H)+。
实施例62.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丙基甲基)-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丙基甲基)-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丙基甲基)-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丙基甲基)-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
在0℃下向15-mL RBF中添加于THF(1mL)中的氢化钠(60%矿物油分散体)(8.3mg,0.203mmol)和(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03 ,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(13mg,0.020mmol)。在0℃下搅拌反应混合物30min,然后添加MeI(6.32μl,0.102mmol)。搅拌混合物且使其从0℃升至环境温度保持18h,用1.0N HCl水溶液淬灭,且用EtOAc萃取。将有机层干燥(MgSO4)且浓缩。将残余物通过色谱(SiO2凝胶,10-40%,EtOAc+10%甲醇/己烷)分离,得到为白色固体的标题化合物。1HNMR(400MHz,CDCl3)δppm 8.08(s,1H),7.70(d,J=8.4Hz,1H),7.19(dd,J=2.2,8.5Hz,1H),7.10(d,J=2.2Hz,1H),6.96-6.90(m,3H),5.90-5.70(m,1H),5.53(dd,J=9.8,14.5Hz,1H),4.32(dd,J=4.7,7.0Hz,1H),4.10(s,2H),3.83(d,J=15.1Hz,1H),3.74-3.66(m,2H),3.28-3.20(m,4H),3.02(dd,J=10.2,15.3Hz,1H),2.84-2.71(m,2H),2.51-2.43(m,1H),2.39-2.18(m,3H),2.14-1.92(m,4H),1.90-1.75(m,3H),1.65-1.50(m,2H),1.47-1.35(m,2H),1.25-1.18(m,1H),1.05(d,J=6.8Hz,3H),0.67-0.58(m,2H),0.34-0.26(m,1H),0.12-0.04(m,1H).m/z(ESI,+ve离子)653.2(M+H)+。
实施例63.(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(2R,3R)-1-环丁基-3-甲基己-5-烯-2-磺酰胺和(2S,3S)-1-环丁基-3-甲基己-5-烯-2-磺酰胺和(2R,3S)-1-环丁基-3-甲基己-5-烯-2-磺酰胺和(2S,3R)-1-环丁基-3-甲基己-5-烯-2-磺酰胺
通过类似于实施例58的步骤2至3中所描述的程序的程序由(R)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(S)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(溴甲基)环丁烷制备标题化合物。
步骤2:(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
通过类似于实施例58的步骤4至5中所描述的程序的程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12)和(2R,3R)-1-环丁基-3-甲基己-5-烯-2-磺酰胺、(2S,3S)-1-环丁基-3-甲基己-5-烯-2-磺酰胺、(2R,3S)-1-环丁基-3-甲基己-5-烯-2-磺酰胺和(2S,3R)-1-环丁基-3-甲基己-5-烯-2-磺酰胺的混合物(来自步骤1)制备标题化合物。通过制备型反相HPLC(GeminiTM Prep C18 5μm柱;50%至95%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)纯化残余物,得到为白色泡沫的较快洗脱异构体的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm 8.09(s,1H),7.70(d,J=8.4Hz,1H),7.16(dd,J=2.2,8.5Hz,1H),7.09(d,J=2.2Hz,1H),6.95-6.88(m,3H),5.82-5.68(m,2H),4.19(dd,J=4.1,7.6Hz,1H),4.08(s,2H),3.93(dd,J=2.5,8.8Hz,1H),3.82(m,1H),3.68(d,J=14.3Hz,1H),3.25(d,J=14.3Hz,1H),3.05(dd,J=9.4,15.3Hz,1H),2.83-2.68(m,3H),2.41(m,1H),2.31(m,1H),2.23-2.10(m,4H),2.08-2.00(m,2H),1.98-1.52(m,12H),1.48-1.33(m,1H),1.01(d,J=6.8Hz,3H);m/z(ESI,+ve离子)653(M+H)+。
实施例64.(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丁基甲基)-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如实施例63中所描述的制备型反相HPLC,得到为第二(较慢)洗脱异构体的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm 8.05(s,J=7.4,7.4Hz,1H),7.70(d,J=8.4Hz,1H),7.17(dd,J=2.2,8.5Hz,1H),7.14-7.08(m,2H),6.97-6.90(m,1H),6.65(m,1H),6.00(m,1H),5.65(dd,J=6.1,15.1Hz,1H),4.19-4.02(m,3H),3.76(m,1H),3.61(m,1H),3.52(m,1H),3.43(d,J=14.5Hz,1H),3.24(m,1H),2.83-2.73(m,2H),2.73-2.62(m,1H),2.55-2.46(m,1H),2.35-2.10(m,5H),2.08-1.96(m,3H),1.95-1.81(m,6H),1.79-1.65(m,5H),1.47(d,J=15.3Hz,1H),1.16-1.07(m,3H);m/z(ESI,+ve离子)653(M+H)+。
实施例65.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(4R,5R)-2,5-二甲基辛-7-烯-4-磺酰胺和(4S,5S)-2,5-二甲基辛-7-烯-4-磺酰胺和(4R,5S)-2,5-二甲基辛-7-烯-4-磺酰胺和(4S,5R)-2,5-二甲基辛-7-烯-4-磺酰胺
通过类似于实施例58的步骤2至3中所描述的程序的程序由(R)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(S)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺(实施例58,步骤1)和异丁基溴制备标题化合物。
步骤2:(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
通过类似于实施例58的步骤4至5中所描述的程序的程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12)和(4R,5R)-2,5-二甲基辛-7-烯-4-磺酰胺、(4S,5S)-2,5-二甲基辛-7-烯-4-磺酰胺、(4R,5S)-2,5-二甲基辛-7-烯-4-磺酰胺和(4S,5R)-2,5-二甲基辛-7-烯-4-磺酰胺的混合物(来自步骤1)制备标题化合物。通过制备型反相HPLC(GeminiTM Prep C18 5μm柱;50%至95%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)纯化残余物,得到为白色泡沫的较快洗脱异构体的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm 8.09(s,1H),7.71(d,J=8.5Hz,1H),7.17(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),6.96-6.90(m,3H),5.86-5.78(m,1H),5.76-5.68(m,1H),4.22-4.12(m,2H),4.09(s,2H),3.84(m,1H),3.69(d,J=14.3Hz,1H),3.26(d,J=14.3Hz,1H),3.05(dd,J=9.4,15.3Hz,1H),2.83-2.70(m,2H),2.46-2.28(m,2H),2.18-1.91(m,8H),1.88-1.76(m,3H),1.76-1.66(m,1H),1.46-1.31(m,2H),1.04-0.98(m,9H);m/z(ESI,+ve离子)641(M+H)+。
实施例66.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如实施例65中所描述的制备型反相HPLC,得到作为单一异构体(第二较慢洗脱峰)的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm 8.11-8.04(m,1H),7.71(d,J=8.4Hz,1H),7.18(dd,J=2.2,8.4Hz,1H),7.15-7.09(m,2H),6.97-6.90(m,1H),6.65(m,1H),6.04(m,1H),5.65(dd,J=6.4,15.4Hz,1H),4.17(m,1H),4.07(q,J=12.2Hz,2H),3.81-3.69(m,2H),3.63(m,1H),3.43(d,J=14.3Hz,1H),3.24(m,1H),2.82-2.71(m,2H),2.56-2.48(m,1H),2.29-2.18(m,1H),2.07-1.82(m,9H),1.81-1.65(m,2H),1.51-1.38(m,3H),1.09(d,J=7.0Hz,3H),1.05-0.93(m,6H);m/z(ESI,+ve离子)641(M+H)+。
实施例67.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-(2-甲基丙基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如实施例65中所描述的制备型反相HPLC,得到为单一异构体(第三洗脱峰)的标题化合物中的一者。1H NMR(400MHz,CD2Cl2)δppm 8.17(br.s.,1H),7.74(d,J=8.6Hz,1H),7.66(d,J=8.8Hz,1H),7.16(s,1H),7.10(d,J=3.1Hz,1H),6.98(d,J=8.2Hz,1H),6.91(s,1H),5.73-5.66(m,2H),4.43(br.s.,1H),4.23(s,2H),4.15-4.04(m,4H),3.90(d,J=15.1Hz,1H),3.70(d,J=14.3Hz,1H),3.33(d,J=12.9Hz,1H),3.22(d,J=14.5Hz,1H),3.11(d,J=15.1Hz,2H),2.75(d,J=5.7Hz,3H),2.51(d,J=6.5Hz,1H),2.07-1.88(m,10H),1.06-1.00(m,9H)m/z(ESI,+ve离子)641(M+H)+。
实施例68.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(4R,5S)-N,N-双(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺酰胺和
(4S,5S)-N,N-双(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺酰胺和
(4S,5R)-N,N-双(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺酰胺和
(4R,5R)-N,N-双(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺酰胺和
按照实施例58的步骤2中所描述的类似程序由(2S)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(2R)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺(来自实施例58,步骤1)与1-溴丙烷制备标题化合物。
步骤2:(4R,5S)-5-甲基-7-辛烯-4-磺酰胺和
(4R,5R)-5-甲基-7-辛烯-4-磺酰胺和
(4S,5S)-5-甲基-7-辛烯-4-磺酰胺和
(4S,5R)-5-甲基-7-辛烯-4-磺酰胺
通过实施例58的步骤3中所描述的类似程序由(4R,5S)-N,N-双(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺酰胺、(4S,5S)-N,N-双(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺酰胺、(4S,5R)-N,N-双(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺酰胺和(4R,5R)-N,N-双(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺酰胺的混合物制备标题化合物。
步骤3:(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5R,6S)-1-羟基-5-甲基-6-氨磺酰基-2-壬烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酸和
(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5R,6R)-1-羟基-5-甲基-6-氨磺酰基-2-壬烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酸和
(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5S,6S)-1-羟基-5-甲基-6-氨磺酰基-2-壬烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酸和
(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5S,6R)-1-羟基-5-甲基-6-氨磺酰基-2-壬烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酸
通过将氩气鼓入反应烧瓶中,将(S)-6'-氯-5-(((1R,2S)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12A,120mg,0.24mmol)的混合物、(4R,5S)-5-甲基-7-辛烯-4-磺酰胺、(4R,5R)-5-甲基-7-辛烯-4-磺酰胺、(4S,5S)-5-甲基-7-辛烯-4-磺酰胺和(4S,5R)-5-甲基-7-辛烯-4-磺酰胺的混合物(来自步骤2,121mg;0.59mmol)于1,2二氯乙烷(2mL)中的混合物引入氩气保持20min。随后添加Hoveyda-Grubbs II。将混合物在环境温度下搅拌2h,浓缩,且将残余物通过色谱(SiO2凝胶,9:1至0:1,己烷/0.3%AcOH+EtOAc)分离,得到为灰色油状物的标题化合物。
步骤4:(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
在0℃下将(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5R,6S)-1-羟基-5-甲基-6-氨磺酰基-2-壬烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酸、(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5R,6R)-1-羟基-5-甲基-6-氨磺酰基-2-壬烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酸、(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5S,6S)-1-羟基-5-甲基-6-氨磺酰基-2-壬烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酸和(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5S,6R)-1-羟基-5-甲基-6-氨磺酰基-2-壬烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酸的混合物(110mg,0.170mmol)添加至于DCM(80mL)中的1-(3-二甲氨基丙基)-3-乙基碳二亚胺、HCl(98mg,0.51mmol)和DMAP(41.7mg,0.341mmol)。随后使反应混合物升至环境温度且搅拌18h。蒸发溶剂,将粗残余物通过色谱(SiO2凝胶,9:1至0:1,己烷/EtOAc+0.3%AcOH)分离,得到灰色油状物(65mg)。通过制备型反相HPLC(GeminiTM Prep C18 5μm柱;25%至75%MeCN/H2O梯度洗脱,其中两种溶剂均含有0.1%TFA,30min方法)进一步纯化油状物,得到为白色固体的标题化合物的第一洗脱异构体。1H NMR(500MHz,CDCl3)δppm 8.07(s,1H),7.70(d,J=8.3Hz,1H),7.19(dd,J=2.0,8.6Hz,1H),7.10(s,1H),6.98-6.88(m,3H),5.93-5.85(m,1H),5.72(dd,J=7.9,15.3Hz,1H),4.26(dd,J=4.0,8.2Hz,1H),4.16-4.06(m,3H),3.83(d,J=14.9Hz,1H),3.70(d,J=14.4Hz,1H),3.24(d,J=14.2Hz,1H),3.03(dd,J=9.8,15.2Hz,1H),2.83-2.72(m,2H),2.45(dd,J=3.7,8.6Hz,1H),2.32(t,J=9.0Hz,1H),2.16-1.94(m,7H),1.91-1.74(m,5H),1.74-1.62(m,2H),1.40(t,J=12.8Hz,1H),1.10-0.98(m,6H).m/z(ESI,+ve离子)627.2(M+H)+。
实施例69.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'Z,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'Z,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'Z,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根据实施例68中的制备型反相HPLC分离,得到为第二洗脱异构体的标题化合物。1H NMR(500MHz,CDCl3)δppm 7.71(d,J=8.3Hz,1H),7.11-7.08(m,1H),7.00-6.87(m,2H),6.84(br s,1H),6.14(br s,1H),5.81(br s,1H),4.23(br s,1H),4.19-4.04(m,3H),3.69(d,J=14.4Hz,2H),3.58(br s,1H),3.40-3.18(br,2H),3.15-3.00(br s,1H),2.85-2.70(m,2H),2.44(br s,1H),2.35(br s,2H),2.18(br s,1H),2.10-1.90(m,3H),1.80-1.63(m,6H),1.63-1.54(m,1H),1.48(br s,1H),1.11(br s,3H),1.05-0.99(m,3H).m/z(ESI,+ve离子)627.2(M+H)+。
实施例70.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羟基-11'-甲基-12'-丙基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根据实施例68中的制备型反相HPLC分离,得到为第三洗脱异构体的标题化合物。1H NMR(500MHz,CDCl3)δppm 8.32(br s,1H),7.70(d,J=8.6Hz,1H),7.23-7.16(m,2H),7.10(s,1H),6.97(d,J=8.3Hz,1H),6.66(br s,1H),6.08(br s,1H),5.66(dd,J=6.2,15.3Hz,1H),4.21(br s,1H),4.15-4.00(m,2H),3.83-3.60(m,3H),3.42(d,J=14.7Hz,1H),3.25(br s,1H),2.85-2.74(m,2H),2.60-2.47(m,2H),2.38-2.18(m,2H),2.15-2.00(m,3H),2.00-1.58(m,9H),1.46(br s,1H),1.17-1.08(m,3H),1.07-0.96(m,3H).m/z(ESI,+ve离子)627.2(M+H)+。
实施例71.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'S)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步骤1:(4S,5R)-N,N-双(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺酰胺和
(4R,5R)-N,N-双(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺酰胺和
(4S,5S)-N,N-双(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺酰胺和
(4R,5S)-N,N-双(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺酰胺
按照实施例58的步骤2中所描述的类似程序由(2S)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺和(2R)-N,N-双(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺酰胺(来自实施例58,步骤1)与1-溴丁烷制备标题化合物。
步骤2:(4S,5R)-4-甲基-1-壬烯-5-磺酰胺和
(4S,5R)-4-甲基-1-壬烯-5-磺酰胺和
(4S,5R)-4-甲基-1-壬烯-5-磺酰胺和
(4S,5R)-4-甲基-1-壬烯-5-磺酰胺
通过实施例58的步骤3中所描述的类似程序由(4S,5R)-N,N-双(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺酰胺、(4R,5R)-N,N-双(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺酰胺、(4S,5S)-N,N-双(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺酰胺、(4R,5S)-N,N-双(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺酰胺的混合物制备标题化合物。
步骤3:(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺酰基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺和
(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺酰基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺和
(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺酰基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺和
(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺酰基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺
使用实施例58的步骤4中所描述的类似程序由(4S,5R)-4-甲基-1-壬烯-5-磺酰胺、(4R,5R)-4-甲基-1-壬烯-5-磺酰胺、(4S,5S)-4-甲基-1-壬烯-5-磺酰胺和(4R,5R)-4-甲基-1-壬烯-5-磺酰胺的混合物(步骤2)和(S)-6'-氯-5-(((1R,2S)-2-((S,E)-1-羟基己-2-烯-1-基)环丁基)甲基)-3',4,4',5-四氢-2H,2'H-螺[苯并[b][1,4]氧氮杂-3,1'-萘]-7-甲酸(中间体AA12A)制备标题化合物。
步骤4:(1S,3'R,6'R,7'S,8'E,11'S,12'R)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'S)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用实施例58的步骤5中所描述的类似程序由以上(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺酰基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺和(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺酰基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺和(3S)-6'-氯-5-(((1R,2R)-2-((1s,2e)-1-羟基-2-己烯-1-基)环丁基)甲基)-N-(((R,3S)-3-(2-丙烯-1-基)-2-庚基)磺酰基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺和(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羟基-2-己烯-1-基)环丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺酰基)-3',4,4',5-四氢-2'H-螺[1,5-苯并氧氮杂-3,1'-萘]-7-甲酰胺的混合物制备标题化合物。1H NMR(500MHz,CDCl3)δppm 8.07(br s,1H),7.70(d,J=8.6Hz,1H),7.19(d,J=8.3Hz,1H),7.11-7.09(m,1H),6.99-6.87(m,3H),5.93-5.86(m,1H),5.72(dd,J=8.2,15.3Hz,1H),4.26(dd,J=3.9,8.3Hz,1H),4.13-4.07(m,3H),3.83(d,J=15.4Hz,1H),3.70(d,J=14.4Hz,1H),3.24(d,J=14.2Hz,1H),3.03(dd,J=9.5,15.2Hz,1H),2.83-2.72(m,2H),2.51-2.39(m,1H),2.32(t,J=9.4Hz,1H),2.20-1.64(m,6H),1.63-1.63(m,7H),1.63-1.53(m,1H),1.50-1.33(m,3H),1.06(d,J=6.8Hz,3H),0.97(t,J=7.3Hz,3H).m/z(ESI,+ve离子)641.2(M+H)+。
实施例72.(1S,3'R,6'R,7'S,8'Z,11'R,12'R)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'Z,11'R,12'S)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'Z,11'S,12'S)-12'-丁基-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根据实施例71中的制备型反相HPLC分离得,到为单一异构体(第二洗脱峰)的标题化合物。1H NMR(500MHz,CDCl3)δ=9.92(br s,1H),7.71(d,J=8.6Hz,1H),7.47(d,J=8.1Hz,1H),7.20-7.12(m,1H),7.12-7.06(m,2H),6.98(d,J=8.3Hz,1H),5.75(br s,1H),5.53(td,J=2.4,2.4,11.8Hz,1H),4.41(br s,1H),4.13-4.01(m,2H),3.88(d,J=15.4Hz,1H),3.64(d,J=14.4Hz,1H),3.57(br s,1H),3.19-2.99(m,2H),2.83-2.71(m,2H),2.29-2.15(m,2H),2.13-2.02(m,2H),2.02-1.87(m,4H),1.77-1.63(m,7H),1.62-1.50(m,1H),1.49-1.31(m,3H),1.12-1.03(m,3H),1.02-0.88(m,3H).m/z(ESI,+ve离子)641.2(M+H)+。
实施例73.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-7'-丁氧基-6-氯-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03, 6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
在0℃下向(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(实施例2;60mg,0.1mmol)于THF(2mL)中的溶液添加于矿物油中的60%氢化钠(20mg,0.5mmol)。在0℃下搅拌混合物30min。添加1-碘丁烷(92mg,54uL,0.5mmol),并将由此得到的混合物在0℃下搅拌4h,HPLC-MS分析表明反应完成。将反应用饱和NH4Cl淬灭且用EtOAc萃取。合并的有机层用盐水洗涤且经MgSO4干燥。减压蒸发溶剂,且通过快速色谱在SiO2凝胶(24g,HP SiO2,Teledyne ISCO)上用15%至65%EtOAc/己烷洗脱来纯化残余物,得到为白色固体的(1S,3'R,6'R,7'S,8'E,11'S,12'R)-7'-丁氧基-6-氯-11',12'-二甲基-3,4-二氢-2h,15'h-螺[萘-1,22'[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(15mg,23%产率)。1H NMR(500MHz,CDCl3)δppm 8.13(s,1H),7.70(d,J=8.4,2.3Hz,1H),7.09(d,J=2.2Hz,1H),6.92–6.95(m,2H),6.89(s,1H),5.80(ddd,J=15.1,9.6,3.2Hz,1H),5.54(dd,J=15.1,9.6Hz,1H),4.31-4.36(m,1H),4.07-4.11(m,2H),3.84(d,J=15.4Hz,1H),3.68-3.74(m,2H),3.39(dt,J=9.3,6.7Hz,1H),3.22-3.27(m,2H),3.00(dd,J=15.2,10.3Hz,1H),2.75-2.83(m,2H),2.41-2.47(m,1H),2.30-2.36(m,1H),2.14-2.21(m,1H),1.94-2.12(m,2H),1.73-1.88(m,4H),1.58-1.62(m,1H),1.48-1.55(m,4H),1.20-1.42(m,4H),1.05(d,J=10.0Hz,3H),0.92(t,J=10.0Hz,3H);MS m/z(ESI,+ve离子)656.0(M+H)+。
实施例74.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-(2-甲氧基乙氧基)-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮-13',13'-二氧化物
向(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例2,100mg,0.167mmol)于DMF(3.34mL)中的溶液(冷却至0℃)添加氢化钠(于矿物油中的60%分散体)(66.8mg,1.67mmol)。在0℃下搅拌反应混合物15min,随后添加2-溴乙基甲醚(Alfa Aesar,0.078mL,0.834mmol)。在环境温度下搅拌反应混合物。48h后,将混合物用NH4Cl水溶液淬灭且用水稀释,随后用EtOAc萃取。有机层经MgSO4干燥且浓缩。通过色谱经由Redi-Sep预装填硅胶柱(12g)用10-40%EtOAc(含有0.3%AcOH)/庚烷洗脱来纯化粗物质,得到标题化合物(61mg,0.093mmol,55.6%产率)。1H NMR(500MHz,CD2Cl2)δ8.02(s,1H),7.70(d,J=8.6Hz,1H),7.17(dd,J=2.2,8.6Hz,1H),7.09(d,J=2.2Hz,1H),6.91(s,2H),6.86(s,1H),5.79(ddd,J=3.3,9.6,15.2Hz,1H),5.54(dd,J=9.8,14.4Hz,1H),4.26(ddd,J=1.0,7.3,14.4Hz,1H),4.12-4.04(m,2H),3.82(d,J=15.2Hz,1H),3.75(dd,J=3.3,9.2Hz,1H),3.69(d,J=14.7Hz,1H),3.53-3.49(m,1H),3.48-3.41(m,2H),3.39-3.34(m,1H),3.32(s,3H),3.25(d,J=14.2Hz,1H),3.02(dd,J=10.3,15.4Hz,1H),2.83-2.70(m,2H),2.49-2.41(m,1H),2.36-2.28(m,1H),2.21-2.13(m,1H),2.13-2.07(m,1H),2.05(d,J=13.7Hz,1H),1.99-1.91(m,3H),1.89-1.77(m,3H),1.71-1.59(m,1H),1.44(d,J=7.3Hz,3H),1.39(t,J=13.1Hz,1H),1.02(d,J=6.8Hz,3H).MS(ESI,+ve离子)m/z 657.1(M+H)+。
实施例75.(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-(2-甲氧基乙氧基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以类似于实施例74中所描述的方式的方式使用(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-羟基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(实施例17)和1-溴-2-甲氧基乙烷(Aldrich)制备标题化合物。1H NMR(400MHz,CD3OD)δ7.75(d,J=8.6Hz,1H),7.19(dd,J=2.2,8.8Hz,1H),7.12(d,J=2.2Hz,1H),7.01(dd,J=1.6,8.2Hz,1H),6.94(d,J=8.2Hz,1H),6.88(d,J=1.6Hz,1H),5.89(ddd,J=6.1,13.1,21.5Hz,1H),5.60(dd,J=9.0,15.1Hz,1H),4.09(dd,J=12.7,15.3Hz,2H),4.05-3.99(m,1H),3.91-3.82(m,2H),3.69(d,J=14.5Hz,1H),3.62-3.57(m,1H),3.53(dd,J=4.1,8.0Hz,2H),3.50-3.45(m,1H),3.38(s,3H),3.08(dd,J=10.3,15.2Hz,1H),2.87-2.73(m,2H),2.55-2.40(m,2H),2.40-2.26(m,2H),2.11(dd,J=7.4,15.1Hz,2H),1.98-1.65(m,10H),1.46(t,J=10.9Hz,1H),1.20(t,J=7.4Hz,3H).m/z(ESI,+ve离子)657.2(M+H)+。
实施例76.(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-(2-甲氧基乙氧基)-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以类似于实施例74中所描述的方式的方式使用(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-羟基-12'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(实施例11)和1-溴-2-甲氧基乙烷(Aldrich)制备标题化合物。1H NMR(400MHz,CD3OD)δ7.72(d,J=8.6Hz,1H),7.16(dd,J=8.5,2.2Hz,1H),7.10(d,J=2.2Hz,1H),6.98(d,J=8.3Hz,1H),6.91(d,J=8.2Hz,1H),6.85(d,J=1.8Hz,1H),5.80-5.87(m,1H),5.58(dd,J=15.5,8.8Hz,1H),4.03-4.18(m,3H),3.80-3.86(m,2H),3.41-3.68(m,5H),3.35(s,3H),3.06(dd,J=15.3,10.4Hz,1H),2.70-2.81(m,2H),2.24-2.53(m,4H),2.09(d,J=13.7Hz,1H),1.68-1.96(m,7H),1.50(d,J=7.0Hz,3H),1.39-1.47(m,2H).m/z(ESI,+ve离子)643.2(M+H)+。
实施例77.(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以类似于实施例74中所描述的方式的方式使用(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例30)和1-溴-2-甲氧基乙烷(Aldrich)制备标题化合物。1H NMR(500MHz,CDCl3)δppm 8.32(s,1H),7.68(d,J=8.6Hz,1H),7.17(dd,J=2.2,8.6Hz,1H),7.09(d,J=2.0Hz,1H),7.05-6.97(m,1H),6.92(d,J=8.1Hz,1H),5.94-5.85(m,1H),5.51(dd,J=7.0,15.3Hz,1H),4.17-4.04(m,2H),3.75-3.68(m,2H),3.66-3.46(m,7H),3.44-3.34(m,4H),2.80-2.72(m 2H),2.45-2.40(m,2H),2.22–2.10(m,3H),2.00-1.75(m,6H),1.75-1.55(m,2H),1.53-1.48(m,1H),1.18(d,J=6.4Hz,3H).m/z(ESI,+ve离子)643.2(M+H)+。
实施例78.(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以类似于实施例74中所描述的方式的方式使用(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-甲氧基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例31)和1-溴-2-甲氧基乙烷(Aldrich)制备标题化合物。1HNMR(500MHz,CDCl3)δppm 8.22(s,1H),7.70(d,J=8.6Hz,1H),7.18(dd,J=2.1,8.4Hz,1H),7.09(d,J=2.0Hz,1H),6.95-6.88(m,2H),6.83(s,1H),5.88-5.80(m,1H),5.56(dd,J=9.0,15.2Hz,1H),4.36(dd,J=4.8,15.3Hz,1H),4.14-4.04(m,2H),3.85-3.78(m,2H),3.71(d,J=14.2Hz,1H),3.60-3.48(m,3H),3.45-3.34(m,4H),3.23(d,J=14.4Hz,1H),3.09-2.91(m,2H),2.84-2.71(m,2H),2.53-2.44(m,1H),2.36-2.23(m,2H),2.13-1.92(m,5H),1.89-1.74(m,3H),1.69-1.54(m,1H),1.39(t,J=12.6Hz,1H),1.16(d,J=6.6Hz,3H).m/z(ESI,+ve离子)643.2(M+H)+。
实施例79.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-(2-(2-甲氧基乙氧基)乙氧基)-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
将无水(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(15mg,0.025mmol)(实施例2)和氢化钠(于矿物油中的60%分散体)(9.9mg,0.43mmol)于DMF中的混合物在氩气下搅拌10min。在环境温度下添加1-(2-溴乙氧基)-2-甲氧基乙烷(22.6mg,0.124mmol)。将反应混合物搅拌18h,用NH4Cl饱和水溶液淬灭,且用EtOAc(X3)萃取。将合并的有机层干燥(MgSO4)且浓缩。将残余物通过色谱(硅胶,0-50%,EtOAc+0.3%HOAc/己烷)分离,得到为白色固体的标题化合物。1H NMR(400MHz,CDCl3)δppm 8.09(s,1H),7.70(d,J=8.6Hz,1H),7.18(dd,J=2.2,8.5Hz,1H),7.09(d,J=2.2Hz,1H),6.95-6.87(m,3H),5.82(ddd,J=3.2,9.4,15.1Hz,1H),5.54(dd,J=9.1,15.2Hz,1H),4.35-4.24(m,1H),4.16-4.05(m,2H),3.87-3.74(m,2H),3.70-3.54(m,8H),3.45-3.44(m,1H),3.40(s,3H),3.23(d,J=14.3Hz,1H),2.99(dd,J=10.2,15.3Hz,1H),2.84-2.71(m,2H),2.53-2.42(m,1H),2.38-2.24(m,1H),2.15-1.93(m,4H),1.90-1.72(m,3H),1.72-1.57(m,3H),1.49(d,J=7.2Hz,3H),1.42-1.35(m,1H),1.05(d,J=6.8Hz,3H).m/z(ESI,+ve离子)701.2(M+H)+。
实施例80.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-(2-(2-(2-甲氧基乙氧基)乙氧基)乙氧基)-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用实施例79中所描述的类似程序用1-溴-2-[2-(2-甲氧基乙氧基)乙氧基]乙烷代替1-(2-溴乙氧基)-2-甲氧基乙烷由(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例2)制备标题化合物。1H NMR(400MHz,CDCl3)δppm 7.97(s,1H),7.70(d,J=8.4Hz,1H),7.19(dd,J=2.2,8.4Hz,1H),7.10(d,J=2.0Hz,1H),6.95-6.87(m,3H),5.86-5.75(m,1H),5.54(dd,J=9.0,15.1Hz,1H),4.35-4.22(m,1H),4.13-4.05(m,2H),3.86-3.76(m,2H),3.72-3.63(m,7H),3.63-3.54(m,5H),3.44-3.42(m,1H),3.40(s,3H),3.23(d,J=14.3Hz,1H),2.99(dd,J=10.1,15.4Hz,1H),2.84-2.71(m,2H),2.48(d,J=10.6Hz,1H),2.38-2.26(m,1H),2.21-1.90(m,4H),1.89-1.72(m,3H),1.70-1.58(m,3H),1.50(d,J=7.2Hz,3H),1.45-1.32(m,1H),1.06(d,J=6.8Hz,3H).m/z(ESI,+ve离子)745.2(M+H)+。
实施例81.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-11',12'-二甲基-7'-(3,6,9,12-四氧杂十三-1-基氧基)-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用实施例79中所描述的类似程序用三乙二醇2-溴乙基甲醚代替1-(2-溴乙氧基)-2-甲氧基乙烷由(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羟基-11',12'-二甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019 ,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例2)制备标题化合物。1HNMR(400MHz,CDCl3)δppm 8.02(s,1H),7.70(d,J=8.6Hz,1H),7.19(dd,J=2.2,8.4Hz,1H),7.09(d,J=2.2Hz,1H),6.94-6.88(m,3H),5.85-5.77(m,1H),5.54(dd,J=8.5,15.4Hz,1H),4.31(q,J=7.4Hz,1H),4.09(s,2H),3.85-3.75(m,2H),3.74-3.62(m,11H),3.62-3.50(m,5H),3.45-3.42(m,1H),3.39(s,3H),3.23(d,J=14.3Hz,1H),3.03-2.95(m,1H),2.83-2.72(m,2H),2.52-2.43(m,1H),2.32(t,J=9.5Hz,1H),2.21-1.92(m,4H),1.90-1.74(m,3H),1.68-1.56(m,3H),1.50(d,J=7.2Hz,3H),1.40(t,J=13.2Hz,1H),1.06(d,J=6.8Hz,3H).m/z(ESI,+ve离子)789.2(M+H)+。
实施例82.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丙基甲基)-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丙基甲基)-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丙基甲基)-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丙基甲基)-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以类似于实施例74中所描述的方式的方式使用(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(环丙基甲基)-7'-羟基-11'-甲基-3,4-二氢-2h,15'h-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例59)和1-溴-2-甲氧基乙烷(Aldrich)制备标题化合物。1H NMR(400MHz,CDCl3)δppm 8.05(s,1H),7.70(d,J=8.6Hz,1H),7.18(dd,J=2.2,8.5Hz,1H),7.09(d,J=2.2Hz,1H),6.96-6.90(m,3H),5.91-5.83(m,1H),5.56(dd,J=9.0,15.1Hz,1H),4.30(dd,J=4.5,7.2Hz,1H),4.09(s,2H),3.87-3.79(m,2H),3.74-3.67(m,1H),3.59-3.50(m,3H),3.48-3.41(m,1H),3.41-3.35(s,3H),3.23(d,J=14.5Hz,1H),3.00(dd,J=10.2,15.3Hz,1H),2.84-2.71(m,2H),2.50(d,J=10.6Hz,1H),2.37-2.16(m,3H),2.13-1.92(m,4H),1.91-1.73(m,3H),1.71-1.52(m,2H),1.51-1.34(m,2H),1.23-1.14(m,1H),1.05(d,J=6.8Hz,3H),0.67-0.58(m,2H),0.29(dd,J=4.4,9.1Hz,1H),0.08(dd,J=4.1,9.0Hz,1H).m/z(ESI,+ve离子)697.3(M+H)+。
实施例83.(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮-13',13'-二氧化物
以类似于实施例74中所描述的方式的方式使用(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-羟基-11'-甲基-3,4-二氢-2H,15'H-螺[萘-1,22'-[20]氧杂[13]硫杂[1,14]二氮杂四环[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(实施例24)和1-溴-2-甲氧基乙烷(Aldrich)制备标题化合物。1H NMR(500MHz,CD2Cl2)δ8.08(s,1H),7.71(d,J=8.6Hz,1H),7.17(dd,J=2.4,8.6Hz,1H),7.09(d,J=2.2Hz,1H),6.91(d,J=0.7Hz,2H),6.87(s,1H),5.82(ddd,J=3.4,9.4,15.3Hz,1H),5.54(dd,J=9.4,15.8Hz,1H),4.11-4.05(m,2H),4.00(dd,J=2.8,9.4Hz,1H),3.82(d,J=14.9Hz,1H),3.78(dd,J=3.2,9.0Hz,1H),3.69(d,J=14.4Hz,1H),3.53(ddd,J=3.4,5.4,9.3Hz,1H),3.45(dt,J=3.7,5.0Hz,2H),3.38(ddd,J=3.4,5.9,9.5Hz,1H),3.32(s,3H),3.25(d,J=14.4Hz,1H),3.02(dd,J=10.3,15.4Hz,1H),2.84-2.70(m,2H),2.45(ddd,J=3.7,10.0,19.1Hz,1H),2.37-2.29(m,1H),2.29-2.19(m,1H),2.13-2.08(m,1H),2.08-2.01(m,2H),2.00-1.89(m,3H),1.89-1.77(m,4H),1.66(quin,J=8.6Hz,1H),1.44-1.35(m,1H),1.28(t,J=7.3Hz,3H),1.02(d,J=6.8Hz,3H).MS(ESI,+ve离子)m/z 671.1(M+H)+;693.1(M+Na)+。
以上描述仅举例说明本发明而无意将本发明限于所公开的化合物、组合物和方法。对本领域的技术人员显而易见的变化和改变旨在在本发明的范围和本质内,如所附权利要求书中所定义。根据以上描述,本领域的技术人员可易于确定本发明的基本特征,且在不脱离本发明的精神和范围的情况下,可对本发明作出各种改变和修改以使其适应各种用途和条件。本文所述的所有专利和其他公开均据此以全文引用的方式并入。
Claims (27)
1.一种式I的化合物:
或其药学上可接受的盐,
其中:
其中以符号表示的b为单化学键或双化学键,其可为顺式或反式的;
R为卤基;
R1为H、C1-6烷基或-(CH2CH2O)nCH3,其中n为1至4的整数;
R2为H或C1-6烷基;
R2A为H或C1-6烷基;
R3为H或C1-6烷基;以及
R3A为H、C1-6烷基、C3-6环烷基或(CH2)m-C3-6环烷基,其中m为1至4的整数。
2.根据权利要求1所述的化合物,其中b指示双键。
3.根据权利要求1或权利要求2所述的化合物,其中R为Cl。
4.根据权利要求1所述的化合物,其中R1为C1-6烷基。
5.根据权利要求4所述的化合物,其中R1为CH3。
6.根据权利要求1-5中任一项所述的化合物,其中R2为H且R2A为C1-6烷基。
7.根据权利要求1-6中任一项所述的化合物,其中R3为H且R3A为C1-6烷基。
8.根据权利要求1所述的化合物,其中所述式I的化合物具有式II:
或其药学上可接受的盐,
其中:
R1、R2、R2A、R3和R3A如上文所定义。
9.一种化合物,其中所述化合物具有选自以下的结构:
或其药学上可接受的盐。
10.一种药物组合物,其包含根据权利要求1-9中任一项所述的化合物或其药学上可接受的盐和药学上可接受的赋形剂。
11.一种化合物,其中所述化合物具有选自以下的结构:
或其药学上可接受的盐。
12.一种药物组合物,其包含根据权利要求11所述的化合物或其药学上可接受的盐和药学上可接受的赋形剂。
13.一种抑制细胞的髓细胞白血病1蛋白(Mcl-1)的方法,其包括使所述细胞与有效抑制所述Mcl-1的量的根据权利要求1-9或11中任一项所述的化合物接触。
14.根据权利要求13所述的方法,其中所述接触包括向受试者施用所述化合物。
15.根据权利要求13所述的方法,其中所述施用经口、经肠胃外、经由注射、经由吸入、经皮或经粘膜进行。
16.根据权利要求13所述的方法,其中所述受试者罹患癌症。
17.一种治疗癌症的方法,其包括向对其有需要的患者施用治疗有效量的根据权利要求1-9或11中任一项所述的化合物,或其药学上可接受的盐。
18.根据权利要求17所述的方法,其中所述癌症为恶性血液病。
19.根据权利要求17所述的方法,其中所述癌症选自乳腺癌、结直肠癌、皮肤癌、黑素瘤、卵巢癌、肾癌、肺癌、非小细胞肺癌、淋巴瘤、非霍奇金氏淋巴瘤、骨髓瘤、多发性骨髓瘤、白血病和急性骨髓性白血病。
20.根据权利要求17所述的方法,其中所述癌症为多发性骨髓瘤。
21.根据权利要求17所述的方法,其还包括向对其有需要的所述患者施用治疗有效量的另外的药物活性化合物。
22.根据权利要求21所述的方法,其中所述另外的药物活性化合物为卡非佐米。
23.根据权利要求1-9或11中任一项所述的化合物用于治疗受试者的癌症的用途。
24.一种根据权利要求1-9或11中任一项所述的化合物,其用于制备治疗癌症的药剂。
25.根据权利要求24所述的化合物,其中所述癌症为恶性血液病。
26.根据权利要求24所述的化合物,其中所述癌症选自乳腺癌、结直肠癌、皮肤癌、黑素瘤、卵巢癌、肾癌、肺癌、非小细胞肺癌、淋巴瘤、非霍奇金氏淋巴瘤、骨髓瘤、多发性骨髓瘤、白血病和急性骨髓性白血病。
27.根据权利要求24所述的化合物,其中所述癌症为多发性骨髓瘤。
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