CN109952290B - Fgfr4抑制剂及其制备方法和应用 - Google Patents
Fgfr4抑制剂及其制备方法和应用 Download PDFInfo
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- CN109952290B CN109952290B CN201780070537.7A CN201780070537A CN109952290B CN 109952290 B CN109952290 B CN 109952290B CN 201780070537 A CN201780070537 A CN 201780070537A CN 109952290 B CN109952290 B CN 109952290B
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- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
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Classifications
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
提供一类作为FGFR4抑制剂的式(I)所示化合物及其药学上可接受的盐,其制备方法及其在制备治疗FGFR4相关病症的药物上的应用。
Description
相关申请的交叉引用
本申请主张2016.11.17提交的中国专利申请CN201611012431.5的优先权,其内容在此并入本申请。
技术领域
本发明涉及了一类作为FGFR4抑制剂的化合物,及其在制备治疗FGFR4相关病症的药物上的应用。具体涉及式(I)所示化合物及其药学上可接受的盐。
背景技术
成纤维细胞生长因子受体4(FGFR4)是由FGFR4基因编译的一种人蛋白。此蛋白是成纤维细胞生长因子受体家族中的一员,FGFR1-4成员之间的氨基酸序列同源性很高,高度相似。由细胞外免疫球蛋白(Ig)样结构域、疏水性跨膜区域和包括酪氨酸激酶区域的细胞质部分所组成的糖蛋白。膜外区域与FGF结合导致FGFR二聚,受体发生自体磷酸化,激活下游信号通路,最终影响细胞的分裂和变异。
在基因结构方面,FGFR4与FGFR1-3有明显的区别,其具有半胱氨酸552(CYS552)特异结构,因此能够实现选择性地抑制FGFR4,而不抑制FGFR1-3抑制剂的开发,能够减少FGFR1-3抑制带来的潜在毒性;据近些年研究表明,FGFR4-FGF19信号轴与肝癌,肾癌,结肠癌,乳腺癌等紧密相关,使得FGFR4成为治疗肝癌,肾癌,结肠癌,乳腺癌等非常有潜力的靶标之一。
FGFR4抑制剂在临床上将不只局限于治疗FGFR4高表达的肝癌,在FGFR4信号通路异常的其他实体瘤中也可以应用,同时还存在和其他疗法联合使用的可能。因此,开发FGFR4抑制剂具有较为广泛的市场空间和应用前景。
发明内容
本发明提供了式(I)所示化合物、其药学上可接受的盐及其互变异构体,
其中,
X、Y、Z分别独立地选自C(R)或N;
R1、R2中一个选自F,另一个选自H或CH3;
A环选自:苯基、5-6元环烷基、5-6元杂环烷基;
R3、R4、R5分别独立地选自H、F、Cl,或者选自任选被1、2或3个R取代的:C1-3烷基、C1-3烷氧基、C1-3烷基-C(=O)-、5-6元杂环烷基;
R选自H,或者选自任选被1、2或3个R’取代的:C1-3烷基、C1-3烷基-C(=O)-、5-6元杂环烷基;
R’选自:CH3、CH2CH3;
所述5-6元杂环烷基之“杂”分别独立选自:-NH-、-O-、N;
以上任何一种情况下,杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中,上述R1选自F,R2选自H或CH3,其他变量如本发明所定义。
本发明的一些方案中,上述R1选自H或CH3,R2选自F,其他变量如本发明所定义。
本发明的一些方案中,上述A环选自:苯基、环己烷基、环戊烷基、四氢吡喃基、四氢呋喃基、吡咯烷基,其他变量如本发明所定义。
本发明的一些方案中,上述R3、R4、R5分别独立地选自H、F、Cl,或者选自任选被1、2或3个R取代的:甲基、乙基、C1-3烷氧基、C1-3烷基-C(=O)-、哌嗪基,其他变量如本发明所定义。
本发明的一些方案中,上述R3选自:H、F、Cl、CH3,其他变量如本发明所定义。
本发明还有一些方案是由上述变量任意组合而来。
本发明的一些方案中,上述化合物、其药学上可接受的盐及其互变异构体,其选自:
其中,R1、R2、R3、R4、R5、Z、X、Y的定义如本发明所定义。
本发明还有提供了下式化合物、其药学上可接受的盐及其互变异构体,选自:
本发明还提供了一种药物组合物,包括治疗有效量的上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供了上述的化合物或其药学上可接受的盐在制备治疗FGFR4相关病症的药物上的应用。
本发明还提供了上述的组合物在制备治疗FGFR4相关病症的药物上的应用。
本发明的一些方案中,上述应用的特征在于,所述药物是治疗肝癌或胃癌的药物。
技术效果
本发明化合物丙烯酰胺和氟烯键母核结构能得到一系列FGFR4高选择的化合物,对FGFR4激酶有优异的抑制活性,而对亚型FGFR1激酶没有活性,选择性至少十或百倍以上。另外发现,双甲氧基二氯苯环的结构中,双氯能够大大提高FGFR4的抑制活性;如实施例1与对照例1相比活性提高70倍;烯键引入氟原子,氟原子靠近二氯苯胺,能够提高FGFR4的靶点活性,如实施例15与对照例2相比,活性提高了近9倍,实施例19与对照例3相比,活性提高近9倍;本发明化合物的氟烯结构,与苄醚结构相比,能够大大提高药物代谢的稳定性,同时也大大提高药物的口服吸收生物利用度;并且本发明化合物具有优良的抗肿瘤活性,对用于治疗各种哺乳动物(包括人类)的肿瘤性疾病,如肝癌,胃癌等有优良的效果。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐(参见Berge et al.,″PharmaceuticalSalts″,Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
优选地,以常规方式使盐与碱或酸接触,再分离母体化合物,由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质,例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物,其中,通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于:碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐,例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐,所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明,用楔形键和虚线键表示一个立体中心的绝对构型,用表示一个立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心,除非另有规定,它们包括E、Z几何异构体。同样地,所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的常规方法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
针对药物或药理学活性剂而言,术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型,组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异,取决于受体的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”,“活性物质”或“活性剂”是指一种化学实体,它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,可以包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即=O)时,意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时,比如-(CRR)0-,表示该连接基团为单键。
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时,表示该取代基是不存在的,比如A-X中X为空缺时表示该结构实际上是A。当一个取代基的键可以交叉连接到一个环上的两个原子时,这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时,这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如,结构单元表示其可在环己基或者环己二烯上的任意一个位置发生取代。
除非另有规定,术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团),包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团,例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)、-S(=O)2-,以及任选被取代的-C(=O)N(H)-、-N(H)-、-C(=NH)-、-S(=O)2N(H)-或-S(=O)N(H)-。
除非另有规定,“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数,例如,“5~7元环”是指环绕排列5~7个原子。除非另有规定,该环任选地包含1~3个杂原子。因此,“5~7元环”包括例如苯基、吡啶和哌啶基;另一方面,术语“5~7元杂环烷基环”包括吡啶基和哌啶基,但不包括苯基。术语“环”还包括含有至少一个环的环系,其中的每一个“环”均独立地符合上述定义。
除非另有规定,术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环,它们可以是饱和的、部分不饱和的或不饱和的(芳族的),它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子,其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p,p是1或2)。氮原子可以是被取代的或未取代的(即N或NR,其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的,本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是,当杂环中S及O原子的总数超过1时,这些杂原子彼此不相邻。另一个优选方案是,杂环中S及O原子的总数不超过1。如本文所用,术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环,它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR,其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p,p是1或2)。值得注意的是,芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于:一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是,一个桥总是将单环转换成三环。桥环中,环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于:吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基,八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基,6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定,术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合,可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基),可以是单取代或多取代的,可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基),可以包括二价或多价原子团,具有指定数量的碳原子(如C1-C12表示1至12个碳,C1-12选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12;C3-12选自C3、C4、C5、C6、C7、C8、C9、C10、C11和C12。)。“烃基”包括但不限于脂肪烃基和芳香烃基,所述脂肪烃基包括链状和环状,具体包括但不限于烷基、烯基、炔基,所述芳香烃基包括但不限于6-12元的芳香烃基,例如苯、萘等。在一些实施例中,术语“烃基”表示直链的或支链的原子团或它们的组合,可以是完全饱和的、单元或多元不饱和的,可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基,以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键,其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基,3-丁炔基,以及更高级的同系物和异构体。
除非另有规定,术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合,有一定数目的碳原子和至少一个杂原子组成。在一些实施例中,术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物,有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中,杂原子选自B、O、N和S,其中氮和硫原子任选地被氧化,氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置,包括该烃基附着于分子其余部分的位置,但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达,是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH=CH-O-CH3、-CH2-CH=N-OCH3和-CH=CH-N(CH3)-CH3。至多两个杂原子可以是连续的,例如-CH2-NH-OCH3。
除非另有规定,术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外,就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言,杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基,3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基,1-哌嗪基和2-哌嗪基。
除非另有规定,术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH2F)或多取代的(如-CF3),可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me),乙基(Et),丙基(如,n-丙基和异丙基),丁基(如,n-丁基,异丁基,s-丁基,t-丁基),戊基(如,n-戊基,异戊基,新戊基)等。
除非另有规定,“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的,可以是一价、二价或者多价。烯基的例子包括乙烯基,丙烯基,丁烯基,戊烯基,己烯基,丁间二烯基,戊间二烯基,己间二烯基等。
除非另有规定,环烷基包括任何稳定的环状或多环烃基,任何碳原子都是饱和的,可以是单取代或多取代的,可以是一价、二价或者多价。这些环烷基的实例包括,但不限于,环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定,术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外,术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如,术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2,2,2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定,卤代烷基的实例包括但不仅限于:三氟甲基、三氯甲基、五氟乙基,和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基,除非另有规定,C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。除非另有规定,术语“芳基”表示多不饱和的芳族烃取代基,可以是单取代或多取代的,可以是一价、二价或者多价,它可以是单环或多环(比如1至3个环;其中至少一个环是芳族的),它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中,杂原子选自B、N、O和S,其中氮和硫原子任选地被氧化,氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定,芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此,术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等),包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基,例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词:aq代表水;HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐;EDC代表N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐;m-CPBA代表3-氯过氧苯甲酸;eq代表当量、等量;CDI代表羰基二咪唑;DCM代表二氯甲烷;PE代表石油醚;DIAD代表偶氮二羧酸二异丙酯;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EtOAc代表乙酸乙酯;EtOH代表乙醇;MeOH代表甲醇;CBz代表苄氧羰基,是一种胺保护基团;BOC代表叔丁基羰基是一种胺保护基团;HOAc代表乙酸;NaCNBH3代表氰基硼氢化钠;r.t.代表室温;O/N代表过夜;THF代表四氢呋喃;Boc2O代表二-叔丁基二碳酸酯;TFA代表三氟乙酸;DIPEA代表二异丙基乙基胺;SOCl2代表氯化亚砜;CS2代表二硫化碳;TsOH代表对甲苯磺酸;NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺;NCS代表1-氯吡咯烷-2,5-二酮;n-Bu4NF代表氟化四丁基铵;iPrOH代表2-丙醇;mp代表熔点;LDA代表二异丙基胺基锂;EGTA代表乙二醇双(2-氨基乙基醚)四乙酸;ATP代表腺嘌呤核苷三磷酸;HEPES代表4-羟乙基哌嗪乙磺酸;MgCl2代表氯化镁;MnCl2代表二氯化锰;EGTA代表乙二醇双(2-氨基乙基醚)四乙酸;DTT代表二硫苏糖醇;DIEA代表N,N-二异丙基乙胺;NaBH4代表硼氢化钠;NBS代表N-溴代琥珀酰亚胺;XPhos代表2-二-叔丁膦基-2′,4′,6′-三异丙基联苯。
具体实施方式
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
流程A
对照例1
对照例1A
在室温条件下(28℃),将水合肼(18.1克,361毫摩尔)滴入3,5-二甲氧基苯甲醛(20克,120毫摩尔)。在室温条件下,搅拌2小时后,经TLC检测3,5-二甲氧基苯甲醛没有反应完全,延长反应时间。继续反应16小时后,向反应瓶中加入乙二胺(21.70克,361毫摩尔)和氯化亚铜(1.19克,12.04毫摩尔)。搅拌30分后,反应液置于冰浴冷却至0℃后,将三溴氟甲烷(81.46克,301毫摩尔)的乙醇(30毫升)溶液经恒压滴液漏斗滴加到反应液中(在滴加过程中有少量气体放出)。滴加完毕后,该反应在0℃下搅拌1小时后,缓慢升至室温(28℃)然后再继续反应1小时。待中间体E-3,5-二甲氧基苯腙完全反应后,过滤,固体用乙酸乙酯洗涤,滤液经减压浓缩蒸除大部分溶剂。用乙酸乙酯(200毫升)稀释,并用柠檬酸(1M,50毫升)水溶液洗涤,分液,水相然后用乙酸乙酯萃取(3×100毫升)。合并的有机相用饱和的食盐水(150毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱分离(流动相:0~15%乙酸乙酯/石油醚)后得到浅黄色液体对照例1A(18.86克,收率:60%)。
1H NMR(400MHz,CHLOROFORM-d)δ6.56(d,J=2.4Hz,2H),6.43-6.39(m,1H),5.92(d,J=32.4Hz,1H),3.80(s,6H).
对照例1B
该对照例1B采用实施例1C的相同的方法合成,分析数据如下;
LCMS(ESI)m/z:294.1[M+1]+
对照例1C
向对照例1B(190毫克,647微摩尔)和2-甲基-3-硝基苯胺(148毫克,971微摩尔)的N,N-甲基乙酰胺溶液中加入三(二亚苄基丙酮)二钯(59毫克,64.69微摩尔),2-二环己基磷-2,4,6-三异丙基联苯(62毫克,129微摩尔),碳酸铯(421毫克,1.29毫摩尔),该混合物在氮气保护的条件下于110℃搅拌2小时。混合物加乙酸乙酯(20毫升),用水(250毫升)洗涤,乙酸乙酯萃取3遍,有机相用无水硫酸钠干燥,过滤,旋干溶液,拌样过柱,得到暗红色对照例1C(197毫克)。
LCMS(ESI)m/z:410.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ(ppm)=8.46(d,J=2.0Hz,1H),8.08(br.s.,1H),7.93(d,J=8.0Hz,1H),7.74(dd,J=2.4,8.4Hz,1H),7.54(d,J=7.6Hz,1H),7.26(s,1H),6.78(d,J=2.0Hz,2H),6.57(d,J=9.2Hz,1H),6.41(t,J=2.0Hz,1H),6.01-6.17(m,1H),3.82(s,6H),2.26(s,3H).
对照例1D
向化对照例1C(197毫克,481微摩尔)的90%乙醇溶液(6.0毫升)中加入铁粉(134毫克,2.41毫摩尔),氯化铵(129毫克,2.41毫摩尔)。该混合物在100℃的条件下搅拌2小时。该混合物用乙酸乙酯(10毫升)稀释,水洗,乙酸乙酯萃取3遍,无水硫酸钠干燥,旋干溶剂,得到对照例1D(189毫克,粗品)。
LCMS(ESI)m/z:380.1[M+1]+
对照例1
在0℃的条件下,向粗品对照例1D(152毫克,401微摩尔)的二氯甲烷(7.0毫升)溶液中依次加入N,N-二异丙基乙胺(104毫克,801微摩尔)和丙烯酰氯(29毫克,320微摩尔)的二氯甲烷(1.0毫升)溶液并搅拌半个小时。该混合物用水(5.0毫升)淬灭,水洗涤,二氯甲烷萃取3遍,后处理得到最终化合物对照例1(20毫克)。
LCMS(ESI)m/z:434.3[M+1]
1H NMR(400MHz,CHLOROFORM-d)δ11.27(br.s.,1H),8.25(br.s.,1H),8.15(s,1H),8.02(d,J=8.0Hz,1H),7.91(d,J=9.2Hz,1H),7.34(dd,J=8.0,8.0Hz,1H),7.13(d,J=7.6Hz,1H),6.75(d,J=1.6Hz,2H),6.50(d,J=9.6Hz,1H),6.45(s,1H),6.35-6.42(m,1H),6.22-6.31(m,1H),6.12(d,J=38.4Hz,1H),5.74(d,J=10.4Hz,1H),3.83(s,6H)
流程B
对照例2
对照例2A
将水合肼(27.11克,541.62毫摩尔)加入到3,5-二甲氧基苯甲醛(30.00克,180.54毫摩尔)的乙醇(300.00毫升)溶液中,80-90℃搅拌2小时。薄层层析板显示反应完成后,低压浓缩除去溶剂得无色油状对照例2A(33.10克)。
1H NMR(400MHz,CHLOROFORM-d)δ3.80(s,6H)5.54(br.s.,2H)6.42(t,J=2.26Hz,1H)6.71(d,J=2.01Hz,2H)7.66(s,1H).
对照例2B
将氨水(54.67克,389.97毫摩尔)和氯化亚铜(1.79克,18.05毫摩尔)加入到对照例2A(32.53克,180.54毫摩尔)的二甲基亚砜(300.00毫升)溶液中。室温搅拌下,将氯仿(136.88克,541.62毫摩尔)缓慢滴加(反应放热明显)到反应液中。完成后,反应置于30-40℃油浴中搅拌26小时。反应完成后冷却至室温,向其中加入1200毫升水,500毫升乙酸乙酯,混合均匀后分层。水相用1200毫升(600毫升*2)乙酸乙酯萃取。有机相经无水硫酸钠干燥后过滤,低压浓缩得到粗品。粗品经快速硅胶柱(石油醚∶乙酸乙酯=20∶1)纯化得到淡黄色对照例2B(14.13克,58.12毫摩尔,32.19%产率)。
1H NMR(400MHz,CHLOROFORM-d)δ6.99-7.06(m,1H)6.86(d,J=2.01Hz,2H)6.39-6.50(m,2H)3.81(s,6H).
对照例2C
在-60到-50℃下,将磺酰氯(19.61克,145.20毫摩尔)缓慢滴加到对照例2B(14.12克,58.08毫摩尔)的四氢呋喃(140.00毫升)溶液中,搅拌5分钟后,薄层层析板监测反应完成。向反应液中加入200毫升水以淬灭反应,再向其中加入100毫升乙酸乙酯,混合均匀后分液。水相用150毫升乙酸乙酯萃取2次。有机相用无水硫酸钠干燥后过滤,低压浓缩得到淡黄色固体对照例2C(19.53克粗品)。
1HNMR(400MHz,CHLOROFORM-d)δ3.87-3.93(m,6H)6.49-6.55(m,1H)6.85-6.93(m,1H)7.10-7.19(m,1H).
对照例2D
将对照例2C(19.53克,62.60毫摩尔)、双联嚬呐醇醇硼酸酯(16.06克,63.23毫尔)、Pd(dppf)Cl2(4.58克,6.26毫摩尔)和乙酸钾(19.29克,125.20毫摩尔)溶于二氧六环(200毫升)溶液中,氮气置换三次后,反应液在80-90℃搅拌18小时。反应完成后,将反应液冷却至室温后过滤。低压浓缩得到粗品。粗品经快速硅胶柱(石油醚∶乙酸乙酯=10∶1)纯化得到白色固体对照例2D(13.15克,36.62毫摩尔,58.51%产率)。
1HNMR(400MHz,CHLOROFORM-d)δ7.31-7.39(m,1H)6.51(s,1H)6.15(d,J=18.82Hz,1H)3.92(s,6H)1.32(s,12H).
对照例2E
往2氯-5溴嘧啶(10克,51.70毫摩尔),对照例2D(20.42g,56.87mmol),Pd(dppf)Cl2(3.78g,5.17mmol),K3PO4(21.95g,103.40mmol)的混合物中加入二氧六环(100.00mL),水(20.00mL)。反应液在100℃搅拌21个小时。点板显示原料反应完毕,加水(100毫升),用乙酸乙酯(100毫升X3)萃取3次,合并有机相,无水硫酸钠干燥,过滤旋干,残余物通过快速硅胶柱纯化得到黄色固体对照例2E(7.56g,17.50mmol,33.85%收率,80%纯度)。
对照例2F
10℃条件下,将氯乙酰氯(18.23克,161.42毫摩尔)的乙酸乙酯(30.00mL)溶液滴加到4-氟-2-甲基苯胺(20.00克,159.82毫摩尔)的乙酸乙酯(160.00mL)和碳酸钠(16.94克,159.82毫摩尔)混悬液中,滴加完成后,该温度下搅拌30分钟;反应完成,加水,乙酸乙酯(30毫升X3)萃取,结合有机层依次用水(20毫升X2)和饱和食盐水(30毫升)洗涤,无水硫酸钠干燥,过滤,真空浓缩,得到对照例2F未进行纯化,直接用于下一步。
1HNMR(400MHz,CHLOROFORM-d)δ8.14(br.s.,1H),7.74(dd,J=5.5,9.5Hz,1H),7.01-6.89(m,2H),4.32-4.20(m,2H),2.35-2.25(m,3H).
对照例2G
0℃条件下,将硝酸(13.39克,146.61毫摩尔)慢慢滴加到对照例2A(29.56克,146.61毫摩尔)的硫酸(150毫升)溶液中,滴加完成后,该温度下搅拌30分钟;反应完成,反应液慢慢倒入到不停搅拌的冰水中,马上析出大量浅紫色固体,过滤,滤饼用水多次冲洗,得到浅紫色对照例2G(34克)未进一步纯化,直接用于下一步。
1HNMR(400MHz,CHLOROFORM-d)δ8.99(br.s.,1H),8.67(d,J=7.0Hz,1H),8.29(br.s.,1H),7.61(dd,J=2.5,7.0Hz,1H),7.30(dd,J=2.5,8.0Hz,1H),7.17(d,J=11.5Hz,1H),4.76(br.s.,1H),4.27(s,2H),4.22(s,1H),2.40(s,3H),2.35(s,2H)
对照例2H
将氢氧化钠水溶液(4摩尔,229.19毫升)加入到对照例2G(34克,137.86毫摩尔)的四氢呋喃(5毫升)溶液中,反应液加热到95℃搅拌2小时;反应完成,冷却,向反应液中加入乙酸乙酯(50毫升)和水(50毫升),乙酸乙酯(100毫升X 5)萃取,结合有机层依次用水(20毫升X 2)和饱和食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱纯化得到黄色固体对照例2H(4.91克,28.86毫摩尔)。
1HNMR(400MHz,DMSO-d6)δ7.65(dd,J=2.3,9.3Hz,1H),7.39(d,J=8.0Hz,1H),7.25-7.05(m,1H),2.23(s,3H).
对照例2I
将Pd(dba)2(169.05毫克,294.00微摩尔),XPhos(280.31毫克,588.00微摩尔)和碳酸钾(1.22克,8.82毫摩尔)加入到对照例2H(500.00毫克,2.94毫摩尔)和对照例2E(1.32克,3.82毫摩尔)的叔丁醇(5.00毫升)溶液中,该混悬液在氮气保护下,加热到110℃,搅拌4小时;反应完成,冷却,过滤,滤液真空浓缩,残余物通过快速硅胶柱纯化得到浅黄色固体产物(2.90克,6.05毫摩尔)。1HNMR(400MHz,CHLOROFORM-d)δ8.55(s,2H),7.75(s,1H),7.62(dd,J=2.9,7.9Hz,1H),7.31(dd,J=2.8,8.3Hz,1H),7.09-6.87m,2H),6.54(s,1H),3.95(s,6H),2.36(s,3H).
LCMS(ESI)m/z:479.0[M+1]+
对照例2J
将N-甲基哌嗪(714.75毫克,6.26毫摩尔)加入到对照例2I(300毫克,625.93微摩尔)的二甲基亚砜(3毫升)溶液中,135℃搅拌18小时。反应完成后冷却至室温,向反应液中加入30毫升乙酸乙酯和35毫升水,混合均匀后分液。水相用15毫升乙酸乙酯萃取2次,有机相用无水硫酸钠干燥,过滤低压浓缩得到粗品。粗品经快速硅胶柱分离(二氯甲烷∶甲醇=15∶1-10∶1),并经薄层层析制备板(二氯甲烷∶甲醇=10∶1)再次纯化得到黄色固体标题对照例2J(20毫克,34.88毫摩尔,5.57%产率)。
LCMS(ESI)m/z:573.3[M+1]+
对照例2K
15Psi氢气压下,将Raney-Ni(400毫克,4.67毫摩尔)加入到对照例2J(20毫克,34.88微摩尔)的乙醇(2毫升)和四氢呋喃(2毫升)混合溶液中,反应液在5-10℃搅拌10分钟。LCMS显示反应完成后,将反应液过滤,低压浓缩即得黄色固体对照例2K(15.00毫克粗品)。
LCMS(ESI)m/z:543.1[M+1]+
对照例2
冰浴下,向对照例2K(15毫克粗品)的二氯甲烷(2毫升)溶液中依次滴加N,N-二异丙基乙胺(7.13毫克,55.20微摩尔)和丙烯酰氯(2.50毫克,27.60微摩尔)。反应液在0℃搅拌15分钟。LCMS监测反应完成后,向反应液中加入10毫升乙酸乙酯和15毫升水。混合均匀后静置分层,将水相用10毫升乙酸乙酯萃取3次,有机相用无水硫酸钠干燥后过滤,低压浓缩得粗品。粗品经液相高效色谱分离(三氟乙酸-乙腈)并冻干即可得到黄色固体对照例2(3.00毫克,5.02微摩尔,18.19%产率)。
LCMS(ESI)m/z:597.1[M+1]+
1H NMR(400MHz,METHANOL-d4)δ1.44(t,J=7.40Hz,3H)2.27(s,3H)3.12-3.31(m,6H)3.68-3.78(m,2H)3.94-4.00(m,8H)5.78(dd,J=10.04,1.76Hz,1H)6.30-6.37(m,1H)6.42-6.51(m,1H)6.83(s,1H)6.93-7.02(m,2H)7.25(d,J=16.81Hz,1H)7.34-7.42(m,1H)8.65-8.88(m,2H).
流程C
对照例3
对照例3A
向对照例2E(300.00毫克,868.03微摩尔,1.00当量)和实施例20E(300.00毫克,1.14毫摩尔,1.31当量)的N-甲基吡咯烷酮(6毫升)溶液中加入碳酸氢钠(150.22毫克,1.79毫摩尔,2.06当量),于100℃反应18个小时。薄层色谱法和液质连用仪检测反应完全,反应液用20毫升水稀释,乙酸乙酯(15毫升每次)萃取2遍,饱和食盐水(10毫升每次)洗涤两遍。有机相用无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱纯化(石油醚/乙酸乙酯=1/0到4/1)得到黄色固体对照例3A(178.00毫克,收率:40.10%)
LCMS(ESI)m/z:511.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.49(s,3H),6.95-7.02(m,2H),6.85-6.92(m,2H),6.52(s,2H),5.61(br s,1H),5.21(br s,1H),4.98(br s,1H),4.75(quin,J=6.52Hz,1H),4.46(br s,1H),4.18(dd,J=6.52,9.02Hz,1H),4.07-4.15(m,4H),3.94(s,9H),3.65-3.73(m,2H),2.04(s,4H),1.39(s,8H).
对照例3B
向对照例3A((40.00毫克,78.22微摩尔,1.00当量)中加入盐酸乙酸乙酯溶液(4摩尔,5毫升,255.69当量),于30℃下反应1小时。液质连用仪检测原料有剩余,反应液继续于100℃下反应16小时。液质连用仪检测反应完全,反应经过滤,真空浓缩,得到黄色固物对照例3B(30.00毫克)直接用于下一步。
LCMS(ESI)m/z:411.0[M+1]+
对照例3
在0℃,向对照例3B(30.00毫克,72.94微摩尔,1.00当量)和N,N-二异丙基乙胺(19.70毫克,152.45毫摩尔,26.63微升,2.09当量)的二氯甲烷(4毫升)溶液中加入丙烯酰氯(0.25摩尔每升,150.00微升,0.51当量),并在0℃下反应0.5小时。液质连用仪检测原料有剩余,继续于0℃下反应1小时。液质连用仪检测反应完全,反应液用水(15毫升)淬灭,用二氯甲烷(10毫升每次)萃取3遍,有机相用无水硫酸钠干燥,过滤,真空浓缩,高效液相色谱法纯化(三氟乙酸体系:柱子:Boston Green ODS150*30 5u;流动相:[水(0.1%三氟乙酸)-乙腈];B%:36%-46%,8min),冷冻干燥,得到白色固体对照例3(6.00毫克,收率:17.68%.)
LCMS(ESI)m/z:465.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.51(br s,2H),6.99-7.05(m,1H),6.85-6.92(m,1H),6.54(s,1H),6.41(br s,1H),6.22-6.28(m,1H),6.03-6.11(m,1H),5.64(d,J=9.03Hz,1H),4.78-4.88(m,2H),4.19(td,J=6.43,9.47Hz,2H),3.91-3.96(m,6H),3.74-3.86(m,3H).
流程X
对照例4
对照例4A
(3R,4R)-3-[(5-溴嘧啶-2-基)胺]四氢-2H-吡喃-4-醇(600.00mg,2.19mmol,)溶于干燥四氢呋喃中(10mL)中,一次性加入三苯基膦(861.19毫克,3.29毫摩尔),再慢慢加入DIAD(663.93毫克,3.29毫摩尔)。反应液在20℃反应3个小时。反应液浓缩干得到粗品,粗品经快速硅胶柱(石油醚∶乙酸乙酯=3/1-1/1)纯化,得到粗品对照例4A(黄色固体,1.3克)。
LCMS(ESI)m/z:402.8,404.8[M+1]+
对照例4B
将对照例4A(400毫克,0.99毫摩尔),溶于含二氧六环(3mL)的单口瓶(50mL)中,再加入双联频钠醇硼酸酯(305毫克,1.2毫摩尔),Pd2(dba)3(90.84毫克,0.1毫摩尔),KOAc(196毫克,2.0毫摩尔),三环己基膦(55.64毫克,0.2毫摩尔),置换3次氮气,然后将反应液在氮气的保护下,90℃的温度下搅拌12小时。将反应液过滤,滤液减压旋干得对照例4B粗品(600毫克)直接用于下一步。
LCMS(ESI)m/z:369.1[M+1]+
对照例4C
对照例4B(550毫克,粗品)溶于四氢呋喃(10mL)中,然后加入双氧水(0.22mL,30%),在室温(15-20℃)下,搅拌2小时。加水10毫升水淬灭,用乙酸乙酯(20毫升×2)萃取,合并有机层,再用饱和食盐水(30毫升)洗涤,无水硫酸钠干燥,过滤,真空浓缩得粗品。粗品经制备板(石油醚∶乙酸乙酯=1/1)分离纯化,得对照例4C(白色固体,200毫克,39%收率)。
LCMS(ESI)m/z:341.1[M+1]+
对照例4D
将对照例4C(170毫克,0.5毫摩尔)溶于含乙腈(5mL)的单口瓶(50mL)中,再加入(2,6-二氟-3,5-二甲氧基苯基)甲基甲烷磺酸(183毫克,0.65毫摩尔),Cs2CO3(325.5毫克,1.0毫摩尔),置于80-90℃下,反应2小时。反应液过滤,滤液浓缩得粗品,粗品经制备板(洗脱剂PE∶EA=1/1)分离纯化,得对照例4D(白色固体,140毫克,43.65%收率)。
LCMS(ESI)m/z:527.1[M+1]+
对照例4E
将对照例4D(100毫克,0.19毫摩尔)溶于乙醇(4.00mL)中,然后水合肼(0.1毫升),将反应液在80-90℃的温度下搅拌2小时。反应液直接真空浓缩,得到粗品,往其中加入二氯甲烷(5毫升)并搅拌5分钟,过滤得到的滤液再浓缩得到粗品。粗品经制备板(洗脱剂DCM/MeOH=10/1)分离纯化,得对照例4E(无色油状物,45毫克,59.77%收率)
LCMS(ESI)m/z:397.1[M+1]+
对照例4
将对照例4E(35毫克,88微摩尔)溶于含二氯甲烷(3mL)的单口瓶(50毫升)中,再加入DIEA(23毫克,176微摩尔),将丙酰氯用二氯甲烷稀释(0.42毫升,0.25摩尔/升)并滴加,10-15℃下搅拌30分钟。加水10毫升水淬灭,用二氯甲烷(20毫升)萃取,合并有机层,再用饱和食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过制备板分离(DCM∶MeOH=10∶1)纯化得到对照例8(白色固体,18毫克,41.53%收率)。
LCMS(ESI)m/z:451.2[M+1]+
1H NMR(400MHz,METHANOL-d4)δ8.03(s,2H),6.81(t,J=8.3Hz,1H),6.13-5.88(m,2H),5.49(dd,J=2.6,9.4Hz,1H),5.00(t,J=1.5Hz,2H),4.31(br s,1H),4.14(td,J=4.1,11.4Hz,1H),3.87(td,J=3.6,11.5Hz,1H),3.77(s,6H),3.75-3.71(m,1H),3.58(dd,J=2.0,11.8Hz,1H),3.47(dt,J=2.8,11.4Hz,1H),1.39-1.27(m,2H)
如下对照例7和对照例8参考对照例4中描述的方法制备。
流程Y
对照例5
对照例5A
在0℃条件下,向2,6-二氯-3,5-二甲氧基苯甲醛(1.00克,4.25毫摩尔)的乙醇(15.00毫升)溶液中分批加入NaBH4(321.56毫克,8.50毫摩尔)。在0℃条件下反应1小时,接着在15℃条件下反应16h。反应结束后于反应液中加入饱和NH4Cl溶液(1毫升),然后用乙酸乙酯萃取(2×10毫升),饱和食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到粗品对照例5A(1.00克,收率99.25%)。1H NMR(400MHz,CHLOROFORM-d)δ6.56(s,1H),5.00(d,J=7.2Hz,2H),3.93(s,6H),2.16(t,J=7.2Hz,1H).
对照例5B
在0℃条件下,向对照例5A(1.00克,4.22毫摩尔)和三乙胺(640.53毫克,6.33毫摩尔)的二氯甲烷(20.00毫升)溶液中逐滴滴加甲烷磺酰氯(580.0毫克,5.06毫摩尔)。反应液于0℃下搅拌反应1小时。反应结束后加入水(10毫升)淬灭反应。然后使用二氯甲烷(2×10毫升)萃取水相。合并有机相,有机相用饱和的食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到对照例5B(1克,收率:96.9%)。
1H NMR(400MHz,CHLOROFORM-d)δ=6.64(s,1H),5.56(s,2H),3.94(s,6H),3.09(s,3H).
对照例5C
将对照例5B(447.2毫克,3.43毫摩尔),4-氯,5-羟基嘧啶(447.2毫克,3.43毫摩尔)和碳酸铯(2.23克,6.85毫摩尔),加入乙腈(15.00毫升)中。然后将反应用油浴加热到回流。搅拌1.0h后,经LCMS检测反应完成。加水(10毫升)稀释,调节pH反应液pH为9。有机相用水洗涤至中性,然后使用饱和的食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到对照例5C(1.02克,收率85.1%)。
1H NMR(400MHz,CHLOROFORM-d)δ8.40(s,2H),6.64(s,1H),5.43(s,2H),3.95(s,6H).
对照例5D
将对照例5C(300.00毫克,0.86毫摩尔),2-甲基-6-硝基苯胺(195.85毫克,1.29毫摩尔),Pd2(dba)3(39.29毫克,42.91微摩尔),XPhos(81.82毫克,171.62微摩尔),碳酸铯(559.19毫克,1.72毫摩尔)和DMA(6.00毫升)。依次置于100毫升的装有回流冷凝管的单口烧瓶中,用氮气置换三次后,将该反应混合物用油浴加热到110℃并反应3小时。反应冷却到室温后,过滤反应液,并向反应液中加入水(10毫升)。然后用乙酸乙酯萃取(10毫升×2),合并的有机相依次用水(10毫升),饱和的食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相:0~25%乙酸乙酯/石油醚)纯化得到白色固体对照例5D(220毫克,,收率:55.1%)。
LCMS(ESI):m/z=465.0,467.0[M+1]+.
1H NMR(400MHz,CHLOROFORM-d)δ8.13(s,2H),7.90(s,1H),7.80(d,J=8.0Hz,1H),7.44(d,J=7.6Hz,1H),7.14(t,J=7.6Hz,1H),6.54(s,1H),5.24(s,2H),3.86(s,6H),2.23(s,3H).
对照例5E
在20℃条件下,将对照例5D(220.00毫克,472.82微摩尔),还原铁粉(132.03毫克,2.36mmol)和氯化铵(126.46毫克,2.36毫摩尔)加入乙醇(8.00毫升)和水(1.60毫升)的混合溶液中,然后将反应用油浴加热到回流,搅拌2小时后,过滤反应液。使用乙酸乙酯萃取反应液(10毫升×2)。合并的有机相用饱和的食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到对照例5E(205.82毫克)
LCMS(ESI):m/z=435.1,437.1[M+1]+.
对照例5
将对照例5E(195.00毫克,447.97μmol),DIEA(173.69毫克,1.34mmol,234.72μL)和DCM(6.00毫升)加入50毫升圆底烧瓶中,并将该溶液用冰水浴冷却至0℃。滴加丙烯酰氯(38.52毫克,425.57μmol,34.70μL)该反应液在0℃反应30min后,经LCMS检测反应完成,加冰水(0.5毫升)萃灭反应并用二氯甲烷萃取(2×10毫升)。合并的二氯甲烷溶液用饱和的食盐水(5毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到残留物。将该粗品采用中性prep-HPLC分离,最终得到目标化合物对照例5(5毫克,收率2.3%)
LCMS(ESI)m/z=489.0,491.0[M+1]+.
1H NMR(400MHz,CHLOROFORM-d)δ=8.25-8.17(m,3H),8.07(br.s.,1H),7.25-7.20(m,1H),7.07(d,J=7.6Hz,1H),6.62(s,1H),6.37-6.29(m,2H),6.23-6.11(m,1H),5.70(d,J=10.4Hz,1H),5.33(s,2H),5.30(s,1H),3.95(s,6H),2.25(s,3H),2.19(s,1H).
流程Z
对照例6
对照例6A
用冰浴将3,5-二甲氧基苯甲醛(1.00g,6.02mmol)的CH3CN(15毫升)溶液冷却至0℃,然后向其中分批加入[2.2.2]辛烷二(四氟硼酸)盐(3.20g,9.03mmol),该反应液在0℃反应1小时后,体系温度缓慢升至15℃,然后继续搅拌16小时。TLC显示原料消失,而且有主要的新点生成。反应液经减压浓缩,得到油状残留物。该残留物用水(10毫升)稀释,然后用饱和的NaHCO3(5%)调节pH=7,经乙酸乙酯萃取(3×10毫升)。合并的乙酸乙酯溶液用饱和的食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到残留物。该粗品再经过快速硅胶柱(流动相:0~30%乙酸乙酯/石油醚)纯化得到浅黄色化合物对照例6A(310毫克,收率:25.5%)。
LCMS(ESI)m/z:202.8[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ10.36(s,1H),6.89(t,J=8.2Hz,1H),3.92(s,6H).
对照例6B
在0℃下,向对照例6A(310毫克,1.53mmol)的乙醇(6.0毫升)溶液中加入硼氢化钠(116毫克,3.06mmol)。该反应液在0℃继续搅拌60分钟(直至没有气体放出)。加入饱和的氯化铵水溶液(5毫升)萃灭反应,减压浓缩除掉大部分乙醇后,用水稀释(20毫升),然后经乙酸乙酯萃取(2×10毫升)。合并的乙酸乙酯溶液用饱和的食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到白色固体对照例6B(290毫克,收率:92.8%)。
对照例6C
在0℃下,向对照例6B(290.00毫克,1.42mmol)和三乙胺(287毫克,2.84mmol)的二氯甲烷(6.0毫升)溶液中缓慢滴加甲烷磺酰氯(195毫克,1.70mmol),该反应液(N2保护)继续在0℃反应1.5小时。加水(5毫升)萃灭反应,分液,水相再经二氯甲烷(2×5毫升)萃取。合并的有机相经饱和的食盐水(5毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到对照例6C(440毫克,粗品)。该粗品不经纯化直接用于下一步反应。
对照例6D
将粗品对照例6C(440毫克,1.56mmol)和2-氯-5-羟基吡啶(203.48毫克,1.56mmol)的CH3CN(8.00毫升)溶液中加入Cs2CO3(762.42毫克,2.34mmol)固体,然后将反应液加热至回流搅拌2小时。经LCMS原料转化完全,有产物生成。待反应液冷却至室温后,加(5毫升)萃灭反应,分液,水相再经乙酸乙酯(2×10毫升)萃取。合并的有机相经饱和的食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到粗品。该粗品经快速硅胶柱(流动相:0~20%乙酸乙酯/石油醚)得到白色固体化合物对照例6D(188.00毫克,收率:33.87%)。
LCMS(ESI)m/z:316.9,318.9[M+1]+
对照例6E
将对照例6D(188毫克,594μmol,),2-甲基-6-硝基苯胺(135毫克,890μmol),Pd(dba)2(34毫克,59μmol),XPhos(56毫克,118μmol),Cs2CO3(386.84毫克,1.19mmol)和DMA(4.0毫升)依次置于20毫升的密闭管中,用氮气置换三次后,将该反应混合物加热到110℃并反应3小时。反应经TLC检测原料完全转化,待反应冷却到室温后,用水稀释(10毫升),然后用乙酸乙酯萃取(3×10毫升)。合并的有机相用饱和的食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相:0~40%乙酸乙酯/石油醚)纯化得到黄色固体化合物对照例6E(202毫克,,收率:78.70%)。
LCMS(ESI)m/z:433.0[M+1]+
对照例6F
在室温条件下,将还原铁粉(129毫克,2.31mmol)和NH4Cl(124毫克,2.31mmol)加入到化合物对照例6E(200毫克,463μmol)的EtOH(5.0毫升)和H2O(1.0毫升)的混合溶液中,然后将反应用油浴加热到回流,搅拌1.0小时。过滤,滤液经减压浓缩得到粗品。该固体用乙酸乙酯(20毫升)稀释,然后用饱和的碳酸氢钠水溶液调剂pH=8,分液,水相用乙酸乙酯(10毫升×2)萃取。合并的乙酸乙酯相经饱和食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液经减压浓缩得到浅黄色固体对照例6F(180.00毫克,收率:96.71%)。
LCMS(ESI)m/z:403.0[M+1]+
对照例6
在0℃下,将丙烯酰氯(40毫克,448μmol)加入对照例6F(180毫克,447μmol)和N-乙基二异丙基胺(116毫克,895μmol)的二氯甲烷(5.0毫升)溶液中,该反应在0℃搅拌30分钟。经LCMS显示反应完成。加冰水(2毫升)萃灭反应,然后经乙酸乙酯萃取(2×5毫升)。合并的有机溶剂用饱和的食盐水(5毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到残留物。该残留物经过快速硅胶柱分离(流动相:0~50%乙酸乙酯/石油醚)得到浅黄色化合物对照例6(155毫克,收率:74.4%)。LCMS(ESI)m/z:457.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.22(br.s.,1H),8.16(s,2H),8.04(d,J=6.0Hz,1H),7.22(t,J=8.0Hz,1H),7.06(d,J=7.6Hz,1H),6.67(t,J=8.0Hz,1H),6.45(br.s.,1H),6.36-6.28(m,1H),6.20-6.11(m,1H),5.68(d,J=11.2Hz,1H),5.12(s,2H),3.88(s,6H),2.22(s,3H).
流程D
实施例1
实施例1A
在室温条件下(28℃),将水合肼(18.1克,361毫摩尔)滴入3,5-二甲氧基苯甲醛(20克,120毫摩尔)。在室温条件下,搅拌2小时后,经TLC检测3,5-二甲氧基苯甲醛没有反应完全,延长反应时间。继续反应16小时后,向反应瓶中加入乙二胺(21.70克,361毫摩尔)和氯化亚铜(1.19克,12.04毫摩尔)。搅拌30分后,反应液置于冰浴冷却至0℃后,将三溴氟甲烷(81.46克,301毫摩尔)的乙醇(30毫升)溶液经恒压滴液漏斗滴加到反应液中(在滴加过程中有少量气体放出)。滴加完毕后,该反应在0℃下搅拌1小时后,缓慢升至室温(28℃)然后再继续反应1小时。待中间体E-3,5-二甲氧基苯腙完全反应后,过滤,固体用乙酸乙酯洗涤,滤液经减压浓缩蒸除大部分溶剂。用乙酸乙酯(200毫升)稀释,并用柠檬酸(1M,50毫升)水溶液洗涤,分液,水相然后用乙酸乙酯萃取(3×100毫升)。合并的有机相用饱和的食盐水(150毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相:0~15%乙酸乙酯/石油醚)纯化得到浅黄色液体实施例1A(18.86克,收率:60%)。
1H NMR(400MHz,CHLOROFORM-d)δ6.56(d,J=2.4Hz,2H),6.43-6.39(m,1H),5.92(d,J=32.4Hz,1H),3.80(s,6H).
实施例1B
将实施例1A(18.86克,72.24毫摩尔)的无水四氢呋喃(360毫升)溶液冷却到-20℃。然后缓慢滴加磺酰氯(24.38克,180.6毫摩尔,18.1毫升),滴加完毕后,该反应液在-20℃继续反应1小时。加水(20毫升)萃灭反应,用5%碳酸氢钠水溶液中和到pH=7。然后用乙酸乙酯萃取(3×100毫升)。合并的有机相经饱和的食盐水(150毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到淡黄色固体实施例1B(21.64克,收率:91%)。
1H NMR(400MHz,CHLOROFORM-d)δ6.56(s,1H),6.11-5.99(d,J=31.6Hz,1H),3.93(s,6H)
实施1C
将实施例1B(600毫克,1.82毫摩尔),3,5-二甲氧基苯硼酸(435毫克,1.82毫摩尔),Pd(dppf)Cl2(133毫克,182微摩尔)和磷酸钾(966毫克,4.55毫摩尔)置于50毫升的密封管中,并分别加入四氢呋喃(9.0毫升)和水(3.0毫升),用氮气置换三次后,将反应液用油浴加热到80℃后反应2小时。反应冷却到室温后,用水稀释(5毫升),然后用乙酸乙酯萃取(2×10毫升)。合并的有机相用饱和的食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相:0~16%乙酸乙酯/石油醚)纯化得到白色固体实施例1C(302毫克,收率:42.6%)LCMS(ESI)m/z:363.8,361.8[M+1]+.
实施例1D
分别将实施例1C(300毫克,827微摩尔),2-甲基-6-硝基苯胺(189毫克,1.24毫摩尔),Pd2(dba)376毫克,微摩尔),Xphos(79毫克,165微摩尔)和N,N-二甲基乙酰胺(6.0毫升)依次置于50毫升的装有回流冷凝管的单口烧瓶中,用氮气置换三次后,将该反应混合物用油浴加热到110℃并反应2小时。反应冷却到室温后,将反应物倒入水中(20毫升),然后用乙酸乙酯萃取(3×10毫升)。合并的有机相依次用水(3×15毫升),饱和的食盐水(15毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相:0~25%乙酸乙酯/石油醚)纯化得到实施例1D(243毫克,收率:71%)。
LCMS(ESI)m/z:363.8,361.8[M+1]+.
实施例1E
在室温条件下,将还原铁粉(142毫克,2.54毫摩尔)加到实施例1D(243毫克,508微摩尔)和氯化铵(136毫克,2.54毫摩尔)的乙醇(95%,6.0毫升)溶液中,然后将反应用油浴加热到回流。搅1.5小时后,反应液趁热过滤,固体用乙醇冲洗,滤液经减压浓缩得到棕色固体。将固体分配到加乙酸乙酯(20毫升)和水(10毫升)中,在加饱和碳酸氢钠调节到pH=9。水相然后用乙酸乙酯萃取(2×5.0毫升)。合并的有机相用饱和的食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相:0~40%乙酸乙酯/石油醚)纯化得到粗品实施例1E(41毫克)。LCMS(ESI)m/z:448.0,450.0[M+1]+.
实施例1
将实施例1E(41毫克,89微摩尔),N,N-二异丙基乙基胺(23毫克,178微摩尔)和二氯甲烷(2.0毫升)加入50毫升圆底烧瓶中,并将该溶液用冰水浴冷却至0℃。滴加丙烯酰氯(7.3毫克,80微摩尔),该反应液在0℃反应30分钟后,经LCMS检测反应完成,加冰水(2.0毫升)萃灭反应,加入5.0毫升二氯甲烷稀释。并用二氯甲烷萃取(2×5.0毫升)。合并的二氯甲烷溶液用饱和的食盐水(5.0毫升)洗涤,后处理得到粗品。该粗品再经过制备高效液相色谱(三氟乙酸体系)分离得到目标化合物实施例1(5.0毫克,收率:11%)。
LCMS(ESI)m/z:502.1,504.1[M+1]+.
1H NMR(400MHz,CHLOROFORM-d)δ11.30(br.s.,1H),8.31(br.s.,1H),8.21(d,J=1.6Hz,1H),8.00(dd,J=8.8,8.8Hz,2H),7.34(dd,J=8.0,8.0Hz,1H),7.13(d,J=7.6Hz,1H),6.61-6.57(m,1H),6.53(d,J=9.6Hz,1H),6.42-6.36(m,1H),6.32-6.20(m,2H),5.75(d,J=10.0Hz,1H),3.98-3.93(m,6H),2.24(s,3H)
如下实施例如实施例1中描述的方法制备。
流程E
实施例2
实施例2A
实施例1A(2.00克,6.06毫摩尔)、双联频那醇硼酸酯(3.08克,12.12毫摩尔)和乙酸钾(1.78克,18.2毫摩尔)的二氧六环(30毫升)的混合物中加入Pd(dppf)Cl2·CH2Cl2(495毫克,606微摩尔),该反应液用氮气置换3次,然后在氮气保护下于90℃搅拌16小时。经TLC检测反应完成,待反应物冷却至室温之后,然后用该混合物用乙酸乙酯稀释,过滤,滤液经减压浓缩得到粗品。该粗品经快速硅胶柱分离(石油醚∶乙酸乙酯=0%-20%),得到白色固体化合物实施例2A(2.25克,收率:98.5%)。1H NMR(400MHz,CHLOROFORM-d)δ6.57-6.41(m,2H),3.92(s,6H),1.36(s,12H).
实施例2B
2-氯嘧啶(3.00克,26.19毫摩尔),2-甲基-6-硝基苯胺(3.98克,26.2毫摩尔),Pd2(dba)3(1.20克,1.31毫摩尔),Xphos(1.25克,2.62毫摩尔),碳酸铯(17.07克,52.4毫摩尔)的N,N-二甲基乙酰胺(100毫升)混合液经氮气置换3次后,氮气保护下在100℃下搅拌3小时。加水100毫升水淬灭,用乙酸乙酯(100毫升×3)萃取,合并有机层再用饱和食盐水(150毫升×2)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例:5/1)纯化得到黄色固体标题化合物实施例2B(4.50克,收率:74.6%)。
LCMS(ESI)m/z:231.0[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.37(d,J=4.8Hz,1H),7.92(br.s.,1H),7.86(d,J=8.4Hz,1H),7.53(d,J=7.2Hz,1H),7.26-7.30(m,1H),6.74(m,1H),2.33(s,3H).
实施例2C
向实施例2B(500毫克,2.17毫摩尔)的氯仿(5毫升)溶液中,加NBS(425毫克,2.39毫摩尔),真空浓缩,残余物通过快速硅胶柱(石油醚/乙酸乙酯比例:5/1)纯化得到棕色固体标题化合物实施例2C(640毫克,收率:95.4%)。
LCMS(ESI)m/z:310.9,312.9[M+1]+
实施例2D
实施例2C(640毫克,2.07毫摩尔)的乙醇(10毫升)溶液中加入铁粉(578毫克,10.4毫摩尔),氯化铵(554毫克,10.4毫摩尔),在90℃下搅拌2小时。过滤,真空浓缩,残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例:3/1)纯化得到黄色固体化合物实施例2D(423毫克,收率:73.4%)。
1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.37(br.s.,2H),6.85(dd,J=7.6,7.6Hz,1H),6.56(d,J=7.6Hz,1H),6.42(d,J=7.2Hz,1H),4.71(s,2H),1.96-2.05(m,3H).
实施例2F
实施例2D(373毫克,1.34毫摩尔),实施例2A(606毫克,1.34毫摩尔),Pd2(dba)3(122毫克,133微摩尔),Xphos(127毫克,267微摩尔),磷酸钾(567毫克,2.67毫摩尔)的乙腈(3.0毫升)和水(1.0毫升)的混合液经氮气置换3次后,氮气保护下在100℃下搅拌2小时。加水10毫升水淬灭,用乙酸乙酯(10毫升×3)萃取,合并有机层再用饱和食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例:3/1)纯化得到黄色油状化合物实施例2F(250毫克,收率:41.5%)。
LCMS(ESI)m/z:449.2,451.2[M+1]+
1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.51-8.80(m,2H),6.92(s,1H),6.88(dd,J=7.6,7.6Hz,1H),6.49-6.64(m,2H),6.45(d,J=7.2Hz,1H),4.74(br.s.,2H),3.82-3.99(m,6H),2.00-2.07(m,3H)
实施例2
向实施例2F(250毫克,556微摩尔)的二氯甲烷(5.0毫升)溶液中,0℃加N,N-二异丙基乙基胺(180毫克,1.39毫摩尔)和丙烯酰氯(50毫克,556微摩尔),在0℃下搅拌30分钟。加水10毫升水淬灭,用二氯甲烷(10毫升×2)萃取,合并有机层,真空浓缩,残余物通过制备HPLC(三氟乙酸体系)纯化得到化合物实施例2(66毫克,收率:23.1%)。
LCMS(ESI)m/z:503.1,505.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.86(s,1H),8.70(br.s.,1H),7.72(d,J=7.6Hz,1H),7.15-7.25(m,1H),7.09(d,J=7.6Hz,1H),6.88-6.96(m,1H),6.64(s,1H),6.47-6.59(m,1H),6.22(d,J=17.2Hz,1H),5.71(d,J=10.4Hz,1H),3.93(s,6H),2.13(s,3H).
如下实施例如实施例2中描述的方法制备。
流程F
实施例7
实施例7A
2-氯-5-吡啶甲醛(4.50克,31.8毫摩尔),2-甲基-6-硝基-苯胺(4.84克,31.8毫摩尔),Pd2(dba)3(2.91克,3.18毫摩尔),Xphos(3.03克,6.36毫摩尔)和碳酸铯(20.7克,63.6毫摩尔)的N,N-二甲基甲酰胺(90毫升)混合液经氮气置换3次后,氮气保护下在110℃下搅拌2小时。待反应冷却至室温后,加水(200毫升)水稀释,然后用乙酸乙酯(50毫升×3)萃取。合并有机层依次用水(50毫升×3),饱和食盐水(50毫升)洗涤,无水硫酸钠干燥,过滤,滤液经减压浓缩。残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例:3/1)纯化得到黄色油状化合物实施例7A(4.00克,收率:48.9%)。LCMS(ESI)m/z:257.9[M+1]+
实施例7B
在20℃下,向实施例7A(4.00克,15.6毫摩尔)的乙醇(30毫升)溶液中加入水合肼(2.34克,46.6毫摩尔),该反应在20℃搅拌2小时。经TLC检测原料转化完全。然后向反应溶液中加入乙二胺(2.80克,46.65毫摩尔)和氯化亚铜(154毫克,1.55毫摩尔),在20℃搅拌30分钟。将反应液用冰浴冷却至0℃,然后滴加三溴氟甲烷(10.52克,38.9毫摩尔),在20℃搅拌16小时。加水(100毫升)水稀释,然后用乙酸乙酯(50毫升×3)萃取。合并有机层用饱和食盐水(50毫升)洗涤,无水硫酸钠干燥,过滤,滤液经减压浓缩。残余物通过快速硅胶柱(石油醚/乙酸乙酯比例:10/1)纯化得到黄色固体化合物实施例7B(1.56克,收率:28.5%)。
LCMS(ESI)m/z:352.0,354.0[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.11(d,J=2.4Hz,1H),7.98-8.08(m,1H),7.90(d,J=8.0Hz,2H),7.66(dd,J=2.4,8.8Hz,1H),7.51(d,J=7.2Hz,2H),7.22(dd,J=8.0,8.0Hz,2H),6.49-6.58(m,2H),5.86(d,J=33.2Hz,1H),2.23(s,3H).
实施例7C
实施例实施例7B(1.56克,4.43毫摩尔),3,5-二甲氧基苯硼酸(802毫克,4.43毫摩尔),Pd2(dba)3(406毫克,443微摩尔),Sphos(3641毫克,886微摩尔)和磷酸钾(2.35克,11.1毫摩尔)的乙腈(3.0毫升)/水(1.0毫升)混合液经氮气置换3次后,氮气保护下在90℃下搅拌3小时。加水(30毫升)稀释,用乙酸乙酯(30毫升×3)萃取。合并有机层用饱和食盐水(30毫升)洗涤,无水硫酸钠干燥,过滤,滤液经减压浓缩。残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例:3/1)纯化得到棕色油状化合物实施例7C(1.4克,收率:67.2%)。
LCMS(ESI)m/z:410.1[M+1]+
实施例7D
在-78℃下,向实施例7C(700毫克,1.71毫摩尔)的四氢呋喃(7.0毫升)溶液中,滴加磺酰氯(577毫克,4.28毫摩尔),在-78℃下搅拌1小时。将-20℃加水20毫升水淬灭,用乙酸乙酯(30毫升×3)萃取,合并有机层,再用饱和食盐水(30毫升)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物未进一步纯化得到黄色油状粗品实施例7D(750毫克,粗品)。
LCMS(ESI)m/z:478.2,480.2[M+1]+
实施例7E
向实施例7D(750毫克,1.57毫摩尔)的乙酸乙酯(10毫升)溶液中加入二水合二氯化锡(1.77克,7.85微摩尔),在80℃下搅拌1小时。反应液经饱和碳酸氢钠调节pH至8,用乙酸乙酯(50毫升×3)萃取,合并有机层再用饱和食盐水(100毫升×2)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物未进一步纯化得到黄色固体粗品实施例7E(500毫克,粗品)。
LCMS(ESI)m/z:448.1,450.1[M+1]+
实施例7
在0℃下,向实施例7E(500毫克,1.12毫摩尔)的二氯甲烷(5.0毫升)溶液中依次加N,N-二异丙基乙基胺(362毫克,2.80毫摩尔)和丙烯酰氯(101毫克,1.12毫摩尔),该反应在0℃搅拌2小时。加水20毫升水淬灭,用二氯甲烷(20毫升×3)萃取,合并有机层,再用饱和食盐水(20毫升)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过制备HPLC(TFA条件)纯化,再经过制备薄层分离纯化(石油醚/乙酸乙酯=1/1)得到标题化合物实施例7(24毫克,收率:3.97%)
LCMS(ESI)m/z:502.0,504.0[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.16-8.33(m,3H),7.83(dd,J=8.8,2.0Hz,1H),7.23-7.29(m,1H),7.06(d,J=7.6Hz,1H),6.60-6.65(m,1H),6.28-6.37(m,2H),6.10-6.24(m,2H),5.64-5.81(m,2H),3.94(s,6H),2.21(s,3H)
如下实施例如实施例7中描述的方法制备。
流程G
实施例10
实施例10A
在氮气保护下,将3,5-二甲氧基-苯甲醛(5.00克,30.1毫摩尔)的四氢呋喃(75毫升)溶液至于250毫升的三口烧瓶中,将该溶液用干冰盐浴冷却至-10℃。缓慢滴加MeMgBr(3.0M,15.0毫升)的乙醚溶液,在滴加过程中保持反应液的温度不超过0℃。滴加完毕后将该反应在0℃下搅拌1小时经LCMS检测原料反应完毕,搅拌1小时后,向反应液中加入饱和的氯化铵溶液,然后加入用乙酸乙酯萃取(2×30毫升)。合并的有机相饱和的食盐水(30毫升)萃取,无水硫酸钠干燥,过滤,滤液经减压浓缩得到化合物实施例10A,为浅粉色固体(5.48克,收率:63.6%)。该化合物不经纯化直接用于下一步。
LCMS(ESI)m/z:164.9[M-17]+
1H NMR(400MHz,CHLOROFORM-d)δ6.54(d,J=2.0Hz,2H),6.40-6.35(m,1H),4.84(q,J=6.4Hz,1H),3.83-3.76(m,6H),1.48(d,J=6.4Hz,3H)
实施例10B
在室温条件下(20℃),将活性二氧化锰(41.8克,481毫摩尔)加入到实施例9A(5.48克,30.1毫摩尔)的四氢呋喃(100毫升)溶液中。将该反应置于油浴中加热回流2小时,经TLC和LCMS检测,实施例9A反应完毕产物生成。过滤,固体经四氢呋喃(2×30毫升)洗涤,合并滤液,经减压浓缩得到粗品。该粗品经快速硅胶柱(石油醚∶乙酸乙酯=30∶1-15∶1)纯化得到淡黄色油状物实施例10B(4.55克,收率:84.0%)。
LCMS(ESI)m/z:181.0[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ7.09(d,J=2.4Hz,2H),6.65(t,J=2.4Hz,1H),3.84(s,6H),2.58(s,3H).
实施例10C
在室温条件下(25℃),将一水合肼(4.17克,83.2毫摩尔,4.05毫升)滴入实施例10B(5.00克,27.8毫摩尔)乙醇(50毫升)溶液中。在28℃下,搅拌16小时后,经TLC检测3,5-二甲氧基苯乙酮反应完全向反应瓶中加入乙二胺(5.51克,83.2毫摩尔)和氯化亚铜(275毫克,2.78毫摩尔)。30分钟后,用冰浴冷却至0℃后,将三溴氟甲烷(18.8克,69.4毫摩尔)的乙醇(50毫升)溶液经恒压滴液漏斗滴加到反应液中(在滴加过程中有少量气体放出)。滴加完毕后,该反应在0℃下搅拌1小时后,升至25℃后再反应72小时。待中间体完全反应后,过滤,固体用乙酸乙酯洗涤,滤液经减压浓缩蒸除大部分溶剂。用乙酸乙酯(200毫升)稀释,并用柠檬酸(1M,50毫升)水溶液洗涤,分液,水相然后用乙酸乙酯萃取(3×100毫升)。合并的有机相用饱和的食盐水(150毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相:0~30%乙酸乙酯/石油醚)纯化得到淡黄色油状物实施例10C(1.27克,收率:16.6%)。
LCMS(ESI)m/z:275.0,277.0[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ6.51(s,1H),6.46-6.41(m,1H),3.82(s,6H),2.10-2.06(m,3H)
实施例10D
在氮气保护下,将5-溴-2-氨基-苯胺(10.0克,57.8毫摩尔)的四氢呋喃(200毫升)溶液至于500毫升的三口烧瓶中,将该溶液用干冰浴冷却至0℃。将钠氢(3.47克,86.7毫摩尔,纯度:60%)分批加入到反应液中。搅拌半个小时后,将2-氟-3-甲基硝基苯胺(13.5克,86.7毫摩尔)的四氢呋喃(5.0毫升)溶液缓慢滴加到该反应液中,滴加完毕后,将该反应升至25℃搅拌16小时。LCMS检测大部分原料反应完毕,向反应液中加入水(40毫升)萃灭反应,然后加入用乙酸乙酯萃取(2×50毫升)。合并的有机相饱和的食盐水(100毫升)萃取,无水硫酸钠干燥,过滤,滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相:0~15%乙酸乙酯/石油醚)纯化得到黄色固体实施例10D(10.0克,收率:56.3%)。
LCMS(ESI)m/z:307.8,309.8[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.21(d,J=2.4Hz,1H),7.98(br.s.,1H),7.92(d,J=8.0Hz,1H),7.60(dd,J=8.8,2.4Hz,1H),7.52(d,J=7.6Hz,1H),7.23(t,J=8.0Hz,1H),6.48(d,J=8.4Hz,1H),2.27-2.20(m,3H).
实施例10E
将实施例10D(1.00克,3.25毫摩尔),双联频那醇硼酸酯(990毫克,3.90毫摩尔),Pd(dppf)Cl2(265毫克,325微摩尔)和醋酸钾(638毫克,6.50毫摩尔)置于50毫升的圆底烧瓶中,并分别加入二氧六环(10.0毫升),用氮气置换三次后,将反应液用油浴加热到90℃并反应16小时(氮气保护)。经TLC(石油醚∶乙酸乙酯=5∶1),检测反应物消失。反应冷却到室温后乙酸乙酯稀释(30毫升)。过滤,滤液经减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相:0~30%乙酸乙酯/石油醚)纯化得到黄色固体化合物实施例10E(1.52克,收率:92.2%,纯度:70%)。
实施例10F
向化合物实施例10C(580毫克,2.11毫摩尔)和实施例10E(899毫克,2.53毫摩尔)的二氧六环溶液(6.0毫升)和水(1.8毫升)的混合溶液中加入Pd(dppf)Cl2(71毫克,106微摩尔)和碳酸钾(583毫克,4.22微摩尔),在氮气保护条件下,混合物在100℃下反应16个小时。经TLC和LCMS检测,反应完全。待反应冷却后,加入水(20毫升)和乙酸乙酯(20毫升)稀释,分液后水相用乙酸乙酯(3×10毫升)萃取3遍。合并的有机相用无水硫酸钠干燥,过滤,滤液经减压浓缩得到油状残留物。该残留物经快速硅胶柱(石油醚∶乙酸乙酯=7∶3)纯化得到黄色固体化合物10F(262毫克,收率:29.3%)。
1H NMR(400MHz,CHLOROFORM-d)δ8.36(s,1H),8.07(br.s.,1H),7.92(d,J=8.0Hz,1H),7.68(dd,J=8.4,2.0Hz,1H),7.54(d,J=7.6Hz,1H),7.22-7.28(m,1H),6.56-6.66(m,3H),6.42(t,J=2.0Hz,1H),4.13(q,J=7.2Hz,1H),3.82(s,6H),2.28(s,3H).
实施例10G
将实施例10F(240毫克,567微摩尔)的无水四氢呋喃(6.0毫升)溶液冷却到-20℃。然后缓慢滴加磺酰氯(191毫克,1.42毫摩尔),滴加完毕后,该反应液在-20℃反应1h。经TLC(石油醚∶乙酸乙酯=5∶1),LCMS检测原料完全转化为产物实施例26D。加水(2.0毫升)萃灭反应,用5%碳酸氢钠水溶液中和到pH=7。然后用乙酸乙酯萃取(3×10毫升)。合并的有机相经饱和的食盐水(10毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到淡黄色固体实施例10G(280毫克)。该化合物直接用于下一步。
LCMS(ESI)m/z:491.1,493.9[M+1]+
实施例10H
在室温条件下(20℃)向实施例10G(260毫克,528微摩尔)的乙醇(15.0毫升)溶液中加入雷尼镍(500毫克,5.84毫摩尔)(氮气保护)。该混合物用氢气置换几次后在20℃下搅拌4小时(15psi)。LCMS检测反应物消失。过滤,减压浓缩,得浅黄色固体化合物实施例10H(220毫克,收率:90.1%),该化合物直接用于下一步。
LCMS(ESI)m/z:462.0,464.0[M+1]+
实施例10
将实施例10H(235毫克,508微摩尔),N,N-二异丙基乙基胺(131毫克,1.02微摩尔)和二氯甲烷(5.0毫升)加入50毫升圆底烧瓶中,并将该溶液用冰水浴冷却至0℃。滴加丙烯酰氯(46毫克,508微摩尔),该反应液在0℃反应30分钟后,经LCMS检测反应完成,加冰水(2毫升)萃灭反应,加入5毫升二氯甲烷稀释。并用二氯甲烷萃取(2×5毫升)。合并的二氯甲烷溶液用饱和的食盐水(5毫升)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到残留物。该粗品再经过制备HPLC(三氟乙酸体系)得到目标化合物实施例10(45毫克,收率:17.0%)。
LCMS(ESI)m/z:516.1,518.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ11.18(br.s.,1H),8.49(br.s.,1H),8.15(br.s.,1H),7.99-7.87(m,2H),7.31(t,J=8.0Hz,1H),7.13(d,J=7.6Hz,1H),6.56(s,2H),6.45-6.35(m,1H),6.34-6.23(m,1H),5.75(d,J=10.8Hz,1H),3.94(s,6H),2.23(s,3H),2.04(d,J=2.8Hz,3H).
流程H
实施例26
实施例26A
2-甲基-6-硝基苯胺(13.28克,87.31毫摩尔),2-氯嘧啶(10.00克,87.31毫摩尔),Pd2(dba)3(4.00克,4.37毫摩尔),XPhos(4.16克,8.73毫摩尔)和Cs2CO3(56.90克,174.62毫摩尔)加入到DMA(250.00mL)中,置换3次氮气,然后将反应液在氮气的保护下,100℃的温度下搅拌3小时。反应液倒入250毫升冰水,用EtOAc(200毫升×3)萃取,合并有机层再用水(50毫升×3)洗涤,饱和食盐水(50毫升)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱(石油醚/乙酸乙酯:5/1)纯化得到棕色固体标题化合物实施例26A(11.00克,54.72%收率)。
LCMS(ESI)m/z:230.9[M+1]+
实施例26B
实施例26A(500.00毫克,2.17毫摩尔),NBS(424.84毫克,2.39毫摩尔)加入到氯仿(5.00mL)中,然后将反应液在30℃的温度下搅拌16小时。反应液直接真空浓缩,残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例:5/1)纯化得到黄色固体实施例26B(540.00毫克,80.50%收率)。
LCMS(ESI)m/z:310.8[M+3]+
1H NMR(400MHz,CHLOROFORM-d)δ8.37(s,2H),7.89(br s,1H),7.83-7.88(m,1H),7.54(d,J=7.53Hz,1H),7.28(t,J=8.03Hz,1H),2.32(s,3H).
实施例26C
实施例16D(2.00克,6.47毫摩尔),实施例26B(3.66克,9.71毫摩尔),磷酸钾(2.75克,12.94毫摩尔),Pd(dppf)Cl2(473.41毫克,647.00微摩尔)加入到二氧六环(30.00毫升)和水(10.00毫升)的混合溶液中,置换3次氮气,然后将反应液在氮气的保护下,100℃的温度下搅拌16小时。反应液倒入50毫升冰水,用EtOAc(30毫升×3)萃取,合并有机层用饱和食盐水(20毫升)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例:3/1)纯化得到黄色固体实施例26C(2.40克,77.39%收率)。
LCMS(ESI)m/z:479.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.63(s,2H),8.02(s,1H),7.88(d,J=7.53Hz,1H),7.55(d,J=7.53Hz,1H),7.27-7.31(m,1H),6.65(s,1H),5.61-5.79(m,1H),3.95(s,6H),2.35-2.37(m,3H).
实施例26D
实施例26C(1.10克,2.30毫摩尔),NBS(1.23克,6.90毫摩尔),加入到醋酸(10.00mL)中,在60℃的温度下搅拌16小时。反应液用碳酸钠水溶液调pH=7,倒入30毫升冰水,用EtOAc(20毫升×3)萃取,合并有机层再用饱和食盐水(10毫升×2)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱(石油醚/乙酸乙酯比例:3/1)纯化得到标题化合物实施例26D(370.00毫克,28.82%收率)。
LCMS(ESI)m/z:558.9[M+3]
实施例26E
实施例26D(200.00毫克,358.31微摩尔),1-乙酰基-哌嗪(91.85毫克,716.62微摩尔),Pd2(dba)3(32.81毫克,35.83微摩尔),XPhos(34.16毫克,71.66微摩尔)和Cs2CO3(233.49毫克,716.62微摩尔)加入到DMA(5.00mL)中,置换3次氮气,然后将反应液在氮气的保护下,120℃的温度下搅拌2小时。反应液倒入10毫升冰水,用EtOAc(10毫升×3)萃取,合并有机层再用水(5毫升×3)洗涤,饱和食盐水(5毫升)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱(石油醚/乙酸乙酯比例:1/1)纯化得到乳白色固体标题化合物实施例26E(70.00毫克,32.27%收率)。
LCMS(ESI)m/z:605.1[M+1]
实施例26F
向实施例26E(80.00毫克,132.13微摩尔)的乙醇(1.00毫升)中加入Raney-Ni(11.32毫克,132.13微摩尔),置换3次氢气,然后在氢气(15psi)的条件下,30℃的温度下搅拌0.5小时。反应液经过滤,真空浓缩,残余物未进一步纯化得到固体粗品实施例26F(68.00毫克,粗品)。
LCMS(ESI)m/z:575.0[M+1]
实施例26
向实施例26F(68.00毫克,118.17微摩尔)的二氯甲烷(2毫升)溶液中,0℃加DIEA(30.54毫克,236.33微摩尔)和丙烯酰氯(10.70毫克,118.17微摩尔),在0℃下搅拌20分钟。加水10毫升水淬灭,用二氯甲烷(10毫升×3)萃取,合并有机层,再用饱和食盐水(5毫升×2)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过制备HPLC(碱性条件)纯化得到标题化合物实施例26(18毫克,24.20%收率)。
LCMS(ESI)m/z:629.3[M+1]
1H NMR(400MHz,CHLOROFORM-d)δ8.63(s,2H),8.04(br s,1H),7.84(br s,1H),6.65(s,1H),6.62(d,J=2.51Hz,1H),6.47(s,1H),6.38(d,J=1.25Hz,1H),6.12-6.21(m,1H),5.72-5.75(m,1H),5.64-5.71(m,1H),3.95(s,6H),3.72-3.78(m,2H),3.57-3.63(m,2H),3.23(td,J=5.11,15.87Hz,4H),2.20(s,3H),2.14(s,3H)
如下实施例如实施例26中描述的方法制备。
流程I
实施例13
实施例13A
实施例13A的合成方法如对照例2H
实施例13B
实施例13A(400毫克,2.35毫摩尔),2-氯嘧啶(269毫克,2.35毫摩尔),Pd2(dba)3(107毫克,0.12毫摩尔),Xphos(112毫克,0.24毫摩尔),K2CO3(974毫克,7.05毫摩尔)在甲苯溶液中(4mL),N2置换3次后,加热到110℃搅拌12小时。点板显示原料消耗完毕。反应液中加入20mL水,乙酸乙酯萃取(20毫升X3)3次,合并有机相,旋干得粗品,经柱层析纯化得到实施例13B(470毫克,80.58%收率)。
1H NMR(400MHz,CHLOROFORM-d)δ8.40(d,J=5.0Hz,2H),8.30(br s,1H),7.97(dd,J=5.6,9.2Hz,1H),7.12-7.00(m,1H),6.80(t,J=4.9Hz,1H).
实施例13C
实施例13B(530毫克,2.14毫摩尔)溶解在氯仿溶液中(7mL),加入NBS(419毫克,2.35毫摩尔)室温下搅拌16小时。点板显示原料消耗完毕。反应液浓缩得粗品,经快速硅胶柱(石油醚∶乙酸乙酯=5∶1)纯化得到黄色固体实施例13C(460毫克,65.71%收率)。
1H NMR(400MHz,CHLOROFORM-d)δ8.40(s,2H),8.25(br s,1H),7.98(dd,J=5.5,9.3Hz,1H),7.11-6.98(m,1H).
实施例13D
实施例13C(1.15克,3.52毫摩尔)的DMSO(10毫升)加入分批乙基哌嗪(4.02克,35.20毫摩尔),在130℃下搅拌16小时。反应液倒入200毫升水,用乙酸乙酯(200毫升×3)萃取,合并有机层再用饱和食盐水(300毫升×2)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱(二氯甲烷/甲醇:10/1)纯化得到黄色油状标题化合物实施例13D(1.30克,87.66%收率)。
1H NMR(400MHz,CHLOROFORM-d)δ8.38(s,2H),8.36(s,1H),7.96(d,J=9.04Hz,1H),6.89(d,J=9.04Hz,1H),3.12(t,J=4.64Hz,4H),2.63(br s,4H),2.50(q,J=7.28Hz,2H),2.18(s,3H),1.13(t,J=7.16Hz,3H).
实施例13E
实施例13D(350毫克,830.786微摩尔),实施例16D(313.24毫克,830.78微摩尔),Pd(dppf)Cl2(60.79毫克,83.08微摩尔)和磷酸钾(352.70毫克,1.66毫摩尔)的二氧六环(9毫升)/水(3毫升)混合液经氮气置换3次后,氮气保护下在100℃下搅拌1小时。加水20毫升水淬灭,用乙酸乙酯(20毫升×3)萃取,合并有机层再用饱和食盐水(50毫升×2)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱(二氯甲烷/甲醇:10/1)纯化得到黄色油状标题化合物实施例13E(400毫克,81.40%收率)。
1H NMR(400MHz,CHLOROFORM-d)δ8.63(s,2H),8.50(s,1H),7.97(d,J=9.04Hz,1H),6.89(d,J=9.04Hz,1H),6.64(s,1H),5.60-5.77(m,1H),3.94(s,6H),3.09-3.18(m,4H),2.65(br s,4H),2.51(q,J=7.20Hz,2H),2.21(s,3H),1.10-1.17(m,3H).
实施例13F
实施例13E(200毫克,338.15微摩尔)的乙醇(10毫升)/四氢呋喃(10毫升)混合液在氮气保护下加入雷尼镍(28.97毫克,338.15微摩尔),在氢气球条件下(15psi),于20℃搅拌0.5小时。过滤,真空浓缩,残余物未进一步纯化得到黄色固体标题化合物实施例13F(200毫克,粗品)。
LCMS(ESI)m/z:561.0(M+1)
实施例13
0℃下向实施例13F(200毫克,356.20微摩尔)的四氢呋喃(5毫升)/水(0.5毫升)溶液中加入氯丙酰氯(47.49毫克,374.01微摩尔),在25℃下搅拌1小时。再加入氢氧化钠(56.99毫克,1.42毫摩尔),在65℃下搅拌5小时。加水20毫升水淬灭,用乙酸乙酯(20毫升×3)萃取,合并有机层,再用饱和食盐水(50毫升×2)洗涤,无水硫酸钠干燥,过滤,真空浓缩,残余物通过制备HPLC纯化得到标题化合物实施例13(30毫克,11.90%收率)。
LCMS(ESI)m/z:615.1(M+1)
1H NMR(400MHz,CHLOROFORM-d)δ8.63(s,2H),7.99(br s,1H),7.81(br d,J=8.54Hz,1H),7.08(d,J=8.78Hz,1H),6.80(s,1H),6.64(s,1H),6.28-6.39(m,1H),6.08-6.22(m,1H),5.61-5.76(m,2H),3.95(s,6H),2.96(t,J=4.64Hz,4H),2.62(br s,3H),2.50(q,J=7.28Hz,2H),2.22(s,3H),1.14(t,J=7.28Hz,3H).
如下1个实施例如实施例13中描述的方法制备。
流程J
实施例16
实施例16A
在0℃,氮气保护的条件下,向三苯基膦(126.28克,481.43毫摩尔,4.00当量)的二氯甲烷(400.00毫升)溶液中加入四溴化碳(79.83克,240.72毫摩尔,2.00当量),并在0℃条件下继续反应5分钟,向反应液中加入3,5-二甲氧基苯甲醛(20.00克,120.36毫摩尔,1.00当量),并在0℃下搅拌4个小时。薄层色谱法检测原料反应完全,有一个极性较大的新点。合并两批反应液,过滤,真空浓缩,用600毫升乙酸乙酯洗涤,过滤,真空浓缩,残余物通过快速硅胶柱(石油醚/乙酸乙酯=20/1)纯化得白色固体实施例16A(39.92克,收率:84.20%)。
1H NMR(400MHz,CHLOROFORM-d)δ7.42(s,1H),6.69(d,J=2.26Hz,2H),6.46(t,J=2.26Hz,1H),3.80(s,6H).
实施例16B
向实施例16A(20.00克,62.11毫摩尔,1.00当量)的甲苯(600毫升)溶液中加入四丁基氟化铵三水合物(195.96克,621.10毫摩尔,10.00当量),在110℃条件下反应16个小时。薄层色谱法检测原料反应完全。反应液用1200毫升水稀释,900毫升乙酸乙酯萃取,有机相用无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱(石油醚/乙酸乙酯=20/1)纯化得到黄色液体实施例16B(12.84克,收率:79.18%)。
1H NMR(400MHz,CHLOROFORM-d)δ6.65(d,J=2.26Hz,1H),6.62(d,J=2.26Hz,2H),6.07-6.16(m,1H),3.80(s,6H).
实施例16C
向实施例16B(24.80克,94.99毫摩尔,1.00当量)的四氢呋喃(500.00毫升)溶液中在-5℃下逐滴滴加磺酰氯(32.05克,237.48毫摩尔,23.74毫升,2.50当量)的四氢呋喃(15毫升)溶液,反应液在-5℃下到5℃之间反应3个小时。补加磺酰氯(1毫升)的四氢呋喃(10毫升)溶液,继续在-5℃下到5℃之间反应1个小时。薄层色谱法检测反应完全,反应液用饱和碳酸氢钠(150毫升)水溶液淬灭,乙酸乙酯(70毫升每次)萃取三遍,有机相用无水硫酸钠干燥,过滤,干燥浓缩,残余物通过快速硅胶柱(石油醚/乙酸乙酯=9/1)得到黄色固体实施例16C(27.75克,收率:88.53%)
1H NMR(400MHz,CHLOROFORM-d)δ6.57(s,1H),5.78-5.87(m,1H),3.94(s,6H)
实施例16D
向实施例16C(20.00克,60.61毫摩尔,1.00当量)和双联频哪醇硼酸酯(30.78克,121.22毫摩尔,2.00当量)的二氧六环(300毫升)溶液中加入三(二亚苄基丙酮)二钯(5.55克,6.06毫摩尔,0.10当量),三环己基膦(6.80克,24.24毫摩尔,0.40当量),乙酸钾(23.79克,242.44毫摩尔,4.00当量),在氮气保护下,于90℃下反应16个小时。薄层色谱法检测反应完全,反应液经过滤,真空浓缩,残余物通过快速硅胶柱(石油醚/乙酸乙酯=4/1)纯化得到黄色固体实施例16D(16.82克,收率73.60%)
1H NMR(400MHz,CHLOROFORM-d)δ6.59(s,1H),4.82-4.97(m,1H),3.92(s,6H),1.25-1.28(m,12H),1.17-1.19(m,1H).
实施例16E
向(3R,4R)-3-氨基-四氢-2H-吡喃-4-醇(2.02克,17.25毫摩尔,1.51当量)和2-氯-5-溴嘧啶(2.21克,11.43毫摩尔,1.00当量)的二氧六环(40.00毫升)溶液中加入N,N-二异丙基乙胺(4.45克,34.43毫摩尔,6.01毫升,3.01当量),于105℃下反应16个小时。薄层色谱法检测反应完全,反应液用30毫升水稀释,乙酸乙酯(50毫升每次)萃取3遍,有机相用无水硫酸钠干燥,过滤,真空浓缩,以石油醚/乙酸乙酯=1/1的比例,再换为二氯甲烷/甲醇=10/1的比例过柱纯化,得到黄色油状物实施例16E(2.60克,收率83.06%)
1H NMR(400MHz,CHLOROFORM-d)δ8.28(s,2H),5.47(br d,J=7.28Hz,1H),4.05-4.18(m,1H),3.95(td,J=4.48,11.60Hz,1H),3.84(dq,J=4.14,7.82Hz,1H),3.70-3.79(m,1H),3.42-3.55(m,4H),3.25(dd,J=8.02,11.28Hz,1H),2.08(ddd,J=2.26,4.58,6.71Hz,1H),2.02-2.11(m,1H),1.70(dtd,J=4.26,9.24,13.64Hz,1H).
实施例16F
向实施例16E(795.00毫克,2.90毫摩尔,1.00当量)和实施例16D(1.44克,3.83毫摩尔,1.32当量)的二氧六环(12.00毫升)和水(4.00毫升)的混合溶液中加入1,1-双(二苯基膦)二茂铁二氯化钯(254.64毫克,348.00微摩尔,0.12当量),磷酸钾(1.54克,7.25毫摩尔,2.50当量),在氮气保护下,于100℃反应1.5个小时。薄层色谱法和液质连用仪检测反应完全,反应液经过滤,用30毫升水稀释,乙酸乙酯(15毫升每次)萃取3遍,有机相用无水硫酸钠干燥,过滤,真空浓缩,残余物通过快速硅胶柱(石油醚/乙酸乙酯=2/3)纯化得到黄色固体实施例16F(513.00毫克,收率:39.82%)
LCMS(ESI):444.2[M+H]+.
1H NMR(400MHz,CHLOROFORM-d)δ8.56(s,2H),6.64(s,1H),5.60-5.73(m,1H),5.33(br d,J=7.02Hz,1H),4.14-4.17(m,1H),3.94-3.97(m,6H),3.77(dt,J=4.38,8.72Hz,1H),3.44-3.54(m,1H),3.27(dd,J=8.78,11.04Hz,1H),2.06-2.12(m,1H),1.65-1.79(m,2H).
实施例16G
向实施例16F(513.00毫克,1.15毫摩尔,1.00当量),邻苯二甲酰亚胺(203.04毫克,1.38毫摩尔1,1.20当量)和三苯基膦(44.28毫克,168.81微摩尔,1.50当量)的四氢呋喃(6.00毫升)溶液中加入偶氮二甲酸二异丙酯(348.81毫克,1.73毫摩尔,335.40微升,1.50当量),在20℃下反应半个小时。薄层色谱法和液质连用仪检测反应完全,反应液经过滤,真空浓缩,残余物通过快速硅胶柱(石油醚/乙酸乙酯=1/1)纯化得到黄色胶状物实施例16G(659.00毫克,收率100.00%)
LCMS(ESI):573.4[M+H]+.
1H NMR(400MHz,CHLOROFORM-d)δ8.74(s,1H),7.72-7.76(m,2H),7.51-7.58(m,6H),6.62(s,1H),5.34-5.47(m,1H),5.34-5.47(m,1H),4.16-4.25(m,1H),4.07-4.15(m,2H),3.93-3.96(m,6H),3.77(dd,J=1.76,12.04Hz,1H),3.39-3.67(m,2H),1.77-1.82(m,1H),1.77-1.82(m,1H).
实施例16H
向实施例16G(659.00毫克,1.15毫摩尔,1.00当量)的乙醇(10.00毫升)溶液中加入一水合肼(230.13毫克,4.60毫摩尔,223.43微升,4.00当量),于80℃下反应1个小时。薄层色谱法检测反应完全,反应液经过滤,真空浓缩,残余物通过快速硅胶柱(二氯甲烷/甲醇=9/1)纯化得到黄色胶状物实施例16H(312.00毫克,收率61.20%)
1H NMR(400MHz,CHLOROFORM-d)δ8.47(s,2H),6.57(s,1H),5.52-5.64(m,1H),4.22-4.32(m,1H),4.05(q,J=7.02Hz,1H),3.93(br s,1H),3.87-3.91(m,6H),3.82(dd,J=3.64,11.66Hz,1H),3.55(dd,J=2.12,11.66Hz,1H),3.44(dt,J=2.88,11.10Hz,1H),3.10(td,J=4.10,10.34Hz,1H),1.66-1.75(m,1H),1.54-1.63(m,1H).
实施例16
向实施例16H(246.00毫克,554.93微摩尔,1.00当量)和N,N-二异丙基乙胺(222.33毫克,1.72毫摩尔,300.45微升,3.10当量)的二氯甲烷(20.00毫升)溶液中,于0℃下,加入丙烯酰氯(44.40毫克,490.55微摩尔,40.00微升,0.88当量),于0℃下反应1个小时。液质连用仪检测反应完全,反应液用20毫升饱和碳酸氢钠水溶液淬灭,乙酸乙酯(10毫升每次)萃取3遍,有机相用无水硫酸钠干燥,过滤,真空浓缩,粗品经高效液相色谱法(三氟乙酸体系)纯化得到实施例16(150.00毫克,收率54.35%)。
LCMS(ESI):497.4[M+H]+.
1H NMR(400MHz,CHLOROFORM-d)δ8.72(br s,1H),8.54(br s,1H),6.80(br d,J=7.52Hz,1H),6.59(s,1H),6.18(dd,J=1.00,17.06Hz,1H),5.94-6.03(m,1H),5.58-5.70(m,1H),5.54-5.58(m,1H),4.27-4.40(m,2H),4.06-4.14(m,1H),3.97(br d,J=10.04Hz,1H),3.89(s,6H),3.46-3.60(m,2H),1.93-2.06(m,1H),1.82(br d,J=10.54Hz,1H).
流程K
实施例19
实施例19A
2,5-二氢呋喃(80.00克,1.14摩尔,86.02毫升)溶于1000毫升二氯甲烷中,然后分批加入间氯过氧苯甲酸(277.74克,1.37摩尔),室温反应14h。反应由TLC监测,反应完后,滤去固体,滤液用饱和亚硫酸钠溶液洗,至使淀粉-KI试纸不变蓝,然后用饱和碳酸氢钠溶液洗涤,至溶液PH=7~8。有机相用无水硫酸钠干燥,过滤并旋干溶剂后,不需进一步纯化,得到48.50克黄色产物实施例19A,产率为49.4%。
1HNMR(400MHz,CHLOROFORM-d)δ3.99(d,J=10.29Hz,2H),3.77(s,2H),3.63(d,J=10.54Hz,2H).
实施例19B
向反应瓶中加入实施例19A(24.00克,278.78毫摩尔)和氨水(218.40克,1.74摩尔,240.00毫升),在100℃下,反应14小时。反应由TLC监测,反应完后,旋干溶剂,得到23.70克棕色油状粗品实施例19B,产率为82.4%。
1HNMR(400MHz,CHLOROFORM-d)δ4.00-4.16(m,3H),3.63-3.81(m,1H),3.48-3.59(m,1H),3.34-3.45(m,1H).
实施例19C
实施例19B(23.70克,229.83毫摩尔)溶于200毫升甲醇中,加入三乙胺(4.65克,45.97毫摩尔,6.37毫升),然后滴加Boc-酸酐(65.21克,298.78毫摩尔,68.64毫升),室温下反应3小时。反应由TLC监测,反应完后,旋干溶剂,然后加入100毫升甲基叔丁基醚,搅拌15分钟,过滤后的滤饼即为产物,不需进一步纯化,得到38.78克淡黄色固体实施例19C,产率为83.0%。
1HNMR(400MHz,CHLOROFORM-d)δ4.78(br s,1H),4.24-4.31(m,1H),3.98-4.13(m,2H),3.94(br s,1H),3.66-3.73(m,1H),3.62(dd,J=2.76,9.29Hz,1H),1.44(s,9H).
实施例19D
实施例19C(38.78克,190.82毫摩尔),邻苯二甲酰亚胺(33.69克,228.98毫摩尔)和三苯基膦(60.06克,228.98毫摩尔)溶于500毫升四氢呋喃中,加入偶氮二甲酸二异丙酯(46.30克,228.98毫摩尔,44.52毫升),室温下反应14小时。反应由TLC监测,反应完后,旋干溶剂,用快速硅胶柱(石油醚/乙酸乙酯=3/1)纯化得到85.50克白色固体产物实施例19D。
1HNMR(400MHz,CHLOROFORM-d)δ7.85-7.88(m,2H),7.74-7.76(m,2H),4.88(br d,J=9.54Hz,1H),4.44-4.55(m,1H),4.37(br t,J=8.16Hz,1H),4.12-4.21(m,2H),3.78-3.90(m,1H),1.10(s,9H).
实施例19E
实施例19D(85.50克,257.26毫摩尔)溶于850毫升无水乙醇中,加入水合肼(75.76克,2572.6毫摩尔,73.55毫升),80℃下反应1小时。反应由TLC监测,反应完后,滤去产生的白色固体,旋干溶剂后,再加入200毫升二氯甲烷,过滤掉不溶解的固体,旋干溶剂后,不需进一步纯化,得到49.6克微黄色固体粗产物实施例19E。
1HNMR(400MHz,CHLOROFORM-d)δ5.32(br s,1H),4.06-4.17(m,1H),3.94-4.05(m,2H),3.52-3.62(m,2H),3.47(dd,J=5.02,9.03Hz,1H),1.36-1.50(m,9H).
实施例19F
实施例19E(14.00克,69.22毫摩尔)和2-氯-5-溴嘧啶(11.38克,58.84毫摩尔)溶于100毫升NMP,加入碳酸氢钠(17.45克,207.66毫摩尔),110℃下反应14小时。反应由TLC监测,反应完后,加入300毫升乙酸乙酯,然后用饱和食盐水溶液(200毫升*3)洗,有机相用无水硫酸钠干燥,过滤并旋干溶剂,再用快速硅胶柱(石油醚/乙酸乙酯=3/1)进行纯化,得到15.66克黄色固体实施例19F,产率为62.97%。
1HNMR(400MHz,CHLOROFORM-d)δ8.30(s,2H),5.71(br s,1H),4.58-4.70(m,1H),4.44(br s,1H),4.03-4.11(m,2H),3.63-3.73(m,2H),2.04(s,4H),1.38(s,9H).
实施例19G
实施例19F(15.62克,43.47毫摩尔),实施例16D(14.90克,39.52毫摩尔)溶于150毫升1,4-二氧六环和75毫升水中,加入Pd(dppf)Cl2(2.89克,3.95毫摩尔)和无水磷酸钾(16.78克,79.04毫摩尔),在氮气保护下,95℃反应14小时。反应由TLC监测,反应完后,加入300mL乙酸乙酯,然后用饱和食盐水溶液(200毫升*3)洗,有机相用无水硫酸钠干燥,过滤并旋干溶剂,残余物用快速硅胶柱(石油醚/乙酸乙酯=1/1)进行纯化,得到4.6克黄色固体实施例19G,产率为21.99%。
1HNMR(400MHz,CHLOROFORM-d)δ8.57(s,2H),6.64(s,1H),5.79(br d,J=6.53Hz,1H),5.58-5.72(m,1H),5.09(br s,1H),4.70-4.80(m,1H),4.47(br s,1H),4.12-4.23(m,2H),3.72(br d,J=6.78Hz,2H),1.39(s,9H).
实施例19H
实施例19G(4.60克,8.69毫摩尔)溶于30毫升DCM中,滴加三氟乙酸(15.40克,135.04毫摩尔,10.00毫升),室温反应30min。反应由LC-MS监测,反应完后,旋干溶剂,不需进一步纯化,得到7.20克棕黄色固体粗产物实施例19H。
LCMS(ESI):429(M+1)+
实施例19
实施例19H(7.20克,13.25毫摩尔)溶于40mL DCM,加入DIEA(6.85克,53.00毫摩尔),反应液冷却至0℃,加入丙烯酰氯(599.63毫克,6.63毫摩尔μL),升至室温反应20min。反应由LC-MS监测,反应完后,加入30毫升水淬灭反应,然后用二氯甲烷(15毫升*3)萃取,合并有机相,再用40mL饱和食盐水洗,无水硫酸钠干燥后,过滤并旋干。用快速硅胶柱(先石油醚/乙酸乙酯=1/1,然后二氯甲烷/甲醇=10/1)纯化,得到的2.7克实施例19(两步收率,64.3%)
实施例20,21
将实施例19(2.7g,5.59mmol)进行SFC(column:OD(250mm*30mm,5μm);mobilephase:[0.1%NH3H2O EtOH];B%:40%-40%,10min)拆分,得到830毫克实施例20(纯度:98.43%)保留时间5.204,610毫克实施例21(纯度:99.22%)保留时间7.294。
实施例20:1H NMR(400MHz,CHLOROFORM-d)δ8.57(s,2H),6.65(s,1H),6.38(br d,J=6.53Hz,1H),6.25(dd,J=1.13,16.94Hz,1H),5.98-6.11(m,1H),5.59-5.78(m,3H),4.70-4.85(m,2H),4.20(ddd,J=6.02,9.47,12.36Hz,2H),3.92-3.98(m,6H),3.70-3.83(m,2H).
实施例21:1H NMR(400MHz,CHLOROFORM-d)δ8.58(s,2H),6.65(s,1H),6.35(br d,J=6.27Hz,1H),6.21-6.29(m,1H),5.99-6.10(m,1H),5.59-5.74(m,3H),4.69-4.82(m,2H),4.20(ddd,J=6.02,9.47,13.11Hz,2H),3.95(s,6H),3.77(ddd,J=4.52,9.54,16.56Hz,2H).
如下3个实施例如实施例19中描述的方法制备。
流程L
实施例34
实施例34A
向N-Boc-2,5-二氢吡咯(25克,147.74毫摩尔)的200毫升二氯甲烷溶液中分批加入间氯过氧苯甲酸(38.24克,221.61毫摩尔),反应液在25℃条件下搅拌16个小时。点板(磷钼酸)显示有个主要新点生产。反应液中用亚硫酸钠饱和溶液(500毫升)萃灭,二氯甲烷(150毫升X2)萃取2次,有机相分层,用碳酸钠水溶液(300毫升X2)洗2次,食盐水(300毫升X2)洗两次,无水硫酸钠干燥,过滤,浓缩得到浅黄色油状产品实施例34A(22.5克,82.22%收率),直接用于下一步。
1H NMR(400MHz,CHLOROFORM-d)δ=3.78(d,J=6.4Hz,1H),3.71(d,J=6.4Hz,1H),3.65-3.63(m,2H),3.31-3.26(m,2H),1.41(s,9H).
实施例34B
实施例34A(9.0克,48.59毫摩尔)的90毫升氨水溶液加热到90℃搅拌4个小时。反应液变成红棕色。反应液旋干,往里面加入二氯甲烷200毫升,甲醇20毫升,无水硫酸钠干燥,过滤,滤液浓缩得到红棕色油状产品实施例34B(8克)直接用于下一步。
实施例34C
向实施例34B(2克,9.89毫摩尔)的20毫升甲苯与10毫升水的混合溶液中加入碳酸钠(5.24克,49.45毫摩尔),氯甲酸苄酯(2.53克,14.84毫摩尔)慢慢滴入,反应液控制温度在10-20℃搅拌4小时。点板检测原料消耗完毕。反应液加入水30毫升,乙酸乙酯萃取(30毫升X2)2次,合并有机相,食盐水洗涤(40毫升),无水硫酸钠干燥,滤液浓缩得到粗品,经过快速硅胶柱(二氯甲烷∶甲醇=10∶1)纯化得到黄色油状产品实施例34C(1.45克,43.59%收率)。
1HNMR(400MHz,CHLOROFORM-d)δ=7.45-7.30(m,5H),5.19-4.87(m,3H),4.27(brs,1H),4.00(br s,1H),3.88-3.75(m,1H),3.72-3.65(m,1H),3.37-3.07(m,2H),1.47(s,9H).
实施例34D
实施例34C(500毫克,1.49毫摩尔)的10毫升二氯甲烷溶液中加入三乙胺(0.41毫升,2.98毫摩尔),再往反应液中滴加甲烷磺酰氯(256毫克,2.24毫摩尔),反应液在10-20℃搅拌1小时。点板检测原料消耗完毕。反应液加10毫升水萃灭,二氯甲烷萃取(20毫升X 2)2次,合并有机相,食盐水洗(20毫升),无水硫酸钠干燥,过滤减压浓缩得黄色固体实施例34D(670毫克,粗品)。
1H NMR(400MHz,METHANOL-d4)δ=7.31-7.13(m,5H),5.06-4.87(m,3H),4.15(brs,1H),3.63-3.51(m,2H),3.50-3.42(m,1H),3.28-3.25(br d,J=11.8Hz,1H),3.07(s,3H),1.42(s,9H)
实施例34E
向含有实施例34D(600毫克,1.45毫摩尔)醋酸钠(237.89毫克,2.90毫摩尔)的5毫升DMF溶液中加入叠氮钠(282.79毫克,4.35毫摩尔),反应液100℃搅拌3小时。点板检测原料消耗完毕。反应液加入20毫升水,乙酸乙酯(20毫升X2)萃取2次。合并有机相,食盐水洗涤(30毫升),无水硫酸钠干燥,得到约35毫升实施例34E乙酸乙酯溶液直接用于下一步。
实施例34F
向实施例34E(00毫克,35毫升的乙酸乙酯溶液)的30毫升甲醇溶液中,N2保护下加入Pd/C(200毫克,干),反应液氢气置换3次,最后在H2(40psi)下搅拌16个小时。点板检测原料消耗完毕。反应液变绿色,过滤旋干得450毫克浅绿色油状物实施例34F(粗品)。
1HNMR(400MHz,METHANOL-d4)δ=3.60-3.49(m,2H),3.42-3.35(m,2H),3.23-3.14(m,2H),1.47(s,9H).
实施例34G
向实施例34F(166毫克,0.83毫摩尔)的3毫升二氧六环溶液,加入DIEA(106.63毫克,0.083毫摩尔),2-氯-5-[(Z)-2-(2,6-二氯-3,5-二甲氧基-苯)-2-氟-乙烯]吡啶(100毫克,0.28毫摩尔),反应液在N2保护下,90-100℃反应8个小时。LCMS检测发现产物生成,原料反应完毕。反应液加入20毫升水,乙酸乙酯萃取(20毫升X2)2次,合并有机相,食盐水洗涤(20毫升),无水硫酸钠干燥,过滤,滤液旋干得到粗品,经过薄层层析板纯化(石油醚∶乙酸乙酯=1∶1)得到无色油状产品实施例34G(45毫克,30.96%收率)。
LCMS(ESI)m/z:528.0(M+1)+
实施例34H
向实施例34G(30毫克,56.78微摩尔)的无水二氯甲烷(2毫升)溶液中加入DIEA(14.68毫克,113.56微摩尔),再加入丙烯酰氯(0.23毫升,0.25摩尔/升的二氯甲烷溶液),0-10℃下搅拌30分钟。LCMS显示产物生产,原料消耗完毕。反应液用水(5毫升)萃灭过滤,二氯甲烷(20毫升)萃取,无水硫酸钠干燥后,浓缩得到粗品黄色油状产物实施例34H(30毫克,粗品)。
LCMS(ESI)m/z:582.1(M+1)+
实施例34I
向实施例34H(30毫克,51.51微摩尔)中加入HCl/EA(4毫升,4摩尔/升),N2保护,25-32℃下搅拌1小时。LCMS显示产物生产,原料消耗完毕。反应液直接浓缩得到无色油状产品实施例34I。LCMS(ESI)m/z:482.1(M+1)+
实施例34
向实施例34I(20毫克,41.47微摩尔)的无水二氯甲烷(2毫升)溶液中加入DIEA(16.08毫克,124.41微摩尔),再加入乙酰氯(0.13毫升,0.25摩尔/升的二氯甲烷溶液),0-10℃下搅拌30分钟。LCMS显示产物生产,原料消耗完毕。反应液用水(10毫升)萃灭过滤,二氯甲烷(20毫升)萃取,无水硫酸钠干燥后,浓缩得到粗品黄色油状产物,经过层析板纯化(石油醚∶乙酸乙酯=1∶1)得到产品实施例34(2毫克,8.35%收率)。LCMS(ESI)m/z:524.1(M+1)+
实验例1:本发明化合物的体外酶活性测试
实验目的
实验方法
将测试化合物进行3倍浓度梯度稀释,终浓度为10μM到0.5nM 10个浓度,每个浓度两个复孔;DMSO在检测反应中的含量为1%。
FGFR4酶反应:
1.94至84ng FGFR1蛋白激酶,2μM Tyr4底物,150μM ATP,50mM HEPES(pH 7.5),0.01%BRIJ-35,10mM MgCl2,2mM MnCl2,1mM EGTA,1mM DTT。检测板为Bar-coded Corning,low volume NBS,black 384-well plate,室温反应60分钟,反应体系为10μμL。
FGFR1酶反应:
1nM FGFR1蛋白激酶,2μM Tyr4 peptide,25μM ATP,50mM HEPES(pH 7.5),10mMMgCl2,1mM EGTA,0.01%BRIJ-35,2mM MnCl2,1mM DTT。检测板为Black Proxiplate 384-Plus plate(PerkinElmer),室温反应60分钟,反应体系为10μμL。
反应检测:
激酶反应液中添加5μL Development reagent B(1∶64)终止反应并于23℃孵育60分钟,Envision仪器读板。
数据分析
将数据转化为磷酸化率和抑制率,使用Model 205 in XLFIT(iDBS)进行曲线拟合,得到化合物IC50数据。若曲线底部不在-20%到20%范围内,将其设为0%;若曲线顶部不在70%到130%范围内,将其设为100%。
表1.Z′-LYTETM检测IC50测试结果
注:单位为nM,N/A,表示未测。
结论:本发明化合物丙烯酰胺和氟烯键母核结构能得到一系列FGFR4高选择的化合物,对FGFR4激酶有优异的抑制活性,而对亚型FGFR1激酶没有活性,选择性至少十或百倍以上。另外发现,双甲氧基二氯苯环的结构中,双氯能够大大提高FGFR4的抑制活性;如实施例子1与对照例1相比活性提高70倍;烯键引入氟原子,氟原子靠近二氯苯胺,能够提高FGFR4的靶点活性,如实施例15与对照例2相比,活性提高了近9倍,实施例19与对照例3相比,活性提高近9倍。
实验例2:本发明化合物的药代动力学评价
实验过程:将1mg/ml在某种溶媒中(见表格2)的试验化合物的澄清溶液经尾静脉注射到雌性Balb/c nude小鼠(上海灵畅生物科技有限公司)体内(过夜禁食,7-9周龄),给药剂量为2mg/kg。将1mg/ml悬浮在对应溶媒中的试验化合物灌胃给予到雌性Balb/c nude小鼠(过夜禁食,7-9周龄),给药剂量为10mg/kg。两组动物均于给药后0.0833、0.25、0.5、1.0、2.0、4.0、6.0、8.0和24h从颈静脉或尾静脉采血约30μL置于添加了EDTA-K2的抗凝管中,离心分离血浆。采用LC-MS/MS法测定血药浓度,使用WinNonlinTM Version 6.3(Pharsight,Mountain View,CA)药动学软件,以非房室模型线性对数梯形法计算相关药代动力学参数。使用溶媒和对应给药剂量见表2.
表2.各化合物小鼠药代动力学实验条件
实验数据结果如表3所示:
表3.各化合物小鼠药代动力学实验结果
注:
血浆清除率(CL)mL/min/kg,稳态表观分布容积(Vdss)L/kg,
消除半衰期(T1/2)和0点到最后一个可定量时间点血浆浓度曲线下面积(AUC0-last)
生物利用度F%,达峰浓度(Cmax)nM,达峰时间Tmax(h)
ND:未检测到数据。
实验结论:
从实验结果来看,具有氟烯结构的实施例16与苄醚结构的对照例4相比,其血浆清除率(CL)为23.9mL/min/kg,稳定性提高了3倍,同时药物口服吸收从0%增加到40%以上;具有氟烯结构的实施例24与苄醚结构的对照例5和对照例6相比,其血浆清除率(CL)为50mL/min/kg,稳定性分别提高了2到3倍以上,同时药物口服吸收从0%增加到14.8%。实施例21比对照例7和对照例8生物利用度也展示了大幅提高。综上,本发明化合物的氟烯结构,与苄醚结构相比,能够大大提高药物代谢的稳定性,同时也大大提高药物的口服吸收生物利用度。
实验例3:肿瘤生长抑制(TGI)分析
肿瘤的演化生长势通过肿瘤体积与时间的关系来进行评价的。皮下肿瘤的长轴(L)和短轴(W)通过测径器每周测定两次,肿瘤的体积(TV)通过公式((LxW2)/2)进行计算。TGI由溶剂组小鼠肿瘤体积的中值和药物组组小鼠肿瘤体积中值得差值来进行计算,以溶剂对照组肿瘤体积中值得百分比来表示,
通过下述公式进行计算:
%TGI=((中间肿瘤体积(对照)-中间肿瘤体积(给药组))/中间肿瘤体积(对照组))×100%
原始统计分析是通过重复方差测定分析来完成。接下来通过Scheffe psot hoc实验方法进行多重比较。单独溶剂(0.5%甲基纤维素+1%吐温水溶液)为阴性对照。实验结果见表4:
表4小鼠体内抗肿瘤活性试验结果
Hep3B移植模型 | TGI%(末次第21天给药) | |
实施例7 | 30mg/kg BID | 108% |
实施例16 | 100mg/kg,BID | 89% |
实施例21 | 100mg/kg,BID | 106% |
注:BID:一天两次.
结论:本发明化合物优异的体外FGFR4酶抑制活性,可以作为小分子的络氨酸激酶抑制剂,具有优良的抗肿瘤活性,对用于治疗各种哺乳动物(包括人类)的肿瘤性疾病,如肝癌,胃癌等有优良的效果。
Claims (20)
11.根据权利要求10所述化合物、其药学上可接受的盐及其互变异构体,其中,R3选自:H和CH3。
16.一种药物组合物,包括治疗有效量的根据权利要求1~15任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
17.根据权利要求1~15任意一项所述的化合物或其药学上可接受的盐在制备治疗FGFR4相关病症的药物上的应用。
18.根据权利要求16所述的组合物在制备治疗FGFR4相关病症的药物上的应用。
19.根据权利要求17所述的应用,其特征在于,所述药物是治疗肝癌或胃癌的药物。
20.根据权利要求18所述的应用,其特征在于,所述药物是治疗肝癌或胃癌的药物。
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WO2014139465A1 (en) * | 2013-03-15 | 2014-09-18 | Hutchison Medipharma Limited | Novel pyrimidine and pyridine compounds and their usage |
CN105899490A (zh) * | 2013-10-18 | 2016-08-24 | 卫材R&D管理有限公司 | 嘧啶fgfr4抑制剂 |
WO2016115412A1 (en) * | 2015-01-18 | 2016-07-21 | Newave Pharmaceutical Llc | Dual-warhead covalent inhibitors of fgfr-4 |
WO2016164703A1 (en) * | 2015-04-09 | 2016-10-13 | Eisai R & D Management Co., Ltd. | Fgfr4 inhibitors |
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CA3043948C (en) | 2021-08-31 |
MX2019005723A (es) | 2019-10-21 |
CN109952290A (zh) | 2019-06-28 |
JP7063899B2 (ja) | 2022-05-09 |
EP3543227A4 (en) | 2019-10-30 |
AU2017359819A1 (en) | 2019-06-20 |
KR102249632B1 (ko) | 2021-05-10 |
IL266659B (en) | 2022-01-01 |
IL266659A (en) | 2019-07-31 |
WO2018090973A1 (zh) | 2018-05-24 |
NZ754218A (en) | 2021-07-30 |
ZA201903845B (en) | 2020-12-23 |
KR20190077085A (ko) | 2019-07-02 |
US20200062716A1 (en) | 2020-02-27 |
AU2017359819B2 (en) | 2020-05-28 |
EP3543227B1 (en) | 2020-12-30 |
US11008292B2 (en) | 2021-05-18 |
CA3043948A1 (en) | 2018-05-24 |
JP2019537613A (ja) | 2019-12-26 |
EP3543227A1 (en) | 2019-09-25 |
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