CN112479956A - 一种用于制备腺苷受体抑制剂中间体的方法 - Google Patents
一种用于制备腺苷受体抑制剂中间体的方法 Download PDFInfo
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Classifications
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- C07C335/04—Derivatives of thiourea
- C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Landscapes
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Abstract
本发明提供了一种用于制备腺苷受体抑制剂中间体的方法。本发明的方法可以用于制备腺苷受体抑制剂,尤其是A2A和/或A2B抑制剂,例如可以用于预防或治疗与A2A和/或A2B活性或表达量相关的疾病。
Description
本申请是分案申请,其母案的中国申请号是202010724029.X,母案申请日是2020年07月24日。
本发明要求中国专利申请CN 201910695723.0的优先权,该优先权文件的说明书和权利要求所记载的内容全文引入本发明的说明书并被作为本发明说明书原始记载的一部分。申请人进一步声明,申请人拥有基于该优先权文件修改本发明的说明书和权利要求书的权利。
技术领域
本发明提供了一类新型杂环化合物,其制备方法及其作为腺苷受体(特别是A2A和/或A2B受体)拮抗剂的应用。
背景技术
检查点抑制剂在免疫治疗领域取得一些突破性进展,大量的临床研究表明,PD-1/PDL-1抗体对多种肿瘤(小细胞肺癌、黑色素瘤、头颈癌、肾癌等)具有一定的临床效果,但单药应答率普遍偏低,一般在20-40%。实体肿瘤不仅包括肿瘤细胞成分,还包括肿瘤组织当中存在的相当多的其他非肿瘤细胞成分,这些细胞成分构成了所谓肿瘤微环境,在肿瘤的浸润、增殖和转移中发挥重要的作用。研究表明PD-1/PDL-1抗体与其他免疫调节小分子(消除肿瘤微环境的免疫耐受)联合用药是解决应答率低的一个有效手段之一。
正常情况下人体可以依赖完整的免疫机制来有效地控制肿瘤细胞,T淋巴细胞、NK细胞和巨噬细胞都对肿瘤细胞有杀伤作用,但是当癌变细胞本身或上述免疫细胞功能发生改变时,其可能逃脱机体免疫系统的清除,恶性增生形成肿瘤。腺苷是一种体内用于限制炎症和免疫应答的信号分子,在代谢障碍及细胞损伤时会大幅升高。激活的腺苷受体参与机体的免疫调节,在许多不同类型的肿瘤微环境中维持较高水平。肿瘤产生的腺苷能与入侵免疫细胞表面上的腺苷受体相互作用,腺苷受体有四种亚型:A1、A2A、A2B和A3,都属于G蛋白偶联受体家族,主要与Gs和Gα蛋白偶联。每个受体对腺苷表现不同的亲和力,A1R、A2AR和A3R是高亲和力受体,可以被较低浓度(250-700nM)的腺苷激活;而A2BR是低亲和力受体,需要较高的腺苷浓度(25μM)激活。腺苷受体也可以根据其引起下游信号小分子cAMP来分类,当A2A和A2B受体激活,受体构象变化导致释放激活Gs蛋白,活化腺苷环化酶,加速ATP转化为cAMP。增加的cAMP浓度,通常伴随着强烈的免疫抑制,而激活A1和A3受体会抑制cAMP的产生,因而激活A1和A3受体一般会认为激活免疫。
腺苷A2A受体主要表达于大脑的纹状体、脾脏、胸腺、淋巴细胞和血小板,在心脏、肺和血管中也发现一定的表达,常表达于免疫系统中的一些细胞,如T细胞、NK细胞、巨噬细胞和树突状细胞。A2A受体拮抗剂早期主要用于神经系统疾病的治疗,例如帕金森病、亨廷顿病、阿尔茨海默病、注意力缺陷相关疾病和精神病等。近期研究发现发现,A2A受体拮抗剂能提高树突细胞抗原呈递、T细胞以及自然杀伤细胞的活化和杀伤能力,抑制调节性T细胞(T-regs)、MDSC和TAM,消除肿瘤免疫耐受,促进抗肿瘤免疫应答的发生,进而导致肿瘤的消退,因而A2A受体拮抗剂有可能成为治疗肿瘤的有效方法之一。A2A受体拮抗剂既可以单独用药又可以与其他抗肿瘤药物联合使用,特别是与免疫检查点抑制剂联合用药是目前的临床研究热点。
腺苷A2B受体表达于多种组织,脉管系统、脑、小肠以及肿瘤等,在不同的细胞中也表达,包括免疫系统中的肥大细胞、树突细胞、中性白细胞、巨噬细胞和淋巴细胞等以及内皮细胞、神经细胞和胶质细胞。A2B受体的广泛表达使之成为多种疾病研究的靶点,包括心血管疾病、肺部疾病、糖尿病以及癌症等。研究表明A2B拮抗剂可以阻止肿瘤(膀胱癌、乳腺癌)的生长,三阴乳腺癌肿瘤病人的A2B高表达也可以导致治疗生存率降低。
国际专利申请公开号WO2018/178338、WO2011/095625、WO2001/92264、WO2003/048165、WO2004/09443、WO2002/055083等公开了用作A2A受体拮抗剂的化合物,国际专利申请公开号WO2005/040155、WO2016/164838、WO2016/150901、WO20161/35048、WO2015/05206、WO2012/076974、WO2011/005871、中国专利申请公开号CN102532137以及美国专利申请公开号US20140142113等公开了用作A2B受体拮抗剂的化合物。然而,仍需要对腺苷受体具有更好抑制效果的抑制剂;特别地,能够同时抑制A2A和A2B受体的拮抗剂具有重要的临床价值和治疗意义,但是目前对其报道很少。现有技术中迫切需要具有更好抑制效果的腺苷抑制剂,特别是能够同时A2A和A2B受体的新型拮抗剂化合物。
发明内容
经过长期而深入的研究,我们意外地发现了一类具有良好的A2A和/或A2B受体抑制活性的杂环化合物。
基于上述发现,在本发明的第一个方面,提供了式(I)化合物或其药学上可接受的盐、前药、同位素衍生物、水合物、异构体、溶剂化物、或其代谢产物,
其中:
R1和R2各自独立地表示:C3-C12环烷基、3-12元杂环烷基、C6-C12芳基、5-12元杂芳基;
其中所述R1和R2任选地各自独立地被0、1、2、3、4或5个选自R4的取代基所取代,其中R4选自C1-C6烷基、羟基(C1-C6烷基)-、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C6-C12芳基、5-12元杂芳基、C1-C6卤代烷基、卤素、氧代、硝基、氰基、-NRaRb、-ORa、-SRa、-SORa、-SO2Ra、-SO3Ra、-NRaC(O)Ra、-NRaC(O)ORa、-NRaS(O)2Ra、-C(O)ORa、-C(O)NRaRb、-C(O)Ra、-(CRaRb)m-ORa、-(CRaRb)m-NRaRb、-(CRaRb)m-NRa-(CRaRb)n-ORa、-(CRaRb)m-O-(CRaRb)n-NRaRb、-(CRaRb)m-O-(CRaRb)n-ORa和-(CRaRb)m-NRa-(CRaRb)n-NRaRb;或者当取代基数目为2,且该2个取代基位于相邻的位置时,其任选地相互环合成为饱和或者不饱和的4-7元环,并且进一步的,该环中任选地包含有0、1或2个选自O、S、N的杂原子;
R3表示氢、C1-C6烷基、羟基(C1-C6烷基)-、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C6-C12芳基、5-12元杂芳基、C1-C6卤代烷基、卤素、硝基、氰基、-NRaRb、-ORa、-SRa、-SORa、-SO2Ra、-SO3Ra、-NRaC(O)Ra、-NRaC(O)ORa、-NRaS(O)2Ra、-C(O)ORa、-C(O)NRaRb、-C(O)Ra、-(CRaRb)m-ORa、-(CRaRb)m-NRaRb、-(CRaRb)m-NRa-(CRaRb)n-ORa、-(CRaRb)m-O-(CRaRb)n-NRaRb、-(CRaRb)m-O-(CRaRb)n-ORa或-(CRaRb)m-NRa-(CRaRb)n-NRaRb;其中,Ra和Rb各自独立地表示氢、卤素、C1-C6烷基、C3-C6环烷基或-(C0-C6亚烷基)-(C6-C12)芳基;
或者,当Ra、Rb与同一个原子连接时,其任选地和与之相连的原子共同环合成饱和或者不饱和的3-7元环,并且该环任选地含有0、1或2个选自N、O、S的杂原子;
n和m分别独立地表示0、1、2、3或4。
优选地,所述式(I)化合物具有以下式(II)结构:
其中,W1选自CR5或N,R5具有与R4相同的定义;R2、R3和R4具有如式(I)所述定义,o为0、1、2或3。
优选地,所述式(I)化合物具有以下式(III)结构:
其中,R6选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷基硫基、卤素、硝基、-NRcRd、氰基、-SO2Rc、-SO3Rc;W1选自CR5或N,R5具有与R4相同的定义;R3和R4具有如式(I)所述定义,o为0、1、2或3。
其中,Rc和Rd各自独立地表示氢、卤素、C1-C6烷基或C3-C6环烷基。
或者,当Rc、Rd与同一个原子连接时,其任选地和与之相连的原子共同环合成饱和或者不饱和的3-7元环,并且该环任选地含有0、1或2个选自N、O、S的杂原子。
优选地,本发明的化合物选自以下结构:
本发明的化合物也可制备成可药用盐的形式,所述可药用盐可以使用例如以下的无机酸或有机酸而形成:盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸或甲苯磺酸。
本发明的可药用盐可通过常规方法制备,例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)中,向其中添加过量的有机酸或无机酸水溶液,以使得盐从所得混合物中沉淀,从中除去溶剂和剩余的游离酸,然后分离所沉淀的盐即可。
具体实施方式
本发明人经过长期而深入的研究,意外地发现了一类具有腺苷受体抑制活性、尤其是A2A和/或A2B抑制活性的如式(I)所示的杂环化合物。基于上述发现,发明人完成了本发明。
在本发明的优选例中,提供但不局限于以下化合物:
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
具体实施例
当未描述制备途径时,意味着相关中间体是可由市售购得的(例如来自SigmaAldrich,Alfa)。
通用过程
使用市售试剂而不需进一步纯化。室温是指20-27℃。1H-NMR谱在Bruker仪器上于500MHz记录。化学位移值以百万分率表示,即δ值。以下简写用于NMR信号的多重性:s=单峰,brs=宽峰,d=二重峰,t=三重峰,m=多重峰。耦合常数以J值列出,以Hz测量。NMR和质谱结果根据背景峰校正。色谱是指使用100筛目硅胶进行并在氮气压力(快速色谱)条件下完成的柱色谱。用于监测反应的TLC指使用特定流动相和来自Merck的硅胶F254作为固定相进行的TLC。
LC-MS实验在以下条件下测量:
仪器:Thermo U3000,ALLtech ELSD,MSQ,UV检测器结合ELSD和MSD(流出比为4:1)。柱:Waters X-Bridge C-18,3.5μm,4.6x50mm;柱温:30℃。梯度【时间(min)/溶剂B在A中(%)】:0.00/5.0,0.70/95,1.40/95,1.41/5,1.50/5。(溶剂A=0.01%三氟乙酸在水中;溶剂B=0.01%三氟乙酸在乙腈中)。UV检测:214/254/280/300nm;DAD检测:200-400nm;流速:4mL/min;MS:ESI,100-1500m/z
制备型HPLC通常使用酸性方法(乙腈和水的梯度,各含有0.1%甲酸)用ThermoU3000AFC-3000;柱:Globalsil C-1812nm,250x 20mm,10μm,或相当;流速:20mL/min,进行分离。
中间体的合成
化合物INT-1的制备:
将2-甲基呋喃(3.28g,40.0mmol)和N,N,N',N'-四甲基乙二胺(17.0g,146mmol)溶于无水四氢呋喃中(80mL)。在-78℃氮气保护条件下缓慢滴加正丁基锂(2.5M的正己烷溶液,16mL),所得反应液在-40℃到-20℃温度区间里搅拌3小时,然后在-78℃条件下加入三丁基氯化锡(13.0g,40.0mmol),所得的反应液缓慢升至室温反应过夜。用饱和氯化铵淬灭反应(60mL),用乙酸乙酯萃取(100mL×3)。合并的有机相用饱和食盐水洗(100mL),无水硫酸钠干燥,过滤,滤液经过硅胶(100g)和氟化钾(10g)的混合色谱柱,用乙酸乙酯淋洗(300mL),洗脱液减压浓缩得到化合物INT-1(12.1g,收率81%)。1H NMR(500MHz,Chloroform-d)δ6.44(d,J=3.0Hz,1H),6.05–5.94(m,1H),2.33(s,3H),1.62–1.48(m,6H),1.37–1.29(m,6H),1.12–0.98(m,6H),0.94–0.87(m,9H).
化合物INT-2的制备:
在冰浴条件下,将化合物INT-2a(1.31g,10.0mmol)加入到氨的乙醇溶液中(2M,7.50mL)。所得反应液在冰浴条件下搅拌1小时。将反应液减压浓缩得到黄色固体化合物INT-2b,无需纯化直接用于下一步(1.31g,收率88%)。
1H NMR(500MHz,Chloroform-d)δ9.20(s,1H),8.29(s,1H),7.11(s,1H),4.25(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).
在冰浴条件下,将碘甲烷(721mg,5.08mmol)和乙醇钠(109mg,1.60mmol)依次加入到溶有化合物INT-2b(215mg,1.45mmol)的乙醇溶液(5mL)。所得反应液在25℃搅拌1小时。将反应液减压浓缩,加入水(20mL),用乙酸乙酯萃取(20mL×3)。合并的有机相用无水硫酸钠干燥,过滤,滤液减压浓缩后经柱层析纯化(PE/EA=5/1)得到橙黄色油状化合物INT-2(200mg,收率85%)。
1H NMR(500MHz,Chloroform-d)δ4.19(q,J=7.1Hz,2H),2.50(s,3H),1.33(t,J=7.1Hz,3H).
化合物INT-3的制备:
在冰浴条件下,将乙氧羰基异硫氰酸酯(9.47g,72.2mmol)加入至溶有5-氨基吡唑INT-3a(6.00g,72.2mmol)的乙酸乙酯溶液(180mL),所得的反应液在冰浴条件下搅拌2小时。反应液减压浓缩得到橙黄色固体化合物INT-3b(15.5g,收率>99%),所得粗品无需纯化直接用于下一步反应。MS:179.1[M+H]+.
将氢氧化钠水溶液(2M,144mL)加入至装有化合物INT-3b(15.5g)粗品的反应瓶中,在15℃条件下搅拌1小时,然后加入乙醇(72mL)和碘甲烷(10.3g,72.2mmol),所得反应液在15℃条件下搅拌1小时。将析出的白色固体过滤,滤饼干燥后得到白色固体化合物INT-3c(12.9g,收率87%)。1H NMR(500MHz,DMSO-d6)δ7.58(s,1H),5.83(s,1H),2.33(s,3H).
将三氯氧磷(75.1g,45.5mL)加入至装有化合物INT-3c(5.00g,24.5mmol)的反应瓶中,然后加入2,6-二甲基吡啶(10.5g,98.0mmol),所得的反应液在100℃条件下搅拌1小时。反应液减压浓缩,然后加入乙酸乙酯(200mL),将所得的悬浮液倒入冰水中(350mL),萃取,分液,水相再用乙酸乙酯萃取(150mL×2)。合并的有机相用水洗(100mL),饱和食盐水洗(150mL),无水硫酸钠干燥,过滤,滤液减压浓缩得到红色固体化合物INT-3d(4.22g,收率86%)。MS:200.9[M+H]+.
将化合物INT-3d(4.30g,21.4mmol),化合物INT-1(8.75g,23.6mmol)和二氯二(三苯基膦)钯(376mg,536μmol)加入反应瓶中,然后加入N-甲基吡咯烷酮(43mL),所得的反应在85℃液氮气保护条件下搅拌1小时。反应液冷却后倒入水中(400mL),用乙酸乙酯萃取(150mL×3)。合并的有机相用水洗(100mL),饱和食盐水洗(100mL),无水硫酸钠干燥,过滤,滤液减压浓缩后得到的粗品用乙酸乙酯(45mL)重结晶得到黄色固体化合物INT-3e(3.62g,收率68%)。1H NMR(500MHz,DMSO-d6)δ8.33(d,J=2.0Hz,1H),8.30(d,J=3.5Hz,1H),6.60(d,J=3.5Hz,1H),6.58(d,J=2.0Hz,1H),2.56(s,3H),2.49(s,3H);MS:247.2[M+H]+.
在15℃条件下,将N-溴代丁二酰亚胺(1.45g,8.12mmol)加入至化合物INT-3e(2.00g,8.12mmol)的二氯甲烷悬浮液中(60mL),所得的反应液在15℃条件下搅拌30min。加入二氯甲烷(150mL),用水洗(50mL),饱和碳酸氢钠水溶液洗(50mL),饱和食盐水洗(50mL),有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到黄色固体化合物INT-3f(2.62g,收率99%)。1H NMR(500MHz,Chloroform-d)δ8.35(d,J=3.5Hz,1H),8.07(s,1H),6.38(d,J=3.5Hz,1H),2.68(s,3H),2.54(s,3H);MS:325.0[M+H]+.
在冰浴条件下,将间氯过氧苯甲酸(1.80g,8.86mmol,85%纯度)加入至溶有化合物INT-3f(2.62g,8.06mmol)的二氯甲烷溶液(80mL),所得的反应液在冰浴条件下搅拌10分钟。加入二氯甲烷(150mL),然后依次用饱和亚硫酸钠水溶液洗(50mL),饱和碳酸氢钠水溶液洗(50mL),饱和食盐水洗(100mL),有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到黄色固体化合物INT-3g(2.63g,收率95%)。MS:341.1[M+H]+.
在装有化合物INT-3g(2.63g,7.71mmol)的反应瓶中加入氨的1,4-二氧六环溶液(0.4M,154mL),所得的反应液在55℃条件下搅拌30分钟。反应液减压浓缩,得到的粗品用1,4-二氧六环重结晶(50mL)得到黄色固体化合物INT-3(1.70g,收率75%)。1H NMR(500MHz,DMSO-d6)δ8.14(s,1H),8.13(d,J=3.5Hz,1H),7.52(s,2H),6.53(d,J=3.5Hz,1H),2.44(s,3H);MS:294.0[M+H]+.
化合物INT-4的制备:
参照化合物INT-3的制备方法,化合物INT-4可由化合物INT-4a经相应的步骤制备得到,谱图信息如下:1H NMR(500MHz,DMSO-d6)δ8.16(d,J=3.5Hz,1H),7.44(s,2H),6.52(d,J=3.5,1H),2.43(s,3H),2.31(s,3H);MS:308.1[M+H]+.
化合物INT-5的制备:
将5-甲基-2-糠酸(200mg,1.59mmol)加入二氯亚砜中(3mL),所得的反应液升温回流反应1小时。反应液减压浓缩得到的酰氯溶于无水乙腈中(2mL),然后将其缓慢滴加到硫氰酸钾(200.6mg,1.98mmol)的乙腈溶液(10mL),在氮气保护下室温搅拌反应2小时。再将5-氯-1H-吡唑-3-胺(186.4mg,1.59mmol)加入到上述反应液中,在氮气保护下继续室温搅拌反应2小时。反应液减压浓缩得到的粗品用水打浆(15mL),过滤,干燥后得到黄色固体化合物INT-5a(434mg,67%纯度,收率64%)。MS:284.9[M+H]+.
将钠氢(60%纯度,分散在矿物油中,53.1mg,1.33mmol)加入到溶有化合物INT-5a(434mg,67%纯度,1.02mmol)的N,N-二甲基甲酰胺溶液(10mL),室温条件下搅拌10分钟,再加入碘甲烷(145mg,1.02mmol),室温条件下继续搅拌反应1小时,然后在氮气保护条件下,升温至150℃反应过夜。反应冷却后减压浓缩得到的粗品用水打浆(10mL),过滤,干燥后得到淡黄色固体化合物INT-5b(140mg,收率48%)。1H NMR(500MHz,DMSO-d6)δ8.18(d,J=3.5Hz,1H),6.73(s,1H),6.60(d,J=3.5Hz,1H),2.55(s,3H),2.49(s,3H);MS:281.1[M+H]+.
在室温条件下,将N-溴代丁二酰亚胺(88.8mg,0.498mmol)加入至化合物INT-5b(140mg,0.498mmol)的二氯甲烷溶液中(5mL),所得的反应液在室温条件下搅拌30min。用二氯甲烷(60mL)稀释后,用水洗(15mL),饱和碳酸氢钠水溶液洗(15mL),饱和食盐水洗(15mL),有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到黄色固体化合物INT-5c(179mg,收率99%)。MS:359.2[M+H]+.
在冰浴条件下,将间氯过氧苯甲酸(106mg,0.523mmol,85%纯度)加入至溶有化合物INT-5c(179mg,0.498mmol)的二氯甲烷溶液(5mL),所得的反应液在冰浴条件下搅拌10分钟。加入二氯甲烷(60mL),然后依次用饱和亚硫酸钠水溶液洗(15mL),饱和碳酸氢钠水溶液洗(15mL),饱和食盐水洗(15mL),有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到黄色固体化合物粗品INT-5d(195mg,92%纯度,收率95%)。MS:374.5[M+H]+.
在装有化合物INT-5d(195mg,92%纯度,0.473mmol)的反应瓶中加入氨的1,4-二氧六环溶液(0.4M,10mL),所得的反应液在55℃条件下搅拌30分钟。反应液减压浓缩,得到的粗品用1,4-二氧六环重结晶(6mL)得到黄色固体化合物INT-5(123mg,收率74%)。1H NMR(500MHz,DMSO-d6)δ8.06(d,J=3.5Hz,1H),7.69(brs,2H),6.56(d,J=3.5Hz,1H),3.57(s,3H),2.46(s,3H);MS:329.1[M+H]+.
化合物INT-6的制备:
参照化合物INT-5的制备方法,化合物INT-6可由化合物INT-6a经相应的步骤制备得到,谱图信息如下:1H NMR(500MHz,DMSO-d6)δ7.99(d,J=3.5Hz,1H),7.66(brs,2H),6.53(d,J=3.5Hz,1H),3.55(s,3H),2.43(s,3H);MS:312.2[M+H]+.
化合物INT-7的制备:
将碘甲烷(2.79g,19.6mmol)和碳酸钾(2.47g,17.8mmol)依次加入到溶有化合物INT-7a(1.00g,8.92mmol)的N,N-二甲基甲酰胺溶液(10mL)。所得反应液在50℃条件下反应过夜。将反应液过滤,滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯=3/7)得到无色油状化合物INT-7b(424mg,收率33%)。
1H NMR(500MHz,DMSO-d6)δ7.80(d,J=2.2Hz,1H),6.71(d,J=2.2Hz,1H),3.90(s,3H),3.76(s,3H).
将氢氧化锂(145mg,6.05mmol)的水溶液(3.5mL)加入到溶有化合物INT-7b(424mg,3.03mmol)的甲醇(3.5mL)和四氢呋喃(3.5mL)混合溶液。所得反应液在室温条件下搅拌2小时。加入水(15mL),用1M的稀盐酸将反应液的pH调至5~6,然后用乙酸乙酯萃取(20mL×5),合并的有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到白色固体化合物INT-7c(292mg,收率76%)。
参照化合物INT-5的制备方法,化合物INT-7可由化合物INT-7c和化合物INT-2a经相应的步骤制备得到,谱图信息如下:1H NMR(500MHz,DMSO-d6)δ8.13(s,1H),7.94(d,J=2.3Hz,1H),7.53(d,J=2.3Hz,1H),7.50(s,2H),4.00(s,3H);MS:294.0[M+H]+.
实施例化合物的合成
实施例1:
将化合物1a(2.07g,10.2mmol)溶于乙腈(10mL)中,随即在0℃加入三甲基氰硅烷(1.52g,15.3mmol,1.91mL)和四丁基氟化铵(1M的四氢呋喃溶液,15.0mL)。反应液在70℃搅拌40分钟,将反应液加入20mL水中,并用50mL乙酸乙酯萃取。分离得到的有机相经50mL饱和食盐水洗,无水硫酸钠干燥后,在真空条件下浓缩得到的粗产物经柱层析纯化(乙酸乙酯/石油醚=1/10)得到无色油状化合物1b(1.22g,收率:81%)。
将化合物1b(800mg,5.36mmol)溶于N,N-二甲基甲酰胺(8mL)中,随即加入化合物1c(1.40g,8.04mmol)。反应液在110℃搅拌1小时,将反应液加入50mL水中,并用50mL乙酸乙酯萃取。分离得到的有机相经水(50mL×2)和饱和食盐水(50mL)洗,无水硫酸钠干燥后,在真空条件下浓缩得到的粗产物经柱层析纯化(乙酸乙酯/石油醚=1/5)得到黄色固体1d(0.75g,收率:69%)。MS:205.6[M+H]+.
将化合物1d(650mg,3.18mmol)溶于乙醇(6mL)中,随即加入水合肼(3.19g,31.8mmol)。反应液在100℃搅拌48小时,将反应液在真空条件下浓缩得到黄色油状的目标粗产物1e(600mg,收率:99%)。1H NMR(500MHz,DMSO-d6)δ11.27(s,1H),7.26–7.23(m,2H),7.10–7.06(m,3H),4.42(s,2H),3.60(s,2H);MS:192.6[M+H]+.
将化合物1e(600mg,3.14mmol)溶于乙酸乙酯(15mL)中,随即在0℃滴加入化合物1f(412mg,3.14mmol)的乙酸乙酯溶液(5mL)。反应液在0℃搅拌2小时,将反应液在真空条件下浓缩后打浆(乙酸乙酯/石油醚=1/1,15mL)得到白色固体状的目标产物1g(523mg,收率:52%)。MS:323.3[M+H]+.
将化合物1g(523mg,1.62mmol)溶于氢氧化钠水溶液(2M,10.5mL)中。反应液在室温搅拌半小时,用1M盐酸调节反应pH值至6后有大量固体析出。将该固体过滤并在真空条件下干燥后得到白色固体状的目标产物1h(448mg,收率:99%)。MS:277.4[M+H]+.
将化合物1h(224mg,811μmol)溶于乙醇(3mL)中,随即依次加入氢氧化钠水溶液(2M,3.24mL)和碘甲烷(115mg,811μmol,75.2μL)。反应液在室温搅拌1小时,用1M盐酸调节反应pH值至5,并用50mL乙酸乙酯萃取。分离得到的有机相经饱和食盐水(30mL)洗,无水硫酸钠干燥后,在真空条件下浓缩得到白色固体状的目标粗产物1i(235mg,收率:99%)。1HNMR(500MHz,DMSO-d6)δ12.79(s,1H),7.89(s,1H),7.32–7.29(m,2H),7.11–7.08(m,2H),3.87(s,2H),2.55(s,3H);MS:291.3[M+H]+.
将化合物1i(242mg,832μmol)加入三氯氧磷(5.11g,33.3mmol,3.09mL)中,随即加入N,N-二甲基苯胺(478mg,3.94mmol,0.5mL)。反应液在90℃搅拌2小时将反应液缓慢滴加入50mL冰水后,在冰浴条件下,用饱和碳酸氢钠溶液将pH调至8,并用50mL乙酸乙酯萃取。分离得到的有机相经稀盐酸(50mL)和饱和食盐水(50mL)洗,无水硫酸钠干燥后,在真空条件下浓缩得到黄色油状的目标粗产物1j(262mg),无需纯化直接用于下一步。MS:309.2[M+H]+.
在氮气保护下,将化合物1j(262mg,848μmol),INT-1(472mg,1.27mmol)和二氯二(三苯基膦)钯(59.6mg,84.7μmol)加入至N-甲基吡咯烷酮(4mL)中。反应体系再用氮气反复置换3次后,在80℃的条件下搅拌40分钟。将反应液倒入水中(50mL),水相用乙酸乙酯萃取(25mL×2)。将有机层合并,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液在真空条件下浓缩得到的粗产物经柱层析纯化(乙酸乙酯/石油醚=1/4)得到黄色固体1k(175mg,收率:58%)。1H NMR(500MHz,Chloroform-d)δ8.34(d,J=3.5Hz,1H),7.92(s,1H),6.99–6.95(m,1H),6.35(d,J=3.5Hz,1H),4.05(s,2H),2.63(s,3H),2.53(s,3H);MS:355.3[M+H]+.
将化合物1k(100mg,282μmol)加入二氯甲烷(3mL)中,随即加入间氯过氧苯甲酸(143mg,705μmol,纯度85%)。反应液在室温下搅拌1小时,加入二氯甲烷(50mL)稀释,并依次用饱和硫代硫酸钠水溶液(50mL),饱和碳酸氢钠溶液(50mL)以及饱和食盐水(50mL)洗。分离得到的有机相经无水硫酸钠干燥后,在真空条件下浓缩得到白色固体状的目标粗产物1l(109mg,收率:99%),无需纯化直接用于下一步。MS:387.3[M+H]+.
将化合物1l(109mg,282μmol)溶于氨甲醇溶液(7M,4mL)中。反应液在60℃搅拌30分钟,将反应液在真空条件下浓缩得到的粗产物经制备高效液相色谱柱层析纯化得到黄色固体1(16mg,收率:18%)。1H NMR(500MHz,DMSO-d6)δ8.19(d,J=3.0Hz,1H),7.94(s,1H),7.30–7.23(m,2H),7.20(s,2H),7.12–7.05(m,2H),6.53(d,J=3.0Hz,1H),3.85(s,2H),2.46(s,3H);MS:324.4[M+H]+.
实施例2:
将化合物2a(4.00g,28.8mmol)溶于1,4-二氧六环(80mL)中,随即加入二氧化硒(1.59g,14.4mmol)。反应液在65℃搅拌48小时。将反应液过滤得到的滤液在真空条件下浓缩得到的粗产物进行柱层析纯化(乙酸乙酯/石油醚=1/1)得到白色固体2b(3.12g,收率:79%)。
将化合物2c(3.55g,20.1mmol)溶于四氢呋喃(25mL)中,随即在0℃加入叔丁醇钾(2.25g,20.1mmol)。反应液在0℃搅拌30分钟后,加入化合物2b(2.62g,19.1mmol),继续在0℃搅拌30分钟。加入水(100mL),并用乙酸乙酯(100mL×2)萃取。分离得到的有机相经无水硫酸钠干燥后,在真空条件下浓缩得到黄色固体状的一对Z/E异构体混合物2d(3.82g)。MS:161.3[M+H]+.
将化合物2d(1.00g,6.24mmol)溶于四氢呋喃(20mL)中,随即在0℃加入氢化钠(375mg,9.36mmol,60%纯度)。反应液在0℃搅拌30分钟后,加入碘甲烷(975mg,6.87mmol,428μL),反应液在室温搅拌18小时。加入水(100mL)并用乙酸乙酯(100mL×2)萃取。分离得到的有机相经无水硫酸钠干燥后过滤,在真空条件下浓缩后,得到黄色油状的目标粗产物2e(1.07g,收率:98%)。MS:175.1[M+H]+.
将化合物2e(1.07g,6.14mmol)溶于甲醇(20mL)中,随即加入钯(10%吸附在活性炭上,100mg)。反应液在室温以及氢气环境下搅拌18小时,过滤,在真空条件下浓缩后,得到黄色油状的目标粗产物2f(1.06g,收率:98%)。1H NMR(500MHz,Chloroform-d)δ7.69(t,J=7.7Hz,1H),7.34(d,J=7.7Hz,1H),7.15(d,J=7.7Hz,1H),4.58(s,2H),3.51(s,3H),3.14(t,J=7.4Hz,2H),2.86(t,J=7.4Hz,2H);MS:177.6[M+H]+.
将化合物2f(3.05g,17.3mmol)溶于N,N-二甲基甲酰胺(8mL)中,随即加入化合物1c(4.52g,26.0mmol,5.36mL)。反应液在140℃搅拌1.5小时。将反应液加入水(100mL)中,并用乙酸乙酯(100mL×2)萃取。分离得到的有机相经水(100mL)和饱和食盐水(100mL)洗,无水硫酸钠干燥后,在真空条件下浓缩得到的粗产物经柱层析纯化(乙酸乙酯/石油醚=1/5)得到黄色油状液体2g(3.86g,收率:96%)。MS:232.6[M+H]+.
将化合物2g(3.86g,16.7mmol)溶于乙醇(30mL)中,随即加入氢溴酸肼(2.83g,25.0mmol)。反应液在80℃搅拌1小时。将反应液在真空条件下浓缩后,在0℃小心加入饱和碳酸氢钠溶液(50mL)并用二氯甲烷/甲醇混合溶液(10:1,50mL×3)进行萃取。分离得到的有机相经无水硫酸钠干燥,在真空条件下浓缩得到粗产物经柱层析纯化(甲醇/二氯甲烷=1/10)得到黄色油状液体2h(1.37g,收率:38%)。1H NMR(500MHz,DMSO-d6)δ7.69(t,J=7.7Hz,1H),7.20(d,J=7.7Hz,1H),7.13(s,1H),7.11(d,J=7.7Hz,1H),4.46(s,2H),3.72(s,2H),3.35(s,3H);MS:219.6[M+H]+.
将化合物2h(500mg,2.29mmol)溶于乙腈(10mL)中,随即加入化合物INT-2(743.21mg,4.58mmol)。反应液在95℃搅拌18小时后,在真空条件下浓缩,随机加入2M氢氧化钠水溶液(11.45mL),反应液在室温搅拌5小时。用1M盐酸水溶液将反应液pH值调至6,有固体析出。将反应液经过滤得到的固体在真空条件下进行干燥后得到黄色固体状的化合物2i(190mg,收率:29%)。MS:287.4[M+H]+.
将化合物2i(20mg,63.0μmol)溶于1,4-二氧六环(3mL)中,随即加入化合物2j(38.2mg,81.9μmol)和N,N-二异丙基乙胺(24.4mg,189μmol)。反应液在50℃搅拌2小时后,恢复室温,随即加入INT-1(46.8mg,126μmol)和二氯二(三苯基膦)钯(4.42mg,6.30μmol),并用氮气换气3次后升温至80℃反应1小时。将反应液倒入水中(50mL),水相用乙酸乙酯萃取(25mL×2)。将有机层合并,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液在真空条件下浓缩得到的粗产物经制备高效液相色谱柱层析纯化得到黄色固体2(5mg,收率:21%)。1HNMR(500MHz,Methanol-d4)δ8.28(d,J=3.5Hz,1H),7.91(s,1H),7.73(t,J=7.8Hz,1H),7.33(d,J=7.8Hz,1H),7.22(d,J=7.8Hz,1H),6.47(d,J=3.5Hz,1H),4.56(s,2H),4.12(s,2H),3.48(s,3H),2.51(s,3H);MS:351.5[M+H]+.
实施例3:
将化合物2i(50mg,175μmol)溶于1,4-二氧六环(6.5mL)中,随即加入化合物2j(106mg,227μmol)和N,N-二异丙基乙胺(67.7mg,524μmol,92.8μL)。反应液在50℃搅拌40分钟后,恢复室温,随即加入3a(130mg,175μmol)和二氯二(三苯基膦)钯(12.3mg,17.5μmol),并用氮气换气3次后升温至100℃反应1小时。将反应液倒入水中(50mL),水相用乙酸乙酯萃取(25mL×2)。将有机层合并,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液在真空条件下浓缩得到的粗产物经制备高效液相色谱柱层析纯化得到黄色固体3(7.5mg,收率:12%)。1HNMR(500MHz,Methanol-d4)δ8.87(d,J=3.9Hz,1H),7.93(d,J=5.0Hz,1H),7.92(s,1H),7.71(t,J=7.7Hz,1H),7.31(d,J=7.7Hz,1H),7.30–7.28(m,1H),7.21(d,J=7.7Hz,1H),4.54(s,2H),4.11(s,2H),3.45(s,3H);MS353.3[M+H]+.
实施例4:
将化合物2i(30mg,105μmol)溶于1,4-二氧六环(4mL)中,随即加入化合物2j(63.5mg,136μmol)和N,N-二异丙基乙胺(40.6mg,314μmol,55.7μL)。反应液在50℃搅拌40分钟后,恢复室温,随即加入4a(130mg,175μmol)和叔丁醇钠(12.1mg,125μmol),并在50℃反应2小时。将反应液倒入水中(50mL),水相用乙酸乙酯萃取(25mL×2)。将有机层合并,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液在真空条件下浓缩得到的粗产物经制备高效液相色谱柱层析纯化得到黄色固体4(15mg,收率:29%)。1H NMR(500MHz,DMSO-d6)δ9.28(d,J=3.0Hz,1H),8.01(s,1H),7.67(t,J=7.7Hz,1H),7.34(s,2H),7.20(d,J=7.7Hz,1H),7.10(d,J=7.7Hz,1H),6.53(d,J=3.0Hz,1H),4.45(s,2H),3.98(s,2H),3.34(s,3H),2.31(s,3H);MS 351.4[M+H]+.
实施例5和6:
将化合物2(33mg,94.2μmol)溶于二氯甲烷(5mL)中,随即在0℃滴加入三溴化硼(1M的二氯甲烷溶液,188μL)。反应液在0℃搅拌15分钟,加入水(30mL),用饱和碳酸氢钠溶液将pH调至8,并用乙酸乙酯(25mL×2)萃取。将有机层合并,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液在真空条件下浓缩得到的粗产物经制备高效液相色谱柱层析纯化得到黄色固体5(10mg,收率:32%)和黄色固体6(7mg,收率:19%)。化合物5和6的谱图信息如下:
化合物5:1H NMR(500MHz,Methanol-d4)δ8.25(d,J=3.5Hz,1H),7.89(s,1H),7.71(t,J=7.8Hz,1H),7.36(d,J=7.8Hz,1H),7.16(d,J=7.8Hz,1H),6.44(d,J=3.5Hz,1H),4.68(s,2H),4.09(s,2H),2.48(s,3H);MS 337.3[M+H]+.
化合物6:1H NMR(500MHz,Methanol-d4)δ8.25(d,J=3.5Hz,1H),7.91(s,1H),7.70(t,J=7.8Hz,1H),7.36(d,J=7.8Hz,1H),7.21(d,J=7.8Hz,1H),6.44(d,J=3.5Hz,1H),4.59(s,2H),4.11(s,2H),2.48(s,3H);MS 399.1[M+H]+.
实施例7:
将化合物5(183mg,544μmol)溶于二氯甲烷(20mL)中,随即在0℃滴加入二氯亚砜(3.24g,27.20mmol,1.97mL)。反应液在40℃搅拌1.5小时,加入水(10mL),用饱和碳酸氢钠溶液将pH调至8,并用二氯甲烷(50mL×3)萃取。将有机层合并,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液在真空条件下浓缩得到的粗产物经柱层析纯化(乙酸乙酯/石油醚=1/1)得到黄色固体7a(41mg,收率:21%)。MS:355.2[M+H]+.
将化合物7b(72.9mg,958μmol)溶于四氢呋喃(8mL)中,随即在0℃加入氢化钠(46.0mg,1.15mmol,60%纯度)。反应液在0℃搅拌5分钟后,加入化合物7a(34mg,95.8μmol)的四氢呋喃溶液(2mL),反应液在室温搅拌1小时。加入水(10mL)并用乙酸乙酯(20mL×2)萃取。分离得到的有机相经无水硫酸钠干燥后过滤,在真空条件下浓缩得到的粗产物经制备高效液相色谱柱层析纯化得到黄色固体7(4.4mg,收率:12%)。1H NMR(500MHz,Methanol-d4)δ8.28(d,J=3.5Hz,1H),7.92(s,1H),7.73(t,J=7.7Hz,1H),7.39(d,J=7.7Hz,1H),7.22(d,J=7.7Hz,1H),6.47(d,J=3.5Hz,1H),4.66(s,2H),4.12(s,2H),3.76–3.72(m,2H),3.65–3.61(m,2H),3.40(s,3H),2.51(s,3H);MS 395.4[M+H]+.
实施例8:
将化合物7a(6.35mg,84.6μmol)和N,N-二异丙基乙胺(10.9mg,84.6μmol,14.0uL)溶于乙腈(2mL)中,随即加入化合物8a(15.0mg,42.3μmol)。反应液在80℃搅拌3小时后,在真空条件下浓缩得到的粗产物经制备高效液相色谱柱层析纯化得到黄色固体8(5.0mg,收率:30%)。1H NMR(500MHz,DMSO-d6)δ8.17(d,J=3.5Hz,1H),7.97(s,1H),7.61(t,J=8.0Hz,1H),7.20(d,J=8.0Hz,1H),7.18(s,2H),7.04(d,J=8.0Hz,1H),6.55–6.49(m,1H),3.97(s,2H),3.80(s,2H),3.40(t,J=5.5Hz,2H),3.22(s,3H),2.71(t,J=5.5Hz,2H),2.44(s,3H);MS 394.4[M+H]+.
实施例9:
将化合物7a(114.59mg,1.97mmol)溶于四氢呋喃(8mL)中,随即在0℃加入氢化钠(94.7mg,2.37mmol,60%纯度)。反应液在0℃搅拌5分钟后,加入化合物9a(70mg,197μmol),反应液在室温搅拌4小时。加入水(15mL)并用乙酸乙酯(30mL×2)萃取。分离得到的有机相经无水硫酸钠干燥后过滤,在真空条件下浓缩得到的粗产物经制备高效液相色谱柱层析纯化得到黄色固体9(4.4mg,收率:5%)。1H NMR(500MHz,Methanol-d4)δ8.25(d,J=3.5Hz,1H),7.89(s,1H),7.70(t,J=7.5Hz,1H),7.30(d,J=7.5Hz,1H),7.19(d,J=7.5Hz,1H),6.44(d,J=3.5Hz,1H),4.64(s,2H),4.10(s,2H),3.48–3.43(m,1H),2.48(s,3H),0.65–0.61(m,2H),0.54–0.47(m,2H);MS 377.4[M+H]+.
实施例10:
参照化合物2h的制备方法,化合物10b可由化合物10a经相应步骤制备得到,化合物10b的谱图信息如下:1H NMR(500MHz,Chloroform-d)δ7.15(s,1H),7.13–7.09(m,1H),6.82–6.78(m,2H),5.05(s,2H),3.68(s,2H).
参照化合物1的制备方法,化合物10可由化合物10b经相应步骤制备得到,化合物10谱图信息如下:1H NMR(500MHz,Chloroform-d)δ8.50(d,J=3.6Hz,1H),7.92(s,1H),7.49–7.42(m,1H),6.83–6.76(m,2H),6.45(d,J=3.6Hz,1H),4.02(s,2H),2.56(s,3H);MS342.3[M+H]+.
实施例11:
参照化合物10的制备方法,化合物11可由化合物11a经相应步骤制备得到,化合物11的谱图信息如下:1H NMR(500MHz,Chloroform-d)δ8.36(d,J=3.5Hz,1H),7.69(s,1H),7.29(s,2H),7.18–7.10(m,1H),6.93–6.88(m,1H),6.87–6.80(m,1H),6.38(d,J=3.5Hz,1H),3.91(s,2H),2.56(s,3H),2.34(s,3H);MS:338.3[M+H]+.
实施例12:
参照化合物10的制备方法,化合物12可由化合物12a经相应步骤制备得到,化合物12的谱图信息如下:1H NMR(500MHz,Chloroform-d)δ8.32(d,J=3.5Hz,1H),7.79(s,1H),6.69–6.61(m,2H),6.34(d,J=3.5Hz,1H),5.26(s,2H),3.95(s,2H),2.52(s,3H);MS:360.3[M+H]+.
实施例13:
参照化合物10的制备方法,化合物13可由化合物13a经相应步骤制备得到,化合物13的谱图信息如下:1H NMR(500MHz,Methanol-d4)δ8.25(d,J=3.5Hz,1H),7.84(s,1H),6.44(d,J=3.5Hz,1H),2.48(s,3H),2.46(d,J=7.0Hz,2H),2.21–2.16(m,1H),2.05–2.00(m,1H),1.72–1.70(m,3H),1.66-1.63(m,1H),1.60–1.55(m,1H),1.23–1.18(m,2H),1.02–0.87(m,2H);MS:312.5[M+H]+.
实施例14:
参照化合物10的制备方法,化合物14可由化合物14a经相应步骤制备得到,化合物14的谱图信息如下:1H NMR(500MHz,Chloroform-d)δ8.38(d,J=3.5Hz,1H),7.90(s,1H),6.38(d,J=3.5Hz,1H),5.42(s,2H),2.55(s,3H),2.20(m,2H),1.89–1.49(m,9H);MS:298.4[M+H]+.
实施例15:
参照化合物10的制备方法,化合物15可由化合物15a经相应步骤制备得到,化合物15的谱图信息如下:1H NMR(500MHz,Chloroform-d)δ8.37(d,J=3.5Hz,1H),7.87(s,1H),6.37(d,J=3.5Hz,1H),5.26(s,2H),2.72(d,J=7.5Hz,2H),2.66(m,1H),2.55(s,3H),2.15–2.07(m,2H),1.91–1.85(m,2H),1.78–1.74(m,2H);MS:284.4[M+H]+.
实施例16:
参照化合物10的制备方法,化合物16可由化合物16a经相应步骤制备得到,化合物16的谱图信息如下:1H NMR(500MHz,Chloroform-d)δ8.36(d,J=3.4Hz,1H),8.04(s,1H),7.45(t,J=7.7Hz,1H),6.76(d,J=7.7Hz,1H),6.55(d,J=7.7Hz,1H),6.35(d,J=3.4Hz,1H),5.32(s,2H),4.04(s,2H),3.94(s,3H),2.53(s,3H);MS 337.4[M+H]+.
实施例17:
将化合物17b(1.55g,17.6mmol)溶于四氢呋喃(45mL)中,随即在0度加入氢化钠(1.06g,26.4mmol,60%纯度)。反应液在0℃搅拌1小时后,加入化合物17a(3.10g,17.6mmol),反应液在60℃搅拌18小时。恢复室温后加入饱和氯化铵溶液(50mL)并用乙酸乙酯(50mL×2)萃取。分离得到的有机相经无水硫酸钠干燥后过滤,在真空条件下浓缩得到粗产物经柱层析纯化得到黄色油状的化合物17c(1.93g,收率:48%)。MS:228.6[M+H]+.
将化合物17c(930mg,4.08mmol)溶于乙腈(10mL)中,随即在0℃加入N-甲基N-氧化吗啉(957mg,8.17mmol)和碘化钾(67.8mg,408μmol)。反应液在70℃搅拌6小时,在真空条件下浓缩,加入水(50mL),并用乙酸乙酯(50mL×2)萃取。分离得到的有机相经无水硫酸钠干燥后过滤,在真空条件下浓缩得到黄色油状的目标粗产物17d(560mg,收率:66%)。MS:208.8[M+H]+.
参照化合物2h的制备方法,化合物17e可由化合物17d经相应步骤制备得到,化合物17e的谱图信息如下:1H NMR(500MHz,Chloroform-d)δ7.64(t,J=7.7Hz,1H),7.31(d,J=7.7Hz,1H),7.26(s,1H),7.09(d,J=7.7Hz,1H),4.66–4.59(m,2H),4.31–4.28(m,1H),4.00–3.93(m,2H),3.89–3.88(m,3H),3.52(s,2H),2.11–2.03(m,2H);MS:275.7[M+H]+.
参照化合物1的制备方法,化合物17可由化合物17e经相应步骤制备得到,相关中间体17f及化合物17的谱图信息如下:
化合物17f:MS:437.3[M+H]+.
化合物17:1H NMR(500MHz,Methanol-d4)δ8.27(d,J=3.5Hz,1H),8.02(s,1H),7.54(d,J=7.8Hz,1H),7.46(t,J=7.8Hz,1H),7.26(d,J=7.8Hz,1H),6.45(d,J=3.5Hz,1H),4.85(d,J=11.0Hz,1H),4.78(d,J=11.0Hz,2H),4.41–4.40(m,1H),4.22(s,2H),3.96–3.91(m,2H),3.87–3.82(m,2H),2.49(s,3H),2.14–2.10(m,2H);MS 423.3[M+H]+.
实施例18:
参照化合物2的制备方法,化合物18可由化合物17e经相应步骤制备得到,化合物18的谱图信息如下:1H NMR(500MHz,Methanol-d4)δ8.28(d,J=3.5Hz,1H),7.92(s,1H),7.73(t,J=7.7Hz,1H),7.36(d,J=7.7Hz,1H),7.22(d,J=7.7Hz,1H),6.47(d,J=3.5Hz,1H),4.66–4.60(m,2H),4.35–4.33(m,1H),4.12(s,2H),3.95–3.90(m,2H),3.86–3.85(m,2H),2.51(s,3H),2.05-2.04(m,2H);MS407.1[M+H]+.
实施例19:
将化合物19a(5.00g,25.0mmol)溶于无水乙醚(80mL)中,随即在0℃滴加入甲基溴化镁(3M的四氢呋喃溶液,12mL)。反应液在0℃搅拌1小时后,加入水(100mL)并用乙酸乙酯(100mL×2)萃取。分离得到的有机相经无水硫酸钠干燥后过滤,在真空条件下浓缩后,得到黄色油状的目标产物19b(5.25g,收率:97%)。1H NMR(500MHz,Chloroform-d)δ7.55(t,J=7.7Hz,1H),7.38–7.34(m,2H),4.07(s,1H),1.54(s,6H);MS:216.3[M+H]+.
将化合物19b(3.95g,18.3mmol)和化合物19c(1.94g,36.6mmol,2.41mL)溶于N,N-二甲基甲酰胺(30mL)中,随即加入三乙胺(3.70g,36.6mmol,5.07mL),三(邻甲基苯基)磷(1.11g,3.66mmol)和醋酸钯(410mg,1.83mmol)。反应体系用氮气反复置换3次后,在100℃的条件下搅拌18小时。反应液经硅藻土过滤后加入水(100mL),并用乙酸乙酯(100mL×2)萃取。合并的有机相经水(100mL×2)和饱和食盐水(50mL)洗,无水硫酸钠干燥后,在真空条件下浓缩得到的粗产物经柱层析纯化(乙酸乙酯/石油醚=1/2)得到黄色油状液体19d(3.2g,收率:93%)。MS:189.5[M+H]+.
参照化合物2的制备方法,化合物19可由化合物19d经相应步骤制备得到,化合物19的谱图信息如下:1H NMR(500MHz,Methanol-d4)δ8.28(d,J=3.5Hz,1H),7.96(s,1H),7.68(t,J=7.8Hz,1H),7.43(d,J=7.8Hz,1H),7.14(d,J=7.8Hz,1H),6.47(d,J=3.5Hz,1H),4.13(s,2H),2.51(s,3H),1.55(s,6H);MS 365.4[M+H]+.
实施例20:
将化合物20a(7.00g,37.2mmol)溶于二甲基亚砜(30mL)中,随即加入2-碘酰基苯甲酸(11.0g,39.1mmol)。反应液在室温搅拌2小时后,加入水(100mL)并过滤。滤液用乙酸乙酯(100mL×2)萃取。分离得到的有机相经饱和碳酸氢钠(100mL),水(100mL×2)和饱和食盐水(100mL)洗,无水硫酸钠干燥后,过滤,在真空条件下浓缩得到白色固体状的目标粗产物20b(6.0g,收率:87%)。1H NMR(500MHz,DMSO-d6)δ9.90(s,1H),8.04–7.96(m,3H).
将化合物2c(5.48g,31.0mmol)溶于四氢呋喃(50mL)中,随即在0℃加入叔丁醇钾(3.47g,31.0mmol)。反应液在0℃搅拌30分钟后,加入化合物20b(5.70g,30.6mmol),继续在0℃搅拌30分钟。加入水(100mL),并用乙酸乙酯(100mL×2)萃取。分离得到的有机相经无水硫酸钠干燥后,在真空条件下浓缩得到黄色固体状的一对Z/E异构体混合物20c(6.40g,收率:99%)。MS:209.3[M+H]+.
将化合物20c(5.55g,26.6mmol)溶于异丙醇(15mL)中,随即加入硼氢化钠(2.01g,53.1mmol)。反应液在80℃搅拌10小时后,加入水(100mL)并用乙酸乙酯(100mL×2)萃取。分离得到的有机相经无水硫酸钠干燥后过滤,在真空条件下浓缩得到的粗产物经柱层析纯化(乙酸乙酯/石油醚=1/1)得到黄色油状液体20d(4.0g,收率:52%)。MS:211.3[M+H]+.
将化合物20d(500mg,2.37mmol)和苄胺(381mg,3.55mmol,388μL)溶于甲苯(10mL)中,随即加入催化剂20e(108mg,118μmol),1,1'-联萘-2,2'-双二苯膦(148mg,237μmol)和叔丁醇钠(319mg,3.32mmol)。反应体系用氮气反复置换3次后,在100℃的条件下搅拌1.5小时。反应液经硅藻土过滤后,在真空条件下浓缩得到的粗产物经柱层析纯化(乙酸乙酯/石油醚=1/2)得到黄色油状液体20f(522mg,收率:93%)。1H NMR(500MHz,Chloroform-d)δ7.38-7.35(m,5H),7.31–7.29(m,1H),6.52(d,J=7.2Hz,1H),6.29(d,J=8.2Hz,1H),4.88(s,1H),4.54(d,J=5.8Hz,2H),2.97(t,J=7.4Hz,2H),2.78(t,J=7.4Hz,2H);MS:238.5[M+H]+.
参照化合物1的制备方法,化合物20可由化合物20f经相应步骤制备得到,化合物20的谱图信息如下:1H NMR(500MHz,Methanol-d4)δ8.36(d,J=3.5Hz,1H),7.95(s,1H),7.44–7.40(m,3H),7.37–7.34(m,2H),7.28(t,J=7.3Hz,1H),6.55(d,J=3.5Hz,1H),6.54(d,J=7.3Hz,1H),6.42(d,J=7.3Hz,1H),4.59(s,2H),4.00(s,2H),2.59(s,3H);MS 412.4[M+H]+.
实施例21:
参照化合物20的制备方法,化合物21可由化合物20d和化合物21a经相应步骤制备得到,具体谱图信息如下:1H NMR(500MHz,Methanol-d4)δ8.36(d,J=3.5Hz,1H),8.02(s,1H),7.48(t,J=8.0Hz,1H),6.57–6.55(m,2H),6.50(d,J=8.5Hz,1H),4.02(s,2H),3.66(t,J=5.4Hz,2H),3.57(t,J=5.4Hz,2H),3.44(s,3H),2.59(s,3H);MS 380.4[M+H]+.
实施例22:
参照化合物20的制备方法,化合物22a可由化合物20d和对甲氧基苄胺经相应步骤制备得到,谱图信息如下:MS 442.5[M+H]+.
将化合物22a(40mg,90.6μmol)溶于三氟乙酸(1mL)。反应液在25℃搅拌2小时,将反应液在真空条件下浓缩后加入乙酸乙酯(30mL)稀释,并用饱和碳酸氢钠水溶液(15mL)洗涤,分离得到的有机相经饱和食盐水(15mL)洗涤,无水硫酸钠干燥以及浓缩得到的粗产物经制备高效液相色谱柱层析纯化得到黄色固体22(15mg,收率:52%)。1H NMR(500MHz,Methanol-d4)δ8.27(d,J=3.5Hz,1H),7.93(s,1H),7.62(t,J=8.0Hz,1H),6.65(d,J=8.0Hz,1H),6.60(d,J=8.0Hz,1H),6.45(d,J=3.5Hz,1H),4.00(s,2H),2.48(s,3H);MS322.3[M+H]+.
实施例23:
参照化合物22的制备方法,化合物23可通过市售试剂制备得到,具体谱图信息如下:1H NMR(500MHz,Methanol-d4)δ8.35(d,J=3.5Hz,1H),7.98(s,1H),7.97(d,J=1.8Hz,1H),7.66(t,J=8.0Hz,1H),6.81(dd,J=3.5,1.8Hz,1H),6.69(d,J=8.0Hz,1H),6.63(d,J=8.0Hz,1H),4.02(s,2H);MS 308.3[M+H]+.
实施例24:
将化合物24a(500mg,4.06mmol)溶于四氢呋喃(5mL)中,随即加入二碳酸二叔丁酯(975mg,4.47mmol,1.03mL)。反应液在30℃搅拌18小时后,加入水(40mL),并用乙酸乙酯(30mL×2)萃取。分离得到的有机相经无水硫酸钠干燥后,在真空条件下浓缩得到黄色油状的粗产物24b(906mg,收率:99%)。
1H NMR(500MHz,Chloroform-d)δ7.45(s,1H),7.28(t,J=7.5Hz,1H),7.22(d,J=7.5Hz,1H),7.04(d,J=7.5Hz,1H),6.49(s,1H),4.67(s,2H),1.52(s,9H).
将化合物24b(150mg,672μmol)和四溴化碳(290mg,874μmol)溶于二氯甲烷(5mL)中,随即加入三苯基膦(229mg,874μmol)。反应液在30℃搅拌3小时后,在真空条件下浓缩得到的粗产物柱层析纯化(乙酸乙酯/石油醚=1/10)得到白色固体24c(140mg,收率:73%)。1H NMR(500MHz,Chloroform-d)δ7.51(s,1H),7.27–7.25(m,1H),7.21-7.19(m,1H),7.07–7.05(m,1H),6.48(s,1H),4.46(s,2H),1.52(s,9H).
在氮气保护下,在锌粉(48.0mg,734μmol)的N,N-二甲基甲酰胺(3mL)的悬浮液中加入碘(8.99mg,35.43μmol),在30℃搅拌直至溶液褪色至无色,随后滴加入化合物24c(140mg,489μmol)的N,N-二甲基甲酰胺(3mL)溶液。反应液在30℃搅拌1小时。将化合物INT-3(71.94mg,244.61μmol),醋酸钯(71.9mg,244.6μmol)和配体24d(23.3mg,48.9μmol)加入反应体系。反应体系再用氮气反复置换3次后,在30℃的条件下搅拌40分钟。反应液倒入水中(50mL),水相用乙酸乙酯萃取(25mL×2)。将有机层合并,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液在真空条件下浓缩得到的粗产物经柱层析纯化(乙酸乙酯/石油醚=1/1)得到黄色固体24e(32mg,收率:31%)。MS:421.5[M+H]+.
将化合物24e(32mg,76.1μmol)溶于二氯甲烷(0.5mL)中,随即滴加入4M的盐酸二氧六环溶液(1.52mL)。反应液在25℃搅拌3小时,将反应液在真空条件下浓缩后打浆(乙酸乙酯,10mL)得到黄色固体状的目标产物24(18mg,收率:66%)。1H NMR(500MHz,Methanol-d4)δ8.47(d,J=3.7Hz,1H),7.97(s,1H),7.49(t,J=7.8Hz,1H),7.43(d,J=7.8Hz,1H),7.32(t,J=1.9Hz,1H),7.25(d,J=7.8Hz,1H),6.58(d,J=3.7Hz,1H),4.10(s,2H),2.52(s,3H);MS:321.3[M+H]+.
测试实施例
A2A/A2B受体拮抗功能实验测试:
A2A细胞系来源于PerkinElmer(产品编号:ES-011-C);A2B细胞系来源于PerkinElmer(产品编号:ES-013-C)。实验步骤参照ACS Medicinal Chemistry Letters(2011)2,213–218;具体测试由北京康龙化成新药技术有限公司完成,步骤如下:室温条件下,依次将10nL化合物的DMSO贮备液(10mM)、10μL A2A或A2B细胞悬液(30000个细胞/mL)转移至384孔板的测定孔中,在室温条件下孵育20分钟。将EC80激活浓度下对应的5’-N-ethylcarboxamidoadenosine的量转移至各个测试孔中,在37℃,5%CO2,95%湿度的条件下进一步孵育30分钟后,依次将Eu-cAMP示踪剂工作溶液和Ulight-anti-cAMP工作溶液以5uL/孔添加至细胞培养板,并用Envision读取细胞板荧光值(激发光波长:320nm,发射光波长:665nm和615nm)。按照下述公式得到每个孔中相对应的抑制率,使用非线性回归模型绘制S型剂量-抑制率曲线并计算得到IC50值。
实施例中所列化合物对于A2A/A2B受体结合亲和力以及拮抗功能活性结果:
Claims (3)
2.如权利要求1所述的方法,其特征在于包括以下步骤:
步骤(1):在冰浴条件下,将化合物INT-2a加入到氨的乙醇溶液中(2M,7.50mL),所得反应液在冰浴条件下搅拌1小时,将反应液减压浓缩得到黄色固体化合物INT-2b,无需纯化直接用于下一步(1.31g,收率88%)。
3.如权利要求1所述的方法,其特征在于包括以下步骤:
步骤(2):在冰浴条件下,将碘甲烷和乙醇钠)依次加入到溶有化合物INT-2b的乙醇溶液(5mL),所得反应液在25℃搅拌1小时;将反应液减压浓缩,加入水,用乙酸乙酯萃取(20mL×3),合并的有机相用无水硫酸钠干燥,过滤,滤液减压浓缩后经柱层析纯化(PE/EA=5/1)得到橙黄色油状化合物INT-2。
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US20210032253A1 (en) * | 2018-02-06 | 2021-02-04 | Jiangsu Hengrui Medicine Co., Ltd. | Pyrazolo[1,5-a][1,3,5]triazine-2-amine derivative, preparation method therefor and medical use thereof |
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2020
- 2020-07-24 CN CN202011471157.4A patent/CN112608316B/zh active Active
- 2020-07-24 CN CN202011471125.4A patent/CN112479956A/zh active Pending
- 2020-07-24 CN CN202010724029.XA patent/CN112028891B/zh active Active
- 2020-07-24 CN CN202011471074.5A patent/CN112592346B/zh active Active
- 2020-07-24 CN CN202011472050.1A patent/CN112500416B/zh active Active
- 2020-07-24 CN CN202011471058.6A patent/CN112574214B/zh active Active
- 2020-07-29 JP JP2022506061A patent/JP7436630B2/ja active Active
- 2020-07-29 US US17/630,887 patent/US20220339160A1/en active Pending
- 2020-07-29 EP EP20847935.2A patent/EP4006033A4/en active Pending
- 2020-07-29 WO PCT/CN2020/105429 patent/WO2021018173A1/zh unknown
Patent Citations (1)
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EP1555264A1 (en) * | 2004-01-15 | 2005-07-20 | Sireen AG | Five-membered heterocyclic compounds as inhibitors of SRC family protein kinase. |
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Title |
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TAM, STEVE Y. K.等: "Nucleosides. 112. Synthesis of some new pyrazolo[1,5-a]-1,3,5-triazines and their C-nucleosides", 《JOURNAL OF ORGANIC CHEMISTRY》, vol. 44, no. 25, 31 December 1979 (1979-12-31), pages 4547 - 53, XP002390906, DOI: 10.1021/jo00393a019 * |
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EP4006033A4 (en) | 2023-05-24 |
CN112592346B (zh) | 2022-04-26 |
CN112500416A (zh) | 2021-03-16 |
CN112592346A (zh) | 2021-04-02 |
CN112608316A (zh) | 2021-04-06 |
US20220339160A1 (en) | 2022-10-27 |
CN112028891B (zh) | 2022-07-05 |
CN112574214B (zh) | 2021-09-28 |
JP7436630B2 (ja) | 2024-02-21 |
WO2021018173A1 (zh) | 2021-02-04 |
JP2022542385A (ja) | 2022-10-03 |
CN112028891A (zh) | 2020-12-04 |
CN112500416B (zh) | 2021-12-17 |
CN112608316B (zh) | 2022-10-21 |
CN112574214A (zh) | 2021-03-30 |
EP4006033A1 (en) | 2022-06-01 |
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