CN105801603B - 一种具有大环结构的alk抑制剂及其制备方法 - Google Patents
一种具有大环结构的alk抑制剂及其制备方法 Download PDFInfo
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- CN105801603B CN105801603B CN201610229246.5A CN201610229246A CN105801603B CN 105801603 B CN105801603 B CN 105801603B CN 201610229246 A CN201610229246 A CN 201610229246A CN 105801603 B CN105801603 B CN 105801603B
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- C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, 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
- C07D515/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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Abstract
本发明公开了一种具有大环结构的ALK抑制剂及其制备方法,该抑制剂包括式(Ⅰ),是在大环化合物长链结构上引入强电负性原子,可用作ALK抑制剂,对ALK活性具有明显的抑制作用,该制备方法简单可行,成本低,制备出的具有大环结构的ALK抑制剂使用小剂量就可起到很好的抑制效果,利用率较高,在使用过程中不易发生不良反应。
Description
技术领域
本发明属于药物化学领域,具体涉及一种具有大环结构的ALK抑制剂及其制备方法。
背景技术
肺癌是世界上最常见的恶性肿瘤,《2014年中国肿瘤登记年报》显示肺癌的发病率与死亡率均居恶性肿瘤之首。其中非小细胞肺癌(non-small cell lung cancer,NSCLC)所占的比例最高,约占80%左右。对于晚期NSCLC患者,常规化疗对改善其预后的效果十分有限,患者生存时间不足1年。与传统治疗方式相比,近年来,通过靶向癌症特异基因突变药物的研究与开发,人们逐渐发现靶向特定位点药物治疗具有选择性好、安全性较高的优点。
ALK(渐变性淋巴激酶)是一种受体型蛋白酪氨酸磷酸激酶,属于胰岛素受体超家族,能够接受细胞外的信号,调控细胞的生长、分化、存活和转化。 ALK基因能够与其他基因融合,表达异常的融合蛋白,促进癌细胞的生长。ALK 基因重排可导致致癌融合蛋白的表达,与NSCLC的发生有关,因此是肺癌治疗中的重要靶点。
2007年在非小细胞肺癌中首次发现了ALK融合基因EML4-ALK之后,引发了靶向ALK抑制剂药物的研发热潮。第一代EML4-ALK融合基因抑制剂克唑替尼于2011年获得美国食品药品管理局(FDA)批准上市,之后有效性与安全性更佳的第二代ALK靶向抑制剂于色瑞替尼也在2014年4月29日经FDA 批准上市。
色瑞替尼是一种口服的、选择性酪氨酸激酶抑制剂,主要作用机制是可剂量依赖性的抑制ALK自身以及ALK介导的下游信号蛋白的磷酸化,继而阻断 ALK阳性癌细胞的增殖。但在给药过程中,依然存在临床给药量大(750mg/天),生物利用度低,剂量依赖性等问题。同时在临床实验中该药也表现出很多不良反应,如腹泻、恶心、呕吐、腹痛等,另外也观察到肝酶、胰腺和血糖水平增高的现象。
发明内容
本发明针对上述不足之处而提供的一种具有大环结构的ALK抑制剂及其制备方法,有效解决了给药量大,利用率低,发生不良反应的问题。
为实现上述目的,本发明解决其技术问题所采用的技术方案是:
一种具有大环结构的ALK抑制剂,包括式(Ⅰ):
其中,R1、R2可以独立地选自氢原子、卤素原子、氨基、氰基、巯基、C1~C3直链或支链烷基;所述烷基上氢原子可以被卤素、羟基、氨基、氰基、羟基、巯基取代;
R3、R4可以独立地选自氢原子、卤素原子或与其连接的碳原子一起形成含有1-2个选自N、O、S的杂原子的5-6元杂芳基;
W可以选自以下基团:
其中哌啶环虚线处可以为单键也可以为双键;
R5为C1~C3直链或支链烷基;
R6为氢原子、C1~C3直链或支链烷基、-SO2Ra、-PO(-ORa)2、-COCHRbRc、 -COORd或-CONHRd;
其中,Ra为氢原子或C1~C3直链或支链烷基;所述烷基上的氢原子可以被卤素、羟基、氨基、氰基、羟基、巯基取代;
Rb为氢原子或C1~C3直链或支链烷基;所述烷基上的氢原子可以被卤素、羟基、氨基、氰基、羟基、巯基取代;
Rc为羟基、巯基、氨基或C1~C3直链或支链烷基;所述烷基上的氢原子可以被卤素、羟基、氨基、氰基、羟基、巯基取代;
Rd为C1~C3直链或支链烷基;所述烷基上的氢原子可以被卤素、羟基、氨基、氰基、羟基、巯基取代;
R9为氢原子、羟基、氨基、氰基、巯基、C1~C3直链或支链烷基;所述烷基上的氢原子可以被卤素、羟基、氨基、氰基、羟基、巯基取代;
G1、G2可以独立地选自碳原子、氧原子、硫原子、磷原子、-C=O、-C=S、 -S=O、-S(=O)2、-P(=O)2、-P=O;
X为C4~C12的烷烃、C4~C12的烯烃、C4~C12的炔烃或含有0、1、2、3、4 个选自O、S、-S=O、-S(=O)2、-P(=O)2基团的C4~C12的烷烃、烯烃或炔烃;
R7、R8可以独立地选自氢原子、C1~C6直链或支链烷基;
进一步优选为含式(Ⅱ)的化合物:
其中,哌啶环虚线处可以为单键也可以为双键;
R1、R2可以独立地选自氢原子、卤素原子、C1~C3直链或支链烷基;
R3、R4可以独立地选自氢原子或卤素原子;
R5为C1~C3直链或支链烷基;
R7、R8可以独立地选自氢原子、C1~C3直链或支链烷基;
G1、G2可以独立地选自碳原子、氧原子、硫原子、-S=O、-S(=O)2;
X为C4~C12的烷烃、C4~C12的烯烃、C4~C12的炔烃或含有0、1、2、3、4 个选自O、S、-S=O、-S(=O)2、-P(=O)2基团的C4~C12的烷烃、烯烃或炔烃;
进一步地,大环结构的ALK抑制剂,选自以下结构:
进一步地,一种具有大环结构的ALK抑制剂,选自以下结构:
本发明提供的一种具有大环结构的ALK抑制剂及其制备方法,具有以下几种有益效果:
(1)本发明提供的大环化合物,是在大环化合物长链结构上引入强电负性原子,可用作ALK抑制剂,对ALK活性具有明显的抑制作用。
(2)该制备方法简单可行,成本低,制备出的具有大环结构的ALK抑制剂使用小剂量就可起到很好的抑制效果,利用率较高,在使用过程中不易发生不良反应。
(3)本发明提供的具有大环结构的ALK抑制剂具有广阔的抗癌症及恶性肿瘤的应用前景,如可治疗非小细胞肺癌、乳腺癌、畸形癌、食管鳞状细胞癌、间变性大细胞淋巴瘤、成神经细胞瘤、淋巴性造血瘤、炎性成肌纤维细胞肿瘤、黑素瘤、精原细胞瘤、胶质瘤、间充质起原的肿瘤、髓性造血瘤等。
具体实施方式
下面的缩写具有如下所示的意义:DMSO表示二甲亚砜;DMF表示N,N- 二甲基甲酰胺;LDA表示二异丙基氨基锂;K2CO3表示碳酸钾;DMAP表示4- 二甲氨基吡啶;TsCl表示对甲基苯磺酰氯;Na2SO4表示硫酸钠;MCPBA表示间氯过氧苯甲酸;THF表示四氢呋喃;KHCO3表示碳酸氢钾;t-BuONa表示叔丁醇钠;浓HCl表示浓盐酸;Ac2O表示乙酸酐;NaI表示碘化钠;KNO3表示硝酸钾;Cs2CO3表示碳酸铯;NaOH表示氢氧化钠;Pd/C表示钯碳;Pd(dppf) Cl2表示1,1-二(二苯膦基)二茂铁二氯化钯;BINAP表示1,1'-联萘-2,2'-双二苯膦;Pd2(dba)3表示三(二亚苄基丙酮)二钯;Grubbs II表示Grubbs二代催化剂;DIEA表示二异丙基乙胺;DCM表示二氯甲烷;TEA表示三乙胺;TFA 表示三氟乙酸;EA表示乙酸乙酯;MeOH表示甲醇;(BOC)2O表示二碳酸二叔丁酯;OTs是表示对甲基苯磺酸酯;m-CPMA是表示间氯过氧苯甲酸;i-PrOH 是表示异丙醇;rt表示室温。
实施例1 24-氯-6,7,9,12,13,14六氢-18-甲基-17-(4-哌啶基)-26H-21,25-亚氨基-20H-二苯并[b,k][1,16,13,4,6,10]二氧杂硫杂三氮杂环二十二碳烯-5,5-二氧化物(化合物1)的制备
合成步骤如下:
具体步骤如下:
步骤1:对甲基苯磺酸-2-烯丙氧基乙酯(1b)的制备
在氮气保护下于0℃,向装有烯丙基羟乙基醚(9.99g,97.72mmol),DMAP (0.39g,2.93mmol),TEA(49.48g,489.08mmol)的DCM(80mL)溶液中慢慢加入TsCl(46.62g,244.54mmol)的DCM(100mL)溶液,之后待反应混合物自然升高到室温并继续搅拌6h,TLC显示原料反应完成后,反应液用水淬灭,用DCM萃取3次,每次100mL,有机相用饱和食盐水洗涤2次,每次50mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=100:1~20: 1)纯化得到目标化合物20g,为无色油状物,产率为79.9%;
步骤2:3,6-二氢-4-[[(三氟甲基)磺酰]氧基]-1(2H)-吡啶甲酸叔丁酯(1d) 的制备
在氮气保护下,于-78℃向装有二异丙胺(9.14g,90.33mmol)的50mL THF 溶液中慢慢滴加n-BuLi(36.28mL,72.57mmol,2mol/L THF),该反应混合物在 -78℃下搅拌1h以后,再滴加含N-Boc-4-哌啶酮(14.98g,75.18mmol)的30mL THF溶液,该反应混合物在-78℃下搅拌2h,然后在室温搅拌30min,再在-78℃下,向反应体系中慢慢滴加N-苯基双(三氟甲烷磺酰)亚胺(28.21g,75.118mmol) 的50mL THF溶液,待反应混合物自然升高到室温并继续搅拌8h,TLC显示反应完成后,反应液用水淬灭,然后用EA萃取3次,每次50mL,有机相用无水 Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=100:1~40:1)纯化得到20.9g目标化合物,为无色油状物,产物为83.9%;
1H NMR(400MHz,CDCl3)δ1.47-1.48(9H,s),2.44-2.45(2H,m),3.63-3.64 (2H,m),4.05-4.06(2H,m),5.77-5.88(1H,m)
步骤3:2-(2-烯丙氧基)乙基硫代苯胺(1f)的制备
在氮气保护下,向装有2-氨基苯硫醇(3.00g,23.96mmol)的30mL甲醇溶液中加入KHCO3(2.42g,28.76mmol)的水溶液10mL,之后再慢慢滴加1b(6.75 g,26.36mmol)的甲醇溶液10mL,反应体系在室温条件下继续搅拌6h,TLC 显示反应完成后,真空蒸发除去体系中的甲醇后,用EA萃取3次,每次20mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=80:1~40:1)纯化得到4.88g目标化合物,为深黄色油状物,产率为97.4%;
步骤4:N-(2-(2-烯丙氧基乙基硫代苯基))-2,5-二氯嘧啶-4-胺(1g)的制备
在室温条件下,向装有2-(2-烯丙氧基)乙基硫代苯胺(2.53g,12.11mmol) 的10mL异丙醇溶液中依次加入DIEA(2.22g,18.16mmol),2,4,5-三氯嘧啶(2.22g,12.105mmol),氮气保护下升温至85℃回流,在回流条件下继续搅拌10h,TLC显示反应完成后,加水淬灭反应体系,用EA萃取3次,每次10mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=60:1~20: 1)纯化得到2.47g目标化合物,为深黄色固体,产率为57.3%;
步骤5:N-(2-(2-烯丙氧基乙基磺酰基苯基))-2,5-二氯嘧啶-4-胺(1h)的制备
在冰盐浴条件下,向装有N-(2-(2-烯丙氧基乙基硫代苯基))-2,5-二氯嘧啶-4-胺(2.17g,6.11mmol)的20mL DCM溶液中慢慢滴加含MCPBA(4.75g, 27.51mmol)的10mLDCM溶液,滴加时控制温度不超过0℃,待反应混合物自然升高到室温并继续搅拌5h,TLC显示反应完成后,用饱和亚硫酸氢钠溶液淬灭反应,之后用饱和碳酸钠溶液调体系pH为7-8,用DCM萃取3次,每次50mL,有机相用水和饱和食盐水洗涤,用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=30:1-10:1)纯化得到2.10g目标化合物,为白色固体,产率为 88.6%;
步骤6:2-溴-4-氟-5-硝基甲苯(1j)的制备
在冰盐浴条件下,向装有2-溴-4-氟甲苯(19.95g,105.544mmol)的100mL 浓硫酸溶液中分三次慢慢加入KNO3(3.26gX 3,105.54mmol)固体,反应体系温度不超过15℃,待反应混合物自然升高到室温并继续搅拌4h,TLC显示反应完成后,反应体系慢慢倒入到冰水中淬灭,用EA萃3次,每次100mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=120:1~60: 1)纯化得到17.98g目标化合物,为黄色固体,产率为72.8%;
步骤7:4-(5-氟-2-甲基-4-硝基苯基)-1,5-二氢吡啶甲酸叔丁酯(1l)的制备在室温氮气条件下,向装有2-溴-4-氟-5-硝基甲苯(14.30g,61.106mmol) 的120mL 1,4-二氧六环溶液中,依次加入联硼酸频哪醇酯(18.62g,73.33mmol), KOAc(20.96g,213.87mmol),最后加入Pd(dppf)Cl2(1.34g,1.83mmol),反应体系升温至100℃,并在该温度下继续搅拌3h,TLC显示反应完成后,反应混合物自然降至室温,向反应混合物中依次加入3,6-二氢-4-[[(三氟甲基)磺酰] 氧基]-1(2H)-吡啶甲酸叔丁酯(20.23g,61.106mmol),K2CO3(19.89g,122.21 mmol),Pd(dppf)Cl2(1.34g,1.83mmol),最后加入水10mL,在氮气保护下,升温至100℃,并在该温度下继续搅拌过夜,TLC显示反应完成后,反应体系慢慢加入水淬灭,用EA萃取3次,每次200mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=120:1~60:1)纯化得到10.54g目标化合物,为白色固体,产率为51.3%;
1H NMR(400MHz,CDCl3)δ1.47-1.50(9H,s),2.31-2.32(5H,m),3.62-3.64 (2H,m),4.06-4.07(2H,m),5.65-5.66(1H,m),7.00-7.02(1H,m),7.87-7.89(1H, d,J=7.6).
步骤8:4-(4-氨基-5-羟基-2-甲基苯基)哌啶甲酸叔丁酯(1n)的制备
在氮气条件下,向装有4-(5-氟-2-甲基-4-硝基苯基)-1,5-二氢吡啶甲酸叔丁酯(10.54g,31.36mmol)的100mL 1,4-二氧六环溶液中,依次加入NaOH (7.53g,188.130mmol),相转移催化剂四丁基硫酸氢铵(1.06g,3.14mmol) 之后反应体系升温至100℃,并在该温度下继续搅拌8h,TLC显示反应完成后,反应混合物自然降至室温,向反应混合物中加水淬灭,用EA萃取3次,每次 100mL,用垫有硅藻土的布氏漏斗抽滤得滤液,滤液用无水Na2SO4充分干燥,真空蒸发后得灰白色粗品固体8.21g,在室温条件下,灰白色固体用200mL甲醇完全溶解,向体系中加入Pd/C(1.24g,10%)并通入氢气(2~3大气压),反应混合物在该条件下继续搅拌24h,TLC显示反应完成后,用垫有硅藻土的布氏漏斗除去Pd/C,收集滤液,滤液真空蒸发后通过快速色谱法(PE:EA=40:1~5:1) 纯化得到2.68g目标化合物,为白色固体,产率为29.6%;
1H NMR(400MHz,d6-DMSO)δ1.52-1.54(9H,s),2.22-2.23(3H,s),2.25-2.33 (2H,m),3.60-3.63(2H,t,J=5.6),4.05-4.06(2H,m),5.64-5.65(1H,m),6.88-6.89(1H, s),7.89-8.00(1H,s),10.41-10.42(1H,s).
说明:如果还原时间不够长,结构中的双键未还原完全,该步骤得到的就为化合物A、B混合物,如下所示:
在此实施例中,得到了A、B混合物(~10:1);此实施例中,下面的步骤中均含有约10%的双键副产品。
A:EM(计算值):306.2;MS(ESI)m/e(M+1H)+:307.3
B:EM(计算值):304.2;MS(ESI)m/e(M+1H)+:305.3
在另一实施例中长时间还原,得到了单一的A化合物。
EM(计算值):306.2;MS(ESI)m/e(M+1H)+:307.3
步骤9:4-(4-氨基-2-甲基-5-(1-戊烯氧基))哌啶甲酸叔丁酯(1o)的制备
在氮气保护冰盐浴条件下,向装有4-(4-氨基-5-羟基-2-甲基苯基)哌啶甲酸叔丁酯(1.10g,3.59mmol)、Cs2CO3(1.76g,5.39mmol)的10mL DMF溶液中慢慢滴加5-溴-1-戊烯(0.54g,3.59mmol)的5mL DMF溶液,滴加时温度不超过0℃,待反应混合物自然升高至室温并继续搅拌5h,TLC显示反应完成后加水淬灭,用EA萃取3次,每次40mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=60:1~20:1)纯化得到0.82g目标化合物,为无色油状物,产率为61.2%;
步骤10:N4-(2-((2-(烯丙氧基)乙基)砜)苯基)-5-氯-N2-(5-甲基-2-(戊-4-烯-1-氧基)-4-哌啶-4-基)苯基)嘧啶-2,4-二胺(1p)的制备
在室温条件下,向装有4-(4-氨基-2-甲基-5-(1-戊烯氧基)苯基)哌啶甲酸叔丁酯(0.82g,2.19mmol)的10ml正丁醇溶液中,依次加入1h(1.02g,2.63 mmol),TFA(1.25g,10.95mmol),在氮气保护下,升温至95℃并在该温度下继续搅拌10h,TLC显示反应完成后加水淬灭,用EA萃取3次,每次30mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(DCM:MeOH=60: 1~5:1)纯化得到0.64g目标化合物,为无色油状物,产率为46.7%;
步骤11:4-(4-((4-((2-((2-(烯丙氧基)乙基)砜)苯基)胺基)-5-氯嘧啶-2-基)胺基)-2-甲基-5-(戊-4-烯-1-氧基)苯基)哌啶-1-甲酸叔丁酯(1q)的制备
在室温条件下,向装有1p(0.64g,0.88mmol)的10mL DCM溶液中,依次加入(Boc)2O(0.24g,1.06mmol),TEA(0.18g,1.762mmol),在氮气保护下,反应混合物继续搅拌6h,TLC显示反应完成后,用DCM萃取3次,每次20mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE: EA=40:1~5:1)纯化得到0.56g目标化合物,为白色固体,产率为87.5%;
步骤1r:24-氯-6,7,9,12,13,14六氢-18-甲基-17-(1-叔丁氧羰基哌啶-4-基) -26H-21,25-亚氨基-20H-二苯并[b,k][1,16,13,4,6,10]二氧杂硫杂三氮杂环二十二碳烯-5,5-二氧化物(1r)的制备
在室温条件下,向装有1q(0.56g,0.771mmol)的400mL DCM溶液中,加入Grubbs II催化剂(60mg,10%,W/W),在氮气保护下,反应混合物继续搅拌60h,TLC显示反应完成后,直接真空蒸发后通过快速色谱法(PE:EA=30: 1~5:1)纯化得到0.30g目标化合物,为灰白色固体,产率为55.8%;
EM(计算值):697.3;MS(ESI)m/e(M+1H)+:698.3
EM(计算值):695.3;MS(ESI)m/e(M+1H)+:696.3
步骤13:化合物1的制备
在室温条件下,向装有1r(0.30g,0.430mmol)的10mL DCM溶液中,加入TFA(0.25g,2.15mmol),氮气保护下反应混合物继续搅拌5h,TLC显示反应完成后,直接真空蒸发后通过反相制备纯化,冻干干燥后得到100mg目标化合物,为白色固体和18mg的含有双键的化合物,为白色固体。结构如下所示:
A1:24-氯-6,7,9,12,13,14六氢-18-甲基-17-(4-哌啶基)-26H-21,25-亚氨基 -20H-二苯并[b,k][1,16,13,4,6,10]二氧杂硫杂三氮杂环二十二碳烯-5,5-二氧化物
A2:24-氯-6,7,9,12,13,14六氢-18-甲基-17-(1,2,3,6-四氢-4-吡啶基) -26H-21,25-亚氨基-20H-二苯并[b,k][1,16,13,4,6,10]二氧杂硫杂三氮杂环二十二碳烯-5,5-二氧化物
A1:1H NMR(400MHz,d6-DMSO)δ1.61-1.63(2H,m),1.64-1.74(2H,m), 1.81-1.82(1H,m),2.25(3H,s),2.51-2.63(2H,m),2.66-2.81(1H,m),3.05-3.33(2H, m),3.41-3.42(2H,m),3.47-3.52(6H,m),3.73-3.75(2H,m),3.80-3.84(2H, m)4.90-4.94(1H,m),5.19-5.22(1H,m),6.92(1H,s),7.17(2H,m),7.78-7.80(1H,d, J=8Hz),8.18(1H,s),8.59-8.61(2H,m),9.60(1H,m).
EM(计算值):597.2;MS(ESI)m/e(M+1H)+:598.3
A2:1H NMR(400MHz,d6-DMSO)δ2.20(3H,s),2.92(1H,m),3.34-3.49(6H, m),3.53-3.57(10H,m),3.72-3.82(4H,m),4.68(3H,m),4.93-4.94(1H,m), 5.19-5.21(1H,m),6.79(1H,m),7.19-7.24(3H,m),7.78-7.80(1H,d,J=8),8.19(1H, m),8.52-8.58(2H,m),9.51(1H,m).
EM(计算值):595.2;MS(ESI)m/e(M+1H)+:596.3
实施例2 25-氯-6,7,9,12,14,15-六氢-19-甲基-18-(4-哌啶基)-27H-22, 26-亚氨基-21H-二苯并[b,k][1,16,21,13,4,6,10]三氧杂硫杂三氮杂环二十三碳烯 -5,5-二氧化物(化合物2)的制备
合成步骤如下所示:
具体步骤如下:
步骤1:3-(2-碘乙氧基)-1-丙烯(2a)的制备
在室温条件下,向装有对甲基苯磺酸-2-烯丙氧基乙酯(7.98g,31.13mmol) 的50mL丙酮溶液中加入NaI(6.99g,46.70mmol),升温至60℃并在该温度下继续搅拌6h,TLC显示反应完成后,用布氏漏斗抽滤得滤液,滤液真空蒸发后的6.87g产品,为深黄色固体;
EM(计算值):212.0;MS(ESI)m/e(M+1H)+:212.1
步骤2:4-(4-氨基-2-甲基-5-(2-丙烯氧基)乙氧基苯基)哌啶甲酸叔丁酯 (2b)的制备
在氮气保护和冰盐浴条件下,向装有4-(4-氨基-5-羟基-2-甲基苯基)哌啶甲酸叔丁酯(1.45g,4.73mmol)、Cs2CO3(2.32g,7.10mmol)的15mL DMF溶液中慢慢滴加3-(2-碘乙氧基)-1-丙烯(0.81g,3.786mmol)的10mL DMF溶液,滴加时温度不超过0℃,待反应混合物自然升高至室温并继续搅拌7h,TLC 显示反应完成后加水淬灭,用EA萃取3次,每次50mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=10:1~5:1)纯化得到630mg目标化合物,为浅黄色油状物;
步骤3:N2-(2-(2-(烯丙氧基)乙氧基)-5-甲基-4-(哌啶-4-基)苯基)-N4-(2-((2-(烯丙氧基)乙基)砜)苯基)-5-氯嘧啶-2,4-二胺(2c)的制备
在室温条件下,向装有4-(4-氨基-2-甲基-5-(2-丙烯氧基)乙氧基苯基) 哌啶甲酸叔丁酯(630mg,1.61mmol)的10mL正丁醇溶液中,依次加入N-(2- (2-烯丙氧基乙基磺酰基苯基))-2,5-二氯嘧啶-4-胺(0.94g,2.42mmol),TFA (0.92g,8.072mmol),在氮气保护下,升温至95℃,并在该温度下继续搅拌 10h,TLC显示反应完成后加水淬灭,用EA萃取3次,每次20mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(DCM:MeOH=40:1~5: 1)纯化得到610mg目标化合物,为无色油状物;
EM(计算值):290.2;MS(ESI)m/e(M)+:290.2
步骤4:4-(5-(2-(烯丙氧基)乙氧基)-4-((4-((2-((2-(烯丙氧基)乙基)砜)苯基)胺基)-5-氯嘧啶-2-基)胺基)-2-甲苯基)哌啶-1-甲酸叔丁酯(2d)的制备
在室温条件下,向装有2c(0.61g,0.950mmol)的10mL DCM溶液中,依次加入(Boc)2O(0.25g,1.14mmol),TEA(0.19g,1.90mmol),在氮气保护下,反应混合物继续搅拌5h,TLC显示反应完成后,用DCM萃取3次,每次20mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE: EA=30:1~3:1)纯化得到0.49g目标化合物,为灰白色固体;
EM(计算值):725.3;MS(ESI)m/e(M)+:726.3
步骤5:25-氯-6,7,9,12,14,15-六氢-19-甲基-18-(1-叔丁氧羰基哌啶-4- 基)-27H-22,26-亚氨基-21H-二苯并[b,k][1,16,21,13,4,6,10]三氧杂硫杂三氮杂环二十三碳烯-5,5-二氧化(2e)的制备
在室温条件下,向装有2d(0.49g,0.66mmol)的300mL DCM溶液中,加入Grubbs II催化剂(50mg,10%,W/W),在氮气保护下,反应混合物继续搅拌60h,TLC显示反应完成后,直接真空蒸发后通过快速色谱法(PE:EA=20: 1~3:1)纯化得到0.13g目标化合物,为白色固体;
EM(计算值):697.3;MS(ESI)m/e(M)+:698.3
步骤6:25-氯-6,7,9,12,14,15-六氢-19-甲基-18-(4-哌啶基)-27H-22, 26-亚氨基-21H-二苯并[b,k][1,16,21,13,4,6,10]三氧杂硫杂三氮杂环二十三碳烯 -5,5-二氧化物(2)的制备
在室温条件下,向装有2e(0.13g,0.182mmol)的5mL DCM溶液中,加入TFA(80mg,0.73mmol),氮气保护下反应混合物继续搅拌5h,TLC显示反应完成后,直接真空蒸发后通过反相制备纯化,冻干后得到40mg目标化合物,为白色固体。
1H NMR(400MHz,d6-DMSO)δ1.50-1.58(2H,m),2.22(3H,s), 2.50-2.51(2H,m),2.61(2H,t,J=10.6),2.71(1H,m),3.02-3.04(2H,m), 3.52-3.57(10H,m),3.61-3.68(1H,m),3.80-3.93(1H,m),4.25(1H,m), 5.16-5.19(2H,m),6.89(1H,s),7.22(1H,d,J=7.2),7.54-7.60(1H,m),7.78-7.80(1H, d,J=8),8.28(2H,s),8.41-8.43(1H,d,J=8.4),9.47(1H,m).
EM(计算值):613.2;MS(ESI)m/e(M+1H)+:614.3。
实施例3 24-氯-6,7,9,12,13,14-六氢-18-甲基-17-(1-叔丁氧羰基哌啶-4-基)-26H-21,25亚氨基-20H-二苯并[b,k][1,13,16,4,6,10]三氧杂三氮杂环二十二碳烯 (化合物3)的制备
合成步骤如下所示:
步骤1:2-乙酰基苯酚(3b)的制备
在室温条件下,向装有2-氨基苯酚(11.49g,105.287mmol)的100mL乙酸乙酯溶液中加入Ac2O(12.9g,126.35mmol),氮气保护下继续搅拌10h,反应混合物有浅褐色固体析出,TLC显示反应完成后,用布氏漏斗抽滤后弃滤液,得滤饼,滤饼用200mL EA洗涤即得产品12.98g,为浅褐色固体,产率为81.6%;
步骤2:N-(2-(2-(烯丙氧基)乙氧基)苯基)(3c)乙酰胺的制备
在室温下,向装有2-乙酰基苯酚(4.99g,33.01mmol)的50mL丙酮溶液中依次加入1b(5.29g,20.66mmol),K2CO3(3.80g,27.54mmol),氮气保护下反应体系升温至60℃,并在该温度下继续搅拌12h,TLC显示反应完成后加水淬灭,用EA萃取3次,每次50mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=60:1~5:1)纯化得到3.98g目标化合物,为棕色油状物,产率为51.2%;
EM(计算值):235.1;MS(ESI)m/e(M+1H)+:236.1
步骤3:2-(2-(烯丙氧基)乙氧基)苯胺(3d)的制备
在室温下,向装有N-(2-(2-(烯丙氧基)乙氧基)苯基)乙酰胺(2.11g, 8.968mmol)的20mL乙醇溶液中慢慢滴加浓HCl(0.9ml,10.762mmol),氮气保护下升温至60℃,并在该温度下继续搅拌8h,TLC显示反应完成后,真空蒸发除去乙醇,用EA萃取3次,每次30mL,有机相用无水Na2SO4充分干燥,真空蒸发后得到1.72g粗品,为黄色油状物,直接用于下一步反应;
EM(计算值):193.1;MS(ESI)m/e(M+1H)+:194.0
步骤4:N-(2-(2-(烯丙氧基)乙氧基)苯基)-2,5-二氯-4-胺(3e)的制备
在室温条件下,向装有2-(2-(烯丙氧基)乙氧基)苯胺(1.72g,8.90mmol) 的20mL异丙醇溶液中依次加入DIEA(1.72g,13.35mmol),2,4,5-三氯嘧啶(1.30g,7.12mmol),在氮气保护下升温至85℃,回流,在回流条件下继续搅拌10h,TLC显示反应完成后,加水淬灭反应体系,用EA萃取3次,每次 30mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE: EA=60:1~15:1)纯化得到1.65g目标化合物,为黄色固体,产率为55.6%;
EM(计算值):339.1;MS(ESI)m/e(M+1H)+:340.1
步骤5:N4-(2-(2-(烯丙氧基)乙氧基)苯基)-5-氯-N2-(5-甲基-2-(戊-4-烯-1-基氧基)-4-(哌啶-4-基)苯基)嘧啶-2,4-二胺(3f)的制备
在室温条件下,向装有4-(4-氨基-2-甲基-5-(1-戊烯氧基))哌啶甲酸叔丁酯(0.3g,0.80mmol)的10mL正丁醇溶液中,依次加入N-(2-(2-(烯丙氧基)乙氧基)苯基)-2,5-二氯-4-胺(0.41g,1.20mmol),TFA(0.46g,4.01mmol),在氮气保护下反应体系升温至95℃,并在该温度下继续搅拌10h,TLC显示反应完成后,加水淬灭,用EA萃取3次,每次30mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(DCM:MeOH=60:1~5:1)纯化得到0.48g 目标化合物,为黄色油状物;
步骤6:4-(4-((4-((2-(2-(烯丙氧基)乙氧基)苯基)胺基)-5-氯嘧啶-2-基)胺基)-2- 甲基-5-(戊-4-烯-1-基氧基)苯基)哌啶-1-甲酸叔丁酯(3g)的制备
在室温条件下,向装有3f(0.48g,0.83mmol)的10mL DCM溶液中,依次加入(Boc)2(0.21g,0.10mmol),TEA(0.17g,1.6mmol),在氮气保护下反应混合物继续搅拌6h,TLC显示反应完成后,用DCM萃取3次,每次30mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=40:1~5: 1)纯化得到260mg目标化合物,为类白色固体,产率为46.4%;
步骤7:24-氯-6,7,9,12,13,14-六氢-18-甲基-17-(1-叔丁氧羰基哌啶-4-基) -26H-21,25亚氨基-20H-二苯并[b,k][1,13,16,4,6,10]三氧杂三氮杂环二十二碳烯 (3h)的制备
在室温条件下,向装有3g(0.26g,0.38mmol)的200mL DCM溶液中,加入Grubbs II催化剂(30mg,10%,W/W),在氮气保护下反应体系继续搅拌60h, TLC显示反应完成后,直接真空蒸发后通过快速色谱法(PE:EA=30:1~5:1) 纯化得到0.12g目标化合物,为灰白色固体,产率为50.3%;
步骤8:24-氯-6,7,9,12,13,14-六氢-18-甲基-17-(4-哌啶基)-26H-21,25亚氨基-20H-二苯并[b,k][1,13,16,4,6,10]三氧杂三氮杂环二十二碳烯(3)的制备
在室温条件下,向装有3s(0.12g,0.19mmol)的5mL DCM溶液中,加入 TFA(0.13g,1.11mmol),在氮气保护下反应体系继续搅拌5h,TLC显示反应完成后,直接真空蒸发后通过反相制备纯化,冻干干燥后得到62mg目标化合物,为白色固体,产率为61.3%。
1H NMR(400MHz,d6-DMSO)δ1.51-1.58(4H,m),1.80-1.82(1H,m),2.22 (3H,s),2.28-2.29(1H,m),2.34(2H,m),2.59-2.61(2H,m),2.62-2.64(1H,m), 3.02-3.05(2H,m),3.34-3.39(4H,m),3.39(2H,m),4.43(2H,m),5.17(1H,m), 5.26(1H,m),6.68-6.69(1H,m),6.82(1H,s),7.02-7.09(3H,m),7.74-7.76(1H,d,J =8Hz),8.02-8.03(1H,s),8.21(1H,m),8.27(1H,m).
EM(计算值):549.2;MS(ESI)m/e(M+1H)+:550.3。
实施例4 3-氯-8,9,10,15,16,17,18,19,20,21,22,23,24,27十四氢-12-甲基-33-(异丙氧基)-7,10-亚乙基-11,14-亚乙烯基-2,6-次氮基-1H-28,1,5,7,15-苯并硫杂四氮杂环三十碳烯-28,28-二氧化物(化合物4)的制备
合成步骤如下所示:
步骤1:2-烯丙基硫代苯胺(4b)的制备
在室温条件下,向装有2-氨基苯硫醇(9.87g,78.84mmol)的100mL MeOH 溶液中加入KHCO3(7.95g,94.61mmol)的水溶液(10mL),氮气保护下慢慢滴加烯丙基溴(11.45g,94.61mmol)的100mLMeOH溶液,反应体系在室温条件下继续搅拌6h,TLC显示反应完成后,真空蒸发除去体系中的甲醇后,用EA萃取3次,每次200mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=80:1~30:1)纯化得到6.35g目标化合物,为黄色油状物,产率为48.7%;
步骤2:N-(2-(烯丙基硫代)苯基)-2,5-二氯嘧啶-4-胺(4c)的制备
在室温条件下,向含有2-烯丙基硫代苯胺(4b)(6.12g,37.03mmol)的50 mL i-PrOH溶液中依次加入DIEA(7.2g,55.55mmol),2,4,5-三氯嘧啶(10.19g, 55.55mmol),氮气保护下反应体系升温至85℃回流10h,TLC显示反应完成后,加水淬灭反应体系,用EA萃取3次,每次50mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=60:1~30:1)纯化得到4.7g目标化合物,为黄色固体,产率为40.7%;
1H NMR(400MHz,CDCl3)δ3.37-3.39(2H,d,J=7.2),4.86-4.97(2H,m), 5.77-5.84(1H,m),7.08-7.10(1H,t,J=1.6),7.41-7.43(1H,t,J=7.2),7.45-7.46(1H, d,J=1.6),8.23(1H,s),8.57-8.59(1H,d,J=7.2),9.05(1H,m).
步骤3:N-(2-(烯丙硫基)苯基)-2-(4-(4-胺基-5-异丙氧基-2-甲苯基)哌啶-1-基)-5-氯嘧啶-4-胺(4e)的制备
在室温条件下,向含有N-(2-(烯丙基硫代)苯基)-2,5-二氯嘧啶-4-胺 (4.70g,15.053mmol)的50mL甲苯溶液中依次加入5-甲基-2-(1-甲基乙氧基)-4-(4-哌啶)-苯胺二盐酸盐(7.26g,22.58mmol),t-BuONa(4.34g,45.16mmol), BINAP(0.24g,5%),Pd2(dba)3(0.24g,5%),在氮气保护下反应体系升温至 115℃回流5h,TLC显示反应完成后,加水淬灭反应体系,用EA萃取3次,每次50mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE: EA=80:1~20:1)纯化得到4.97g目标化合物,为白色固体,产率为63.7%;
1H NMR(400MHz,CDCl3)δ1.29(6H,d,J=6.4Hz),1.62-1.64(2H,m), 1.83-1.86(2H,m),2.85-2.91(1H,m),2.94-3.01(2H,m),3.39(2H,d,J=7.2Hz), 3.65(1H,brs),4.39-4.45(1H,m),4.83-4.89(2H,m),4.93-4.98(2H,m),5.79-5.89 (1H,m),6.55(1H,s),6.62(1H,s),6.98-7.02(1H,m),7.33-7.37(1H,m),7.55(1H, dd,J=7.6,1.6Hz),8.04(1H,s),8.56(1H,dd,J=8.4,1.2Hz),8.65(1H,s).
步骤4:(4-(1-(4-((2-(烯丙硫基)苯基)胺基)-5-氯嘧啶-2-基)哌啶-4-基)-2-异丙氧基-5-甲苯基)甲酸叔丁酯(4f)的制备
在室温条件下,向含有4e(1.87g,3.57mmol)的20mL DCM溶液中,依次加入(Boc)2(1.17g,5.35mmol),TEA(0.65g,6.42mmol),在氮气保护下反应体系继续搅拌过夜,TLC显示反应完成后,用DCM萃取3次,每次50mL,有机相用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=60: 1~30:1)纯化得到1.57g目标化合物,为黄色油状物,产率为70.7%;
EM(计算值):623.3;MS(ESI)m/e(M+1H)+:624.3
步骤5::(4-(1-(4-((2-(烯丙砜基)苯基)胺基)-5-氯嘧啶-2-基)哌啶-4-基)-2-异丙氧基-5-甲苯基)甲酸叔丁酯(4g)的制备
在冰盐浴条件下,向装有4f(1.39g,2.23mmol)的15mL DCM溶液中慢慢滴加MCPBA(1.35g,7.793mmol)的10mL DCM溶液,滴加时控制温度不超过0℃,待反应混合物自然升高到室温并继续搅拌5h,TLC显示反应完成后,用饱和亚硫酸氢钠溶液淬灭反应体系,再用饱和碳酸钠溶液调体系pH为7-8,,,用DCM萃取3次,每次40mL,有机相用水和饱和食盐水洗涤,用无水Na2SO4充分干燥,真空蒸发后通过快速色谱法(PE:EA=50:1~20:1)纯化得到0.60g目标化合物,为黄色油状物,产率为41.1%;
EM(计算值):655.3;MS(ESI)m/e(M+1H)+:656.3
步骤6:(4-(1-(4-((2-((12-溴十二烷基-2-烯-1-基)砜)苯基)胺基)-5-氯嘧啶-2- 基)哌啶-4-基)-2-异丙氧基-5-甲苯基)甲酸叔丁酯(4h)的制备
在室温条件下,向含有4g(0.27g,0.49mmol)的50mL DCM溶液中,加入Grubbs II催化剂(30mg,10%,W/W),氮气保护下反应体系升温至45℃,并搅拌反应10h,TLC显示反应完成后,直接真空蒸发后通过快速色谱法(PE: EA=50:1~20:1)纯化得到0.26g目标化合物,为黄色油状物,产率为62.2%;
EM(计算值):859.3;MS(ESI)m/e(M+1H)+:860.3
步骤7:2-(4-(4-胺基-5-异丙氧基-2-甲苯基)哌啶-1-基)-N-(2-((12-溴十二烷基 -2-烯-1-基)砜)苯基)-5-氯嘧啶-4-胺(4i)的制备
在室温条件下,向含有4h(0.25g,0.33mmol)的10mL DCM溶液中,加入TFA(0.11g,0.99mmol),氮气保护下反应体系继续搅拌10h,TLC显示反应完成后,直接真空蒸发后通过快速色谱法(PE:EA=15:1~8:1)纯化得到0.18g 目标化合物,为黄色油状物,产率为72.4%;
步骤7:3-氯-8,9,10,15,16,17,18,19,20,21,22,23,24,27十四氢-12-甲基-33-(异丙氧基)-7,10-亚乙基-11,14-亚乙烯基-2,6-次氮基-1H-28,1,5,7,15-苯并硫杂四氮杂环三十碳烯-28,28-二氧化物(4)的制备
在室温条件下,向装有4i(300mg,0.40mmol)的10mL乙腈溶液中,加入K2CO3(17mg,0.12mmol),氮气保护下反应体系升温至65℃,继续搅拌反应 10h,TLC显示反应完成后,直接真空蒸发后通过快速色谱法(PE:EA=10:1~5: 1)纯化得到28mg目标化合物,为黄色固体,产率为10.3%;
1H NMR(400MHz,CDCl3)δ0.80-0.82(6H,m),0.86-0.88(2H,m),1.23-1.25 (17H,m),1.42-1.43(2H,m),2.01-2.04(1H,m),2.22-2.23(3H,s),2.92-3.08(4H,m), 3.72-3.74(2H,d,J=7.2),4.33-4.35(1H,m),4.90-4.95(1H,m),5.19-5.33(2H,m), 6.44-6.47(2H,m),7.20-7.26(1H,m),7.57-7.59(1H,m),7.77-7.78(1H,d,J=1.6), 8.11-8.14(2H,m),8.77-8.78(1H,m).
EM(计算值):679.3;MS(ESI)m/e(M+1H)+:680.3。
试验例1:体外ALK抑制激酶活性试验
1:试验材料
ALK(Carna产品,货号08-105,批号08CBS-0112);
底物多肽FAM-P22(GL Biochem产品,货号112393,批号 P120828-JC112393);
腺苷三磷酸(Sigma产品,批号A7699-1G,批号987-65-5);
DMSO(Sigma产品,货号D2650,批号474382);
四乙酸二氨基乙烷(Sigma产品,货号E5134,批号60-00-4);
96-孔板(Corning产品,货号3365,批号22008026);
384-孔板(Corning产品,货号3573,批号12608008);
阳性对照物:星孢菌素(Sigma产品,货号S4400-1MG,批号046K4080);
检测仪器:Caliper EZ Reader
2:试验原理
微流体芯片技术的迁移率检测技术(Mobility-Shift Assay),该技术将毛细管电泳的基本理念应用到微流体环境中,用于实验的底物是带有荧光标记的多肽,在反应体系中酶的作用下,底物转变为产物,其所带的电荷也发生了相应的变化,Mobility-ShiftAssay正是利用底物和产物所带电荷的不同,将二者进行分离,并分别进行检测,检测结果由转化率表达出来。
3:试验方法
(1)配置待测样品:用100%DMSO稀释至反应终浓度的50倍即50umol/L;
(2)稀释:50umol/L为起始浓度,然后以4倍浓度稀释,稀释10个浓度梯度;
(3)阳性对照和阴性对照孔中分别加入100%DMSO;
(4)将配好的10个浓度的化合物分别用1倍激酶缓冲液稀释10倍;其中激酶缓冲液中包含浓度为50mmol/L,pH为7.5的羟乙基哌嗪乙硫磺酸、0.01%的十二烷基聚乙二醇醚、10mmol/L的氯化镁、2mmol/L的二硫苏糖醇;
(5)配制2.5倍酶溶液:将激酶加入1倍激酶缓冲液,形成2.5倍酶溶液;
(6)配制2.5倍的底物溶液:将FAM标记的多肽和ATP加入1倍激酶缓冲液,形成2.5倍底物溶液;
(7)向384孔板中加入酶溶液:384孔反应板中已有5μL的10%DMSO 溶解的5倍化合物,然后再加入10μL的2.5倍酶溶液,室温下孵育10分钟;
(8)向384孔板中加入底物溶液:在384孔反应板中加入10μL的2.5倍底物溶液;
(9)激酶反应和终止:28℃下孵育1h,然后加25μL终止液终止反应;其中终止液中包含浓度为100mmol/L,pH为7.5的羟乙基哌嗪乙硫磺酸、0.015%的十二烷基聚乙二醇醚、0.2%的3号表面试剂、20mmol/L的乙二胺四乙酸;
(10)Caliper读取数据Caliper上读取转化率数据;
(11)抑制率计算从Caliper上复制转化率数据。
把转化率转化成抑制率数据,其中max是指DMSO对照的转化率,min是无酶活对照的转化率。
Percent inhibition=(max-conversion)/(max-min)*100.
各实施例对ALK激酶抑制活性结果如下:
由上述结果可知,实施例2、3均对ALK活性具有明显的抑制作用,与阳性对照物色瑞替尼作用大致相当,说明这种具有大环结构化合物的设计具有可行性,尤其是在大环的链上增加强电负性原子可能会具有更强的抑制效果。因此,本发明所设计的大环化合物可用作ALK抑制剂,具有广阔的抗恶性肿瘤的应用前景。
根据本发明的上述内容,本领域人员还可以进行其它多种形式的修改、替换或变更。因此上述内容并非本发明的限定,在不脱离本发明构思的前提下,尤其是这种大环设计与合成方法的构思和在环化长链上增加强电负性原子的构思,任何在此构思下作出的更改都是在本发明的保护范围之内。
Claims (4)
1.一种具有大环结构的ALK抑制剂,其特征在于,包括式(Ⅰ):
其中,R1、R2、R4为氢原子;R3为卤素;
W可以选自以下基团:
R5为C1~C3直链或支链烷基;
R9为氢原子;
G1为O或-S(=O)2;
G2为O或-S(=O)2;
X为含有0、1、2、3、4个选自O、S、-S=O、-S(=O)2、-P(=O)2基团的C4~C12的烯烃;
R7、R8为氢原子。
2.一种具有大环结构的ALK抑制剂,其特征在于,含式(Ⅱ)的化合物:
其中,哌啶环虚线处可以为单键也可以为双键;
R1、R2、R4为氢原子;
R3为卤素;
R5为C1~C3直链或支链烷基;
R7、R8为氢原子;
G1为O或-S(=O)2;
G2为O或-S(=O)2;
X为含有0、1、2、3、4个选自O、S、-S=O、-S(=O)2、-P(=O)2基团的C4~C12的烯烃。
3.根据权利要求1或2所述的具有大环结构的ALK抑制剂,选自以下结构:
4.如权利要求3所述的化合物2的制备方法,其合成路线为:
包括以下步骤:
(1)向含有化合物1b的丙酮溶液中加入NaI,在60℃反应6h,用布氏漏斗抽滤得滤液,滤液真空蒸发得化合物2a;其中化合物1b在丙酮溶液中的浓度为0.14-0.2g/mL;化合物1b与NaI的摩尔比为1:1.5-2;
(2)在氮气保护和冰盐浴条件下,向含有化合物1n和Cs2CO3的DMF溶液中滴加含有化合物2a的DMF溶液,滴加时温度不超过0℃,待反应混合物自然升高至室温后反应7h,得化合物2b;其中化合物1n在DMF溶液中的浓度为0.09-0.12g/mL;化合物1n和Cs2CO3的摩尔比为1:1.2-2;化合物1n和化合物2a的摩尔比为1-1.5:1;
(3)室温条件下,向含有化合物2b的正丁醇溶液中,依次加入化合物1h和TFA,在氮气保护下,升温至95℃反应10h得化合物2c;其中化合物2b在正丁醇溶液中的浓度为0.05-0.1g/mL;化合物2b与化合物1h的摩尔比为1:1-2;化合物2b与TFA的摩尔比为1:5-6;
(4)室温条件下,向含有化合物2c的DCM溶液中,依次加入(Boc)2O、TEA,在氮气保护下,搅拌反应5-6h得化合物2d;其中化合物2c在DCM溶液中的浓度为0.06-0.1g/mL;化合物2c、(Boc)2O和TEA的摩尔比为1:1-1.5:1.2-2.5;
(5)室温条件下,向含有化合物2d的DCM溶液中,加入Grubbs II,在氮气保护下,搅拌反应5-6h得化合物2e;其中化合物2d在DCM溶液中的浓度为1.6-2mg/mL;化合物2d和GrubbsII的质量比为9-12:1;
(6)室温条件下,向含有化合物2e的DCM溶液中,加入TFA,在氮气保护下,搅拌反应5-6h得化合物2,化合物2e在DCM溶液中的浓度为1.6-2mg/mL;化合物2e和TFA的摩尔比为1:4-6。
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