CN103044311B - 一种多取代吲哚类化合物及其制备方法和应用 - Google Patents
一种多取代吲哚类化合物及其制备方法和应用 Download PDFInfo
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- CN103044311B CN103044311B CN201210574525.7A CN201210574525A CN103044311B CN 103044311 B CN103044311 B CN 103044311B CN 201210574525 A CN201210574525 A CN 201210574525A CN 103044311 B CN103044311 B CN 103044311B
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Abstract
本发明属于医药技术领域,具体公开了一种如通式I所示的多取代吲哚类化合物,其制备方法以及含有一个或多个此类化合物的组合物在抗肿瘤药物中的应用,
Description
技术领域
本发明涉及有机化合物合成及医药应用领域,尤其涉及一类多取代吲哚类化合物及其制备方法和制药用途。
背景技术
磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase,PI3K)/蛋白激酶B(protein kinase B,PKB,Akt)信号传导通路在细胞生长与存活中起着关键作用。PI3K/Akt通路过度激活在急、慢性白血病,淋巴瘤,骨髓瘤及卵巢癌、胰腺癌、子宫内膜癌、肝癌、前列腺癌、结肠直肠癌、滤泡状甲状腺癌和肺癌等多种肿瘤中常见;该通路的激活是肿瘤发生的早期事件,正常细胞暴露于致癌物质下,该通路可以很快地被激活并引起持续增殖;该通路的持续过度活化在很多肿瘤中是预后不好的标志;该通路的激活与肿瘤治疗耐药性有关,抑制该通路可增加化疗或放疗的效果。(参见Nakanishi K;Sakamoto M:Akt phosphorylation is a risk factor forearly disease recurrence and poor prognosis in hepatocellular carcinoma.Cancer.2005,103:307-312。)PI3K/Akt信号传导通路的持续激活被认为是癌细胞生长与存活的决定因素,阻断该通路的持续活化为靶向治疗癌症提供了新策略,此信号通路的抑制剂成为肿瘤,尤其是对于由PI3K/Akt信号通路的持续活化所引起的肿瘤的潜在治疗药物。丝氨酸/苏氨酸蛋白激酶Akt是PI3K的下游靶标,在细胞生存和生长过程中发挥着重要作用。研究发现,在40%的乳腺癌和卵巢癌及超过50%的前列腺癌中发现有高活性的Akt1,在30-40%的胰腺癌和卵巢癌中观测到高活性的Akt2,在雌激素受体缺陷型乳腺癌和雄激素不敏感型前列腺癌细胞株中发现了高活性的Akt3,超过60%的原发肿瘤PTEN缺失或改变。无论是Akt激酶本身还是Akt激酶上游调节分子,例如PTEN和PI3K,在超过50%的人类肿瘤中均有异常变化,所以Akt是发现抗肿瘤药物的一个重要靶标。(参见Cheng GZ;Park S:Advances ofAKT pathwayin human oncogenesis and as a target for anti-cancer drug discovery.Curr Cancer Drug Targets.2008,8:2-6。)
发明内容
本发明的目的在于提供一类具有蛋白激酶B抑制活性的多取代吲哚类化合物;本发明的另一目的在于提供该多取代吲哚类化合物的制备方法及其制药用途。
发明综述:
吲哚类化合物对Akt具有一定的抑制作用,本发明对取代吲哚类化合物进行结构优化,在吲哚环上同时引入了2,4,7位取代基,合成了以吲哚为母体的四取代吲哚类化合物,活性试验表明,该类化合物具有良好的PC-3细胞生长抑制活性和对Akt1的抑制作用。
1、多取代吲哚类化合物
本发明的多取代吲哚类化合物,结构如通式(Ⅰ)所示:
通式I
其中,R1是氢,苯基,五元杂芳基,羟基,卤素,硝基,氰基,氨基,取代氨基,C1~6直链或支链烷氧基,C1~6直链或支链烷基;R2是氢,C1~6烷基;R3是氢,苯基,五元杂芳基,羟基,卤素,硝基,氰基,氨基,取代氨基,C1~6直链或支链烷氧基,C1~6直链或支链烷基,C1~6直链或支链羰基烷氧基,羧基,酰胺基,酰肼基,羟基酰胺基;R4是C1~6直链或支链烷胺基,C1~6环烷胺基,C1~6直链或支链羰基烷氧基。
优选的,R1是苯基,甲氧基,溴或氯;R2是氢或甲基;R3是羧基甲酯,羧基,酰胺基,酰肼基,羟基酰胺基或3-甲基噁二唑-5-基;R4是2-氨基乙基,3-氨基丙基,(S)-2-氨基-3-苯基丙基,(R)-2-氨基-3-苯基丙基,(S)-2-氨基-3-(1H-吲哚-3-基)丙基,(R)-2-氨基-3-(1H-吲哚-3-基)丙基,(S)-四氢吡咯-2-基亚甲基,(S)-2-氨基-3-(4-甲氧基苯基)丙基,(S)-2-氨基-4-甲硫基丁基,(2S,3S)-2-氨基-3-甲基戊基或(S)-2-氨基-4-甲基戊基。
进一步优选的,本发明的多取代吲哚类化合物是下列之一:
4-(3-氨基丙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯盐酸盐(5a)、
4-(2-氨基乙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯盐酸盐(5b)、
1-甲基-4-(2-氨基乙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯盐酸盐(5c)、
4-(3-氨基丙氧基)-7-苯基-1H-吲哚-2-甲酸盐酸盐(10a)、
4-(2-氨基乙氧基)-7-苯基-1H-吲哚-2-甲酸盐酸盐(10b)、
4-(3-氨基丙氧基)-7-苯基-1H-吲哚-2-甲酰胺盐酸盐(11a)、
4-(2-氨基乙氧基)-7-苯基-1H-吲哚-2-甲酰胺盐酸盐(11b)、
4-(3-氨基丙氧基)-7-苯基-1H-吲哚-2-羟基甲酰胺盐酸盐(12a)、
4-(3-氨基丙氧基)-7-苯基-1H-吲哚-2-甲酰肼盐酸盐(13a)、
4-(2-氨基乙氧基)-7-苯基-1H-吲哚-2-甲酰肼盐酸盐(13b)、
1-甲基-4-(2-氨基乙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐(19a)、
(S)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐(19b)、
(S)-1-甲基-4-((2-氨基-4-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐(19c)、
(S)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐(19d)、
(S)-1-甲基-4-((2-氨基-4-甲硫基)丁氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐(19e)、
(R)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐(19f)、
1-甲基-4-(((2S,3S)-2-氨基-3-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐(19g)、
(S)-1-甲基-4-((2-氨基-3-(4-甲氧基苯基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯(19h)、
(R)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐(19i)、
(S)-1-甲基-4-((四氢吡咯-2-基)甲氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐(19j)、
(S)-3-甲基-5-(1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐(23a)、
(R)-3-甲基-5-(1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐(23b)、
(S)-3-甲基-5-(1-甲基-4-(2-氨基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐(23c)、
(R)-3-甲基-5-(1-甲基-4-(2-氨基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐(23d)、
(S)-3-甲基-5--(1-甲基-4-(2-氨基-3-(4-甲氧基苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐(23e)、
(S)-3-甲基-5-(1-甲基-4-((2-氨基-4-甲硫基)丁氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐(23f)、
(S)-3-甲基-5-(1-甲基-4-((2-氨基-4-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐(23g)、
(S)-3-甲基-5-(1-甲基-4-(四氢吡咯-2-基亚甲氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐(23h)、
(S)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐(27aa)、
(R)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐(27ab)、
(S)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐(27ac)、
(R)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐(27ad)、
(S)-1-甲基-4-((2-氨基-3-(4-甲氧基苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐(27ae)、
(S)-1-甲基-4-((四氢吡咯-2-基)亚甲氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐(27af)、
(S)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐(27ba)、
(R)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐(27bb)、
(R)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐(27bc)、
(S)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐(27bd)、
(S)-1-甲基-4-((2-氨基-3-(4-甲氧基苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐(27be)或
(S)-1-甲基-4-((四氢吡咯-2-基)亚甲氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐(27bf)。
上述优选的40个化合物名称后的括号中为其相应的代号,为叙述方便和表达简洁,上述括号中的代号在本说明书以下内容中将被直接应用。
2、多取代吲哚类化合物的制备方法
本发明化合物多取代吲哚类化合物的制备方法包括以下步骤:
合成路线:
试剂及条件:(IA)苯硼酸,四三苯基膦钯,碳酸铯,95°C;(IB)钯碳,甲醇/四氢呋喃,氢气,室温;(IC)BocNH(CH2)nBr,碳酸铯,DMF,室温;(IE)碳酸氢铵,二氯甲烷,2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉,室温;(IF)羟肟酸钾,甲醇,室温;(IG)水合肼,乙醇,回流;(IH)氯化氢的乙酸乙酯溶液,室温;(IIA)氢氧化钾,四氢呋喃/水,回流;(IIB)氢化钠,甲醇,DMF,碘化亚铜,120°C;(IIC)硫酸二甲酯,氢化钠,DMF,0°C;(IIIA)乙酰胺肟,碳酸铯,DMF,微波800W,150°C;(IIIB)三氯化铝,N,N-二甲苯胺,二氯甲烷,0°C~室温;(IID)手性取代醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0°C~室温,氯化氢的乙酸乙酯溶液,室温。
具体步骤如下:
(1)起始原料1与四三苯基膦钯,在碳酸铯和苯硼酸存在下反应得苯基吲哚类中间体2;
(2)中间体2或中间体16,在四氢呋喃/甲醇混合液中,钯碳催化氢气,脱掉苄基,得吲哚醇中间体3或中间体17;
(3)中间体3与Boc保护的氨基溴代烷,在DMF溶液中碳酸铯存在下,发生缩合,得重要中间体4;
(5)中间体4或起始原料1在氢氧化钾溶液中水解,得羧酸衍生物中间体6或14;
(6)中间体6在2-乙氧基-1-乙氧羰基-1,2-二氢喹啉存在下,与碳酸氢铵发生反应,得酰胺衍生物中间体7;
(7)中间体4与羟肟酸钾在无水甲醇中反应,得羟肟酸衍生物中间体8;
(8)中间体4与水合肼在乙醇反应,得酰肼类中间体9;
(9)中间体4,6,7,8,9分别与氯化氢的乙酸乙酯溶液反应,脱掉Boc保护基,得目标产物5,10,11,12,13;
(10)中间体14在无水甲醇中,在碘化亚铜和氢化钠存在下反应,得甲氧基吲哚中间体15;
(11)中间体15或起始原料1在氢化钠催化下,与硫酸二甲酯反应,得甲基化中间体16或24;
(12)中间体16在碳酸铯存在下,微波催化与乙酰胺肟反应,得噁二唑类中间体20;
(13)中间体20或24在N,N-二甲基苯胺存在下,与三氯化铝反应,脱掉苄基,得吲哚醇类中间体21或25;
(14)吲哚醇类中间体17,21或25在三苯基磷,偶氮二甲酸二异丙酯存在下,与手性取代醇反应后,与氯化氢的乙酸乙酯溶液反应,脱掉Boc保护基,得目标产物19,23或27。
优选的,
(1)化合物5a-5c,10a-10b,11a-11b,12a和13a-13b的制备方法如下:
(i)将起始原料1a、碳酸铯、四三苯基膦钯和苯硼酸按摩尔比1:4:0.1:2加入到二氧六环/水混合液中(每0.5毫摩尔中间体1a用二氧六环6毫升,水1毫升),氮气保护下加热至85°C,反应4h,冷至室温,减压蒸除溶剂,用丙酮洗涤残留物至无荧光,合并丙酮溶液,减压蒸除溶剂,固体用无水甲醇/丙酮重结晶,得中间体2a;
(ii)将2a溶解于干燥的DMF中(每2毫摩尔2a用DMF10毫升),冰浴下缓慢加入氢化钠(2a与氢化钠摩尔比为1;15),搅拌0.5h,缓慢滴加硫酸二甲酯(2a与硫酸二甲酯摩尔比为1;1.5),滴加完毕,0°C反应0.5h后,室温反应4h,将反应液倾入10倍DMF体积冰水中,析出沉淀,过滤,乙酸乙酯/石油醚重结晶得中间体2b;
(iii)将中间体2a或2b溶解于四氢呋喃/甲醇混合液中,加入钯碳,通入氢气,密闭反应过夜,过滤除去钯碳,柱层析得中间体3a或3b;
(iv)将中间体3a或3b与碳酸铯、N-2-溴乙基-叔丁氧基甲酰胺或N-3-溴丙基-叔丁氧基甲酰胺按摩尔比1:2:1.5加入到DMF中,每1毫摩尔中间体3用DMF10毫升,60°C搅拌过夜,将反应液倾入10倍DMF体积冰水中,乙酸乙酯萃取,柱层析,分别得中间体4a,4b,4c;
(v)将中间体4a或4b与氢氧化钾按摩尔比1:4在4:1(体积比)四氢呋喃/水混合液中,每1毫摩尔中间体4用混合液25毫升,回流过夜,冷至室温,减压蒸除溶剂,加入100mL水,用饱和柠檬酸溶液调节pH至5,析出沉淀,过滤,固体用乙酸乙酯/石油醚重结晶得中间体6a或6b;
(vi)将中间体6a或6b分别与2-乙氧基-1-乙氧羰基-1,2-二氢喹啉(EEDQ)、碳酸氢铵按摩尔比1:1.2:8加入到干燥的二氯甲烷中,每1毫摩尔中间体6用二氯甲烷40毫升,室温反应24h,反应液依次用水、饱和氯化钠溶液洗涤后,减压蒸除溶剂,得淡黄色油状物,柱层析得中间体7a,7b;
(vii)将中间体4a与羟肟酸钾按摩尔比1:2加入绝对无水甲醇中,每1毫摩尔中间体6用甲醇14毫升,室温反应36h,柱层析,洗脱系统为石油醚/丙酮=3:1,得中间体8a;
(viii)将中间体4a或4b分别与水合肼按摩尔比1:8加入乙醇中,回流72h,减压蒸除溶剂,残留物用乙酸乙酯溶解,有机相依次用1mol/L柠檬酸溶液、饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压蒸除溶剂,得黄色固体,用乙酸乙酯/石油醚重结晶,得中间体9a或9b。
(ix)将中间体4a,4b,4c,6a,6b,7a,7b,8a,9a或9b(0.5mmol)分别加入到25mL烧瓶中,加入氯化氢的乙酸乙酯溶液15mL,室温搅拌1h,减压蒸除溶剂,甲醇/乙醚重结晶分别得目标产物5a,5b,5c,10a,10b,11a,11b,12a,13a或13b。
合成路线如下:
试剂及条件:(a1)苯硼酸,四三苯基膦钯,碳酸铯,二氧六环/水,95°C;(b1)硫酸二甲酯,氢化钠,DMF,0°C;(c1)10%钯碳,甲醇/四氢呋喃,氢气,室温;(d1)BocNH(CH2)nBr,碳酸铯,DMF,室温;(e1)氯化氢的乙酸乙酯溶液,室温;(f1)氢氧化钾,四氢呋喃/水,回流;(g1)羟肟酸钾,甲醇,室温;(h1)水合肼,乙醇,回流;(i1)碳酸氢铵,二氯甲烷,2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉,室温。
(2)化合物19a-19j的制备方法如下:
(i)将起始原料1a与氢氧化钾按摩尔比1:4加入烧瓶中,加入THF/水混合液,体积比10:3,每20mmol起始原料1a用混合液130mL,回流过夜,冷至室温,减压蒸除溶剂,加入200mL水,用浓盐酸调节pH至1,过滤,固体干燥后,乙酸乙酯/石油醚重结晶得中间体14;
(ii)将氢化钠,中间体14,碘化亚铜以摩尔比10:1:1加入绝对无水甲醇和DMF混合液中,每7.5mmol甲醇钠用甲醇20mL,DMF22mL,氮气保护,回流5h,冷却至室温,将反应液倾入10倍体积DMF冰水中,浓盐酸调节pH至1,析出沉淀,过滤,乙酸乙酯/石油醚重结晶,得中间体15;
(iii)将中间体15,氢化钠与硫酸二甲酯以摩尔比1:3:3加入干燥的DMF中,每2.7mmol中间体15用DMF10mL,室温反应过夜,将反应液倾入100mL冰水中,过滤,固体干燥,柱层析即得中间体16;
(iv)将中间体16溶解于四氢呋喃/甲醇混合液中,加入钯碳,通入氢气,密闭反应过夜,过滤除去钯碳,柱层析得中间体17;
(v)将中间体17与碳酸铯、N-2-溴乙基-叔丁氧基甲酰胺按摩尔比1:2:1.5加入到DMF中,每1毫摩尔中间体3用DMF10毫升,氮气保护,60°C搅拌过夜,将反应液倾入10倍DMF体积冰水中,乙酸乙酯100mL×3萃取,合并有机相,依次用水、饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压蒸除溶剂,得中间体18a;
(vi)将三苯基磷,偶氮二甲酸二异丙酯,手性取代醇与中间体17以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0°C反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚(1:3)混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体18(b~i);
(vii)将三苯基磷,偶氮二甲酸二异丙酯,(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇与中间体17以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0°C反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚(1:3)混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体18j。
(viii)将中间体18a,18(b~i)或18j(0.5mmol)分别加入到25mL烧瓶中,加入氯化氢的乙酸乙酯溶液15mL,室温搅拌1h,减压蒸除溶剂,甲醇/乙醚重结晶分别得目标产物19a,19(b~i)或19j。
合成路线如下:
试剂及条件:(a2)氢氧化钾,四氢呋喃/水,回流;(b2)氢化钠,甲醇,DMF,碘化亚铜,120°C;(c2)硫酸二甲酯,氢化钠,DMF,0°C;(d2)10%钯碳,甲醇/四氢呋喃,氢气,室温;(e2)BocNH(CH2)2Br,碳酸铯,DMF,室温;(f2)氯化氢的乙酸乙酯溶液,室温;(g2)手性取代醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0°C~室温;(h2)(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0°C~室温。
(3)化合物23a-23h的制备方法如下:
(i)将中间体16,乙酰胺肟与碳酸铯按摩尔比1:2:2加入到DMF中,每2mmol中间体16用DMF10mL,微波800W,150°C反应5min,冷至室温,将反应液倾入100mL冰水中,乙酸乙酯100mL×3萃取,合并有机相,依次用水、饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压蒸除溶剂,得固体,柱层析分离纯化得中间体20;
(ii)将中间体20,N,N-二甲基苯胺与三氯化铝按摩尔比1:4:4加入到冰浴下的绝对无水二氯甲烷中,每1.7mmol中间体20用二氯甲烷12mL,室温搅拌1.5h,0°C下缓慢滴加1mol/L盐酸20mL,水20mL,用乙酸乙酯50mL×3萃取,合并有机相,依次用1mol/L盐酸,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压蒸除溶剂,得固体,柱层析分离纯化,得中间体21;
(iii)将三苯基磷,偶氮二甲酸二异丙酯,手性取代醇与中间体21以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0°C反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚(1:3)混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体22(a~g);
(iv)将三苯基磷,偶氮二甲酸二异丙酯,(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇与中间体17以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0°C反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚(1:3)混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体22h;
(v)将中间体22a~22g或22h(0.5mmol)分别加入到25mL烧瓶中,加入氯化氢的乙酸乙酯溶液15mL,室温搅拌1h,减压蒸除溶剂,甲醇/乙醚重结晶分别得目标产物23(a~g)或23h。
合成路线如下:
试剂及条件:(a3)乙酰胺肟,碳酸铯,DMF,微波800W,150°C;(b3)三氯化铝,N,N-二甲苯胺,二氯甲烷,0°C~室温;(c3)手性取代醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0°C~室温;(d3)氯化氢的乙酸乙酯溶液,室温;(e3)(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0°C~室温。
(4)化合物27aa-27af,27ba-27bf的制备方法如下:
(i)将中间体1a或1b,氢化钠与硫酸二甲酯以摩尔比1:1.2:1.2加入干燥的DMF中,每2.7mmol中间体1用DMF10mL,室温反应过夜,将反应液倾入100mL冰水中,搅拌,过滤,固体用柱层析分离纯化,得中间体24a或24b;
(ii)将中间体24a或24b,N,N-二甲基苯胺与三氯化铝按摩尔比1:4:4加入到冰浴下的绝对无水二氯甲烷中,每1.7mmol中间体20或24用二氯甲烷12mL,室温搅拌1.5h,0°C下缓慢滴加1mol/L盐酸20mL,然后加入水20mL,用乙酸乙酯50mL×3萃取,合并有机相,依次用1mol/L盐酸,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压蒸除溶剂,柱层析分离纯化,得中间体25a或25b;
(iii)将三苯基磷,偶氮二甲酸二异丙酯,手性取代醇与中间体25a或25b以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0°C反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚(1:3)混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体26(aa~ae),26(ba~26be);
(iv)将三苯基磷,偶氮二甲酸二异丙酯,(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇与中间体25a或25b以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0°C反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚(1:3)混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体26af或26bf;
(iv)将中间体26(aa~af),26(ba~bf),26af或26bf(0.5mmol)分别加入到25mL烧瓶中,加入氯化氢的乙酸乙酯溶液15mL,室温搅拌1h,减压蒸除溶剂,甲醇/乙醚重结晶分别得目标产物27(aa~ae),27(ba~be),27af或27bf。
合成路线如下:
试剂及条件:(a4)硫酸二甲酯,DMF,氢化钠,0°C~室温;(b4)三氯化铝,N,N-二甲苯胺,二氯甲烷,0°C~室温;(c4)手性取代醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0°C~室温;(d4)氯化氢的乙酸乙酯溶液,室温;(e4)(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0°C~室温。
上述制备方法(2)、(3)、(4)所使用的手性取代醇用通式(II)表示,其化学名及结构式如下:
通式(II)
3、本发明通式I的多取代吲哚类化合物的应用
本发明的多取代吲哚类化合物具有抑制Akt1活性和抑制人类前列腺癌细胞株(PC-3)生长活性,用于制备抗肿瘤药物。
与现有技术相比本发明的优良效果:
本发明设计合成了结构不同的含有取代吲哚结构的化合物,其创新点是在吲哚上引入羧基甲酯,3-甲基噁二唑-5-基,含有氨基的侧链。本发明的多取代吲哚类化合物对Akt1的抑制活性和对PC-3细胞的生长抑制活性明显较强,其中化合物(S)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐(19b),(R)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐(19f),(S)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐(27ac),(R)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐(27bc),(S)-1-甲基-4-((2-氨基-3-(4-甲氧基苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐(27be)和(R)-3-甲基-5-(1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐(23b)在浓度为10nM对Akt1的抑制率分别为72.5%、70.3%、73.0%、73.5%、76.9%和78.6%,对PC-3细胞的半数生长抑制浓度均低于10.18μM。
以下实验例仅用于说明本发明的技术效果,但所述的实验例不用于限制本发明。
实验例.化合物对Akt1抑制活性测试及对PC-3细胞的生长抑制测定实验
化合物对PC-3细胞的生长抑制测定,采用文献报道的方法进行。(具体参见:Peng Wang,Jianzhen Liu,Hualu Xing,Yang Liu,Wencheng Xie,Guisen Zhao.Synthesis and anticanceractivity ofnovel5-(indole-2-yl)-3-substituted1,2,4-oxadiazoles[J].Drug Discoveries&Therapeutics,2012;6(3):133-139.)
化合物对Akt1抑制活性测试:
(1)细胞培养及裂解液的制备:
取对数生长期的PC-3细胞接种于6孔板上,细胞密度为每孔7×105个细胞。孵育过夜后,加入DMSO溶解后的化合物10μL,终浓度为10nM。空白对照组加入等体积的DMSO10μL。细胞孵育1h后,冲洗消化收集细胞,用80μL裂解液裂解细胞,离心,将上清液分为两部分,20μL为样品A,用来检测Akt总量;60μL为样品B,用于免疫共沉淀磷酸化的Akt1。
(2)Akt1的免疫共沉淀及体外酶活实验
取20μL Immobilized Phospho-Akt(Ser473)(D9E)Rabbit mAb(Bead Conjugate)加入到上述的样品B60μL裂解液中,4°C孵育过夜。将含抗体的裂解液4°C14000×G离心30s,弃上清,残留物用500μL细胞裂解缓冲液洗两次,再用500μL激酶缓冲液洗一次,加入50μL激酶缓冲液、1μL10nM的ATP和1μLGSK-3α/β(Ser21/9)蛋白,30°C孵育0.75h。加入50μL的loadingbuffer中止反应,煮沸5min,得每个化合物,空白或阳性对照的检测样品。置于-80°C保存。
(3)Western blotting
配制5%~12%SDS-PAGE凝胶,每孔加入化合物,空白或阳性对照的检测样品15μL。电压90V0.5h,然后130V1h展开。将蛋白条带从凝胶转移至PVDF膜。转膜完成后,PVDF膜用25mL TBST清洗PVDF膜5min,然后加入10mL的封闭液室温封闭1h。封闭完成后,取出PVDF膜,利用TBST清洗三次,每次用15mL TBST清洗5min。用稀释的一抗4°C孵育过夜。对总Akt测定利用pan-Akt抗体(兔源),对磷酸化GSK-3α/β(Ser21/9)测定利用磷酸化GSK-3α/β(Ser21/9)抗体(兔源)。孵育完成后,利用TBST清洗PVDF膜三次,每次用15mL TBST清洗5min,然后用稀释的兔二抗室温孵育1h,TBST清洗三次,每次用15mL TBST清洗5min。
(4)GSK-3α/β(Ser21/9)的定量
将PVDF膜置于Bio-Rad中,加入显影液显影,利用Image Lab软件对条带的荧光密度(Fluorescence Intensity,FI)进行定量。得到FIgsk-3(sample)和FIgsk-3(DMSO)。
(5)总Akt的定量
取样品A,利用western blotting检测样品A中Akt的总量,得到FIAkt(sample)和FIAkt(DMSO)。
(6)抑制率的计算公式为:
其中,FIgsk-3(sample)表示加药组的GSK-3α/β(Ser21/9)条带的荧光密度;FIgsk-3(DMSO)表示空白对照GSK-3α/β(Ser21/9)条带的荧光密度;FIAkt(sample)表示加药组的总Akt条带的荧光密度;FIAkt(DMSO)表示空白对照总Akt条带的荧光密度。
化合物活性实验结果见表1~表4。
表1.目标化合物5,10,11,12和13的化学结构及活性测定数据
ND:表示未测定.
表1实验数据表明,化合物5c对Akt1的抑制活性和对PC-3肿瘤细胞的生长抑制活性较好。
表2.目标化合物19a~19j的化学结构及活性测定数据
表2实验数据表明,化合物19d,19f和19g对Akt1的抑制活性和对PC-3肿瘤细胞的生长抑制活性均有所提高。
表3.目标化合物23的化学结构及活性测定数据
表3实验数据表明,化合物23a,23b和23d对Akt1的抑制活性和对PC-3肿瘤细胞的生长抑制活性较好。
表4.目标化合物27的化学结构及活性测定数据
表4实验数据表明,化合物27aa,27ab,27ac,27bb,27bc,27bd和27be对Akt1的抑制活性和对PC-3肿瘤细胞的生长抑制活性较强。
具体实施方式
下面结合实施例进一步描述本发明,以利更深入理解本发明及其优点和效果,但所述实施例仅用于说明本发明而不是限制本发明。
实施例1
1)中间体2a的制备
将4-苄氧基-7-溴-1H-吲哚-2-甲酸甲酯1a(0.17g,0.5mmol),碳酸铯(0.65g,2mmol)加入到25mL二颈瓶中,加入二氧六环6mL,水1mL,超声除氧,持续通氮气条件下加入四三苯基膦钯(0.06g,10%mol),苯硼酸(0.12g,1mmol),密闭,氮气保护,加热至85°C,反应4h,冷至室温,减压蒸除溶剂,用丙酮洗涤残留物至无荧光,合并丙酮溶液,减压蒸除溶剂,固体用无水甲醇/丙酮重结晶,得中间体2a,白色固体,收率85%,1H NMR(600MHz,DMSO-d6):δ=11.36(s,1H),7.58(d,J=7.8Hz,2H),7.54(d,J=7.8Hz,2H),7.48(t,J=7.8Hz,1H),7.43(t,J=7.8Hz,2H),7.34-7.39(m,2H),7.27(s,1H),7.18(dd,J=8.4Hz andJ=1.8Hz),6.77(d,J=7.8Hz,2H),5.30(s,2H),3.84(s,3H).MS(ESI):m/z=358.1[M+H]+.
2)中间体2b的制备
将4-苄氧基-7-苯基-1H-吲哚-2-甲酸甲酯2a(0.71g,2mmol)加入到100mL烧瓶中,加入干燥得DMF10mL,冰浴下缓慢加入氢化钠(0.12g,3mmol),搅拌0.5h,缓慢滴加硫酸二甲酯(0.38g,3mmol),滴加完毕,0℃反应0.5h,室温反应4h,将反应液倾入100mL冰水中,过滤得固体,用乙酸乙酯/石油醚重结晶得中间体1-甲基-4-苄氧基-7-苯基-1H-吲哚-2-甲酸甲酯2b,白色固体,收率90%,1H NMR(600MHz,DMSO-d6):δ=7.59(d,J=7.8Hz,2H),7.53(d,J=7.8Hz,2H),7.50(t,J=7.8Hz,1H),7.41(t,J=7.8Hz,2H),7.33-7.41(m,2H),7.23(s,1H),7.13(dd,J=8.4Hz andJ=1.8Hz),6.73(d,J=7.8Hz,2H),5.28(s,2H),4.28(s,3H),3.81(s,3H).MS(ESI):m/z=371.4[M+H]+.
3)中间体3的制备
将中间体2(2mmol)加入到100mL二颈瓶中,加入THF15mL,无水甲醇6mL,加入钯碳(20%mol,Pd/C为含水65%,含钯10%),通入氢气,密闭反应过夜,过滤除去钯碳,柱层析分离纯化的中间体3,洗脱系统为石油醚/乙酸乙酯=6:1。
上述的中间体2分别选用2a或2b,分别得到以下化合物3a或3b。
3a:4-羟基-7-苯基-1H-吲哚-2-甲酸甲酯,白色固体,收率80%,1H NMR(600MHz,DMSO-d6):δ=11.10(s,1H),9.92(s,1H),7.55(d,J=7.2Hz,2H),7.47(t,J=7.8Hz,2H),7.35(t,J=7.2Hz,1H),7.32(d,J=1.8Hz,1H),7.08(d,J=7.8Hz,1H),6.53(d,J=7.8Hz,1H),3.83(s,3H).MS(ESI):m/z=268.3[M+H]+.
3b:1-甲基-4-羟基-7-苯基-1H-吲哚-2-甲酸甲酯,白色固体,收率65%,1H NMR(600MHz,DMSO-d6):δ=7.53(d,J=7.8Hz,2H),7.39-7.47(m,7H),7.36(s,1H),7.34(t,J=7.2Hz,1H),7.03(d,J=7.8Hz,1H),6.75(d,J=7.8Hz,1H),5.29(s,2H),3.82(s,3H),3.48(s,3H).MS(ESI):m/z=282.4[M+H]+.
4)中间体4的制备
将中间体3(1mmol)加入到100mL烧瓶中,加入10mL DMF溶解,加入碳酸铯(0.65g,2mmol),氮气保护,缓慢加入N-溴代烷基叔丁氧基甲酰胺(1.5mmol)的DMF溶液(5mL),升温至60°C,搅拌过夜,将反应液倾入150mL冰水中,用乙酸乙酯150mL×3萃取,合并乙酸乙酯层,依次用水(100mL×1)、饱和氯化钠溶液(100mL×3)洗涤,无水硫酸钠干燥,减压蒸除溶剂,柱层析分离纯化,洗脱系统为石油醚/乙酸乙酯=10:1.
上述的中间体3分别选用3a或3b,N-溴代烷基叔丁氧基甲酰胺分别选用N-(3-溴丙基)叔丁氧基甲酰胺或N-(2-溴乙基)叔丁氧基甲酰胺,分别得到以下化合物4a,4b或4c。
4a:4-((3-叔丁氧羰酰胺基)丙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯,白色固体,收率58%,mp123.3-127.6°C.1H NMR(600MHz,CDCl3-d3):δ=9.98(s,1H),7.57(d,J=7.8Hz,2H),7.51(t,J=7.8Hz,2H),7.39~7.41(m,2H),7.24(d,J=7.8Hz,1H),6.59(d,J=7.8Hz,2H),4.98(br,s,1H),4.23(t,J=6.0Hz,2H),3.41(d,J=6.0Hz,2H),2.09(d,J=6.0Hz,2H),1.41(s,9H).MS(ESI):m/z=425.5[M+H]+.
4b:4-((2-叔丁氧羰酰胺基)乙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯,白色固体,收率62%,mp142.6-145.2°C.1H NMR(600MHz,DMSO-d6):δ=11.28(s,1H),7.57(d,J=7.8Hz,2H),7.48(t,J=7.8Hz,2H),7.35~7.38(m,2H),7.16(d,J=7.8Hz,1H),7.14(t,J=6.0Hz,1H),6.65(d,J=7.8Hz,1H),4.08(t,J=6.0Hz,2H),3.84(s,3H),3.41(q,J=6.0Hz,2H),1.40(s,9H).MS(ESI):m/z=411.5[M+H]+.
4c:1-甲基-4-((2-叔丁氧羰酰胺基)乙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯,白色固体,收率65%,mp139.6-141.2°C.1H NMR(600MHz,DMSO-d6):δ=7.44-7.47(m,3H),7.39-7.42(m,3H),7.14(t,J=6.0Hz,1H),7.02(d,J=7.8Hz,1H),6.62(d,J=7.8Hz,1H),4.08(t,J=5.4Hz,2H),3.81(s,3H),3.48(s,3H),(td,J=5.4Hz and0.6Hz,2H),3.32(s,3H).MS(ESI):m/z=425.4[M+H]+.
5)中间体6的制备
将中间体4(1mmol)加入到100mL烧瓶中,加入THF20mL,水5mL,加入氢氧化钾(0.23g,4mmol),回流过夜,冷至室温,减压蒸溶剂,加入100mL水,用饱和柠檬酸溶液调节pH至5,过滤,得固体,用乙酸乙酯/石油醚重结晶得中间体11。
上述的中间体4分别选用4a或4b,分别得到以下化合物6a或6b。
6a:4-((3-叔丁氧羰酰胺基)丙氧基)-7-苯基-1H-吲哚-2-甲酸,白色固体,收率85%,mp197.6-200.1°C.1H NMR(600MHz,DMSO-d6):δ=10.92(s,1H),7.58(d,J=7.2Hz,2H),7.48(t,J=7.8Hz,2H),7.36(t,J=7.2Hz,1H),7.16~7.18(m,2H),6.65(d,J=8.4Hz,1H),4.15(t,J=6.0Hz,2H),3.16(t,J=6.0Hz,2H),1.91~1.96(m,2H),1.38(s,9H).MS(ESI):m/z=411.5[M+H]+.
6b:4-((2-叔丁氧羰酰胺基)乙氧基)-7-苯基-1H-吲哚-2-甲酸,白色固体,收率88%,mp194.8-197.2°C.1H NMR(600MHz,DMSO-d6):δ=10.94(s,1H),7.58(d,J=7.2Hz,2H),7.48(t,J=7.8Hz,2H),7.36(t,J=7.2Hz,1H),7.27(d,J=1.2Hz,1H),7.15(d,J=8.4Hz,1H),7.13(t,J=6.0Hz,1H),6.64(d,J=7.8Hz,1H),4.09(t,J=5.4Hz,2H),3.41(m,2H),1.40(s,9H).MS(ESI):m/z=397.5[M+H]+.
6)中间体7的制备
将中间体6(0.5mmol)加入到50mL烧瓶中,加入20mL二氯甲烷,EEDQ(0.16g,0.6mmol),碳酸氢铵(0.24g,4mmol),室温反应24h,反应液依次用水30mL×2、饱和氯化钠溶液30mL×2洗涤,无水硫酸钠干燥,减压蒸除溶剂,得淡黄色油,柱层析分离纯化的中间体7,洗脱系统为石油醚/丙酮=6:1。
上述的中间体6分别选用6a或6b,分别得到以下化合物7a或7b。
7a:4-((叔丁氧羰酰胺基)丙氧基)-7-苯基-1H-吲哚-2-甲酰胺,白色固体,收率45%,mp157.6-161.4°C.1H NMR(600MHz,DMSO-d6):δ=10.53(s,1H),8.10(s,1H),7.59(d,J=7.2Hz,2H),7.51(t,J=7.8Hz,2H),7.40(t,J=7.8Hz,1H),7.37(s,1H),7.26(d,J=1.8Hz,1H),7.15(d,J=8.0Hz,1H),6.93(t,J=5.4Hz,1H),6.65(d,J=7.8Hz,1H),4.15(t,J=6.0Hz,2H),3.17(q,J=6.0Hz,2H),1.94(m,2H),1.38(s,9H).MS(ESI):m/z=410.6[M+H]+.
7b:4-((叔丁氧羰酰胺基)乙氧基)-7-苯基-1H-吲哚-2-甲酰胺,白色固体,收率56%,mp176.8-180.9°C.1H NMR(600MHz,DMSO-d6):δ=10.57(s,1H),8.05(s,1H),7.58(d,J=7.2Hz,2H),7.51(t,J=7.8Hz,2H),7.38(t,J=7.8Hz,1H),7.35(s,1H),7.27(s,1H),7.11~7.15(m,2H),6.65(d,J=7.8Hz,1H),4.11(t,J=5.4Hz,2H),3.39(d,J=5.4Hz,2H),1.40(s,9H).MS(ESI):m/z=396.4[M+H]+.
7)中间体8a的制备
将4-((叔丁氧羰酰胺基)丙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯4a(1mmol)加入到25mL二颈瓶中,加入14mL无水甲醇,氮气保护,加入新制的1.5mLNH2OK的甲醇溶液,室温反应36h,柱层析分离纯化得中间体8a,洗脱系统为石油醚/丙酮=3:1。白色固体,产率35%,mp178.6-181.2°C.H NMR(600MHz,DMSO-d6):δ=11.20(s,1H),10.63(s,1H),9.10(s,1H),7.59(d,J=7.8Hz,2H),7.50(t,J=7.8Hz,2H),7.38(t,J=7.8Hz,1H),7.12~7.15(m,2H),6.94(t,J=5.4Hz,1H),6.64(d,J=7.8Hz,1H),4.14(t,J=6.0Hz,2H),3.16(q,J=6.0Hz,2H),1.92~1.95(m,2H),1.39(s,9H).MS(ESI):m/z=426.5[M+H]+.
8)中间体9的制备
将中间体4(0.5mmol)加入到25mL无水乙醇中,加入水合肼(0.21g,4mmol,含量为80%),回流72h,减压蒸除溶剂,残留物加100mL乙酸乙酯溶解,依次用1mol/L柠檬酸溶液(50mL×2)、饱和氯化钠溶液(50mL×2)洗涤,无水硫酸钠干燥,减压蒸除溶剂,得黄色固体,用乙酸乙酯/石油醚重结晶,得淡黄色固体。
上述的中间体4分别选用4a或4b,分别得到以下化合物9a或9b。
9a:4-((叔丁氧羰酰胺基)丙氧基)-7-苯基-1H-吲哚-2-甲酰肼,白色固体,产率75%,mp124.3-127.6°C.1H NMR(600MHz,DMSO-d6):δ=10.67(s,1H),10.58(s,1H),9.88(s,1H),7.63(br,s,1H)7.59(d,J=7.2Hz,2H),7.53(t,J=7.8Hz,2H),7.407.38(t,J=7.8Hz,1H),7.37(s,1H),7.22(s,1H),7.11~7.15(m,2H),6.66(d,J=7.8Hz,1H),4.15(m,2H),3.17(m,2H),1.94(m,2H),1.38(s,9H).MS(ESI):m/z=425.4[M+H]+.
9b:4-((叔丁氧羰酰胺基)乙氧基)-7-苯基-1H-吲哚-2-甲酰肼,白色固体,产率75%,mp180.2-183.1°C.1H NMR(600MHz,DMSO-d6):δ=10.70(s,1H),9.80(s,1H),7.58(d,J=7.2Hz,2H),7.51(t,J=7.2Hz,2H),7.39(t,J=7.2Hz,1H),7.26(s,1H),7.13(d,J=7.8Hz,2H),6.64(d,J=7.8Hz,1H),4.49(br,s,2H),4.10(t,J=5.4Hz,2H),3.40(t,J=6.0Hz,2H),1.40(s,9H).MS(ESI):m/z=411.5[M+H]+.
9)目标产物5,10,11,12或13的制备
将1-取代-4-((叔丁氧羰酰胺基)烷氧基)-7-苯基-1H-吲哚-2-甲酸甲酯衍生物(0.5mmol)加入到25mL烧瓶中,加入HCl的乙酸乙酯溶液15mL,室温搅拌1h。减压蒸除溶剂,用甲醇/乙醚重结晶得目标产物。
上述的1-取代-4-((叔丁氧羰酰胺基)烷氧基)-7-苯基-1H-吲哚-2-甲酸甲酯衍生物分别选用4a,4b,4c,6a,6b,7a,7b,8a,9a或9b,分别得到以下目标产物5a,5b,5c,10a,10b,11a,11b,12a,13a和13b。
5a:4-(3-胺基丙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,产率75%,mp:162.3-164.4°C。1H NMR(600MHz,DMSO-d6)δ=11.36(s,1H),8.06(br,s,3H),7.58(d,J=7.8Hz,2H),7.49(t,J=7.8Hz,2H),7.38(t,J=7.8Hz,1H),7.30(s,1H),7.20(d,J=7.8Hz,1H),6.68(d,J=7.8Hz,1H),4.24(t,J=6.0Hz,2H),3.85(s,3H),3.05(m,2H),2.13(m,2H).HRMS(ESI):m/z for C19H21N2O3[M+H]+:calculated325.1547found325.1549.
5b:4-(2-胺基乙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯盐酸,白色固体,产率82%,mp:220.8-221.6°C。1H NMR(600MHz,DMSO-d6):δ=11.32(s,1H),8.26(br,s,3H),7.61(s,1H),7.58(d,J=7.8Hz,2H),7.49(t,J=7.8Hz,2H),7.38(t,J=7.8Hz,1H),7.20(d,J=7.8Hz,1H),6.70(d,J=7.8Hz,1H),4.33(t,J=6.0Hz,2H),3.85(s,3H),3.33(t,J=6.0Hz,2H).HRMS(ESI):m/z for C18H19N2O3[M+H]+:calculated311.1390found311.1395.
5c:1-甲基-4-(2-胺基乙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,产率85%,mp:234.8-276.5°C。1H NMR(600MHz,DMSO-d6):δ=8.28(s,3H),7.68(s,1H),7.47(t,J=7.2Hz,2H),7.40-7.43(m,3H),7.05(d,J=8.4Hz,1H),6.67(d,J=7.8Hz,1H),4.33(t,J=4.8Hz,2H),3.83(s,3H),3.48(s,3H),3.32(d,J=8.4Hz,2H).HRMS(ESI):m/z for C12H15N2O3[M+H]+:calculated325.1547found325.1554.
10a:4-(3-胺基丙氧基)-7-苯基-1H-吲哚-2-甲酸盐酸盐,白色固体,产率81%,mp:254.1-256.5°C。1H NMR(600MHz,DMSO-d6)δ:12.95(br,s,1H),11.02(s,1H),7.88(br,s,3H),7.58(d,J=7.8Hz,2H),7.50(t,J=7.8Hz,2H),7.38(t,J=7.8Hz,1H),7.23(s,1H),7.20(d,J=7.8Hz,1H),6.68(d,J=7.8Hz,1H),4.24(t,J=6.0Hz,2H),3.06(m,2H),2.13(m,2H).HRMS(ESI):m/z for C18H19N2O3[M+H]+:calculated311.1390found311.1393.
10b:4-(2-胺基乙氧基)-7-苯基-1H-吲哚-2-甲酸盐酸盐,白色固体,产率75%,mp:258.5-260.1°C。1H NMR(600MHz,DMSO-d6)δ:12.95(br,s,1H),11.02(s,1H),8.35(br,s,3H),7.58(d,J=7.8Hz,2H),7.52(d,J=1.8Hz,1H),7.48(t,J=7.8Hz,2H),7.38(t,J=7.8Hz,1H),7.19(d,J=7.8Hz,1H),6.68(d,J=7.8Hz,1H),4.33(t,J=4.8Hz,2H),3.32(t,J=4.8Hz,2H).HRMS(ESI):m/z for C17H17N2O3[M+H]+:calculated297.1234found297.1234.
11a:4-(3-胺基丙氧基)-7-苯基-1H-吲哚-2-甲酰胺盐酸盐,白色固体,产率88%,mp:261.2-263.9°C。1H NMR(600MHz,DMSO-d6)δ:10.61(s,1H),8.13(br,s,4H),7.59(d,J=7.8Hz,2H),7.51(t,J=7.8Hz,2H),7.39(t,J=7.8Hz,1H),7.38(br,s,1H),7.27(d,J=1.8Hz,1H),7.16(d,J=7.8Hz,1H),6.68(d,J=7.8Hz,1H),4.24(t,J=6.0Hz,2H),3.04(m,2H),2.14(m,2H).HRMS(ESI):m/z for C18H20N3O2[M+H]+:calculated310.1550found310.1553.
11b:4-(2-胺基乙氧基)-7-苯基-1H-吲哚-2-甲酰胺盐酸盐,白色固体,产率76%,mp:254.1-258.0°C。1H NMR(600MHz,DMSO-d6)δ:10.78(s,1H),8.37(br,s,3H),8.12(br,s,1H),7.60(d,J=7.8Hz,2H),7.52(t,J=7.8Hz,2H),7.45(d,J=1.8Hz,1H),7.40(t,J=7.8Hz,1H),7.39(br,s,1H),7.16(d,J=7.8Hz,1H),6.68(d,J=7.8Hz,1H),4.35(t,J=4.8Hz,2H),3.30(t,J=4.8Hz,2H).HRMS(ESI):m/z for C17H18N3O2[M+H]+:calculated296.1394found296.1397.
12a:4-(3-胺基丙氧基)-7-苯基-1H-吲哚-2-羟基甲酰胺盐酸盐,白色固体,产率80%,mp:245.5-246.8°C。1H NMR(600MHz,DMSO-d6)δ:11.27(s,1H),10.72(br,s,1H),9.13(br,s,1H),8.07(br,s,3H),7.59(d,J=7.8Hz,2H),7.52(t,J=7.8Hz,2H),7.39(t,J=7.8Hz,1H),7.18(s,1H),7.15(d,J=7.8Hz,1H),6.68(d,J=7.8Hz,1H),4.24(t,J=6.0Hz,2H),3.04(m,2H),2.14(m,2H).HRMS(ESI):m/z for C18H20N3O3[M+H]+:calculated326.1499found326.1503.
13a:4-(3-胺基丙氧基)-7-苯基-1H-吲哚-2-甲酰肼盐酸盐,白色固体,产率84%,mp:259.1-262.7°C。1H NMR(600MHz,DMSO-d6)δ:11.71(s,1H),11.29(s,1H),10.45~10.90(br,s,2H),8.25(br,s,3H),7.61(d,J=7.8Hz,2H),7.52(t,J=7.8Hz,2H),7.46(d,J=1.8Hz,1H),7.39(t,J=7.8Hz,1H),7.20(d,J=7.8Hz,1H),6.70(d,J=7.8Hz,1H),4.26(t,J=6.0Hz,2H),3.04(m,2H),2.16(m,2H).HRMS(ESI):m/zfor C18H21N4O2[M+H]+:calculated325.1659found325.1661.
13b:4-(2-胺基乙氧基)-7-苯基-1H-吲哚-2-甲酰肼盐酸盐,白色固体,产率80%,mp:248.9-251.6°C。1H NMR(600MHz,DMSO-d6)δ:11.69(s,1H),11.32(s,1H),10.72(br,s,2H),8.41(br,s,3H),7.68(d,J=1.8Hz,1H),7.63(d,J=7.8Hz,2H),7.53(t,J=7.8Hz,2H),7.41(t,J=7.8Hz,1H),7.22(d,J=7.8Hz,1H),6.72(d,J=7.8Hz,1H),4.36(t,J=4.8Hz,2H),3.21(t,J=4.8Hz,2H).HRMS(ESI):m/z for C17H19N4O2[M+H]+:calculated311.1503found311.1504.
10)中间体14的制备
将4-苄氧基-7-溴-1H-吲哚-2-甲酸甲酯1a(7.2g,20mmol)加入到250mL烧瓶中,加入THF100mL,水30mL,加入氢氧化钾(4.6g,80mmol),回流过夜。反应完毕,冷至室温,旋蒸除去溶剂,加入200mL水,浓盐酸溶液调节pH至1,过滤,固体干燥,乙酸乙酯/石油醚重结晶得中间体4-苄氧基-7-溴-1H-吲哚-2-甲酸14,白色固体,收率98%,mp248.6-249.8°C,1HNMR(600MHz,DMSO-d6):δ=5.25(s,2H),6.63(d,J=7.8Hz,1H),7.20(d,J=2.4Hz,1H),7.34(t,J=7.8Hz,1H),7.36(d,J=8.4Hz,1H),7.41(t,J=7.8Hz,2H),7.51(d,J=7.8Hz,2H),11.75(s,1H),13.05(br s,1H).MS(ESI):m/z=346.3[M+H]+.
11)中间体15的制备
将氢化钠(3g,75mmol)分批缓慢加入到20mL绝对无水甲醇中,无气泡放出后,加入4-苄氧基-7-溴-1H-吲哚-2-甲酸14(2.6g,7.5mmol)的干燥DMF溶液(22mL),碘化亚铜(1.43g,7.5mmol),氮气保护,密闭,回流反应5h,冷却至室温,将反应液倾入500mL冰水中,浓盐酸调节pH至1,过滤,得固体,乙酸乙酯/石油醚重结晶即得中间体4-苄氧基-7-甲氧基-1H-吲哚-2-甲酸15,白色固体,收率80%,mp235.2-236.5°C.1H NMR(600MHz,DMSO-d6):δ=3.85(s,3H),5.23(s,2H),6.59(d,J=7.8Hz,1H),7.22(d,J=2.4Hz,1H),7.34(t,J=7.8Hz,1H),7.38(d,J=8.4Hz,1H),7.42(t,J=7.8Hz,2H),7.50(d,J=7.8Hz,2H),11.85(s,1H),12.95(br s,1H).MS(ESI):m/z=298.4[M+H]+.
12)中间体16的制备
将4-苄氧基-7-甲氧基-1H-吲哚-2-甲酸15(0.8g,2.7mmol)加入到干燥DMF中(10mL),0℃缓慢加入氢化钠(0.33g,8.1mmol),反应0.5h,0℃缓慢滴加硫酸二甲酯(1.02g,8.1mmol),室温反应过夜,将反应液倾入100mL冰水中得固体,过滤,干燥,柱层析分离纯化,洗脱系统为石油醚/乙酸乙酯=10:1,得中间体1-甲基-4-苄氧基-7-甲氧基-1H-吲哚-2-甲酸甲酯16,白色固体,收率87.3%,mp100.1-101.8°C,1H NMR(600MHz,DMSO-d6):δ=3.82(s,3H),3.85(s,3H),4.26(s,3H),5.16(s,2H),6.51(d,J=7.8Hz,1H),6.69(d,J=9.0Hz,1H),7.21(s,1H),7.33(t,J=7.8Hz,1H),7.40(t,J=7.8Hz,2H),7.49(d,J=7.2Hz,2H).MS(ESI):m/z=236.3[M+H]+.
13)中间体17的制备
将中间体16(2mmol)加入到100mL二颈瓶中,加入THF15mL,无水甲醇6mL,溶解后放入预先加热好的油浴中(35°C),加入钯碳(20%mol,Pd/C为含水65%,含钯10%),通入氢气,排除空气30s,密闭反应过夜。反应毕,过滤除去钯碳,柱层析分离纯化,洗脱系统为石油醚/乙酸乙酯=6:1,得中间体1-甲基-4-羟基-7-甲氧基-1H-吲哚-2-甲酸甲酯17,白色固体,收率94%,mp100.1-101.8°C。1H NMR(600MHz,DMSO-d6):δ=9.31(s,1H),7.27(s,1H),6.63(d,J=7.8Hz,1H),6.29(d,J=7.8Hz,1H),4.24(s,3H),3.82(s,3H),3.81(s,3H).MS(ESI):m/z=236.1[M+H]+.
14)中间体18a的制备
将中间体17(1mmol)加入到100mL烧瓶中,加入10mLDMF溶解,加入碳酸铯(0.65g,2mmol),氮气保护,缓慢加入N-(2-溴乙基)叔丁氧基甲酰胺(1.5mmol)的DMF溶液(5mL),升温至60°C,搅拌过夜。将反应液倾入150mL冰水中,用乙酸乙酯150mL×3萃取,合并乙酸乙酯层,依次用水(100mL×1)、饱和氯化钠溶液(100mL×3)洗涤,无水硫酸钠干燥,减压蒸除溶剂,柱层析分离纯化,洗脱系统为石油醚/乙酸乙酯=10:1得中间体1-甲基-4-(2-叔丁氧羰酰胺基)乙氧基-7-甲氧基-1H-吲哚-2-甲酸甲酯18a,白色固体,收率60%,mp138.4-140.0°C。1H NMR(600MHz,DMSO-d6):δ=7.28(s,1H),7.08(t,J=5.4Hz,1H),6.68(d,J=8.4Hz,1H),6.39(d,J=8.4Hz,1H),4.26(s,3H),3.96(t,J=6.0Hz,2H),3.85(s,3H),3.82(s,3H),3.35(q,J=6.6Hz,2H),1.40(s,9H).MS(ESI):m/z=378.7[M+H]+.
15)中间体18b~18j的制备
将三苯基磷(0.41g,2mmol)加入50mL三颈瓶中,加入5mL无水的四氢呋喃,密闭,氮气保护,0℃下缓慢加入偶氮二甲酸二异丙酯(DIAD,0.41g,2mmol),搅拌0.5h,缓慢加入手性取代醇或(S)-(1-(叔丁氧羰基)四氢吡咯-2-基)甲醇(3mmol)的四氢呋喃(5mL)溶液,0.5h后加入1-甲基-4-羟基-7-甲氧基-1H-吲哚-2-甲酸甲酯17(0.24g,1mmol)的四氢呋喃(10mL)溶液,室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚混合液(1:3,10mL×4)洗涤,合并有机相,柱层析分离纯化,洗脱系统为石油醚/乙酸乙酯=15:1,得中间体18b~18j。
18b:(S)-1-甲基-4-(((2-叔丁氧羰酰胺基)-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯,白色固体,收率57%,mp155.4-157.8°C。1H NMR(600MHz,DMSO-d6):δ=7.34(s,1H),7.23-7.28(m,4H),7.19(t,J=7.2HZ,1H),7.08(d,J=8.4HZ,1H),6.68(d,J=8.4HZ,1H),6.35(d,J=8.4HZ,1H),4.26(s,3H),4.05(m,1H),3.87-3.94(m,2H),3.85(s,3H),3.83(s,3H),2.94(dd,J=6.0,13.8HZ,1H),2.81(dd,J=9.0,13.8HZ,1H),1.34(s,9H).MS(ESI):m/z=469.5[M+H]+.
18c:(S)-1-甲基-4-(((2-叔丁氧羰酰胺基)-4-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯,白色固体,收率52%,mp132.7-135.6°C。1H NMR(600MHz,DMSO-d6):δ=7.26(s,1H),6.84(d,J=9.0HZ,1H),6.68(d,J=8.4HZ,1H),6.39(d,J=8.4HZ,1H),4.25(s,3H),3.87-3.92(m,2H),3.85(s,3H),3.82(s,3H),3.80-3.83(m,1H),1.67(m,1H),1.44(m,1H),1.40(s,9H),1.32(m,1H),0.91(d,J=7.2HZ,3H),0.87(d,J=7.2HZ,3H).MS(ESI):m/z=435.5[M+H]+.
18d:(S)-1-甲基-4-(((2-叔丁氧羰酰胺基)-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯,白色固体,收率50%,mp187.1-188.9°C。1H NMR(600MHz,DMSO-d6):δ=10.81(s,1H),7.54(d,J=7.8HZ,1H),7.34(m,2H),7.10(d,J=1.8HZ,1H),7.06(m,2H),6.95(t,J=7.8HZ,1H),6.64(d,J=8.4HZ,1H),6.31(d,J=8.4HZ,1H),4.26(s,3H),4.12(m,1H),3.91-4.04(m,2H),3.84(s,3H),3.83(s,3H),3.03(dd,J=6.6,14.4HZ,1H),2.92(dd,J=7.8,14.4HZ,1H),1.38(s,9H).MS(ESI):m/z=508.7[M+H]+.
18e:(S)-1-甲基-4-(((2-叔丁氧羰酰胺基)-4-甲硫基)丁氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯,白色固体,收率49%,mp122.3-124.6°C。1H NMR(600MHz,DMSO-d6):δ=7.26(s,1H),6.96(d,J=8.4HZ,1H),6.69(d,J=7.8HZ,1H),6.41(d,J=8.4HZ,1H),4.26(s,3H),3.93(m,2H),3.89(m,1H),3.85(s,3H),3.82(s,3H),2.05-2.55(m,2H),2.05(s,3H),1.67(m,1H),1.44(m,1H),1.40(s,9H).MS(ESI):m/z=453.5[M+H]+.
18f:(R)-1-甲基-4-(((2-叔丁氧羰酰胺基)-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯,,无色油,收率54%。1HNMR(600MHz,DMSO-d6):δ=10.82(s,1H),7.55(d,J=7.8HZ,1H),7.35(m,2H),7.11(d,J=1.8HZ,1H),7.07(m,2H),6.96(t,J=7.8HZ,1H),6.65(d,J=8.4HZ,1H),6.32(d,J=8.4HZ,1H),4.25(s,3H),4.12(m,1H),3.91-4.05(m,2H),3.85(s,3H),3.83(s,3H),3.03(dd,J=6.6,14.4HZ,1H),2.93(dd,J=7.8,14.4HZ,1H),1.39(s,9H).MS(ESI):m/z=508.7[M+H]+.
18g:1-甲基-4-(((2S,3S)-2-叔丁氧羰酰胺基-3-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯,白色固体,收率43%,mp148.2-149.6°C。1H NMR(600MHz,DMSO-d6):δ=7.26(s,1H),6.89(d,J=9.0HZ,1H),6.68(d,J=7.8HZ,1H),6.40(d,J=8.4HZ,1H),4.25(s,3H),4.01(m,1H),3.91(m,1H),3.85(s,3H),3.81(s,3H),3.70(m,1H),1.65(m,1H),1.49(m,1H),1.40(s,9H),1.16(m,1H),0.87(t,J=7.2HZ,3H),0.85(d,J=7.2HZ,3H).MS(ESI):m/z=435.5[M+H]+.
18h:(S)-1-甲基-4-(((2-叔丁氧羰酰胺基)-3-(4-甲氧基苯基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯,白色固体,收率52%,mp149.2-151.6°C。1H NMR(600MHz,DMSO-d6):δ=7.34(s,1H),7.14(d,J=8.4HZ,2H),7.03(d,J=9.0HZ,1H),6.83(d,J=9.0HZ,2H),6.67(d,J=7.8HZ,1H),6.34(d,J=8.4HZ,1H),4.26(s,3H),3.99(m,1H),3.91(m,1H),3.87(m,1H),3.85(s,3H),3.83(s,3H),3.71(s,3H),2.86(dd,J=6.0,13.8HZ,1H),2.74(dd,J=8.4,13.8HZ,1H),1.36(s,9H).MS(ESI):m/z=499.5[M+H]+.
18i:(R)-1-甲基-4-(((2-叔丁氧羰酰胺基)-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯,白色固体,收率55%,mp150.2-153.0°C。1H NMR(600MHz,DMSO-d6):δ=7.34(s,1H),7.23-7.28(m,4H),7.19(t,J=7.2HZ,1H),7.08(d,J=8.4HZ,1H),6.68(d,J=8.4HZ,1H),6.35(d,J=8.4HZ,1H),4.26(s,3H),4.05(m,1H),3.87-3.94(m,2H),3.85(s,3H),3.83(s,3H),2.94(dd,J=6.0,13.8HZ,1H),2.81(dd,J=9.0,13.8HZ,1H),1.34(s,9H).MS(ESI):m/z=469.4[M+H]+.
18j:(S)-1-甲基-4-((1-(叔丁氧羰基)四氢吡咯-2-基)甲氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯,白色固体,收率49%,mp154.3-157.2°C。1H NMR(600MHz,DMSO-d6):δ=7.15(s,1H),6.69(d,J=8.4HZ,1H),6.48(d,J=7.2HZ,1H),4.26(s,3H),4.08(m,2H),3.99(m,1H),3.85(s,3H),3.83(s,3H),3.31(m,2H),1.98(m,2H),1.83(m,2H),1.40(s,9H).MS(ESI):m/z=419.4[M+H]+.
16)目标产物19的制备
分别将中间体18a~18j(0.5mmol)加入到25mL烧瓶中,加入HCl的乙酸乙酯溶液15mL,室温搅拌1h,减压蒸除溶剂,用甲醇/乙醚重结晶得目标产物19a~19j。
19a:1-甲基-4-(2-氨基乙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率85%,mp230.5-234.9°C。1H NMR(600MHz,DMSO-d6)δ:8.18(br.s,3H),7.53(s,1H),6.71(d,J=8.4Hz,1H),6.45(d,J=8.4Hz,1H),4.27(s,3H),4.20(m,2H),3.86(s,3H),3.84(s,3H),3.27(s,2H).HRMS(ESI):m/z for C14H19N2O4[M+H]+:calculated279.1339found279.1341.
19b:(S)-1-甲基-4-((2-胺基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率84%,mp196.2-201.8°C,[α]D 25:+50.0°(c1,MeOH)。1H NMR(600MHz,DMSO-d6)δ:8.38(s,3H),7.61(s,1H),7.32~7.34(m,2H),7.26~7.28(m,3H),6.66(d,J=8.4Hz,1H),6.34(d,J=8.4Hz,1H),4.27(s,3H),4.09(dd,J=2.4Hz and10.2Hz,1H),3.90(dd,J=5.4Hz and10.2Hz,1H),3.86(s,3H),3.84(s,3H),3.82~3.85(m,1H),3.13(dd,J=5.4Hz and13.2Hz,1H),3.04~3.08(m,1H).HRMS(ESI):m/zfor C21H25N2O4[M+H]+:calculated369.1809found369.1815.
19c:(S)-1-甲基-4-((2-胺基-4-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率90%,mp189.1-192.0°C,[α]D 25:+14.3°(c1,MeOH)。1H NMR(600MHz,DMSO-d6)δ:8.28(s,3H),7.57(s,1H),6.71(d,J=8.4Hz,1H),6.46(d,J=8.4Hz,1H),4.27(s,3H),4.22(dd,J=2.4Hz and10.2Hz,1H),4.06(dd,J=5.4Hz and10.2Hz,1H),3.86(s,3H),3.84(s,3H),3.55~3.57(m,1H),1.76~1.80(m,1H),1.58~1.64(m,2H),0.93(d,J=6.6Hz,3H),0.92(d,J=6.6Hz,3H).HRMS(ESI):m/zfor C18H27N2O4[M+H]+:calculated335.1963found335.1970.
19d:(S)-1-甲基-4-((2-胺基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率92%,mp213.9-217.4°C,[α]D 25:+38.5°(c1,MeOH)。1H NMR(600MHz,DMSO-d6)δ:11.03(s,1H),8.40(s,3H),7.63(s,1H),7.61(d,J=7.8Hz,1H),7.36(d,J=7.8Hz,1H),7.21(d,J=2.4Hz,1H),7.08(t,J=7.8Hz,1H),6.97(t,J=7.8Hz,1H),6.65(d,J=8.4Hz,1H),6.32(d,J=8.4Hz,1H),4.27(s,3H),4.16(dd,J=2.4Hz and10.2Hz,1H),4.01(dd,J=5.4Hz and10.2Hz,1H),3.85(s,3H),3.84(s,3H),3.81(s,1H),3.21~3.25(m,2H).HRMS(ESI):m/zfor C23H26N3O4[M+H]+:calculated408.1918found408.1926.
19e:(S)-1-甲基-4-((2-胺基-4-甲硫基)丁氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率80%,mp219.8-223.0°C,[α]D 25:+13.3°(c1,MeOH)。1H NMR(600MHz,DMSO-d6)δ:8.36(br.s,3H),7.56(s,1H),6.72(d,J=8.4Hz,1H),6.47(d,J=8.4Hz,1H),4.27(s,3H),4.25(m,1H),4.10~4.13(m,1H),3.86(s,3H),3.84(s,3H),3.66(s,1H),2.65~2.67(m,2H),2.08(s,3H),2.00~2.05(m,2H).HRMS(ESI):m/zfor C17H25N2O4S[M+H]+:calculated353.1530found353.1534.
19f:(R)-1-甲基-4-((2-胺基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率87%,mp201.2-203.6°C,[α]D 25:-85.7°(c1,MeOH)。1H NMR(600MHz,DMSO-d6)δ:11.02(s,1H),8.30(s,3H),7.62(s,1H),7.61(d,J=7.8Hz,1H),7.37(d,J=7.8Hz,1H),7.20(s,1H),7.09(t,J=7.8Hz,1H),6.97(t,J=7.8Hz,1H),6.66(d,J=8.4Hz,1H),6.32(d,J=8.4Hz,1H),4.27(s,3H),4.16(dd,J=2.4Hz and10.2Hz,1H),3.99~4.01(m,1H),3.85(s,3H),3.84(s,3H),3.84~3.86(m,1H),3.20(m,2H).HRMS(ESI):m/z for C23H26N3O4[M+H]+:calculated408.1918found408.1925.
19g:1-甲基-4-(((2S,3S)-2-胺基-3-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率88%,mp187.0-189.1°C,[α]D 25:+20.0°(c1,MeOH)。1H NMR(600MHz,DMSO-d6)δ:8.31(s,3H),7.56(s,1H),6.71(d,J=8.4Hz,1H),6.49(d,J=8.4Hz,1H),4.27(s,3H),4.22(dd,J=2.4Hz and10.2Hz,1H),4.11~4.14(m,1H),3.86(s,3H),3.84(s,3H),3.45(br.s,1H),1.91~1.95(m,1H),1.57~1.61(m,1H),1.25~1.30(m,1H),0.98(d,J=7.2Hz,3H),0.92(t,J=7.2Hz,3H).HRMS(ESI):m/z for C18H27N2O4[M+H]+:calculated335.1965found335.1970.
19h:(S)-1-甲基-4-((2-胺基-3-(4-甲氧基苯基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯,白色固体,收率77%,mp200.1-203.9°C,[α]D 25:+36.4°(c1,MeOH)。1H NMR(600MHz,DMSO-d6)δ:8.38(s,3H),7.60(s,1H),7.17(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),6.67(d,J=8.4Hz,1H),6.35(d,J=8.4Hz,1H),4.27(s,3H),4.09(dd,J=2.4Hz and10.2Hz,1H),3.91(dd,J=5.4Hz and10.2Hz,1H),3.85(s,3H),3.84(s,3H),3.76(m,1H),3.72(s,3H),3.06(dd,J=5.4Hzand13.2Hz,1H),2.97~3.01(m,1H).HRMS(ESI):m/zfor C22H27N2O5[M+H]+:calculated399.1914found399.1922.
19i:(R)-1-甲基-4-((2-胺基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率89%,mp188.3-189.9°C,[α]D 25:-75.0°(c1,MeOH)。1H NMR(600MHz,DMSO-d6)δ:8.44(br,s,3H),7.61(s,1H),7.25~7.34(m,5H),6.67(d,J=8.4Hz,1H),6.34(d,J=8.4Hz,1H),4.27(s,3H),4.10(dd,J=3.0Hz and10.2Hz,1H),3.91(dd,J=4.8Hz and10.8Hz,1H),3.86(s,3H),3.85(s,3H),3.82~3.85(m,1H),3.13~3.16(m,1H),3.06~3.08(m,1H).HRMS(ESI):m/z for C21H25N2O4[M+H]+:calculated369.1809found369.1814.
19j:(S)-1-甲基-4-((四氢吡咯-2-基)甲氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率82%,mp192.2-194.1°C,[α]D 25:+28.6°(c1,MeOH)。1H NMR(600MHz,DMSO-d6)δ:9.58(s,1H),8.99(s,1H),7.38(s,1H),6.72(d,J=8.4Hz,1H),6.47(d,J=8.4Hz,1H),4.33(dd,J=3.6Hz and10.2Hz,1H),4.27(s,3H),4.15(t,J=10.2Hz,1H),3.95(m,1H),3.86(s,3H),3.84(s,3H),3.20~3.27(m,2H),2.12~2.18(m,1H),1.91~2.03(m,2H),1.73~1.79(m,1H).HRMS(ESI):m/z for C17H23N2O4[M+H]+:calculated319.1652found319.1657.
17)3-甲基-5-(1-甲基-4-苄氧基-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑的制备
将1-甲基-4-苄氧基-7-甲氧基-1H-吲哚-2-甲酸甲酯16(0.65g,2mmol),乙酰胺肟(0.3g,4mmol),碳酸铯(1.3g,4mmol)加入25mL烧瓶中,加入DMF10mL,微波800W,150°C反应5min,冷至室温,将反应液倾入100mL冰水中,用乙酸乙酯100mL×3萃取,合并有机相,依次用水、饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压蒸除溶剂,柱层析分离纯化,洗脱剂为石油醚/乙酸乙酯=5:1,得3-甲基-5-(1-甲基-4-苄氧基-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑中间体20,白色固体,收率87%,mp145.8~147.6°C。1HNMR(600MHz,DMSO-d6):δ=2.44(s,3H),3.87(s,3H),4.38(s,3H),5.20(s,2H),6.56(d,J=8.4Hz,1H),6.73(d,J=8.4Hz,1H),7.34,(t,J=7.8Hz,1H),7.38(s,1H),7.41(t,J=7.8Hz,2H),7.52(d,J=7.8Hz,2H).HRMS-ESI:m/z[M+H]+calcdfor C20H20N3O3:350.1499;found350.1504.
18)3-甲基-5-(1-甲基-4-羟基-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑的制备
将中间体20(0.6g,1.7mmol)置于100mL烧瓶中,加入12mL无水二氯甲烷溶解,加入N,N-二甲基苯胺(0.83g,6.9mmol),0℃下缓慢加入三氯化铝粉末(0.92g,6.9mmol),室温反应1.5h,缓慢滴加1mol/L盐酸20mL,水20mL,用乙酸乙酯50mL×3萃取,合并有机相,依次用1mol/L盐酸、饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,加压蒸除溶剂,柱层析分离纯化,洗脱剂为石油醚/乙酸乙酯=3:1,得3-甲基-5-(1-甲基-4-羟基-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑中间体21,蓝绿色固体,收率89%,mp125.8~127.6°C。1H NMR(600MHz,DMSO-d6):δ=9.30(s,1H),7.23(s,1H),6.63(d,J=7.8Hz,1H),6.28(d,J=7.8Hz,1H),4.24(s,3H),3.82(s,3H),2.46(s,3H).MS(ESI):m/z=260.2[M+H]+.
19)中间体22的制备
将三苯基磷(0.41g,2mmol)加入50mL三颈瓶中,加入5mL无水的四氢呋喃,密闭,氮气保护,0℃下缓慢加入偶氮二甲酸二异丙酯(DIAD,0.41g,2mmol),搅拌0.5h,缓慢加入手性取代醇或(S)-(1-(叔丁氧羰基)四氢吡咯-2-基)甲醇(3mmol)的四氢呋喃(5mL)溶液,反应0.5h,中间体21(1mmol)的四氢呋喃溶液(10mL),室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚混合液(1:3,10mL×4)洗涤,合并有机相,柱层析分离纯化,洗脱系统为石油醚/乙酸乙酯=15:1,得中间体22a~22h。
22a:(S)-3-甲基-5-(1-甲基-4-((2-叔丁氧羰酰胺基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑,白色固体,收率58.1%,mp175.2-178.2°C。1H NMR(600MHz,DMSO-d6):δ=7.53(s,1H),7.24-7.28(m,4H),7.19(d,J=7.2HZ,1H),7.08(d,J=8.4HZ,1H),6.71(d,J=8.4HZ,1H),6.40(d,J=8.4HZ,1H),4.29(s,3H),4.07(m,1H),3.87-3.94(m,2H),3.84(s,3H),2.95(dd,J=6.6,13.2HZ,1H),2.83(dd,J=8.4,13.2HZ,1H),2.44(s,3H),1.34(s,9H).
22b:(R)-3-甲基-5-(1-甲基-4-((2-叔丁氧羰酰胺基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑,白色固体,收率53.7%,mp165.6-169.5°C。1H NMR(600MHz,DMSO-d6):δ=7.53(s,1H),7.23-7.28(m,4H),7.19(d,J=7.2HZ,1H),7.08(d,J=8.4HZ,1H),6.71(d,J=8.4HZ,1H),6.40(d,J=8.4HZ,1H),4.37(s,3H),4.07(m,1H),3.91-3.96(m,2H),3.87(s,3H),2.95(dd,J=6.6,13.2HZ,1H),2.83(dd,J=8.4,13.2HZ,1H),2.44(s,3H),1.34(s,9H).
22c:(S)-3-甲基-5-(1-甲基-4-(2-叔丁氧羰酰胺基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑,白色固体,收率49.6%,mp97.0-100.2°C。1H NMR(600MHz,DMSO-d6):δ=10.81(s,1H),7.53(s,1H),7.34(m,2H),7.06-7.12(m,3H),6.93-6.98(m,1H),6.68(d,J=8.4HZ,1H),6.36(d,J=8.4HZ,1H),4.38(s,3H),4.13(m,1H),3.94-3.96(m,2H),3.87(s,3H),3.04(dd,J=6.6,13.2HZ,1H),2.92(dd,J=8.4,13.2HZ,1H),2.44(s,3H),1.36(s,9H).
22d:(R)-3-甲基-5-(1-甲基-4-(2-叔丁氧羰酰胺基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑,白色固体,收率42.9%,mp98.4-101.9°C。1H NMR(600MHz,DMSO-d6):δ=10.81(s,1H),7.53(s,1H),7.34(m,2H),7.06-7.12(m,3H),6.93-6.98(m,1H),6.68(d,J=8.4HZ,1H),6.36(d,J=8.4HZ,1H),4.38(s,3H),4.13(m,1H),3.94-3.96(m,2H),3.87(s,3H),3.04(dd,J=6.6,13.2HZ,1H),2.92(dd,J=8.4,13.2HZ,1H),2.44(s,3H),1.36(s,9H).
22e:(S)-3-甲基-5--(1-甲基-4-(2-叔丁氧羰酰胺基-3-(4-甲氧基苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑,白色固体,收率52.7%,mp151.0-152.3°C。1H NMR(600MHz,DMSO-d6):δ=7.52(s,1H),7.15(d,J=9.0HZ,2H),7.05(d,J=8.4HZ,1H),6.83(d,J=8.4HZ,2H),6.71(d,J=8.4HZ,1H),6.40(d,J=7.8HZ,1H),4.38(s,3H),4.10(m,1H),3.92(m,2H),3.87(s,3H),3.70(s,3H),2.87(dd,J=6.6,13.2HZ,1H),2.66(dd,J=8.4,13.2HZ,1H),2.44(s,3H),1.36(s,9H).
22f:(S)-3-甲基-5-(1-甲基-4-((2-叔丁氧羰酰胺基-4-甲硫基)丁氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑,白色固体,收率47.9%,mp109.4-113.1°C。1H NMR(600MHz,DMSO-d6):δ=7.44(s,1H),6.98(d,J=8.4HZ,1H),6.73(d,J=8.4HZ,1H),6.46(d,J=7.8HZ,1H),4.37(s,3H),3.94(m,3H),3.88(s,3H),2.61(m,1H),2.44(s,3H),2.39(m,1H),2.05(s,3H),1.36(s,9H).MS(ESI):m/z=477.5[M+H]+.
22g:(S)-3-甲基-5-(1-甲基-4-((2-叔丁氧羰酰胺基-4-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑,无色油,收率39.4%。1H NMR(600MHz,DMSO-d6):δ=7.78(s,1H),6.75(d,J=8.4Hz,1H),6.52(d,J=8.4Hz,1H),4.37(s,3H),4.25(dd,J=3.0Hz and10.2Hz,1H),4.06~4.08(m,1H),3.89(s,3H),3.61(m,1H),2.46(s,3H),1.76~1.80(m,1H),1.60~1.62(m,2H),1.36(s,9H),0.94(d,J=6.6Hz,3H),0.92(d,J=6.6Hz,3H).
22h:(S)-3-甲基-5-(1-甲基-4-((1-(叔丁氧羰基)四氢吡咯-2-基)甲氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑,无色油,收率45.6%。1H NMR(600MHz,DMSO-d6):δ=7.58(s,1H),6.76(d,J=8.4Hz,1H),6.53(d,J=8.4Hz,1H),4.39(s,3H),4.36~4.37(m,1H),4.14~4.19(m,1H),3.97(br.s,3H),3.89(s,3H),3.24~3.28(m,1H),2.45(s,3H),2.13~2.17(m,1H),1.94~2.04(m,2H),1.74~1.80(m,1H),1.36(s,9H).
20)目标产物23a~23h的制备
分别将中间体22a~22h(0.5mmol)加入到25mL烧瓶中,加入HCl的乙酸乙酯溶液15mL,室温搅拌1h,减压蒸除溶剂,用甲醇/乙醚重结晶得目标产物23a~23h.
23a:(S)-3-甲基-5-(1-甲基-4-((2-胺基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐,白色固体,收率85%,mp:155.5-158.6°C,[α]D 25:+47.1°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ=8.43(s,3H),7.82(s,1H),7.32~7.35(m,2H),7.25~7.28(m,3H),6.70(d,J=8.4Hz,1H),6.39(d,J=8.4Hz,1H),4.39(s,3H),4.12(dd,J=2.4Hz and10.2Hz,1H),3.93~3.96(m,1H),3.88(s,3H),3.84(m,1H),3.15(dd,J=5.4Hz and13.2Hz,1H),3.06~3.09(m,1H),2.45(s,3H).HRMS(ESI):m/z for C22H25N3O4[M+H]+:calculated393.1921found393.1928.
23b:(R)-3-甲基-5-(1-甲基-4-((2-胺基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐,白色固体,收率80%,mp:155.5-157.9°C,[α]D 25:+-58.3°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ=8.39(s,3H),7.82(s,1H),7.32~7.35(m,2H),7.26~7.29(m,3H),6.71(d,J=7.8Hz,1H),6.39(d,J=7.8Hz,1H),4.35(s,3H),4.13(dd,J=2.4Hz and10.2Hz,1H),3.93~3.96(m,1H),3.88(s,3H),3.84(m,1H),3.14(dd,J=5.4Hz and13.2Hz,1H),3.06~3.09(m,1H),2.45(s,3H).HRMS(ESI):m/z for C22H25N3O4[M+H]+:calculated393.1921found393.1928.
23c:(S)-3-甲基-5-(1-甲基-4-(2-胺基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐,白色固体,收率84%,mp:169.7-173.9°C,[α]D 25:+30.8°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ=11.05(s,1H),8.48(s,3H),7.85(s,1H),7.63(d,J=7.8Hz,1H),7.37(d,J=8.4Hz,1H),7.23(s,1H),7.09(t,J=7.8Hz,1H),6.98(t,J=7.8Hz,1H),6.69(d,J=8.4Hz,1H),6.37(d,J=8.4Hz,1H),4.38(s,3H),4.18(dd,J=2.4Hz and10.2Hz,1H),4.03~4.05(m,1H),3.87(s,3H),3.83(m,1H),3.21~3.29(m,2H),2.45(s,3H).HRMS(ESI):m/z for C24H26N5O3[M+H]+:calculated432.2030found432.2038.
23d:(R)-3-甲基-5-(1-甲基-4-(2-胺基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐,白色固体,收率92%,mp:169.9-173.5°C,[α]D 25:-46.7°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ=11.02(s,1H),8.31(s,3H),7.84(s,1H),7.61(d,J=8.4Hz,1H),7.37(d,J=8.4Hz,1H),7.23(d,J=1.8Hz,1H),7.09(t,J=7.8Hz,1H),6.98(t,J=7.8Hz,1H),6.70(d,J=8.4Hz,1H),6.38(d,J=8.4Hz,1H),4.39(s,3H),4.18(dd,J=3.0Hz and10.2Hz,1H),4.02~4.04(m,1H),3.87(s,3H),3.87(m,1H),3.22(d,J=7.8Hz,2H),2.45(s,3H).HRMS(ESI):m/z for C24H26N5O3[M+H]+:calculated432.2030found432.2038.
23e:(S)-3-甲基-5--(1-甲基-4-(2-氨基-3-(4-甲氧基苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐,白色固体,收率79%,mp:190.6-194.2°C,[α]D 25:+61.5°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ=8.29(s,3H),7.80(s,1H),7.18(d,J=8.4Hz,2H),7.89(d,J=8.4Hz,2H),6.71(d,J=8.4Hz,1H),6.41(d,J=8.4Hz,1H),4.35(s,3H),4.11(dd,J=2.4Hz and10.2Hz,1H),3.93~3.96(m,1H),3.90(s,3H),3.80(br.s,1H),3.74(s,3H),2.98~3.06(m,2H),2.45(s,3H).HRMS(ESI):m/zfor C23H27N4O4[M+H]+:calculated423.2027found423.2033.
23f:(S)-3-甲基-5-(1-甲基-4-((2-胺基-4-甲硫基)丁氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐,白色固体,收率84%,mp:209.4-213.2°C,[α]D 25:+15.4°(c1,MeOH).1HNMR(600MHz,DMSO-d6)δ=8.17(s,3H),7.77(s,1H),6.76(d,J=7.8Hz,1H),6.53(d,J=7.8Hz,1H),4.38(s,3H),4.28(dd,J=2.4Hz and10.2Hz,1H),4.10~4.13(m,1H),3.89(s,3H),3.70(br.s,1H),2.65(t,J=7.8Hz,2H),2.45(s,3H),2.08(s,3H),1.99~2.03(m,2H).HRMS(ESI):m/z for C18H25N4O3[M+H]+:calculated377.1642found377.1648.
23g:(S)-3-甲基-5-(1-甲基-4-((2-胺基-4-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐,白色固体,收率93%,mp:214.3-216.5°C,[α]D 25:+17.6°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ=8.22(s,3H),7.78(s,1H),6.75(d,J=8.4Hz,1H),6.52(d,J=8.4Hz,1H),4.37(s,3H),4.25(dd,J=3.0Hz and10.2Hz,1H),4.06~4.08(m,1H),3.89(s,3H),3.61(br.s,1H),2.46(s,3H),1.76~1.80(m,1H),1.60~1.62(m,2H),0.94(d,J=6.6Hz,3H),0.92(d,J=6.6Hz,3H).HRMS(ESI):m/z for C19H27N4O3[M+H]+:calculated359.2078found359.2084.
23h:(S)-3-甲基-5-(1-甲基-4-(四氢吡咯-2-基亚甲氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐,白色固体,收率88%,mp:215.4-217.6°C,[α]D 25:+35.7°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ=9.68(br.s,1H),9.05(br.s,1H),7.58(s,1H),6.76(d,J=8.4Hz,1H),6.53(d,J=8.4Hz,1H),4.39(s,3H),4.36~4.37(m,1H),4.14~4.19(m,1H),3.97(br.s,3H),3.89(s,3H),3.24~3.28(m,2H),2.45(s,3H),2.13~2.17(m,1H),1.94~2.04(m,2H),1.74~1.80(m,1H).HRMS(ESI):m/z for C18H23N4O3[M+H]+:calculated343.1765found343.1771.
21)中间体24的制备
将4-苄氧基-7-溴-1H-吲哚-2-甲酸甲酯1a或4-苄氧基-7-氯-1H-吲哚-2-甲酸甲酯1b(2.7mmol)加入到干燥DMF(10mL)中,0℃下缓慢加入氢化钠(0.13g,3mmol),反应0.5h,缓慢滴加硫酸二甲酯(0.38g,3mmol),室温反应过夜,将反应液倾入100mL冰水中,过滤,得固体,干燥,柱层析分离纯化,洗脱系统为石油醚/乙酸乙酯=10:1,得中间体24a或24b.
24a:1-甲基-4-苄氧基-7-溴-1H-吲哚-2-甲酸甲酯,白色固体,收率91.2%,mp108.6-109.9°C。1H NMR(600MHz,DMSO-d6):δ=7.50(d,J=6.6Hz,2H),7.44(d,J=9.0Hz,1H),7.41(t,J=7.2Hz,2H),7.35(t,J=7.2Hz,1H),7.27(s,1H),6.65(d,J=8.4Hz,1H),5.24(s,2H),4.35(s,3H),3.84(s,3H).MS(ESI):m/z=374.3[M+H]+.
24b:1-甲基-4-苄氧基-7-氯-1H-吲哚-2-甲酸甲酯,白色固体,收率89.2%,mp102.5-104.8°C。1H NMR(600MHz,DMSO-d6):δ=7.50(d,J=7.8Hz,2H),7.41(t,J=7.8Hz,2H),7.34(t,J=7.8Hz,1H),7.23-7.26(m,2H),6.67(d,J=7.8Hz,1H),5.25(s,2H),4.35(s,3H),3.87(s,3H).MS(ESI):m/z=330.8[M+H]+.
22)中间体25的制备
将中间体24a或24b(0.6g,1.7mmol)置于100mL烧瓶中,加入12mL无水二氯甲烷溶解,加入N,N-二甲基苯胺(0.83g,6.9mmol),0℃下缓慢加入三氯化铝粉末(0.92g,6.9mmol),室温反应1.5h,缓慢滴加1mol/L盐酸20mL,水20mL,用乙酸乙酯萃取(50mL×3),合并有机相,依次用1mol/L盐酸、饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压蒸除溶剂,柱层析分离纯化,洗脱剂为石油醚/乙酸乙酯=3:1,中间体25a或25b.
25a:1-甲基-4-羟基-7-溴-1H-吲哚-2-甲酸甲酯,白色固体,收率68.5%,mp106.5-109.6°C。1H NMR(600MHz,DMSO-d6)δ=10.07(s,1H),7.32(d,J=2.4Hz,1H),7.25(dd,J=7.8Hzand2.4Hz,1H),6.40(dd,J=7.8Hz and2.4Hz,1H),4.26(s,3H),3.86(s,3H).MS(ESI):m/z=283.9[M+H]+.
25b:1-甲基-4-羟基-7-氯-1H-吲哚-2-甲酸甲酯,白色固体,收率55.4%,mp101.7-103.1°C。1H NMR(600MHz,DMSO-d6)δ=10.08(s,1H),7.31(d,J=2.4Hz,1H),7.26(dd,J=7.8Hzand2.4Hz,1H),6.41(dd,J=7.8Hz and2.4Hz,1H),4.26(s,3H),3.86(s,3H).MS(ESI):m/z=240.2[M+H]+.
23)中间体26的制备
将三苯基磷(0.41g,2mmol)加入50mL三颈瓶中,加入5mL无水的四氢呋喃,密闭,氮气保护,0℃下缓慢加入偶氮二甲酸二异丙酯(DIAD,0.41g,2mmol),搅拌0.5\h,缓慢加入手性取代醇或(S)-(1-(叔丁氧羰基)四氢吡咯-2-基)甲醇(3mmol)的四氢呋喃溶液(5mL),搅拌0.5h,加入中间体25a或25b(1mmol)的四氢呋喃溶液(10mL),室温反应过夜,减压蒸除去溶剂,得油状物,用乙酸乙酯/石油醚混合液(1:3)洗涤(10mL×4),合并有机相,柱层析分离纯化,洗脱系统为石油醚/乙酸乙酯=15:1,得中间体26aa~26af或26ba~26bf。
26aa:(S)-1-甲基-4-((2-叔丁氧碳酰胺基-3-苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯,白色固体,收率56.3%,mp176.2-179.4°C。1H NMR(600MHz,DMSO-d6)δ=7.44(s,1H),7.41(d,J=8.4HZ,1H),7.23-7.28(m,4H),7.19(t,J=7.2HZ,1H),7.12(d,J=8.4HZ,1H),6.48(d,J=7.8HZ,1H),4.35(s,3H),4.08(m,1H),4.00(dd,J=4.8,9.6HZ,1H),3.93(dd,J=5.4,9.6HZ,1H),3.85(s,3H),2.92(dd,J=6.0,13.2HZ,1H),2.82(dd,J=8.4,13.2HZ,1H),1.34(s,9H).
26ab:(R)-1-甲基-4-((2-叔丁氧碳酰胺基-3-苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯,白色固体,收率52.4%,mp176.6-179.9°C。1H NMR(600MHz,DMSO-d6)δ=7.44(s,1H),7.41(d,J=8.4HZ,1H),7.23-7.28(m,4H),7.19(t,J=7.2HZ,1H),7.12(d,J=8.4HZ,1H),6.48(d,J=7.8HZ,1H),4.35(s,3H),4.08(m,1H),4.00(m,1H),3.93(m,1H),3.85(s,3H),2.92(dd,J=6.0,13.2HZ,1H),2.82(dd,J=8.4,13.2HZ,1H),1.34(s,9H).
26ac:(S)-1-甲基-4-((2-叔丁氧碳酰胺基-3-(1H-吲哚-3-基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯,白色固体,收率48.6%,mp199.6-202.4°C。1H NMR(600MHz,DMSO-d6)δ=10.80(s,1H),7.53(d,J=7.8HZ,1H),7.43(s,1H),7.33(d,J=8.4HZ,1H),7.20(d,J=8.4HZ,1H),7.11(m,2H),7.05(t,J=7.8HZ,1H),6.94(t,J=7.2HZ,1H),6.46(d,J=7.8HZ,1H),4.34(s,3H),4.15(m,1H),3.96-4.04(m,2H),3.85(s,3H),3.03(dd,J=6.6,14.4HZ,1H),2.94(dd,J=7.8,14.4HZ,1H),1.39(s,9H).
26ad:(R)-1-甲基-4-((2-叔丁氧碳酰胺基-3-(1H-吲哚-3-基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯,白色固体,收率39.6%,mp198.6-199.5°C。1H NMR(600MHz,DMSO-d6)δ=10.80(s,1H),7.53(d,J=7.8HZ,1H),7.43(s,1H),7.33(d,J=8.4HZ,1H),7.20(d,J=8.4HZ,1H),7.11(m,2H),7.05(t,J=7.8HZ,1H),6.94(t,J=7.2HZ,1H),6.46(d,J=7.8HZ,1H),4.34(s,3H),4.15(m,1H),3.96-4.04(m,2H),3.85(s,3H),3.03(dd,J=6.6,14.4HZ,1H),2.94(dd,J=7.8,14.4HZ,1H),1.38(s,9H).
26ae:(S)-1-甲基-4-((2-叔丁氧碳酰胺基-3-(4-甲氧基苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯,色固体,收率51.4%,mp187.1-189.5°C。1H NMR(600MHz,DMSO-d6)δ=7.45(s,1H),7.24(d,J=8.4HZ,1H),7.15(m,2H),7.08(d,J=8.4HZ,1H),6.83(m,2H),6.50(d,J=8.4HZ,1H),4.34(s,3H),3.99(m,2H),3.92(m,1H),3.85(s,3H),3.70(s,3H),2.87(dd,J=6.6,14.4HZ,1H),2.78(dd,J=7.8,14.4HZ,1H),1.38(s,9H).
26af:(S)-1-甲基-4-((1-(叔丁氧羰基)四氢吡咯-2-基)甲氧基)-7-溴-1H-吲哚-2-甲酸甲酯,无色油,收率47.6%。1H NMR(600MHz,DMSO-d6)δ=7.48(s,1H),7.47(d,J=8.4Hz,1H),6.60(d,J=8.4Hz,1H),4.42(dd,J=3.6Hz and10.2Hz,1H),4.36(s,3H),4.21(dd,J=3.6Hz and10.2Hz,1H),3.94~3.99(m,1H),3.87(s,3H),3.21~3.30(m,2H),2.13~2.18(m,1H),1.94~2.03(m,2H),1.72~1.79(m,1H),1.38(s,9H).
26ba:(S)-1-甲基-4-((2-叔丁氧碳酰胺基-3-苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯,白色固体,收率47.2%,mp178.3-179.6°C。1H NMR(600MHz,DMSO-d6)δ=7.44(s,1H),7.23-7.29(m,5H),7.19(t,J=7.2HZ,1H),7.11(d,J=8.4HZ,1H),6.51(d,J=8.4HZ,1H),4.34(s,3H),4.08(m,1H),4.00(m,1H),3.93(m,1H),3.84(s,3H),2.92(dd,J=6.0,13.2HZ,1H),2.82(dd,J=8.4,13.2HZ,1H),1.34(s,9H).
26bb:(R)-1-甲基-4-((2-叔丁氧碳酰胺基-3-苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯,白色固体,收率50.8%,mp177.1-179.2°C。1H NMR(600MHz,DMSO-d6)δ=7.44(s,1H),7.23-7.29(m,5H),7.19(t,J=7.2HZ,1H),7.11(d,J=8.4HZ,1H),6.51(d,J=8.4HZ,1H),4.34(s,3H),4.08(m,1H),4.00(m,1H),3.93(m,1H),3.85(s,3H),2.92(dd,J=6.0,13.2HZ,1H),2.82(dd,J=8.4,13.2HZ,1H),1.34(s,9H).
26bc:(R)-1-甲基-4-((2-叔丁氧碳酰胺基-3-(1H-吲哚-3-基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯,白色固体,收率48.2%,mp198.2-199.4°C。1H NMR(600MHz,DMSO-d6)δ=10.81(s,1H),7.53(d,J=7.8HZ,1H),7.43(s,1H),7.32(d,J=8.4HZ,1H),7.20(d,J=8.4HZ,1H),7.11(m,2H),7.05(t,J=7.8HZ,1H),6.94(t,J=7.2HZ,1H),6.46(d,J=7.8HZ,1H),4.34(s,3H),4.15(m,1H),3.96-4.04(m,2H),3.85(s,3H),3.03(dd,J=6.6,14.4HZ,1H),2.94(dd,J=7.8,14.4HZ,1H),1.38(s,9H).
26bd:(S)-1-甲基-4-((2-叔丁氧碳酰胺基-3-(1H-吲哚-3-基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯,白色固体,收率44.7%,mp201.2-202.5°C。1H NMR(600MHz,DMSO-d6)δ=10.81(s,1H),7.53(d,J=7.8HZ,1H),7.43(s,1H),7.32(d,J=7.8HZ,1H),7.20(d,J=8.4HZ,1H),7.11(m,2H),7.05(t,J=7.8HZ,1H),6.94(t,J=7.2HZ,1H),6.46(d,J=7.8HZ,1H),4.34(s,3H),4.15(m,1H),3.96-4.04(m,2H),3.85(s,3H),3.03(dd,J=6.6,14.4HZ,1H),2.94(dd,J=7.8,14.4HZ,1H),1.38(s,9H).
26be:(S)-1-甲基-4-((2-叔丁氧碳酰胺基-3-(4-甲氧基苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯,白色固体,收率40.9%,mp193.5-195.2°C。1H NMR(600MHz,DMSO-d6)δ=7.44(s,1H),7.23(d,J=8.4HZ,1H),7.14(m,2H),7.08(d,J=8.4HZ,1H),6.83(m,2H),6.50(d,J=8.4HZ,1H),4.34(s,3H),3.98(m,2H),3.92(m,1H),3.85(s,3H),3.70(s,3H),2.85(dd,J=6.6,14.4HZ,1H),2.76(dd,J=7.8,14.4HZ,1H),1.35(s,9H).
26bf:(S)-1-甲基-4-((1-(叔丁氧羰基)四氢吡咯-2-基)甲氧基)-7-氯-1H-吲哚-2-甲酸甲酯,无色油,收率43.5%。1H NMR(600MHz,DMSO-d6)δ=7.49(s,1H),7.30(d,J=8.4Hz,1H),6.63(d,J=8.4Hz,1H),4.41(dd,J=3.6Hz and10.2Hz,1H),4.35(s,3H),4.24~4.27(m,1H),3.99~4.05(m,1H),3.87(s,3H),3.22~3.28(m,2H),2.13~2.18(m,1H),1.94~2.04(m,2H),1.73~1.79(m,1H),1.38(s,9H).
24)目标产物27的制备
分别将中间体26aa~26af或26ba~26bf(0.5mmol)加入到25mL烧瓶中,加入HCl的乙酸乙酯溶液15mL,室温搅拌1h,减压蒸除溶剂,用甲醇/乙醚重结晶得目标产物27aa~27af或27ba~27bf.
27aa:(S)-1-甲基-4-((2-胺基-3-苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率85.6%,mp230.3-232.5°C,[α]D 25:+25.0°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:8.58(s,3H),7.74(s,1H),7.42(d,J=7.8Hz,1H),7.31~7.34(m,2H),7.25~7.27(m,3H),6.45(d,J=7.8Hz,1H),4.36(s,3H),4.18(d,J=10.2Hz,1H),3.97~3.99(m,1H),3.88(s,3H),3.85~3.87(m,1H),3.18~3.20(m,1H),3.04~3.08(m,1H).HRMS(ESI):m/zfor C20H22BrN2O3[M+H]+:calculated417.0808found417.0816.
27ab:(R)-1-甲基-4-((2-胺基-3-苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率92.5%,mp228.2-230.9°C,[α]D 25:-62.5°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:8.68(br,s,3H),7.74(s,1H),7.41(d,J=7.8Hz,1H),7.31~7.32(m,2H),7.25~7.27(m,3H),6.45(d,J=7.8Hz,1H),4.36(s,3H),4.19(dd,J=3.0Hz and10.8Hz,1H),3.97~3.99(m,1H),3.88(s,3H),3.82~3.83(m,1H),3.20~3.23(m,1H),3.04~3.08(m,1H).HRMS(ESI):m/z for C20H22BrN2O3[M+H]+:calculated417.0808found417.0816.
27ac:(S)-1-甲基-4-((2-胺基-3-(1H-吲哚-3-基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率84.6%,mp223.9-224.8°C,[α]D 25:+50.0°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:11.02(s,1H),8.36(br,s,3H),7.51(s,1H),7.59(d,J=7.8Hz,1H),7.41(d,J=8.4Hz,1H),7.37(d,J=7.8Hz,1H),7.21(d,J=2.4Hz,1H),7.08(t,J=7.8Hz,1H),6.96(t,J=7.2Hz,1H),6.45(d,J=8.4Hz,1H),4.36(s,3H),4.21~4.24(m,1H),4.05~4.07(m,1H),3.88(s,3H),3.85~3.87(m,1H),3.20~3.22(m,1H).HRMS(ESI):m/z for C22H23BrN3O3[M+H]+:calculated456.0917found456.0924.
27ad:(R)-1-甲基-4-((2-胺基-3-(1H-吲哚-3-基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率79.8%,mp223.9-224.6°C,[α]D 25:-63.6°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:11.3(s,1H),8.46(br,s,3H),7.76(s,1H),7.60(dd,J=3.0Hz and7.8Hz,1H),7.41(d,J=8.4Hz,1H),7.37(d,J=7.8Hz,1H),7.21(d,J=2.4Hz,1H),7.08(t,J=7.8Hz,1H),6.96(t,J=7.2Hz,1H),6.45(d,J=8.4Hz,1H),4.36(s,3H),4.22(dd,J=2.4Hz and10.2Hz,1H),4.05~4.07(m,1H),3.88(s,3H),3.83~3.85(m,1H),3.19~3.25(m,1H).HRMS(ESI):m/z for C22H23BrN3O3[M+H]+:calculated456.0917found456.0925.
27ae:(S)-1-甲基-4-((2-胺基-3-(4-甲氧基苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率84.5%,mp242.9-244.8°C,[α]D 25:+61.5°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:8.47(br,s,1H),7.73(s,1H),7.42(d,J=7.8Hz,1H),7.17(d,J=8.4Hz,2H),6.88(d,J=8.4Hz,2H),6.47(d,J=8.4Hz,1H),4.36(s,3H),4.17(dd,J=3.0Hz and10.2Hz,1H),3.96~3.99(m,1H),3.88(s,3H),3.76~3.80(m,1H),3.71(s,3H),3.07~3.11(m,1H),2.97~3.01(m,1H).HRMS(ESI):m/zfor C21H24BrN2O4[M+H]+:calculated447.0914found447.0923.
27af:(S)-1-甲基-4-((四氢吡咯-2-基)亚甲氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率75.1%,mp217.6-219.1°C,[α]D 25:+26.7°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:9.01~9.50(br,2H),7.48(s,1H),7.47(d,J=8.4Hz,1H),6.60(d,J=8.4Hz,1H),4.42(dd,J=3.6Hz and10.2Hz,1H),4.36(s,3H),4.21(dd,J=3.6Hz and10.2Hz,1H),3.94~3.99(m,1H),3.87(s,3H),3.21~3.30(m,2H),2.13~2.18(m,1H),1.94~2.03(m,2H),1.72~1.79(m,1H).HRMS(ESI):m/z for C16H20BrN2O3[M+H]+:calculated367.0652found367.0659.
27ba:(S)-1-甲基-4-((2-胺基-3-苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率87.9%,mp235.4-237.1°C,[α]D 25:+33.3°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:8.56(br.s,3H),7.74(s,1H),7.31~7.34(m,2H),7.25~7.27(m,3H),7.24(d,J=8.4Hz,1H),6.50(d,J=8.4Hz,1H),4.35(s,3H),4.18(dd,J=3.0Hz and10.2Hz,1H),3.97~4.00(m,1H),3.88(s,3H),3.84~3.86(m,1H),3.18(dd,J=4.8Hz and13.2Hz,1H),3.04~3.08(m,1H).HRMS(ESI):m/zfor C20H22ClN2O3[M+H]+:calculated373.1313found373.1321.
27bb:(R)-1-甲基-4-((2-胺基-3-苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率80.5%,mp228.8-230.6°C,[α]D 25:-92.3°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:8.40(s,3H),7.73(s,1H),7.32~7.34(m,2H),7.24~7.28(m,4H),6.51(d,J=8.4Hz,1H),4.35(s,3H),4.17(dd,J=2.4Hz and10.2Hz,1H),3.96~3.99(m,1H),3.88(s,3H),3.87(m,1H),3.13~3.15(m,1H),3.04~3.08(m,1H).HRMS(ESI):m/z for C20H22ClN2O3[M+H]+:calculated373.1313found373.1319.
27bc:(R)-1-甲基-4-((2-胺基-3-(1H-吲哚-3-基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率88.2%,mp223.2-226.6°C,[α]D 25:-83.3°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:11.03(s,1H),8.45(s,3H),7.76(s,1H),7.60(d,J=7.8Hz,1H),7.37(d,J=8.4Hz,1H),7.21~7.24(m,2H),7.08(t,J=7.2Hz,1H),6.97(t,J=7.2Hz,1H),6.48(d,J=8.4Hz,1H),4.35(s,3H),4.23(dd,J=2.4Hz and10.2Hz,1H),4.07(dd,J=5.4Hz and10.2Hz,1H),3.88(s,3H),3.84(br.s,1H),3.21~3.24(m,2H).HRMS(ESI):m/zfor C22H23ClN3O3[M+H]+:calculated412.1422found412.1430.
27bd:(S)-1-甲基-4-((2-胺基-3-(1H-吲哚-3-基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率80.1%,mp223.3-225.9°C,[α]D 25:+64.3°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:11.02(s,1H),8.38(s,3H),7.76(s,1H),7.60(d,J=7.8Hz,1H),7.37(d,J=7.8Hz,1H),7.23(d,J=8.4Hz,1H),7.21(d,J=1.8Hz,1H),7.09(t,J=7.2Hz,1H),6.97(t,J=7.2Hz,1H),6.48(d,J=8.4Hz,1H),4.35(s,3H),4.23(dd,J=2.4Hz and10.2Hz,1H),4.07(dd,J=5.4Hz and10.2Hz,1H),3.88(s,3H),3.85(br.s,1H),3.18~3.25(m,2H).HRMS(ESI):m/zfor C22H23ClN3O3[M+H]+:calculated412.1422found412.1429.
27be:(S)-1-甲基-4-((2-胺基-3-(4-甲氧基苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率74.6%,mp241.1-244.0°C,[α]D 25:+50.0°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:8.30(br,s,3H),7.73(s,1H),7.25(d,J=8.4Hz,1H),7.17(d,J=8.4Hz,2H),6.89(d,J=8.4Hz,2H),6.51(d,J=8.0Hz,1H),4.35(s,3H),4.16(dd,J=3.0Hz and10.2Hz,1H),3.96~3.98(m,1H),3.88(s,3H),3.79~3.81(m,3H),3.72(s,3H),3.03~3.06(m,1H),2.96~2.99(m,1H).HRMS(ESI):m/zfor C21H24ClN2O4[M+H]+:calculated403.1419found403.1427.
27bf:(S)-1-甲基-4-((四氢吡咯-2-基)亚甲氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐,白色固体,收率78.5%,mp204.1-206.5°C,[α]D 25:+47.1°(c1,MeOH).1H NMR(600MHz,DMSO-d6)δ:9.75(br.s,1H),9.19(s,1H),7.49(s,1H),7.30(d,J=8.4Hz,1H),6.63(d,J=8.4Hz,1H),4.41(dd,J=3.6Hz and10.2Hz,1H),4.35(s,3H),4.24~4.27(m,1H),3.99(m,1H),3.87(s,3H),3.22~3.28(m,2H),2.13~2.18(m,1H),1.94~2.04(m,2H),1.73~1.79(m,1H).HRMS(ESI):m/z for C16H20ClN2O3[M+H]+:calculated323.1157found323.1163。
Claims (5)
1.一种多取代吲哚类化合物,结构如通式(Ⅰ)所示,
通式(I)
其中,
R1是苯基,甲氧基,溴或氯;R2是氢或甲基;R3是羧基甲酯,羧基,氨基甲酰基,肼基甲酰基,羟氨基甲酰基或3-甲基噁二唑-5-基;R4是2-氨基乙基,3-氨基丙基,(S)-2-氨基-3-苯基丙基,(R)-2-氨基-3-苯基丙基,(S)-2-氨基-3-(1H-吲哚-3-基)丙基,(R)-2-氨基-3-(1H-吲哚-3-基)丙基,(S)-四氢吡咯-2-基亚甲基,(S)-2-氨基-3-(4-甲氧基苯基)丙基,(S)-2-氨基-4-甲硫基丁基,(2S,3S)-2-氨基-3-甲基戊基或(S)-2-氨基-4-甲基戊基。
2.一种多取代吲哚类化合物,其特征在于是下述化合物之一:
4-(3-氨基丙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯盐酸盐、
4-(2-氨基乙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯盐酸盐、
1-甲基-4-(2-氨基乙氧基)-7-苯基-1H-吲哚-2-甲酸甲酯盐酸盐、
4-(3-氨基丙氧基)-7-苯基-1H-吲哚-2-甲酸盐酸盐、
4-(2-氨基乙氧基)-7-苯基-1H-吲哚-2-甲酸盐酸盐、
4-(3-氨基丙氧基)-7-苯基-1H-吲哚-2-甲酰胺盐酸盐、
4-(2-氨基乙氧基)-7-苯基-1H-吲哚-2-甲酰胺盐酸盐、
4-(3-氨基丙氧基)-7-苯基-1H-吲哚-2-羟基甲酰胺盐酸盐、
4-(3-氨基丙氧基)-7-苯基-1H-吲哚-2-甲酰肼盐酸盐、
4-(2-氨基乙氧基)-7-苯基-1H-吲哚-2-甲酰肼盐酸盐、
1-甲基-4-(2-氨基乙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((2-氨基-4-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((2-氨基-4-甲硫基)丁氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐、
(R)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐、
1-甲基-4-(((2S,3S)-2-氨基-3-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((2-氨基-3-(4-甲氧基苯基))丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯、
(R)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((四氢吡咯-2-基)甲氧基)-7-甲氧基-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-3-甲基-5-(1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐、
(R)-3-甲基-5-(1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐、
(S)-3-甲基-5-(1-甲基-4-(2-氨基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐、
(R)-3-甲基-5-(1-甲基-4-(2-氨基-3-(1H-吲哚-3-基))丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐、
(S)-3-甲基-5--(1-甲基-4-(2-氨基-3-(4-甲氧基苯基)丙氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐、
(S)-3-甲基-5-(1-甲基-4-((2-氨基-4-甲硫基)丁氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐、
(S)-3-甲基-5-(1-甲基-4-((2-氨基-4-甲基)戊氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐、
(S)-3-甲基-5-(1-甲基-4-(四氢吡咯-2-基亚甲氧基)-7-甲氧基-1H-吲哚-2-基)-1,2,4-噁二唑盐酸盐、
(S)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐、
(R)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐、
(R)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((2-氨基-3-(4-甲氧基苯基)丙氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((四氢吡咯-2-基)亚甲氧基)-7-溴-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐、
(R)-1-甲基-4-((2-氨基-3-苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐、
(R)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((2-氨基-3-(1H-吲哚-3-基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐、
(S)-1-甲基-4-((2-氨基-3-(4-甲氧基苯基)丙氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐或
(S)-1-甲基-4-((四氢吡咯-2-基)亚甲氧基)-7-氯-1H-吲哚-2-甲酸甲酯盐酸盐。
3.权利要求2所述的化合物的制备方法,其特征在于,
化合物5a-5c,10a-10b,11a-11b,12a和13a-13b的制备方法如下:
合成路线如下:
试剂及条件:(a1)苯硼酸,四三苯基膦钯,碳酸铯,二氧六环/水,95℃;(b1)硫酸二甲酯,氢化钠,DMF,0℃;(c1)10%钯碳,甲醇/四氢呋喃,氢气,室温;(d1)BocNH(CH2)nBr,碳酸铯,DMF,室温;(e1)氯化氢的乙酸乙酯溶液,室温;(f1)氢氧化钾,四氢呋喃/水,回流;(g1)羟肟酸钾,甲醇,室温;(h1)水合肼,乙醇,回流;(i1)碳酸氢铵,二氯甲烷,2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉,室温;
具体步骤如下:
(i)将起始原料1a、碳酸铯、四三苯基膦钯和苯硼酸按摩尔比1:4:0.1:2加入到二氧六环/水混合液中,每0.5毫摩尔中间体1a用二氧六环6毫升,水1毫升,氮气保护下加热至85℃,反应4h,冷至室温,减压蒸除溶剂,用丙酮洗涤残留物至无荧光,合并丙酮溶液,减压蒸除溶剂,固体用无水甲醇/丙酮重结晶,得中间体2a;
(ii)将2a溶解于干燥的DMF中,每2毫摩尔2a用DMF 10毫升,冰浴下缓慢加入氢化钠,2a与氢化钠摩尔比为1:1.5,搅拌0.5h,缓慢滴加硫酸二甲酯,2a与硫酸二甲酯摩尔比为1:1.5,滴加完毕,0℃反应0.5h后,室温反应4h,将反应液倾入10倍DMF体积冰水中,析出沉淀,过滤,乙酸乙酯/石油醚重结晶得中间体2b;
(iii)将中间体2a或2b溶解于四氢呋喃/甲醇混合液中,加入钯碳,通入氢气,密闭反应过夜,过滤除去钯碳,柱层析得中间体3a或3b;
(iv)将中间体3a或3b与碳酸铯、N-2-溴乙基-叔丁氧基甲酰胺或N-3-溴丙基-叔丁氧基甲酰胺按摩尔比1:2:1.5加入到DMF中,每1毫摩尔中间体3a或3b用DMF 10毫升,60℃搅拌过夜,将反应液倾入10倍DMF体积冰水中,乙酸乙酯萃取,柱层析,分别得中间体4a,4b,4c;
(v)将中间体4a或4b与氢氧化钾按摩尔比1:4在4:1体积比四氢呋喃/水混合液中,每1毫摩尔中间体4a或4b用混合液25毫升,回流过夜,冷至室温,减压蒸除溶剂,加入100mL水,用饱和柠檬酸溶液调节pH至5,析出沉淀,过滤,固体用乙酸乙酯/石油醚重结晶得中间体6a或6b;
(vi)将中间体6a或6b分别与2-乙氧基-1-乙氧羰基-1,2-二氢喹啉、碳酸氢铵按摩尔比1:1.2:8加入到干燥的二氯甲烷中,每1毫摩尔中间体6a或6b用二氯甲烷40毫升,室温反应24h,反应液依次用水、饱和氯化钠溶液洗涤后,减压蒸除溶剂,得淡黄色油状物,柱层析得中间体7a,7b;
(vii)将中间体4a与羟肟酸钾按摩尔比1:2加入绝对无水甲醇中,每1毫摩尔中间体4a用甲醇14毫升,室温反应36h,柱层析,洗脱系统为石油醚/丙酮=3:1,得中间体8a;
(viii)将中间体4a或4b分别与水合肼按摩尔比1:8加入乙醇中,回流72h,减压蒸除溶剂,残留物用乙酸乙酯溶解,有机相依次用1mol/L柠檬酸溶液、饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压蒸除溶剂,得黄色固体,用乙酸乙酯/石油醚重结晶,得中间体9a或9b;
(ix)将中间体4a,4b,4c,6a,6b,7a,7b,8a,9a或9b 0.5mmol分别加入到25mL烧瓶中,加入氯化氢的乙酸乙酯溶液15mL,室温搅拌1h,减压蒸除溶剂,甲醇/乙醚重结晶分别得目标产物5a,5b,5c,10a,10b,11a,11b,12a,13a或13b;
化合物19a-19j的制备方法如下:
合成路线如下:
试剂及条件:(a2)氢氧化钾,四氢呋喃/水,回流;(b2)氢化钠,甲醇,DMF,碘化亚铜,120℃;(c2)硫酸二甲酯,氢化钠,DMF,0℃;(d2)10%钯碳,甲醇/四氢呋喃,氢气,室温;(e2)BocNH(CH2)2Br,碳酸铯,DMF,室温;(f2)氯化氢的乙酸乙酯溶液,室温;(g2)手性取代醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0℃~室温;(h2)(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0℃~室温;
具体步骤如下:
(i)将起始原料1a与氢氧化钾按摩尔比1:4加入烧瓶中,加入THF/水混合液,体积比10:3,每20mmol起始原料1a用混合液130mL,回流过夜,冷至室温,减压蒸除溶剂,加入200mL水,用浓盐酸调节pH至1,过滤,固体干燥后,乙酸乙酯/石油醚重结晶得中间体14;
(ii)将氢化钠,中间体14,碘化亚铜以摩尔比10:1:1加入绝对无水甲醇和DMF混合液中,每7.5mmol氢化钠用甲醇20mL,DMF 22mL,氮气保护,回流5h,冷却至室温,将反应液倾入10倍体积DMF冰水中,浓盐酸调节pH至1,析出沉淀,过滤,乙酸乙酯/石油醚重结晶,得中间体15;
(iii)将中间体15,氢化钠与硫酸二甲酯以摩尔比1:3:3加入干燥的DMF中,每2.7mmol中间体15用DMF 10mL,室温反应过夜,将反应液倾入100mL冰水中,过滤,固体干燥,柱层析即得中间体16;
(iv)将中间体16溶解于四氢呋喃/甲醇混合液中,加入钯碳,通入氢气,密闭反应过夜,过滤除去钯碳,柱层析得中间体17;
(v)将中间体17与碳酸铯、N-2-溴乙基-叔丁氧基甲酰胺按摩尔比1:2:1.5加入到DMF中,每1毫摩尔中间体17用DMF 10毫升,氮气保护,60 ℃搅拌过夜,将反应液倾入10倍DMF体积冰水中,乙酸乙酯100mL×3萃取,合并有机相,依次用水、饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压蒸除溶剂,得中间体18a;
(vi)将三苯基磷,偶氮二甲酸二异丙酯,手性取代醇与中间体17以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0℃反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用1:3的乙酸乙酯/石油醚混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体18(b~i);
(vii)将三苯基磷,偶氮二甲酸二异丙酯,(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇与中间体17以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0℃反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用1:3的乙酸乙酯/石油醚混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体18j;
(viii)将0.5mmol中间体18a,18(b~i)或18j分别加入到25mL烧瓶中,加入氯化氢的乙酸乙酯溶液15mL,室温搅拌1h,减压蒸除溶剂,甲醇/乙醚重结晶分别得目标产物19a,19(b~i)或19j;
化合物23a-23h的制备方法如下:
合成路线如下:
试剂及条件:(a3)乙酰胺肟,碳酸铯,DMF,微波800W,150℃;(b3)三氯化铝,N,N-二甲苯胺,二氯甲烷,0℃~室温;(c3)手性取代醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0℃~室温;(d3)氯化氢的乙酸乙酯溶液,室温;(e3)(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0℃~室温;
具体步骤如下:
(i)将中间体16,乙酰胺肟与碳酸铯按摩尔比1:2:2加入到DMF中,每2mmol中间体16用DMF 10mL,微波800W,150℃反应5min,冷至室温,将反应液倾入100mL冰水中,乙酸乙酯100mL×3萃取,合并有机相,依次用水、饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压蒸除溶剂,得固体,柱层析分离纯化得中间体20;
(ii)将中间体20,N,N-二甲基苯胺与三氯化铝按摩尔比1:4:4加入到冰浴下的绝对无水二氯甲烷中,每1.7mmol中间体20用二氯甲烷12mL,室温搅拌1.5h,0℃下缓慢滴加1mol/L盐酸20mL,水20mL,用乙酸乙酯50mL×3萃取,合并有机相,依次用1mol/L盐酸,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压蒸除溶剂,得固体,柱层析分离纯化,得中间体21;
(iii)将三苯基磷,偶氮二甲酸二异丙酯,手性取代醇与中间体21以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0℃反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚1:3混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体22(a~g);
(iv)将三苯基磷,偶氮二甲酸二异丙酯,(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇与中间体21以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0℃反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚为1:3的混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体22h;
(v)将0.5mmol中间体22a~22g或22h分别加入到25mL烧瓶中,加入氯化氢的乙酸乙酯溶液15mL,室温搅拌1h,减压蒸除溶剂,甲醇/乙醚重结晶分别得目标产物23(a~g)或23h;
化合物27aa-27af,27ba-27bf的制备方法如下:
合成路线如下:
试剂及条件:(a4)硫酸二甲酯,DMF,氢化钠,0℃~室温;(b4)三氯化铝,N,N-二甲苯胺,二氯甲烷,0℃~室温;(c4)手性取代醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0℃~室温;(d4)氯化氢的乙酸乙酯溶液,室温;(e4)(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇,三苯基磷,偶氮二甲酸二异丙酯,四氢呋喃,0℃~室温;
具体步骤如下:
(i)将中间体1a或1b,氢化钠与硫酸二甲酯以摩尔比1:1.2:1.2加入干燥的DMF中,每2.7mmol中间体1a或1b用DMF 10mL,室温反应过夜,将反应液倾入100mL冰水中,搅拌,过滤,固体用柱层析分离纯化,得中间体24a或24b;
(ii)将中间体24a或24b,N,N-二甲基苯胺与三氯化铝按摩尔比1:4:4加入到冰浴下的绝对无水二氯甲烷中,每1.7mmol中间体24a或24b用二氯甲烷12mL,室温搅拌1.5h,0℃下缓慢滴加1mol/L盐酸20mL,然后加入水20mL,用乙酸乙酯50mL×3萃取,合并有机相,依次用1mol/L盐酸,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压蒸除溶剂,柱层析分离纯化,得中间体25a或25b;
(iii)将三苯基磷,偶氮二甲酸二异丙酯,手性取代醇与中间体25a或25b以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0℃反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚为1:3的混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体26(aa~ae),26(ba~be);
(iv)将三苯基磷,偶氮二甲酸二异丙酯,(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇与中间体25a或25b以摩尔比2:2:3:1冰浴下顺次加入到无水四氢呋喃中,每2mmol三苯基磷用20mL四氢呋喃,0℃反应0.5h,室温反应过夜,减压蒸除溶剂,得油状物,用乙酸乙酯/石油醚1:3混合液10mL洗涤4次,合并有机相,减压蒸除溶剂,柱层析分离纯化得中间体26af或26bf;
(v)将0.5mmol中间体26(aa~af),26(ba~bf),26af或26bf分别加入到25mL烧瓶中,加入氯化氢的乙酸乙酯溶液15mL,室温搅拌1h,减压蒸除溶剂,甲醇/乙醚重结晶分别得目标产物27(aa~ae),27(ba~be),27af或27bf;
以上制备路线中的W如通式(II)中所述;
制备方法中所使用的手性取代醇用通式(II)表示,其化学名及结构式如下:
通式(II)
4.一种抗肿瘤药物组合物,包含权利要求1或2所述化合物以及一种或多种药学上可接受载体或赋形剂。
5.权利要求1或2所述化合物在制备抗肿瘤的药物中的应用。
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