CN107936043B - 一种具有抗肿瘤活性物质及其合成方法 - Google Patents
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Abstract
本发明公开了一种具有抗肿瘤活性物质N, N’‑[(2’S,3’S)‑2’‑甲基‑3’‑苄氧基‑3’‑异丙基四氢噻吩]‑12,13‑吲哚并[2,3‑a]恶唑并[4,5‑c]咔唑及其合成方法。本发明所用的合成条件和方法，一方面可以提高目标产物的产率和手性纯度，另一方面大大简化工艺操作，缩短了生产周期，为后续药学试验提供大量的N,N’‑[(2’S,3’ S)‑2’‑甲基‑3’‑苄氧基‑3’‑异丙基四氢噻吩]‑12,13‑吲哚并[2,3‑a]恶唑并[4,5‑c]咔唑。
Description
技术领域
本发明领域属于药物合成领域，具体涉及一种具有抗肿瘤活性物质N,N’-[(2’S, 3’S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑及其合成工艺。
背景技术
酪氨酸激酶（tyrosine kinase）是在细胞中催化磷酸基团从ATP中转移到蛋白质的酪氨酸残基上的酶，起到调控细胞中信号通路的“开”与“关”。酪氨酸的活性部位激酶各自具有一个结合位点的ATP。由酪氨酸激酶催化的酶的酶活性是所述末端磷酸从ATP转移至酪氨酸残基上的基片，称为蛋白酪氨酸磷酸化的一个过程。酪氨酸激酶的一些突变可使其一直处于“活跃”状态，能引起细胞的不受抑制的生长，最终演变为癌症。因此一些酪氨酸激酶抑制剂，如伊马替尼等被作为抗癌药物研发出来，并具有良好的市场前景。
K252a是从诺卡氏菌物种（Nocardiopsis species）中分离的吲哚咔唑生物碱，其显示出对蛋白激酶C和环核苷酸依赖性蛋白激酶的有效抑制活性。最近，已经发现K252a也是体外TRK酪氨酸激酶活性的有效抑制剂。然而，小鼠实验表明，K252a缺乏抗肿瘤活性。
在K252a分子结构的基础上，运用生物电子等排、优势结构变换以及骨架跃迁等，设计并合成具有TRK抑制效果的类似物。化合物N,N’-[(2’S,3’S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑具有抑制肿瘤细胞中TRK酪氨酸激酶活性的作用，有很大的药学应用前景。
发明内容
本发明所述的化合物N,N’-[(2’S,3’S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑在体中的抗肿瘤活性。
本发明还提供了一种快速简洁的制备N,N’-[(2’S,3’S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑的方法。本发明采用如下的路线合成具有抗肿瘤活性物质N,N’-[(2’S,3’S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑。
N,N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2的合成条件为：
将N,N’-[(2’S,3’S)-2’-甲基-3’-氧代-二氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑1、添加剂（2.0 - 3.0当量）和溶剂S1（1 - 10倍）混合，氮气保护下，于-40 - 0℃下搅拌30 - 60分钟，向体系中加入异丙基溴化镁（2.0 - 3.0当量），搅拌10 - 16小时，向体系中加入饱和氯化铵溶液和乙酸乙酯，分液得到有机相，有机相浓缩，加入溶剂S2（1 -10倍），升温至50 - 70 ℃，搅拌1 - 3小时，降温至0 - 10 ℃，析晶2 - 6小时，过滤得到N, N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2。
添加剂选自add-1、add-2、add-3、add-4或add-5；优选的添加剂是add-2、add-4或add-5；最优选的添加剂是add-4；其结构如下所示：
。
溶剂S1选自乙醚、正己烷、正庚烷、甲苯、二氧六环或四氢呋喃；优选的溶剂是乙醚、二氧六环或四氢呋喃；最优选的溶剂是四氢呋喃。
溶剂S2选自甲醇、乙醇、异丙醇、水或其混合溶剂；优选的溶剂是混合溶剂；最优选的溶剂是甲醇与水的混合溶剂。
N,N’-[(2’S,3’S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑的合成条件为：
将N,N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2、碱（1.5 - 3.0当量）和溶剂S3（1 - 20倍）混合，于0 - 20 ℃下搅拌10 – 60分钟，向体系中加入苄溴（1.0 - 2.0当量），搅拌1 - 5小时，向体系中加入溶剂S4（1 - 20倍），搅拌1 - 3小时，过滤得到化合物N,N’-[(2’S,3’S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑。
碱选自碳酸钾、氢氧化钾、NaH、三乙胺或二异丙基乙基胺；优选的碱是碳酸钾、NaH或氢氧化钾；最优选的碱是氢氧化钾。
溶剂S3选自二氯甲烷、二甲基甲酰胺、二甲基乙酰胺或N-甲基吡咯烷酮；优选的溶剂是二甲基甲酰胺或二甲基乙酰胺。
溶剂S4选自甲醇、乙醇、异丙醇或水；最优选的溶剂是水。
本发明所用的合成条件和方法，一方面可以提高目标产物的产率和手性纯度，另一方面大大简化工艺操作，缩短了生产周期，为后续药学试验提供大量的N,N’-[(2’S,3’ S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑。
具体实施方式
下面结合具体实施例对本发明作进一步说明：
实施例1
N,N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2的合成方法
将N,N’-[(2’S,3’S)-2’-甲基-3’-氧代-二氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑1（76.5 g）、add-4（200.5 g）和四氢呋喃（750 mL）混合，氮气保护下，于-40 -0 ℃下搅拌40分钟，向体系中加入异丙基溴化镁（1 M in ether，400 mL），搅拌12小时。向体系中加入饱和氯化铵溶液（10 L）和乙酸乙酯（15 L），分液得到有机相，有机相浓缩，加入甲醇与水的混合溶剂（v/v = 1:1，7.5 L），升温至60 ℃，搅拌1.5小时，降温至0 - 10 ℃，析晶5小时，过滤得到浅黄色固体（76.2 g，90％），即为N,N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2，HPLC纯度97％，手性纯度95%（保留时间: 9.28 min.）; mp 252-257 °C; IR (KBr): ν 1735, 1680, 1460,1395, 1315, 1272 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 0.93 (d, 6H), 1.63 (s,3H), 1.70 (m, 1H), 2.12 (dd, 1H), 2.34 (dd, 1H), 4.95 (t, 1H), 6.24 (brs,1H), 7.37 (m, 2H), 7.45 (d, 2H), 7.64 (d, 2H), 7.82 (s, 1H), 8.19 (d, 2H)ppm; 13C NMR (100 MHz, DMSO-d6): δ = 153.7, 150.0, 140.1, 136.5, 110.8, 120.5,109.6, 124.4, 125.4, 121.4, 140.6, 121.7, 119.8, 85.0, 64.5, 61.5, 35.8,27.2, 17.5, 17.0 ppm; m/z (MS-ESI): 454.56 [M + 1]+.
实施例2
N,N’-[(2’S,3’S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑的合成方法
将N,N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2（70.2 g）、氢氧化钾（17.4 g）和二甲基甲酰胺（150 mL）混合，于10 ℃下搅拌40分钟，向体系中加入苄溴（40.0 g），搅拌4小时，向体系中加入水（300 mL），搅拌2小时，过滤得到浅黄色固体（77.9 g, 92%），即为化合物N,N’-[(2’S,3’S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑。HPLC纯度99％，手性纯度96%，（保留时间：7.35 min.）; mp: 230-243 ℃; IR (KBr): ν 3412,3063, 2837, 1668, 1587, 1458, 1123 cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 0.92(d, 6H), 1.64 (s, 3H), 1.71 (m, 1H), 2.12 (dd, 1H), 2.34 (dd, 1H), 4.68 (s,2H), 4.95 (t, 1H), 7.28-7.35 (m, 6H), 7.45 (d, 2H), 7.64 (d, 2H), 7.82 (s,1H), 8.19 (d, 2H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 153.7, 150.0, 140.1,136.5, 110.8, 120.5, 128.8, 109.6, 124.4, 125.4, 121.4, 140.6, 121.7, 119.8,127.4, 128.6, 127.8, 85.0, 64.5, 61.5, 35.8, 27.2, 17.5, 17.0 ppm; m/z (MS-ESI): 544.69 [M + 1]+.
生物活性测定
实施例3 激酶试验-生化TrkA，TrkB和TrkC抑制:
TrkA和TrkC生化检测由HTRF法进行。反应混合物包含1μM多肽底物，1μM ATP，和1.8nM TrkA或34 nM TrkC反应缓冲液(50mM HEPES pH 7.1，10mM MgCl2，2mM MnCl2，0.01%BSA，2.5mM DTT 和0.1mM Na3VO4)，最终体积为10微升。所有反应于室温下在白色ProxiPlate™ 384孔正极板上进行，60分钟时用5微升0.2mM EDTA淬灭反应。加入5微升检测试剂(每孔2.5 ng PT66K 和0.05μg SAXL)，板在室温下培养1小时，然后在EnVision阅读器上读取。将化合物在测试混合物中(终DMSO 0.5%)稀释，确定IC50值。
TrkB的生物化学测定通过卡尺微流体法进行。反应混合物包括1μM 多肽底物，10μM ATP，和2 nM TrkB的反应缓冲液，缓冲液包含100 mM HEPES，pH 7.5，5 mM MgCl2，0.01%Triton X-100，0.1% BSA，1mM DTT，10 ΜNa3VO4，和10μΜ Beta-甘油磷酸盐。反应在室温下进行3小时，产物由Caliper EZ阅读器测定。化合物在测试混合物(终DMSO 1%)中稀释，确定IC50值。
Claims (8)
1.一种具有抗肿瘤活性物质的合成方法，其特征在于所述工艺的路线如下；
；
N,N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2的合成条件为：
将N,N’-[(2’S,3’S)-2’-甲基-3’-氧代-二氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑1、添加剂和溶剂S1混合，氮气保护下，于-40 - 0 ℃下搅拌30 - 60分钟；
向体系中加入异丙基溴化镁，搅拌10 - 16小时；
向体系中加入饱和氯化铵溶液和乙酸乙酯，分液得到有机相；
有机相浓缩，加入溶剂S2，升温至50 - 70 ℃，搅拌1 - 3小时；
降温至0 - 10 ℃，析晶2 - 6小时，过滤得到N,N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2；
其中添加剂选自add-1、add-2、add-3、add-4或add-5，其结构如下所示：
；
添加剂与N,N’-[(2’S,3’S)-2’-甲基-3’-氧代-二氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑1的摩尔用量比为2.0 - 3.0：1.0；
溶剂S1选自乙醚、正己烷、正庚烷、甲苯、二氧六环或四氢呋喃，与N,N’-[(2’S,3’S)-2’-甲基-3’-氧代-二氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑1的体积用量比为1-10：1；
溶剂S2选自甲醇、乙醇、异丙醇、水或其混合溶剂，与N,N’-[(2’S,3’S)-2’-甲基-3’-氧代-二氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑1的体积用量比为1-10：1；
异丙基溴化镁与N,N’-[(2’S,3’S)-2’-甲基-3’-氧代-二氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑1的摩尔用量比为2.0 - 3.0：1。
2.如权利要求1所述的合成方法，其特征在于溶剂S1是乙醚、二氧六环或四氢呋喃。
3.如权利要求1所述的合成方法，其特征在于溶剂S2是甲醇与水的混合溶剂。
4.如权利要求1所述的合成方法，其特征在于添加剂选自add-2、add-4或add-5。
5.如权利要求1所述的合成方法，其特征在于，所述具有抗肿瘤活性物质的合成条件为：
所述的具有抗肿瘤活性物质为N,N’-[(2’S,3’S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑；
将N,N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2、碱和溶剂S3混合，于0 - 20 ℃下搅拌10 - 60分钟；
向体系中加入苄溴，搅拌1 - 5小时；
向体系中加入溶剂S4，搅拌1 - 3小时，过滤得到化合物N,N’-[(2’S,3’S)-2’-甲基-3’-苄氧基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑；
其中碱选自碳酸钾、氢氧化钾、NaH、三乙胺或二异丙基乙基胺，与N,N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2的摩尔用量比为1.5 - 3.0：1；
苄溴与N,N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2的摩尔用量比为1.0 - 2.0：1.0；
溶剂S3选自二氯甲烷、二甲基甲酰胺、二甲基乙酰胺或N-甲基吡咯烷酮，与N,N’-[(2’ S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2的体积用量比为1 - 20：1；
溶剂S4选自甲醇、乙醇、异丙醇或水，与N,N’-[(2’S,3’S)-2’-甲基-3’-羟基-3’-异丙基四氢噻吩]-12,13-吲哚并[2,3-a]恶唑并[4,5-c]咔唑2的体积用量比为1 - 20：1。
6.如权利要求5所述的合成方法，其特征在于溶剂S3是二甲基甲酰胺、或二甲基乙酰胺。
7.如权利要求5所述的合成方法，其特征在于溶剂S4是水。
8.如权利要求5所述的合成方法，其特征在于碱选自碳酸钾、NaH或氢氧化钾。
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