CN105541891B - 巴瑞替尼的中间体及其制备方法及由该中间体制备巴瑞替尼的方法 - Google Patents
巴瑞替尼的中间体及其制备方法及由该中间体制备巴瑞替尼的方法 Download PDFInfo
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- CN105541891B CN105541891B CN201610080433.1A CN201610080433A CN105541891B CN 105541891 B CN105541891 B CN 105541891B CN 201610080433 A CN201610080433 A CN 201610080433A CN 105541891 B CN105541891 B CN 105541891B
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Abstract
本发明公开了一种巴瑞替尼的中间体及其制备方法及由该中间体制备巴瑞替尼的方法,中间体的结构如式(5)所示;中间体的制备方法包括:碱催化下,氰甲基磷酸二乙酯与1‑boc‑3‑氮杂环丁酮反应,得式(2)的化合物2;脱去化合物2的Boc基团,得式(3)的化合物3;碱性条件下,化合物3与乙基磺酰氯反应,得式(4)的化合物4;1,8‑二氮杂双环[5,4,0]十一碳‑7‑烯存在下,化合物4与4‑吡唑硼酸频哪醇酯反应,得中间体。由中间体制备巴瑞替尼的方法包括:钯催化剂和氟化铯存在下,中间体与6‑氯‑7‑脱氮嘌呤进行Suzuki偶联反应,得巴瑞替尼。本发明巴瑞替尼制备方法,原料易得、工艺简洁,适合工业化生产。
Description
技术领域
本发明涉及小分子药物制备,尤其涉及一种吡咯并嘧啶类JAK抑制剂药物巴瑞替尼的中间体及其制备方法及由该中间体制备巴瑞替尼的方法。
背景技术
类风湿关节炎(rheumatoid arthritis,RA)是一种以持续滑膜炎和多关节进行性骨破坏为特点,发病机制尚未完全明了的自身免疫性疾病。研究表明,RA患者免疫紊乱主要由TNF-α,IL-1,IL-6等细胞因子介导,这些细胞因子通过特定的信号通路激活,发挥其生物学效应。JAK-STAT信号通路(Janus-activited kinase-signal transducer andcativator of transcriptions,JAK-STAT)是重要的信号转导途径之一,其广泛参与调节疾病的病理生理过程,尤其在调节机体炎症反应中扮演重要角色。已有针对JAK-STAT信号通路为靶点的药物用于治疗RA,深入研究JAK-STAT信号通路在RA中的作用,有助于揭示RA的发病机制,并为寻找治疗RA新靶点提供依据。
JAK/STAT信号通路是一条由多种细胞因子受体刺激的信号转导通路,这些因子包括白介素类(如IL-2~7,IL-9,IL-10,IL-15,IL-21等)、干扰素类(包括IFN-α,IFN-β,IFN-γ等)、促红细胞生成素(EPO)、粒细胞和巨噬细胞集落刺激因子(GMCSF)、促生长素(GH)、催乳素(PRL)、促血小板生成素(TPO)、血小板衍生因子(PDGF)以及表皮细胞生长因子(EGF)等,其在参与免疫调节、免疫细胞增殖等生物学过程中起关键作用。不同受体可激活不同亚型的JAK激酶,从而表现差异化的生物学功能。
RA是由多种免疫细胞(B淋巴细胞、T淋巴细胞及巨噬细胞等)及相关细胞因子参与介导的复杂疾病,发病机制尚未完全明确。研究表明,IL-2,IL-6,IL-17,IL-21,IFNs及GM-CSF等在RA滑膜细胞和滑膜组织中的水平明显升高,这些因子可通过不同途径激活JAK/STAT信号通路。例如:IL-6,IL-15和IFNs可与JAK1结合;GM-CSF,EGF,IFN-γ和IL-6可与JAK2结合;IL-15可与JAK3结合;IFN-α和IFN-β可与TYK2结合。
不同通路在不同细胞或RA发病的不同阶段表现不同功能。IL-6是STAT3和STAT1的主要激活因子。Wang等发现RA滑液的单核细胞中,STAT3具有显著的DNA结合活性,并且RA滑液中的可溶性因子能有效激活STAT3。随后的动物模型中同样表明STAT3失调能够改变关节炎的炎症过程。Kasperkovitz等通过免疫组织化学方法对RA患者的滑液进行研究,结果表明STAT1的表达明显增加并主要分布在T细胞和B细胞中。STAT2与STAT1及IRF9形成异二聚体转录复合物,推测在RA发病过程中,STAT2与STAT1通过共同作用发挥功能。就STAT4而言,Th1细胞主要通过其传递IL-12信号,进而加速Th1和Th2之间的免疫失衡。IL-2对RA患者的T细胞中STAT5过度激活,引起了IL-2信号传导的异常放大效应,其在RA发病过程中同样发挥重要作用。在蛋白多糖诱导的关节炎模型表明,IL-4可通过STAT6调控炎症。JAK/STAT信号通路与RA发病机制具有重要关系,靶向该通路的RA治疗药物已获一定成效,特别是选择性JAK抑制剂。
巴瑞替尼(Baricitinib)由礼来公司与Incyte公司联合开发,为可口服的小分子JAK抑制剂,主要用于治疗RA、银屑病和糖尿病性肾病,同时也有治疗癌症、克罗恩病、溃疡性结肠炎、关节固定性脊柱炎、银屑病性关节炎和反应性关节炎(莱特尔综合征)等疾病的潜在功效。一种可选择性抑制JAK1和JAK2的新型和高效小分子药物,能抑制IL-6和IL-23等多种炎性细胞因子的细胞内信号传导。Baricitinib能优先抑制JAK1(IC50=5.9nmol·L-1)和JAK2(IC50=5.7nmol·L-1),对JAK1和JAK2的选择性较对Tyk2高10倍及对JAK3高70倍,且其能在全血中抑制IL-6刺激的STAT3磷酸化(IC50=128nmol·L-1)。
巴瑞替尼的化学名称为1-(乙基磺酰基)-3-[4-(7H-吡咯并[2,3-D]嘧啶-4-基)-1H-吡唑-1-基]-3-氮杂环丁烷乙腈,结构如下:
近年来,国内外有大量有关巴瑞替尼的合成方法的报道,主要由以下方法合成:Incyte公司在专利WO2009114512中报道了一条巴瑞替尼的合成路线,如下所示:
分析上述合成路线,反应路线繁多,副产物复杂大大限制了该化合物的工业化生产。
发明内容
发明目的:针对现有技术中存在的问题,本发明的目的是提供一种巴瑞替尼的中间体及其制备方法,本发明的另一个目的是提供由该中间体制备巴瑞替尼的方法,原料易得、工艺简洁、经济环保且适合工业化生产。
技术方案:本发明所述的巴瑞替尼的中间体,结构如式(5)所示:
本发明所述的中间体的制备方法,包括:
(a)碱催化下,氰甲基磷酸二乙酯与1-boc-3-氮杂环丁酮反应,得如式(2)结构的化合物2:
(b)脱去所述化合物2的Boc基团,得如式(3)结构的化合物3:
碱性条件下,所述的化合物3与乙基磺酰氯反应,得如式(4)结构的化合物4:
(c)在1,8-二氮杂双环[5,4,0]十一碳-7-烯存在下,所述的化合物4与4-吡唑硼酸频哪醇酯反应,得所述的中间体。
步骤(a)中,所述的碱为氢化钠或叔丁醇钾,优选为氢化钠。
步骤(a)中,反应在惰性气体保护的有机溶剂中进行,所述的有机溶剂选自乙醚、二氧六环、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、二氯甲烷、苯、甲苯、乙苯、叔丁苯和二甲苯中的一种或几种,优选为四氢呋喃、二氯甲烷、二氧六环和甲基叔丁基醚中的一种或几种,更优选为四氢呋喃。所述的惰性气体即与反应体系中各原料不发生反应的保护气体,如氮气。
步骤(a)中,反应温度为20~35℃,反应时间为12~24h。在该反应温度及反应时间下,反应进行的完全,目标产物的产率高。优选的,反应温度为20~30℃,反应时间为12~18h,更优选的,反应温度为23~27℃,反应时间为12~14h。
具体的,步骤(a)为:惰性气体保护下,将碱催化剂溶于有机溶剂中,冷却至0~5℃,加入溶有化合物7的有机溶剂,20~35℃反应1~2小时,冷却至0~5℃,再缓慢加入溶有化合物1的有机溶剂,20~35℃反应,从反应液中分离纯化得化合物2。
步骤(b)中,可采用酸脱去化合物2的Boc保护基,具体方法为:将化合物2溶于有机溶剂中,滴加酸进行反应,有机溶剂可采用乙腈,酸可采用盐酸、甲酸、乙酸、三氟乙酸、甲磺酸、乙磺酸、三氟甲磺酸、磷酸和硫酸氢钠水溶液中的一种或几种,优选为三氟乙酸,反应时间为4~6小时,以使保护基脱除彻底。
步骤(b)中,碱性条件可采用一些本领域常见的碱调节剂进行调节,一般调整pH至8~9,碱调节剂的选择要有利于产物的分离纯化,较好的采用N,N-二异丙基乙胺(DIEA)。脱Boc基团反应中,采用三氟乙酸可彻底脱除boc基团,得到化合物3,采用N,N-二异丙基乙胺(DIEA)可除去多余的三氟乙酸,无需纯化可直接进行下一步反应。
反应温度、反应时间及溶剂选择对最终的目标产物产率影响较大。步骤(b)中,化合物3与乙基磺酰氯的反应在有机溶剂中进行,反应温度为20~35℃,反应时间为12~24h,优选的,反应温度为20~30℃,反应时间为12~18h,更优选的,反应温度为23~27℃,反应时间为12~14h;有机溶剂选自二氯甲烷、乙腈、氯仿、四氯化碳和四氢呋喃中的一种或几种,优选为乙腈或/和二氯甲烷。
具体的,步骤(b)为:将化合物2溶于有机溶剂中,滴加酸进行反应,反应结束后,0~5℃条件下加入碱调节剂和乙基磺酰氯,20~35℃反应,从反应液中分离纯化得化合物4。
步骤(c)中,反应在有机溶剂中进行,反应温度为40~80℃,反应时间为3~8h。优选的,反应温度为60~80℃,反应时间为3~6h,更优选的,反应温度为60~68℃,反应时间为3~5h。
步骤(c)中,有机溶剂选自二氯甲烷、二氯乙烷、异丙醇、乙腈、四氢呋喃、2-甲基四氢呋喃、甲醇、乙醇和二氧六环中的一种或几种,优选为乙腈、二氯甲烷、二氧六环、乙醇和异丙醇中的一种或几种,更优选为乙腈或异丙醇。
本发明所述的由所述的中间体制备巴瑞替尼的方法,包括:
在钯催化剂和氟化铯存在下,所述的中间体与6-氯-7-脱氮嘌呤进行Suzuki偶联反应,得式(6)所示的所述的巴瑞替尼:
所述的钯催化剂选自Pd-127、Pd(dppf)Cl2、Pd(dba)3/PCy3、Pd(OAc)2和Pd(PPh3)4Cl2中的一种或几种,优选为Pd(PPh3)4Cl2。
所述Suzuki偶联反应的反应温度为90~110℃,反应时间为不少于32h,优选的,反应温度为90~100℃,反应时间为32~60h,更优选的,反应温度为95~100℃,反应时间为40~60h。
Suzuki偶联反应的溶剂由正丁醇、叔丁醇、二氧六环、苯、甲苯、乙苯、叔丁苯、二甲苯、二甲基甲酰胺和二甲基亚砜中的一种或几种与水配制而成,较优的由甲苯、叔丁醇和水配制而成,比例为1:1:1。
Suzuki偶联反应时,还可向反应体系中加入2.5~3.5当量的其他种类的碱与氟化铯配合使用,所述的碱选择碳酸钾、磷酸钾、乙酸钾、氢氧化钠、氢氧化钾、醋酸钾、碳酸钠、碳酸铯、碳酸锂和氟化钾中的一种或几种。
钯催化剂的加入量一般为0.1~0.2当量,氟化铯的加入量为2.5~3.5当量。
本发明制备方法的各步骤中,各主原料的配比可根据化学式中的摩尔比确定,并可根据实验条件所发生的损耗适当的灵活调整,为本领域技术人员所熟知,其中,主原料不包括催化剂、pH调节剂、溶剂,如步骤(a)中,化合物1与化合物7的摩尔比可为1:(1~1.5)。
与现有技术相比,本发明的有益效果为:
(1)本发明提供了一种新的中间体,名称为:2-(1-(乙基磺酰基)-3-(4-(4,4,5,5-四甲基-1,3,2–二氧杂硼酸频哪醇酯-2-基)-1氢-吡唑-1-基)氮杂环丁-3-基)乙腈,结构如式5所示,该中间体可应用于合成吡咯并嘧啶类JAK抑制剂药物巴瑞替尼。
(2)本发明还提供了所述中间体的制备方法,工艺路线简单、条件温和,各步目标产物的得率高。
(3)本发明还提供给了利用所述的中间体来制备吡咯并嘧啶类JAK抑制剂药物巴瑞替尼的方法。
本发明中,加上所述中间体的合成步骤,巴瑞替尼的制备共四步,与背景技术中Incyte公司公开的路线相比,本发明新的合成路线同样以1-boc-3-氮丁环酮作为起始原料,但本发明优化了化合物4的制备过程,在Horner-Emmons反应中,以氢化钠替换叔丁醇钾,可使产率达到84%。在DBU的催化作用下,化合物4和9(4-吡唑硼酸频哪醇酯)顺利反应,获得新的化合物5(即本发明所述的中间体)。从而在最后一步的Suzuki偶联反应中,化合物11(6-氯-7-脱氮嘌呤)不需要进行氨基基团保护,最后再脱保护,从而很大程度上缩短了反应时间,提高整体反应效率,适用于工业操作。另外,从目标产物的结构上分析,巴瑞替尼是由一个四氮杂环接一个五元环再接一个吡咯并嘧啶环,Incyte公司是先将中间的五元吡唑环连接吡咯并嘧啶环,再连接四元氮杂环,本发明改变了三个部分结构的连接顺序,从而在最后一步的反应中,不需要对吡咯并嘧啶环上的氨基先进行保护最后再脱保护。
本发明经四步反应合成吡咯并嘧啶类JAK抑制剂药物巴瑞替尼,工艺步骤简单,反应条件温和,可控性强,因而不需要繁琐反应和后续处理过程,且收率高,成本低,产物纯度高,适合工业化生产。本发明每步均可达到较高的收率,所得产品总收率可高达90%,具有良好的市场应用前景。
本发明的方法中所使用的原料可以通过商业途径购买,也可以根据本领域的常规化学合成方法制备。
具体实施方式
下面结合具体实施例对本发明作进一步阐述。
本发明巴瑞替尼的合成路线为:
其中:
化合物1的名称为:1-boc-3-氮杂环丁酮,结构如式(1)所示;
化合物2的名称为:2-(1-(叔丁氧羰基)氮杂环丁-3-亚基)乙腈,结构如式(2)所示;
化合物3的名称为:2-(氮杂环丁-3-亚基)乙腈,结构如式(3)所示;
化合物4的名称为:2-(1-(乙基磺酰基)氮杂环丁-3-亚基)乙腈,结构如式(4)所示;
化合物5的名称为:2-(1-(乙基磺酰基)-3-(4-(4,4,5,5-四甲基-1,3,2–二氧杂硼酸频哪醇酯-2-基)-1氢-吡唑-1-基)氮杂环丁-3-基)乙腈,结构如式(5)所示;
化合物6的名称为:2-(3-(4-(5氢-吡咯并[3,4-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(乙基磺酰基)氮杂环丁-3-基)乙腈,结构如式(6)所示;
化合物7的名称为:氰甲基磷酸二乙酯,结构如式(7)所示;
化合物8的名称为:乙基磺酰氯,结构如式(8)所示;
化合物9的名称为:4-吡唑硼酸频哪醇酯,结构如式(9)所示;
化合物10的名称为:1,8-二氮杂双环[5,4,0]十一碳-7-烯(DBU);
化合物11的名称为:6-氯-7-脱氮嘌呤,结构如式(11)所示。
实施例1
(1)制备化合物1
化合物1的制备为现有技术,可参照国际公布号为WO 2009/114512Al的专利申请所公开的方法,本实施例中化合物1直接从公司购买。
(2)制备化合物2
合成路线为:
制备例1-1
将氢化钠(0.260g,0.011mol)溶于四氢呋喃溶剂通氮气保护的三口瓶中,冷却至0℃,将化合物7(1100ml,6.72mmol,1.15equiv)溶于四氢呋喃溶剂中,缓慢加入前面溶液中。混合液升至室温(25℃)反应1小时,再冷却至0℃,反应1小时。将化合物1(1.0g,5.84mmol)溶于四氢呋喃溶剂中,缓慢加入上述混合液,搅拌1小时。升至室温(25℃),反应过夜(12h)。冷水淬灭,旋蒸除溶剂四氢呋喃。用乙酸乙酯萃取,水层分离,有机层再用盐水洗涤。无水硫酸镁干燥,过滤,浓缩,柱层析纯化,得0.939g白色固体,产率83%。
目标产物化合物2的HNMR的数据如下:
1H-NMR(300MHz,DMSO-d6)δ:
1.4610(s,9H),4.6191(t,J=1.95,2H),4.7010(t,J=3.23,2H),5.3794(t,J=2.34,1H)
制备例1-2
将碱催化剂氢化钠替换为叔丁醇钾,其他反应条件不变,同制备例1-1,最终目标化合物2的产率为67%。
制备例1-3
将溶剂四氢呋喃分别替换为二氯甲烷、二氧六环、甲基叔丁基醚,其他反应条件不变,同制备例1-1,最终目标化合物2的产率如下表。
组别 | 溶剂 | 产率 |
1-3-1 | 二氯甲烷 | 75% |
1-3-2 | 二氧六环 | 69% |
1-3-3 | 甲基叔丁基醚 | 73% |
制备例1-4
将加入化合物1后的反应温度由室温分别替换为10℃、20℃、30℃,其他反应条件不变,同制备例1-1,最终目标化合物2的产率如下表。
组别 | 反应温度(℃) | 产率 |
1-4-1 | 10 | 53% |
1-4-2 | 20 | 77% |
1-4-3 | 30 | 80% |
实施例2制备化合物4
合成路线如下:
制备例2-1:
将化合物2(0.250g,1.29mmol)溶于乙腈中,缓慢滴加三氟乙酸(3ml)。室温搅拌4小时,点板跟踪。待反应完全后,旋干溶剂,将获得物溶于乙腈,冷却至0℃,缓慢加入N,N-二异丙基乙胺(DIEA),保持温度不高于5℃。缓慢加入化合物8(0.184ml,1.94mmol,1.5equiv),在T<5℃,搅拌1小时,升至室温,反应过夜。TLC跟踪反应完全,减压浓缩,粗产物用二氯甲烷稀释,再用盐水洗涤,水相用二氯甲烷萃取,集中有机相,用无水硫酸钠干燥,柱层析纯化,得0.192g白色固体,产率为81%。
目标产物化合物4的HNMR的数据如下:
1H-NMR(300MHz,DMSO-d6)δ:
1.3715(m,J=6.73,3H),3.0398(m,J=7.39,2H),4.6968(t,J=2.54,2H),4.7697(t,J=2.84,2H),5.4305(t,J=2.43,1H),
制备例2-2:
将化合物2(0.362g,1.86mmol)溶于二氯甲烷中,缓慢滴加三氟乙酸(4ml)。室温搅拌4小时,点板跟踪。待反应完全后,旋干溶剂,将获得物溶于二氯甲烷,冷却至0℃,缓慢加入DIEA至pH8~9,保持温度不高于5℃。缓慢加入化合物8(0.266ml,2.80mmol,1.5equiv),在T<5℃,搅拌1小时,升至室温,反应过夜。TLC跟踪反应完全,减压浓缩,粗产物用二氯甲烷稀释,再用盐水洗涤,水相用二氯甲烷萃取,集中有机相,用无水硫酸钠干燥,柱层析纯化,得0.277g白色固体,产率为79.83%。
制备例2-3
将加入化合物8后的反应温度由室温分别替换为10℃、20℃、30℃,其他反应条件不变,同制备例2-1,最终目标化合物4的产率如下表。
组别 | 反应温度(℃) | 产率 |
2-3-1 | 10 | 45% |
2-3-2 | 20 | 76% |
2-3-3 | 30 | 79% |
实施例3
制备化合物5
合成路线为:
制备例3-1:
在溶剂异丙醇中,加入化合物10:1,8-二氮杂双环[5,4,0]十一碳-7-烯(0.061ml),化合物9(0.156g,0.80mmol,1.01equiv),化合物4(0.149g,0.80mmol),室温下形成悬浮液,回流半小时,形成均匀溶液。再于60℃回流反应3小时,TLC跟踪。冷却至室温,减压抽滤,柱层析纯化得白色固体0.255g,产率84%。
目标产物化合物5的HNMR的数据如下:
1H-NMR(300MHz,DMSO-d6)δ:
1.2234(t,J=7.37,3H),1.2705(s,12H),3.1959(m,J=7.34,2H),3.5908(s,2H),4.1468(d,J=8.97,2H),4.4464(d,J=9.00,2H),7.7718(s,1H),8.3499(s,1H)
制备例3-2:
在溶剂乙腈中,加入1,8-二氮杂双环[5,4,0]十一碳-7-烯(0.037ml),化合物9(0.096g,0.50mmol),化合物4(0.091g,0.49mmol),室温下形成悬浮液,回流半小时,形成均匀溶液。再于65℃回流反应4小时,TLC跟踪。冷却至室温,减压抽滤,柱层析纯化得浅黄白色固体0.157g,产率84%。
制备例3-3
将溶剂异丙醇分别替换为二氯甲烷、二氧六环、乙醇,其他反应条件不变,同制备例3-1,最终目标化合物2的产率如下表。
组别 | 溶剂 | 产率 |
3-3-1 | 二氯甲烷 | 60% |
3-3-2 | 二氧六环 | 73% |
3-3-3 | 乙醇 | 63% |
制备例3-4
经回流反应的温度分别替换为25℃、40℃、65℃、80℃,其他反应条件不变,同制备例3-1,最终目标化合物5的产率如下表。
组别 | 反应温度(℃) | 产率 |
3-4-1 | 25 | ---- |
3-4-2 | 40 | 55% |
3-4-3 | 65 | 84% |
3-4-4 | 80 | 81% |
实施例4
制备化合物6
合成路线为:
制备例4-1:
将化合物5(0.086g,0.23mmol,1.1equiv),化合物11(0.033g,0.21mmol),氟化铯(0.118g),碳酸钠(0.045g)和Pd(PPh3)4(0.024g)加入二氧六环和水(5:1)的混合溶剂中,氮气保护,90℃回流反应48小时,冷却至室温,硅藻土过滤。用乙酸乙酯冲洗硅藻土,收集滤液,分离有机层,水层用乙酸乙酯萃取,有机层浓缩,干燥,柱层析纯化得白色固体0.064g,产率79%。
目标产物化合物6的HNMR的数据如下:
1H-NMR(300MHz,DMSO-d6)δ:
1.2509(t,J=7.31,3H),3.2360(m,J=7.32,2H),3.6954(s,2H),4.2432(d,J=9.06,2H),4.6058(d,J=9.09,2H),7.0814(s,1H),7.6178(s,1H),8.4731(s,1H),8.7101(s,1H),8.9248(s,1H),12.1233(s,1H)
制备例4-2:
将化合物5(0.075g,0.20mmol,1.0equiv),化合物11(0.033g,0.21mmol),碳酸钠(0.045g)和Pd(PPh3)4(0.024g)加入二氧六环和水(5:1)的混合溶剂中,氮气保护,90℃回流反应48小时,冷却至室温,TLC监测,不反应。
制备例4-3:
将化合物5(0.087g,0.23mmol,1.1equiv,),化合物11(0.029g,0.019mmol),氟化铯(0.118g),碳酸钾(0.068g)和Pd(PPh3)4(0.024g)加入甲苯,乙醇和水(2:1:1)的混合溶剂中,氮气保护,110℃回流反应48小时,冷却至室温,硅藻土过滤。用乙酸乙酯冲洗硅藻土,收集滤液,分离有机层,水层用乙酸乙酯萃取,有机层浓缩,干燥,柱层析纯化得白色固体0.052g,产率79%。
制备例4-4:
将化合物5(0.080g,0.21mmol,1.05equiv),化合物11(0.030g,0.20mmol),氟化铯(0.112g)和Pd(PPh3)4(0.024g)加入甲苯,叔丁醇和水(1:1:1)的混合溶剂中,氮气保护,100℃回流反应48小时,冷却至室温,硅藻土过滤。用乙酸乙酯冲洗硅藻土,收集滤液,分离有机层,水层用乙酸乙酯萃取,有机层浓缩,干燥,柱层析纯化得白色固体0.056g,产率84%。
制备例4-5:
将化合物5(0.092g,0.24mmol),化合物11(0.037g,0.24mmol),氟化铯(0.129g)和Pd(PPh3)4(0.028g)加入甲苯,叔丁醇和水(1:1:1)的混合溶剂中,氮气保护,100℃回流反应48小时,冷却至室温,硅藻土过滤。用乙酸乙酯冲洗硅藻土,收集滤液,分离有机层,水层用乙酸乙酯萃取,有机层浓缩,干燥,柱层析纯化得白色固体0.060g,产率90%。
制备例4-6
经回流反应温度由90℃分别替换为80℃、95℃、100℃、110℃,其他反应条件不变,同制备例4-1,最终目标化合物6的产率如下表。
组别 | 反应温度(℃) | 产率 |
4-6-1 | 80 | 70% |
4-6-2 | 95 | 85% |
4-6-3 | 100 | 82% |
4-6-4 | 110 | 79% |
制备例4-7
将回流反应时间由48h分别替换为24h,32h,40h,60h,其他反应条件不变,同制备例4-1,最终目标化合物6的产率如下表。
组别 | 反应时间(h) | 产率 |
4-7-1 | 24 | 55% |
4-7-2 | 32 | 73% |
4-7-3 | 40 | 89% |
4-7-4 | 60 | 87% |
Claims (9)
1.一种巴瑞替尼的中间体的制备方法,其特征在于,包括:
(a)碱催化下,氰甲基磷酸二乙酯与1-boc-3-氮杂环丁酮反应,得如式(2)结构的化合物2:
(b)脱去所述化合物2的Boc基团,得如式(3)结构的化合物3:
碱性条件下,所述的化合物3与乙基磺酰氯反应,得如式(4)结构的化合物4:
(c)在1,8-二氮杂双环[5,4,0]十一碳-7-烯存在下,所述的化合物4与4-吡唑硼酸频哪醇酯反应,得巴瑞替尼的中间体,所述巴瑞替尼的中间体的结构如式(5)所示:
2.根据权利要求1所述的制备方法,其特征在于,步骤(a)中,反应在惰性气体保护的有机溶剂中进行,反应温度为20~35℃,反应时间为12~24h。
3.根据权利要求2所述的制备方法,其特征在于,步骤(a)中,所述的碱为氢化钠或叔丁醇钾;所述的有机溶剂选自乙醚、二氧六环、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、二氯甲烷、苯、甲苯、乙苯、叔丁苯和二甲苯中的一种或几种。
4.根据权利要求1所述的制备方法,其特征在于,步骤(b)中,所述化合物3与乙基磺酰氯的反应在有机溶剂中进行,反应温度为20~35℃,反应时间为12~24h。
5.根据权利要求4所述的制备方法,其特征在于,步骤(b)中,所述的有机溶剂选自二氯甲烷、乙腈、氯仿、四氯化碳和四氢呋喃中的一种或几种。
6.根据权利要求1所述的制备方法,其特征在于,步骤(c)中,反应在有机溶剂中进行,反应温度为40~80℃,反应时间为3~8h;所述的有机溶剂选自二氯甲烷、二氯乙烷、异丙醇、乙腈、四氢呋喃、2-甲基四氢呋喃、甲醇、乙醇和二氧六环中的一种或几种。
7.一种制备巴瑞替尼的方法,其特征在于,包括:
在钯催化剂和氟化铯存在下,中间体与6-氯-7-脱氮嘌呤进行Suzuki偶联反应,得式(6)所示的巴瑞替尼:
所述中间体的结构如式(5)所示:
8.根据权利要求7所述的制备方法,其特征在于,所述的钯催化剂选自Pd(dppf)Cl2、Pd(OAc)2和Pd(PPh3)4中的一种或几种。
9.根据权利要求7所述的制备方法,其特征在于,所述Suzuki偶联反应的反应温度为90~110℃,反应时间为不少于32h。
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