CN110408660A - 一种脂肪酶催化合成双吲哚类化合物的方法 - Google Patents
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Abstract
本发明属于生物催化技术领域,具体涉及一种脂肪酶在纯水相中催化芳香醛,杂环醛,脂肪醛与吲哚类化合物进行级联反应合成双吲哚类化合物的方法。本发明提供一种以脂肪酶TLIM为催化剂,以芳香醛(产物收率85%‑99%),杂环醛(产物收率89%)或脂肪醛(产物收率80%‑87%)与吲哚类化合物为底物经过级联反应制备双吲哚类化合物的方法,该方法可在纯水相中进行,反应条件温和,催化剂用量少10mg/mmol醛且可回收,产物收率高。
Description
技术领域
本发明涉及一种脂肪酶催化合成双吲哚类化合物的方法,尤其是一种脂肪酶在纯水相中催化芳香醛,杂环醛,脂肪醛与吲哚类化合物进行级联反应合成双吲哚类化合物的方法,属于生物催化技术领域。
背景技术
双吲哚类化合物因其活跃的药理和生物活性而在药理学和材料科学领域被广泛应用。它可用作免疫刺激性G蛋白偶联受体GPR84 1的激动剂,用作杜氏利什曼原虫的拮抗剂,还可用作监测蛋白质相互作用的探针。双吲哚类化合物还被用于治疗多种癌症,比如前列腺癌,结肠癌,胰腺癌和乳腺癌等。双吲哚类化合物一般由吲哚类化合物和芳香醛,杂环醛,脂肪醛通过级联反应得到。目前,合成双吲哚类化合物的方法多种多样。比如采用沸石催化(来自Catal Commun,2004,5:371-375),SDS催化(来自Tetrahedron Lett,2006,47:1441-1443),超声条件下己烯酸钠盐催化(来自Ultrason Sonochem,2010,17:298-300),纳米粒子ZrO2–Al2O3–Fe3O4催化(来自Catal.Sci.Technol,2014,4:71-80),负载在磁性纳米粒子Fe3O4@SiO2上的离子液体催化(来自RSC Advances,2017,7:4237-4242),氧化石墨烯催化(来自Catal Commun,2017,89:138-142)等。其中,大多数合成方法使用易挥发的有机溶剂,需要相对较高的反应温度,需要过量的底物,催化剂昂贵或制备困难或难以回收使用。
酶作为一种特殊的生物催化剂,具有专一性、高效性、反应条件温和、环境友好、催化活性可调控等特点,已在化工、医药、食品、和环境治理等众多领域得到广泛应用。近年来,酶在有机合成中发挥了越来越重要的作用,在Aldol缩合,Mannich反应,Henry反应,Knoevenagel缩合,Michael加成,Baylis-Hillman反应等重要的C-C键形成的反应中的应用被相继报道。脂肪酶TLIM被用于在35℃无水正己烷中催化芳香醛和1,3-环己二酮或达米酮的Knoevenagel缩合-Michael加成级联反应,生成氧杂蒽酮类化合物;脂肪酶RMIM被用于45℃的纯水相中催化芳香醛和4-羟基香豆素的Knoevenagel缩合-Michael加成级联反应,生成双香豆素类化合物。脂肪酶PPL(150mg/mmol醛)被用于含水1,4-环氧六环(含水80%)中催化吲哚和芳香醛或脂肪醛的反应,其中吲哚与含有推电子基的芳香醛反应时,产物收率为50%-87%,吲哚与脂肪醛反应时,只可获得38%收率的产物。值得一提的是,该研究并没有考察吲哚与杂环醛的反应情况(来自Amino acids,2013,45:937-945)。ɑ-糜蛋白酶被用于乙醇水溶液(含水70%)中催化吲哚和芳香醛的反应,当吲哚与含有推电子基的芳香醛反应时,产物收率为68%-79%。同样的,该研究提出,当吲哚与脂肪醛反应时,最好的收率只有20%,该反应体系也没有考察吲哚与杂环醛的反应情况。目前,酶法催化合成双吲哚类化合物的研究中,鲜有研究吲哚与杂环醛的反应,而且吲哚与含有推电子基的芳香醛或脂肪醛反应时,产物收率较低。
现有技术中吲哚与醛类的级联反应基本都以化学催化的方法进行,酶法催化合成双吲哚类化合物的研究中,所采用的催化剂都不可回收利用且反应体系(含水有机溶剂)较为复杂。酶法催化合成双吲哚类化合物鲜有研究吲哚与杂环醛的反应,而且吲哚与含有推电子基的芳香醛(产物收率50%-87%)或脂肪醛(产物收率20%-38%)反应时,产物收率较低。
发明内容
本发明解决的技术问题是:提出一种脂肪酶催化合成双吲哚类化合物的方法,本发明提供一种以脂肪酶为催化剂,以芳香醛(产物收率85%-99%),杂环醛(产物收率89%)或脂肪醛(产物收率80%-87%)与吲哚类化合物为底物经过级联反应制备双吲哚类化合物的方法,该方法可在纯水相中进行,反应条件温和,催化剂用量少(10mg/mmol醛)且可回收,产物收率高。
为了解决上述技术问题,本发明提出的技术方案是:一种脂肪酶催化合成双吲哚类化合物的方法,其特征在于:包括以式1吲哚类化合物为底物,利用脂肪酶TLIM来自疏棉状嗜热丝孢菌的脂肪酶催化进行亲电取代级联反应与式II化合物生成式III双吲哚类化合物,反应方程式为:
其中,R1为H,Cl,Me,OMe中的一种;
R2为H或Me;
Ar为4-ClC6H4,2-NO2C6H4,3-NO2C6H4,4-NO2C6H4,4-OHC6H4,2-OHC6H4,4-CNC6H4,2-FC6H4,C6H5,4-MeC6H4,4-OMeC6H4,2-OH-3-OMeC6H3,4-OH-3-OMeC6H3,2,6-Cl2C6H3,4-t-C4H9C6H4,2-SC4H3,,2-NC5H4,CH3C5H11,C3H7中的一种;
所述反应的溶剂为水
优选的,所述所述的式II化合物和式Ⅰ化合物的摩尔比为1:0.5-4。
优选的,所述的脂肪酶在所述反应中总体积浓度为c,其中0<c≤30mg/mL,。
优选的,所述反应的反应温度为25-65℃。
优选的,所述反应的反应时间为2-72h。
优选的,所述所述的式II化合物和式Ⅰ化合物的摩尔比为1:2,所述的脂肪酶在所述反应中总体积为2mg/mL,所述反应的反应温度为为55℃。
优选的,将脂肪酶加入式II化合物和式Ⅰ化合物的混合溶液中,催化反应生成双吲哚类化合物。
优选的,还包括反应完毕后过滤并回收溶剂或回收酶的步骤。
优选的,所述的回收酶包括:过滤反应体系,向滤渣中加入1,4-环氧六环溶解并过滤回收酶。
优选的,所述脂肪酶催化合成双吲哚类化合物的方法,还包括反应完毕的后处理步骤,包括:
(1)将反应完毕后的反应混合液过滤;
(2)滤渣中加入1,4-环氧六环,之后过滤回收酶;
(3)将步骤(2)得到的滤液蒸除溶剂,所余固体产物过柱分离即得目标产物。
本发明的有益效果
(1)提供了产物的新的合成方法。以脂肪酶TLIM为催化剂,可在纯水相中催化,提供了反应条件温和,操作简单,生产成本低,产率高,副产物少,底物适用范围广,对环境污染小,催化剂用量少且可回收的双吲哚类化合物合成方法。
(2)发掘了脂肪酶的新用途,特别是以吲哚类化合物和杂环醛或脂肪醛或含有推电子基的芳香醛为底物的级联反应。
(3)本发明所述的方法,产物收率为80%~98%,相对于其他合成方法,具备较强的竞争优势。
(4)脂肪酶可重复使用,重复使用5次后仍具有较高的催化活性(脂肪酶重复使用五次后仍可获得86%收率的产物)。
(5)脂肪酶TLIM被用于在35℃无水正己烷中催化芳香醛和1,3-环己二酮或达米酮的Knoevenagel缩合-Michael加成级联反应,生成氧杂蒽酮类化合物,但是本发应是吲哚与芳香醛,杂环醛或脂肪醛的亲电取代反应,反应底物与反应类型都不一样。
(6)脂肪酶TLIM在45℃无水正己烷中催化吲哚与醛的亲电取代反应时,只可获得11.6%收率的产物。脂肪酶TLIM在45℃纯水中催化吲哚与醛的亲电取代反应时,可获得93%收率的产物。反应类型和反应底物不一样时,脂肪酶TLIM会在不同的溶剂中发挥最佳催化效果。
附图说明
下面结合附图对本发明的作进一步说明。
图1是实施例1制得的4-(di(1H-indol-3-yl)methyl)benzonitrile核磁共振氢谱图。
图2是实施例3制得的3,3'-((4-methoxyphenyl)methylene)bis(1H-indole)核磁共振氢谱图。
图3是实施例5制得的3,3'-((4-chlorophenyl)methylene)bis(5-chloro-1H-indole)核磁共振氢谱图。
图4是实施例6制得的3,3'-(thiophen-2-ylmethylene)bis(1H-indole)核磁共振氢谱图。
图5是实施例7制得的3,3'-(butane-1,1-diyl)bis(1H-indole)核磁共振氢谱图。
图6是实施例8制得的3,3'-((4-chlorophenyl)methylene)bis(5-methyl-1H-indole)核磁共振氢谱图。
图7是实施例10制得的3,3'-((1H-pyrrol-2-yl)methylene)bis(1H-indole)核磁共振氢谱图。
图8是实施例11制得的3,3'-((4-chlorophenyl)methylene)bis(5-methoxy-1H-indole)核磁共振氢谱图。
图9是实施例22制得的3,3'-((4-chlorophenyl)methylene)bis(2-methyl-1H-indole)核磁共振氢谱图。
图10温度对产物收率的影响.a反应条件:TLIM(50mg),4-氯苯甲醛(1mmol),吲哚(2mmol),水(5mL),18h.b液相收率
具体实施方式
本发明所涉及的生物酶及其他试剂均为市场购买,其中试剂均未进一步纯化;核磁共振氢谱(1HNMR)用Bruker Advance 2B 300核磁共振波谱仪进行测定,频率为300MHz,溶剂为氘代氯仿,内标为四甲基硅(TMS)。
实施例1:
将1mmol对氰基苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入10mg脂肪酶TLIM,5mL水,45℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。20h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为98%,m.p.:210℃-211℃;1HNMR(300MHz,Chloroform-d)δ8.00(s,2H),7.57(d,J=8.2Hz,2H),7.45(d,J=8.1Hz,2H),7.36(dd,J=14.4,8.1Hz,4H),7.20(t,J=7.6Hz,2H),7.03(t,J=7.5Hz,2H),6.67(s,2H),5.94(s,1H).13C NMR(75MHz,Chloroform-d)δ149.76,136.68,132.12,129.48,126.69,123.64,122.25,119.55,119.52,119.15,118.18,111.24,109.95,40.36.HRMS(ESI-TOF)m/z[M+Na]+:347.4130,found:347.4099.
实施例2:
将1mmol苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入150mg脂肪酶RMIM,5mL水,65℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。36h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为98%,m.p.:90℃-91℃;1H NMR(300MHz,Chloroform-d)δ7.88(s,2H),7.48–7.33(m,6H),7.30(d,J=7.0Hz,2H),7.23–7.13(m,3H),7.01(t,J=7.4Hz,2H),6.65(s,2H),5.90(s,1H).HRMS(ESI-TOF)m/z[M+Na]+:322.4013,found:322.4019.
实施例3:
将1mmol对甲氧基苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入5mg脂肪酶TLIM,5mL水,25℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。10h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为95%,m.p.:187℃-189℃;1HNMR(300MHz,Chloroform-d)δ7.92(s,2H),7.37(dd,J=14.3,8.1Hz,4H),7.25(d,J=6.3Hz,2H),7.16(t,J=7.5Hz,2H),7.00(t,J=7.5Hz,2H),6.82(d,J=8.5Hz,2H),6.64(s,2H),5.84(s,1H),3.78(s,3H).HRMS(ESI-TOF)m/z[M+Na]+:352.4322,found:352.4310.
实施例4:
将1mmol对叔丁基苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入10mg脂肪酶TLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。72h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为95%,70℃-72℃;1H NMR(300MHz,Chloroform-d)δ7.59(s,2H),7.39(d,J=7.8Hz,2H),7.35–7.18(m,6H),7.13(t,J=7.4Hz,2H),6.98(t,J=7.4Hz,2H),6.50(s,2H),5.83(s,1H),1.30(s,9H).13C NMR(75MHz,Chloroform-d)δ148.71,140.82,136.67,128.22,127.16,125.00,123.51,121.82,119.97,119.11,110.96,104.53,39.64,34.35,31.43.HRMS(ESI-TOF)m/z[M+Na]+:378.5124,found:378.5087.
实施例5:
将1mmol4-氯苯甲醛和2mmol5-氯吲哚,加入10mL反应瓶中,然后加入70mg脂肪酶Novozym435,5mL正己烷,45℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。36h后,过滤回收正己烷,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为粉色固体,收率为90%,m.p.:175℃-176℃;1H NMR(300MHz,Chloroform-d)δ7.96(s,2H),7.30(d,J=7.2Hz,4H),7.26(s,2H),7.22(d,J=8.5Hz,2H),7.19–7.06(m,2H),6.65(s,2H),5.74(s,1H).13C NMR(75MHz,Chloroform-d)δ141.33,136.83,128.70,128.60,127.42,127.17,124.19,121.20,120.82,119.63,113.73,112.19,34.79.HRMS(ESI-TOF)m/z[M+Na]+:424.0311,found:424.0315.
实施例6:
将1mmol2-噻吩甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入2.5mg脂肪酶TLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。72h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为粉色固体,收率为89%,m.p.:186℃-188℃;1HNMR(300MHz,Chloroform-d)δ7.90(s,2H),7.47(d,J=7.9Hz,2H),7.35(d,J=8.1Hz,2H),7.24–7.12(m,3H),7.04(t,J=7.4Hz,2H),6.92(d,J=4.5Hz,2H),6.84(s,2H),6.17(s,1H).13C NMR(75MHz,Chloroform-d)δ147.62,135.53,125.72,125.37,124.09,122.55,122.13,120.97,118.71,118.64,118.32,110.08,34.29,.HRMS(ESI-TOF)m/z[M+Na]+:328.4310,found:328.4296.
实施例7:
将1mmol丁醛和2mmol吲哚,加入10mL反应瓶中,然后加入10mg脂肪酶TLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。72h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为橙色固体,收率为87%,m.p.:153℃-155℃;1H NMR(300MHz,Chloroform-d)δ7.57(s,2H),7.46(d,J=7.8Hz,2H),7.10(t,J=10.0Hz,2H),7.00(t,J=7.4Hz,2H),6.89(p,J=8.9,8.4Hz,2H),6.81–6.56(m,2H),4.34(t,J=7.4Hz,1H),2.05(q,J=7.5Hz,2H),1.27(dt,J=18.0,9.3Hz,2H),0.82(t,J=7.3Hz,3H).13C NMR(75MHz,Chloroform-d)δ136.60,127.22,121.71,121.47,120.53,119.68,119.00,111.14,38.20,33.70,21.45,14.25.HRMS(ESI-TOF)m/z[M+Na]+:288.3942,found:288.4051.
实施例8:
将1mmol 4-氯苯甲醛和3mmol5-甲基吲哚,加入10mL反应瓶中,然后加入100mg脂肪酶TLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。20h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为98%,m.p.:148℃-150℃;1H NMR(300MHz,Chloroform-d)δ7.76(s,2H),7.24(d,J=9.2Hz,6H),7.18(s,2H),7.03(d,J=8.2Hz,2H),6.56(s,2H),5.81(s,1H),2.38(s,6H).13C NMR(75MHz,Chloroform-d)δ130.05,128.59,128.31,123.82,123.69,119.32,118.81,110.76,39.48,21.45.HRMS(ESI-TOF)m/z[M+Na]+:384.9001,found:384.9005.
实施例9:
将1mmol 4-羟基-3-甲氧基苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入10mg脂肪酶TLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。36h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为88%,m.p.:102℃-103℃;1H NMR(300MHz,Chloroform-d)δ7.87(s,2H),7.42(d,J=7.9Hz,2H),7.32(d,J=8.1Hz,2H),7.18(t,J=7.5Hz,2H),7.02(t,J=7.4Hz,2H),6.90(s,1H),6.83(s,2H),6.60(s,2H),5.83(s,1H),3.74(s,3H),2.08(s,1H).HRMS(ESI-TOF)m/z[M+Na]+:368.4335,found:368.4373.
实施例10:
将1mmol正己醛和2mmol吲哚,加入10mL反应瓶中,然后加入20mg脂肪酶TLIM,5mL水,35℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。60h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为80%,m.p.:67℃-69℃;1H NMR(300MHz,Chloroform-d)δ11.15(s,2H),7.61(dd,J=7.5,1.6Hz,2H),7.33(dd,J=7.4,1.6Hz,2H),7.24(s,2H),7.06(td,J=7.5,1.5Hz,2H),6.98(td,J=7.5,1.7Hz,2H),4.59(t,J=7.0Hz,1H),1.77(q,J=7.7Hz,2H),1.37–1.21(m,6H),1.08–0.44(m,3H).HRMS(ESI-TOF)m/z[M+Na]+:316.4511,found:316.4513.
实施例11:
将1mmol 4-氯苯甲醛和2mmol5-甲氧基吲哚,加入10mL反应瓶中,然后加入50mg脂肪酶TLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。36h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为粉固体,收率为88%,m.p.:172℃-173℃;1HNMR(300MHz,Chloroform-d)δ7.84(s,2H),7.27(d,J=5.1Hz,4H),7.23(s,2H),6.95–6.76(m,4H),6.63(s,2H),5.77(s,1H),3.73(s,6H).13C NMR(75MHz,Chloroform-d)13C NMR(75MHz,Chloroform-d)δ153.79,142.50,134.69,130.07,128.33,127.30,124.45,118.74,111.98,111.78,110.92,101.99,55.91,39.70.HRMS(ESI-TOF)m/z[M+Na]+:416.1299,found:416.1301.
实施例12:
将1mmol对甲氧基苯甲醛和4mmol吲哚,加入10mL反应瓶中,然后加入100mg木瓜蛋白酶,5mL甲苯,25℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。48h后,过滤回收甲苯,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为85%,m.p.:187℃-189℃;1H NMR(300MHz,Chloroform-d)δ7.92(s,2H),7.37(dd,J=14.3,8.1Hz,4H),7.25(d,J=6.3Hz,2H),7.16(t,J=7.5Hz,2H),7.00(t,J=7.5Hz,2H),6.82(d,J=8.5Hz,2H),6.64(s,2H),5.84(s,1H),3.78(s,3H).HRMS(ESI-TOF)m/z[M+Na]+:352.4322,found:352.4310.
实施例13:
将1mmol对甲氧基苯甲醛和3mmol吲哚,加入10mL反应瓶中,然后加入50mg脂肪酶CRL5mL水,35℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。72h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为88%,m.p.:187℃-189℃;1H NMR(300MHz,Chloroform-d)δ7.92(s,2H),7.37(dd,J=14.3,8.1Hz,4H),7.25(d,J=6.3Hz,2H),7.16(t,J=7.5Hz,2H),7.00(t,J=7.5Hz,2H),6.82(d,J=8.5Hz,2H),6.64(s,2H),5.84(s,1H),3.78(s,3H).HRMS(ESI-TOF)m/z[M+Na]+:352.4322,found:352.4310.
实施例14:
将1mmol对甲氧基苯甲醛和3mmol吲哚,加入10mL反应瓶中,然后加入50mg脂肪酶BCL,5mL水,35℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。72h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为75%,由于反应条件不是优选条件,所以收率中等。m.p.:187℃-189℃;1H NMR(300MHz,Chloroform-d)δ7.92(s,2H),7.37(dd,J=14.3,8.1Hz,4H),7.25(d,J=6.3Hz,2H),7.16(t,J=7.5Hz,2H),7.00(t,J=7.5Hz,2H),6.82(d,J=8.5Hz,2H),6.64(s,2H),5.84(s,1H),3.78(s,3H).HRMS(ESI-TOF)m/z[M+Na]+:352.4322,found:352.4310.
实施例15:
将1mmol对甲氧基苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入50mg木瓜蛋白酶,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。72h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为77%,由于反应条件不是优选条件,所以收率中等。m.p.:187℃-189℃;1H NMR(300MHz,Chloroform-d)δ7.92(s,2H),7.37(dd,J=14.3,8.1Hz,4H),7.25(d,J=6.3Hz,2H),7.16(t,J=7.5Hz,2H),7.00(t,J=7.5Hz,2H),6.82(d,J=8.5Hz,2H),6.64(s,2H),5.84(s,1H),3.78(s,3H).HRMS(ESI-TOF)m/z[M+Na]+:352.4322,found:352.4310.
实施例16:
将1mmol对甲氧基苯甲醛和1mmol吲哚,加入10mL反应瓶中,然后加入30mgTLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。72h后,过滤回水收,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为82%,m.p.:187℃-189℃;1H NMR(300MHz,Chloroform-d)δ7.92(s,2H),7.37(dd,J=14.3,8.1Hz,4H),7.25(d,J=6.3Hz,2H),7.16(t,J=7.5Hz,2H),7.00(t,J=7.5Hz,2H),6.82(d,J=8.5Hz,2H),6.64(s,2H),5.84(s,1H),3.78(s,3H).HRMS(ESI-TOF)m/z[M+Na]+:352.4322,found:352.4310.
实施例17:
将1mmol对甲氧基苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入10mgPPL,5mL1,4-环氧六环,35℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。72h后,过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为72%,由于反应条件不是优选条件,所以收率中等。m.p.:187℃-189℃;1H NMR(300MHz,Chloroform-d)δ7.92(s,2H),7.37(dd,J=14.3,8.1Hz,4H),7.25(d,J=6.3Hz,2H),7.16(t,J=7.5Hz,2H),7.00(t,J=7.5Hz,2H),6.82(d,J=8.5Hz,2H),6.64(s,2H),5.84(s,1H),3.78(s,3H).HRMS(ESI-TOF)m/z[M+Na]+:352.4322,found:352.4310.
实施例18:
将1mmol对甲氧基苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入10mgRMIM,5mL乙醇,45℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。72h后,过滤回收酶,滤液减压旋蒸回收乙醇,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为73%,由于反应条件不是优选条件,所以收率中等。m.p.:187℃-189℃;1H NMR(300MHz,Chloroform-d)δ7.92(s,2H),7.37(dd,J=14.3,8.1Hz,4H),7.25(d,J=6.3Hz,2H),7.16(t,J=7.5Hz,2H),7.00(t,J=7.5Hz,2H),6.82(d,J=8.5Hz,2H),6.64(s,2H),5.84(s,1H),3.78(s,3H).HRMS(ESI-TOF)m/z[M+Na]+:352.4322,found:352.4310.
实施例19:
将1mmol对甲氧基苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入10mgTLIM,5mLDMSO,45℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。72h后,过滤回收酶,滤液减压旋蒸回收DMSO,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为72%,由于反应条件不是优选条件,所以收率中等。m.p.:187℃-189℃;1H NMR(300MHz,Chloroform-d)δ7.92(s,2H),7.37(dd,J=14.3,8.1Hz,4H),7.25(d,J=6.3Hz,2H),7.16(t,J=7.5Hz,2H),7.00(t,J=7.5Hz,2H),6.82(d,J=8.5Hz,2H),6.64(s,2H),5.84(s,1H),3.78(s,3H).HRMS(ESI-TOF)m/z[M+Na]+:352.4322,found:352.4310.
实施例20:
将1mmol对甲基苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入10mgTLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。14h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为橙色固体,收率为90%,m.p.:95℃-97℃;1H NMR(300MHz,Chloroform-d)δ7.66(s,2H),7.42(d,J=7.8Hz,2H),7.26(t,J=7.3Hz,4H),7.18(t,J=7.4Hz,2H),7.10(d,J=7.7Hz,2H),7.03(t,J=7.3Hz,2H),6.54(s,2H),5.86(s,1H),2.35(s,3H).13C NMR(75MHz,Chloroform-d)δ140.98,136.69,135.45,128.88,128.54,127.11,126.08,123.51,121.84,119.94,119.16,110.97,39.77,21.04.HRMS(ESI-TOF)m/z[M+Na]+:336.4313,found:336.4311.
实施例21:
将1mmol2-氟苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入10mgTLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。30h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为99%,m.p.:221℃-222℃;1H NMR(300MHz,Chloroform-d)δ7.93(s,2H),7.38(dd,J=13.0,8.1Hz,4H),7.24–7.13(m,4H),7.09(d,J=9.6Hz,1H),7.00(q,J=6.9,6.1Hz,3H),6.73(s,2H),6.23(s,1H).HRMS(ESI-TOF)m/z[M+Na]+:340.3921,found:340.3930.
实施例22:
将1mmol4-氯苯甲醛和2mmol2-甲基吲哚,加入10mL反应瓶中,然后加入10mgTLIM,5mL水,35℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。32h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为93%,m.p.:162℃-163℃;1H NMR(300MHz,Chloroform-d)δ7.78(s,2H),7.28(s,2H),7.24(d,J=8.9Hz,4H),7.07(t,J=7.4Hz,2H),7.00(d,J=7.8Hz,2H),6.94–6.86(m,2H),5.98(s,1H),2.07(s,6H).13C NMR(75MHz,Chloroform-d)δ135.03,131.80,130.40,129.34,128.17,120.74,119.18,112.86,109.99,104.56,38.74,12.41.HRMS(ESI-TOF)m/z[M+Na]+:384.1400,found:384.1389.
实施例23:
将10mmol4-氯苯甲醛和20mmol吲哚,加入10mL反应瓶中,然后加入10mgTLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。32h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为94%,m.p.:76℃-77℃;1H NMR(400MHz,Chloroform-d)δ7.92(s,2H),7.35(dd,J=8.1,2.7Hz,4H),7.29–7.21(m,4H),7.20–7.12(m,2H),7.10–6.91(m,2H),6.62(dd,J=2.4,1.0Hz,2H),5.85(s,1H).HRMS(ESI-TOF)m/z[M+Na]+:356.8511,found:356.8514.
实施例24:
将1mmol4-氯苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入30mg已使用过1次的脂肪酶TLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。48h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为92%,m.p.:76℃-77℃;1H NMR(400MHz,Chloroform-d)δ7.92(s,2H),7.35(dd,J=8.1,2.7Hz,4H),7.29–7.21(m,4H),7.20–7.12(m,2H),7.10–6.91(m,2H),6.62(dd,J=2.4,1.0Hz,2H),5.85(s,1H).HRMS(ESI-TOF)m/z[M+Na]+:356.8511,found:356.8514.
实施例25:
将1mmol4-氯苯甲醛和2mmol吲哚,加入10mL反应瓶中,然后加入50mg已使用过4次的脂肪酶TLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。48h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为86%,m.p.:76℃-77℃;1H NMR(400MHz,Chloroform-d)δ7.92(s,2H),7.35(dd,J=8.1,2.7Hz,4H),7.29–7.21(m,4H),7.20–7.12(m,2H),7.10–6.91(m,2H),6.62(dd,J=2.4,1.0Hz,2H),5.85(s,1H).HRMS(ESI-TOF)m/z[M+Na]+:356.8511,found:356.8514.
实施例26:
将1mmol乙醛和2mmol吲哚,加入10mL反应瓶中,然后加入10mg脂肪酶TLIM,5mL水,55℃下搅拌反应,TLC(石油醚/乙酸乙酯,3/1,v/v)监测反应进程。72h后,过滤回收水,滤渣加1,4-环氧六环溶解并过滤回收酶,滤液减压旋蒸回收1,4-环氧六环,滤渣过柱分离获得纯化的目标产物,目标产物为红色固体,收率为80%,m.p.:232℃-234℃;1H NMR(400MHz,Chloroform-d)δ11.14(s,2H),7.59(dd,J=7.6,1.5Hz,2H),7.33(dd,J=7.3,1.5Hz,2H),7.21(s,2H),7.06(td,J=7.5,1.5Hz,2H),6.98(td,J=7.5,1.7Hz,2H),4.86(q,J=6.9Hz,1H),1.60(d,J=6.8Hz,3H).HRMS(ESI-TOF)m/z[M+Na]+:260.3421,found:260.3413.
实施例27
表1.酶源对产物收率的影响
a反应条件:酶(10mg),4-氯苯甲醛(1mmol),吲哚(2mmol),水(5mL),55℃,36h.
b液相收率.
c在丙酮中处理24h得到失活的TLIM.
脂肪酶TLIM催化吲哚与醛的反应,可获得较高收率的产物(93%),脂肪酶RMIM,CRL,PPL,BCL和Novozym435在该反应体系下的催化效果却不明显。非脂肪酶类如木瓜蛋白酶和牛血清蛋白在该反应体系下催化效果也不明显。变性的脂肪酶对该反应只有7%的催化效果。
表2.溶剂种类对产物收率的影响
a反应条件:TLIM(50mg),4-氯苯甲醛(1mmol),吲哚(2mmol),溶剂(5mL),45℃,18h.
b液相收率.
有文献报道ɑ-糜蛋白酶被用于乙醇水溶液(含水70%)中催化吲哚和芳香醛的反应,在我们的反应体系中,脂肪酶TLIM在乙醇中却完全没有催化效果。脂肪酶TLIM在纯水相中的催化效果明显高于乙醇。
表3.酶量和反应时间对产物收率的影响
a反应条件:TLIM,4-氯苯甲醛(1mmol),吲哚(2mmol),水(5mL),55℃.
b液相收率
传统酶催化反应需要较高的酶量。比如150mg/mmol醛(来自Amino acids,2013,45:937-945),200mg/mmol醛(Eur.J.Org.Chem,2017,31:4571-4579)。本发明的优选酶量为10mg/mmol醛,远低于一般酶催化反应所需的酶量。
表4.TLIM催化的不同双吲哚类化合物
a反应条件:TLIM(10mg),醛(1mmol),吲哚(2mmol),水(5mL),55℃.
b液相收率.
c分离收率.
d反应条件:TLIM(100mg),4-氯苯甲醛(10mmol),吲哚(20mmol),水(50mL),55℃,液相收率.
e 3a的液相收率(TLIM重复使用一次).
f 3a的液相收率(TLIM重复使用两次)
g 3a的液相收率(TLIM重复使用三次)
h 3a的液相收率(TLIM重复使用四次)
i 3a的液相收率(TLIM重复使用五次)
现有技术中吲哚与醛类的级联反应基本都以化学催化的方法进行,酶法催化合成双吲哚类化合物鲜有研究吲哚与杂环醛的反应,而且吲哚与含有推电子基的芳香醛(产物收率50%-87%)或脂肪醛(产物收率20%-38%)反应时,产物收率较低,且催化剂不可回收利用。本发明中脂肪酶TLIM催化芳香醛(产物收率85%-99%),杂环醛(产物收率89%)或脂肪醛(产物收率80%-87%)与吲哚类化合物经过级联反应制备双吲哚类化合物的方法,产物收率高且催化剂可回收利用。脂肪酶使用五次后,仍可催化该反应获得86%收率的产物。
本发明的不局限于上述实施例所述的具体技术方案,凡采用等同替换形成的技术方案均为本发明要求的保护范围。
Claims (10)
1.一种脂肪酶催化合成双吲哚类化合物的方法,其特征在于:包括以式1吲哚类化合物为底物,利用脂肪酶TLIM来自疏棉状嗜热丝孢菌的脂肪酶催化进行亲电取代级联反应与式II化合物生成式III双吲哚类化合物,反应方程式为:
其中,R1为H,Cl,Me,OMe中的一种;
R2为H或Me;
Ar为4-ClC6H4,2-NO2C6H4,3-NO2C6H4,4-NO2C6H4,4-OHC6H4,2-OHC6H4,4-CNC6H4,2-FC6H4,C6H5,4-MeC6H4,4-OMeC6H4,2-OH-3-OMeC6H3,4-OH-3-OMe,2,6-Cl2C6H3,4-t-C4H9C6H4,2-SC4H3,2-NC5H4,CH3,C5H11,C3H7中的一种;
所述反应的溶剂为水。
2.根据权利要求1所述脂肪酶催化合成双吲哚类化合物的方法,其特征在于:所述所述的式II化合物和式Ⅰ化合物的摩尔比为1:0.5-4。
3.根据权利要求1所述脂肪酶催化合成双吲哚类化合物的方法,其特征在于:所述的脂肪酶在所述反应中总体积浓度为c,其中0<c≤30mg/mL。
4.根据权利要求1所述脂肪酶催化合成双吲哚类化合物的方法,其特征在于:所述反应的反应温度为25-65℃。
5.根据权利要求1所述脂肪酶催化合成双吲哚类化合物的方法,其特征在于:所述反应的反应时间为2-72h。
6.根据权利要求1所述脂肪酶催化合成双吲哚类化合物的方法,其特征在于:所述所述的式II化合物和式Ⅰ化合物的摩尔比为1:2,所述的脂肪酶在所述反应中总体积为2mg/mL,所述反应的反应温度为为55℃。
7.根据权利要求1所述脂肪酶催化合成双吲哚类化合物的方法,其特征在于:包括如下步骤:将脂肪酶加入式II化合物和式Ⅰ化合物的混合溶液中,催化反应生成双吲哚类化合物。
8.根据权利要求7所述脂肪酶催化合成双吲哚类化合物的方法,其特征在于:还包括反应完毕后过滤并回收溶剂或回收酶的步骤。
9.根据权利要求8所述脂肪酶催化合成双吲哚类化合物的方法,其特征在于:所述的回收酶包括:过滤反应体系,向滤渣中加入1,4-环氧六环溶解并过滤回收酶。
10.根据权利要求9所述脂肪酶催化合成双吲哚类化合物的方法,其特征在于:所述脂肪酶催化合成双吲哚类化合物的方法,还包括反应完毕的后处理步骤,包括:
(1)将反应完毕后的反应混合液过滤;
(2)滤渣中加入1,4-环氧六环,之后过滤回收酶;
(3)将步骤(2)得到的滤液蒸除溶剂,所余固体产物过柱分离即得目标产物。
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