CN114685298A - 一种基于光催化迁移策略合成巴氯芬的方法 - Google Patents
一种基于光催化迁移策略合成巴氯芬的方法 Download PDFInfo
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- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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Abstract
本发明公开了一种基于光催化迁移策略合成巴氯芬的方法,该方法包括:步骤(1):4‑氯苯甲酰甲酸甲酯和乙烯基格式试剂通过亲核加成反应制得中间体1;步骤(2):将步骤(1)所得中间体1和吡啶盐通过光催化反应制得巴氯芬;其中,光催化反应参数包括:中间体1、吡啶盐和光催化剂的摩尔比为1~3:1~5:0.001~0.05。本发明利用了光催化苯基迁移策略来实现巴氯芬核心骨架的构筑,进一步合成巴氯芬,从而解决条件苛刻、步骤繁琐等缺点。
Description
技术领域
本发明涉及药物合成及光催化技术领域,具体涉及到一种基于光催化迁移策略合成巴氯芬的方法。
背景技术
可见光催化是一种以绿色、安全、廉价、丰富且可再生的太阳能为驱动力的有机合成技术,是当前有机合成化学中非常活跃的研究领域之一。在过去的几十年里,可见光介导的光氧化还原催化已经发展成为一种强大而温和的工具,通过独特的单电子转移或能量转移途径,在温和的条件下构筑新的化学键。自由基重排反应是一种基于自由基中间体的重排反应,可用于构筑一些用传统化学手段难以合成的化学键。近几年,随着光氧化还原催化技术的不断反应,光催化自由基重排反应也受到越来越多科学家的重视。然而,利用光催化自由基重排反应来合成上市药物的例子相对较少。
目前,关于巴氯芬的合成方法之一,合成路线如图1所示,其包括:以对氯苯甲醛和丙二酸为主要初始原料,吡啶作为溶剂哌啶催化下经Knoevenagel-Doebner反应得到对氯肉桂酸(中间体2),再在硫酸氢钾催化下与甲醇进行酯化得到对氯肉桂酸酸甲酯(中间体3),然后与硝基甲烷在-78-0℃下经Michael加成得到3-硝基甲基对氯肉桂酸甲酯(中间体4),再经水解得到3-硝基甲基-3-对氯苯基丙酸(中间体5),最后经催化氢化及成盐制得盐酸巴氯芬。该方法中Knoevenagel-Doebner反应采用吡啶作为反应溶剂,哌啶作为催化剂,试剂气味较大,且具有一定的毒性,后处理相对麻烦,不符合绿色化学的要求。此外,路线较长,不符合步骤经济性。
另一巴氯芬的合成方法,合成路线如图2所示,其包括:以对氯苯甲醛和硝基甲烷为主要起始原料,在醇钠催化下得到β-硝基对氯苯乙烯(中间体6),再与丙二酸二乙酯经Michael加成得到中间体7,经催化氢化还原、脱羧、酸化成盐后即得到盐酸巴氯芬。该路线中温度调节较为苛刻,工业上难度较大,成本较高。而且需要高压加氢,对设备要求较高,另外也实现了毒性较大且比较危险的硝基甲烷,环境污染严重。
发明内容
针对上述的不足,本发明的目的是提供一种基于光催化迁移策略合成巴氯芬的方法,有效避免了大气味、高毒性试剂的使用;同时,也将光催化迁移策略有效的利用到药物合成中,对后续药物的合成具有实际的指导作用。
为达上述目的,本发明采取如下的技术方案:
本发明提供一种基于光催化迁移策略合成巴氯芬的方法,包括以下步骤:
步骤(1):4-氯苯甲酰甲酸甲酯和乙烯基格式试剂通过亲核加成反应制得中间体1;
步骤(2):将步骤(1)所得中间体1和吡啶盐通过光催化反应制得巴氯芬;其中,光催化反应参数包括:中间体1、吡啶盐和光催化剂的摩尔比为1~3:1~5:0.001~0.05。
进一步地,步骤(1)中亲核加成反应的具体步骤为:惰性气体氛围和0℃下,将乙烯基格式试剂滴加到4-氯苯甲酰甲酸甲酯溶液中,反应1~3小时后对反应体系分离纯化,制得中间体1;其中,4-氯苯甲酰甲酸甲酯和乙烯基格式试剂的摩尔比为1~2:1~2。
进一步地,4-氯苯甲酰甲酸甲酯和乙烯基格式试剂的摩尔比为1:1。
进一步地,中间体1、吡啶盐和光催化剂的摩尔比为1:1~5:0.01。
进一步地,步骤(2)中光催化剂优选为基于萘酰亚胺骨架的有机光催化剂,其结构式如下所示:
进一步地,步骤(2)中光催化反应参数还包括:有机碱和四甲基乙二胺;白光照射5~24小时,优选为12小时。
进一步地,步骤(2)中反应结束后对体系进行脱溶剂处理,无需进一步纯化。
进一步地,有机碱优选为DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯),其摩尔用量为中间体1的1~5倍,优选为3倍。
进一步地,四甲基乙二胺摩尔用量为中间体1的0.5~5倍,优选为1倍。
进一步地,综上所述,本发明具有以下优点:
1、本发明利用了光催化苯基迁移策略来实现巴氯芬核心骨架的构筑,进一步合成巴氯芬,从而解决条件苛刻、步骤繁琐等缺点。
2、本发明中基于光催化迁移策略合成巴氯芬的方法具有反应条件温和、成本低和反应收率高等特点。
附图说明
图1为巴氯芬的现有合成路线图一;
图2为巴氯芬的现有合成路线图二;
图3为本发明中巴氯芬的合成路线。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明,即所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。
因此,以下对提供的本发明的实施例的详细描述并非旨在限制要求保护的本发明的范围,而是仅仅表示本发明的选定实施例。基于本发明的实施例,本领域技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
合成光催化剂N-正丁基-4-咔唑-1,8-萘酰亚胺(NI-Cz,3a)
在50ml双口或单口圆底烧瓶中,加入碘化亚铜(3.68mmol),18-冠醚-6(0.1mmol),碳酸钾(11mmol),咔唑(2.8mmol)后再加入N,N-二甲基乙酰胺(DMA)(15ml),在氮气氛围中165℃加热搅拌2小时,之后加入N-正丁基-4-溴-1,8-萘酰亚胺(0.463g,1.4mmol),混合物加热回流16小时后,反应体系倒入150ml冰水中,使用乙酸乙酯萃取(25ml*3),合并有机相,使用无水硫酸钠干燥,之后将滤液真空旋干,通过快速柱层析纯化产物(PE/EA=20:1-10:1),最终得到黄色固体(3a)(43%yield),1H NMR(400MHz,CDCl3):δ8.79(d,J=7.72Hz,1H),δ8.67-8.65(m,1H),δ8.22-8.20(m,2H),δ7.91(d,J=7.72Hz,1H)δ7.79-7.77(m,1H)δ7.63-7.59(m,1H)δ7.39-7.34(m,4H)δ7.03-7.01(m,2H)δ4.27-4.23(m,2H)δ1.81-1.74(m,2H)δ1.54-1.45(m,2H)δ1.01(t,J=7.32Hz,3H);13C NMR(101MHz,CDCl3):δ163.9,163.5,141.7,140.2,131.9,131.5,130.0,129.6,127.6,127.3,126.3,123.7,123.4,122.8,120.6,120.5,109.9,40.4,30.2,29.6,20.4,13.8.
实施例2
本例提供一种基于光催化迁移策略合成巴氯芬的方法,其合成路线如图3所示,包括:
(1)在单口圆底烧瓶中,将4-氯苯甲酰甲酸甲酯(10mmol)溶解到无水四氢呋喃(25mL)中,进行氮气置换处理,然后降温至0摄氏度,将乙烯基格式试剂(10mmol)逐滴加入到体系中,反应2小时之后,用饱和氯化铵淬灭(体系无气泡、热量再放出为止),乙酸乙酯(5mL)萃取三次,混合的有机相用饱和食盐水洗,柱层析得到目标产物1;(注意:乙烯基格式试剂不要过量)
(2)称取0.1mmol的吡啶盐和光催化剂NI-Cz(1mol%,3a,实施例1所得)溶解到三氟乙醇(0.05M)中,然后将1(0.1mmol)、DBU(0.3mmol)、TMEDA(0.1mmol)依次加入,随后进行脱气处理,经白光照射12h完成反应,体系进行脱溶剂处理,无需进一步纯化;体系中分别加入碘化钠(2当量)、次磷酸的水溶液(40Wt%in H2O)和乙酸(0.1M),然后经回流过夜,反应之后的体系直接加入甲基磺酸(0.1M),在水中进行回流24h,过滤掉不溶性杂质,调节pH到6.5-7之间,得到巴氯芬,为白色固体
本例中巴氯芬的总收率为88%,产物巴氯芬的表征数据如下所示:1H NMR(Deuterium Oxide,600MHz):δ(ppm)7.3–7.3(m,2H),7.2–7.1(m,2H),3.2–3.1(m,2H),3.1(dd,J=12.6,10.0Hz,1H),2.5(dd,J=14.5,6.5Hz,1H),2.4–2.3(m,1H)。
实施例3
本例提供一种基于光催化迁移策略合成巴氯芬的方法,与实施例1的区别仅在于:光催化剂NI-Cz用量调整为0.5mol%,其余步骤及参数均相同。
本例中巴氯芬的总收率为78%。
实施例3
本例提供一种基于光催化迁移策略合成巴氯芬的方法,与实施例1的区别仅在于:光催化剂NI-Cz用量调整为2mol%,白光照射时长为8小时,其余步骤及参数均相同。
本例中巴氯芬的总收率为81%。
实施例4
本例提供一种基于光催化迁移策略合成巴氯芬的方法,与实施例1的区别仅在于:本例中未添加四甲基乙二胺,其余步骤及参数均相同。
本例中巴氯芬的总收率为51%。
实验例1
本例在实施例1的基础上,通过仅调整催化剂的类型来筛选不同光催化剂对巴氯芬的总收率的影响,结果如表1所示。
表1催化剂类型对反应的影响
实验例2
本例在实施例1的基础上,通过仅调整碱的类型来筛选不同光催化剂对巴氯芬的总收率的影响,结果如表2所示。
表2碱类型对反应的影响
以上内容仅仅是对本发明结构所作的举例和说明,所属本领域的技术人员不经创造性劳动即对所描述的具体实施例做的修改或补充或采用类似的方式替代仍属本专利的保护范围。
Claims (8)
1.一种基于光催化迁移策略合成巴氯芬的方法,其特征在于,包括以下步骤:
步骤(1):4-氯苯甲酰甲酸甲酯和乙烯基格式试剂通过亲核加成反应制得中间体1;
步骤(2):将步骤(1)所得中间体1和吡啶盐通过光催化反应制得巴氯芬;其中,光催化反应参数包括:中间体1、吡啶盐和光催化剂的摩尔比为1~3:1~5:0.001~0.05。
2.如权利要求1所述的基于光催化迁移策略合成巴氯芬的方法,其特征在于,所述步骤(1)中亲核加成反应的具体步骤为:惰性气体氛围和0℃下,将乙烯基格式试剂滴加到4-氯苯甲酰甲酸甲酯溶液中,反应1~3小时后对反应体系分离纯化,制得中间体1;其中,4-氯苯甲酰甲酸甲酯和乙烯基格式试剂的摩尔比为1~2:1~2。
3.如权利要求2所述的基于光催化迁移策略合成巴氯芬的方法,其特征在于,所述4-氯苯甲酰甲酸甲酯和乙烯基格式试剂的摩尔比为1:1。
4.如权利要求1所述的基于光催化迁移策略合成巴氯芬的方法,其特征在于,所述中间体1、吡啶盐和光催化剂的摩尔比为1:1~5:0.01。
5.如权利要求4所述的基于光催化迁移策略合成巴氯芬的方法,其特征在于,所述光催化剂为有机Ni光催化剂。
6.如权利要求4所述的基于光催化迁移策略合成巴氯芬的方法,其特征在于,所述光催化反应参数还包括:有机碱和四甲基乙二胺;白光照射5~24小时。
7.如权利要求6所述的基于光催化迁移策略合成巴氯芬的方法,其特征在于,所述有机碱为DBU。
8.如权利要求1所述的基于光催化迁移策略合成巴氯芬的方法,其特征在于,步骤(2)中反应结束后对体系进行脱溶剂处理,无需进一步纯化。
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