CN113651663B - 一种氘代芳香羰基类化合物的制备方法 - Google Patents

一种氘代芳香羰基类化合物的制备方法 Download PDF

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CN113651663B
CN113651663B CN202110959779.XA CN202110959779A CN113651663B CN 113651663 B CN113651663 B CN 113651663B CN 202110959779 A CN202110959779 A CN 202110959779A CN 113651663 B CN113651663 B CN 113651663B
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高章华
江之江
吴涛
孔俊华
陈佳
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Abstract

本发明公开了一种氘代芳香羰基类化合物的制备方法，以式2所示的芳香羰基衍生物为原料，在惰性气氛保护下，经催化体系作用与氘源试剂发生氘代反应，反应产物经过分离提纯，获得式1所示的芳香羰基衍生物邻位氘代产物。本发明通过一步合成完成氘代，具有安全、绿色、廉价的特点。

Description

一种氘代芳香羰基类化合物的制备方法
技术领域
本发明涉及有机合成技术领域，特别涉及一种氘代芳香羰基类化合物的制备方法。
背景技术
随着对含氘有机物认识的增加，含氘有机物变得越来越重要。在核磁检测中，氘代试剂如CDCl3，氘代DMSO等可以用于避免普通溶剂的氢原子的干扰，从而可以准确地分析出有机分子的氢元素比例；由于氘的质量相对较大，碳氘键比碳氢键更为稳定，所以在药物以及功能材料等方面的氘代研究逐渐发展起来。
芳香羰基衍生物是一种重要的有机化合物，是有机合成的核心砌块之一，通过它可以实现一系列官能团衍生化，因此以氘代的芳香醛为底物可进一步衍生出一系列氘代有机化合物。芳香羰基衍生物在功能材料、医药以及石油化工等方面有着广泛应用。如包含酸酐、酰胺及酰亚胺官能团的芳基衍生物作为光电材料时，由于其较好的迁移率，是一种理想的n-型半导体。而且具有多变的构象和良好的生物活性，还具有独特的形成共振结构的能力，使其在酸性、碱性、高温以及其它化学物质的存在下都表现出很高的稳定性。所以是常见的中间体。
目前芳香羰基衍生物的芳香环上的氘代研究仍处于起步阶段，多数氘代芳香羰基衍生物采用化学手段进行制备，且多以经典的有机反应为基础从全氘代苯出发经多步骤的反应制备，反应较为繁杂；近年来，过渡金属对芳香环上的氢氘交换反应的催化有Ru、Rh、Ir、Pd等过渡金属，比如钌配体催化时在NaH2PO4作为助剂时在高温时对芳香羰基衍生物的芳香环上的氘代有不错的效果。铑配体在NaOAc作为助剂条件下也可以在芳香环上进行氘代；铱配体在氘气条件下有不错的氘代效果；而Pd催化剂是实际工艺中最为常见且催化机制最为稳定的贵金属催化剂，开发相应的方法具有较好的可操作性和稳定性，催化效率高，产物易分离等特点。
发明内容
本发明的目的在于提供一种氘代芳香羰基类化合物的制备方法，该方法以活泼性氘试剂为氘源，在合适的配体进行邻位活化的基础上，在酸性环境下完成芳香羰基衍生物邻位氘代产物的生成，具有可操作性高、氘代效果好的优点。
本发明解决其技术问题所采用的技术方案是：
一种氘代芳香羰基类化合物的制备方法，以式2所示的芳香羰基衍生物为原料，在惰性气氛保护下，经催化体系作用与氘源试剂发生氘代反应，反应产物经过分离提纯，获得式1所示的芳香羰基衍生物邻位氘代产物；所述催化体系包括钯催化剂、配体和助剂；
作为优选，所述R1基团选自氢原子，甲基，乙基，正丙基，异丙基，叔丁基，苯基，取代苯基，羟基，氨基，二甲氨基中的一种。
作为优选，所述R2基团选自苯基，取代苯基，1-萘基，2-萘基，2-噻吩基，9-菲基，2-苯并噻吩基，4-咔唑基，3-吡啶基，3-喹啉基中的一种。
作为优选，所述取代苯基的取代基选自氢原子，氟原子，氯原子，溴原子，甲基，乙基，异丙基，叔丁基，异戊基，苯基，硝基，甲磺酰基，氰基，甲氧基，苯氧基，乙二醚，二氟甲二醚，二氟甲氧基，吗啉基，二甲基氨基，二苯基氨基中的一种或多种。
作为优选，所述氘源试剂选自重水、氘代乙酸、氘代三氟乙酸中的一种或多种。
作为优选，所述惰性气氛为由氮气或氩气所构成的气体环境。
作为优选，所述钯催化剂选自醋酸钯、氯化钯、三氟甲磺酸钯、溴化钯中的一种或多种。
作为优选，所述配体为式3所述的氨基酸，其中R1为氢原子、甲基、乙基、正丙基、异丙基、叔丁基、苯基、苄基、羟基、氨基中的一种；R2为氢原子、甲基、乙基、正丙基、异丙基、叔丁基、苯基、苄基、羟基、氨基中的一种；
作为优选，所述助剂包括无机氧化剂、有机醇和有机强酸，其中无机氧化剂为三氟乙酸银、三氟甲磺酸银、碳酸银、三氟甲磺酸铜、三氟乙酸铜、乙酸亚铜、三氟乙酸钾、三氟乙酸钠中的一种；有机醇为六氟异丙醇、三氯乙醇、三氟乙醇中的一种；有机强酸为三氟甲磺酸、三氟乙酸、甲磺酸、KMD酸中的一种。
作为优选，反应中各物料的摩尔用量比为芳香羰基类化合物：氘源试剂：钯催化剂：配体：无机氧化剂：有机醇：有机强酸＝1：10-500：0.01-0.10：0.01-0.30：0.5-1.5：5.0-12.0：0.5-6.0。
本发明的有益效果是：在常规条件下即可完成，一锅法反应无需中途替换溶剂，且反应可操作性高，氘代效果好；工艺方法普适性好，可用于多种芳香羰基衍生物氘代产物的制备；具有安全、绿色、廉价的特点。
具体实施方式
下面通过具体实施例，对本发明的技术方案作进一步的具体说明。
本发明中，若非特指，所采用的原料和设备等均可从市场购得或是本领域常用的。下述实施例中的方法，如无特别说明，均为本领域的常规方法。
总实施方案
一种氘代芳香羰基类化合物的制备方法，以式2所示的芳香羰基衍生物为原料，在惰性气氛保护下，经催化体系作用与氘源试剂发生氘代反应，反应产物经过分离提纯，获得式1所示的芳香羰基衍生物邻位氘代产物；所述催化体系包括钯催化剂、配体和助剂；
所述R1基团选自氢原子，甲基，乙基，正丙基，异丙基，叔丁基，苯基，取代苯基，羟基，氨基，二甲氨基中的一种。所述R2基团选自苯基，取代苯基，1-萘基，2-萘基，2-噻吩基，9-菲基，2-苯并噻吩基，4-咔唑基，3-吡啶基，3-喹啉基中的一种。所述取代苯基的取代基选自氢原子，氟原子，氯原子，溴原子，甲基，乙基，异丙基，叔丁基，异戊基，苯基，硝基，甲磺酰基，氰基，甲氧基，苯氧基，乙二醚，二氟甲二醚，二氟甲氧基，吗啉基，二甲基氨基，二苯基氨基中的一种或多种。
所述氘源试剂选自重水、氘代乙酸、氘代三氟乙酸中的一种或多种。
所述惰性气氛为由氮气或氩气所构成的气体环境。
所述钯催化剂选自醋酸钯、氯化钯、三氟甲磺酸钯、溴化钯中的一种或多种。
所述配体为式3所述的氨基酸，其中R1为氢原子、甲基、乙基、正丙基、异丙基、叔丁基、苯基、苄基、羟基、氨基中的一种；
所述助剂为无机氧化剂、有机醇和有机强酸的组合，其中无机氧化剂为三氟乙酸银、三氟甲磺酸银、碳酸银、三氟甲磺酸铜、三氟乙酸铜、乙酸亚铜、三氟乙酸钾、三氟乙酸钠中的一种；有机醇为六氟异丙醇、三氯乙醇、三氟乙醇中的一种；有机强酸为三氟甲磺酸、三氟乙酸、甲磺酸、KMD酸中的一种。
反应中各物料的摩尔用量比为芳香羰基类化合物：氘源试剂：钯催化剂：配体：无机氧化剂：有机醇：有机强酸＝1：10-500：0.01-0.10：0.01-0.30：0.5-1.5：5.0-12.0：0.5-6.0。
具体实施方案
实施例1对叔丁基苯甲醛邻位氘代产物的合成
于15mL干燥的封管中，依次加入叔亮氨酸20mol％(26.2mg)，三氟乙酸银1.0eq(220.8mg)，醋酸钯6mol％(13.5mg)，对叔丁基苯甲醛1mmol，HFIP:TFA＝19:1(v/v，1mL)，D2O(99.9％，3mL)，在氮气气氛中置于120℃下反应72h。反应结束后，依次加入4mL DCM,1mL1N HCl,2mL H2O，在室温下搅拌约1小时。
反应完成后，5mLDCM稀释，抽滤后用3mLDCM洗涤。滤液用水洗涤，DCM萃取，合并的滤液干燥，浓缩的得到粗产物。粗产物进行柱分离，湿法装柱。过柱分离后浓缩，后用油泵抽干得到。1H NMR(399MHz,Chloroform-d)δ9.98(s,1H),7.82(d,J＝8.6Hz,0.12H),7.55(s,2H),1.37(s,9H)；MS(EI)164.2。
同样条件下，从各取代的芳香羰基衍生物出发，在上述条件下得到式1所示的芳香羰基衍生物氘代产物，其结果如下表所示：
4-methyl benzaldehyde-2,6-d2(4-甲基苯甲醛-2,6-d2)(2-d).1H NMR(399MHz,Chloroform-d)δ9.96(s,1H),7.77(d,J＝8.2Hz,0.16H),7.33(s,2H),2.45(s,3H)；MS(EI)122.1.
4-ethyl benzaldehyde-2,6-d2(3-d).4-乙基苯甲醛
1H NMR(399MHz,Chloroform-d)δ9.97(s,1H),7.80(d,J＝8.3Hz,0.20H),7.36(s,2H),2.75(q,J＝7.6Hz,2H),1.29(t,J＝7.6Hz,3H)；MS(EI)136.1.
4-isopropyl benzaldehyde-2,6-d2(4-d)4-异丙基苯甲醛
1H NMR(399MHz,Chloroform-d)δ9.97(s,1H),7.81(d,J＝8.3Hz,0.23H),7.39(s,2H),3.00(hept,J＝6.8Hz,1H),1.30(d,J＝6.9Hz,6H)；MS(EI)150.2.
4-isobutyl benzaldehyde-2,6-d2(5-d).4-异丁基苯甲醛
1H NMR(399MHz,Chloroform-d)δ9.97(s,1H),7.79(d,J＝8.3Hz,0.16H),7.30(s,2H),2.57(d,J＝7.2Hz,2H),1.93(dp,J＝13.7,6.8Hz,1H),0.93(d,J＝6.6Hz,6H)；MS(EI)164.2.benzaldehyde-2,6-d2(6-d).苯甲醛1H NMR(399MHz,Chloroform-d)δ10.02(s,1H),7.88(dd,J＝8.1,1.4Hz,0.24H),7.64(dd,J＝7.9,6.9Hz,1H),7.58–7.49(m,2H)；MS(EI)108.1.
2-methyl benzaldehyde-6-d1(7-d).2-甲基苯甲醛1H NMR(399MHz,Chloroform-d)δ10.26(s,1H),7.80(dd,J＝7.6,1.5Hz,0.55H),7.48(td,J＝7.5,1.3Hz,1H),7.40–7.33(m,1H),7.26(d,J＝7.5Hz,1H),2.69(s,3H)；MS(EI)119.1,120.1,121.1.
2,3-dimethyl benzaldehyde-6-d1(8-d).2,3-二甲基苯甲醛1H NMR(399MHz,Chloroform-d)δ10.31(s,1H),7.68–7.63(m,0.39H),7.38(d,J＝7.5Hz,1H),7.29–7.23(m,1H),2.60(s,3H),2.36(s,3H)；MS(EI)134.1,135.1.
2,4-dimethyl benzaldehyde-6-d1(9-d).2,4-二甲基苯甲醛1H NMR(399MHz,Chloroform-d)δ10.19(s,1H),7.69(d,J＝7.8Hz,0.64H),7.16(dt,J＝4.4,1.7Hz,1H),7.07(s,1H),2.65(s,3H),2.40(s,3H)；MS(EI)133.1,134.1,135.1.
3-methyl benzaldehyde-2,6-d2(10-d).3-甲基苯甲醛1H NMR(399MHz,Chloroform-d)δ9.98(s,1H),7.70–7.68(s,0.14H),7.67(d,J＝2.3Hz,0.03H),7.47–7.40(m,2H),2.45(s,3H)；MS(EI)122.1.
3,4-dimethyl benzaldehyde-2,6-d2(11-d)3,4-二甲基苯甲醛1H NMR(399MHz,Chloroform-d)δ9.93(s,1H),7.64(s,0.13H),7.61(d,J＝7.7Hz,0.06H),7.29(s,1H),2.36(s,3H),2.35(s,3H)；MS(EI)136.1.
[1,1'-biphenyl]-3,5-d2-4-carbaldehyde(12-d).[1,1'-联苯]-3,5-d2-4-甲醛1H NMR(399MHz,Chloroform-d)δ10.06(s,1H),7.96(d,J＝8.4Hz,0.36H),7.76(s,2H),7.64(dd,J＝8.2,1.3Hz,2H),7.52–7.46(m,2H),7.45–7.40(m,1H)；MS(EI)183.1,184.1.
[1,1'-biphenyl]-2',3,6'-d3-2-carbaldehyde(13-d).[1,1'-联苯]-2',3,6'-d32-甲醛1H NMR(399MHz,Chloroform-d)δ9.98(d,J＝0.8Hz,1H),8.03(dd,J＝7.8,1.5Hz,0.07H),7.65(t,J＝7.5Hz,1H),7.53–7.41(m,5H),7.40–7.37(m,0.15H)；MS(EI)184.1,185.1.
[1,1'-biphenyl]-2,2',4,6'-d4-3-carbaldehyde(14-d).[1,1'-联苯]-2,2',4,6'-d4-3-甲醛1H NMR(399MHz,Chloroform-d)δ10.09(s,1H),8.11(d,J＝1.9Hz,0.80H),7.87(dd,J＝7.8,1.8Hz,0.99H),7.69–7.58(m,2.66H),7.48(t,J＝7.4Hz,2H),7.44–7.37(m,1H)；MS(EI)182.1,183.1.
2-fluorobenzaldehyde-6-d1(15-d).2-氟苯甲醛1H NMR(399MHz,Chloroform-d)δ10.36(s,1H),7.87(td,J＝7.4,1.9Hz,0.08H),7.61(dddd,J＝8.3,7.3,5.4,0.8Hz,1H),7.30–7.24(m,1H),7.21–7.14(m,1H)；MS(EI)125.1.
2-chlorobenzaldehyde-6-d1(16-d).2-氯苯甲醛1H NMR(399MHz,Chloroform-d)δ10.48(s,1H),7.92(dd,J＝7.8,1.8Hz,0.28H),7.53(ddd,J＝7.8,7.2,0.5Hz,1H),7.45(ddd,J＝8.1,1.3,0.5Hz,1H),7.42–7.36(m,1H)；MS(EI)140.1,142.1,143.1.
2-bromobenzaldehyde-6-d1(17-d).2-溴苯甲醛1H NMR(399MHz,Chloroform-d)δ10.35(d,J＝0.7Hz,1H),7.93–7.88(m,0.45H),7.68–7.62(m,1H),7.48–7.39(m,2H)；MS(EI)184.0,185.0,186.0.
4-fluorobenzaldehyde-2,6-d2(19-d).4-氟苯甲醛1H NMR(399MHz,Chloroform-d)δ9.96(s,1H),7.91(dd,J＝8.9,5.4Hz,0.98H),7.26–7.17(m,2H)；MS(EI)124.1,125.1.
4-chlorobenzaldehyde-2,6-d2(20-d).4-氯苯甲醛1H NMR(399MHz,Chloroform-d)δ9.98(s,1H),7.82(d,J＝8.6Hz,1.20H),7.55–7.49(m,2H)；MS(EI)140.1,141.1.
4-bromobenzaldehyde-2,6-d2(21-d).4-溴苯甲醛1H NMR(399MHz,Chloroform-d)δ9.97(s,1H),7.75(d,J＝8.5Hz,1.35H),7.71–7.66(m,2H)；MS(EI)183.9,184.9,185.9.
4-nitrobenzaldehyde-2,6-d2(22-d).4-硝基苯甲醛1H NMR(399MHz,Chloroform-d)δ10.14(s,1H),8.38(d,J＝8.5Hz,2H),8.06(d,J＝8.9Hz,1.48H)；MS(EI)151.1.
4-(methylsμLfonyl)benzaldehyde-2,6-d2(23-d).4-甲基磺酰基苯甲醛1H NMR(399MHz,Chloroform-d)δ10.12(s,1H),8.13(d,J＝8.1Hz,2H),8.08(d,J＝8.5Hz,1.56H),3.11(s,3H)；MS(EI)184.1,185.1.
2-chloro-3-fluorobenzaldehyde-6-d1(27-d).2-氯-3-氟苯甲醛1H NMR(399MHz,Chloroform-d)δ10.46(d,J＝0.7Hz,1H),7.75–7.72(m,0.21H),7.43–7.35(m,2H)；MS(EI)158.0.
2-methoxy benzaldehyde-6-d1(28-d).2-甲氧基苯甲醛1H NMR(399MHz,Chloroform-d)δ10.45(d,J＝0.7Hz,1H),7.82(dd,J＝7.6,1.9Hz,0.06H),7.54(dd,J＝8.4,7.3Hz,1H),7.02(d,J＝7.3Hz,1H),6.98(d,J＝8.4Hz,1H),3.93(s,3H)；MS(EI)137.1.
4-methoxy benzaldehyde-2,6-d2(29-d).4-甲氧基苯甲醛1H NMR(399MHz,Chloroform-d)δ9.88(s,1H),7.83(d,J＝8.9Hz,0.66H),7.00(s,2H),3.90(s,3H)；MS(EI)137.1,138.1.
3-methoxy benzaldehyde-2,6-d2(30-d).3-甲氧基苯甲醛1H NMR(399MHz,Chloroform-d)δ9.97(s,1H),7.47–7.41(m,1.04H),7.39(d,J＝2.8Hz,0.06H),7.18(d,J＝8.2Hz,1H),3.88(s,3H)；MS(EI)138.1.
4-phenoxy benzaldehyde-2,6-d2(31-d).4-苯氧基苯甲醛1H NMR(399MHz,Chloroform-d)δ9.92(s,1H),7.84(d,J＝9.0Hz,0.50H),7.41(dd,J＝8.5,7.4Hz,2H),7.23(tt,J＝7.1,1.1Hz,1H),7.09(dd,J＝8.6,1.1Hz,2H),7.06(s,2H)；MS(EI)199.1,200.1.
4-(difluoromethoxy)benzaldehyde-2,6-d2(32-d).4-二氟甲氧基苯甲醛1H NMR(399MHz,Chloroform-d)δ9.96(s,1H),7.90(d,J＝8.8Hz,1.12H),7.27–7.23(m,2H),6.62(t,J＝72.6Hz,1H)；MS(EI)171.1,172.1,173.1,174.1.
2,3-dihydrobenzo[b][1,4]dioxine-5,7-d2-6-carbaldehyde 2,3-二氢苯并[b][1,4]二恶英-5,7-d2-6-甲醛(33-d).1H NMR(399MHz,Chloroform-d)δ9.81(s,1H),7.40(t,J＝4.1Hz,0.10H),6.98(s,1H),4.36–4.32(m,2H),4.32–4.28(m,2H)；MS(EI)166.1.
2,2-difluorobenzo[d][1,3]dioxole-4,6-d2-5-carbaldehyde 2,2-二氟苯并[d][1,3]二恶英-4,6-d2-5-甲醛(34-d).1H NMR(399MHz,Chloroform-d)δ9.91(s,1H),7.67(dd,J＝8.1,1.3Hz,0.78H),7.61(d,J＝1.3Hz,0.61H),7.23(d,J＝8.1Hz,1H)；MS(EI)185.1,186.1,187.1.
4-morpholino benzaldehyde-2,3,5,6-d4(35-d).4-吗啉基苯甲醛1H NMR(399MHz,Chloroform-d)δ9.78(s,1H),7.76(s,1.73H),6.91(d,J＝9.2Hz,0.11H),3.88–3.83(m,4H),3.37–3.32(m,4H)；MS(EI)193.2.
4-(dimethylamino)benzaldehyde-2,3,5,6-d4(36-d).4-二甲氨基苯甲醛1H NMR(399MHz,Chloroform-d)δ9.73(s,1H),7.73(s,1.72H),6.70(d,J＝9.2Hz,0.11H),3.10(s,6H)；MS(EI)150.2,151.2.
4-(bis(phenyl-2,4,6-d3)amino)benzaldehyde-2,3,5,6-d4(37-d).4-(双(苯基-2,4,6-d3)氨基)苯甲醛-2,3,5,6-d4 1H NMR(399MHz,Chloroform-d)δ9.80(s,1H),7.68(s,1.75H),7.34(s,4H),7.18(d,J＝8.5Hz,1.17H),7.02(d,J＝9.0Hz,0.41H)；MS(EI)279.2,280.2,281.2.
2-methoxy-1-naphthaldehyde-8-d1(39-d).2-甲氧基-1-萘甲醛1H NMR(399MHz,Chloroform-d)δ10.89(s,1H),9.27(dq,J＝8.7,0.8Hz,0.92H),8.06(d,J＝9.1Hz,1H),7.80–7.75(m,1H),7.62(ddd,J＝8.6,6.8,1.4Hz,1H),7.42(ddd,J＝8.0,6.8,1.1Hz,1H),7.29(d,J＝9.1Hz,1H),4.06(s,3H)；MS(EI)185.1,186.1,187.1.
2-naphthaldehyde-1,3-d2(41-d).2-萘甲醛1H NMR(399MHz,Chloroform-d)δ10.16(s,1H),8.34(s,0.40H),8.01(dd,J＝8.0,0.9Hz,1H),7.96(d,J＝8.5Hz,0.10H),7.93(s,1H),7.91(dd,J＝7.9,0.7Hz,1H),7.65(ddd,J＝8.2,6.9,1.4Hz,1H),7.59(ddd,J＝8.1,6.9,1.4Hz,1H)；MS(EI)157.1,158.1.
benzo[b]thiophene-3-d1-2-carbaldehyde(42-d)苯并噻吩-3-d1-2-甲醛1H NMR(399MHz,Chloroform-d)δ10.10(d,J＝1.0Hz,1H),8.02(d,J＝0.8Hz,0.45H),7.97–7.91(m,1H),7.89(dt,J＝8.1,1.0Hz,1H),7.50(ddd,J＝8.2,7.1,1.3Hz,1H),7.43(ddd,J＝8.1,7.1,1.1Hz,1H)；MS(EI)162.1,163.1.
thiophene-2,4,5-d3-3-carbaldehyde(43-d).噻吩-2,4,5-d3-3-苯甲醛1H NMR(399MHz,Chloroform-d)δ9.92(s,1H),8.12(dd,J＝2.9,1.2Hz,0.37H),7.56–7.53(m,0.89H),7.38(ddd,J＝5.1,2.9,0.8Hz,1H)；MS(EI)112.1,113.1,114.1.
9-ethyl-9H-carbazole-2,4,6,8-d4-3-carbaldehyde(46-d).9-乙基-9H-咔唑-2,4,6,8-d4-3-脲醛1H NMR(399MHz,Chloroform-d)δ10.08(s,1H),8.60(s,0.17H),8.15(s,1H),8.00(d,J＝8.4Hz,0.07H),7.57–7.50(m,1H),7.46(d,J＝8.3Hz,1.31H),7.32(t,J＝7.5Hz,0.10H),4.41(q,J＝7.2Hz,2H),1.48(t,J＝7.2Hz,3H)；MS(EI)226.2,227.2.
1-(phenyl-2,6-d2)ethan-1-one(47-d).1-(苯基-2,6-d2)乙烷-1-酮1H NMR(399MHz,Chloroform-d)δ7.98–7.94(m,1.61H),7.59–7.54(m,1H),7.50–7.43(m,2H),2.59(p,J＝2.2Hz,0.17H)；MS(EI)123.2.
10,10-dimethylanthracen-9(10H)-one-1,8-d2(48-d).10,10-二甲基蒽-9-酮-1,8-d2 1H NMR(399MHz,Chloroform-d)1H NMR(399MHz,Chloroform-d)δ8.36(ddd,J＝7.8,1.5,0.6Hz,1.21H),7.70(dd,J＝8.0,1.4Hz,2H),7.67–7.62(m,2H),7.46–7.41(m,2H),1.76(s,6H)；MS(EI)222.1,223.1,224.1。
实施例2邻硝基苯甲醛邻位氘代产物的合成
方法同实施例1，不同之处是将120℃换为150℃，氘代度为40％，产率为78％。
同样条件下，从各取代的芳香羰基化合物出发，从上述条件下得到式1所示的芳香羰基化合物氘代产物，其结果如下表所示：
化合物编号 氘代度(％) 产率(％)
18-d 40 78
24-d 35 25
25-d 40 48
26-d 26 74
。
2-nitrobenzaldehyde-6-d1(18-d).2-硝基苯甲醛1H NMR(399MHz,Chloroform-d)δ10.41(s,1H),8.11(dd,J＝7.9,1.1Hz,1H),7.95(dd,J＝7.4,1.7Hz,0.72H),7.82–7.73(m,2H)；MS(EI)131.1,132.1.
4-formyl benzonitrile-3,5-d2(24-d).4-甲酰基苯甲腈1H NMR(399MHz,Chloroform-d)δ10.09(s,1H),7.99(d,J＝8.4Hz,1.38H),7.88–7.82(m,2H)；MS(EI)130.1,131.1,132.1.
4-(trifluoromethyl)benzaldehyde-2,6-d2(25-d).4-三氟甲基苯甲醛1H NMR(399MHz,Chloroform-d)δ10.10(s,1H),8.01(d,J＝8.0Hz,1.30H),7.81(dd,J＝5.7,2.6Hz,2H)；MS(EI)173.1,174.1,175.1.
3-nitrobenzaldehyde-6-d1(26-d).3-硝基苯甲醛1H NMR(399MHz,Chloroform-d)δ10.12(s,1H),8.71(ddd,J＝2.2,1.4,0.5Hz,1H),8.49(ddd,J＝8.2,2.3,1.1Hz,1H),8.23(dt,J＝7.6,1.3Hz,0.76H),7.80–7.73(m,1H)；MS(EI)150.1,151.1,152.1。
实施例3 1-萘甲醛邻位氘代产物的合成
方法同实施例1，不同之处是将120℃换为150℃，HFIP:TFA＝19:1(v/v,2mL)氘代度为32％，产率为92％。
同样条件下，从联苯类、杂环类、萘环类芳香醛化合物出发，从上述条件下得到化合物1(式1所示的氘代产物)，其结果如下表所示：
化合物编号 氘代度(％) 产率(％)
38-d 32 92
40-d 40 83
。
1-naphthaldehyde-8-d1(38-d).1-萘甲醛1H NMR(399MHz,Chloroform-d)δ10.40(s,1H),9.25(dd,J＝8.5,1.1Hz,0.67H),8.10(dt,J＝8.2,1.0Hz,1H),7.99(dd,J＝7.0,1.4Hz,1H),7.93(dt,J＝8.1,1.0Hz,1H),7.70(ddd,J＝8.5,6.9,1.4Hz,1H),7.62(ddd,J＝13.7,8.2,7.0Hz,2H)；MS(EI)155.1,156.1,157.1.
phenanthrene-8-d1-9-carbaldehyde(40-d).菲-8-d1-9-甲醛1H NMR(399MHz,Chloroform-d)δ10.37(s,1H),9.39–9.34(m,0.60H),8.73–8.69(m,1H),8.69–8.65(m,1H),8.24(s,1H),8.03(dd,J＝7.9,1.4Hz,1H),7.81(ddd,J＝8.4,7.0,1.4Hz,1H),7.77–7.70(m,2H),7.67(ddd,J＝8.0,7.0,1.1Hz,1H)；MS(EI)206.1,207.1。
以上所述的实施例只是本发明的一种较佳的方案，并非对本发明作任何形式上的限制，在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。

Claims (3)

1.一种氘代芳香羰基类化合物的制备方法，其特征在于，以式2所示的芳香羰基衍生物为原料，在惰性气氛保护下，经催化体系作用与氘源试剂发生氘代反应，反应产物经过分离提纯，获得式1所示的芳香羰基衍生物邻位氘代产物；所述催化体系包括钯催化剂、配体和助剂；
所述R1基团选自氢原子，甲基，乙基中的一种；
所述R2基团选自氢原子，氟原子，氯原子，溴原子，甲基，乙基，异丙基，叔丁基，异戊基，苯基，硝基，甲磺酰基，氰基，甲氧基，苯氧基，乙二醚，二氟甲二醚，二氟甲氧基，吗啉基，二甲基氨基，二苯基氨基中的一种或多种；
所述钯催化剂选自醋酸钯、氯化钯、三氟甲磺酸钯、溴化钯中的一种或多种；
所述配体为叔亮氨酸；
所述助剂包括无机氧化剂、有机醇和有机强酸，其中无机氧化剂为三氟乙酸银、三氟甲磺酸银、碳酸银中的一种；有机醇为六氟异丙醇、三氯乙醇、三氟乙醇中的一种；有机强酸为三氟甲磺酸、三氟乙酸、甲磺酸、KMD酸中的一种；
反应中各物料的摩尔用量比为芳香羰基衍生物：氘源试剂：钯催化剂：配体：无机氧化剂：有机醇：有机强酸 = 1：10-500：0.01-0.10：0.01-0.30：0.5-1.5：5.0-12.0：0.5-6.0。
2.根据权利要求1所述的制备方法，其特征在于，所述氘源试剂选自重水、氘代乙酸、氘代三氟乙酸中的一种或多种。
3.根据权利要求1所述的制备方法，其特征在于，所述惰性气氛为由氮气或氩气所构成的气体环境。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007023135A1 (en) * 2005-08-22 2007-03-01 Nycomed Gmbh Isotopically substituted benzimidazole derivatives
CN104341425A (zh) * 2013-08-08 2015-02-11 上海医药集团股份有限公司 氘代乙炔衍生物、其药物组合物及应用
CN107709333A (zh) * 2015-06-23 2018-02-16 法国施维雅药厂 新的羟基酯衍生物、其制备方法以及含有它们的药物组合物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX378389B (es) * 2015-04-29 2025-03-10 Janssen Pharmaceutica Nv Compuestos de bencimidazolona y benzotiazolona y su uso como moduladores del receptor ampa.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007023135A1 (en) * 2005-08-22 2007-03-01 Nycomed Gmbh Isotopically substituted benzimidazole derivatives
CN104341425A (zh) * 2013-08-08 2015-02-11 上海医药集团股份有限公司 氘代乙炔衍生物、其药物组合物及应用
CN107709333A (zh) * 2015-06-23 2018-02-16 法国施维雅药厂 新的羟基酯衍生物、其制备方法以及含有它们的药物组合物

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
H-D Exchange Dewteration of Arenes at Room Temperature;Yoshinari Sawama et al.;Org. Process Res. Dev.;第23卷(第4期);648-653 *
Ortho-Deuteration of Aromatic Aldehydes via a Transient Directing Group-Enabled Pd-Catalyzed Hydrogen Isotope Exchange;Junhua Kong et al.;The Journal of Organic Chemistry;第86卷(第19期);13350-13359 *
氘代Rigosertib类似物的合成;陈锞等;合成化学;第23卷(第6期);557-559 *

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