CN116425703B - 一种饱和环醚类化合物c2位环外甲基氘代的方法 - Google Patents

一种饱和环醚类化合物c2位环外甲基氘代的方法 Download PDF

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CN116425703B
CN116425703B CN202310304832.1A CN202310304832A CN116425703B CN 116425703 B CN116425703 B CN 116425703B CN 202310304832 A CN202310304832 A CN 202310304832A CN 116425703 B CN116425703 B CN 116425703B
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摆建飞
吴涛
高章华
江之江
唐剑波
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Ningbo Cuiying Chemical Technology Co ltd
Zhejiang University of Science and Technology ZUST
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Abstract

本发明公开了一种饱和环醚类化合物C2位环外甲基氘代的方法，以式Ⅰ所示的炔醇化合物为原料，在惰性气氛保护下，经催化体系作用，与亲核试剂反应生成四取代的氘代环醚化合物粗产物，粗产物经过分离提纯，获得式Ⅱ所示的饱和环醚类氘代产物；所述催化体系包括催化剂、溶剂和氘源。本发明具有底物耐受性好，适用于多种亲核试剂，且操作简单，氘代度高，分离简单，试剂环保友好的优点。

Description

一种饱和环醚类化合物C2位环外甲基氘代的方法
技术领域
本发明涉及氘代合成技术领域，特别涉及一种饱和环醚类化合物C2位环外甲基氘代的方法。
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；由于其在制药业、机理研究、化学分析和材料科学方面的重要性，氘标记的化合物已经受到了极大的关注。特别是在药物化学领域，在药物的活性部位用氘取代氢后会影响药物的吸收、分布、代谢和排泄，这些在20世纪70年代和80年代被科学家们认识到，并在21世纪初应用于药物，由于其独特的优势，现在正成为新药开发的一个热门领域。
饱和含氧杂环是生物活性天然产物和药物中普遍存在的核心结构，此外，神奇的甲基效应已经在药物化学中被广泛观察到，因此，如何实现饱和环醚化合物的环外甲基的氘化是非常有意义的。其氘代的饱和环醚化合物可以作为氘代砌块合成各种具有生物活性的氘代化合物。
有两种传统方法，一种是直接通过HIE，另一种是通过化学合成。直接HIE被认为是快速获得氘代化合物的最直接的方法，但由于饱和共价分子的惰性，其挑战性极大。在过去的二十年里，人们一直在探索用过渡金属(包括钯、铱、铂)作为催化剂的直接HIE反应，但氘替代的结果是不尽如意。另一种使用氘代丁二醇作为原料进行成环反应的策略由于昂贵的氘代前体原料而无法大规模应用。到目前为止，使用过渡金属包括Ir、Pd、Ru、Au和Cu作为催化剂的直接化学合成反应已经被充分探索。
发明内容
本发明的目的在于提供一种饱和环醚类化合物C2位环外甲基氘代的方法，具有底物耐受性好，适用于多种亲核试剂，且操作简单，氘代度高，分离简单，试剂环保友好的优点。
本发明解决其技术问题所采用的技术方案是：
一种饱和环醚类化合物C2位环外甲基氘代的方法，
以式Ⅰ所示的炔醇化合物为原料，在惰性气氛保护下，经催化体系作用，与亲核试剂反应生成四取代的氘代环醚化合物粗产物，粗产物经过分离提纯，获得式Ⅱ所示的饱和环醚类氘代产物；所述催化体系包括催化剂、溶剂和氘源。
本发明以活泼性氘试剂为氘源，在合适的催化剂基亲核试剂的作用下进行串联反应，首先是催化剂活化炔烃，导致羟基氧进攻炔基生成烯醇醚类化合物，然在酸性条件下发生双键的转移转化为环醚氧鎓离子中间体，接着与亲核试剂加成得到目标成品。在双键转移的过程中，在质子氘源存在的前提下实现环外甲基的氘代。
所述R选自氢、烷基(C1～C12)、烷氧基(OC1～OC12)、芳基(Ph-,4-MePh-,3-MePh-,2-MePh-,4-MeOPh-,4-EtPh-,4-ClPh-,3-ClPh-,2-ClPh-,4-BrPh-,4-FPh-,4-CNPh-,4-NO2Ph-等)、酯基(-CO2Me,-CO2Et,-CO2CH(CH3)2,-CO2Bn,等)、脂肪羟基(-CH2OH,-C2H4OH,-(CH3)2COH,-CH2(CH3)2COH,等)、炔基(PhC≡C-,CH3C≡C-,BnC≡C-,TMSC≡C-,等)中的一种或多种。R可以是同一位置的一个或多个取代，也可以是不同位置的多个取代。
所述氘源试剂选自重水、单氘代甲醇、单氘代乙醇、氘代丙酮中一种或两种。
所述惰性气氛为由氮气或氩气所构成的气体环境。
所述催化剂选自B(C6F5)3、氯化铜、溴化铜、三氟甲磺酸铜、碘、Tf2NH、三氟乙酸银、Bi(OTf)3、BiCl3、HgCl2、锌盐中的一种或多种。
氘源试剂优选重水，催化剂优选B(C6F5)3。本发明可以使用不同的重水用量来控制其氘代度，部分底物可以通过不同的催化剂用量来控制得到其5元或6元环状氘代化合物。路易斯酸B(C6F5)3价格低廉且耐水；使用重水直接作为氘源进行炔醇的关环反应时，同时实现环醚C2-位环外甲基的氘代，反应底物耐受性好，适用于多种亲核试剂，且操作简单，氘代度高，分离简单，试剂环保友好。
所述亲核试剂选自TMSCN、烯丙基TMS、呋喃、2-甲基呋喃、苯并呋喃、噻吩、2-甲基噻吩、苯并噻吩、N-甲基吡咯，N-苄基吡咯、N-甲基吲哚、吲哚、1-萘酚、1,3-二甲氧基苯中的一种。
Nu代表亲核试剂。Nu具体可优选：
所述溶剂选自甲苯、二甲苯、三甲苯、二氯甲烷、1,2-二氯乙烷，1,1,2,2-四氯乙烷、氯仿、环己烷中的一种或多种。
反应中各物料的摩尔用量比为炔醇化合物：氘源试剂：催化剂：亲核试剂：溶剂＝1.00：10-30：0.05-0.20：2.0-4.0：10-50。
反应温度控制为65-120℃，反应时间3-16小时。
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C2位环外氘代甲基四取代饱和环醚类化合物的制备；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。
实施例1：1a’-d的合成
于25mL干燥的Schlenk tube中，依次加入炔醇1a 0.3mmol(71mg)，催化剂20mol％B(C6F5)3(31mg)，溶剂DCE 2.5mL，重水180mg，TMSCN 0.9mmol(99mg)，在氮气气氛中置于85℃下反应3h。反应结束后，加入2mL碳酸氢钠饱和溶液，在室温下搅拌约1小时。
反应完成后，加入2.5mL DCM稀释，抽滤后用3mL DCM洗涤。DCM萃取，合并的滤液干燥，过滤，于25mL容量瓶中稀释至刻度线，然后用移液枪取用400μL于10mL容量瓶并用乙醇稀释至刻度线，然后取样检测HPLC，用外标法计算其收率93％。油相浓缩得到粗产物。粗产物进行柱分离，湿法装柱。过柱分离后浓缩，后用油泵抽干得到白色固体物质58mg，收率73％，氘代度89％。
NMR data for 1a’-d:1H NMR(400MHz,DMSO-d6)δ7.43(m,2H),7.34–7.27(m,6H),7.19(m,2H),4.67(dd,J＝9.4,1.0Hz,1H),4.47(d,J＝9.4Hz,1H),3.37–3.31(d,J＝13.5Hz,1H),2.85(d,J＝13.5Hz,1H),1.53(d,J＝7.1Hz,0.33H)。
实施例2：2a’-d的合成
于25mL干燥的Schlenk tube中，依次加入炔醇2a 0.3mmol(71mg)，催化剂20mol％的B(C6F5)3(31mg)，溶剂DCE 2.5mL，重水180mg，TMSCN 0.9mmol(99mg)，在氮气气氛中置于85℃下反应3h。反应结束后，加入2mL碳酸氢钠饱和溶液，在室温下搅拌约1小时。
反应完成后，加入2.5mL DCM稀释，抽滤后用3mL DCM洗涤。DCM萃取，合并的滤液干燥，过滤，于25mL容量瓶中稀释至刻度线，然后用移液枪取用400μL于10mL容量瓶并用乙醇稀释至刻度线，然后取样检测HPLC，用外标法计算其收率93％。油相浓缩的得到粗产物。粗产物进行柱分离，湿法装柱。过柱分离后浓缩，后用油泵抽干得到白色固体物质39mg，收率73％，氘代度88％。
NMR data for 2a’-d:1H NMR(400MHz,Chloroform-d)δ4.53(d,J＝9.9Hz,1H),4.36(d,J＝9.9Hz,1H),3.80(s,3H),3.78(s,3H),3.03(d,J＝13.9Hz,1H),2.63(d,J＝13.9Hz,1H),1.69(m,0.36H)。
实施例3：3a’-d的合成
于25mL干燥的Schlenk tube中，依次加入炔醇3a 0.3mmol(71mg)，催化剂20mol％的B(C6F5)3(31mg)，溶剂DCE 2.5mL，重水180mg，TMSCN 0.9mmol(99mg)，在氮气气氛中置于85℃下反应3h。反应结束后，加入2mL碳酸氢钠饱和溶液，在室温下搅拌约1小时。
反应完成后，加入2.5mL DCM稀释，抽滤后用3mL DCM洗涤。DCM萃取，合并的滤液干燥，过滤，于25mL容量瓶中并稀释至刻度线，然后用移液枪取用400μL于10mL容量瓶用乙醇稀释至刻度线，然后取样检测HPLC，用外标法计算其收率93％。油相浓缩的得到粗产物。粗产物进行柱分离，湿法装柱。过柱分离后浓缩，后用油泵抽干得到白色固体物质59mg，收率77％，氘代度92％。
NMR data for 3a’-d:1H NMR(400MHz,Chloroform-d)δ3.69(d,J＝3.4Hz,2H),2.27–2.25(m,1H),1.77–1.74(m,1H),1.65–1.60(m,0.24H),1.23(s,3H),1.13(s,3H)。
从各取代的炔醇衍生物出发，在上述条件下得到四取代饱和环醚类氘代产物，其结果如下表所示：
化合物编号 重水当量equiv. 反应时间h 氘代度(％D) 产率(％)
4a’-d 30 16 97 73
5a’-d 30 3 96 65
6a’-d 30 3 90 70
1b’-d 30 3 83 28
2b’-d 30 3 84 75
3b’-d 30 3 87 86
4b’-d 30 3 65 73
5b’-d 30 16 85 84
6b’-d 30 16 97 71
。
NMR data for 4a’-d:1H NMR(400MHz,Chloroform-d)δ7.36–7.20(m,8H),7.15–7.08(m,2H),3.88(d,J＝3.1Hz,2H),2.93(s,2H),2.74(s,2H),2.43(s,1H),1.93(s,1H),1.42–1.42(m,0.09H)。
NMR data for 5a’-d:1H NMR(400MHz,Chloroform-d)δ3.70(d,J＝1.3Hz,1H),2.84(dd,J＝16.7,2.7Hz,1H),2.64(d,J＝13.5Hz,1H),2.44(ddd,J＝16.7,2.6,1.1Hz,1H),1.95(t,J＝2.6Hz,1H),1.80(dt,J＝12.4,5.8Hz,1H),1.72–1.64(m,1H),1.64(s,1H),1.62(s,0.12H),1.58(dt,J＝12.7,6.0Hz,1H),1.44–1.37(m,1H),1.33–1.21(m,1H),1.02(s,3H),0.95(s,3H)。
NMR data for 6a’-d(two diastereomers):1H NMR(400MHz,Chloroform-d)δ8.10–7.96(m,2H),7.62–7.54(m,1H),7.46(td,J＝7.7,7.3,1.5Hz,2H),4.50(d,J＝11.3Hz,0.5H),4.44(d,J＝11.3Hz,0.5H),4.32(s,1H),4.08(d,J＝9.9Hz,0.5H),4.03(d,J＝9.8Hz,0.5H),4.00(d,J＝9.8Hz,0.5H),3.95(d,J＝9.9Hz,0.5H),2.63(d,J＝2.7Hz,1H),2.60–2.42(m,1.0H),2.12–1.92(m,1.0H),1.75–1.70(m,0.3H)。
NMR data for 1b’-d:1H NMR(400MHz,Chloroform-d)δ7.31–7.22(m,8H),7.16(ddt,J＝8.3,5.1,2.3Hz,2H),5.78(ddt,J＝17.3,10.2,7.3Hz,1H),5.09–4.91(m,2H),4.50(dd,J＝9.4,2.5Hz,1H),4.38–4.30(m,1H),2.70(d,J＝13.4Hz,1H),2.47(d,J＝12.6Hz,1H),2.29–2.07(m,2H),1.10–1.03(m,0.51H)。
NMR data for 2b’-d:1H NMR(400MHz,Chloroform-d)δ7.69–7.63(m,1H),7.43–7.38(m,2H),7.31(dd,J＝8.6,7.0Hz,2H),7.27–7.04(m,10H),6.87(s,0.56H),4.80(d,J＝9.2Hz,1H),4.30(d,J＝9.2Hz,1H),3.66(s,3H),3.27(s,1H),2.99(s,1H),1.50(d,J＝6.9Hz,0.48H)。
NMR data for 3b’-d:1H NMR(400MHz,Chloroform-d)δ7.40–7.33(m,2H),7.32–7.26(m,2H),7.26–7.12(m,6H),5.95(d,J＝3.1Hz,1H),5.79(d,J＝3.0Hz,1H),4.73(d,J＝9.2Hz,1H),4.28(d,J＝9.3Hz,1H),3.24(s,1H),2.68(s,1H),2.25–2.14(m,1.56H),1.37(t,J＝3.7Hz,0.39H)。
NMR data for 4b’-d:1H NMR(400MHz,Chloroform-d)δ7.37–7.31(m,2H),7.31–7.11(m,11H),7.07–6.99(m,2H),6.52(t,J＝2.5Hz,1H),6.45(t,J＝2.0Hz,1H),6.01(dd,J＝2.8,1.8Hz,1H),4.91(s,2H),4.62(d,J＝9.3Hz,1H),4.36(d,J＝9.2Hz,1H),3.11(d,J＝13.0Hz,1H),2.79(d,J＝12.4Hz,0.23H),1.41(d,J＝7.0Hz,0.69H)。
NMR data for 5b’-d:1H NMR(400MHz,Chloroform-d)δ7.55–7.43(m,3H),7.33(t,J＝7.7Hz,2H),7.23–7.16(m,3H),7.16–7.05(m,3H),6.49(d,J＝2.4Hz,0.71H),6.44(dd,J＝8.5,2.4Hz,0.26H),4.89(dd,J＝9.2,1.3Hz,1H),4.11(d,J＝9.2Hz,1H),3.85(s,3H),3.80(s,3H),3.09(d,J＝13.3Hz,1H),3.02(d,J＝13.4Hz,1H),1.35(s,1.05H)。
NMR data for 6b’-d:1H NMR(400MHz,Chloroform-d)δ7.41–7.25(m,4H),7.25–7.09(m,6H),6.60(d,J＝3.4Hz,1H),6.50(dd,J＝3.5,1.3Hz,1H),4.77(d,J＝9.4Hz,1H),4.29(d,J＝9.4Hz,1H),3.19(s,1H),2.87(s,1H),2.38(d,J＝1.1Hz,3H),1.47–1.37(m,0.09H)。
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)

1.一种饱和环醚类化合物C2位环外甲基氘代的方法，其特征在于，
以式Ⅰ所示的炔醇化合物为原料，在惰性气氛保护下，经催化体系作用，与亲核试剂反应生成四取代的氘代环醚化合物粗产物，粗产物经过分离提纯，获得式Ⅱ所示的饱和环醚类氘代产物；所述催化体系包括催化剂、溶剂和氘源；
所述氘源试剂为重水；
所述催化剂为B(C6F5)3；
所述亲核试剂为TMSCN；
所述溶剂为1,2-二氯乙烷；
饱和环醚类氘代产物具体为以下之一：
、/>、/>、/>、/>。
2.根据权利要求1所述的方法，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。
3.根据权利要求1所述的方法，其特征在于，反应温度控制为65-120℃，反应时间3-16小时。
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