CN112811981B - 一种羟基化合物及其氘代化合物的制备方法 - Google Patents
一种羟基化合物及其氘代化合物的制备方法 Download PDFInfo
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Abstract
本申请公开了一种化合物I的制备方法,包括含有碳氧双键的化合物II与水或氘水的反应体系,制备得到所述化合物I。该方法是在金属镁和烷基卤化物的存在下,由包括含有碳氧双键的化合物II与水或氘水反应制备得到。该方法首次以金属镁为还原剂,烷基卤化物为引发剂,实现了羰基化合物极性翻转,进一步被还原制备得到含羟基化合物及其含氘代化合物的核心骨架化合物I。
Description
技术领域
本申请涉及一种制备羟基化合物及其氘代化合物的制备方法,属于有机合成领域。
背景技术
目前通过羰基的还原是合成醇类化合物有以下几种常用方法:1:在铂、钯、镍等催化剂作用下,对羰基加氢还原成醇;2:用氢化锂铝或硼氢化钠进行还原;3:用乙硼烷对羰基进行还原;4:用活泼金属如钠、铝,镁和酸碱水醇等作用,将酮还原为醇。虽然这些合成策略非常实用,但利用廉价且当量的氢源作为还原试剂却仍然是非常具有挑战性且报道很少。
1931年Harold C.Urey发现了氢的同位素氘后,对于氘或含氘的化合物引发了科学家广泛的研究。含氘的药物和化合物与未氘代的化合物有着不同的生理活性;我们还可以通过氘代做很多机理实验,例如动力学同位素效应等。通过酮还原成醇制备氘代醇类化合物常用的方法为利用氘代还原剂如氘代硼氢化钠(NaBD4)、氘代硼氢化锂(LiBD4)和氘代氢化锂铝(LiAlD4)对羰基进行还原。此种方法氘代试剂昂贵;反应条件较为剧烈,许多官能团如烯烃,酯基等在体系中也可能被还原。因此发展简单廉价的反应体系,实现酮的还原,合成含氘的醇类化合物,对氘代化合物及具有生理活性的氘代醇类化合物具有重要的意义。
发明内容
根据本申请的一个方面,提供一种制备羟基化合物及其氘代化合物的制备方法。该方法是在金属镁和烷基卤化物的存在下,由包括含有碳氧双键的化合物II与水或氘水反应制备得到。该方法首次以金属镁为还原剂,烷基卤化物为引发剂,实现了羰基化合物极性翻转,进一步被还原制备得到含羟基化合物及其含氘代化合物的核心骨架化合物I。
所述化合物I的制备方法,其特征在于,包括含有碳氧双键的化合物II与水或氘水的反应体系,制备得到所述化合物I;
所述化合物I为含有式I所示结构单元的化合物中的至少一种;
所述含有碳氧双键的化合物II选自含有式II所示结构单元的化合物中的至少一种;
其中,A为H或D;
n独立地选自0、1、2、3或4;
R111、R112独立地选自芳基、取代芳基、杂芳基、取代杂芳基、芳基或杂芳基连接的羰基中的一种;
R121、R122独立地选自亚芳基、取代亚芳基、亚杂芳基、取代亚杂芳基中的一种。
可选地,R111、R112独立地选自C4~C10的芳基、卤素取代的C4~C10芳基、烷氧基取代的C4~C10的芳基、烷基取代的C4~C10的芳基、氰基取代的C4~C10的芳基、胺基取代的C4~C10的芳基、酰氧基取代的C4~C10的芳基、烯烃基取代的C4~C10的芳基、芳基取代的C4~C10的芳基、C4~C10的杂芳基、芳基连接的羰基中的一种;
R121、R122独立地选自C4~C10的亚芳基、卤素取代的C4~C10亚芳基、烷氧基取代的C4~C10的亚芳基、烷基取代的C4~C10的亚芳基、氰基取代的C4~C10的亚芳基、胺基取代的C4~C10的亚芳基、酰氧基取代的C4~C10的亚芳基、烯烃基取代的C4~C10的亚芳基、芳基取代的C4~C10的亚芳基、C4~C10的亚杂芳基中的一种;
可选地,R111、R112独立地选自C4~C10的亚芳基、卤素取代的C4~C10亚芳基、C1~C3的烷基取代的C4~C10的芳基、C1~C3的烷氧基取代的C4~C10的芳基、氰基取代的C4~C10的芳基、C1~C4的胺基取代的C4~C10的芳基、C1~C3的酰氧基取代的C4~C10的芳基、C1~C3的烯烃基取代的C4~C10的芳基、C4~C6的芳基取代的C4~C10的芳基、C4~C10的亚杂芳基中的一种。
可选地,R121、R122独立地选自C4~C10的亚芳基、卤素取代的C4~C10亚芳基、C1~C3的烷基取代的C4~C10的亚芳基、C1~C3的烷氧基取代的C4~C10的亚芳基、氰基取代的C4~C10的亚芳基、C1~C4的胺基取代的C4~C10的亚芳基、C1~C3的酰氧基取代的C4~C10的亚芳基、C1~C3的烯烃基取代的C4~C10的亚芳基、C4~C6的芳基取代的C4~C10的亚芳基、C4~C10的亚杂芳基中的一种。
可选地,R111、R112独立地选自式III所示的结构中的一种;
其中,m独立地选自1或2;
R411、R412、R413、R414、R415独立地选自H、卤素、酯基取代的烷氧基、烷基取代的C4~C10的芳基、烷氧基取代的C4~C10的芳基、氰基取代的C4~C10的芳基、胺基取代的C4~C10的芳基、酰氧基取代的C4~C10的芳基、烯烃基取代的C4~C10的芳基、芳基取代的C4~C10的芳基中的一种;
X11、X12、X13、X14、X15、X16独立地选自N、C中的一种;
R121、R122独立地选自,具有式IV所示的结构的化合物;
式V中,R511、R512、R513、R514独立地选自H、卤素中的一种;
X21、X22、X23、X24、X25、X26独立地选自N、C中的一种。
可选地,反应体系中还包括催化剂;
所述催化剂含有金属镁和烷基卤化物。
可选地,所述烷基卤化物选自烷基溴化物、烷基碘化物中的至少一种。
可选地,所述烷基卤化物选自1,2-二溴乙烷、溴丁烷中的至少一种。
本领域技术人员可根据实际需要,选择反应中各原料的比例;
优选地,所述含有碳氧双键的化合物II、水或氘水、烷基卤化物与金属镁的摩尔比例为:
含有碳氧双键的化合物II:水或氘水:烷基卤化物引发剂:金属镁=1:1~10:0.2~5:0.5~20。
优选地,所述含有碳氧双键的化合物II、水或氘水、烷基卤化物引发剂与金属镁的摩尔比例为:含有碳氧双键的化合物II:水或氘水:烷基卤化物引发剂:金属镁=1:2~8:0.4~4:1~10。
可选地,所述反应的反应温度为室温至90℃,反应时间为10min至10h。
可选地,所述反应的温度为50℃至70℃,反应时间为2h至4h。
可选地,所述反应的反应温度的上限选自室温、40℃、50℃、60℃、70℃、80℃或90℃,下限选自40℃、50℃、60℃、70℃或80℃。
可选地,所述反应时间的上限选自10min、1h、2h、3h、4h、5h、6h、7h、8h、9h或10h;下限选自10min、1h、2h、3h、4h、5h、6h、7h、8h或9h。
可选地,反应体系中还包括醚类溶剂;
所述醚类溶剂选自四氢呋喃、乙醚、乙二醇二甲醚、异丙醚中的至少一种。
优选地,所述的体系中的溶剂为四氢呋喃,乙醚。
可选地,所述含有碳氧双键的化合物II的摩尔数与醚类溶剂的体积比为1:1~4。
作为一种实施方式,所述的制备方法,至少包括以下步骤:
a)将含有金属镁、溶剂、烷基卤化物、含有碳氮双键的化合物II和水或氘水的反应体系置于反应容器中,于室温~90℃下搅拌30min~10小时后冷却至室温;
b)加入氯化铵饱和溶液淬灭,二氯甲烷或乙酸乙酯萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离,即得化合物I。
在本申请中,“C4~C10”等均是指基团中所包含的碳原子数。
在本申请中,“芳基”意指芳族化合物分子上失去芳环上的一个氢原子所形成的基团。此处,所述芳族化合物也涵盖芳环之间连接有烷基的基团。
在本申请中,“杂芳基”意指芳环中含有O、N、S杂原子的芳族化合物(简称杂芳化合物)分子上失去芳环上的一个氢原子所形成的基团。
在本申请中,“亚芳基”意指芳族化合物分子上失去芳环上的两个氢原子所形成的基团。此处,所述芳族化合物也涵盖芳环之间连接有烷基的基团。
在本申请中,“亚杂芳基”意指芳环中含有O、N、S杂原子的芳族化合物(简称杂芳化合物)分子上失去芳环上的两个氢原子所形成的基团。
本申请中,“取代芳基”是芳香族化合物芳香环上的氢原子被其它取代基取代,所形成的基团。
本申请中,所述“取代杂芳基”是芳香环中含有O、N、S杂原子的芳香族化合物(简称杂芳化合物)芳香环上的氢原子被其它取代基取代,所形成的基团。在本申请中,“卤素”是指氟、氯、溴、碘中的至少一种。
本申请中,“C1~C3的烷基取代的C4~C10的芳基”、“C1~C3的烷氧基取代的C4~C10的芳基”、“氰基取代的C4~C10的芳基”、“C1~C4的胺基取代的C4~C10的芳基”、“C1~C3的酰氧基取代的C4~C10的芳基”、“C1~C3的烯烃基取代的C4~C10的芳基”、“C4~C6的芳基取代的C4~C10的芳基”均为带有取代基的C4~C10的芳基;例如“C1~C3的烷基取代的C4~C10的芳基”为“C1~C3的烷基”取代的“C4~C10的芳基”,其中烷基的碳原子数为1~3,芳基的碳原子数为4~10。
本申请能产生的有益效果包括:
1)本申请所提供的方法,具有原料和催化剂廉价、反应条件温和、操作简单、反应高效等优点。
2)本申请所提供的方法,首次以金属镁为还原剂,烷基卤化物为引发剂,实现了羰基化合物极性翻转,进一步被还原得到羟基化合物及其含氘代化合物的核心骨架。
具体实施方式
下面结合实施例详述本申请,但本申请并不局限于这些实施例。
实施例中,核磁共振数据在布鲁克公司(Bruker)400AVANCEⅢ型或JEOL600分光仪(Spectrometer)上测定;产物分离采用Teledyne Isco的RF+UV-VIS型全自动快速制备色谱系统。
化合物I的产率,以含有羟基的化合物I的量为基准,通过以下公式计算得到:
产率%=(目标产物实际得到的质量÷目标产物理论上应得到的质量)×100%。
当使用氘水时,含有羟基的化合物I中氘代的比例,通过以下公式计算得到:
化合物I的氘代%=(1-化合物I中A位置上实际的氢原子个数÷化合物I中A位置全部为氢时的理论氢原子个数)×100%。
实施例1
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入70度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200ul,2.0eq.)。将二苯甲酮182mg(1.0mmol,1.0eq.),H2O 27mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在70度下搅拌2小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物1-2,共150.9mg,产率为82%。
产物样品1-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.40–7.29(m,8H),7.29–7.21(m,2H),5.80(d,J=3.1Hz,1H),2.36(d,J=3.4Hz,1H).13C NMR(101MHz,CDCl3)δ143.83,128.52,127.59,126.58,76.26.
实施例2
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入70度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将二苯甲酮182mg(1.0mmol,1.0eq.),D2O 30mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在70度下搅拌2小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物2-2,共154.4mg,产率为83%,>98%D。
产物样品2-2的核磁检测数据如下:
1H NMR(600MHz,CDCl3)δ7.40–7.32(m,8H),7.31–7.27(m,2H),5.80(S,0.02H),2.57(S,1H).13C NMR(151MHz,CDCl3)δ143.88,128.62,127.68,126.69,76.04,75.89,75.89(t,J=22.6Hz).
实施例3
新刨的镁屑240mg(10.0mmol,10.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。加入2mL四氢呋喃、1-溴丁烷(3.0mmol,322uL,3.0eq.)。将4-氟二苯甲酮200mg(1.0mmol,1.0eq.),H2O 54mg(3.0mmol,3.0eq.)溶于2mL四氢呋喃中,滴加到反应液中。在室温下搅拌10小时,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物3-2,共125.3mg,产率为62%。
产物样品3-2的核磁检测数据如下:
1H NMR(400MHz,Acetone-d6)δ7.46–7.38(m,4H),7.30(t,J=7.6Hz,2H),7.24–7.18(m,1H),7.09–7.02(m,2H),5.84(d,J=3.9Hz,1H),4.98(d,J=3.9Hz,1H).13C NMR(101MHz,Acetone-d6)δ162.97,160.56,145.39,141.77,141.73,128.33,128.25,128.15,126.94,126.38,114.76,114.55,74.53.19F NMR(376MHz,Acetone-d6)δ-117.69.
实施例4
新刨的镁屑168mg(7.0mmol,7.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入50度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(1.0mmol,100uL,1.0eq.)。将4-氟二苯甲酮200mg(1.0mmol,1.0eq.),D2O 40mg(2.0mmol,2.0eq.)溶于1mL四氢呋喃中,滴加到反应液中。在50度下搅拌4小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物4-2,共142.5mg,产率为70%,>99%D。
产物样品4-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.34–7.22(m,7H),6.98(t,J=8.7Hz,2H),2.56(s,1H).13C NMR(101MHz,CDCl3)δ162.18(d,J=245.7Hz),143.61,139.52(d,J=3.1Hz),128.63,128.27(d,J=8.1Hz),127.78,126.51,115.33(d,J=21.4Hz),75.16(t,J=22.2Hz).19FNMR(376MHz,CDCl3)δ-114.99.
实施例5
新刨的镁屑192mg(8.0mmol,7.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入50度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将5-1(4-氯二苯甲酮218mg,1.0mmol,1.0eq.),D2O 60mg(3.0mmol,3.0eq.)溶于1mL四氢呋喃中,滴加到反应液中。在50度下搅拌4小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物5-2,共164.3mg,产率为75%,>98%D。
产物样品5-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.34–7.20(m,9H),2.56(br,1H).13C NMR(100MHz,CDCl3)δ143.38,142.17,133.28,128.69,128.63,127.92,127.89,126.55,75.17(t,J=22.2Hz).
实施例6
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入30度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将6-1(207mg 1.0mmol,1.0eq.),D2O 30mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在30度下搅拌6小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物6-2,共105mg,产率为50%,>97%D。
产物样品5-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.58(d,J=8.3Hz,2H),7.48(d,J=8.3Hz,2H),7.37–7.26(m,5H),2.76(br,1H).13C NMR(100MHz,CDCl3)δ148.91,142.78,132.30,128.90,128.30,127.03,126.70,118.90,111.02,75.17(t,J=22.2Hz).
实施例7
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入50度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将7-1(240mg,1.0mmol,1.0eq.),D2O 30mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在50度下搅拌1小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物7-2,共170mg,产率为70%,>96%D。
产物样品7-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.99(d,J=8.3Hz,2H),7.46(d,J=8.4Hz,2H),7.35–7.23(m,5H),3.89(s,3H).13C NMR(100MHz,CDCl3)δ166.95,148.66,143.21,129.80,129.23,128.70,127.97,126.65,126.33,75.50(t,J=22.2Hz),52.13.
实施例8
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入70度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将8-1(208mg,1.0mmol,1.0eq.),D2O 30mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在70度下搅拌1小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物8-2,共121mg,产率为57%,>96%D。
产物样品8-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.38–7.21(m,9H),6.68(dd,J=17.6,10.9Hz,1H),5.72(d,J=17.6Hz,1H),5.22(d,J=10.9Hz,1H),2.37(br,1H).13C NMR(100MHz,CDCl3)δ143.67,143.33,136.93,136.46,128.55,127.64,126.74,126.55,126.37,113.97,75.61(t,J=22.2Hz).
实施例9
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入70度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将9-1(196mg,1.0mmol,1.0eq.),D2O 30mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在70度下搅拌2小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物9-2,共158mg,产率为79%,>99%D。
产物样品9-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.37–7.26(m,4H),7.25–7.17(m,3H),7.11(d,J=7.9Hz,2H),2.45(br,1H),2.30(s,3H).13C NMR(100MHz,CDCl3)δ143.97,140.97,137.30,129.24,128.51,127.50,126.60,126.52,75.66(t,J=22.2Hz),21.21.
实施例10
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入70度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将10-1(258mg,1.0mmol,1.0eq.),D2O 30mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在70度下搅拌2小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物10-2,共225mg,产率为89%,>98%D。
产物样品10-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.56–7.50(m,4H),7.43–7.35(m,6H),7.35–7.28(m,3H),7.28–7.22(m,1H),2.54(br,1H).13C NMR(100MHz,CDCl3)δ143.77,142.85,140.84,140.51,128.87,128.65,127.73,127.40,127.33,127.17,127.07,126.64,75.64(t,J=23.2Hz).
实施例11
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入70度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将11-1(212mg,1.0mmol,1.0eq.),D2O 30mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在70度下搅拌2小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物11-2,共177mg,产率为82%,>98%D。
产物样品11-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.35–7.28(m,4H),7.26–7.20(m,3H),6.83(d,J=8.6Hz,2H),3.74(s,3H),2.51(br,1H).13C NMR(100MHz,CDCl3)δ159.01,144.03,136.18,128.48,127.96,127.46,126.45,113.89,75.35(t,J=22.2Hz),55.31.
实施例12
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入70度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将12-1(225mg,1.0mmol,1.0eq.),D2O 30mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在70度下搅拌2小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物12-2,共110mg,产率为48%,>89%D。
产物样品12-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.38(d,J=7.3Hz,2H),7.32(t,J=7.5Hz,2H),7.27–7.15(m,3H),6.68(d,J=8.7Hz,2H),5.76(s,0.11H,CHOH of the undeuterated compound),2.92(s,6H),2.18(br,1H).13C NMR(100MHz,CDCl3)δ150.17,144.25,131.96,128.34,127.77,127.18,126.37,112.53,75.98(CHOH of undeuterated compound),75.56,(t,J=22.2Hz),40.66.
实施例13
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入70度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将13-1(232mg,1.0mmol,1.0eq.),D2O 30mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在70度下搅拌2小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物13-2,共172mg,产率为73%,>98%D。
产物样品13-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.80–7.68(m,4H),7.47–7.40(m,2H),7.38–7.33(m,3H),7.32–7.20(m,3H),2.65(br,1H).13C NMR(100MHz,CDCl3)δ143.63,141.14,133.30,132.93,128.61,128.40,128.17,127.77,127.73,126.78,126.27,126.05,125.09,124.86,75.94(t,J=22.2Hz).
实施例14
新刨的镁屑72mg(7.0mmol,7.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入60度的加热器中搅拌,加入1mL乙醚、1,2-二溴乙烷(1.0mmol,100uL,1.0eq.)。将14-1化合物183mg(1.0mmol,1.0eq.),D2O 40mg(2.0mmol,2.0eq.)溶于1mL乙醚中,滴加到反应液中。在50度下搅拌6小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=5/1-1/1),得到目标产物14-2,共93mg,产率为50%,87%D。
产物样品14-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ8.54(d,J=4.6Hz,1H),7.60(td,J=7.7,1.4Hz,1H),7.44–7.21(m,5H),7.20–7.05(m,2H),5.75(s,0.13H),5.35(broad,1H).13C NMR(101MHz,CDCl3)δ160.87,147.87,143.18,136.91,128.61,127.86,127.07,122.49,121.39,75.02,74.61(t,J=22.2Hz).
实施例15
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入40度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将15-1化合物180mg(1.0mmol,1.0eq.),D2O 24mg(1.2mmol,1.2eq.)溶于1mL四氢呋喃中,滴加到反应液中。在40度下搅拌1小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物15-2,共128.3mg,产率为70%,>97%D。
产物样品15-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.60(dd,J=10.8,7.5Hz,4H),7.36(t,J=7.2Hz,2H),7.29(t,J=7.3Hz,2H),5.49(d,J=9.8Hz,0H),2.05(s,1H).13C NMR(101MHz,CDCl3)δ145.60,140.04,129.09,127.83,125.18,119.99,74.83(t,J=23.2Hz).
实施例16
新刨的镁屑240mg(10.0mmol,10.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入80度的加热器中搅拌,加入2mL四氢呋喃、1,2-二溴乙烷(4.0mmol,400uL,4.0eq.)。将16-1化合物210mg(1.0mmol,1.0eq.),D2O 60mg(3.0mmol,3.0eq.)溶于2mL四氢呋喃中,滴加到反应液中。在80度下搅拌3小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物16-2,共106.7mg,产率为50%,>98%D。
产物样品16-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.91(d,J=7.4Hz,2H),7.51(t,J=7.4Hz,1H),7.33(tt,J=21.8,7.3Hz,7H),5.98(s,0.02H),4.57(s,1H).13C NMR(101MHz,CDCl3)δ198.98,138.95,133.98,133.45,129.18,128.73,128.62,127.78,75.81(t,J=23.2Hz).
实施例17
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入40度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(2.0mmol,200uL,2.0eq.)。将17-1化合物360mg(1.0mmol,1.0eq.),D2O 30mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在40度下搅拌30min,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=10/1-2/1),得到目标产物17-2,共90.8mg,产率为25%,>97%D。
产物样品17-2的核磁检测数据如下:
1H NMR(400MHz,CDCl3)δ7.29(s,4H),7.18(d,J=8.8Hz,2H),6.80(d,J=8.7Hz,2H),5.75(s,0.03H),5.06(p,J=6.3Hz,1H),2.26(s,1H),1.57(s,6H),1.20(d,J=6.3Hz,6H).13C NMR(151MHz,CDCl3)δ173.77,155.26,142.31,136.88,133.23,128.61,127.90,127.57,118.96,79.20,74.80(t,J=2 1.1Hz),69.11,25.43,21.64.
实施例18
新刨的镁屑120mg(5.0mmol,5.0eq.)加入到带有搅拌子的schlenk tube,在抽真空状态下用加热枪加热,冷却,氮气置换;循环三次。将反应管放入70度的加热器中搅拌,加入1mL四氢呋喃、1,2-二溴乙烷(0.2mmol,13uL,0.2eq.)。将二苯甲酮182mg(1.0mmol,1.0eq.),H2O 27mg(1.5mmol,1.5eq.)溶于1mL四氢呋喃中,滴加到反应液中。在70度下搅拌2小时,冷却至室温,用10mL饱和氯化胺溶液淬灭,二氯甲烷萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离(PE/EA=20/1-3/1),得到目标产物18-2,共92mg,产率为50%。
产物样品18-2的核磁检测数据详见1-2。
以上所述,仅是本申请的几个实施例,并非对本申请做任何形式的限制,虽然本申请以较佳实施例揭示如上,然而并非用以限制本申请,任何熟悉本专业的技术人员,在不脱离本申请技术方案的范围内,利用上述揭示的技术内容做出些许的变动或修饰均等同于等效实施案例,均属于技术方案范围内。
Claims (12)
1.一种化合物I的制备方法,其特征在于,包括含有碳氧双键的化合物II与水或氘水的反应体系,制备得到所述化合物I;
所述化合物I为含有式I所示结构单元的化合物中的至少一种;
所述含有碳氧双键的化合物II选自含有式II所示结构单元的化合物中的至少一种;
其中,A为H或D;
n独立地选自0、1、2、3或4;
R111、R112独立地选自C4~C10的芳基、卤素取代的C4~C10芳基、烷氧基取代的C4~C10的芳基、烷基取代的C4~C10的芳基、氰基取代的C4~C10的芳基、胺基取代的C4~C10的芳基、酰氧基取代的C4~C10的芳基、烯烃基取代的C4~C10的芳基、芳基取代的C4~C10的芳基、C4~C10的杂芳基中的一种;
R121、R122独立地选自C4~C10的亚芳基、卤素取代的C4~C10亚芳基、烷氧基取代的C4~C10的亚芳基、烷基取代的C4~C10的亚芳基、氰基取代的C4~C10的亚芳基、胺基取代的C4~C10的亚芳基、酰氧基取代的C4~C10的亚芳基、烯烃基取代的C4~C10的亚芳基、芳基取代的C4~C10的亚芳基、C4~C10的亚杂芳基中的一种;
所述反应体系中还包括催化剂和引发剂;
所述催化剂为金属镁;
所述引发剂为烷基卤化物;
所述烷基卤化物选自烷基溴化物、烷基碘化物中的至少一种。
6.根据权利要求1或5中任一项所述的制备方法,其特征在于,所述烷基卤化物选自1,2-二溴乙烷、溴丁烷、CH3I中的至少一种。
7.根据权利要求6所述的制备方法,其特征在于,所述含有碳氧双键的化合物II、水或氘水、烷基卤化物与金属镁的摩尔比例为:
含有碳氧双键的化合物II:水或氘水:烷基卤化物:金属镁=1:1~10:0.2~5:0.5~20。
8.根据权利要求1或5中任一项所述的制备方法,其特征在于,所述反应的反应温度为室温至90℃,反应时间为10min至10h。
9.根据权利要求8所述的制备方法,其特征在于,所述反应的温度为50℃至70℃,反应时间为2h至4h。
10.根据权利要求1或5中任一项所述的制备方法,其特征在于,反应体系中还包括醚类溶剂;
所述醚类溶剂选自四氢呋喃、乙醚、乙二醇二甲醚、异丙醚中的至少一种。
11.根据权利要求9所述的制备方法,其特征在于,所述含有碳氧双键的化合物II的摩尔数与醚类溶剂的体积比为1:1~4。
12.根据权利要求1或5中任一项所述的制备方法,其特征在于,至少包括以下步骤:
a)将含有金属镁、溶剂、烷基卤化物、含有碳氧双键的化合物II和水或氘水的反应体系置于反应容器中,于室温~90℃下搅拌30min~10小时后冷却至室温;
b)加入氯化铵饱和溶液淬灭,二氯甲烷或乙酸乙酯萃取,无水硫酸镁干燥,过滤,经减压蒸馏除去溶剂、柱色谱分离,即得化合物I。
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