CN117447311A - 一种脂肪醇二氟甲基醚化反应方法及其应用 - Google Patents
一种脂肪醇二氟甲基醚化反应方法及其应用 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 61
- 238000006266 etherification reaction Methods 0.000 title claims abstract description 46
- -1 alkyl difluoromethyl ether compounds Chemical class 0.000 claims abstract description 62
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
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- 150000002191 fatty alcohols Chemical class 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
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- IOCGMLSHRBHNCM-UHFFFAOYSA-N difluoromethoxy(difluoro)methane Chemical class FC(F)OC(F)F IOCGMLSHRBHNCM-UHFFFAOYSA-N 0.000 claims description 4
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- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/54—Radicals substituted by oxygen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
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- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
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Abstract
本发明公开了一种脂肪醇二氟甲基醚化反应方法及其应用,涉及烷基二氟甲基醚类化合物的合成技术领域。一种脂肪醇二氟甲基醚化反应方法,将脂肪醇类化合物和二氟甲基试剂,在溶剂中发生醚化反应,制得脂肪醇二氟甲基醚类化合物;所述的二氟甲基试剂的结构式如下:本发明能够在不添加任何催化剂、引发剂、活化剂、添加剂或碱的情况下,仅简单的将脂肪醇类化合物和二氟甲基试剂在溶剂中室温搅拌即可进行高效的二氟甲基醚化反应,方法简便,过程简单,绿色环保、成本低、反应高效,经济实用。
Description
技术领域
本发明涉及烷基二氟甲基醚类化合物的合成技术领域,尤其涉及一种脂肪醇二氟甲基醚化反应方法及其应用。
背景技术
二氟甲基砌块的引入可以赋予化合物特殊的物理、化学及生物特性,往往可以有效提高化合物的生物活性和靶点特异性,这使得它在创新药物设计中有非常重要的作用。所以向有机小分子引入二氟甲基基团,是进行药物结构修饰、改造,获得潜在药物分子的重要方法和途径。尤其是二氟甲氧基砌块(OCF2H)常常出现在药物分子中,如酶抑制剂/激动剂、抗菌药及麻醉剂等。
二氟甲氧基(OCF2H)的强吸电子特性可以减少药物分子的电子密度,从而减少药物分子被体内细胞色素P450酶氧化代谢的可能性,延长了药物的半衰期。另外,OCF2H基团中的质子作为氢键给体,可以提高药物分子与靶点的亲和力和选择性,从而提高药物的药理活性和特异性。近几年来,多种具有抗病毒活性、激酶抑制活性的烷基二氟甲基醚类化合物申请了化合物专利。如T细胞激活剂A【WO2020006018 A1】,RORγ拮抗剂B【WO2020011147A1】,抗乙肝病毒(HBV)化合物C【WO2020086533 A1】和D【WO2019086142 A1】,激酶抑制剂E【WO2019074962A1】和F【WO 2019147782 A1】,抗HIV G【WO 2019209667 A1】和H【EP3305789A1】,MCL-1抑制剂I【US2019352271A1】等。
二氟甲基醚类化合物在自然界和天然产物中从未有发现过,目前其唯一的获取途径是人工合成。但是,由于环境友好、稳定高效的二氟甲基试剂的缺乏,目前二氟甲基醚类化合物的有效合成方法不多,尽管报道了一些方法,但是由于氟化试剂及其氟化方法本身固有的缺陷,大多都存在效率不高,产率较低、普适性差、浪费较大、污染比严重等诸多问题。如氟利昂R22气体(HCF2Cl),使用量大,效率低下,破坏臭氧层(ODS),环境危害性大。所以,发展便捷高效、环境友好的绿色合成方法显得尤为重要,具有较高的学术意义和应用价值。而且,目前已有的方法绝大部分是用于(硫)酚的O-二氟甲基化制备芳基二氟甲基(硫)醚类化合物。而由脂肪醇的O-二氟甲基化反应制备烷基二氟甲基(硫)醚方法仍非常缺乏。
2016年,沈其龙小组使用二氟甲基硫叶立德作为二氟甲基试剂,对烷基醇进行了二氟甲基醚化【J.Zhu,Y.Liu and Q.Shen,Angew.Chem.,Int.Ed.,2016,55,9050.】。2017年,胡金波教授等使用Me3SiCF2Br作为二氟卡宾前体试剂,实现了对烷基醇进行了二氟甲基醚化【Q.Xie,C.Ni,R.Zhang,L.Li,J.Rong and J.Hu,Angew.Chem.,Int.Ed.,2017,56,3206.】。2016年Mykhailiuk等使用FSO2CF2COOH,报道了一种铜催化脂肪醇的二氟甲基醚化【Kostiantyn Levchenko,Olexandr P.Datsenko,Oleh Serhiichuk,Andrei Tolmachev,Viktor O.Iaroshenko,and Pavel K.Mykhailiuk,J.Org.Chem.2016,81,5803-5813】。2019年,公开的一种稳定S-(二氟甲基)二芳基硫鎓盐作为二氟卡宾前体试剂,实现了对脂肪醇的二氟甲基醚化衍生【G.K.Liu,X.Li,W.B.Qin,X.S.Peng,Henry.N.C.Wong,L.Zhang,X.Zhang,Chem.Commun.2019,55(52),7446-7449】。然而,这几种报道的方法需要加入多种过量的活化剂和/或碱,或者过量的氟化剂,或者需要过渡金属催化剂。
因此,发展一种更加绿色、经济和高效的脂肪醇的二氟甲基醚化方法尤为重要,具有较高的实用价值和广阔的应用前景。
发明内容
针对现有的脂肪醇二氟甲基醚化方法缺乏,且现有的二氟甲基醚化方法需要加入多种过量的活化剂和/或碱,或者过量的氟化剂,或者需要过渡金属催化剂,不够绿色、环保、经济的技术问题。
本发明旨在发明一种脂肪醇二氟甲基醚化反应方法,能够在不添加相转移催化剂的情况下,将脂肪醇类化合物和特殊的二氟甲基试剂在溶剂中进行醚化反应,反应过程不加入过量的活化剂和/或碱,无需过量的氟化剂、过渡金属催化剂,绿色环保、成本低、经济。
本发明的技术路线和方法是通过以下技术方案实现的:本发明提供一种脂肪醇二氟甲基醚化反应方法,将脂肪醇类化合物和二氟甲基试剂,在溶剂中发生醚化反应,制得脂肪醇二氟甲基醚类化合物;
所述的二氟甲基试剂的结构式如下:
优选的,所述溶剂选自乙酸乙酯、甲酸乙酯、乙腈、二氯甲烷、氯仿、四氢呋喃中的至少一种。更为优选的,所述溶剂为二氯甲烷。
优选的,所述醚化反应的反应温度为-30至80℃。更为优选的,所述醚化反应的反应温度为0-50℃。
优选的,所述醚化反应的反应时间为6-24h。
优选的,所述醚化反应中,加水。
本发明还提供上述的脂肪醇二氟甲基醚化反应方法在制备脂肪醇二氟甲基醚类化合物中的应用。
有益效果:
本发明采用特殊的二氟甲基试剂,与脂肪醇类化合物在溶剂中进行醚化反应,反应过程中无需加入任何催化剂,引发剂,活化剂,添加剂和/或碱,或者过量的氟化剂,同时该反应的产率高,;具有绿色、环保、经济、便捷、高效的特点。
附图说明
为了更清楚地说明本发明实施例技术方案,下面将对实施例描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明二氟甲基试剂的制备反应实施过程的示意图;
图2为本发明脂肪醇二氟甲基醚化反应方法的实施过程的示意图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动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。
应当理解,当在本说明书和所附权利要求书中使用时,术语“包括”和“包含”指示所描述特征、整体、步骤、操作、元素的存在,但并不排除一个或多个其它特征、整体、步骤、操作、元素和/或其集合的存在或添加。
还应当理解,在此本发明说明书中所使用的术语仅仅是出于描述特定实施例的目的而并不意在限制本发明。还应当进一步理解,在本发明说明书和所附权利要求书中使用的术语“和/或”是指相关联列出的项中的一个或多个的任何组合以及所有可能组合,并且包括这些组合。
一、二氟甲基试剂的合成
如图1,二氟甲基试剂的合成实施过程:
第一步:实施过程取一干燥的500mL圆底烧瓶,加入2-溴苯硫酚(5.7克,30.0毫摩尔,1.0当量),再加入100mL纯净水和100mL乙腈,加入适当大小搅拌子后,在零度情况下加入氢氧化钠(3.6克,90.0毫摩尔,3.0当量),10分钟后,再逐滴加入溴二氟甲基磷酸二乙酯(16.0克,60.0毫摩尔,2.0当量),反应过夜,完成反应后,用100mL石油醚与反应液萃取两次,收集石油醚,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到2-溴-二氟甲基苯硫醚[1-3]。
产物的谱图数据表征:
按照上述方法,制备得到下式化合物:
2-溴-二氟甲基苯硫醚
(2-bromophenyl)(difluoromethyl)sulfane
白色液体;Rf=0.8(石油醚);6.57克,92%的分离收率;1H-NMR(CDCl3):6.87(t,1H,JH-F=57.50Hz),7.20-7.26(m,1H),7.28-7.34(m,1H),7.60-7.68(m,2H).13C-NMR(CDCl3):120.6(t,J=277Hz),128.50,128.52,129.3,131.2,134.0,136.619F-NMR(CDCl3):-92.65(d,J=57.50Hz).
第二步:
实施过程:取一干燥的250mL圆底烧瓶,加入2-溴-二氟甲基苯硫醚(7.17克,30.0毫摩尔,1.0当量),再加入100mL二氯甲烷,在零度条件下,缓慢加入间氯过氧苯甲酸(5.2克,30.0毫摩尔,1.0当量),反应过夜,完成反应后,用100mL的饱和碳酸钠水溶液与反应液萃取两次,收集二氯甲烷相,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-((二氟甲基)亚砜基)-2-溴苯[4]。
按照上述方法,制备得到下式化合物:
1-((二氟甲基)亚砜基)-2-溴苯
1-((difluoromethyl)sulfinyl)-2-phenoxybenzen
白色固体;Rf=0.4(石油醚:乙酸乙酯=10:1);6.71克,88%的分离收率;1H NMR(400MHz,CDCl3)δ7.94(dd,J=7.9,1.6Hz,1H),7.72–7.62(m,2H),7.52(dd,J=7.6,1.6Hz,1H),6.36(s,1H).19F NMR(377MHz,CDCl3)δ-105.44–-130.57(m).
第三步:
实施过程取一干燥的100mL反应瓶,加入1-((二氟甲基)亚砜基)-2-溴苯(7.6克,30.0毫摩尔,1.0当量),再加入苯酚(5.6克,60.0毫摩尔,2.0当量),碘化亚铜(5.7克,30.0毫摩尔,1.0当量)和正丁基咪唑(3.7克,30.0毫摩尔,1.0当量),放入手套箱中,加入30毫升甲苯,密闭,取出,在150℃下反应12小时,完成反应后,用二氯甲烷50mL萃取反应液两次,收集二氯甲烷相,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-((二氟甲基)亚砜基)-2-苯氧基苯。
按照上述方法,制备得到下式化合物:
1-((二氟甲基)亚砜基)-2-苯氧基苯
1-((difluoromethyl)sulfinyl)-2-phenoxybenzen
淡黄色液体;Rf=0.3(石油醚:乙酸乙酯=10:1);6.67克,83%的分离收率;1HNMR(500MHz,CDCl3)δ7.93(dd,J=7.8,1.5Hz,1H),7.51–7.44(m,1H),7.41(t,J=7.7Hz,2H),7.35(t,J=7.6Hz,1H),7.23(t,J=7.5Hz,1H),7.09–7.05(m,2H),6.86(d,J=8.3Hz,1H),6.41(t,J=54.8Hz,1H).13C NMR(151MHz,CDCl3)δ155.03,154.81,133.77,130.27,126.83,125.24,124.05,120.35,120.32(t,J=293.9Hz),119.91,116.75.19F NMR(471MHz,CDCl3)δ-120.01(ddd,J=2688.0,252.6,54.5Hz).HRMS(ESI):m/z[M+H]+calcd forC14H10F2O2S+269.0403,found269.0440.
第四步:
实施过程;取一干燥的250mL圆底反应瓶,加入1-((二氟甲基)亚砜基)-2-苯氧基苯(24.1克,90.0毫摩尔,1.0当量),再加入90mL乙醚,在0℃情况下,逐滴加入三氟甲磺酸酐(25.6克,90.0毫摩尔,1当量),15分钟后,通过薄层色谱硅胶确认反应完全,反应完全后除去乙醚,加入100mL二氯甲烷溶解反应物,再用100mL四氟硼酸钠(1M)进行负离子交换4次,最后减压蒸馏二氯甲烷相至粘稠,在-10℃情况下逐滴加入乙醚,重结晶得到产物S-(二氟甲基)吩噁噻四氟硼酸盐。
按照上述方法,制备得到下式化合物:
S-(二氟甲基)吩噁噻四氟硼酸盐
Difluoromethyl Phenoxathiinium Tetrafluoroborate
淡黄色固体;25.25克,84%的重结晶收率;1H NMR(500MHz,CDCl3)δ8.23(dd,J=8.0,1.4Hz,2H),7.93(td,J=7.9,1.6Hz,2H),7.71–7.56(m,4H),7.56–7.34(t,1H).19F NMR(471MHz,CDCl3)δ-103.96(d,J=54.7Hz),-148.95(d,J=25.3Hz).13C NMR(101MHz,CDCl3)δ152.53,138.29,133.46,127.40,120.27,118.77(t,J=303.3Hz),95.72.HRMS(ESI):m/z[M-BF4]+calcd for C13H10F2OS+251.0337,found 251.0335.Melting point:97-99℃.
二、脂肪醇二氟甲基醚化反应方法
一种脂肪醇二氟甲基醚化反应方法,
将脂肪醇类化合物和二氟甲基试剂,在溶剂中发生醚化反应,制得脂肪醇二氟甲基醚类化合物;
所述的二氟甲基试剂的结构式如下:
溶剂选自乙酸乙酯、甲酸乙酯、乙腈、二氯甲烷、氯仿、四氢呋喃中的至少一种,优选为二氯甲烷。
醚化反应的反应温度为-30至80℃,优选的,反应温度为0-50℃,更为优选的为室温;醚化反应的反应时间为6-24小时,优选的,反应时间为10-18h,更为优选的为12h。
醚化反应过程中,还可加入相转移催化剂,所述催化剂选自20%Bu4NI、20%Bu4NBF4、20%Bu4NOTF中的至少一种(此处的“%”为摩尔百分含量)。
优选的,醚化反应中,加水。
且在醚化反应后,进行蒸馏、纯化,分离脂肪醇二氟甲基醚类化合物;纯化可为硅胶柱层析。
实施过程:
优化过程:
反应条件和参数:以2-(萘-1-基)-1-乙醇为模板底物(1aa),试剂1为二氟甲基试剂,反应条件是否加水,优选加水;反应条件是否添加相转移催化剂20%Bu4NI、20%Bu4NBF4、20%Bu4NOTF(其中,“%”为摩尔百分含量),优选不添加相转移催化剂;反应溶剂选用乙酸乙酯、甲酸乙酯、乙腈、二氯甲烷、氯仿、四氢呋喃中的至少一种,优选溶剂为二氯甲烷;反应温度为-30℃至80℃,优选0℃至50℃,更为优选的为室温条件;反应完成后(TLC监控),停止搅拌,减压蒸馏除去溶剂,粗品用硅胶柱层析纯化,得纯品1-(2-(二氟甲氧基)乙基)萘(3a)。
具体的,实施例1:取一干燥的10mL Schlenk管,加入底物1aa(例如,2-(萘-1-基)-1-乙醇或其他脂肪醇类,0.2毫摩尔,1.0当量)、二氟甲基试剂(200.4毫克,0.6毫摩尔,3.0当量),加入1毫升二氯甲烷和1毫升水作溶剂,室温下(约25℃)搅拌过夜(约12h)反应完成后,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到脂肪醇二氟甲基醚类化合物3a。
以实施例1的具体反应方法作为反应通式,如图2。
实施例2-16按照与实施例1相同的制备方法进行脂肪醇二氟甲基醚化反应。具体的,实施例2-16与实施例1的区别仅在于,使用的脂肪醇类化合物(底物)不同,因此,制得的脂肪醇二氟甲基醚类化合物(目的产物)也不同。
实施例2-16采用的脂肪醇类化合物,生成的脂肪醇二氟甲基化合物及其分离收率如表1所示。
表1
即实施例1-16按照与实施例1相同的方法,制备以下化合物(目的产物),其结构式如下:
各产物数据表征:
按照前述通式方法,制备得到下式化合物(实施例1):
1-(2-(二氟甲氧基)乙基)萘
1-(2-(difluoromethoxy)ethyl)naphthalene
无色透明液体;Rf=0.3(石油醚);36.4毫克,82%的分离收率;1H NMR(400MHz,CDCl3)δ8.02(d,J=8.3Hz,1H),7.87(dd,J=8.0,1.5Hz,1H),7.77(d,J=7.9Hz,1H),7.52(ddd,J=12.9,8.1,1.3Hz,2H),7.45–7.36(m,2H),6.21(t,J=74.7Hz,1H),4.19(t,J=7.4Hz,2H),3.44(t,J=7.5Hz,2H).19F NMR(377MHz,CDCl3)δ-84.01(d,J=74.8Hz).化合物已知[5]。
按照前述通式方法,制备得到下式化合物(实施例2):
1-(2-(二氟甲氧基)乙基)-4-甲氧基苯
1-(2-(difluoromethoxy)ethyl)-4-methoxybenzene
无色透明液体;Rf=0.3(石油醚/乙酸乙酯=50;1);35.9毫克,89%的分离收率;1H NMR(400MHz,CDCl3)δ7.17–7.09(m,2H),6.89–6.77(m,2H),6.17(t,J=74.9Hz,1H),4.01(t,J=7.1Hz,2H),3.78(s,3H),2.89(t,J=7.1Hz,2H).19F NMR(377MHz,CDCl3)δ-84.02(d,J=74.6Hz).化合物已知[5]。
按照前述通式方法,制备得到下式化合物(实施例3):
1-((二氟甲氧基)甲基)-4-硝基苯
1-((difluoromethoxy)methyl)-4-nitrobenzene
无色透明液体;Rf=0.3(石油醚/乙酸乙酯=20;1);22.3毫克,55%的分离收率;1H NMR(400MHz,CDCl3)δ8.33–8.14(m,2H),7.58–7.48(m,2H),6.38(t,J=73.4Hz,1H),5.01(s,2H).19F NMR(377MHz,CDCl3)δ-84.78(d,J=73.1Hz).化合物已知[5]。
按照前述通式方法,制备得到下式化合物(实施例4):
4-((二氟甲氧基)甲基)-1,1'-联苯
4-((difluoromethoxy)methyl)-1,1'-biphenyl
无色透明液体;Rf=0.3(石油醚/乙酸乙酯=50:1);35.6毫克,76%的分离收率;1H NMR(400MHz,CDCl3)δ7.59(dd,J=8.4,6.5Hz,4H),7.44(t,J=7.5Hz,4H),7.39–7.32(m,1H),7.13–6.95(m,1H),6.32(t,J=74.4Hz,1H),4.93(s,2H).19F NMR(377MHz,CDCl3)δ-84.15(d,J=74.6Hz).化合物已知[5]。
按照前述通式方法,制备得到下式化合物(实施例5):
5-((二氟甲氧基)甲基)苯并[d][1,3]二恶茂
5-((difluoromethoxy)methyl)benzo[d][1,3]dioxole
无色透明液体;Rf=0.3(石油醚);25.1毫克,62%的分离收率;1H NMR(400MHz,CDCl3)δ6.88(d,J=1.4Hz,1H),6.86–6.80(m,2H),6.30(t,J=74.5Hz,1H),6.00(s,2H),4.81(s,2H).19F NMR(377MHz,CDCl3)δ-84.12(d,J=74.5Hz).化合物已知[5]。
按照前述通式方法,制备得到下式化合物(实施例6):
2-((二氟甲氧基)甲基)-2,3-二氢苯并[b][1,4]二恶烷
2-((difluoromethoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxine
无色透明液体;Rf=0.3(石油醚:乙酸乙酯=50:1);22.0毫克,51%的分离收率;1H NMR(400MHz,CDCl3)δ6.99–6.67(m,1H),6.28(t,J=73.8Hz,0H),4.39(dtd,J=7.5,5.5,2.3Hz,0H),4.30(dd,J=11.5,2.4Hz,0H),4.18–3.97(m,1H).19F NMR(377MHz,CDCl3)δ-85.01(dd,J=73.7,5.2Hz).化合物已知[5]。
按照前述通式方法,制备得到下式化合物(实施例7):
(5-(二氟甲氧基)戊-1-炔-1-基)苯
(5-(difluoromethoxy)pent-1-yn-1-yl)benzene
无色透明液体;Rf=0.3(石油醚:乙酸乙酯=50:1);31.9毫克,76%的分离收率;1H NMR(400MHz,CDCl3)δ7.39(h,J=3.4,2.8Hz,2H),7.30–7.24(m,3H),6.21(t,J=75.0Hz,1H),4.00(t,J=6.2Hz,2H),2.53(t,J=7.0Hz,2H),1.93(p,J=6.6Hz,2H).19F NMR(377MHz,CDCl3)δ-83.94(d,J=74.8Hz).化合物已知[5]。
按照前述通式方法,制备得到下式化合物(实施例8):
3-(3-(二氟甲氧基)丙基)-1H-吲哚
3-(3-(difluoromethoxy)propyl)-1H-indole
无色透明液体;Rf=0.3(石油醚:乙酸乙酯=20:1);33.3毫克,74%的分离收率;1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.59(dd,J=7.9,1.1Hz,1H),7.34(dt,J=8.2,0.9Hz,1H),7.22–7.18(m,1H),7.16–7.11(m,1H),7.03(d,J=2.3Hz,1H),6.20(t,J=75.1Hz,1H),4.11(t,J=7.2Hz,2H),3.11(t,J=7.2Hz,2H).19F NMR(377MHz,CDCl3)δ-83.65(d,J=75.0Hz).化合物已知[5]。
按照前述通式方法,制备得到下式化合物(实施例9):
3-(2-(二氟甲氧基)乙基)噻吩
3-(2-(difluoromethoxy)ethyl)thiophene
无色透明液体;Rf=0.3(石油醚);25.0毫克,74%的分离收率;1H NMR(400MHz,CDCl3)δ7.31(dd,J=4.9,3.0Hz,1H),7.10–7.05(m,1H),7.01(d,J=4.9Hz,1H),6.23(t,J=74.7Hz,1H),4.09(t,J=6.9Hz,2H),3.02(t,J=6.9Hz,2H).19F NMR(377MHz,CDCl3)δ-84.18(d,J=74.7Hz).化合物已知[5]。
按照前述通式方法,制备得到下式化合物(实施例10):
1-溴-10-(二氟甲氧基)癸烷
1-bromo-10-(difluoromethoxy)decane
无色透明液体;Rf=0.3(石油醚);50.9毫克,85%的分离收率;1H NMR(400MHz,CDCl3)δ6.18(t,J=75.4Hz,1H),3.83(t,J=6.6Hz,2H),3.41(t,J=6.9Hz,2H),1.85(p,J=6.9Hz,2H),1.63(p,J=6.7Hz,2H),1.45–1.26(m,15H).19F NMR(377MHz,CDCl3)δ-83.76(d,J=75.3Hz).化合物已知[5]。
照前述通式方法,制备得到下式化合物(实施例11):
1-(二氟甲氧基)十八烷
1-(difluoromethoxy)octadecane
无色透明液体;Rf=0.3(石油醚);57.0毫克,89%的分离收率;1H NMR(400MHz,CDCl3)δ6.17(t,J=75.3Hz,1H),3.82(t,J=6.6Hz,2H),1.63(p,J=6.8Hz,2H),1.26(s,30H),0.88(t,J=6.9Hz,3H).19F NMR(377MHz,CDCl3)δ-83.81(d,J=75.4Hz).化合物已知[5]。
照前述通式方法,制备得到下式化合物(实施例12):
2-(二氟甲氧基)十三烷
2-(difluoromethoxy)tridecane
无色透明液体;Rf=0.3(石油醚);34.0毫克,68%的分离收率;1H NMR(400MHz,CDCl3)δ6.23(s,1H),4.23(h,J=6.2Hz,1H),1.62(ddd,J=16.7,9.1,4.4Hz,1H),1.50(ddt,J=14.1,10.6,4.9Hz,1H),1.37–1.25(m,21H),0.91(t,J=6.9Hz,3H).19F NMR(377MHz,CDCl3)δ-73.00–-92.52(m).化合物已知[5]。
照前述通式方法,制备得到下式化合物(实施例13):
(二氟甲氧基)环十二烷
(difluoromethoxy)cyclododecane
无色透明液体;Rf=0.3(石油醚);28.2毫克,61%的分离收率;1H NMR(400MHz,CDCl3)δ6.21(t,J=75.9Hz,1H),4.26(td,J=7.4,3.8Hz,1H),1.74(dq,J=13.4,6.7Hz,2H),1.56(tt,J=11.0,5.8Hz,2H),1.36(dd,J=17.8,6.5Hz,18H).19F NMR(377MHz,CDCl3)δ-80.04(d,J=75.9Hz).化合物已知[5]。
照前述通式方法,制备得到下式化合物(实施例14):
(3-(二氟甲氧基)-3-甲基丁基)苯
(3-(difluoromethoxy)-3-methylbutyl)benzene
无色透明液体;Rf=0.3(石油醚);14毫克,34%的分离收率;1H NMR(400MHz,CDCl3)δ7.31–7.27(m,2H),7.21–7.17(m,3H),6.32(t,J=76.8Hz,1H),2.75–2.70(m,2H),1.91–1.86(m,2H),1.41(s,6H).19F NMR(377MHz,CDCl3)δ-76.49(d,J=77.0Hz).化合物已知[5]。
照前述通式方法,制备得到下式化合物(实施例15):
2-(10-(二氟甲氧基)癸基)-5,6-二甲氧基-3-甲基环己-2,5-二烯-1,4-二酮
2-(10-(difluoromethoxy)decyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione
黄色固体;Rf=0.3(石油醚/乙酸乙酯=10:1);68毫克,87%的分离收率;1H NMR(400MHz,CDCl3)δ6.19(t,J=75.4Hz,1H),3.99(d,J=1.6Hz,6H),3.83(t,J=6.6Hz,2H),2.49–2.42(m,2H),2.01(s,3H),1.67–1.57(m,2H),1.45–1.28(m,14H).19F NMR(377MHz,CDCl3)δ-83.77(d,J=75.4Hz).化合物已知[5]。
照前述通式方法,制备得到下式化合物(实施例16):
(3S,5S,8R,9R,10S,13S,14S)-3-(二氟甲氧基)-8,10,13-三甲基十六氢-17H-环戊并[a]菲-17-酮
(3S,5S,8R,9R,10S,13S,14S)-3-(difluoromethoxy)-8,10,13-trimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one
黄色固体;Rf=0.3(石油醚/乙酸乙酯=10:1);68毫克,87%的分离收率;1H NMR(400MHz,CDCl3)δ6.23(t,J=75.8Hz,1H),4.04(tt,J=11.3,5.0Hz,1H),2.44(ddd,J=19.2,9.0,1.1Hz,1H),2.07(dt,J=19.2,9.1Hz,1H),1.97–1.72(m,6H),1.69–1.45(m,6H),1.37–1.25(m,5H),1.16(tt,J=12.2,3.5Hz,1H),1.05–0.93(m,2H),0.86(d,J=5.5Hz,6H),0.70(ddd,J=12.2,10.5,4.1Hz,1H).19F NMR(377MHz,CDCl3)δ-80.07(dd,J=75.8,8.6Hz).化合物已知[5]。
其中,上标[1-5]为参考文献,具体如下:
[1].Prakash,G.K.S.;Krishnamoorthy,S.;Kar,S.;Olah,G.A.,Direct S-difluoromethylation of thiols using the Ruppert–Prakash reagent.J FluorineChem 2015,180,186-191.
[2].Wu,J.;Gu,Y.;Leng,X.;Shen,Q.,Copper-promoted sandmeyerdifluoromethylthiolation of aryl and heteroaryl diazonium salts.Angew ChemInt Ed Engl 2015,54(26),7648-52.
[3].Wang,W.;Zhang,S.;Zhao,H.;Wang,S.,Visible light-promoteddifluoromethylthiolation of aryldiazonium salts.Org Biomol Chem 2018,16(44),8565-8568.
[4].Prakash,G.K.S.;Weber,C.;Chacko,S.;Olah,G.A.,New electrophilicdifluoromethylating reagent.Organic Letters 2007,9(10),1863-1866.
[5].Liu,G.K.;Li,X.;Qin,W.B.;Peng,X.S.;Wong,H.N.C.;Zhang,L.;Zhang,X.,Faciledifluoromethylation of aliphatic alcohols with an S-(difluoro-methyl)sulfonium salt:reaction,scope and mechanistic study.Chem Commun 2019,55(52),7446-7449.
Claims (8)
1.一种脂肪醇二氟甲基醚化反应方法,其特征在于,将脂肪醇类化合物和二氟甲基试剂,在溶剂中发生醚化反应,制得脂肪醇二氟甲基醚类化合物;
所述的二氟甲基试剂的结构式如下:
2.根据权利要求1所述的脂肪醇二氟甲基醚化反应方法,其特征在于,所述溶剂选自乙酸乙酯、甲酸乙酯、乙腈、二氯甲烷、氯仿、四氢呋喃中的至少一种。
3.根据权利要求1所述的脂肪醇二氟甲基醚化反应方法,其特征在于,所述醚化反应的反应温度为-30至80℃。
4.根据权利要求1所述的脂肪醇二氟甲基醚化反应方法,其特征在于,所述醚化反应的反应时间为6-24h。
5.根据权利要求1所述的脂肪醇二氟甲基醚化反应方法,其特征在于,所述醚化反应中,加水。
6.根据权利要求2所述的脂肪醇二氟甲基醚化反应方法,其特征在于,所述溶剂为二氯甲烷。
7.根据权利要求3所述的脂肪醇二氟甲基醚化反应方法,其特征在于,所述醚化反应的反应温度为0-50℃。
8.根据权利要求1-7任意一项所述的脂肪醇二氟甲基醚化反应方法在制备脂肪醇二氟甲基醚类化合物中的应用。
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