CN108947819A - 一种氘代芳香族化合物的制备方法 - Google Patents
一种氘代芳香族化合物的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 150000001491 aromatic compounds Chemical class 0.000 title claims abstract description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 24
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical class [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims abstract description 21
- -1 deuterium anions Chemical class 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 12
- 239000003446 ligand Substances 0.000 claims abstract description 11
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- 239000011261 inert gas Substances 0.000 claims abstract description 4
- 239000000463 material Substances 0.000 claims abstract description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 30
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 15
- 239000004215 Carbon black (E152) Substances 0.000 claims description 11
- 229930195733 hydrocarbon Natural products 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- ZBCKWHYWPLHBOK-UHFFFAOYSA-N cyclohexylphosphane Chemical compound PC1CCCCC1 ZBCKWHYWPLHBOK-UHFFFAOYSA-N 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 229910052805 deuterium Inorganic materials 0.000 abstract description 5
- 229910052736 halogen Inorganic materials 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000006722 reduction reaction Methods 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 2
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- 150000004945 aromatic hydrocarbons Chemical class 0.000 abstract 1
- 239000000575 pesticide Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
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- 150000001558 benzoic acid derivatives Chemical class 0.000 description 3
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- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
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- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 2
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- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- MKJIEFSOBYUXJB-VFJJUKLQSA-N (3r,11br)-3-(2-methylpropyl)-9,10-bis(trideuteriomethoxy)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-one Chemical compound C1CN2C[C@@H](CC(C)C)C(=O)C[C@@H]2C2=C1C=C(OC([2H])([2H])[2H])C(OC([2H])([2H])[2H])=C2 MKJIEFSOBYUXJB-VFJJUKLQSA-N 0.000 description 1
- ORPVVAKYSXQCJI-UHFFFAOYSA-N 1-bromo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Br ORPVVAKYSXQCJI-UHFFFAOYSA-N 0.000 description 1
- MFHFWRBXPQDZSA-UHFFFAOYSA-N 2-(4-bromophenyl)acetonitrile Chemical compound BrC1=CC=C(CC#N)C=C1 MFHFWRBXPQDZSA-UHFFFAOYSA-N 0.000 description 1
- ONMSBNJJCUCYED-UHFFFAOYSA-N 2-bromo-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1Br ONMSBNJJCUCYED-UHFFFAOYSA-N 0.000 description 1
- HCOPIUVJCIZALB-UHFFFAOYSA-N 3-bromopyridine-2-carbonitrile Chemical compound BrC1=CC=CN=C1C#N HCOPIUVJCIZALB-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 1
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- DULCUDSUACXJJC-UHFFFAOYSA-N Ethyl phenylacetate Chemical class CCOC(=O)CC1=CC=CC=C1 DULCUDSUACXJJC-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- SNZXMAHBUQXQSE-UHFFFAOYSA-N acetonitrile;benzene Chemical class CC#N.C1=CC=CC=C1 SNZXMAHBUQXQSE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 229950005031 deutetrabenazine Drugs 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical class CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- VEDDBHYQWFOITD-UHFFFAOYSA-N para-bromobenzyl alcohol Chemical compound OCC1=CC=C(Br)C=C1 VEDDBHYQWFOITD-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
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Abstract
本发明属于化学合成领域,具体涉及一种氘代芳香族化合物制备方法。通过氘负离子参与的钯催化碳卤键还原反应,以卤代芳烃为起始原料,氘代甲酸钠为氘代试剂,二甲基亚砜为溶剂,金属钯为催化剂,有机膦为配体,在惰性气体保护下,60‑100摄氏度下充分反应,合成目标化合物。该方法条件温和,在反应过程中避免使用昂贵的氘代试剂做溶剂,降低了生产成本,适合大规模生产。所得氘代芳香族化合物的氘代率均达到98%以上,可应用于有机光电材料、医药农药等领域。
Description
技术领域
本发明属于化学合成领域,具体涉及一种氘代芳香族化合物制备方法。
背景技术
氘是氢同位素的一种,由一个中子及一个质子组成。氘代化合物广泛的应用于生命,环境及核磁共振等有机物鉴定领域。2017年,全球首例氘代药物AUSTEDO获得美国食品药品管理局(FDA)的批准上市,这标志着FDA承认了氘在药物设计中有别于普通氢元素的作用。这一举措将加快氘代作为一种常规手段应用于药物分子设计中。
芳香族化合物是药物分子中最常见的结构,一般芳香族化合物是通过芳环上官能团的反应引入到药物分子中的。因此,开发一种能与多类官能团兼容的高效合成氘代芳香族化合物的方法十分重要。目前,已报道的合成氘代芳香族化合物方法有以下缺点:一,需要在高温高压或强酸强碱条件下制备,其官能团兼容性较差(Bull.Chem.Soc.Jpn.2011,1368-1370);二,使用氘代试剂做溶剂,生产成本较高(Org.Biomol.Chem.,2016,14,3091-3097);三,氘代率普遍偏低,一般只能达到80%-95%,无法满足药物研发领域对氘代率98%的要求(Chem.Eur.J.2009,15,10397-10404)。针对以上问题,申请人曾开发出一种高效氘代方法,但此方法需要使用对空气极为敏感的三叔丁基膦作为配体,此配体价格昂贵而且操作十分不方便,从而限制了此方法的应用价值(Org.Chem.Front.2015,2,1071-1075)。基于以上研究,申请人对催化剂体系进行了改进,发明了一种经济、实用、高效合成各种官能化氘代芳香族化合物的方法。
发明内容
本发明所解决的技术问题是:以卤代芳香族化合物为起始原料,在惰性气体保护体系下,通过钯催化的卤素还原反应,为各种官能化的氘代芳香族化合物的合成提供一种高效的合成方法。
为了解决上述技术问题,本发明所采用的技术方案是:提供一种氘代芳香族化合物的制备方法,该方法以卤代芳烃为原料,钯为催化剂,有机膦为配体,氘代甲酸钠为氘代试剂,二甲基亚砜为溶剂,反应温度60-100摄氏度,惰性气体保护体系下,充分反应,合成目标氘代芳香族化合物,其中,目标化合物的合成反应方程式为:
X=Br,I,OTf,OMs
优选的,所述卤代芳烃与氘代甲酸钠投料摩尔比为1:2。
优选的,反应以钯与有机膦配体的配合物为催化剂,催化剂用量为卤代芳烃2%-5%。
优选的,所述钯催化剂为醋酸钯,双(二亚苄基丙酮)钯,氯化钯,四(三苯基膦)钯;
优选的,所述有机膦配体为三苯基膦,三环己基膦。
优选的,所述卤代芳烃在反应中作为离去基团的X为Br,I,OTf,OMs。
本发明所述氘代芳香族化合物的制备方法在含有氘代芳基的药物的制备和生产方面的应用。
本发明所述氘代芳香族化合物的制备方法在含有氘代芳基的光电功能材料制备方面的应用。
本发明的有益效果是:与现有技术相比,本发明的优点如下:本发明所述氘代芳香族化合物的制备方法条件温和,在反应过程中以当量的氘代甲酸钠为氘源及廉价的非氘代溶剂,避免使用昂贵的氘代试剂做溶剂,降低了生产成本,适合大规模生产。所得氘代芳香族化合物的氘代率均达到98%以上。
附图说明
图1 4-氘代苯乙腈的核磁氢谱图
具体实施方式
下面将结合说明书附图,对本发明作进一步的说明
本发明所述方法涉及氘负离子参与的钯催化碳卤键还原反应,以卤代芳烃为起始原料,氘代甲酸钠为氘代试剂,二甲基亚砜为溶剂,金属钯为催化剂,有机膦为配体,在氮气保护下,80摄氏度下反应8-16小时,合成目标化合物。
所述钯催化剂为四(三苯基膦)钯、醋酸钯,氯化钯或双(二亚苄基丙酮)钯,用量为卤代芳烃摩尔量的2%-5%。
所述有机膦配体为三苯基膦、三环己基膦,用量与钯催化剂等摩尔量。
所述氘代甲酸钠的用量是卤代芳烃摩尔量的2倍当量。
上述氘代芳香族化合物的通用合成反应式为:
其中,离去基团X为卤素或类卤素,包括Br,I,OTf,OMs等。在反应过程中仅使用2当量的氘代甲酸钠作为氘代试剂,非氘代的二甲亚砜做为溶剂,所得氘代芳香族化合物氘代纯度极高,氘代率均保持在98%以上。在反应过程中避免了使用昂贵的氘代溶剂,降低了生产成本,适合大规模生产。
具体的氘代芳香族化合物产物结构如下:
R=COOH,COOEt,CN,NO2,NH2,CHO,CH2OH,OH
下面结合具体实施例,进一步阐述本发明。
实施例1:4-氘代苯甲酸乙酯的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(1.38g,20mmol),对溴苯甲酸乙酯(2.28g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应8小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到4-氘代苯甲酸乙酯,收率95%。氘代率>98%。
1H NMR(CDCl3,ppm):δ8.02(d,J=10.2Hz,2H),7.41(d,J=10.2Hz,2H),4.36(d,J=8.4Hz,2H),1.38(t,J=7.8Hz,3H);13C NMR(CDCl3,ppm):δ166.6,132.5(t,J=23.75Hz),130.5,129.5,128.2,60.9,14.3。
实施例2:4-氘代苯甲酸的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(2.07g,30mmol),对溴苯甲酸(2.01g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应8小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到4-氘代苯甲酸,收率85%。氘代率>98%。1H NMR(CDCl3,ppm):δ8.02(d,J=10.2Hz,2H),7.41(d,J=10.2Hz,2H);13C NMR(CDCl3,ppm):δ166.6,132.5(t,J=23.75Hz),130.5,129.5,128.2;
实施例3:4-氘代二苯甲酮的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(1.38g,20mmol),4-溴二苯甲酮(2.60g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应8小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到4-氘代二苯甲酮,收率90%。氘代率>98%。1H NMR(CDCl3,ppm):δ7.78~7.80(m,4H),7.57(t,J=9.0Hz,1H),7.45~7.48(m,4H);13C NMR(CDCl3,ppm):δ196.8,137.7,132.5,132.2(t,J=25.0Hz),130.1,128.4,128.2;
实施例4:4-氘代苯甲腈的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(1.38g,20mmol),4-溴苯甲腈(1.81g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应8小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到4-氘代苯甲腈,收率82%。氘代率>98%。1H NMR(CDCl3,ppm):δ7.64(d,J=9.6Hz,2H),7.46(d,J=9.6Hz,2H);13C NMR(CDCl3,ppm):δ132.5(t,J=25.0Hz),132.2,129.0,118.9,112.4。
实施例5:4-氘代-硝基苯的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(1.38g,20mmol),4-溴-硝基苯(2.02g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应8小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到4-氘代-硝基苯,收率94%。氘代率>98%。1H NMR(CDCl3,ppm):δ8.21(d,J=0.2Hz,2H),7.53(d,J=9.6Hz,2H);13C NMR(CDCl3,ppm):δ148.4,134.5(t,J=25.0Hz),129.4,123.6;
实施例6:4-氘代-N,N-二甲基苯胺的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(1.38g,20mmol),4-溴-N,N-二甲基苯胺(2.00g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应8小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到4-氘代-N,N-二甲基苯胺,收率80%。氘代率>98%。1H NMR(CDCl3,ppm):δ7.30(d,J=9.6Hz,2H),6.81(d,J=10.8Hz,2H),3.00(s,6H);13C NMR(CDCl3,ppm):δ150.8,129.1,116.6(t,J=25.0Hz),112.9,40.8。
实施例7:4-氘代苯胺的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(2.76g,40mmol),4-溴苯胺(1.70g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应8小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到4-氘代苯胺,收率75%。氘代率>98%。1H NMR(CDCl3,ppm):δ7.40(d,J=9.6Hz,2H),6.86(d,J=10.8Hz,2H);13C NMR(CDCl3,ppm):δ151.8,129.1,116.6(t,J=25.0Hz),112.9;
实例8:4-氘代苯甲醛的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(1.38g,20mmol),4-溴苯甲醛(1.85g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应8小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到4-氘代苯甲醛,收率87%。氘代率>98%。1H NMR(CDCl3,ppm):δ9.96(s,1H),7.82(d,J=9.6Hz,2H),7.47(d,J=9.0Hz,2H);13C NMR(CDCl3,ppm):δ192.3,136.4,134.1(t,J=25.0Hz),129.7,128.8;
实施例9:4-氘代苯酚的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(2.07g,30mmol),4-溴苯酚(1.72g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应16小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到4-氘代苯酚,收率82%。氘代率>98%。1H NMR(CDCl3,ppm):δ9.02(d,J=6.6Hz,1H),7.81(d,J=9.0Hz,1H),7.73(d,J=9.6Hz,1H),7.43~7.46(m,2H);13C NMR(CDCl3,ppm):δ155.4,129.6,120.6(t,J=25.0Hz),115.3;
实施例10:4-氘代苄醇的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(2.07g,30mmol),4-溴苄醇(1.86g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应16小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到4-氘代苄醇,收率94%。氘代率>98%。1H NMR(CDCl3,ppm):δ7.35(s,4H),4.67(s,2H);13C NMR(CDCl3,ppm):δ140.9,128.6,127.5(t,J=25.0Hz),127.1,65.5;
实施例11:4-氘代苯乙酸乙酯的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(1.38g,20mmol),4-溴苯乙酸乙酯(2.43g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应16小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到4-氘代苯乙酸乙酯,收率93%。氘代率>98%。1H NMR(CDCl3,ppm):δ7.28(dd,J=10.2Hz,J=18.6Hz,4H),4.13(q,J=9.0Hz,2H),3.59(s,2H),1.23(t,J=8.4Hz,3H);13C NMR(CDCl3,ppm):δ171.6,134.1,129.2,128.4,126.7(t,J=25.0Hz),60.8,41.4,14.1;
实施例12:3-氘代-2-氰基吡啶的制备方法
向100mL三颈瓶中依次加入双(二亚苄基丙酮)钯(183mg,0.2mmol),三苯基膦(105mg,0.4mmol),氘代甲酸钠(1.38g,20mmol),3-溴-2-氰基吡啶(1.82g,10mmol)及二甲亚砜(10mL)。高纯氮气置换三次,80oC反应16小时后,加入饱和氯化铵溶液淬灭反应,用二氯甲烷萃取混合液,合并有机相,浓缩有机溶剂,柱层析进一步纯化产品,得到3-氘代-2-氰基吡啶,收率93%。氘代率>98%。1H NMR(CDCl3,ppm):δ8.70~8.72(m,1H),7.82(d,J=9.6Hz,1H),7.51(dd,J=6.0Hz,J=9.0Hz,1H);13C NMR(CDCl3,ppm):δ151.4,137.1,134.2,128.4(t,J=25.0Hz),127.1,117.3;
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (8)
1.一种氘代芳香族化合物的制备方法,其特征在于,该方法以卤代芳烃为原料,钯为催化剂,有机膦为配体,氘代甲酸钠为氘代试剂,二甲基亚砜为溶剂,反应温度60-100摄氏度,惰性气体保护体系下,充分反应,合成目标氘代芳香族化合物,其中,目标化合物的合成反应方程式为:
X=Br,I,OTf,OMs。
2.根据权利要求1所述一种氘代芳香族化合物的制备方法,其特征在于,所述卤代芳烃与氘代甲酸钠投料摩尔比为1:2。
3.根据权利要求1所述一种氘代芳香族化合物的制备方法,其特征在于,反应以钯催化剂与有机膦配体的配合物为催化剂,催化剂用量为卤代芳烃2%-5%。
4.根据权利要求1所述一种氘代芳香族化合物的制备方法,其特征在于,所述钯催化剂为醋酸钯,双(二亚苄基丙酮)钯,氯化钯,四(三苯基膦)钯,所述有机膦配体为三苯基膦,三环己基膦。
5.根据权利要求1所述的一种氘代芳香族化合物的制备方法,其特征在于,所述卤代芳烃在反应中作为离去基团的X为Br,I,OTf,OMs。
6.权利要求1所述的一种制备氘代芳香族化合物的方法在含有氘代芳基的药物的制备和生产方面的应用。
7.权利要求1所述的一种氘代芳香族化合物的制备方法在含有氘代芳基的光电功能材料制备方面的应用。
8.根据权利要求1所述氘代芳香族化合物的制备方法,其中,氘代芳香族化合物产物结构如下所示:
R=COOH,COOEt,CN,NO2,NH2,CHO,CH2OH,OH。
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