CN104744356B - 二取代脲类化合物的合成方法 - Google Patents
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及一种二取代脲类化合物的合成方法。该方法的具体步骤为：①在空气气氛下，将酰胺、芳胺、碘化亚铜、1,10‑菲啰啉按1:(1.0～2.0):(0.1～0.2):(0.2～0.4)的摩尔比加入到N,N‑二甲基甲酰胺溶剂中，于110～130 oC下搅拌至反应原料消失；②反应结束后，体系中加入过量的饱和食盐水，用乙酸乙酯萃取产物，有机相用饱和食盐水洗涤，经干燥、用旋转蒸发仪除去有机相中的溶剂后得粗产物；③粗产物用硅胶柱层析纯化，展开剂根据薄层层析情况和产物的极性情况选择，即得到相应的二取代脲类化合物。本发明方法原料简单易得，催化剂廉价，使用常规的反应溶剂，以空气为氧化剂。操作简单，产率中等到优秀，在工业生产中有很好的发展前景。
Description
技术领域
本发明涉及一种脲类化合物的合成方法，特别是一种是铜催化下通过碳-碳键活化的二取代脲类化合物的简便合成方法。
背景技术
脲类化合物，因其具有较高的生物活性、生理药理活性，而受到人们的广泛关注。例如，Norvir是一种强效蛋白酶抑制剂，主要用于抗HIV病毒(见参考文献：Debnath，A.K.etal.J.Med.Chem.1999,42,249)。又如，格列吡嗪控释片(Glipizide)适用于治疗II型糖尿病患者的高血糖及其相关症状(见参看文献：Pedersen,J.M.et al.J.Med.Chem.2008,51,3275)。全美2012年度市场前200位畅销药ACTOS中也含有脲的骨架，同样适用于治疗II型糖尿病(见参看文献：Greene,A.S.et al.J.Med.Chem.2012,55,8260)。此外，目前市场较流行的医药化妆品原料芦荟中，其所具消炎、软化角质及迅速愈合伤口的主要功能，得益于其中含有一定量的尿囊素(见参考文献：Sakamoto,A.et al.Plant.Cell.Environ.2014,37,1022)。
除此以外，由于脲类化合物结构上的特殊性，它可以作为重要的有机合成砌块，用于构建结构更加复杂的化合物。例如，邻位卤素取代的芳基脲在碱性条件下发生关环反应，形成咪唑啉酮类化合物(见参考文献：Bolm,C.etal.Org.Lett.2011,13,2876)。又例如，氰基乙酰基取代的脲在金属的催化下形成一类具有消炎作用的2,4-二羰基嘧啶类化合物(见参考文献：Müller,C.E.Heterocycles.2000,53,347)。
文献中报道过的合成脲类化合物的方法主要有以下几种：
(一)异氰酸酯与胺的反应。这是最常见的方法，主要应用于制备二取代脲(见参考文献：Ganachaud,F.Chem.Rev.2013,113,80)。此类方法的缺点是:原料异氰酸酯需要通过复杂的方法制备，异氰酸酯类化合物有强烈刺激性，为剧毒品，且不稳定，容易聚合，需要在低温、无光照条件下存储等。
2005年，Clayden小组报道了先用异氰酸酯与胺形成二取代脲，然后发生N-烷基化反应得到三取代的脲(见参考文献：Clayden,J.Org.Lett.2005,7,3147)。
(二)通过一氧化碳或者二氧化碳与胺在金属的催化下制备脲。此类方法主要得到对称的二取代脲。这类方法的缺点是：需使用昂贵的催化剂或者只能用于合成对称的二取代脲，方法的局限性很大。
2006年，Angelici小组报道了伯胺与一氧化碳和氧气在金催化下反应，得到对称的二取代脲。其机理是在金的催化氧气的氧化下形成异氰酸酯中间体与第二分子的胺反应形成脲(见参考文献：Angelici,R.J.J.Am.Chem.Soc.2006,128,14460)。
2011年，McElwee-White小组报道了伯胺与一氧化碳在钒催化下得到对称的二取代脲(见参考文献：McElwee-White,L.Eur.J.Org.Chem.2011,2011,6261)。
(三)通过异腈在过氧化物或者氮氧化物等强氧化剂条件下，先形成异氰酸酯之后再与胺反应得到。这类方法的缺点是：原料需要多步制备，采用过氧化物为氧化剂比较危险。
2004年，Zakrzewski小组报道了异腈经m-CPBA氧化，然后与二级胺反应得到三取代脲(见参考文献：Zakrzewski,J.Org.Lett.2004,6,695)。
2010年，Ichikawa小组报道了异腈在吡啶氮氧化物作用下生成异氰酸酯，然后与仲胺反应生成三取代脲(见参考文献：Ichikawa，J.J.Org.Chem.2010,2010,6331)
(四)Ukaji小组报道了二羰基咪唑与伯胺在水中反应可以得到对称的二取代脲和非对称的三取代脲(见参考文献：Padiya,K.J.Org.Lett.2012,14,2814)。
综上所述，脲类化合物的合成方法有以上几种，但是这些反应的底物都相对较为复杂，毒性较大，活着使用昂贵的金属作为催化剂，或者经过多步反应才能得到产物。
发明内容
本发明的目的在于提供一种二取代脲类化合物的合成方法。
为达到上述目的，本发明方法采用的反应机理为：
一种二取代脲类化合物的合成方法，其特征在于该方法具有如下步骤：将酰胺、芳胺、碘化亚铜、1,10-菲啰啉按1:(1.0～2.0):(0.1～0.2):(0.2～0.4)的摩尔比加入到N,N-二甲基甲酰胺溶剂中，于110～130℃下搅拌至反应原料消失；反应结束后，体系中加入过量的饱和食盐水，用乙酸乙酯萃取产物，有机相用饱和食盐水洗涤，除去溶剂后得粗产物；该粗产物经分离纯化得到二取代脲类化合物，其结构式为：所述的酰胺的结构式为：所述的芳胺的结构式为：其中：R＝氢、氟、氯、溴、甲氧基、-硼酸频哪醇酯，其中：X＝N，CH-。
本发明的二取代脲类化合物是一类重要的有机反应中间体，通过不同类型的有机化学反应，如催化加一氧化碳环化(见参考文献：Matthias，B.Angew.Chem.Int.Ed.1999,38,1454)、脱水反应(见参考文献：Palomo,C.Synthesis,1981,5,373)、付克酰基化反应，N-烷基化反应等，可方便、快捷地合成出一系列的多取代脲，环状脲的衍生物,以及二亚胺类化合物。
本发明方法采用对硝基苯乙酰苯基(吡啶)酰胺为反应原料简单易得，催化剂廉价，使用常规的反应溶剂，以空气为氧化剂。操作简单，产率中等到优秀，在工业生产中有很好的发展前景。
具体实施方式
实施例一：N-苯基-N’-(2-吡啶基)脲
N-苯基-N’-(2-吡啶基)脲采用下述步骤：①在250毫升反应釜中加入25.7克对硝基苯乙酰2-吡啶酰胺，苯胺10毫升，碘化亚铜1.9克，1,10-菲啰啉3.6克，N,N-二甲基甲酰胺200毫升，加热至120℃。用薄层层析方法跟踪反应，至反应原料消失；②反应结束后，体系中加入过量的饱和食盐水，用乙酸乙酯萃取，合并有机相，有机相用饱和食盐水洗涤，有机相经干燥后去除溶剂后得粗产物；③粗产物用柱层析梯度洗脱(石油醚:乙酸乙酯＝1:5至1:3)纯化，得到N-苯基-N’-(2-吡啶基)脲15.8克，产率为74％。
1H NMR(DMSO-d6,500MHz):δ10.47(s,1H),9.40(s,1H),8.25-8.22(m,1H),7.72-7.69(m,1H),7.49-7.46(m,3H),7.28-7.26(m,2H),7.01-6.96(m,2H)；
13C NMR(DMSO-d6,125MHz):δ152.9,152.2,146.9,139.0,138.6,128.9,122.5118.8；
LC-MS(ESI)m/z:213[M+Na].
实施例二：N-(4-溴苯基)-N’-(2-吡啶基)脲
N-(4-溴苯基)-N’-(2-吡啶基)脲采用下述步骤：①在250毫升反应釜中加入25.7克对硝基苯乙酰2-吡啶酰胺，4-溴苯胺25克，碘化亚铜1.9克，1,10-菲啰啉3.6克，N,N-二甲基甲酰胺200毫升，加热至120℃。用薄层层析方法跟踪反应，至反应原料消失；②反应结束后，体系中加入过量的饱和食盐水，用乙酸乙酯萃取，合并有机相，有机相用饱和食盐水洗涤，有机相经干燥后去除溶剂后得粗产物；③粗产物用柱层析(石油醚:乙酸乙酯＝1:5)纯化，得到N-(4-溴苯基)-N’-(2-吡啶基)脲17.5克，产率为60％。
1H NMR(DMSO-d6,500MHz):δ10.65(s,1H),9.50(s,1H),8.27(td,J＝7.5,2.0Hz,1H),7.55-7.45(m,5H)；
13C NMR(DMSO-d6,125MHz):δ153.1,152.5,147.3,139.0,138.9,132.0,121.2,118.0,114.4,112.4；
LC-MS(ESI)m/z:291[M+Na].
实施例三：N-(4-氯苯基)-N’-(2-吡啶基)脲
N-(4-氯苯基)-N’-(2-吡啶基)脲采用下述步骤：①在250毫升反应釜中加入25.7克对硝基苯乙酰2-吡啶酰胺，4-氯苯胺25.4毫升，碘化亚铜3.8克，1,10-菲啰啉7.2克，N,N-二甲基甲酰胺200毫升，加热至110℃。用薄层层析方法跟踪反应，至反应原料消失；②反应结束后，体系中加入过量的饱和食盐水，用乙酸乙酯萃取，合并有机相，有机相用饱和食盐水洗涤，有机相经干燥后去除溶剂后得粗产物；③粗产物用柱层析(石油醚:乙酸乙酯＝1:5)纯化，得到N-(4-氯苯基)-N’-(2-吡啶基)脲15.3克，产率为62％。
1H NMR(DMSO-d6,500MHz):δ10.65(s,1H),9.49(s,1H),8.29-8.26(m,1H),7.77-7.73(m,1H),7.58-7.54(m,2H),7.47(d,J＝8.0Hz,1H),7.39-7.33(m,2H),7.04-6.98(m,1H)；
13C NMR(DMSO-d6,125MHz):δ152.7,152.1,146.9,138.6,138.0,128.7,126.0120.3,117.6,111.9；
LC-MS(ESI)m/z:247[M+Na].
实施例四：N-(4-氟苯基)-N’-(2-吡啶基)脲
N-(4-氟苯基)-N’-(2-吡啶基)脲采用下述步骤：①在250毫升反应釜中加入25.7克对硝基苯乙酰2-吡啶酰胺，4-氟苯胺14.5克，碘化亚铜2.5克，1,10-菲啰啉4.7克，N,N-二甲基甲酰胺200毫升，加热至130℃。用薄层层析方法跟踪反应，至反应原料消失；②反应结束后，体系中加入过量的饱和食盐水，用乙酸乙酯萃取，合并有机相，有机相用饱和食盐水洗涤，有机相经干燥后去除溶剂后得粗产物；③粗产物用柱层析(石油醚:乙酸乙酯＝1:5)纯化，得到N-(4-氟苯基)-N’-(2-吡啶基)脲16.9克，产率为73％。
1H NMR(DMSO-d6,500MHz):δ10.57(s,1H),9.44(s,1H),8.30-8.25(m,1H),7.77-7.71(m,1H),7.58-7.52(m,2H),7.46(d,J＝8.0Hz,1H),7.15(t,J＝9.0Hz,2H),7.00(m,1H)；
13C NMR(DMSO-d6,125MHz):δ158.6,156.7,152.8,152.2,146.8,138.5,135.3,120.6,117.4,115.4,115.2,111.9；
LC-MS(ESI)m/z:231[M+Na].
实施例五：N-(4-硼酸频哪醇酯-苯基)-N’-(2-吡啶基)脲
N-(4-硼酸频哪醇酯-苯基)-N’-(2-吡啶基)脲采用下述步骤：①在250毫升反应釜中加入25.7克对硝基苯乙酰2-吡啶酰胺，4-硼酸频哪醇酯-苯胺26.3毫升，碘化亚铜2.3克，1,10-菲啰啉4.4克，N,N-二甲基甲酰胺200毫升，加热至110℃。用薄层层析方法跟踪反应，至反应原料消失；②反应结束后，体系中加入过量的饱和食盐水，用乙酸乙酯萃取，合并有机相，有机相用饱和食盐水洗涤，有机相经干燥后去除溶剂后得粗产物；③粗产物用柱层析梯度洗脱(石油醚:乙酸乙酯＝1:5至1:3)纯化，得到N-(4-硼酸频哪醇酯-苯基)-N’-(2-吡啶基)脲21.8克，产率为64％。
1H NMR(DMSO-d6,500MHz):δ10.70(s,1H),9.53(s,1H),8.31-8.28(m,1H),7.78-7.73(m,1H),7.65-7.60(m,2H),7.58-7.53(m,2H),7.51-7.46(m,1H),7.04-7.00(m,1H),1.28(s,12H)；
13C NMR(DMSO-d6,125MHz):δ152.7,152.0,146.9,142.0,138.6,135.5,117.7,117.6,111.9,83.4,24.7；
LC-MS(ESI)m/z:341[M+Na].
实施例六：N-苯基-N’-苯基脲
N-苯基-N’-苯基脲采用下述步骤：①在250毫升反应釜中加入25.7克对硝基苯乙酰苯胺酰胺，苯胺10毫升，碘化亚铜2.85克，1,10-菲啰啉5.4克，N,N-二甲基甲酰胺200毫升，加热至120℃。用薄层层析方法跟踪反应，至反应原料消失；②反应结束后，体系中加入过量的饱和食盐水，用乙酸乙酯萃取，合并有机相，有机相用饱和食盐水洗涤，有机相经干燥后去除溶剂后得粗产物；③粗产物用柱层析梯度洗脱(石油醚:乙酸乙酯＝1:5至1:3)纯化，得到N-苯基-N’-苯基脲11.7克，产率为55％。
1H NMR(DMSO-d6,500MHz):δ8.65(s,2H),7.45(d,J＝7.5Hz 1H),7.28(t,J＝8.0Hz,4H),6.96(t,J＝8.0Hz,2H)；
13C NMR(DMSO-d6,125MHz):δ152.5,139.7,128.7,121.8,118.1；
LC-MS(ESI)m/z:212[M+Na].
实施例七：N-(4-甲氧基苯基)-N’-苯基脲
N-(4-甲氧基苯基)-N’-苯基脲采用下述步骤：①在250毫升反应釜中加入25.7克对硝基苯乙酰苯胺酰胺，对甲氧基苯胺14克，碘化亚铜2.0克，1,10-菲啰啉4.0克，N,N-二甲基甲酰胺200毫升，加热至120℃。用薄层层析方法跟踪反应，至反应原料消失；②反应结束后，体系中加入过量的饱和食盐水，用乙酸乙酯萃取，合并有机相，有机相用饱和食盐水洗涤，有机相经干燥后去除溶剂后得粗产物；③粗产物用柱层析梯度洗脱(石油醚:乙酸乙酯＝1:5至1:3)纯化，得到N-(4-甲氧基苯基)-N’-苯基脲22.7克，产率为94％。
1H NMR(DMSO-d6,500MHz):δ10.40(s,1H),9.38(s,1H),8.28-8.24(m,1H),7.75-7.69(m,1H),7.47-7.40(m,3H),7.01-6.96(m,1H),6.92-6.86(m,2H),3.72(s,3H)；
13C NMR(DMSO-d6,125MHz):δ154.9,153.0,152.3,146.8,138.4,132.0,120.6,117.2,114.0,111.8,55.2；
LC-MS(ESI)m/z:242[M+Na]。
Claims (1)
1.一种二取代脲类化合物的合成方法，其特征在于该方法具有如下步骤：将酰胺、芳胺、碘化亚铜、1,10-菲啰啉按1:(1.0～2.0):(0.1～0.2):(0.2～0.4)的摩尔比加入到N,N-二甲基甲酰胺溶剂中，于110～130℃下搅拌至反应原料消失；反应结束后，体系中加入过量的饱和食盐水，用乙酸乙酯萃取产物，有机相用饱和食盐水洗涤，除去溶剂后得粗产物；该粗产物经分离纯化得到二取代脲类化合物，其结构式为：所述的酰胺的结构式为：所述的芳胺的结构式为：其中：R＝氢、氟、氯、溴、甲氧基、硼酸频哪醇酯，其中：X＝N，CH。
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