CN110028451A - 一种全取代吡唑衍生物制备方法 - Google Patents
一种全取代吡唑衍生物制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical class C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 title claims abstract description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 239000012141 concentrate Substances 0.000 claims abstract description 5
- 239000000376 reactant Substances 0.000 claims abstract description 5
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- 239000002904 solvent Substances 0.000 claims abstract description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- -1 substituted-phenyl substituent group Chemical group 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 3
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 1
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- 238000012805 post-processing Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 68
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
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- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000003217 pyrazoles Chemical class 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
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- 230000008901 benefit Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000007857 hydrazones Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- XITPERBRJNUFSB-BVBGJJFLSA-N (2s)-2-[[(e)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)\C=C\C1=CC=C(O)C(O)=C1 XITPERBRJNUFSB-BVBGJJFLSA-N 0.000 description 1
- KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical group OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
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- 238000007689 inspection Methods 0.000 description 1
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- 238000001819 mass spectrum Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明涉及有机化学合成技术领域，其目的在于提供了一种全取代吡唑衍生物制备方法，按反应图解通过通式Ⅱ所示的化合物、通式Ⅲ所示化合物溶解于二氯甲烷中，加入三乙胺，室温反应；待反应物Ⅱ完全消失，将反应混合物在减压条件下除去溶剂，浓缩物经硅胶柱层析洗脱得到目标化合物Ⅰ，该方法反应条件温和，后处理操作简单，可以大量制备，在有机化学、药物化学等重要领域具有广阔的应用前景。
Description
技术领域
本发明涉及有机化学合成技术领域，具体涉及一种全取代吡唑衍生物制备方法。
背景技术
吡唑是一种特殊的含氮芳香化合物，与咪唑互为同分异构体。含有吡唑骨架药物分子具有多样的生物活性，它们的合成一直是有机化学研究者和药物化学家的重要研究目标之一。关于吡唑的合成，已经发表的文献方法有很多，主要包括金属催化的偶联方法(R.Goikhman,T.L.Jacques and D.Sames,J.Am.Chem.Soc.,2009,131,3042-3048；K.M.Clapham,A.S.Batsanov,M.R.Bryce and B.Tarbit,Org.Biomol.Chem.,2009,7,2155-2161)，芳基肼和1,3双亲电试剂的缩合反应(B.S.Gerstenberger,M.R.Rauckhorst andJ.T.Starr,Org.Lett.,2009,11,2097-2100；A.R.Katritzky,M.Wang,S.Zhang,M.V.Voronkov and P.J.Steel,J.Org.Chem.,2001,66,6787-6791)以及1,3-偶极环加成反应(A.Alizadeh,L.Moafi and L.-G.Zhu,Synlett,2015,27,595-598；S.Dadiboyena andA.T.HammeⅡ,Eur.J.Org.Chem.,2013,2013,7567-7574；S.Dadiboyena,E.J.Valente andA.T.HammeⅡ,Tetrahedron Lett.,2010,51,1341；K.Liu,X.Shang,Y.Cheng,X.Chang,P.Liand W.Li,Org.Biomol.Chem.,2018,16,7811-7814；O.
A.Miqdad,N.M.Abunada and H.M.Hassaneen,Heteroat.Chem.,2011,22,131-136)。而本发明方法利用含硫吡啶内鎓盐与常用的卤代腙在温和的条件下进行反应，可以很容易生成一类全取代吡唑衍生物，反应过程经过一个[[3+3]-1]的反应历程，即先生成六元环再缩环成五元吡唑环，这一合成方法在文献中属于首例。该方法反应条件温和，后处理操作简单，可以大量制备，在有机化学、药物化学等重要领域具有广阔的应用前景。
发明内容
本发明的目的是提出一种全取代吡唑衍生物制备方法，利用卤代腙和含硫吡啶内鎓盐作为合成子，三乙胺作为碱，在室温条件下合成多样性的全取代吡唑骨架，同时提供该合成的实施方法，所得吡唑类化合物可望在医药等相关领域得到广泛应用。
一种全取代吡唑衍生物制备方法，其特征在于：所述制备方法如下式：
即将通式Ⅱ所示的化合物、通式Ⅲ所示化合物溶解于二氯甲烷中，加入三乙胺，室温反应；待反应物Ⅱ完全消失，将反应混合物在减压条件下除去溶剂，浓缩物经硅胶柱层析洗脱得到目标化合物Ⅰ；
其中，Ar为苯基或者取代苯基取代基(包含4-硝基、4-甲基)；R1为苯基或者取代苯基取代基(包含4-甲氧羰基、4-硝基、2-氟、4-氯、2,6-二氯、4-溴、4-甲基、3-甲氧基)，稠环取代基(2-萘基)，杂环取代基(2-吡啶基、2-呋喃基)，烷基取代基(叔丁基、苄基、乙氧羰基)；R2和R3为下列取代基中一种或者两种：甲氧羰基取代基，乙氧羰基取代基，苯甲酰基和三氟甲基。
如上所述全取代吡唑衍生物，其吡唑环上同时带有四个取代基，其中R2和R3可以相同或者不同。
所述制备过程中，参与反应的各化合物的最优摩尔比(当量比)为：
Ⅱ：Ⅲ：三乙胺＝1:1.5:1.8，
最优浓度为0.1M，即0.1摩尔每升，即可得到目标化合物Ⅰ。
所述制备过程中三乙胺替代物有DIPEA(二异丙基乙基胺)、碳酸铯、碳酸氢钠。
所述制备过程中溶剂二氯甲烷替代物有甲醇、乙腈。
本发明的有益效果为：本发明所实施的方法使用含硫吡啶内鎓盐作为制备吡唑的合成子，该试剂制备和使用方便，具有较强的稳定性，常温下为固态。本方法无需使用金属催化剂，反应过程和后处理简单易操作，室温下进行，无危险性，合成产率为77％-99％，普遍较高，可实现大量制备且产率无显著影响。在有机化学、药物化学等重要领域具有广阔的应用前景。
附图说明
图1是本发明实施例所得到的产物Ⅰ-1的核磁共振氢谱图；
图2是本发明实施例所得到的产物Ⅰ-1的核磁共振碳谱图。
具体实施方式
为了更好地理解本发明的实质性内容，进行以下说明：
以下是本发明的一个制备化合物的最佳实施例。在以下所有实施例中，核磁谱检测通过Varian 300,Bruker 400,JEOL 400and Varian 600MHz仪器在CDCl3中获得。δ值为内标相对值(CDCl3定标δ7.26 1H NMR和77.00 13C NMR)。高分辨质谱(HRMS)通过4Gquadrupole time-of-flight(QTof)质谱仪器得到。
实施例1：
实施例1的反应式，具体使用的化合物Ⅱ-1以及产物Ⅰ-1的结构如下。
具体实验步骤是：即将69mg(0.30mmol，1.0当量)通式Ⅱ-1所示的化合物和114mg(0.45mmol，1.5当量)通式Ⅲ-1所示化合物溶解于二氯甲烷溶剂中，然后加入三乙胺0.08mL(0.54mmol，1.8当量)，在室温条件下反应，待反应物Ⅱ-1完全消失，将反应混合物在减压条件下除去易挥发物，浓缩物经硅胶柱层析洗脱得到目标化合物I-1。
制备本发明的其它化合物(化合物Ⅰ-2至化合物Ⅰ-21)的实施例所用的方法与实施例1相同，反应条件如下：即将通式Ⅱ所示的化合物(0.3mmol)、通式Ⅲ所示化合物(0.45mmol，1.5当量)溶解于二氯甲烷溶剂3mL中，然后加入三乙胺(0.54mmol，1.8当量)，在室温条件下反应，待反应物Ⅱ完全消失，将反应混合物在减压条加下除去易挥发物，浓缩物经硅胶柱层析洗脱得到目标化合物I。
各产物结构以及数据表征如下：
I-1(96mg,Y＝95％)白色固体；mp 152-154℃.1H NMR(300MHz,CDCl3)δ7.76(dd,J＝6.9,1.8Hz,2H),7.75(dd,J＝7.5,1.2Hz,2H),7.49-7.43(m,6H),3.86(s,3H),3.83(s,3H).
I-2(117mg,Y＝99％)白色固体；mp 124-125℃.1H NMR(400MHz,CDCl3)δ8.10(d,J＝8.4Hz,2H),7.84(d,J＝8.0Hz,2H),7.54-7.46(m,5H),3.92(s,3H),3.85(s,3H),3.82(s,3H)；13C NMR(100MHz,CDCl3)δ166.7,163.0,160.4,150.8,138.7,137.1,135.7,130.2,129.3,129.2,128.7,124.3,114.1,53.2,52.2,52.1,(1C missing)；ESI-HRMS m/z calcdFor C21H18N2O6+Na(M+Na):417.1057,found 417.1056.
I-3(88mg,Y＝77％)黄色油.1H NMR(400MHz,CDCl3)δ8.29(d,J＝9.2Hz,2H),7.98(d,J＝8.8Hz,2H),7.55-7.49(m,5H),3.88(s,3H),3.85(s,3H).
I-4(95mg,Y＝90％)白色固体；mp 149-150℃.1H NMR(400MHz,CDCl3)δ7.61(td,J＝9.2,1.6Hz,1H),7.56-7.52(m,2H),7.51-7.39(m,4H),7.23(td,J＝8.4,0.8Hz,1H),7.18-7.13(m,1H),3.88(s,3H),3.78(s,3H)；13C NMR(100MHz,CDCl3)δ162.5,160.8,160.2(d,J＝248Hz),147.3,138.8,136.9,131.0(d,J＝2.0Hz),130.8(d,J＝8.0Hz),129.2,129.1,124.2,124.0(d,J＝3.0Hz),119.7(d,J＝14.0Hz),115.4,(d,J＝22.0Hz),115.0,53.3,52.0；ESI-HRMS m/z calcd for C19H15FN2O4+Na(M+Na):377.0908,found 377.0906.
I-5(110mg,Y＝99％)黄色油.1H NMR(300MHz,CDCl3)δ7.73(d,J＝8.4Hz,2H),7.55-7.46(m,5H),7.42(d,J＝8.7Hz,2H),3.87(s,3H),3.83(s,3H).
I-6(111mg,Y＝91％)黄色固体；mp 102-103℃.1H NMR(400MHz,CDCl3)δ7.58(d,J＝7.2Hz,2H),7.50-7.43(m,3H),7.40(d,J＝8.0Hz,2H),7.31-7.27(m,1H),3.90(s,3H),3.69(s,3H)；13C NMR(100MHz,CDCl3)δ161,6,161.1,148.4,138.6,137.3,135.7,130.6,130.4,129.3,129.0,127.6,123.7,114.4,53.4,51.9；ESI-HRMS m/z calcd forC19H14Cl2N2O4+Na(M+Na):427.0223,found 427.0219.
I-7(119mg,Y＝96％)黄色油.1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.8Hz,2H),7.57-7.44(m,7H),3.86(s,3H),3.83(s,3H).
I-8(104mg,Y＝99％)黄色油.1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.0Hz,2H),7.54-7.40(m,5H),7.24(d,J＝8.0Hz,2H),3.84(s,3H),3.82(s,3H),2.38(s,3H).
I-9(109mg,Y＝99％)无色油.1H NMR(300MHz,CDCl3)δ7.56-7.45(m,5H),7.38-7.31(m,3H),6.99-6.94(m,1H),3.86(s,3H),3.84(s,3H),3.84(s,3H)；13C NMR(100MHz,CDCl3)δ163.4,160.5,159.4,151.6,139.0,136.6,132.5,129.2,129.1,129.1,124.6,121.1,115.0,114.4,113.9,55.3,53.1,52.2；ESI-HRMS m/z calcd for C20H18N2O5[M+Na]+389.1108,found 389.1107.
I-10(109mg,Y＝94％)黄色固体；mp 119-120℃.1H NMR(400MHz,CDCl3)δ8.32(s,1H),7.94-7.88(m,4H),7.60(d,J＝7.2Hz,2H),7.53-7.45(m,5H),3.89(s,3H),3.86(s,3H)；13C NMR(100MHz,CDCl3)δ163.3,160.6,151.8,138.9,136.8,133.3,132.9,129.2,129.1,128.6,128.4,128.1,127.6,127.6,126.4,126.3,126.1,124.4,114.2,53.1,52.2；ESI-HRMS m/z calcd for C23H18N2O4+H(M+H):387.1339,found 387.1336.
I-11(81mg,Y＝80％)黄色固体；mp 111-112℃.1H NMR(400MHz,CDCl3)δ8.63(d,J＝5.2Hz,1H),7.97(d,J＝10.4Hz,1H),7.73(td,J＝12.8,2.4Hz,1H),7.49(s,5H),7.28-7.24(m,1H),3.96(s,3H),3.81(s,3H)；13C NMR(100MHz,CDCl3)δ164.7,158.9,149.9,149.4,139.3,136.4,133.4,129.2,128.8,125.6,123.3,121.4,117.6,52.7,52.6,(1Cmissing)；ESI-HRMS m/z calcd for C18H15N3O4+H(M+H):338.1135,found 338.1131.
I-12(93mg,Y＝95％)黄色油.1H NMR(400MHz,CDCl3)δ7.54-7.51(m,3H),7.50-7.45(m,3H),7.26(d,J＝4.4Hz,1),7.73(dd,J＝3.2,1.6Hz,1H),3.90(s,3H),3.85(s,3H).
I-13(82mg,Y＝86％)黄色固体；mp 78-79℃.1H NMR(400MHz,CDCl3)δ7.44-7.43(m,4H),7.42-7.39(m,1H),3.85(s,3H),3.79(s,3H),1.43(s,9H)；13C NMR(100MHz,CDCl3)δ164.3,160.7,159.9,139.1,136.1,129.0,128.6,124.5,114.3,52.8,52.1,33.6,29.2；ESI-HRMS m/z calcd for C17H20N2O4+Na(M+Na):339.1315,found 339.1312.
I-14(102mg,Y＝97％)黄色固体；mp 80-81℃.1H NMR(400MHz,CDCl3)δ7.50(d,J＝7.6Hz,2H),7.46-7.39(m,3H),7.34(d,J＝7.6Hz,2H),7.27(t,J＝7.6Hz,2H),7.18(t,J＝7.2Hz,1H),4.30(s,2H),3.83(s,3H),3.78(s,3H)；13C NMR(100MHz,CDCl3)δ162.5,161.6,153.3,138.7,138.5,137.7,129.2,128.7,128.2,126.1,123.6,112.7,53.2,51.6,33.2,(1C missing)；ESI-HRMS m/z calcd for C20H18N2O4+Na(M+Na):373.1159,found373.1153.
I-15(89mg,Y＝89％)黄色固体；mp 84-85℃.1H NMR(400MHz,CDCl3)δ7.47-7.44(m,3H),7.42-7.39(m,2H),4.40(q,J＝6.8Hz,2H),3.94(s,3H),3.76(s,3H),1.36(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ163.2,160.3,157.9,141.0,138.8,133.0,129.7,128.8,125.7,121.0,61.8,52.9,52.8,14.0；ESI-HRMS m/z calcd for C16H16N2O6+Na(M+Na):355.0901,found 355.0899.
I-16(100mg,Y＝88％)黄色固体；mp 106-107℃.1H NMR(400MHz,CDCl3)δ8.37(d,J＝8.8Hz,2H),7.77-7.71(m,4H),7.48-7.44(m,3H),3.92(s,3H),3.85(s,3H)；13C NMR(100MHz,CDCl3)δ163.0,160.0,152.6,147.2,143.6,136.2,130.6,129.2,128.5,128.3,124.9,124.6,115.9,53.4,52.4；ESI-HRMS m/z calcd for C19H15N3O6+Na(M+Na):404.0853,found 404.0851.
I-17(104mg,Y＝99％)黄色固体；mp 97-98℃.1H NMR(400MHz,CDCl3)7.77(dd,J＝7.6,1.6Hz,2H),7.48-7.42(m,5H),7.29(d,J＝8.0Hz,2H),3.87(s,3H),3.84(s,3H),2.42(s,3H)；13C NMR(100MHz,CDCl3)δ163.3,160.6,151.7,139.1,136.6,136.4,131.2,129.6,128.8,128.7,128.1,124.2,113.7,53.1,52.1,21.0；ESI-HRMS m/z calcd for C20H18N2O4+H(M+H):351.1339,found 351.1333.
I-18(108mg,Y＝99％)黄色油.1H NMR(400MHz,CDCl3)δ7.77(dd,J＝7.6,2.0Hz,2H),7.55(dd,J＝8.0,1.2Hz,2H),7.50-7.40(m,6H),4.32(q,J＝7.2Hz,2H),4.31(q,J＝7.2Hz,2H),1.28(t,J＝7.2Hz,3H),1.24(t,J＝7.2Hz,3H).
I-19(112mg,Y＝97％)黄色固体；mp 125-126℃.1H NMR(400MHz,CDCl3)δ7.88-7.85(m,4H),7.61(t,J＝7.2Hz,1H),7.50-7.45(m,7H),7.37-7.32(m,3H),3.44(s,3H)；13CNMR(75MHz,CDCl3)δ188.0,162.5,153.0,143.6,138.5,136.4,134.2,131.2,129.3,129.2,129.1,128.9,128.7,127.9,124.1,113.1,51.3,(1C missing)；ESI-HRMS m/z calcd forC24H18N2O3+H(M+H):383.1390,found 383.1387.
I-20(112mg,Y＝88％)黄色固体；mp 134-135℃.1H NMR(400MHz,(CD3)2CO)δ7.74(dd,J＝8.4,1.2Hz,2H),7.65-7.60(m,4H),7.57-7.52(m,3H),7.48-7.40(m,4H),7.37-7.30(m,5H),7.26(t,J＝8.0Hz,2H)；13C NMR(100MHz,(CD3)2CO)δ191.3,187.8,152.0,143.4,140.2,139.0,137.7,134.9,133.9,132.8,130.1,130.1,129.5,129.5,129.4,129.3,129.1,125.4,123.8,(C missing)；ESI-HRMS m/z calcd for C29H20N2O2+H(M+H):429.1598,found 429.1600.
I-21(94mg,Y＝87％)黄色固体；mp 56-57℃.1H NMR(400MHz,CDCl3)δ7.73(d,J＝5.2Hz,2H),7.57-7.47(m,8H),4.35(q,J＝6.8Hz,2H),1.25(t,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3)δ159.2,150.7,138.8,135.2(q,J＝2.0Hz),130.9,129.2,129.1,129.1,128.8,128.3,124.7,122.0(q,J＝266.0Hz),111.7(q,J＝37.0Hz),62.8,13.5；ESI-HRMSm/z calcd for C19H15F3N2O2+H(M+H):361.1158,found 361.1153.
上述数据中，产物Ⅰ-1的核磁谱图(氢谱和碳谱)如图1-2所示。
对于本领域技术人员而言，显然本发明不限于上述示范性实施例的细节，而且在不背离本发明的精神或基本特征的情况下，能够以其他的具体形式实现本发明。因此，无论从哪一点来看，均应将实施例看作是示范性的，而且是非限制性的，本发明的范围由所附权利要求而不是上述说明限定，因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。不应将权利要求中的任何附图标记视为限制所涉及的权利要求。
此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。
Claims (5)
1.一种全取代吡唑衍生物制备方法，其特征在于：所述制备方法如下所示：
即将通式Ⅱ所示的化合物、通式Ⅲ所示化合物溶解于二氯甲烷中，加入三乙胺，室温反应；待反应物Ⅱ完全消失，将反应混合物在减压条件下除去溶剂，浓缩物经硅胶柱层析洗脱得到目标化合物Ⅰ；
其中，Ar为苯基或者取代苯基取代基(包含4-硝基、4-甲基)；R1为苯基或者取代苯基取代基(包含4-甲氧羰基、4-硝基、2-氟、4-氯、2,6-二氯、4-溴、4-甲基、3-甲氧基)，稠环取代基(2-萘基)，杂环取代基(2-吡啶基、2-呋喃基)，烷基取代基(叔丁基、苄基、乙氧羰基)；R2和R3为下列取代基中一种或者两种：甲氧羰基取代基，乙氧羰基取代基，苯甲酰基和三氟甲基。
2.根据权利要求1所述的一种全取代吡唑衍生物制备方法，其特征在于：所述全取代吡唑环上同时带有四个取代基，其中R2和R3可以相同或者不同。
3.根据权利要求1所述的一种全取代吡唑衍生物制备方法，其特征在于：所述制备过程中，参与反应的各化合物的最优摩尔比为：
Ⅱ：Ⅲ：三乙胺＝1:1.5:1.8，
最优浓度为0.1M，即0.1摩尔每升，即可得到目标化合物Ⅰ。
4.根据权利要求1所述的一种全取代吡唑衍生物制备方法，其特征在于：所述制备过程中三乙胺替代物有DIPEA(二异丙基乙基胺)、碳酸铯、碳酸氢钠。
5.根据权利要求1所述的一种全取代吡唑衍生物制备方法，其特征在于：所述制备过程中溶剂二氯甲烷替代物有甲醇、乙腈。
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