CN103664796A - Synthesis method of 5-[2-(5-carboxyl-pyrimidyl)]-1,3-benzene dicarboxylic acid - Google Patents

Synthesis method of 5-[2-(5-carboxyl-pyrimidyl)]-1,3-benzene dicarboxylic acid Download PDF

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CN103664796A
CN103664796A CN201310648660.6A CN201310648660A CN103664796A CN 103664796 A CN103664796 A CN 103664796A CN 201310648660 A CN201310648660 A CN 201310648660A CN 103664796 A CN103664796 A CN 103664796A
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acid
compound
carboxy
yl
pyrimidin
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邢永恒
王继虓
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辽宁师范大学
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms

Abstract

The invention discloses a synthesis method of 5-[2-(5-carboxyl-pyrimidyl)]-1,3-benzene dicarboxylic acid, the synthesis method is as follows: first, synthesizing a compound A 5-[2-(4,4,5,5-tetramethyl-1,3,2-boric acid ether)]-1,3-benzoic acid dimethyl ester, then in argon or nitrogen protection conditions, performing a reflux reaction of the compound A and ethyl 2-chloropyrimidine-5-carboxylate in an organic solvent by adding of a catalyst to produce the final target compound B 5-[2-(5-carboxyl-pyrimidyl)]-1,3-benzene dicarboxylic acid, and compared with the prior art, the synthesis method has the advantages of low synthesis cost, high yield and high product purity.

Description

5- [2- (5-羧基-嘧啶基)]-1, 3-苯二羧酸的合成方法 5- [2- (5-carboxy - pyrimidin-yl)] - 1,3-benzenedicarboxylic acid synthesis

技术领域 FIELD

[0001] 本发明涉及一种含氮杂环联苯三角羧酸配体化合物的合成方法,特别是一种5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法。 [0001] The present invention relates to a method for synthesizing a nitrogen-containing heterocyclic ligands biphenyl triangle acid compound, in particular a 5- [2- (5-carboxy - pyrimidin-yl)] _ 1,3-benzenedicarboxylic acid synthetic methods.

背景技术 Background technique

[0002] 三角羧酸类配体具有良好的孔道结构、大的内表面积,使它们配合物在气体的贮存、分离、发光材料等方面具有潜在的应用。 [0002] Triangle acid ligands with good pore structure, large internal surface area, that they are complex was stored gas separation, luminescent materials have potential applications. 而含氮杂环联苯三角羧酸配体使其化合物的结构发生改变,并且使其气孔内电子环境得到优化从而提高了上述应用性能。 And nitrogen-containing heterocyclic ligand biphenyl triangle acid compound changes its structure and electronic environment so that the pores has been optimized to improve the performance of said application. 此外,三角羧酸类配体所合成的化合物在光学、催化、磁性、功能材料等领域具有潜在的应用价值,使其成为当今研究的热点之一。 In addition, the compounds of the triangular acids synthesized ligands have potential applications in the field of optical, catalytic, magnetic, functional materials, etc., making it one of the research hotspot. 然而,大尺寸的多羧酸化合物合成及其困难。 However, the large size of the polycarboxylic acid compound synthesized extremely difficult. 因此本发明中所涉及的5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸是一种具有巨大潜在商业价值的配体。 Therefore 5- [2- (5-carboxy - pyrimidin-yl)] The present invention relates to 1,3-benzenedicarboxylic acid _ it is a ligand having huge commercial potential. 但目前文献报道的合成方法成本昂贵,产率较低,很大程度限制了对其应用价值的研究探索。 But the current synthesis methods reported in the literature expensive, low yield, to a large extent limited the application of research and exploration of its value.

发明内容 SUMMARY

[0003] 本发明的目的是提供一种合成成本低、产率高、产品纯度高的5-[2-(5_羧基-嘧啶基)]-1, 3-苯二羧酸的合成方法,克服现有技术的不足。 [0003] The object of the present invention is to provide a synthetic low cost, high yield, high purity 5- [2- (5_-carboxy - pyrimidin-yl)] - synthesis of 1,3-benzene dicarboxylic acid, to overcome the deficiencies of the prior art.

[0004] 本发明的5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法,合成步骤为: (i )在氩气或氮气保护的条件下,以5-溴异肽酸二甲脂、联硼酸频那醇酯和乙酸钾按摩尔比1: 0.8~1.5: 2.8~3.5混合后溶于二氧六环,5-溴异肽酸二甲脂与二氧六环的用量比是I毫摩:2.6~2.8毫升,加入适量的催化剂,在110~130°C油浴下回流反应10~35小时,冷却后先用水稀释再用二氯甲烷对体系进行萃取,然后用浓盐水对有机层进行洗涤,收集有机相并用无水硫酸镁对其进行除水处理,过滤,真空浓缩,最后以石油醚和乙酸乙酯按体积比为10: 0.8~1.2的混合溶剂为洗脱剂用柱色谱法分离提纯得到目标化合物A:5_[2-(4,4,5,5-四甲基-1,3,2-硼酸醚)]_1,3-苯甲酸二甲酯; [0004] The present invention is 5- [2- (5-carboxy - pyrimidin-yl)] _ synthesis of 1,3-benzenedicarboxylic acid, synthetic steps: (i) under conditions of argon or nitrogen, to 5-bromo-isopeptide acid dimethyl ester, biphenyl boronic acid pinacol ester and potassium acetate molar ratio of 1: 0.8 to 1.5: 2.8 to 3.5 after mixing was dissolved in dioxane, 5-bromo-isopeptide acid dimethyl ester and of dioxane with I mmol ratio is: 2.6 to 2.8 ml, adding an appropriate amount of catalyst, the reaction was refluxed at 110 ~ 130 ° C oil bath for 10 to 35 hours, cooled and diluted with dichloromethane first water system was extracted, and then the organic layer was washed with brine, the organic phase was collected and dried over anhydrous magnesium sulfate and subjected to other treatment, filtered, concentrated in vacuo, and finally with petroleum ether and ethyl acetate at a volume ratio of 10: 0.8 to 1.2 a mixed solvent as eluent to give the title compound isolated and purified by column chromatography a: 5_ [2- (4,4,5,5-tetramethyl-1,3,2 borate ether)] _ 1,3-phenylene acid dimethyl ester;

(ϋ )在氩气或氮气保护下,将上步得到的A与2-氯嘧啶-5-羧酸乙酯按摩尔比1.2: (Ϋ) under argon or nitrogen atmosphere, the obtained in step A and 2-chloro-5-carboxylate at a molar ratio of 1.2:

I混合溶AK2CO3溶液、乙醇和甲苯按体积比1: 0.8~1.2: 2.8~3.2的混合溶剂中,A与K2CO3溶液的用量比是I晕摩:0.6~0.9毫升,加入适量催化剂,在9CT11CTC油浴下反应10-40小时,冷却后先用水稀释再用二氯甲烷对体系进行萃取,收集有机相并用无水硫酸镁对其进行除水处理,过滤,真空浓缩,然后以二氯甲烷和丙酮按体积比为99: 0.5~1.5为洗脱剂,用柱色谱法分离提纯得到白色产物,将白色产物水解,酸化至ρΗ=2白色固体析出,真空干燥得最终化合物B:5_[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸。 I mixed solution AK2CO3 solution, ethanol and toluene at a volume ratio 1: 9CT11CTC oil 0.6 to 0.9 ml, adding an appropriate amount of catalyst, in: 0.8 to 1.2: a mixed solvent of 2.8 to 3.2, A is and K2CO3 solution with ratio is I halo mol the reaction bath 10-40 hours, the system was extracted with dichloromethane after cooling and then diluted with water, the organic phase was collected and dried over anhydrous magnesium sulfate and subjected to other treatment, filtered, concentrated in vacuo, and then methylene chloride and acetone a volume ratio of 99: 0.5 to 1.5 as eluent, separated by column chromatography to give a white product, a white product was hydrolyzed, acidified ρΗ = 2 to precipitate a white solid, and dried in vacuo to give final compound B: 5_ [2- ( 5-carboxy - pyrimidin-yl)] _ 1,3-benzenedicarboxylic acid.

[0005] 本发明的5-[2-(5-羧基-喃唳基)]_1,3-苯二羧酸的合成方法,以5_溴异肽酸二甲脂、联硼酸频那醇酯和乙酸钾按摩尔比1:1: 3合成化合物A。 [0005] The present invention is 5- [2- (5-carboxy - thiopyran Li-yl)] _ 1,3-benzenedicarboxylic acid synthesis to 5_ bromo isopeptide acid dimethyl ester, boronic acid pinacol ester with and potassium acetate molar ratio of 1: 1: A. synthesis of compound 3

[0006] 本发明的5- [2- (5-羧基-嘧啶基)]-1,3-苯二羧酸的合成方法,制备化合物A使用的催化剂为[1,1'-双(二苯基膦)二戊铁]二氯化钯,用量为参与反应物总质量的0.2~ [0006] 5- [2- (5-carboxy - pyrimidin-yl)] - 1,3-synthesis method of the present invention are benzene dicarboxylic acid, a catalyst was prepared using Compound A is [1,1'-bis (diphenylphosphino phosphine) iron dipentyl] palladium dichloride, mass of the total amount of reactants participating in the 0.2 ~

0.5%。 0.5%. [0007] 本发明的5- [2- (5-羧基-嘧啶基)]-1,3-苯二羧酸的合成方法,制备化合物B所用溶剂SK2CO3溶液、乙醇和甲苯按体积比1:1: 3的混合溶剂,K2CO3溶液的浓度为2 M。 [0007] The present invention is 5- [2- (5-carboxy - pyrimidin-yl)] - 1,3-benzenedicarboxylic acid synthesis method, the solvent used in preparation of compound B SK2CO3 solution, ethanol and toluene at a volume ratio of 1: 1 : 3 mixed solvent, concentration of the solution of K2CO3 2 M.

[0008] 本发明的5- [2- (5-羧基-嘧啶基)]-1,3-苯二羧酸的合成方法,制备化合物B时所用催化剂为四三苯基膦钯,用量为参与反应物总质量的0.2~0.5%。 [0008] 5- [2- (5-carboxy - pyrimidin-yl)] - 1,3-synthesis method of the present invention is terephthalic acid, the preparation of the compound B used catalyst is tetrakis (triphenylphosphine) palladium, in an amount of participation 0.2 to 0.5% of the total mass of reactants.

[0009] 本发明的5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法,制备化合物A柱色谱法分离时用的洗脱剂为石油醚和乙酸乙酯体积比为10: I的混合溶剂。 [0009] The present invention is 5- [2- (5-carboxy - pyrimidin-yl)] _ synthetic method of 1,3-benzenedicarboxylic acid, the separation of the eluent Preparation of Compound A column chromatography petroleum ether and acetic acid ethyl volume ratio of 10: I of a mixed solvent.

[0010] 本发明的5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法,制备化合物B柱色谱法分离时用的洗脱剂为二氯甲烷和丙酮体积比为99: I的混合溶剂。 [0010] The present invention is 5- [2- (5-carboxy - pyrimidin-yl)] _ synthetic method of 1,3-benzenedicarboxylic acid, eluent B during preparation of the compounds isolated by column chromatography and methylene chloride acetone volume ratio of 99: I of a mixed solvent.

[0011] 本发明的5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法与现有技术相比具有合成成本低、产率高、产品纯度高的优点。 [0011] The present invention is 5- [2- (5-carboxy - pyrimidin-yl)] _ synthesis of 1,3-benzenedicarboxylic acid as compared with the prior art synthesis of low cost, high yield, product purity advantage.

附图说明 BRIEF DESCRIPTION

[0012] 图1本发明中化合物A的化学式示意图; [0012] The present invention in FIG. 1 A schematic compound of formula;

图2本发明中化合物A的合成路线示意图; Scheme A Compound of the present invention in a schematic view of FIG. 2;

图3本发明中化合物B的合成路线示意图; Scheme B Compound of the present invention in a schematic view of FIG. 3;

图4本发明中化合物A的红外谱图; A compound of the present invention in FIG. 4 A, IR spectrum;

图5本发明中化合物B的红外谱图。 5 IR spectrum of compound of the present invention, the B.

具体实施方式 Detailed ways

[0013] 先合成化合物A:5_[2-(4,4,5,5_四甲基_1,3,2_硼酸醚)]_1,3_苯甲酸二甲酯,然后在氩气或氮气保护条件下加入催化剂让其与2-氯嘧啶-5-羧酸乙酯在有机溶剂中回流反应,生成最终目标化合物B:5_[2- (5-羧基-嘧啶基)]-1, 3-苯二羧酸。 [0013] First Synthesis of Compound A: 5_ [2- (4,4,5,5_ _1,3,2_ acid tetramethyl ether)] _ 1,3_ dimethyl terephthalate, or argon and then the catalyst was added and allowed to 2-chloro-5-carboxylate was refluxed in an organic solvent, to yield the final target compound B under a nitrogen blanket: 5_ 1, 3 - [2- (5-carboxy - pyrimidin-yl)] - benzenedicarboxylic acid.

[0014] 本发明的5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法,合成步骤为: [0014] The present invention is 5- [2- (5-carboxy - pyrimidin-yl)] _ synthesis method, the step of synthesizing 1,3-benzenedicarboxylic acid is:

(i )在氩气或氮气保护的条件下,以5-溴异肽酸二甲脂、联硼酸频那醇酯和乙酸钾按摩尔比1: 0.8~1.5: 2.8~3.5混合后溶于二氧六环,5-溴异肽酸二甲脂与二氧六环的用量比是I毫摩:2.6~2.8毫升,加入适量的催化剂,在110~130°C油浴下回流反应10~35小时,冷却后先用水稀释再用二氯甲烷对体系进行萃取,然后用浓盐水对有机层进行洗涤,收集有机相并用无水硫酸镁对其进行除水处理,过滤,真空浓缩,最后以石油醚和乙酸乙酯按体积比为10: 0.8~1.2的混合溶剂为洗脱剂用柱色谱法分离提纯得到目标化合物A:5_[2-(4,4,5,5-四甲基-1,3,2-硼酸醚)]-1,3-苯甲酸二甲酯; (I) under conditions of argon or nitrogen, to 5-bromo-isopeptide acid dimethyl ester, biphenyl boronic acid pinacol ester and potassium acetate molar ratio of 1: 0.8 to 1.5: 2.8 to 3.5 after mixing was dissolved in diethyl oxygen dioxane, 5-bromo-isopeptide acid dimethyl ester and with dioxane mmol ratio is I: 2.6 to 2.8 ml, adding an appropriate amount of catalyst, the reaction was refluxed at 10 ~ 35 110 ~ 130 ° C oil bath hours, diluted with dichloromethane after cooling the system was extracted with water, then the organic layer was washed with brine, the organic phase was collected and dried over anhydrous magnesium sulfate and subjected to other treatment, filtered, concentrated in vacuo, and finally with petroleum ether and ethyl acetate at a volume ratio of 10: 1.2 mixed solvent of 0.8 to separation and purification to give the title compound a by column chromatography eluting agent: 5_ [2- (4,4,5,5-tetramethyl-1 , 3,2 borate ether)] - 1,3-dimethyl benzoic acid;

(ϋ )在氩气或氮气保护下,将上步得到的A与2-氯嘧啶-5-羧酸乙酯按摩尔比1.2: (Ϋ) under argon or nitrogen atmosphere, the obtained in step A and 2-chloro-5-carboxylate at a molar ratio of 1.2:

I混合溶AK2CO3溶液、乙醇和甲苯按体积比1: 0.8~1.2: 2.8~3.2的混合溶剂中,A与K2CO3溶液的用量比是I晕摩:0.6~0.9毫升,加入适量催化剂,在9CT11CTC油浴下反应10-40小时,冷却后先用水稀释再用二氯甲烷对体系进行萃取,收集有机相并用无水硫酸镁对其进行除水处理,过滤,真空浓缩,然后以二氯甲烷和丙酮按体积比为99: 0.5~ I mixed solution AK2CO3 solution, ethanol and toluene at a volume ratio 1: 9CT11CTC oil 0.6 to 0.9 ml, adding an appropriate amount of catalyst, in: 0.8 to 1.2: a mixed solvent of 2.8 to 3.2, A is and K2CO3 solution with ratio is I halo mol the reaction bath 10-40 hours, the system was extracted with dichloromethane after cooling and then diluted with water, the organic phase was collected and dried over anhydrous magnesium sulfate and subjected to other treatment, filtered, concentrated in vacuo, and then methylene chloride and acetone a volume ratio of 99: 0.5

1.5为洗脱剂,用柱色谱法分离提纯得到白色产物,将白色产物水解,酸化至ρΗ=2白色固体析出,真空干燥得最终化合物B:5_[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸。 1.5 as eluent, separated by column chromatography to give a white product, a white product was hydrolyzed, acidified ρΗ = 2 to precipitate a white solid, and dried in vacuo to give final compound B: 5_ [2- (5- carboxy - pyrimidin-yl)] _1,3- benzenedicarboxylic acid.

[0015] 本发明的5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法,以5_溴异肽酸二甲脂、联硼酸频那醇酯和·乙酸钾按摩尔比1:1: 3合成化合物A。 [0015] The present invention is 5- [2- (5-carboxy - pyrimidin-yl)] _ 1,3-benzenedicarboxylic acid synthesis to 5_ bromo isopeptide acid dimethyl ester, biphenyl boronic acid pinacol ester and · potassium acetate molar ratio of 1: 1: A. synthesis of compound 3 [0016] 本发明的5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法,制备化合物A使用的催化剂为[1,1'-双(二苯基膦)二戊铁]二氯化钯,用量为参与反应物总质量的0.2~ [0016] The present invention is 5- [2- (5-carboxy - pyrimidin-yl)] _ synthesis of 1,3-benzenedicarboxylic acid, the catalyst is used in the preparation of compound A [1,1'-bis (diphenylphosphino phosphine) iron dipentyl] palladium dichloride, mass of the total amount of reactants participating in the 0.2 ~

0.5%。 0.5%.

[0017] 本发明的5- [2- (5-羧基-嘧啶基)]-1,3-苯二羧酸的合成方法,制备化合物B所用溶剂SK2CO3溶液、乙醇和甲苯按体积比1:1: 3的混合溶剂,K2CO3溶液的浓度为2 M。 [0017] The present invention is 5- [2- (5-carboxy - pyrimidin-yl)] - 1,3-benzenedicarboxylic acid synthesis method, the solvent used in preparation of compound B SK2CO3 solution, ethanol and toluene at a volume ratio of 1: 1 : 3 mixed solvent, concentration of the solution of K2CO3 2 M.

[0018] 本发明的5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法,制备化合物B时所用催化剂为四三苯基膦钯,用量为参与反应物总质量的0.2~0.5%。 [0018] 5- [2- (5-carboxy - pyrimidin-yl)] _ according to the present invention synthesis of 1,3-benzenedicarboxylic acid, the preparation of the compound B used catalyst is tetrakis (triphenylphosphine) palladium, in an amount of participating in the reaction 0.2 to 0.5% of the total mass of the composition.

[0019] 本发明的5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法,制备化合物A柱色谱法分离时用的洗脱剂为石油醚和乙酸乙酯体积比为10: I的混合溶剂。 [0019] The present invention is 5- [2- (5-carboxy - pyrimidin-yl)] _ synthetic method of 1,3-benzenedicarboxylic acid, the separation of the eluent Preparation of Compound A column chromatography petroleum ether and acetic acid ethyl volume ratio of 10: I of a mixed solvent.

[0020] 本发明的5- [2- (5-羧基-嘧啶基)]-1,3-苯二羧酸的合成方法,制备化合物B柱色谱法分离时用的洗脱剂为二氯甲烷和丙酮体积比为99: I的混合溶剂。 [0020] 5- [2- (5-carboxy - pyrimidin-yl)] - synthetic method of the present invention is 1,3-phenylene dicarboxylic acid, eluent B during preparation of the compounds isolated by column chromatography methylene chloride volume ratio of acetone and 99: I of a mixed solvent.

[0021] 具体实施例如下: [0021] Specific embodiments are as follows:

如图1、2所示:(i)在氮气保护的条件下,以5-溴异肽酸二甲脂2.0 g(7.32 mmol)、联硼酸频那醇酯1.85 g(7.32 mmol)和乙酸钾2.16 g(22 mmol)按摩尔比1: 1:3混合后溶于20 ml 二氧六环,加入160 mg (3%) [I, 1' -双(二苯基膦)二戊铁]二氯化钯催化剂,在128 1:油浴下回流反应24小时。 FIG 1 and 2: (i) under conditions of nitrogen, to 5-bromo-isopeptide acid dimethyl ester 2.0 g (7.32 mmol), with boronic acid (7.32 mmol) and potassium acetate esters that 1.85 g 2.16 g (22 mmol) at a molar ratio of 1: 1: 3 mixture is dissolved in 20 ml of dioxane, was added 160 mg (3%) [I, 1 '- bis (diphenylphosphino) dipentyl iron] bis palladium chloride catalyst, in 1281: an oil bath to reflux for 24 hours. 冷却后先加入20 ml水稀释,接着分四次共计加入80 ml二氯甲烷对体系进行萃取,然后用80 ml浓盐水对有机层进行洗涤,收集有机相并用无水硫酸镁对其进行除水处理,过滤,真空浓缩,最后以石油醚和乙酸乙酯按体积比为10:1的混合溶剂为洗脱剂用柱色谱法分离提纯得到化合物A 2.09 g,产率89.13%。 After cooling, diluted with 20 ml of water was added first, followed by a total of four times 80 ml of methylene chloride was added to the system was extracted, and then the organic layer was washed with 80 ml brine, the organic phase was collected and subjected to removal of water and dried over anhydrous magnesium sulfate , filtered, concentrated in vacuo, and finally with petroleum ether and ethyl acetate at a volume ratio of 10: 1 mixed solvent of separation and purification to give compound a 2.09 g, 89.13% yield by column chromatography as eluent.

[0022]红外谱图见图 4,主要峰归属如下:2987,2861 (C_H);1730 (C=0);1604, 1459 (苯环特征峰);1250, 1140 (COC)0 [0022] IR spectrum shown in Figure 4, the main peak assignments are as follows: 2987,2861 (C_H); 1730 (C = 0); 1604, 1459 (benzene characteristic peak); 1250, 1140 (COC) 0

[0023] 如图3所示:(ii)在氮气保护下,将化合物A 1.00 g (5.36 mmol)与2_氯嘧啶-5-羧酸乙酯2.00 g(6.25 mmol)按摩尔比1.2:1混合后倒入烧瓶中,加入4 ml 2 MK2CO3溶液、4 ml乙醇和12 ml甲苯的混合溶剂,加入0.31 g(0.26 mmol)四三苯基膦钯为催化剂,在101 °C油浴下反应24小时。 [0023] As shown in FIG 3: (ii) Under nitrogen, compound A 1.00 g (5.36 mmol) and 2_-chloro-5-carboxylate 2.00 g (6.25 mmol) molar ratio of 1.2: 1 after the mixture was poured into a flask, was added 4 ml 2 MK2CO3 a mixed solvent solution, 4 ml of ethanol and 12 ml of toluene, was added 0.31 g (0.26 mmol) tetrakis (triphenylphosphine) palladium as a catalyst, the reaction at 101 ° C oil bath for 24 hour. 冷却后先加入20 ml水稀释,接着分四次加入80ml 二氯甲烷对体系进行萃取,收集有机相并用无水硫酸镁对其进行除水处理,过滤,真空浓缩,然后以二氯甲烷和丙酮按体积比为99:1为洗脱剂,用柱色谱法分离提纯得到白色产物。 After cooling, diluted with 20 ml of water was added first, followed by four times with dichloromethane and then added 80ml acetone, the system was extracted with dichloromethane, the organic phase was collected and dried over anhydrous magnesium sulfate and subjected to other treatment, filtered, concentrated in vacuo, a volume ratio of 99: 1 as eluent, separated by column chromatography to give a white product. 在室温下,用5 ml 5 M KOH溶液、5 ml四氢呋喃和5 ml乙醇混合溶剂对白色产物进行水解24小时,过滤,倒入25 ml水稀释,用4 M HCl将其酸化至pH=2,白色固体析出,过滤,真空干燥得化合物B 0.74g,产率47.40%。 At room temperature with 5 ml 5 M KOH solution, 5 ml of tetrahydrofuran and 5 ml ethanol mixed solvent of white product was hydrolyzed for 24 hours, filtered, Pour 25 ml of water was diluted with 4 M HCl acidified to pH = 2, a white solid was precipitated, filtered, and dried in vacuo to give compound B 0.74g, yield 47.40%. 1H NMR (300 MHz, DMS0_d6) δ 9.29 (s, 2H), 1H NMR (300 MHz, DMS0_d6) δ 9.29 (s, 2H),

9.17 (d, J = 1.2 Hz, 2H), and 8.61 (d, J = 1.5 Hz, 2 H) ppm; 13C NMR (100 MHz,DMS0-d6) δ 166.2,164.8,164.1, 158.7,137.2,132.8,132.6,132.2,and 132.3ppm。 9.17 (d, J = 1.2 Hz, 2H), and 8.61 ppm (d, J = 1.5 Hz, 2 H); 13C NMR (100 MHz, DMS0-d6) δ 166.2,164.8,164.1, 158.7,137.2,132.8, 132.6,132.2, and 132.3ppm.

[0024] 红外谱图见图5,主要峰归属如下:3079 (=C_H);2919,2856 (C_H);2719~2520 (羧酸特征峰);1706 (C=O) ; 1602,1440 (苯环特征峰)。 [0024] IR spectrum shown in Figure 5, the main peak attributed as follows: 3079 (= C_H); 2919,2856 (C_H); 2719 ~ 2520 (carboxylic characteristic peak); 1706 (C = O); 1602,1440 (benzene loop characteristic peaks).

[0025] 上述的具体实施例中各成份的用量还可选择技术方案中所给出的数值范围中的下限值或上限值或数值范围中的任意数值。 Any value may be selected in the ranges of values ​​given in the technical solutions in the upper or lower limit value or the numerical range of the ingredients in the amounts embodiment [0025] The above specific embodiments.

[0026] 本发明的5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法具有合成成本低、产率高、产品纯度高的优点。 5- [2- (5-carboxy - pyrimidin-yl)] [0026] The synthesis of the present invention is a low cost, high yield and high purity synthesis of advantages _ 1,3-benzenedicarboxylic acid having.

Claims (7)

1.一种5-[2-(5-羧基-嘧啶基)]-1,3-苯二羧酸的合成方法,其特征在于:合成步骤为: (i )在氩气或氮气保护的条件下,以5-溴异肽酸二甲脂、联硼酸频那醇酯和乙酸钾按摩尔比1: 0.8~1.5: 2.8~3.5混合后溶于二氧六环,5-溴异肽酸二甲脂与二氧六环的用量比是I毫摩:2.6~2.8毫升,加入适量的催化剂,在110~130°C油浴下回流反应.10~35小时,冷却后先用水稀释再用二氯甲烷对体系进行萃取,然后用浓盐水对有机层进行洗涤,收集有机相并用无水硫酸镁对其进行除水处理,过滤,真空浓缩,最后以石油醚和乙酸乙酯按体积比为10: 0.8~1.2的混合溶剂为洗脱剂用柱色谱法分离提纯得到目标化合物A:5- [2- (4,4,5,5-四甲基-1,3,2-硼酸醚)]-1,3-苯甲酸二甲酯; (ii)在氩气或氮气保护下,将上步得到的A与2-氯嘧啶-5-羧酸乙酯按摩尔比1.2:I混合溶入K2CO3溶液、乙醇和甲苯按体积比1: 0.8~1. A 5- [2- (5-carboxy - pyrimidin-yl)] - 1,3-benzenedicarboxylic acid synthesis method, which is characterized in that: the synthesis steps of: (i) conditions of argon or nitrogen next, using 5-bromo-isopeptide acid dimethyl ester, biphenyl boronic acid pinacol ester and potassium acetate molar ratio of 1: 0.8 to 1.5: 2.8 to 3.5 after mixing was dissolved in dioxane, 5-bromo-isopeptide acid methyl ester and with dioxane ratio is I mmol: 2.6 to 2.8 ml, adding an appropriate amount of catalyst, the reaction was refluxed at 110 ~ 130 ° C oil bath for .10 to 35 hours. after cooling with water diluted with diethyl the system was extracted with dichloromethane, and the organic layer was washed with brine, the organic phase was collected and dried over anhydrous magnesium sulfate and subjected to other treatment, filtered, concentrated in vacuo, and finally with petroleum ether and ethyl acetate at a volume ratio of 10 : a mixed solvent of 0.8 to 1.2 as the eluent was purified by column chromatography to give the title compound a: 5- [2- (4,4,5,5- tetramethyl-1,3,2 borate ether)] 1,3-dimethyl benzoic acid; (ii) under argon or nitrogen atmosphere, the obtained in step a and 2-chloro-5-carboxylate at a molar ratio of 1.2: I mixing K2CO3 dissolved solution, ethanol and toluene at a volume ratio of 1: 0.8 to 1. 2: 2.8~3.2的混合溶剂中,A与K2CO3溶液的用量比是I晕摩:0.6~0.9毫升,加入适量催化剂,在9CT11CTC油浴下反应10-40小时,冷却后先用水稀释再用二氯甲烷对体系进行萃取,收集有机相并用无水硫酸镁对其进行除水处理,过滤,真空浓缩,然后以二氯甲烷和丙酮按体积比为99: 0.5~.1.5为洗脱剂,用柱色谱法分离提纯得到白色产物,将白色产物水解,酸化至ρΗ=2白色固体析出,真空干燥得最终化合物B:5_[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸。 2: a mixed solvent of 2.8 to 3.2, A is the ratio of K2CO3 solution used is halo Mount I: 0.6 to 0.9 ml, adding an appropriate amount of the catalyst, the reaction 9CT11CTC an oil bath at 10-40 hours, cooled and then diluted with water two the system was extracted with dichloromethane, the organic phase was collected and subjected to treatment except with anhydrous magnesium sulfate, filtered, concentrated in vacuo, and then methylene chloride and acetone in a volume ratio of 99: 0.5 to .1.5 as eluent, with isolated and purified by column chromatography to give a white product, a white product was hydrolyzed, acidified ρΗ = 2 to precipitate a white solid, and dried in vacuo to give final compound B: 5_ [2- (5- carboxy - pyrimidin-yl)] 1,3-benzene dicarboxylic _ acid.
2.根据权利要求1所述的一种5- [2- (5-羧基-嘧啶基)]-1,3-苯二羧酸的合成方法,其特征在于:以5-溴异肽酸二甲脂、联硼酸频那醇酯和乙酸钾按摩尔比1:1: 3合成化合物A。 In bromo isopeptide acid: synthesis of 1,3-benzenedicarboxylic acid, wherein - A 5- [(- 5-carboxy-pyrimidin-yl) 2-] according to claim 1 methyl ester, biphenyl boronic acid pinacol ester and potassium acetate molar ratio of 1: 1: A. synthesis of compound 3
3.根据权利要求2所述的一种5- [2- (5-羧基-嘧啶基)]-1, 3-苯二羧酸的合成方法,其特征在于:制备化合物A使用的催化剂为[1,1'-双(二苯基膦)二戊铁]二氯化钯,用量为参与反应物总质量的0.2~0.5%。 3. A crystal of 5- [2- (5-carboxy - pyrimidin-yl)] - 2 according to claim 1, Synthesis of 3-benzene dicarboxylic acid, wherein: A catalyst used for the preparation of Compound [ 1,1'-bis (diphenylphosphino) diamyl iron] dichloropalladium, participating in an amount of 0.2 to 0.5% of the total mass of reactants.
4.根据权利要求3所述的一种5- [2- (5-羧基-嘧啶基)]-1, 3-苯二羧酸的合成方法,其特征在于:制备化合物B所用溶剂为K2CO3溶液、乙醇和甲苯按体积比1:1: 3的混合溶剂,K2CO3溶液的浓度为2 M0 According to claim 3 A crystal of 5- [2- (5-carboxy - pyrimidin-yl)] - 1, 3- benzenedicarboxylic acid synthesis method, which is characterized in that: Preparation of Compound B used as a solvent solution of K2CO3 , ethanol and toluene at a volume ratio of 1: 1: 3 mixed solvent, concentration of the solution is 2 M0 K2CO3
5.根据权利要求4所述的一种5-[2-(5-羧基-嘧啶基)]_1,3-苯二羧酸的合成方法,其特征在于:制备化合物B时所用催化剂为四三苯基膦钯,用量为参与反应物总质量的.0.2 ~0.5%ο 5. According to one of the claims 5-4 [2- (5-carboxy - pyrimidin-yl)] _ synthetic method of 1,3-benzenedicarboxylic acid, comprising: preparing the catalyst used was Compound B forty-three triphenylphosphine palladium, in an amount of participation .0.2 to 0.5% of the total mass of reactants ο
6.根据权利要求5所述的一种5-[2- (5-羧基-嘧啶基)]-1, 3-苯二羧酸的合成方法,其特征在于:制备化合物A柱色谱法分离时用的洗脱剂为石油醚和乙酸乙酯体积比为10:I的混合溶剂。 6. According to one of the claims 5-5 [2- (5-carboxy - pyrimidin-yl)] - 1, 3- benzenedicarboxylic acid synthesis method, which is characterized in that: Preparation of Compound A isolated by column chromatography upon with eluent petroleum ether and ethyl acetate of a volume ratio of 10: I of a mixed solvent.
7.根据权利要求8所述的一种5- [2- (5-羧基-嘧啶基)]-1, 3-苯二羧酸的合成方法,其特征在于:制备化合物B柱色谱法分离时用的洗脱剂为二氯甲烷和丙酮体积比为99: I的混合溶剂。 7. A crystal of 5- [2- (5-carboxy - pyrimidin-yl)] - 8 according to claim 1, Synthesis of 3-benzene dicarboxylic acid, which is characterized in that: Preparation of Compound B isolated by column chromatography upon eluent of methylene chloride and acetone to a volume ratio of 99: I mixed solvent.
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