CN109020853A - 一种金属螯合配基及其制备方法 - Google Patents
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- 229910052751 metal Inorganic materials 0.000 title claims abstract description 64
- 239000002184 metal Substances 0.000 title claims abstract description 64
- 239000003446 ligand Substances 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 72
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims abstract description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 36
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000001413 amino acids Chemical class 0.000 claims abstract description 13
- 239000011593 sulfur Substances 0.000 claims abstract description 12
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 12
- 150000001408 amides Chemical class 0.000 claims abstract description 10
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 9
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
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- 238000003756 stirring Methods 0.000 claims description 25
- 239000008367 deionised water Substances 0.000 claims description 20
- 229910021641 deionized water Inorganic materials 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 238000004821 distillation Methods 0.000 claims description 14
- 238000013517 stratification Methods 0.000 claims description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 10
- 235000001014 amino acid Nutrition 0.000 claims description 10
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 claims description 9
- 239000012071 phase Substances 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- 229940113088 dimethylacetamide Drugs 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 2
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- 229910052708 sodium Inorganic materials 0.000 claims description 2
- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 claims 1
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- 125000005586 carbonic acid group Chemical group 0.000 claims 1
- 238000002242 deionisation method Methods 0.000 claims 1
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- 239000003638 chemical reducing agent Substances 0.000 abstract description 5
- 239000002738 chelating agent Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 7
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000013522 chelant Substances 0.000 description 6
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- 238000010521 absorption reaction Methods 0.000 description 5
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001042 affinity chromatography Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
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- 150000002500 ions Chemical class 0.000 description 3
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- 229920000936 Agarose Polymers 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- NBZBKCUXIYYUSX-UHFFFAOYSA-N iminodiacetic acid Chemical compound OC(=O)CNCC(O)=O NBZBKCUXIYYUSX-UHFFFAOYSA-N 0.000 description 2
- 229910001453 nickel ion Inorganic materials 0.000 description 2
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 2
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- 238000012360 testing method Methods 0.000 description 2
- -1 thio sulphur Chemical compound 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 1
- 241000080590 Niso Species 0.000 description 1
- IDIDJDIHTAOVLG-VKHMYHEASA-N S-methylcysteine Chemical compound CSC[C@H](N)C(O)=O IDIDJDIHTAOVLG-VKHMYHEASA-N 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 229910001431 copper ion Inorganic materials 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
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- 239000011806 microball Substances 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- JLKDVMWYMMLWTI-UHFFFAOYSA-M potassium iodate Chemical compound [K+].[O-]I(=O)=O JLKDVMWYMMLWTI-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/22—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/12—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by reactions not involving the formation of mercapto groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
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- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
- C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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Abstract
本发明涉及一种金属螯合配基及其制备方法，属于化学领域。所述金属螯合配基是在含硫氨基酸的氨基上连接两个相同的羧酸而成，本发明还提供了上述金属螯合配基的制备方法，将酰胺和含硫氨基酸在碳酸盐、碘化钾和氮气存在的条件下反应，然后将反应产物进行分离纯化，制得上述金属螯合配基。本发明的金属螯合配基能够耐受金属螯合剂、还原剂和高浓度盐，并且制备方法简单。
Description
技术领域
本发明涉及分离纯化技术领域，具体涉及一种金属螯合配基及其制备方法。
背景技术
目前用于金属螯合层析介质的配基主要有两种类型，一种是以亚氨基二乙酸(IDA)为主的高载量类型配基，一种是以氮川三乙酸(NTA)为主的低耐受类型配基，由于低耐受类型配基可以耐受低浓度的金属螯合剂和还原剂，对于需要分离纯化的样品适用范围更广，通过这种低耐受类型的金属螯合配基螯合金属镍离子的层析介质通常是纯化含有组氨酸标签样品的首选，所以低耐受类型的金属螯合配基选择，直接关系到纯化组氨酸标签样品的适用范围和纯化效果。由于氮川三乙酸(NTA)是在一个氨基上连接三个乙酸基团，微溶于水，其制备成金属螯合层析介质的工艺复杂耗时，并且组氨酸标签样品中的盐浓度会影响组氨酸与螯合的金属离子结合，对高盐样品的吸附载量和纯度有较大影响，利用现有金属螯合配基对高盐组氨酸标签样品的分离纯化效率不高。
发明内容
本发明为了解决上述技术问题，提供一种可以耐受金属螯合剂、还原剂和高浓度盐的金属螯合配基。
本发明解决上述技术问题的技术方案如下：一种金属螯合配基，在含硫氨基酸的氨基上连接两个相同的羧酸而成，其结构式如下：
其中R2为C1～C3烷基中的一种。
在上述技术方案的基础上，本发明还可以做如下改进。
进一步，所述含硫氨基酸为L-胱氨酸、L-半胱氨酸、N-乙酰半胱氨酸、羧甲基半胱氨酸中的任一种。
本发明的有益效果是：本发明的金属螯合配基具有金属螯合剂和还原剂的耐受性，本发明的金属螯合配基制备成金属镍螯合层析介质时，镍离子的六个螯合价位中，四个螯合价位连接该金属螯合配基中的四个配位键，剩下两个螯合价位对样品中的组氨酸进行特异性结合，该金属螯合配基与金属离子螯合价位越多越稳定，其耐受性也就越强；本发明的金属螯合配基具有高盐浓度耐受性，R1和R2提高了配基的疏水性，样品在高盐环境中暴露于表面的疏水残基与金属螯合配基的弱疏水性基团之间的结合作用，从而实现可以在高盐浓度条件下的样品直接上样，进行分离纯化，从而不需要对高盐的样品进行脱盐处理。
本发明还提供了一种上述金属螯合配基的制备方法，包括以下步骤：
(1)将酰胺与含硫氨基酸在碳酸盐、碘化钾和氮气存在的条件下反应，反应方程式为：
R2为C1～C3烷基中的一种，R3为H或甲酰基，R4为H或甲基；
(2)将反应产物进行分离纯化，制得所述金属螯合配基。
在上述技术方案的基础上，本发明还可以做如下改进。
进一步，步骤(1)的具体步骤为：将酰胺加入反应釜中，然后依次加入碳酸盐、碘化钾和含硫氨基酸，以酰胺为基准，单位以L计，加入的碳酸盐、碘化钾和含硫氨基酸的质量分别为50～5000g、5～500g和10～1000g，向反应釜中通入氮气，加热至20～60℃，200～500rpm下搅拌反应1～5h，反应完成后，停止通入氮气。
其中，所述酰胺为乙酰胺、丙酰胺、丁酰胺、二甲基乙酰胺中的任一种。
所述碳酸盐为碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾中的任一种。
进一步，步骤(2)的具体步骤为反应结束反应釜降温后，依次用乙酸乙酯-水混合溶液、硫代硫酸钠溶液、去离子水、稀盐酸、去离子水室温下对反应产物进行搅拌洗涤，每次洗涤后静置分层弃去水相保留有机相，然后蒸馏得到所述金属螯合配基。
进一步，所述乙酸乙酯-水溶液中乙酸乙酯的体积分数为5％～50％，所述硫代硫酸钠溶液的质量分数为5％～50％，所述稀盐酸的浓度为0.01～1M,搅拌的时间为10～60min，静置分层的时间为10～60min。
蒸馏的温度为20～60℃，蒸馏的时间为24～48h。
酰胺在高温加热和还原剂碘化钾的作用下发生还原反应生成胺和羧酸，生成的羧酸随即与含有氨基、羧基、硫等功能基团的氨基酸在氮气的保护下反应得到金属螯合配基。
本发明的制备方法的有益效果是：该制备方法只需要一次反应就可以得到本发明的金属螯合配基，生产周期短，成本低，工艺简单。
附图说明
图1为本发明实施例1-7的金属螯合配基制备的镍金属螯合层析介质的外观颜色图，其中自左至右分别为实施例1、实施例2、实施例3、实施例4、
实施例5、实施例6和实施例7；
具体实施方式
以下结合附图及具体实施例对本发明的原理和特征进行描述，所举实例只用于解释本发明，并非用于限定本发明的范围。
实施例1
量取10L的二甲基乙酰胺加入通风柜中的100L玻璃反应釜中，称取3000g的碳酸钠加入通风柜中的100L玻璃反应釜中，100rpm恒速搅拌，分别称取300g和500g的碘化钾和L-胱氨酸加入通风柜中的反应釜中，然后将氮气通过管路向反应釜内通入氮气，加热控制温度为80℃,300rpm恒速搅拌反应2h，反应完成后，停止通入氮气，将反应釜内温度降至20℃，记录有机相清洗前的体积；
将30L体积分数为50％的乙酸乙酯-水混合溶液加入反应釜中，室温100rpm恒速搅拌10min，停止搅拌，静置分层10min后将下层水相溶液放出，保留上层有机相在反应釜中，然后分别用10L质量分数为5％的硫代硫酸钠、20L去离子水、30L 0.01M的盐酸溶液、20L去离子水依次洗涤，最后去离子水洗涤过后将下层水相放出，保留上层有机相在反应釜中，在反应釜中加装蒸馏装置，加热控制温度至50℃，100rpm恒速搅拌24h蒸馏有机相，得到的固体即为金属螯合配基，将金属螯合配基放入密封棕色瓶中冲入氮气冷藏保存，记录蒸馏后配基质量和配基外观颜色。
实施例2
量取10L的二甲基乙酰胺加入通风柜中的100L玻璃反应釜中，称取3000g的碳酸钠加入通风柜中的100L玻璃反应釜中，100rpm恒速搅拌，分别称取300g和500g的碘化钾和N-乙酰半胱氨酸加入通风柜中的反应釜中，然后将氮气通过管路向反应釜内通入氮气，加热控制温度为80℃,300rpm恒速搅拌反应2h，反应完成后，停止通入氮气，将反应釜内温度降至20℃，记录有机相清洗前的体积；
将30L体积分数为50％的乙酸乙酯-水混合溶液加入反应釜中，室温100rpm恒速搅拌10min，停止搅拌，静置分层10min后将下层水相溶液放出，保留上层有机相在反应釜中，然后分别用10L质量分数为5％的硫代硫酸钠、20L去离子水、30L 0.01M的盐酸溶液、20L去离子水依次洗涤，最后去离子水洗涤过后将下层水相放出，保留上层有机相在反应釜中，在反应釜中加装蒸馏装置，加热控制温度至50℃，100rpm恒速搅拌24h蒸馏有机相，得到的固体即为金属螯合配基，将金属螯合配基放入密封棕色瓶中冲入氮气冷藏保存，记录蒸馏后配基质量和配基外观颜色。
实施例3
量取10L的二甲基乙酰胺加入通风柜中的100L玻璃反应釜中，称取3000g的碳酸钠加入通风柜中的100L玻璃反应釜中，100rpm恒速搅拌，分别称取300g和500g的碘化钾和L-半胱氨酸加入通风柜中的反应釜中，然后将氮气通过管路向反应釜内通入氮气，加热控制温度为80℃,300rpm恒速搅拌反应2h，反应完成后，停止通入氮气，将反应釜内温度降至20℃，记录有机相清洗前的体积；
将30L体积分数为50％的乙酸乙酯-水混合溶液加入反应釜中，室温100rpm恒速搅拌10min，停止搅拌，静置分层10min后将下层水相溶液放出，保留上层有机相在反应釜中，然后分别用10L质量分数为5％的硫代硫酸钠、20L去离子水、30L 0.01M的盐酸溶液、20L去离子水依次洗涤，最后去离子水洗涤过后将下层水相放出，保留上层有机相在反应釜中，在反应釜中加装蒸馏装置，加热控制温度至50℃，100rpm恒速搅拌24h蒸馏有机相，得到的固体即为金属螯合配基，将金属螯合配基放入密封棕色瓶中冲入氮气冷藏保存，记录蒸馏后配基质量和配基外观颜色。
实施例4
量取10L的二甲基乙酰胺加入通风柜中的100L玻璃反应釜中，称取3000g的碳酸钠加入通风柜中的100L玻璃反应釜中，100rpm恒速搅拌，分别称取300g和500g的碘化钾和羧甲基半胱氨酸加入通风柜中的反应釜中，然后将氮气通过管路向反应釜内通入氮气，加热控制温度为80℃,300rpm恒速搅拌反应2h，反应完成后，停止通入氮气，将反应釜内温度降至20℃，记录有机相清洗前的体积；
将30L体积分数为50％的乙酸乙酯-水混合溶液加入反应釜中，室温100rpm恒速搅拌10min，停止搅拌，静置分层10min后将下层水相溶液放出，保留上层有机相在反应釜中，然后分别用10L质量分数为5％的硫代硫酸钠、20L去离子水、30L 0.01M的盐酸溶液、20L去离子水依次洗涤，最后去离子水洗涤过后将下层水相放出，保留上层有机相在反应釜中，在反应釜中加装蒸馏装置，加热控制温度至50℃，100rpm恒速搅拌24h蒸馏有机相，得到的固体即为金属螯合配基，将金属螯合配基放入密封棕色瓶中冲入氮气冷藏保存，记录蒸馏后配基质量和配基外观颜色。
实施例5
量取10L的乙酰胺加入通风柜中的100L玻璃反应釜中，称取3000g的碳酸钠加入通风柜中的100L玻璃反应釜中，100rpm恒速搅拌，分别称取300g和500g的碘化钾和L-胱氨酸加入通风柜中的反应釜中，然后将氮气通过管路向反应釜内通入氮气，加热控制温度为80℃,300rpm恒速搅拌反应2h，反应完成后，停止通入氮气，将反应釜内温度降至20℃，记录有机相清洗前的体积；
将30L体积分数为50％的乙酸乙酯-水混合溶液加入反应釜中，室温100rpm恒速搅拌10min，停止搅拌，静置分层10min后将下层水相溶液放出，保留上层有机相在反应釜中，然后分别用10L质量分数为5％的硫代硫酸钠、20L去离子水、30L 0.01M的盐酸溶液、20L去离子水依次洗涤，最后去离子水洗涤过后将下层水相放出，保留上层有机相在反应釜中，在反应釜中加装蒸馏装置，加热控制温度至50℃，100rpm恒速搅拌24h蒸馏有机相，得到的固体即为金属螯合配基，将金属螯合配基放入密封棕色瓶中冲入氮气冷藏保存，记录蒸馏后配基质量和配基外观颜色。
实施例6
量取10L的乙酰胺加入通风柜中的100L玻璃反应釜中，称取3000g的碳酸钠加入通风柜中的100L玻璃反应釜中，100rpm恒速搅拌，分别称取300g和800g的碘化钾和L-半胱氨酸加入通风柜中的反应釜中，然后将氮气通过管路向反应釜内通入氮气，加热控制温度为80℃,300rpm恒速搅拌反应2h，反应完成后，停止通入氮气，将反应釜内温度降至20℃，记录有机相清洗前的体积；
将30L体积分数为50％的乙酸乙酯-水混合溶液加入反应釜中，室温100rpm恒速搅拌10min，停止搅拌，静置分层10min后将下层水相溶液放出，保留上层有机相在反应釜中，然后分别用10L质量分数为5％的硫代硫酸钠、20L去离子水、30L 0.01M的盐酸溶液、20L去离子水依次洗涤，最后去离子水洗涤过后将下层水相放出，保留上层有机相在反应釜中，在反应釜中加装蒸馏装置，加热控制温度至50℃，100rpm恒速搅拌24h蒸馏有机相，得到的固体即为金属螯合配基，将金属螯合配基放入密封棕色瓶中冲入氮气冷藏保存，记录蒸馏后配基质量和配基外观颜色。
实施例7
量取10L的乙酰胺加入通风柜中的100L玻璃反应釜中，称取3000g的碳酸钾加入通风柜中的100L玻璃反应釜中，100rpm恒速搅拌，分别称取300g和500g的碘化钾和L-胱氨酸加入通风柜中的反应釜中，然后将氮气通过管路向反应釜内通入氮气，加热控制温度为80℃,300rpm恒速搅拌反应2h，反应完成后，停止通入氮气，将反应釜内温度降至20℃，记录有机相清洗前的体积；
将30L体积分数为50％的乙酸乙酯-水混合溶液加入反应釜中，室温100rpm恒速搅拌10min，停止搅拌，静置分层10min后将下层水相溶液放出，保留上层有机相在反应釜中，然后分别用10L质量分数为5％的硫代硫酸钠、20L去离子水、30L 0.01M的盐酸溶液、20L去离子水依次洗涤，最后去离子水洗涤过后将下层水相放出，保留上层有机相在反应釜中，在反应釜中加装蒸馏装置，加热控制温度至50℃，100rpm恒速搅拌24h蒸馏有机相，得到的固体即为金属螯合配基，将金属螯合配基放入密封棕色瓶中冲入氮气冷藏保存，记录蒸馏后配基质量和配基外观颜色。
试验例及结果
表1为实施例1-实施例7的金属螯合配基清洗前的体积、蒸馏前的体积、蒸馏后的质量和配基外观颜色。
表1
将实施例1-7制备的金属螯合配基在相同条件下制备成金属螯合层析介质记录检测螯合铜离子的载量、镍金属螯合层析介质的外观颜色和不同浓度条件下对组氨酸标签蛋白的吸附载量，具体步骤如下：
称量10g的琼脂糖微球，加入到50ml离心管中，加入10ml的2M NaOH溶液混匀，加入5ml的甘油醚，在恒温摇床中50℃振荡反应18h，反应完成后，100ml去离子水清洗微球。将甘油醚活化琼脂糖微球加入到50ml离心管中，加入10ml的1M NaOH溶液混匀，加入4g的本发明制备的金属螯合配基，在恒温摇床中50℃振荡反应18h，反应完成后，100ml去离子水清洗微球，取样检测Cu离子载量，将待检测样品用0.25M CuSO4清洗后用含100mM EDTA溶液将螯合的Cu洗脱下来，检测Cu的紫外吸收波长，根据Cu离子标曲公式计算Cu离子的结合载量。将金属螯合琼脂糖微球加入到50ml离心管中，加入10ml的5％的NiSO4溶液混匀，在恒温摇床中室温振荡反应1h，反应完成后，100ml去离子水清洗微球，得到Ni-亲和层析填料，取样装柱，用20mM PB,500mM NaCl，20mM咪唑，pH7.4的平衡缓冲液平衡预装柱，将His蛋白样品上样到预装柱中，用平衡液清洗后，再用20mM PB,500mM NaCl，500mM咪唑，pH7.4的洗脱缓冲液将His蛋白洗脱下来，检测蛋白紫外吸收波长，根据His蛋白的标曲公式计算His蛋白载量。
不同时实施例的检测结果如表2所示，随着盐离子浓度升高，金属螯合层析介质对组氨酸标签蛋白的吸附载量下降，但是下降不明显，证明本发明的金属螯合配基对高盐具有耐受性，不同实施例的金属螯合配基制备的镍金属螯合层析介质的外观颜色如图1所示。
表2
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (9)
1.一种金属螯合配基，其特征在于，在含硫氨基酸的氨基上连接两个相同的羧酸而成，其结构式如下：
R2为C1～C3烷基中的一种。
2.根据权利要求1所述的金属螯合配基，其特征在于，所述含硫氨基酸为L-胱氨酸、L-半胱氨酸、N-乙酰半胱氨酸、羧甲基半胱氨酸中的任一种。
3.一种如权利要求1-2任一所述的金属螯合配基的制备方法，其特征在于，包括以下步骤：
(1)将酰胺与含硫氨基酸在碳酸盐、碘化钾和氮气存在的条件下反应，反应方程式为：
R2为C1～C3烷基中的一种，R3为H或甲酰基，R4为H或甲基；
(2)将反应产物进行分离纯化，制得所述金属螯合配基。
4.根据权利要求3所述的金属螯合配基的制备方法，其特征在于，所述步骤(1)的具体步骤为：将酰胺加入反应釜中，然后依次加入碳酸盐、碘化钾和含硫氨基酸，以酰胺为基准，单位以L计，加入的碳酸盐、碘化钾和含硫氨基酸的质量分别为50～5000g、5～500g和10～1000g，向反应釜中通入氮气，加热至20～60℃，200～500rpm下搅拌反应1～5h，反应完成后，停止通入氮气。
5.根据权利要求4所述的金属螯合配基的制备方法，其特征在于，所述酰胺为乙酰胺、丙酰胺、丁酰胺、二甲基乙酰胺中的任一种。
6.根据权利要求4所述的金属螯合配基的制备方法，其特征在于，所述碳酸盐为碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾中的任一种。
7.根据权利要求3所述的金属螯合配基的制备方法，其特征在于，所述步骤(2)的具体步骤为：反应结束反应釜降温后，依次用乙酸乙酯-水混合溶液、硫代硫酸钠溶液、去离子水、稀盐酸、去离子水室温下对反应产物进行搅拌洗涤，每次洗涤后静置分层弃去水相保留有机相，然后蒸馏，得到所述金属螯合配基。
8.根据权利要求7所述的金属螯合配基的制备方法，其特征在于，所述乙酸乙酯-水溶液中乙酸乙酯的体积分数为5％～50％，所述硫代硫酸钠溶液的质量分数为5％～50％，所述稀盐酸的浓度为0.01～1M，搅拌的时间为10～60min，静置分层的时间为10～60min。
9.根据权利要求8所述的金属螯合配基的制备方法，其特征在于，蒸馏的温度为20～60℃，蒸馏的时间为24～48h。
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| CN111574406A (zh) * | 2020-05-28 | 2020-08-25 | 陕西科技大学 | 一种多羧基螯合剂及其制备方法和应用 |
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