CN111675625A - 一种催化合成四氮唑乙酸及其衍生物的方法 - Google Patents
一种催化合成四氮唑乙酸及其衍生物的方法 Download PDFInfo
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- JUNAPQMUUHSYOV-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)acetic acid Chemical compound OC(=O)CC=1N=NNN=1 JUNAPQMUUHSYOV-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000007036 catalytic synthesis reaction Methods 0.000 title description 2
- 239000003054 catalyst Substances 0.000 claims abstract description 50
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- HVJJYOAPXBPQQV-UHFFFAOYSA-N ethyl 2-azidoacetate Chemical compound CCOC(=O)CN=[N+]=[N-] HVJJYOAPXBPQQV-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002608 ionic liquid Substances 0.000 claims abstract description 19
- 239000002105 nanoparticle Substances 0.000 claims abstract description 16
- -1 cyano compound Chemical class 0.000 claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 230000000694 effects Effects 0.000 claims abstract description 5
- 238000012650 click reaction Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000010992 reflux Methods 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 19
- 239000012295 chemical reaction liquid Substances 0.000 claims description 11
- MSMGXWFHBSCQFB-UHFFFAOYSA-N ethyl cyanoformate Chemical compound CCOC(=O)C#N MSMGXWFHBSCQFB-UHFFFAOYSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- OBWFJXLKRAFEDI-UHFFFAOYSA-N methyl cyanoformate Chemical compound COC(=O)C#N OBWFJXLKRAFEDI-UHFFFAOYSA-N 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims description 4
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical compound CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 claims description 3
- ZTGQZSKPSJUEBU-UHFFFAOYSA-N 3-bromopropan-1-amine Chemical compound NCCCBr ZTGQZSKPSJUEBU-UHFFFAOYSA-N 0.000 claims description 3
- KSCAZPYHLGGNPZ-UHFFFAOYSA-N 3-chloropropyl(triethoxy)silane Chemical compound CCO[Si](OCC)(OCC)CCCCl KSCAZPYHLGGNPZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052681 coesite Inorganic materials 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 3
- 229910052906 cristobalite Inorganic materials 0.000 claims description 3
- 230000000911 decarboxylating effect Effects 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052682 stishovite Inorganic materials 0.000 claims description 3
- 229910052905 tridymite Inorganic materials 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- ZSLKGAAJYMFQFI-UHFFFAOYSA-N acetic acid;azidoethane Chemical compound CC(O)=O.CCN=[N+]=[N-] ZSLKGAAJYMFQFI-UHFFFAOYSA-N 0.000 abstract description 5
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 238000006114 decarboxylation reaction Methods 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 27
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 238000003760 magnetic stirring Methods 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 238000001514 detection method Methods 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
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- 238000009210 therapy by ultrasound Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
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- 238000004519 manufacturing process Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 description 1
- 229960003408 cefazolin sodium Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- WGJJZRVGLPOKQT-UHFFFAOYSA-K lanthanum(3+);trifluoromethanesulfonate Chemical compound [La+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F WGJJZRVGLPOKQT-UHFFFAOYSA-K 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/24—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from hydantoins
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
- B01J31/0281—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member
- B01J31/0284—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member of an aromatic ring, e.g. pyridinium
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0292—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature immobilised on a substrate
- B01J31/0295—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature immobilised on a substrate by covalent attachment to the substrate, e.g. silica
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- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
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Abstract
本发明公开一种催化合成四氮唑乙酸及其衍生物的方法,该方法实现叠氮乙酸乙酯与氰基化合物的Click反应制备得到四氮唑乙酸及其衍生物。所述方法包括:以超顺磁纳米颗粒负载离子液体为催化剂,60‑100℃和常压下,在溶剂中,叠氮乙酸乙酯与氰基化合物通过Click反应,反应8‑14小时,然后水解脱羧得到相应的四氮唑乙酸及其衍生物。经验证,反应结束后,催化剂经外加磁场简单回收,可多次重复使用,活性未见明显下降。该催化体系操作简单、收率高、可重复使用性好,具有良好的工业化前景。
Description
技术领域
本发明涉及一种化合物的制备方法,尤其是一种绿色、高效、以超顺磁纳米颗粒负载离子液体为催化剂制备四氮唑乙酸及其衍生物的方法。
背景技术
四氮唑乙酸是制备头孢唑啉钠等抗生素药物的重要中间体,年需求量较大,国内仅有两三个厂家生产,受技术路线的制约,其产能无法满足国内制药企业的需求。因此,四氮唑乙酸的合成研究备受关注。四氮唑化合物传统的合成方法采用氯化锌、溴化锌、三氯化铝、三氯化铁、三氟甲磺酸镧、硫酸氢铁等Lewis酸作为催化剂,由腈类和叠氮化钠制备而成。而四氮唑乙酸国内的生产厂家普遍采用是叠氮酯法,以氰甲酸乙酯、叠氮乙酸乙酯为主要原料,但是,此工艺反应时间长(50h以上),工艺操作繁琐,收率不高,这些因素严重制约了生产企业的产能扩大;或者采用氯化铜、氯化亚铜等Lewis酸作为催化剂,重金属污染较重。近些年来,超顺磁纳米颗粒负载的催化剂催化技术已经作为一种绿色反应技术广泛用于有机合成生产中,我们设计了超顺磁纳米颗粒负载离子液体为催化剂,用于制备四氮唑乙酸及其衍生物。与传统的相工艺相比,收率高、反应温度低、反应时间短(8-14h)、操作简便等优点,且催化剂催化活性好(高比表面积)、回收简便(外加磁场回收),催化剂可以重复使用。
发明内容
本发明的目的利用新型的超顺磁纳米颗粒负载离子液体催化剂,催化合成四氮唑乙酸及其衍生物的方法。
本发明的技术方案为:一种催化合成四氮唑乙酸及其衍生物的方法,所述方法包括以超顺磁纳米颗粒负载离子液体为催化剂,60-100℃和常压下,在溶剂中,叠氮乙酸乙酯与氰基甲酸乙酯、氰基甲酸甲酯通过Click反应,反应8-14小时,然后水解脱羧得到相应的四氮唑乙酸及其衍生物。其中,其中,所述催化剂为:
超顺磁纳米颗粒负载离子液体催化剂的制备:3-氯丙基三乙氧基硅烷、咪唑、干燥甲苯在N2保护下回流反应,通过柱层析法分离得到中间体;该中间体与取Fe3O4/SiO2固体颗粒在无水甲苯搅拌反应,反应结束后用磁铁收集的固体与溴丙胺在无水甲苯中回流反应,反应结束后用磁铁收集得到负载咪唑胺型功能离子液体PA-IL@MNP,再与乙酰基吡啶在无水甲苯中回流反应;反应液冷却至室温,用磁体收集,得到超顺磁纳米颗粒负载离子液体,最后,取超顺磁纳米颗粒负载离子液体和醋酸铜在丙酮中搅拌回流,反应液冷却后用磁体收集,洗涤干燥,得到催化剂7;经元素分析,催化剂的有效负载量为0.72mmol/g。反应公式为:
其中:叠氮乙酸乙酯与氰基甲酸乙酯、氰基甲酸甲酯的摩尔比为1:1-2:1。
其中:所述催化剂的摩尔比为叠氮乙酸乙酯的0.001-0.02倍。
其中:所述溶剂为甲醇、乙醇、醋酸乙酯、三氯甲烷、二氯甲烷、四氢呋喃、叔丁基甲醚、甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜。
其中:所述溶剂的质量比为叠氮乙酸乙酯的1-10倍。
反应结束后,催化剂经外加磁场回收,乙醇洗涤后,经过60℃真空干燥5小时,可多次重复使用,活性未见明显下降。
本发明的优点在于:经验证,反应结束后,催化剂经外加磁场简单回收,可多次重复使用,活性未见明显下降。该催化体系操作简单、收率高、可重复使用性好,具有良好的工业化前景。
具体实施方式
一种催化合成四氮唑乙酸及其衍生物的制备方法,本发明所使用的超顺磁纳米颗粒负载离子液体催化剂的制备过程:分别称取3-氯丙基三乙氧基硅烷1(12ml,50mmol),咪唑2(3.4g,50mmol)于反应容器中,加入50ml干燥甲苯,N2保护下回流搅拌反应24h,通过柱层析法分离得到中间体3(展开剂为EA);取1g Fe3O4/SiO2固体颗粒于反应容器中,加入50ml无水甲苯,超声1h,超声结束后取0.5g中间体3溶于20ml无水甲苯中然后滴加到该反应体系中,N2保护下回流搅拌反应48h,反应结束后用磁铁收集并用乙醇洗涤三次,真空烘干得到固体颗粒4;取2g固体颗粒4于反应容器中,加入100ml无水甲苯,超声1h,超声结束后取4mmol(0.55g)溴丙胺溶于20ml无水甲苯中然后滴加到该反应体系中,N2保护下回流反应48h,反应结束后用磁铁收集并用乙醇洗涤三次,真空烘干即得到负载咪唑胺型功能离子液体PA-IL@MNP 5,最终得到的灰色纳米颗粒质量为2.0g,取2g PA-IL@MNP 5的和0.5g乙酰基吡啶,加入30ml无水甲苯,超声1h,在氮气保护下110℃机械搅拌回流3h。反应液冷却至室温,得到的褐色固体用磁体收集,用乙醇冲洗,60℃真空干燥10h,得到超顺磁纳米颗粒负载离子液体6,最后,取1g 6和0.75g醋酸铜,在20ml丙酮中,室温下机械搅拌回流4h,得到的褐色固体用磁体收集,用乙醇冲洗,60℃真空干燥10h,得到催化剂7。经元素分析,催化剂的有效负载量为0.72mmol/g。反应公式为:
四氮唑乙酸及其衍生物的制备过程是:在装有磁力搅拌装置的三口烧瓶中,依次加入叠氮乙酸乙酯8、氰基化合物9、溶剂和催化剂Cat.,其中叠氮乙酸乙酯与氰基化合物的摩尔比为1:1-2:1;催化剂的摩尔比为叠氮乙酸乙酯的0.001-0.02倍;60-100℃和常压下,在溶剂中,叠氮乙酸乙酯与氰基化合物通过Click反应,反应8-14小时,用外加磁场吸住催化剂,倾倒反应液,反应液中化合物10水解脱羧后得到四氮唑乙酸11;外加磁场回收的催化剂,用乙醇洗涤后,经过60℃真空干燥5小时,可多次重复使用,活性未见明显下降。
反应公式为:
实施例1
在装有磁力搅拌装置的100ml三口烧瓶中,依次加入叠氮乙酸乙酯(0.02mol,2.6g)、氰基甲酸乙酯(0.02mol,1.7g)、25ml无水甲醇和催化剂(28mg,0.02mmol),升温回流8-14h,HPLC跟踪监测,待原料消失,用外加磁场吸住催化剂,倾出反应液到100ml的三口烧瓶中,加入30%盐酸溶液5ml,60℃搅拌1h后,冷却到室温,用二氯甲烷萃取(3*20ml),合并有机层,减压去除有机溶剂,真空干燥得到四氮唑乙酸2.38g,收率93%,含量97%(HPLC检测)。
实施例2
在装有磁力搅拌装置的100ml三口烧瓶中,依次加入叠氮乙酸乙酯(0.02mol,2.6g)、氰基甲酸乙酯(0.02mol,1.7g)、25ml无水乙醇和催化剂(28mg,0.02mmol),升温回流8-14h,HPLC跟踪监测,待原料消失,用外加磁场吸住催化剂,倾出反应液到100ml的三口烧瓶中,加入30%盐酸溶液5ml,60℃搅拌1h后,冷却到室温,用二氯甲烷萃取(3*20ml),合并有机层,减压去除有机溶剂,真空干燥得到四氮唑乙酸2.33g,收率91%,含量96.5%(HPLC检测)。
实施例3
在装有磁力搅拌装置的100ml三口烧瓶中,依次加入叠氮乙酸乙酯(0.02mol,2.6g)、氰基甲酸乙酯(0.02mol,1.7g)、25ml无水甲苯和催化剂(28mg,0.02mmol),升温回流8-14h,HPLC跟踪监测,待原料消失,用外加磁场吸住催化剂,倾出反应液到100ml的三口烧瓶中,加入30%盐酸溶液5ml,60℃搅拌1h后,冷却到室温,用二氯甲烷萃取(3*20ml),合并有机层,减压去除有机溶剂,真空干燥得到四氮唑乙酸2.28g,收率89%,含量96%(HPLC检测)。
实施例4
在装有磁力搅拌装置的100ml三口烧瓶中,依次加入叠氮乙酸乙酯(0.02mol,2.6g)、氰基甲酸甲酯(0.02mol,1.7g)、25ml无水甲醇和催化剂(28mg,0.02mmol),升温回流8-14h,HPLC跟踪监测,待原料消失,用外加磁场吸住催化剂,倾出反应液到100ml的三口烧瓶中,加入30%盐酸溶液5ml,60℃搅拌1h后,冷却到室温,用二氯甲烷萃取(3*20ml),合并有机层,减压去除有机溶剂,真空干燥得到四氮唑乙酸2.25g,收率88%,含量96.5%(HPLC检测)。
实施例5
在装有磁力搅拌装置的100ml三口烧瓶中,依次加入叠氮乙酸乙酯(0.02mol,2.6g)、氰基甲酸乙酯(0.02mol,1.7g)、25ml无水甲醇和催化剂(56mg,0.04mmol),升温回流8-14h,HPLC跟踪监测,待原料消失,用外加磁场吸住催化剂,倾出反应液到100ml的三口烧瓶中,加入30%盐酸溶液5ml,60℃搅拌1h后,冷却到室温,用二氯甲烷萃取(3*20ml),合并有机层,减压去除有机溶剂,真空干燥得到四氮唑乙酸2.40g,收率94%,含量97.5%(HPLC检测)。
实施例6
在装有磁力搅拌装置的100ml三口烧瓶中,依次加入叠氮乙酸乙酯(0.022mol,2.86g)、氰基甲酸乙酯(0.02mol,1.7g)、25ml无水甲醇和催化剂(28mg,0.02mmol),升温回流8-14h,HPLC跟踪监测,待原料消失,用外加磁场吸住催化剂,倾出反应液到100ml的三口烧瓶中,加入30%盐酸溶液5ml,60℃搅拌1h后,冷却到室温,用二氯甲烷萃取(3*20ml),合并有机层,减压去除有机溶剂,真空干燥得到四氮唑乙酸2.40g,收率94%,含量98%(HPLC检测)。
实施例7
在装有磁力搅拌装置的100ml三口烧瓶中,依次加入叠氮乙酸乙酯(0.022mol,2.86g)、氰基甲酸乙酯(0.02mol,1.7g)、25ml无水甲醇和催化剂(28mg,0.02mmol),升温回流8-14h,HPLC跟踪监测,待原料消失,用外加磁场吸住催化剂,倾出反应液到100ml的三口烧瓶中,加入30%盐酸溶液5ml,60℃搅拌1h后,冷却到室温,用二氯甲烷萃取(3*20ml),合并有机层,减压去除有机溶剂,真空干燥得到四氮唑乙酸2.41g,收率94.5%,含量98%(HPLC检测)。
实施例8
在装有磁力搅拌装置的100ml三口烧瓶中,依次加入叠氮乙酸乙酯(0.02mol,2.6g)、氰基甲酸乙酯(0.02mol,1.87g)、25ml无水甲醇和催化剂(28mg,0.02mmol),升温回流8-14h,HPLC跟踪监测,待原料消失,用外加磁场吸住催化剂,倾出反应液到100ml的三口烧瓶中,加入30%盐酸溶液5ml,60℃搅拌1h后,冷却到室温,用二氯甲烷萃取(3*20ml),合并有机层,减压去除有机溶剂,真空干燥得到四氮唑乙酸2.38g,收率93%,含量97.5%(HPLC检测)。
实施例9
在装有磁力搅拌装置的100ml三口烧瓶中,依次加入叠氮乙酸乙酯(0.02mol,2.6g)、氰基甲酸乙酯(0.02mol,1.87g)、25ml无水甲醇和催化剂(28mg,0.02mmol),升温回流8-14h,HPLC跟踪监测,待原料消失,用外加磁场吸住催化剂,倾出反应液到100ml的三口烧瓶中,加入30%氢氧化钠溶液5ml,50℃搅拌1h后,冷却到室温,用二氯甲烷萃取(3*20ml),合并有机层,减压去除有机溶剂,真空干燥得到四氮唑乙酸2.38g,收率93%,含量97.5%(HPLC检测)。催化剂重复使用5次,收率未见明显下降,具体结果见表1。
需要说明的是,上述发明内容及具体实施方式意在证明本发明所提供技术方案的实际应用,不应解释为对本发明保护范围的限定。本领域技术人员在本发明的精神和原理中,当可作各种修改、等同替换、或改进。本发明的保护范围以所附权利要求书为准。
Claims (6)
1.一种催化合成四氮唑乙酸及其衍生物的方法,其特征在于:所述方法包括以超顺磁纳米颗粒负载离子液体为催化剂,60-100℃和常压下,在溶剂中,叠氮乙酸乙酯与氰基甲酸乙酯、氰基甲酸甲酯通过Click反应,反应8-14小时,然后水解脱羧得到相应的四氮唑乙酸及其衍生物;其中,所述催化剂为:
超顺磁纳米颗粒负载离子液体催化剂的制备:3-氯丙基三乙氧基硅烷、咪唑、干燥甲苯在N2保护下回流反应,通过柱层析法分离得到中间体;该中间体与取Fe3O4/SiO2固体颗粒在无水甲苯搅拌反应,反应结束后用磁铁收集的固体与溴丙胺在无水甲苯中回流反应,反应结束后用磁铁收集得到负载咪唑胺型功能离子液体PA-IL@MNP,再与乙酰基吡啶在无水甲苯中回流反应;反应液冷却至室温,用磁体收集,得到超顺磁纳米颗粒负载离子液体,最后,取超顺磁纳米颗粒负载离子液体和醋酸铜在丙酮中搅拌回流,反应液冷却后用磁体收集,洗涤干燥,得到催化剂7;反应公式为:
2.根据权利要求1所述催化合成四氮唑乙酸及其衍生物的方法,其特征在于:叠氮乙酸乙酯与氰基甲酸乙酯、氰基甲酸甲酯的摩尔比为1:1-2:1。
3.根据权利要求1所述催化合成四氮唑乙酸及其衍生物的方法,其特征在于:所述催化剂的摩尔比为叠氮乙酸乙酯的0.001-0.02倍。
4.根据权利要求1所述催化合成四氮唑乙酸及其衍生物的方法,其特征在于:所述溶剂为甲醇、乙醇、醋酸乙酯、三氯甲烷、二氯甲烷、四氢呋喃、叔丁基甲醚、甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜。
5.根据权利要求1所述催化合成四氮唑乙酸及其衍生物的方法,其特征在于:所述溶剂的质量比为叠氮乙酸乙酯的1-10倍。
6.根据权利要求1所述催化合成四氮唑乙酸及其衍生物的方法,其特征在于:反应结束后,催化剂经外加磁场回收,乙醇洗涤后,经过60℃真空干燥5小时,可多次重复使用,活性未见明显下降。
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