CN114805235B - 一种多取代异恶唑烷酮及其中间体的合成制备方法 - Google Patents
一种多取代异恶唑烷酮及其中间体的合成制备方法 Download PDFInfo
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- polysubstituted
- isoxazolidinone
- sodium
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- QXDOFVVNXBGLKK-UHFFFAOYSA-N 3-Isoxazolidinone Chemical class OC1=NOCC1 QXDOFVVNXBGLKK-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 7
- -1 acrylic compound Chemical class 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006845 Michael addition reaction Methods 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
- 230000009471 action Effects 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 5
- 150000002431 hydrogen Chemical group 0.000 claims 3
- 239000002585 base Substances 0.000 claims 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 239000000543 intermediate Substances 0.000 abstract description 9
- 230000007613 environmental effect Effects 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- LXZYXGPGJLIZKU-UHFFFAOYSA-N 5,5-dimethyl-1,2-oxazolidin-3-one Chemical compound CC1(C)CC(=O)NO1 LXZYXGPGJLIZKU-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- YYPNJNDODFVZLE-UHFFFAOYSA-N 3-methylbut-2-enoic acid Chemical compound CC(C)=CC(O)=O YYPNJNDODFVZLE-UHFFFAOYSA-N 0.000 description 2
- 125000002355 alkine group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000004886 process control Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- XXGCNPKEAMJDDB-UHFFFAOYSA-N 5-prop-2-enyl-1,2-oxazol-3-one Chemical compound C=CCC1=CC(=O)NO1 XXGCNPKEAMJDDB-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 1
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- HVHMXMSNIOHNTP-UHFFFAOYSA-N n-hydroxy-3-methylbut-2-enamide Chemical compound CC(C)=CC(=O)NO HVHMXMSNIOHNTP-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
Abstract
本发明涉及医药中间体有机合成技术领域,具体涉及一种多取代异恶唑烷酮及其中间体的合成制备方法,该方法用a,β‑不饱和羟肟酸类化合物(Ⅰ)为原料在碱的作用下发生分子内的Michael加成反应环合成异恶唑烷酮类化合物(Ⅱ)。该发明的优点是操作简单,条件温和,原料易得,安全性高,环保。制得的产品纯度好,可以大规模的工业化生产。
Description
技术领域
本发明涉及医药中间体合成领域,具体涉及一种多取代异恶唑烷酮及其中间体的合成制备方法。
背景技术
多取代异恶唑烷酮类化合物在有机合成中有着广泛的应用,此类化合物作为活性中间体在医药、农药等药物化学领域都有着极其重要的应用,尤其用来合成卤代异恶唑类化合物。目前来说,异恶唑烷酮类化合物是用羟基脲和丙烯酸酯类化合物反应制得,但是此路线原料成本高,不易于工业化生产。
发明内容
本发明要解决的技术问题是:通过对上述现有技术问题缺陷的解决方法进行广泛研究,本发明人已经发现了一种更为经济的合成路线,且目标化合物纯度高,收率好,它具有与操作简单,工艺环保等特点。
为了解决上述问题,本发明提供的技术方案如下:
一种多取代异恶唑烷酮及其中间体的合成制备方法,所述多取代异恶唑烷酮中间体为化合物(Ⅰ),经过环合反应得到多取代异恶唑烷酮,即化合物(Ⅱ),具体反应式如下:
所述R1、R2、R3选自H、C1~6烷基、C3~7环烷基、C1~6烯烃基、C1~6炔烃基、芳香基、杂环基或杂芳基。
本申请中术“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至6个碳原子的烷基,更优选1至4个碳原子的烷基。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至7个碳原子,更优选包含3至5个碳原子。
“炔基”指(CH≡C-),其中所述的炔基可以进一步被其他相关基团取代。
芳香基指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环。
杂环基指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。包括氧杂环丁烷基、吡咯烷基、吡咯烷酮基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等。
杂芳基指包含1至4个杂原子、6至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为6至10元,更优选为6元或7元,例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等。
烷氧基,通常用RO-表示,是有机化合物分子中的一类取代基,由一个烷基和一个氧原子构成。根据烷基的大小,烷氧基还可以再分成:甲氧基(CH3O-)、乙氧基(C2H5O-)、丙氧基(C3H7O-)等。
进一步的,所述R1、R2、R3选自H、C1~4烷基、C3~5环烷基、C1~4烯烃基、C1~4炔烃基。
进一步的,所述多取代异恶唑烷酮中间体化合物(Ⅰ)由丙烯酸类化合物和羟胺反应制得,所述丙烯酸类化合物结构式如下:即a,β-不饱和羟肟酸化合物(Ⅰ)可以由丙烯酸类化合物和羟胺反应制得。
进一步的,所述C1~6烷基、C3~7环烷基、C1~6烯烃基、C1~6炔烃基、芳香基、杂环基或杂芳基任选地被氢、卤素、羟基、氰基、硝基、烷氧基或芳香基单取代。
进一步的,所述C1~6烷基、C3~7环烷基、C1~6烯烃基、C1~6炔烃基、芳香基、杂环基或杂芳基任选地被氢、卤素、羟基、氰基、硝基、烷氧基或芳香基相同或不同的多取代。
进一步的,所述C1~4烷基、C3~5环烷基、C1~4烯烃基、C1~4炔烃基任选地被氢、卤素、羟基、氰基、硝基、烷氧基或芳香基单取代。
进一步的,所述C1~4烷基、C3~5环烷基、C1~4烯烃基、C1~4炔烃基任选地被氢、卤素、羟基、氰基、硝基、烷氧基或芳香基相同或不同的多取代。
进一步的,所述反应加入了碱,所述碱选自磷酸氢钠、磷酸二氢钠、叔丁基醇钠、碳酸氢钠、碳酸氢钾、碳酸钡、碳酸钙、氢氧化锂、氢氧化钡、钠氢、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、甲醇钠、乙醇钠、甲醇钾、乙醇钾、三乙胺、吡啶中的一种或几种。
本发明人新开发了一种路线,与现有技术相比,该方法用a,β-不饱和羟肟酸类化合物(式Ⅰ)为原料在碱的作用下发生分子内的Michael加成反应环合成异恶唑烷酮类化合物(式Ⅱ)。用a,β-不饱和羟肟酸类化合物直接环合成异恶唑烷酮类化合物,而a,β-不饱和羟肟酸可以由丙烯酸类化合物和羟胺反应制得。该发明的优点是操作简单,条件温和,原料易得,安全性高,环保。制得的产品纯度好,可以大规模的工业化生产。
本发明中化合物的中文命名与结构式有冲突的,以结构式为准;结构式有明显错误的除外。
具体实施方式
以下结合实例说明本发明,但不限制本发明。在本领域内,技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案内。
实施例1:
3,3-二甲基丙烯羟肟酸的合成
在氮气保护下,250ml四口瓶中加入溶剂1,2二氯乙烷(60g),然后加入原料3,3-二甲基丙烯酸(10g,0.1mol),催化量的N,N-二甲基甲酰胺,常温下搅拌10min,然后快速加入氯化亚砜(14.4g,0.12mol),并且升温至60℃搅拌反应1小时。反应结束后降温至50℃减压蒸出未反应的氯化亚砜,剩余体系即为制得的酰氯,干燥保存待用。
在氮气保护下,250ml四口瓶中加入溶剂二氯甲烷(50g),盐酸羟胺(14g,0.2mol),三乙胺(20.2g,0.2mol),30℃下搅拌反应2小时,然后降温至零下10℃,缓慢滴加干燥保存待用的酰氯,过程控制温度在零下10℃,滴加完毕后体系继续保温反应3小时。反应结束后,体系过滤,滤液旋干后用乙酸乙酯重结晶,得白色固体10.5g,收率91.2%,定性纯度95%。
1H NMR(400MHz,DMSO):δ10.37(s,1H),8.68(s,1H),5.46(s,1H),2.07(s,3H),1.77(s,3H)。
实施例2:
5,5-二甲基异恶唑酮的合成
在氮气保护下,100ml四口瓶中加入溶剂乙醇(50g),加入实施例1的3,3-二甲基丙烯羟肟酸(5.75g,0.05mol),常温下搅拌溶解,然后滴加30%的NaOH水溶液(13.4g,0.1mol),升温回流反应6个小时。反应结束后,体系减压蒸出乙醇,然后剩余体系加水溶解用盐酸调pH值1~2,然后用二氯甲烷反复萃取三次,有机相脱溶后得白色固体4.1g,收率71.3%,定性含量96%。
1H NMR(400MHz,DMSO):δ10.97(s,1H),2.47(s,2H),1.31(s,6H)。
实施例3:
5,5-二甲基异恶唑酮的合成
在氮气保护下,100ml四口瓶中加入溶剂乙醇(50g),加入实施例1的3,3-二甲基丙烯羟肟酸(5.75g,0.05mol),常温下搅拌溶解,然后滴加30%的KOH水溶液(18.7g,0.1mol),升温回流反应6个小时。反应结束后,体系减压蒸出乙醇,然后剩余体系加水溶解用盐酸调pH值1~2,然后用二氯甲烷反复萃取三次,有机相脱溶后得白色固体4.5g,收率78.2%,定性含量95.5%。
1H NMR(400MHz,DMSO):δ10.97(s,1H),2.47(s,2H),1.31(s,6H)。
实施例4:
5,5-二甲基异恶唑酮的合成
在氮气保护下,100ml四口瓶中加入溶剂甲醇(50g),加入实施例1的3,3-二甲基丙烯羟肟酸(5.75g,0.05mol),常温下搅拌溶解,然后滴加30%的甲醇钠甲醇溶液(18g,0.1mol),升温回流反应6个小时。反应结束后,体系减压蒸出乙醇,然后剩余体系加水溶解用盐酸调pH值1~2,然后用二氯甲烷反复萃取三次,有机相脱溶后得白色固体4.2g,收率73%,定性含量96%。
1H NMR(400MHz,DMSO):δ10.97(s,1H),2.47(s,2H),1.31(s,6H)。
实施例5:
2-丙烯基丙烯羟肟酸的合成
在氮气保护下,250ml四口瓶中加入溶剂1,2二氯乙烷(60g),然后加入原料2-丙烯基丙烯酸酸(11.2g,0.1mol),催化量的N,N-二甲基甲酰胺,常温下搅拌10min,然后快速加入氯化亚砜(14.4g,0.12mol),并且升温至60℃搅拌反应1小时。反应结束后降温至50℃减压蒸出未反应的氯化亚砜,剩余体系即为制得的酰氯,干燥保存待用。
在氮气保护下,250ml四口瓶中加入溶剂二氯甲烷(50g),盐酸羟胺(14g,0.2mol),三乙胺(20.2g,0.2mol),30℃下搅拌反应2小时,然后降温至零下10℃,缓慢滴加干燥保存待用的酰氯,过程控制温度在零下10℃,滴加完毕后体系继续保温反应3小时。反应结束后,体系过滤,滤液旋干后用乙酸乙酯重结晶,得白色固体11.8g,收率93.1%,定性纯度96%。
1H NMR(400MHz,DMSO):δ10.55(s,1H),8.87(s,1H),7.05-6.96(m,1H),6.39-5.88(m,2H),5.72(d,J=15.4Hz,1H),1.77(d,J=5.2Hz,3H)。
实施例6:
5-(2-丙烯基)-异恶唑酮的合成
在氮气保护下,100ml四口瓶中加入溶剂乙醇(50g),加入实施例5的2-丙烯基丙烯羟肟酸(6.35g,0.05mol),常温下搅拌溶解,然后滴加30%的NaOH水溶液(13.4g,0.1mol),升温回流反应6个小时。反应结束后,体系减压蒸出乙醇,然后剩余体系加水溶解用盐酸调pH值1~2,然后用二氯甲烷反复萃取三次,有机相脱溶后得白色固体3.9g,收率61.4%,定性含量90%。
1H NMR(400MHz,DMSO):δ10.86(s,1H),5.65-5.53(m,2H),4.55-4.43(m,1H),2.65-2.14(m,2H),2.47(s,2H),1.61(d,J=5.2Hz,3H)。
以上所述的仅是本发明的优选实施方式,应当指出,对于本领域的普通技术人员来说,在不脱离本发明创造构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。
Claims (8)
1.一种多取代异恶唑烷酮的合成制备方法,其特征在于,所述多取代异恶唑烷酮中间体,即化合物(Ⅰ),为原料在碱的作用下发生分子内的Michael加成反应环合成多取代异恶唑烷酮,即化合物(Ⅱ),具体反应式如下:
所述R1、R2、R3选自H、C1~6烷基、C3~7环烷基、C1~6烯烃基、C1~6炔烃基、芳香基、杂环基或杂芳基。
2.如权利要求1所述的一种多取代异恶唑烷酮的合成制备方法,其特征在于,所述R1、R2、R3选自H、C1~4烷基、C3~5环烷基、C1~4烯烃基、C1~4炔烃基。
3.如权利要求1或2所述的一种多取代异恶唑烷酮的合成制备方法,其特征在于,所述多取代异恶唑烷酮中间体化合物(Ⅰ)由丙烯酸类化合物和羟胺反应制得,所述丙烯酸类化合物结构式如下:
4.如权利要求1所述的一种多取代异恶唑烷酮的合成制备方法,其特征在于,所述C1~6烷基、C3~7环烷基、C1~6烯烃基、C1~6炔烃基、芳香基、杂环基或杂芳基任选地被氢、卤素、羟基、氰基、硝基、烷氧基或芳香基单取代。
5.如权利要求1所述的一种多取代异恶唑烷酮的合成制备方法,其特征在于,所述C1~6烷基、C3~7环烷基、C1~6烯烃基、C1~6炔烃基、芳香基、杂环基或杂芳基任选地被氢、卤素、羟基、氰基、硝基、烷氧基或芳香基相同或不同的多取代。
6.如权利要求2所述的一种多取代异恶唑烷酮的合成制备方法,其特征在于,所述C1~4烷基、C3~5环烷基、C1~4烯烃基、C1~4炔烃基任选地被氢、卤素、羟基、氰基、硝基、烷氧基或芳香基单取代。
7.如权利要求2所述的一种多取代异恶唑烷酮的合成制备方法,其特征在于,所述C1~4烷基、C3~5环烷基、C1~4烯烃基、C1~4炔烃基任选地被氢、卤素、羟基、氰基、硝基、烷氧基或芳香基相同或不同的多取代。
8.如权利要求1所述的一种多取代异恶唑烷酮的合成制备方法,其特征在于,所述反应加入了碱,所述碱选自磷酸氢钠、磷酸二氢钠、叔丁基醇钠、碳酸氢钠、碳酸氢钾、碳酸钡、碳酸钙、氢氧化锂、氢氧化钡、钠氢、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、甲醇钠、乙醇钠、甲醇钾、乙醇钾、三乙胺、吡啶中的一种或几种。
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