CN116283819B - Preparation method and application of isothiazole-5(2H)-imine compounds - Google Patents
Preparation method and application of isothiazole-5(2H)-imine compounds Download PDFInfo
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- CN116283819B CN116283819B CN202310283827.7A CN202310283827A CN116283819B CN 116283819 B CN116283819 B CN 116283819B CN 202310283827 A CN202310283827 A CN 202310283827A CN 116283819 B CN116283819 B CN 116283819B
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- isothiazole
- imine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- UQXKLPYMCBSXOY-UHFFFAOYSA-N N=C1C=CNS1 Chemical class N=C1C=CNS1 UQXKLPYMCBSXOY-UHFFFAOYSA-N 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- -1 thioacrylamide compound Chemical class 0.000 claims abstract description 34
- GKZNVLJEHYUFIC-UHFFFAOYSA-N 1,2-thiazol-5-amine Chemical compound NC1=CC=NS1 GKZNVLJEHYUFIC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 26
- 150000002497 iodine compounds Chemical class 0.000 claims abstract description 23
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 37
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 239000012752 auxiliary agent Substances 0.000 claims description 11
- 239000004305 biphenyl Substances 0.000 claims description 11
- 235000010290 biphenyl Nutrition 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000001624 naphthyl group Chemical group 0.000 claims description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 8
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 4
- DEUJSGDXBNTQMY-UHFFFAOYSA-N 1,2,2-trifluoroethanol Chemical compound OC(F)C(F)F DEUJSGDXBNTQMY-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 3
- DQDCGTUHSVXZIS-UHFFFAOYSA-N iodobenzene;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.IC1=CC=CC=C1 DQDCGTUHSVXZIS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- QOKOPGGFKCHASB-UHFFFAOYSA-N (3-hydroxy-4-iodophenyl) phenylmethanesulfonate Chemical compound OC1=C(C=CC(=C1)OS(=O)(=O)CC1=CC=CC=C1)I QOKOPGGFKCHASB-UHFFFAOYSA-N 0.000 claims description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- BDOLQESNFGCNSC-UHFFFAOYSA-N iodylbenzene Chemical compound O=I(=O)C1=CC=CC=C1 BDOLQESNFGCNSC-UHFFFAOYSA-N 0.000 claims 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 2
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- 229910052736 halogen Inorganic materials 0.000 description 13
- 150000002367 halogens Chemical class 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 6
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- CQMJEZQEVXQEJB-UHFFFAOYSA-N 1-hydroxy-1,3-dioxobenziodoxole Chemical compound C1=CC=C2I(O)(=O)OC(=O)C2=C1 CQMJEZQEVXQEJB-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- IHRLABACBKPYLT-UHFFFAOYSA-N prop-2-enethioamide Chemical compound NC(=S)C=C IHRLABACBKPYLT-UHFFFAOYSA-N 0.000 description 4
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 3
- 241000801593 Pida Species 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 3
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 241000238631 Hexapoda Species 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- QVPDLDZAXIPRCG-UHFFFAOYSA-N CNC(C)=C(C(C)=O)C(=O)NC1=CC=CC=C1 Chemical compound CNC(C)=C(C(C)=O)C(=O)NC1=CC=CC=C1 QVPDLDZAXIPRCG-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001240 enamine group Chemical group 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- IFPHDUVGLXEIOQ-UHFFFAOYSA-N ortho-iodosylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I=O IFPHDUVGLXEIOQ-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种异噻唑‑5(2H)‑亚胺类化合物的制备方法及其应用，该方法以式I所示的硫代丙烯酰胺类化合物为原料，其在有机高价碘化合物作用下发生成环反应可得到式II所示的多取代异噻唑‑5(2H)‑亚胺类化合物。与现有技术中多取代异噻唑‑5(2H)‑亚胺类化合物的制备方法相比，本发明利用有机高价碘化合物参与硫代丙烯酰胺类化合物的成环反应，实现了多取代异噻唑‑5(2H)‑亚胺类化合物的制备。该合成方法具有原料易得、反应条件温和、无安全风险和无需使用金属催化剂的优点。The present invention provides a method for preparing an isothiazole-5(2H)-imine compound and its application. The method uses a thioacrylamide compound shown in formula I as a raw material, and a polysubstituted isothiazole-5(2H)-imine compound shown in formula II undergoes a ring-forming reaction under the action of an organic high-valent iodine compound. Compared with the preparation method of polysubstituted isothiazole-5(2H)-imine compounds in the prior art, the present invention utilizes an organic high-valent iodine compound to participate in the ring-forming reaction of the thioacrylamide compound, thereby realizing the preparation of polysubstituted isothiazole-5(2H)-imine compounds. The synthesis method has the advantages of easy availability of raw materials, mild reaction conditions, no safety risks, and no need to use a metal catalyst.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method and application of an isothiazole-5 (2H) -imine compound.
Background
The isothiazole-5 (2H) -imine compounds are five-membered heterocyclic compounds widely existing in natural products and artificially synthesized compounds, have biological activity and pharmacological activity, can be used in various fields of chemistry, biology, medicine and the like, and are reported to be used as CB 2 receptor modulators for treating pains, can also be used in the field of pesticides, and can effectively inhibit insect vital activities.
The traditional method for preparing the isothiazole-5 (2H) -imine compound mainly comprises the following two steps of (1) utilizing a 3-amino thioacrylamide derivative to perform a cyclization reaction under the action of trimethyl oxonium tetrafluoroborate, liquid bromine or azodicarbonate compound, wherein the trimethyl oxonium tetrafluoroborate is high in price, the liquid bromine has strong toxicity and corrosiveness, the azodicarbonate compound is easy to explode, the potential safety hazard is high, the application of the compound is greatly limited, and (2) the method is prepared through the ring opening and cyclization reaction of an isothiazole compound mixture, but the method needs to synthesize the isothiazole precursor in advance, and the synthetic route is long and the step is complex.
Disclosure of Invention
In view of the above, the present invention aims to provide a preparation method and application of an isothiazole-5 (2H) -imine compound. The method has the advantages of easily available raw materials, mild reaction conditions, simple operation and easy realization.
In order to achieve the purpose, the invention adopts the following technical scheme:
In a first aspect, the invention provides a method for preparing an isothiazole-5 (2H) -imine compound, comprising the following steps:
The thioacrylamide compound shown in the formula I is subjected to cyclization reaction under the action of an organic high-valence iodine compound to obtain an isothiazole-5 (2H) -imine compound shown in the formula II;
Wherein each R 1、R2、R3、R4 is independently selected from-A, -Ar, or-Het;
the-A is selected from a substituted or unsubstituted C 1～C30 alkyl or a substituted or unsubstituted C 3～C7 cycloalkyl;
the-Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl and substituted or unsubstituted naphthyl;
The Het is selected from a substituted or unsubstituted unsaturated monocyclic heterocyclic group of C 5～C10 or a substituted or unsubstituted unsaturated bicyclic heterocyclic group of C 5～C10, the number of heteroatoms in the unsaturated monocyclic heterocyclic group and the unsaturated bicyclic heterocyclic group is respectively and independently selected from 1-4, and the heteroatoms are selected from one or more of N, O or S.
The organic hypervalent iodine compounds are well known to those skilled in the art, wherein the iodine is in a trivalent or pentavalent state.
Preferably, the-a is selected from a substituted or unsubstituted C 1～C10 alkyl group or a substituted or unsubstituted C 3～C7 cycloalkyl group.
Preferably, the-Het is selected from a substituted or unsubstituted unsaturated monocyclic heterocyclyl of C 5～C7 or a substituted or unsubstituted unsaturated bicyclic heterocyclyl of C 8～C12.
Preferably, the-Ar is selected from substituted phenyl, substituted biphenyl or substituted naphthyl, and the substituents in the substituted phenyl, substituted biphenyl or substituted naphthyl are each independently selected from any one or more of C 1～C10 alkoxy, -A, -COA, -COOA, -CN or-NO 2.
More preferably, the-a is selected from a substituted or unsubstituted alkyl group of C 1～C5 or a substituted or unsubstituted cycloalkyl group of C 3～C7.
More preferably, the substituents in the substituted phenyl, substituted biphenyl or substituted naphthyl groups are each independently selected from any one or more of C 1～C5's alkoxy, -A, -COA, -COOA, -CN or-NO 2.
Preferably, the organic hypervalent iodine compound is selected from any one or more of iodosyl benzene, iodobenzene diacetate, iodobenzene di (trifluoroacetic acid), hydroxy p-toluenesulfonyl oxyiodobenzene, 2-iodosyl benzoic acid, iodosyl benzene or dess-martin periodate reagent.
Preferably, the molar ratio of the thioacrylamide compound to the organic hypervalent iodine compound is 1 (0.5-5).
Preferably, the reaction is carried out in the presence of an organic solvent selected from any one or more of dichloromethane, chloroform, 1, 2-dichloroethane, N-dimethylformamide, ethanol, diethyl ether, acetonitrile, tetrahydrofuran, ethyl acetate or 1, 4-dioxane.
Preferably, the reaction is carried out in the presence of an auxiliary selected from any one or more of trifluoroacetic acid, boron trifluoride etherate, 2-trifluoroethanol, hexafluoroisopropanol, acetic acid, p-toluenesulfonic acid or elemental iodine.
Preferably, the molar ratio of the thioacrylamide compound to the auxiliary agent is 1 (0.5-4).
Preferably, the reaction temperature is 0-100 ℃ and the reaction time is 0.1-10 h.
In a second aspect, the invention provides a medicament comprising the isothiazole-5 (2H) -imine compound prepared by the preparation method.
Compared with the prior art, the invention has the beneficial effects that:
compared with the prior art, the method for preparing the isothiazole-5 (2H) -imine compound provided by the invention has the advantages that the organic high-valence iodine compound is utilized to activate the enamine group in the thioacrylamide compound, and the thioacrylamide compound is guided to generate a ring reaction, so that the synthesis of the isothiazole-5 (2H) -imine compound is realized. The method has the advantages that the organic high-valence iodine compound and the thioacrylamide compound are used as experimental raw materials, the method is simple and easy to obtain, the price is relatively lower, the reaction condition is mild, the safety risk is avoided, a metal catalyst is not needed, a plurality of substituent groups can exist in the prepared isothiazole-5 (2H) -imine compound, the application range of the preparation method is wide, and the preparation method provided by the invention can accurately synthesize a corresponding target product through nuclear magnetic resonance spectrum analysis hydrogen spectrum and carbon spectrum test.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
All the raw materials according to the present invention are not particularly limited in their sources and can be purchased commercially or prepared according to conventional technical means well known to those skilled in the art.
Aiming at the problems of high raw material cost, complex reaction and safety risk existing in the preparation method of the isothiazole-5 (2H) -imine compound in the prior art, the invention provides a preparation method of the isothiazole-5 (2H) -imine compound, which comprises the following steps:
The thioacrylamide compound shown in the formula I is subjected to cyclization reaction under the action of an organic high-valence iodine compound to obtain an isothiazole-5 (2H) -imine compound shown in the formula II;
Wherein each R 1、R2、R3、R4 is independently selected from-A, -Ar, or-Het;
The group-A is selected from the group consisting of alkyl of substituted or unsubstituted C 1～C30 or cycloalkyl of substituted or unsubstituted C 3～C7, preferably from the group consisting of alkyl of substituted or unsubstituted C 1～C20 or cycloalkyl of substituted or unsubstituted C 3～C7, more preferably from the group consisting of alkyl of substituted or unsubstituted C 1～C10 or cycloalkyl of substituted or unsubstituted C 3～C7, even more preferably from the group consisting of alkyl of substituted or unsubstituted C 1～C5 or cycloalkyl of substituted or unsubstituted C 3～C7, and most preferably from the group consisting of alkyl of substituted or unsubstituted C 1～C3 or cycloalkyl of substituted or unsubstituted C 3～C7. Wherein the number of substituents in the substituted C 1～C30 alkyl group is preferably 1 to 20, more preferably 1 to 15, still more preferably 1 to 10, still more preferably 1 to 5, still more preferably 1 to 3, most preferably 1 to 2, and the substituents are preferably-Ar and/or-Het.
The-Het is selected from the group consisting of a substituted or unsubstituted C 4～C7 unsaturated monocyclic heterocyclic group or a substituted or unsubstituted C 7～C12 unsaturated bicyclic heterocyclic group, more preferably a substituted or unsubstituted C 5～C7 unsaturated monocyclic heterocyclic group or a substituted or unsubstituted C 8～C12 unsaturated bicyclic heterocyclic group, still more preferably a substituted or unsubstituted C 5～C6 unsaturated monocyclic heterocyclic group or a substituted or unsubstituted C 9～C12 unsaturated bicyclic heterocyclic group, the number of heteroatoms in the unsaturated monocyclic heterocyclic group and the unsaturated bicyclic heterocyclic group are each independently selected from 1 to 4, and the heteroatoms are selected from N, any of O or S one or more of them. wherein the number of substituents in the unsaturated monocyclic heterocyclic group of substituted C 5～C10 or the unsaturated bicyclic heterocyclic group of substituted C 7～C12 is each independently preferably 1 to 3, more preferably 1 or 2, and each of the substituents is independently preferably halogen, alkoxy of C 1～C30, or the like, any one or more of-A, -COA, -COOA, -CN or-NO 2, more preferably halogen, one or more of C 1～C20 alkoxy, -A, -COA, -COOA, -CN and-NO 2, still more preferably halogen, Any one or more of alkoxy, -A, -COA, -COOA, -CN or-NO 2 of C 1～C10, more preferably any one or more of halogen, alkoxy, -A, -COA, -COOA, -CN or-NO 2 of C 1～C5, most preferably halogen, CN or-NO, One or more of alkoxy, -A, -COA, -COOA, -CN or-NO 2 of C 1～C3, wherein halogen is preferably any one or more of F, cl, br or I, and the content of A in the technical scheme is the same as that of the related content, and is not repeated here.
The Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, the number of substituents in the substituted phenyl, substituted biphenyl or substituted naphthyl is preferably 1-5, more preferably 1-3, and still more preferably 1-2, the position of the substituents in the substituted phenyl, substituted biphenyl or substituted naphthyl is preferably ortho-position and/or para-position, the substituents in the substituted phenyl, substituted biphenyl or substituted naphthyl are each independently preferably halogen, any one or more of alkoxy of C 1～C30, -A, -COA, -COOA, -CN or-NO 2, more preferably halogen, any one or more of alkoxy of C 1～C20, -A, -COA, -COOA, -CN or-NO 2, still more preferably halogen, any one or more of alkoxy of C 1～C10, -A, -COA, -COOA, -CN or-NO 2, further preferably halogen, alkoxy of C 1～C5, -A, -COA, -COOA, -CN or-NO 623, any one or more of halogen, -C35A, -C35 and/or more of halogen, and any one or more of halogen, -C35-Cl, -C35 and/or more of these are the above-mentioned schemes.
In some embodiments of the invention, the structural formulas of the thioacrylamide compound and the polysubstituted isothiazol-5 (2H) -imine compound are shown in formula I and formula II, respectively, wherein R 1、R2、R3 is preferably selected from C 1～C5 alkyl, phenyl or substituted phenyl, more preferably from C 1～C3 alkyl, phenyl or substituted phenyl, and R 4 is preferably selected from phenyl or substituted phenyl. The substituent in the substituted phenyl is preferably any one or more of C 1～C5 alkyl, C 1～C5 alkoxy or-Cl, more preferably any one or more of C 1～C3 alkyl, C 1～C3 alkoxy or-Cl, and the number of the substituent is preferably 1-3, more preferably 1-2.
In some embodiments of the present invention, the structural formulas of the thioacrylamide compound and the polysubstituted isothiazol-5 (2H) -imine compound are shown in formula I and formula II, respectively, R 1、R2、R3 is preferably a chain alkyl of C 1～C5, R 4 is preferably a phenyl group or a substituted phenyl group, the substituent in the substituted phenyl group is preferably any one or more of an alkyl of C 1～C5, an alkoxy of C 1～C5 or-Cl, and the number of the substituents in the substituted phenyl group is preferably 1 to 3.
In some embodiments of the present invention, the iodine in the organic hypervalent iodine compound is trivalent or pentavalent, and may be specifically selected from any one or more of trivalent iodosyl benzene (PhIO), iodobenzene diacetate (PIDA), iodobenzene di (trifluoroacetic acid) (PIFA), hydroxy p-toluenesulfonyl iodobenzene (HTIB), or pentavalent 2-iodoylbenzoic acid (IBX), iodobenzene (PhIO 2), or dess-martin periodate reagent (DMP), preferably any one or more of PhIO, PIDA, PIFA, IBX or DMP, and most preferably PIFA. As a result of the study, if the amount of the thioacrylamide compound added is too high, the reaction is incomplete, and if the amount of the thioacrylamide compound added is too low, the organic high-valent iodine compound is wasted greatly, so that the molar ratio of the thioacrylamide compound to the organic high-valent iodine compound is preferably 1 (0.5 to 5), more preferably 1 (0.5 to 3), still more preferably 1 (1 to 2.5), and most preferably 1 (1.5 to 2). In some embodiments of the invention, the molar ratio of thioacrylamide compound to organic high valent iodine compound may specifically be 1:1.2, 1:1.5, 1:2, or 1:3.
In some embodiments of the present invention, the thioacrylamide compound and the organic high-valence iodine compound are preferably reacted in the presence of an auxiliary agent, wherein the auxiliary agent can enable the organic high-valence iodine compound to enter an activated state in advance, so as to facilitate the subsequent cyclization reaction of the thioacrylamide compound, and the auxiliary agent can be specifically selected from any one or more of trifluoroacetic acid, boron trifluoride diethyl ether, 2-trifluoroethanol, hexafluoroisopropanol, acetic acid, p-toluenesulfonic acid or iodine simple substance. In some embodiments of the present invention, it is further preferred that the yield of the reaction product is further enhanced by the addition of an auxiliary agent when the organohigh iodine compound is selected from PhIO, IBX or DMP.
In some embodiments of the present invention, the thioacrylamide-based compound, the organic high-valent iodine compound, and the optional auxiliary are preferably reacted in the presence of an organic solvent, which is soluble, and may be specifically selected from any one or more of dichloromethane, chloroform, 1, 2-dichloroethane, N-dimethylformamide, ethanol, diethyl ether, acetonitrile, tetrahydrofuran, ethyl acetate, or 1, 4-dioxane, preferably any one or more of dichloromethane, chloroform, or 1, 2-dichloroethane, and the like. In some embodiments of the present invention, the organic high-valence iodine compound, the optional auxiliary agent and the organic solvent are preferably mixed first, and then the mixing is preferably performed under a stirring condition, so that the organic high-valence iodine compound is brought into an activated state in advance, and then the thioacrylamide compound is added for reaction, wherein the concentration of the thioacrylamide compound in the reaction system is preferably 0.025-0.1 mmol/mL. The reaction temperature is preferably 0-100 ℃, more preferably 10-60 ℃, most preferably 15-35 ℃, and the reaction time is preferably 0.1-10 h, more preferably 0.5-6 h.
The above-mentioned "optional auxiliary agent" means that the auxiliary agent may be added to the reaction system according to actual needs, that is, may be added, or may not be added.
In some embodiments of the present invention, the reaction preferably further comprises a post-purification treatment operation after completion, and the obtained reaction solution is preferably poured into a saturated aqueous sodium chloride solution and then extracted with an organic solvent, wherein the organic solvent can be specifically selected from any one or more of dichloromethane, chloroform, 1, 2-dichloroethane, diethyl ether or ethyl acetate. After the extraction is completed, the extract is preferably dried, filtered and the solvent is removed, and then the isothiazole-5 (2H) -imine compound shown in formula II is obtained through silica gel column chromatography. In some embodiments of the invention, the drying is preferably carried out by sucking off the liquid from the extract using anhydrous sodium sulfate, and the filtration and removal of the solvent are carried out according to conventional techniques well known to those skilled in the art. In some embodiments of the present invention, the eluent in the silica gel column chromatography is preferably a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably (5-11): 1, more preferably (8-11): 1, and most preferably 10:1.
The method utilizes the organic high-valence iodine compound to participate in the cyclization reaction of the thioacrylamide compound to synthesize the isothiazole-5 (2H) -imine compound. The method has the advantages of easily available raw materials, simple operation, mild reaction conditions, and wide application range, and R 1～R4 can be a plurality of different substituents.
Through nuclear magnetic resonance spectrum analysis hydrogen spectrum and nuclear magnetic resonance carbon spectrum tests, the preparation method provided by the invention can accurately synthesize the corresponding isothiazole-5 (2H) -imine compounds, and has higher yield. The isothiazole-5 (2H) -imine compounds can be used for preparing medicaments which can relieve pain or inhibit insect activities.
In order to further illustrate the present invention, the following examples are provided. The experimental materials used in the following examples of the present invention are commercially available or prepared according to conventional preparation methods well known to those skilled in the art.
Wherein, the thioacrylamide compound shown in the formula I is preferably prepared according to a method reported in a synthetic method (ARKIVOC, 2009, (xii), 98) reported in a literature;
the hydrogen and carbon spectra of all compounds in the examples below were determined by Bruker AV-300 type nuclear magnetic resonance spectrometer and the mass spectrum data by LTQ Orbitrap Velos Pro type high resolution mass spectrometer.
Example 1
This example provides a2, 3-dimethyl-4-acetyl-N-phenylisothiazole-5 (2H) -imine prepared as follows:
Under the stirring condition at room temperature, 1.5mmol of PIFA and 10.0mL of dichloromethane are added into a 50mL round-bottomed flask, and after being uniformly mixed, 1.0mmol of 2-acetyl-3-methylamino-N-phenylbut-2-enamide is added, and the mixture is reacted for 2.0 hours at room temperature. After the reaction is finished, 2, 3-dimethyl-4-acetyl-N-phenylisothiazole-5 (2H) -imine is obtained, the yield is 84 percent, and the purity is more than 99 percent;
The 2, 3-dimethyl-4-acetyl-N-phenylisothiazol-5 (2H) -imine obtained in example 1 was analyzed by nuclear magnetic resonance spectroscopy to obtain its nuclear magnetic hydrogen spectrum, the results were as follows:
1H NMR(300MHz,CDCl3):δ2.55(s,3H),2.69(s,3H),3.26(s,3H),6.98(d,J＝7.5Hz,2H),7.08(t,J＝7.5Hz,1H),7.35(t,J＝7.5Hz,2H).
example 2
This example provides a 2-benzyl-3-methyl-4-acetyl-N-phenylisothiazole-5 (2H) -imine prepared as follows:
Under the condition of 50 ℃ stirring, 2.5mmol of PIDA and 10.0mL of ethyl acetate are added into a 50mL round-bottomed flask, and after being uniformly mixed, 1.0mmol of 2-acetyl-3- (benzylamino) -N-phenylbut-2-ene thioamide is added for reaction for 6.0 hours. After the reaction was completed, the reaction solution was poured into 50.0mL of a saturated aqueous NaCl solution, followed by extraction three times with 20.0mL of ethyl acetate, the organic phases were combined, 3.0g of anhydrous sodium sulfate was added to dry, the solid was removed by filtration, and the organic solvent was removed again, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=8:1) to give 2-benzyl-3-methyl-4-acetyl-N-phenylisothiazole-5 (2H) -imine in a yield of 64% and a purity of >99%.
The 2-benzyl-3-methyl-4-acetyl-N-phenylisothiazol-5 (2H) -imine obtained in example 2 was analyzed by nuclear magnetic resonance spectroscopy to obtain its nuclear magnetic carbon spectrum, the result was as follows:
13C NMR(75MHz,CDCl3):δ15.7,32.0,51.7,114.8,120.1,124.4,127.0,128.7,129.2,129.9,134.4,164.8,195.8.
example 3
This example provides a 2, 3-dimethyl-4-acetyl-N- (3-methylphenyl) isothiazol-5 (2H) -imine prepared by the following method:
5.0mmol PhIO, 7.5mmol acetic acid and 20.0mL methylene chloride are added into a 50mL round bottom flask under stirring at room temperature, and after being mixed uniformly, 1.0mmol 2-acetyl-3-methylamino-N- (m-tolyl) but-2-ene thioamide is added for reaction for 3.5 hours. After the reaction was completed, the reaction solution was poured into 50.0mL of a saturated aqueous NaCl solution, followed by extraction with 20.0mL of dichloromethane three times, the organic phases were combined, 3.0g of anhydrous sodium sulfate was added to dry, the solid was removed by filtration, and the organic solvent was removed again, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give 2, 3-dimethyl-4-acetyl-N- (3-methylphenyl) isothiazole-5 (2H) -imine in a yield of 65% and a purity of >99%.
The 2, 3-dimethyl-4-acetyl-N- (3-methylphenyl) isothiazol-5 (2H) -imine obtained in example 3 was analyzed by nuclear magnetic resonance spectroscopy to obtain its nuclear magnetic carbon spectrum, the results were as follows:
1H NMR(300MHz,CDCl3):δ2.34(s,3H),2.57(s,3H),2.68(s,3H),3.28(s,3H),7.80(d,J＝7.5Hz,1H),6.82(s,1H),6.92(d,J＝7.5Hz,1H),7.24(t,J＝7.5Hz,1H).
example 4
This example provides a 2, 3-dimethyl-4-acetyl-N- (4-nitrophenyl) isothiazol-5 (2H) -imine prepared as follows:
after 1.0mmol of PIFA and 30.0mL of 1, 2-dichloroethane were added to a 50mL round bottom flask and mixed uniformly under stirring at 75 ℃,1.0 mmol of 2-acetyl-3- (methylamino) -N- (4-nitrophenyl) but-2-enylthioamide was further added and reacted for 5.0 hours. After the reaction was completed, the reaction solution was poured into 50.0mL of saturated aqueous NaCl, followed by extraction with 20.0mL of 1, 2-dichloroethane three times, the organic phases were combined, dried over 3.0g of anhydrous sodium sulfate, filtered to remove the solid, and then the organic solvent was removed, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give 2, 3-dimethyl-4-acetyl-N- (4-nitrophenyl) isothiazol-5 (2H) -imine in 69% yield with a purity of >99%.
The 2, 3-dimethyl-4-acetyl-N- (4-nitrophenyl) isothiazol-5 (2H) -imine obtained in example 4 was analyzed by nuclear magnetic resonance spectrum to obtain its nuclear magnetic hydrogen spectrum, the result was as follows:
1H NMR(300MHz,CDCl3):δ2.12(s,3H),2.54(s,3H),3.34(s,3H),7.04(d,J＝9.0Hz,2H),8.16(d,J＝9.0Hz,2H).
Example 5
This example provides a2, 3-dimethyl-4-propionyl-N-phenylisothiazol-5 (2H) -imine prepared by the following method:
After adding 2.0mmol of PIFA, 1.0mmol of hexafluoroisopropanol and 30.0mL of chloroform to a 50mL round bottom flask under stirring at 30 ℃ and mixing uniformly, 1.0mmol of 2-propionyl-3- (methylamino) -N-phenylbut-2-enylthioamide was added and reacted for 4.5 hours. After the reaction was completed, the reaction solution was poured into 50.0mL of a saturated aqueous NaCl solution, followed by extraction with 20.0mL of dichloromethane three times, the organic phases were combined, 3.0g of anhydrous sodium sulfate was added to dry, the solid was removed by filtration, and the organic solvent was removed again, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give 2, 3-dimethyl-4-propionyl-N-phenylisothiazol-5 (2H) -imine in 73% yield with purity >99%.
The 2, 3-dimethyl-4-propionyl-N-phenylisothiazol-5 (2H) -imine obtained in example 5 was analyzed by nuclear magnetic resonance spectrum to obtain the mass spectrum data, the result is as follows:
HRMS (ESI) calcd for C 14H17N2OS[M+H]+ theory 261.1056, found 261.1068.
Example 6
This example provides a2, 3-dimethyl-4-acetyl-N-phenylisothiazole-5 (2H) -imine prepared as follows:
1.5mmol of IBX, 0.5mmol of trifluoroacetic acid and 35.0mL of dichloromethane are added into a 50mL round-bottomed flask under stirring at 0 ℃ to be uniformly mixed, and then 1.0mmol of 2-acetyl-3- (methylamino) -N-phenylbut-2-enylthioamide is added to react for 1.5 hours. After the reaction was completed, the reaction solution was poured into 50.0mL of saturated aqueous NaCl, followed by extraction with 20.0mL of dichloromethane three times, the organic phases were combined, 3.0g of anhydrous sodium sulfate was added to dry, the solid was removed by filtration, and the organic solvent was removed again, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give 2, 3-dimethyl-4-acetyl-N-phenylisothiazole-5 (2H) -imine in 78% yield with a purity of >99%.
Example 7
This example provides a 2-methyl-3-phenyl-4-propionyl-N-phenylisothiazol-5 (2H) -imine prepared by the following method:
Under the condition of stirring at 35 ℃, 3.0mmol of PIFA and 30.0mL of diethyl ether are added into a 50mL round-bottomed flask, and after being uniformly mixed, 1.0mmol of 2-acetyl-3-methylamino-3-phenyl-N-phenylthioacrylamide is added for reaction for 6.0 hours. After the reaction was completed, the reaction solution was poured into 50.0mL of a saturated aqueous NaCl solution, followed by extraction three times with 20.0mL of ethyl acetate, the organic phases were combined, 3.0g of anhydrous sodium sulfate was added to dry, the solid was removed by filtration, and the organic solvent was removed again, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=9:1) to give 2-methyl-3-phenyl-4-propionyl-N-phenylisothiazol-5 (2H) -imine in a yield of 51% with a purity of >99%.
Analysis of 2-methyl-3-phenyl-4-propionyl-N-phenylisothiazol-5 (2H) -imine obtained in example 7 by nuclear magnetic resonance spectroscopy gave the following mass spectrum data:
HRMS (ESI) calcd for C 19H19N2OS[M+H]+ theory 323.1213, found 323.1223.
Example 8
This example provides a2, 3-dimethyl-4-benzoyl-N- (4-methoxyphenyl) isothiazol-5 (2H) -imine prepared by the following method:
After 1.5mmol of PIFA and 20.0mL of acetonitrile were added to a 50mL round-bottomed flask and mixed uniformly under stirring at 25 ℃,1.0 mmol of 2-benzoyl-3- (methylamino) -N- (4-methoxyphenyl) but-2-enylthioamide was added thereto and reacted for 3.5 hours. After the reaction was completed, the reaction solution was poured into 50.0mL of a saturated aqueous NaCl solution, followed by extraction with 20.0mL of dichloromethane three times, the organic phases were combined, 3.0g of anhydrous sodium sulfate was added to dry, the solid was removed by filtration, and the organic solvent was removed again, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=8:1) to give 2, 3-dimethyl-4-benzoyl-N- (4-methoxyphenyl) isothiazole-5 (2H) -imine in 58% yield with a purity of >99%.
Analysis of the 2, 3-dimethyl-4-benzoyl-N- (4-methoxyphenyl) isothiazol-5 (2H) -imine obtained in example 8 by nuclear magnetic resonance spectroscopy gave the following mass spectrum data:
HRMS (ESI) calcd for C 19H19N2O2S[M+H]+ theory 339.1162, found 339.1156.
Example 9
This example provides a2, 3-dimethyl-4-acetyl-N- (4-methoxyphenyl) isothiazole-5 (2H) -imine prepared by the following method:
2.5mmol of DMP and 2.5mmol of 2, 2-trifluoroethanol (40.0 mL) of methylene chloride are added into a 50mL round-bottomed flask under the condition of stirring at 25 ℃ to be uniformly mixed, and then 1.0mmol of 2-acetyl-3- (methylamino) -N-phenylbut-2-ene thioamide is added to react for 1.0 hour. After the reaction was completed, the reaction solution was poured into 50.0mL of saturated aqueous NaCl, followed by extraction with 20.0mL of dichloromethane three times, the organic phases were combined, 3.0g of anhydrous sodium sulfate was added to dry, the solid was removed by filtration, and the organic solvent was removed again, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=8:1) to give 2, 3-dimethyl-4-acetyl-N- (4-methoxyphenyl) isothiazole-5 (2H) -imine in a yield of 64% and a purity of >99%.
The 2, 3-dimethyl-4-acetyl-N- (4-methoxyphenyl) isothiazol-5 (2H) -imine obtained in example 9 was analyzed by nuclear magnetic resonance spectrum to obtain nuclear magnetic hydrogen spectrum, and the result was as follows:
1H NMR(300MHz,CDCl3):δ2.59(s,3H),2.70(s,3H),3.30(s,3H),3.82(s,3H),6.91(d,J＝9.0Hz,2H),6.93(d,J＝9.0Hz,2H).
Example 10
This example provides a2, 3-dimethyl-4-acetyl-N- (2-chlorophenyl) isothiazole-5 (2H) -imine prepared by the following method:
2.0mmol PhIO, 3.0mmol trifluoroacetic acid and 20.0mL 1, 2-dichloroethane are added to a 50mL round bottom flask and mixed evenly under 15 ℃ condition, 1.0mmol N- (2-chlorophenyl) -2-acetyl-3-methylaminobut-2-ene thioamide is added and reacted for 8.0 hours. After the reaction was completed, the reaction solution was poured into 50.0mL of saturated aqueous NaCl, followed by extraction with 20.0mL of dichloromethane three times, the organic phases were combined, 3.0g of anhydrous sodium sulfate was added to dry, the solid was removed by filtration, and the organic solvent was removed again, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give 2, 3-dimethyl-4-acetyl-N- (2-chlorophenyl) isothiazole-5 (2H) -imine in a yield of 55% and purity >99%.
The 2, 3-dimethyl-4-acetyl-N- (2-chlorophenyl) isothiazol-5 (2H) -imine obtained in example 10 was analyzed by nuclear magnetic resonance spectroscopy to obtain its nuclear magnetic hydrogen spectrum as follows:
1H NMR(300MHz,CDCl3):δ2.59(s,3H),2.74(s,3H),3.30(s,3H),6.99-7.06(m,2H),7.22(dd,J1＝7.8Hz,J2＝1.2Hz,1H),7.45(d,J＝7.8Hz,1H).
Comparative example 1
3.1Mmol of N- (4-nitrophenyl) -2-nitro-3, 3-dianiline thioacrylamide was added to 6.2mL of DMF under stirring at room temperature to form a solution, 3.3mmol of diethyl azodicarboxylate was added thereto, reacted for 1.0 hour (monitored by TLC), then poured into ice water, the yellow solid precipitated was filtered, washed with a large amount of water, and dried overnight in a vacuum oven to give 1.1g of 2-phenyl-3-anilino-4-nitro-N- (4-nitrophenyl) isothiazole-5 (2H) -imine in 84% yield. (Helv.Chim. Acta,1997,80,273.)
The method only discusses the cyclization reaction of the thioacrylamide with the 2-position being a nitro structure, the azodicarbonate compound needed in the reaction is easy to explode and has a certain potential safety hazard, and in the raw material synthesis process, two alkylthio groups needed to be removed for synthesizing one molecule of raw material N- (4-nitrophenyl) -2-nitro-3, 3-dianilino thioacrylamide generate two molecules of mercaptan, the atomic economy of the reaction is poor, and the mercaptan has strong toxicity.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (7)
1. The preparation method of the isothiazole-5 (2H) -imine compound is characterized by comprising the following steps of:
The thioacrylamide compound shown in the formula I is subjected to cyclization reaction under the action of an organic high-valence iodine compound to obtain an isothiazole-5 (2H) -imine compound shown in the formula II;
Wherein each R 1、R2、R3、R4 is independently selected from-A, -Ar, or-Het;
the-A is selected from a substituted or unsubstituted C 1～C30 alkyl or a substituted or unsubstituted C 3～C7 cycloalkyl;
the-Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl and substituted or unsubstituted naphthyl;
The Het is selected from a substituted or unsubstituted unsaturated monocyclic heterocyclic group of C 5～C10 or a substituted or unsubstituted unsaturated bicyclic heterocyclic group of C 5～C10, the number of heteroatoms in the unsaturated monocyclic heterocyclic group and the unsaturated bicyclic heterocyclic group is respectively and independently selected from 1-4, and the heteroatoms are selected from one or more of N, O or S;
The organic hypervalent iodine compound is selected from any one or more of iodosobenzene, iodobenzene diacetate, di (trifluoroacetic acid) iodobenzene, hydroxy-p-toluenesulfonyloxy iodobenzene, 2-iodoxybenzoic acid, iodoxybenzene or dess-Martin periodate reagent;
The reaction is carried out in the presence of an auxiliary agent;
the auxiliary agent is selected from any one or more of trifluoroacetic acid, boron trifluoride diethyl ether, 2-trifluoroethanol, hexafluoroisopropanol, acetic acid, p-toluenesulfonic acid or iodine simple substance.
2. The method of preparation according to claim 1, wherein-a is selected from the group consisting of substituted or unsubstituted C 1～C10 alkyl or substituted or unsubstituted C 3～C7 cycloalkyl;
the-Het is selected from a substituted or unsubstituted unsaturated monocyclic heterocyclyl of C 5～C7 or a substituted or unsubstituted unsaturated bicyclic heterocyclyl of C 8～C12;
The substituent groups in the substituted phenyl, the substituted biphenyl or the substituted naphthyl are each independently selected from any one or more of C 1～C10 alkoxy, -A, -COA, -COOA, -CN or-NO 2.
3. The method of preparation according to claim 2, wherein-a is selected from the group consisting of substituted or unsubstituted C 1～C5 alkyl or substituted or unsubstituted C 3～C7 cycloalkyl;
The substituent groups in the substituted phenyl, the substituted biphenyl or the substituted naphthyl are each independently selected from any one or more of C 1～C5 alkoxy, -A, -COA, -COOA, -CN or-NO 2.
4. The method according to claim 1, wherein the molar ratio of the thioacrylamide compound to the organic hypervalent iodine compound is 1 (0.5 to 5).
5. The process according to claim 1, wherein the reaction is carried out in the presence of an organic solvent;
The organic solvent is selected from any one or more of dichloromethane, chloroform, 1, 2-dichloroethane, N-dimethylformamide, ethanol, diethyl ether, acetonitrile, tetrahydrofuran, ethyl acetate and 1, 4-dioxane.
6. The preparation method of claim 1, wherein the molar ratio of the thioacrylamide compound to the auxiliary agent is 1 (0.5-4).
7. The method according to claim 1, wherein the reaction is carried out at a temperature of 0 to 100 ℃ for a time of 0.1 to 10 hours.
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