CN117247349A - Quinoline oxynitride C 2 Process for the dithiocarbamation of H - Google Patents
Quinoline oxynitride C 2 Process for the dithiocarbamation of H Download PDFInfo
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- CN117247349A CN117247349A CN202311097664.XA CN202311097664A CN117247349A CN 117247349 A CN117247349 A CN 117247349A CN 202311097664 A CN202311097664 A CN 202311097664A CN 117247349 A CN117247349 A CN 117247349A
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- quinoline
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 238000000034 method Methods 0.000 title claims abstract description 28
- 230000008569 process Effects 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- -1 quinoline nitroxide Chemical class 0.000 claims abstract description 26
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical compound NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000012990 dithiocarbamate Substances 0.000 claims abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 8
- 150000001412 amines Chemical class 0.000 claims abstract description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000005886 esterification reaction Methods 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 125000006575 electron-withdrawing group Chemical group 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 88
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 239000000047 product Substances 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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 19
- 239000012074 organic phase Substances 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 239000003480 eluent Substances 0.000 claims description 11
- 239000003208 petroleum Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 6
- NIEVKYPIXJDDNI-UHFFFAOYSA-N [N]=O.N1=CC=CC2=CC=CC=C12 Chemical compound [N]=O.N1=CC=CC2=CC=CC=C12 NIEVKYPIXJDDNI-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 238000011097 chromatography purification Methods 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 4
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 230000002209 hydrophobic effect Effects 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 150000001350 alkyl halides Chemical group 0.000 claims 1
- 238000004587 chromatography analysis Methods 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 description 7
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 150000004659 dithiocarbamates Chemical class 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000010499 C–H functionalization reaction Methods 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 230000002365 anti-tubercular Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- QKJAZPHKNWSXDF-UHFFFAOYSA-N 2-bromoquinoline Chemical class C1=CC=CC2=NC(Br)=CC=C21 QKJAZPHKNWSXDF-UHFFFAOYSA-N 0.000 description 1
- ZGIKWINFUGEQEO-UHFFFAOYSA-N 3-bromoquinoline Chemical compound C1=CC=CC2=CC(Br)=CN=C21 ZGIKWINFUGEQEO-UHFFFAOYSA-N 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- AWLGLUBASOBKNM-UHFFFAOYSA-N 6-bromo-4-methoxyquinoline Chemical compound C1=C(Br)C=C2C(OC)=CC=NC2=C1 AWLGLUBASOBKNM-UHFFFAOYSA-N 0.000 description 1
- HFDLDPJYCIEXJP-UHFFFAOYSA-N 6-methoxyquinoline Chemical compound N1=CC=CC2=CC(OC)=CC=C21 HFDLDPJYCIEXJP-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 241000223221 Fusarium oxysporum Species 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- QUIJNHUBAXPXFS-XLJNKUFUSA-N bedaquiline Chemical compound C1([C@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 QUIJNHUBAXPXFS-XLJNKUFUSA-N 0.000 description 1
- 229960000508 bedaquiline Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 238000005732 thioetherification reaction Methods 0.000 description 1
- 229940070527 tourmaline Drugs 0.000 description 1
- 229910052613 tourmaline Inorganic materials 0.000 description 1
- 239000011032 tourmaline Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
- C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of compound synthesis, and particularly discloses a quinoline oxynitride C 2 Process for the dithiocarbamate of-H, quinoline nitroxide of formula 1 CS 2 Mixing amine of formula 2 and the auxiliary agent of formula 3 in an organic solvent and performing dithiocarbamic acid esterification reaction to obtain a product of formula 4; r is R 7 Is an electron withdrawing group or an aromatic group; the organic solvent is at least one of halogenated alkane, acetone and DMF. The invention fills the quinoline oxynitride C 2 The technical blank of H dithiocarbamate and the unexpected synergy achieved by the combined control of the preparation parameters described, the preparation of the reaction can be improved.
Description
Technical Field
The invention belongs to the field of organic synthesis, and relates to a synthesis method and application of a quinoline heterocycle-containing dithio carbamate compound.
Background
Quinoline is an important nitrogenous heterocyclic compound and has good anti-tumor, antibacterial, anti-tuberculosis, antimalarial, antioxidant, anti-HIV and other biological activities. For example, quinine is a natural drug effective to treat malaria, camptothecine is a plant anticancer drug, and has obvious curative effects on liver cancer and head and neck cancer with fewer side effects. Bedaquinoline TMC207 is the first antitubercular new drug approved by the FDA for the last 40 years and belongs to the diaryl quinoline class of antibiotics. In addition, quinoline compounds are used in functional materials, dyes and optical fields.
Because of the diverse biological activities and wide-ranging uses of quinolines, C-H functionalization reactions based on quinoline backbones have attracted considerable research interest to chemists. For example, functionalization reactions such as alkylation, arylation, alkoxylation, amination, thioetherification, cyanation, phosphorylation, acylation, fluoroalkylation of quinoline C-H bond are reported in the literature. However, there is no report of the introduction of aminodithioformate fragments into quinoline heterocycles by quinoline C-H functionalization. In 2019, the group Wu Zhiyong of Henan university of agriculture reported a copper-catalyzed method for preparing quinoline-containing heterocyclic dithiocarbamates by coupling bromoquinolines with tetraalkylthiuram disulfide (Eur. J. Org. Chem.2019, 2941-2949). However, the harsh conditions of transition metal (cuprous oxide), strong base (cesium carbonate), high temperature (110 ℃), very long reaction time (48 h), etc. limit the application of such methods in industrial production.
The dithiocarbamic acid ester has important application in biological medicine, and particularly has excellent biological activity in the aspects of resisting tumor, leprosy bacillus, fusarium oxysporum and the like. The active dithiocarbamic acid ester fragment is grafted on the quinoline skeleton to prepare a series of novel quinoline derivatives, and the novel high-activity drug molecules are quite possible to be obtained. Therefore, the development of a technical method for introducing a dithiocarbamate fragment into a quinoline heterocycle, and the preparation of various quinoline heterocycle-containing dithiocarbamate compounds is a need for new drug creation, which is one of the hot spots and the key points of research in the field at present, and is the motive force for the completion of the present invention.
Disclosure of Invention
The invention aims to provide a practical synthesis method of a quinoline heterocycle-containing dithiocarbamic acid ester compound, which is simple to operate, mild in condition and easy to post-treat. In order to achieve the above object, the present invention adopts the following technical scheme:
quinoline nitroxide compound C 2 Process for the dithiocarbamate of-H, quinoline nitroxide of formula 1 CS 2 Amine of formula 2, co-agent of formula 3Mixing the agents in an organic solvent and performing dithiocarbamic acid esterification reaction to prepare a product of the formula 4;
1 (1)
2, 2
3
4. The method is to
Said R is 1 ～R 4 Independently H, alkyl, substituted alkyl, halogen, alkoxy, substituted alkoxy, cyano, nitro or ester group; or wherein adjacent groups are cyclized to form a ring structure;
said R is 5 Is alkyl, substituted alkyl, phenyl or cycloalkyl, said R 6 Is H, alkyl, substituted alkyl, phenyl or cycloalkyl; alternatively, R 5 、R 6 Mutually ring-closing to form a ring structure;
R 7 is an electron withdrawing group or an aromatic group;
the organic solvent is at least one of halogenated alkane, acetone and DMF.
To fill quinoline nitroxide compound C 2 Blank of dithiocarbamation of H (referring to H on carbon 2), and resolution of quinoline nitroxide C 2 H difficult dithiocarbamate problem, the present invention innovatively treats the reaction products of formulas 1 and CS 2 The amine of formula 2 is nucleophilic coupled and removed with the aid of the special solvent system and the auxiliary agent of formula 3, thus obtaining the formula with high yield and high selectivity in one pot4, a product of the structure. In addition, the method does not need transition metal and strong alkali, has mild conditions and has no pre-halogenation risk.
In the present invention, the alkyl group may be a C1-C6 alkyl group, and the substituted alkyl group may be a substituted alkyl group having a substituent on the carbon chain of the C1-C6 alkyl group. The alkoxy can be C1-C6 alkoxy, and the substituted alkoxy can be substituted alkoxy with substituent groups on the carbon chain of C1-C6. In the present invention, the ring structure refers to any saturated, partially unsaturated or aromatic ring, and the number of ring atoms may be 3 to 10.
In the present invention, the quinoline oxynitride compound may be any N-O oxide having a quinoline ring. For example, in the formula 1, R is 1 H.
Said R is 2 An alkoxy group of H, C to C6;
said R is 3 、R 4 H, C1C 6 alkyl, C1C 6 alkyl with substituents, C1C 6 alkoxy with substituents or halogen;
the substituent can be at least one of halogen, phenyl, benzyl, nitro, ester, acyl and alkoxy.
In the present invention, the amine may be any organic amine, and in consideration of material cost, R in the formula 2 5 、R 6 Independently is C1-C6 alkyl or C1-C6 alkyl with substituent; the substituent is at least one of halogen, phenyl, benzyl, nitro, ester, acyl and alkoxy;
alternatively, R 5 、R 6 The ring structure formed by mutually ring-closing is a five-membered or more ring including an N atom, preferably a saturated ring. The ring structure is pyrrole ring or morpholine ring containing N.
In the present invention, CS 2 The amine of formula 2 may be used in an appropriate excess, e.g. quinoline nitroxide of formula 1, CS 2 The molar ratio of the amine in the formula 2 is 1:1-2.5:1-2.5, and thenThe one step can be 1:1.2-1.6:1.2-1.6.
In the invention, the synergistic combination of the solvent and the auxiliary agent of the formula 3 is to solve the problem of quinoline oxynitride C 2 H is critical for difficult dithiocarbamate.
In the invention, in the formula 3, R is 7 Is at least one of trifluoromethyl, phenyl, substituted phenyl and pyridyl. Preferably, the substituted phenyl is phenyl with at least one substituent selected from C1-C6 alkyl, C1-C6 alkoxy, nitro, halogen and trifluoromethyl. The research of the invention surprisingly shows that R is as follows 7 Preferably aromatic rings such as phenyl groups, substituted phenyl groups, a more excellent synergistic effect can be unexpectedly obtained, and the effect of the preparation can be further improved.
In the invention, the molar ratio of the quinoline oxynitride compound shown in the formula 1 to the auxiliary agent shown in the formula 3 is 1:1 to 2.5, and further 1:1.1 to 1.8.
In the invention, the organic solvent is halogenated alkane. The preferred combination of solvent and auxiliary of formula 3 may further improve the synergy and contribute to further improvement of the reaction.
In the invention, the halogenated alkane is more than one halogen substituted alkane with C1-C4, preferably at least one of dichloromethane and dichloroethane;
in the present invention, the concentration of the quinoline oxynitride compound of formula 1 in the reaction starting solution is not particularly limited, and may be 0.01 to 1M, and further may be 0.1 to 0.5M in view of the treatment cost.
In the present invention, the reaction temperature is not particularly limited, and when the temperature is low, the reaction time can be suitably prolonged, and when the temperature is high, the reaction time can be suitably shortened, for example, in the present invention, the temperature in the dithiocarbamate reaction stage is 4℃or higher, preferably 15 to 50℃and further room temperature (e.g., 20 to 35 ℃).
In the present invention, the reaction time can be controlled as desired, for example, based on a known chromatography-in-control method. As shown by experimental summary, the reaction time of the invention can be basically completed within 60min, and further can be 10-60 min.
In the present invention, the atmosphere during the reaction is not particularly limited, and may be, for example, an air atmosphere in view of the easiness of the process.
In the present invention, after the completion of the reaction, the product may be collected from the reaction system according to conventional means. For example, in the present invention, after the completion of the dithiocarbamate reaction, water and a hydrophobic solvent are added to the reaction system, and extraction treatment is performed to obtain an organic phase loaded with the product, which is concentrated to obtain a crude product of formula 4. The hydrophobic solvent can be at least one of ethyl acetate, DCM and DCE.
In the present invention, a purified product can be obtained from the crude product of formula 4 based on known means, for example, as an exemplified scheme, the crude product of formula 4 can be subjected to chromatographic purification to obtain a pure product of formula 4;
in the invention, the chromatographic purification process can be regulated and controlled based on known means and principles, for example, the eluent in the chromatographic purification stage is petroleum ether/ethyl acetate mixed solvent with the volume ratio of 1-6:1.
The beneficial effects are that:
the dithiocarbamic acid ester compound has important application value in the aspect of biological medicine. However, methods for synthesizing such compounds are limited. Moreover, most of the existing methods for synthesizing dithiocarbamates are benzene ring substituted dithiocarbamates, few reports of heterocyclic substituted dithiocarbamates are made, and particularly, no general method is available at present for quinoline substituted dithiocarbamates. Aiming at the problem, the invention innovatively adopts the combination of the auxiliary agent and the solvent, and can be based on a brand new reaction thought, and the direct dithiocarbamic acid esterification of quinoline oxynitride C2-H can be realized in a one-pot, mild and high-efficiency manner.
The preparation method has the advantages of simple process and device, few reaction steps, low cost, high yield, good functional group compatibility and the like.
Drawings
FIG. 1 is a diagram of the product of example 1 1 H-NMR chart;
FIG. 2 is a diagram of the product of example 1 13 C-NMR chart;
the specific embodiment is as follows:
the invention is further illustrated by the following specific examples, it being understood that the examples of the preparation of the invention are intended to illustrate the invention and are not to be limiting thereof; on the premise of the inventive concept, simple improvements of the preparation method of the invention belong to the protection scope of the invention.
It should also be noted that each of the preferable technical features of the technical method of the present invention mentioned above and each of the specific technical features in the embodiments specifically described below may be combined together, and all of the numerical ranges in which each combination of the technical features is specifically disclosed by the present invention as upper and lower limits, etc. are within the scope of the present invention.
The experimental methods used in the following examples are conventional methods unless otherwise specified.
The materials used in the examples below, reagents, unless otherwise specified, were either commercially available or synthesized from commercially available starting materials.
In the present invention, as a typical example, the method for synthesizing a quinoline heterocycle-containing dithiocarbamate compound preferably comprises the steps of:
(1) Sequentially adding quinoline oxynitride, dichloromethane, carbon disulfide, secondary amine substituted by different substituents and p-toluenesulfonic anhydride into a reaction tube provided with a magnetic stirrer at room temperature, and stirring for reaction at room temperature;
(2) After the reaction is finished, deionized water is added into the reaction liquid, the mixture is uniformly mixed, the crude product is extracted from the reaction liquid by taking methylene dichloride as an extracting agent through liquid separation extraction operation each time, the extracting liquid is combined, the organic solvent is removed through a rotary evaporator, the residue is purified through silica gel column chromatography, the specification of silica gel is 200-300 meshes, and the eluent is petroleum ether: ethyl acetate v/v= (6-2): 1, and the quinoline heterocycle substituted dithiocarbamic acid ester compound is prepared.
The substituted secondary amine is 1.0-2.5 times of the mass of quinoline oxynitride, preferably 1.5 times of the mass;
the carbon disulfide is 1.0-2.5 times of the mass of quinoline nitrogen oxide, preferably 1.5 times of the mass;
the auxiliary agent is 1.0-2.5 times of the mass of quinoline nitrogen oxide, preferably 1.5 times of the mass;
the organic solvent comprises dichloromethane;
the reaction is carried out in an air atmosphere at normal temperature, the reaction process is monitored by thin layer chromatography, and the reaction time is generally not more than half an hour;
the invention provides a quinoline nitrogen oxide deoxidized C2-H functionalization reaction based on auxiliary agent activation to construct a dithiocarbamic acid ester compound containing quinoline heterocycle, wherein the specific reaction process and the synthesis mechanism are preferably as follows: firstly, quinoline nitrogen oxide is activated by an auxiliary agent, and receives nucleophilic attack of dithiocarbamic acid generated in situ by secondary amine and carbon disulfide, and the formed active intermediate further undergoes elimination reaction to obtain a target product.
The preparation method disclosed by the invention has a typical reaction mechanism as follows:
in the following cases, the room temperature was 20 to 35℃unless specifically stated.
The following are specific exemplary embodiments:
example 1:
quinoline oxynitride (0.3 mmol), dichloromethane (solvent, 3 mL), carbon disulfide (0.45 mmol), diethylamine (0.45 mmol) and p-toluenesulfonic anhydride (activating reagent, 0.45 mmol) were sequentially added to a 10mL reaction tube equipped with a magnetic stirrer at room temperature, stirring was carried out at room temperature for about 30min, TLC (thin layer chromatography) was carried out to the reaction solution, dichloromethane (10 mL) and deionized water (10 mL) were added after completion of the reaction, mixing was uniform, an organic phase was extracted, the aqueous phase was extracted twice with dichloromethane (2X 10 mL), the organic phase was combined, and the organic solvent was removed by a rotary evaporator, the residue was purified by silica gel column chromatography with a silica gel size of 200-300 mesh, an eluent of petroleum ether/ethyl acetate (6:1 v/v) to give the objective product of 68.2mg, and the yield was 82%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,Chloroform-d)δ8.13(d,J＝8.4Hz,2H),7.80(d,J＝8.1Hz,1H),7.70(t,J＝8.6Hz,2H),7.55(t,J＝7.4Hz,1H),3.99(q,J＝6.8Hz,2H),3.83(q,J＝6.8Hz,2H),1.39(t,J＝6.9Hz,3H),1.26(t,J＝7.0Hz,3H)； 13 C{ 1 H}NMR(100MHz,Chloroform-d)δ192.8,153.9,148.2,136.2,129.6,129.5,129.3,127.5,127.4,127.3,49.1,47.7,12.7,11.4；HRMS(ESI)m/z calcd.for C 14 H 17 N 2 S 2 [M+H] + :277.0828,found 277.0829.
on the basis of example 1, the following controls were made on the activating reagent and the solvent in the treatment process, and the results were respectively:
a conditions are as follows: 1a (0.1 mmol,1 equiv.), 2a (0.15 mmol,1.5 equiv.), an activating reagent (0.15 mmol,1.5 equiv.), solvent (1 mL), r.t.,0.5h. b Yield of 3aa by 1 HNMR determination. PyBroP, tripyrrolidinyl phosphonium bromide hexafluorophosphate.
Example 2:
to a 10mL reaction tube equipped with a magnetic stirrer, 3-bromoquinoline oxynitride (0.3 mmol), methylene chloride (3 mL), carbon disulfide (0.45 mmol), diethylamine (0.45 mmol) and p-toluenesulfonic anhydride (0.45 mmol) were sequentially added at room temperature, stirring was performed for about 30min at room temperature, TLC plate monitoring was performed, methylene chloride (10 mL) and deionized water (10 mL) were added to the reaction solution after completion of the reaction, mixing was completed, an organic phase was extracted, the aqueous phase was extracted twice with methylene chloride (2×10 mL), the organic phase was combined, and the organic solvent was removed by a rotary evaporator, the residue was purified by silica gel column chromatography with a silica gel size of 200-300 mesh, and an eluent of petroleum ether/ethyl acetate (6:1 v/v) to give the objective product of 67.1mg, yield 63%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,Chloroform-d)δ8.44(s,1H),8.14(d,J＝8.5Hz,1H),7.82–7.72(m,2H),7.61(t,J＝7.5Hz,1H),4.04(q,J＝7.0Hz,2H),3.87(q,J＝7.1Hz,2H),1.45(t,J＝7.1Hz,3H),1.32(t,J＝7.0Hz,3H)； 13 C{ 1 H}NMR(100MHz,Chloroform-d)δ190.9,153.4,147.0,139.9,130.1,129.7,128.7,128.6,126.6,124.1,49.1,48.3,13.0,11.5；HRMS(ESI)m/z calcd.for C 14 H 16 BrN 2 S 2 [M+H] + :354.9933,found 354.9937.
example 3:
6-Methoxyquinoline oxynitride (0.3 mmol), dichloromethane (3 mL), carbon disulfide (0.45 mmol), diethylamine (0.45 mmol) and p-toluenesulfonic anhydride (0.45 mmol) were sequentially added to a 10mL reaction tube equipped with a magnetic stirrer at room temperature, stirred at room temperature for about 30min, monitored by TLC plates, dichloromethane (10 mL) and deionized water (10 mL) were added to the reaction solution after completion of the reaction, the organic phase was extracted uniformly, the aqueous phase was extracted twice with dichloromethane (2X 10 mL), the organic phases were combined, the organic solvent was removed by a rotary evaporator, the residue was purified by silica gel column chromatography with a silica gel size of 200-300 mesh, the eluent was petroleum ether/ethyl acetate (6:1 v/v), and the target product was obtained in 77.4mg, 84% yield.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,Chloroform-d)δ8.05(t,J＝8.2Hz,2H),7.67(d,J＝8.4Hz,1H),7.36(d,J＝9.2Hz,1H),7.09(s,1H),4.02(q,J＝6.9Hz,2H),3.94(s,3H),3.87(q,J＝7.0Hz,2H),1.43(t,J＝7.0Hz,3H),1.28(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,Chloroform-d)δ193.7,158.7,150.9,144.6,135.2,131.2,130.0,128.8,122.5,105.1,55.6,49.3,47.7,12.8,11.5；HRMS(ESI)m/z calcd.for C 15 H 19 N 2 OS 2 [M+H] + :307.0933,found 307.0933.
example 4:
6-bromo-4-methoxyquinoline oxynitride (0.3 mmol), dichloromethane (3 mL), carbon disulfide (0.45 mmol), diethylamine (0.45 mmol) and p-toluenesulfonic anhydride (0.45 mmol) were sequentially added to a 10mL reaction tube equipped with a magnetic stirrer at room temperature, stirring was performed at about 30min at room temperature, the TLC plate was monitored, after completion of the reaction, dichloromethane (10 mL) and deionized water (10 mL) were added to the reaction solution, the organic phase was extracted, the aqueous phase was extracted twice with dichloromethane (2X 10 mL), the organic phases were combined, the organic solvent was removed by a rotary evaporator, the residue was purified by silica gel column chromatography, silica gel size was 200-300 mesh, eluent was petroleum ether/ethyl acetate (2:1 v/v), 83.2mg of the target product was obtained, and the yield was 72%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,Chloroform-d)δ8.33(s,1H),7.92(d,J＝8.9Hz,1H),7.75(d,J＝9.3Hz,1H),7.15(s,1H),4.08–3.97(m,5H),3.85(q,J＝6.9Hz,2H),1.41(t,J＝7.0Hz,3H),1.29(t,J＝6.9Hz,3H)； 13 C{ 1 H}NMR(100MHz,Chloroform-d)δ192.4,161.1,155.3,147.4,133.5,130.8,124.5,122.0,120.8,109.2,56.1,49.2,47.8,12.8,11.5；HRMS(ESI)m/z calcd.for C 15 H 18 BrN 2 OS 2 [M+H] + :385.0038,found385.0034.
example 5:
quinoline oxynitride (0.3 mmol), dichloromethane (3 mL), carbon disulfide (0.45 mmol), di-n-propylamine (0.45 mmol) and p-toluenesulfonic anhydride (0.45 mmol) are sequentially added into a 10mL reaction tube provided with a magnetic stirrer at room temperature, stirring is carried out for about 30min at normal temperature, TLC (thin layer chromatography) is carried out, dichloromethane (10 mL) and deionized water (10 mL) are added into the reaction liquid after the reaction is completed, the mixture is uniformly mixed, an organic phase is extracted, the aqueous phase is extracted twice (2X 10 mL) by dichloromethane, the organic phase is combined, the organic solvent is removed by a rotary evaporator, the residue is purified by silica gel column chromatography, the silica gel specification is 200-300 meshes, the eluent is petroleum ether/ethyl acetate (2:1 v/v), and 78.7mg of a target product is obtained, and the yield is 86%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,Chloroform-d)δ8.12(d,J＝8.4Hz,2H),7.80(d,J＝8.0Hz,1H),7.69(t,J＝9.1Hz,2H),7.55(t,J＝7.4Hz,1H),3.94–3.81(m,2H),3.79–3.66(m,2H),1.95–1.71(m,4H),1.00(t,J＝7.1Hz,3H),0.91(t,J＝7.2Hz,3H)； 13 C{ 1 H}NMR(100MHz,Chloroform-d)δ193.2,154.1,148.1,136.1,129.6,129.4,129.2,127.5,127.4,127.3,56.3,55.3,20.9,19.5,11.1；HRMS(ESI)m/z calcd.for C 16 H 21 N 2 S 2 [M+H] + :305.1141,found 305.1144.
example 6:
quinoline oxynitride (0.3 mmol), dichloromethane (3 mL), carbon disulfide (0.45 mmol), pyrrole (0.45 mmol) and p-toluenesulfonic anhydride (0.45 mmol) are sequentially added into a 10mL reaction tube provided with a magnetic stirrer at room temperature, stirring is carried out for about 30min at normal temperature, a TLC (thin layer chromatography) plate is adopted to monitor the reaction, dichloromethane (10 mL) and deionized water (10 mL) are added into the reaction liquid after the completion of the reaction, the mixture is uniformly mixed, an organic phase is extracted, the aqueous phase is extracted twice (2X 10 mL) by dichloromethane, the organic phases are combined, the organic solvent is removed by a rotary evaporator, the residue is purified by a silica gel column chromatography, the silica gel specification is 200-300 meshes, the eluent is petroleum ether/ethyl acetate (2:1 v/v), and the target product is obtained in 71.8mg, and the yield is 87%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,Chloroform-d)δ8.18(d,J＝8.5Hz,1H),8.13(d,J＝8.5Hz,1H),7.83(d,J＝8.1Hz,1H),7.79–7.68(m,2H),7.58(t,J＝7.5Hz,1H),3.91(t,J＝6.9Hz,2H),3.81(t,J＝6.8Hz,2H),2.15–2.07(m,2H),2.04–1.95(m,2H)； 13 C{ 1 H}NMR(100MHz,Chloroform-d)δ190.0,153.5,148.3,136.4,129.7,129.6,129.1,127.7,127.6,127.5,54.8,51.5,26.3,24.4；HRMS(ESI)m/z calcd.for C 14 H 15 N 2 S 2 [M+H] + :275.0671,found 275.0674.
example 7:
quinoline oxynitride (0.3 mmol), dichloromethane (3 mL), carbon disulfide (0.45 mmol), tourmaline (0.45 mmol) and p-toluenesulfonic anhydride (0.45 mmol) are sequentially added into a 10mL reaction tube provided with a magnetic stirrer at room temperature, stirring is carried out for about 30min at normal temperature, a TLC (thin layer chromatography) plate is adopted to monitor, dichloromethane (10 mL) and deionized water (10 mL) are added into a reaction liquid after the reaction is completed, the mixture is uniformly mixed, an organic phase is extracted, the aqueous phase is extracted twice (2X 10 mL) by using dichloromethane, the organic phase is combined, the organic solvent is removed through a rotary evaporator, the residue is purified through silica gel column chromatography, the silica gel specification is 200-300 meshes, the eluent is petroleum ether/ethyl acetate (2:1 v/v), and the target product 72.5mg is obtained, and the yield is 83%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,Chloroform-d)δ8.21–8.12(m,2H),7.85(d,J＝8.1Hz,1H),7.78–7.66(m,2H),7.60(t,J＝7.5Hz,1H),4.43–3.96(m,4H),3.85–3.76(m,4H)； 13 C{ 1 H}NMR(100MHz,Chloroform-d)δ194.5,153.4,148.4,136.6,129.9,129.6,128.9,127.8,127.6,127.5,66.3,66.0,51.4,51.0；HRMS(ESI)m/z calcd.for C 14 H 15 N 2 OS 2 [M+H] + :291.0620,found 291.0624.
example 8:
at room temperature, a reaction tube of 10mL equipped with a magnetic stirrer is sequentially added with cloquintocet-mexyl-quinoline oxynitride (0.3 mmol), dichloromethane (3 mL), carbon disulfide (0.45 mmol), diethylamine (0.45 mmol) and p-toluenesulfonic anhydride (0.45 mmol), stirring is carried out at normal temperature for about 30min, a TLC (thin layer chromatography) plate is used for monitoring, after the reaction is completed, dichloromethane (10 mL) and deionized water (10 mL) are added into the reaction liquid, the organic phase is extracted uniformly, the aqueous phase is extracted twice with dichloromethane (2X 10 mL), the organic phases are combined, the organic solvent is removed through a rotary evaporator, the residue is purified through a silica gel column chromatography, the silica gel specification is 200-300 meshes, the eluent is petroleum ether/ethyl acetate (2:1 v/v), and the target product is obtained in 71.8mg, and the yield is 87%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,Chloroform-d)δ8.47(d,J＝8.7Hz,1H),7.88(d,J＝8.7Hz,1H),7.48(d,J＝8.4Hz,1H),6.89(d,J＝8.4Hz,1H),4.98(q,J＝6.2Hz,1H),4.91(s,2H),3.99(q,J＝6.6Hz,2H),3.83(q,J＝6.7Hz,2H),1.59–1.48(m,1H),1.44–1.34(m,4H),1.28–1.08(m,12H),0.86–0.78(m,3H)； 13 C{ 1 H}NMR(100MHz,Chloroform-d)δ192.4,168.2,154.4,152.9,140.4,132.9,130.8,127.0,126.4,123.3,110.6,72.5,66.7,49.1,47.8,35.5,31.4,24.8,22.4,19.8,13.8,12.8,11.4；HRMS(ESI)m/z calcd.for C 23 H 32 ClN 2 O 3 S 2 [M+H] + :483.1537,found483.1542。
Claims (10)
1. quinoline nitroxide compound C 2 A process for the dithiocarbamate of H, characterized in that a quinoline nitroxide compound of formula 1, CS 2 An amine of formula 23, mixing the auxiliary agent in an organic solvent and performing dithiocarbamic acid esterification reaction to obtain a product of the formula 4;
said R is 1 ～R 4 Independently H, alkyl, substituted alkyl, halogen, alkoxy, substituted alkoxy, cyano, nitro or ester group; or wherein adjacent groups are cyclized to form a ring structure;
said R is 5 Is alkyl, substituted alkyl, phenyl or cycloalkyl, said R 6 Is H, alkyl, substituted alkyl, phenyl or cycloalkyl; alternatively, R 5 、R 6 Mutually ring-closing to form a ring structure;
R 7 is an electron withdrawing group or an aromatic group;
the organic solvent is at least one of halogenated alkane, acetone and DMF.
2. Quinoline oxynitride C according to claim 1 2 A process for the dithiocarbamate of H, characterized in that in formula 1, R is 1 Is H;
preferably, R 2 An alkoxy group of H, C to C6;
preferably, R 3 、R 4 H, C1C 6 alkyl, C1C 6 alkyl with substituents, C1C 6 alkoxy with substituents or halogen;
the substituent is at least one of halogen, phenyl, benzyl, nitro, ester, acyl and alkoxy.
3. Quinoline oxynitride C according to claim 1 2 A process for the dithiocarbamate of H, characterized in that in formula 2, R is 5 、R 6 Independently is C1-C6 alkyl or C1-C6 alkyl with substituent; the substituent is halogen, phenyl, benzyl, nitro, ester group and acylAt least one of an alkoxy group;
alternatively, R 5 、R 6 The ring structure formed by mutual cyclization is a five-membered or more ring including N atoms, preferably a saturated ring;
preferably, the ring structure is a pyrrole ring or morpholine ring including N.
4. A quinoline nitroxide compound C as defined in any one of claims 1-3 2 A process for the dithiocarbamate of H, characterized in that a quinoline nitroxide compound of formula 1, CS 2 The molar ratio of the amine of formula 2 is 1:1-2.5:1-2.5.
5. Quinoline oxynitride C according to claim 1 2 A process for the dithiocarbamate of H, characterized in that in formula 3, R is 7 Is at least one of trifluoromethyl, phenyl, substituted phenyl and pyridyl;
preferably, the substituted phenyl is phenyl with at least one substituent selected from C1-C6 alkyl, C1-C6 alkoxy, nitro, halogen and trifluoromethyl.
6. Quinoline oxynitride C according to claim 1 or 5 2 -a process for the dithiocarbamate of H, characterized in that the molar ratio of quinoline oxynitride of formula 1, auxiliary of formula 3 is 1:1 to 2.5.
7. The method for dithiocarbamation of quinoline nitroxide compounds C2-H according to claim 1, wherein the organic solvent is a haloalkane;
preferably, the halogenated alkane is more than one halogen substituted C1-C4 alkane, preferably at least one of dichloromethane and dichloroethane;
preferably, the concentration of the quinoline nitroxide compound of formula 1 in the reaction starting solution is 0.01 to 1M, and further may be 0.1 to 0.5M.
8. The process for the dithiocarbamation of quinoline nitroxide compounds C2-H according to claim 1, wherein the temperature in the dithiocarbamation reaction stage is above 4 ℃, preferably between 15 and 50 ℃ and further at room temperature.
9. The method for dithiocarbamic acid esterification of quinoline nitrogen oxide C2-H according to claim 1, wherein after the end of the dithiocarbamic acid esterification reaction, water and hydrophobic solvent are added into the reaction system, extraction treatment is carried out, and the organic phase loaded with the product is obtained, and is concentrated, thus obtaining the crude product of the product of formula 4.
10. The method for dithiocarbamation of quinoline nitroxide compound C2-H according to claim 9, wherein the crude product of formula 4 is purified by chromatography to obtain pure product of formula 4;
preferably, the eluent in the chromatographic purification stage is petroleum ether/ethyl acetate mixed solvent with the volume ratio of 1-6:1.
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