CN113735777B - Method for preparing cyclic thiourea compound - Google Patents
Method for preparing cyclic thiourea compound Download PDFInfo
- Publication number
- CN113735777B CN113735777B CN202110951281.9A CN202110951281A CN113735777B CN 113735777 B CN113735777 B CN 113735777B CN 202110951281 A CN202110951281 A CN 202110951281A CN 113735777 B CN113735777 B CN 113735777B
- Authority
- CN
- China
- Prior art keywords
- cyclic thiourea
- reaction
- thiourea compound
- cyclic
- preparing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 title claims abstract description 73
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title claims abstract description 52
- -1 cyclic thiourea compound Chemical class 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 28
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 229910052987 metal hydride Inorganic materials 0.000 claims abstract description 11
- 150000004681 metal hydrides Chemical class 0.000 claims abstract description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 5
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims description 14
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 239000002994 raw material Substances 0.000 abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 12
- 229910052751 metal Inorganic materials 0.000 abstract description 12
- 239000002184 metal Substances 0.000 abstract description 12
- 238000003756 stirring Methods 0.000 abstract description 8
- 238000006555 catalytic reaction Methods 0.000 abstract description 7
- 238000004809 thin layer chromatography Methods 0.000 abstract description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000741 silica gel Substances 0.000 abstract description 6
- 229910002027 silica gel Inorganic materials 0.000 abstract description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 abstract description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract description 5
- 238000001035 drying Methods 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 5
- 239000012044 organic layer Substances 0.000 abstract description 5
- 239000000843 powder Substances 0.000 abstract description 5
- BBOLNFYSRZVALD-UHFFFAOYSA-N 1,2-diiodobenzene Chemical compound IC1=CC=CC=C1I BBOLNFYSRZVALD-UHFFFAOYSA-N 0.000 abstract description 4
- 238000004440 column chromatography Methods 0.000 abstract description 4
- 239000005457 ice water Substances 0.000 abstract description 4
- 238000002156 mixing Methods 0.000 abstract description 4
- 238000010791 quenching Methods 0.000 abstract description 4
- 238000005406 washing Methods 0.000 abstract description 3
- 238000001914 filtration Methods 0.000 abstract description 2
- 238000012544 monitoring process Methods 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000008204 material by function Substances 0.000 description 2
- 239000010814 metallic waste Substances 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 229940117953 phenylisothiocyanate Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- RNFJDJUURJAICM-UHFFFAOYSA-N 2,2,4,4,6,6-hexaphenoxy-1,3,5-triaza-2$l^{5},4$l^{5},6$l^{5}-triphosphacyclohexa-1,3,5-triene Chemical compound N=1P(OC=2C=CC=CC=2)(OC=2C=CC=CC=2)=NP(OC=2C=CC=CC=2)(OC=2C=CC=CC=2)=NP=1(OC=1C=CC=CC=1)OC1=CC=CC=C1 RNFJDJUURJAICM-UHFFFAOYSA-N 0.000 description 1
- HJKLEAOXCZIMPI-UHFFFAOYSA-N 2,2-diethoxyethanamine Chemical compound CCOC(CN)OCC HJKLEAOXCZIMPI-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- WVVOBOZHTQJXPB-UHFFFAOYSA-N N-anilino-N-nitronitramide Chemical compound [N+](=O)([O-])N(NC1=CC=CC=C1)[N+](=O)[O-] WVVOBOZHTQJXPB-UHFFFAOYSA-N 0.000 description 1
- FULZLIGZKMKICU-UHFFFAOYSA-N N-phenylthiourea Chemical compound NC(=S)NC1=CC=CC=C1 FULZLIGZKMKICU-UHFFFAOYSA-N 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- DUEPRVBVGDRKAG-UHFFFAOYSA-N carbofuran Chemical compound CNC(=O)OC1=CC=CC2=C1OC(C)(C)C2 DUEPRVBVGDRKAG-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003063 flame retardant Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 150000005171 halobenzenes Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002541 isothioureas Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000006362 organocatalysis Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/84—Sulfur atoms
Abstract
The invention discloses a method for preparing a cyclic thiourea compound, which is characterized in that metal hydride is suspended in anhydrous THF and stirred, the cyclic thiourea is dropwise added in the stirring process, the mixture is stirred at room temperature after the addition, diiodobenzene is then added, the mixture is continuously stirred at room temperature, and TLC (thin layer chromatography) monitoring reaction is completed. After the reaction is completed, adding ice water and tetrahydrofuran to quench the reaction, extracting by ethyl acetate, combining organic layers, washing by saturated sodium chloride solution, drying by anhydrous sodium sulfate, filtering, spin-drying the solvent, adding a proper amount of silica gel powder for sample mixing, and separating by rapid column chromatography to obtain the product of the cyclic thiourea compound. The method for preparing the cyclic thiourea compound by using the reaction system which is free of metal catalysis, low in raw material cost and non-air-sensitive is very significant.
Description
Technical Field
The invention belongs to organic synthesis, and particularly relates to a method for preparing a cyclic thiourea compound.
Background
Aryl thiourea compounds have wide application in agriculture, chemistry and medicine, attracting great interest to many chemists and pharmacologists. In agriculture, isothiourea derivatives can be used as herbicides, insecticides, acaricides and the like. Chemically synthesized, isothiourea structured compounds can be used as catalysts and ligands for transition metal catalysis. The application in medicine is wider, and the product has good antiviral and antihistamine activities. Therefore, more and more isothiourea drug molecules are synthesized and designed, and have very significant biological effects, so that the development of the medical field is effectively promoted, and studies on HIV-1 inhibitors, anti-infective agents, central nervous agents, valine protein inhibitors and the like are carried out [ (a) Ma C, wu A, wu Y, et al ]. Arch. Pharm. 2013, 346, 891-900. (b) Mugnaini C, Manetti F, Este J A, Clotet-Codina I, et al. Bioorg. Med. Chem. Lett.2006, 16, 3541-3544. (c) Srivastava V K, Kumar P, Agarwal J C, et al. Pharmazie. 1981, 36, 441. (d) Rogovoy B, Vvedenskiy V, Cai X, et al. WO 2003095396, 2003]：
In the prior art, a metathesis exchange reaction between isothiourea and aryl isocyanate and an S-arylation reaction between diazonium salt and N-phenylthiourea are used, but raw materials are not easy to obtain, the preparation is complex, the atom economy is poor, and the industrial synthesis cost is high. Although the metal catalyzed process is generally applicable to the synthesis of various cyclic thiourea compounds, it also has some drawbacks. If high temperature is needed, the reaction time is long, the catalyst loading is large, the reagent price is high, and the pollution of metal waste is easy to cause. Therefore, it is highly desirable to develop a reaction system that is free of metal catalysis, inexpensive in raw materials, and non-air sensitive to produce cyclic thiourea compounds.
Disclosure of Invention
The invention discloses a method for preparing a cyclic thiourea compound, which is very simple and convenient to operate, does not need metal catalysis, has low-cost and easily-obtained raw materials and good functional group tolerance. Provides an excellent scheme for the drug synthesis of S-aryl isothiourea building blocks, and has great significance for the future drug synthesis development.
The invention adopts the following technical scheme:
a method for preparing a cyclic thiourea compound uses cyclic thiourea and iodobenzene as substrates, and the cyclic thiourea compound is obtained by reacting in a solvent in the presence of metal hydride.
In the invention, the chemical structural formula of the iodobenzene is as follows:
the chemical structural formula of the cyclic thiourea is as follows:
the chemical structural formula of the cyclic thiourea compound of the invention is as follows:
in the structural formula, R is selected from hydrogen, halogen, alkyl, fluoroalkyl or alkoxy; further, in the cyclic thiourea, the substituent may be one or more.
The reaction of the cyclic thiourea and the iodobenzene is carried out in the presence of metal hydride and in a solvent without other substances, and the cyclic thiourea compound is obtained as a single product after the reaction is carried out for 2 to 10 hours at room temperature.
In the invention, the metal hydride is sodium hydride, potassium hydride, calcium hydride, lithium hydride and the like; the dosage of the metal hydride is 3-5 times of the molar quantity of the cyclic thiourea. Further, the dosage of the iodobenzene is 1 to 3 times of the molar quantity of the cyclic thiourea.
In the invention, the solvent is one or more of dimethylacetamide DMA, tetrahydrofuran THF, acetonitrile CH3CN, ethylene glycol dimethyl ether DME and Toluene tolene, preferably THF and DMA, and the volume ratio of the two is preferably (4-8) to 1.
Metal catalysis can be used for synthesizing the cyclic thiourea compound, but has the defects of high temperature, long reaction time, large catalyst loading, high reagent price and easy pollution of metal waste. Therefore, it is highly desirable to develop a reaction system that is free of metal catalysis, inexpensive in raw materials, and non-air sensitive to produce cyclic thiourea compounds. In recent years, chemists have been trying to directly use N-substituted imidazole to react with disulfide for nucleophilic substitution, and a metal catalyst is not required to conveniently generate S-arylated imidazole, but N-BuLi is required to carry out deprotonation, so that the reaction needs no water or oxygen atmosphere, and the safety is poor. According to the invention, nucleophilic addition reaction is carried out by using iodobenzene and a cyclic thiourea compound under the action of NaH, so that the first time of utilizing cyclic thiourea as a first reaction raw material to directly carry out iodobenzene and C-S coupling to generate the cyclic thiourea compound is realized, and the method has good regioselectivity. The scheme is very simple and convenient to operate, metal catalysis is not needed, raw materials are cheap and easy to obtain, and the tolerance of functional groups is good. Provides an excellent scheme for the drug synthesis of the cyclic thiourea compound block, and has great significance for the future drug synthesis development.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of compound 10 x.
Detailed Description
The structure of the cyclic thiourea compound exists in a plurality of chemical molecules, is widely applied to the fields of functional materials and medicaments, and attracts great interest of scientists. In recent years, thiourea derivatives have also begun to become powerful tools for asymmetric organocatalysis. For the synthesis of cyclic thiourea compounds, halobenzene or phenylboronic acid is usually used for C-S coupling of thiourea under a metal catalyst, but the experimental method has harsh reaction conditions (air sensitivity, strong alkali/high temperature), large catalyst loading and serious metal reagent pollution. In addition, sulfur-containing species can rapidly and irreversibly deactivate various metal catalysts, making metal-catalyzed C-S bond formation schemes less preferred by a wide range of organic synthesizers.
The invention takes the cyclic thiourea and the iodobenzene as substrates, can finish the reaction in the presence of metal hydride and solvent, and obtains the cyclic thiourea compound with high yield without other substances, thereby solving the problems of the prior art that metal catalysts, format reagents and the like are needed.
The nuclear magnetic H spectrum of the compound is detected by an Agilent 400 MHz instrument and a Bruker 400 MHz instrument, the C spectrum is detected by the Bruker 400 MHz instrument, and the sample solvent is deuterated reagent (CDCl) 3 Or (b)d 6 DMSO), all containing TMS internal standard, nuclear magnetic data report including: chemical shift, integration of peak area, coupling constant, peak pattern, etc. The single crystal was detected by using an X-ray single crystal diffractometer (D8 Quest). TLC thin layer chromatography plate is produced by yellow sea chemical plant of tobacco table, and is visually monitored at 254nm or 365nm wavelength, and the color-developing agent is KMnO 4 Iodine, phosphomolybdic acid and dinitrophenylhydrazine, and the silica gel mesh number used for the flash column chromatography is 200-300 meshes. All reagents are commercially available analytically pure or chemically pure, and are directly used without special description. The anhydrous solvents are either the distilled solvents or commercially available dry solvents (carbofuran).
Unless otherwise indicated, the present invention employs conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy. Unless specifically defined otherwise, terms used herein in the description of analytical chemistry, organic synthetic chemistry, and the like are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis. In the present specification, the groups and substituents thereof may be selected by one skilled in the artTo provide stable moieties and compounds. When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2 O-is equivalent to-OCH 2 -. Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
In the present invention, halogen means fluorine, chlorine, bromine or iodine; hydroxy refers to an-OH group; hydroxyalkyl refers to alkyl substituted with hydroxy (-OH); carbonyl refers to a-C (=o) -group; nitro refers to-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the Cyano refers to-CN; amino means-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the Carboxyl refers to-COOH.
The raw materials involved in the invention are all existing products, are commercially available and can be prepared according to the existing method.
Preparation of Synthesis example raw Material 9x-9ae
Taking R as hydrogen to prepare raw material 9x as an example, phenyl isothiocyanate (4.0 mmol, 1.0 equiv) and aminoacetaldehyde diethyl acetal (4.0 mmol, 1.0 equiv) were stirred at room temperature in a two-necked flask for 1h, and TLC monitored that the phenyl isothiocyanate raw material was reacted. To the reaction solution was added a catalytic amount of 37% concentrated hydrochloric acid (0.4. 0.4 mL, 10 mol%) and stirred at room temperature for 5min, then transferred to an oil bath at 110 ℃ for reflux under heating, and after 3h the reaction was completed by TLC monitoring the progress of the reaction. Cooling the reaction liquid to room temperature, spin-drying toluene solvent in the reaction liquid, adding 1N NaOH aqueous solution for washing, extracting with ethyl acetate for 5 times, combining organic layers, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, spin-drying solvent, mixing with a proper amount of silica gel powder, performing column separation by rapid column chromatography (PE: EA=2:1) to obtain a white solid product with a yield of 60% which is 9x as a raw material, 1 H NMR (400 MHz, CDCl 3 ) δ 12.50 (s, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.3 Hz, 2H), 7.39 (t, J = 7.1 Hz, 1H), 6.81 (d, J = 18.5 Hz, 2H)。
the structural formula of part of raw materials is as follows:
example 1
NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL) and stirred, during stirring, thiocyclic urea 9 (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) was added dropwise, after the addition was completed, stirred at room temperature for 2min, then diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2 mL THF) was added, stirring was continued at room temperature and TLC monitored for reaction completion. After the reaction is completed, ice water and tetrahydrofuran are added to quench the reaction, ethyl acetate is used for extraction for 3 times, the organic layers are combined, the mixture is washed by saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered, the solvent is dried by spin, a proper amount of silica gel powder is added for sample mixing, and the product of the cyclothiourea compound 10 is obtained through rapid column chromatography separation.
When R is hydrogen, the reaction is finished for 3 hours, and the yield is 70%; when R is 4-Cl, the reaction is finished for 2 hours, and the yield is 88%; when R is 3-Cl, the reaction is finished for 10 hours, and the yield is 64%; r is 3-CF 3 At the end of the reaction for 4 hours, the yield was 68%; when R is 4-Me, the reaction is finished for 4 hours, and the yield is 66%; when R is 2-Me, the reaction is finished for 4 hours, and the yield is 50%; when R was 4-MeO, the reaction was completed for 10 hours, and the yield was 59%.
Example two
NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL) and stirred, during stirring, thiocyclic 9ae (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) was added dropwise, after the addition was completed, stirred at room temperature for 1.5min, then diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2 mL THF) was added, stirring was continued at room temperature and TLC monitored for reaction completion. After the reaction is completed for 4 hours, ice water and tetrahydrofuran are added to quench the reaction, ethyl acetate is extracted for 3 times, the organic layers are combined, the mixture is washed by saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered, the solvent is dried by spin, a proper amount of silica gel powder is added for sample mixing, and the product of the cyclothiourea compound 10ae is obtained through rapid column chromatography separation, and the yield is 60%.
The nuclear magnetic data of the cyclic thiourea compound of the above-mentioned product are as follows:
1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (dd, J = 7.9, 1.3 Hz, 1H), 7.40 – 7.35 (m, 3H), 7.33 (d, J = 1.3 Hz, 1H), 7.29 (d, J = 1.3 Hz, 1H), 7.24 – 7.20 (m, 2H), 7.20 – 7.15 (m, 1H), 6.90 (dd, J = 8.0, 1.5 Hz, 1H), 6.81 (td, J = 7.8, 1.5 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 140.58, 139.59, 138.74, 137.23, 131.10, 129.29, 128.99, 128.87, 128.75, 127.77, 125.83, 124.39, 97.31。
1 H NMR (400 MHz, CDCl 3 ) δ 7.70 (dd, J = 7.9, 1.3 Hz, 1H), 7.36 (m, 3H), 7.26 (s, 1H), 7.22 – 7.13 (m, 3H), 6.90 (dd, J = 8.0, 1.5 Hz, 1H), 6.83 (td, J = 7.7, 1.5 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 140.24, 139.75, 138.92, 135.72, 134.79, 131.33, 129.54, 129.08, 128.97, 128.00, 127.14, 124.26, 97.50。
1 H NMR (400 MHz, CDCl 3 ) δ 7.70 (dd, J = 7.9, 1.3 Hz, 1H), 7.38 – 7.30 (m, 3H), 7.27 (d, J = 0.8 Hz, 1H), 7.22 – 7.18 (m, 2H), 7.15 – 7.09 (m, 1H), 6.95 (dd, J = 8.0, 1.5 Hz, 1H), 6.84 (td, J = 7.8, 1.5 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 139.97, 139.71, 139.05, 138.15, 134.84, 131.23, 130.28, 129.45, 128.98, 128.93, 128.10, 126.20, 124.15, 124.14, 97.91。
1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (dd, J = 7.9, 1.3 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.47 – 7.39 (m, 2H), 7.35 (d, J = 1.4 Hz, 1H), 7.30 (d, J = 1.4 Hz, 1H), 7.21 – 7.15 (m, 1H), 6.93 (dd, J = 8.0, 1.5 Hz, 1H), 6.86 – 6.78 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 139.85, 139.74, 139.19, 137.65, 131.86 (d, J = 33.3 Hz), 131.41, 129.72 (d, J = 70.7 Hz), 129.34, 128.96, 128.15, 125.59 (q, J = 11.1 Hz), 124.67, 124.20, 122.94 (q, J = 11.1 Hz), 121.96, 97.74. 19 F NMR (377 MHz, CDCl 3 ) δ -62.73。
1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (dd, J = 7.9, 1.1 Hz, 1H), 7.41 (d, J = 1.1 Hz, 1H), 7.35 (d, J = 1.2 Hz, 1H), 7.31 – 7.25 (m, 3H), 7.20 (d, J = 8.3 Hz, 2H), 6.97 (dd, J = 8.0, 1.3 Hz, 1H), 6.90 (td, J = 7.7, 1.4 Hz, 1H), 2.46 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 140.81, 139.60, 138.84, 138.72, 134.77, 131.03, 129.87, 128.88, 127.70, 125.61, 124.47, 97.18, 21.24。
1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (dd, J = 7.9, 1.3 Hz, 1H), 7.32 (m, 2H), 7.28 – 7.25 (m, 1H), 7.21 – 7.16 (m, 1H), 7.15 – 7.10 (m, 2H), 7.04 (dd, J = 7.9, 1.5 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.84 – 6.77 (m, 1H), 1.98 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 140.03, 139.61, 139.51, 136.27, 135.35, 131.11, 130.98, 129.89, 129.50, 128.74, 127.96, 127.55, 126.65, 124.36, 98.49, 17.54。
1 H NMR (400 MHz, CDCl 3 ) δ 7.69 (dd, J = 7.9, 1.2 Hz, 1H), 7.31 (d, J = 1.2 Hz, 1H), 7.24 (d, J = 1.2 Hz, 1H), 7.18 (td, J = 8.0, 1.3 Hz, 1H), 7.15 – 7.09 (m, 2H), 6.87 (dt, J = 4.2, 2.7 Hz, 3H), 6.81 (td, J = 7.7, 1.5 Hz, 1H), 3.81 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 159.74, 140.84, 139.60, 138.96, 130.97, 130.20, 128.87, 127.70, 127.08, 124.68, 114.42, 97.18, 55.68。
11 H NMR (400 MHz, CDCl 3 ) δ 7.98 – 7.81 (m, 2H), 7.58 – 7.47 (m, 2H), 7.46 – 7.34 (m, 3H), 7.31 (s, 1H), 7.23 (dd, J = 10.6, 8.5 Hz, 2H), 7.16 – 7.06 (m, 2H), 6.79 – 6.64 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 140.81, 139.88, 139.43, 134.11, 133.61, 130.93, 130.16, 130.06, 129.85, 128.73, 128.28, 127.97, 127.46, 126.79, 125.56, 125.30, 125.10, 122.34, 98.92。
example III
KH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL THF) and stirred, thiourea 9x (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) was added dropwise during stirring, stirring was performed at room temperature for 2min after the addition was completed, then diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2 mL THF) was added, stirring was continued at room temperature, after 3h, quenching reaction was performed by adding ice water and tetrahydrofuran, ethyl acetate extraction was performed 3 times, the organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, spin-dried solvent was added, a proper amount of silica gel powder was added and the mixture was subjected to flash column chromatography separation to obtain the product of the cyclic thiourea compound.
According to the invention, iodobenzene is used for nucleophilic addition reaction with cyclic thiourea under the action of NaH, so that the cyclic thiourea compound is generated by directly performing C-S coupling on the iodobenzene and thiourea for the first time, the cyclic thiourea compound can be directly used, and further, the product of the invention is provided with iodobenzene and can react with alkynyl, sulfhydryl, piperazine and other groups by adopting a conventional method to obtain more drug molecules. In addition, the existence of halogen and sulfur also enables the product of the invention to be used as a flame retardant modifier for functional materials, and has great significance for the future development of small molecule synthesis.
Claims (7)
1. A method for preparing a cyclic thiourea compound is characterized in that the cyclic thiourea compound is prepared by taking cyclic thiourea and iodobenzene as substrates and reacting in a solvent in the presence of metal hydride;
the chemical structural formula of the iodobenzene is as follows:
the chemical structural formula of the cyclic thiourea is as follows:
the chemical structural formula of the cyclic thiourea compound is as follows:
r is selected from hydrogen, halogen, alkyl, fluoroalkyl or alkoxy.
2. The method of preparing a cyclic thiourea compound of claim 1 wherein the cyclic thiourea has one or more substituents.
3. The method for producing a cyclic thiourea compound according to claim 1, wherein the metal hydride is sodium hydride.
4. The process for preparing a cyclic thiourea compound according to claim 1, wherein the reaction is carried out in the presence of a metal hydride in a solvent without other substances at room temperature for 2 to 10 hours.
5. The method for producing a cyclic thiourea compound according to claim 1, wherein the metal hydride is used in an amount of 3 to 5 times the molar amount of the cyclic thiourea; the dosage of the iodobenzene is 1 to 3 times of the molar quantity of the cyclic thiourea.
6. The method for producing a cyclic thiourea compound according to claim 5, wherein the metal hydride is used in an amount of 4 times the molar amount of the cyclic thiourea; the amount of iodobenzene is 2 times the molar amount of the cyclic thiourea.
7. The method for producing a cyclic thiourea compound according to claim 1, wherein the solvent is one or more of dimethylacetamide, tetrahydrofuran, acetonitrile, ethylene glycol dimethyl ether, toluene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110951281.9A CN113735777B (en) | 2021-08-18 | 2021-08-18 | Method for preparing cyclic thiourea compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110951281.9A CN113735777B (en) | 2021-08-18 | 2021-08-18 | Method for preparing cyclic thiourea compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113735777A CN113735777A (en) | 2021-12-03 |
| CN113735777B true CN113735777B (en) | 2023-05-02 |
Family
ID=78731694
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110951281.9A Active CN113735777B (en) | 2021-08-18 | 2021-08-18 | Method for preparing cyclic thiourea compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113735777B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024011414A1 (en) * | 2022-07-12 | 2024-01-18 | 苏州大学 | Reaction method for secondary amine and o-diiodobenzene |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7994205B2 (en) * | 2006-03-31 | 2011-08-09 | Takeda Pharmaceutical Company Limited | Aryl-or heteroaryl-sulfonyl compounds as acid secretion inhibitors |
| CN107892691B (en) * | 2017-12-19 | 2020-04-28 | 西安交通大学 | 2,8, 9-trisubstituted-9H-purine compound and salt and application thereof |
| CN112979400B (en) * | 2021-02-21 | 2023-06-06 | 苏州大学 | Method for preparing 2-iodo-aryl ether under action of alkali metal hydride |
-
2021
- 2021-08-18 CN CN202110951281.9A patent/CN113735777B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113735777A (en) | 2021-12-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107880079B (en) | Cyclic N-heterocyclic bis-carbene-palladium complex and preparation method and application thereof | |
| CN113735751B (en) | Method for preparing aryl isothiourea | |
| CN111420709A (en) | Application of N-heterocyclic carbene-based mixed nickel (II) complex in reaction for synthesizing 2-linear alkyl benzothiazole compound | |
| CN113735777B (en) | Method for preparing cyclic thiourea compound | |
| CN111205279A (en) | Polysubstituted benzodihydrofuran heterocyclic compound and preparation method and application thereof | |
| CN106000465A (en) | Method for oxidative coupling reaction of aldehyde and secondary amide | |
| CN113735752B (en) | Method for preparing isothiourea compound based on substituted iodobenzene | |
| CN108017548B (en) | Method for synthesizing deuterated dimethylamine salt by using deuterated methanol | |
| CN117105845A (en) | Electrophilic trifluoro methyl selenizing reagent and preparation method and application thereof | |
| CN112441981B (en) | 1,2, 5-polysubstituted imidazole derivative and synthesis method and application thereof | |
| CN113004248B (en) | Method for synthesizing carbazole compound by catalyzing hydrocarbon amination reaction with cobalt | |
| CN113121401B (en) | N-substituted carbonyl fluorosulfonamide compound, preparation method and application thereof | |
| CN112939829A (en) | Synthetic method of aryl trifluoromethyl thioether | |
| CN106966948A (en) | A kind of synthetic method together with difluoro substituted pyrrolidone compound | |
| CN102786466B (en) | Synthetic method of chiral Salan ligand | |
| CN113024475B (en) | Synthetic method of quinoxalinone compound | |
| CN112110800B (en) | 3-aryl-2-propyne-1-alcohol derivative and preparation method thereof | |
| CN116462611A (en) | Method for preparing polyarylguanidine by using diaryl hypervalent iodine reagent | |
| CN111777559B (en) | Method for preparing polysubstituted pyrazole based on terminal alkyne | |
| CN112479968B (en) | Synthetic method for preparing 2-methylpyrrolidine compound by catalyzing hydroamination reaction | |
| KR101522464B1 (en) | New process for the production of arensulfonyl chloride from arensulfonic acid | |
| CN110669097B (en) | Synthesis method of oleanoline derivative | |
| KR101554539B1 (en) | Development of Method for Amide Bond Formation via Metal-Free Aerobic Oxidative Amination of Aldehydes | |
| Pan et al. | Photo‐Induced In Situ Generation of Brønsted Acid for Catalytic Friedel–Crafts Alkylation of Indoles | |
| CN112209901B (en) | Preparation method of 4- (2- (N, N-dimethylamino) ethyl) morpholine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20211203 Assignee: Nanjing Yaotan Biotechnology Co.,Ltd. Assignor: Shanghai yaotan pharmaceutical research and Development Co.,Ltd. Contract record no.: X2024980001830 Denomination of invention: A method for preparing cyclic thiourea compounds Granted publication date: 20230502 License type: Common License Record date: 20240202 |