CN116082253A - 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative and preparation method thereof - Google Patents
1-N-substituted 1,2, 3-triazole-4-carboxamide derivative and preparation method thereof Download PDFInfo
- Publication number
- CN116082253A CN116082253A CN202310164485.7A CN202310164485A CN116082253A CN 116082253 A CN116082253 A CN 116082253A CN 202310164485 A CN202310164485 A CN 202310164485A CN 116082253 A CN116082253 A CN 116082253A
- Authority
- CN
- China
- Prior art keywords
- methanone
- triazol
- piperidin
- triazole
- substituted
- 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.)
- Pending
Links
- OSKSVLBJJXQUPI-UHFFFAOYSA-N 2h-triazole-4-carboxamide Chemical class NC(=O)C1=CNN=N1 OSKSVLBJJXQUPI-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- -1 azidophenyl Chemical class 0.000 claims abstract description 64
- 239000002904 solvent Substances 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 150000001335 aliphatic alkanes Chemical group 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000012044 organic layer Substances 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- LFQUGMGXNTYNNR-UHFFFAOYSA-N (1-phenyltriazol-4-yl)-piperidin-1-ylmethanone Chemical compound C=1N(C=2C=CC=CC=2)N=NC=1C(=O)N1CCCCC1 LFQUGMGXNTYNNR-UHFFFAOYSA-N 0.000 claims description 20
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 9
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- QENIALCDPFDFHX-UHFFFAOYSA-N 1,4-dibromo-2,5-dimethylbenzene Chemical compound CC1=CC(Br)=C(C)C=C1Br QENIALCDPFDFHX-UHFFFAOYSA-N 0.000 claims description 3
- FEWLNYSYJNLUOO-UHFFFAOYSA-N 1-Piperidinecarboxaldehyde Chemical compound O=CN1CCCCC1 FEWLNYSYJNLUOO-UHFFFAOYSA-N 0.000 claims description 3
- BINXXPQGQDPFRA-UHFFFAOYSA-N [1-(3-chlorophenyl)triazol-4-yl]-piperidin-1-ylmethanone Chemical compound ClC1=CC=CC(N2N=NC(=C2)C(=O)N2CCCCC2)=C1 BINXXPQGQDPFRA-UHFFFAOYSA-N 0.000 claims description 3
- OTCHQAIBGVJAIX-UHFFFAOYSA-N [1-(4-chlorophenyl)triazol-4-yl]-piperidin-1-ylmethanone Chemical compound C1=CC(Cl)=CC=C1N1N=NC(C(=O)N2CCCCC2)=C1 OTCHQAIBGVJAIX-UHFFFAOYSA-N 0.000 claims description 3
- WCQOGJCHHPWTON-UHFFFAOYSA-N [1-(4-fluorophenyl)triazol-4-yl]-piperidin-1-ylmethanone Chemical compound C1=CC(F)=CC=C1N1N=NC(C(=O)N2CCCCC2)=C1 WCQOGJCHHPWTON-UHFFFAOYSA-N 0.000 claims description 3
- WUWLQEMSSNXHJI-UHFFFAOYSA-N [1-(4-methoxyphenyl)triazol-4-yl]-piperidin-1-ylmethanone Chemical compound C1=CC(OC)=CC=C1N1N=NC(C(=O)N2CCCCC2)=C1 WUWLQEMSSNXHJI-UHFFFAOYSA-N 0.000 claims description 3
- QOZLAEHIWRLHJD-UHFFFAOYSA-N [1-(4-methylphenyl)triazol-4-yl]-piperidin-1-ylmethanone Chemical compound C1=CC(C)=CC=C1N1N=NC(C(=O)N2CCCCC2)=C1 QOZLAEHIWRLHJD-UHFFFAOYSA-N 0.000 claims description 3
- 150000007529 inorganic bases Chemical group 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 229920001223 polyethylene glycol Polymers 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 44
- 239000007787 solid Substances 0.000 description 42
- CTRLRINCMYICJO-UHFFFAOYSA-N phenyl azide Chemical compound [N-]=[N+]=NC1=CC=CC=C1 CTRLRINCMYICJO-UHFFFAOYSA-N 0.000 description 32
- 238000002844 melting Methods 0.000 description 21
- 230000008018 melting Effects 0.000 description 21
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 20
- 239000007858 starting material Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- DMLAVOWQYNRWNQ-UHFFFAOYSA-N azobenzene Chemical compound C1=CC=CC=C1N=NC1=CC=CC=C1 DMLAVOWQYNRWNQ-UHFFFAOYSA-N 0.000 description 6
- WHSJSMSBFMDFHK-UHFFFAOYSA-N 1-azido-4-bromobenzene Chemical group BrC1=CC=C(N=[N+]=[N-])C=C1 WHSJSMSBFMDFHK-UHFFFAOYSA-N 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FFTOUVYEKNGDCM-OWOJBTEDSA-N (e)-1,3,3-trifluoroprop-1-ene Chemical compound F\C=C\C(F)F FFTOUVYEKNGDCM-OWOJBTEDSA-N 0.000 description 1
- 150000000177 1,2,3-triazoles Chemical class 0.000 description 1
- PNFFQZGQSSKAQX-UHFFFAOYSA-N 1-azido-2,4-dibromobenzene Chemical compound BrC1=CC=C(N=[N+]=[N-])C(Br)=C1 PNFFQZGQSSKAQX-UHFFFAOYSA-N 0.000 description 1
- PDVUXRITYOFJPB-UHFFFAOYSA-N 1-azido-2,4-dichlorobenzene Chemical compound ClC1=CC=C(N=[N+]=[N-])C(Cl)=C1 PDVUXRITYOFJPB-UHFFFAOYSA-N 0.000 description 1
- GJYJWUDHKGKGGR-UHFFFAOYSA-N 1-azido-2-bromo-4-chlorobenzene Chemical compound ClC1=CC=C(N=[N+]=[N-])C(Br)=C1 GJYJWUDHKGKGGR-UHFFFAOYSA-N 0.000 description 1
- MZJSXPJOTBZLEC-UHFFFAOYSA-N 1-azido-2-bromo-4-fluorobenzene Chemical compound FC1=CC=C(N=[N+]=[N-])C(Br)=C1 MZJSXPJOTBZLEC-UHFFFAOYSA-N 0.000 description 1
- WJKCMCWZWIONIO-UHFFFAOYSA-N 1-azido-2-chloro-4-fluorobenzene Chemical compound FC1=CC=C(N=[N+]=[N-])C(Cl)=C1 WJKCMCWZWIONIO-UHFFFAOYSA-N 0.000 description 1
- MHTPYRQIAMETSQ-UHFFFAOYSA-N 1-azido-2-chlorobenzene Chemical compound ClC1=CC=CC=C1N=[N+]=[N-] MHTPYRQIAMETSQ-UHFFFAOYSA-N 0.000 description 1
- ZKGVLNVASIPVAU-UHFFFAOYSA-N 1-azido-2-methylbenzene Chemical compound CC1=CC=CC=C1N=[N+]=[N-] ZKGVLNVASIPVAU-UHFFFAOYSA-N 0.000 description 1
- NTTKOAYXVOKLEH-UHFFFAOYSA-N 1-azido-3-chlorobenzene Chemical compound ClC1=CC=CC(N=[N+]=[N-])=C1 NTTKOAYXVOKLEH-UHFFFAOYSA-N 0.000 description 1
- WRMGCIOUNQGMSR-UHFFFAOYSA-N 1-azido-3-methylbenzene Chemical compound CC1=CC=CC(N=[N+]=[N-])=C1 WRMGCIOUNQGMSR-UHFFFAOYSA-N 0.000 description 1
- QNHZUKXPSZACNB-UHFFFAOYSA-N 1-azido-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(N=[N+]=[N-])C=C1 QNHZUKXPSZACNB-UHFFFAOYSA-N 0.000 description 1
- HZVGOEUGZJFTNN-UHFFFAOYSA-N 1-azido-4-chlorobenzene Chemical compound ClC1=CC=C(N=[N+]=[N-])C=C1 HZVGOEUGZJFTNN-UHFFFAOYSA-N 0.000 description 1
- VHFLTICYUZLEII-UHFFFAOYSA-N 1-azido-4-fluorobenzene Chemical compound FC1=CC=C(N=[N+]=[N-])C=C1 VHFLTICYUZLEII-UHFFFAOYSA-N 0.000 description 1
- YVXDRCDGBCOJHX-UHFFFAOYSA-N 1-azido-4-methylbenzene Chemical compound CC1=CC=C(N=[N+]=[N-])C=C1 YVXDRCDGBCOJHX-UHFFFAOYSA-N 0.000 description 1
- KPUSZZFAYGWAHZ-UHFFFAOYSA-N 3-azabicyclo[2.2.2]octane Chemical compound C1CC2CCC1NC2 KPUSZZFAYGWAHZ-UHFFFAOYSA-N 0.000 description 1
- CPTIGEURUINHDD-UHFFFAOYSA-N 4-azido-2-chloro-1-fluorobenzene Chemical compound FC1=CC=C(N=[N+]=[N-])C=C1Cl CPTIGEURUINHDD-UHFFFAOYSA-N 0.000 description 1
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 1
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- PPKDSHDYUBDVKL-UHFFFAOYSA-N diazonio-(4-methoxyphenyl)azanide Chemical group COC1=CC=C([N-][N+]#N)C=C1 PPKDSHDYUBDVKL-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative and a preparation method thereof, wherein the structural formula of the compound is as follows:
the R is 1 Is a variety of substituted phenyl groups; r is R 2 Is a heterocyclic aryl or an alkane group; r is R 3 Is an alkane group. The preparation method comprises the following steps: dissolving azidophenyl derivative and amine compound in two-phase solvent, adding alkali and phase transfer catalyst, adding alpha-trifluoromethyl propylene compound, stirring at a certain temperature until the raw materials react; the obtained reaction system is extracted, the organic layer is decompressed and concentrated to obtain a residue, and the residue is subjected to silica gel column chromatography to obtain the 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative. The preparation method provided by the invention has the advantages of simple operation, easily obtained raw materials, good tolerance of the functional groups of the reaction, excellent product yield, easy separation and the like.
Description
Technical Field
The invention belongs to a synthesis method of a compound, and particularly relates to a 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative and a preparation method thereof.
Background
The 1,2, 3-triazole compounds are important heterocyclic compounds and are widely applied to synthesis, medicine and material chemistry. 1-N-substituted 1,2, 3-triazole-4-carboxamide derivatives are of great significance and are commonly used as the basic core backbone for many biologically and pharmaceutically active molecules, which have a wide range of properties, as inhibitors of Hsp90 and as antiepileptic and antibacterial agents. The relevant structure is as follows:
currently, the most common route for the synthesis of 1-N-substituted 1,2, 3-triazole-4-carboxamide derivatives is mainly achieved by a two-step process, involving azide-olefin cyclization and amidation reactions. The existing synthesis method of the 1,4/1, 5-diode of the 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative has low 1,4/1, 5-diode selectivity, and most of the 1,2, 3-triazole-4-carboxamide derivatives need precious metal catalysis, so that metal residues in products are still a troublesome problem, in particular in the pharmaceutical industry.
Disclosure of Invention
An object of embodiments of the present application is to provide a 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative and a method for preparing the same, aiming at the problems existing in the prior art.
According to a first aspect of embodiments of the present application, there is provided a 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative having the structural formula:
wherein R is 1 Is phenyl, R 2 Is a heterocyclic aryl or an alkane group, R 3 Is an alkane group.
Further, the 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative is any one of the following:
(1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
piperidin-1-yl (1- (p-tolyl) -1H-1,2, 3-triazol-4-yl) methanone;
(1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
piperidin-1-yl (1- (4- (trifluoromethyl) phenyl) -1H-1,2, 3-triazol-4-yl) methanone;
(1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
piperidin-1-yl (1- (m-tolyl) -1H-1,2, 3-triazol-4-yl) methanone;
(1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
piperidin-1-yl (1- (o-tolyl) -1H-1,2, 3-triazol-4-yl) methanone;
(1- (2-bromo-4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (2, 4-dibromobenzene) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (2-bromo-4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (2, 4-dichlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (2-chloro-4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (3-chloro-4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) (morpholinyl) methanone;
(1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) (pyrrolidin-1-yl) methanone;
1- (4-bromophenyl) -N, N-diethyl-1H-1, 2, 3-triazole-4-carboxamide;
1- (4-bromophenyl) -N-isopropyl-1H-1, 2, 3-triazole-4-carboxamide.
According to a second aspect of embodiments of the present application, there is provided a process for the preparation of a 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative as described in the first aspect, comprising the steps of:
step (1), dissolving azidophenyl derivatives and amine compounds in a two-phase solvent, adding alkali and a phase transfer catalyst, then adding alpha-trifluoromethyl propylene compounds, and stirring at a certain temperature until the raw materials react;
the structural formula of the azidophenyl derivative is as follows:
wherein R is 1 Is a variety of substituted phenyl groups;
the structural formula of the amine compound is as follows:
wherein R is 2 Is a heterocyclic aryl or an alkane group, R 3 Is an alkane group;
the structural formula of the alpha-trifluoromethyl propylene compound is as follows:
step (2), extracting the reaction system obtained in the step (1), concentrating an organic layer obtained by extraction under reduced pressure to obtain a residue, and performing silica gel column chromatography on the residue to obtain a 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative, wherein the 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative has the structural formula:
further, in the step (1), the mol ratio of the azidophenyl derivative to the amine compound is 1:5, and the mol ratio of the azidophenyl derivative to the two-phase solvent is 1mol:2L, the mol ratio of the azidophenyl derivative to the alkali is 1:3, and the mol ratio of the azidophenyl derivative to the alpha-trifluoromethyl propylene compound is 1mol:2L.
Further, the stirring temperature in the step (1) is 50-150 ℃, preferably 140 ℃.
In the step (1), the two-phase solvent is selected from one or more of water, acetone, tetrahydrofuran, toluene, N-dimethylformamide, anhydrous methanol and acetonitrile, preferably tetrahydrofuran and water, and is further prepared by mixing tetrahydrofuran and water according to a volume ratio of 3:1.
Further, the concentration of the two-phase solvent was 0.5mmol/mL.
Further, in the step (1), the base is selected from inorganic bases or organic bases, wherein the inorganic bases comprise potassium carbonate, sodium hydroxide and lithium hydroxide; the organic base includes 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 4-diazabicyclo [2.2.2] octane (DABCO), N-Dimethylaniline (DMA), N-Diisopropylethylamine (DIPEA), triethylamine, 4-Dimethylaminopyridine (DMAP), wherein N, N-diisopropylethylamine is preferred.
Further, in the step (1), the phase transfer catalyst is selected from DL-A-tocopheryl methoxypolyethylene glycol succinate solution (TPGS-750-M), 18-crown ether-6, tetrabutylammonium Bisulfate (TBAHS), wherein 18-crown ether-6 is preferable.
The technical scheme provided by the embodiment of the application can comprise the following beneficial effects:
from the above examples, the present application will dissolve azidophenyl derivatives and amine compounds in a two-phase solvent, and add a base and a phase transfer catalyst, followed by addition of an α -trifluoromethyl-acryl compound to construct a 1-N-substituted 1,2, 3-triazole-4-carboxamide structure. Compared with the conventional synthesis method, the method has the advantages of high reaction temperature selectivity, no need of heavy/noble metal, convenient post-treatment and potential bioactivity of the compound. The reaction yield is high, the purification is easy, and the separation yield of most products is more than 60 percent; the applicability of the substrate is wide, and various substrate structures can endure the reaction conditions.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the application.
Detailed Description
Reference will now be made in detail to exemplary embodiments, and implementations described in the following exemplary embodiments are not representative of all implementations consistent with the present application.
The terminology used in the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application. As used in this application and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and/or" as used herein refers to and encompasses any or all possible combinations of one or more of the associated listed items.
The invention will now be further illustrated by way of examples.
Example 1 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) are dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), 18-crown-6 (1.0 mmol,1.0 eq.) is added followed by DIPEA (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene are added and stirred at 140 ℃ until the starting material is reacted. After the reaction is completed, the reaction system is extracted, and the organic layer is decompressed and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:3) to give a white solid in 68% yield.
White solid was found to be 68% yield. Melting point: 144.7-145.5 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.48(s,1H),7.77–7.75(m,2H),7.57-7.53(m,2H),7.49-7.46(m,1H),4.19(d,J＝5.2Hz,2H),3.75(t,J＝4.8Hz,2H),1.72(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ159.6,145.30,136.6,129.9,129.2,126.0,120.7,48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 14 H 16 N 4 O+H + :257.1397,found:257.1394.
Example 1 comparison of yields under different reaction conditions
| Sequence(s) | Catalyst | Alkali | Temperature (. Degree. C.) | Yield [%] |
| 1 | / | LiOH | 50℃ | Trace |
| 2 | / | / | 50℃ | Trace |
| 3 | / | DABCO | 50℃ | 9％ |
| 4 | / | DBU | 50℃ | 3％ |
| 5 | / | Et 3 N | 50℃ | 4％ |
| 6 | / | DABCO | 80℃ | 13％ |
| 7 | TPGS-750-M | DABCO | 80℃ | 16％ |
| 8 | TPGS-750-M | DABCO | 100℃ | 33％ |
| 9 | 18-crown-6 | DABCO | 100℃ | 36％ |
| 10 | TBAHS | DABCO | 100℃ | 28％ |
| 11 | TPGS-750-M | DABCO | 120℃ | 35％ |
| 12 | 18-crown-6 | DABCO | 120℃ | 44％ |
| 13 | TBAHS | DABCO | 120℃ | 38％ |
| 14 | 18-crown-6 | DABCO | 140℃ | 46％ |
| 15 | 18-crown-6 | DMAP | 140℃ | 38％ |
| 16 | 18-crown-6 | DMA | 140℃ | 50％ |
| 17 | 18-crown-6 | DIPEA | 140℃ | 68％ |
Comparative example 1 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) were dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), followed by addition of LiOH (3.0 mmol,3.0 eq.) and finally addition of 2mL of (trans) -1-chloro-3, -trifluoropropene and stirring at 50 ℃ until the starting materials were reacted. After the reaction is completed, almost no product is produced.
Comparative example 2 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) were dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), and finally 2mL of (trans) -1-chloro-3, -trifluoropropene were added and stirred at 50 ℃ until the starting materials were reacted. After the reaction is completed, almost no product is produced.
Comparative example 3 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) were dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), DABCO (3.0 mmol,3.0 eq.) was then added, and finally 2mL of (trans) -1-chloro-3, -trifluoropropene was added and stirred at 50℃until the starting material was reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 9%.
Comparative example 4 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) were dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), followed by addition of DBU (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene were added and stirred at 50 ℃ until the starting materials were reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 3%.
Comparative example 5 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) were dissolved in 2mL of solvent (tetrahydrofuran: water=3:1) followed by Et addition 3 N (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, 3-trifluoropropene were added and stirred at 50℃until the starting material was reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 4%.
Comparative example 6 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) were dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), DABCO (3.0 mmol,3.0 eq.) was then added, and finally 2mL of (trans) -1-chloro-3, -trifluoropropene was added and stirred at 80℃until the starting material was reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 13%.
Comparative example 7 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) were dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), TPGS-750-M (1.0 mmol,1.0 eq.) was added followed by DABCO (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene were added and stirred at 80℃until the starting material was reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 16%.
Comparative example 8 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) were dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), TPGS-750-M (1.0 mmol,1.0 eq.) was added followed by DABCO (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene were added and stirred at 100℃until the starting material was reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 33%.
Comparative example 9 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) are dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), 18-crown-6 (1.0 mmol,1.0 eq.) is added, DABCO (3.0 mmol,3.0 eq.) is then added, and finally 2mL of (trans) -1-chloro-3, -trifluoropropene are added, and stirred at 100℃until the starting material is reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 36%.
Comparative example 10 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) are dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), TBAHS (1.0 mmol,1.0 eq.) is added followed by DABCO (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene are added and stirred at 100deg.C until the starting materials are reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 28%.
Comparative example 11 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) were dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), TPGS-750-M (1.0 mmol,1.0 eq.) was added followed by DABCO (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene were added and stirred at 120℃until the starting material was reacted. After the reaction was completed, the yield was calculated by HPLC analysis and found to be 35%.
Comparative example 12 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) are dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), 18-crown-6 (1.0 mmol,1.0 eq.) is added followed by DABCO (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene are added and stirred at 120℃until the starting material is reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 44%.
Comparative example 13 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) are dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), TBAHS (1.0 mmol,1.0 eq.) is added followed by DABCO (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene are added and stirred at 120℃until the starting material is reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 38%.
Comparative example 14 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) are dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), 18-crown-6 (1.0 mmol,1.0 eq.) is added followed by DABCO (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene are added and stirred at 140℃until the starting material is reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 46%.
Comparative example 15 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) are dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), 18-crown-6 (1.0 mmol,1.0 eq.) is added, followed by DMAP (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene are added and stirred at 140℃until the starting material is reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 38%.
Comparative example 16 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) were dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), 18-crown-6 (1.0 mmol,1.0 eq.) was added followed by DMA (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene were added and stirred at 140℃until the starting materials were reacted. After the reaction was completed, the yield was calculated by HPLC analysis to be 50%.
Comparative example 17 (1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone
Azidobenzene (1.0 mmol,1.0 eq.) and piperidine (5.0 mmol,5.0 eq.) are dissolved in 2mL of solvent (tetrahydrofuran: water=3:1), 18-crown-6 (1.0 mmol,1.0 eq.) is added followed by DIPEA (3.0 mmol,3.0 eq.) and finally 2mL of (trans) -1-chloro-3, -trifluoropropene are added and stirred at 140 ℃ until the starting material is reacted. After the reaction was completed, the yield was calculated by HPLC analysis and found to be 68%.
Example 2 (1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-4-chlorobenzene to give a white solid in 52% yield.
White solid with a yield of 52%. Melting point: 215.9-216.5 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.47(s,1H),7.71(d,J＝8.8Hz,2H),7.52(d,J＝8.8Hz,2H),4.17(s,2H),3.74(s,2H),1.71(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ159.4,145.5,135.1,135.1,130.1,126.0,121.8,48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 14 H 15 ClN 4 O+H + :291.1007,found:291.1005.
Example 3 (1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was as in example 1 except that the azidobenzene was replaced with 1-azido-4-bromobenzene to give a white solid in 72% yield.
White solid with a yield of 72%. Melting point: 223.0-223.6 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.47(s,1H),7.70–7.67(m,2H),7.66–7.64(m,2H),4.17(d,J＝5.6Hz,2H),3.74(t,J＝4.8Hz,2H),1.71(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ159.4,145.6,135.6,133.1,125.9,123.0,122.0,48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 14 H 15 BrN 4 O+H + :335.0502,found:335.0505.
Example 4 (1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-4-fluorobenzene to give a white solid in 51% yield.
White solid with a yield of 51%. Melting point: 128.6-129.4 ℃. 1 H NMR(500MHz,CDCl 3 ):δ8.44(s,1H),7.75-7.72(m,2H),7.26-7.23(m,2H),4.18(d,J＝4.5Hz,2H),3.75(d,J＝5.5Hz,2H),1.71(s,6H)； 13 C NMR(126MHz,CDCl 3 ):δ163.7,161.7,159.5,145.5,126.2,122.7(122.72,122.65,d,J＝8.8Hz),116.9(117.0,116.8,d,J＝22.5Hz),48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 14 H 15 FN 4 O+H + :275.1303,found:275.1306.
EXAMPLE 5 piperidin-1-yl (1- (p-tolyl) -1H-1,2, 3-triazol-4-yl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-4-methylbenzene to give a white solid in 35% yield.
White solid with a yield of 35%. Melting point: 184.3-184.9 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.43(s,1H),7.62(d,J＝8.4Hz,2H),7.33(d,J＝8.0Hz,2H),4.19(d,J＝5.2Hz,2H),3.75(d,J＝5.2Hz,2H),2.43(s,3H),1.71(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ159.7,145.2,139.4,134.3,130.4,126.0,120.6,48.0,43.9,26.8,25.8,24.7,21.1；HRMS calcd for C 15 H 18 N 4 O+H + :271.1553,found:271.1557.
EXAMPLE 6 (1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was as in example 1 except that the azidobenzene was replaced with 1-azido-4-methoxybenzene to give a white solid in 33% yield.
White solid, yield 33%. Melting point: 171.6-172.3 ℃. 1 H NMR(500MHz,CDCl 3 ):δ8.39(s,1H),7.65(d,J＝9.0Hz,2H),7.04(d,J＝9.0Hz,2H),4.19(s,2H),3.88(s,3H),3.75(d,J＝5.0Hz,2H),1.72(s,6H)； 13 C NMR(125MHz,CDCl 3 ):δ160.2,147.7,145.1,130.0,126.1,122.3,115.0,55.7,48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 15 H 18 N 4 O2+H + :287.1503,found:287.1501.
EXAMPLE 7 piperidin-1-yl (1- (4- (trifluoromethyl) phenyl) -1H-1,2, 3-triazol-4-yl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-4- (trifluoromethyl) benzene to give a white solid in 54% yield.
White solid with 54% yield. Melting point: 213.1-213.7 ℃. 1 H NMR(500MHz,CDCl 3 ):δ8.56(s,1H),7.93(d,J＝8.5Hz,2H),7.83(d,J＝8.5Hz,2H),4.18(d,J＝5.5Hz,2H),3.75(d,J＝5.0Hz,2H),1.72(s,6H)； 13 C NMR(125MHz,CDCl 3 ):δ159.3,145.8,139.0,131.4,131.2,127.3(127.33,127.30,127.27,127.24,q,J＝3.8Hz),126.0,124.5,122.4,120.7,48.0,44.0,26.8,25.8,24.6；HRMS calcd for C 15 H 15 F 3 N 4 O+H + :325.1271,found:325.1274.
Example 8 (1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-3-chlorobenzene to give a white solid in 43% yield.
White solid with 43% yield. Melting point: 132.0-132.6 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.48(s,1H),7.83(t,J＝2.0Hz,1H),7.65(dt,J＝7.2,1.8Hz,1H),7.51-7.44(m,2H),4.17(d,J＝5.2Hz,2H),3.74(t,J＝1.2Hz,2H),1.72(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ159.4,145.6,137.5,135.8,131.0,129.3,126.0,121.0,118.6,48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 14 H 15 ClN 4 O+H + :291.1007,found:291.1005.
EXAMPLE 9 piperidin-1-yl (1- (m-tolyl) -1H-1,2, 3-triazol-4-yl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-3-methylbenzene to give a white solid in 17% yield.
White solid, yield 17%. Melting point: 119.7-121.1 ℃. 1 H NMR(500MHz,CDCl 3 ):δ8.45(s,1H),7.58(s,1H),7.52(d,J＝8.0Hz,1H),7.41(t,J＝8.0Hz,1H),7.28(d,J＝7.5Hz,1H),4.19(d,J＝5.0Hz,2H),3.74(d,J＝5.0Hz,2H),2.46(s,3H),1.72(s,6H)； 13 C NMR(125MHz,CDCl 3 ):δ159.7,145.2,140.2,136.6,130.0,129.7,126.1,121.3,117.7,48.0,43.9,26.8,25.8,24.7,21.4；HRMS calcd for C 15 H 18 N 4 O+H + :271.1553,found:271.1557.
Example 10 (1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-2-chlorobenzene to give a white solid in 25% yield.
White solid with 25% yield. Melting point: 114.5-115.2 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.46(s,1H),7.63-7.59(m,2H),7.51–7.44(m,2H),4.20(s,2H),3.75(t,J＝4.8Hz,2H),1.72(s,6H)； 13 C NMR(125MHz,CDCl 3 ):δ159.5,144.5,134.5,131.1,130.9,130.0,128.9,128.0,127.7,48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 14 H 15 ClN 4 O+H + :291.1007,found:291.1005.
EXAMPLE 11 piperidin-1-yl (1- (o-tolyl) -1H-1,2, 3-triazol-4-yl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-2-methylbenzene to give a white solid in 19% yield.
White solid with a yield of 19%. Melting point: 111.3-112.0 ℃. 1 H NMR(500MHz,CDCl 3 ):δ8.24(s,1H),7.45–7.42(m,1H),7.39(d,J＝7.5Hz,1H),7.35–7.33(m,2H),4.24(s,2H),3.75(t,J＝5.0Hz,2H),2.24(s,3H),1.73(s,6H)； 13 C NMR(125MHz,CDCl 3 ):δ159.7,144.6,136.0,133.7,131.6,130.2,129.6,127.0,125.9,48.0,44.0,26.8,25.8,24.7,17.9；HRMS calcd for C 15 H 18 N 4 O+H + :271.1553,found:271.1557.
Example 12 (1- (2-bromo-4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was followed as in example 1 except for the conversion of azidobenzene to 1-azido-2-bromo-4-chlorobenzene to give a white solid in 79% yield.
White solid with 79% yield. Melting point: 114.8-115.3 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.42(s,1H),7.79(t,J＝1.2Hz,1H),7.50(d,J＝1.2Hz,2H),4.20(d,J＝4.8Hz,2H),3.75(t,J＝5.0Hz,2H),1.73(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ159.4,144.7,137.0,134.8,133.7,130.0,128.9,128.7,119.3,48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 14 H 14 BrClN 4 O+H + :369.0112,found:369.0114.
Example 13 (1- (2, 4-dibromobenzene) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-2, 4-dibromobenzene to give a white solid in 77% yield.
White solid, yield 77%. Melting point: 130.2-131.0 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.42(s,1H),7.94(d,J＝2.4Hz,1H),7.64(dd,J＝8.4,2.0Hz,1H),7.43(d,J＝8.4Hz,1H),4.19(s,2H),3.74(t,J＝4.8Hz,2H),1.72(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ159.3,144.7,136.5,135.2,131.9,130.0,129.0,124.8,119.4,48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 14 H 14 Br 2 N 4 O+H + :412.9607,found:412.9609.
EXAMPLE 14 (1- (2-bromo-4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was followed in example 1, except for replacing the azidobenzene with 1-azido-2-bromo-4-fluorobenzene, to give a white solid in 86% yield. White solid with 86% yield. Melting point: 97.5-98.0 ℃. 1 H NMR(500MHz,CDCl 3 ):δ8.38(s,1H),7.56–7.51(m,2H),7.25–7.21(m,1H),4.20(s,2H),3.77–3.75(t,J＝5.0Hz,2H),1.73(s,6H)； 13 C NMR(125MHz,CDCl 3 ):δ163.9,161.8,159.4,144.6,130.2,129.4(129.39,129.31,d,J＝10.0Hz),121.3(121.41,121.21,d,J＝25.0Hz),119.8(119.84,119.76,d,J＝10.0Hz),115.9(115.95,115.77,d,J＝22.5Hz),48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 14 H 14 BrFN 4 O+H + :353.0408,found:353.0406.
Example 15 (1- (2, 4-dichlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-2, 4-dichlorobenzene to give a white solid in 62% yield.
White solid with 62% yield. Melting point: 135.8-136.3 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.45(s,1H),7.62(d,J＝2.0Hz,1H),7.57(d,J＝8.4Hz,1H),7.45(dd,J＝8.4,2.4Hz,1H),4.18(s,2H),3.75(t,J＝4.6Hz,2H),1.73(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ159.3,144.7,136.7,133.1,130.8,129.9,129.6,128.4,100.0,48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 14 H 14 Cl 2 N 4 O+H + :325.0617,found:325.0618.
EXAMPLE 16 (1- (2-chloro-4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was followed in example 1, except that the azidobenzene was changed to 1-azido-2-chloro-4-fluorobenzene to give a white solid in 78% yield.
White solid with 78% yield. Melting point: 141.3-141.8 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.42(s,1H),7.60(dd,J＝8.8,5.2Hz,1H),7.35(dd,J＝8.0,2.8Hz,1H),7.21 -7.16(m,1H),4.19(s,2H),3.74(t,J＝4.6Hz,2H),1.72(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ164.1,161.6,159.4,144.7,130.4(130.46,130.35,d,J＝11.0Hz),130.1,129.1(129.13,129.04,d,J＝9.0Hz),118.4(118.40,118.14,d,J＝26.0Hz),115.4(115.52,115.29,d,J＝23.0Hz),48.0,44.0,26.8,25.8,24.7；HRMS calcd for C 14 H 14 ClFN 4 O+H + :309.0913,found:309.0911.
EXAMPLE 17 (1- (3-chloro-4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone
The procedure was followed in example 1, except that the azidobenzene was changed to 4-azido-2-chloro-1-fluorobenzene to give a white solid in 95% yield.
White solid with a yield of 95%. Melting point: 163.4-164.1 ℃. 1 H NMR(500MHz,CDCl 3 ):δ8.45(s,1H),7.89(dd,J＝6.5,3.0Hz,1H),7.65–7.62(m,1H),7.33(t,J＝8.5Hz,1H),4.17(d,J＝5.0Hz,2H),3.74(t,J＝5.0Hz,2H),1.72(t,J＝8.5Hz,6H)； 13 C NMR(125MHz,CDCl 3 ):δ159.3,157.3,145.7,133.1,126.1,123.3,122.8(122.91,122.76,d,J＝18.8Hz),120.4(120.43,120.37,d,J＝7.5Hz),117.8(117.91,117.72,d,J＝23.8Hz),48.0,44.0,26.8,25.8,24.6；HRMS calcd for C 14 H 14 ClFN 4 O+H + :309.0913,found:309.0911.
EXAMPLE 18 (1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) (morpholinyl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-4-bromobenzene and piperidine was changed to morpholine to give a white solid in 71% yield.
White solid was found to be 71% yield. Melting point: 213.4-214.1 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.52(s,1H),7.71–7.68(m,2H),7.66–7.64(m,2H),4.40–4.38(m,2H),3.81(d,J＝8.8Hz,6H)； 13 C NMR(100MHz,CDCl 3 ):δ159.4,145.1,135.4,133.2,126.4,123.2,122.1 67.3,66.9,47.4,43.2；HRMS calcd for C 13 H 13 BrN 4 O 2 +H + :337.0295,found:337.0294.
EXAMPLE 19 (1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) (pyrrolidin-1-yl) methanone
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-4-bromobenzene and piperidine was changed to pyrrolidine to give a white solid in 51% yield.
White solid, yield 51%. Melting point: 218.6-219.3 ℃. 1 H NMR(500MHz,CDCl 3 ):δ8.55(s,1H),7.70 -7.65(m,4H),4.16(t,J＝7.0Hz,2H),3.70(t,J＝7.0Hz,2H),2.04(p,J＝6.5Hz,2H),1.94(p,J＝6.5Hz,2H)； 13 C NMR(125MHz,CDCl 3 ):δ159.1,146.0,135.6,133.1,125.5,123.0,122.0,48.8,47.1,26.6,23.8；HRMS calcd for C 13 H 13 BrN 4 O+H + :321.0346,found:321.0348.
EXAMPLE 20 1- (4-bromophenyl) -N, N-diethyl-1H-1, 2, 3-triazole-4-carboxamide
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-4-bromobenzene and piperidine was changed to diethylamine to give a white solid in 51% yield.
White solid, yield 51%. Melting point: 182.2-183.0 ℃. 1 H NMR(500MHz,CDCl 3 ):δ8.51(s,1H),7.69-7.64(m,4H),4.01(q,J＝7.0Hz,2H),3.57(q,J＝7.0Hz,2H),1.35(t,J＝7.0Hz,3H),1.26(t,J＝7.0Hz,3H)； 13 C NMR(125MHz,CDCl 3 ):δ160.1,145.9,135.6,133.1,126.0,123.0,122.0,43.1,41.4,14.8,12.8；HRMS calcd for C 13 H 15 BrN 4 O+H + :323.0502,found:323.0505.
EXAMPLE 21 1- (4-bromophenyl) -N-isopropyl-1H-1, 2, 3-triazole-4-carboxamide
The procedure was as in example 1 except that the azidobenzene was changed to 1-azido-4-bromobenzene and piperidine was changed to isopropylamine to give a white solid in 25% yield.
White solid, yield 25%. Melting point: 217.6-218.1 ℃. 1 H NMR(500MHz,CDCl 3 ):δ8.48(s,1H),7.70–7.68(m,2H),7.65–7.63(m,2H),7.03(d,J＝7.0Hz,1H),4.34–4.27(m,1H),1.30(d,J＝6.5Hz,6H)； 13 C NMR(125MHz,CDCl 3 ):δ158.8,144.4,135.6,133.1,126.4,123.2,122.1,41.4,22.8；HRMS calcd for C 12 H 13 BrN 4 O+H + :309.0346,found:309.0343.
In the above embodiments, the solvent is preferably formed by mixing tetrahydrofuran and water according to a volume ratio of 3:1, where the solvent may be selected from one or more of water, acetone, tetrahydrofuran, toluene, N-Dimethylformamide (DMF), anhydrous methanol, acetonitrile, preferably tetrahydrofuran and water.
The base is selected from N, N-Diisopropylethylamine (DIPEA) and is preferably selected from potassium carbonate, sodium hydroxide, lithium hydroxide, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 4-diazabicyclo [2.2.2] octane (DABCO), N-Dimethylaniline (DMA), N-Diisopropylethylamine (DIPEA), triethylamine, 4-Dimethylaminopyridine (DMAP).
It will be understood that the present application is not limited to what has been described above, and that various modifications and changes may be made without departing from the scope thereof. The scope of the application is limited only by the appended claims.
Claims (10)
1. A 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative, characterized in that the 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative has the structural formula:
wherein R is 1 For all kinds ofSubstituted phenyl, R 2 Is a heterocyclic aryl or an alkane group, R 3 Is an alkane group.
2. The 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative according to claim 1, wherein the 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative is any one of the following:
(1-phenyl-1H-1, 2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
piperidin-1-yl (1- (p-tolyl) -1H-1,2, 3-triazol-4-yl) methanone;
(1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
piperidin-1-yl (1- (4- (trifluoromethyl) phenyl) -1H-1,2, 3-triazol-4-yl) methanone;
(1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
piperidin-1-yl (1- (m-tolyl) -1H-1,2, 3-triazol-4-yl) methanone;
(1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
piperidin-1-yl (1- (o-tolyl) -1H-1,2, 3-triazol-4-yl) methanone;
(1- (2-bromo-4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (2, 4-dibromobenzene) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (2-bromo-4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (2, 4-dichlorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (2-chloro-4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (3-chloro-4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) (piperidin-1-yl) methanone;
(1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) (morpholinyl) methanone;
(1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) (pyrrolidin-1-yl) methanone;
1- (4-bromophenyl) -N, N-diethyl-1H-1, 2, 3-triazole-4-carboxamide;
1- (4-bromophenyl) -N-isopropyl-1H-1, 2, 3-triazole-4-carboxamide.
3. A process for the preparation of 1-N-substituted 1,2, 3-triazole-4-carboxamide derivatives according to claim 1, comprising the steps of:
step (1), dissolving azidophenyl derivatives and amine compounds in a two-phase solvent, adding alkali and a phase transfer catalyst, then adding alpha-trifluoromethyl propylene compounds, and stirring at a certain temperature until the raw materials react;
the structural formula of the azidophenyl derivative is as follows:
wherein R is 1 Is a variety of substituted phenyl groups;
the structural formula of the amine compound is as follows:
wherein R is 2 Is a heterocyclic aryl or an alkane group, R 3 Is an alkane group;
the structural formula of the alpha-trifluoromethyl propylene compound is as follows:
step (2), extracting the reaction system obtained in the step (1), concentrating an organic layer obtained by extraction under reduced pressure to obtain a residue, and performing silica gel column chromatography on the residue to obtain a 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative, wherein the 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative has the structural formula:
4. the process according to claim 3, wherein the molar ratio of the azidophenyl derivative to the amine compound in the step (1) is 1:5, and the ratio of the azidophenyl derivative to the two-phase solvent is 1mol:2L, the mol ratio of the azidophenyl derivative to the alkali is 1:3, and the mol ratio of the azidophenyl derivative to the alpha-trifluoromethyl propylene compound is 1mol:2L.
5. The process according to claim 3, wherein the stirring in the step (1) is carried out at a temperature of 50℃to 150 ℃.
6. The process according to claim 3, wherein in the step (1), the two-phase solvent is one or more selected from the group consisting of water, acetone, tetrahydrofuran, toluene, N-dimethylformamide, anhydrous methanol, and acetonitrile.
7. The method of claim 3, wherein the two-phase solvent is prepared by mixing tetrahydrofuran and water in a volume ratio of 3:1.
8. The process according to claim 3, wherein the concentration of the two-phase solvent is 0.5mmol/mL.
9. A process according to claim 3, wherein in step (1), the base is selected from inorganic bases including potassium carbonate, sodium hydroxide, lithium hydroxide, and organic bases; the organic base comprises 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, N-dimethylaniline, N-diisopropylethylamine, triethylamine and 4-dimethylaminopyridine.
10. The process according to claim 3, wherein in the step (1), the phase transfer catalyst is selected from the group consisting of DL- Α -tocopheryl methoxy polyethylene glycol succinate solution, 18-crown ether-6, tetrabutylammonium bisulfate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310164485.7A CN116082253A (en) | 2023-02-25 | 2023-02-25 | 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310164485.7A CN116082253A (en) | 2023-02-25 | 2023-02-25 | 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116082253A true CN116082253A (en) | 2023-05-09 |
Family
ID=86199222
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310164485.7A Pending CN116082253A (en) | 2023-02-25 | 2023-02-25 | 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116082253A (en) |
-
2023
- 2023-02-25 CN CN202310164485.7A patent/CN116082253A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5656952B2 (en) | Piperazine derivative oxalate crystals | |
| RU2563630C1 (en) | Method of obtaining hydrochloride of 1-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one and intermediate compounds, applied in it | |
| US11708362B2 (en) | Process for preparing aminopyrimidine derivatives | |
| JP2018519280A (en) | Method for preparing {1- (ethylsulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] azetidin-3-yl} acetonitrile and Intermediate | |
| CN112047888B (en) | Method for synthesizing enzalutamide | |
| CN114149427A (en) | Synthesis method of non-neferitone and intermediate thereof | |
| Khan et al. | Parikh–Doering oxidation–dehydration–Ugi cyclization cascade in the development of lactams from formidoalkanols (3> chain length> 7) | |
| CN107935997A (en) | A kind of difficult to understand this replaces the synthetic method of Buddhist nun | |
| CN116082253A (en) | 1-N-substituted 1,2, 3-triazole-4-carboxamide derivative and preparation method thereof | |
| EP3307717B1 (en) | A novel process for preparing enzalutamide | |
| KR102597449B1 (en) | Method for producing 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine or its salt | |
| CN105272921A (en) | Method for preparing Ceritinib and intermediate compound of Ceritinib | |
| CN109020977B (en) | Preparation method of Acaraburtinib | |
| CN101628904A (en) | Synthesis method of 2-nitro-3-aryl-2,3,5,7-tetrahydrobenzofuran-4-one derivative | |
| CN103980283B (en) | A kind of aromatic yl azide and the synthetic method of aryl 1,2,3 triazole type spiro-compound | |
| JPH061776A (en) | Production of substituted pyrazinecarbonitrile | |
| CN113754597B (en) | Benzhydryl piperazine compound containing linear olefin and preparation method thereof | |
| WO2002076958A1 (en) | Process for producing 5-substituted oxazole compounds and 5-substituted imidazole compounds | |
| US11932614B2 (en) | Method for preparing diazoxide | |
| CN111440147B (en) | Synthesis method of N- (2-methyl-5-aminophenyl) -4- (3-pyridyl) -2-pyrimidinamine | |
| CN118440004A (en) | Synthesis method of chiral gamma-carbonyl sulfone compound | |
| CN105111217A (en) | Method for synthesizing isoindole dihyroquinazoline derivative | |
| KR20240068167A (en) | Novel synthetic method of 5-aminoimidazole derivatives, a novel compound prepared using the same, and prepartion method of a novel compound | |
| CN118164970A (en) | Synthesis method of antiviral drug Entecavir fumarate and intermediate thereof | |
| EP4375282A1 (en) | Preparation method for hepatitis b virus nucleocapsid inhibitor |
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 |