CN115594674A - Green synthesis method of C-3 methyl mercapto tetrazole substituted imidazopyridine - Google Patents
Green synthesis method of C-3 methyl mercapto tetrazole substituted imidazopyridine Download PDFInfo
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- CN115594674A CN115594674A CN202211276543.7A CN202211276543A CN115594674A CN 115594674 A CN115594674 A CN 115594674A CN 202211276543 A CN202211276543 A CN 202211276543A CN 115594674 A CN115594674 A CN 115594674A
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- methyl mercapto
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- mercapto tetrazole
- potassium
- substituted imidazopyridine
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- ZBXNFTFKKOSPLD-UHFFFAOYSA-N 5-methylsulfanyl-2h-tetrazole Chemical group CSC1=NN=NN1 ZBXNFTFKKOSPLD-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000001308 synthesis method Methods 0.000 title claims abstract description 15
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 150000005232 imidazopyridines Chemical class 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 238000004440 column chromatography Methods 0.000 claims description 8
- XWNSFEAWWGGSKJ-UHFFFAOYSA-N 4-acetyl-4-methylheptanedinitrile Chemical compound N#CCCC(C)(C(=O)C)CCC#N XWNSFEAWWGGSKJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000004153 Potassium bromate Substances 0.000 claims description 7
- 229940094037 potassium bromate Drugs 0.000 claims description 7
- 235000019396 potassium bromate Nutrition 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- -1 methionyl tetrazole Chemical class 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- QLOKJRIVRGCVIM-UHFFFAOYSA-N 1-[(4-methylsulfanylphenyl)methyl]piperazine Chemical compound C1=CC(SC)=CC=C1CN1CCNCC1 QLOKJRIVRGCVIM-UHFFFAOYSA-N 0.000 claims description 2
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 claims description 2
- 229940107816 ammonium iodide Drugs 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- VKJKEPKFPUWCAS-UHFFFAOYSA-M potassium chlorate Chemical compound [K+].[O-]Cl(=O)=O VKJKEPKFPUWCAS-UHFFFAOYSA-M 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- JLKDVMWYMMLWTI-UHFFFAOYSA-M potassium iodate Chemical compound [K+].[O-]I(=O)=O JLKDVMWYMMLWTI-UHFFFAOYSA-M 0.000 claims description 2
- 239000001230 potassium iodate Substances 0.000 claims description 2
- 235000006666 potassium iodate Nutrition 0.000 claims description 2
- 229940093930 potassium iodate Drugs 0.000 claims description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- SBPIDKODQVLBGV-UHFFFAOYSA-N 1h-imidazole;pyridine Chemical group C1=CNC=N1.C1=CC=NC=C1 SBPIDKODQVLBGV-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 150000003536 tetrazoles Chemical group 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 abstract description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract 3
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 abstract 1
- 238000001228 spectrum Methods 0.000 description 19
- 239000000047 product Substances 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000012043 crude product Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- CMGDVUCDZOBDNL-UHFFFAOYSA-N 4-methyl-2h-benzotriazole Chemical compound CC1=CC=CC2=NNN=C12 CMGDVUCDZOBDNL-UHFFFAOYSA-N 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 description 3
- 238000005987 sulfurization reaction Methods 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 2
- 229960001475 zolpidem Drugs 0.000 description 2
- SIDJEDFUSPSLPY-UHFFFAOYSA-N 2-(furan-2-yl)imidazo[1,2-a]pyridine Chemical compound C1=COC(C=2N=C3C=CC=CN3C=2)=C1 SIDJEDFUSPSLPY-UHFFFAOYSA-N 0.000 description 1
- BZACBBRLMWHCNM-UHFFFAOYSA-N 2-methylimidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC(C)=CN21 BZACBBRLMWHCNM-UHFFFAOYSA-N 0.000 description 1
- KDHWCFCNNGUJCP-UHFFFAOYSA-N 2-phenylimidazo[1,2-a]pyridine Chemical compound N1=C2C=CC=CN2C=C1C1=CC=CC=C1 KDHWCFCNNGUJCP-UHFFFAOYSA-N 0.000 description 1
- HZILEJRCRXMSNM-UHFFFAOYSA-N 2-thiophen-2-ylimidazo[1,2-a]pyridine Chemical compound C1=CSC(C=2N=C3C=CC=CN3C=2)=C1 HZILEJRCRXMSNM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NCFTXMQPRQZFMZ-WERGMSTESA-M Cefoperazone sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C([O-])=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 NCFTXMQPRQZFMZ-WERGMSTESA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- JRTIDHTUMYMPRU-UHFFFAOYSA-N alpidem Chemical compound N1=C2C=CC(Cl)=CN2C(CC(=O)N(CCC)CCC)=C1C1=CC=C(Cl)C=C1 JRTIDHTUMYMPRU-UHFFFAOYSA-N 0.000 description 1
- 229950008673 alpidem Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 229960001372 aprepitant Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- 229960003791 cefmenoxime Drugs 0.000 description 1
- MPTNDTIREFCQLK-UNVJPQNDSA-N cefmenoxime hydrochloride Chemical compound [H+].[Cl-].S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C.S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C MPTNDTIREFCQLK-UNVJPQNDSA-N 0.000 description 1
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 description 1
- 229960003585 cefmetazole Drugs 0.000 description 1
- 229960002417 cefoperazone sodium Drugs 0.000 description 1
- SRZNHPXWXCNNDU-RHBCBLIFSA-N cefotetan Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CS[C@@H]21)C(O)=O)=O)C(=O)C1SC(=C(C(N)=O)C(O)=O)S1 SRZNHPXWXCNNDU-RHBCBLIFSA-N 0.000 description 1
- 229960005495 cefotetan Drugs 0.000 description 1
- PWAUCHMQEXVFJR-PMAPCBKXSA-N cefpiramide Chemical compound C1=NC(C)=CC(O)=C1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 PWAUCHMQEXVFJR-PMAPCBKXSA-N 0.000 description 1
- 229960005446 cefpiramide Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- JPAWFIIYTJQOKW-UHFFFAOYSA-N olprinone Chemical compound N1C(=O)C(C#N)=CC(C2=CN3C=CN=C3C=C2)=C1C JPAWFIIYTJQOKW-UHFFFAOYSA-N 0.000 description 1
- 229950005421 olprinone Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- LIFDPEORUVTOCP-UHFFFAOYSA-N saripidem Chemical compound N1=C2C=CC=CN2C(CN(C)C(=O)CCC)=C1C1=CC=C(Cl)C=C1 LIFDPEORUVTOCP-UHFFFAOYSA-N 0.000 description 1
- 229950007359 saripidem Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000004764 thiosulfuric acid derivatives Chemical class 0.000 description 1
Images
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a green synthesis method of C-3-methyl mercapto tetrazole substituted imidazopyridine, which comprises the following steps: in the presence of a catalyst, water is used as a solvent, imidazole [1,2-a ] pyridine and methyl mercapto tetrazole react, and after the reaction is finished, the C-3 methyl mercapto tetrazole substituted imidazopyridine is obtained through post-treatment. The synthesis method mainly takes water as a solvent, is green and environment-friendly, has high reaction yield and mild reaction conditions, does not need to add reagents such as metal, alkali, strong acid and iodine, and is simple and convenient to operate.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a green synthesis method of C-3 methyl mercapto tetrazole substituted imidazopyridine.
Background
Imidazo [1,2-a ] pyridine structures are widely found in natural products and drug molecules and have a wide range of biological activities, such as: antiviral, antiulcer, antibacterial, anticancer, and antitubercular properties. More importantly, imidazo [1,2-a ] pyridines are key building blocks in many commercial drugs, such as: aprepitant (Alpidem), surimid (saripidem), zolpidem (Zolpidem), olprinone (Olprione). The methiazole tetrazolium widely exists in the molecular structure of the medicine and is used as an intermediate of medicines such as cefoperazone sodium, cefamandole, cefmenoxime hydrochloride, cefmetazole, cefotetan, cefpiramide and the like. Different substitutions at the C-3 position of imidazo [1,2-a ] pyridines lead to different pharmaceutical properties. Therefore, the development of structural diversity of the imidazo [1,2-a ] pyridine derivative and the development of an efficient and green synthesis method for preparing the methidazole substituted imidazopyridine derivative at the C-3 position which is easy to further functionalize have great significance.
In recent years, the C-3 position sulfurization reaction of imidazo [1,2-a ] pyridine has been receiving much attention. These vulcanizing agents include: disulfides, elemental sulfur, thioethers, thiosulfates, sodium sulfinates and sulfonyl hydrazides, aryl thiophenols. Although these strategies are successfully used for the sulfurization of imidazo [1,2-a ] pyridine, the sulfurization reagent, highly pre-functionalized, requires several steps to prepare and, in addition, the reaction conditions are too severe, such as the addition of reagents of metals, bases, strong acids and iodine, and the reaction solvents used are mostly organic solvents and not environmentally friendly.
Disclosure of Invention
Therefore, the invention provides a green synthesis method of C-3 methyl mercapto tetrazole substituted imidazopyridine, which mainly comprises the following steps: 1) The environment-friendly and easily-obtained water is used as a reaction solvent, so that the green chemical concept is met; 2) No metal, acid, alkali and iodine reagent is needed to be added, and the operation process is simple and easy to implement; 3) The reaction raw materials are cheap and easy to obtain, and the reaction yield is high; 4) The substrate applicability of the reaction is relatively wide, and various C-3 methyl mercapto tetrazole substituted imidazopyridine derivatives can be efficiently synthesized; 5) The reaction condition is mild, and the atom economy is high.
The technical scheme of the invention is realized as follows:
a green synthesis method of C-3 methyl mercapto tetrazole substituted imidazopyridine comprises the following steps:
in the presence of a catalyst, water is used as a solvent, imidazo [1,2-a ] pyridine and methyl mercapto tetrazole react to prepare the C-3-methyl mercapto tetrazole substituted imidazopyridine derivative. The imidazo [1,2-a ] pyridine has a structure shown as a formula (I), the methine tetrazole has a structure shown as a formula (II), and the methine tetrazole substituted imidazopyridine at the C-3 position has a structure shown as a formula (III):
the chemical reaction that takes place in the above process is shown by the following formula:
further, in the formula (I) and the formula (III), R 1 Is one of hydrogen, alkyl, alkoxy, halogen atom, nitro, cyano, trifluoromethyl, ester group and the like; r is 2 The phenyl group is one of alkyl, alkoxy, phenyl, 4-methylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-chlorophenyl, 2-methylphenyl, 2-fluorophenyl, 2-thienyl, 2-furyl and ester groups.
Further, said R 1 、R 2 Are all C 1 ～C 4 Alkyl or C 1 ～C 4 An alkoxy group.
Furthermore, the molar ratio of the imidazo [1,2-a ] pyridine to the methyl mercapto tetrazole is 1 (1-2). Preferably, the molar ratio of the imidazo [1,2-a ] pyridine to the methyl mercapto tetrazole is 1.2.
Further, the catalyst is one of potassium fluoride, potassium chloride, potassium bromide, potassium iodide, potassium chlorate, potassium bromate, potassium iodate, ammonium iodide, cuprous iodide, iodobenzene diacetate, potassium peroxodisulfate, potassium chromate or manganese dioxide. Preferably, the catalyst is potassium bromate, and the yield is higher.
Furthermore, the reaction temperature is 0-100 ℃, and the reaction time is 1-36 hours. Preferably, the reaction temperature is 70-90 ℃, the reaction time is 10-14 hours, the reaction is fully completed, and the yield is higher.
Further, after the reaction is finished, separating and purifying the product by adopting column chromatography, wherein the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention takes water as a reaction solvent, and is relatively green and environment-friendly;
(2) The reaction conditions are mild, the whole operation process is simple and convenient, and the steps are simple;
(3) The method has high reaction yield and wide substrate applicability, and can synthesize various types of functional group-substituted C-3-methyl mercapto tetrazole substituted imidazopyridine derivatives.
Drawings
FIG. 1 is a hydrogen spectrum of Compound 1 of example 1 of the present invention.
FIG. 2 is a carbon spectrum of Compound 1 of example 1 of the present invention.
FIG. 3 is a hydrogen spectrum of Compound 2 of example 2 of the present invention.
FIG. 4 is a carbon spectrum of Compound 2 of example 2 of the present invention.
FIG. 5 is a hydrogen spectrum of Compound 3 of example 3 of the present invention.
FIG. 6 is a carbon spectrum of Compound 3 of example 3 of the present invention.
FIG. 7 is a hydrogen spectrum of Compound 4 of example 4 of the present invention.
FIG. 8 is a carbon spectrum of Compound 4 of example 4 of the present invention.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.
The reaction formula in the embodiment of the invention is as follows:
example 1
2-phenylimidazo [1,2-a ] pyridine (97.1mg, 0.5mmol), tolyltriazole (69.7mg, 0.6 mmol) and potassium bromate (16.7mg, 0.1mmol) were sequentially added to a sealed tube, and then 2mL of water was added thereto and the reaction was stirred in a sealed tube at 70 ℃ for 10 hours. After the reaction is finished, ethyl acetate is used for extraction for 3 times, organic layers are combined, a crude product obtained by concentration is further separated and purified through column chromatography, eluent is a mixed solvent of petroleum ether and ethyl acetate, and a product 123.3mg is obtained, wherein the yield is as follows: 80 percent.
The physical properties and the spectrum data of the product obtained in this example are as follows:
white solid with melting point of 108-109 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.54-8.52(m,1H),8.00-7.99(m,2H),7.71-7.68(m,1H),7.48-7.36(m,4H),7.02-6.97(m,1H),3.75(s,3H)； 13 C NMR(101MHz,CDCl 3 ) Delta 152.52,150.24,147.79,132.75,129.24,128.99,128.69,127.81,125.01,117.97,117.94,113.96,99.77 and 34.15, the hydrogen spectrum is shown in figure 1, and the carbon spectrum is shown in figure 2.
From the above data, the structure of the resulting product is shown below:
example 2
2-methylimidazo [1,2-a ] pyridine (66.1mg, 0.5mmol), tolyltriazole (69.7mg, 0.6 mmol), and potassium bromate (16.7mg, 0.1mmol) were sequentially added to a sealed tube, and then 2mL of water was added thereto and the reaction was stirred under a sealed condition at 90 ℃ for 12 hours. After the reaction is finished, extracting for 3 times by utilizing ethyl acetate, combining organic layers, further separating and purifying a crude product obtained by concentrating through column chromatography, wherein an eluent is a mixed solvent of petroleum ether and ethyl acetate to obtain a product of 98.5mg, and the yield is as follows: 80 percent.
The physical properties and the spectrum data of the product obtained in this example are as follows:
white solid with a melting point of 56-57 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.35-8.33(m,1H),7.58-7.56(m,1H),7.33-7.26(m,1H),6.93-6.90(m,1H),4.03(s,3H),2.56(s,3H)； 13 C NMR(101MHz,CDCl 3 ) Delta 151.88,150.84,147.67,127.31,124.77,117.23,113.49,100.17,34.16,14.16, the hydrogen spectrum is shown in FIG. 3 and the carbon spectrum is shown in FIG. 4.
From the above data, the structure of the resulting product is shown below:
example 3
2-furyl imidazo [1,2-a ] pyridine (149.2mg, 0.5 mmol), methyl mercapto tetrazole (69.7 mg,0.6 mmol) and potassium bromate (16.7 mg,0.1 mmol) are added in turn in a sealed tube, then 2mL of water is added, and the mixture is sealed and stirred at 80 ℃ for reaction for 14 hours. After the reaction is finished, extracting for 3 times by using ethyl acetate, combining organic layers, further separating and purifying a crude product obtained by concentration through column chromatography, wherein an eluent is a mixed solvent of petroleum ether and ethyl acetate, 125.3mg of a product is obtained, and the yield is as follows: 84 percent.
The physical properties and the spectrogram data of the product obtained in the embodiment are as follows:
white solid with melting point of 108-109 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.52-8.50(m,1H),7.63-7.62(m,1H),7.56(m,1H),7.37-7.33(m,1H),7.14-7.13(m,1H),6.97-6.94(m,1H),6.52(m,1H)，3.97(s,3H)； 13 C NMR(101MHz,CDCl 3 ) Delta 150.04,147.85,147.78,143.50,143.30,128.01,124.80,117.64,113.98,111.86,110.86,98.70 and 34.24, the hydrogen spectrum is shown in figure 5, and the carbon spectrum is shown in figure 6.
From the above data, the structure of the resulting product is shown below:
example 4
2-Thienylimidazo [1,2-a ] pyridine (149.2mg, 0.5 mmol), tolyltriazole (69.7 mg,0.6 mmol) and potassium bromate (16.7 mg,0.1 mmol) were sequentially added to a sealed tube, and then 2mL of water was added thereto, and the mixture was sealed and stirred at 80 ℃ for 12 hours. After the reaction is finished, extracting for 3 times by using ethyl acetate, combining organic layers, further separating and purifying a crude product obtained by concentration through column chromatography, wherein an eluent is a mixed solvent of petroleum ether and ethyl acetate to obtain 135.2mg of a product, and the yield is as follows: 86 percent.
The physical properties and the spectrum data of the product obtained in this example are as follows:
white solid with melting point of 108-109 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.48-8.46(m,1H),7.92-7.91(m,1H),7.66-7.63(m,1H),7.43-7.41(m,1H),7.38-7.34(m,1H),7.14-7.12(m,1H),6.99-6.95(m,1H),3.93(s,3H)； 13 C NMR(101MHz,CDCl 3 ) Delta 150.07,147.81,146.98,135.33,128.06,127.91,127.67,127.49,124.87,117.65,114.01,98.32,34.37, the hydrogen spectrum is shown in FIG. 7 and the carbon spectrum is shown in FIG. 8.
From the above data, the structure of the resulting product is shown below:
Claims (8)
1. a green synthesis method of C-3 methyl mercapto tetrazole substituted imidazopyridine is characterized by comprising the following steps:
in the presence of a catalyst, water is used as a solvent, imidazo [1,2-a ] pyridine and methyl mercapto tetrazole react to prepare a C-3-methyl mercapto tetrazole substituted imidazopyridine derivative;
the structure of the imidazo [1,2-a ] pyridine is shown as a formula (I), the structure of the methionyl tetrazole is shown as a formula (II), and the structure of the methionyl tetrazole substituted imidazopyridine is shown as a formula (III):
2. the green of claim 1, wherein the C-3 methyl mercapto tetrazole substituted imidazopyridineA process for color synthesis, characterized in that R in the formulae (I) and (III) 1 Is one of hydrogen, alkyl, alkoxy, halogen atom, nitro, cyano, trifluoromethyl, ester group and the like; r is 2 The phenyl group is one of alkyl, alkoxy, phenyl, 4-methylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-chlorophenyl, 2-methylphenyl, 2-fluorophenyl, 2-thienyl, 2-furyl and ester groups.
3. The green synthesis method of C-3 methyl mercapto tetrazole substituted imidazopyridine of claim 1, wherein R in formula (I) and formula (III) 1 、R 2 Are all C 1 ～C 4 Alkyl or C 1 ～C 4 An alkoxy group.
4. The green synthesis method of C-3 methyl mercapto tetrazole substituted imidazopyridine of claim 1, wherein the molar ratio of imidazo [1,2-a ] pyridine to methyl mercapto tetrazole is 1 (1-2).
5. The green synthesis method of C-3 methyl mercapto tetrazole substituted imidazopyridine of claim 1, wherein the molar ratio of imidazo [1,2-a ] pyridine to methyl mercapto tetrazole is 1.
6. The green synthesis method of imidazole pyridine substituted with tetrazole of methyl mercapto at C-3 position as claimed in claim 1, wherein said catalyst is one of potassium fluoride, potassium chloride, potassium bromide, potassium iodide, potassium chlorate, potassium bromate, potassium iodate, ammonium iodide, cuprous iodide, iodobenzene diacetate, potassium peroxodisulfate, potassium chromate or manganese dioxide.
7. The green synthesis method of C-3 methyl mercapto tetrazole substituted imidazopyridine as claimed in claim 1, wherein the reaction temperature is 70-90 ℃, and the reaction time is 10-14 hours.
8. The green synthesis method of C-3 methyl mercapto tetrazole substituted imidazopyridine as in any one of claims 1 to 7, wherein after the reaction is finished, a product is separated and purified by column chromatography, and an eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.
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