CN117736157A - Preparation method of tetrazole-substituted acetophenone compound - Google Patents
Preparation method of tetrazole-substituted acetophenone compound Download PDFInfo
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- CN117736157A CN117736157A CN202211108091.1A CN202211108091A CN117736157A CN 117736157 A CN117736157 A CN 117736157A CN 202211108091 A CN202211108091 A CN 202211108091A CN 117736157 A CN117736157 A CN 117736157A
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- acid ester
- acid
- azodicarboxylic
- azodicarboxylic acid
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- -1 tetrazole-substituted acetophenone compound Chemical class 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 150000003536 tetrazoles Chemical class 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- SPXOTSHWBDUUMT-UHFFFAOYSA-N 138-42-1 Chemical compound OS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229940117389 dichlorobenzene Drugs 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229940078552 o-xylene Drugs 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- KCTAHLRCZMOTKM-UHFFFAOYSA-N tripropylphosphane Chemical compound CCCP(CCC)CCC KCTAHLRCZMOTKM-UHFFFAOYSA-N 0.000 claims description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 2
- 150000003738 xylenes Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 abstract description 2
- 125000003831 tetrazolyl group Chemical group 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- 150000002576 ketones Chemical class 0.000 description 21
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical group C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- WZWWEVCLPKAQTA-UHFFFAOYSA-N 2-bromo-1-(2-chlorophenyl)ethanone Chemical compound ClC1=CC=CC=C1C(=O)CBr WZWWEVCLPKAQTA-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- 239000004305 biphenyl Chemical group 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QNEUPDOKMWBPGA-UHFFFAOYSA-N 1-(2-chlorophenyl)-2-(tetrazol-1-yl)ethanone Chemical compound ClC1=CC=CC=C1C(=O)CN1N=NN=C1 QNEUPDOKMWBPGA-UHFFFAOYSA-N 0.000 description 1
- SLILCNKDGFOZOJ-UHFFFAOYSA-N 1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethanone Chemical compound ClC1=CC=CC=C1C(=O)CN1N=NC=N1 SLILCNKDGFOZOJ-UHFFFAOYSA-N 0.000 description 1
- ZDOYHCIRUPHUHN-UHFFFAOYSA-N 1-(2-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1Cl ZDOYHCIRUPHUHN-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical class CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- NCBFTYFOPLPRBX-UHFFFAOYSA-N dimethyl azodicarboxylate Substances COC(=O)N=NC(=O)OC NCBFTYFOPLPRBX-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- NCBFTYFOPLPRBX-AATRIKPKSA-N methyl (ne)-n-methoxycarbonyliminocarbamate Chemical compound COC(=O)\N=N\C(=O)OC NCBFTYFOPLPRBX-AATRIKPKSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of a novel carbamate compound intermediate tetrazole substituted acetophenone compound, which comprises the reaction of a hydroxyacetophenone compound and a tetrazole compound, and solves the technical problem that the prior art is urgently required to develop more alternative processes suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicines, and particularly provides a preparation method of a tetrazole-substituted acetophenone compound.
Background
(R) -1-aryl-2-tetrazol-2-yl ethyl carbamate compounds (hereinafter "carbamate compounds") are useful in the treatment of central nervous system disorders, and in particular (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl ethyl carbamate was developed by the Korean SK biopharmaceutical company, and was approved by the FDA in 2019 for use in the treatment of partial seizures in adult patients.
The synthetic route is reported for the first time in patent CN101228138B from SK company:
wherein, the 1-position and the 2-position of the 1H-tetrazole can react to respectively generate 1N alcohol and 2N alcohol, and column chromatography separation is needed, and the reaction formula is as follows:
subsequently, SK company in its patent CN102803233B, CN102574821B discloses a new preparation method, the synthetic route is as follows:
in 2020, the SK company further filed patent CN114901647a, in which 1H-tetrazole is claimed to be preferentially reacted with an inorganic base to prepare a metal salt of 1H-tetrazole, and then 2-bromo-2' -chloroacetophenone is added to increase the yield of 2N ketone, and then 1N ketone is further found to be unstable at high temperature and can be decomposed into oxazole at high temperature and high pressure, and is cleaned by acid washing, so that 2N ketone with higher purity is obtained. The 1N ketone decomposition reaction formula is as follows:
at present, other synthesis routes of the (R) -1-aryl-2-tetrazol-2-ylethyl carbamate compound are not reported except the SK company related patent, and more alternative processes suitable for industrial production are required to be developed.
Disclosure of Invention
The invention aims to provide a preparation method of a novel carbamate compound intermediate tetrazole substituted acetophenone compound, which has the advantages of low-cost and easily-obtained reaction reagent, simple post-reaction treatment and suitability for large-scale industrial production.
The technical scheme adopted by the invention is as follows:
a process for preparing a compound of formula (I), comprising:
reacting a compound of formula (II) with tetrazole to obtain a compound of formula (I)
Wherein R is 1 -R 5 Independently selected from hydrogen, halogen, cyano, nitro, and optionally halogen-substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl and C 2-10 Alkynyl groups.
Further preferably, R 1 -R 5 Independently selected from hydrogen, halogen, trifluoromethyl.
Further preferably, R 1 -R 4 Is hydrogen, R 5 Halogen is preferably fluorine, chlorine, bromine or iodine, more preferably chlorine.
In one embodiment, the reaction is carried out under acid catalysis.
The reaction temperature is 10-200 ℃, preferably room temperature or reflux temperature.
The acid is an organic acid and/or an inorganic acid, preferably sulfuric acid, phosphoric acid, hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, methanesulfonic acid and/or trifluoromethanesulfonic acid, more preferably sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and/or trifluoromethanesulfonic acid.
The reaction is carried out in the absence of a solvent or in the presence of a solvent which is one or more of halogenated hydrocarbons, unsubstituted aromatic hydrocarbons, mono-or polyalkyl-substituted aromatic hydrocarbons, mono-or polyhalogenated aromatic hydrocarbons, nitriles, ethers, amide solvents, preferably benzene, toluene, o-xylene, p-xylene, m-xylene, mixed xylenes, chlorobenzene and/or dichlorobenzene.
In another embodiment, the reaction is carried out in the presence of a solvent, a tri-dentate phosphorus compound and an azodicarboxylic acid ester.
The reaction temperature is 10-50 ℃, preferably room temperature.
The tri-coordinated phosphorus compound is a trialkylphosphine, tricycloalkylphosphine, triarylphosphine and/or trialkyl substituted arylphosphine, preferably tripropylphosphine, tributylphosphine, tricyclohexylphosphine, triphenylphosphine and/or tri-o-tolylphosphine, more preferably tricyclohexylphosphine or triphenylphosphine.
The azodicarboxylic acid ester is dibenzyl azodicarboxylic acid ester and/or dialkyl azodicarboxylic acid ester, preferably dibenzyl azodicarboxylic acid ester, dimethyl azodicarboxylic acid ester, diethyl azodicarboxylic acid ester, dipropyl azodicarboxylic acid ester, diisopropyl azodicarboxylic acid ester, dibutyl azodicarboxylic acid ester and/or di-tert-butyl azodicarboxylic acid ester, more preferably dimethyl azodicarboxylic acid ester or diisopropyl azodicarboxylic acid ester.
The solvent is one or more of halogenated alkane, unsubstituted aromatic hydrocarbon, mono-or poly-alkyl substituted aromatic hydrocarbon, mono-or poly-halogenated aromatic hydrocarbon, nitrile, ether, amide solvent, preferably tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1, 4-dioxane and/or toluene, more preferably tetrahydrofuran.
[ define and explain ]
The following terms used herein have the following meanings, unless otherwise indicated.
The term "halogen" includes fluorine, chlorine, bromine or iodine.
The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, and the like.
The term "cycloalkyl" refers to saturated mono-or polycyclic hydrocarbons such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like.
The term "alkoxy" refers to the group-O-alkyl, the term "alkenyl" refers to an alkyl group having at least one carbon-carbon double bond in the molecule, and the term "alkynyl" refers to an alkyl group having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above.
The term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which may be mono-, di-or polysubstituted, which may be monovalent, divalent or multivalent, and which may be monocyclic or polycyclic (e.g. 1 to 3 rings), which are fused together or covalently linked. Non-limiting examples of aryl groups include phenyl, naphthyl, biphenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl.
The term "aromatic hydrocarbon" means a polyunsaturated aromatic hydrocarbon, which may be mono-, di-or polysubstituted, and which may be mono-or polycyclic (e.g. 1 to 3 rings), which are fused together or covalently linked. Non-limiting examples of aromatic hydrocarbons include benzene, naphthalene, biphenyl.
Detailed Description
The present invention will be explained in more detail with reference to the following examples, which are only for illustrating the technical aspects of the present invention, and the spirit and scope of the present invention are not limited thereto.
Comparative example 1
Acetic acid (120 mL), o-chloroacetophenone (60.0 g), liquid bromine (76.0 g), p-toluenesulfonic acid (6.0 g) were added to the four-necked flask, and the reaction mixture was heated to 40 to 50℃and reacted for 6 hours after the completion of the addition. The reaction mixture was cooled to 20 to 30℃and 600mL of methylene chloride was added thereto, the mixture was washed twice with water (600 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 90.1g of 2-bromo-2' -chloroacetophenone.
A separate flask was charged with acetonitrile (230 mL), 1H-tetrazole (29.6 g), potassium carbonate (60.0 g), and a solution of 2-bromo-2' -chloroacetophenone (90.1 g) in DMF (90 mL) was added dropwise, followed by stirring at 45℃for 2 hours, and distillation under reduced pressure was carried out to remove about 1500mL of the solvent. The concentrate was diluted with ethyl acetate (2000 mL) and washed with 10% brine (3×2000 mL). The separated organic layer was distilled under reduced pressure to obtain an oily solid residue. To a solution of the solid residue in ethyl acetate (432 mL) was slowly added heptane (600 mL). The precipitate formed was filtered off at room temperature and washed to give 38.6g of 1- (2-chlorophenyl) -2- (1, 2,3, 4-tetrazol-1-yl) ethan-1-one (hereinafter referred to as "1N ketone"). The filtrate was continued to be concentrated and dissolved in isopropanol (100 mL), and then heptane (360 mL) was added thereto to complete crystallization. Filtration and washing at 0 to 5℃gave 20.8g of solid 1- (2-chlorophenyl) -2- (1, 2,3, 4-tetrazol-2-yl) ethan-1-one (hereinafter referred to as "2N-one").
Example 1
20.0g of 1- (2-chlorophenyl) -2-hydroxyethyl-1-ketone is placed in a flask, toluene (250 mL), 1H-tetrazole (9.03 g) and p-toluenesulfonic acid (4.0 g) are added and heated to reflux for 16 hours, TLC monitors the disappearance of the raw materials, no 1N ketone is detected by HPLC, the reaction solution is cooled to below 40 ℃,300mL of 10% sodium carbonate solution is added for washing once, 300mL of 10% brine is added for washing once, the organic phase is concentrated to no fraction, 100mL of isopropanol is added for dissolving, then gradient cooling to 5 ℃ is carried out for preserving heat and crystallizing for 2 hours, suction filtration is carried out, the filter cake is leached by isopropanol of ice, wet products are dried to constant weight at 40 ℃ by blowing to obtain 2N ketone, 5.3g of off-white solid, and the purity is 98.48%.
Example 2
20.0g of 1- (2-chlorophenyl) -2-hydroxyethyl-1-one is placed in a flask, trifluoromethanesulfonic acid (100 mL) is added, the temperature is reduced to less than or equal to 10 ℃, 1H-tetrazole (9.12 g) is added, then the reaction is carried out for 4 hours at room temperature, TLC monitors that the reaction of the raw materials is finished, 1N ketone is not detected by HPLC, the reaction solution is slowly poured into 500g ice water for quenching, saturated sodium carbonate solution is added to adjust the pH to 8, dichloromethane is used for extraction twice (400 mL multiplied by 2), the combined dichloromethane phases are washed once by 400mL saturated brine, anhydrous sodium sulfate is dried, filtered and filtrate is concentrated to obtain a 2N ketone crude product, 100mL isopropanol is added for recrystallization, and 7.7g of 2N ketone pure product is obtained, and the purity is 99.42%.
Example 3
20.0g of 1- (2-chlorophenyl) -2-hydroxyethyl-1-ketone is placed in a flask, mixed xylene (250 mL) and 1H-tetrazole (12.3 g) are added, methanesulfonic acid (4.0 g) is heated to 110-120 ℃ for reaction for 16 hours, TLC monitors the disappearance of raw materials, no 1N ketone is detected by HPLC, the reaction solution is cooled to below 40 ℃,300mL of 10% sodium carbonate solution is added for washing once, 300mL of 10% brine is added for washing once, an organic phase is concentrated to a fraction which is not discharged, 100mL of isopropanol is added for dissolving and clearing, then the temperature is reduced to 5 ℃ for heat preservation and crystallization for 2 hours, suction filtration is carried out, a filter cake is leached by ice isopropanol, wet products are dried to constant weight at 40 ℃ by blowing to obtain 2N ketone, off-white solid is 12.1g, and the purity is 99.52%.
Example 4
100mL of concentrated sulfuric acid is put into a flask, 1H-tetrazole (4.52 g) is slowly added, after stirring for 10 minutes, 10.0g of 1- (2-chlorophenyl) -2-hydroxyethyl-1-one is added in batches at room temperature, the temperature is raised to 40-50 ℃ for reaction for 24 hours, TLC monitors the disappearance of raw materials, 1N ketone is not detected by HPLC, the reaction solution is cooled to room temperature and poured into 300g of ice for quenching, 200mL of ethyl acetate is added for extraction and liquid separation, an organic phase is washed once by 200mL of 10% brine, liquid separation and concentration are carried out until no fraction is obtained, 40mL of isopropanol is added for dissolving, gradient cooling is carried out to 5 ℃ for heat preservation and crystallization for 2 hours, suction filtration is carried out, a filter cake is leached by isopropanol of ice, wet products are dried to constant weight at 40 ℃ by blowing, and 2.6g of white solid is obtained, and the purity is 97.25%.
Example 5
5.0g of 1- (2-chlorophenyl) -2-hydroxyethyl-1-one was placed in a flask, and 50mL of tetrahydrofuran, 1H-tetrazole (2.46 g), triphenylphosphine (9.23 g) and diisopropyl azodicarboxylate (7.11 g) were added. After the completion of the addition, the reaction was carried out at room temperature for 16 hours, and a mixture of 2N ketone and 1N ketone was confirmed by HPLC. 80mL of 1M hydrochloric acid, 100mL of ethyl acetate was added, the mixture was washed and separated, and the organic phase was concentrated to no fraction. 80mL isopropyl ether is added for beating extraction twice, the filtrate is concentrated to obtain a 2N ketone crude product, and the crude product is recrystallized by 20mL isopropyl alcohol to obtain 1.2g of 2N ketone with the purity of 99.1 percent.
Example 6
5.0g of 1- (2-chlorophenyl) -2-hydroxyethyl-1-one was placed in a flask, and 50mL of tetrahydrofuran, 1H-tetrazole (2.46 g), tricyclohexylphosphine (9.86 g), and dimethyl azodicarboxylate (5.14 g) were added. After the completion of the addition, the mixture was reacted at 40 to 50℃for 16 hours, and the mixture was confirmed by HPLC as a mixture of 2N ketone and 1N ketone. 80mL of 1M hydrochloric acid, 100mL of ethyl acetate was added, the mixture was washed and separated, and the organic phase was concentrated to no fraction. 80mL isopropyl ether is added for beating extraction twice, the filtrate is concentrated to obtain a 2N ketone crude product, and the crude product is recrystallized by 20mL isopropyl alcohol to obtain 1.1g of 2N ketone with the purity of 98.6 percent.
Although the invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the invention.
Claims (7)
1. A process for preparing a compound of formula (I), comprising:
reacting a compound of formula (II) with tetrazole to obtain a compound of formula (I)
Wherein R is 1 -R 5 Independently selected from hydrogen, halogen, cyano, nitro, and optionally halogen-substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl and C 2-10 Alkynyl groups.
2. The method of claim 1, wherein: the reaction is carried out under the catalysis of acid, and the reaction temperature is 10-200 ℃.
3. The method of claim 1, wherein: the reaction is carried out in the presence of a solvent, a tri-dentate phosphorus compound and an azodicarboxylic acid ester at a temperature of 10 to 50 ℃, preferably at room temperature.
4. The method of claim 2, wherein: the acid is an organic acid and/or an inorganic acid, preferably sulfuric acid, phosphoric acid, hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, methanesulfonic acid and/or trifluoromethanesulfonic acid; the reaction is carried out in the absence of a solvent or in the presence of a solvent which is one or more of halogenated hydrocarbons, unsubstituted aromatic hydrocarbons, mono-or polyalkyl-substituted aromatic hydrocarbons, mono-or polyhalogenated aromatic hydrocarbons, nitriles, ethers, amide solvents, preferably benzene, toluene, o-xylene, p-xylene, m-xylene, mixed xylenes, chlorobenzene and/or dichlorobenzene.
5. A method as claimed in claim 3, wherein: the tri-coordination phosphorus compound is trialkylphosphine, tricycloalkylphosphine, triarylphosphine and/or trialkyl substituted arylphosphine, preferably tripropylphosphine, tributylphosphine, tricyclohexylphosphine, triphenylphosphine and/or tri-o-tolylphosphine, more preferably tricyclohexylphosphine or triphenylphosphine; the azodicarboxylic acid ester is dibenzyl azodicarboxylic acid ester and/or dialkyl azodicarboxylic acid ester, preferably dibenzyl azodicarboxylic acid ester, dimethyl azodicarboxylic acid ester, diethyl azodicarboxylic acid ester, dipropyl azodicarboxylic acid ester, diisopropyl azodicarboxylic acid ester, dibutyl azodicarboxylic acid ester and/or di-tert-butyl azodicarboxylic acid ester, more preferably dimethyl azodicarboxylic acid ester or diisopropyl azodicarboxylic acid ester; the solvent is one or more of halogenated alkane, unsubstituted aromatic hydrocarbon, mono-or poly-alkyl substituted aromatic hydrocarbon, mono-or poly-halogenated aromatic hydrocarbon, nitrile, ether, amide solvent, preferably tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1, 4-dioxane and/or toluene.
6. The method of any one of claims 1-5, wherein: r is R 1 -R 5 Independently selected from hydrogen, halogen, trifluoromethyl.
7. The method of any one of claims 1-6, wherein: r is R 1 -R 4 Is hydrogen, R 5 Halogen, preferably chlorine.
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