CN117903074A - Preparation method of 4, 5-dihydro-isoxazole-3-carboxylic acid compound - Google Patents
Preparation method of 4, 5-dihydro-isoxazole-3-carboxylic acid compound Download PDFInfo
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- CN117903074A CN117903074A CN202410054241.8A CN202410054241A CN117903074A CN 117903074 A CN117903074 A CN 117903074A CN 202410054241 A CN202410054241 A CN 202410054241A CN 117903074 A CN117903074 A CN 117903074A
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- acid
- optionally substituted
- compound
- alkyl
- formula
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- -1 4, 5-dihydro-isoxazole-3-carboxylic acid compound Chemical class 0.000 title abstract description 59
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 48
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 24
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 17
- 235000010288 sodium nitrite Nutrition 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- 239000011777 magnesium Substances 0.000 claims description 12
- 229910052749 magnesium Inorganic materials 0.000 claims description 12
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- ZIHQUWYJSTVYAT-UHFFFAOYSA-N [NH-][N+]([O-])=O Chemical compound [NH-][N+]([O-])=O ZIHQUWYJSTVYAT-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 239000012044 organic layer Substances 0.000 description 17
- 125000000217 alkyl group Chemical group 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- IWYBVQLPTCMVFO-UHFFFAOYSA-N ethyl 2,2-dichloroacetate Chemical compound CCOC(=O)C(Cl)Cl IWYBVQLPTCMVFO-UHFFFAOYSA-N 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- MWKVXOJATACCCH-UHFFFAOYSA-N isoxadifen-ethyl Chemical compound C1C(C(=O)OCC)=NOC1(C=1C=CC=CC=1)C1=CC=CC=C1 MWKVXOJATACCCH-UHFFFAOYSA-N 0.000 description 3
- HKMLRUAPIDAGIE-UHFFFAOYSA-N methyl 2,2-dichloroacetate Chemical compound COC(=O)C(Cl)Cl HKMLRUAPIDAGIE-UHFFFAOYSA-N 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 125000004781 2,2-dichloro-2-fluoroethyl group Chemical group [H]C([H])(*)C(F)(Cl)Cl 0.000 description 2
- ZYOLEJJQEKZBEU-UHFFFAOYSA-N 2-methyl-2-(4-methylphenyl)cyclopropane-1-carboxylic acid Chemical compound C1=CC(C)=CC=C1C1(C)C(C(O)=O)C1 ZYOLEJJQEKZBEU-UHFFFAOYSA-N 0.000 description 2
- ZYDBNGULYNHMSF-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole-3-carboxylic acid Chemical class OC(=O)C1=NOCC1 ZYDBNGULYNHMSF-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000006298 dechlorination reaction Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- HBYYFHBROCTZIF-UHFFFAOYSA-N ethyl 2,2-diphenylcyclopropane-1-carboxylate Chemical compound CCOC(=O)C1CC1(C=1C=CC=CC=1)C1=CC=CC=C1 HBYYFHBROCTZIF-UHFFFAOYSA-N 0.000 description 2
- SRGUIJLJERBBCM-UHFFFAOYSA-N ethyl 2-phenylcyclopropane-1-carboxylate Chemical compound CCOC(=O)C1CC1C1=CC=CC=C1 SRGUIJLJERBBCM-UHFFFAOYSA-N 0.000 description 2
- YNZGZAJXHXGDBF-UHFFFAOYSA-N ethyl 5-phenyl-4,5-dihydro-1,2-oxazole-3-carboxylate Chemical compound C1C(C(=O)OCC)=NOC1C1=CC=CC=C1 YNZGZAJXHXGDBF-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 2
- 235000021286 stilbenes Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- UXAWXZDXVOYLII-UHFFFAOYSA-N tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1NC2 UXAWXZDXVOYLII-UHFFFAOYSA-N 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- UXYRXGFUANQKTA-UHFFFAOYSA-N 1,2-oxazole-3-carboxylic acid Chemical compound OC(=O)C=1C=CON=1 UXYRXGFUANQKTA-UHFFFAOYSA-N 0.000 description 1
- 125000006083 1-bromoethyl group Chemical group 0.000 description 1
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- 125000004780 2-chloro-2,2-difluoroethyl group Chemical group [H]C([H])(*)C(F)(F)Cl 0.000 description 1
- 125000004779 2-chloro-2-fluoroethyl group Chemical group [H]C([H])(*)C([H])(F)Cl 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical class C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000000392 cycloalkenyl 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
- 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
- 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
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- CWJRNKXXSWYYTJ-UHFFFAOYSA-N ethyl 1,3-benzoxazole-2-carboxylate Chemical compound C1=CC=C2OC(C(=O)OCC)=NC2=C1 CWJRNKXXSWYYTJ-UHFFFAOYSA-N 0.000 description 1
- UXOLDCOJRAMLTQ-UHFFFAOYSA-N ethyl 2-chloro-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(Cl)=NO UXOLDCOJRAMLTQ-UHFFFAOYSA-N 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 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
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([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
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MMSLOZQEMPDGPI-UHFFFAOYSA-N p-Mentha-1,3,5,8-tetraene Chemical compound CC(=C)C1=CC=C(C)C=C1 MMSLOZQEMPDGPI-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical group O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- JBTISLVNJCYZCH-UHFFFAOYSA-N propan-2-yl 2,2-dichloroacetate Chemical compound CC(C)OC(=O)C(Cl)Cl JBTISLVNJCYZCH-UHFFFAOYSA-N 0.000 description 1
- 238000007342 radical addition reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical group O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method 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
- 238000012546 transfer Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a preparation method of a 4, 5-dihydro-isoxazole-3-carboxylic acid compound, which comprises the following synthetic route: Wherein R 1、R2, X and n are defined as in the specification.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a4, 5-dihydro-isoxazole-3-carboxylic acid compound.
Background
The 4, 5-dihydro-isoxazole compounds are compounds with good biological activity and potential medicinal value, wherein 4, 5-dihydro-isoxazole-3-carboxylic acid compounds such as 5-phenyl-4, 5-dihydro-isoxazole-3-carboxylic acid ethyl ester (ethyl monobenzoate) and 5, 5-diphenyl-4, 5-dihydro-isoxazole-3-carboxylic acid ethyl ester (ethyl bisbenzoate) can be used as herbicide safeners. The existing method for synthesizing ethyl bisbenzoxazolate and ethyl monobenzoxazolate has the problems of longer route or lower yield or using more expensive raw materials, such as the synthetic route of ethyl bisbenzoxazolate provided by patent CN108440435A (shown below), and the yield of the cyclization step of the ethyl bisbenzoxazolate and the ethyl chloroximinoacetate is only about 34 percent (example 1)
Literature (KatrinThommes,OlefinCyclopropanationsviaSequentialAtomTransferRadical Addition-DechlorinationReactions,Chimia.2010;64(3):188-190) reports a synthetic method of ethyl monobenzoate intermediate (shown below), which is to obtain 1-phenyl-2-carboxylic acid ethyl ester cyclopropane through two steps of reactions, wherein the first step is Ru-catalyzed atom transfer radical addition, and the second step is dechlorination.
The route uses a relatively expensive ruthenium catalyst, and increases the preparation cost of the compound.
Disclosure of Invention
Aiming at the defects of low yield, high price of metal catalyst and the like existing in the prior art for preparing 4, 5-dihydro-isoxazole-3-carboxylic acid compounds, the invention provides a method with simple preparation method, high yield and low production cost.
Specifically, the invention provides a preparation method of a compound of formula I, which comprises the following steps:
Step one, reacting a compound of formula III with dichloroacetic acid or ester thereof and magnesium metal in the presence of DMF and/or DMAC to prepare a compound of formula II;
step two, preparing a compound of the formula I from the compound of the formula II in the presence of acid and sodium nitrite,
The synthetic route is as follows:
wherein,
X is selected from optionally substituted alkyl, optionally substituted alkoxy, cyano, ester, nitro, amide, halogen, haloalkyl;
R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy-alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted aryl;
R 2 is selected from hydrogen, optionally substituted alkyl;
n is selected from natural numbers from 0 to 5, particularly preferably 0, 1,2 and 3.
The beneficial effects of the invention are that
1. In the synthetic route of the invention, the stilbene reacts with ethyl dichloroacetate to generate the three-membered ring derivative, and then reacts with sodium nitrite to generate the isoxazole ring, the yield of the two steps can reach 96%, and the yield is greatly improved.
2. The invention adopts a completely different reaction route from the prior art, and carries out the reaction by different reaction mechanisms, does not need expensive catalyst, has easily obtained raw materials and mild reaction conditions, and is more suitable for industrial production.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. In addition, numerous specific details are set forth in the following description in order to provide a better illustration of the invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details. In some embodiments, raw materials, auxiliary materials, methods, means, etc. well known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.
Throughout the specification and claims, unless explicitly stated otherwise, the term "comprise" or variations thereof such as "comprises" or "comprising" and the like will be understood to include the stated active ingredient without excluding other active ingredients that may be present.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
The term "halogen" in the present invention refers to fluorine, chlorine, bromine and iodine.
The term "alkyl" (and in the case of other groups comprising alkyl groups, such as alkyl moieties of alkoxy groups, alkyl moieties of arylalkyl groups) in the present invention denotes in each case straight-chain or branched alkyl groups having generally from 1 to 20 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, in particular from 1 to 3 carbon atoms. Examples of C 1-C4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1-dimethylethyl (tert-butyl). Examples of C 1-C6 alkyl are, in addition to the radicals mentioned for C1-C4 alkyl, also n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2-dimethylpropyl, 1-ethylpropyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2-trimethylpropyl, 1, 2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl. Examples of the C 1-C10 alkyl group include, but are not limited to, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 1-ethylhexyl, 2-ethylhexyl, 1, 2-dimethylhexyl, 1-propylpentyl, 2-propylpentyl, nonyl, decyl, 2-propylheptyl and 3-propylheptyl groups in addition to the groups mentioned for the C 1-C6 alkyl group. The term "alkoxy" according to the invention refers to an-OR group, wherein R is an alkyl group as defined above, a straight-chain OR branched alkyl group, often of 1 to 6 carbon atoms, preferably of 1 to 4 carbon atoms, especially of 1 to 3 carbon atoms. For example, but not limited to, methoxy, ethoxy, propoxy, or 2-propoxy, n-butoxy, isobutoxy, or t-butoxy.
The term "amide group" in the present invention means a group containing "-NHCO-" or "-CONHCO-" in the group, for example, but not limited to ,-NHCOCH3、-NHCOH、-NHCOCH2CH3、-NHCOCH2CH2CH3、-NHCOCH(CH3)2、-N(COCH3)2、-CONH2、-CON(CH3)2、-CONHCH3、-CONHCH2CH3、-CON(CH2CH3)2、-CONHCH(CH3)2、-CONHCH2CH2CH3、-CONHCH2CH2CH2CH3、 phthalimide group, succinimide group, glutarimide group, maleimide group, etc.
The term "ester group" in the present invention means that the group contains "-COO-" such as, but not limited to ,-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2CH3、-COOCH2CH2CH2CH3,.
The term "haloalkyl" according to the invention denotes partially or fully halogenated alkyl groups, which have the meaning given above for alkyl groups, wherein the halogen atom is in particular fluorine, chlorine and/or bromine, i.e. for example chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-difluoroethyl, 2-chloro-2-fluoroethyl, 2, 2-trifluoroethyl group, 2-chloro-1, 2-trifluoroethyl group, 2-chloro-2, 2-difluoroethyl group, 2-bromo-2, 2-difluoroethyl group, 2, 2-dichloro-2-fluoroethyl group, 2-trichloroethyl group, 1, 2-tetrafluoroethyl group, 1, 2-tetrachloroethyl group, pentafluoroethyl group, 2, 2-dichloro-2-fluoroethyl group, 2-trichloroethyl group, 1, 2-tetrafluoroethyl, 1, 2-tetrachloroethyl, pentafluoroethyl.
The term "cycloalkyl" according to the invention refers to a monocyclic monovalent hydrocarbon group of three to eight carbon atoms, which may be saturated or contain one double bond. Cycloalkyl groups may be unsubstituted or substituted with one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxy, or cyano, but are not limited thereto. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocyclopropyl-1-yl, 1-cyanomethylcyclopropan-1-yl, 3-fluorocyclohexyl and the like. When cycloalkyl contains a double bond, it may be referred to herein as cycloalkenyl.
The term "heterocycle" according to the present invention refers to a saturated or partially unsaturated carbocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Preferred examples are aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, tetrahydrofuran, dioxane, 2, 5-diazabicyclo [2, 1] heptane and 3, 7-diazabicyclo [3, 0] octane, and further preferred are aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2, 5-diazabicyclo [2, 1] heptane and 3, 7-diazabicyclo [3, 0] octane.
"Aryl" in the present invention means a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, such as phenyl or naphthyl, especially phenyl, but is not limited thereto.
The term "optionally substituted" means that the relevant group may or may not be substituted with a substituent. Where the groups are said to be optionally substituted, there are preferably from 1 to 5 substituents, more preferably from 1 to 3 substituents, still more preferably 1 or 2 substituents. Where a group is said to be optionally substituted, and where more than one substituent is present for said optional substitution of the group, the more than one substituents may be the same or different. The substituent may be an alkyl group, a halogen group, a cyano group, a nitro group, an aryl group, a cycloalkyl group, a heterocyclic group, an amide group, an ester group, or the like, but is not limited thereto.
The invention provides a preparation method of a compound shown in a formula (I), which comprises the following steps:
Step one, reacting a compound of formula III with dichloroacetic acid or ester thereof and magnesium metal in the presence of DMF and/or DMAC to prepare a compound of formula II;
step two, preparing a compound of the formula I from the compound of the formula II in the presence of acid and sodium nitrite,
The synthetic route is as follows:
wherein,
X is selected from one of optionally substituted alkyl, optionally substituted alkoxy, cyano, ester, nitro, amide, halogen and haloalkyl; preferably optionally substituted C 1-C6 alkyl, optionally substituted C 1-C6 alkoxy, cyano, ester, nitro, amide, fluoro and fluoro C 1-C6 alkyl; particularly preferred is one of -CH3、-C2H5、-C3H7、-C4H9、-C5H11、-C6H13、-OCH3、-OC2H5、-OC3H7、-OC4H9、-OC5H11、-OC6H13、-CN、-COO(CH3)、-COO(C2H5)、-COO(C3H7)、-COO(C4H9)、-COO(C5H11)、-COO(C6H13)、-NO2、-CO(NH2)、-F、-CF3、-CHF2 and CH 2 F;
r 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy-alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted aryl; preferably hydrogen, optionally substituted C 1-C6 alkyl, optionally substituted C 1-C6 alkoxy-C 1-C6 alkyl, optionally substituted C 3-C8 cycloalkyl, optionally substituted heterocyclyl, Particularly preferred are -H、-CH3、-C2H5、-C3H7、-C4H9、-C5H11、-C6H13、-CH2OCH3、-CH2OC2H5、-CH2OC3H7、-CH2OC4H9、-CH2CH2OCH3、-CH2CH2OC2H5、-CH2CH2OC3H7、-CH2CH2OC4H9、-C3H6OCH3、-C3H6OC2H5、-C3H6OC3H7、-C4H8OCH3、-C4H8OC2H5、-C5H10OCH3、In one of the above-mentioned steps,
R 2 is selected from hydrogen, optionally substituted alkyl; preferably one of hydrogen, methyl and ethyl;
n is selected from natural numbers from 0 to 5, particularly preferably 0, 1,2 and 3.
Preferably, in the preparation method, the first step comprises adding a compound of formula III, magnesium metal, dichloroacetic acid or an ester thereof, DMF and/or DMAC into a solvent, and reacting at-10-100 ℃ for 1-8h.
More preferably, in the first step, one of the compound of formula III, magnesium metal, dichloroacetic acid or an ester thereof, DMF and/or DMAC is added in portions or drops to the reaction system, so that the reaction can be prevented from being too fast.
Preferably, in step one, the molar ratio of magnesium, the compound of formula III and dichloroacetic acid or its esters is from 1 to 5:1:1 to 3, and DMF and/or DMAC is added in an amount of from 1 to 100 equivalents of the compound of formula III. The solvent in the first step can be one or more of DMF, DMAC, diethyl ether, tetrahydrofuran, acetonitrile, DMSO, toluene, isopropyl ether, 1, 4-dioxane and methyl tertiary butyl ether; when the solvent in the first step is DMF and/or DMAC, magnesium, the compound of formula III and dichloroacetic acid or ester thereof are respectively added into a solvent system of DMF and/or DMAC for reaction. Preferably, after the reaction in the first step is finished, pouring the mixture into acid water for quenching, and taking an organic layer or taking the organic layer after extraction by toluene to remove a solvent to obtain the compound of the formula II.
In the second step of the preparation method, a proper amount of solvent is taken, the compound of the formula II, acid and sodium nitrite are added, and the reaction is carried out for 1 to 8 hours at the temperature of 0 to 100 ℃ to obtain the compound of the formula I after the reaction is finished. Wherein the solvent is one or more of ethyl acetate, acetone, acetic acid, petroleum ether, acetonitrile, cyclohexane, tetrahydrofuran, 1, 4-dioxane, diethyl ether, isopropyl ether, methyl tertiary butyl ether and toluene, and the acid is inorganic acid or organic acid, and the inorganic acid is preferably one of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; the organic acid is preferably one or more of formic acid, acetic acid, oxalic acid, methanesulfonic acid and trifluoroacetic acid.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; the reagents, materials, etc. used in the examples described below are commercially available unless otherwise specified.
EXAMPLE 1 Synthesis of 5-phenyl-4, 5-dihydroisoxazole-3-carboxylic acid ethyl ester
50Ml of diethyl ether was taken, 2.08g of styrene, 1.2g of magnesium and 3.14g of ethyl dichloroacetate were added, 2.5gDMF g of ethyl dichloroacetate were added dropwise at 25 ℃ and reacted for 1 hour, after the reaction was completed, the mixture was poured into aqueous hydrochloric acid solution to quench, and the organic layer was taken and concentrated to remove the solvent to obtain 3.74g of ethyl 2-phenylcyclopropanecarboxylate.
50Ml of ethyl acetate was taken, 3.74g of ethyl 2-phenylcyclopropanecarboxylate, 0.39g of concentrated hydrochloric acid and 1.52g of sodium nitrite were added to react for 3 hours at 5 ℃, water was added after the reaction was completed, and the ethyl acetate layer was taken to concentrate and remove the solvent to obtain 4.24g of ethyl 5-phenyl-4, 5-dihydroisoxazole-3-carboxylate, the total yield was 96.7%, and the purity was 99.8%.
1HNMR(300MHz,CDCl3)δ7.27-7.43(m,5H),δ5.77-5.83(t,1H),δ4.34-4.41(q,2H),δ3.60-3.71(q,1H),δ3.19-3.28(q,1H),δ1.37-1.42(t,3H)
EXAMPLE 2 Synthesis of 5-methyl-5-p-toluene-4, 5-dihydroisoxazole-3-carboxylic acid
50Ml of DMF was taken, 2.64g of 1-isopropenyl-4-methylbenzene and 2.58g of dichloroacetic acid were added, 1.5g of magnesium was added in portions, the mixture was reacted at 80℃for 1 hour, after the reaction was completed, the mixture was cooled to room temperature and poured into aqueous hydrochloric acid for quenching, and after toluene extraction, an organic layer was taken and the solvent was concentrated and removed to obtain 3.73g of 2-methyl-2-p-tolylcyclopropane carboxylic acid.
50Ml of acetic acid is taken, 3.73g of 2-methyl-2-p-tolylcyclopropane carboxylic acid, 0.42g of sulfuric acid and 1.38g of sodium nitrite are added for reaction for 2 hours at 40 ℃, water is added after the reaction is finished, an organic layer is taken after toluene extraction, and the solvent is removed by concentration to obtain 4.22g of 5-methyl-5-p-toluene-4, 5-dihydro-isoxazole-3-carboxylic acid, the total yield is 96.2%, and the purity is 99.4%.
EXAMPLE 3 Synthesis of 5- (3, 5-dimethoxy-phenyl) -5-methoxymethyl-4, 5-dihydroisoxazole-3-carboxylic acid methyl ester
250Ml of acetonitrile was added, followed by addition of 16.68g of 1, 3-dimethoxy-5- (1-methoxymethyl-vinyl) -benzene, 4.0g of magnesium and 10.6 gDMAC. Mu.l of a solution of methyl dichloroacetate in acetonitrile (containing 11.44g of methyl dichloroacetate) at 50℃were added dropwise, the mixture was allowed to react for 2 hours, cooled to room temperature, poured into an aqueous sulfuric acid solution and quenched, and after extraction with toluene, the organic layer was concentrated to remove the solvent to obtain 22.08g of methyl 2- (3, 5-dimethoxy-phenyl) -2-methoxymethyl-cyclopropanecarboxylate.
80Ml of tetrahydrofuran, 5.52g of methyl 2- (3, 5-dimethoxy-phenyl) -2-methoxymethyl-cyclopropanecarboxylate, 0.38g of nitric acid and 2.07g of sodium nitrite are taken and reacted for 1.5 hours at 50 ℃, water is added after the reaction, and after toluene extraction, an organic layer is taken and concentrated to remove a solvent to obtain 5.93g of methyl 5- (3, 5-dimethoxy-phenyl) -5-methoxymethyl-4, 5-dihydro-isoxazole-3-carboxylate, wherein the total yield is 95.9 percent and the purity is 99.3 percent.
EXAMPLE 4 Synthesis of 5- (3, 5-dimethoxy-phenyl) -5-methoxymethyl-4, 5-dihydroisoxazole-3-carboxylic acid methyl ester
80Ml of tetrahydrofuran, 5.52g of methyl 2- (3, 5-dimethoxy-phenyl) -2-methoxymethyl-cyclopropanecarboxylate (sample synthesized in example 3), 0.36g of acetic acid and 2.07g of sodium nitrite were taken and reacted at 50℃for 1.5 hours, water was added after the reaction was completed, and after extraction of toluene, an organic layer was taken and concentrated to remove the solvent to obtain 5.36g of methyl 5- (3, 5-dimethoxy-phenyl) -5-methoxymethyl-4, 5-dihydroisoxazole-3-carboxylate, the total synthesis yield was 86.6% and the purity was 98.1%.
EXAMPLE 5 Synthesis of 5- (3, 5-dimethoxy-phenyl) -5-methoxymethyl-4, 5-dihydroisoxazole-3-carboxylic acid methyl ester
80Ml of tetrahydrofuran, 5.52g of methyl 2- (3, 5-dimethoxy-phenyl) -2-methoxymethyl-cyclopropanecarboxylate (sample synthesized in example 3), 0.36g of acetic acid and 2.07g of sodium nitrite are taken and reacted at 50 ℃ for 6 hours, water is added after the reaction, an organic layer is taken after toluene extraction and concentrated to remove a solvent to obtain 5.88g of methyl 5- (3, 5-dimethoxy-phenyl) -5-methoxymethyl-4, 5-dihydro-isoxazole-3-carboxylate, the total synthesis yield is 95.1 percent, and the purity is 99.1 percent.
EXAMPLE 6 Synthesis of 5-cyclohexyl-5- (3, 4, 5-trimethyl-phenyl) -4, 5-dihydroisoxazole-3-carboxylic acid isopropyl ester
100Ml of toluene was taken, 4.57g of 5- (1-cyclohexyl-vinyl) -1,2, 3-trimethylbenzene, 3.42g of isopropyl dichloroacetate and 17.4gDMAC g of magnesium were added in portions at 5℃and after 3 hours of reaction, 2.2g of magnesium was added and quenched by pouring into an aqueous sulfuric acid solution, and the organic layer was concentrated to remove the solvent to give 6.37g of isopropyl 2-cyclohexyl-2- (3, 4, 5-trimethyl-phenyl) -cyclopropanecarboxylate.
80Ml of acetonitrile was taken, 6.37g of isopropyl 2-cyclohexyl-2- (3, 4, 5-trimethyl-phenyl) -cyclopropanecarboxylate, 0.92g of formic acid, 1.38g of sodium nitrite were added for reaction at 70 ℃ for 1 hour, water was added after the reaction was completed, and after toluene extraction, the organic layer was taken and concentrated to remove the solvent to obtain 6.38g of isopropyl 5-cyclohexyl-5- (3, 4, 5-trimethyl-phenyl) -4, 5-dihydro-isoxazole-3-carboxylate, which was 89.2% in total yield and 98.3% in purity.
EXAMPLE 7 Synthesis of 5, 5-diphenyl-4, 5-dihydroisoxazole-3-carboxylic acid ethyl ester
80Ml of DMF was taken, 3.60g of stilbene and 3.14g of ethyl dichloroacetate were added, 0.98g of magnesium was added in portions at 60℃and after 2h of reaction, the mixture was cooled to room temperature and poured into aqueous hydrochloric acid for quenching, after extraction with toluene the organic layer was taken and concentrated to remove 5.22g of ethyl 2, 2-diphenyl-cyclopropanecarboxylate as solvent.
80Ml of acetone is taken, 5.22g of ethyl 2, 2-diphenyl-cyclopropanecarboxylate, 0.68g of trifluoroacetic acid and 1.8g of sodium nitrite are added for reaction for 3 hours at 25 ℃, water is added after the reaction is finished, an organic layer is taken after toluene extraction, and the solvent is removed by concentration to obtain 5.70g of ethyl 5, 5-diphenyl-4, 5-dihydro-isoxazole-3-carboxylate, the total yield is 96.5 percent, and the purity is 99.5 percent.
1HNMR(300MHz,DMSO)δ7.26-7.44(m,10H),δ4.19-4.26(q,2H),δ3.60-3.71(q,1H),δ3.90(s,2H),δ1.21-1.26(t,3H)
EXAMPLE 8 Synthesis of 5- (2-cyano-4-fluoro-5-nitro-phenyl) -5-pyridin-3-yl-4, 5-dihydroisoxazole-3-carboxylic acid methyl ester
400Ml of tetrahydrofuran are taken, 21.52g of 5-fluoro-4-nitro-2- (1-pyridin-3-yl-vinyl) -benzonitrile, 11.44g of methyl dichloroacetate and 29.2gDMF g of magnesium are added in portions at 50℃and after 2h of reaction, cooled to room temperature and quenched in aqueous hydrochloric acid, the organic layer is extracted with toluene and concentrated to remove 25.92g of methyl 2- (2-cyano-4-fluoro-5-nitro-phenyl) -2-pyridin-3-ylcyclopropane carboxylate as solvent.
100Ml of diethyl ether, 6.48g of methyl 2- (2-cyano-4-fluoro-5-nitro-phenyl) -2-pyridin-3-yl cyclopropane carboxylate, 1.17g of phosphoric acid, 1.93g of sodium nitrite and the reaction at 30 ℃ for 1 hour are taken, water is added after the reaction is finished, and an organic layer is taken and concentrated to obtain 6.68g of methyl 5- (2-cyano-4-fluoro-5-nitro-phenyl) -5-pyridin-3-yl-4, 5-dihydro isoxazole-3-carboxylate, wherein the total yield is 90.2 percent and the purity is 98.9 percent.
EXAMPLE 9 Synthesis of 5- (2-cyano-4-fluoro-5-nitro-phenyl) -5-pyridin-3-yl-4, 5-dihydroisoxazole-3-carboxylic acid methyl ester
100Ml of diethyl ether, 6.48g of methyl 2- (2-cyano-4-fluoro-5-nitro-phenyl) -2-pyridin-3-yl cyclopropane carboxylate (a synthetic sample of example 8), 1.08g of oxalic acid, 1.93g of sodium nitrite are taken and reacted for 1 hour at 30 ℃, water is added after the reaction is finished, and an organic layer is taken and concentrated to obtain 6.03g of methyl 5- (2-cyano-4-fluoro-5-nitro-phenyl) -5-pyridin-3-yl-4, 5-dihydro-isoxazole-3-carboxylate, wherein the total synthetic yield is 81.4% and the purity is 97.4%.
EXAMPLE 10 Synthesis of 5- (2-cyano-4-fluoro-5-nitro-phenyl) -5-pyridin-3-yl-4, 5-dihydroisoxazole-3-carboxylic acid methyl ester
100Ml of diethyl ether, 6.48g of methyl 2- (2-cyano-4-fluoro-5-nitro-phenyl) -2-pyridin-3-yl cyclopropane carboxylate (a synthetic sample of example 8), 1.08g of oxalic acid, 1.93g of sodium nitrite are taken and reacted for 7 hours at 30 ℃, water is added after the reaction is finished, and an organic layer is taken and concentrated to obtain 6.64g of methyl 5- (2-cyano-4-fluoro-5-nitro-phenyl) -5-pyridin-3-yl-4, 5-dihydro-isoxazole-3-carboxylate, wherein the total synthetic yield is 89.7 percent and the purity is 98.7 percent.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; those of ordinary skill in the art will appreciate that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (9)
1. A process for the preparation of a compound of formula I comprising the steps of:
Step one, reacting a compound of formula III with dichloroacetic acid or ester thereof and magnesium metal in the presence of DMF and/or DMAC to prepare a compound of formula II;
step two, preparing a compound of the formula I from the compound of the formula II in the presence of acid and sodium nitrite,
The synthetic route is as follows:
wherein,
X is selected from one of optionally substituted alkyl, optionally substituted alkoxy, cyano, ester, nitro, amide, halogen and haloalkyl;
R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy-alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted aryl;
R 2 is selected from hydrogen, optionally substituted alkyl;
n is selected from natural numbers from 0 to 5.
2. The method according to claim 1, wherein,
X is selected from one of optionally substituted C 1-C6 alkyl, optionally substituted C 1-C6 alkoxy, cyano, ester, nitro, amide, fluoro and fluoro C 1-C6 alkyl;
R 1 is selected from the group consisting of hydrogen, optionally substituted C 1-C6 alkyl, optionally substituted C 1-C6 alkoxy-C 1-C6 alkyl, optionally substituted C 3-C8 cycloalkyl, optionally substituted heterocyclyl,
R 2 is selected from one of hydrogen, methyl and ethyl.
3. The preparation method according to claim 1 or 2, wherein X is selected from one of -CH3、-C2H5、-C3H7、-C4H9、-C5H11、-C6H13、-OCH3、-OC2H5、-OC3H7、-OC4H9、-OC5H11、-OC6H13、-CN、-COO(CH3)、-COO(C2H5)、-COO(C3H7)、-COO(C4H9)、-COO(C5H11)、-COO(C6H13)、-NO2、-CO(NH2)、-F、-CF3、-CHF2 and CH 2 F;
r 1 is selected from -H、-CH3、-C2H5、-C3H7、-C4H9、-C5H11、-C6H13、-CH2OCH3、-CH2OC2H5、-CH2OC3H7、-CH2OC4H9、-CH2CH2OCH3、-CH2CH2O C2H5、-CH2CH2O C3H7、-CH2CH2OC4H9、-C3H6OCH3、-C3H6O C2H5、-C3H6O C3H7、-C4H8OCH3、-C4H8O C2H5、-C5H10O CH3、 One of them;
n is selected from 0, 1,2 and 3.
4. The process according to claim 1, wherein step one comprises adding a compound of formula iii, magnesium, dichloroacetic acid or an ester thereof, DMF and/or DMAC to a solvent and reacting at-10-100 ℃.
5. The process according to claim 1 or 4, wherein in the first step, one of the compound of formula III, magnesium, dichloroacetic acid or an ester thereof, DMF and/or DMAC is added in portions or added dropwise to the reaction system.
6. The process according to claim 5, wherein in the step one, the molar ratio of magnesium, the compound of formula III and dichloroacetic acid or an ester thereof is 1 to 5:1:1 to 3, and DMF and/or DMAC is added in an amount of 1 to 100 equivalents of the compound of formula III.
7. The process according to claim 6, wherein the solvent in the first step is one or more of DMF, DMAC, diethyl ether, tetrahydrofuran, acetonitrile, DMSO, toluene, isopropyl ether, 1, 4-dioxane, and methyl tert-butyl ether.
8. The process according to any one of claims 1 to 7, wherein in step two, the compound of formula i is prepared by adding the compound of formula ii, an acid and sodium nitrite in a suitable amount of solvent and reacting at 0 to 100 ℃.
9. The preparation method according to claim 8, wherein the solvent in the second step is one or more of ethyl acetate, acetone, acetic acid, petroleum ether, acetonitrile, cyclohexane, tetrahydrofuran, 1, 4-dioxane, diethyl ether, isopropyl ether, methyl tertiary butyl ether and toluene; the acid in the second step is an inorganic acid or an organic acid, the inorganic acid is preferably one or more of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and the organic acid is preferably one or more of formic acid, acetic acid, oxalic acid, methanesulfonic acid and trifluoroacetic acid.
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