CN112358454A - Preparation method of 4, 5-dihydroisoxazole derivative - Google Patents
Preparation method of 4, 5-dihydroisoxazole derivative Download PDFInfo
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- CN112358454A CN112358454A CN202011060808.0A CN202011060808A CN112358454A CN 112358454 A CN112358454 A CN 112358454A CN 202011060808 A CN202011060808 A CN 202011060808A CN 112358454 A CN112358454 A CN 112358454A
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- hydroxylamine
- phase transfer
- transfer catalyst
- chloride
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical class C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 title claims abstract description 16
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 84
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 29
- 125000003118 aryl group Chemical group 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 15
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 8
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- NXPHCVPFHOVZBC-UHFFFAOYSA-N hydroxylamine;sulfuric acid Chemical compound ON.OS(O)(=O)=O NXPHCVPFHOVZBC-UHFFFAOYSA-N 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 84
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 56
- 239000000203 mixture Substances 0.000 claims description 34
- 239000003960 organic solvent Substances 0.000 claims description 33
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 229910001868 water Inorganic materials 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 claims description 14
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 claims description 14
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 claims description 4
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 4
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 230000036632 reaction speed Effects 0.000 abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 31
- 238000004128 high performance liquid chromatography Methods 0.000 description 29
- -1 p-trifluoromethylphenyl Chemical group 0.000 description 25
- 239000007787 solid Substances 0.000 description 23
- 230000003595 spectral effect Effects 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 14
- 239000007795 chemical reaction product Substances 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 235000005513 chalcones Nutrition 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000007341 Heck reaction Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- CRCTZWNJRMZUIO-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropane Chemical group FC(F)(F)[CH]C(F)(F)F CRCTZWNJRMZUIO-UHFFFAOYSA-N 0.000 description 2
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- DENKGPBHLYFNGK-UHFFFAOYSA-N 4-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Br)C=C1 DENKGPBHLYFNGK-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- 238000005481 NMR spectroscopy Methods 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
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000003106 haloaryl group Chemical group 0.000 description 2
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 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
- 239000000126 substance Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006019 1-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- SEPQTYODOKLVSB-UHFFFAOYSA-N 3-methylbut-2-enal Chemical compound CC(C)=CC=O SEPQTYODOKLVSB-UHFFFAOYSA-N 0.000 description 1
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 1
- DIYSFZUJSGOINT-UHFFFAOYSA-N 5,5-dimethyl-4h-1,2-oxazole Chemical compound CC1(C)CC=NO1 DIYSFZUJSGOINT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 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
- 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
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 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 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application discloses a preparation method of a 4, 5-dihydroisoxazole derivative. Namely, formula (II)
A preparation method of the 4, 5-dihydroisoxazole derivative comprises the following steps: reacting hydroxylamine hydrochloride or hydroxylamine sulphate with a compound shown in a formula (I) in the presence of inorganic base and a phase transfer catalyst,
Description
Technical Field
The embodiment of the application relates to a preparation method of a 4, 5-dihydroisoxazole derivative, belonging to the field of medicine or pesticide preparation.
Background
Many active natural products contain isoxazoline or oxazoline which is an unsaturated analogue thereof, and compounds containing a dihydro isoxazoline structural unit (such as 4, 5-dihydro isoxazole derivatives) often have a plurality of pharmaceutical activities such as anti-inflammation, anti-fungus and anti-bacteria, and the existing preparation process often needs high-temperature and high-pressure conditions and has higher preparation cost, so that the development of a preparation method of the compounds (such as the 4, 5-dihydro isoxazole derivatives) with mild conditions, high reaction speed and low cost has important practical significance.
Disclosure of Invention
The embodiment of the application provides a preparation method of a 4, 5-dihydroisoxazole derivative, and the method has the advantages of high reaction speed, mild reaction conditions, simple reaction and low cost.
At least one embodiment of the present application provides a composition of formula (II)
A preparation method of the 4, 5-dihydroisoxazole derivative comprises the following steps: reacting hydroxylamine hydrochloride or hydroxylamine sulphate with a compound shown in a formula (I) in the presence of inorganic base and a phase transfer catalyst,
wherein R1 is aryl, substituted aryl or hydrogen atom, R2 is C1-C6 alkyl, C1-C6 substituted alkyl, aryl or substituted aryl, R3 is C1-C6 alkyl, C1-C6 substituted alkyl, aryl or substituted aryl.
According to a preferred embodiment, the reaction of hydroxylamine hydrochloride or hydroxylamine sulfate with the compound of formula (I) in the presence of an inorganic base and a phase transfer catalyst comprises:
in the presence of water, inorganic base is contacted with hydroxylamine hydrochloride or hydroxylamine sulfate to obtain hydroxylamine;
adding a phase transfer catalyst, an organic solvent and the compound shown in the formula (I) and mixing.
According to a preferred embodiment, the inorganic base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
According to a preferred embodiment, the phase transfer catalyst is at least one of tetrabutylammonium bromide, benzyltriethylammonium chloride, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, PEG200 and PEG 400. Further preferably, the phase transfer catalyst is a mixture of benzyltriethylammonium chloride and dodecyltrimethylammonium chloride, and still further preferably, the molar ratio of benzyltriethylammonium chloride to dodecyltrimethylammonium chloride is (3-6): 1.
according to a preferred embodiment, the organic solvent is at least one of pentane, hexane, cyclohexane, tetrahydrofuran and toluene. Further preferably, the organic solvent is a mixture of tetrahydrofuran and toluene, and still further preferably, the mass ratio of tetrahydrofuran to toluene is 1: (2-5).
According to a preferred embodiment, the mass ratio of water to organic solvent is 1: (2-15), more preferably 1: (5-10).
According to a preferred embodiment, the reaction conditions include: the temperature is 0-65 ℃.
According to a preferred embodiment, the molar ratio of hydroxylamine, phase transfer catalyst, compound of formula (I) is 1: (0.01-0.05): (0.9-1).
According to the preparation method of the 4, 5-dihydroisoxazole derivative provided by the embodiment of the application, the hydroxylamine hydrochloride or hydroxylamine sulfate with low price is used as a raw material, so that the preparation cost is low; the reaction speed is high, the reaction condition is mild, the high-temperature and high-pressure condition is not needed, and the requirement on equipment is low; and the reaction is simple, extensive and strong in tolerance, and is suitable for large-scale production.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
At least one embodiment of the present application provides a composition of formula (II)
A preparation method of the 4, 5-dihydroisoxazole derivative comprises the following steps: reacting hydroxylamine hydrochloride or hydroxylamine sulphate with a compound shown in a formula (I) in the presence of inorganic base and a phase transfer catalyst,
wherein R1 is aryl, substituted aryl or hydrogen atom, R2 and R3 are respectively and independently C1-C6 alkyl, C1-C6 substituted alkyl, aryl or substituted aryl.
In the present application, it should be understood by those skilled in the art that the 4, 5-dihydroisoxazole derivative is a substance obtained by correspondingly substituting groups of 4, 5-dihydroisoxazole at positions R1, R2 and R3.
In the present application, substituted aryl and substituted alkyl may be understood as aryl containing a substituent group and alkyl containing a substituent group, respectively, and the aforementioned substituent groups may include: halogen atom, nitro group, cyano group, hydroxyl group, amino group, (C1-C6) alkyl group, (C1-C6) haloalkyl group, (C3-C6) cycloalkyl group, (C2-C6) alkenyl group, (C2-C6) alkynyl group, (C1-C6) alkoxy group, phenyl group, phenoxy group and the like. For example, the substituted aryl group may be a halogenated aryl group or a heteroaryl group, and the substituted alkyl group may be a halogenated alkyl group or a heteroalkyl group.
In the present application, in R1, the substituted aryl group may be a halogenated aryl group, and the halogenated aryl group may be a fluorinated aryl group, a chlorinated aryl group, a brominated aryl group, or an iodoaryl group.
In the present application, specifically, R1 may be at least one of phenyl, p-trifluoromethylphenyl, p-bromophenyl, and hydrogen.
In the application, R2 and R3 can be respectively and independently C1-C6 alkyl, C1-C6 haloalkyl, aryl or haloaryl, and preferably, R2 and R3 can be respectively and independently C1-C4 alkyl, C1-C4 substituted alkyl (such as C1-C4 haloalkyl), aryl or substituted aryl (haloaryl).
Wherein, the alkyl group of C1-C6 refers to a straight or branched chain alkyl group having 1-6 carbon atoms, including but not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
C1-C4 alkyl refers to straight or branched chain alkyl groups having 1-4 carbon atoms, including but not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl and the like.
The haloalkyl group having C1 to C6 means a straight-chain or branched alkyl group having 1 to 6 carbon atoms which is substituted with the same or different 1 to 13 halogen atoms which may be a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like. For example, the halogen atom is fluorine atom, and the C1-C6 haloalkyl group includes but is not limited to: fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2, 2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3, 3-pentafluoropropyl, 2,2, 2-trifluoro-1-trifluoromethylethyl, heptafluoropropyl, 1,2,2, 2-tetrafluoro-1-trifluoromethylethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2,2,3,3,4, 4-heptafluorobutyl, 5-fluoropentyl, 6-fluorohexyl and the like. And other halogenated alkyl groups of C1-C6 containing other halogen atoms, wherein the fluorine atom is replaced by the corresponding halogen atom, and the description is omitted.
The haloalkyl group having C1-C4 means a straight-chain or branched alkyl group having 1-4 carbon atoms which is substituted with the same or different 1-9 halogen atoms which may be fluorine atom, chlorine atom, bromine atom, iodine atom, etc. For example, the halogen atom is fluorine atom, and the C1-C4 haloalkyl group includes but is not limited to: fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2, 2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3, 3-pentafluoropropyl, 2,2, 2-trifluoro-1-trifluoromethylethyl, heptafluoropropyl, 1,2,2, 2-tetrafluoro-1-trifluoromethylethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2,2,3,3,4, 4-heptafluorobutyl and the like. And other halogenated alkyl groups of C1-C4 containing other halogen atoms, wherein the fluorine atom is replaced by the corresponding halogen atom, and the description is omitted.
(C3-C6) cycloalkyl refers to cycloalkyl groups having 3-6 carbon atoms, including but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
(C2-C6) alkenyl refers to straight or branched chain alkenyl groups having 2 to 6 carbon atoms, including but not limited to: vinyl, 1-propenyl, isopropenyl, 2-propenyl, 1-butenyl, 1-methyl-1-propenyl, 2-butenyl, 1, 3-butadienyl, 1-pentenyl, 1-hexenyl and the like.
(C2-C6) alkynyl refers to straight or branched chain alkynyl groups having 2-6 carbon atoms, including but not limited to: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 2-butynyl, 1-pentynyl, 1-hexynyl and the like.
(C1-C6) alkoxy means (C1-C6) alkyl-O- (here, (C1-C6) alkyl is as previously defined), including but not limited to: methoxy, ethoxy, propoxy, isopropoxy, butoxy, secondary butoxy, isobutoxy, tertiary butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, and the like.
In the present application, in R2 and R3, the substituted aryl group may be a halogenated aryl group, and the halogenated aryl group may be a fluorinated aryl group, a chlorinated aryl group, a brominated aryl group, or an iodoaryl group.
In the present application, specifically, R2 and R3 may each independently be at least one of a phenyl group, a p-methoxyphenyl group, a p-cyanophenyl group, and a methyl group.
According to a preferred embodiment, the reaction of hydroxylamine hydrochloride or hydroxylamine sulfate with the compound of formula (I) in the presence of an inorganic base and a phase transfer catalyst comprises:
in the presence of water, inorganic base is contacted with hydroxylamine hydrochloride or hydroxylamine sulfate to obtain hydroxylamine;
adding a phase transfer catalyst, an organic solvent and the compound shown in the formula (I) and mixing.
Specifically, the foregoing embodiment may further include:
in the presence of water, inorganic base is contacted with hydroxylamine hydrochloride or hydroxylamine sulfate to obtain hydroxylamine;
adding a phase transfer catalyst and mixing;
adding an organic solvent and the compound shown in the formula (I) and mixing.
According to a preferred embodiment, the inorganic base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. The amount of the inorganic base used is not particularly limited, and may be, for example: the dosage of the catalyst can be just enough to completely react with hydroxylamine hydrochloride or hydroxylamine sulfate.
According to a preferred embodiment, the phase transfer catalyst is at least one of tetrabutylammonium bromide, benzyltriethylammonium chloride, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, PEG200 and PEG 400. The inventors of the present application further found in their research that selecting a specific kind of phase transfer catalyst (i.e., benzyltriethylammonium chloride and dodecyltrimethylammonium chloride mixed in a specific ratio as a phase transfer catalyst) can further improve the yield and purity of the reaction product, and therefore, in order to improve the yield and purity of the reaction product, it is further preferable that the phase transfer catalyst is a mixture of benzyltriethylammonium chloride and dodecyltrimethylammonium chloride, and it is still further preferable that the molar ratio of benzyltriethylammonium chloride to dodecyltrimethylammonium chloride is (3-6): 1.
according to a preferred embodiment, the organic solvent is at least one of pentane, hexane, cyclohexane, tetrahydrofuran and toluene. The inventors of the present application have further found in their studies that selection of a specific kind of organic solvent (i.e., tetrahydrofuran and toluene mixed in a specific ratio as an organic solvent) can further improve the yield and purity of the reaction product, and therefore, in order to improve the yield and purity of the reaction product, it is further preferred that the organic solvent is a mixture of tetrahydrofuran and toluene, and it is further preferred that the mass ratio of tetrahydrofuran to toluene is 1: (2-5).
According to a preferred embodiment, the mass ratio of water to organic solvent is 1: (2-15), the inventors of the present application further found in their studies that the mass ratio of water to organic solvent was 1: (5-10), the yield and purity of the reaction product can be further improved, and therefore, in order to improve the yield and purity of the reaction product, it is further preferable that the mass ratio of water to the organic solvent is 1: (5-10).
In the present application, the amount of the organic solvent used is not particularly limited as long as the organic solvent is used in an amount that can dissolve the compound represented by the formula (I) and satisfies the use ratio of the organic solvent to water so that the reaction can proceed.
According to a preferred embodiment, the reaction conditions include: the temperature is 0 to 65 ℃ and more preferably 20 to 35 ℃. The reaction of the present application can be completed in a short time, such as: the reaction time is 4-10 h.
According to a preferred embodiment, in order to increase the yield and purity of the reaction product, the molar ratio of hydroxylamine, phase transfer catalyst, compound of formula (I) is 1: (0.01-0.05): (0.9-1).
In the present application, the water may be water from various sources commonly used in the art, such as tap water, deionized water, distilled water, and the like.
Examples
Unless otherwise specified, the materials used are all the respective materials commonly used in the art and are commercially available.
In each of examples and comparative examples, the yield was calculated by the formula: yield-actual mass of product-purity/theoretical mass of product.
Preparation example 1
According to the Journal of the American Chemical Society,140(10), 3514-; 2018, using isopropenylaldehyde and phenylmagnesium bromide as initial raw materials to synthesize a compound shown in a formula (I), wherein: r1 is phenyl, R2 is methyl, R3 is methyl. The yield was 70% based on isopentenal.
Preparation example 2
According to the literature Tetrahedron Letters,59(8), 771-; 2018, using chalcone and iodobenzene as raw materials, and synthesizing a compound shown in a formula (I) through a Heck reaction, wherein: r1 is phenyl, R2 is phenyl, R3 is phenyl. The yield was 90% based on chalcone.
Preparation example 3
According to Tetrahedron Letters,61(21), 151887; the process described in 2020, which comprises synthesizing a compound represented by the formula (I) wherein: r1 is phenyl, R2 is methyl, R3 is phenyl. The yield was 75% based on benzophenone.
Preparation example 4
According to the literature Tetrahedron Letters,59(8), 771-; 2018, using chalcone and p-methoxy bromobenzene as raw materials, and synthesizing a compound shown in a formula (I) through a Heck reaction, wherein: r1 is phenyl, R2 is phenyl, and R3 is p-methoxyphenyl. The yield was 80% based on chalcone.
Preparation example 5
According to the document Angewandte Chemie, International Edition,58(22),7318 and 7323; 2019, synthesizing a compound represented by a formula (I) by using p-bromobenzoyl chloride and stilbene as raw materials, wherein: r1 is p-bromophenyl, R2 is phenyl, and R3 is phenyl. The yield was 85% based on p-bromobenzoyl chloride.
Preparation example 6
According to the literature Tetrahedron Letters,59(8), 771-; 2018, using chalcone and p-cyanoborobenzene as raw materials, and carrying out Heck reaction to synthesize the compound shown in the formula (I), wherein: r1 is phenyl, R2 is phenyl, and R3 is p-cyanophenyl. The yield was 87% based on chalcone.
Preparation example 7
According to the document Angewandte Chemie, International Edition,58(22),7318 and 7323; 2019, synthesizing a compound represented by the formula (I) by using p-trifluoromethyl formyl chloride and stilbene as raw materials, wherein: r1 is p-trifluoromethylphenyl, R2 is phenyl, and R3 is phenyl. The yield was 83% based on p-trifluoromethylcarbonyl chloride.
Example 1
(1) Adding 6.94g (namely 0.1mol) of hydroxylamine hydrochloride and 30g of water into a reaction bottle at 25 ℃, and stirring to dissolve;
(2) adding 4.0g of sodium hydroxide, stirring, and completely decomposing the salt of hydroxylamine hydrochloride to obtain hydroxylamine;
(3) adding 0.69g (total 0.003mol, wherein the molar ratio of the benzyltriethylammonium chloride to the dodecyltrimethylammonium chloride is 5: 1) of a mixture of the benzyltriethylammonium chloride and the dodecyltrimethylammonium chloride, and stirring for dissolving;
(4) 240g of a mixture of tetrahydrofuran and toluene (wherein the mass ratio of tetrahydrofuran to toluene was 1:4) and 15.22g of the compound represented by the formula (I) (having a relative molecular weight of 160.22, i.e., 0.095mol) were added, and the reaction was stirred for 4 hours. Wherein, the compound shown in the formula (I) is as follows: r1 is phenyl, R2 is methyl, R3 is methyl.
HPLC (HPLC assay instrument from Agilent, model 1260 Infinity II, same below) detects complete reaction of the compound of formula (I), separates the liquids, dries the organic phase with anhydrous sodium sulfate, and then concentrates under reduced pressure to obtain a white solid, which is assayed:
nuclear magnetic (Bruker, 400M HZ, same below) data are as follows:
1H NMR(400MHz,CDCl3)：δ1.49(6H,s),3.10(2H,s),7.38-7.40(3H, m),7.64-7.66(2H,m)
mass spectrometry (mass spectrometer instrument from Agilent, model 6545LC/TOF, same below) data were as follows:
ESI-MS:Found:m/z 176.1075.Calcd for C11H14NO:(M+H)+176.1075
the purity by HPLC analysis was 98.8%, and the yield by hydroxylamine hydrochloride was 84.7%.
Example 2
(1) Adding 8.2g (namely 0.05mol) of hydroxylamine sulfate and 30g of water into a reaction bottle at the temperature of 30 ℃, and stirring to dissolve;
(2) adding 6.91g of potassium carbonate, and stirring to completely decompose the hydroxylamine sulfate to obtain hydroxylamine;
(3) adding 0.24g (total 0.001mol, wherein the molar ratio of the benzyltriethylammonium chloride to the dodecyltrimethylammonium chloride is 3: 1) of a mixture of the benzyltriethylammonium chloride and the dodecyltrimethylammonium chloride, and stirring for dissolving;
(4) 150g of a mixture of tetrahydrofuran and toluene (wherein the mass ratio of tetrahydrofuran to toluene was 1:2) and 15.22g of the compound represented by the formula (I) (same as in example 1) were added thereto, and the mixture was stirred and reacted for 4 hours.
HPLC detection of the complete reaction of the compound of formula (I), liquid separation, drying of the organic phase with anhydrous sodium sulfate, concentration under reduced pressure to give a white solid, determined by:
the NMR data and mass spectrum data were as in example 1, with 98.6% purity by HPLC and 83.5% yield based on hydroxylamine sulfate.
Example 3
(1) Adding 6.94g (namely 0.1mol) of hydroxylamine hydrochloride and 30g of water into a reaction bottle at the temperature of 20 ℃, and stirring to dissolve;
(2) adding 8.4g of sodium bicarbonate, and stirring to completely decompose the hydroxylamine hydrochloride to obtain hydroxylamine;
(3) adding 1.17g (total 0.005mol, wherein the molar ratio of the benzyltriethylammonium chloride to the dodecyltrimethylammonium chloride is 6: 1) of a mixture of the benzyltriethylammonium chloride and the dodecyltrimethylammonium chloride, and stirring for dissolving;
(4) 300g of a mixture of tetrahydrofuran and toluene (wherein the mass ratio of tetrahydrofuran to toluene was 1:5) and 16.02g of the compound represented by the formula (I) (same as in example 1) were added thereto, and the mixture was stirred and reacted for 4 hours.
HPLC detection of the complete reaction of the compound of formula (I), liquid separation, drying of the organic phase with anhydrous sodium sulfate, concentration under reduced pressure to give a white solid, determined by:
the NMR data and mass spectrum data were as in example 1, with 98.5% purity by HPLC and 83.9% yield based on hydroxylamine hydrochloride.
Example 4
The process of example 1 was followed except that, in step (3), the total number of moles of benzyltriethylammonium chloride and dodecyltrimethylammonium chloride was unchanged, and the molar ratio of benzyltriethylammonium chloride to dodecyltrimethylammonium chloride was 1: 1.
the resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 98.2%, and the yield by hydroxylamine hydrochloride was 81.4%.
Example 5
The procedure of example 1 was followed except that in step (3), the total molar amount of the phase transfer catalyst was not changed and 0.68g of benzyltriethylammonium chloride was used instead of the mixture of benzyltriethylammonium chloride and dodecyltrimethylammonium chloride.
The resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 98.1%, and the yield by hydroxylamine hydrochloride was 79.1%.
Example 6
The procedure of example 1 was followed except that in step (3), the total number of moles of the phase transfer catalyst was unchanged, and 0.79g of dodecyltrimethylammonium chloride was used instead of the mixture of benzyltriethylammonium chloride and dodecyltrimethylammonium chloride.
The resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 98.3%, and the yield by hydroxylamine hydrochloride was 79.3%.
Example 7
The procedure is as in example 1, except that in step (3), the total moles of phase transfer catalyst are unchanged, and 1.21g of trioctylmethylammonium chloride is used instead of the mixture of benzyltriethylammonium chloride and dodecyltrimethylammonium chloride.
The resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 98.1%, and the yield by hydroxylamine hydrochloride was 80.1%.
Example 8
The procedure is as in example 1, except that in step (3), the total moles of phase transfer catalyst are unchanged, and 0.97g of tetrabutylammonium bromide is used instead of the mixture of benzyltriethylammonium chloride and dodecyltrimethylammonium chloride.
The resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 98.2%, and the yield by hydroxylamine hydrochloride was 80.3%.
Example 9
The procedure of example 1 was followed except that, in step (3), the total molar amount of the phase transfer catalyst was not changed, and 0.97g of PEG200 was used instead of the mixture of benzyltriethylammonium chloride and dodecyltrimethylammonium chloride.
The resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 97.7%, and the yield by hydroxylamine hydrochloride was 78.2%.
Example 10
The procedure of example 1 was followed except that, in step (3), the total moles of the phase transfer catalyst were unchanged, and 0.97g of PEG400 was used instead of the mixture of benzyltriethylammonium chloride and dodecyltrimethylammonium chloride.
The resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 97.5%, and the yield by hydroxylamine hydrochloride was 77.2%.
Example 11
The procedure was followed as in example 1, except that in step (4), the total mass of the organic solvent was unchanged, and the mass ratio of tetrahydrofuran and toluene was 1: 1.
The resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 98.4%, and the yield by hydroxylamine hydrochloride was 82.2%.
Example 12
The procedure is as in example 1, except that in step (4), tetrahydrofuran is used instead of the mixture of tetrahydrofuran and toluene, with the exception that the total mass of the organic solvent is unchanged.
The resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 98.2%, and the yield by hydroxylamine hydrochloride was 81.7%.
Example 13
The procedure is as in example 1, except that in step (4), the total mass of the organic solvent is unchanged, and toluene is used instead of the mixture of tetrahydrofuran and toluene.
The resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 98.3%, and the yield by hydroxylamine hydrochloride was 81.9%.
Example 14
The procedure is as in example 1, except that in step (4), the total mass of organic solvent is unchanged, and pentane is used instead of the mixture of tetrahydrofuran and toluene.
The resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 98.2%, and the yield by hydroxylamine hydrochloride was 80.3%.
Example 15
The procedure is as in example 1, except that in step (4), the total mass of organic solvent is unchanged, and cyclohexane is used instead of the mixture of tetrahydrofuran and toluene.
The resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 97.8%, and the yield by hydroxylamine hydrochloride was 79.5%.
Example 16
The process of example 1 was followed except that, in step (4), the organic solvent was a mixture of tetrahydrofuran and toluene in a mass ratio of 1:4, but the mass of the organic solvent was 60g, i.e., the mass ratio of water to the organic solvent was 1: 2.
the resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 98.5%, and the yield by hydroxylamine hydrochloride was 81.6%.
Example 17
The process of example 1 was followed except that, in step (4), the organic solvent was a mixture of tetrahydrofuran and toluene in a mass ratio of 1:4, but the mass of the organic solvent was 450g, i.e., the mass ratio of water to the organic solvent was 1: 15.
the resulting white solid was examined and the nuclear magnetic data and mass spectral data were the same as in example 1. The purity by HPLC analysis was 98.5%, and the yield by hydroxylamine hydrochloride was 82.2%.
Example 18
The procedure is as in example 1, except that, in step (4), equimolar amounts of the compound of formula (I) are as follows: r1 is phenyl, R2 is phenyl, R3 is phenyl.
The white solid obtained was examined and the nuclear magnetic data were as follows:
1H NMR(400MHz,CDCl3)：δ3.98(2H,s),7.23-7.28(2H,m),7.32-7.36(7H, m),7.46-7.48(4H,m),7.67-7.70(2H,m)；
mass spectral data were as follows:
ESI-MS:Found:m/z 300.1385.Calcd for C21H18NO:(M+H)+300.1388
the purity by HPLC analysis was 98.7%, and the yield by hydroxylamine hydrochloride was 82.6%.
Example 19
The procedure is as in example 1, except that, in step (4), equimolar amounts of the compound of formula (I) are as follows: r1 is phenyl, R2 is methyl, R3 is phenyl.
The white solid obtained was examined and the nuclear magnetic data were as follows:
1H NMR(400MHz,CDCl3)：δ1.81(3H,s),3.46(1H,d),3.53(1H,d), 7.25-7.29(1H,m),7.35-7.39(5H,m),7.48-7.50(2H,m),7.63-7.67(2H,m)
mass spectral data were as follows:
ESI-MS:Found:m/z 238.1231.Calcd for C16H16NO:(M+H)+238.1232
the purity by HPLC analysis was 98.6%, and the yield by hydroxylamine hydrochloride was 82.5%.
Example 20
The procedure is as in example 1, except that, in step (4), equimolar amounts of the compound of formula (I) are as follows: r1 is phenyl, R2 is phenyl, and R3 is p-methoxyphenyl.
The white solid obtained was examined and the nuclear magnetic data were as follows:
1H NMR(400MHz,CDCl3)：δ3.78(3H,s),3.92(1H,d),3.98(1H,d,),6.86 (2H,d,),7.25-7.47(10H,m),7.68-7.70(2H,m)
mass spectral data were as follows:
ESI-MS:Found:m/z 330.1495.Calcd for C22H20NO2:(M+H)+330.1494
the purity by HPLC analysis was 98.5%, and the yield by hydroxylamine hydrochloride was 82.2%.
Example 21
The procedure is as in example 1, except that, in step (4), equimolar amounts of the compound of formula (I) are as follows: r1 is p-trifluoromethylphenyl, R2 is phenyl, and R3 is phenyl.
The white solid obtained was examined and the nuclear magnetic data were as follows:
1H NMR(400MHz,CDCl3)：δ3.99(2H,s),7.23-7.29(2H,m),7.33-7.36 (4H,m),7.46-7.47(4H,m),7.63(2H,d,J＝8.0Hz),7.79(2H,d)
mass spectral data were as follows:
ESI-MS:Found:m/z 368.1265.Calcd for C22H17F3NO:(M+H)+368.1262.
the purity by HPLC analysis was 98.2%, and the yield by hydroxylamine hydrochloride was 82.6%.
Example 22
The procedure is as in example 1, except that, in step (4), equimolar amounts of the compound of formula (I) are as follows: r1 is p-bromophenyl, R2 is phenyl, and R3 is phenyl.
The white solid obtained was examined and the nuclear magnetic data were as follows:
1H NMR(400MHz,CDCl3)：δ3.95(2H,s),7.25-7.29(2H,m),7.33-7.37 (4H,m),7.44-7.46(4H,m),7.50-7.56(4H,m)
mass spectral data were as follows:
ESI-MS:Found:m/z 378.0499.Calcd for C21H17BrNO:(M+H)+378.0494
the purity by HPLC analysis was 98.5%, and the yield by hydroxylamine hydrochloride was 81.9%.
Example 23
The procedure is as in example 1, except that, in step (4), equimolar amounts of the compound of formula (I) are as follows: r1 is phenyl, R2 is phenyl, and R3 is p-cyanophenyl.
The white solid obtained was examined and the nuclear magnetic data were as follows:
1H NMR(400MHz,CDCl3)：δ3.90(1H,d),4.08(1H,d),7.26-7.45(8H, m),7.59-7.69(6H,m)；
mass spectral data were as follows:
ESI-MS:Found:m/z 325.1346.Calcd for C22H17N2O:(M+H)+325.1341
the purity by HPLC analysis was 98.9%, and the yield by hydroxylamine hydrochloride was 83.1%.
Example 24
(1) Adding 6.94g (namely 0.1mol) of hydroxylamine hydrochloride and 30g of water into a reaction bottle at 25 ℃, and stirring to dissolve;
(2) adding 4.0g of sodium hydroxide, stirring, and completely decomposing the salt of hydroxylamine hydrochloride to obtain hydroxylamine;
(3) adding 0.69g (total 0.003mol, wherein the molar ratio of the benzyltriethylammonium chloride to the dodecyltrimethylammonium chloride is 5: 1) of a mixture of the benzyltriethylammonium chloride and the dodecyltrimethylammonium chloride, and stirring for dissolving;
(4) 240g of a mixture of tetrahydrofuran and toluene (wherein the mass ratio of tetrahydrofuran to toluene is 1:4) and 8.4g of the compound represented by the formula (I) (having a relative molecular weight of 84.12) were added, and the mixture was stirred and reacted for 4 hours. Wherein, the compound shown in the formula (I) is as follows: r1 is hydrogen, R2 is methyl and R3 is methyl.
After the compound of formula (I) was completely reacted by HPLC, liquid was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 8.8g of an oily liquid, which had a purity of 94.2% by HPLC and a yield of 83.7% by hydroxylamine hydrochloride.
Comparative example 1
(1) Adding 10g of isopropenal and 11.7ml of dichloromethane into a reaction bottle at 25 ℃, and stirring to dissolve;
(2) adding 9.75g of hydroxylamine sulfate and then 9.22g of 48% sodium hydroxide aqueous solution, and stirring;
(3) under ice cooling, 2.68ml of trifluoroacetic acid was added thereto, and the mixture was stirred at 45 ℃ for 20 hours, and then 12ml of a saturated aqueous sodium bicarbonate solution was added thereto and stirred.
Separating, drying the organic phase by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the 5, 5-dimethyl-4, 5-dihydroisoxazole, wherein nuclear magnetic data are as follows:
1H NMR(400MHz,CDCl3)：δ1.40(6H,s),2.75(2H,d),7.06(1H,br s),
mass spectral data were as follows: ESI (M + H):102.08
The purity was 79% by HPLC and the yield was 71% by hydroxylamine sulfate.
Comparing the results of the examples and the comparative example 1, the method of the present application can prepare the reaction product with high purity and yield, and has the advantages of simple preparation process, high reaction speed and mild reaction conditions.
And those skilled in the art should know that when the yield is as high as 70% or more, it is difficult to increase the yield by 10% to 80% on the basis, and further, it is more obvious to increase the yield by 3% -5% to 83% -85%.
Comparing the results of example 1 and examples 4 to 10, it can be seen that the phase transfer catalyst is a mixture of benzyltriethylammonium chloride and dodecyltrimethylammonium chloride, which can improve the yield and purity of the reaction product, when the molar ratio of benzyltriethylammonium chloride to dodecyltrimethylammonium chloride is (3-6): 1, the yield and purity of the reaction product can be further improved.
Comparing the results of example 1 and examples 11 to 15, it can be seen that the yield and purity of the reaction product can be improved when the organic solvent is a mixture of tetrahydrofuran and toluene, and when the mass ratio of tetrahydrofuran to toluene is 1: (2-5), the yield and purity of the reaction product can be further improved.
Comparing the results of example 1 and examples 16 to 17, the mass ratio of water to organic solvent is 1: (5-10), the yield and purity of the reaction product can be further improved.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the content of the present invention as long as it does not depart from the gist of the present invention.
Claims (10)
1. Formula (II)
The preparation method of the 4, 5-dihydroisoxazole derivative is characterized by comprising the following steps: reacting hydroxylamine hydrochloride or hydroxylamine sulphate with a compound shown in a formula (I) in the presence of inorganic base and a phase transfer catalyst,
wherein R1 is aryl, substituted aryl or hydrogen atom, R2 and R3 are respectively and independently C1-C6 alkyl, C1-C6 substituted alkyl, aryl or substituted aryl.
2. The method of claim 1, wherein the reacting hydroxylamine hydrochloride or hydroxylamine sulfate with the compound of formula (I) in the presence of an inorganic base and a phase transfer catalyst comprises:
in the presence of water, inorganic base is contacted with hydroxylamine hydrochloride or hydroxylamine sulfate to obtain hydroxylamine;
adding a phase transfer catalyst, an organic solvent and the compound shown in the formula (I) and mixing.
3. The process of claim 1 or 2, wherein the inorganic base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
4. The process of claim 1 or 2, wherein the phase transfer catalyst is at least one of tetrabutylammonium bromide, benzyltriethylammonium chloride, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, PEG200 and PEG 400.
5. The process according to claim 4, wherein the phase transfer catalyst is a mixture of benzyltriethylammonium chloride and dodecyltrimethylammonium chloride, preferably, the molar ratio of benzyltriethylammonium chloride to dodecyltrimethylammonium chloride is (3-6): 1.
6. the method of claim 2, wherein the organic solvent is at least one of pentane, hexane, cyclohexane, tetrahydrofuran, and toluene.
7. The method according to claim 6, wherein the organic solvent is a mixture of tetrahydrofuran and toluene, preferably the mass ratio of tetrahydrofuran to toluene is 1: (2-5).
8. The method according to claim 2, wherein the mass ratio of water to organic solvent is 1: (2-15), preferably 1: (5-10).
9. The process of claim 1 or 2, wherein the conditions of the reaction comprise: the temperature is 0-65 ℃.
10. The process according to claim 1 or 2, wherein the molar ratio of hydroxylamine, phase transfer catalyst, compound of formula (I) is 1: (0.01-0.05): (0.9-1).
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| CN115028596A (en) * | 2021-03-03 | 2022-09-09 | 帕潘纳(北京)科技有限公司 | Process for preparing topramezone intermediates |
| CN116178294A (en) * | 2023-01-08 | 2023-05-30 | 湖南吴赣药业有限公司 | Method for preparing 5, 5-dimethyl-4, 5-dihydro-isoxazole |
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| CN103562178A (en) * | 2011-06-03 | 2014-02-05 | 住友化学株式会社 | Method of manufacturing isoxazoline compound |
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| CN103562178A (en) * | 2011-06-03 | 2014-02-05 | 住友化学株式会社 | Method of manufacturing isoxazoline compound |
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| CN115028596A (en) * | 2021-03-03 | 2022-09-09 | 帕潘纳(北京)科技有限公司 | Process for preparing topramezone intermediates |
| CN115028596B (en) * | 2021-03-03 | 2024-06-07 | 帕潘纳(北京)科技有限公司 | Method for preparing topramezone intermediate |
| CN116178294A (en) * | 2023-01-08 | 2023-05-30 | 湖南吴赣药业有限公司 | Method for preparing 5, 5-dimethyl-4, 5-dihydro-isoxazole |
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