CN116947837A - Topramezone intermediate and preparation method thereof - Google Patents
Topramezone intermediate and preparation method thereof Download PDFInfo
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- CN116947837A CN116947837A CN202210390195.XA CN202210390195A CN116947837A CN 116947837 A CN116947837 A CN 116947837A CN 202210390195 A CN202210390195 A CN 202210390195A CN 116947837 A CN116947837 A CN 116947837A
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- ester group
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- sodium
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- IYMLUHWAJFXAQP-UHFFFAOYSA-N topramezone Chemical compound CC1=C(C(=O)C2=C(N(C)N=C2)O)C=CC(S(C)(=O)=O)=C1C1=NOCC1 IYMLUHWAJFXAQP-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 94
- 125000004185 ester group Chemical group 0.000 claims abstract description 56
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 31
- 150000001408 amides Chemical group 0.000 claims abstract description 28
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims description 97
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 40
- -1 peroxy compound Chemical class 0.000 claims description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- 230000015572 biosynthetic process Effects 0.000 claims description 21
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 19
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000007800 oxidant agent Substances 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 230000001590 oxidative effect Effects 0.000 claims description 12
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 235000011181 potassium carbonates Nutrition 0.000 claims description 11
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 11
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000011736 potassium bicarbonate Substances 0.000 claims description 9
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 9
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 9
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 9
- 235000017550 sodium carbonate Nutrition 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 8
- 239000005977 Ethylene Substances 0.000 claims description 8
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 7
- 150000002923 oximes Chemical class 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 claims description 6
- 150000003457 sulfones Chemical class 0.000 claims description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 230000002140 halogenating effect Effects 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- JMARSTSWTFXHMC-UHFFFAOYSA-N 2-methyl-1h-pyrazol-3-one Chemical compound CN1NC=CC1=O JMARSTSWTFXHMC-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 claims description 4
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- 238000006462 rearrangement reaction Methods 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- SPBWDKFNGQZARC-UHFFFAOYSA-N COCOC.C(=O)N(C)C Chemical compound COCOC.C(=O)N(C)C SPBWDKFNGQZARC-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- FWMUJAIKEJWSSY-UHFFFAOYSA-N sulfur dichloride Chemical compound ClSCl FWMUJAIKEJWSSY-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 239000003570 air Substances 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- 230000017105 transposition Effects 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- 238000003786 synthesis reaction Methods 0.000 description 19
- 239000000047 product Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 14
- 150000002367 halogens Chemical group 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000009987 spinning Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 150000001263 acyl chlorides Chemical class 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- JHIDHJCCPYAESR-UHFFFAOYSA-N 3-(4,5-dihydro-1,2-oxazol-3-yl)-2-methyl-4-methylsulfonylbenzoic acid Chemical compound CC1=C(C(O)=O)C=CC(S(C)(=O)=O)=C1C1=NOCC1 JHIDHJCCPYAESR-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- 240000008042 Zea mays Species 0.000 description 3
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 235000005822 corn Nutrition 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000032798 delamination Effects 0.000 description 3
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 238000010907 mechanical stirring Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000007789 gas Substances 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
- XHXXWWGGXFUMAJ-UHFFFAOYSA-N methanethiol;sodium Chemical compound [Na].SC XHXXWWGGXFUMAJ-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- NQSNZVWJOPFLDF-UHFFFAOYSA-N 3-(4,5-dihydro-1,2-oxazol-3-yl)-2-methyl-4-methylsulfonylbenzoyl chloride Chemical compound CC1=C(C(Cl)=O)C=CC(S(C)(=O)=O)=C1C1=NOCC1 NQSNZVWJOPFLDF-UHFFFAOYSA-N 0.000 description 1
- XEWKOMSWWONEMR-UHFFFAOYSA-N 3-hydroxy-2-methyl-1H-pyrazol-5-one Chemical compound CN1NC(=O)C=C1O XEWKOMSWWONEMR-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 102000016680 Dioxygenases Human genes 0.000 description 1
- 108010028143 Dioxygenases Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000209504 Poaceae Species 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 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
- 238000011161 development Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000002560 nitrile group Chemical group 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
- 125000002347 octyl 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])[H] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P13/00—Herbicides; Algicides
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
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- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
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- 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
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a novel 3-formyl-2-methyl-4- (methylthio) benzoate compound shown in a general formula VI, wherein R is an ester group, carboxylic acid, amide or cyano. The invention also provides a synthesis method of the intermediate in the formula VI and application of the intermediate in preparation of topramezone. The reaction selectivity of the topramezone prepared by the formula VI is higher, the whole process route is more suitable for realizing industrial production,
Description
Technical Field
The invention relates to an intermediate of topramezone, a preparation method and application thereof, in particular to a 3-formyl-2-methyl-4- (methylthio) benzoate compound, a preparation method and application thereof.
Background
Topramezone is a benzyl ester pyrazolone herbicide developed by Pasteur for the first time, belongs to a p-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor, has the English common name topramezone and the Chinese name topramezone or topramezone, and has the commodity name campusR or bract. The topramezone can effectively prevent and remove annual gramineae weeds and broadleaf weeds in corn, is safe to corn, has the application range gradually expanded to crops such as rice and sugarcane, and can be safely compounded with other pesticides. The global topramezone market size in 2018 was about 1.09 billion dollars, the total amount of active ingredients applied was about 269.35t, with the corn field market being 65.55% and other crops being about 34.45%. The topramezone has excellent drug effect and wide market prospect, but the extremely difficult synthesis process makes the topramezone high in selling price, and therefore, the wide application of the topramezone is limited.
The preparation process of the topramezone reported at present mainly comprises the following two steps:
route 1:
the preparation of the compound (8) in the route is as follows, (see patent: CN 103788083A) needs nitrous acid ester to be subjected to ultralow temperature reaction to construct oxime, and two methyl groups on benzene rings have selectivity problems, and meanwhile, the intermediate is used for synthesizing topramezone, and extremely toxic carbon monoxide and an expensive metal palladium catalyst are used, so that the cost is high.
Route 2:
wherein the intermediate compound (7) in this route is reported as the following preparation method:
1) See patent nos.: US6100421
The starting materials required for the preparation of the intermediate are not easily available, and although the strong electron-withdrawing effect of the methylsulfonyl activates the next bromination reaction to a certain extent, steric hindrance selection problems exist in bromination, so that the yield is lower. In addition, when the methyl sulfonyl aldehyde is used for preparing the topramezone, the steric hindrance of the methyl sulfonyl is larger, so that the yield of the subsequent cyclization reaction with ethylene is lower.
2) See patent nos.: CN201410083163
The source of the initial raw materials in the route is difficult, carbon dioxide is used in the process of converting into carboxyl, n-butyllithium reacts at the ultralow temperature of minus 100 ℃ to minus 60 ℃, and industrial production is difficult;
3) See patent nos.: CN 110183392A
The starting materials in this route are also difficult to source, and because hydroxylamine has double reactive functional groups during the reaction of hydroxylamine with nitrile groups, a large amount of impurities are inevitably produced, resulting in lower yields, and the need to carry out deamination of diazotization increases the risk of the reaction.
In conclusion, the existing method has the defects of large three wastes, high cost, severe production environment and the like when the topramezone intermediate compound is prepared, and is also a factor which causes high cost and no residence of the topramezone preparation. Therefore, the development of a process route which is mild in reaction condition, green and environment-friendly and reduces the cost of preparing topramezone is particularly urgent.
Disclosure of Invention
Aiming at some defects and defects of the technical route of topramezone in the current market, the invention provides a process for preparing topramezone, which has the advantages of mild reaction conditions, environment friendliness and low cost.
In order to achieve the above purpose, the invention adopts the following technical scheme that the preparation method of topramezone comprises the following steps:
step one, a compound of a formula VI is subjected to oxime formation with a salt of hydroxylamine under alkaline conditions, and the prepared product oxime is subjected to ring closure with ethylene to prepare a compound of a formula VII, wherein the salt of hydroxylamine is preferably hydroxylamine hydrochloride or hydroxylamine sulfate;
oxidizing the compound of the formula VII by an oxidant to obtain a corresponding sulfone product, and performing alkaline hydrolysis on the sulfone product to obtain a formula VIII;
step three, reacting a compound shown in a formula VIII with an acylating agent to obtain an acylated product, forming ester by the acylated product and 1-methyl-5-hydroxypyrazol, and then preparing the topramezone technical product through a rearrangement reaction under the condition of a catalyst;
wherein, the structures of the formula VI, the formula VII, the formula VIII and the topramezone are as follows:
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
Preferably, there is provided a process for preparing a compound of formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
More optionally, a preparation method of the formula VI is provided, which comprises the following steps of carrying out substitution reaction on a compound of the formula V and sodium methyl mercaptide in a polar aprotic solvent under alkaline conditions to obtain the formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The invention also provides an application of the formula VI in preparing topramezone.
In addition, the invention provides compounds of formula V, formula IV and formula III,
wherein,,
the compound of formula V,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The compound of the formula IV,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
A compound of the formula III,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The invention also provides a preparation method of the compounds shown in the formula III, the formula IV and the formula V and application of the compounds in preparation of topramezone.
The intermediate for preparing the topramezone has the advantages of mild preparation conditions, environment-friendly process, easily available raw material sources and relatively low price, and the intermediate for preparing the topramezone, the preparation method and the application of the intermediate in preparing the topramezone have good effects.
The invention has the beneficial effects that:
1. the topramezone intermediate prepared by the method has higher selectivity, can avoid using extremely toxic carbon monoxide and expensive metallic palladium catalyst in the prior art, reduces the cost of topramezone preparation, and is favorable for popularization and application of topramezone.
2. The method avoids the need of ultralow temperature construction of the isoxazole ring in the prior art in the process of synthesizing the compound of the formula VII by using the compound of the formula VI, and has mild condition and high selectivity in the reaction process of constructing the isoxazole ring.
3. The compounds of the formula VI, the formula V, the formula IV, the formula III and the like are easy to synthesize, the reaction condition is mild, and the process is environment-friendly, so that the synthesized topramezone has higher yield, and plays a great role in reducing the synthesis cost of the topramezone.
Drawings
Fig. 1: nuclear magnetic hydrogen spectrum of 4-chloro-3-formyl-2-methyl ethyl benzoate
Fig. 2: nuclear magnetic hydrogen spectrum of 3-formyl-2-methyl-4- (methylthio) ethyl benzoate
Fig. 3: nuclear magnetic hydrogen spectrum of 3- (4, 5-dihydro-isoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoic acid
Detailed Description
Hereinafter, embodiments of the present invention are described in detail. However, these embodiments are exemplary, the invention is not limited thereto, and the invention is defined by the scope of the claims.
As used herein, when no specific definition is otherwise provided, the following terms used in the specification and claims have the following meanings.
The ester group in the present invention means-COOR 1; wherein R1 is alkyl, substituted or substituted aryl or heteroaryl;
the amide group in the present invention means-CONR 2R3; wherein R2 and R3 are the same or different hydrogen, alkyl, substituted or substituted aryl or heteroaryl;
alkyl or alkane in the context of the present invention means a straight-chain or branched alkyl group, preferably C 1 -C 10 Alkyl groups, specifically for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, more preferably lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl and the like.
Aryl in the present invention is preferably phenyl or naphthyl.
Heteroaryl group: refers to five-membered or six-membered rings containing 1 or more N, O, S heteroatoms. For example, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyridazinonyl, indolyl, benzofuranyl, benzoxazolyl, benzothienyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzopyrazolyl, quinoxalinyl, and the like.
"cyano" refers to-CN.
HMPA refers to hexamethylphosphoric triamide.
DMSO refers to dimethylsulfoxide.
When the group is substituted, the substituents are alkyl, halogen, -OH, NO2, -CN, amino.
Halogen means fluorine, chlorine, bromine and iodine, and haloalkane means that hydrogen on alkane is partially or completely substituted by halogen.
The invention provides a preparation method of topramezone, which comprises the following steps:
step one, reacting a compound of the formula VI with a salt of hydroxylamine under alkaline conditions to form oxime, and then closing a ring with ethylene to obtain a compound of the formula VII, wherein the salt of hydroxylamine is preferably hydroxylamine hydrochloride or hydroxylamine sulfate;
oxidizing the compound of the formula VII by an oxidant to obtain a corresponding sulfone product, and performing alkaline hydrolysis to obtain a formula VIII;
step three, reacting a compound shown in a formula VIII with an acylating reagent to obtain a corresponding acyl chloride compound, forming ester with 1-methyl-5-hydroxypyrazol, and carrying out rearrangement reaction on an esterification product under the condition of a catalyst to obtain the topramezone technical product;
the structures of formula VI, formula VII, formula VIII and topramezone are as follows:
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
Wherein, the reaction formula of the step (I) is as follows:
step (one) forming an oxime by reacting a compound of formula VI with a salt of hydroxylamine, preferably hydroxylamine hydrochloride or hydroxylamine sulfate, under basic conditions, wherein the base is an inorganic base, preferably one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, more preferably one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate; the reaction is carried out in an organic solvent, wherein the solvent can be one of acetonitrile, ethyl acetate and dichloromethane, preferably acetonitrile, the reaction temperature is preferably room temperature, and the reaction time is 1-10h, preferably 2-8h. The process of preparing the compound of the formula VII by closing the ring with ethylene further comprises the steps of adding alkali and oxidant, wherein the alkali is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide, more preferably one or more of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; the oxidant is sodium hypochlorite, preferably a sodium hypochlorite solution, most preferably an 8% sodium hypochlorite solution. The further product oxime is then cyclized with ethylene to give the compound of the formula VII, the cyclizing reaction being carried out in an autoclave, the pressure in the autoclave preferably being 2-8MPa. It has been found that the reaction temperature during the ring closure should not be too high, preferably between-10 ℃ and 10 ℃, more preferably between-5 ℃ and 0 ℃, since too high a reaction temperature will result in oxidation of a small amount of dimethyl sulphide. The molar ratio of oxidizing agent to compound of formula VI is preferably 1:1.2-2.2, more preferably 1:1.6-2.
Wherein, the reaction formula in the step (2) is as follows:
the oxidizing agent in step (two) is peroxide, oxygen or hypochlorite, and the peroxy compound is preferably hydrogen peroxide, peroxybenzoic acid, more preferably hydrogen peroxide, and most preferably a 30% hydrogen peroxide solution. The reaction temperature in the oxidation process is 80-120 ℃, preferably 90-110 ℃, and researches show that the oxidation effect is not good due to the too low reaction temperature. The base used in the alkaline hydrolysis of the further sulfone product is selected from one of sodium hydroxide, potassium hydroxide, preferably aqueous solutions of sodium hydroxide and potassium hydroxide, and the hydrolysis is carried out in a solvent selected from one of toluene, xylene, nitrobenzene, preferably toluene. The hydrolysis is carried out at a relatively high temperature, preferably 100-120 ℃, and the reaction is too low to hydrolyze completely, and too high a temperature can decompose part of the oxazole ring.
Wherein, in the step (III), the reaction formula is as follows:
step (III), reacting the compound shown in the formula VIII with an acylating reagent to obtain a corresponding acyl chloride compound, wherein the acyl chloride reagent is thionyl chloride, sulfonyl chloride, oxalyl chloride, phosphorus oxychloride and the like, and the thionyl chloride is preferred; the reaction is carried out in a solvent, preferably dichloroethane, ethyl acetate; the reaction temperature is preferably 70-75 ℃; the reaction time is preferably 1 to 5 hours; the molar ratio of compound of formula VIII to acylating agent 1:1-1.5, preferably 1:1.05-1.2 when the molar ratio is less than 1: at 1.05 the reaction was incomplete.
Further, the obtained acyl chloride compound is reacted with 1-methyl-5-hydroxypyrazolol at a low temperature in the presence of an acid binding agent, wherein the acid binding agent is one of triethylamine, pyridine, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, and triethylamine is preferred. The reaction temperature is preferably from-5 to 25℃and preferably from 0 to 10 ℃.
Furthermore, adding potassium carbonate powder and a catalyst into the obtained esterified product solution, and preparing the topramezone technical product through a rearrangement reaction; the catalyst is 4-Dimethylaminopyridine (DMAP) and acetone cyanohydrin.
The invention also provides a compound of formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
The compound of the formula VI is prepared by the following method, which comprises the following steps of carrying out substitution reaction on the compound of the formula V and sodium methyl mercaptide in a polar aprotic solvent under alkaline conditions to prepare the compound of the formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is Cl or Br.
In the preparation method of the compound of the formula VI, the alkali is organic alkali or inorganic alkali; the inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; the organic base is preferably one or more of sodium methoxide, sodium ethoxide, sodium acetate and ammonium acetate; more preferably sodium bicarbonate, sodium acetate, ammonium acetate; the aprotic polar solvent is any one or a combination of a plurality of hexamethylphosphoric triamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and dioxane; preferably hexamethylphosphoric triamide, dimethyl sulfoxide, N, N-dimethylformamide; the molar ratio of the compound of formula V to the alkali to the sodium methyl mercaptide is 1:0.1-2:1-4, preferably 1:0.1-0.5:1-3. The reaction temperature was room temperature. The invention has mild reaction temperature condition and can well complete the reaction at room temperature.
The invention also provides application of the compound shown in the formula VI in preparation of topramezone. The preparation of topramezone by using the compound of the formula VI is more suitable for industrial production, and avoids the use of toxic gas, expensive catalyst and harsh reaction conditions in the prior art.
The present invention also provides a compound of formula V,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The invention also provides a compound of the formula V and a preparation method thereof, wherein the reaction formula is as follows:
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
In the method for preparing the compound shown in the formula V, the oxidant used in the oxidation reaction is one or more of air, hydrogen peroxide, sodium hypochlorite, sulfur powder, sulfur dioxide, thionyl chloride, sulfonyl chloride, concentrated sulfuric acid, sulfur dichloride and sulfur trioxide, and is preferably hydrogen peroxide, thionyl chloride and sulfur powder. The preferred reaction temperature for the above reactions is in the range of 30 ℃ to 50 ℃; the reaction time is 1-5h; the molar ratio of the formula IV to the oxidant is 1:0.1-5, preferably 1:1-2.
The invention also provides application of the compound shown in the formula V in preparation of topramezone.
The present invention provides a compound of formula IV,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The invention also provides the compound of the formula IV and a preparation method thereof, and the reaction formula is as follows:
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The hydrolysis reaction in the above preparation method is hydrolysis under acidic conditions, and the acid includes sulfuric acid, phosphoric acid, nitric acid and hydrochloric acid, preferably hydrochloric acid. The temperature during the above reaction is in the range of 0 to 30 ℃, preferably 10 to 25 ℃. The hydrolysis reaction yield is higher under the above conditions. Further, the hydrolysis reaction is carried out by adding organic solvent, which is halogenated alkane, preferably dichloromethane and dichloroethane. The invention also provides application of the compound shown in the formula IV in preparation of topramezone.
The present invention provides a compound of formula III,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The invention also provides a compound of the formula III and a preparation method thereof, the preparation method comprises the following steps of preparing the compound of the formula III by halogenating the compound of the formula II,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The halogenating reagent used in the halogenation reaction is one of phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, thionyl chloride, sulfonyl chloride, oxalyl chloride, solid light, carbon tetrachloride, NBS and NCS, preferably sulfonyl chloride, solid light, oxalyl chloride, phosphorus oxychloride and phosphorus oxybromide; in the preparation method, the molar ratio of the compound of the formula (II) to the halogenating agent is 1:0.1-3, preferably 1:0.3-1.5. Wherein the compound of formula II is prepared by reacting a compound of formula (I) with N, N-dimethylformamide methylal or DMF and dimethyl sulfate complex,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group. The reaction temperature of the reaction is 60-110 ℃, preferably 80-100 ℃. The research shows that the N, N-dimethylformamide has better effect than the reaction of DMF and dimethyl sulfate complex, the reaction temperature is too high, the yield is lower, and the reaction is insufficient if the reaction temperature is too low.
The invention further provides a process for the preparation of a compound of formula VI,
the method comprises the following reaction steps:
step (1) preparation of formula II
Step (2) preparation of formula III
Step (3) preparation of formula IV
Step (4) preparation of formula V
Step (5) preparation of formula VI
Wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group, and X is halogen, preferably Cl or Br. The preparation method of the formula II, the formula III, the formula IV, the formula V and the formula VI is as described above.
The present invention will be described in detail by examples. The amounts of reactants and products in the following examples were determined by liquid chromatography (Agilent HPLC 1260). In the following examples, the conversion and selectivity of the reaction were calculated by the following formulas:
conversion = (molar amount of raw material charged-molar amount of raw material remaining in product)/molar amount of raw material charged x 100% selectivity = actual molar amount of target product/theoretical molar amount of target product x 100%
Example 1
Synthesis of Compound 3- ((dimethylamino) methylene) -2-methyl-4-oxocyclohex-1-ene-1-carboxylic acid ethyl ester
Into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser tube, 19g of Hagman ethyl ester (0.1 mol) and 12g of N, N-dimethylformamide methylal (0.11 mol) were charged, and then the reaction was continued at a temperature of 95℃for 3 hours, after which the reaction was completed under a medium control, a crude product was obtained in a quantitative yield of 90%. EI-MS (m/e); 237 (M).
Example 2 the starting material used was N, N-dimethylformamide and dimethyl sulfate complex, the remaining reaction conditions were referred to in example 1, the reaction temperatures of examples 3 and 4 were different from those of example 1, and the remaining reaction conditions were referred to in example 1. The reaction results for examples 1-4 are as follows:
TABLE 1 results of examples 1-4 reactions
Example 5
Synthesis of Compound 4-chloro-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylic acid ethyl ester
To a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser were added 23.7g of ethyl 3- ((dimethylamino) methylene) -2-methyl-4-oxocyclohex-1-ene-1-carboxylate (0.1 mol) and 200g of Dichloromethane (DCM), and 14g of oxalyl chloride (0.11 mol) was slowly added dropwise at a temperature of below 10℃to complete the reaction for 0.5 hour under thermal insulation, followed by completion of the reaction under central control to give ethyl 4-chloro-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylate as a compound in a quantitative yield of 89%. EI-MS (m/e); 255 (M)
Examples 6 to 9 use phosphorus oxychloride, sulfonyl chloride, solid phosgene and thionyl chloride in place of the oxalyl chloride in example 5, respectively, the molar ratios of phosphorus oxychloride, sulfonyl chloride, solid phosgene, thionyl chloride and oxalyl chloride used were the same or different, and the remaining conditions were referred to example 5, and the reaction results of examples 5 to 9 were as follows:
table 2 experimental results for examples 5-9
Examples | Raw materials | Molar ratio of | Conversion (%) | Yield (%) |
5 | Oxalyl chloride | 1.1 | 99 | 89 |
6 | Phosphorus oxychloride | 0.5 | 99 | 85 |
7 | Sulfonyl chloride | 1.1 | 97 | 83 |
8 | Solid phosgene | 0.5 | 99 | 86 |
9 | Thionyl chloride | 1.2 | 98 | 75 |
Example 10
Synthesis of Compound 4-bromo-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylic acid ethyl ester
In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 23.7g (0.1 mol) of 3- ((dimethylamino) methylene) -2-methyl-4-oxocyclohex-1-ene-1-carboxylate and 200g of Dichloromethane (DCM) were added, and 14g (0.05 mol) of phosphorus tribromoxide was slowly added dropwise at a temperature below 10℃to complete the reaction for 0.5 hour under thermal insulation, and the reaction was completed under central control to obtain the compound 4-chloro-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylate in a yield of 88%. EI-MS (m/e); 299 (M)
Example 11
Synthesis of 4-chloro-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester
In a four-necked flask equipped with mechanical stirring, a thermometer and a condenser, 27g of 4-chloro-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylic acid ethyl ester (0.1 mol) and 100g of DCM were added, 10g (36.5%) of hydrochloric acid and 50g of water were then added, stirring was carried out at room temperature for 1 hour, the reaction was completed under a medium control, the mixture was allowed to stand for delamination, and the organic phase was dried by spinning to obtain the compound 4-chloro-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester in a yield of 99%. CI-MS (m/e); 229 (M+1)
Example 12
Synthesis of 4-bromo-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester
In a four-necked flask equipped with mechanical stirring, a thermometer and a condenser tube, 30g of the compound 4-bromo-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylic acid ethyl ester (0.1 mol) and 100g of DCM were added, 10g of hydrochloric acid and 50g of water were then added, stirring was carried out at room temperature for 1 hour, the reaction was completed under a medium control, the mixture was allowed to stand for delamination, and the organic phase was dried by spinning to obtain the compound 4-bromo-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester in a yield of 99%. CI-MS (m/e); 273 (M+1).
Example 13
Synthesis of 4-chloro-3-formyl-2-methylbenzoic acid ethyl ester
Into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser tube, 22.8g of 4-chloro-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester (0.1 mol), 200g of DCM and 14.1g of thionyl chloride (0.12 mol) were slowly added dropwise at room temperature, and after the completion of the dropwise addition, the temperature was raised to 40℃for 2 hours, and the reaction was completed by sampling and central control. ( 1 H NMR(500MHz,CDCl 3 ) δ=10.61 (s, 1H), 7.83 (d, j= 8.4,1H), 7.36 (d, j= 8.4,1H), 4.38 (q, j= 7.1,2H), 2.70 (s, 3H), 1.40 (t, j= 7.1,3H), yield 80%. CI-MS (m/e); 227 (M+1)
The amount of thionyl chloride used in example 14 was varied from example 13, the remaining conditions were the same, and example 15 replaced the thionyl chloride used in example 13 with sulfur dichloride, the molar ratio used was slightly varied, and the remainder was made reference to example 14. The reaction results of examples 13 to 15 are as follows.
TABLE 3 reaction results for examples 13-15
Examples | Raw materials | Molar ratio of | Conversion (%) | Yield (%) |
13 | Thionyl chloride | 1.2 | 99 | 80 |
14 | Hydrogen peroxide (30%) | 1 | 99 | 92 |
15 | Sulfur powder | 1.2 | 98 | 88 |
Example 16
Synthesis of 4-bromo-3-formyl-2-methylbenzoic acid ethyl ester
Into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser tube, 27.8g (0.1 mol) of 4-bromo-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester, 200g of DCM and 14.1g (0.12 mol) of thionyl chloride were slowly added dropwise at room temperature, the temperature was raised to 40℃after the completion of the dropwise addition and the reaction was carried out for 2 hours, and the sampling and the central control reaction were completed to obtain the compound ethyl 4-bromo-3-formyl-2-methylbenzoate, the yield was 88%. CI-MS (m/e); 271 (M+1)
Example 17
Synthesis of the Compound ethyl 3-formyl-2-methyl-4- (methylthio) benzoate
22.6g of 4-chloro-3-formyl-2-methylbenzoic acid ethyl ester (0.1 mol) and 100g of HMPA are added into a four-port bottle provided with a mechanical stirring device, a thermometer and a condenser, 4.2g of sodium bicarbonate (0.05 mol) is added, 105g of 20% sodium methyl mercaptan solution (0.3 mol) is slowly added dropwise at room temperature, the dropwise reaction is carried out for 0.5 hour after the heat preservation, the central control reaction is complete, 100g of DCM (DCM), 100g of water are added into the reaction solution, the mixture is extracted and layered, and the organic phase is dried by spinning to obtain the compound 3-formyl-2-methyl-4- (methylthio) ethyl benzoate 1 H NMR(400MHz,CDCl 3 ) δ=10.65 (s, 1H), 7.91 (d, j= 8.6,1H), 7.22 (d, j= 8.6,1H), 4.38 (q, j= 7.1,2H), 2.84 (s, 3H), 2.48 (s, 3H), 1.40 (t, j= 7.1,3H), yield 95%. CI-MS (m/e); 239 (M+1).
Examples 18-23 the remaining reaction conditions were as described in example 17 by varying the respective sodium methyl mercaptide, the type of solvent and the type and amount of base. The reaction results are shown in the following table.
TABLE 4 EXAMPLES 17-23 EXAMPLES reaction results
Example 24
Synthesis of the Compound ethyl 3-formyl-2-methyl-4- (methylthio) benzoate
In a four-port bottle equipped with a mechanical stirrer, a thermometer and a condenser tube, 27g (0.1 mol) of ethyl 4-bromo-3-formyl-2-methylbenzoate and 100g of DMSO are added, then 4.2g (0.05 mol) of sodium bicarbonate is added, 105g (0.3 mol) of 20% sodium methyl mercaptan solution is slowly added dropwise at room temperature, the dropwise addition is completed for 0.5 hour of thermal insulation reaction, the medium control reaction is complete, 100g of DCM (DCM), 100g of water are added into the reaction solution, the extraction and delamination are carried out, and the organic phase is dried by spinning, thus obtaining the compound 3-formyl-2-methyl-4- (methylthio) ethyl benzoate with the yield of 93%. CI-MS (m/e); 239 (M+1)
Example 25
Synthesis of Compound 3- ((hydroxyimino) methyl) -2-methyl-4- (methylthio) benzoic acid ethyl ester
23.8g (0.1 mol) of ethyl 3-formyl-2-methyl-4- (methylthio) benzoate was weighed into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, dissolved in 200g of acetonitrile, 7.9g of sodium carbonate (0.74 mol), 9g of hydroxylamine hydrochloride (0.13 mol) were added, stirred at room temperature for 5 hours, after the completion of the reaction, the solvent was concentrated, 100g of water was added, 100g of DCM was extracted and separated, and the organic phase was concentrated to give ethyl 3- ((hydroxyimino) methyl) -2-methyl-4- (methylthio) benzoate as a compound in a yield of 98%. CI-MS (m/e); 254 (M+1)
Example 26
Synthesis of Compound 3- (4, 5-dihydro-isoxazol-3-yl) -2-methyl-4- (methylthio) benzoic acid ethyl ester
25.3g (0.1 mol) of the compound 3- ((hydroxyimino) methyl) -2-methyl-4- (methylthio) ethyl benzoate, 4.2g of sodium bicarbonate (0.05 mol), 200g of DCM and 187g (0.2 mol) of 8% sodium hypochlorite solution are slowly added dropwise at-5 ℃ for half an hour after the dropwise addition, 4MPa ethylene gas is introduced into the autoclave at the reaction temperature of lower than 0 ℃ until the pressure of the autoclave is not reduced, after the reaction, the pH of the reaction solution is adjusted to 4-5, the mixture is stood for layering, the organic phase is dried by spinning, and the yield is 95%. CI-MS (M/e), 280 (M+1).
Example 27
Synthesis of Compound 3- (4, 5-dihydro-isoxazol-3-yl) -2-methyl-4- (methylthio) benzoic acid ethyl ester
25.3g (0.1 mol) of the compound 3- ((hydroxyimino) methyl) -2-methyl-4- (methylthio) ethyl benzoate, 4.2g of sodium bicarbonate (0.05 mol), 200g of DCM and 280g (0.2 mol) of 8% sodium hypochlorite solution are slowly added dropwise at-5 ℃ for half an hour after the dropwise addition, 4MPa ethylene gas is introduced into the autoclave at room temperature, the air pressure of the autoclave is continuously supplemented until the air pressure of the autoclave is not reduced, after the reaction is finished, the pH value of the reaction solution is adjusted to 4-5, the reaction solution is kept still for layering, and the organic phase is dried by spinning, so that about 30% of sulfoxide product is formed. CI-MS (m/e); 280 (M+1), 296 (M+1).
Example 28
Synthesis of Compound 3- (4, 5-Dihydroisoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoic acid ethyl ester
27.9g (0.1 mol) of ethyl 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4- (methylthio) benzoate as a compound is weighed in a four-port bottle provided with a mechanical stirrer, a thermometer and a condenser, 200g of toluene, 1g of concentrated sulfuric acid, 3g of acetic acid and 0.3g of sodium tungstate are added, the temperature is raised to 75 ℃, 45.5g (0.4 mol) of 30% hydrogen peroxide is slowly added dropwise, after the dropwise addition is completed, the temperature is raised to reflux for 3 hours, and after the reaction is completed, cooling, standing and layering are carried out, and the quantitative yield is 98%. CI-MS (m/e); 312 (M+1)
Example 29
Synthesis of the Compound 3- (4, 5-Dihydroisoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoic acid
31.1g (0.1 mol) of ethyl 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoate as a compound was weighed into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 200g of toluene and 80g of 10% sodium hydroxide solution (0.2 mol) were added, the temperature was raised to reflux for 2 hours, and after the reaction was completed, the mixture was allowed to stand and separate, the pH of the aqueous phase was adjusted to 2-3, a white solid was precipitated, and the yield was 99% 1 H NMR(500MHz,DMSO)δ=8.02(d,J=8.3,1H),7.97(d,J=8.3,1H),4.48(t,J=10.0,2H),3.32(t,J=10.0,2H),3.25(s,3H),2.42(s,3H)。CI-MS(m/e);282(M-1)
Example 30
Synthesis of 3- (4, 5-dihydro-isoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoyl chloride
28.3g (0.1 mol) of 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoic acid, 200g of DCE and 1mL of DMF are weighed into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, the temperature is raised to 75 ℃, 14.2g of thionyl chloride (0.12 mol) is slowly added dropwise, the reaction is carried out for 3 hours after the dropwise addition, and the superfluous thionyl chloride is distilled off after the reaction is finished, so that the yield is 99%. CI-MS (m/e); 312 (M+OCH3+1)
Example 31
Synthesis of 1-methyl-1H-pyrazol-5-yl-3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoate
9.8g of 1-methyl-5-hydroxypyrazole (0.1 mol) and 100g of DCE are weighed in a four-mouth bottle with a mechanical stirrer, a thermometer and a condenser, 15g of triethylamine is added, the temperature is reduced to below 10 ℃, the acyl chloride solution is slowly added dropwise, the reaction is kept for half an hour after the dropwise addition, sampling monitoring is carried out, standing and layering are carried out after the reaction is completed, and the organic phase is refluxed and dehydrated, so that the yield is 97%. CI-MS (m/e); 364 (M+1)
Example 32
Synthesis of topramezone
To the above solution, 20.7g (0.15 mol) of potassium carbonate powder and 1g of DMAP were added, the temperature was raised to reflux, the reaction was allowed to proceed for about 5 hours, after the completion of the reaction, the reaction was cooled to room temperature, 200g of water was added and the pH was adjusted to about 3, and the organic phase was concentrated, purified and the yield was 93%. CI-MS (m/e); 364 (M+1)
According to the method for preparing the 3-formyl-2-methyl-4- (methylthio) benzoate compound, higher reaction conversion rate and selectivity can be obtained, and the cost is greatly reduced.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
Claims (21)
1. The preparation method of topramezone is characterized by comprising the following steps:
step one, a compound of a formula VI is subjected to oxime formation with a salt of hydroxylamine under alkaline conditions, and the prepared product oxime is subjected to ring closure with ethylene to prepare a compound of a formula VII, wherein the salt of hydroxylamine is preferably hydroxylamine hydrochloride or hydroxylamine sulfate;
oxidizing the compound of the formula VII by an oxidant to obtain a corresponding sulfone product, and performing alkaline hydrolysis on the sulfone product to obtain a formula VIII;
step three, reacting a compound shown in a formula VIII with an acylating agent to obtain an acylated product, forming ester by the acylated product and 1-methyl-5-hydroxypyrazol, and then preparing the topramezone technical product through a rearrangement reaction under the condition of a catalyst;
wherein, the structures of the formula VI, the formula VII, the formula VIII and the topramezone are as follows:
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
2. The process according to claim 1, wherein the base in step (one) is an inorganic base, and the inorganic base is one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide, preferably sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
3. The method of claim 1, wherein the oxidizing agent in step (two) is one of peroxy compound, oxygen, and hypochlorite, preferably one of hydrogen peroxide, oxygen, and sodium hypochlorite, most preferably hydrogen peroxide.
4. The method according to claim 1, wherein the acid chloride reagent in step (iii) is one of thionyl chloride, sulphuryl chloride, oxalyl chloride and phosphorus oxychloride, preferably thionyl chloride; the transposition catalyst is one of 4-dimethylaminopyridine and acetone cyanohydrin.
5. The compound of the formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
6. A process for the preparation of a compound of formula VI as claimed in claim 5, comprising the step of substitution reaction of a compound of formula V with sodium methyl mercaptide in a polar aprotic solvent to give a compound of formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
7. The preparation method according to claim 6, wherein a base is further added in the reaction, and the base may be an organic base or an inorganic base; the inorganic alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; the organic base is preferably one or more of sodium methoxide, sodium ethoxide, sodium acetate and ammonium acetate; more preferably one or more of sodium bicarbonate, sodium acetate, ammonium acetate; the polar aprotic solvent is any one or a combination of more than one of hexamethylphosphoric triamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dioxane; preferably one or a combination of more than one of hexamethylphosphoric triamide, dimethyl sulfoxide and N, N-dimethylformamide; the molar ratio of the compound of formula V to the alkali to the sodium methyl mercaptide is 1:0.1-2:1-4, preferably 1:0.1-0.5:1-3.
8. The use of a compound of formula VI as claimed in claim 5 for the preparation of topramezone.
9. The compound of formula V,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
10. The process for preparing a compound of formula V as claimed in claim 9, comprising the steps of oxidizing a compound of formula IV with an oxidizing agent to obtain a compound of formula V;
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
11. The method according to claim 10, wherein the oxidizing agent is one of air, hydrogen peroxide, sodium hypochlorite, sulfur powder, sulfur dioxide, thionyl chloride, sulfonyl chloride, concentrated sulfuric acid, sulfur dichloride and sulfur trioxide, preferably one of hydrogen peroxide, thionyl chloride and sulfur powder; the molar ratio of the compound of formula IV to the amount of oxidant is 1:0.1-5, preferably 1:1-2, and the reaction temperature is 10-50 ℃.
12. The use of a compound of formula V according to claim 9 for the preparation of topramezone.
13. The compound of the formula IV,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
14. The compound of formula IV of claim 13The preparation method of the compound is characterized by comprising the following steps of preparing a compound of a formula IV by hydrolysis reaction of the compound of the formula III;
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
15. The process for the preparation of a compound of formula IV according to claim 14, wherein the hydrolysis reaction conditions are reaction at room temperature under the action of an acid selected from one or more of sulfuric acid, hydrochloric acid, nitric acid, preferably hydrochloric acid.
16. The use of a compound of formula IV as defined in claim 13 for the preparation of topramezone.
17. A compound of the formula III,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
18. A process for the preparation of a compound of formula III as claimed in claim 17, comprising the step of reacting a compound of formula II with a halogenating agent to produce a compound of formula III,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is Cl or Br.
19. The method according to claim 18, wherein the halogenated reagent is one of phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, thionyl chloride, sulfuryl chloride, oxalyl chloride, solid light, carbon tetrachloride, N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS), preferably one of sulfuryl chloride, solid light, oxalyl chloride, phosphorus oxychloride and phosphorus oxybromide; the molar ratio of the compound of formula (II) to the halogenating agent is 1:0.1-3, preferably 1:0.3-1.5, and the reaction temperature is in the range of-10 ℃ to 30 ℃.
20. The process according to claim 18 or 19, comprising the step of reacting a compound of formula II with N, N-dimethylformamide methylal or a complex of N, N-dimethylformamide and dimethyl sulfate,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; the reaction temperature of the reaction is 60-110 ℃, preferably 80-110 ℃.
21. The use of a compound of formula III according to claim 17 for the preparation of topramezone.
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