CN115210220A - 用于制备5-氯-3-烷基硫烷基-吡啶-2-甲酸酰胺和甲酸酯的方法 - Google Patents
用于制备5-氯-3-烷基硫烷基-吡啶-2-甲酸酰胺和甲酸酯的方法 Download PDFInfo
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- CN115210220A CN115210220A CN202180018538.3A CN202180018538A CN115210220A CN 115210220 A CN115210220 A CN 115210220A CN 202180018538 A CN202180018538 A CN 202180018538A CN 115210220 A CN115210220 A CN 115210220A
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- compound
- hydrogen
- pyridyl
- pyridine
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- 238000000034 method Methods 0.000 title claims description 21
- 238000002360 preparation method Methods 0.000 title description 19
- 150000004675 formic acid derivatives Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 33
- -1 C 1 -C 4 Hydroxyalkyl radical Chemical class 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- ZBPYOEMMLMVVQT-UHFFFAOYSA-N 5-chloropyridine-2-carboxamide Chemical compound NC(=O)C1=CC=C(Cl)C=N1 ZBPYOEMMLMVVQT-UHFFFAOYSA-N 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 3
- 150000008041 alkali metal carbonates Chemical group 0.000 claims description 3
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 150000002431 hydrogen Chemical class 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- OSDAWKAYCWGGSK-UHFFFAOYSA-N ClC=1C=C(C(=NC=1)C(=O)N)SCC Chemical compound ClC=1C=C(C(=NC=1)C(=O)N)SCC OSDAWKAYCWGGSK-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- QIRSAVRBVNYEMF-UHFFFAOYSA-N 3,5-dichloropyridine-2-carboxamide Chemical compound NC(=O)C1=NC=C(Cl)C=C1Cl QIRSAVRBVNYEMF-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical group CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003905 agrochemical Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000006177 thiolation reaction Methods 0.000 description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 2
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 description 2
- JYKZCYLZWZCQFP-UHFFFAOYSA-N 3,5-dichloropyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=C(Cl)C=C1Cl JYKZCYLZWZCQFP-UHFFFAOYSA-N 0.000 description 2
- RISGCNIMLSEKCB-UHFFFAOYSA-N ClC=1C=C(C(=NC=1)C(=O)NC1=CC=CC=C1)SCC Chemical compound ClC=1C=C(C(=NC=1)C(=O)NC1=CC=CC=C1)SCC RISGCNIMLSEKCB-UHFFFAOYSA-N 0.000 description 2
- HDGGNIXWVAQPOD-UHFFFAOYSA-N ClC=1C=C(C(=NC=1)C(=O)NC1CCCC1)SCC Chemical compound ClC=1C=C(C(=NC=1)C(=O)NC1CCCC1)SCC HDGGNIXWVAQPOD-UHFFFAOYSA-N 0.000 description 2
- OMEPMPYBJGAWHI-UHFFFAOYSA-N ClC=1C=C(C(=NC=1)C(=O)NCC)SCC Chemical compound ClC=1C=C(C(=NC=1)C(=O)NCC)SCC OMEPMPYBJGAWHI-UHFFFAOYSA-N 0.000 description 2
- OKZRYTQVIDYOOG-UHFFFAOYSA-N ClC=1C=C(C(=NC=1)C(=O)O)SCC Chemical compound ClC=1C=C(C(=NC=1)C(=O)O)SCC OKZRYTQVIDYOOG-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- CNLIIAKAAMFCJG-UHFFFAOYSA-N 2,3,5-trichloropyridine Chemical compound ClC1=CN=C(Cl)C(Cl)=C1 CNLIIAKAAMFCJG-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- ATUOLSDAAPMVJJ-UHFFFAOYSA-N 3,5-dichloropyridine-2-carbonitrile Chemical compound ClC1=CN=C(C#N)C(Cl)=C1 ATUOLSDAAPMVJJ-UHFFFAOYSA-N 0.000 description 1
- RNRLTTNKVLFZJS-UHFFFAOYSA-N 5,6-dichloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(Cl)C(Cl)=C1 RNRLTTNKVLFZJS-UHFFFAOYSA-N 0.000 description 1
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 1
- GJLOKYIYZIOIPN-UHFFFAOYSA-N 5-chloropyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)C=N1 GJLOKYIYZIOIPN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- DCCXNHXRYAIMFA-UHFFFAOYSA-N ClC=1C(=NC=C(C=1)Cl)C(=O)NC1=CC=CC=C1 Chemical compound ClC=1C(=NC=C(C=1)Cl)C(=O)NC1=CC=CC=C1 DCCXNHXRYAIMFA-UHFFFAOYSA-N 0.000 description 1
- DSNMTUFXHNIIPZ-UHFFFAOYSA-N ClC=1C(=NC=C(C=1)Cl)C(=O)NC1CCCC1 Chemical compound ClC=1C(=NC=C(C=1)Cl)C(=O)NC1CCCC1 DSNMTUFXHNIIPZ-UHFFFAOYSA-N 0.000 description 1
- ZISAPFSJPFLUTR-UHFFFAOYSA-N ClC=1C(=NC=C(C=1)Cl)C(=O)NC=1C(=NC=C(C=1)C(F)(F)F)NC Chemical compound ClC=1C(=NC=C(C=1)Cl)C(=O)NC=1C(=NC=C(C=1)C(F)(F)F)NC ZISAPFSJPFLUTR-UHFFFAOYSA-N 0.000 description 1
- NRVHTVNGDCSVRS-UHFFFAOYSA-N ClC=1C(=NC=C(C=1)Cl)C(=O)NCC Chemical compound ClC=1C(=NC=C(C=1)Cl)C(=O)NCC NRVHTVNGDCSVRS-UHFFFAOYSA-N 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000005910 aminocarbonylation reaction Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000006229 isopropoxyethyl group Chemical group [H]C([H])([H])C([H])(OC([H])([H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- MVILWLLYYQVYNH-UHFFFAOYSA-N pyridine-2-carboxamide Chemical compound NC(=O)C1=CC=CC=N1.NC(=O)C1=CC=CC=N1 MVILWLLYYQVYNH-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical group [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Abstract
提供了一种用于制备具有式(I)的化合物的方法:其中R1和R2是如在说明书中所定义的。
Description
本发明涉及可用作用于制备农用化学品的中间体的5-氯吡啶-2- 甲酸酰胺以及具有3-含硫取代基的甲酸酯的制备。
更特别地,本发明涉及具有式I的5-氯吡啶-2-甲酸酰胺或具有式 (I)的化合物的农用化学上可接受的盐,并且涉及其制备方法
其中R1是氢、C1-C4烷基、C1-C4羟烷基、C3-C7环烷基、芳基或任选地取代的杂芳基;优选地,R1是C1-C4烷基或氢,更优选地R1是氢;R2是C1-C4烷基;优选地,R2是乙基。
本发明还涉及具有式II的5-氯吡啶-2-甲酸及其盐,并且涉及其制备方法
其中R3是H、Li、Na或K;R2是C1-C4烷基
某些具有3-烷基硫烷基取代基的5-卤代-吡啶-2-甲酸(及其某些对应的酯、酰胺和盐)可用作用于制备农用化学工业中的生物活性化合物的中间体,如先前例如在以下中描述的:WO 2016/005263、WO 2016/030229、WO 2016/059145、WO 2016/096584、WO 2016/104746、 WO 2018/059145、WO 2019/065568和JP 2019081800。
如本文使用的,术语“C1-C4烷基”是指具有1至4个碳原子的经由这些碳原子中任一个附接的饱和直链或支链烃基,例如以下基团中的任一个:甲基、乙基、正丙基、丁基、仲丁基、叔丁基。
卤代烷基基团优选地具有1至4个碳原子的链长。C1-C4卤代烷基是例如氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、2,2,2-三氟乙基、2-氟乙基、2-氯乙基、2,2-二氟乙基、五氟乙基、1,1-二氟-2,2,2-三氯乙基、2,2,3,3-四氟乙基和2,2,2-三氯乙基。
羟烷基基团优选地具有1个至4个碳原子的链长。C1-C4羟烷基是例如甲氧基甲基、甲氧基乙基、乙氧基甲基、乙氧基乙基、正丙氧基甲基、正丙氧基乙基、异丙氧基甲基或异丙氧基乙基。
如本文使用的,术语“芳基”是指仅由碳原子和氢原子组成的芳香族环体系,该芳香族环体系可以是单环的、二环的或三环的。此类环体系的实例包括苯基、萘基、蒽基、茚基或菲基;优选苯基。
如本文使用的,术语“杂芳基”一般是指包含1、2、3或4个单独地选自氮、氧和硫的杂原子的5-或6-元单环芳香族环基团。杂芳基基团经碳原子键合至分子的剩余部分。杂芳基的实例可包括吡啶基、嘧啶基、吡咯基、吡唑基、呋喃基、噻吩基、咪唑基、异噁唑基、噁唑基、噻唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡嗪基、哒嗪基、三嗪基、吡喃基;优选吡啶基。
在一个实施例中,杂芳基任选地被例如,1个或2个选自氨基、 C1-C4烷基氨基(优选甲基氨基)和C1-C4卤代烷基(优选三氟甲基) 的取代基取代。
如本文使用的,术语“C3-C7环烷基”是指3-7元环烷基基团,如环丙烷、环丁烷、环戊烷、环己烷和环庚烷。
5-卤代-吡啶-2-甲酸以及具有3-烷基硫烷基取代基的甲酸酯的已知合成涉及许多反应步骤。例如,已经报道了获得5-溴衍生物的两种途径(途径A:CN 105218437;途径B:US 2012/0165338或J.Org.Chem. [有机化学期刊]2009,74,4547-4553),并且这两种途径示于方案 1中(R1是H、C1-C4烷基或碱金属离子)。
方案1.获得5-Br衍生物的途径
在WO 2016/104746中已报道了如方案2中所示从可商购的5,6- 二氯烟酸在七个步骤中获得相应的5-碘衍生物。
方案2.获得5-碘衍生物的途径
先前未报道过含有5-氯取代基的具有式(II)的甲酸酯或具有式 (II)的酰胺,然而原则上可使用本领域技术人员熟知的方法如上所述类似地进行制备。尽管如此,此类费时且费力的合成由于总产率低且产生大量废物而不适用于制备大量材料。
因此,获得对这些有用的中间体更有效且更经济的途径将是有利的。
3,5-二氯吡啶-2-甲酸的酰胺是方便的起始原料,因为它们可通过标准方法从可商购的3,5-二氯吡啶-2-甲酸及其酯或者通过氨基羰基化从2,3,5-三氯吡啶容易地制备。3,5-二氯吡啶-2-甲酰胺也可以通过使用标准方法将可商购的3,5-二氯吡啶-2-甲腈半水解来制备。然后在3-位置对氯进行选择性置换将产出具有式(I)的化合物,其中R1和R2是如先前所定义的。如有需要,可以使用标准方法水解具有结构(I)的化合物,以产出具有式(II)的化合物,其中R3是H、Li、Na或K(方案3)。
方案3.从(VIII)或(IX)到(VI)或(VII)的设想的途径
已在Synth.Comm.[合成通讯杂志]1995,899中报道了苯基系列中卤素的邻位选择性置换(方案4),吡啶甲酸系列中的类似转化是未知的。
方案4.苯基系列中的邻位选择性置换
然而,将针对具有式(III)的化合物的转化报道的条件直接应用于具有式(I)的化合物导致非常低的选择性或者完全形成不需要的异构体作为主要产物。
因此,根据本发明,提供了一种用于制备具有式I的化合物的方法:
其中R1是氢、C1-C4烷基、C1-C4羟烷基、C3-C7环烷基、芳基或任选地取代的杂芳基;优选地,R1是C1-C4烷基或氢,更优选地R1是氢;并且R2是C1-C4烷基;优选地,R2是乙基;该方法包括:
在合适的碱的存在下,在介电常数小于15的适当的溶剂(或稀释剂)中,使具有式(III)的化合物
与硫醇化合物R4-S-R2反应,其中R2是如在式I中所定义的并且 R4是H或碱金属离子;优选地,R4是H、钠、钾或锂;
以产生具有式(I)的化合物或其盐
在碱性或酸性条件下水解该具有式(I)的化合物或其盐;以产生具有式(II)的化合物,其中R2是C1-C4烷基;优选地,R2是乙基,并且R3是氢、钠、钾或锂;优选地,R3是氢。
在一个实施例中,R1是氢、C1-C4烷基、C1-C4羟烷基、C3-C7环烷基、芳基或任选地取代的杂芳基,并且R2是C1-C4烷基;优选地, R1是C1-C4烷基或氢,并且R2是乙基;更优选地,R1是氢,并且R2是乙基。
在另一个实施例中,R1是氢、C1-C2烷基、C1-C2羟烷基、C3-C5环烷基、苯基、吡啶基或者可以被氨基、甲基氨基或三氟甲基单或双取代的吡啶基,并且R2是C1-C2烷基;优选地,R1是甲基或氢,并且 R2是乙基。
在另外的实施例中,R1是氢、甲基、乙基、苯基、环丙基、环戊基、羟甲基、羟乙基、吡啶基或2-(甲基氨基)-5-(三氟甲基)-3-吡啶基,并且R2是乙基;优选地,R1是氢、乙基、苯基、环戊基、羟乙基或 2-(甲基氨基)-5-(三氟甲基)-3-吡啶基,并且R2是乙基。
此方法被证明具有很大的有用性,因为它允许相对于先前所述途径以更高的产率和更有利的条件合成用于制备农用化学品的关键结构单元。
出人意料地发现,在非质子和质子非极性溶剂中均观察到对3,5- 二氯吡啶甲酸酰胺的硫醇化的高邻位选择性。特别地,发现该选择性受到溶剂性质的显著影响:在具有高相对介电常数的溶剂(即,DMF [介电常数为36.7])中,观察到对“对”异构体(V)的高选择性,而在具有低相对介电常数的溶剂(即,THF、吡啶、苯甲醚…[介电常数为7.6、12.4、4.3])中,观察到“邻”异构体(由具有式IV的化合物表示的具有式(I)的化合物)的选择性形成。此外,使用低介电常数溶剂极大地减少了具有式(VI)的化合物的形成。此概念示于方案 5中。
方案5.(III)的硫醇化的观察到的选择性
在本发明的另一个实施例中,提供了一种由具有式IV的化合物或具有式IV的化合物的农用化学上可接受的盐表示的具有式I的化合物,其中R1是如针对具有式I的化合物所定义的:
在具有式IV的化合物中,可以提及如下化合物,其中R1是氢、 C1-C4烷基、C1-C4羟烷基、C3-C7环烷基、芳基或任选地取代的杂芳基;优选地,R1是C1-C4烷基或氢,更优选地R1是氢。
在一个实施例中,R1是氢、C1-C2烷基、C1-C2羟烷基、C3-C5环烷基、苯基、吡啶基或者可以被氨基、甲基氨基或三氟甲基单或双取代的吡啶基;优选地,R1是甲基或氢,更优选地,R1是氢。
在另外的实施例中,R1是氢、甲基、乙基、苯基、环丙基、环戊基、羟甲基、羟乙基、吡啶基或2-(甲基氨基)-5-(三氟甲基)-3-吡啶基;优选地,R1是氢、乙基、苯基、环戊基、羟乙基或2-(甲基氨基)-5-(三氟甲基)-3-吡啶基。
在本发明的另外的实施例中,提供了一种由具有式IIa的化合物表示的具有式II的化合物:
其中R3是氢、钠、钾或锂;优选地,R3是氢。
参照方案5对根据本发明的用于制造具有式(I)的化合物的方法的某些方面进行进一步详述和解释。应当理解的是,具有式I的化合物在方案5中由具有式IV的化合物表示。
在根据本发明的用于制造具有式(I)的化合物的方法(方案5) 中,合适的碱的实例是碱金属氢氧化物或碱金属碳酸盐。可以提及的实例是氢氧化钠、碳酸钠、氢氧化锂、氢氧化钾和碳酸钾;优选碱金属碳酸盐,更优选碳酸钠或碳酸钾。
在根据本发明的制造具有式(I)的化合物的方法(方案5)中,适当的溶剂(或稀释剂)的实例是介电常数小于15的那些;更优选地,介电常数小于12的溶剂(或稀释剂);甚至更优选地,介电常数小于 10的溶剂(或稀释剂)。在另一个实施例中,适当的溶剂(或稀释剂) 的介电常数小于6。适当的溶剂(或稀释剂)的实例是二噁烷、四氢呋喃、2-甲基四氢呋喃、甲苯、苯甲醚、吡啶、丙酮、甲基异丁基酮、乙酸乙酯、叔丁醇、桉树油;更优选地,非极性有机溶剂选自二噁烷、 2-甲基四氢呋喃或四氢呋喃;最优选地,适当的溶剂是介电常数在从 1.5至15范围内的那些。
在一个实施例中,在根据本发明的制造具有式(I)的化合物的方法(方案5)中,反应在从大约0℃至大约+100℃,优选从大约0℃至大约+50℃的温度范围内有利地进行,在许多情况下在环境温度与大约+40℃之间的范围内进行。在优选的实施例中,反应在环境温度下进行。
在一个优选的实施例中,本发明提供了在可扩大的条件下使用乙硫醇钠或乙硫醇以及碱在选择的质子或非质子非极性溶剂(介电常数小于15)中的具有式(III)的3,5-二氯吡啶甲酸酰胺化合物的高度选择性硫醇化反应,其中R1是如在式I中所定义的,产生(例如,烷基或与R1相对应的其他部分)具有式(IV)的5-氯-3-乙基硫烷基-吡啶 -2-甲酰胺中间体。
其中R1(包括R1的优选实施例中的任一个)是如上所定义的。
制备实例:
使用1,3,5-三甲氧基苯作为内标,用定量1H NMR确定起始材料和产物的纯度。
实例1:5-氯-3-乙基硫烷基-吡啶-2-甲酰胺的制备
将3,5-二氯吡啶-2-甲酰胺(6.50g,95%纯度,32.5mmol)和EtSNa (3.33g,82%纯度,32.5mmol)悬浮于MeTHF(100ml)中,并在环境温度下搅拌浅棕色悬浮液。在2h和4h的反应时间后,添加额外量的EtSNa(2x 0.167g,82%纯度,1.62mmol)。在5h的总反应时间后,用水(50ml)萃取反应溶液,用EtOAc(2x 50ml)萃取水相,并且将合并的有机层用盐水洗涤,经无水MgSO4干燥,并在减压下蒸发。在高真空下干燥得到呈白色粉末的5-氯-3-乙基硫烷基-吡啶-2-甲酰胺(7.36g,94%纯度,97%产率)。
1H NMR(400MHz,DMSO-d6)δppm 8.35(d,J=2.2Hz,1H), 8.01(br s,1H),7.85(d,J=2.2Hz,1H),7.61(br s,1H),2.93(q,J=7.3 Hz,2H),1.25(t,J=7.3Hz,3H)
实例1a:用于制备5-氯-3-乙基硫烷基-吡啶-2-甲酰胺的替代性程序
在具有顶置式搅拌器的1L双层夹套玻璃反应器中装入3,5-二氯吡啶-2-甲酰胺(100.0g,0.52mol)和Me-THF(400g)。固体在搅拌下溶解,得到均匀的无色溶液。以单份添加固体NaOH(31.5g,0.79 mol)。经40min向该悬浮液中滴加乙硫醇(32.5g,0.52mol),同时添加时施加放热冷却以保持Ti=25℃。完全添加后,将混合物在 Ti=25℃搅拌90min,然后加热到Ti=65℃持续120min。在此期间之后,达到完全完成,添加水(100g),并将双相混合物在Ti=65℃下搅拌10min。分离各相,并将有机层在Ti=65℃下用水(2x 60g) 洗涤。通过蒸馏出250g的溶剂将有机相部分浓缩。在Ti=65℃下添加抗溶剂甲基环己烷(150g),并且经60min将均匀的混合物冷却至Ti=25℃。在冷却过程中,产物开始从溶液结晶。
将固体过滤,用2x 50g的甲基环己烷洗涤,并在减压下干燥,得到呈白色固体的5-氯-3-乙基硫烷基-吡啶-2-甲酰胺(96g,80%产率)。
实例2:用于制备5-氯-3-乙基硫烷基-吡啶-2-甲酰胺的溶剂筛选
将3,5-二氯吡啶-2-甲酰胺(50-100mg)和NaSEt(1.1eq)悬浮于/溶解于给定的溶剂中,并在环境温度下搅拌5h。然后,将反应混合物用EtOAc稀释,用水和盐水洗涤,将有机层经无水MgSO4干燥并在减压下蒸发。通过1H NMR分析所得粗混合物,得到下表所示的产物比率。
实例3:5-氯-3-乙基硫烷基-吡啶-2-甲酸的制备
将5-氯-3-乙基硫烷基-吡啶-2-甲酰胺(0.500g,95%纯度,2.19 mmol)悬浮于水性3M NaOH(3.3ml,6.6mmol)中,并将所得混合物在100℃下加热20h。将反应混合物冷却至环境温度,并用2M HCl酸化至约pH 3。将所得沉淀物滤出,用冷水在过滤器上洗涤并在高真空下干燥,以产出呈淡粉色粉末的5-氯-3-乙基硫烷基-吡啶-2-甲酸(0.505g,91%纯度,96%产率)。
1H NMR(400MHz,DMSO-d6)δppm 8.44(s,1H),7.95(d,J= 2.2Hz,1H),3.14(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3H)
实例4:5-氯-N-乙基-3-乙基硫烷基-吡啶-2-甲酰胺的制备
向3,5-二氯-N-乙基-吡啶-2-甲酰胺(0.100g,0.456mmol)在THF (1.4ml)中的溶液中添加NaSEt(0.052g,82%纯度,0.502mmol),并将所得悬浮液在rt下搅拌3h。将反应混合物用EtOAc稀释,用水和盐水洗涤。将有机层经无水MgSO4干燥并在减压下蒸发,以产出呈灰白色粉末的5-氯-N-乙基-3-乙基硫烷基-吡啶-2-甲酰胺(0.103g,80%纯度,75%产率)。除了约15%未反应的起始材料外,还检测到约3%的不希望的异构体。
1H NMR(400MHz,CDCl3)δppm 8.17(d,J=1.8Hz,1H),7.87 (br s,1H),7.59(d,J=1.8Hz,1H),3.52-3.43(m,2H),2.88(q,J=7.5 Hz,2H),1.42(t,J=7.3Hz,3H),1.25(t,J=7.3Hz,3H)
实例5:5-氯-3-乙基硫烷基-N-苯基-吡啶-2-甲酰胺的制备
向3,5-二氯-N-苯基-吡啶-2-甲酰胺(0.100g,0.374mmol)在THF (1.2ml)中的溶液中添加NaSEt(0.042g,82%纯度,0.412mmol),并将所得悬浮液在rt下搅拌3h。将反应混合物用EtOAc稀释,用水和盐水洗涤。将有机层经无水MgSO4干燥并在减压下蒸发,以产出呈橙色固体的5-氯-3-乙基硫烷基-N-苯基-吡啶-2-甲酰胺(0.096g,83%纯度,73%产率)。约10%未反应的起始材料,但也未检测到不希望的异构体。
1H NMR(400MHz,CDCl3)δppm 9.92(br s,1H),8.26(d,J=1.8 Hz,1H),7.80-7.75(m,2H),7.66(d,J=1.8Hz,1H),7.41-7.35(m,2H), 7.17-7.12(m,1H),2.94(q,J=7.3Hz,2H),1.46(t,J=7.3Hz,3H)
实例6:5-氯-N-环戊基-3-乙基硫烷基-吡啶-2-甲酰胺的制备
向3,5-二氯-N-环戊基-吡啶-2-甲酰胺(0.100g,0.386mmol)在 THF(1.2ml)中的溶液中添加NaSEt(0.044g,82%纯度,0.43mmol),并将所得悬浮液在rt下搅拌3h。将反应混合物用EtOAc稀释,用水和盐水洗涤。将有机层经无水MgSO4干燥并在减压下蒸发,以产出呈橙色固体的5-氯-N-环戊基-3-乙基硫烷基-吡啶-2-甲酰胺(0.091g,87%纯度,72%产率)。约10%未反应的起始材料,但也未检测到不希望的异构体。
1H NMR(400MHz,CDCl3)δppm 8.16(d,J=2.2Hz,1H),7.85 (br s,1H),7.58(d,J=2.2Hz,1H),4.41-4.30(m,1H),2.88(q,J=7.3 Hz,2H),2.13-2.02(m,2H),1.79-1.49(m,6H),1.42(t,J=7.3Hz,3H)
实例7:5-氯-3-乙基硫烷基-N-(2-羟乙基)吡啶-2-甲酰胺的制备
向3,5-二氯-N-(2-羟乙基)吡啶-2-甲酰胺(0.100g,93%纯度,0.396 mmol)在THF(1.2ml)中的溶液中添加NaSEt(0.045g,82%纯度, 0.44mmol),并将所得悬浮液在rt下搅拌3h。将反应混合物用EtOAc 稀释,用水和盐水洗涤。将有机层经无水MgSO4干燥并在减压下蒸发,以产出呈橙色固体的5-氯-3-乙基硫烷基-N-(2-羟乙基)吡啶-2-甲酰胺 (0.084g,82%纯度,67%产率)。除了11%未反应的起始材料外,还检测到约1%的不希望的异构体。
1H NMR(400MHz,CDCl3)δppm 8.28(br s,1H),8.19(d,J=1.8 Hz,1H),7.60(d,J=1.8Hz,1H),3.87-3.81(m,2H),3.66-3.59(m,2H), 2.90(q,J=7.3Hz,2H),2.38(br s,1H),1.43(t,J=7.3Hz,3H)
实例8:5-氯-3-乙基硫烷基-N-[2-(甲基氨基)-5-(三氟甲基)-3-吡啶基]吡啶-2-
甲酰胺的制备
将3,5-二氯-N-[2-(甲基氨基)-5-(三氟甲基)-3-吡啶基]吡啶-2-甲酰胺(1.500g,94%纯度,3.85mmol)溶解于THF(15.4ml)中,并将EtSNa(0.647g,80%纯度,6.15mmol)添加至混合物中。将反应在65℃下搅拌1h 15min(褐色溶液),然后在室温下搅拌过夜。然后将其用水(10ml)淬灭,用EtOAc(20ml)稀释,分离各相,并将水相用EtOAc(2x20ml)萃取两次。然后将合并的有机层用盐水 (2x20ml)洗涤,经固体Na2SO4干燥,过滤,并且蒸发溶剂,产出粗产物(1.5595g,纯度90%,化学产率94%)。然后将粗品通过柱色谱法纯化,产出呈黄色固体的5-氯-3-乙基硫烷基-N-[2-(甲基氨基)-5-(三氟甲基)-3-吡啶基]吡啶-2-甲酰胺(1.396g,纯度93%,分离产率91%)。
1H NMR(400MHz,CDCl3)δppm 9.47(s,1H),8.35(d,J=2.2 Hz,1H),8.27(d,J=2.2Hz,1H),7.93(d,J=2.2Hz,1H),7.68(d,J= 2.2Hz,1H),5.05(bd,J=4.4Hz,1H),5.05(bd,J=4.4Hz,1H),3.09 (d,J=5.1Hz,3H),2.95(q,J=7.4Hz,2H),1.46(t,J=7.4Hz,3H)。
Claims (10)
1.一种用于制备具有式I的5-氯吡啶-2-甲酸酰胺或具有式(I)的化合物的农用化学上可接受的盐的方法:
其中R1是氢、C1-C4烷基、C1-C4羟烷基、C3-C7环烷基、芳基或任选地取代的杂芳基;并且R2是C1-C4烷基;所述方法包括:
在合适的碱的存在下,在介电常数小于15的适当的溶剂(或稀释剂)中,使具有式(III)的化合物
与硫醇化合物R4-S-R2反应,其中R2是如在式I中所定义的并且R4是H或碱金属离子;
以产生具有式(I)的化合物或其盐,以及任选地,
在碱性或酸性条件下水解所述具有式(I)的化合物或其盐;以产生具有式(II)的化合物;
其中R2是如在式I中所定义的并且R3是氢、钠、钾或锂。
2.如权利要求1所述的方法,其中R1是氢、C1-C2烷基、C1-C2羟烷基、C3-C5环烷基、苯基、吡啶基或者可以被氨基、甲基氨基或三氟甲基单或双取代的吡啶基,并且R2是C1-C2烷基;优选地,R1是甲基或氢,并且R2是乙基。
3.如权利要求1或权利要求2所述的方法,其中所述合适的碱选自碱金属碳酸盐或碱金属氢氧化物,更优选地碳酸钠或碳酸钾或氢氧化钠,最优选地氢氧化钠。
4.如权利要求1或权利要求2所述的方法,其中所述适当的溶剂(或稀释剂)选自介电常数在从1.5至15范围内的那些。
5.如权利要求4所述的方法,其中所述适当的溶剂(或稀释剂)选自二噁烷、THF、甲基四氢呋喃、甲苯、苯甲醚、吡啶、丙酮、甲基异丁基酮、tBuOH;优选地二噁烷、甲基四氢呋喃或甲基异丁基酮。
6.如前述权利要求中任一项所述的方法,其中所述方法是在0℃至100℃,优选从0℃至50℃的温度范围内进行的。
7.如权利要求6所述的方法,其中所述方法是在环境温度下进行的。
9.如权利要求8所述的化合物,其中R1是氢、C1-C2烷基、C1-C2羟烷基、C3-C5环烷基、苯基、吡啶基或者可以被氨基、甲基氨基或三氟甲基单或双取代的吡啶基。
10.如权利要求8所述的化合物,其中R1是氢、甲基、乙基、苯基、环丙基、环戊基、羟甲基、羟乙基、吡啶基或2-(甲基氨基)-5-(三氟甲基)-3-吡啶基;优选地,R1是氢、乙基、苯基、环戊基、羟乙基或2-(甲基氨基)-5-(三氟甲基)-3-吡啶基。
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