CN114746403A - 用于制备5-氯-吡啶-2-甲酸以及具有3-含硫取代基的甲酸酯的方法 - Google Patents
用于制备5-氯-吡啶-2-甲酸以及具有3-含硫取代基的甲酸酯的方法 Download PDFInfo
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- CN114746403A CN114746403A CN202080082674.4A CN202080082674A CN114746403A CN 114746403 A CN114746403 A CN 114746403A CN 202080082674 A CN202080082674 A CN 202080082674A CN 114746403 A CN114746403 A CN 114746403A
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- sodium
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- 238000000034 method Methods 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title description 18
- 150000002148 esters Chemical class 0.000 title description 6
- GJLOKYIYZIOIPN-UHFFFAOYSA-N 5-chloropyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)C=N1 GJLOKYIYZIOIPN-UHFFFAOYSA-N 0.000 title description 3
- 239000011593 sulfur Substances 0.000 title description 3
- 229910052717 sulfur Inorganic materials 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 239000011541 reaction mixture Substances 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 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 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- -1 chloro-pyridine compound Chemical class 0.000 claims description 10
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 229910052744 lithium Chemical group 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 239000011591 potassium Chemical group 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-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
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 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 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- NXYRHXIAYWCCSP-UHFFFAOYSA-M ClC=1C(=NC=C(C=1)Cl)C(=O)[O-].[Na+] Chemical compound ClC=1C(=NC=C(C=1)Cl)C(=O)[O-].[Na+] NXYRHXIAYWCCSP-UHFFFAOYSA-M 0.000 description 6
- LAEIKIMICGKPNQ-UHFFFAOYSA-N ClC=1C(=NC=C(C=1)SCC)C(=O)OCC Chemical compound ClC=1C(=NC=C(C=1)SCC)C(=O)OCC LAEIKIMICGKPNQ-UHFFFAOYSA-N 0.000 description 6
- 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 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006177 thiolation reaction Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000003905 agrochemical Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- QPUSANCBJDDXSA-UHFFFAOYSA-N ethanethiol;sodium Chemical compound [Na].CCS QPUSANCBJDDXSA-UHFFFAOYSA-N 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 238000004807 desolvation Methods 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- UTKYMIOWCSAXQM-UHFFFAOYSA-N ClC=1C(=NC=C(C=1)SCC)C(=O)O Chemical compound ClC=1C(=NC=C(C=1)SCC)C(=O)O UTKYMIOWCSAXQM-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- GDANWGXDANXYNZ-UHFFFAOYSA-N ethyl 3,5-dichloropyridine-2-carboxylate Chemical compound CCOC(=O)C1=NC=C(Cl)C=C1Cl GDANWGXDANXYNZ-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-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
- 150000005819 5-chloropyridine-2-carboxylic acid Chemical class 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- NYMVVIHWZKOBMX-UHFFFAOYSA-N ClC=1C=C(C(=NC=1)C(=O)OCC)SCC Chemical compound ClC=1C=C(C(=NC=1)C(=O)OCC)SCC NYMVVIHWZKOBMX-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
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- 239000012267 brine Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
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- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 150000002496 iodine Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- ZUHZZVMEUAUWHY-UHFFFAOYSA-N n,n-dimethylpropan-1-amine Chemical compound CCCN(C)C ZUHZZVMEUAUWHY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
- 238000004366 reverse phase liquid chromatography 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
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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是如说明书中所定义的。
Description
本发明涉及为用于制备农用化学品的有用中间体的5-氯-吡啶-2-甲酸以及具有3-含硫取代基的甲酸酯的制备。
更具体地,本发明涉及具有式I的5-氯-吡啶-2-甲酸并且涉及其制备方法
其中R1是H或C1-C4烷基;R2是C1-C4烷基;或具有式(I)的化合物的农用化学上可接受的盐。
5-卤素-吡啶-2-甲酸以及具有3-烷基硫烷基取代基的甲酸酯是用于制备农用化学工业中的生物活性化合物的有用中间体,如先前例如在以下项中描述的:WO 2016/005263、WO 2016/023954、WO 2016/030229、WO 2016/046071、WO 2016/059145、WO 2016/096584、WO 2016/104746、和WO 2019/065568。
5-卤素-吡啶-2-甲酸以及具有3-烷基硫烷基取代基的甲酸酯(Y)的已知合成涉及很多反应步骤。例如,已经报道了获得5-溴化合物(Y)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),如方案1所示(R1为H、C1-C4烷基或碱金属离子)
方案1.获得5-Br化合物(Y)的途径
在WO 2016/104746中已经报道了从可商购的5,6-二氯烟酸在七个步骤中获得相应的5-碘化合物(Y),如方案2中所示。
方案2.5-碘化合物(Y)
显然,此类长而费力的合成由于总产率低和产生的大量废物而不适用于制备大量材料。因此,获得对这些中间体更有效且更经济的途径将是有利的。
此外,在5-卤素-3-烷基硫烷基-吡啶-2-甲酸酯的种类内,未披露5-氯-3-烷基硫烷基-吡啶-2-甲酸和相应的酯,并且其制备途径尚不清楚。由于具有式(I)的氯化中间体的不可获得性,迄今为止,合成界已被提示使用溴和碘类似物来制备生物活性农用化学品(WO2016/005263、WO 2016/096584、WO 2016/104746 WO 2016/023954、WO 2016/046071、WO2016/087265、WO 2016/087257、WO 2016/030229、WO 2016/121997、WO 2016/104746)。然而,在这些合成中使用具有式(I)的结构单元将非常有利于减少在随后的5位官能化反应(金属催化的交叉偶联反应,亲核芳族取代等)中形成含溴和碘的废物,有利于更良性的含氯废物。此外,具有式(I)的化合物可以被认为是替代的便利中间体,以显著缩短最初对其设计了费力且长的途径的其他农用化学品的合成(WO 2019/065568、WO 2019/124529、WO2020/050212)。
可商购的3,5-二氯吡啶-2-甲酸(VIII)及其相应的酯(IX)(其中R1是C1-C4烷基)可以是具有式(VI)和(VII)的中间体的方便起始材料。原则上,所有需要的是用乙基硫醇盐选择性置换甲酸酯基团邻位的氯(方案3)。
方案3.从(VIII)或(IX)到(VI)或(VII)的设想的途径
然而,由于2-甲酸酯部分使“邻”位空间上较不可接近并且不利于所需的3-烷基硫烷基产物的形成,因此此种选择性是可实现的不是显而易见的。实际上,使具有式(IXa)的化合物在用于亲核芳族取代反应的标准条件下进行反应,优先在所有测试溶剂中获得不希望的异构体(Xa)(方案4)。
方案4.(IXa)的反应的观察到的选择性
具有游离酸部分的多氯化芳族化合物的邻位选择性硫醇化反应具挑战性,很少描述,并且通常是通过羧酸酯定向的乌尔曼(Ullmann)型偶联而铜介导的(如,例如SambiagioC.,Marsden S.P.,Blacker A.J.,McGowan P.C.Chem.Soc.Rev.[化学会评论],2014,43,3525-3550中所述的),如方案5中所示。
方案5.在氯化苯甲酸上的Cu-介导的乌尔曼型偶联
对于多氯化吡啶甲酸,从未报道过此反应的实例。
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(方案6):
其中R1是H或C1-C4烷基;优选地,R1是甲基、乙基或叔丁基,更优选地,R1是乙基;并且R2是C1-C4烷基;优选地,R2是乙基;该方法包括:
(A)在合适的碱的存在下,在具有小于15的介电常数的适当溶剂(或稀释剂)中使具有式II的化合物
其中Xa是氟或氯;优选地Xa是氯;
与硫醇化合物R3-S-R2反应,其中R2是如在式I中所定义的并且R3是H或碱金属离子;优选地R3是H、钠、钾或锂;
以产生具有式(Ia)的化合物或其盐
在具有式ROH的化合物的存在下酯化所述具有式(Ia)的化合物或其盐,其中R是C1-4烷基;以产生所述具有式(I)的化合物,其中R1是C1-C4烷基。
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。
通过本发明的方法制备的具有至少一个碱性中心的具有式I的化合物可以例如与以下形成例如酸加成盐:强无机酸(例如矿物酸,例如高氯酸、硫酸、硝酸、亚硝酸、磷酸或氢卤酸),强有机羧酸(例如未经取代的或例如被卤素取代的C1-C4烷羧酸,例如乙酸,例如饱和或不饱和的二羧酸,例如草酸、丙二酸、琥珀酸、马来酸、富马酸或邻苯二甲酸,例如羟基羧酸,例如抗坏血酸、乳酸、苹果酸、酒石酸或柠檬酸,或例如苯甲酸),或有机磺酸(例如未经取代的或例如被卤素取代的C1-C4烷磺酸或芳基磺酸,例如甲烷磺酸或对甲苯磺酸)。具有至少一个酸性基团的具有式I的化合物可以例如与碱形成盐,例如矿物盐,例如碱金属或碱土金属盐,例如钠盐、钾盐、锂盐或镁盐;或与氨或有机胺(例如吗啉,哌啶,吡咯烷,单、二或三低级烷基胺,例如乙胺、二乙胺、三乙胺或二甲基丙基胺,或单、二或三羟基低级烷基胺,例如单乙醇胺、二乙醇胺或三乙醇胺)形成盐。
在每种情况下,通过根据本发明的方法制备的具有式(I)的化合物是处于游离形式或处于盐的形式(例如农艺学上可用的盐的形式)。
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、异丙基、正丁基、仲丁基、异丁基、叔丁基。
出人意料地发现,在不存在任何铜催化剂的情况下,在非质子非极性溶剂中观察到对3,5-二氯吡啶甲酸(由式(VIII)表示的具有式(II)的化合物)的硫醇化的高邻位选择性。特别是,发现所述选择性受到溶剂性质的显著影响:在具有高的相对介电常数的溶剂(即,DMSO[介电常数为46.7])中,观察到对“对”异构体(XV)的高选择性,而在具有低的相对介电常数的溶剂(即,二噁烷、甲苯、2-MeTHF…[介电常数为2.25、2.38、6.97])中,观察到“邻”异构体(由式(XIV)表示的具有式(Ia)的化合物)的选择性形成。此概念示于方案6中。
方案6.(VIII)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Ia的化合物表示的具有式I的化合物,或具有式Ia的化合物的农用化学上可接受的盐:
在本发明的另一个实施例中,提供了一种由具有式Ia-1的化合物表示的具有式I的化合物:
其中M是钠、钾或锂;优选地钠或锂。
在本发明的又另一个实施例中,提供了一种由具有式I-2的化合物表示的具有式I的化合物,或具有式I-2的化合物的农用化学上可接受的盐:
其中R1a是C1-4烷基;优选地R1a是甲基、乙基或叔丁基,更优选地R1a是乙基。
在本发明的另一个实施例中,提供了一种具有式I-2a的化合物,或具有式I-2a的化合物的农用化学上可接受的盐:
其中R1b是C1-4烷基;优选地R1b是甲基、乙基或叔丁基,更优选地R1b是乙基;并且
n是1或2;优选地n是2。
可以通过经由已知方法(如WO 2016/005263中所述的方法)氧化具有式I-2的化合物来制备具有式I-2a的化合物。
在根据本发明的制造具有式(I)的化合物的方法(方案6)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;优选地碱金属碳酸盐,更优选碳酸钠或碳酸钾,最优选碳酸钾。
在根据本发明的制造具有式(I)的化合物的方法(方案6)中,适当溶剂(或稀释剂)的实例是具有小于15的介电常数那些;更优选地,具有小于12的介电常数的溶剂(或稀释剂);甚至更优选地,具有小于10的介电常数的溶剂(或稀释剂)。在另一个实施例中,适当溶剂(或稀释剂)具有小于6的介电常数。适当溶剂(或稀释剂)的实例是二噁烷、甲基四氢呋喃、甲苯、苯甲醚、吡啶;更优选地,非极性有机物(选自二噁烷、甲基四氢呋喃或甲苯);最优选地,适当溶剂是具有在从1.5至15范围内的介电常数的那些。
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6)中,反应有利地在从约0℃至约+140℃、优选从约0℃至约+100℃的温度范围内进行,在许多情况下在环境温度与约+80℃之间的范围内进行。在优选的实施例中,步骤a.的反应是在0℃与反应混合物沸点之间的温度下进行的,更优选地在20℃与100℃之间的温度下进行,最优选在60℃-100℃温度范围内进行。
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具有小于15的介电常数的非质子非极性溶剂中的3,5-二氯吡啶甲酸化合物和相应的具有式(II)的羧酸盐的高度选择性的硫醇化反应,其中R1是如在式I中所定义的,产生具有式(Ia)和(Ib)的5-氯-3-乙基硫烷基-吡啶-2-甲酸烷基酯中间体。
其中R4=C1-4烷基
附图说明
在以概括的方式对本发明进行描述之后,现在将参考附图,其中:图1是示出针对溶剂介电常数的观察到的选择性的图。更具体地,图1示出了根据本发明的一个实施例的所观察到的邻-对-硫醇化选择性与溶剂的介电常数之间的相关性。
进一步探索了这种溶剂依赖性现象,并建立了观察到的选择性与溶剂介电常数之间的相关性(Lide,D.R.编辑(2005)CRC Handbook of Chemistry and Physics[化学和物理手册](第86版)Boca Raton[波卡拉顿](FL):CRC出版社ISBN 0-8493-0486-5),如图1所示。
制备实例:
在整个本说明书中,LC/MS意指液相色谱质谱法,并且以下方法用于分析化合物:
方法A:在来自沃特斯公司(Waters)的质谱仪(SQD、SQDII单四极杆质谱仪)上记录光谱,所示质谱仪配备有电喷射源(极性:正离子和负离子,毛细管:3.00kV,锥孔范围:30V,萃取器:2.00V,源温度:150℃,去溶剂化温度:350℃,锥孔气体流量:50l/h,去溶剂化气体流量:650l/h;质量范围:100至900Da)以及来自沃特斯公司的Acquity UPLC:二元泵、经加热的柱室、二极管阵列检测器和ELSD检测器。柱:Waters UPLC HSS T3,1.8μm,30×2.1mm,温度:60℃,DAD波长范围(nm):210至500,溶剂梯度:A=水+5%MeOH+0.05%HCOOH,B=乙腈+0.05%HCOOH;梯度:10%-100%B,在1.2min内;流量(ml/min)0.85。
方法B:在来自沃特斯公司的质谱仪(SQD单四极杆质谱仪)上记录光谱,所述质谱仪配备有电喷雾源(极性:正离子或负离子,全扫描,毛细管:3.00kV,锥孔范围:41V,源温度:150℃,脱溶剂化温度:500℃,锥孔气体流量:50L/Hr,脱溶剂化气体流量:1000L/Hr,质量范围:110Da至800Da)以及来自沃特斯公司的H-Class UPLC:二元泵,经加热的柱室以及二极管阵列检测器。柱:沃特斯公司UPLC HSS T3 C18,1.8μm,30×2.1mm,温度:40℃,DAD波长范围(nm):200至400,溶剂梯度:A=水+5%乙腈+0.1%HCOOH,B=乙腈+0.05%HCOOH;梯度:0min 10%B;0.-0.2min 10%-50%B;0.2-0.7min 50%-100%B;0.7-1.3min 100%B;1.3-1.4min 100%-10%B;1.4-1.6min 10%B;流量(mL/min)0.6。
实例1:3,5-二氯吡啶-2-甲酸钠(XIIIa)的制备
将3,5-二氯吡啶-2-甲酸(20.0g,104mmol)和氢氧化钠(在水中1M,100mL,100mmol,0.96当量)的混合物在室温下搅拌2小时。过滤溶液,并将水减压浓缩以得到所需产物(94%,22.0g,96.6mmol,93%产率),将其不经进一步纯化而使用。
1H NMR(400MHz,DMSO-d6)δppm 8.04(d,J=2.20Hz,1H)8.38(d,J=2.20Hz,1H)。
实例2:5-氯-3-乙基硫烷基-吡啶-2-甲酸(VI)的制备
向圆底烧瓶中装入3,5-二氯吡啶-2-甲酸钠(94%,4.00g,17.2mmol)。将烧瓶用氩气吹扫,并在氩气下添加预先脱氧的2-甲基四氢呋喃(86mL)。将反应混合物加热至70℃,并添加乙硫醇钠(1.82g,20.6mmol,1.19当量)。然后将其在70℃下搅拌7小时。减压浓缩反应混合物。将所得残余物溶解在水(29mL)和乙腈(12mL)中。滤出不溶性颗粒。将滤液加热至80℃,并添加另外的水(10mL)和乙腈(5mL)。在80℃下,逐滴添加热的1N盐酸(45℃,16mL),并将其保持搅拌几分钟。将获得的沉淀物热过滤并减压干燥以得到所需产物(94%,2.30g,9.95mmol,58%产率)。
LC-MS(方法A):保留时间0.77min,m/z 218[M+H+]。
1H NMR(400MHz,DMSO-d6)δppm 1.25(t,J=7.34Hz,3H)3.02(q,J=7.34Hz,2H)7.93(d,J=1.83Hz,1H)8.41(d,J=1.83Hz,1H)。
实例3:5-氯-3-乙基硫烷基-吡啶-2-甲酸(VI)的制备
在室温下,向3,5-二氯吡啶-2-甲酸(1.00g,5.21mmol)和碳酸钠(0.662g,6.25mmol,1.20当量)在预先脱氧的2-甲基四氢呋喃(13mL)中的搅拌的溶液中添加乙硫醇钠(0.920g,10.9mmol,2.10当量)。将反应混合物加热至50℃并且搅拌3小时。添加另外的2-甲基四氢呋喃(13mL),并将反应混合物在50℃下搅拌18小时。冷却至室温后,将反应混合物用水稀释,并真空除去2-甲基四氢呋喃。添加乙腈(6mL),然后逐滴添加1N盐酸(21mL)。将所得沉淀物过滤并减压干燥以得到所需产物(71%,1.00g,3.27mmol,63%产率)。
实例4:3-氯-5-乙基硫烷基-吡啶-2-甲酸(XVI)的制备
制备3,5-二氯吡啶-2-甲酸(0.500g,2.47mmol)在二甲基亚砜(5.5mL)中的溶液,并将其加热至100℃。添加碳酸钾(0.378g,2.60mmol,1.05当量),并将反应混合物在100℃下搅拌1小时。然后添加乙硫醇钠(0.250g,2.97mmol,1.20当量),并将反应混合物在100℃下保持搅拌过夜。冷却至室温后,将反应混合物用乙酸乙酯和水稀释。然后将水层酸化并用更多的乙酸乙酯萃取。将合并的有机层用盐水洗涤、经硫酸钠干燥,过滤并减压浓缩。通过反相色谱法纯化粗物质得到呈白色固体的所需产物(0.536mmol,22%产率)。
LC-MS(方法A):保留时间0.74min,m/z 218[M+H+]。
1H NMR(400MHz,DMSO-d6)δppm 1.26(t,J=7.15Hz,3H)3.10-3.18(q,J=7.15Hz,2H)7.95(d,J=2.20Hz,1H)8.44(s,1H)。
实例5:5-氯-3-乙基硫烷基-吡啶-2-甲酸乙酯的制备
在室温下,向5-氯-3-乙基硫烷基-吡啶-2-甲酸(2.35g,10.6mmol)在乙醇(26mL)中的悬浮液中缓慢添加硫酸(0.575mL,10.6mmol,1.00当量)。将反应混合物加热至70℃并且搅拌15小时。冷却至室温后,将反应混合物减压浓缩。将获得的残余物用乙酸乙酯稀释,用碳酸氢钠饱和水溶液洗涤两次,经硫酸钠干燥,过滤并减压浓缩,以得到所需产物(90%,2.55g,9.34mmol,88%产率),将其不经进一步纯化而使用。
LC-MS(方法A):保留时间0.99min,m/z 246[M+H+]。
1H NMR(400MHz,氯仿-d)δppm 1.39-1.47(m,6H)2.93(q,J=7.34Hz,2H)4.48(q,J=7.21Hz,2H)7.62(d,J=2.20Hz,1H)8.37(d,J=1.83Hz,1H)。
实例6:3-氯-5-乙基硫烷基-吡啶-2-甲酸乙酯(VIIa)的制备
在0℃下,向3,5-二氯吡啶-2-甲酸乙酯(96%,0.200g,0.873mmol)在甲苯(2mL)中的搅拌的溶液中添加乙硫醇钠(0.122g,1.31mmol,1.50当量)。使反应混合物达到室温,并首先在此温度下搅拌24小时,并且然后在80℃下搅拌15小时。冷却至室温后,测量LC-MS样品以确定所形成的产物VIIa和Xa的比率。结果给出了60%的起始材料转化率和1:1.9比率的VIIa:Xa的形成。
LC-MS(方法B):保留时间1.08min,m/z 246[M+H+]。
1H NMR(400MHz,氯仿-d)δppm 1.36-1.47(m,6H)3.04(q,J=7.42Hz,2H)4.47(q,J=7.09Hz,2H)7.62(d,J=2.08Hz,1H)8.42(d,J=1.96Hz,1H)。
实例7:3-氯-5-乙基硫烷基-吡啶-2-甲酸乙酯(VIIa)的制备
在0℃下,向3,5-二氯吡啶-2-甲酸乙酯(95%,0.200g,0.863mmol)在1-甲基-2-吡咯烷酮(2mL)中的搅拌的溶液中添加乙硫醇钠(0.099g,1.04mmol,1.20当量)。使反应混合物达到室温,并搅拌6小时。测量LC-MS样品以确定所形成的产物VIIa和Xa的比率。结果给出了70%的起始材料转化率和1:10.2比率的VIIa:Xa的形成。
LC-MS(方法B):保留时间1.08min,m/z 246[M+H+]。
1H NMR(400MHz,氯仿-d)δppm 1.36-1.47(m,6H)3.04(q,J=7.42Hz,2H)4.47(q,J=7.09Hz,2H)7.62(d,J=2.08Hz,1H)8.42(d,J=1.96Hz,1H)。
实例8:3,5-二氯吡啶-2-甲酸钠(XIIIa)上的硫醇化反应上的溶剂影响
向5mL微波小瓶中装入3,5-二氯吡啶-2-甲酸钠(94%,100mg,0.422mmol)。将小瓶用氩气吹扫,并在氩气下添加预先脱氧的溶剂(2.2mL)。将反应混合物加热至80℃,并添加乙硫醇钠(42.6mg,0.507mmol,1.20当量)。将反应混合物在80℃下搅拌3.5小时。冷却至室温后,使反应混合物停止并且测量NMR样品以确定所形成的产物(XIV)和(XV)的比率。结果总结在下表中。
Claims (10)
1.一种用于制备具有式(I)的氯-吡啶化合物的方法:
其中R1是H或C1-C4烷基;优选地,R1是甲基、乙基或叔丁基,更优选地,R1是乙基;并且R2是C1-C4烷基;优选地,R2是乙基;该方法包括:
(A)在合适的碱的存在下,在具有小于15的介电常数的适当溶剂(或稀释剂)中使具有式II的化合物
其中Xa是氟或氯;优选地Xa是氯;
与硫醇化合物R3-S-R2反应,其中R2是如在式I中所定义的并且R3是H或碱金属离子;优选地R3是H或钠;
以产生具有式(Ia)的化合物或其盐
在具有式ROH的化合物的存在下酯化所述具有式(Ia)的化合物或其盐,其中R是C1-4烷基;以产生所述具有式(I)的化合物,其中R1是C1-C4烷基。
2.根据权利要求1所述的方法,其中,
Xa是氯;
R1是乙基;
R2是乙基;并且
R3是钠。
3.根据权利要求1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,最优选地碳酸钾。
4.根据权利要求1所述的方法,其中,所述适当溶剂(或稀释剂)选自具有在从1.5至15范围内的介电常数的那些。
5.根据权利要求4所述的方法,其中,所述适当溶剂(或稀释剂)选自二噁烷、甲基四氢呋喃、甲苯、苯甲醚、吡啶;优选地二噁烷、甲基四氢呋喃或甲苯。
6.根据权利要求1所述的方法,其中,步骤a.的反应是在0℃与反应混合物沸点之间的温度下进行的,更优选地在20℃与100℃之间的温度下进行,最优选在60℃-100℃的温度范围内进行。
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