CN114790150B - 一种2,3-吡啶二羧酸酯衍生物中间体及2,3-吡啶二羧酸酯衍生物的制备方法 - Google Patents
一种2,3-吡啶二羧酸酯衍生物中间体及2,3-吡啶二羧酸酯衍生物的制备方法 Download PDFInfo
- Publication number
- CN114790150B CN114790150B CN202110095640.5A CN202110095640A CN114790150B CN 114790150 B CN114790150 B CN 114790150B CN 202110095640 A CN202110095640 A CN 202110095640A CN 114790150 B CN114790150 B CN 114790150B
- Authority
- CN
- China
- Prior art keywords
- general formula
- reaction
- dicarboxylic acid
- acid ester
- pyridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- GJAWHXHKYYXBSV-UHFFFAOYSA-N pyridinedicarboxylic acid Natural products OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 title claims abstract description 25
- -1 2, 3-Pyridine dicarboxylic acid ester Chemical class 0.000 title abstract description 21
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000002253 acid Substances 0.000 claims abstract description 18
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 5
- 238000001308 synthesis method Methods 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 3
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- ROAYSRAUMPWBQX-UHFFFAOYSA-N ethanol;sulfuric acid Chemical compound CCO.OS(O)(=O)=O ROAYSRAUMPWBQX-UHFFFAOYSA-N 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 2
- WCYAALZQFZMMOM-UHFFFAOYSA-N methanol;sulfuric acid Chemical compound OC.OS(O)(=O)=O WCYAALZQFZMMOM-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- KGTHLJCKWSGDQZ-UHFFFAOYSA-N [Li+].[Na+].CC(C)(C)[O-].CC(C)(C)[O-] Chemical compound [Li+].[Na+].CC(C)(C)[O-].CC(C)(C)[O-] KGTHLJCKWSGDQZ-UHFFFAOYSA-N 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 5
- 229910021529 ammonia Inorganic materials 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 239000000575 pesticide Substances 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract 2
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical class O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 description 3
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ZQHJVIHCDHJVII-OWOJBTEDSA-N (e)-2-chlorobut-2-enedioic acid Chemical compound OC(=O)\C=C(\Cl)C(O)=O ZQHJVIHCDHJVII-OWOJBTEDSA-N 0.000 description 2
- SDJCUCIUEZOXIC-UHFFFAOYSA-N 2-methoxycarbonyl-5-methylpyridine-3-carboxylic acid Chemical compound COC(=O)C1=NC=C(C)C=C1C(O)=O SDJCUCIUEZOXIC-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XVOKUMIPKHGGTN-UHFFFAOYSA-N Imazethapyr Chemical compound OC(=O)C1=CC(CC)=CN=C1C1=NC(C)(C(C)C)C(=O)N1 XVOKUMIPKHGGTN-UHFFFAOYSA-N 0.000 description 2
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- PNNFEYPWPCDLOC-UPHRSURJSA-N (z)-2,3-dichlorobut-2-enedioic acid Chemical compound OC(=O)C(\Cl)=C(\Cl)C(O)=O PNNFEYPWPCDLOC-UPHRSURJSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ODBGMUFRWHFMEG-UHFFFAOYSA-N 2-ethoxycarbonyl-5-ethylpyridine-3-carboxylic acid Chemical compound C(C)OC(=O)C1=NC=C(C=C1C(=O)O)CC ODBGMUFRWHFMEG-UHFFFAOYSA-N 0.000 description 1
- GMLDCZYTIPCVMO-UHFFFAOYSA-N 2-methylidenebutanal Chemical compound CCC(=C)C=O GMLDCZYTIPCVMO-UHFFFAOYSA-N 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000005693 branched-chain amino acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- HAUKUGBTJXWQMF-UHFFFAOYSA-N lithium;propan-2-olate Chemical compound [Li+].CC(C)[O-] HAUKUGBTJXWQMF-UHFFFAOYSA-N 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/19—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton
- C07C255/21—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton the carbon skeleton being further substituted by doubly-bound oxygen atoms
-
- 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
- C07D213/80—Acids; Esters in position 3
-
- 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
- C07D213/803—Processes of preparation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明涉及农药化学领域，具体涉及一种2,3‑吡啶二羧酸酯衍生物中间体及2,3‑吡啶二羧酸酯衍生物的制备方法，包括如下步骤：将通式Ⅱ和通式Ⅲ溶于有机溶剂中，加入强碱反应，反应结束后用无水酸的醇溶液酸化处理得到中间体I的酸化反应液；将中间体I的酸化反应液热处理，然后滴加通式Ⅳ，反应结束后，经过简单的后处理即得到通式Ⅴ。本发明提供的制备2,3‑吡啶二羧酸酯及其衍生物的方法，两步反应可以通过一锅煮的方法进行，第二步生成游离的氨提供吡啶成环的氨源，整个工艺安全环保，原子利用率高，经济高效，适合工业化生产。
Description
技术领域
本发明涉及农药化学领域，尤其涉及一种2,3-吡啶二羧酸酯衍生物中间体及2,3-吡啶二羧酸酯衍生物的制备方法。
背景技术
咪唑啉酮类化合物作为高效性除草剂，作用机制主要抑制乙酸羟酸合成酶(AHAs)的活性,影响3种支链氨基酸——缬氨酸、亮氨酸与异亮氨酸的生物合成,最终破坏蛋白质的合成,干扰DNA合成及细胞分裂和生长。而甲氧咪草烟，甲基咪草烟，乙基咪草烟是咪唑啉酮类除草剂的重要组成部分。
专利US4948896A和US5047542A中公开了马来酸二烷基酯衍生物合成吡啶-2,3-二羧酸酯的方法，总体收率66-88％，产品纯度69-93％，收率和纯度均不够理想，此外还存在有机三废高的问题，难以解决。
中国发明专利CN1062724A、CN1057456A分别公开了由氯代马来酸酯、二氯代马来酸二烷基酯制备吡啶-2,3-二羧酸二烷基酯的方法，其原料简单易得，但是转化率低，而且氯代马来酸酯遇到高热和碱性物质会发生分解，中间体稳定性较差，反应时间长达16～72小时，一定程度上增加工业化的难度。
美国专利US4816588A和US5597924A公开了用喹啉衍生物经过过氧化物氧化得到产品，氧化本身属于危险工艺，具有较高的危险性，而且收率很低仅为48～69％，原子利用率差。
美国专利US5334576A和US4798619A公开了以苯胺类衍生物为原料制备吡啶-2,3-二羧酸酯的方法，收率较低且危险。
中国发明专利CN104447527A公开了一种吡啶-2,3-二羧酸二烷基酯的方法，收率虽然能做到82～96％，但是需要用到危险的催化剂氨基钠、钠氢或三苯甲基钠，不利于工业化生产，另外反应温度高，引起副反应多，并且不易控制反应，工艺复杂。
因此，作为咪唑啉酮类化合物合成的重要中间体，现有的吡啶-2,3-二羧酸酯合成方法均不够理想，亟需一种反应步骤短、原料易得、反应温和、产品收率和纯度较高的吡啶-2,3-二羧酸酯合成方法。
发明内容
本发明要解决的技术问题是：提供一种反应步骤短、原料易得、反应温和、产品收率和纯度较高的吡啶-2,3-二羧酸酯中间体及其合成方法。
本发明解决上述技术问题的技术方案如下：
一种吡啶-2,3-二羧酸酯衍生物的中间体，其结构如式Ⅰ所示：
其中，R1选自C1～6烷基；X选自卤素，C1～4的烷氧基或C1～4的烷硫基。
本发明的第二目的是提供一种基于上述中间体的吡啶-2,3-二羧酸酯衍生物的合成方法，包括如下步骤：
(1)将通式Ⅱ化合物和通式Ⅲ化合物溶于有机溶剂中，加入强碱反应，反应结束后用无水酸的醇溶液酸化处理得到含有中间体I的酸化反应液；将酸化反应液直接投入下步反应或分离得到中间体I后投入下步反应；
(2)将含有中间体I的酸化反应液热处理，然后加入通式IV化合物；或将中间体I加入无水酸的醇溶液中，再加入通式IV化合物；反应结束后，经后处理即得到通式Ⅴ；
具体反应式如下：
其中，R1和R2独立的选自C1～6烷基；X选自卤素，C1～4的烷氧基或C1～4的烷硫基；
Y选自氢、卤素、C1～6烷基，C1～4烷氧羰基，氨基羰基，苯硫基，苯氧基或苯基；以及被一个或多个卤素、羟基、C1～4的烷氧基或C1～4的烷硫基取代的C1～6烷基，C1～4烷氧羰基，氨基羰基，苯硫基，苯氧基或苯基；当R1与R2不相同时，得到的产物为混合物。
优选的，所述步骤(1)中的有机溶剂为醇类，如甲醇，乙醇或正丁醇；芳烃类，如甲苯或二甲苯等。
优选的，所述步骤(1)中的反应温度为-10～80℃，进一步的5～50℃。
优选的，所述步骤(1)中的强碱选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、碳酸锂、甲醇钠、甲醇钾、甲醇锂、乙醇钠、乙醇钾、乙醇锂、异丙醇钠、异丙醇钾、异丙醇、锂叔丁醇钠、叔丁醇钾、叔丁醇锂、氢化钠、氨基钠、三乙胺或吡啶等各种常见无机碱和三级有机碱。
优选的，所述步骤(1)中的无水酸的醇溶液为盐酸甲醇溶液、盐酸乙醇溶液、硫酸甲醇溶液或硫酸乙醇溶液等。
优选的，所述步骤(1)中的通式Ⅱ、通式Ⅲ、强碱和无水酸的摩尔比为1：1.0～5.0：1.0～5.0：1.0～15.0；
进一步的，述步骤(1)中的通式Ⅱ、通式Ⅲ、强碱和无水酸的摩尔比为1：1.0～1.5：1.0～1.5：1.0～4.0。
更进一步的，述步骤(1)中的通式Ⅱ、通式Ⅲ、强碱和无水酸的摩尔比为1：1.01～1.3：1.0～1.5：1.3～2.5。
优选的，所述步骤(2)中反应温度为-10～120℃；进一步的40～90℃。
优选的，所述步骤(2)中的中间体I、通式IV、酸的投料摩尔比为1：1.0～2.0：0～2。
进一步的，所述步骤(2)中的中间体I、通式IV、酸的投料摩尔比为1：1.1～1.2：0～1.2。
本发明中化合物的中文命名与结构式有冲突的，以结构式为准；结构式有明显错误的除外。
本发明提供的2,3-吡啶二羧酸酯衍生物中间体及2,3-吡啶二羧酸酯衍生物的制备方法，两步反应可以通过一锅煮的方法进行，第二步生成游离的氨提供吡啶成环的氨源，整个工艺安全环保，原子利用率高，经济高效，适合工业化生产。
具体实施方式
以下结合实例说明本发明，但不限制本发明。在本领域内，技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案内。
实施例1：
①3-氯-3-氰基-2-氧代丙酸甲酯的制备：
将118.09g(1mol)的草酸二甲酯和180.1g的30％甲醇钠甲醇溶液(1mol)室温搅拌溶解，控制15～20℃缓慢滴加90.60g的氯乙腈(1.2mol)，滴加用时3h，滴加完毕后保温搅拌1h。取样合格后降温至5～10℃，缓慢加入182.5g的30％盐酸甲醇溶液(1.5mol)，酸化到pH值小于4，过滤，蒸干甲醇得到160g的3-氯-3-氰基-2-氧代丙酸甲酯，定性含量94％，收率93.4％。1H NMR(400MHz,DMSO)δ7.07(s,1H),3.83(s,3H).
②5-甲基吡啶-2,3-二羧酸甲酯的制备：
将步骤①得到的160g的94％的3-氯-3-氰基-2-氧代丙酸甲酯(0.93mol)加入136g的30％盐酸甲醇溶液(1.1mol)，升温至65℃，缓慢滴加78.2g的2-甲基丙烯醛(1.1mol)，用时5h，滴加完毕后保温搅拌5h。取样合格后蒸干甲醇，加水溶液，二氯乙烷萃取，蒸干溶剂得到黄色固体185.03g，定性含量95％，收率90.3％，1H NMR(400MHz,DMSO)δ8.67-8.62(m,1H),8.11(dd,J＝1.9,0.7Hz,1H),3.85(s,6H),2.41(s,3H)。
实施例2：
①3-氯-3-氰基-2-氧代丙酸甲酯的制备：
将118.09g的草酸二甲酯(1mol)和270.1g的30％甲醇钠甲醇溶液(1.5mol)室温搅拌溶解，控制15～20℃缓慢滴加98.15g的氯乙腈(1.3mol)，滴加用时3h，滴加完毕后保温搅拌1h。取样合格后降温至5-10℃，缓慢加入304.17g的30％盐酸甲醇溶液(2.5mol)，酸化到pH值小于4，得到593.89g的3-氯-3-氰基-2-氧代丙酸甲酯的酸化反应液，不分离直接进行下一步反应。
②5-甲基吡啶-2,3-二羧酸甲酯的制备：
将实施例2步骤①得到的593.89g的3-氯-3-氰基-2-氧代丙酸甲酯的酸化反应液升温至60℃，缓慢滴加78.2g的2-甲基丙烯醛(1.1mol)，用时5h，滴加完毕后保温搅拌5h。取样合格后蒸干甲醇，加水溶液，二氯乙烷萃取，蒸干溶剂得到黄色固体194.56g，定性含量96％，两步总收率89.3％。1H NMR(400MHz,DMSO)δ8.67-8.62(m,1H),8.11(dd,J＝1.9,0.7Hz,1H),3.85(s,6H),2.41(s,3H).
实施例3：
①3-甲氧基-3-氰基-2-氧代丙酸乙酯的制备：
将146.14g的草酸二乙酯(1mol)和102.1g的乙醇钠(1.5mol)溶于500g甲苯中，控制30～35℃缓慢滴加78.1g的氯乙腈(1.03mol)，滴加用时2h，滴加完毕后保温搅拌2h。取样合格后降温至5-10℃，缓慢加入158.28g的30％盐酸乙醇溶液(1.3mol)，酸化到pH值小于4，过滤，蒸干溶剂得到154.04g的3-甲氧基-3-氰基-2-氧代丙酸乙酯，定性含量95％，收率85.5％。1H NMR(400MHz,DMSO)δ10.85(s,1H),4.28-4.22(m,2H),3.71(s,3H),1.26(t,J＝7.1Hz,3H).
②5-乙基吡啶-2,3-二羧酸乙酯的制备：
将实施例3步骤①得到的154.04g的95％的3-甲氧基-3-氰基-2-氧代丙酸乙酯加入117.5g的30％盐酸乙醇溶液(0.966mol)，升温至80℃，缓慢滴加79.11g的2-乙基丙烯醛(0.94mol)，用时3h，滴加完毕后保温搅拌6h。取样合格后蒸干甲醇，加水溶液，二氯甲烷萃取，蒸干溶剂得到黄色固体197.66g，定性含量94％，收率86.5％。1H NMR(400MHz,DMSO)δ8.69(d,J＝2.0Hz,1H),8.13(d,J＝2.0Hz,1H),4.43-4.23(m,4H),2.76(q,J＝7.6Hz,2H),1.33(td,J＝7.1,1.5Hz,6H),1.27-1.17(m,3H).
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。
Claims (6)
1.一种吡啶-2,3-二羧酸酯衍生物的中间体，其结构如式Ⅰ所示：
其中，R1选自C1～6烷基；X选自卤素，C1～4的烷氧基或C1～4的烷硫基。
2.一种吡啶-2,3-二羧酸酯衍生物的合成方法，其特征在于包括如下步骤：
(1)将通式Ⅱ化合物和通式Ⅲ化合物溶于有机溶剂中，加入强碱反应，反应结束后用无水酸的醇溶液酸化处理得到含有中间体I的酸化反应液；将酸化反应液直接投入下步反应或分离得到中间体I后投入下步反应；
(2)将含有中间体I的酸化反应液热处理，然后加入通式Ⅳ化合物；或将中间体I加入无水酸的醇溶液中，再加入通式Ⅳ化合物；反应结束后，经后处理即得到通式Ⅴ；
具体反应式如下：
其中，R1和R2独立的选自C1～6烷基；X选自卤素，C1～4的烷氧基或C1～4的烷硫基；
Y选自甲基或乙基；所述步骤(1)中的有机溶剂为甲醇、乙醇、正丁醇、甲苯或二甲苯；所述步骤(1)中的强碱选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、碳酸锂、甲醇钠、甲醇钾、甲醇锂、乙醇钠、乙醇钾、乙醇锂、异丙醇钠、异丙醇钾、异丙醇、锂叔丁醇钠、叔丁醇钾、叔丁醇锂、氢化钠、氨基钠、三乙胺或吡啶；所述步骤(1)中的无水酸的醇溶液为盐酸甲醇溶液、盐酸乙醇溶液、硫酸甲醇溶液或硫酸乙醇溶液；所述步骤(2)中反应温度为-10～120℃。
3.如权利要求2所述的吡啶-2,3-二羧酸酯衍生物的合成方法，其特征在于，所述步骤(1)中的通式Ⅱ、通式Ⅲ、强碱和无水酸的摩尔比为1：1.0～5.0：1.0～5.0：1.0～15.0。
4.如权利要求3所述的吡啶-2,3-二羧酸酯衍生物的合成方法，其特征在于，述步骤(1)中的通式Ⅱ、通式Ⅲ、强碱和无水酸的摩尔比为1：1.0～1.5：1.0～1.5：1.0～4.0。
5.如权利要求2～4任一项所述的吡啶-2,3-二羧酸酯衍生物的合成方法，其特征在于，所述步骤(2)中的中间体I、通式Ⅳ、酸的投料摩尔比为1：1.0～2.0：0～2。
6.如权利要求5所述的吡啶-2,3-二羧酸酯衍生物的合成方法，其特征在于，所述步骤(2)中的中间体I、通式Ⅳ、酸的投料摩尔比为1：1.1～1.2：0～1.2。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110095640.5A CN114790150B (zh) | 2021-01-25 | 2021-01-25 | 一种2,3-吡啶二羧酸酯衍生物中间体及2,3-吡啶二羧酸酯衍生物的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110095640.5A CN114790150B (zh) | 2021-01-25 | 2021-01-25 | 一种2,3-吡啶二羧酸酯衍生物中间体及2,3-吡啶二羧酸酯衍生物的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114790150A CN114790150A (zh) | 2022-07-26 |
| CN114790150B true CN114790150B (zh) | 2024-05-24 |
Family
ID=82459875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110095640.5A Active CN114790150B (zh) | 2021-01-25 | 2021-01-25 | 一种2,3-吡啶二羧酸酯衍生物中间体及2,3-吡啶二羧酸酯衍生物的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114790150B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115286567B (zh) * | 2022-08-12 | 2024-04-19 | 镇江中智化学科技有限公司 | 一锅法合成3-溴吡啶 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5232940A (en) * | 1985-12-20 | 1993-08-03 | Hatton Leslie R | Derivatives of N-phenylpyrazoles |
| CN107759516A (zh) * | 2016-08-16 | 2018-03-06 | 沈阳化工研究院有限公司 | 一种烷基醚取代吡啶‑2，3‑二羧酸衍生物的制备方法 |
| WO2018123918A1 (ja) * | 2016-12-26 | 2018-07-05 | 科研製薬株式会社 | ピラゾール誘導体及びそれを含有する医薬 |
| CN109265463A (zh) * | 2018-12-18 | 2019-01-25 | 上海肇钰医药科技有限公司 | 作为parp抑制剂的吡唑并喹唑啉酮衍生物及其用途 |
| CN109467548A (zh) * | 2017-09-08 | 2019-03-15 | 沈阳科创化学品有限公司 | 一种咪唑啉酮化合物的制备方法 |
-
2021
- 2021-01-25 CN CN202110095640.5A patent/CN114790150B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5232940A (en) * | 1985-12-20 | 1993-08-03 | Hatton Leslie R | Derivatives of N-phenylpyrazoles |
| CN107759516A (zh) * | 2016-08-16 | 2018-03-06 | 沈阳化工研究院有限公司 | 一种烷基醚取代吡啶‑2，3‑二羧酸衍生物的制备方法 |
| WO2018123918A1 (ja) * | 2016-12-26 | 2018-07-05 | 科研製薬株式会社 | ピラゾール誘導体及びそれを含有する医薬 |
| CN109467548A (zh) * | 2017-09-08 | 2019-03-15 | 沈阳科创化学品有限公司 | 一种咪唑啉酮化合物的制备方法 |
| CN109265463A (zh) * | 2018-12-18 | 2019-01-25 | 上海肇钰医药科技有限公司 | 作为parp抑制剂的吡唑并喹唑啉酮衍生物及其用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114790150A (zh) | 2022-07-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20090221817A1 (en) | Process for trans-4-amino-1-cyclohexanecarboxilic acid derivatives | |
| NZ554119A (en) | Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide | |
| CN101367760B (zh) | 2-氯烟酸的合成方法 | |
| CN105254603A (zh) | 呋喃铵盐的合成工艺 | |
| CN109232311B (zh) | 一种绿色高效的普瑞巴林合成方法 | |
| CN114790150B (zh) | 一种2,3-吡啶二羧酸酯衍生物中间体及2,3-吡啶二羧酸酯衍生物的制备方法 | |
| CN108264469A (zh) | 一种制备2-（亚环己烯基）丙二酸衍生物的方法及其应用 | |
| CN105330598A (zh) | 一种吡非尼酮的制备方法 | |
| DK170974B1 (da) | 2-Aza-4-(alkoxycarbonyl)spiro[4,5]decan-3-oner samt fremgangsmåde og mellemprodukt til fremstilling deraf | |
| CN108623455B (zh) | 一种抗心衰药物的中间体 | |
| US20030114690A1 (en) | Process for the preparation of aniline compounds | |
| CN101709050B (zh) | 合成2,5-二氯吡啶的方法 | |
| CN102898357A (zh) | 用于制备依托考昔的中间体1-(6-甲基吡啶-3-基)-2-[4-(甲磺酰基)苯基]乙酮的新方法 | |
| CN108794468A (zh) | 一种四氢吡啶并吲哚类化合物的制备方法 | |
| CN113149899A (zh) | 一种制备4-三氟甲基烟酸的方法 | |
| EP1732899B1 (en) | Process for preparing cyclohexanediacetic acid monoamide | |
| CN109574938B (zh) | 一种瑞舒伐他汀钠的合成方法 | |
| CN104292133A (zh) | 一种抗癌药物伏立诺他的合成方法 | |
| CN114644565B (zh) | 一种咪唑啉酮类化合物关键中间体的合成方法 | |
| CN111320570A (zh) | 一种兰索拉唑关键中间体的制备方法 | |
| CN101088999A (zh) | 3－氨基奎宁二盐酸盐的合成方法 | |
| CN104892608B (zh) | 一种米氮醇的合成方法 | |
| CN115894518B (zh) | 一种唑啉草酯代谢物m3的合成方法 | |
| CN112694427A (zh) | 一种制备2,3-二甲基苯甲硫醚的方法 | |
| CN110862311B (zh) | 一种1-羟基环丙烷羧酸以及羧酸酯的合成方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |