CN104876861B - 一种生产2‑氯烟酸的方法 - Google Patents
一种生产2‑氯烟酸的方法 Download PDFInfo
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- CN104876861B CN104876861B CN201410069184.7A CN201410069184A CN104876861B CN 104876861 B CN104876861 B CN 104876861B CN 201410069184 A CN201410069184 A CN 201410069184A CN 104876861 B CN104876861 B CN 104876861B
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 23
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 title abstract 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims abstract description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229940043279 diisopropylamine Drugs 0.000 claims abstract description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- 230000007062 hydrolysis Effects 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 87
- 239000000460 chlorine Substances 0.000 claims description 67
- 229910052801 chlorine Inorganic materials 0.000 claims description 67
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- 238000001556 precipitation Methods 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- -1 diisopropylamino methacrylaldehyde Chemical compound 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 19
- 125000004494 ethyl ester group Chemical group 0.000 claims description 19
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 13
- 239000007789 gas Substances 0.000 claims description 13
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 10
- 238000006555 catalytic reaction Methods 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 6
- 150000008282 halocarbons Chemical class 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 238000005292 vacuum distillation Methods 0.000 claims description 6
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 claims description 5
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical group 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- NLFIMXLLXGTDME-UHFFFAOYSA-N propyl 2-cyanoacetate Chemical compound CCCOC(=O)CC#N NLFIMXLLXGTDME-UHFFFAOYSA-N 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
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 150000003138 primary alcohols Chemical class 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- UCTLHLZWKJIXJI-LXIBVNSESA-N [(3s,8r,9s,10r,13s,14s)-17-chloro-16-formyl-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C([C@@H]12)C[C@]3(C)C(Cl)=C(C=O)C[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 UCTLHLZWKJIXJI-LXIBVNSESA-N 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 150000001336 alkenes Chemical class 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- CHMCGINTTUEJGQ-UHFFFAOYSA-N C(=O)C=C.C(C)(C)NC(C)C Chemical compound C(=O)C=C.C(C)(C)NC(C)C CHMCGINTTUEJGQ-UHFFFAOYSA-N 0.000 abstract 2
- VFPFQHQNJCMNBZ-UHFFFAOYSA-N ethyl gallate Chemical compound CCOC(=O)C1=CC(O)=C(O)C(O)=C1 VFPFQHQNJCMNBZ-UHFFFAOYSA-N 0.000 abstract 2
- 239000004262 Ethyl gallate Substances 0.000 abstract 1
- PMIMPBYTPPRBGD-UHFFFAOYSA-N ethyl 2-chloropyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC=CN=C1Cl PMIMPBYTPPRBGD-UHFFFAOYSA-N 0.000 abstract 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 abstract 1
- 235000019277 ethyl gallate Nutrition 0.000 abstract 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 26
- STNJBCKSHOAVAJ-UHFFFAOYSA-N Methacrolein Chemical compound CC(=C)C=O STNJBCKSHOAVAJ-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012071 phase Substances 0.000 description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- KWCIVMHACSABTB-UHFFFAOYSA-N n,n-di(propan-2-yl)prop-1-en-1-amine Chemical group CC=CN(C(C)C)C(C)C KWCIVMHACSABTB-UHFFFAOYSA-N 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- XHTYQFMRBQUCPX-UHFFFAOYSA-N 1,1,3,3-tetramethoxypropane Chemical compound COC(OC)CC(OC)OC XHTYQFMRBQUCPX-UHFFFAOYSA-N 0.000 description 2
- JGAMOQYFDMQPRJ-UHFFFAOYSA-N 3-(dimethylamino)-2-methylprop-2-enal Chemical compound CN(C)C=C(C)C=O JGAMOQYFDMQPRJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-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
- 239000003905 agrochemical Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 239000005740 Boscalid Substances 0.000 description 1
- 239000005507 Diflufenican Substances 0.000 description 1
- 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 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 239000005586 Nicosulfuron Substances 0.000 description 1
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- WYEMLYFITZORAB-UHFFFAOYSA-N boscalid Chemical compound C1=CC(Cl)=CC=C1C1=CC=CC=C1NC(=O)C1=CC=CN=C1Cl WYEMLYFITZORAB-UHFFFAOYSA-N 0.000 description 1
- 229940118790 boscalid Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- WYEHFWKAOXOVJD-UHFFFAOYSA-N diflufenican Chemical compound FC1=CC(F)=CC=C1NC(=O)C1=CC=CN=C1OC1=CC=CC(C(F)(F)F)=C1 WYEHFWKAOXOVJD-UHFFFAOYSA-N 0.000 description 1
- 125000005670 ethenylalkyl group Chemical group 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- RTCOGUMHFFWOJV-UHFFFAOYSA-N nicosulfuron Chemical compound COC1=CC(OC)=NC(NC(=O)NS(=O)(=O)C=2C(=CC=CN=2)C(=O)N(C)C)=N1 RTCOGUMHFFWOJV-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960000916 niflumic acid Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 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
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002912 waste gas 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
- C07D213/803—Processes of preparation
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种生产2‑氯烟酸的方法，将丙炔醇和二异丙胺经催化氧化得到二异丙胺基丙烯醛，再与氰基乙酸乙酯发生Konevenagel反应生成2‑氰基‑5‑二异丙胺基‑2，4‑戊二烯酸乙酯，通入干燥氯化氢，将得到2‑氯烟酸乙酯经碱性水解，酸化后得到2‑氯烟酸。与现有技术相比，本发明采用易于采购的原料，工艺无苛刻条件，对环境友好且适合工业化生产。
Description
技术领域
本发明涉及农药和医药中间体的工业生产领域，尤其是涉及一种生产2-氯烟酸的方法。
背景技术
2-氯烟酸是一种用途广泛的吡啶类农药和医药中间体。在农药上2-氯烟酸主要用来合成除草剂烟嘧磺隆、吡氟草胺和杀菌剂啶酰菌胺等，这些都是新型高效的农药品种，对环境友好，在国内外市场已成为了主导品种。在医药上2-氯烟酸主要用来合成抗艾滋病药物奈韦拉平、抗抑郁药物米氮平、非甾体消炎镇痛药尼氟灭酸、烟甲灭酸等。
目前文献和专利报道合成2-氯烟酸的合成工艺有以下几种：
1.专利US408145中报道以3-氰基吡啶或烟酸为原料，生成氮氧化物，经氯化和水解，得到2-氯烟酸。该路线是目前国内生产2-氯烟酸的主流路线。然而工艺过程中需大量使用三氯氧磷和三乙胺，从而产生大量难于处理的的含磷、含氮废水，同时有毒的强酸废气也带来了极大的环境危害。
2.专利JP28076863中报道氰基乙酸乙酯与四甲氧基丙烷进缩合、环合和水解反应得2-氯烟酸。该路线步骤少，产品收率和纯度都很高，但四甲氧基丙烷价格昂贵，原料成本过高。
3.专利US5493028中报道氰基乙酸乙酯先氯化，再与丙烯醛Michael加成，然后环化和水解得2-氯烟酸。该路线原料易得，价格低廉，但需要使用丙烯醛、三氯化磷等剧毒危险品，收率也不高，环境危害性较大。
4.专利DE3840954中报道氰基乙酸乙酯与3-二甲胺基丙烯醛经脑文格(Knoevenagel)缩合、环化和水解得2-氯烟酸。中间体3-二甲胺基丙烯醛可由DMF与乙烯基烷基醚在三氯氧磷、草酰氯、光气和固体光气等的作用下合成。该路线选择性好，收率高，反应条件温和，适宜工业化研发。然而，该路线仍使用三氯氧磷等毒性加大的氯化剂，以及会副产等摩尔二甲胺，均对环境存在较大危害。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种操作无苛刻条件，工艺简单且环境友好的生产2-氯烟酸的方法。
本发明的目的可以通过以下技术方案来实现：
一种生产2-氯烟酸的方法，将丙炔醇和二异丙胺经催化氧化得到二异丙胺基丙烯醛，再与氰基乙酸乙酯反应生成2-氰基-5-二异丙胺基-2，4-戊二烯酸乙酯，通入干燥氯化氢，将得到2-氯烟酸乙酯经碱性水解，酸化后得到2-氯烟酸，具体采用以下步骤：
1)丙炔醇和二异丙胺按摩尔比为1∶1混合溶解于甲苯中，加入二氧化锰作为催化剂，通入空气或氧气，于30-110℃和0.5-2Mpa下，反应8-20小时，过滤除去催化剂，滤液脱溶得到二异丙胺基丙烯醛；
2)二异丙胺基丙烯醛溶于甲苯后，加入氰基乙酸酯和催化剂，二异丙胺基丙烯醛与氰基乙酸酯的摩尔比为1∶0.9-1.5回流6-12小时，脱溶得到2-氰基-5-二异丙胺基-2，4-戊二烯酸酯；
3)2-氰基-5-二异丙胺基-2，4-戊二烯酸乙酯溶解在乙醇中，通入干燥氯化氢气体，于5-50℃和0.8-2Mpa下反应12-36小时，脱溶后油相用甲苯溶解后水洗至pH为1-5，减压除去甲苯再高真空蒸馏得到2-氯烟酸乙酯；
4)2-氯烟酸乙酯加入2N氢氧化钠，加热至回流，冷却后调节pH值至1-2，抽滤得到白色固体即为2-氯烟酸。
步骤1)中的反应温度优选为60-80℃。
步骤1)中脱溶采用的溶剂包括惰性卤代烃、一级或多级醇、芳香烃或非质子性溶剂，优选芳香烃或一级醇。
步骤2)中所述的催化剂为有机碱或无机碱，有机酸或无机酸，或它们的混合物。
作为优选的实施方式，有机碱包括三乙胺、吡啶或哌啶；无机碱为碳酸钠或碳酸钾；有机酸包括对甲苯磺酸、甲酸或乙酸；无机酸为盐酸或硫酸。
步骤2)中脱溶采用的溶剂包括惰性卤代烃、一级或多级醇、芳香烃或非质子性溶剂，优选芳香烃。
步骤2)中所述的氰基乙酸酯包括氰基乙酸甲酯、氰基乙酸乙酯、氰基乙酸丙酯或氰基乙酸丁酯，优选氰基乙酸甲酯。
步骤3)中通入的氯化氢气体压力为0.8-2Mpa，优选1.0-1.2Mpa。
步骤3)中脱溶采用的溶剂包括惰性卤代烃、一级或多级醇、芳香烃或非质子性溶剂，优选一级或多级醇。
与现有技术相比，本发明采用了丙炔醇、二异丙胺和氰基乙酸乙酯为原料，整个工艺中第一、二和三步反应收率很高，副反应很少，因而只需在第三步反应结束后进行一次蒸馏纯化，用纯化后的2-氯烟酸乙酯进行水解、酸化，纯的产品2-氯烟酸即析出，所有操作无苛刻条件，操作简单且环境友好，具有显著的经济效益和社会效益。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
实施例1
一种生产2-氯烟酸的方法，将丙炔醇和二异丙胺经催化氧化得到二异丙胺基丙烯醛，再与氰基乙酸乙酯发生Konevenagel反应生成2-氰基-5-二异丙胺基-2，4-戊二烯酸乙酯，通入干燥氯化氢，将得到2-氯烟酸乙酯经碱性水解，酸化后得到2-氯烟酸，反应如下所示：
二异丙胺基丙烯醛的制备
在0.5L的高压反应釜中依次加入51g二异丙胺51g、28g丙炔醇、2.5g二氧化锰和200mL甲苯，关闭反应釜。升温到80℃后通入氧气，保持反应釜内压0.1-0.2Mpa，保温8-10h。经检测原料反应完全后，过滤反应液，少量溶剂洗涤滤饼后与滤液合并，得到酒红色溶液，可直接进行下步反应。反应液经外标检测收率85.2％。
2-氰基-5-二异丙胺基-2,4-戊二烯酸乙酯的制备
在500mL三口烧瓶中，装上温度计和恒压滴液漏斗，依次加入二异丙胺基丙烯醛溶液、1g哌啶、2.5g乙酸和52.2g氰基乙酸乙酯，升温至回流，保温4-6h，冷却后先用5％的碳酸氢钠水溶液洗涤后，水洗两次，有机相用20g无水硫酸钠干燥。过滤后滤液浓缩，纯度>96％，收率88.2％。
2-氯烟酸乙酯的制备
在2L的高压反应釜中依次加入事例2中的2-氰基-5-二异丙胺基-2,4-戊二烯酸乙酯，250mL无水乙醇，关闭反应釜。在5-25℃下，缓慢通入干燥的氯化氢气体，保持压力1Mpa，搅拌8h后检测原料完全消失。先用氮气赶走体系中残存的氯化氢气体，除去乙醇，250mL甲苯溶解后用氨水洗涤至中性，水相用50mL甲苯萃取两次后合并有机相。16g无水硫酸钠干燥后浓缩得到2-氯烟酸乙酯，收率94.6％。
2-氯烟酸的制备
在500mL三口烧瓶中，装上温度计，依次加入43g2N的氢氧化钠和15g2-氯烟酸乙酯，升温到80度，保温2小时冷却，盐酸调节PH到1-2，有白色固体析出，过滤后到清水洗涤，烘干后得到2-氯烟酸，收率为95.2％，纯度>99.5％。
实施例2
一种生产2-氯烟酸的方法，采用以下步骤：
1)丙炔醇和二异丙胺按摩尔比为1∶1混合溶解于甲苯中，加入二氧化锰作为催化剂，通入空气，于30℃和2Mpa下，反应20小时，过滤除去催化剂，采用甲醇为溶剂，滤液脱溶得到二异丙胺基丙烯醛；
2)二异丙胺基丙烯醛溶于甲苯后，加入氰基乙酸甲酯和催化剂三乙胺，二异丙胺基丙烯醛与氰基乙酸酯的摩尔比为1∶0.95回流6小时，采用乙醇为溶剂，脱溶得到2-氰基-5-二异丙胺基-2,4-戊二烯酸酯；
3)2-氰基-5-二异丙胺基-2,4-戊二烯酸乙酯溶解在乙醇中，通入干燥氯化氢气体，氯化氢气体压力为0.8Mpa，然后在5℃和2Mpa的条件下反应36小时，采用乙醇为溶剂，脱溶后油相用甲苯溶解后水洗至pH为1，减压除去甲苯再高真空蒸馏得到2-氯烟酸乙酯；
4)2-氯烟酸乙酯加入2N氢氧化钠，加热至回流，冷却后调节pH值至1，抽滤得到白色固体即为2-氯烟酸。
实施例3
一种生产2-氯烟酸的方法，采用以下步骤：
1)丙炔醇和二异丙胺按摩尔比为1∶1混合溶解于甲苯中，加入二氧化锰作为催化剂，通入氧气，于60℃和1Mpa下，反应12小时，过滤除去催化剂，以甲苯为溶剂，滤液脱溶得到二异丙胺基丙烯醛；
2)二异丙胺基丙烯醛溶于甲苯后，加入氰基乙酸乙酯和催化剂碳酸钠，二异丙胺基丙烯醛与氰基乙酸酯的摩尔比为1∶0.9回流8小时，以甲苯为溶剂，脱溶得到2-氰基-5-二异丙胺基-2,4-戊二烯酸酯；
3)2-氰基-5-二异丙胺基-2,4-戊二烯酸乙酯溶解在乙醇中，通入干燥氯化氢气体，氯化氢气体压力为1.0Mpa，于20℃和1Mpa下反应18小时，以甲苯为溶剂，脱溶后油相用甲苯溶解后水洗至pH为2，减压除去甲苯再高真空蒸馏得到2-氯烟酸乙酯；
4)2-氯烟酸乙酯加入2N氢氧化钠，加热至回流，冷却后调节pH值至1，抽滤得到白色固体即为2-氯烟酸。
实施例4
一种生产2-氯烟酸的方法，采用以下步骤：
1)丙炔醇和二异丙胺按摩尔比为1∶1混合溶解于甲苯中，加入二氧化锰作为催化剂，通入空气或氧气，于80℃和1.5Mpa下，反应18小时，过滤除去催化剂，以乙醇为溶剂，滤液脱溶得到二异丙胺基丙烯醛；
2)二异丙胺基丙烯醛溶于甲苯后，加入氰基乙酸丙酯和催化剂对甲苯磺酸，二异丙胺基丙烯醛与氰基乙酸酯的摩尔比为1∶1.5回流12小时，以乙醇为溶剂，脱溶得到2-氰基-5-二异丙胺基-2,4-戊二烯酸酯；
3)2-氰基-5-二异丙胺基-2,4-戊二烯酸乙酯溶解在乙醇中，通入干燥氯化氢气体，于40℃和1.2Mpa下反应24小时，以乙醇为溶剂，脱溶后油相用甲苯溶解后水洗至pH为3，减压除去甲苯再高真空蒸馏得到2-氯烟酸乙酯；
4)2-氯烟酸乙酯加入2N氢氧化钠，加热至回流，冷却后调节pH值至2，抽滤得到白色固体即为2-氯烟酸。
实施例5
一种生产2-氯烟酸的方法，将丙炔醇和二异丙胺经催化氧化得到二异丙胺基丙烯醛，再与氰基乙酸乙酯发生Konevenage1反应生成2-氰基-5-二异丙胺基-2，4-戊二烯酸乙酯，通入干燥氯化氢，将得到2-氯烟酸乙酯经碱性水解，酸化后得到2-氯烟酸，具体采用以下步骤：
1)丙炔醇和二异丙胺按摩尔比为1∶1混合溶解于甲苯中，加入二氧化锰作为催化剂，通入空气或氧气，于110℃和0.5Mpa下，反应8-20小时，过滤除去催化剂，滤液脱溶得到二异丙胺基丙烯醛；
2)二异丙胺基丙烯醛溶于甲苯后，加入氰基乙酸丁酯和催化剂盐酸，二异丙胺基丙烯醛与氰基乙酸酯的摩尔比为1∶1回流12小时，脱溶得到2-氰基-5-二异丙胺基-2，4-戊二烯酸酯；
3)2-氰基-5-二异丙胺基-2，4-戊二烯酸乙酯溶解在乙醇中，通入干燥氯化氢气体，于50℃和0.8Mpa下反应12小时，脱溶后油相用甲苯溶解后水洗至pH为5，减压除去甲苯再高真空蒸馏得到2-氯烟酸乙酯；
4)2-氯烟酸乙酯加入2N氢氧化钠，加热至回流，冷却后调节pH值至2，抽滤得到白色固体即为2-氯烟酸。
Claims (14)
1.一种生产2-氯烟酸的方法，其特征在于，该方法将丙炔醇和二异丙胺经催化氧化得到二异丙胺基丙烯醛，再与氰基乙酸乙酯反应生成2-氰基-5-二异丙胺基-2,4-戊二烯酸乙酯，通入干燥氯化氢，将得到2-氯烟酸乙酯经碱性水解，酸化后得到2-氯烟酸；
具体采用以下步骤：
1)丙炔醇和二异丙胺按摩尔比为1︰1混合溶解于甲苯中，加入二氧化锰作为催化剂，通入空气或氧气，于30-110℃和0.5-2Mpa下，反应8-20小时，过滤除去催化剂，滤液脱溶得到二异丙胺基丙烯醛；
2)二异丙胺基丙烯醛溶于甲苯后，加入氰基乙酸酯和催化剂，二异丙胺基丙烯醛与氰基乙酸酯的摩尔比为1:0.9-1.5，回流6-12小时，脱溶得到2-氰基-5-二异丙胺基-2,4-戊二烯酸酯；
3)2-氰基-5-二异丙胺基-2,4-戊二烯酸乙酯溶解在乙醇中，通入干燥氯化氢气体，于5-50℃和0.8-2Mpa下反应12-36小时，脱溶后油相用甲苯溶解后水洗至pH为1-5，减压除去甲苯再高真空蒸馏得到2-氯烟酸乙酯；
4)2-氯烟酸乙酯加入2N氢氧化钠，加热至回流，冷却后调节pH值至1-2，抽滤得到白色固体即为2-氯烟酸。
2.根据权利要求1所述的一种生产2-氯烟酸的方法，其特征在于，步骤1)中的反应温度优选为60-80℃。
3.根据权利要求1所述的一种生产2-氯烟酸的方法，其特征在于，步骤1)中脱溶采用的溶剂为惰性卤代烃、一级或多级醇、芳香烃或非质子性溶剂。
4.根据权利要求3所述的一种生产2-氯烟酸的方法，其特征在于，步骤1)中脱溶采用的溶剂为芳香烃或一级醇。
5.根据权利要求1所述的一种生产2-氯烟酸的方法，其特征在于，步骤2)中所述的催化剂为有机碱或无机碱，有机酸或无机酸，或它们的混合物。
6.根据权利要求5所述的一种生产2-氯烟酸的方法，其特征在于，所述的有机碱为三乙胺、吡啶或哌啶；无机碱为碳酸钠或碳酸钾；有机酸为对甲苯磺酸、甲酸或乙酸；无机酸为盐酸或硫酸。
7.根据权利要求1所述的一种生产2-氯烟酸的方法，其特征在于，步骤2)中脱溶采用的溶剂为惰性卤代烃、一级或多级醇、芳香烃或非质子性溶剂。
8.根据权利要求7所述的一种生产2-氯烟酸的方法，其特征在于，步骤2)中脱溶采用的溶剂为芳香烃。
9.根据权利要求1所述的一种生产2-氯烟酸的方法，其特征在于，步骤2)中所述的氰基乙酸酯为氰基乙酸甲酯、氰基乙酸乙酯、氰基乙酸丙酯或氰基乙酸丁酯。
10.根据权利要求9所述的一种生产2-氯烟酸的方法，其特征在于，步骤2)中所述的氰基乙酸酯为氰基乙酸甲酯。
11.根据权利要求1所述的一种生产2-氯烟酸的方法，其特征在于，步骤3)中通入的氯化氢气体压力为0.8-2Mpa。
12.根据权利要求11所述的一种生产2-氯烟酸的方法，其特征在于，步骤3)中通入的氯化氢气体压力为1.0-1.2Mpa。
13.根据权利要求1所述的一种生产2-氯烟酸的方法，其特征在于，步骤3)中脱溶采用的溶剂为惰性卤代烃、一级或多级醇、芳香烃或非质子性溶剂。
14.根据权利要求13所述的一种生产2-氯烟酸的方法，其特征在于，步骤3)中脱溶采用的溶剂为一级或多级醇。
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