CN111393361A - 一种安全环保的2-氯烟酸合成方法 - Google Patents
一种安全环保的2-氯烟酸合成方法 Download PDFInfo
- Publication number
- CN111393361A CN111393361A CN201911396056.2A CN201911396056A CN111393361A CN 111393361 A CN111393361 A CN 111393361A CN 201911396056 A CN201911396056 A CN 201911396056A CN 111393361 A CN111393361 A CN 111393361A
- Authority
- CN
- China
- Prior art keywords
- chloronicotinic acid
- reaction
- synthesizing
- cyanopyridine
- oxide
- 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.)
- Pending
Links
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000001308 synthesis method Methods 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- WOOVSQCALYYUDO-UHFFFAOYSA-N 1-oxidopyridin-1-ium-3-carbonitrile Chemical compound [O-][N+]1=CC=CC(C#N)=C1 WOOVSQCALYYUDO-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000001914 filtration Methods 0.000 claims abstract description 16
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 15
- 239000007787 solid Substances 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 13
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000007062 hydrolysis Effects 0.000 claims abstract description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 11
- 239000012044 organic layer Substances 0.000 claims abstract description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 9
- 239000010410 layer Substances 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 8
- 239000000706 filtrate Substances 0.000 claims abstract description 8
- 238000010992 reflux Methods 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 230000007613 environmental effect Effects 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- KERBAAIBDHEFDD-UHFFFAOYSA-N n-ethylformamide Chemical compound CCNC=O KERBAAIBDHEFDD-UHFFFAOYSA-N 0.000 claims description 3
- SUUDTPGCUKBECW-UHFFFAOYSA-N n-propylformamide Chemical compound CCCNC=O SUUDTPGCUKBECW-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- QQGNLKJAIVSNCO-UHFFFAOYSA-N N-butylformamide Chemical compound CCCCNC=O QQGNLKJAIVSNCO-UHFFFAOYSA-N 0.000 claims description 2
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- 229940078552 o-xylene Drugs 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000002351 wastewater Substances 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000011521 glass Substances 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 3
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 239000005586 Nicosulfuron Substances 0.000 description 2
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 2
- -1 alkenyl ether Chemical compound 0.000 description 2
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 2
- 229960001785 mirtazapine Drugs 0.000 description 2
- 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 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 229960003101 pranoprofen Drugs 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- XHTYQFMRBQUCPX-UHFFFAOYSA-N 1,1,3,3-tetramethoxypropane Chemical compound COC(OC)CC(OC)OC XHTYQFMRBQUCPX-UHFFFAOYSA-N 0.000 description 1
- RKVUCIFREKHYTL-UHFFFAOYSA-N 2-chloro-3-methylpyridine Chemical compound CC1=CC=CN=C1Cl RKVUCIFREKHYTL-UHFFFAOYSA-N 0.000 description 1
- JAUPUQRPBNDMDT-UHFFFAOYSA-N 2-chloropyridine-3-carbonitrile Chemical compound ClC1=NC=CC=C1C#N JAUPUQRPBNDMDT-UHFFFAOYSA-N 0.000 description 1
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 description 1
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 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
- 239000002253 acid Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- XGCUJZHZZAXYDW-UHFFFAOYSA-N methyl 2-cyanobut-2-enoate Chemical compound COC(=O)C(=CC)C#N XGCUJZHZZAXYDW-UHFFFAOYSA-N 0.000 description 1
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 1
- NZMAJUHVSZBJHL-UHFFFAOYSA-N n,n-dibutylformamide Chemical compound CCCCN(C=O)CCCC NZMAJUHVSZBJHL-UHFFFAOYSA-N 0.000 description 1
- REPVNSJSTLRQEQ-UHFFFAOYSA-N n,n-dimethylacetamide;n,n-dimethylformamide Chemical compound CN(C)C=O.CN(C)C(C)=O REPVNSJSTLRQEQ-UHFFFAOYSA-N 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960000916 niflumic acid Drugs 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 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
- C07D213/80—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)
- Pyridine Compounds (AREA)
Abstract
本发明涉及2‑氯烟酸的合成领域，针对现有制备2‑氯烟酸的方法存在废水量大、污染严重的问题，提供一种安全环保的2‑氯烟酸合成方法，将3‑氰基吡啶N‑氧化物和固体光气加入到有机溶剂中，再加入催化剂，升温回流进行氯化反应，反应完全后降至室温，加水搅拌后静置分层，有机层蒸馏回收溶剂，水层加入脱色剂后，加热至50~110℃，同时进行氰基水解和脱色反应，反应结束后趁热过滤，滤液降温至0~5℃，过滤，干燥，得2‑氯烟酸，含量99.0%以上。反应条件温和，操作简便、安全，废水量少，生产成本低。
Description
技术领域
本发明涉及2-氯烟酸的合成领域，尤其是涉及一种安全环保的2-氯烟酸合成方法。
背景技术
2-氯烟酸又名2-尼古丁酸，化学名为2-氯-3-吡啶甲酸，是重要的精细化工中间体。由于具有特殊的生理活性被广泛用作农药、医药中间体，主要用于制备新型高效除草剂烟嘧磺隆(Nicosulfuron)、非甾体抗炎症药物高效消炎镇痛药尼氟灭酸(Niflumicacid)、普拉洛芬(Pranoprofen)、抗抑郁药米氮平(Mirtazapine)和HIV逆转录酶抑制剂奈韦拉平(Nevirapine)等。
2-氯烟酸的文献报道的合成方法主要有以下几种：①烯基醚或烯基胺与氰乙酸乙酯成环法；②氰乙酸乙酯氯化法；③烟酸(酯)或氰基吡啶经氧化、氯化、水解法；④2-氯-3-甲基吡啶氧化法；⑤丙二醛与氰基乙酸乙酯反应法；⑥1,1,3,3-四甲氧基丙烷与氰基乙酸甲酯反应法；⑦用DMF-DMA与2-氰基-2-丁烯酸甲酯反应法。这些方法均存在一定的缺点，比如原料价格较高，反应收率较低，工艺路线长，安全性低等，对工业化生产带来难度。
目前国内厂家主要采用第③种方法，即以3-氰基吡啶为原料，经氧化、氯化、水解、脱色等反应，制备2-氯烟酸。该方法中的氯化，采用三氯氧磷为氯化试剂和反应溶剂，同时反应过程中需要加入三乙胺或其他试剂作为缚酸剂，必须严格控制原料及所有试剂的水分和反应过程中的温度，一不小心极易造成冲料或者爆炸。同时，三氯氧磷的使用也会产生大量含磷废水，造成环境污染。另外，所得的2-氯-3-氰基吡啶采用氢氧化钠水溶液进行水解，然后用盐酸调节pH至中性后，再加入活性炭脱色，最后用盐酸将pH调至1～2，过滤，才能得到固体2-氯烟酸。整个生产过程操作繁琐，废水量大，污染严重。据此需要一种理想的2-氯烟酸合成方法。
发明内容
本发明为了克服现有制备2-氯烟酸的方法存在废水量大、污染严重的问题，提供一种安全环保的2-氯烟酸合成方法，反应条件温和，操作简便、安全，废水量少，生产成本低。
为了实现上述目的，本发明采用以下技术方案：
一种安全环保的2-氯烟酸合成方法，将3-氰基吡啶N-氧化物和固体光气加入到有机溶剂中，再加入催化剂，升温回流进行氯化反应，反应完全后降至室温，加水搅拌后静置分层，有机层蒸馏回收溶剂，水层加入脱色剂后，加热至50～110℃，同时进行氰基水解和脱色反应，反应结束后趁热过滤，滤液降温至0～5℃，过滤，干燥，得2-氯烟酸，含量99.0％以上。
本发明的反应式为：
本发明以3-氰基吡啶N氧化物为原料，在固体光气(BTC)和催化剂的作用下，进行氯化反应，得到2-氯-3-氰基吡啶，然后加入水将过量的BTC破坏，所得的水溶液为强酸性，可直接进行氰基的水解。有机层回收溶剂后可作为下一批次氯化反应的溶剂。在进行氰基水解的同时，加入脱色剂脱色，将原本分开的两步操作合并，缩短生产周期的同时，也大大减少了废水的产生量，从源头上减少污染。采用更加安全、环保的固体光气(BTC)代替危险性高、污染大的三氯氧磷为氯化试剂，大大降低了生产的危险性，也避免了含磷废水的产生，可降低企业的三废处理费用；再者，由于BTC对水分要求较低，并不需要所用的原料和溶剂严格无水，反应条件相对温和。
作为优选，所述的有机溶剂选自甲苯、对二甲苯、间二甲苯、邻二甲苯、混合二甲苯、二氯甲烷、二氯乙烷、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸正丁酯、丙酮、氯仿、四氯化碳、二硫化碳、硝基苯、硝基甲烷、石油醚、环己烷、正己烷、正庚烷、2-甲基四氢呋喃中的一种。
作为优选，有机溶剂的质量为3-氰基吡啶N-氧化物质量的2～8倍。更优选的是4～6倍。
作为优选，所述的催化剂选自N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、N,N-二丁基甲酰胺、N,N-二正丙基甲酰胺、N-甲基甲酰胺、N-乙基甲酰胺、N-正丁基甲酰胺、N-正丙基甲酰胺中的一种。
作为优选，催化剂的质量为3-氰基吡啶N-氧化物质量的0.01～0.5倍。更优选的是0.05～0.2倍。
作为优选，所述固体光气的质量为3-氰基吡啶N-氧化物质量的0.9～3倍。更优选的是1～1.5倍。
作为优选，所述氯化反应的时间为1～10小时。更优选的是3～7小时。
作为优选，所述的水的质量为3-氰基吡啶N-氧化物质量的2～8倍。更优选的是4～6倍。
作为优选，所述的脱色剂为活性炭，活性炭的质量为3-氰基吡啶N-氧化物质量的0.01～1倍。更优选的是0.05～0.3倍。
作为优选，氰基水解的反应时间为1～10小时。更优选的是1～5小时。
作为优选，氰基水解的温度为80～100℃。
因此，本发明具有如下有益效果：(1)采用更加安全、环保的固体光气代替危险性高、污染大的三氯氧磷为氯化试剂，大大降低了生产的危险性，也避免了含磷废水的产生，可降低企业的三废处理费用；而且由固体光气对水分要求较低，并不需要所用的原料和溶剂严格无水，反应条件相对温和；(2)有机层回收溶剂后可作为下一批次氯化反应的溶剂，环保节约；(3)在进行氰基水解的同时，加入脱色剂脱色，将原本分开的两步操作合并，缩短生产周期的同时，也大大减少了废水的产生量，从源头上减少污染。
具体实施方式
下面通过具体实施例，对本发明的技术方案做进一步说明。
本发明中，若非特指，所采用的原料和设备等均可从市场购得或是本领域常用的，实施例中的方法，如无特别说明，均为本领域的常规方法。
实施例1
往30L玻璃釜中，加入2.0kg的3-氰基吡啶N-氧化物和10.0kg二甲苯，开启搅拌，然后加入2.4kg的BTC和0.2kg的N,N-二甲基甲酰胺，加热回流反应5小时，降温至室温，缓慢加入4.0kg工艺水，搅拌30分钟后，静置15分钟，分层，有机层蒸馏回收溶剂；水层转料至20L玻璃釜，加入0.3kg活性炭，加热升温至95℃反应3小时，趁热过滤，滤液降温至0～5℃后，过滤，固体用少量清水洗涤后真空干燥，得2-氯烟酸1.8kg，收率68.6％，HPLC检测含量为99.3％。
实施例2
往30L玻璃釜中，加入2.0kg的3-氰基吡啶N-氧化物和4.0kg二氯乙烷，开启搅拌，然后加入1.8kg的BTC和0.02kg的N-乙基甲酰胺，加热回流反应2小时，降温至室温，缓慢加入8.0kg工艺水，搅拌30分钟后，静置15分钟，分层，有机层蒸馏回收溶剂；水层转料至20L玻璃釜，加入0.02kg活性炭，加热升温至50℃反应10小时，趁热过滤，滤液降温至0～5℃后，过滤，固体用少量清水洗涤后真空干燥，得2-氯烟酸，收率48.1％，HPLC检测含量为99.1％。
实施例3
往30L玻璃釜中，加入1.0kg的3-氰基吡啶N-氧化物和8.0kg乙酸乙酯，开启搅拌，然后加入3.0kg的BTC和0.5kg的N-正丙基甲酰胺，加热回流反应10小时，降温至室温，缓慢加入8.0kg工艺水，搅拌30分钟后，静置15分钟，分层，有机层蒸馏回收溶剂；水层转料至20L玻璃釜，加入1.0kg活性炭，加热升温至110℃反应1小时，趁热过滤，滤液降温至0～5℃后，过滤，固体用少量清水洗涤后真空干燥，得2-氯烟酸，收率40.4％，HPLC检测含量为99.0％。
实施例4
往30L玻璃釜中，加入2.0kg的3-氰基吡啶N-氧化物和8.0kg丙酮，开启搅拌，然后加入2.0kg的BTC和0.4kg的N,N-二丁基甲酰胺，加热回流反应3小时，降温至室温，缓慢加入4.0kg工艺水，搅拌30分钟后，静置15分钟，分层，有机层蒸馏回收溶剂；水层转料至20L玻璃釜，加入0.1kg活性炭，加热升温至80℃反应5小时，趁热过滤，滤液降温至0～5℃后，过滤，固体用少量清水洗涤后真空干燥，得2-氯烟酸，收率57.2％，HPLC检测含量为99.3％。
实施例5
往30L玻璃釜中，加入1.0kg的3-氰基吡啶N-氧化物和6.0kg正己烷，开启搅拌，然后加入1.5kg的BTC和0.2kg的N-甲基甲酰胺，加热回流反应7小时，降温至室温，缓慢加入6.0kg工艺水，搅拌30分钟后，静置15分钟，分层，有机层蒸馏回收溶剂；水层转料至20L玻璃釜，加入0.3kg活性炭，加热升温至100℃反应2小时，趁热过滤，滤液降温至0～5℃后，过滤，固体用少量清水洗涤后真空干燥，得2-氯烟酸，收率50.9％，HPLC检测含量为99.3％。
本发明得到的2-氯烟酸含量在99.0％以上，纯度较高。优选条件下收率可达68.6％。相比现有技术反应条件更温和，安全环保。
以上所述，仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专业的技术人员，在不脱离本发明技术方案范围内，当可利用上述揭示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。
Claims (10)
1.一种安全环保的2-氯烟酸合成方法，其特征在于，将3-氰基吡啶N-氧化物和固体光气加入到有机溶剂中，再加入催化剂，升温回流进行氯化反应，反应完全后降至室温，加水搅拌后静置分层，有机层蒸馏回收溶剂，水层加入脱色剂后，加热至50~110℃，同时进行氰基水解和脱色反应，反应结束后趁热过滤，滤液降温至0~5℃，过滤，干燥，得2-氯烟酸，含量99.0%以上。
2.根据权利要求1所述的一种安全环保的2-氯烟酸合成方法，其特征在于，所述的有机溶剂选自甲苯、对二甲苯、间二甲苯、邻二甲苯、混合二甲苯、二氯甲烷、二氯乙烷、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸正丁酯、丙酮、氯仿、四氯化碳、二硫化碳、硝基苯、硝基甲烷、石油醚、环己烷、正己烷、正庚烷、2-甲基四氢呋喃中的一种。
3.根据权利要求1或2所述的一种安全环保的2-氯烟酸合成方法，其特征在于，有机溶剂的质量为3-氰基吡啶N-氧化物质量的2~8倍。
4.根据权利要求1所述的一种安全环保的2-氯烟酸合成方法，其特征在于，所述的催化剂选自N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、 N,N-二丁基甲酰胺、N,N-二正丙基甲酰胺、N-甲基甲酰胺、N-乙基甲酰胺、N-正丁基甲酰胺、N-正丙基甲酰胺中的一种。
5.根据权利要求1或4所述的一种安全环保的2-氯烟酸合成方法，其特征在于，催化剂的质量为3-氰基吡啶N-氧化物质量的0.01~0.5倍。
6.根据权利要求1所述的一种安全环保的2-氯烟酸合成方法，其特征在于，所述固体光气的质量为3-氰基吡啶N-氧化物质量的0.9~3倍。
7.根据权利要求1所述的一种安全环保的2-氯烟酸合成方法，其特征在于，所述氯化反应的时间为1~10小时。
8.根据权利要求1所述的一种安全环保的2-氯烟酸合成方法，其特征在于，所述的水的质量为3-氰基吡啶N-氧化物质量的2~8倍。
9.根据权利要求1所述的一种安全环保的2-氯烟酸合成方法，其特征在于，所述的脱色剂为活性炭，活性炭的质量为3-氰基吡啶N-氧化物质量的0.01~1倍。
10.根据权利要求1所述的一种安全环保的2-氯烟酸合成方法，其特征在于，氰基水解的反应时间为1~10小时。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911396056.2A CN111393361A (zh) | 2019-12-30 | 2019-12-30 | 一种安全环保的2-氯烟酸合成方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911396056.2A CN111393361A (zh) | 2019-12-30 | 2019-12-30 | 一种安全环保的2-氯烟酸合成方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111393361A true CN111393361A (zh) | 2020-07-10 |
Family
ID=71428395
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911396056.2A Pending CN111393361A (zh) | 2019-12-30 | 2019-12-30 | 一种安全环保的2-氯烟酸合成方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111393361A (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113620870A (zh) * | 2021-07-15 | 2021-11-09 | 老河口市天和科技有限公司 | 2-氯烟酸的制备方法及含该2-氯烟酸的杀虫喷雾剂 |
| CN114181139A (zh) * | 2021-12-27 | 2022-03-15 | 四川仁安药业有限责任公司 | 一种5-卤代烟酸的合成方法 |
| CN115181062A (zh) * | 2022-06-22 | 2022-10-14 | 八叶草健康产业研究院(厦门)有限公司 | 一种6-氯-3-甲基-2-吡啶羧酸甲酯的制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101117332A (zh) * | 2006-08-04 | 2008-02-06 | 浙江医药股份有限公司新昌制药厂 | 2-氯烟酸的制备方法 |
| CN101941943A (zh) * | 2010-09-07 | 2011-01-12 | 浙江工业大学 | 2-氯-3-氰基吡啶的合成方法 |
-
2019
- 2019-12-30 CN CN201911396056.2A patent/CN111393361A/zh active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101117332A (zh) * | 2006-08-04 | 2008-02-06 | 浙江医药股份有限公司新昌制药厂 | 2-氯烟酸的制备方法 |
| CN101941943A (zh) * | 2010-09-07 | 2011-01-12 | 浙江工业大学 | 2-氯-3-氰基吡啶的合成方法 |
Non-Patent Citations (1)
| Title |
|---|
| 葛林丹: "2-氯烟酸的绿色合成工艺研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113620870A (zh) * | 2021-07-15 | 2021-11-09 | 老河口市天和科技有限公司 | 2-氯烟酸的制备方法及含该2-氯烟酸的杀虫喷雾剂 |
| CN114181139A (zh) * | 2021-12-27 | 2022-03-15 | 四川仁安药业有限责任公司 | 一种5-卤代烟酸的合成方法 |
| CN114181139B (zh) * | 2021-12-27 | 2023-12-08 | 四川仁安药业有限责任公司 | 一种5-卤代烟酸的合成方法 |
| CN115181062A (zh) * | 2022-06-22 | 2022-10-14 | 八叶草健康产业研究院(厦门)有限公司 | 一种6-氯-3-甲基-2-吡啶羧酸甲酯的制备方法 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111393361A (zh) | 一种安全环保的2-氯烟酸合成方法 | |
| CN107641106A (zh) | 法匹拉韦中间体以及法匹拉韦的合成方法 | |
| JP2023532317A (ja) | カンプトテシン誘導体を合成するための中間体及びその製造方法並びに用途 | |
| WO2020114025A1 (zh) | β-内酰胺衍生物的制备方法 | |
| CN104311485B (zh) | 一种治疗白血病的药物博舒替尼的制备方法 | |
| CN103980188A (zh) | 一种吡仑帕奈的合成方法及其中间体和中间体的合成方法 | |
| Nishiwaki et al. | Novel functionalization of 1-methyl-2-quinolone; dimerization and denitration of trinitroquinolone | |
| CN110734398B (zh) | 一种新的2-氯代烟酸的制备方法 | |
| CN109251168B (zh) | 一种利用2-op精馏残渣制备吡啶-2-甲酸的方法 | |
| CN109851599B (zh) | 一种2-氨基苯并呋喃化合物的制备方法 | |
| CN114349690B (zh) | 一种多拉韦林中间体合成方法 | |
| CN113444041A (zh) | 一种光催化合成多取代喹啉类化合物的方法 | |
| CN106946811B (zh) | 一种环保型2-氰基吩噻嗪的工业制备方法 | |
| Guo et al. | Synthesis of Quinoline and 1, 2, 3, 4‐Tetrahydroquinoline Derivatives from Substituted o‐Nitrotoluenes via Cesium‐promoted [2+ 4] Cycloaddition | |
| WO2020051853A1 (zh) | 3,3-二取代氧化吲哚及其制备方法 | |
| CN110724094A (zh) | 一种喹啉类化合物及其合成方法 | |
| Babushkin et al. | A Practical Synthesis of 4’-Fluorospiro [cyclopropane-1, 3’-indol]-2’(1’H)-one: a Valuable Terminal Building-Block for Biologically Active Podands | |
| CN107162983B (zh) | 一种甲巯咪唑的合成及精制方法 | |
| CN111170933A (zh) | 一种2-氯-5-硝基吡啶的制备方法 | |
| CN111004250B (zh) | 一种1，4-环氧基-2，3-二氰基-1，2，3，4-四氢萘的合成方法 | |
| CN112174966B (zh) | 一种制备盐酸吡西卡尼的新方法 | |
| CN106188047B (zh) | 一种制备6-(1-苯基-乙基)-吡咯并[3,4-b]吡啶-5,7-二酮的方法 | |
| CN113087669B (zh) | 一种4-氰基-5-溴嘧啶的制备方法 | |
| CN113979928B (zh) | 一种2-氯-5-硝基吡啶的制备方法 | |
| CN110218211B (zh) | 一种奈韦拉平的简便制备方法 |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200710 |