WO2021056811A1 - Imine salt derivative and preparation method therefor, and preparation method for nicotine - Google Patents
Imine salt derivative and preparation method therefor, and preparation method for nicotine Download PDFInfo
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- WO2021056811A1 WO2021056811A1 PCT/CN2019/121980 CN2019121980W WO2021056811A1 WO 2021056811 A1 WO2021056811 A1 WO 2021056811A1 CN 2019121980 W CN2019121980 W CN 2019121980W WO 2021056811 A1 WO2021056811 A1 WO 2021056811A1
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- Prior art keywords
- reaction
- nicotine
- solution
- acid
- add
- Prior art date
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- -1 Imine salt Chemical class 0.000 title claims abstract description 81
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 title claims abstract description 74
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 title claims abstract description 60
- 229960002715 nicotine Drugs 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 106
- 239000002904 solvent Substances 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 17
- 239000002243 precursor Substances 0.000 claims abstract description 13
- 239000000243 solution Substances 0.000 claims description 61
- 239000002253 acid Substances 0.000 claims description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 43
- 239000000126 substance Substances 0.000 claims description 37
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000003960 organic solvent Substances 0.000 claims description 23
- 238000010992 reflux Methods 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 20
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 19
- 239000011259 mixed solution Substances 0.000 claims description 17
- SCVLPUZALILIEN-UHFFFAOYSA-N 1-methyl-3-(pyridine-3-carbonyl)pyrrolidin-2-one Chemical compound O=C1N(C)CCC1C(=O)C1=CC=CN=C1 SCVLPUZALILIEN-UHFFFAOYSA-N 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 238000006482 condensation reaction Methods 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- 229960001238 methylnicotinate Drugs 0.000 claims description 15
- 235000001968 nicotinic acid Nutrition 0.000 claims description 14
- 239000011664 nicotinic acid Substances 0.000 claims description 14
- 229960003512 nicotinic acid Drugs 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 150000005838 radical anions Chemical class 0.000 claims description 12
- 238000006722 reduction reaction Methods 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 150000005837 radical ions Chemical class 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 9
- 229910052700 potassium Inorganic materials 0.000 claims description 9
- 239000011591 potassium Substances 0.000 claims description 9
- 230000002378 acidificating effect Effects 0.000 claims description 8
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 7
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 7
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 239000012141 concentrate Substances 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 6
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- OIXUJRCCNNHWFI-UHFFFAOYSA-N 1,2-dioxane Chemical compound C1CCOOC1 OIXUJRCCNNHWFI-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 238000005292 vacuum distillation Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003759 ester based solvent Substances 0.000 claims description 4
- 239000004210 ether based solvent Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000007975 iminium salts Chemical class 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 16
- 230000015572 biosynthetic process Effects 0.000 abstract description 15
- 230000008569 process Effects 0.000 abstract description 13
- 238000010791 quenching Methods 0.000 abstract description 5
- 230000000171 quenching effect Effects 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 15
- 239000000376 reactant Substances 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 10
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 230000007935 neutral effect Effects 0.000 description 9
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- 230000007246 mechanism Effects 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229910002651 NO3 Inorganic materials 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 229950005499 carbon tetrachloride Drugs 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000011736 potassium bicarbonate Substances 0.000 description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229940063013 borate ion Drugs 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- 235000005985 organic acids Nutrition 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229940085991 phosphate ion Drugs 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 241000208125 Nicotiana Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- QLZHNIAADXEJJP-UHFFFAOYSA-N Phenylphosphonic acid Chemical compound OP(O)(=O)C1=CC=CC=C1 QLZHNIAADXEJJP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 description 2
- AIAXOZVCSOIQTJ-UHFFFAOYSA-N [O-][N+](C1=CC=CC=C1OP(O)=O)=O Chemical compound [O-][N+](C1=CC=CC=C1OP(O)=O)=O AIAXOZVCSOIQTJ-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- QLZHNIAADXEJJP-UHFFFAOYSA-L dioxido-oxo-phenyl-$l^{5}-phosphane Chemical compound [O-]P([O-])(=O)C1=CC=CC=C1 QLZHNIAADXEJJP-UHFFFAOYSA-L 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- HDJBTCAJIMNXEW-PPHPATTJSA-N 3-[(2s)-1-methylpyrrolidin-2-yl]pyridine;hydrochloride Chemical compound Cl.CN1CCC[C@H]1C1=CC=CN=C1 HDJBTCAJIMNXEW-PPHPATTJSA-N 0.000 description 1
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 229940122578 Acetylcholine receptor agonist Drugs 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- BOQRPPFUUSHFGW-UHFFFAOYSA-N CN(CCC1)C1(c1cccnc1)O Chemical compound CN(CCC1)C1(c1cccnc1)O BOQRPPFUUSHFGW-UHFFFAOYSA-N 0.000 description 1
- IDJSUMLCHHFHAN-UHFFFAOYSA-N C[NH+](CCCC(c1cccnc1)=O)[O-] Chemical compound C[NH+](CCCC(c1cccnc1)=O)[O-] IDJSUMLCHHFHAN-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N O=C1OCCC1 Chemical compound O=C1OCCC1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 241000208292 Solanaceae Species 0.000 description 1
- 235000002634 Solanum Nutrition 0.000 description 1
- 241000207763 Solanum Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 238000010669 acid-base reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3834—Aromatic acids (P-C aromatic linkage)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
Definitions
- the present invention relates to the field of organic synthesis preparation, in particular to an imine salt derivative, a preparation method thereof and a preparation method of nicotine.
- Nicotine commonly known as nicotine, is an alkaloid that exists in Solanaceae (Solanum) and an important component of tobacco. It is also a typical nicotinic acetylcholine receptor agonist. The central nervous system has a regulatory role.
- Nicotine can make people addicted or dependent. Repeated use of nicotine also increases heart speed and blood pressure and reduces appetite. Large doses of nicotine can cause vomiting and nausea, and death can occur in severe cases. At the same time, nicotine and its derivatives are effective drugs for treating Parkinson's syndrome, Alzheimer's disease, schizophrenia, epilepsy and depression.
- the starting materials of the method are very expensive, and the intermediate pyrrolidol reduction step has the problems of incomplete reaction and low conversion rate, which is not suitable for industrial large-scale production.
- the object of the present invention is to provide an imine salt derivative which can synthesize nicotine.
- Another object of the present invention is to provide a method for preparing imine salt derivatives using niacin as the main raw material
- Another object of the present invention is to provide a preparation method for preparing nicotine by using imine salt derivatives, which has low starting materials, mild reaction conditions, and high nicotine synthesis yield.
- novel imine salt derivative of the present invention is represented by the following general formula (I) or (II):
- X 1 and X 2 are respectively represented as acid radical anions.
- the X 1 and X 2 represent the same acid radical ion; or the X 1 and X 2 represent different acid radical ions.
- X 1 and/or X 2 respectively represent inorganic acid anions or organic acid anions, that is, X 1 and X 2 can be non-polar acid anions at the same time, or there can be no organic acid anions at the same time, or X 1 and X 2 can be organic Acid radical anion, the other is inorganic acid radical anion.
- the present invention also provides a preparation method of imine salt derivatives, including the following steps:
- reaction solution is cooled to below 10°C for extraction treatment, and the organic layers are combined; and the organic layer is concentrated under reduced pressure at 50-65°C to obtain 1-methyl-3-nicotinoyl -2-pyrrolidone;
- the catalyst is thionyl chloride or oxalyl chloride.
- the first quencher is an alkaline aqueous solution.
- the extractant is an acidic aqueous solution.
- the present invention further provides a method for preparing nicotine, which includes the following steps:
- the general formula described in claim 1 is The iminium salt derivative and reducing agent are added to the solvent for reduction reaction, and the general formula is The racemic nicotine solution;
- the reducing agent is one of sodium thiosulfate, sodium borohydride, potassium borohydride, lithium aluminum tetrahydrogen, formic acid, ammonium formate, potassium formate, hydrogen, and palladium/carbon.
- the second quencher is an alkaline substance.
- the extractant is one or more of ether solvents, ester solvents or chlorinated hydrocarbon solvents.
- the beneficial effects of the present invention are: the first niacin, common organic acids and/or inorganic acids are used as raw materials, and the imine salt is synthesized under relatively mild process conditions (such as room temperature, about 100°C reflux reaction, extraction treatment, etc.)
- relatively mild process conditions such as room temperature, about 100°C reflux reaction, extraction treatment, etc.
- Starting material reducing agents eg, sodium thiosulfate, sodium borohydride, potassium borohydride, lithium tetrahydroaluminum, formic acid, ammonium formate, potassium formate
- the reaction temperature is controlled at -10 to 100°C, even at room temperature
- the intermediate of the imine salt derivative is reduced to obtain racemic nicotine. Therefore, compared with the existing nicotine synthesis process, the method has the advantages of mild synthesis process conditions, simple equipment requirements, and the product has the advantages of high purity and synthesis rate, and is particularly suitable for industrial production.
- Figure 1 is a flow chart of the imine salt synthesis process of the present invention
- Figure 2 is a flow chart of the nicotine synthesis process of the present invention.
- X 1 and X 2 are respectively represented as acid radical anions.
- X 1 and X 2 are respectively represented as acid radical anions, and these acid radical ions may be inorganic acid radical ions or organic acid radical ions.
- inorganic acid anions include, but are not limited to, chloride, sulfate, phosphate, carbonate, nitrate, perchlorate or borate ions; organic acid anions include but are not limited to carbon-containing C 1 -C 30 carboxylate ion (e.g., formate ion, methyl propionate ion, valerate ion, benzoate ion, p-dibenzoate ion, etc.), carbon-containing C 3 -C 30 sulfonate ion (e.g., methyl Sulfonate ion, phenyl sulfonate ion, sodium dodecyl sulfonate ion, etc.), or carbon-containing C 3 -C 30 phosphonate ion (
- X 1 and X 2 may be the same acid ion, such as chloride ion, sulfate ion, phosphate ion, carbonate ion, nitrate ion, Perchlorate ion, borate ion, carbon-containing C 1 -C 30 carboxylate ion, carbon-containing C 3 -C 30 sulfonate ion or carbon-containing C 3 -C 30 phosphonate ion, etc.; or
- X 1 and X 2 may also be different acid ions; for example, X 1 is sulfate ion, X 2 is formate ion; X 1 is borate ion, X 2 is C 30 sulfonate ion; or X 1 is C 8 phosphonate ion, X 2 is perchlorate ion, etc.
- X 1 and X 2 are the same acid radical ion or different acid radical ion needs to be determined according to the acid added twice before and after the preparation process. If the acid added twice before and after is the same substance, X 1 and X 2 are the same acid radical ion; otherwise, X 1 and X 2 are different acid radical ions.
- the preparation method of the above-mentioned imine salt derivative is as follows:
- the molar ratio of niacin to catalyst is 1:5, and the catalyst is thionyl chloride or oxalyl chloride, preferably thionyl chloride; toluene is used as a solvent to dissolve nicotinic acid and the catalyst, which is beneficial to the reaction.
- niacin and the catalyst are insoluble in toluene at room temperature, it is necessary to heat to 50-80°C (preferably 70°C) and stir while heating during the dissolution process.
- the oil temperature heating method is used for 10min-60min, preferably 30min. A colorless and transparent mixed solution was obtained.
- an alcohol solvent such as methanol, propanol, ethylene glycol, etc.
- it may also be an ether solvent, or an aldehyde solvent, or a chloroform solvent or the like.
- the first quencher is added to the reactor, and an alkaline aqueous solution is selected.
- the solute can be one of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
- One or more than two types; the first quencher is used to neutralize the acid radical ions in the reactant to ensure that the reaction stops and avoid the production of other by-products.
- an ester extractant such as ethyl acetate, methyl acetate, ethyl propionate, etc.
- the extractant can also be an ether solvent (e.g., diethyl ether, dimethyl diethyl ether, etc.). ), or one or more of chlorinated hydrocarbons (e.g., dichloroethane, tetrachloromethane, etc.) solvents.
- the extraction is generally repeated multiple times, and the organic layer obtained after the extraction is concentrated under reduced pressure to remove the solvent to obtain methyl nicotinate.
- the methyl nicotinate is dissolved in an organic solvent to obtain a methyl nicotinate solution, and it is determined that there is no significant exotherm.
- the first organic solvent includes toluene, tetrahydrofuran or 1,2-dioxane.
- alkaline reagents include sodium hydride, potassium hydride, sodium ethoxide, potassium and sodium tert-butoxide, or potassium and butyl lithium, lithium bis(trimethylsilyl)amide (LiHMDS) and lithium diisopropylamide ( One or more of LDA).
- the second organic solvent includes one or more of toluene, tetrahydrofuran and 1,2-dioxane.
- the obtained reaction liquid is cooled to below 10°C, the extractant is added dropwise, and acidic aqueous solutions (eg, niacin, nitric acid, sulfuric acid, phosphoric acid, and organic acids with C 3 ⁇ C 30) are selected.
- acidic aqueous solutions eg, niacin, nitric acid, sulfuric acid, phosphoric acid, and organic acids with C 3 ⁇ C 30
- Is used to stop the condensation reaction neutralize the alkali solution in the reaction system at the same time, and adjust the pH of the reaction system solution to be 8-9, and then perform repeated extraction and separation with EA solvent to obtain the organic layer and combine it for subsequent extraction.
- the acid substance can be an organic acid or an inorganic acid, wherein the acid radical anion corresponding to the inorganic acid includes but not limited to chloride ion, sulfate ion, phosphate ion, carbonate ion, nitrate ion, perchlorate ion or boric acid Root ion.
- the acid radical anions corresponding to organic acids include, but are not limited to, carbon-containing C 1 -C 30 carboxylate ions, carbon-containing C 3 -C 30 sulfonate ions, or carbon-containing C 3 -C 30 phosphonate ions.
- the acid substance is added to 1-methyl-3-nicotinoyl-2-pyrrolidone to perform exothermic reaction first to obtain a light yellow reaction liquid, and then reflux reaction at 110°C for 24h; after the reflux reaction stops, the reaction system The temperature is lowered to 10°C; then the reaction system solution is subjected to vacuum distillation treatment to remove water, and acetone is added to recrystallize for purification treatment, and the general formula is The imine salt derivative.
- the recrystallization purification is carried out by adding acetone, ethanol or ethyl acetate to the reaction solution after the vacuum distillation treatment for recrystallization purification treatment.
- X 1 and X 2 are the same acid radical anion; if the acid substance added in the reflux reaction in step j is mixed with acid substance, then X 1 and X 2 are different acid radical anions.
- the nicotine salt compound prepared by the above method is used to prepare nicotine, and the process flow is as follows:
- the general formula is The imine salt derivative of and the reducing agent are added to the solvent to perform the reduction reaction to obtain racemic nicotine; wherein, X 1 and X 2 are both acid radical anions;
- X 1 and X 1 may be inorganic acid anions or organic acid anions.
- inorganic acid anions include, but are not limited to, chloride, sulfate, phosphate, carbonate, nitrate, perchlorate or borate ions
- organic acid anions include but are not limited to carbon-containing C 1 -C 30 carboxylate ion, carbon-containing C 3 -C 30 sulfonate ion or carbon-containing C 3 -C 30 phosphonate ion.
- the reducing agent is generally selected to be an inorganic acidic substance or an organic acidic substance; for example, sodium thiosulfate, sodium borohydride, potassium borohydride, lithium aluminum tetrahydrogen, formic acid, ammonium formate, potassium formate; or a reducing agent It is possible to select a substance that can provide acid radical ions through the reduction reaction, for example, one of hydrogen and palladium/carbon.
- X 1 and X 2 can be the same acid ion, such as chloride ion, sulfate ion, phosphate ion, carbonate ion, nitrate ion, perchlorate ion, borate ion, carbon-containing C 1- C 30 carboxylate ion, carbon-containing C 3 -C 30 sulfonate ion or carbon-containing C 3 -C 30 phosphonate ion, etc.; or
- X 1 and X 2 may also be different acid ions; for example, X 1 is sulfate ion, X 2 is formate ion; X 1 is borate ion, X 2 is C 30 sulfonate ion; or X 1 is C 8 phosphonate ion, X 2 is perchlorate ion, etc.
- the imine salt derivative is a cyclic organic substance, and solvents such as alcohol solvents, ether solvents, ester solvents, or chlorinated hydrocarbons are generally selected for dissolution.
- solvents such as alcohol solvents, ether solvents, ester solvents, or chlorinated hydrocarbons
- other organic solvents aldehyde-based solvents, ketone-based solvents, etc.
- inorganic solvents such as water
- the temperature of the reduction reaction can be controlled at room temperature of -10 to 100°C, preferably 25°C, so that the temperature control operation is convenient, and no additional heating or cooling control equipment is required.
- the molar ratio of the intermediate to the reducing agent is controlled at 1:50; according to the chemical reaction rate mechanism, the excess of reactants is beneficial to speed up the reaction speed and convert the reactants into products as much as possible.
- an excessive amount of reducing agent with low raw material price to convert the intermediate into more target product racemic nicotine.
- the reducing agent reactant is excessive.
- the target product racemic nicotine has been obtained; if the excessive reducing agent reactant continues to exist, it will, Further reaction produces undesirable products, so it is necessary to add a quencher.
- the principle of quenching is to react with another compound that is more likely to react with the excess compound.
- the reducing agent reactant is an acidic reactant, and the most likely reaction of an acidic substance is an acid-base reaction. Therefore, an alkaline substance is selected as the quencher.
- an alkaline substance is added as the second quencher, such as one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. .
- the concentration range of the second quencher (reactant) is selected from 0.1 to 10 mol/L. Because, the inhibitory effect of different concentration of the second quencher, its principle is consistent with the chemical reaction rate mechanism.
- the chemical reaction rate (v) is equal to the decrease ( ⁇ c) of a certain reactant concentration per unit time ( ⁇ t), namely:
- the second quencher is used as a reactant, and the concentration of the second quencher affects the rate of the quenching reaction, which directly reflects whether there is a significant inhibitory effect in a short time.
- step S12 the reaction temperature is controlled at -5 after adding a quencher ⁇ 50°C, preferably room temperature 25°C.
- step S3 in order to extract the nicotine substance from the nicotine precursor solution (ie, the reaction mixture solution), a solvent needs to be added to the nicotine precursor solution.
- This solvent can more easily dissolve nicotine, and the solvent after dissolving nicotine It shows a layering phenomenon with the mixed solution, and then removes the mixed solution to obtain a solvent solution that dissolves nicotine; this solvent is also called an extractant.
- the extractant is preferably ether solvents (such as diethyl ether, dimethyl diethyl ether, etc.), ester solvents (such as carboxylate, phenyl acetate, or methyl carbonate, etc.) or chlorinated hydrocarbon solvents (Eg, dichloroethane, tetrachloromethane, etc.) one or more than two.
- ether solvents such as diethyl ether, dimethyl diethyl ether, etc.
- ester solvents such as carboxylate, phenyl acetate, or methyl carbonate, etc.
- chlorinated hydrocarbon solvents Eg, dichloroethane, tetrachloromethane, etc.
- step S3 the reaction temperature control during the extraction process with the addition of extractant At -5 to 50°C, preferably at room temperature 25°C.
- the first nicotinic acid, common organic acids and/or inorganic acids are used as raw materials to synthesize imine salt derivatives under relatively mild process conditions (such as room temperature, about 100°C reflux reaction, extraction treatment, etc.) And re-use of cheap initial raw material reducing agents (such as sodium thiosulfate, sodium borohydride, potassium borohydride, lithium tetrahydroaluminum, formic acid, ammonium formate, potassium formate), also under a relatively mild condition ( For example, the reaction temperature is controlled at -10 to 100°C, even at room temperature) to reduce the intermediate of the imine salt derivative to obtain racemic nicotine. Therefore, compared with the existing nicotine synthesis process, the method has the advantages of mild synthesis process conditions, simple equipment requirements, and the product has the advantages of high purity and synthesis rate, and is particularly suitable for industrial production.
- relatively mild process conditions such as room temperature, about 100°C reflux reaction, extraction treatment, etc.
- initial raw material reducing agents such as sodium thios
- Example 2 The difference from Example 1 is that: the first quencher is an aqueous potassium hydroxide solution; the alcohol extractant is ethyl acetate; the alkaline reagent used in the condensation reaction is sodium ethoxide; the acid substance used in the reflux reaction is different. Sulfuric acid is used in the example.
- Example 2 The difference from Example 1 is that the catalyst is acid chloride; the first quencher is sodium carbonate aqueous solution; the alcohol extractant is ethyl propionate; the alkaline reagents used in the condensation reaction are potassium and sodium tert-butoxide; the reflux reaction is used
- the acid substance is different, and nitric acid is used in this example.
- Nitric acid was added to the 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g) aqueous solution, exothermic heat, the reaction liquid was light yellow, refluxed at 110°C for 24h, cooled to 10°C, and distilled under reduced pressure to remove water. It was recrystallized with ethanol to obtain the intermediate nitrate (1.4g).
- Example 1 The difference from Example 1 is that: the first quencher is an aqueous ammonia solution; the ether extractant is ether; the alkaline reagents used in the condensation reaction are potassium and butyl lithium; the acid substance used in the reflux reaction is different. Perchloric acid is used in it.
- Example 2 The difference from Example 1 is that the first quencher is potassium carbonate aqueous solution; the ether extractant is dimethyl diethyl ether; the alkaline reagent used in the condensation reaction is lithium bis(trimethylsilyl)amide (LiHMDS) ; The first and second organic solvents are respectively mixed solvents of toluene and tetrahydrofuran; the acid substances used in the reflux reaction are different, and boric acid is used in this embodiment.
- the first quencher is potassium carbonate aqueous solution
- the ether extractant is dimethyl diethyl ether
- the alkaline reagent used in the condensation reaction is lithium bis(trimethylsilyl)amide (LiHMDS) )
- the first and second organic solvents are respectively mixed solvents of toluene and tetrahydrofuran; the acid substances used in the reflux reaction are different, and boric acid is used in this embodiment.
- Example 1 The difference from Example 1 is that: the first quencher is an aqueous sodium bicarbonate solution; the chlorinated hydrocarbon extractant is dichloroethane; the alkaline reagent used in the condensation reaction is lithium diisopropylamide (LDA); The first and second organic solvents are 1,2-dioxane respectively; the acid substance used in the reflux reaction is different, and benzoic acid is used in this example.
- the first quencher is an aqueous sodium bicarbonate solution
- the chlorinated hydrocarbon extractant is dichloroethane
- the alkaline reagent used in the condensation reaction is lithium diisopropylamide (LDA)
- the first and second organic solvents are 1,2-dioxane respectively
- the acid substance used in the reflux reaction is different, and benzoic acid is used in this example.
- Benzoic acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), exothermic, the reaction liquid was light yellow, refluxed at 110°C for 24h, cooled to 10°C, and distilled under reduced pressure to remove water It was recrystallized by adding ethyl acetate to obtain the intermediate benzoate (1.6g).
- Example 2 The difference from Example 1 is that: the first quencher is an aqueous potassium bicarbonate solution; the alkaline reagents used in the condensation reaction are sodium hydride and sodium ethoxide; the first and second organic solvents are tetrahydrofuran; the acid substance used in the reflux reaction is not Similarly, camphor sulfonic acid is used in this example.
- Camphorsulfonic acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), the reaction solution was light yellow, and the reaction was refluxed at 110°C for 24 hours. The temperature was reduced to 10°C and evaporated under reduced pressure. Water and ethanol were recrystallized to obtain the intermediate camphor sulfonate (1.8 g).
- Example 2 The difference from Example 1 is that the first quencher is a mixed aqueous solution of potassium bicarbonate and potassium carbonate; the chlorinated hydrocarbon extractant is tetrachloromethane; the alkaline reagent used in the condensation reaction is potassium hydride; the first and second organic
- the solvents were mixed solvents of toluene, tetrahydrofuran and 1,2-dioxane; the acid substances used in the reflux reaction were different, and a mixed acid of phenylphosphonic acid and nitric acid was used in this embodiment.
- Phenylphosphonic acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), the reaction solution was light yellow, and the reaction was refluxed at 110°C for 24 hours. The temperature was lowered to 10°C and then distilled under reduced pressure. The water was removed, acetone was added for recrystallization, and the intermediate nitrophenyl phosphonate (1.61 g) was obtained.
- the intermediate was selected as the hydrochloride salt of the intermediate prepared in Example 1.
- the mixture of the intermediate hydrochloride (1.5g, 0.0088mol) and potassium formate (1.6g, 0.0052mol) was heated to reflux at 100°C for 2h in 10mL of absolute ethanol. After the reaction, the ethanol was left under reduced pressure. The residue was dissolved in water, and 3N sodium hydroxide solution was added to react at 25°C to make it neutral. The resulting oily substance was extracted with ether at 25°C, and the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.4 g of nicotine with a purity of 99.4%.
- the intermediate was selected as the nitrate of the intermediate prepared in Example 3.
- the intermediate was selected as the sulfate salt of the intermediate prepared in Example 2.
- the intermediate perchlorate prepared in Example 4 was selected as the intermediate.
- the intermediate was selected as the borate of the intermediate prepared in Example 5.
- the mixture of borate (1.5g) and ammonium formate (1.4g) of the intermediate was heated to reflux at 90°C for 2h in 10 mL of ethyl acetate. After the reaction, the ethyl acetate was removed under reduced pressure, and the residue was dissolved in Water, and add 0.5mol/L potassium carbonate solution to make the reaction become neutral at 0°C. The resulting oily substance was extracted with ether at 0°C, the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.41 g of nicotine with a purity of 99.3%.
- the benzoate of the intermediate prepared in Example 6 was selected as the intermediate.
- the intermediate was selected as the camphorsulfonate of the intermediate prepared in Example 7.
- Example 8 the intermediate phenylphosphonate prepared in Example 8 was selected as the intermediate.
- the borate of the intermediate prepared in Example 1 was selected as the intermediate.
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Abstract
Disclosed are an imine salt derivative and a preparation method therefor, and a preparation method for nicotine. The preparation method for nicotine comprises the following steps: adding an imine salt derivative having a general formula of (I) or (II) and a reducing agent into a solvent and allowing reaction to occur to obtain a solution of racemic nicotine; adding a second quenching agent into the solution of racemic nicotine to obtain a solution of a nicotine precursor; and adding an extractant into the solution of a nicotine precursor, performing vacuum concentration, and removing the solvent by drying to obtain nicotine. In the present invention, racemic nicotine is obtained by reducing an imine salt derivative intermediate, which is synthesized for the first time, using an inexpensive reducing agent under relatively mild conditions. Compared with existing nicotine synthesis processes, the method of the present invention has the advantages of having mild synthesis process conditions, simple equipment requirements, and high product purity and synthesis rates, and is particularly suitable for industrial production.
Description
本发明涉及有机合成的制备领域，尤其涉及一种亚胺盐衍生物、其制备方法及尼古丁的制备方法。The present invention relates to the field of organic synthesis preparation, in particular to an imine salt derivative, a preparation method thereof and a preparation method of nicotine.
尼古丁(Nicotine)，俗称烟碱，是一种存在于茄科植物(茄属)中的生物碱，也是烟草的重要成分，还是典型的烟碱乙酰胆碱受体激动剂，对烟碱乙酰胆碱受体及中枢神经***均有调节作用。Nicotine, commonly known as nicotine, is an alkaloid that exists in Solanaceae (Solanum) and an important component of tobacco. It is also a typical nicotinic acetylcholine receptor agonist. The central nervous system has a regulatory role.
尼古丁会使人上瘾或产生依赖性，重复使用尼古丁也增加心脏速度和升高血压并降低食欲。大剂量的尼古丁会引起呕吐以及恶心，严重时人会死亡。同时尼古丁及其衍生物是治疗帕金森综合征、阿尔茨海默病、精神***、癫痫和抑郁症的有效药物。Nicotine can make people addicted or dependent. Repeated use of nicotine also increases heart speed and blood pressure and reduces appetite. Large doses of nicotine can cause vomiting and nausea, and death can occur in severe cases. At the same time, nicotine and its derivatives are effective drugs for treating Parkinson's syndrome, Alzheimer's disease, schizophrenia, epilepsy and depression.
近年来，随着电子烟行业的迅猛发展，尼古丁作为电子烟重要活性成分，市场需求激增。目前市场尼古丁主要来源为烟草植物提取，受到了原材料、气候和生长周期等多方面因素的影响，同时提取尼古丁中含有烟草特有的尼古丁相关杂质，长期使用存在潜在健康危害。合成尼古丁能够克服以上缺陷，近年来吸引了广泛关注。In recent years, with the rapid development of the e-cigarette industry, nicotine, as an important active ingredient of e-cigarettes, has seen a surge in market demand. At present, the main source of nicotine in the market is extracted from tobacco plants, which is affected by various factors such as raw materials, climate and growth cycle. At the same time, the extracted nicotine contains tobacco-specific nicotine-related impurities, and long-term use has potential health hazards. Synthetic nicotine can overcome the above shortcomings and has attracted widespread attention in recent years.
文献J.Heterocycl.Chem.2009,46(6):1252–1258报道了一种尼古丁的制备方法，该制备方法起始原料3-溴吡啶昂贵，并且丁基锂反应条件苛刻，不适合工业放大生产。The literature J.Heterocycl.Chem.2009,46(6):1252–1258 reported a preparation method of nicotine. The starting material 3-bromopyridine is expensive, and the butyllithium reaction conditions are harsh, which is not suitable for industrial scale-up. produce.
中国专利CN 107011321A报到了使用4-N-甲基-1-(3-吡啶基)-丁酮盐酸盐为起始原料合成尼古丁的方法，反应机理如下:Chinese patent CN107011321A reports a method for synthesizing nicotine using 4-N-methyl-1-(3-pyridyl)-butanone hydrochloride as the starting material. The reaction mechanism is as follows:
该方法起始原料十分昂贵，同时中间体吡咯烷醇还原步骤存在反应不完全，转化率低的问题，不适合工业大规模生产。The starting materials of the method are very expensive, and the intermediate pyrrolidol reduction step has the problems of incomplete reaction and low conversion rate, which is not suitable for industrial large-scale production.
发明内容Summary of the invention
本发明的目的是提供一种可以合成尼古丁的亚胺盐衍生物。The object of the present invention is to provide an imine salt derivative which can synthesize nicotine.
本发明的另一目的是提供一种采用烟酸为主要原料制备亚胺盐衍生物的方法；Another object of the present invention is to provide a method for preparing imine salt derivatives using niacin as the main raw material;
本发明的再一目的是提供一种采用亚胺盐衍生物制备尼古丁的制备方法中，该方法起始原料低廉、反应条件温和，且尼古丁合成收率高。Another object of the present invention is to provide a preparation method for preparing nicotine by using imine salt derivatives, which has low starting materials, mild reaction conditions, and high nicotine synthesis yield.
本发明的技术方案如下：The technical scheme of the present invention is as follows:
本发明新的亚胺盐衍生物，用下列通式(Ⅰ)或(Ⅱ)表示：The novel imine salt derivative of the present invention is represented by the following general formula (I) or (II):
其中，X
1和X
2分别表示为酸根负离子。
Among them, X 1 and X 2 are respectively represented as acid radical anions.
上述亚胺盐衍生物的表征数据：
11H NMR(400MHz)D
2O(δ＝9.28,1H,s),(δ＝8.97,1H,d,J＝9.00),(δ＝8.91,1H,d,J＝8.92),(δ＝8.15,1H,t,J＝8.15),(δ＝3.3,2H,m),(δ＝3.07,2H,m),(δ＝2.65,3H,s),(δ＝1.95,2H,m)；
13C NMR(400MHz)D
2O(δ＝13.3,20.7,30.7,32.8,35.6,48.1,61.9,127.6,134.6,142.0,144.8,145.1,175.0,196.8)；MS ESI
+161.1(M
2+)。
Characterization data of the above-mentioned imine salt derivatives: 11 H NMR (400MHz) D 2 O (δ=9.28, 1H, s), (δ=8.97, 1H, d, J=9.00), (δ=8.91, 1H, d, J = 8.92), (δ = 8.15, 1H, t, J = 8.15), (δ = 3.3, 2H, m), (δ = 3.07, 2H, m), (δ = 2.65, 3H, s) ,(δ=1.95,2H,m); 13 C NMR(400MHz) D 2 O(δ=13.3,20.7,30.7,32.8,35.6,48.1,61.9,127.6,134.6,142.0,144.8,145.1,175.0,196.8 ); MS ESI + 161.1 (M 2+ ).
上述亚胺盐衍生物中，所述X
1和X
2表示为相同的酸根离子；或者所述X
1和X
2表示为不相同的酸根离子。
In the above-mentioned imine salt derivative, the X 1 and X 2 represent the same acid radical ion; or the X 1 and X 2 represent different acid radical ions.
上述X
1和/或X
2分别表示为无机酸根负离子或者有机酸根负离子，即X
1和X
2可以同时为无极酸根负离子，也可以同时无有机酸根负离子，或者X
1和X
2可以一个为有机酸根负离子，另一个为无机酸根负离子。
The above X 1 and/or X 2 respectively represent inorganic acid anions or organic acid anions, that is, X 1 and X 2 can be non-polar acid anions at the same time, or there can be no organic acid anions at the same time, or X 1 and X 2 can be organic Acid radical anion, the other is inorganic acid radical anion.
本发明的还提供了亚胺盐衍生物的制备方法，包括如下步骤：The present invention also provides a preparation method of imine salt derivatives, including the following steps:
a、依次将烟酸、甲苯及催化剂加入反应器中，在搅拌和加热条件下进行反应，得到混合溶液；对所述混合溶液减压浓缩处理，去除溶剂，得到白色固体；随后接着加入醇类溶剂，室温下搅拌，继续反应；a. Add nicotinic acid, toluene and catalyst to the reactor in turn, and react under stirring and heating conditions to obtain a mixed solution; the mixed solution is concentrated under reduced pressure to remove the solvent to obtain a white solid; then add alcohols Solvent, stir at room temperature, continue the reaction;
b、往反应器中加入第一淬灭剂，停止反应，并调整反应后的混合液的pH＝9，得到碱性混合溶液；采用萃取剂对碱性混合溶液反复萃取处理，得到烟酸甲酯；将所述烟酸甲酯溶于有有机溶剂中，得到烟酸甲酯溶液；b. Add the first quencher to the reactor, stop the reaction, and adjust the pH of the reaction mixture to be 9 to obtain an alkaline mixed solution; use the extractant to repeatedly extract the alkaline mixed solution to obtain nicotinic acid Ester; The methyl nicotinate is dissolved in an organic solvent to obtain a methyl nicotinate solution;
c、将碱性试剂加入甲苯中，室温搅拌，随后加入反应试剂N-甲基吡咯烷酮，室温下搅拌后，得到反应体系溶液，往该反应体系溶液中滴加烟酸甲酯溶液；接着升温至70～95℃下持续缩合反应；c. Add the alkaline reagent to toluene, stir at room temperature, and then add the reaction reagent N-methylpyrrolidone. After stirring at room temperature, the reaction system solution is obtained, and the methyl nicotinate solution is added dropwise to the reaction system solution; then the temperature is raised to Continuous condensation reaction at 70～95℃;
d、缩合反应停止后，对得到的反应溶液降温至10℃以下进行萃取处理，合并有机层；、对有机层于50～65℃下减压浓缩处理，得到1-甲基-3-烟酰基-2-吡咯酮；d. After the condensation reaction is stopped, the obtained reaction solution is cooled to below 10°C for extraction treatment, and the organic layers are combined; and the organic layer is concentrated under reduced pressure at 50-65°C to obtain 1-methyl-3-nicotinoyl -2-pyrrolidone;
e、将酸物质加入1-甲基-3-烟酰基-2-吡咯酮中进行回流反应；待回流反应停止后，降温至10℃；再对反应体系溶液进行减压蒸馏处理，并经重结晶纯化，得到结构式为
的亚胺盐衍生物；其中，X
1和X
2分 别表示为酸根负离子。
e. Add the acid substance to 1-methyl-3-nicotinoyl-2-pyrrolidone for reflux reaction; after the reflux reaction stops, the temperature is lowered to 10°C; then the reaction system solution is subjected to vacuum distillation treatment, and Crystallization and purification, the structural formula is The iminium salt derivative; wherein, X 1 and X 2 are respectively represented as acid radical anions.
上述亚胺盐衍生物的制备方法的步骤S1中，所述催化剂为二氯亚砜或草酰氯。In step S1 of the method for preparing the imine salt derivative, the catalyst is thionyl chloride or oxalyl chloride.
上述亚胺盐衍生物的制备方法的步骤S2中，所述第一淬灭剂为碱性水溶液。In step S2 of the method for preparing the imine salt derivative, the first quencher is an alkaline aqueous solution.
上述亚胺盐衍生物的制备方法的步骤S2中，所述萃取剂为酸性水溶液。In step S2 of the method for preparing the imine salt derivative, the extractant is an acidic aqueous solution.
本发明再提供了一种尼古丁的制备方法，包括如下步骤：The present invention further provides a method for preparing nicotine, which includes the following steps:
S1、将权利要求1中所述的通式为
的亚胺盐衍生物及还原剂加入溶剂中进行还原反应，获得通式为
的消旋尼古丁溶液；
S1, the general formula described in claim 1 is The iminium salt derivative and reducing agent are added to the solvent for reduction reaction, and the general formula is The racemic nicotine solution;
S2、向所述消旋尼古丁溶液中加入第二淬灭剂，停止还原反应，获得尼古丁前驱体溶液；S2. Add a second quencher to the racemic nicotine solution to stop the reduction reaction to obtain a nicotine precursor solution;
S3、向所述尼古丁前驱体溶液中加入提取剂，浓缩尼古丁前驱体溶液，然后干燥去除溶剂，得到通式为
的尼古丁。
S3. Add an extractant to the nicotine precursor solution, concentrate the nicotine precursor solution, and then dry to remove the solvent to obtain the general formula: Nicotine.
上述尼古丁的制备方法步骤S1中，所述还原剂为硫代硫酸钠、硼氢化钠、硼氢化钾、四氢铝锂、甲酸、甲酸铵、甲酸钾、氢气与钯/碳中的一种。In step S1 of the method for preparing nicotine, the reducing agent is one of sodium thiosulfate, sodium borohydride, potassium borohydride, lithium aluminum tetrahydrogen, formic acid, ammonium formate, potassium formate, hydrogen, and palladium/carbon.
上述尼古丁的制备方法步骤S2中，所述第二淬灭剂为碱性物质。In step S2 of the foregoing nicotine preparation method, the second quencher is an alkaline substance.
上述尼古丁的制备方法步骤S3中，所述提取剂为醚类溶剂、酯类溶剂或氯代烃类溶剂中的一种或两种以上。In step S3 of the method for preparing nicotine, the extractant is one or more of ether solvents, ester solvents or chlorinated hydrocarbon solvents.
本发明的有益效果为：通过首次烟酸、常见的有机酸和/或无机酸等为原料，在相对温和的工艺条件下(如室温、100℃左右回流反应、萃取处理等)合成亚胺盐衍生物中间体，并再次使用廉价的初始原料还原剂(如，硫代硫酸钠、硼 氢化钠、硼氢化钾、四氢铝锂、甲酸、甲酸铵、甲酸钾)，也是在一个相对较温和条件下(如，反应温度控制在-10～100℃，甚至常温下)还原亚胺盐衍生物中间体，得到消旋尼古丁。因此，与现有尼古丁合成工艺相比，该方法具有合成工艺条件温和，设备要求简便，产品具有纯度和合成率高的优点，特别适合工业化生产。The beneficial effects of the present invention are: the first niacin, common organic acids and/or inorganic acids are used as raw materials, and the imine salt is synthesized under relatively mild process conditions (such as room temperature, about 100°C reflux reaction, extraction treatment, etc.) Derivative intermediates, and the use of cheap starting material reducing agents (eg, sodium thiosulfate, sodium borohydride, potassium borohydride, lithium tetrahydroaluminum, formic acid, ammonium formate, potassium formate) is also in a relatively mild Under conditions (for example, the reaction temperature is controlled at -10 to 100°C, even at room temperature), the intermediate of the imine salt derivative is reduced to obtain racemic nicotine. Therefore, compared with the existing nicotine synthesis process, the method has the advantages of mild synthesis process conditions, simple equipment requirements, and the product has the advantages of high purity and synthesis rate, and is particularly suitable for industrial production.
图1为本发明的亚胺盐合成工艺流程图；Figure 1 is a flow chart of the imine salt synthesis process of the present invention;
图2为本发明的尼古丁合成工艺流程图。Figure 2 is a flow chart of the nicotine synthesis process of the present invention.
下面结合附图，对本发明的较佳实施例作进一步详细说明。The preferred embodiments of the present invention will be described in further detail below in conjunction with the accompanying drawings.
本发明提供的亚胺盐衍生物，其通式(Ⅰ)或(Ⅱ)表示如下：The general formula (I) or (II) of the imine salt derivative provided by the present invention is expressed as follows:
其中，X
1和X
2分别表示为酸根负离子。
Among them, X 1 and X 2 are respectively represented as acid radical anions.
上述亚胺盐衍生物的表征数据：
1H NMR(400MHz)D
2O(δ＝9.28,1H,s),(δ＝8.97,1H,d,J＝9.00),(δ＝8.91,1H,d,J＝8.92),(δ＝8.15,1H,t,J＝8.15),(δ＝3.3,2H,m),(δ＝3.07,2H,m),(δ＝2.65,3H,s),(δ＝1.95,2H,m)；
13C NMR(400MHz)D
2O(δ＝13.3,20.7,30.7,32.8,35.6,48.1,61.9,127.6,134.6,142.0,144.8,145.1,175.0,196.8)；MS ESI
+161.1(M
2+)。
Characterization data of the above-mentioned imine salt derivatives: 1 H NMR (400MHz) D 2 O (δ = 9.28, 1H, s), (δ = 8.97, 1H, d, J = 9.00), (δ = 8.91, 1H, d, J = 8.92), (δ = 8.15, 1H, t, J = 8.15), (δ = 3.3, 2H, m), (δ = 3.07, 2H, m), (δ = 2.65, 3H, s) ,(δ=1.95,2H,m); 13 C NMR(400MHz) D 2 O(δ=13.3,20.7,30.7,32.8,35.6,48.1,61.9,127.6,134.6,142.0,144.8,145.1,175.0,196.8 ); MS ESI + 161.1 (M 2+ ).
在亚胺盐衍生物中，X
1和X
2分别表示为酸根负离子，这些酸根离子可以是无机酸根离子，也可以是有机酸根离子。其中，无机酸根负离子包括但不限于氯离子、硫酸根离子、磷酸根离子、碳酸根离子、硝酸根离子、高氯酸根离子或硼酸根离子；有机酸根负离子包括但不限于含碳C
1-C
30羧酸根离子(如，甲酸 根离子、甲基丙酸根离子、戊酸根离子、苯甲酸根离子、对二苯甲酸根离子等)、含碳C
3-C
30磺酸根离子(如，甲基磺酸根离子、苯基磺酸根离子、十二烷基磺酸钠离子等)，或含碳C
3-C
30膦酸根离子(如，甲基膦酸根离子、苯基膦酸根离子、十二烷基膦酸根离子等)。上述X
1和X
2可以同时为无极酸根负离子，也可以同时无有机酸根负离子，或者X
1和X
2可以一个为有机酸根负离子，另一个为无机酸根负离子。
In the imine salt derivative, X 1 and X 2 are respectively represented as acid radical anions, and these acid radical ions may be inorganic acid radical ions or organic acid radical ions. Among them, inorganic acid anions include, but are not limited to, chloride, sulfate, phosphate, carbonate, nitrate, perchlorate or borate ions; organic acid anions include but are not limited to carbon-containing C 1 -C 30 carboxylate ion (e.g., formate ion, methyl propionate ion, valerate ion, benzoate ion, p-dibenzoate ion, etc.), carbon-containing C 3 -C 30 sulfonate ion (e.g., methyl Sulfonate ion, phenyl sulfonate ion, sodium dodecyl sulfonate ion, etc.), or carbon-containing C 3 -C 30 phosphonate ion (eg, methyl phosphonate ion, phenyl phosphonate ion, dodecane Phosphonate ions, etc.). The foregoing X 1 and X 2 may be non-polar acid anions or organic acid anions at the same time, or X 1 and X 2 may be organic acid anions and the other inorganic acid anions.
上述亚胺盐衍生物中，对于X
1和X
2而言；X
1和X
2可以为相同的酸根离子，如，氯离子、硫酸根离子、磷酸根离子、碳酸根离子、硝酸根离子、高氯酸根离子、硼酸根离子、含碳C
1-C
30羧酸根离子、含碳C
3-C
30磺酸根离子或含碳C
3-C
30膦酸根离子等；或者
In the above-mentioned imine salt derivatives, for X 1 and X 2 ; X 1 and X 2 may be the same acid ion, such as chloride ion, sulfate ion, phosphate ion, carbonate ion, nitrate ion, Perchlorate ion, borate ion, carbon-containing C 1 -C 30 carboxylate ion, carbon-containing C 3 -C 30 sulfonate ion or carbon-containing C 3 -C 30 phosphonate ion, etc.; or
X
1和X
2也可以为不相同的酸根离子；如，X
1为硫酸根离子，X
2为甲酸根离子；X
1为硼酸根离子，X
2为C
30磺酸根离子；或者X
1为C
8膦酸根离子，X
2为高氯酸根离子等。
X 1 and X 2 may also be different acid ions; for example, X 1 is sulfate ion, X 2 is formate ion; X 1 is borate ion, X 2 is C 30 sulfonate ion; or X 1 is C 8 phosphonate ion, X 2 is perchlorate ion, etc.
对于X
1和X
2是为相同的酸根离子还是不相同的酸根离子，需要根据制备过程中，前后两次所添加的酸而定。如果前后两次添加的酸均为同一物质，则X
1和X
2为相同的酸根离子；否则，X
1和X
2为不相同的酸根离子。
Whether X 1 and X 2 are the same acid radical ion or different acid radical ion needs to be determined according to the acid added twice before and after the preparation process. If the acid added twice before and after is the same substance, X 1 and X 2 are the same acid radical ion; otherwise, X 1 and X 2 are different acid radical ions.
如图1所示，上述亚胺盐衍生物，其制备方法工艺步骤如下：As shown in Figure 1, the preparation method of the above-mentioned imine salt derivative is as follows:
a、依次将烟酸、甲苯及催化剂加入反应器中，在搅拌和加热条件下进行反应，得到混合溶液；对混合溶液减压浓缩处理，去除溶剂，得到白色固体；随后加入醇类溶剂，室温下搅拌，继续反应。a. Add nicotinic acid, toluene and catalyst to the reactor in turn, and react under stirring and heating conditions to obtain a mixed solution; concentrate the mixed solution under reduced pressure to remove the solvent to obtain a white solid; then add alcohol solvent at room temperature Stir down and continue the reaction.
本步骤中，烟酸与催化剂的摩尔比例为1:5，催化剂为二氯亚砜或草酰氯，优选二氯亚砜；甲苯作为溶剂，用于溶解烟酸和催化剂的作用，有利于反应进行。由于烟酸与催化剂在室温下不溶于甲苯，因此，在溶解过程中，需要进行加热到50～80℃(优选70℃)，边加热边搅拌。反应过程中，为确保恒温加热，采用油温加热方法处理10min～60min，优选30min。得到无色透明的混合溶液。In this step, the molar ratio of niacin to catalyst is 1:5, and the catalyst is thionyl chloride or oxalyl chloride, preferably thionyl chloride; toluene is used as a solvent to dissolve nicotinic acid and the catalyst, which is beneficial to the reaction. . Since niacin and the catalyst are insoluble in toluene at room temperature, it is necessary to heat to 50-80°C (preferably 70°C) and stir while heating during the dissolution process. During the reaction, in order to ensure constant heating, the oil temperature heating method is used for 10min-60min, preferably 30min. A colorless and transparent mixed solution was obtained.
本步骤中，将上述无色透明的混合溶液继续加热3h以上，通过TLC观察原 料反应完全，将反应液于50～70℃(优选60℃)减压浓缩，去除甲苯溶剂，达到白色固体。In this step, continue heating the colorless and transparent mixed solution for more than 3 hours, observe the complete reaction of the raw materials by TLC, and concentrate the reaction solution under reduced pressure at 50-70°C (preferably 60°C) to remove the toluene solvent to reach a white solid.
本步骤中，往反应其中的白色固体中加入醇类溶剂，如，甲醇、丙醇、乙二醇等溶剂。在其他实施例中，也可以是醚类溶剂，或醛类溶剂，或氯仿类溶剂等。加入甲醇溶剂后，室温下缴费30min,继续反应。In this step, an alcohol solvent, such as methanol, propanol, ethylene glycol, etc., is added to the white solid in the reaction. In other embodiments, it may also be an ether solvent, or an aldehyde solvent, or a chloroform solvent or the like. After the methanol solvent was added, the fee was paid for 30 minutes at room temperature, and the reaction was continued.
b、往反应器中加入第一淬灭剂，停止反应，并调整反应后的混合液的pH＝9，得到碱性混合溶液；采用萃取剂对碱性混合溶液反复萃取处理，得到烟酸甲酯；将所述烟酸甲酯溶于第一有机溶剂中，得到烟酸甲酯溶液。b. Add the first quencher to the reactor, stop the reaction, and adjust the pH of the reaction mixture to be 9 to obtain an alkaline mixed solution; use the extractant to repeatedly extract the alkaline mixed solution to obtain nicotinic acid Ester; the methyl nicotinate is dissolved in the first organic solvent to obtain a methyl nicotinate solution.
本步骤中，往反应器中加入第一淬灭剂，选用碱性水溶液，其中溶质可以为氢氧化钠、氢氧化钾、碳酸钠、氨水、碳酸钾、碳酸氢钠、碳酸氢钾中的一种或两种以上；第一淬灭剂，用于中和反应物中的酸根离子，确保反应停止，避免反应生产其他的副产物，同时还通过碱性溶液，调整反应后的混合溶液的pH＝9。In this step, the first quencher is added to the reactor, and an alkaline aqueous solution is selected. The solute can be one of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. One or more than two types; the first quencher is used to neutralize the acid radical ions in the reactant to ensure that the reaction stops and avoid the production of other by-products. At the same time, the pH of the mixed solution after the reaction is adjusted through the alkaline solution = 9.
本步骤中，采用酯类萃取剂，如，乙酸乙酯，乙酸甲酯，丙酸乙酯等，其他实施例中，萃取剂也可以是醚类溶剂(如，***、二甲基二***等)、或氯代烃类(如，二氯乙烷，四氯甲烷等)溶剂中的一种或两种以上。为了萃取干净，一般采用反复多次萃取，并对萃取后得到有机层进行减压浓缩，去除溶剂，达到烟酸甲酯。In this step, an ester extractant, such as ethyl acetate, methyl acetate, ethyl propionate, etc., is used. In other embodiments, the extractant can also be an ether solvent (e.g., diethyl ether, dimethyl diethyl ether, etc.). ), or one or more of chlorinated hydrocarbons (e.g., dichloroethane, tetrachloromethane, etc.) solvents. In order to extract cleanly, the extraction is generally repeated multiple times, and the organic layer obtained after the extraction is concentrated under reduced pressure to remove the solvent to obtain methyl nicotinate.
本步骤中，将所述烟酸甲酯溶于有机溶剂中，得到烟酸甲酯溶液，确定无明显放热。其中，第一有机溶剂包括甲苯、四氢呋喃或1,2-二氧六环。In this step, the methyl nicotinate is dissolved in an organic solvent to obtain a methyl nicotinate solution, and it is determined that there is no significant exotherm. Wherein, the first organic solvent includes toluene, tetrahydrofuran or 1,2-dioxane.
c、将碱性试剂加入第二有机溶剂中，室温搅拌，随后加入反应试剂N-甲基吡咯烷酮，室温下搅拌后，得到反应体系溶液，往该反应体系溶液中滴加烟酸甲酯溶液；接着升温至70～95℃下持续缩合反应。c. Add the alkaline reagent to the second organic solvent, stir at room temperature, and then add the reaction reagent N-methylpyrrolidone. After stirring at room temperature, a reaction system solution is obtained, and methyl nicotinate solution is added dropwise to the reaction system solution; Then the temperature is raised to 70-95°C and the condensation reaction is continued.
本步骤中，将碱性试剂加入第二有机溶剂中，室温下搅拌溶解10min，然后加入N-甲基吡咯烷酮，室温下继续搅拌反应15min，确定无明显放热后，滴加烟酸甲酯溶液，室温下搅拌后，得到反应体系溶液，往该反应体系溶液中滴加 烟酸甲酯溶液；接着升温至70～95℃(优选90℃)下持续缩合反应1～3h(优选2h)。其中，碱性试剂包括氢化钠、氢化钾、乙醇钠、钾与叔丁醇钠、或钾与丁基锂、二(三甲基硅基)氨基锂(LiHMDS)及二异丙基氨基锂(LDA)中的一种或两种以上。其中，第二有机溶剂包括甲苯、四氢呋喃及1,2-二氧六环中的一种或两种以上。In this step, add the alkaline reagent to the second organic solvent, stir and dissolve at room temperature for 10 minutes, then add N-methylpyrrolidone, continue to stir and react at room temperature for 15 minutes, after confirming that there is no obvious exotherm, add methyl nicotinate solution dropwise After stirring at room temperature, a reaction system solution is obtained, and methyl nicotinate solution is added dropwise to the reaction system solution; then the temperature is raised to 70-95° C. (preferably 90° C.) and the condensation reaction is continued for 1 to 3 hours (preferably 2 hours). Among them, alkaline reagents include sodium hydride, potassium hydride, sodium ethoxide, potassium and sodium tert-butoxide, or potassium and butyl lithium, lithium bis(trimethylsilyl)amide (LiHMDS) and lithium diisopropylamide ( One or more of LDA). Wherein, the second organic solvent includes one or more of toluene, tetrahydrofuran and 1,2-dioxane.
d、缩合反应停止后，对反应溶液降温至10℃以下进行萃取处理，合并有机层；对有机层于50～65℃下减压浓缩处理，得到1-甲基-3-烟酰基-2-吡咯酮。d. After the condensation reaction is stopped, the reaction solution is cooled to below 10°C for extraction treatment, and the organic layers are combined; the organic layer is concentrated under reduced pressure at 50-65°C to obtain 1-methyl-3-nicotinoyl-2- Pyrrolidone.
本步骤中，缩合反应结束后，将得到的反应液降温至10℃以下，滴加萃取剂，选用酸性水溶液(如，烟酸、硝酸、硫酸、磷酸，以及C
3～C
30的有机酸等)，用于停止缩合反应，同时中和反应体系中的碱溶液，并调整反应体系溶液的pH＝8～9，然后用EA溶剂进行反复萃取分液，得到有机层并合并，以便后续萃取。
In this step, after the condensation reaction is completed, the obtained reaction liquid is cooled to below 10°C, the extractant is added dropwise, and acidic aqueous solutions (eg, niacin, nitric acid, sulfuric acid, phosphoric acid, and organic acids with C 3 ～C 30) are selected. ) Is used to stop the condensation reaction, neutralize the alkali solution in the reaction system at the same time, and adjust the pH of the reaction system solution to be 8-9, and then perform repeated extraction and separation with EA solvent to obtain the organic layer and combine it for subsequent extraction.
e、将酸物质加入1-甲基-3-烟酰基-2-吡咯酮中进行回流反应；待回流反应停止后，降温至10℃；再对反应体系溶液进行减压蒸馏处理，并重结晶纯化，得到通式为
的亚胺盐衍生物；其中，X
1和X
2分别为酸根负离子。
e. Add the acid substance to 1-methyl-3-nicotinoyl-2-pyrrolidone for reflux reaction; after the reflux reaction stops, the temperature is lowered to 10°C; then the reaction system solution is subjected to vacuum distillation treatment, and recrystallization purification , The general formula is The iminium salt derivative; wherein, X 1 and X 2 are acid radical anions.
本步骤中，酸物质可以是有机酸或无机酸，其中无机酸对应的酸根负离子包括但不限于氯离子、硫酸根离子、磷酸根离子、碳酸根离子、硝酸根离子、高氯酸根离子或硼酸根离子。有机酸对应的酸根负离子包括但不限于含碳C
1-C
30羧酸根离子、含碳C
3-C
30磺酸根离子或含碳C
3-C
30膦酸根离子。
In this step, the acid substance can be an organic acid or an inorganic acid, wherein the acid radical anion corresponding to the inorganic acid includes but not limited to chloride ion, sulfate ion, phosphate ion, carbonate ion, nitrate ion, perchlorate ion or boric acid Root ion. The acid radical anions corresponding to organic acids include, but are not limited to, carbon-containing C 1 -C 30 carboxylate ions, carbon-containing C 3 -C 30 sulfonate ions, or carbon-containing C 3 -C 30 phosphonate ions.
将酸物质加入1-甲基-3-烟酰基-2-吡咯酮中首先进行放热反应，得到浅黄色的反应液，然后于110℃下进行回流反应24h；待回流反应停止后，反应体系降温至10℃；再对反应体系溶液进行减压蒸馏处理，去除水，并加入丙酮重结 晶，进行纯化处理，得到通式为
的亚胺盐衍生物。
The acid substance is added to 1-methyl-3-nicotinoyl-2-pyrrolidone to perform exothermic reaction first to obtain a light yellow reaction liquid, and then reflux reaction at 110°C for 24h; after the reflux reaction stops, the reaction system The temperature is lowered to 10°C; then the reaction system solution is subjected to vacuum distillation treatment to remove water, and acetone is added to recrystallize for purification treatment, and the general formula is The imine salt derivative.
本步骤中，重结晶纯化是通过加入往减压蒸馏处理后的反应溶液中加入丙酮、乙醇或乙酸乙酯进行重结晶纯化处理。In this step, the recrystallization purification is carried out by adding acetone, ethanol or ethyl acetate to the reaction solution after the vacuum distillation treatment for recrystallization purification treatment.
尼古丁盐化合物的制备过程中，如果步骤j回流反应所加的酸物质为单一酸物质，则X
1和X
2为相同的酸根负离子；如果步骤j回流反应所加的酸物质混合酸物质，则X
1和X
2为不相同的酸根负离子。
In the preparation process of the nicotine salt compound, if the acid substance added in the reflux reaction in step j is a single acid substance, X 1 and X 2 are the same acid radical anion; if the acid substance added in the reflux reaction in step j is mixed with acid substance, then X 1 and X 2 are different acid radical anions.
如图2所示，将上述方法制得的尼古丁盐化合物，用于制备尼古丁，其工艺流程如下：As shown in Figure 2, the nicotine salt compound prepared by the above method is used to prepare nicotine, and the process flow is as follows:
S1、将通式为
的亚胺盐衍生物及还原剂加入溶剂中进行还原反应，获得消旋尼古丁；其中，X
1和X
2均为酸根负离子；
S1, the general formula is The imine salt derivative of and the reducing agent are added to the solvent to perform the reduction reaction to obtain racemic nicotine; wherein, X 1 and X 2 are both acid radical anions;
S2、向所述消旋尼古丁溶液中加入第二淬灭剂，停止还原反应，获得尼古丁前驱体溶液；S2. Add a second quencher to the racemic nicotine solution to stop the reduction reaction to obtain a nicotine precursor solution;
S3、向所述尼古丁前驱体溶液中加入提取剂，浓缩尼古丁前驱体溶液，然后干燥去除溶剂，得到通式为
的尼古丁。
S3. Add an extractant to the nicotine precursor solution, concentrate the nicotine precursor solution, and then dry to remove the solvent to obtain the general formula: Nicotine.
在步骤S1中，X
1和X
1可以为无机酸根负离子，也可以为有机酸根负离子。其中，无机酸根负离子包括但不限于氯离子、硫酸根离子、磷酸根离子、碳酸根离子、硝酸根离子、高氯酸根离子或硼酸根离子；有机酸根负离子包括但不限于含碳C
1-C
30羧酸根离子、含碳C
3-C
30磺酸根离子或含碳C
3-C
30膦酸根离子。
In step S1, X 1 and X 1 may be inorganic acid anions or organic acid anions. Among them, inorganic acid anions include, but are not limited to, chloride, sulfate, phosphate, carbonate, nitrate, perchlorate or borate ions; organic acid anions include but are not limited to carbon-containing C 1 -C 30 carboxylate ion, carbon-containing C 3 -C 30 sulfonate ion or carbon-containing C 3 -C 30 phosphonate ion.
上述步骤S1中，还原剂一般选择为无机酸性物质或有机酸性物质；如，硫代硫酸钠、硼氢化钠、硼氢化钾、四氢铝锂、甲酸、甲酸铵、甲酸钾；或者还原剂还可以选择通过还原反应后可提供酸根离子的物质，如，氢气与钯/碳中的 一种。In the above step S1, the reducing agent is generally selected to be an inorganic acidic substance or an organic acidic substance; for example, sodium thiosulfate, sodium borohydride, potassium borohydride, lithium aluminum tetrahydrogen, formic acid, ammonium formate, potassium formate; or a reducing agent It is possible to select a substance that can provide acid radical ions through the reduction reaction, for example, one of hydrogen and palladium/carbon.
在步骤S1中，X
1和X
2可以为相同的酸根离子，如，氯离子、硫酸根离子、磷酸根离子、碳酸根离子、硝酸根离子、高氯酸根离子、硼酸根离子、含碳C
1-C
30羧酸根离子、含碳C
3-C
30磺酸根离子或含碳C
3-C
30膦酸根离子等；或者
In step S1, X 1 and X 2 can be the same acid ion, such as chloride ion, sulfate ion, phosphate ion, carbonate ion, nitrate ion, perchlorate ion, borate ion, carbon-containing C 1- C 30 carboxylate ion, carbon-containing C 3 -C 30 sulfonate ion or carbon-containing C 3 -C 30 phosphonate ion, etc.; or
X
1和X
2也可以为不相同的酸根离子；如，X
1为硫酸根离子，X
2为甲酸根离子；X
1为硼酸根离子，X
2为C
30磺酸根离子；或者X
1为C
8膦酸根离子，X
2为高氯酸根离子等。
X 1 and X 2 may also be different acid ions; for example, X 1 is sulfate ion, X 2 is formate ion; X 1 is borate ion, X 2 is C 30 sulfonate ion; or X 1 is C 8 phosphonate ion, X 2 is perchlorate ion, etc.
在选择X
1和X
2对应的酸性物质时，可以根据实际试验或生产工艺需要，按照成本低、合成产率高、生产条件简单的原则进行相应选择。
When selecting the acidic substances corresponding to X 1 and X 2, the corresponding selection can be made according to actual test or production process requirements, according to the principles of low cost, high synthesis yield, and simple production conditions.
在步骤S1中，亚胺盐衍生物为环状有机物，一般都会选择醇类溶剂、醚类溶剂、酯类溶剂或氯代烃类等溶剂进行溶解。当然，也可以根据需要，选择其他的有机溶剂(醛类溶剂、酮类溶剂等)或无机溶剂(如，水)。In step S1, the imine salt derivative is a cyclic organic substance, and solvents such as alcohol solvents, ether solvents, ester solvents, or chlorinated hydrocarbons are generally selected for dissolution. Of course, other organic solvents (aldehyde-based solvents, ketone-based solvents, etc.) or inorganic solvents (such as water) can also be selected as required.
在步骤S1的还原反应中，为了有利于反应进行，还原反应的温度可以控制在-10～100℃，优选25℃的室温，这样温度控制操作方便，无需额外的升温或降温控制设备。同时，根据反应合成比例，中间体与还原剂的摩尔比为控制在1:50；按照化学反应速率机理，反应物过量，有利于加快反应速度，使反应物尽可能转化为生成物，这里我们选择原料价格低的还原剂过量，使中间体转化为更多的目标产物消旋尼古丁。In the reduction reaction of step S1, in order to facilitate the progress of the reaction, the temperature of the reduction reaction can be controlled at room temperature of -10 to 100°C, preferably 25°C, so that the temperature control operation is convenient, and no additional heating or cooling control equipment is required. At the same time, according to the reaction synthesis ratio, the molar ratio of the intermediate to the reducing agent is controlled at 1:50; according to the chemical reaction rate mechanism, the excess of reactants is beneficial to speed up the reaction speed and convert the reactants into products as much as possible. Here we Choose an excessive amount of reducing agent with low raw material price to convert the intermediate into more target product racemic nicotine.
在亚胺盐衍生物与还原剂的还原反应中，还原剂反应物是过量的,当还原反应进行到一定程度,目标产物消旋尼古丁已经获得；如果该过量还原剂反应物继续存在的话会，进一步反应生成不希望的产物,所以需要加入淬灭剂。In the reduction reaction between the imine salt derivative and the reducing agent, the reducing agent reactant is excessive. When the reduction reaction progresses to a certain extent, the target product racemic nicotine has been obtained; if the excessive reducing agent reactant continues to exist, it will, Further reaction produces undesirable products, so it is necessary to add a quencher.
淬灭的原理是用另一种更易与该过量化合物反应的化合物与之反应。本发明中，还原剂反应物为酸性反应物，酸性物质最易发生的反应就是酸碱反应，因此，淬灭剂选用碱性物质。The principle of quenching is to react with another compound that is more likely to react with the excess compound. In the present invention, the reducing agent reactant is an acidic reactant, and the most likely reaction of an acidic substance is an acid-base reaction. Therefore, an alkaline substance is selected as the quencher.
故，在步骤S2中，加入碱性物质作为第二淬灭剂，如氢氧化钠、氢氧化钾、碳酸钠、氨水、碳酸钾、碳酸氢钠、碳酸氢钾中的一种或两种以上。Therefore, in step S2, an alkaline substance is added as the second quencher, such as one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. .
第二淬灭剂在淬灭过程中，不同浓度的第二淬灭剂，对淬灭反应的抑制作用不一样，第二淬灭剂浓度多高或过低，其抑制效果不明显。所以本发明中，第二淬灭剂(反应物)的浓度范围选自0.1～10mol/L。因为，不同第二淬灭剂浓度的抑制效果，其原理与化学反应速率机理相一致。In the quenching process of the second quencher, different concentrations of the second quencher have different inhibitory effects on the quenching reaction. How high or too low the concentration of the second quencher is, the inhibitory effect is not obvious. Therefore, in the present invention, the concentration range of the second quencher (reactant) is selected from 0.1 to 10 mol/L. Because, the inhibitory effect of different concentration of the second quencher, its principle is consistent with the chemical reaction rate mechanism.
化学反应速率(v)等于单位时间(△t)内某一反应物浓度的减小量(△c)，即：The chemical reaction rate (v) is equal to the decrease (△c) of a certain reactant concentration per unit time (△t), namely:
v＝△c/△t。v=△c/△t.
因此，可知，第二淬灭剂作为反应物，其浓度的高低影响到淬灭反应的速率，直接体现在短时间内是否有明显的抑制效果。Therefore, it can be known that the second quencher is used as a reactant, and the concentration of the second quencher affects the rate of the quenching reaction, which directly reflects whether there is a significant inhibitory effect in a short time.
按照化学反应速率机理，增大反应温度，加速化学反应由反应物向生成物方向，但是温度过高，则会破坏反应机理，因此，步骤S12中，加入淬灭剂后反应温度控制在-5～50℃，优选室温25℃。According to the chemical reaction rate mechanism, increase the reaction temperature to accelerate the chemical reaction from reactants to products, but if the temperature is too high, the reaction mechanism will be destroyed. Therefore, in step S12, the reaction temperature is controlled at -5 after adding a quencher ~50°C, preferably room temperature 25°C.
在步骤S3中，为了从尼古丁前驱体溶液(即反应混合溶液)提取尼古丁物质，则需要向尼古丁前驱体溶液中加入一种溶剂，这种溶剂可以将更易于溶解尼古丁，且溶解尼古丁后的溶剂与混合溶液呈现分层现象，然后去除混合溶液，获得溶解尼古丁的溶剂溶液；这种溶剂也称为提取剂。一般而言，提取剂优选醚类溶剂(如，***、二甲基二***等)、酯类溶剂(如，羧酸酯、苯乙酸酯、或碳酸甲酯等)或氯代烃类溶剂(如，二氯乙烷，四氯甲烷等)中的一种或两种以上。In step S3, in order to extract the nicotine substance from the nicotine precursor solution (ie, the reaction mixture solution), a solvent needs to be added to the nicotine precursor solution. This solvent can more easily dissolve nicotine, and the solvent after dissolving nicotine It shows a layering phenomenon with the mixed solution, and then removes the mixed solution to obtain a solvent solution that dissolves nicotine; this solvent is also called an extractant. Generally speaking, the extractant is preferably ether solvents (such as diethyl ether, dimethyl diethyl ether, etc.), ester solvents (such as carboxylate, phenyl acetate, or methyl carbonate, etc.) or chlorinated hydrocarbon solvents (Eg, dichloroethane, tetrachloromethane, etc.) one or more than two.
按照化学反应速率机理，增大反应温度，加速化学反应由反应物向生成物方向，但是温度过高，则会破坏反应机理，因此，步骤S3中，加入提取剂的提取过程中的反应温度控制在-5～50℃，优选室温25℃。According to the chemical reaction rate mechanism, increase the reaction temperature and accelerate the chemical reaction from reactants to products, but if the temperature is too high, the reaction mechanism will be destroyed. Therefore, in step S3, the reaction temperature control during the extraction process with the addition of extractant At -5 to 50°C, preferably at room temperature 25°C.
本发明中，通过首次烟酸、常见的有机酸和/或无机酸等为原料，在相对温和的工艺条件下(如室温、100℃左右回流反应、萃取处理等)合成亚胺盐衍生物中间体，并再次使用廉价的初始原料还原剂(如，硫代硫酸钠、硼氢化钠、硼氢化钾、四氢铝锂、甲酸、甲酸铵、甲酸钾)，也是在一个相对较温和条件下 (如，反应温度控制在-10～100℃，甚至常温下)还原亚胺盐衍生物中间体，得到消旋尼古丁。因此，与现有尼古丁合成工艺相比，该方法具有合成工艺条件温和，设备要求简便，产品具有纯度和合成率高的优点，特别适合工业化生产。In the present invention, the first nicotinic acid, common organic acids and/or inorganic acids are used as raw materials to synthesize imine salt derivatives under relatively mild process conditions (such as room temperature, about 100°C reflux reaction, extraction treatment, etc.) And re-use of cheap initial raw material reducing agents (such as sodium thiosulfate, sodium borohydride, potassium borohydride, lithium tetrahydroaluminum, formic acid, ammonium formate, potassium formate), also under a relatively mild condition ( For example, the reaction temperature is controlled at -10 to 100°C, even at room temperature) to reduce the intermediate of the imine salt derivative to obtain racemic nicotine. Therefore, compared with the existing nicotine synthesis process, the method has the advantages of mild synthesis process conditions, simple equipment requirements, and the product has the advantages of high purity and synthesis rate, and is particularly suitable for industrial production.
下面通过一些具体实施例来进一步说明。The following further illustrates through some specific embodiments.
实施例1Example 1
亚胺盐衍生物，即中间体盐酸盐化合物的合成Synthesis of imine salt derivatives, that is, intermediate hydrochloride compounds
依次加入烟酸1.0g(8.1mmoL，1eq)、甲苯3mL、二氯亚砜3mL(41.3mmoL，5eq)，室温下搅拌不溶，油温70℃加热反应0.5h溶清，得到无色透明溶液；加热反应3h后TLC显示原料反应完全。将上述反应液60℃下减压浓缩，得到白色固体，加入甲醇6mL，室温(30℃)搅拌0.5h后，用5％的碳酸钠水溶液调pH＝9(试纸显示墨绿色)，用30mL乙酸乙酯萃取二次，减压浓缩得到0.67g烟酸甲酯。Add niacin 1.0g (8.1mmoL, 1eq), toluene 3mL, and thionyl chloride 3mL (41.3mmoL, 5eq) in sequence, stir insoluble at room temperature, and heat at 70°C for 0.5h to dissolve to obtain a colorless transparent solution; After heating the reaction for 3 hours, TLC showed that the reaction of the raw materials was complete. The above reaction solution was concentrated under reduced pressure at 60°C to obtain a white solid, 6mL of methanol was added, and after stirring for 0.5h at room temperature (30°C), pH=9 was adjusted with 5% aqueous sodium carbonate solution (test paper showed dark green), and 30mL of acetic acid The ethyl ester was extracted twice, and concentrated under reduced pressure to obtain 0.67 g of methyl nicotinate.
取NaH(2.4g)加入20mL甲苯中，室温(25℃)下搅拌10min，加入N-甲基吡咯烷酮(3.65g)并室温(25℃)搅拌15min，无明显放热；取4.10g烟酸甲酯溶于10mL甲苯中，滴加到反应体系，无明显放热。升至油温90℃加热反应2h，反应液冰浴降至10℃以下，滴加稀盐酸(2M)调pH＝8～9，分液，将水层用EA(60mL)萃取两次，合并有机层，65℃下减压浓缩得到1-甲基-3-烟酰基-2-吡咯酮(5.2g)，HPLC显示纯度＞98％。Take NaH (2.4g) into 20mL of toluene, stir at room temperature (25℃) for 10min, add N-methylpyrrolidone (3.65g) and stir at room temperature (25℃) for 15min, there is no obvious exotherm; take 4.10g nicotinic acid methyl The ester was dissolved in 10 mL of toluene and added dropwise to the reaction system without significant exotherm. Raise the oil temperature to 90℃ and heat the reaction for 2h. The reaction liquid will be cooled to below 10℃ in an ice bath. Dilute hydrochloric acid (2M) is added dropwise to adjust the pH=8-9, the liquids are separated, the water layer is extracted twice with EA (60mL) and combined The organic layer was concentrated under reduced pressure at 65°C to obtain 1-methyl-3-nicotinoyl-2-pyrrolidone (5.2 g). HPLC showed that the purity was >98%.
将浓盐酸加入1-甲基-3-烟酰基-2-吡咯酮(2.0g)中，放热，反应液为浅黄色，110℃回流反应24h，降温至10℃，减压蒸馏除去水，加丙酮重结晶， 得到中间体的尼古丁盐酸盐(1.5g)化合物。Concentrated hydrochloric acid was added to 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), exothermic heat, the reaction solution was light yellow, refluxed at 110°C for 24h, cooled to 10°C, and distilled under reduced pressure to remove water. Acetone was added for recrystallization to obtain an intermediate nicotine hydrochloride (1.5 g) compound.
上述化合物的表征数据：
11H NMR(400MHz)D
2O(δ＝9.28,1H,s),(δ＝8.97,1H,d,J＝9.00),(δ＝8.91,1H,d,J＝8.92),(δ＝8.15,1H,t,J＝8.15),(δ＝3.3,2H,m),(δ＝3.07,2H,m),(δ＝2.65,3H,s),(δ＝1.95,2H,m)；
13C NMR(400MHz)D
2O(δ＝13.3,20.7,30.7,32.8,35.6,48.1,61.9,127.6,134.6,142.0,144.8,145.1,175.0,196.8)；MS ESI
+161.1(M
2+)。
Characterization data of the above compounds: 11 H NMR (400MHz) D 2 O (δ = 9.28, 1H, s), (δ = 8.97, 1H, d, J = 9.00), (δ = 8.91, 1H, d, J = 8.92),(δ=8.15,1H,t,J=8.15),(δ=3.3,2H,m),(δ=3.07,2H,m),(δ=2.65,3H,s),(δ= 1.95, 2H, m); 13 C NMR (400MHz) D 2 O (δ = 13.3, 20.7, 30.7, 32.8, 35.6, 48.1, 61.9, 127.6, 134.6, 142.0, 144.8, 145.1, 175.0, 196.8); MS ESI + 161.1 (M 2+ ).
实施例2Example 2
与实施例1的区别在于：第一淬灭剂选用氢氧化钾水溶液；醇类萃取剂选用乙酸乙酯；缩合反应采用的碱性试剂为乙醇钠；回流反应使用的酸物质不一样，本实施例中采用了硫酸。The difference from Example 1 is that: the first quencher is an aqueous potassium hydroxide solution; the alcohol extractant is ethyl acetate; the alkaline reagent used in the condensation reaction is sodium ethoxide; the acid substance used in the reflux reaction is different. Sulfuric acid is used in the example.
将浓硫酸加入1-甲基-3-烟酰基-2-吡咯酮(2.0g)水溶液中，放热，反应液为浅黄色，110℃回流反应24h，降温至10℃，减压蒸馏除去水，加丙酮重结晶，得到中间体的硫酸盐(1.6g)。Concentrated sulfuric acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), exothermic, the reaction liquid was light yellow, refluxed at 110°C for 24h, cooled to 10°C, and distilled under reduced pressure to remove water , And recrystallized with acetone to obtain the intermediate sulfate (1.6g).
实施例3Example 3
与实施例1的区别在于：催化剂为酰氯；第一淬灭剂选用碳酸钠水溶液；醇类萃取剂选用丙酸乙酯；缩合反应采用的碱性试剂为钾与叔丁醇钠；回流反应使用的酸物质不一样，本实施例中采用了硝酸。The difference from Example 1 is that the catalyst is acid chloride; the first quencher is sodium carbonate aqueous solution; the alcohol extractant is ethyl propionate; the alkaline reagents used in the condensation reaction are potassium and sodium tert-butoxide; the reflux reaction is used The acid substance is different, and nitric acid is used in this example.
将硝酸加入1-甲基-3-烟酰基-2-吡咯酮(2.0g)水溶液中，放热，反应液为浅黄色，110℃回流反应24h，降温至10℃，减压蒸馏除去水，加乙醇重结晶，得到中间体的硝酸盐(1.4g)。Nitric acid was added to the 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g) aqueous solution, exothermic heat, the reaction liquid was light yellow, refluxed at 110°C for 24h, cooled to 10°C, and distilled under reduced pressure to remove water. It was recrystallized with ethanol to obtain the intermediate nitrate (1.4g).
实施例4Example 4
与实施例1的区别在于：第一淬灭剂选用氨水溶液；醚类萃取剂选用***；缩合反应采用的碱性试剂为钾与丁基锂；回流反应使用的酸物质不一样，本实施例中采用了高氯酸。The difference from Example 1 is that: the first quencher is an aqueous ammonia solution; the ether extractant is ether; the alkaline reagents used in the condensation reaction are potassium and butyl lithium; the acid substance used in the reflux reaction is different. Perchloric acid is used in it.
将高氯酸加入1-甲基-3-烟酰基-2-吡咯酮(2.0g)水溶液中，放热，反应 液为浅黄色，110℃回流反应24h，降温至10℃，减压蒸馏除去水，加乙酸乙酯重结晶，得到中间体的高氯酸盐(1.6g)。Perchloric acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), exothermic, the reaction solution was light yellow, refluxed at 110°C for 24h, cooled to 10°C, and removed by distillation under reduced pressure Water was added with ethyl acetate to recrystallize to obtain the intermediate perchlorate (1.6g).
实施例5Example 5
与实施例1的区别在于：第一淬灭剂选用碳酸钾水溶液；醚类萃取剂选用二甲基二***；缩合反应采用的碱性试剂为二(三甲基硅基)氨基锂(LiHMDS)；第一、二有机溶剂分别采用甲苯和四氢呋喃混合溶剂；回流反应使用的酸物质不一样，本实施例中采用了硼酸。The difference from Example 1 is that the first quencher is potassium carbonate aqueous solution; the ether extractant is dimethyl diethyl ether; the alkaline reagent used in the condensation reaction is lithium bis(trimethylsilyl)amide (LiHMDS) ; The first and second organic solvents are respectively mixed solvents of toluene and tetrahydrofuran; the acid substances used in the reflux reaction are different, and boric acid is used in this embodiment.
将硼酸加入1-甲基-3-烟酰基-2-吡咯酮(2.0g)水溶液中，放热，反应液为浅黄色，110℃回流反应24h，降温至10℃，减压蒸馏除去水，加丙酮重结晶，得到中间体的硼酸盐(1.6g)。Boric acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), the reaction solution was light yellow, and the reaction was refluxed at 110°C for 24 hours. The temperature was reduced to 10°C and the water was distilled off under reduced pressure. It was recrystallized with acetone to obtain the intermediate borate (1.6 g).
实施例6Example 6
与实施例1的区别在于：第一淬灭剂选用碳酸氢钠水溶液；氯代烃类萃取剂选用二氯乙烷；缩合反应采用的碱性试剂为二异丙基氨基锂(LDA)；第一、二有机溶剂分别采用1,2-二氧六环；回流反应使用的酸物质不一样，本实施例中采用了苯甲酸。The difference from Example 1 is that: the first quencher is an aqueous sodium bicarbonate solution; the chlorinated hydrocarbon extractant is dichloroethane; the alkaline reagent used in the condensation reaction is lithium diisopropylamide (LDA); The first and second organic solvents are 1,2-dioxane respectively; the acid substance used in the reflux reaction is different, and benzoic acid is used in this example.
将苯甲酸加入1-甲基-3-烟酰基-2-吡咯酮(2.0g)水溶液中，放热，反应液为浅黄色，110℃回流反应24h，降温至10℃，减压蒸馏除去水，加乙酸乙酯重结晶，得到中间体的苯甲酸盐(1.6g)。Benzoic acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), exothermic, the reaction liquid was light yellow, refluxed at 110°C for 24h, cooled to 10°C, and distilled under reduced pressure to remove water It was recrystallized by adding ethyl acetate to obtain the intermediate benzoate (1.6g).
实施例7Example 7
与实施例1的区别在于：第一淬灭剂选用碳酸氢钾水溶液；缩合反应采用的碱性试剂为氢化钠和乙醇钠；第一、二有机溶剂分别采用四氢呋喃；回流反应使用的酸物质不一样，本实施例中采用了樟脑磺酸。The difference from Example 1 is that: the first quencher is an aqueous potassium bicarbonate solution; the alkaline reagents used in the condensation reaction are sodium hydride and sodium ethoxide; the first and second organic solvents are tetrahydrofuran; the acid substance used in the reflux reaction is not Similarly, camphor sulfonic acid is used in this example.
将樟脑磺酸加入1-甲基-3-烟酰基-2-吡咯酮(2.0g)水溶液中，放热，反 应液为浅黄色，110℃回流反应24h，降温至10℃，减压蒸馏除去水，加乙醇重结晶，得到中间体的樟脑磺酸盐(1.8g)。Camphorsulfonic acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), the reaction solution was light yellow, and the reaction was refluxed at 110°C for 24 hours. The temperature was reduced to 10°C and evaporated under reduced pressure. Water and ethanol were recrystallized to obtain the intermediate camphor sulfonate (1.8 g).
实施例8Example 8
与实施例1的区别在于：第一淬灭剂选用碳酸氢钾和碳酸钾混合水溶液；氯代烃类萃取剂选用四氯甲烷；缩合反应采用的碱性试剂为氢化钾；第一、二有机溶剂分别采用甲苯、四氢呋喃及1,2-二氧六环混合溶剂；回流反应使用的酸物质不一样，本实施例中采用了苯基膦酸和硝酸的混合酸。The difference from Example 1 is that the first quencher is a mixed aqueous solution of potassium bicarbonate and potassium carbonate; the chlorinated hydrocarbon extractant is tetrachloromethane; the alkaline reagent used in the condensation reaction is potassium hydride; the first and second organic The solvents were mixed solvents of toluene, tetrahydrofuran and 1,2-dioxane; the acid substances used in the reflux reaction were different, and a mixed acid of phenylphosphonic acid and nitric acid was used in this embodiment.
将苯基膦酸加入1-甲基-3-烟酰基-2-吡咯酮(2.0g)水溶液中，放热，反应液为浅黄色，110℃回流反应24h，降温至10℃，减压蒸馏除去水，加丙酮重结晶，得到中间体的硝基苯基膦酸盐(1.61g)。Phenylphosphonic acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), the reaction solution was light yellow, and the reaction was refluxed at 110°C for 24 hours. The temperature was lowered to 10°C and then distilled under reduced pressure. The water was removed, acetone was added for recrystallization, and the intermediate nitrophenyl phosphonate (1.61 g) was obtained.
实施例9Example 9
本实施例中，中间体选用实施例1制得中间体的盐酸盐。In this example, the intermediate was selected as the hydrochloride salt of the intermediate prepared in Example 1.
将中间体的盐酸盐(1.5g,0.0088mol)与甲酸钾(1.6g，0.0052mol)的混合物在无水乙醇10mL中于100℃下加热回流2h，反应后,减压留去乙醇,将残留物溶解于水,并加3N氢氧化钠溶液于25℃下反应使之成为中性。生成的油状物质用***于25℃下萃取,有机溶剂使用饱和食盐水3次洗净,无水硫酸钠干燥。过滤去除以无机物,残留物减压蒸馏得到1.4g尼古丁，纯度99.4％。The mixture of the intermediate hydrochloride (1.5g, 0.0088mol) and potassium formate (1.6g, 0.0052mol) was heated to reflux at 100°C for 2h in 10mL of absolute ethanol. After the reaction, the ethanol was left under reduced pressure. The residue was dissolved in water, and 3N sodium hydroxide solution was added to react at 25°C to make it neutral. The resulting oily substance was extracted with ether at 25°C, and the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.4 g of nicotine with a purity of 99.4%.
实施例10Example 10
本实施例中，中间体选用实施例3制得中间体的硝酸盐。In this example, the intermediate was selected as the nitrate of the intermediate prepared in Example 3.
将中间体的硝酸盐(1.5g)与硫代硫酸钠(2g)的混合物在无水乙醇10mL中于75℃下加热回流2h，反应后,减压留去乙醇,将残留物溶解于水,并加3mol/L氢氧化钾溶液于10℃下反应使之成为中性。生成的油状物质用***于10℃下萃取,有机溶剂使用饱和食盐水3次洗净,无水硫酸钠干燥。过滤去除以无机物, 残留物减压蒸馏得到1.3g尼古丁，纯度99.5％。The mixture of intermediate nitrate (1.5g) and sodium thiosulfate (2g) was heated to reflux at 75°C for 2h in 10mL of absolute ethanol. After the reaction, the ethanol was left under reduced pressure, and the residue was dissolved in water. And add 3mol/L potassium hydroxide solution to react at 10℃ to make it neutral. The resulting oily substance was extracted with ether at 10°C, the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.3 g of nicotine with a purity of 99.5%.
实施例11Example 11
本实施例中，中间体选用实施例2制得中间体的硫酸盐。In this example, the intermediate was selected as the sulfate salt of the intermediate prepared in Example 2.
将中间体的硫酸盐(1.6g)与硼氢化钠(1.8g)的混合物在无水***10mL中于室温25℃下反应2h，反应后,减压留去***,将残留物溶解于水,并加4mol/L碳酸钠溶液于25℃下反应使之成为中性。生成的油状物质用甲酸乙酯于25℃下萃取,有机溶剂使用饱和食盐水3次洗净,无水硫酸钠干燥。过滤去除以无机物,残留物减压蒸馏得到1.35g尼古丁，纯度99.3％。A mixture of intermediate sulfate (1.6g) and sodium borohydride (1.8g) was reacted in 10mL of anhydrous ether at room temperature and 25°C for 2h. After the reaction, the ether was left under reduced pressure, and the residue was dissolved in water. And add 4mol/L sodium carbonate solution to react at 25℃ to make it neutral. The resulting oily substance was extracted with ethyl formate at 25°C, the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.35 g of nicotine with a purity of 99.3%.
实施例12Example 12
本实施例中，中间体选用实施例4制得中间体的高氯酸盐。In this example, the intermediate perchlorate prepared in Example 4 was selected as the intermediate.
将中间体的高氯酸盐(1.5g)与四氢铝锂(1.5g)的混合物在无水甲醚10mL中于室温25℃反应2h，反应后,减压留去甲醚,将残留物溶解于水,并加2mol/L氨水溶液于-5℃下反应使之成为中性。生成的油状物质用丙酸乙酯于-5℃下萃取,有机溶剂使用饱和食盐水3次洗净,无水硫酸钠干燥。过滤去除以无机物,残留物减压蒸馏得到1.38g尼古丁，纯度99.3％。The mixture of intermediate perchlorate (1.5g) and lithium tetrahydroaluminum (1.5g) was reacted in 10 mL of anhydrous methyl ether at room temperature and 25°C for 2 hours. After the reaction, the methyl ether was removed under reduced pressure and the residue Dissolve in water and add 2mol/L ammonia solution to react at -5°C to make it neutral. The resulting oily substance was extracted with ethyl propionate at -5°C, the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.38 g of nicotine with a purity of 99.3%.
实施例13Example 13
本实施例中，中间体选用实施例5制得中间体的硼酸盐。In this example, the intermediate was selected as the borate of the intermediate prepared in Example 5.
将中间体的硼酸盐(1.5g)与甲酸铵(1.4g)的混合物在乙酸乙酯10mL中于90℃下加热回流2h，反应后,减压留去乙酸乙酯,将残留物溶解于水,并加0.5mol/L碳酸钾溶液使于0℃下反应之成为中性。生成的油状物质用***于0℃下萃取,有机溶剂使用饱和食盐水3次洗净,无水硫酸钠干燥。过滤去除以无机物,残留物减压蒸馏得到1.41g尼古丁，纯度99.3％。The mixture of borate (1.5g) and ammonium formate (1.4g) of the intermediate was heated to reflux at 90°C for 2h in 10 mL of ethyl acetate. After the reaction, the ethyl acetate was removed under reduced pressure, and the residue was dissolved in Water, and add 0.5mol/L potassium carbonate solution to make the reaction become neutral at 0℃. The resulting oily substance was extracted with ether at 0°C, the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.41 g of nicotine with a purity of 99.3%.
实施例14Example 14
本实施例中，中间体选用实施例6制得中间体的苯甲酸盐。In this example, the benzoate of the intermediate prepared in Example 6 was selected as the intermediate.
将中间体的苯甲酸盐(1.5g)与钯/碳(0.5g)的混合物在甲酸甲酯10mL中，充入氢气，于室温25℃下反应2h，反应后,减压留去甲酸甲酯,将残留物溶解于水,并加0.1mol/L碳酸氢钠溶液于25℃下反应使之成为中性。生成的油状物质用二氯甲烷于25℃下萃取,有机溶剂使用饱和食盐水3次洗净,无水硫酸钠干燥。过滤去除以无机物,残留物减压蒸馏得到1.45g尼古丁，纯度99.1％。The mixture of intermediate benzoate (1.5g) and palladium/carbon (0.5g) in 10 mL of methyl formate was filled with hydrogen and reacted at room temperature and 25°C for 2 hours. After the reaction, the formate was removed under reduced pressure. Ester, dissolve the residue in water, and add 0.1mol/L sodium bicarbonate solution to react at 25°C to make it neutral. The resulting oily substance was extracted with dichloromethane at 25°C, the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.45 g of nicotine with a purity of 99.1%.
实施例15Example 15
本实施例中，中间体选用实施例7制得中间体的樟脑磺酸盐。In this example, the intermediate was selected as the camphorsulfonate of the intermediate prepared in Example 7.
将中间体的樟脑磺酸盐(1.5g)与甲酸铵(1.7g)的混合物在无水二氯甲烷10mL中，于室温25℃下反应2h，反应后,减压留去二氯甲烷,将残留物溶解于水,并加10mol/L碳酸氢钾溶液于50℃下反应使之成为中性。生成的油状物质用四氯甲烷于50℃下萃取,有机溶剂使用饱和食盐水3次洗净,无水硫酸钠干燥。过滤去除以无机物,残留物减压蒸馏得到1.45g尼古丁，纯度99.1％。The mixture of camphorsulfonate (1.5g) and ammonium formate (1.7g) of the intermediate was reacted in 10 mL of anhydrous dichloromethane at room temperature and 25°C for 2 hours. After the reaction, the dichloromethane was removed under reduced pressure. The residue was dissolved in water, and 10mol/L potassium bicarbonate solution was added to react at 50℃ to make it neutral. The resulting oily substance was extracted with tetrachloromethane at 50°C, the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.45 g of nicotine with a purity of 99.1%.
实施例16Example 16
本实施例中，中间体选用实施例8制得中间体的苯基膦酸盐。In this example, the intermediate phenylphosphonate prepared in Example 8 was selected as the intermediate.
将中间体的硝基苯基膦酸盐(1.5g)与甲酸钾(1.6g)的混合物在无水四氯甲烷10mL中，于-10℃低温下反应2h，反应后,减压留去四氯甲烷,将残留物溶解于水,并加3mol/L氢氧化钠和氨水溶液于40℃下反应使之成为中性。生成的油状物质用***于40℃下萃取,有机溶剂使用饱和食盐水3次洗净,无水硫酸钠干燥。过滤去除以无机物,残留物减压蒸馏得到1.45g尼古丁，纯度99.1％。The mixture of intermediate nitrophenyl phosphonate (1.5g) and potassium formate (1.6g) was reacted in 10mL of anhydrous tetrachloromethane at a low temperature of -10°C for 2h. After the reaction, the mixture was left under reduced pressure. Methyl chloride, dissolve the residue in water, and add 3mol/L sodium hydroxide and ammonia solution to react at 40℃ to make it neutral. The resulting oily substance was extracted with ether at 40°C, the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.45 g of nicotine with a purity of 99.1%.
实施例17Example 17
本实施例中，中间体选用实施例1制得中间体的硼酸盐。In this example, the borate of the intermediate prepared in Example 1 was selected as the intermediate.
将中间体的硼酸盐(1.5g)与硼氢化钠(1.4g)的混合物在无水乙醇10mL中，于室温25℃下反应2h，反应后,减压留去乙醇,将残留物溶解于水,并加6mol/L氢氧化钠溶液于25℃下反应使之成为中性。生成的油状物质用***于25℃下萃取,有机溶剂使用饱和食盐水3次洗净,无水硫酸钠干燥。过滤去除以无机物,残留物减压蒸馏得到1.45g尼古丁，纯度99.1％。The mixture of intermediate borate (1.5g) and sodium borohydride (1.4g) was reacted in 10 mL of absolute ethanol at room temperature and 25°C for 2 hours. After the reaction, the ethanol was removed under reduced pressure, and the residue was dissolved in Water, and add 6mol/L sodium hydroxide solution to react at 25℃ to make it neutral. The resulting oily substance was extracted with ether at 25°C, and the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.45 g of nicotine with a purity of 99.1%.
应当理解的是，上述针对本发明较佳实施例的表述较为详细，并不能因此而认为是对本发明专利保护范围的限制，本发明的专利保护范围应以所附权利要求为准。It should be understood that the above description of the preferred embodiments of the present invention is more detailed and should not be considered as a limitation on the scope of patent protection of the present invention. The scope of patent protection of the present invention shall be subject to the appended claims.
Claims (10)
- 下述通式(Ⅰ)或(Ⅱ)亚胺盐衍生物：The following general formula (I) or (II) imine salt derivatives:
其中，X 1和X 2分别表示为酸根负离子。 Among them, X 1 and X 2 are respectively represented as acid radical anions. - 根据权利要求1的亚胺盐衍生物，其特征在于，所述X 1和X 2表示为相同的酸根离子；或者所述X 1和X 2表示为不相同的酸根离子。 The imine salt derivative according to claim 1, wherein said X 1 and X 2 represent the same acid radical ion; or said X 1 and X 2 represent different acid radical ions.
- 一种如权利要求书1所述亚胺盐衍生物的制备方法，包括如下步骤：A method for preparing the imine salt derivative according to claim 1, comprising the following steps:a、依次将烟酸、甲苯及催化剂加入反应器中，在搅拌和加热条件下进行反应，得到混合溶液；对混合溶液减压浓缩处理，去除溶剂，得到白色固体；随后加入醇类溶剂，室温下搅拌，继续反应；a. Add nicotinic acid, toluene and catalyst to the reactor in turn, and react under stirring and heating conditions to obtain a mixed solution; concentrate the mixed solution under reduced pressure to remove the solvent to obtain a white solid; then add alcohol solvent at room temperature Stir down and continue the reaction;b、往反应器中加入第一淬灭剂，停止反应，并调整反应后的混合液的pH＝9，得到碱性混合溶液；采用萃取剂对碱性混合溶液反复萃取处理，得到烟酸甲酯；将所述烟酸甲酯溶于第一有机溶剂中，得到烟酸甲酯溶液；b. Add the first quencher to the reactor, stop the reaction, and adjust the pH of the reaction mixture to be 9 to obtain an alkaline mixed solution; use the extractant to repeatedly extract the alkaline mixed solution to obtain nicotinic acid Ester; the methyl nicotinate is dissolved in the first organic solvent to obtain a methyl nicotinate solution;c、将碱性试剂加入第二有机溶剂中，室温搅拌，随后加入反应试剂N-甲基吡咯烷酮，室温下搅拌后，得到反应体系溶液，往该反应体系溶液中滴加烟酸甲酯溶液；接着升温至70～95℃下持续缩合反应；c. Add the alkaline reagent to the second organic solvent, stir at room temperature, and then add the reaction reagent N-methylpyrrolidone. After stirring at room temperature, a reaction system solution is obtained, and methyl nicotinate solution is added dropwise to the reaction system solution; Then the temperature is increased to 70～95℃ to continue the condensation reaction;d、缩合反应停止后，对反应溶液降温至10℃以下进行萃取处理，合并有机层；对有机层于50～65℃下减压浓缩处理，得到1-甲基-3-烟酰基-2-吡咯酮；d. After the condensation reaction is stopped, the reaction solution is cooled to below 10°C for extraction treatment, and the organic layers are combined; the organic layer is concentrated under reduced pressure at 50-65°C to obtain 1-methyl-3-nicotinoyl-2- Pyrrolidonee、将酸物质加入1-甲基-3-烟酰基-2-吡咯酮中进行回流反应；待回流反应停止后，降温至10℃；再对反应体系溶液进行减压蒸馏处理，并经重 结晶纯化，得到所述通式为的亚胺盐衍生物；其中，X 1和X 2分别表示为酸根负离子。 e. Add the acid substance to 1-methyl-3-nicotinoyl-2-pyrrolidone for reflux reaction; after the reflux reaction stops, the temperature is lowered to 10°C; then the reaction system solution is subjected to vacuum distillation treatment, and Crystallization and purification, the general formula is
The iminium salt derivative; wherein, X 1 and X 2 are respectively represented as acid radical anions. - 根据权利要求书3所述亚胺盐衍生物的制备方法，其特征在于，步骤a中，所述催化剂为二氯亚砜或草酰氯。The method for preparing imine salt derivatives according to claim 3, characterized in that, in step a, the catalyst is thionyl chloride or oxalyl chloride.
- 根据权利要求书3所述亚胺盐衍生物的制备方法，其特征在于，步骤b中，所述第一淬灭剂为碱性水溶液；所述萃取剂为酸性水溶液。The method for preparing imine salt derivatives according to claim 3, wherein in step b, the first quencher is an alkaline aqueous solution; the extractant is an acidic aqueous solution.
- 根据权利要求书3所述亚胺盐衍生物的制备方法，其特征在于，步骤c中，所述第二有机溶剂包括甲苯、四氢呋喃及1,2-二氧六环中的一种或两种以上。The method for preparing imine salt derivatives according to claim 3, wherein in step c, the second organic solvent includes one or two of toluene, tetrahydrofuran and 1,2-dioxane the above.
- 一种尼古丁的制备方法，其特征在于，包括如下步骤：A method for preparing nicotine, which is characterized in that it comprises the following steps:S1、将权利要求1中所述通式为的亚胺盐衍生物及还原剂加入溶剂中进行还原反应，获得消旋尼古丁溶液； S1, the general formula described in claim 1 is
The imine salt derivative of and the reducing agent are added to the solvent to perform a reduction reaction to obtain a racemic nicotine solution;S2、向所述消旋尼古丁溶液中加入第二淬灭剂，停止还原反应，获得尼古丁前驱体溶液；S2. Add a second quencher to the racemic nicotine solution to stop the reduction reaction to obtain a nicotine precursor solution;S3、向所述尼古丁前驱体溶液中加入提取剂，浓缩尼古丁前驱体溶液，然后干燥去除溶剂，得到通式为的尼古丁。 S3. Add an extractant to the nicotine precursor solution, concentrate the nicotine precursor solution, and then dry to remove the solvent to obtain the general formula:
Nicotine. - 根据权利要求7所述的制备方法，其特征在于，步骤S1中，所述还原剂为硫代硫酸钠、硼氢化钠、硼氢化钾、四氢铝锂、甲酸、甲酸铵、甲酸钾、氢气与钯/碳中的一种。The preparation method according to claim 7, wherein in step S1, the reducing agent is sodium thiosulfate, sodium borohydride, potassium borohydride, lithium aluminum tetrahydrogen, formic acid, ammonium formate, potassium formate, hydrogen With one of palladium/carbon.
- 根据权利要求7所述的制备方法，其特征在于，步骤S2中，所 述第二淬灭剂为碱性物质。The preparation method according to claim 7, wherein in step S2, the second quencher is an alkaline substance.
- 根据权利要求7所述的制备方法，其特征在于，步骤S3中，所述提取剂为醚类溶剂、酯类溶剂或氯代烃类溶剂中的一种或两种以上。The preparation method according to claim 7, characterized in that, in step S3, the extractant is one or more of ether solvents, ester solvents or chlorinated hydrocarbon solvents.
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