CN113475739A - Preparation method of S-nicotine - Google Patents
Preparation method of S-nicotine Download PDFInfo
- Publication number
- CN113475739A CN113475739A CN202110781163.8A CN202110781163A CN113475739A CN 113475739 A CN113475739 A CN 113475739A CN 202110781163 A CN202110781163 A CN 202110781163A CN 113475739 A CN113475739 A CN 113475739A
- Authority
- CN
- China
- Prior art keywords
- nicotine
- pyridine
- amino
- butanone
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960002715 nicotine Drugs 0.000 title claims abstract description 75
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 28
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 24
- -1 nicotinate ester Chemical class 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 238000005576 amination reaction Methods 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 16
- 235000001968 nicotinic acid Nutrition 0.000 claims abstract description 13
- 239000011664 nicotinic acid Substances 0.000 claims abstract description 13
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims abstract description 12
- PHDOOOFAAKSEEP-VIFPVBQESA-N (1S)-4-amino-1-pyridin-3-ylbutan-1-ol Chemical compound NCCC[C@@H](C1=CC=CN=C1)O PHDOOOFAAKSEEP-VIFPVBQESA-N 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 5
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 13
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 12
- 239000007859 condensation product Substances 0.000 claims description 11
- 229960003512 nicotinic acid Drugs 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 229910000287 alkaline earth metal oxide Inorganic materials 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000010992 reflux Methods 0.000 abstract description 5
- 238000005902 aminomethylation reaction Methods 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 230000001939 inductive effect Effects 0.000 abstract description 3
- 238000005660 chlorination reaction Methods 0.000 abstract description 2
- UOALEFQKAOQICC-UHFFFAOYSA-N chloroborane Chemical compound ClB UOALEFQKAOQICC-UHFFFAOYSA-N 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 12
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 11
- 230000035484 reaction time Effects 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical group COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 5
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 229960001238 methylnicotinate Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HFMNHVQBLYDLAJ-UHFFFAOYSA-N 4-amino-1-pyridin-3-ylbutan-1-one Chemical compound NCCCC(=O)C1=CC=CN=C1 HFMNHVQBLYDLAJ-UHFFFAOYSA-N 0.000 description 2
- ZCTPFQRLEGLYEO-UHFFFAOYSA-N 4-chloro-1-pyridin-3-ylbutan-1-one Chemical compound ClCCCC(=O)C1=CC=CN=C1 ZCTPFQRLEGLYEO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003571 electronic cigarette Substances 0.000 description 2
- 229940064982 ethylnicotinate Drugs 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WWSJZGAPAVMETJ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-ethoxypyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)OCC WWSJZGAPAVMETJ-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- DFGKGUXTPFWHIX-UHFFFAOYSA-N 6-[2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]acetyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)C1=CC2=C(NC(O2)=O)C=C1 DFGKGUXTPFWHIX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FUJCRWPEOMXPAD-UHFFFAOYSA-N Li2O Inorganic materials [Li+].[Li+].[O-2] FUJCRWPEOMXPAD-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- XEUXMLHLHMFWAB-VIFPVBQESA-N NCCC[C@@H](C1=CC=CN=C1)Cl Chemical compound NCCC[C@@H](C1=CC=CN=C1)Cl XEUXMLHLHMFWAB-VIFPVBQESA-N 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N Na2O Inorganic materials [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- XUCJHNOBJLKZNU-UHFFFAOYSA-M dilithium;hydroxide Chemical compound [Li+].[Li+].[OH-] XUCJHNOBJLKZNU-UHFFFAOYSA-M 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/10—Chemical features of tobacco products or tobacco substitutes
- A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes
- A24B15/167—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes in liquid or vaporisable form, e.g. liquid compositions for electronic cigarettes
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/10—Chemical features of tobacco products or tobacco substitutes
- A24B15/12—Chemical features of tobacco products or tobacco substitutes of reconstituted tobacco
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/10—Chemical features of tobacco products or tobacco substitutes
- A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/18—Treatment of tobacco products or tobacco substitutes
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/18—Treatment of tobacco products or tobacco substitutes
- A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
Abstract
The invention discloses a preparation method of S-nicotine, which comprises the steps of condensing under the action of an alkaline catalyst in sequence, carrying out reflux reaction with concentrated hydrochloric acid to obtain 4-chloro-1- (3-pyridine) -1-butanone through ring opening, carrying out reaction with an amination reagent under an alkaline condition to obtain 4-amino-1- (3-pyridine) -1-butanone, inducing by (+) -B-diisopinocampheyl chloroborane to generate chiral hydroxyl to obtain (S) -4-amino-1- (pyridine-3-yl) butan-1-ol, carrying out chlorination, carrying out ring closing under the action of alkali to obtain S-demethyl nicotine, and finally carrying out aminomethylation to obtain S-nicotine. The method has the advantages of mild reaction conditions, easy operation, high selectivity for obtaining the S-nicotine with a single configuration, high yield and purity of the S-nicotine, simple steps, low cost by taking the nicotinate ester and the gamma-butyrolactone which are cheap and easy to obtain as starting raw materials, and particular suitability for industrialized production of the S-nicotine.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of S-nicotine.
Background
With the rapid development of the electronic cigarette industry, the demand of nicotine as one of the important active ingredients of electronic cigarettes is increasing, and among them, nicotine with optical activity in a single configuration is receiving wide attention. S-nicotine, formula C10H14N2The CAS number is 54-11-5, the structural formula is
At present, the preparation method of S-nicotine is less researched. S-nicotine is basically obtained by a chiral resolution method, but a chiral resolution reagent is expensive and is not beneficial to industrial production.
The patent with publication number CN104341390A discloses a preparation method of S-nicotine, which uses cyclic imine as starting material, needs expensive chiral catalyst, and high pressure hydrogen equipment, and is not suitable for large-scale industrial production. The patent publication No. CN11233829A discloses a method for preparing optically active nicotine, in which a chiral ligand containing nitrogen or phosphorus is used to prepare an organometallic catalyst, and an imine salt derivative is used as a starting material to prepare S-nicotine, and the preparation of the organometallic catalyst is complicated, the production cost is high, and the yield of S-nicotine is low.
Therefore, the application provides a preparation method of S-nicotine, which adopts cheaper and easily available raw materials and has higher yield of the prepared S-nicotine.
Disclosure of Invention
In order to improve the yield of S-nicotine, the present application provides a method for preparing S-nicotine.
In a first aspect, the present application provides a method for preparing S-nicotine, which is implemented by the following technical scheme:
a method for preparing S-nicotine, comprising the following steps:
s1, nicotinic acid ester and gamma-butyrolactone are added into an organic solvent I and condensed under the action of an alkaline catalyst to obtain a condensation product, and the condensation product is subjected to ring opening under the condition of hydrochloric acid to obtain 4-chloro-1- (3-pyridine) -1-butanone;
s2, 4-chloro-1- (3-pyridine) -1-butanone reacts with amination reagent under alkaline condition to obtain 4-amino-1- (3-pyridine) -1-butanone;
s3, 4-amino-1- (3-pyridine) -1-butanone and (+) -B-diisopinocampheylchloroborane react in an organic solvent II at the temperature of-30 to 10 ℃ to obtain (S) -4-amino-1- (pyridine-3-yl) butan-1-ol;
s4, reacting (S) -4-amino-1- (pyridine-3-yl) butyl-1-alcohol with a chlorinated reagent to obtain (S) -4-amino-1- (pyridine-3-yl) butyl-1-chlorine;
s5, (S) -4-amino-1- (pyridine-3-yl) butane-1-chlorine cyclizes under the action of alkali to obtain S-demethyl nicotine;
s6, reacting the S-demethyl nicotine with an amine methylation reagent to obtain an S-nicotine crude product, and purifying to obtain the S-nicotine.
By adopting the technical scheme, the nicotinate and the gamma-butyrolactone which are cheap and easily available are used as raw materials, the (+) -B-diisopinocampheylchloroborane is used for reducing the carbonyl of the intermediate to obtain a target chiral center, the (+) -B-diisopinocampheylchloroborane is used for inducing to generate chiral hydroxyl, then chloro ring closure is carried out to construct chiral S-demethyl nicotine, and finally aminomethylation is carried out to obtain the photochemical active S-nicotine. The preparation method of S-nicotine provided by the application has the advantages of high purity, simple steps, easiness in operation, high yield and mild reaction conditions, and the S-nicotine with a single configuration is obtained, has a high ee value and is suitable for industrial production.
In the application, the nicotinic acid ester is methyl nicotinate or ethyl nicotinate.
Preferably, in the step S1, the molar ratio of the nicotinic acid ester, the gamma-butyrolactone and the basic catalyst is 1 (1-2) to (1.2-3); more preferably, the molar ratio of the nicotinic acid ester, the gamma-butyrolactone and the basic catalyst is 1:1: 2.
Preferably, in the step S1, the basic catalyst is selected from one or more of alkali metal alkoxide, alkaline earth metal hydride, alkaline earth metal oxide, amine, metal salt of amine, hydroxide, carbonate and bicarbonate.
In the present application, the alkali metal alkoxide includes, but is not limited to, any one of sodium tert-butoxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide.
In the present application, the alkaline earth metal hydride includes, but is not limited to, one or more of NaH, LiH, and KH.
In the present application, the alkaline earth metal oxide includes, but is not limited to, Na2O、Li2O and K2One or more of O.
In the present application, the amine includes, but is not limited to, triethylamine and/or diisopropylethylamine.
In the present application, the metal salt of the amine includes, but is not limited to, sodium bis (trimethylsilyl) amide and/or lithium diisopropylamide.
In the present application, the hydroxide includes, but is not limited to, one or more of sodium hydroxide, lithium hydroxide, and magnesium hydroxide.
In the present application, the carbonate includes, but is not limited to, one or more of sodium carbonate, potassium carbonate, and cesium carbonate.
In the present application, the bicarbonate includes, but is not limited to, sodium bicarbonate and/or potassium bicarbonate.
More preferably, the basic catalyst is selected from any one of sodium tert-butoxide, NaH and potassium tert-butoxide.
In this application, in the step S1, the organic solvent I is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, dimethyl tetrahydrofuran and 1, 4-dioxane; preferably, the organic solvent I is 1, 4-dioxane.
In the present application, in the step S1, the reaction needs to be carried out in N2The method is carried out under the atmosphere, and the charging sequence of the nicotinate, the gamma-butyrolactone and the basic catalyst is as follows: firstly adding gamma-butyrolactone, then adding basic catalyst and finally adding nicotinic acid ester.
In the application, the reaction temperature of the gamma-butyrolactone and the alkaline catalyst is 0 ℃, and the reaction time is 30 min; the reaction temperature of the added nicotinic acid ester, gamma-butyrolactone and alkaline catalyst is 25 ℃.
In this application, in the step S1, the hydrochloric acid is concentrated hydrochloric acid, and the concentration of the concentrated hydrochloric acid is 12 mol/L.
In the step S1, the molar ratio of the condensation product to HCl in hydrochloric acid is 1 (1-6); preferably, the molar ratio of the condensation product to HCl in hydrochloric acid is 1:1.
In the step S1, the reflux reaction time of the condensation product and hydrochloric acid at 70-90 ℃ is 0.5-1.5 h; preferably, the condensation product is reacted with hydrochloric acid at 80 ℃ under reflux for 1 h.
In the present application, in the step S1, the condensation product is subjected to ring opening under hydrochloric acid condition and then to post-treatment to obtain 4-chloro-1- (3-pyridine) -1-butanone; the post-treatment operation is as follows: diluting with saline water, neutralizing with alkaline substance, extracting, collecting organic phase, and spin-drying solvent to obtain 4-chloro-1- (3-pyridine) -1-butanone.
In the application, 4-chloro-1- (3-pyridine) -1-butanone obtained in the step S1 needs to be dissolved by a solvent before the step S2 is reacted. The solvent includes, but is not limited to, one or more of acetonitrile, 1, 4-dioxane, dichloromethane, DMF, and tetrahydrofuran; preferably, the solvent is acetonitrile.
In the step S2, the reaction temperature of the 4-chloro-1- (3-pyridine) -1-butanone and the amination reagent under an alkaline condition is 60 to 100 ℃, and the reaction time is 6 to 10 hours; preferably, the 4-chloro-1- (3-pyridine) -1-butanone and the amination reagent are reacted under alkaline conditions at a temperature of 80 ℃ for 8 h.
Preferably, in the step S2, the molar ratio of the 4-chloro-1- (3-pyridine) -1-butanone to the amination reagent is 1 (1-3); more preferably, the molar ratio of 4-chloro-1- (3-pyridine) -1-butanone to the amination reagent is 1: 2.
Preferably, in the step S2, the amination reagent is ammonia or formamide; more preferably, the amination reagent is formamide.
In the step S2, the pH of the alkaline environment in the reaction of the 4-chloro-1- (3-pyridine) -1-butanone and the amination reagent under alkaline conditions is 8 to 12; preferably, the pH of the alkaline environment of the reaction of the 4-chloro-1- (3-pyridine) -1-butanone and the amination reagent under alkaline conditions is 9. The alkaline environment may be adjusted by 52 wt% aqueous NaOH.
In this application, the step S2 further includes a post-processing step, where the post-processing step is: and (3) adding acid to adjust the pH value to 6-7, extracting, and spin-drying the solvent by an organic phase to obtain the 4-amino-1- (3-pyridine) -1-butanone.
In the present application, in the step S3, it is necessary to dissolve the 4-amino-1- (3-pyridine) -1-butanone obtained in the step S2 in an organic solvent II.
Preferably, in the step S3, the organic solvent II is one or more selected from tetrahydrofuran, dimethyltetrahydrofuran and 1, 4-dioxane; more preferably, the organic solvent II is tetrahydrofuran.
Preferably, in the step S3, the molar ratio of the 4-amino-1- (3-pyridine) -1-butanone to the (+) -B-diisopinocampheylchloroborane is 1 (1-3); more preferably, the molar ratio of the 4-amino-1- (3-pyridine) -1-butanone to the (+) -B-diisopinocampheylchloroborane is 1 (1.5-2).
Preferably, in the step S3, the reaction temperature of the 4-amino-1- (3-pyridine) -1-butanone and the (+) -B-diisopinocampheylchloroborane is 0 ℃, and the reaction time is 2 h.
In the present application, the step S3 further includes an extraction step, where the extraction agent is dichloromethane, and the solvent is dried by spinning after extraction to obtain (S) -4-amino-1- (pyridin-3-yl) butan-1-ol.
In the present application, in the step S4, (S) -4-amino-1- (pyridin-3-yl) butan-1-ol prepared in the step S3 needs a solvent to be dissolved and then reacts with a chlorinating agent. Such solvents include, but are not limited to, 1, 4-dioxane.
Preferably, the reaction temperature of the step S4 is-10 to 10 ℃; more preferably, the reaction temperature of the S4 step is 0 ℃.
In the application, the reaction time of the step S4 is 20-40 min; preferably, the reaction time of the step S4 is 30 min.
Preferably, in the step S4, the chlorinating reagent is selected from oxalyl chloride, thionyl chloride, PCl3And PCl5(ii) a More preferably, the chlorinating reagent is oxalyl chloride.
Preferably, in the step S4, the molar ratio of the (S) -4-amino-1- (pyridine-3-yl) butan-1-ol to the oxalyl chloride is 1 (1-2); more preferably, the molar ratio of (S) -4-amino-1- (pyridin-3-yl) butan-1-ol and oxalyl chloride is 1: 1.5.
In this application, in the step S4, after the reaction of (S) -4-amino-1- (pyridin-3-yl) butan-1-ol with oxalyl chloride, a quenching reaction is required, and water may be selected as a quenching reagent, to obtain a mixture containing (S) -4-amino-1- (pyridin-3-yl) butan-1-chloride.
In the present application, in the step S5, the mixture containing (S) -4-amino-1- (pyridin-3-yl) but-1-chloro prepared in the step S4 is subjected to ring closure under the action of a base to form S-demethyl nicotine.
Preferably, in the S5 step, the base is hydroxide or carbonate.
In the present application, the hydroxide includes, but is not limited to, one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, and magnesium hydroxide.
In the present application, the carbonate includes, but is not limited to, one or more of sodium carbonate, potassium carbonate, and cesium carbonate.
More preferably, the base is sodium hydroxide.
In the present application, in the step S5, the molar ratio of the (S) -4-amino-1- (pyridin-3-yl) butane-1-chlorine to the sodium hydroxide is 1 (1.5 to 2.5); preferably, the molar ratio of (S) -4-amino-1- (pyridin-3-yl) butane-1-chloro and sodium hydroxide is 1: 2.
In the step S5, the reaction temperature of the mixture containing (S) -4-amino-1- (pyridin-3-yl) but-1-chloro prepared in the step S4 and the alkali is 55 to 65 ℃, and the reaction time is 2 to 3 hours; preferably, the reaction temperature of the mixture containing (S) -4-amino-1- (pyridin-3-yl) butan-1-yl chloride prepared in the step S4 and the alkali is 60 ℃, and the reaction time is 2 h.
In the present application, the step S5 results in a mixture comprising S-demethylated nicotine.
In the present application, in the step S6, the aminomethylating agent is methyl iodide.
In the step S6, the molar ratio of S-demethylated nicotine to methyl iodide in the S-demethylated nicotine-containing mixture is 1 (1.1 to 1.4); preferably, the molar ratio of S-demethylnicotine to methyl iodide in the S-demethylnicotine-containing mixture is 1: 1.2.
In the step S6, the reaction temperature of the mixture containing S-demethylated nicotine and the aminomethylating agent is 20 to 30 ℃, and the reaction time is 2 to 4 hours; preferably, the temperature of the reaction of the S-demethylated nicotine-containing mixture with the aminomethylating agent is 25 ℃ and the reaction time is 3 h.
In this application, in the step S6, the pH of the S-demethylated nicotine-containing mixture after reaction with the aminomethylating agent is adjusted to 6 by acid, extraction is performed, and the organic phase is Na-treated2SO4Drying, and concentrating under reduced pressure to obtain S-nicotine crude product.
In this application, in the step S6, the purification is distillation purification, and the specific operations are as follows: the normal pressure distillation extraction is carried out twice, and the obtained product is a high-purity levorotatory sample.
In summary, the present application has the following beneficial effects:
the application takes the nicotinate and the gamma-butyrolactone which are cheap and easy to obtain as the initial raw materials, so that the cost is low, and the application provides a new route for synthesizing the S-nicotine. Condensing under the action of an alkaline catalyst in sequence, carrying out reflux reaction with concentrated hydrochloric acid to carry out ring opening to obtain 4-chloro-1- (3-pyridine) -1-butanone, reacting with an amination reagent under an alkaline condition to obtain 4-amino-1- (3-pyridine) -1-butanone, inducing by (+) -B-diisopinocampheyl chloroborane to generate chiral hydroxyl to obtain (S) -4-amino-1- (pyridine-3-yl) butan-1-ol, carrying out chlorination, closing the ring under the action of alkali to obtain S-demethyl nicotine, and finally carrying out aminomethylation to obtain the S-nicotine. The method has the advantages of simple reaction route, mild reaction conditions, easy operation, high selectivity for obtaining S-nicotine with single configuration, high S-nicotine yield, high S-nicotine purity, simple steps and particular suitability for industrial S-nicotine production.
Detailed Description
The present application will be described in further detail with reference to examples.
The raw materials used in the present application are commercially available, and those not mentioned in the present application are purchased from national pharmaceutical group chemical agents limited, unless otherwise specified.
Examples 1-20 provide a method of producing S-nicotine, and are described below with reference to example 1.
The method of preparing S-nicotine provided in example 1, wherein the nicotinic acid ester is methyl nicotinate, the synthetic route is shown in reaction formula 1:
the preparation method comprises the following specific steps:
s1, adding 86.1g (1mol, 1eq) of gamma-butyrolactone (CAS number 96-48-0) into 1L of 1, 4-dioxane at 0 ℃, mixing, adding 48g (2mol, 2eq) of sodium hydride, reacting for 0.5h at 0 ℃, adding 137.1g (1mol) of methyl nicotinate (CAS number 93-60-7) for condensation reaction at 25 ℃, and monitoring the reaction by TCL until the reaction is finished to obtain a condensation product; adding 0.083L 12mol/L (1mol, 1eq) hydrochloric acid into the condensation product, refluxing and reacting for 1h at 80 ℃, adding saturated saline solution for extraction, adding sodium bicarbonate to ensure that the pH value of the system is 7, extracting for 3 times by using dichloromethane, combining organic phases, and removing the solvent by spin drying to obtain the 4-chloro-1- (pyridine-3-yl) -1-butanone.
S2, dissolving the 4-chloro-1- (pyridin-3-yl) -1-butanone obtained in the S1 step with 1L acetonitrile, adjusting the pH of the system to 9 by using 52 wt% NaOH aqueous solution, adding 90.1g (2mol, 2eq) of formamide, reacting at 80 ℃ for 8 hours, adjusting the pH to 6 by using 4mol/L hydrochloric acid after reaction, extracting by using ethyl acetate, taking an organic phase, and removing the solvent by rotary evaporation to obtain the 4-amino-1- (pyridin-3-yl) -1-butanone.
S3, dissolving the 4-amino-1- (pyridin-3-yl) -1-butanone obtained in the S2 step with 5L tetrahydrofuran, adding 641.5g (2mol, 2eq) (+) -B-diisopinocampheylchloroborane at 0 ℃, reacting for 2h at 0 ℃, extracting with dichloromethane for three times, and spin-drying the solvent to obtain (S) -4-amino-1- (pyridin-3-yl) butan-1-ol.
S4, adding 2L of 1, 4-dioxane into the (S) -4-amino-1- (pyridine-3-yl) butan-1-ol obtained in the step S3, mixing, adding 190.4g (1.5mol, 1.5eq) of oxalyl chloride at 0 ℃, reacting at 0 ℃ for 30min, adding 10mL of water to quench the reaction, and obtaining a mixture containing (S) -4-amino-1- (pyridine-3-yl) butan-1-chloro.
S5, adding 80g (2mol, 2eq) of NaOH into the mixture containing (S) -4-amino-1- (pyridine-3-yl) butane-1-chlorine prepared in the step S4, and reacting for 2 hours at 60 ℃ while stirring and dissolving to obtain a mixture containing S-demethyl nicotine; s6, adding 170.3g (1.2mol, 1.2eq) of methyl iodide into the mixture containing S-demethylated nicotine prepared in the S5 step, reacting for 3h at 25 ℃, adjusting the pH of the system to be 6 by using 12mol/L hydrochloric acid, extracting by using dichloromethane, taking an organic phase, adding Na into the organic phase2SO4Drying, concentrating under reduced pressure to remove solvent to obtain S-nicotine crude product; the S-nicotine crude product is distilled and purified once under normal pressure to obtain the S-nicotine with the yield of 52 percent, the ee value of 98 percent and the purity of 99 percent.
It is to be noted that the mass and the specific molar amount in the examples of the present application can be selected according to the size of the container for industrial production, and it is only necessary to keep the equivalent ratio between the reaction raw materials consistent.
Examples 2-3, which differ from example 1 only in that: in the reaction of step S1, the type of the basic catalyst was adjusted as shown in table 1.
TABLE 1 Effect of alkaline catalyst selection on S-nicotine yield
| Numbering | Selection of basic catalyst | Yield of S-nicotine (%) |
| Example 1 | Sodium hydride | 52 |
| Example 2 | Sodium tert-butoxide | 42 |
| Example 3 | Potassium tert-butoxide | 43 |
Example 4, which differs from example 1 only in that: in the reaction of step S2, the kind of aminating agent was adjusted as shown in table 2.
TABLE 2 Effect of amination reagent selection on S-nicotine yield
| Numbering | Amination reagent selection | Yield of S-nicotine (%) |
| Example 1 | Carboxamides | 52 |
| Example 4 | Aqueous ammonia | 48 |
Examples 5-6, which differ from example 1 only in that: in the reaction of step S2, the amount of the aminating agent used was adjusted as shown in table 3.
TABLE 3 Effect of amination reagent dosage on S-nicotine yield
| Numbering | Equivalent number of aminating reagents (eq) | Yield of S-nicotine (%) |
| Example 1 | 2 | 52 |
| Example 5 | 3 | 48 |
| Example 6 | 1 | 45 |
Examples 7 to 9, differing from example 1 only in that: in the reaction of the step S3, the amount of (+) -B-diisopinocampheylchloroborane was adjusted as shown in Table 4.
TABLE 4 Effect of (+) -B-diisopinocampheylchloroborane amount on S-nicotine yield
Examples 10 to 12 differ from example 1 only in that: in the reaction of step S3, the kind of the organic solvent II was adjusted as shown in table 5.
TABLE 5 influence of organic solvent II selection on S-nicotine yield
| Numbering | Selection of organic solvent II | Yield of S-nicotine (%) |
| Example 1 | Tetrahydrofuran (THF) | 52 |
| Example 10 | 1, 4-dioxane | 50 |
| Example 11 | Methyl tert-butyl ether | 25 |
| Example 12 | Anhydrous diethyl ether | 48 |
Examples 13-15, which differ from example 1 only in that: in the reaction of the step S3, the reaction temperature was adjusted as shown in table 6.
TABLE 6 influence of reaction temperature on S-nicotine yield
| Numbering | Reaction temperature (. degree.C.) | Yield of S-nicotine (%) |
| Example 1 | 0 | 52 |
| Example 13 | -30 | 50 |
| Example 14 | 10 | 45 |
| Example 15 | 5 | 48 |
Examples 16 to 17 differ from example 1 only in that: in the reaction of the step S4, the reaction temperature was adjusted as shown in table 7.
TABLE 7 influence of reaction temperature on S-nicotine yield
| Numbering | Reaction temperature (. degree.C.) | Yield of S-nicotine (%) |
| Example 1 | 0 | 52 |
| Example 16 | 10 | 43 |
| Example 17 | -10 | 48 |
Examples 18 to 19 differ from example 1 only in that: in the reaction in the step S4, the amount of oxalyl chloride used was adjusted as shown in table 8.
TABLE 8 Effect of oxalyl chloride usage on S-nicotine yield
| Numbering | Number of equivalents of oxalyl chloride (eq) | Yield of S-nicotine (%) |
| Example 1 | 1.5 | 52 |
| Example 18 | 1 | 48 |
| Example 19 | 2 | 35 |
Example 20, which differs from example 1 only in that: in the step of S1, the equimolar replacement of methyl nicotinate by ethyl nicotinate (CAS No. 614-18-6) can produce S-nicotine with yield of 52%, ee value of 98% and purity of 99%.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. A preparation method of S-nicotine is characterized by comprising the following steps:
s1, nicotinic acid ester and gamma-butyrolactone are added into an organic solvent I and condensed under the action of an alkaline catalyst to obtain a condensation product, and the condensation product is subjected to ring opening under the condition of hydrochloric acid to obtain 4-chloro-1- (3-pyridine) -1-butanone;
s2, 4-chloro-1- (3-pyridine) -1-butanone reacts with amination reagent under alkaline condition to obtain 4-amino-1- (3-pyridine) -1-butanone;
s3, 4-amino-1- (3-pyridine) -1-butanone and (+) -B-diisopinocampheylchloroborane react in an organic solvent II at the temperature of-30 to 10 ℃ to obtain (S) -4-amino-1- (pyridine-3-yl) butan-1-ol;
s4, reacting (S) -4-amino-1- (pyridine-3-yl) butyl-1-alcohol with a chlorinated reagent to obtain (S) -4-amino-1- (pyridine-3-yl) butyl-1-chlorine;
s5, (S) -4-amino-1- (pyridine-3-yl) butane-1-chlorine cyclizes under the action of alkali to obtain S-demethyl nicotine;
s6, reacting the S-demethyl nicotine with an amine methylation reagent to obtain an S-nicotine crude product, and purifying to obtain the S-nicotine.
2. A process for preparing S-nicotine according to claim 1, wherein in step S3, the molar ratio of 4-amino-1- (3-pyridine) -1-butanone to (+) -B-diisopinocampheylchloroborane is 1 (1-3).
3. A process according to claim 1, wherein in step S3, the organic solvent II is selected from one or more of tetrahydrofuran, dimethyltetrahydrofuran and 1, 4-dioxane.
4. A method of S-nicotine according to claim 1, wherein in the step of S4, the chlorinating agent is oxalyl chloride; the molar ratio of the (S) -4-amino-1- (pyridine-3-yl) butane-1-alcohol to oxalyl chloride is 1 (1-3).
5. A process according to claim 4, wherein the reaction temperature in step S4 is-10 to 10 ℃.
6. A method of preparing S-nicotine according to claim 1, wherein in step S2, the amination reagent is ammonia or formamide.
7. A process for preparing S-nicotine according to claim 1, wherein in step S2, the molar ratio of 4-chloro-1- (3-pyridine) -1-butanone to amination reagent is 1 (1-3).
8. A process for preparing S-nicotine according to claim 1, wherein in step S1, the molar ratio of nicotinic acid ester, gamma-butyrolactone and basic catalyst is 1 (1-2) to (1.2-3).
9. A method of preparing S-nicotine according to claim 1, wherein in the step of S1, the basic catalyst is selected from one or more of alkali metal alkoxide, alkaline earth metal hydride, alkaline earth metal oxide, amine, metal salt of amine, hydroxide, carbonate and bicarbonate.
10. A process of S-nicotine according to claim 1, wherein in step S5, the base is hydroxide or carbonate.
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| CN114276204A (en) * | 2021-12-24 | 2022-04-05 | 大庆雾泰化工科技有限公司 | Preparation method of (S) - (-) -nicotine |
| CN114437031A (en) * | 2022-02-16 | 2022-05-06 | 深圳市真味生物科技有限公司 | Synthetic method of 6-methyl nicotine |
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| CN114276204B (en) * | 2021-12-24 | 2024-02-27 | 大庆雾泰化工科技有限公司 | Preparation method of (S) - (-) -nicotine |
| CN114437031A (en) * | 2022-02-16 | 2022-05-06 | 深圳市真味生物科技有限公司 | Synthetic method of 6-methyl nicotine |
Also Published As
| Publication number | Publication date |
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| EP4140992A4 (en) | 2023-12-06 |
| EP4140992A1 (en) | 2023-03-01 |
| WO2023284057A1 (en) | 2023-01-19 |
| CN113475739B (en) | 2022-11-11 |
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