EP4140992A1 - Method for preparing s-nicotine - Google Patents
Method for preparing s-nicotine Download PDFInfo
- Publication number
- EP4140992A1 EP4140992A1 EP21810886.8A EP21810886A EP4140992A1 EP 4140992 A1 EP4140992 A1 EP 4140992A1 EP 21810886 A EP21810886 A EP 21810886A EP 4140992 A1 EP4140992 A1 EP 4140992A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- nicotine
- pyridin
- amino
- preparation
- butanone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960002715 nicotine Drugs 0.000 title claims abstract description 67
- 238000000034 method Methods 0.000 title description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 32
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 238000005576 amination reaction Methods 0.000 claims abstract description 16
- 150000001412 amines Chemical class 0.000 claims abstract description 15
- 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 14
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims abstract description 14
- UOALEFQKAOQICC-UHFFFAOYSA-N chloroborane Chemical compound ClB UOALEFQKAOQICC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000011664 nicotinic acid Substances 0.000 claims abstract description 14
- 235000001968 nicotinic acid Nutrition 0.000 claims abstract description 14
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 11
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 9
- 230000011987 methylation Effects 0.000 claims abstract description 9
- 238000007069 methylation reaction Methods 0.000 claims abstract description 9
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- 239000002585 base Substances 0.000 claims description 26
- 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 14
- 239000003960 organic solvent Substances 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 239000007859 condensation product Substances 0.000 claims description 11
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 6
- -1 alkali metal alkoxide Chemical class 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-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
- 239000000908 ammonium hydroxide Substances 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000009776 industrial production Methods 0.000 abstract description 5
- 238000010992 reflux Methods 0.000 abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 230000001939 inductive effect Effects 0.000 abstract 1
- 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
- 230000035484 reaction time Effects 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 238000000605 extraction Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical group COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-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
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229960001238 methylnicotinate Drugs 0.000 description 4
- 238000012805 post-processing Methods 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
- 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
- 238000004821 distillation Methods 0.000 description 3
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-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
- 230000000171 quenching effect Effects 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-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
- 239000007832 Na2SO4 Substances 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 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
- 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
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000002524 organometallic group Chemical group 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
- 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-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
- 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000004480 active ingredient 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
- 230000009286 beneficial effect Effects 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction 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
- 238000004090 dissolution Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 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
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-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
- NOTVAPJNGZMVSD-UHFFFAOYSA-N potassium monoxide Inorganic materials [K]O[K] NOTVAPJNGZMVSD-UHFFFAOYSA-N 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 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
Definitions
- the present invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of S-nicotine.
- S-Nicotine has a molecular formula of C 10 H 14 N 2 , a CAS number of 54-11-5, and a structural formula of
- S-nicotine is basically obtained by a chiral resolution method, but chiral resolution reagents are expensive, which is not conducive to industrial production.
- a patent with a publication No. CN104341390A discloses a preparation method of S-nicotine. According to the method, cyclic imine is used as a starting material, an expensive chiral catalyst is required, high-pressure hydrogen equipment is required, and the production cost is relatively high, so that the method is not suitable for large-scale industrial production.
- a patent with a publication No. CN11233829A discloses a preparation method of nicotine with optical activity.
- a chiral ligand containing nitrogen or phosphorus is used to prepare an organometallic catalyst, an imide derivative is used as a stating material to prepare S-nicotine, the preparation of the organometallic catalyst is relatively complicated, the production cost is relatively high, and the yield of S-nicotine is relatively low.
- the present application provides a preparation method of S-nicotine, cheaper and readily available raw materials are used, and the yield of prepared S-nicotine is higher.
- the present application provides a preparation method of S-nicotine.
- the present application provides a preparation method of S-nicotine, which is implemented by adopting the following technical solutions: a preparation method of S-nicotine, including the following steps:
- nicotinate and ⁇ -butyrolactone are used as raw materials, nicotinate and ⁇ -butyrolactone are both cheap and readily available raw materials, (+)-B-diisopinocampheyl chloroborane is used to reduce a carbonyl group of an intermediate and obtain a target chiral center; the (+)-B-diisopinocampheyl chloroborane induces the production of a chiral hydroxyl group, chlorination and cyclization are performed to form chiral S-demethylnicotine, and finally amine methylation is performed to obtain S-nicotine with photochemical activity.
- the preparation method of S-nicotine provided in the present application has the advantages of high purity, simple process, easy operation, high yield and mild reaction conditions, and S-nicotine in a single configuration is obtained with a high ee value, which is suitable for industrial production.
- the nicotinate is methyl nicotinate or ethyl nicotinate.
- a molar ratio of the nicotinate to the ⁇ -butyrolactone to the base catalyst is 1: (1-2): (1.2-3); and more preferably, the molar ratio of the nicotinate to the ⁇ -butyrolactone to the base catalyst is 1: 1: 2.
- the base catalyst is selected from one or more of alkali metal alkoxide, alkaline earth metal hydride, alkaline earth metal oxide, amine, a metal salt of amine, hydroxide, carbonate, and bicarbonate.
- the alkali metal alkoxide includes, but is not limited to, any one of sodium tert-butoxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide.
- the alkaline earth metal hydride includes, but is not limited to, one or more of NaH, LiH, and KH.
- the alkaline earth metal oxide includes, but is not limited to, one or more of Na 2 O, Li 2 O, and K 2 O.
- the amine includes, but is not limited to, triethylamine and/or diisopropylethyl amine.
- the metal salt of amine includes, but is not limited to, sodium bis(trimethylsilyl)amide and/or lithium diisopropylamide.
- the hydroxide includes, but is not limited to, one or more of sodium hydroxide, lithium hydroxide, and magnesium hydroxide.
- the carbonate includes, but is not limited to, one or more of sodium carbonate, potassium carbonate, and cesium carbonate.
- the bicarbonate includes, but is not limited to, sodium bicarbonate and/or potassium bicarbonate.
- the base catalyst is selected from any one of sodium tert-butoxide, NaH, and potassium tert-butoxide.
- the organic solvent I is selected from one or more of tetrahydrofuran, methyl tertiary butyl ether, dimethyl tetrahydrofuran, and 1,4-dioxane; and preferably, the organic solvent I is 1,4-dioxane.
- the reaction needs to be performed under an N 2 atmosphere, and an adding order of the nicotinate, the ⁇ -butyrolactone and the base catalyst is that: the ⁇ -butyrolactone is added first, followed by the base catalyst and finally the nicotinate.
- the reaction temperature of the ⁇ -butyrolactone and the base catalyst is 0°C, and the reaction time is 30 min; and the reaction temperature of the nicotinate, the ⁇ -butyrolactone and the base catalyst is 25°C.
- the hydrochloric acid is concentrated hydrochloric acid, and the concentration of the concentrated hydrochloric acid is 12 mol/L.
- a molar ratio of the condensation product to HCl in the hydrochloric acid is 1: (1-6); and preferably, the molar ratio of the condensation product to the HCl in the hydrochloric acid is 1: 1.
- the reflux reaction time of the condensation product and the hydrochloric acid at 70 to 90°C is 0.5 to 1.5 h; and preferably, the reflux reaction time of the condensation product and the hydrochloric acid at 80°C is 1 h.
- post-processing is further required to obtain the 4-chloro-1-(3-pyridin)-1-butanone, wherein the post-processing includes: diluting with saline, neutralizing with a base substance, extracting, taking an organic phase, and performing rotary drying for removing the solvent to obtain the 4-chloro-1-(3-pyridin)-1-butanone.
- the 4-chloro-1-(3-pyridin)-1-butanone obtained at S1 needs to be dissolved in a solvent.
- the solvent includes, but is not limited to, one or more of acetonitrile, 1,4-dioxane, dichloromethane, DMF, and tetrahydrofuran; and preferably, the solvent is acetonitrile.
- the reaction temperature of the 4-chloro-1-(3-pyridin)-1-butanone and the animation reagent under the alkaline conditions is 60 to 100°C, and the reaction time is 6 to 10 h; and preferably, the reaction temperature of the 4-chloro-1-(3-pyridin)-1-butanone and the animation reagent under the alkaline conditions is 80°C, and the reaction time is 8 h.
- a molar ratio of the 4-chloro-1-(3-pyridin)-1-butanone to the animation reagent is 1: (1-3); and more preferably, the molar ratio of the 4-chloro-1-(3-pyridin)-1-butanone to the animation reagent is 1: 2.
- the amination reagent is ammonium hydroxide or formamide; and more preferably, the amination reagent is formamide.
- the pH of an alkaline environment in the reaction of the 4-chloro-1-(3-pyridin)-1-butanone and the amination reagent under the alkaline conditions is 8 to 12; and preferably, the pH of the alkaline environment in the reaction of the 4-chloro-1-(3-pyridin)-1-butanone and the amination reagent under the alkaline conditions is 9.
- the alkaline environment can be adjusted with a 52 wt% NaOH aqueous solution.
- S2 further includes a post-processing step, wherein the post-processing step includes: adjusting the pH to 6 to 7 by adding an acid, extracting, performing rotary drying on an organic phase for removing the solvent to obtain the 4-amino-1-(3 -pyridin)-1 -butanone.
- the 4-amino-1-(3-pyridin)-1-butanone prepared at S2 needs to be dissolved in the organic solvent II.
- the organic solvent II is selected from one or more of tetrahydrofuran, dimethylte trahydrofuran, and 1,4-dioxane; and more preferably, the organic solvent II is tetrahydrofuran.
- a molar ratio of the 4-amino-1-(3-pyridin)-1-butanone to the (+)-B-diisopinocampheyl chloroborane is 1: (1-3); and more preferably, the molar ratio of the 4-amino-1-(3-pyridin)-1-butanone to the (+)-B-diisopinocampheyl chloroborane is 1: (1.5-2).
- the reaction temperature of the 4-amino-1-(3-pyridin)-1-butanone and the (+)-B-diisopinocampheyl chloroborane is 0°C, and the reaction time is 2 h.
- S3 further includes an extraction step, wherein an extraction agent is methylene chloride, after the extraction, rotary drying for removing the solvent is performed to obtain the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol.
- an extraction agent is methylene chloride
- the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol prepared at S3 needs to be dissolved in a solvent and then react with the chlorination reagent.
- the solvent includes, but is not limited to, 1,4-dioxane.
- the reaction temperature of S4 is -10 to 10°C; and more preferably, the reaction temperature of S4 is 0°C.
- reaction time of S4 is 20 to 40 min; and preferably, the reaction time of S4 is 30 min.
- the chlorination reagent is selected from oxalyl chloride, thionyl chloride, PCl3, and PCl5; and more preferably, the chlorination reagent is oxalyl chloride.
- a molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol to the oxalyl chloride is 1: (1-2); and more preferably, the molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol to the oxalyl chloride is 1: 1.5.
- quenching is required to obtain a mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine, wherein a quenching reagent may be water.
- the base is hydroxide or carbonate.
- 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.
- the carbonate includes, but is not limited to, one or more of sodium carbonate, potassium carbonate, and cesium carbonate.
- the base is sodium hydroxide.
- a molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine and the sodium hydroxide is 1: (1.5-2.5); and preferably, the molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine and the sodium hydroxide is 1: 2.
- the reaction temperature of the mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine prepared at S4 and the base is 55 to 65°C, and the reaction time is 2 to 3 h; and preferably, the reaction temperature of the mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine prepared at S4 and the base is 60°C, and the reaction time is 2 h.
- the amine methylation reagent is methyl iodide.
- a molar ratio of S-demethylnicotine in the mixture containing S-demethylnicotine to the methyl iodide is 1: (1.1-1.4); and preferably, the molar ratio of the S-demethylnicotine in the mixture containing S-demethylnicotine to the methyl iodide is 1: 1.2.
- the reaction temperature of the mixture containing S-demethylnicotine and the amine methylation reagent is 20 to 30°C, and the reaction time is 2 to 4 h; and preferably, the reaction temperature of the mixture containing S-demethylnicotine and the amine methylation reagent is 25°C, and the reaction time is 3 h.
- the pH needs to be adjusted to 6 by using an acid, extraction is performed, an organic phase is dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the crude S-nicotine.
- the purification is distillation purification, and specifically includes: performing atmospheric distillation extraction two times to obtain a levorotatory sample with high purity.
- the present application has the following beneficial effects:
- the present application provides a novel route for synthesizing S-nicotine by using cheap and readily available nicotinate and ⁇ -butyrolactone as starting materials, and the cost is low.
- Condensation is performed in the presence of a base catalyst, cyclization is performed through a reflux reaction with concentrated hydrochloric acid to obtain 4-chloro-1-(3-pyridin)-1-butanone, a reaction is performed with an amination reagent under alkaline conditions to obtain 4-amino-1-(3-pyridin)-1-butanone, the production of a chiral hydroxyl group is induced by (+)-B-diisopinocampheyl chloroborane to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol, chlorination and cyclization in the presence of a base are performed to obtain S-demethylnicotine, and finally amine methylation is performed to obtain S
- the reaction route is simple, the reaction conditions are mild and easy to operate, S-nicotine in a single configuration is obtained with high selectivity, the yield and the purity of S-nicotine are high, and the steps are simple, so that the method is particularly suitable for industrial production of S-nicotine.
- the raw materials used in the present application can be obtained commercially, and if there is no special description, the raw materials not mentioned in the present application are purchased from Sinopharm Chemical Reagent Co., Ltd.
- Embodiments 1 to 20 provide a preparation method of S-nicotine, which will be described below by taking Embodiment 1 as an example.
- Embodiment 1 provides a preparation method of S-nicotine, wherein nicotinate is methyl nicotinate, and a synthetic route is shown as Reaction Formula 1:
- each mass and specific molar weight in the embodiments of the present application can be selected according to the size of an industrially produced vessel as long as the equivalence ratio of each reaction raw material is consistent.
- Embodiments 2 to 3 A difference between Embodiments 2 to 3 and Embodiment 1 is that: in the reaction of S1, the kind of the base catalyst was adjusted as specifically shown in Table 1. Table 1 Effect of selection of base catalyst on the yield of S-nicotine Serial number Selection of base catalyst Yield of S-nicotine (%) Embodiment 1 Sodium hydride 52 Embodiment 2 Sodium tert-butoxide 42 Embodiment 3 Potassium tert-butoxide 43
- Embodiment 4 A difference between Embodiment 4 and Embodiment 1 is that: in the reaction of S2, the kind of the amination reagent was adjusted as specifically shown in Table 2.
- Table 2 Effect of selection of amination reagent on the yield of S-nicotine Serial number Selection of amination reagent Yield of S-nicotine (%) Embodiment 1 Formamide 52 Embodiment 4 Ammonium hydroxide 48
- Embodiments 5 to 6 and Embodiment 1 A difference between Embodiments 5 to 6 and Embodiment 1 is that: in the reaction of S2, the usage amount of the amination reagent was adjusted as specifically shown in Table 3. Table 3 Effect of usage amount of amination reagent on the yield of S-nicotine Serial number Equivalent quantity (eq) of amination reagent Yield of S-nicotine (%) Embodiment 1 2 52 Embodiment 5 3 48 Embodiment 6 1 45
- Embodiments 7 to 9 and Embodiment 1 A difference between Embodiments 7 to 9 and Embodiment 1 is that: in the reaction of S3, the usage amount of the (+)-B-diisopinocampheyl chloroborane was adjusted as specifically shown in Table 4.
- Table 4 Effect of usage amount of (+)-B-diisopinocampheyl chloroborane on the yield of S-nicotine Serial number Equivalent quantity (eq) of (+)-B-diisopinocampheyl chloroborane Yield of S-nicotine (%) Embodiment 1 2 52 Embodiment 7 1 42 Embodiment 8 3 46 Embodiment 9 1.5 48
- Embodiments 10 to 12 and Embodiment 1 A difference between Embodiments 10 to 12 and Embodiment 1 is that: in the reaction of S3, the kind of the organic solvent II was adjusted as specifically shown in Table 5. Table 5 Effect of selection of organic solvent II on the yield of S-nicotine Serial number Selection of organic solvent II Yield of S-nicotine (%) Embodiment 1 Tetrahydrofuran 52 Embodiment 10 1,4-dioxane 50 Embodiment 11 Methyl tertiary butyl ether 25 Embodiment 12 Absolute ether 48
- Embodiments 13 to 15 A difference between Embodiments 13 to 15 and Embodiment 1 is that: in the reaction of S3, the reaction temperature was adjusted as specifically shown in Table 6. Table 6 Effect of reaction temperature on the yield of S-nicotine Serial number Reaction temperature (°C) Yield of S-nicotine (%) Embodiment 1 0 52 Embodiment 13 -30 50 Embodiment 14 10 45 Embodiment 15 5 48
- Embodiments 16 to 17 and Embodiment 1 A difference between Embodiments 16 to 17 and Embodiment 1 is that: in the reaction of S4, the reaction temperature was adjusted as specifically shown in Table 7. Table 7 Effect of reaction temperature on the yield of S-nicotine Serial number Reaction temperature (°C) Yield of S-nicotine (%) Embodiment 1 0 52 Embodiment 16 10 43 Embodiment 17 -10 48
- Embodiments 18 to 19 A difference between Embodiments 18 to 19 and Embodiment 1 is that: in the reaction of S4, the usage amount of the oxalyl chloride was adjusted as specifically shown in Table 8. Table 8 Effect of usage amount of oxalyl chloride on the yield of S-nicotine Serial number Equivalent quantity (eq) of oxalyl chloride Yield of S-nicotine (%) Embodiment 1 1.5 52 Embodiment 18 1 48 Embodiment 19 2 35
- Embodiment 20 A difference between Embodiment 20 and Embodiment 1 is that: at S1, the methyl nicotinate was replaced with equimolar ethyl nicotinate (with a CAS No. of 614-18-6), and produced S-nicotine had a yield of 52%, an ee value of 98%, and a purity of 99%.
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Abstract
Description
- The present invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of S-nicotine.
- With the rapid development of e-cigarette industry, the demand of nicotine, which is one of the important active ingredients of e-cigarette, is increasing, among which nicotine in a single configuration with optical activity is widely concerned. S-Nicotine has a molecular formula of C10H14N2, a CAS number of 54-11-5, and a structural formula of
- At present, there are few studies on the preparation methods of S-nicotine. S-nicotine is basically obtained by a chiral resolution method, but chiral resolution reagents are expensive, which is not conducive to industrial production.
- A patent with a publication No.
CN104341390A discloses a preparation method of S-nicotine. According to the method, cyclic imine is used as a starting material, an expensive chiral catalyst is required, high-pressure hydrogen equipment is required, and the production cost is relatively high, so that the method is not suitable for large-scale industrial production. A patent with a publication No.CN11233829A discloses a preparation method of nicotine with optical activity. According to the method, a chiral ligand containing nitrogen or phosphorus is used to prepare an organometallic catalyst, an imide derivative is used as a stating material to prepare S-nicotine, the preparation of the organometallic catalyst is relatively complicated, the production cost is relatively high, and the yield of S-nicotine is relatively low. - Therefore, the present application provides a preparation method of S-nicotine, cheaper and readily available raw materials are used, and the yield of prepared S-nicotine is higher.
- In order to increase the yield of S-nicotine, the present application provides a preparation method of S-nicotine.
- In a first aspect, the present application provides a preparation method of S-nicotine, which is implemented by adopting the following technical solutions:
a preparation method of S-nicotine, including the following steps: - S1: adding nicotinate and γ-butyrolactone into an organic solvent I, performing condensation in the presence of a base catalyst to obtain a condensation product, and performing cyclization on the condensation product in the presence of hydrochloric acid to obtain 4-chloro-1-(3-pyridin)-1-butanone;
- S2: reacting the 4-chloro-1-(3-pyridin)-1-butanone with an amination reagent under alkaline conditions to obtain 4-amino-1-(3-pyridin)-1-butanone;
- S3: adding the 4-amino-1-(3-pyridin)-1-butanone and (+)-B-diisopinocampheyl chloroborane into an organic solvent II, and reacting at -30 to 10°C to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol;
- S4: reacting the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol with a chlorination reagent to obtain (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine;
- S5: performing cyclization on the (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine in the presence of a base to obtain S-demethylnicotine; and
- S6: reacting the S-demethylnicotine with an amine methylation reagent to obtain crude S-nicotine, and purifying to obtain S-nicotine.
- By adopting the above technical solution, nicotinate and γ-butyrolactone are used as raw materials, nicotinate and γ-butyrolactone are both cheap and readily available raw materials, (+)-B-diisopinocampheyl chloroborane is used to reduce a carbonyl group of an intermediate and obtain a target chiral center; the (+)-B-diisopinocampheyl chloroborane induces the production of a chiral hydroxyl group, chlorination and cyclization are performed to form chiral S-demethylnicotine, and finally amine methylation is performed to obtain S-nicotine with photochemical activity. The preparation method of S-nicotine provided in the present application has the advantages of high purity, simple process, easy operation, high yield and mild reaction conditions, and S-nicotine in a single configuration is obtained with a high ee value, which is suitable for industrial production.
- In the present application, the nicotinate is methyl nicotinate or ethyl nicotinate.
- Preferably, at S1, a molar ratio of the nicotinate to the γ-butyrolactone to the base catalyst is 1: (1-2): (1.2-3); and more preferably, the molar ratio of the nicotinate to the γ-butyrolactone to the base catalyst is 1: 1: 2.
- Preferably, at S1, the base catalyst is selected from one or more of alkali metal alkoxide, alkaline earth metal hydride, alkaline earth metal oxide, amine, a 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, one or more of Na2O, Li2O, and K2O.
- In the present application, the amine includes, but is not limited to, triethylamine and/or diisopropylethyl amine.
- In the present application, the metal salt of 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 base catalyst is selected from any one of sodium tert-butoxide, NaH, and potassium tert-butoxide.
- In the present application, at S1, the organic solvent I is selected from one or more of tetrahydrofuran, methyl tertiary butyl ether, dimethyl tetrahydrofuran, and 1,4-dioxane; and preferably, the organic solvent I is 1,4-dioxane.
- In the present application, at S1, the reaction needs to be performed under an N2 atmosphere, and an adding order of the nicotinate, the γ-butyrolactone and the base catalyst is that: the γ-butyrolactone is added first, followed by the base catalyst and finally the nicotinate.
- In the present application, the reaction temperature of the γ-butyrolactone and the base catalyst is 0°C, and the reaction time is 30 min; and the reaction temperature of the nicotinate, the γ-butyrolactone and the base catalyst is 25°C.
- In the present application, at S1, the hydrochloric acid is concentrated hydrochloric acid, and the concentration of the concentrated hydrochloric acid is 12 mol/L.
- In the present application, at S1, a molar ratio of the condensation product to HCl in the hydrochloric acid is 1: (1-6); and preferably, the molar ratio of the condensation product to the HCl in the hydrochloric acid is 1: 1.
- In the present application, at S1, the reflux reaction time of the condensation product and the hydrochloric acid at 70 to 90°C is 0.5 to 1.5 h; and preferably, the reflux reaction time of the condensation product and the hydrochloric acid at 80°C is 1 h.
- In the present application, at S1, after cyclization is performed on the condensation product in the presence of hydrochloric acid, post-processing is further required to obtain the 4-chloro-1-(3-pyridin)-1-butanone, wherein the post-processing includes: diluting with saline, neutralizing with a base substance, extracting, taking an organic phase, and performing rotary drying for removing the solvent to obtain the 4-chloro-1-(3-pyridin)-1-butanone.
- In the present application, before the reaction of S2, the 4-chloro-1-(3-pyridin)-1-butanone obtained at S1 needs to be dissolved in a solvent. The solvent includes, but is not limited to, one or more of acetonitrile, 1,4-dioxane, dichloromethane, DMF, and tetrahydrofuran; and preferably, the solvent is acetonitrile.
- In the present application, at S2, the reaction temperature of the 4-chloro-1-(3-pyridin)-1-butanone and the animation reagent under the alkaline conditions is 60 to 100°C, and the reaction time is 6 to 10 h; and preferably, the reaction temperature of the 4-chloro-1-(3-pyridin)-1-butanone and the animation reagent under the alkaline conditions is 80°C, and the reaction time is 8 h.
- Preferably, at S2, a molar ratio of the 4-chloro-1-(3-pyridin)-1-butanone to the animation reagent is 1: (1-3); and more preferably, the molar ratio of the 4-chloro-1-(3-pyridin)-1-butanone to the animation reagent is 1: 2.
- Preferably, at S2, the amination reagent is ammonium hydroxide or formamide; and more preferably, the amination reagent is formamide.
- In the present application, at S2, the pH of an alkaline environment in the reaction of the 4-chloro-1-(3-pyridin)-1-butanone and the amination reagent under the alkaline conditions is 8 to 12; and preferably, the pH of the alkaline environment in the reaction of the 4-chloro-1-(3-pyridin)-1-butanone and the amination reagent under the alkaline conditions is 9. The alkaline environment can be adjusted with a 52 wt% NaOH aqueous solution.
- In the present application, S2 further includes a post-processing step, wherein the post-processing step includes: adjusting the pH to 6 to 7 by adding an acid, extracting, performing rotary drying on an organic phase for removing the solvent to obtain the 4-amino-1-(3 -pyridin)-1 -butanone.
- In the present application, at S3, the 4-amino-1-(3-pyridin)-1-butanone prepared at S2 needs to be dissolved in the organic solvent II.
- Preferably, at S3, the organic solvent II is selected from one or more of tetrahydrofuran, dimethylte trahydrofuran, and 1,4-dioxane; and more preferably, the organic solvent II is tetrahydrofuran.
- Preferably, at S3, a molar ratio of the 4-amino-1-(3-pyridin)-1-butanone to the (+)-B-diisopinocampheyl chloroborane is 1: (1-3); and more preferably, the molar ratio of the 4-amino-1-(3-pyridin)-1-butanone to the (+)-B-diisopinocampheyl chloroborane is 1: (1.5-2).
- Preferably, at S3, the reaction temperature of the 4-amino-1-(3-pyridin)-1-butanone and the (+)-B-diisopinocampheyl chloroborane is 0°C, and the reaction time is 2 h.
- In the present application, S3 further includes an extraction step, wherein an extraction agent is methylene chloride, after the extraction, rotary drying for removing the solvent is performed to obtain the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol.
- In the present application, at S4, the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol prepared at S3 needs to be dissolved in a solvent and then react with the chlorination reagent. The solvent includes, but is not limited to, 1,4-dioxane.
- Preferably, the reaction temperature of S4 is -10 to 10°C; and more preferably, the reaction temperature of S4 is 0°C.
- In the present application, the reaction time of S4 is 20 to 40 min; and preferably, the reaction time of S4 is 30 min.
- Preferably, at S4, the chlorination reagent is selected from oxalyl chloride, thionyl chloride, PCl3, and PCl5; and more preferably, the chlorination reagent is oxalyl chloride.
- Preferably, at S4, a molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol to the oxalyl chloride is 1: (1-2); and more preferably, the molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol to the oxalyl chloride is 1: 1.5.
- In the present application, at S4, after the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol reacts with the oxalyl chloride, quenching is required to obtain a mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine, wherein a quenching reagent may be water.
- In the present application, at S5, cyclization is performed on the mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine prepared at S4 in the presence of a base to form the S-demethylnicotine.
- Preferably, at S5, 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, at S5, a molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine and the sodium hydroxide is 1: (1.5-2.5); and preferably, the molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine and the sodium hydroxide is 1: 2.
- In the present application, at S5, the reaction temperature of the mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine prepared at S4 and the base is 55 to 65°C, and the reaction time is 2 to 3 h; and preferably, the reaction temperature of the mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine prepared at S4 and the base is 60°C, and the reaction time is 2 h.
- In the present application, a mixture containing S-demethylnicotine is obtained at S5.
- In the present application, at S6, the amine methylation reagent is methyl iodide.
- In the present application, at S6, a molar ratio of S-demethylnicotine in the mixture containing S-demethylnicotine to the methyl iodide is 1: (1.1-1.4); and preferably, the molar ratio of the S-demethylnicotine in the mixture containing S-demethylnicotine to the methyl iodide is 1: 1.2.
- In the present application, at S6, the reaction temperature of the mixture containing S-demethylnicotine and the amine methylation reagent is 20 to 30°C, and the reaction time is 2 to 4 h; and preferably, the reaction temperature of the mixture containing S-demethylnicotine and the amine methylation reagent is 25°C, and the reaction time is 3 h.
- In the present application, at S6, after the mixture containing S-demethylnicotine reacts with the amine methylation reagent, the pH needs to be adjusted to 6 by using an acid, extraction is performed, an organic phase is dried over Na2SO4 and concentrated under reduced pressure to obtain the crude S-nicotine.
- In the present application, at S6, the purification is distillation purification, and specifically includes: performing atmospheric distillation extraction two times to obtain a levorotatory sample with high purity.
- In summary, the present application has the following beneficial effects:
The present application provides a novel route for synthesizing S-nicotine by using cheap and readily available nicotinate and γ-butyrolactone as starting materials, and the cost is low. Condensation is performed in the presence of a base catalyst, cyclization is performed through a reflux reaction with concentrated hydrochloric acid to obtain 4-chloro-1-(3-pyridin)-1-butanone, a reaction is performed with an amination reagent under alkaline conditions to obtain 4-amino-1-(3-pyridin)-1-butanone, the production of a chiral hydroxyl group is induced by (+)-B-diisopinocampheyl chloroborane to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol, chlorination and cyclization in the presence of a base are performed to obtain S-demethylnicotine, and finally amine methylation is performed to obtain S-nicotine. The reaction route is simple, the reaction conditions are mild and easy to operate, S-nicotine in a single configuration is obtained with high selectivity, the yield and the purity of S-nicotine are high, and the steps are simple, so that the method is particularly suitable for industrial production of S-nicotine. - The present application will be described in detail below in conjunction with embodiments.
- The raw materials used in the present application can be obtained commercially, and if there is no special description, the raw materials not mentioned in the present application are purchased from Sinopharm Chemical Reagent Co., Ltd.
- Embodiments 1 to 20 provide a preparation method of S-nicotine, which will be described below by taking Embodiment 1 as an example.
-
- Specific preparation steps were as follows:
- S1: 86.1 g (1 mol, 1 eq) of γ-butyrolactone (with a CAS No. of 96-48-0) was added into 1 L of 1,4-dioxane at 0°C and mixed, 48 g (2 mol, 2 eq) of sodium hydride was added, a reaction was performed at 0°C for 0.5 h, 137.1 g (1 mol) of methyl nicotinate (with a CAS No. of 93-60-7) was added, a condensation reaction was performed at 25°C and monitored by TLC until the end of the reaction to obtain a condensation product, 0.083 L of 12 mol/L (1 mol, 1 eq) hydrochloric acid was added into the condensation product, a reflux reaction was performed at 80°C for 1 h, a saturated salt solution was added for extraction, sodium bicarbonate was added to adjust the pH of the system to 7, extraction was performed three times by using dichloromethane, and organic phases were combined and subjected to rotary drying for removing the solvent to obtain 4-chloro-1-(pyridin-3-yl)-1-butanone.
- S2: the 4-chloro-1-(pyridin-3-yl)-1-butanone obtained at S1 was dissolved in 1 L of acetonitrile, a 52 wt% NaOH aqueous solution was used to adjust pH of the system to 9, 90.1 g (2 mol, 2 eq) of formamide was added, a reaction was performed at 80°C for 8 h, after the reaction, 4 mol/L hydrochloric acid was used to adjust the pH to 6, extraction was performed by using ethyl acetate, an organic phase was taken and subjected to rotary evaporation for removing the solvent to obtain 4-amino-1-(pyridin-3-yl)-1-butanone.
- S3: the 4-amino-1-(pyridin-3-yl)-1-butanone obtained at S2 was dissolved in 5 L of tetrahydrofuran, after the dissolution, 641.5 g (2 mol, 2 eq) of (+)-B-diisopinocampheyl chloroborane was added at 0°C, a reaction was performed at 0°C for 2 h, extraction was performed three times by using dichloromethane, and rotary drying for removing the solvent was performed to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol.
- S4: 2 L of 1,4-dioxane was added into the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol obtained at S3 and mixed, 190.4 g (1.5 mol, 1.5 eq) of oxalyl chloride was added at 0°C, a reaction was performed at 0°C for 30 min, and quenching was performed by adding 10 mL of water to obtain a mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine.
- S5: 80 g (2 mol, 2 eq) of NaOH was added into the mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine prepared at S4 and dissolved under stirring, and at the same time, a reaction was performed at 60°C for 2 h to obtain a mixture containing S-demethylnicotine; and
- S6: 170.3 g (1.2 mol, 1.2 eq) of methyl iodide was added into the mixture containing S-demethylnicotine prepared at S5, a reaction was performed at 25°C for 3 h, the pH of the system was adjusted to 6 by using 12 mol/L hydrochloric acid, extraction was performed by using dichloromethane, an organic phase was taken, dried over Na2SO4, and concentrated under reduced pressure for removing the solvent to obtain crude S-nicotine, and the crude S-nicotine was further purified once by atmospheric distillation to obtain S-nicotine with a yield of 52%, an ee value of 98%, and a purity o 99%.
- It is worthwhile to note that each mass and specific molar weight in the embodiments of the present application can be selected according to the size of an industrially produced vessel as long as the equivalence ratio of each reaction raw material is consistent.
- A difference between Embodiments 2 to 3 and Embodiment 1 is that: in the reaction of S1, the kind of the base catalyst was adjusted as specifically shown in Table 1.
Table 1 Effect of selection of base catalyst on the yield of S-nicotine Serial number Selection of base catalyst Yield of S-nicotine (%) Embodiment 1 Sodium hydride 52 Embodiment 2 Sodium tert-butoxide 42 Embodiment 3 Potassium tert-butoxide 43 - A difference between Embodiment 4 and Embodiment 1 is that: in the reaction of S2, the kind of the amination reagent was adjusted as specifically shown in Table 2.
Table 2 Effect of selection of amination reagent on the yield of S-nicotine Serial number Selection of amination reagent Yield of S-nicotine (%) Embodiment 1 Formamide 52 Embodiment 4 Ammonium hydroxide 48 - A difference between Embodiments 5 to 6 and Embodiment 1 is that: in the reaction of S2, the usage amount of the amination reagent was adjusted as specifically shown in Table 3.
Table 3 Effect of usage amount of amination reagent on the yield of S-nicotine Serial number Equivalent quantity (eq) of amination reagent Yield of S-nicotine (%) Embodiment 1 2 52 Embodiment 5 3 48 Embodiment 6 1 45 - A difference between Embodiments 7 to 9 and Embodiment 1 is that: in the reaction of S3, the usage amount of the (+)-B-diisopinocampheyl chloroborane was adjusted as specifically shown in Table 4.
Table 4 Effect of usage amount of (+)-B-diisopinocampheyl chloroborane on the yield of S-nicotine Serial number Equivalent quantity (eq) of (+)-B-diisopinocampheyl chloroborane Yield of S-nicotine (%) Embodiment 1 2 52 Embodiment 7 1 42 Embodiment 8 3 46 Embodiment 9 1.5 48 - A difference between Embodiments 10 to 12 and Embodiment 1 is that: in the reaction of S3, the kind of the organic solvent II was adjusted as specifically shown in Table 5.
Table 5 Effect of selection of organic solvent II on the yield of S-nicotine Serial number Selection of organic solvent II Yield of S-nicotine (%) Embodiment 1 Tetrahydrofuran 52 Embodiment 10 1,4-dioxane 50 Embodiment 11 Methyl tertiary butyl ether 25 Embodiment 12 Absolute ether 48 - A difference between Embodiments 13 to 15 and Embodiment 1 is that: in the reaction of S3, the reaction temperature was adjusted as specifically shown in Table 6.
Table 6 Effect of reaction temperature on the yield of S-nicotine Serial number Reaction temperature (°C) Yield of S-nicotine (%) Embodiment 1 0 52 Embodiment 13 -30 50 Embodiment 14 10 45 Embodiment 15 5 48 - A difference between Embodiments 16 to 17 and Embodiment 1 is that: in the reaction of S4, the reaction temperature was adjusted as specifically shown in Table 7.
Table 7 Effect of reaction temperature on the yield of S-nicotine Serial number Reaction temperature (°C) Yield of S-nicotine (%) Embodiment 1 0 52 Embodiment 16 10 43 Embodiment 17 -10 48 - A difference between Embodiments 18 to 19 and Embodiment 1 is that: in the reaction of S4, the usage amount of the oxalyl chloride was adjusted as specifically shown in Table 8.
Table 8 Effect of usage amount of oxalyl chloride on the yield of S-nicotine Serial number Equivalent quantity (eq) of oxalyl chloride Yield of S-nicotine (%) Embodiment 1 1.5 52 Embodiment 18 1 48 Embodiment 19 2 35 - A difference between Embodiment 20 and Embodiment 1 is that: at S1, the methyl nicotinate was replaced with equimolar ethyl nicotinate (with a CAS No. of 614-18-6), and produced S-nicotine had a yield of 52%, an ee value of 98%, and a purity of 99%.
- The specific embodiments are merely an explanation of the present application and are not intended to limit the present application. After reading the present description, those skilled in the art can make modifications to the present embodiments as required without any inventive contribution, and these modifications shall fall within the scope of protection of the present application.
Claims (10)
- A preparation method of S-nicotine, characterized by comprising the following steps:S1: adding nicotinate and γ-butyrolactone into an organic solvent I, performing condensation in the presence of a base catalyst to obtain a condensation product, and performing cyclization on the condensation product in the presence of hydrochloric acid to obtain 4-chloro-1-(3-pyridin)-1-butanone;S2: reacting the 4-chloro-1-(3-pyridin)-1-butanone with an amination reagent under alkaline conditions to obtain 4-amino-1-(3-pyridin)-1-butanone;S3: adding the 4-amino-1-(3-pyridin)-1-butanone and (+)-B-diisopinocampheyl chloroborane into an organic solvent II, and reacting at -30 to 10°C to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol;S4: reacting the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol with a chlorination reagent to obtain (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine;S5: performing cyclization on the (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine in the presence of a base to obtain S-demethylnicotine; andS6: reacting the S-demethylnicotine with an amine methylation reagent to obtain crude S-nicotine, and purifying to obtain S-nicotine.
- The preparation method of S-nicotine according to claim 1, characterized in that at S3, a molar ratio of the 4-amino-1-(3-pyridin)-1-butanone to the (+)-B-diisopinocampheyl chloroborane is 1: (1-3).
- The preparation method of S-nicotine according to claim 1, characterized in that at S3, the organic solvent II is selected from one or more of tetrahydrofuran, dimethyl tetrahydrofuran, and 1,4-dioxane.
- The preparation method of S-nicotine according to claim 1, characterized in that at S4, the chlorination reagent is oxalyl chloride; and a molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol to the oxaloyl chloride is 1: (1-3).
- The preparation method of S-nicotine according to claim 4, characterized in that at S4, the reaction temperature is -10 to 10°C.
- The preparation method of S-nicotine according to claim 1, characterized in that at S2, the amination reagent is ammonium hydroxide or formamide.
- The preparation method of S-nicotine according to claim 1, characterized in that at S2, a molar ratio of the 4-chloro-1-(3-pyridin)-1-butanone to the amination reagent is 1: (1-3).
- The preparation method of S-nicotine according to claim 1, characterized in that at S1, a molar ratio of the nicotinate to the γ-butyrolactone to the base catalyst is 1: (1-2): (1.2-3).
- The preparation method of S-nicotine according to claim 1, characterized in that at S1, the base catalyst is selected from one or more of alkali metal alkoxide, alkaline earth metal hydride, alkaline earth metal oxide, amine, a metal salt of amine, hydroxide, carbonate, and bicarbonate.
- The preparation method of S-nicotine according to claim 1, characterized in that at S5, the base is hydroxide or carbonate.
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PCT/CN2021/112793 WO2023284057A1 (en) | 2021-07-10 | 2021-08-16 | Method for preparing s-nicotine |
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CN114437031B (en) * | 2022-02-16 | 2023-06-27 | 深圳市真味生物科技有限公司 | Synthesis method of 6-methyl nicotine |
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US5045550A (en) * | 1990-09-20 | 1991-09-03 | Warner-Lambert Co. | Substituted tetrahydropyridines as central nervous system agents |
US5187280A (en) * | 1990-09-20 | 1993-02-16 | Warner-Lambert Company | Substituted tetrahydropyridines and their use as central nervous system agents |
US5648541A (en) * | 1995-09-28 | 1997-07-15 | Nps Pharmaceuticals, Inc. | Chiral reductions of imines leading to the syntheses of optically active amines |
JPH11312351A (en) | 1998-04-28 | 1999-11-09 | Sony Corp | Disk loading device |
CN1106892C (en) * | 2000-10-16 | 2003-04-30 | 云南万芳生物技术有限公司 | Process for extracting pure tobacco oil, melanoid and nicotine and preparing composite fertilizer |
US20030224435A1 (en) * | 2002-05-16 | 2003-12-04 | Scott Seiwert | Detection of abused substances and their metabolites using nucleic acid sensor molecules |
US8367837B2 (en) * | 2011-02-14 | 2013-02-05 | Divi's Laboratories, Ltd. | Process for the preparation of (R,S)-nicotine |
CN104341390B (en) | 2014-11-04 | 2016-09-07 | 南开大学 | A kind of botanical pesticide nicotine and the method for asymmetric synthesis of anabasine |
US9809567B2 (en) * | 2014-12-09 | 2017-11-07 | Njoy, Llc | Synthesis and resolution of nicotine |
CN107011321A (en) * | 2017-03-27 | 2017-08-04 | 华健 | A kind of preparation method of artificial synthesized raceme nicotine |
CN107382916A (en) * | 2017-08-30 | 2017-11-24 | 成都化润药业有限公司 | The high purity synthetic process of 3 tetrahydrofurfuryl carbinols |
SG11202005639UA (en) * | 2017-12-22 | 2020-07-29 | Siegfried Ag | Preparation of racemic nicotine by reaction of ethyl nicotinate with n-vinylpyrrolidone in the presence of an alcoholate base and subsequent process steps |
CN110256403B (en) * | 2019-07-02 | 2020-06-19 | 深圳市馨艺坊生物科技有限公司 | Method for preparing artificial synthetic nicotine |
CN110357853B (en) * | 2019-08-05 | 2020-07-10 | 济南悟通生物科技有限公司 | Synthesis method of (R, S-) nicotine |
CN110627769A (en) * | 2019-09-27 | 2019-12-31 | 深圳黑尔格科技有限公司 | Iminium salt derivative, process for producing the same, and process for producing nicotine |
CN111004212A (en) * | 2019-12-24 | 2020-04-14 | 深圳雾芯科技有限公司 | Method for preparing nicotine |
CN111233829A (en) * | 2019-12-27 | 2020-06-05 | 深圳黑尔格科技有限公司 | Preparation method of nicotine with optical activity |
KR102653443B1 (en) * | 2020-03-25 | 2024-03-29 | 선전 필라이프 라이프 사이언스 컴퍼니., 리미티드. | Preparation method of artificially synthesized racemic nicotine salt |
CN113527187B (en) * | 2020-04-22 | 2023-12-26 | 凯特立斯(深圳)科技有限公司 | Asymmetric preparation method of nicotine |
CN112409327A (en) * | 2020-11-18 | 2021-02-26 | 山东金城医药化工有限公司 | Preparation method of high-optical-purity nicotine |
CN112409329A (en) * | 2020-12-11 | 2021-02-26 | 山东金城医药化工有限公司 | Process for the preparation of S-nicotine |
CN112745294B (en) * | 2020-12-30 | 2022-02-22 | 山东金城柯瑞化学有限公司 | Synthesis method of (R, S-) nicotine |
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