CN115611858B - Method for preparing nicotine and its derivatives - Google Patents
Method for preparing nicotine and its derivatives Download PDFInfo
- Publication number
- CN115611858B CN115611858B CN202211222256.8A CN202211222256A CN115611858B CN 115611858 B CN115611858 B CN 115611858B CN 202211222256 A CN202211222256 A CN 202211222256A CN 115611858 B CN115611858 B CN 115611858B
- Authority
- CN
- China
- Prior art keywords
- compound
- nicotine
- derivatives
- reaction
- reacted
- 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.)
- Active
Links
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 title claims abstract description 46
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 229960002715 nicotine Drugs 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 28
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical class O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 77
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 17
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 claims description 15
- 239000012279 sodium borohydride Substances 0.000 claims description 12
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 230000009471 action Effects 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 11
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- -1 nicotinic acid ester Chemical class 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- 229960003512 nicotinic acid Drugs 0.000 abstract 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 abstract 1
- 235000001968 nicotinic acid Nutrition 0.000 abstract 1
- 239000011664 nicotinic acid Substances 0.000 abstract 1
- 239000005416 organic matter Substances 0.000 abstract 1
- 238000004904 shortening Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 51
- 239000000243 solution Substances 0.000 description 47
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000002500 ions Chemical class 0.000 description 12
- 235000011181 potassium carbonates Nutrition 0.000 description 12
- 238000005303 weighing Methods 0.000 description 11
- 150000002466 imines Chemical class 0.000 description 10
- 229960001238 methylnicotinate Drugs 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000208125 Nicotiana Species 0.000 description 6
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 238000007142 ring opening reaction Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- SWNIAVIKMKSDBJ-UHFFFAOYSA-N 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine Chemical group CN1CCCC1C1=CC=C(C)N=C1 SWNIAVIKMKSDBJ-UHFFFAOYSA-N 0.000 description 3
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- SWNIAVIKMKSDBJ-NSHDSACASA-N 2-methyl-5-[(2s)-1-methylpyrrolidin-2-yl]pyridine Chemical compound CN1CCC[C@H]1C1=CC=C(C)N=C1 SWNIAVIKMKSDBJ-NSHDSACASA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 241000208292 Solanaceae Species 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000006272 natural pesticide Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The application relates to the technical field of organic matter synthesis, and particularly discloses a brand-new preparation method of nicotine and derivatives thereof, wherein R-substituted nicotinic acid ester and gamma-butyrolactone are used as raw materials, and a target product is obtained through three steps, wherein the structural formula of the target product is as follows:
Description
Technical Field
The present application relates to the technical field of organic synthesis, and more particularly, to a method for preparing nicotine and derivatives thereof.
Background
Nicotine is widely existing in Solanaceae plants, is the main component of nitrogenous alkaloid in tobacco, has content of 3-4% in tobacco leaf, and can be used as natural pesticide or smoking stopping medicine. In addition, clinical studies prove that the nicotine is expected to be a medicament for treating senile dementia, depression and other diseases.
Nicotine is currently derived primarily from waste tobacco extraction, and the extraction of purified nicotine from plants such as tobacco generally contains many other tobacco compounds that are unhealthy to the human system and which have proven to be carcinogenic; meanwhile, the extraction and purification of nicotine from plants such as tobacco can be influenced by various factors such as raw materials, climate, land resources and period.
In the related art, 3-bromopyridine is used as a raw material to prepare nicotine, and the reaction formula (1) is as follows:
the reaction formula (1) uses 3-bromopyridine as a starting material, the 3-bromopyridine is expensive, the condition of ultralow temperature (-78 ℃) is required, the experimental condition is severe, the reaction formula is not suitable for industrial production, and the product is racemic nicotine.
Some of them react with nicotine using methyllithium as a methyl source to synthesize 6-methylnicotine, and the reaction formula (2) is as follows:
the reaction in the reaction formula (2) requires anhydrous conditions, and has harsh conditions at the low temperature of-70 ℃, and the methyl substitution position of the synthesized product is uncertain, so that the high-purity 6-methyl nicotine is difficult to separate and has low practical production value.
Also using t-butyl hydroperoxide as the methyl source, methyl nicotine substituted at different sites is likewise available, which is represented by the following reaction formula (3):
although substituted methylnicotine at different sites can be obtained in the above reaction formula (3), the same separation and selectivity problems remain with methylnicotine at different sites.
Therefore, in order to increase the yield and purity of the synthesized nicotine and its derivatives and to reduce the complexity of the process, it is necessary to provide a synthetic route for the synthesis of nicotine and its derivatives.
Disclosure of Invention
In order to improve the yield and purity of the synthesized brand new nicotine and derivatives thereof, reduce the cost and realize industrial production, the application provides a preparation method of the nicotine and derivatives thereof.
The preparation method of the nicotine and the derivative thereof provided by the application adopts the following technical scheme:
a preparation method of nicotine and its derivatives comprises preparing compound of formula P3 of completely new nicotine as follows:
wherein R is hydrogen, methyl or ethyl, and R is at the 2-, 4-, 5-or 6-position of the pyridine;
the steps for synthesizing the compound P2 by the one-pot method are as follows:
dissolving a compound P1 in a second solvent, adding a second base and methylamine hydrochloride to carry out ring opening and nucleophilic reaction, and then adding a reducing agent to reduce to obtain a compound P2; the compound P2 is reacted to the compound P3.
By adopting the technical scheme, two steps of reactions are involved in the synthesis of the compound P2, and the compound P2 can be obtained by a one-pot method without further purification in the middle; in the application, the one-pot method is not a simple step of combining a plurality of reactions, the compound P1 can realize a three-step one-pot method of ring opening, nucleophilic addition and reduction, and the generated imine intermediate has the potential of controlling the chirality of a final product, provides a substrate for further optimizing a target product P3, and is beneficial to improving the purity of the target product; wherein, the one-pot method is an organic synthesis method, the multi-step reaction in the one-pot method can be started from relatively simple and easily obtained raw materials, and molecules with complex structures can be directly obtained without intermediate separation, thus being more beneficial to economy and environment friendliness.
Preferably, the second base is selected from one or any combination of potassium carbonate, cesium carbonate and sodium carbonate;
the second solvent is selected from one or any combination of methanol, ethanol, n-propanol and isopropanol;
the reducing agent is selected from one of sodium cyanoborohydride, sodium borohydride, diisobutylaluminum hydride, lithium aluminum hydride and imine reductase; when the reducing agent is imine reductase, adding a step of adjusting the pH value to the pH value most suitable for the imine reductase before adding the imine reductase;
the ratio of the amount of the compound P1 to the amount of the substance of methylamine hydrochloride is 1 (2-4).
In some embodiments, the second base is selected from one or any combination of potassium carbonate, cesium carbonate, and sodium carbonate.
In some embodiments, the second solvent is selected from one or any combination of methanol, ethanol, n-propanol, and isopropanol.
In some embodiments, the reducing agent is selected from one of sodium cyanoborohydride, sodium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, and imine reductase; when the reducing agent is imine reductase, the step of adjusting the pH value to the pH value most suitable for the imine reductase is added before adding the imine reductase.
In some embodiments, the ratio of the amount of compound P1 to the amount of methylamine hydrochloride is 1 (2-4).
By adopting the technical scheme, R is substituted to obtain methyl nicotinate which is used as a raw material, the methyl nicotinate and gamma-butyrolactone are subjected to condensation reaction under the action of first alkali to obtain a compound P1, then the compound P1 is subjected to ring opening under the action of second alkali and methylamine hydrochloride and is reduced to obtain a compound P2, and finally the compound P2 is subjected to halogenation reaction and ring closing under the action of third alkali to obtain a target product P3 racemic nicotine or a derivative thereof;
compared with the prior art, the production conditions of the raceme nicotine are harsh, the method is not suitable for industrial production, the methyl substitution position of the derivative is uncertain, the high-purity raceme nicotine derivative is difficult to separate and obtain, and the actual production value is low; in the application, the multiple steps of products in the route of synthesizing the racemic nicotine and the derivative thereof do not need excessive purification, the next reaction can be carried out by simple treatment, the operation is simple, the multiple steps are carried out in a one-pot method, the condition is mild, the reaction is not carried out at an excessively high or excessively low temperature, the yield and the purity of the racemic nicotine and the derivative thereof are relatively high, and the cost of manpower and material resources is reduced.
Preferably, the compound P1 is added into ethanol, reacts with methylamine hydrochloride and potassium carbonate for 7-9 hours at 50-70 ℃, then sodium borohydride is added under the low temperature condition, and the reaction is carried out for 4-6 hours at room temperature, thus obtaining the compound P2.
In some embodiments, 1 equivalent of the compound P1 is added to ethanol, reacted with 3 equivalents of methylamine hydrochloride and 4 equivalents of potassium carbonate at 50-70 ℃ for 7-9 hours, then 1 equivalent of sodium borohydride is added at low temperature, and reacted at room temperature for 4-6 hours to obtain the compound P2.
Preferably, the method further comprises the following steps of synthesizing the compound P3 by a one-pot method:
and (3) dissolving the compound P2 in a third solvent to react with a chloro reagent, regulating the pH value by using a third base after the reaction is completed, and adding KI to carry out cyclization reaction to obtain the compound P3.
Preferably, the third base is selected from one or any combination of potassium carbonate, cesium carbonate and sodium carbonate;
the third solvent is selected from one or any combination of 1, 4-dioxane and tetrahydrofuran;
the mass ratio of the compound P2 to the substance of the chlorinating agent is 1 (3-5).
In some embodiments, the third base is selected from one or any combination of potassium carbonate, cesium carbonate, and sodium carbonate.
In some embodiments, the third solvent is selected from one or any combination of 1, 4-dioxane, tetrahydrofuran.
In some embodiments, the ratio of the amounts of the substances of the compound P2 to the chlorinating agent is 1 (3-5)
Preferably, the compound P2 is reacted in 1, 4-dioxane with 8N hydrochloric acid at 90-100 ℃ for 2-4h under stirring, and K is used at low temperature 2 CO 3 Adjusting the pH value to be 8-10, and then adding potassium iodide at the temperature of 90-100 ℃ to react to obtain the compound P3.
In some embodiments, compound P2 is reacted in 1, 4-dioxane with 4 equivalents of 8N hydrochloric acid at 90-100deg.C for 2-4h with K at low temperature 2 CO 3 Adjusting the pH to be 8-10, and reacting at the temperature of 90-100 ℃ under the condition of 0.1 equivalent of potassium iodide to obtain the compound P3.
Preferably, the synthesis of said compound P3 is as follows:
the compound P1 is reacted with methylamine hydrochloride in ethanol solvent at 50-70 ℃ under the action of potassium carbonate, and then reacted with a reducing agent at room temperature to obtain a compound P2;
the compound P2 is reacted with hydrochloric acid in 1, 4-dioxane at 90-100 ℃ completely, then the PH is regulated to 8-10 by potassium carbonate, and then the compound P3 is obtained by reacting at 90-100 ℃ under potassium iodide.
Preferably, the compound P1 is reacted with methylamine hydrochloride and potassium carbonate in ethanol at 60 ℃ for about 8 hours, then about 1 equivalent of sodium borohydride is added in portions at about 0 ℃ and reacted at room temperature for about 5 hours to obtain P2 without further purification; the compound P2 obtained in the last step is reacted with 8N hydrochloric acid in 1, 4-dioxane under stirring for 3h at 95 ℃ and K at 0 DEG C 2 CO 3 And (3) adjusting the pH to be 8-10, and reacting at 95 ℃ under the condition of adding potassium iodide to obtain the compound P3.
In some embodiments, about 1 equivalent of compound P1 is reacted in ethanol with about 3 equivalents of methylamine hydrochloride, and about 4 equivalents of potassium carbonate at about 60 ℃ for about 8 hours, then about 1 equivalent of sodium borohydride is added in portions at about 0 ℃ and reacted at room temperature for about 5 hours to yield P2 without further purification;
the compound P2 obtained in the last step isIn 1, 4-dioxane, about 4 equivalents of about 8N hydrochloric acid are reacted with stirring at about 95℃for about 3 hours at about 0℃with K 2 CO 3 The ph=8 to 10 was adjusted and then reacted at about 95 ℃ with about 0.1 equivalent of added potassium iodide to give compound P3.
By adopting the technical scheme, two reactions are involved in the process of synthesizing the compound P3 from the compound P2, and the target product P3 can be obtained by a one-pot method without further purification in the middle; in addition, in the step, two-molecule polymerization products are not easy to occur, the two-molecule polymerization may be related to temperature and feeding amount, and become impurities after polymerization, so that the conversion rate and yield are reduced, namely, the yield of the compound P3 is effectively improved.
Preferably, the step of synthesizing the compound P1 is also included as follows:
in a first solvent, R substituted methyl nicotinate and gamma-butyrolactone undergo condensation reaction under the action of a first base to obtain a compound P1.
Preferably, the first solvent is selected from one or any combination of tetrahydrofuran, 1, 4-dioxane and toluene; the first base is selected from one or any combination of potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium hydride;
the ratio of the amounts of substances of R-substituted methyl nicotinate and gamma-butyrolactone is 1 (1-2).
In some embodiments, the first solvent is selected from one or any combination of tetrahydrofuran, 1, 4-dioxane, and toluene;
in some embodiments, the first base is selected from one or any combination of potassium tert-butoxide, sodium methoxide, sodium ethoxide, and sodium hydride;
in some embodiments, the ratio of the amounts of the substances of R-substituted methyl nicotinate and gamma-butyrolactone is 1 (1-2).
Unless specifically stated or apparent from the context, all numbers provided herein are modified by the term about. The term "about" is understood to be within normal tolerances in the art, for example within 2 standard deviations of the mean. About is understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the specified value.
When a chemical group is directed to the center of a ring through a bond, it means that the chemical group may be substituted at a position where the ring can be substituted, such as:
represented by formula a, b, c, d:
in summary, the present application has the following beneficial effects:
1. the invention adopts R-substituted methyl nicotinate and gamma-butyrolactone as raw materials, is cheap and easy to obtain, simultaneously concentrates the reaction steps into three steps, shortens the working procedures while improving the yield and purity, and obviously reduces the production cost of the racemized nicotine and the derivatives thereof.
2. The compound P1 can realize a three-step one-pot method of ring opening, nucleophilic addition and reduction, and the generated imine intermediate has the potential of controlling the chirality of a final product, provides a substrate for further optimizing a target product P3, and is beneficial to improving the purity of the target product.
3. The purity of the target product P3 prepared by the method is not lower than 99%, the yield of the target product P3 is not lower than 79%, and the method has the advantages of simple synthesis steps, easiness in operation, high yield and mild reaction conditions, and the product has high purity and is suitable for industrial production.
Drawings
FIG. 1 is an H-NMR spectrum of nicotine in example 1 of the present application.
FIG. 2 is a MS spectrum of compound P1 in example 1 of the present application.
Figure 3 is an MS spectrum of nicotine in example 1 of the present application.
Detailed Description
The present application is described in further detail below with reference to the drawings and examples. The specific description is as follows: the following examples, in which the specific conditions are not specified, are conducted under conventional conditions or conditions recommended by the manufacturer, and the raw materials used in the following examples are commercially available from ordinary sources except for the specific descriptions.
The synthetic route of the racemic nicotine and its derivatives of the present invention is shown below:
examples
Example 1
The method for synthesizing the racemic nicotine (P3) in the embodiment specifically comprises the following steps:
step 1) Synthesis of Compound P1
At 0 ℃, N 2 Under the protection, weighing 8.61g of gamma-butyrolactone (100 mmol) and adding the gamma-butyrolactone into a 250mL three-necked flask, then adding 150mL of tetrahydrofuran solution into the three-necked flask, stirring to dissolve the gamma-butyrolactone in the tetrahydrofuran solution, and weighing 8.0g of NaH (200 mmol) with 60% content after the gamma-butyrolactone is dissolved, and adding the NaH into the three-necked flask in batches, wherein the NaH is added in batches for five times; reacting for 0.5h at 0 ℃; 13.71g of methyl nicotinate (100 mmol) is then weighed into a three-necked flask, the ice bath pan is removed, the temperature of the three-necked flask is raised to 25 ℃ for reaction for 4 hours, and after the reaction is completed, the reaction solution is filtered to obtain the compound P1. Yield of compound P1: 17.68g, hplc purity: 96.5%; yield: 92.5%.
MS(ESI,pos.ion)m/z:192.08[M+H]+。
Step 2) Synthesis of Compound P2
15.30g of Compound P1 (80 mmol) was weighed and dissolved in 160mL of ethanol, then 16.20g of methylamine hydrochloride (240 mmol) and 44.23g of potassium carbonate (320 mmol) were added respectively, and the mixture was heated to 60℃to react for 8 hours; then cooling to 0 ℃ by ice bath, and then adding 3.03g of sodium borohydride (80 mmol) into the reaction liquid in batches, wherein the sodium borohydride is added in batches for five times; recovering the reaction at room temperature for 5h, filtering the reaction solution, concentrating the filtrate to remove the solvent to obtain a concentrated solution, extracting the concentrated solution with EA, and washing with water to obtain the compound P2.
MS(ESI,pos.ion)m/z:181.18[M+H]+；
Step 3) Synthesis of racemic Nicotine (P3)
Dissolving compound P2 (80 mmol) in 50mL of 1, 4-dioxane solution, adding 32mL of 8N hydrochloric acid solution, stirring at 95deg.C for 3h, cooling to 0deg.C, and adding K 2 CO 3 The pH of the solution was adjusted to 9, then 1.33g of potassium iodide (8 mmol) was added and the reaction was continued at 95℃for 24 hours, after the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated to remove the solvent to obtain a concentrated solution, the concentrated solution was extracted with EA, and then washed with saturated brine, and finally the organic phase was concentrated to obtain a crude product, which was purified by column chromatography to obtain 11.16g of the target product P3, the GC-MS detection purity of which was 99.5%.
MS(ESI,pos.ion)m/z:163.2[M+H]+；
1 H NMR(500MHz,Chloroform-d)δ8.50(d,J＝2.3Hz,1H),8.46(dd,J＝4.8,1.7Hz,1H),7.66(dt,J＝7.9,2.0Hz,1H),7.22(dd,J＝7.9,4.8Hz,1H),3.21(ddd,J＝9.7,8.1,2.2Hz,1H),3.05(t,J＝8.4Hz,1H),2.28(q,J＝9.1Hz,1H),2.21–2.14(m,1H),2.13(s,3H),1.97–1.88(m,1H),1.80(dddd,J＝12.2,6.5,4.8,2.0Hz,1H),1.73–1.65(m,1H)。
Wherein, the combined yield of the two steps S2 and S3 is 86%, and the total yield of the three steps S1, S2 and S3 is 79.55% through calculation.
Example 2
The nicotine (P3) synthesis method of the present embodiment specifically includes the following steps:
s1, at 0 ℃, N 2 Under the protection, weighing 8.61g of gamma-butyrolactone (100 mmol) and adding the gamma-butyrolactone into a 250mL three-necked flask, then adding 150mL of 1, 4-dioxane solution into the three-necked flask, stirring to dissolve the gamma-butyrolactone into the 1, 4-dioxane solution, and weighing 19.22g of sodium tert-butoxide (200 mmol) after the gamma-butyrolactone is dissolved and adding the sodium tert-butoxide into the three-necked flask in batches, wherein the sodium tert-butoxide is added in batches for five times; reacting for 0.5h at 0 ℃; 13.71g of methyl nicotinate (100 mmol) was then weighed into a three-necked flask, the ice bath was removed, the temperature of the flask was raised to 25℃for 4 hours, the reaction was completed, and the reaction solution was filtered to give compound P1, yield: 17.62g, yield 92.2%; HPLC purity: 96.3%. MS (ESI, pos.ion) m/z 92.08[ M+H ]]+；
S2, weighing 15.30g of compound P1 (80 mmol) and dissolving in 160mL of ethanol, then adding 16.20g of methylamine hydrochloride (240 mmol) and 33.9g of sodium carbonate (320 mmol) respectively, and heating to 60 ℃ to react for 8h; then cooling to 0 ℃ in an ice bath, and then adding sodium cyanoborohydride (80 mmol) into the reaction liquid in batches, wherein the sodium cyanoborohydride is added according to the severe reaction condition, and the sodium cyanoborohydride is added in batches for five times in a small amount for many times; recovering the reaction at room temperature for 5h, filtering the reaction solution, concentrating the filtrate to remove the solvent to obtain a concentrated solution, extracting the concentrated solution with EA, and washing with water to obtain the compound P2.MS (ESI, pos.ion) m/z 181.18[ M+H ] +.
S3, dissolving the compound P2 (80 mmol) in 50mL of 1, 4-dioxane solution, then adding 32mL of 8N hydrochloric acid solution, stirring at 95 ℃ for reaction for 3h, cooling to 0 ℃ after the reaction is completed, and adding K 2 CO 3 The pH of the solution was adjusted to 9, then 1.2g of sodium iodide (8 mmol) was added and the reaction was continued at 95℃for 24 hours, after the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to remove the solvent to give a concentrated solution, and thenExtracting the concentrated solution with EA, washing with saturated brine, concentrating the organic phase to obtain a crude product, purifying the crude product by column chromatography to obtain 11.16g of target product P3, wherein the detection purity of GC-MS is 99.65%; MS (ESI, pos.ion) m/z 163.2[ M+H ]]+；
Wherein, the combined yield of the two steps S2 and S3 is 86.3 percent, and the total yield of the three steps S1, S2 and S3 is 79.52 percent.
Example 3
The nicotine (P3) synthesis method of the present embodiment specifically includes the following steps:
s1, at 0 ℃, N 2 Under the protection, weighing 8.61g (100 mmol) of gamma-butyrolactone, adding into a 250mL three-necked flask, adding 150mL of toluene solution into the three-necked flask, stirring to dissolve the gamma-butyrolactone into the toluene solution, and weighing 10.80g of sodium methoxide (200 mmol) after the gamma-butyrolactone is dissolved, and adding into the three-necked flask in batches, wherein the sodium methoxide is added in batches for five times; reacting for 0.5h at 0 ℃; 13.71g of methyl nicotinate (100 mmol) was then weighed into a three-necked flask, the ice bath was removed, the temperature of the flask was raised to 25℃for 4 hours, the reaction was completed, and the reaction solution was filtered to give compound P1, yield: 17.78g, 93.04% yield and 96.6% HPLC purity. MS (ESI, pos.ion) m/z 192.08[ M+H ]]+。
S2, weighing 15.30g of compound P1 (80 mmol) and dissolving in 160mL of ethanol, then adding 16.20g of methylamine hydrochloride (240 mmol) and 33.9g of sodium carbonate (320 mmol) respectively, and heating to 60 ℃ to react for 8h; then cooling to 0 ℃ in an ice bath, and then adding sodium cyanoborohydride (80 mmol) into the reaction liquid in batches, wherein the sodium cyanoborohydride is added in batches for five times; recovering room temperature for 5 hr, filtering the reaction solution, concentrating the filtrate to remove solvent to obtain concentrated solution, extracting the concentrated solution with EA, and washing with water to obtain compound P2, MS (ESI, pos.ion) m/z 181.18[ M+H ] +;
s3, dissolving a compound P2 (80 mmol) in 50mL of 1, 4-dioxane solution, then adding 32mL of 8N hydrochloric acid solution, stirring at 95 ℃ for reaction for 3h, cooling to 0 ℃ after the reaction is completed, adding K2CO3 solution to adjust the pH to 9, then adding 1.2g of sodium iodide (8 mmol) and continuing to react at 95 ℃ for 24h, filtering the reaction solution after the reaction is completed, concentrating the filtrate to remove the solvent to obtain a concentrated solution, extracting the concentrated solution with EA, washing with saturated brine, concentrating the organic phase to obtain a crude product, and purifying the crude product by column chromatography to obtain 11.16g of target product P3, wherein the detection purity of GC-MS is 99.58%; MS (ESI, pos.ion) m/z 163.2[ M+H ] +.
Wherein, the combined yield of the two steps S2 and S3 is 86.3 percent, and the total yield of the three steps S1, S2 and S3 is 79.66 percent through calculation.
Example 4
The nicotine (P3) synthesis method of the present embodiment specifically includes the following steps:
s1, at 0 ℃, N 2 Under the protection, weighing 12.92g of gamma-butyrolactone (150 mmol) and adding the gamma-butyrolactone into a 250mL three-necked flask, then adding 150mL of tetrahydrofuran solution into the three-necked flask, stirring to dissolve the gamma-butyrolactone in the tetrahydrofuran solution, and weighing 8.0g of NaH (200 mmol) with 60% content after the gamma-butyrolactone is dissolved, and adding the NaH into the three-necked flask in batches, wherein the NaH is added in batches for five times; reacting for 0.5h at 0 ℃; 13.71g of methyl nicotinate (100 mmol) was then weighed into a three-necked flask, the ice bath was removed, the three-necked flask was warmed to 25℃and reacted for 4 hours, the reaction was completed, and the reaction solution was filtered to give compound P1, yield: 17.72g, 92.7% yield; HPLC purity 96.1%; MS (ESI, pos.ion) m/z 192.08[ M+H ]]+。
S2, weighing 15.30g of compound P1 (80 mmol) and dissolving in 160mL of ethanol, then adding 21.60g of methylamine hydrochloride (320 mmol) and 58.97g of potassium carbonate (426.67 mmol) respectively, and heating to 60 ℃ for reaction for 8h; then cooling to 0 ℃ in an ice bath, and then adding 3.03g of sodium borohydride (80 mmol) into the reaction liquid in batches, wherein the sodium borohydride is added according to the severe reaction condition, and the sodium borohydride is added in batches for five times in a small amount for many times; recovering room temperature for 5 hr, filtering the reaction solution, concentrating the filtrate to remove solvent to obtain concentrated solution, extracting the concentrated solution with EA, and washing with water to obtain compound P2, MS (ESI, pos.ion) m/z 181.18[ M+H ] +;
s3, dissolving the compound P2 (80 mmol) in 50mL of 1, 4-dioxane solution, then adding 32mL of 8N hydrochloric acid solution, stirring at 95 ℃ for reaction for 3h, and completely reactingCooling to 0deg.C, adding K 2 CO 3 The pH of the solution is regulated to 9, then 1.33g of potassium iodide (8 mmol) is added and the reaction is continued for 24 hours at 95 ℃, after the reaction is completed, the reaction liquid is filtered, the filtrate is concentrated to remove the solvent to obtain concentrated solution, then the concentrated solution is extracted by EA, then saturated brine is used for washing, finally the organic phase is concentrated to obtain a crude product, 11.16g of target product P3 is obtained after the crude product is purified by column chromatography, and the detection purity of GC-MS is 99.6%; MS (ESI, pos.ion) m/z 163.2[ M+H ]]+。
Wherein, the combined yield of the two steps S2 and S3 is 86.4%, and the total yield of the three steps S1, S2 and S3 is 79.58% through calculation.
The present embodiment is merely illustrative of the present application and is not intended to be limiting, and those skilled in the art, after having read the present specification, may make modifications to the present embodiment without creative contribution as required, but is protected by patent laws within the scope of the claims of the present application.
Claims (4)
1. A preparation method of nicotine and derivatives thereof, which is characterized in that the compound shown in the structural formula P3 of the nicotine and derivatives thereof is as follows:
wherein R is hydrogen, methyl or ethyl, and R is at the 2-, 4-, 5-or 6-position of the pyridine;
the synthesis of compound P3 is as follows:
the compound P1 is reacted with methylamine hydrochloride in ethanol solvent at 50-70 ℃ under the action of potassium carbonate, and then reacted with a reducing agent at room temperature to obtain a compound P2;
the compound P2 is reacted with hydrochloric acid in 1, 4-dioxane at 90-100 ℃ completely, then the PH is regulated to 8-10 by potassium carbonate, and then the compound P3 is obtained by reacting at 90-100 ℃ under potassium iodide.
2. A process for the preparation of nicotine and derivatives thereof as claimed in claim 1,
the compound P1 is reacted with methylamine hydrochloride and potassium carbonate in ethanol for 8 hours at 60 ℃, 1 equivalent of sodium borohydride is added in batches at 0 ℃, and the mixture is reacted for 5 hours at room temperature to obtain P2 without further purification;
the compound P2 obtained in the last step reacts with 8N hydrochloric acid in 1, 4-dioxane under stirring at 95 ℃ for 3 hours, the pH value is regulated to be 8-10 by potassium carbonate at 0 ℃, and then the compound P3 is obtained under the condition of adding potassium iodide at 95 ℃.
3. The method of preparing nicotine and derivatives thereof according to claim 1, further comprising the step of synthesizing compound P1 as follows:
in a first solvent, SM and gamma-butyrolactone undergo condensation reaction under the action of a first base to obtain a compound P1.
4. A process for the preparation of nicotine and derivatives thereof as claimed in claim 3,
the first solvent is tetrahydrofuran;
the first base is selected from one or any combination of potassium tert-butoxide, sodium ethoxide and sodium hydride;
the ratio of the amounts of the substances of SM and gamma-butyrolactone is 1 (1-2).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211222256.8A CN115611858B (en) | 2022-10-08 | 2022-10-08 | Method for preparing nicotine and its derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211222256.8A CN115611858B (en) | 2022-10-08 | 2022-10-08 | Method for preparing nicotine and its derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115611858A CN115611858A (en) | 2023-01-17 |
| CN115611858B true CN115611858B (en) | 2024-03-29 |
Family
ID=84861314
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211222256.8A Active CN115611858B (en) | 2022-10-08 | 2022-10-08 | Method for preparing nicotine and its derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115611858B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114874134A (en) * | 2022-04-26 | 2022-08-09 | 凯特立斯（深圳）科技有限公司 | Process for preparing nicotine asymmetrically without protection |
-
2022
- 2022-10-08 CN CN202211222256.8A patent/CN115611858B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114874134A (en) * | 2022-04-26 | 2022-08-09 | 凯特立斯（深圳）科技有限公司 | Process for preparing nicotine asymmetrically without protection |
Non-Patent Citations (3)
| Title |
|---|
| Chemical studies on tobacco smoke. LI. Studies on non-volatile nitrosamines in tobacco;Hecht, Stephen S.;Beitraege zur Tabakforschung;第9卷(第1期);1-6 * |
| Highly Enantioselective Borane Reduction of Heteroaryl and Heterocyclic Ketoxime Ethers Catalyzed by Novel Spiroborate Ester Derived from Diphenylvalinol: Application to the Synthesis of Nicotine Analogues;Huang, Kun;Journal of Organic Chemistry;第73卷(第11期);4017-4026 * |
| SYNTHESISOF N-NITROSAMTNO ALDEHYDES;StephenS. Hecht;Tetrahedron Letters;第8卷;596-596 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115611858A (en) | 2023-01-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110357853B (en) | Synthesis method of (R, S-) nicotine | |
| CN114437031B (en) | Synthesis method of 6-methyl nicotine | |
| CN111170855A (en) | Compound and method for synthesizing 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedioic acid by using same | |
| CN110551023A (en) | Method for preparing alkyl diacid monobenzyl ester | |
| CN115611858B (en) | Method for preparing nicotine and its derivatives | |
| JP2020536948A (en) | Manufacturing methods and intermediates for synthesizing intermediates for the antitumor drug Nilaparib | |
| EP2131843B1 (en) | Process for the synthesis of glyt-1 inhibitors | |
| CN110092786B (en) | Method for preparing evodiamine | |
| CN111574444A (en) | Preparation method of bedaquiline | |
| CN111233931A (en) | Synthesis method of Reidesciclovir | |
| CN109053496B (en) | Synthetic method of 3-Boc-aminomethyl cyclobutanone | |
| CN112062669A (en) | Process for preparing aromatic compounds | |
| CN113278021B (en) | Preparation method of 1, 7-diazaspiro [3.5] nonane-7-tert-butyl formate and oxalate thereof | |
| CN106045995B (en) | A kind of synthetic method of 5 bromine 1H pyrrolo-es [2,3 b] pyridines | |
| CN114702425A (en) | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate | |
| CN111440154A (en) | Synthetic method of tegaserod dimer impurity | |
| CN110746340A (en) | Synthetic method of 5-methoxy-2-methyltryptamine | |
| EP1817273B1 (en) | Method for preparing diastereoisomers of 4-hydroxy isoleucine | |
| JPH04169583A (en) | Phenothiazine derivative and its production | |
| JP7344983B2 (en) | Method for preparing chenodeoxycholic acid derivatives | |
| CN117105909A (en) | Preparation method of intermediate of lasmidbody | |
| WO2024103319A1 (en) | Method for synthesizing methyl (1r,2s,5s)-6,6-dimethyl-3-azabicyclo[3,1,0]hexyl-2-carboxylate hydrochloride | |
| CN114805220A (en) | Preparation method of quinazolinone compound | |
| CN106117190B (en) | A kind of synthetic method of times of good fortune Pulan | |
| CN116396272A (en) | Preparation method of 2, 5-dihydropyrrolidine derivative and racemic nicotine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |