CN115611858A - Preparation method of brand new nicotine and derivatives thereof - Google Patents
Preparation method of brand new nicotine and derivatives thereof Download PDFInfo
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- CN115611858A CN115611858A CN202211222256.8A CN202211222256A CN115611858A CN 115611858 A CN115611858 A CN 115611858A CN 202211222256 A CN202211222256 A CN 202211222256A CN 115611858 A CN115611858 A CN 115611858A
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- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 title claims abstract description 54
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229960002715 nicotine Drugs 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical class O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 43
- 238000005580 one pot reaction Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 91
- 238000006243 chemical reaction Methods 0.000 claims description 49
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 25
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical class COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 19
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000012279 sodium borohydride Substances 0.000 claims description 15
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 15
- 150000002466 imines Chemical class 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 229960001238 methylnicotinate Drugs 0.000 claims description 11
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 7
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 5
- 238000007142 ring opening reaction Methods 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 3
- 239000012320 chlorinating reagent Substances 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- -1 lithium aluminum hydride Chemical compound 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
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 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
- 238000007344 nucleophilic reaction Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 235000001968 nicotinic acid Nutrition 0.000 abstract description 2
- 239000011664 nicotinic acid Substances 0.000 abstract description 2
- 239000005416 organic matter Substances 0.000 abstract description 2
- 150000002814 niacins Chemical class 0.000 abstract 1
- 239000000047 product Substances 0.000 description 18
- 150000002500 ions Chemical class 0.000 description 12
- 235000011181 potassium carbonates Nutrition 0.000 description 12
- 238000005303 weighing Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 241000208125 Nicotiana Species 0.000 description 6
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- SWNIAVIKMKSDBJ-UHFFFAOYSA-N 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine Chemical class 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
- 239000000543 intermediate Substances 0.000 description 3
- 238000001228 spectrum 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
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000007858 starting material Substances 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
- 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
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 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
- 229960003512 nicotinic acid Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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-
- 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
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- Chemical & Material Sciences (AREA)
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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, which takes R-substituted nicotinate and gamma-butyrolactone as raw materials to obtain a target product through three steps, wherein the structural formula of the target product is as follows:
Description
Technical Field
The application relates to the technical field of organic matter synthesis, in particular to a brand new preparation method of nicotine and derivatives thereof.
Background
Nicotine is widely present 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 and smoking stopping medicine. In addition, clinical research proves that nicotine is expected to be a medicine for treating diseases such as senile dementia, depression and the like.
At present, nicotine is mainly extracted from waste tobacco, and nicotine extracted and purified from plants such as tobacco and the like usually contains a plurality of other tobacco compounds which are unhealthy to human body systems and are proved to be carcinogenic; meanwhile, the nicotine extracted from tobacco and other plants is influenced by various factors such as raw materials, climate, land resources, period and the like.
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) takes 3-bromopyridine as a starting material, the 3-bromopyridine is expensive and needs ultralow temperature (-78 ℃) condition, the experimental condition is harsh, the method is not suitable for industrial production, and the product is racemate nicotine.
Some of them can synthesize 6-methyl nicotine by taking methyl lithium as a methyl source to react with nicotine, and the reaction formula (2) is as follows:
the reaction in the reaction formula (2) needs anhydrous conditions, is at low temperature of-70 ℃, is harsh, has uncertain methyl substitution positions of synthetic products, is difficult to separate and obtain high-purity 6-methyl nicotine, and has low actual production value.
Also, using t-butyl hydroperoxide as the methyl source, various site-substituted methyl nicotines can be obtained as well, according to the following equation (3):
although different positions of substituted methyl nicotine can be obtained in the above reaction formula (3), the same separation and selectivity problems still exist for different positions of methyl nicotine.
Therefore, in order to improve the yield and purity of the synthesized nicotine and derivatives thereof and reduce the process complexity, it is necessary to provide a new synthesis process route of nicotine and derivatives thereof.
Disclosure of Invention
In order to improve the yield and purity of synthesized brand new nicotine and derivatives thereof, reduce the cost and realize industrial production, the application provides a brand new preparation method of nicotine and derivatives thereof.
The application provides a brand-new preparation method of nicotine and derivatives thereof, which adopts the following technical scheme:
a method for preparing brand-new nicotine and derivatives thereof is disclosed, wherein the compound of the brand-new nicotine shown in the structural formula P3 is as follows:
wherein R is hydrogen, methyl or ethyl, and R is at the 2-, 4-, 5-or 6-position of pyridine;
the method comprises the following steps of synthesizing the compound P2 by a one-pot method:
dissolving a compound P1 in a second solvent, adding a second alkali and methylamine hydrochloride to perform ring-opening and nucleophilic reactions, 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-step reaction is involved in the synthesis of the compound P2, no further purification is needed in the middle, and the compound P2 can be obtained by a one-pot method; in the application, the one-pot method is not a simple step of combining a plurality of reactions, the compound P1 can realize three steps of the 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, so that a substrate is provided for further optimizing a target product P3 subsequently, and the purity of the target product is improved; wherein, the one-pot method is an organic synthesis method, the multistep reaction in the one-pot method can directly obtain molecules with complex structures from relatively simple and easily obtained raw materials without separating intermediates, and is more favorable in economic and environmental protection.
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, diisobutyl aluminum hydride, lithium aluminum hydride and imine reductase; when the reducing agent is imine reductase, before adding the imine reductase, adding a step of adjusting the pH value to the pH value which is most suitable for the imine reductase;
the mass ratio of the compound P1 to the 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; and when the reducing agent is imine reductase, adding a step of adjusting the pH value to the pH value which is most suitable for the imine reductase before adding the imine reductase.
In some embodiments, the ratio of the amount of substance of compound P1 to methylamine hydrochloride is 1 (2-4).
By adopting the technical scheme, the methyl nicotinate obtained by substituting R 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 racemic nicotine are strict, the method is not suitable for industrial production, the methyl substitution position of the derivative is uncertain, the high-purity racemic nicotine derivative is difficult to separate, and the actual production value is not high; in the method, products in multiple steps in the synthesis route of the racemic nicotine and the derivatives thereof do not need to be purified too much, the next step of reaction can be carried out through simple treatment, the operation is simple, multiple steps are carried out in a one-pot method, the conditions are mild, excessive high or low temperature reaction does not exist, the yield and the purity of the racemic nicotine and the derivatives thereof are relatively high, and the cost in multiple aspects of manpower and material resources is reduced.
Preferably, the compound P1 is added into ethanol, reacts with methylamine hydrochloride and potassium carbonate at 50-70 ℃ for 7-9h, then sodium borohydride is added at low temperature, and the reaction is carried out at room temperature for 4-6h, so as to obtain the compound P2.
In some schemes, 1 equivalent of the compound P1 is added into ethanol, and reacts with 3 equivalents of methylamine hydrochloride and 4 equivalents of potassium carbonate at 50-70 ℃ for 7-9h, then 1 equivalent of sodium borohydride is added at low temperature, and the reaction is carried out at room temperature for 4-6h, so as to obtain the compound P2.
Preferably, the method also comprises the following steps of synthesizing the compound P3 by a one-pot method:
dissolving the compound P2 in a third solvent to react with a chlorinated reagent, adjusting the pH value with a third alkali after the reaction is completed, and adding KI to perform cyclization reaction to obtain a 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 chlorinating reagent 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 mass ratio of compound P2 to chlorinating agent is 1 (3-5)
Preferably, the compound P2 is reacted with 8N hydrochloric acid in 1, 4-dioxane at 90-100 ℃ for 2-4h under stirring and at low temperature by using K 2 CO 3 Adjusting pH to 8-10, and adding potassium iodide at 90-100 deg.C to obtain compound P3.
In some embodiments, compound P2 is reacted with 4 equivalents of 8N hydrochloric acid in 1, 4-dioxane at 90-100 deg.C with stirring for 2-4h, and K is added at low temperature 2 CO 3 Adjusting pH =8-10, and reacting at 90-100 deg.C under 0.1 equivalent of potassium iodide to obtain compound P3.
Preferably, the synthesis of said compound P3 is as follows:
the compound P1 reacts with methylamine hydrochloride completely at 50-70 ℃ in an ethanol solvent under the action of potassium carbonate, and then reacts with a reducing agent at room temperature to obtain a compound P2;
the compound P2 reacts with hydrochloric acid in 1, 4-dioxane at 90-100 ℃, the PH value is adjusted to 8-10 by potassium carbonate, and then the compound P3 is obtained by reaction at 90-100 ℃ under potassium iodide.
Preferably, after the compound P1 reacts with methylamine hydrochloride and potassium carbonate in ethanol at 60 ℃ for about 8 hours, about 1 equivalent of sodium borohydride is added in batches at about 0 ℃ and reacts at room temperature for about 5 hours to obtain P2 without further purification; the compound P2 obtained in the last step reacts with 8N hydrochloric acid in 1, 4-dioxane under the condition of stirring at 95 ℃ for 3h, and K is used at 0 DEG C 2 CO 3 The reaction was carried out at a pH of 8 to 10, and at 95 ℃ with the addition of potassium iodide to obtain 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, followed by about 0 ℃ with about 1 equivalent of sodium borohydride in portions and at room temperature for about 5 hours to provide P2 without further purification;
the compound P2 obtained in the previous step is reacted with about 4 equivalents of about 8N hydrochloric acid in 1, 4-dioxane with stirring at about 95 ℃ for about 3h and at about 0 ℃ with K 2 CO 3 The reaction was carried out at about 95 ℃ with the addition of about 0.1 equivalent of potassium iodide to obtain compound P3, while adjusting pH = 8-10.
By adopting the technical scheme, two reactions are involved in the process of synthesizing the compound P3 by the compound P2, no further purification is needed in the middle, and the target product P3 can be obtained by a one-pot method; in addition, in the step, two-molecule polymerization products are not easy to occur, the two-molecule polymerization is possibly related to the temperature and the feeding amount, and the two-molecule polymerization products become impurities after the polymerization, so that the conversion rate and the yield are reduced, namely the yield of the compound P3 is effectively improved.
Preferably, the method further comprises the following steps of synthesizing the compound P1:
in a first solvent, the R-substituted methyl nicotinate and the gamma-butyrolactone are subjected to condensation reaction under the action of a first alkali 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 mass ratio of the R-substituted methyl nicotinate to the 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 potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium hydride, alone or in any combination;
in some embodiments, the ratio of the amounts of R-substituted methyl nicotinate and γ -butyrolactone material is 1 (1-2).
All numerical values provided herein are modified by the term about unless otherwise indicated herein or otherwise clearly contradicted by context. The term "about" should be understood to be within the normal tolerance of the art, e.g., within 2 standard deviations of the mean. About may be 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 stated value.
When a chemical group is attached to the center of a ring via a bond, it means that the chemical group may be substituted at a position where the ring can be substituted, such as:
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, and simultaneously concentrates the reaction step into three steps, thereby improving the yield and the purity, shortening the working procedures and obviously reducing the production cost of the racemic nicotine and the derivatives thereof.
2. The compound P1 can realize a one-pot method of three steps of ring opening, nucleophilic addition and reduction, and the generated imine intermediate has the potential of controlling the chirality of a final product, thereby providing a substrate for further optimizing a target product P3 subsequently and being 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, mild reaction conditions and high product purity, and is suitable for industrial production.
Drawings
FIG. 1 is a H-NMR spectrum of nicotine in example 1 of this application.
FIG. 2 is a MS spectrum of compound P1 in example 1 of the present application.
Figure 3 is a MS spectrum of nicotine from example 1 of this application.
Detailed Description
The present application will be described in further detail with reference to the following drawings and examples. The special description is as follows: the following examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer, and the starting materials used in the following examples were obtained from ordinary commercial sources unless otherwise specified.
The synthetic route of the racemic nicotine and the derivatives thereof of the invention is shown as follows:
examples
Example 1
The method for synthesizing racemic nicotine (P3) of this embodiment specifically includes the following steps:
step 1) Synthesis of Compound P1
At 0 ℃ N 2 Under protection, weighing 8.61g of gamma-butyrolactone (100 mmol) and adding the gamma-butyrolactone into a 250mL three-necked bottle, then adding 150mL of tetrahydrofuran solution into the three-necked bottle, stirring to dissolve the gamma-butyrolactone into the tetrahydrofuran solution, and after the gamma-butyrolactone is dissolved, weighing 8.0g of NaH (200 mmol) with the content of 60% and adding the NaH into the three-necked bottle in batches, wherein the NaH is added in batches for five times; reacting for 0.5h at 0 ℃; then 13.71g of nicotinic acid is weighedAdding methyl ester (100 mmol) into a three-necked bottle, removing an ice bath kettle, heating the three-necked bottle to 25 ℃ for reacting for 4h, and filtering the reaction solution after the reaction is finished to obtain a compound P1. Yield of compound P1: 17.68g, HPLC purity: 96.5 percent; yield: 92.5 percent.
MS(ESI,pos.ion)m/z:192.08[M+H]+。
Step 2) Synthesis of Compound P2
Weighing 15.30g of compound P1 (80 mmol) and dissolving in 160mL of ethanol, then respectively adding 16.20g of methylamine hydrochloride (240 mmol) and 44.23g of potassium carbonate (320 mmol), heating to 60 ℃ and reacting 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 in batches five times; and (3) recovering to react for 5 hours at room temperature, finally 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 a 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 95 deg.C for reaction for 3h, cooling to 0 deg.C, and adding K 2 CO 3 Adjusting the pH value of the solution to 9, then adding 1.33g of potassium iodide (8 mmol) and continuing to react at 95 ℃ for 24 hours, after the reaction is completed, filtering the reaction solution, concentrating the filtrate to remove the solvent to obtain a concentrated solution, then extracting the concentrated solution with EA, washing with saturated salt water, finally concentrating the organic phase to obtain a crude product, purifying the crude product by column chromatography to obtain 11.16g of a target product P3, and detecting the purity by GC-MS to be 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 percent, and the total yield of the three steps S1, S2 and S3 is 79.55 percent.
Example 2
The method for synthesizing nicotine (P3) of the present embodiment specifically includes the following steps:
s1, at 0 ℃, N 2 Under protection, 8.61g of gamma-butyrolactone (100 mmol) is weighed and added into a 250mL three-necked bottle, then 150mL of 1, 4-dioxane solution is added into the three-necked bottle, the gamma-butyrolactone is dissolved into the 1, 4-dioxane solution through stirring, after the gamma-butyrolactone is dissolved, 19.22g of sodium tert-butoxide (200 mmol) is weighed and added into the three-necked bottle in batches, wherein the sodium tert-butoxide is added in batches for five times; reacting for 0.5h at 0 ℃; then 13.71g of methyl nicotinate (100 mmol) is weighed and added into a three-necked bottle, the ice bath kettle is removed, the three-necked bottle is heated to 25 ℃ for 4 hours, the reaction is completed, and the reaction solution is filtered to obtain a compound P1 with the yield: 17.62g, yield 92.2%; HPLC purity: 96.3 percent. MS (ESI, pos.ion) m/z of 92.08[ m ] +H]+；
S2, weighing 15.30g of the compound P1 (80 mmol), dissolving in 160mL of ethanol, then respectively adding 16.20g of methylamine hydrochloride (240 mmol) and 33.9g of sodium carbonate (320 mmol), heating to 60 ℃ and reacting for 8h; then cooling to 0 ℃ in an ice bath, and then adding sodium cyanoborohydride (80 mmol) to the reaction liquid in batches, wherein the sodium cyanoborohydride is added in small quantities for multiple times according to the violent reaction condition and is added in batches for five times; and (3) recovering to react for 5 hours at room temperature, finally 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 a 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, and adding 32mL of 8N saltAcid solution, stirring at 95 deg.C for 3 hr, cooling to 0 deg.C, and adding K 2 CO 3 Adjusting the pH value of the solution to 9, then adding 1.2g of sodium iodide (8 mmol) and continuing to react at 95 ℃ for 24 hours, after the reaction is completed, filtering the reaction solution, concentrating the filtrate to remove the solvent to obtain a concentrated solution, then extracting the concentrated solution with EA, washing with saturated salt water, finally concentrating the organic phase to obtain a crude product, purifying the crude product by column chromatography to obtain 11.16g of a target product P3, and detecting the purity by GC-MS to be 99.65%; MS (ESI, pos.ion) m/z 163.2[ 2 ], [ M + H ]]+；
Wherein, the combined yield of the S2 and the S3 is 86.3 percent and the total yield of the S1, the S2 and the S3 is 79.52 percent.
Example 3
The method for synthesizing nicotine (P3) of the present embodiment specifically includes the following steps:
s1, at 0 ℃, N 2 Under protection, weighing 8.61g (100 mmol) of gamma-butyrolactone, adding the gamma-butyrolactone into a 250mL three-necked bottle, then adding 150mL of toluene solution into the three-necked bottle, stirring to dissolve the gamma-butyrolactone in the toluene solution, weighing 10.80g of sodium methoxide (200 mmol) after the gamma-butyrolactone is dissolved, and adding the sodium methoxide into the three-necked bottle in batches, wherein the sodium methoxide is added in batches for five times; reacting for 0.5h at 0 ℃; then weighing 13.71g of methyl nicotinate (100 mmol) and adding into a three-neck flask, removing an ice bath kettle, heating the three-neck flask to 25 ℃ for 4 hours to complete the reaction, and filtering the reaction solution to obtain a compound P1 with yield: 17.78g, 93.04% yield, 96.6% HPLC purity. MS (ESI, pos.ion) m/z 192.08[ m ] +H]+。
S2, weighing 15.30g of the compound P1 (80 mmol), dissolving in 160mL of ethanol, then respectively adding 16.20g of methylamine hydrochloride (240 mmol) and 33.9g of sodium carbonate (320 mmol), heating to 60 ℃ and reacting for 8h; then cooling to 0 ℃ in an ice bath, and then adding sodium cyanoborohydride (80 mmol) to the reaction liquid in batches, wherein the sodium cyanoborohydride is added in batches five times; recovering the reaction solution to react for 5h at room temperature, finally filtering the reaction solution, concentrating the filtrate to remove the solvent to obtain a concentrated solution, then extracting the concentrated solution by EA, and washing by water to obtain a 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 and reacting at 95 ℃ for 3h, cooling to 0 ℃ after the reaction is completed, adding a K2CO3 solution to adjust the pH to 9, then adding 1.2g of sodium iodide (8 mmol), 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, then extracting the concentrated solution with EA, washing with saturated salt water, finally concentrating the organic phase to obtain a crude product, purifying the crude product by column chromatography to obtain 11.16g of a target product P3, and detecting the purity by GC-MS to be 99.58%; MS (ESI, pos.ion) m/z 163.2[ M + H ] +.
Wherein, the combined yield of the S2 step and the S3 step is 86.3 percent, and the total yield of the S1 step, the S2 step and the S3 step is 79.66 percent.
Example 4
The method for synthesizing nicotine (P3) of the present embodiment specifically includes the following steps:
s1, at 0 ℃, N 2 Under protection, weighing 12.92g of gamma-butyrolactone (150 mmol) and adding the gamma-butyrolactone into a 250mL three-necked bottle, then adding 150mL of tetrahydrofuran solution into the three-necked bottle, stirring to dissolve the gamma-butyrolactone into the tetrahydrofuran solution, and after the gamma-butyrolactone is dissolved, weighing 8.0g of NaH (200 mmol) with the content of 60% and adding the NaH into the three-necked bottle in batches, wherein the NaH is added in batches for five times; reacting for 0.5h at 0 ℃; then weighing 13.71g of methyl nicotinate (100 mmol) and adding into a three-necked bottle, removing an ice bath kettle, heating the three-necked bottle to 25 ℃ for reaction for 4 hours, completing the reaction, and filtering the reaction solution to obtain a compound P1 with yield: 17.72g, yield 92.7%; HPLC purity 96.1%; MS (ESI, pos.ion) m/z 192.08[ m ] +H]+。
S2, weighing 15.30g of the compound P1 (80 mmol), dissolving in 160mL of ethanol, then respectively adding 21.60g of methylamine hydrochloride (320 mmol) and 28.97g of potassium carbonate (426.67 mmol), heating to 60 ℃ and reacting 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 violent reaction condition, a small amount of sodium borohydride is added for multiple times, and the sodium borohydride is added in batches for five times; recovering the reaction at room temperature for 5h, finally filtering the reaction solution, concentrating the filtrate to remove the solvent to obtain a concentrated solution, then extracting the concentrated solution by EA, and washing by water to obtain a 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 and reacting at 95 ℃ for 3 hours, cooling to 0 ℃ after complete reaction, adding K 2 CO 3 Adjusting the pH value of the solution to 9, then adding 1.33g of potassium iodide (8 mmol) and continuing to react at 95 ℃ for 24 hours, after the reaction is completed, filtering the reaction solution, concentrating the filtrate to remove the solvent to obtain a concentrated solution, then extracting the concentrated solution with EA, washing with saturated salt, finally concentrating the organic phase to obtain a crude product, purifying the crude product by column chromatography to obtain 11.16g of a target product P3, and detecting the purity by GC-MS to be 99.6%; MS (ESI, pos.ion) m/z 163.2[ M ] +H]+。
Wherein, the combined yield of the S2 step and the S3 step is 86.4 percent, and the total yield of the S1 step, the S2 step and the S3 step is 79.58 percent.
The specific embodiments are only for explaining the present application and are not limiting to the present application, and those skilled in the art can make modifications to the embodiments without inventive contribution as required after reading the present specification, but all the embodiments are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. A method for preparing brand-new nicotine and derivatives thereof is disclosed, wherein the compound of the brand-new nicotine shown in the structural formula P3 is as follows:
wherein R is hydrogen, methyl or ethyl, and R is at the 2-, 4-, 5-or 6-position of pyridine;
the method is characterized by comprising the following steps of synthesizing a compound P2 by a one-pot method:
dissolving a compound P1 in a second solvent, adding a second alkali and methylamine hydrochloride to perform ring-opening and nucleophilic reactions, and then adding a reducing agent to reduce to obtain a compound P2;
and reacting the compound P2 to obtain a compound P3.
2. The method for preparing nicotine and its derivatives according to claim 1, wherein the nicotine and its derivatives are selected from the group consisting of nicotine,
the second base is selected from one or any combination of potassium carbonate, cesium carbonate and sodium carbonate;
optionally, the second solvent is selected from one or any combination of methanol, ethanol, n-propanol and isopropanol;
optionally, 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, before adding the imine reductase, adding a step of adjusting the pH value to the pH value which is most suitable for the imine reductase;
optionally, the mass ratio of the compound P1 to methylamine hydrochloride is 1 (2-4).
3. The method for preparing nicotine and its derivatives as claimed in claim 1, wherein the compound P1 is added in ethanol, reacted with methylamine hydrochloride and potassium carbonate at 50-70 ℃ for 7-9h, then added with sodium borohydride at low temperature, and reacted at room temperature for 4-6h to obtain the compound P2.
4. The method for preparing nicotine and its derivatives as claimed in claim 1, further comprising the step of synthesizing compound P3 by one-pot method as follows:
and dissolving the compound P2 in a third solvent to react with the chlorinated reagent, adjusting the pH value with a third alkali after the reaction is completed, and adding KI to perform cyclization reaction to obtain a compound P3.
5. The method for preparing nicotine and its derivatives according to claim 4, wherein the nicotine and its derivatives are selected from the group consisting of nicotine,
the third base is selected from one or any combination of potassium carbonate, cesium carbonate and sodium carbonate;
optionally, the third solvent is selected from one or any combination of 1, 4-dioxane and tetrahydrofuran;
optionally, the mass ratio of the compound P2 to the chlorinating agent is 1 (3-5).
6. A process according to claim 4, wherein the compound P2 is reacted with 8N HCl in 1, 4-dioxane under stirring at 90-100 deg.C for 2-4h, and K is added at low temperature 2 CO 3 Adjusting pH =8-10, and adding potassium iodide at 90-100 deg.C to obtain compound P3.
7. The process for the preparation of nicotine and its derivatives as claimed in claim 1, wherein the compound P3 is synthesized as follows:
the compound P1 reacts with methylamine hydrochloride completely at 50-70 ℃ in an ethanol solvent under the action of potassium carbonate, and then reacts with a reducing agent at room temperature to obtain a compound P2;
the compound P2 reacts with hydrochloric acid in 1, 4-dioxane at 90-100 ℃, the PH value is adjusted to 8-10 by potassium carbonate, and then the compound P3 is obtained by reaction at 90-100 ℃ under the condition of potassium iodide.
8. The novel process for the preparation of nicotine and its derivatives as claimed in claim 7,
reacting the compound P1 with methylamine hydrochloride and potassium carbonate in ethanol at 60 ℃ for about 8 hours, adding sodium borohydride with about 1 equivalent in batches at about 0 ℃, and reacting at room temperature for about 5 hours to obtain P2 without further purification;
the compound P2 obtained in the last step reacts with 8N hydrochloric acid in 1, 4-dioxane under the condition of stirring at 95 ℃ for 3h, and K is used at 0 DEG C 2 CO 3 Adjusting pH =8-10, and reacting at 95 deg.C with potassium iodide to obtain compound P3.
9. The method according to claim 1,4 or 7, further comprising the step of synthesizing compound P1 as follows:
in a first solvent, R-substituted methyl nicotinate and gamma-butyrolactone are subjected to condensation reaction under the action of a first alkali to obtain a compound P1.
10. The method for preparing nicotine and its derivatives according to claim 7,
the first solvent is one or any combination of tetrahydrofuran, 1, 4-dioxane and toluene;
optionally, the first base is selected from one or any combination of potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium hydride; optionally, the mass ratio of the R-substituted methyl nicotinate to the gamma-butyrolactone is 1 (1-2).
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