WO2024077407A1 - Chiral reducing agent and method for synthesizing chiral nicotine - Google Patents
Chiral reducing agent and method for synthesizing chiral nicotine Download PDFInfo
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- WO2024077407A1 WO2024077407A1 PCT/CN2022/123930 CN2022123930W WO2024077407A1 WO 2024077407 A1 WO2024077407 A1 WO 2024077407A1 CN 2022123930 W CN2022123930 W CN 2022123930W WO 2024077407 A1 WO2024077407 A1 WO 2024077407A1
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- WIPO (PCT)
- Prior art keywords
- chiral
- compound
- nicotine
- reducing agent
- synthesizing
- Prior art date
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- 229960002715 nicotine Drugs 0.000 title claims abstract description 57
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 title claims abstract description 54
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 title claims abstract description 51
- 239000003638 chemical reducing agent Substances 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 27
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 20
- 229940125904 compound 1 Drugs 0.000 claims abstract description 20
- 229940125782 compound 2 Drugs 0.000 claims abstract description 20
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims abstract description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 7
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- -1 propylidene protecting group Chemical group 0.000 claims description 4
- GBJFSZCDZHSAOP-UHFFFAOYSA-N 2,3-dihydroxy-4-methoxy-4-oxobutanoic acid Chemical compound COC(=O)C(O)C(O)C(O)=O GBJFSZCDZHSAOP-UHFFFAOYSA-N 0.000 claims description 3
- 150000004792 aryl magnesium halides Chemical class 0.000 claims description 3
- 229910000085 borane Inorganic materials 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 238000000638 solvent extraction Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 230000003287 optical effect Effects 0.000 abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000004296 chiral HPLC Methods 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 229940126214 compound 3 Drugs 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 5
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 4
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 4
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 description 4
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 2
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OERWZBOKIXAFQK-UHFFFAOYSA-M [Cl-].C1=CC=CC2=CC([Mg+])=CC=C21 Chemical compound [Cl-].C1=CC=CC2=CC([Mg+])=CC=C21 OERWZBOKIXAFQK-UHFFFAOYSA-M 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- OTUWUWOJDWSEHL-UHFFFAOYSA-M magnesium;1h-naphthalen-1-ide;chloride Chemical compound [Mg+2].[Cl-].[C-]1=CC=CC2=CC=CC=C21 OTUWUWOJDWSEHL-UHFFFAOYSA-M 0.000 description 2
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 229940125907 SJ995973 Drugs 0.000 description 1
- PZIIGUMPOSVMSD-UHFFFAOYSA-M [Br-].C1=CC=C2C([Mg+])=CC=CC2=C1 Chemical compound [Br-].C1=CC=C2C([Mg+])=CC=CC2=C1 PZIIGUMPOSVMSD-UHFFFAOYSA-M 0.000 description 1
- IUSBIEHGCOJPOI-UHFFFAOYSA-M [I-].C1=CC=C2C([Mg+])=CC=CC2=C1 Chemical compound [I-].C1=CC=C2C([Mg+])=CC=CC2=C1 IUSBIEHGCOJPOI-UHFFFAOYSA-M 0.000 description 1
- BEXDCHGGLXAWPS-UHFFFAOYSA-M [I-].C1=CC=CC2=CC([Mg+])=CC=C21 Chemical compound [I-].C1=CC=CC2=CC([Mg+])=CC=C21 BEXDCHGGLXAWPS-UHFFFAOYSA-M 0.000 description 1
- SNIYGPDAYLBEMK-UHFFFAOYSA-M [I-].[Mg+]C1=CC=CC=C1 Chemical compound [I-].[Mg+]C1=CC=CC=C1 SNIYGPDAYLBEMK-UHFFFAOYSA-M 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000005888 cyclopropanation reaction Methods 0.000 description 1
- 238000007256 debromination reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- YLVLCBHNULZXLQ-UHFFFAOYSA-M magnesium;2h-naphthalen-2-ide;bromide Chemical compound [Mg+2].[Br-].C1=[C-]C=CC2=CC=CC=C21 YLVLCBHNULZXLQ-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- 229940124024 weight reducing agent Drugs 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
Definitions
- the present invention relates to the technical field of nicotine synthesis, and in particular to a chiral reducing agent and a method for synthesizing chiral nicotine.
- Nicotine also known as nicotine, is a naturally occurring liquid alkaloid with strong physiological activity. Nicotine is usually found in natural tobacco and has important uses in agriculture, chemical industry, medicine and other fields. The levorotatory nicotine currently used in the market is mainly derived from plant extraction, and is therefore affected by many factors such as raw materials, climate, and cycle, while racemic nicotine can only be obtained through synthesis.
- U.S. Patent US20160326134A1 reports a method for preparing optically active nicotine by chiral splitting. This method requires the use of tartaric acid ester as a splitting agent, and about 50% of the R-configuration nicotine will be discarded. The produced S-configuration nicotine is expensive.
- Patent CN 110357853 B states a method for synthesizing (R, S) nicotine, using 3-bromopyridine and magnesium chips as raw materials to prepare the Grignard reagent of 3-bromopyridine; adding N-methylpyrrolidone to the system, carrying out condensation and hydrolysis reactions, adjusting the pH to alkaline, concentrating, and distilling to obtain an enamine intermediate; then carrying out a reduction reaction in the presence of a metal reduction catalyst such as Pd/C, Pt/C, and Raney nickel to obtain a racemic product R, S-nicotine, as shown below:
- a metal reduction catalyst such as Pd/C, Pt/C, and Raney nickel
- Chinese patent CN104341390A reports the use of cyclic imine As the starting material, in the presence of a chiral catalyst
- the chiral nicotine precursor is obtained under the catalysis of high-pressure hydrogen, and then S-nicotine is obtained through reduction, debromination and methylation.
- This method uses expensive chiral ligands and precious metal catalysts, as well as high-pressure hydrogenation equipment, which greatly increases the technical difficulty while also increasing the raw material and processing costs.
- the present invention aims to provide a chiral reducing agent and a method for synthesizing chiral nicotine using the chiral reducing agent.
- chiral nicotine can be prepared by reduction and hydrolysis reaction with dehydronicotine as a raw material.
- the chiral reagent can be recycled, the price is low, the reaction conditions are mild, and the yield and optical purity of nicotine synthesis are high.
- the present invention provides a chiral reducing agent, wherein the chiral reducing agent is compound 1 , compound 2 , or a stereoisomer of compound 1 or compound 2 ;
- the substituent group Ar is phenyl, 1-naphthyl or 2-naphthyl.
- the present invention also provides an intermediate compound as an intermediate for synthesizing a chiral reducing agent, wherein the chiral intermediate is 1,1,4,4-
- the present invention also provides a method for synthesizing chiral nicotine via a chiral reducing agent compound 1 or compound 2 , wherein the chiral reducing agent compound 1 or compound 2 is used to reduce dehydronicotine in the presence of a solvent, and then hydrolyzes and quenches to obtain chiral nicotine.
- the present invention has the following advantages and beneficial effects:
- the embodiments of the present invention provide a chiral reducing agent and a method for synthesizing chiral nicotine.
- chiral nicotine can be prepared by reduction and hydrolysis reaction with dehydronicotine as a raw material.
- the starting raw material is inexpensive, the reaction conditions are mild, and the yield and optical purity of nicotine synthesis are high.
- references to "one embodiment,” “an embodiment,” “an example,” or “an example” mean that a particular feature, structure, or characteristic described in conjunction with the embodiment or example is included in at least one embodiment of the present invention. Therefore, the phrases “one embodiment,” “an embodiment,” “an example,” or “an example” appearing in various places throughout the specification do not necessarily all refer to the same embodiment or example. Furthermore, particular features, structures, or characteristics may be combined in one or more embodiments or examples in any suitable combination and/or subcombination. Furthermore, it will be understood by those of ordinary skill in the art that the term “and/or” as used herein includes any and all combinations of one or more of the associated listed items.
- the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
- the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
- the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
- the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
- the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
- distillate is a colorless liquid, which is the chiral nicotine product; the reduction reaction yield is 86%, the HPLC purity is 98.1%, and the chiral HPLC analysis shows that the chiral purity is 97.3%.
- the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
- the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Disclosed in the present invention are a chiral reducing agent and a method for synthesizing chiral nicotine. The chiral reducing agent is a compound 1 or a compound 2, or a stereoisomer of the compound 1 and the compound 2. The structural formulae of the compound 1 and the compound 2 are as shown below, wherein a substituent group Ar is phenyl, 1-naphthyl or 2-naphthyl. In the present invention, the chiral reducing agent, i.e., the compound 1 or the compound 2, is used for reducing dehydronicotine in the presence of a solvent, and the resulting product is hydrolyzed to obtain chiral nicotine. In the present invention, by using the chiral reducing agent, dehydronicotine can be reduced by means of chiral reducing agents 1 and 2, and then subjected to a hydrolysis reaction, so as to prepare chiral nicotine. The starting raw material has a low price, the reaction conditions are mild, and the synthesis yield and optical purity of nicotine are high.
Description
本发明涉及尼古丁合成技术领域，具体而言，涉及一种手性还原剂及合成手性尼古丁的方法。The present invention relates to the technical field of nicotine synthesis, and in particular to a chiral reducing agent and a method for synthesizing chiral nicotine.
烟碱又称为尼古丁，是一种天然生成的液态生物碱，具有强烈的生理活性。烟碱通常主要存在于天然烟草中，在农业、化工、医药等领域有着重要的用途。目前市场上所用的左旋烟碱主要来源于植物提取，因此受到了原材料、气候，以及周期等多方面因素的影响，而消旋烟碱只能通过合成得到。Nicotine, also known as nicotine, is a naturally occurring liquid alkaloid with strong physiological activity. Nicotine is usually found in natural tobacco and has important uses in agriculture, chemical industry, medicine and other fields. The levorotatory nicotine currently used in the market is mainly derived from plant extraction, and is therefore affected by many factors such as raw materials, climate, and cycle, while racemic nicotine can only be obtained through synthesis.
现有文献J.Heterocycl.Chem.2009，46(6):1252-1258报道了一种尼古丁的制备方法，该制备方法的起始原料为昂贵的3-溴吡啶，并且使用昂贵的丁基锂，反应条件苛刻，不适合工业放大生产。其路线如下所示：The existing document J. Heterocycl. Chem. 2009, 46 (6): 1252-1258 reports a method for preparing nicotine. The starting material of the method is expensive 3-bromopyridine, and expensive butyl lithium is used. The reaction conditions are harsh and not suitable for industrial scale-up production. The route is as follows:
文献Journal of Organic Chemistry,1990,55(6),1736-1744报道了从吡略烷出发，经四步反应合成消旋烟碱的方法，如下所示：The literature Journal of Organic Chemistry, 1990, 55(6), 1736-1744 reported a method for synthesizing racemic nicotine from pyrrolidine via a four-step reaction, as shown below:
该文献中涉及到叔丁基锂、-120℃极低温和氧化反应等苛刻条件，增加了工业化生产的难度，并且该方法的收率较低。This document involves harsh conditions such as tert-butyl lithium, extremely low temperature of -120°C and oxidation reaction, which increases the difficulty of industrial production, and the yield of this method is low.
美国专利US20160326134A1报道了一种通过手性拆分的方法制备具有光学活性尼古丁，该方法需要使用酒石酸酯作为拆分试剂，同时50％左右的R构型尼古丁将被抛弃，生产的S构型尼古丁价格昂贵。U.S. Patent US20160326134A1 reports a method for preparing optically active nicotine by chiral splitting. This method requires the use of tartaric acid ester as a splitting agent, and about 50% of the R-configuration nicotine will be discarded. The produced S-configuration nicotine is expensive.
专利CN 110357853 B声明了一种(R,S)尼古丁的合成方法，以3-溴吡啶和镁屑为原料制 备3-溴吡啶的格氏试剂；在体系中加入N-甲基吡咯烷酮，进行缩合、水解反应，调节pH为碱性，浓缩，蒸馏得到烯胺中间体；然后在Pd/C，Pt/C，雷尼镍等金属还原催化剂存在的条件下，进行还原反应，得到消旋产物R，S-尼古丁，如下所示：Patent CN 110357853 B states a method for synthesizing (R, S) nicotine, using 3-bromopyridine and magnesium chips as raw materials to prepare the Grignard reagent of 3-bromopyridine; adding N-methylpyrrolidone to the system, carrying out condensation and hydrolysis reactions, adjusting the pH to alkaline, concentrating, and distilling to obtain an enamine intermediate; then carrying out a reduction reaction in the presence of a metal reduction catalyst such as Pd/C, Pt/C, and Raney nickel to obtain a racemic product R, S-nicotine, as shown below:
中国专利CN104341390A报道了以环状亚胺
为起始原料，在手性催化剂
和高压氢气的催化下得到手性尼古丁前体，后续经过还原去溴化和甲基化得到S-尼古丁，该方法使用昂贵的手性配体和贵金属催化剂，同时使用高压氢化设备，在大幅增加了技术难度的同时还增加了原料和加工成本。
Chinese patent CN104341390A reports the use of cyclic imine As the starting material, in the presence of a chiral catalyst The chiral nicotine precursor is obtained under the catalysis of high-pressure hydrogen, and then S-nicotine is obtained through reduction, debromination and methylation. This method uses expensive chiral ligands and precious metal catalysts, as well as high-pressure hydrogenation equipment, which greatly increases the technical difficulty while also increasing the raw material and processing costs.
其他使用不对称C-N键形成策略合成S-尼古丁(Org.Biomol.Chem.2005,3,3266-3268)、不对称烷基化策略合成S-尼古丁(J.Org.Chem.2011,76,5 936-5953)、手性助剂策略合成S-尼古丁(Tetrahedron Letters 40(1999)7847-7850,Tetrahedron:Asymmetry 12(2001)1625-1634,)、化学计量不对称硼氢化反应策略合成S-尼古丁(Tetrahedron:Asymmetry 12(2001)1121-1124)、不对称环丙烷化策略合成S-尼古丁(Chem.Eur.J.2015,21,4975-4987)，均只能以中等收率和中等光学纯度制备得到S-尼古丁，成本昂贵，反应条件苛刻，无法大规模工业生产。Other methods for synthesizing S-nicotine include asymmetric C-N bond formation strategy (Org. Biomol. Chem. 2005, 3, 3266-3268), asymmetric alkylation strategy (J. Org. Chem. 2011, 76, 5 936-5953), and chiral auxiliary strategy (Tetrahedron Letters 40 (1999) 7847-7850, Tetrahedron: Asymmetry 12 (2001) 1625-1634,), the stoichiometric asymmetric hydroboration reaction strategy for synthesizing S-nicotine (Tetrahedron: Asymmetry 12 (2001) 1121-1124), and the asymmetric cyclopropanation strategy for synthesizing S-nicotine (Chem. Eur. J. 2015, 21, 4975-4987), can only prepare S-nicotine with medium yield and medium optical purity, which is expensive and has harsh reaction conditions and cannot be produced on a large scale in industry.
有鉴于此，特提出本申请。In view of this, this application is hereby filed.
发明内容Summary of the invention
为了解决上述问题，本发明目的在于提供一种手性还原剂及使用该手性还原剂合成手性尼古丁的方法，利用本发明的手性还原剂，能够以脱氢尼古丁作为原料通过还原、水解反应制得手性尼古丁，手性试剂可以循环使用，价格低廉、反应条件温和，尼古丁合成的收率和光学纯度高。In order to solve the above problems, the present invention aims to provide a chiral reducing agent and a method for synthesizing chiral nicotine using the chiral reducing agent. By using the chiral reducing agent of the present invention, chiral nicotine can be prepared by reduction and hydrolysis reaction with dehydronicotine as a raw material. The chiral reagent can be recycled, the price is low, the reaction conditions are mild, and the yield and optical purity of nicotine synthesis are high.
本发明提供一种手性还原剂，所述手性还原剂为化合物
1、化合物
2、化合物
1或化合物
2的立体异构体；
The present invention provides a chiral reducing agent, wherein the chiral reducing agent is compound 1 , compound 2 , or a stereoisomer of compound 1 or compound 2 ;
化合物
1结构式如下所示：
The structural formula of compound 1 is shown below:
化合物
2结构式如下所示：
The structural formula of compound 2 is shown below:
其中，取代基团Ar为苯基、1-萘基或者2-萘基。Wherein, the substituent group Ar is phenyl, 1-naphthyl or 2-naphthyl.
进一步的，化合物
1或化合物
2的合成路线如下所示：
Further, the synthetic route of compound 1 or compound 2 is as follows:
化合物1或化合物2的具体合成方法如下：The specific synthesis method of compound 1 or compound 2 is as follows:
1)将芳基卤化镁(ArMgX)与丙叉保护的手性酒石酸甲酯(化合物3)在合适的条件下反应得到四芳基衍生物(化合物4)(Ar＝Ph，1-Naph或2-Naph)；1) reacting an aryl magnesium halide (ArMgX) with a propylidene-protected chiral methyl tartrate (compound 3) under appropriate conditions to obtain a tetraaryl derivative (compound 4) (Ar＝Ph, 1-Naph or 2-Naph);
2)将四芳基衍生物(化合物4)经催化氢解和水解去除丙叉保护基后得到手性的1,1,4,4-四芳基2，3-丁二醇(
6)；
2) removing the propylidene protecting group from the tetraaryl derivative (compound 4) by catalytic hydrogenolysis and hydrolysis to obtain chiral 1,1,4,4-tetraaryl 2,3-butanediol ( 6 );
3)将四芳基2，3-丁二醇(
6)与金属硼氢化物或者硼烷反应得到化合物
1或化合物
2。
3) Tetraaryl 2,3-butanediol ( 6 ) is reacted with a metal borohydride or borane to obtain compound 1 or compound 2 .
本发明还提供一种中间化合物，作为合成手性还原剂的中间体，手性中间体为1,1,4,4-The present invention also provides an intermediate compound as an intermediate for synthesizing a chiral reducing agent, wherein the chiral intermediate is 1,1,4,4-
四芳基-2,3-丁二醇
6或其立体异构体，其结构式如下所示：
Tetraaryl-2,3-butanediol 6 or its stereoisomers, the structural formula of which is shown below:
本发明还提供一种经由手性还原剂化合物
1或化合物
2合成手性尼古丁的方法，利用手性还原剂化合物
1或化合物
2在溶剂存在下还原脱氢尼古丁、水解淬灭后得到手性尼古丁。
The present invention also provides a method for synthesizing chiral nicotine via a chiral reducing agent compound 1 or compound 2 , wherein the chiral reducing agent compound 1 or compound 2 is used to reduce dehydronicotine in the presence of a solvent, and then hydrolyzes and quenches to obtain chiral nicotine.
进一步的，手性尼古丁的合成路线和操作步骤具体如下所示：Furthermore, the synthesis route and operation steps of chiral nicotine are specifically as follows:
(1)将本发明所述手性还原剂
1或者
2、脱氢尼古丁和溶剂混合，搅拌反应至脱氢尼古丁消失；
(1) mixing the chiral reducing agent 1 or 2 of the present invention, dehydronicotine and a solvent, and stirring the mixture until the dehydronicotine disappears;
(2)向反应液中加入盐酸或者其它酸，水解淬灭反应；(2) adding hydrochloric acid or other acid to the reaction solution to hydrolyze and quench the reaction;
(3)用甲苯或者其它溶剂萃取回收手性中间体
6，回收的化合物
6可以套用；
(3) Extracting and recovering chiral intermediate 6 with toluene or other solvents, the recovered compound 6 can be used in a variety of ways;
(4)加入NaOH或者其它碱中和，用醋酸乙酯或者其它溶剂萃取、浓缩即得到手性尼古丁。(4) Add NaOH or other bases for neutralization, extract with ethyl acetate or other solvents, and concentrate to obtain chiral nicotine.
本发明与现有技术相比，具有如下的优点和有益效果：Compared with the prior art, the present invention has the following advantages and beneficial effects:
本发明实施例提供的一种手性还原剂及合成手性尼古丁的方法，利用本发明的手性还原剂，能够以脱氢尼古丁作为原料通过还原、水解反应制得手性尼古丁，起始原料价格低廉、反应条件温和，尼古丁合成的收率和光学纯度高。The embodiments of the present invention provide a chiral reducing agent and a method for synthesizing chiral nicotine. By using the chiral reducing agent of the present invention, chiral nicotine can be prepared by reduction and hydrolysis reaction with dehydronicotine as a raw material. The starting raw material is inexpensive, the reaction conditions are mild, and the yield and optical purity of nicotine synthesis are high.
为使本发明的目的、技术方案和优点更加清楚明白，下面结合实施例，对本发明作进一步的详细说明，本发明的示意性实施方式及其说明仅用于解释本发明，并不作为对本发明的限定。In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments. The illustrative embodiments of the present invention and their description are only used to explain the present invention and are not intended to limit the present invention.
在以下描述中，为了提供对本发明的透彻理解阐述了大量特定细节。然而，对于本领域普通技术人员显而易见的是：不必采用这些特定细节来实行本发明。在其他实施例中，为了避免混淆本本发明，未具体描述公知的材料或方法。In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present invention. However, it is apparent to one of ordinary skill in the art that these specific details need not be employed to practice the present invention. In other embodiments, in order to avoid obscuring the present invention, well-known materials or methods are not specifically described.
在整个说明书中，对“一个实施例”、“实施例”、“一个示例”或“示例”的提及意味着：结合该实施例或示例描述的特定特征、结构或特性被包含在本发明至少一个实施例中。因此，在整个说明书的各个地方出现的短语“一个实施例”、“实施例”、“一个示例”或“示例”不一定都指 同一实施例或示例。此外，可以以任何适当的组合和、或子组合将特定的特征、结构或特性组合在一个或多个实施例或示例中。此外，本领域普通技术人员应当理解，这里使用的术语“和/或”包括一个或多个相关列出的项目的任何和所有组合。Throughout the specification, references to "one embodiment," "an embodiment," "an example," or "an example" mean that a particular feature, structure, or characteristic described in conjunction with the embodiment or example is included in at least one embodiment of the present invention. Therefore, the phrases "one embodiment," "an embodiment," "an example," or "an example" appearing in various places throughout the specification do not necessarily all refer to the same embodiment or example. Furthermore, particular features, structures, or characteristics may be combined in one or more embodiments or examples in any suitable combination and/or subcombination. Furthermore, it will be understood by those of ordinary skill in the art that the term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
在本发明的描述中，术语“前”、“后”、“左”、“右”、“上”、“下”、“竖直”、“水平”、“高”、“低”“内”、“外”等指示的方位或位置关系，仅是为了便于描述本发明和简化描述，而不是指示或暗示所指的装置或元件必须具有特定的方位、以特定的方位构造和操作，因此不能理解为对本发明保护范围的限制。In the description of the present invention, terms such as "front", "rear", "left", "right", "up", "down", "vertical", "horizontal", "high", "low", "inside" and "outside" to indicate directions or positional relationships are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the referred device or element must have a specific direction, be constructed and operated in a specific direction, and therefore should not be understood as limiting the scope of protection of the present invention.
实施例1Example 1
本发明实施例提供一种经由手性还原剂合成手性尼古丁的方法，包括如下步骤：The embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
1)将芳基卤化镁(ArMgX)与丙叉保护的手性酒石酸甲酯
3在合适的条件下反应得到四芳基衍生物
4(Ar＝Ph或1-Naph或2-Naph)；
1) reacting an aryl magnesium halide (ArMgX) with a propylidene-protected chiral methyl tartrate 3 under appropriate conditions to obtain a tetraaryl derivative 4 (Ar＝Ph or 1-Naph or 2-Naph);
2)将四芳基衍生物
4经催化氢解和水解去除丙叉保护基后得到手性的1,1,4,4-四芳基2，3-丁二醇
6；
2) subjecting the tetraaryl derivative 4 to catalytic hydrogenolysis and hydrolysis to remove the propylidene protecting group to obtain chiral 1,1,4,4-tetraaryl 2,3-butanediol 6 ;
3)将1,1,4,4-四芳基2,3-丁二醇
6与金属硼氢化物或者硼烷反应得到化合物
1或化合物
2；
3) reacting 1,1,4,4-tetraaryl 2,3-butanediol 6 with a metal borohydride or borane to obtain compound 1 or compound 2 ;
4)利用手性还原剂化合物
1、化合物
2、化合物
1的立体异构体或化合物
2的立体异构体在溶剂存在下还原脱氢尼古丁、并水解后得到手性尼古丁。
4) using a chiral reducing agent, Compound 1 , Compound 2 , a stereoisomer of Compound 1 or a stereoisomer of Compound 2 in the presence of a solvent to reduce dehydronicotine and hydrolyze it to obtain chiral nicotine.
进一步的，手性尼古丁的合成路线如下所示：Further, the synthesis route of chiral nicotine is as follows:
实施例2Example 2
本发明实施例提供一种经由手性还原剂合成手性尼古丁的方法，包括如下步骤：The embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
1.1化合物
6a(Ar＝Ph)的合成
1.1 Synthesis of compound 6a (Ar＝Ph)
1)氮气保护下，将2.0M苯基氯化镁(也可采用苯基溴化镁(PhMgBr)、苯基碘化镁(PhMgI)为原料)的四氢呋喃溶液(250mL，0.5mol)滴加入化合物
3(L-酒石酸构型，21.8g，0.1mol)的四氢呋喃溶液中，在40℃搅拌反应90min，反应完毕，加入稀盐酸水溶液调节pH至中性，用甲苯萃取两次，萃取液经浓缩得到中间体
4a(Ar＝Ph)；
1) Under nitrogen protection, a 2.0M tetrahydrofuran solution (250 mL, 0.5 mol) of phenylmagnesium chloride (phenylmagnesium bromide (PhMgBr) or phenylmagnesium iodide (PhMgI) can also be used as a raw material) was added dropwise to a tetrahydrofuran solution of compound 3 (L-tartaric acid configuration, 21.8 g, 0.1 mol), and the mixture was stirred at 40°C for 90 min. After the reaction was completed, a dilute hydrochloric acid solution was added to adjust the pH to neutral, and the mixture was extracted twice with toluene. The extract was concentrated to obtain intermediate 4a (Ar＝Ph);
2)将中间体化合物
4a的粗品溶解于甲醇(250mL)，加入Raney Ni(5.0g)，经氮气置换后，通入氢气搅拌反应4小时至TLC显示
4a完全消失，过滤去除催化剂，真空浓缩，得到脱去丙叉保护的中间体
5a(Ar＝Ph)；
2) The crude intermediate compound 4a was dissolved in methanol (250 mL), and Raney Ni (5.0 g) was added. After nitrogen replacement, hydrogen was introduced and stirred for 4 hours until TLC showed that 4a completely disappeared. The catalyst was filtered out and concentrated in vacuo to obtain the intermediate 5a (Ar＝Ph) with deprotected propylidene.
3)向残液中加入0.5M盐酸(200mL),搅拌反应2小时，用醋酸乙酯萃取，有机相经浓缩得到化合物
6a(Ar＝Ph)的粗品；经硅胶柱层析(7:1正己烷/醋酸乙酯)后得到(2S,3S)-
6a纯品；基于化合物
3的三步总收率72％，HPLC显示纯度99.3％，Chiral-HPLC显示手性纯度99.5％，LC-MS显示m/e＝395.5(MH
+)，
1H和
13C NMR(CDCl
3)均符合相应数据；
3) 0.5 M hydrochloric acid (200 mL) was added to the residual liquid, the mixture was stirred for reaction for 2 hours, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to obtain a crude product of compound 6a (Ar＝Ph); after silica gel column chromatography (7:1 n-hexane/ethyl acetate), pure (2S,3S)- 6a was obtained; the total yield of three steps based on compound 3 was 72%, HPLC showed a purity of 99.3%, Chiral-HPLC showed a chiral purity of 99.5%, LC-MS showed m/e＝395.5 (MH + ), and 1 H and 13 C NMR (CDCl 3 ) were consistent with the corresponding data;
另外使用D-酒石酸构型的化合物
3和苯基氯化镁为起始原料，按照上述步骤可得到(2S,3S)-
6a，其收率为76％，HPLC纯度99.5％，Chiral-HPLC纯度99.1％，LC-MS显示m/e＝395.2(MH
+)，
1H、
13C NMR均符合相应数据；
In addition, using D-tartaric acid-configured compound 3 and phenylmagnesium chloride as starting materials, (2S,3S)- 6a was obtained according to the above steps with a yield of 76%, HPLC purity of 99.5%, Chiral-HPLC purity of 99.1%, LC-MS showed m/e=395.2 (MH + ), and 1 H and 13 C NMR were consistent with the corresponding data;
1.2化合物
1a的合成和应用于手性烟碱的合成
1.2 Synthesis of compound 1a and its application in the synthesis of chiral nicotine
1)将化合物
6a(Ar＝Ph，0.1mol)加入LiBH
4(0.1mol)(也可采用NaBH
4或者KBH
4)的THF溶液中，室温搅拌2-8小时，至无氢气气泡产生为止，即获得化合物
1a(Ar＝Ph)的THF溶液。降温至-10～10℃，加入脱氢烟碱(0.1mol)，逐渐升温至20-40℃搅拌反应，反应完毕，加入盐酸调节酸碱度至pH1-3，用甲苯萃取回收手性中间体
6a；
1) Add compound 6a (Ar＝Ph, 0.1mol) to a THF solution of LiBH 4 (0.1mol) (NaBH 4 or KBH 4 may also be used), and stir at room temperature for 2-8 hours until no hydrogen bubbles are generated, thereby obtaining a THF solution of compound 1a (Ar＝Ph). Cool to -10～10°C, add dehydronicotine (0.1mol), gradually raise the temperature to 20-40°C, stir and react, and after the reaction is complete, add hydrochloric acid to adjust the pH to 1-3, and extract with toluene to recover the chiral intermediate 6a ;
2)将20％NaOH加入萃取后的水溶液中，调节pH至碱性，用甲苯萃取，减压浓缩，所得残液进行减压蒸馏，馏出物即为手性尼古丁产品(无色液体)；基于脱氢烟碱的收率为78％，HPLC纯度99.2％，手性HPLC分析显示手性纯度为99.7％。LC-MS，
1H、
13CNMR结果与符合尼古丁的数据。
2) Add 20% NaOH to the aqueous solution after extraction, adjust the pH to alkaline, extract with toluene, concentrate under reduced pressure, and distill the residue under reduced pressure. The distillate is the chiral nicotine product (colorless liquid); the yield based on dehydronicotine is 78%, the HPLC purity is 99.2%, and the chiral HPLC analysis shows that the chiral purity is 99.7%. The results of LC-MS, 1 H, 13 CNMR are consistent with the data of nicotine.
实施例3Example 3
本发明实施例提供一种经由手性还原剂合成手性尼古丁的方法，包括如下步骤：The embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
1.1化合物
6b(Ar＝1-Naph)的合成
1.1 Synthesis of compound 6b (Ar＝1-Naph)
1)在氮气保护下，将1.0M 1-萘基氯化镁(也可采用1-萘基溴化镁(PhMgBr)、1-萘基碘化镁(PhMgI))的四氢呋喃溶液(250mL，0.5mol)滴加入化合物
3(L-酒石酸构型，10.9g，0.05mol)的四氢呋喃溶液中，在40℃搅拌反应90min，反应完毕，加入稀盐酸水溶液调节pH至中性。用甲苯萃取两次，萃取液经浓缩得到中间体
4b(Ar＝1-Naph)；
1) Under nitrogen protection, a 1.0M tetrahydrofuran solution (250 mL, 0.5 mol) of 1-naphthylmagnesium chloride (1-naphthylmagnesium bromide (PhMgBr) or 1-naphthylmagnesium iodide (PhMgI)) was added dropwise to a tetrahydrofuran solution of compound 3 (L-tartaric acid configuration, 10.9 g, 0.05 mol), and the mixture was stirred at 40°C for 90 min. After the reaction was completed, a dilute hydrochloric acid solution was added to adjust the pH to neutral. The mixture was extracted twice with toluene, and the extract was concentrated to obtain intermediate 4b (Ar＝1-Naph);
2)将化合物
4b的粗品溶解于甲醇(150mL)，加入Raney Ni(3.0g)，经氮气置换后，通入氢气搅拌反应4小时至TLC显示
4b完全消失，过滤去除催化剂，真空浓缩，得到脱去丙叉保护的中间体
5b；
2) The crude compound 4b was dissolved in methanol (150 mL), and Raney Ni (3.0 g) was added. After nitrogen replacement, hydrogen was introduced and stirred for 4 hours until TLC showed that 4b completely disappeared. The catalyst was filtered out and concentrated in vacuo to obtain the intermediate 5b without propylidene protection;
3)向残液中加入0.5M盐酸(200mL),搅拌反应2小时，用醋酸乙酯萃取，有机相经浓缩得到化合物
6b(Ar＝1-Naph)的粗品，经硅胶柱层析(5:1正己烷/醋酸乙酯)后得到(2R,3R)-
6b纯品；基于化合物
3的三步总收率60％。HPLC显示纯度99.6％，Chiral-HPLC显示手性纯度99.2％，LC-MS显示m/e＝595.5(MH
+)，
1H、
13C NMR(CDCl
3)符合相应数据。
3) 0.5M hydrochloric acid (200 mL) was added to the residual liquid, and the mixture was stirred for 2 hours. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to obtain a crude compound 6b (Ar=1-Naph). The crude compound (2R,3R) -6b was purified by silica gel column chromatography (5:1 n-hexane/ethyl acetate). The total yield of the three steps based on compound 3 was 60%. HPLC showed a purity of 99.6%, Chiral-HPLC showed a chiral purity of 99.2%, and LC-MS showed m/e=595.5 (MH + ). 1 H and 13 C NMR (CDCl 3 ) were consistent with the corresponding data.
另外使用D-酒石酸构型的化合物
3和1-萘基氯化镁为起始原料，按照上述步骤可得到(2S,3S)-
6b，其收率为66％，HPLC纯度99.6％，Chiral-HPLC纯度99.7％，LC-MS显示MS：m/e＝595.5(MH
+)；
1H、
13C NMR均符合相应数据；
In addition, using D-tartaric acid-configured compound 3 and 1-naphthylmagnesium chloride as starting materials, (2S,3S)- 6b can be obtained according to the above steps with a yield of 66%, HPLC purity of 99.6%, Chiral-HPLC purity of 99.7%, LC-MS showed MS: m/e=595.5 (MH + ); 1 H, 13 C NMR were consistent with the corresponding data;
1.2化合物
1b的合成和应用于手性烟碱的合成
1.2 Synthesis of compound 1b and its application in the synthesis of chiral nicotine
1)将化合物
6b(Ar＝1-Naph，0.1mol)加入LiBH
4(0.1mol)(NaBH
4或者KBH
4)的THF溶液中，室温搅拌2-8小时，至无氢气气泡产生为止，即获得化合物
1b(Ar＝1-Naph)的THF溶液。降温至-10～10℃，加入脱氢烟碱(0.1mol)，逐渐升温至20-40℃搅拌反应。反应完毕，加入盐酸调节酸碱度至pH1-3，用甲苯萃取回收手性中间体
6b；
1) Add compound 6b (Ar = 1-Naph, 0.1 mol) to a THF solution of LiBH 4 (0.1 mol) (NaBH 4 or KBH 4 ) and stir at room temperature for 2-8 hours until no hydrogen bubbles are generated, thereby obtaining a THF solution of compound 1b (Ar = 1-Naph). Cool to -10-10°C, add dehydronicotine (0.1 mol), gradually heat to 20-40°C and stir for reaction. After the reaction is complete, add hydrochloric acid to adjust the pH to 1-3, and extract with toluene to recover the chiral intermediate 6b ;
2)将20％NaOH加入萃取后的水溶液中，调节pH至碱性，用甲苯萃取，减压浓缩，所得残液进行减压蒸馏，馏出物即为手性尼古丁产品(无色液体)；基于脱氢烟碱的收率为83％，HPLC纯度99.2％，手性HPLC分析显示手性纯度为99.3％；LC-MS，
1H、
13CNMR符合相应数据。
2) adding 20% NaOH to the aqueous solution after extraction, adjusting the pH to alkaline, extracting with toluene, concentrating under reduced pressure, distilling the obtained residue under reduced pressure, and the distillate is the chiral nicotine product (colorless liquid); the yield based on dehydronicotine is 83%, the HPLC purity is 99.2%, and the chiral HPLC analysis shows that the chiral purity is 99.3%; LC-MS, 1 H, 13 C NMR are consistent with the corresponding data.
实施例4Example 4
本发明实施例提供一种经由手性还原剂合成手性尼古丁的方法，包括如下步骤：The embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
1.1化合物
6c(Ar＝2-Naph)的合成
1.1 Synthesis of compound 6c (Ar＝2-Naph)
1)在氮气保护下，将1.0M 2-萘基氯化镁(也可采用2-萘基溴化镁(PhMgBr)、2-萘基碘 化镁(PhMgI))的四氢呋喃溶液(250mL，0.5mol)滴加入化合物
3(L-酒石酸构型，10.9g，0.05mol)的四氢呋喃溶液中，在40℃搅拌反应90min，反应完毕，加入稀盐酸水溶液调节pH至中性。用甲苯萃取两次，萃取液经浓缩得到中间体
4c(Ar＝2-Naph)；
1) Under nitrogen protection, a 1.0M tetrahydrofuran solution of 2-naphthylmagnesium chloride (2-naphthylmagnesium bromide (PhMgBr) or 2-naphthylmagnesium iodide (PhMgI)) (250 mL, 0.5 mol) was added dropwise to a tetrahydrofuran solution of compound 3 (L-tartaric acid configuration, 10.9 g, 0.05 mol), and the mixture was stirred at 40°C for 90 min. After the reaction was completed, a dilute hydrochloric acid solution was added to adjust the pH to neutral. The mixture was extracted twice with toluene, and the extract was concentrated to obtain intermediate 4c (Ar = 2-Naph);
2)将化合物
4c的粗品溶解于甲醇(150mL)，加入Raney Ni(3.0g)，经氮气置换后，通入氢气搅拌反应4小时至TLC显示
4c完全消失，过滤去除催化剂，真空浓缩，得到脱去丙叉保护的中间体
5c；
2) The crude compound 4c was dissolved in methanol (150 mL), and Raney Ni (3.0 g) was added. After nitrogen replacement, hydrogen was introduced and stirred for 4 hours until TLC showed that 4c completely disappeared. The catalyst was filtered out and concentrated in vacuo to obtain the intermediate 5c after deprotection of propylidene;
3)向残液中加入0.5M盐酸(200mL),搅拌反应2小时，用醋酸乙酯萃取，有机相经浓缩得到化合物
6c(Ar＝2-Naph)的粗品，经硅胶柱层析(5:1正己烷/醋酸乙酯)后得到(2R,3R)-6c纯品；基于化合物
3的三步总收率60％。HPLC显示纯度99.6％，Chiral-HPLC显示手性纯度99.5％，LC-MS显示m/e＝595.5(MH
+)，
1H、
13C NMR(CDCl
3)符合相应数据；
3) 0.5M hydrochloric acid (200 mL) was added to the residual liquid, and the mixture was stirred for 2 hours. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to obtain a crude compound 6c (Ar = 2-Naph). The crude compound (2R, 3R)-6c was purified by silica gel column chromatography (5:1 n-hexane/ethyl acetate). The total yield of the three steps based on compound 3 was 60%. HPLC showed a purity of 99.6%, Chiral-HPLC showed a chiral purity of 99.5%, and LC-MS showed m/e = 595.5 (MH + ). 1 H and 13 C NMR (CDCl 3 ) were consistent with the corresponding data.
另外使用D-酒石酸构型的化合物
3和2-萘基氯化镁为起始原料，按照上述步骤可得到(2S,3S)-
6c，其收率为66％，HPLC纯度99.6％，Chiral-HPLC纯度99.7％，LC-MS显示MS：m/e＝595.5(MH+)；
1H NMR、
13C NMR(CDCl
3)均符合相应数据；
In addition, using D-tartaric acid-configured compound 3 and 2-naphthylmagnesium chloride as starting materials, (2S,3S)- 6c can be obtained according to the above steps with a yield of 66%, HPLC purity of 99.6%, Chiral-HPLC purity of 99.7%, LC-MS showed MS: m/e=595.5 (MH+); 1 H NMR, 13 C NMR (CDCl 3 ) were consistent with the corresponding data;
1.2化合物
1c的合成和应用于手性烟碱的合成
1.2 Synthesis of compound 1c and its application in the synthesis of chiral nicotine
1)将化合物
6c(Ar＝2-Naph，0.1mol)加入LiBH
4(0.1mol)(NaBH
4或者KBH
4)的THF溶液中，室温搅拌2-8小时，至无氢气气泡产生为止，即获得化合物
1c(Ar＝2-Naph)的THF溶液；降温至-10～10℃，加入脱氢烟碱(0.1mol)，逐渐升温至20-40℃搅拌反应。反应完毕，加入盐酸调节酸碱度至pH1-3，用甲苯萃取回收手性中间体
6c；
1) Add compound 6c (Ar = 2-Naph, 0.1 mol) to a THF solution of LiBH 4 (0.1 mol) (NaBH 4 or KBH 4 ), stir at room temperature for 2-8 hours until no hydrogen bubbles are generated, to obtain a THF solution of compound 1c (Ar = 2-Naph); cool to -10-10°C, add dehydronicotine (0.1 mol), gradually heat to 20-40°C and stir for reaction. After the reaction is complete, add hydrochloric acid to adjust the pH to 1-3, and extract with toluene to recover the chiral intermediate 6c ;
2)将20％NaOH加入萃取后的水溶液中，调节pH至碱性，用甲苯萃取，减压浓缩，所得残液进行减压蒸馏，馏出物即为手性尼古丁产品(无色液体)；基于脱氢烟碱的收率为83％，HPLC纯度99.2％，手性HPLC分析显示手性纯度为99.3％；LC-MS，
1H、
13CNMR符合相应数据。
2) adding 20% NaOH to the aqueous solution after extraction, adjusting the pH to alkaline, extracting with toluene, concentrating under reduced pressure, distilling the obtained residue under reduced pressure, and the distillate is the chiral nicotine product (colorless liquid); the yield based on dehydronicotine is 83%, the HPLC purity is 99.2%, and the chiral HPLC analysis shows that the chiral purity is 99.3%; LC-MS, 1 H, 13 C NMR are consistent with the corresponding data.
实施例5Example 5
本发明实施例提供一种经由手性还原剂合成手性尼古丁的方法，包括如下步骤：The embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
在实施例2的基础上合成化合物
2a和制备手性烟碱
Synthesis of Compound 2a and Preparation of Chiral Nicotine Based on Example 2
1)将化合物
6a(Ar＝Ph，0.1mol)加入LiBH
4(0.1mol)(NaBH
4或者KBH
4)的THF溶液中，加入HCl/THF溶液(0.1mol)，室温搅拌2-8小时，至无氢气气泡产生为止，即获得手性化合物
2a(Ar＝Ph)；降温至-10～10℃，加入脱氢烟碱(0.05-0.1mol)，逐渐升温至20-40℃搅拌反应，反应完毕，加入盐酸调节酸碱度至pH1-3，用甲苯萃取回收中间体
6a；
1) Add compound 6a (Ar＝Ph, 0.1mol) to a THF solution of LiBH 4 (0.1mol) (NaBH 4 or KBH 4 ), add HCl/THF solution (0.1mol), and stir at room temperature for 2-8 hours until no hydrogen bubbles are generated, thereby obtaining chiral compound 2a (Ar＝Ph); cool to -10-10°C, add dehydronicotine (0.05-0.1mol), gradually heat to 20-40°C, stir to react, and after the reaction is complete, add hydrochloric acid to adjust the pH to 1-3, and extract with toluene to recover intermediate 6a ;
2)将20％NaOH加入萃取后的水溶液中，调节pH至碱性，用甲苯萃取，减压浓缩，所 得残液进行减压蒸馏，馏出物无色液体即为手性尼古丁产品；还原反应收率86％，HPLC纯度98.1％，手性HPLC分析显示手性纯度为97.3％。2) adding 20% NaOH to the aqueous solution after extraction, adjusting the pH to alkaline, extracting with toluene, concentrating under reduced pressure, and distilling the obtained residual liquid under reduced pressure. The distillate is a colorless liquid, which is the chiral nicotine product; the reduction reaction yield is 86%, the HPLC purity is 98.1%, and the chiral HPLC analysis shows that the chiral purity is 97.3%.
实施例6Example 6
本发明实施例提供一种经由手性还原剂合成手性尼古丁的方法，包括如下步骤：The embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
在实施例3的基础上合成化合物
2b和制备手性烟碱
Synthesis of Compound 2b and Preparation of Chiral Nicotine Based on Example 3
1)将化合物
6b(Ar＝1-Naph，0.1mol)加入LiBH
4(0.1mol)(NaBH
4或者KBH
4)的THF溶液中，加入HCl/THF溶液(0.1mol)，室温搅拌2-8小时，至无氢气气泡产生为止，即获得手性化合物
2b(Ar＝1-Naph)；降温至-10～10℃，加入脱氢烟碱(0.05-0.1mol)，逐渐升温至20-40℃搅拌反应，反应完毕，加入盐酸调节酸碱度至pH1-3，用甲苯萃取回收手性中间体
6b；
1) Compound 6b (Ar = 1-Naph, 0.1 mol) is added to a THF solution of LiBH 4 (0.1 mol) (NaBH 4 or KBH 4 ), and HCl/THF solution (0.1 mol) is added, and stirred at room temperature for 2-8 hours until no hydrogen bubbles are generated, thereby obtaining a chiral compound 2b (Ar = 1-Naph); the temperature is lowered to -10 to 10°C, dehydronicotine (0.05 to 0.1 mol) is added, and the temperature is gradually raised to 20 to 40°C for stirring and reaction. After the reaction is completed, hydrochloric acid is added to adjust the pH to 1 to 3, and the chiral intermediate 6b is recovered by extraction with toluene;
2)将20％NaOH加入萃取后的水溶液中，调节pH至碱性。用甲苯萃取，减压浓缩，所得残液进行减压蒸馏，馏出物无色液体即为手性尼古丁产品；还原反应收率86％，HPLC纯度98.1％，手性HPLC分析显示手性纯度为97.3％。2) Add 20% NaOH to the aqueous solution after extraction to adjust the pH to alkaline. Extract with toluene, concentrate under reduced pressure, and distill the residue under reduced pressure. The distillate is a colorless liquid, which is the chiral nicotine product; the reduction reaction yield is 86%, the HPLC purity is 98.1%, and the chiral HPLC analysis shows that the chiral purity is 97.3%.
实施例7Example 7
本发明实施例提供一种经由手性还原剂合成手性尼古丁的方法，包括如下步骤：The embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
在实施例4的基础上合成化合物
2c和制备手性烟碱
Synthesis of Compound 2c and Preparation of Chiral Nicotine Based on Example 4
1)将化合物
6c(Ar＝2-Naph，0.1mol)加入LiBH
4(0.1mol)(NaBH
4或者KBH
4)的THF溶液中，加入HCl/THF溶液(0.1mol)，室温搅拌2-8小时，至无氢气气泡产生为止，即获得手性化合物
2c(Ar＝2-Naph)；降温至-10～10℃，加入脱氢烟碱(0.05-0.1mol)，逐渐升温至20-40℃搅拌反应，反应完毕，加入盐酸调节酸碱度至pH1-3，用甲苯萃取回收手性中间体
6c；
1) Compound 6c (Ar = 2-Naph, 0.1 mol) is added to a THF solution of LiBH 4 (0.1 mol) (NaBH 4 or KBH 4 ), and HCl/THF solution (0.1 mol) is added, and stirred at room temperature for 2-8 hours until no hydrogen bubbles are generated, thereby obtaining a chiral compound 2c (Ar = 2-Naph); the temperature is lowered to -10 to 10°C, dehydronicotine (0.05 to 0.1 mol) is added, and the temperature is gradually raised to 20 to 40°C for stirring and reaction. After the reaction is completed, hydrochloric acid is added to adjust the pH to 1 to 3, and the chiral intermediate 6c is recovered by extraction with toluene;
2)将20％NaOH加入萃取后的水溶液中，调节pH至碱性。用甲苯萃取，减压浓缩，所得残液进行减压蒸馏，馏出物无色液体即为手性尼古丁产品；还原反应收率86％，HPLC纯度98.1％，手性HPLC分析显示手性纯度为97.3％。2) Add 20% NaOH to the aqueous solution after extraction to adjust the pH to alkaline. Extract with toluene, concentrate under reduced pressure, and distill the residue under reduced pressure. The distillate is a colorless liquid, which is the chiral nicotine product; the reduction reaction yield is 86%, the HPLC purity is 98.1%, and the chiral HPLC analysis shows that the chiral purity is 97.3%.
以上所述的具体实施方式，对本发明的目的、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本发明的具体实施方式而已，并不用于限定本发明的保护范围，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.
Claims (4)
- 一种手性还原剂，其特征在于，所述手性还原剂为化合物 1、化合物 2、化合物 1或化合物 2的立体异构体； A chiral reducing agent, characterized in that the chiral reducing agent is compound 1 , compound 2 , or a stereoisomer of compound 1 or compound 2 ;化合物 1结构式如下所示： The structural formula of compound 1 is shown below:
化合物 2结构式如下所示： The structural formula of compound 2 is shown below:
其中，取代基团Ar为苯基、1-萘基或者2-萘基。Wherein, the substituent group Ar is phenyl, 1-naphthyl or 2-naphthyl. - 根据权利要求1所述一种手性还原剂，其特征在于，所述化合物 1或化合物 2的合成方法如下： A chiral reducing agent according to claim 1, characterized in that the synthesis method of compound 1 or compound 2 is as follows:1)将芳基卤化镁与丙叉保护的手性酒石酸甲酯 3反应得到四芳基衍生物 4； 1) reacting an aryl magnesium halide with a propylidene-protected chiral methyl tartrate 3 to obtain a tetraaryl derivative 4 ;2)将四芳基衍生物 4经催化氢解和水解去除丙叉保护基团后得到手性的1,1,4,4-四芳基-2,3-丁二醇 6； 2) subjecting the tetraaryl derivative 4 to catalytic hydrogenolysis and hydrolysis to remove the propylidene protecting group to obtain chiral 1,1,4,4-tetraaryl-2,3-butanediol 6 ;3)将四芳基丁二醇 6与金属硼氢化物或者硼烷反应得到化合物 1或化合物 2。 3) The tetraarylbutanediol 6 is reacted with a metal borohydride or borane to obtain compound 1 or compound 2 .其合成路线如下所示：Its synthetic route is as follows:
- 一种用于合成权利要求1-2任一所述手性还原剂的手性中间体，其特征在于，手性中间体为1,1,4,4-四芳基-2,3-丁二醇 6或其立体异构体，其结构式如下所示： A chiral intermediate for synthesizing a chiral reducing agent according to any one of claims 1 to 2, characterized in that the chiral intermediate is 1,1,4,4-tetraaryl-2,3-butanediol 6 or a stereoisomer thereof, and its structural formula is as follows:
- 一种经由手性还原剂合成手性尼古丁的方法，其特征在于，手性尼古丁的合成路线和操作步骤如下所示：A method for synthesizing chiral nicotine via a chiral reducing agent, characterized in that the synthesis route and operation steps of chiral nicotine are as follows:
(1)将权利要求1所述手性还原剂、脱氢尼古丁和溶剂混合，搅拌反应至脱氢尼古丁消失；(1) mixing the chiral reducing agent described in claim 1, dehydronicotine and a solvent, and stirring the mixture until the dehydronicotine disappears;(2)向反应液中加入酸，水解淬灭反应；(2) adding acid to the reaction solution to hydrolyze and quench the reaction;(3)用溶剂萃取回收手性中间体 6，回收的化合物 6可以套用； (3) Recovering chiral intermediate 6 by solvent extraction, the recovered compound 6 can be used in a variety of ways;(4)加入碱中和，用溶剂萃取、浓缩即得到手性尼古丁。(4) Add alkali for neutralization, extract with solvent and concentrate to obtain chiral nicotine.
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| CN104341390A (en) * | 2014-11-04 | 2015-02-11 | 南开大学 | Asymmetric synthesis method for botanical pesticide nicotine and anabasine |
| KR20180060319A (en) * | 2016-11-28 | 2018-06-07 | 가천대학교 산학협력단 | New synthetic method for [10B]-L-4-boronophenylalanine (LBPA) using [10B]pinacolborane |
| CN110357853A (en) * | 2019-08-05 | 2019-10-22 | 济南悟通生物科技有限公司 | The synthetic method of (R, S-) nicotine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104341390A (en) * | 2014-11-04 | 2015-02-11 | 南开大学 | Asymmetric synthesis method for botanical pesticide nicotine and anabasine |
| KR20180060319A (en) * | 2016-11-28 | 2018-06-07 | 가천대학교 산학협력단 | New synthetic method for [10B]-L-4-boronophenylalanine (LBPA) using [10B]pinacolborane |
| CN110357853A (en) * | 2019-08-05 | 2019-10-22 | 济南悟通生物科技有限公司 | The synthetic method of (R, S-) nicotine |
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| CRIEGEE, RUDOLF : "Über den Verlauf der Ozonspaltung (III. Mitteilung) = Ozonization cleavage. III.", JUSTUS LIEBIGS ANNALEN DER CHEMIE, VERLAG CHEMIE GMBH., DE, vol. 583, no. 1, 8 October 1953 (1953-10-08), DE , pages 1 - 36, XP009554463, ISSN: 0075-4617, DOI: 10.1002/jlac.19535830102 * |
| JÖRG PIETRUSZKA: "Enantiomerically pure cyclopropylboronic esters: auxiliary- versus substrate-control", ROYAL CHEMICAL SOCIETY. JOURNAL. PERKIN TRANSACTIONS 1, ROYAL SOCIETY OF CHEMISTRY, GB, no. 24, 1 January 2000 (2000-01-01), GB , pages 4293 - 4300, XP093159469, ISSN: 1470-4358, DOI: 10.1039/b006970l * |
| MASAKO NAKAGAWA ET AL.: "Asymmetric reductions of imines and ketiones by chiral oxaborolidines", TETRAHEDRON, vol. 49, no. 9, 31 December 1993 (1993-12-31), pages 1739 - 1748, XP026608057, DOI: 10.1016/S0040-4020(01)80531-7 * |
| TOMOHIKO KAWATE: "Asymmetric Reduction of Imines with Chiral Dia~koxyboranes", TETRAHEDRON: ASYMMETRY, vol. 3, no. 2, 1 January 1992 (1992-01-01), pages 227 - 230, XP093159468 * |
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