WO2023004918A1 - 一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法 - Google Patents
一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法 Download PDFInfo
- Publication number
- WO2023004918A1 WO2023004918A1 PCT/CN2021/115386 CN2021115386W WO2023004918A1 WO 2023004918 A1 WO2023004918 A1 WO 2023004918A1 CN 2021115386 W CN2021115386 W CN 2021115386W WO 2023004918 A1 WO2023004918 A1 WO 2023004918A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- chiral
- nicotine
- tert
- preparation
- butylsulfinamide
- Prior art date
Links
- 229960002715 nicotine Drugs 0.000 title claims abstract description 72
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 title claims abstract description 70
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 title claims abstract description 55
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 20
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims abstract description 18
- SWTDOBDFYXFIPN-UHFFFAOYSA-M magnesium;2-ethyl-1,3-dioxane;bromide Chemical compound [Mg+2].[Br-].[CH2-]CC1OCCCO1 SWTDOBDFYXFIPN-UHFFFAOYSA-M 0.000 claims abstract description 10
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical group [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims description 10
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- GXTVPHUMJMZDSF-UHFFFAOYSA-N 3-(3,4-dihydro-2h-pyrrol-2-yl)pyridine Chemical compound N1=CCCC1C1=CC=CN=C1 GXTVPHUMJMZDSF-UHFFFAOYSA-N 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- LFILDSDQMSCNBV-LURJTMIESA-N propane-2-sulfinamide Chemical compound CC(C)[S@@](N)=O LFILDSDQMSCNBV-LURJTMIESA-N 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 150000003456 sulfonamides Chemical class 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- YHWCPXVTRSHPNY-UHFFFAOYSA-N butan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-] YHWCPXVTRSHPNY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- HKJYVRJHDIPMQB-UHFFFAOYSA-N propan-1-olate;titanium(4+) Chemical compound CCCO[Ti](OCCC)(OCCC)OCCC HKJYVRJHDIPMQB-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 3
- 150000001408 amides Chemical class 0.000 claims 2
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 229910052719 titanium Inorganic materials 0.000 claims 1
- 239000010936 titanium Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 51
- 239000002994 raw material Substances 0.000 abstract description 11
- 239000003054 catalyst Substances 0.000 abstract description 10
- 230000002378 acidificating effect Effects 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 238000005902 aminomethylation reaction Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 229930182840 (S)-nicotine Natural products 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- -1 cyclic imine Chemical class 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000007069 methylation reaction Methods 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- MYKUKUCHPMASKF-VIFPVBQESA-N (S)-nornicotine Chemical compound C1CCN[C@@H]1C1=CC=CN=C1 MYKUKUCHPMASKF-VIFPVBQESA-N 0.000 description 3
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 3
- GXTVPHUMJMZDSF-VIFPVBQESA-N 3-[(2S)-3,4-dihydro-2H-pyrrol-2-yl]pyridine Chemical compound C1C[C@H](N=C1)c1cccnc1 GXTVPHUMJMZDSF-VIFPVBQESA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- BMQNAHRVOYMEED-XYOKQWHBSA-N (ne)-2-methyl-n-(pyridin-3-ylmethylidene)propane-2-sulfinamide Chemical compound CC(C)(C)S(=O)\N=C\C1=CC=CN=C1 BMQNAHRVOYMEED-XYOKQWHBSA-N 0.000 description 2
- BMQNAHRVOYMEED-AWEZNQCLSA-N 2-methyl-n-(pyridin-3-ylmethylidene)propane-2-sulfinamide Chemical compound CC(C)(C)[S@](=O)N=CC1=CC=CN=C1 BMQNAHRVOYMEED-AWEZNQCLSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- JYNXRXBIEHSSLR-UHFFFAOYSA-M [Br-].[Mg+]CCC1OCCCO1 Chemical compound [Br-].[Mg+]CCC1OCCCO1 JYNXRXBIEHSSLR-UHFFFAOYSA-M 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003571 electronic cigarette Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SNICXCGAKADSCV-SNVBAGLBSA-N (+)-nicotine Chemical group CN1CCC[C@@H]1C1=CC=CN=C1 SNICXCGAKADSCV-SNVBAGLBSA-N 0.000 description 1
- 229930182841 (R)-nicotine Natural products 0.000 description 1
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
- CESUXLKAADQNTB-ZETCQYMHSA-N 2-methylpropane-2-sulfinamide Chemical group CC(C)(C)[S@@](N)=O CESUXLKAADQNTB-ZETCQYMHSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 238000001308 synthesis method Methods 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the invention relates to the technical field of chemical synthesis, in particular to a preparation method for synthesizing chiral nicotine from chiral tert-butylsulfinamide.
- the patent with the publication number CN104341390A discloses a preparation method of chiral nicotine, which uses a cyclic imine as a starting material and requires an expensive chiral catalyst, and uses a chiral catalyst to induce the formation of a chiral center.
- the patent with publication number CN11233829A discloses a preparation method of optically active nicotine, using nitrogen-containing or phosphorus-containing chiral ligands to prepare organometallic catalysts, and preparing chiral nicotine with imide salt derivatives as starting materials.
- an organometallic catalyst prepared with a nitrogen-containing or phosphorus-containing chiral ligand is used as a chiral catalyst to induce the formation of a chiral center.
- the preparation method of the organometallic catalyst is relatively complicated and the production cost is relatively high. The applicant found that the use of a chiral catalyst makes the whole synthesis of chiral nicotine more reaction steps, resulting in a lower yield of chiral nicotine.
- Chiral tert-butyl sulfinamide is a widely sourced and inexpensive raw material, but there is no report on the synthesis of chiral nicotine using chiral tert-butyl sulfinamide as a raw material.
- the present application provides a preparation method for synthesizing chiral nicotine with chiral tert-butyl sulfinamide.
- the present application provides a preparation method for synthesizing chiral nicotine from chiral tert-butylsulfinamide, which is realized by the following technical scheme:
- a preparation method for synthesizing chiral nicotine by chiral tert-butyl sulfinamide comprising the steps:
- this application uses chiral tert-butyl sulfinamide as the starting raw material, chiral tert-butyl sulfinamide and 3-pyridine formaldehyde condensation reaction, and then through (1,3-dioxane-2 -Ethyl)magnesium bromide reaction, ring closure under acidic conditions, and finally reduction and amine methylation to obtain chiral nicotine.
- the reaction route for the synthesis of chiral nicotine in the present application is relatively short, and the raw materials are easy to obtain and cheap, which can reduce the production cost of chiral nicotine, and the reaction operation and processing operation of each step of the present application are all simple, and the chiral nicotine generated by the reaction can be recovered. High rate, high ee value.
- the preparation method for synthesizing chiral nicotine from chiral tert-butylsulfinamide provided by this application is a better method for synthesizing nicotine with a single configuration.
- the molar ratio of the 3-pyridinecarbaldehyde, chiral tert-butylsulfinamide and titanate is 1:1:(1 ⁇ 3); more preferably, the 3- The molar ratio of pyridinecarbaldehyde, chiral tert-butylsulfinamide and titanate is 1:1:2.
- the chiral tert-butyl sulfinamide can be (S)-tert-butyl sulfinamide or (R)-tert-butyl sulfinamide, which is determined by the configuration of the final product chiral nicotine .
- chiral tert-butyl sulfinamide is (S)-tert-butyl sulfinamide
- chiral nicotine is (S)-nicotine
- chiral tert-butyl sulfinamide is (R)-tert-butyl sulfinamide
- the chiral nicotine is (R)-nicotine.
- the titanate is selected from one or more of tetraethyl titanate, tetrapropyl titanate and tetrabutyl titanate; more preferably, the titanate For tetraethyl titanate.
- the solvent used in the S1 step is anhydrous tetrahydrofuran or dimethyltetrahydrofuran; preferably, the solvent used in the S1 step is anhydrous tetrahydrofuran.
- the temperature of the S1 step is 50-90°C; more preferably, the temperature of the S1 step is 60-80°C; most preferably, the temperature of the S1 step is 70°C.
- reaction time of the S1 step is 1.5-2.5 hours; preferably, the reaction time of the S1 step is 2 hours.
- the condensation reaction in the S1 step is carried out under nitrogen atmosphere.
- the nitrogen atmosphere can improve the activity of 3-pyridinecarbaldehyde, reduce the generation of other side reactions, and keep the configuration of chiral tert-butylsulfinamide, thereby improving the chiral 2-methyl-N-(pyridin-3-ylmethylene ) ee value and yield of propane-2-sulfinamide.
- post-treatment is required after the condensation reaction in step S1 to obtain chiral 2-methyl-N-(pyridin-3-ylmethylene)propane-2-sulfinamide.
- the post-treatment mainly includes adding brine to vigorous stirring, filtering, washing, liquid separation, extraction, water removal and solvent removal.
- the chiral-2-methyl-N-(pyridin-3-ylmethylene)propane-2-sulfinamide and (1,3-dioxane-2- The molar ratio of magnesium bromide is 1:(1.1 ⁇ 1.3); more preferably, the chiral-2-methyl-N-(pyridin-3-ylmethylene)propane-2-ylidene
- the molar ratio of sulfonamide to (1,3-dioxan-2-ylethyl)magnesium bromide is 1:1.225.
- the solvent used in the S2 step is tetrahydrofuran.
- the feeding sequence in the S2 step is: adding the chiral 2-methyl-N-(pyridin-3-ylmethylene)propane-2-sulfinamide prepared in the S1 step into tetrahydrofuran, and then The (1,3-dioxan-2-ylethyl)magnesium bromide solution was added dropwise.
- the reaction stage of the S2 step includes the reaction under nitrogen atmosphere and the reaction under sealing.
- the temperature of the reaction under the nitrogen atmosphere is -30° C., and the reaction time is 30 minutes.
- the temperature of the reaction under sealing is 0° C., and the reaction time is 3 h.
- the reaction solution needs to be heated, and the quenching reaction is performed after heating to 25°C.
- the reagent used in the quenching reaction is a mixed solution of saturated NH 4 Cl aqueous solution and ethyl acetate, and the volume ratio of saturated NH 4 Cl aqueous solution and ethyl acetate is 5:3.
- a post-treatment step is required to obtain chiral N-(3-(1,3-dioxan-2-yl)-1-(pyridin-3-yl) Propylene)-2-methylpropane-2-sulfinamide.
- the post-treatment steps mainly include liquid separation, extraction, washing, water removal and solvent removal.
- the pH of the acidic condition is 2-4; preferably, the pH of the acidic condition is 3, and the reagent used is a methanolic hydrochloric acid solution with an HCl content of 20 wt%.
- the chiral N-(3-(1,3-dioxan-2-yl)-1-(pyridin-3-yl)propylene)-2-methylpropane prepared in the S2 step -2-sulfinamide needs to be dissolved in tetrahydrofuran before it can be cyclized in methanolic hydrochloric acid solution.
- the reaction temperature of the cyclization in the step S3 is 20-30°C, and the reaction time is 1.5-2.5h; preferably, the reaction temperature of the cyclization in the step S3 is 25°C, and the reaction time is 2h.
- the cyclization reaction in the step S3 obtains a mixture containing chiral-3-(3,4-dihydro-2H-pyrrol-2-yl)pyridine.
- the reducing agent used in the reduction is sodium borohydride.
- Sodium borohydride reduces chiral 3-(3,4-dihydro-2H-pyrrol-2-yl)pyridine to chiral normethylnicotine.
- the molar ratio of the sodium borohydride to the chiral 3-(3,4-dihydro-2H-pyrrol-2-yl)pyridine is (1.5-2.5):1; more preferably Yes, the molar ratio of sodium borohydride to chiral 3-(3,4-dihydro-2H-pyrrol-2-yl)pyridine reduction is 2:1.
- the reaction temperature of the reduction is -5-5°C, and the reaction time is 2.5-3.5h; preferably, the reaction temperature of the reduction is 0°C, and the reaction time is 3h.
- the pH of the system needs to be adjusted to be alkaline before the amine methylation reaction.
- the amine methylation reaction requires the use of cesium carbonate and methyl iodide.
- the molar ratio of the chiral demethyl nicotine, cesium carbonate and methyl iodide is 1:(1.3 ⁇ 1.8):(1.1 ⁇ 1.3); more preferably, the chiral demethyl nicotine, cesium carbonate
- the molar ratio of cesium and methyl iodide is 1:1.5:1.2.
- the reaction temperature of the amine methylation reaction is 20-30°C, preferably 25°C, and the reaction time is 3h.
- This application provides a new synthesis method of chiral nicotine, using chiral tert-butyl sulfinamide as the starting raw material, the raw material is easy to get and cheap, chiral tert-butyl sulfinamide has provided a chiral center, no need High or complex chiral catalysts can be prepared to reduce the raw material cost of chiral nicotine.
- the chiral tert-butyl sulfinamide is condensed with 3-pyridine formaldehyde, then reacted with (1,3-dioxan-2-ylethyl)magnesium bromide, cyclized under acidic conditions, and finally reduced and Aminomethylation yields chiral nicotine.
- the reaction route of the whole synthesis is short, the operation of each reaction step is simple, the yield of the prepared chiral nicotine is high, the ee value is high, high purity can be realized after one purification, and the production cost of the chiral nicotine is reduced.
- the raw materials used in this application can all be obtained from the market. Unless otherwise specified, the raw materials not mentioned in this application were all purchased from Sinopharm Chemical Reagent Co., Ltd.
- Examples 1-15 provide a preparation method for synthesizing chiral nicotine from chiral tert-butylsulfinamide, and the following uses Example 1 as an example to illustrate.
- reaction solution was heated to 25° C., and a mixed solution of 0.5 L saturated NH 4 Cl aqueous solution and 0.3 L ethyl acetate was added to quench the reaction.
- Embodiment 2-3 differs from Example 1 only in that: in the S1 step reaction, the amount of titanate is adjusted, as shown in Table 1.
- Example 4 differs from Example 1 only in that in the S1 step reaction, the type of titanate is adjusted, as shown in Table 2 for details.
- Examples 5-7 differ from Example 1 only in that: in the S1 step reaction, the reaction temperature is adjusted, as shown in Table 3 for details.
- Examples 8-9 differ from Example 1 only in that: in the S1 step reaction, the type of solvent is adjusted, as shown in Table 4 for details.
- Examples 10-11 differ from Example 1 only in that: in the S2 step reaction, the amount of (1,3-dioxan-2-ylethyl)magnesium bromide is adjusted, as shown in the table 5.
- Example 12 differs from Example 1 only in that: in the S3 step reaction, the acidic conditions are adjusted, as shown in Table 6 for details.
- Example 13-14 The only difference between Examples 13-14 and Example 1 is that in the S4 step reaction, the reduction conditions are adjusted, as shown in Table 7 for details.
- Example 15 the only difference from Example 1 is that in the S1 step reaction, (S)-tert-butylsulfinamide is replaced by (R)-tert-butylsulfinamide in equimolar amounts, (R)- The yield of nicotine is 71%, the ee value is 98%, and the purity is 98%.
- Comparative Example 1 the only difference from Example 1 is: in the S1 step reaction, titanate is replaced by cesium carbonate in an equimolar manner, the yield of (S)-nicotine is 28%, the ee value is 97%, and the purity is 92% .
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,包括如下步骤:3-吡啶甲醛与手性叔丁基亚磺酰胺在钛酸酯的作用下进行缩合反应;再经(1,3-二恶烷-2-基乙基)溴化镁反应;经酸性条件下环合;最后经还原和胺甲基化,得手性尼古丁。本申请提供了一种新的手性尼古丁的合成方法,反应路线短,以手性叔丁基亚磺酰胺为起始原材料,原料易得、廉价,无需高昂或制备复杂的手性催化剂,且每步反应操作简单,反应生成的手性尼古丁的收率高、ee值高,降低了手性尼古丁的生产成本。
Description
本发明涉及化学合成技术领域,尤其是涉及一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法。
随着电子烟行业的迅猛发展,尼古丁作为电子烟的重要活性成分之一,需求日益增大,其中具有光学活性的单一构型的尼古丁受到人们的广泛关注。然而目前手性尼古丁的制备方法研究较少,基本是通过手性拆分的方法获得的,但手性拆分试剂昂贵,不利于工业化生产。
公开号为CN104341390A的专利公开了一种手性尼古丁的制备方法,以环状亚胺为起始原料,需要昂贵的手性催化剂,采用的是手性催化剂诱导形成手性中心。公开号为CN11233829A的专利公开了一种光学活性的尼古丁的制备方法,采用含氮或含磷的手性配体制备有机金属催化剂,以亚胺盐衍生物为起始原料制备了手性尼古丁,同样也是以含氮或含磷的手性配体制备的有机金属催化剂为手性催化剂诱导形成手性中心,该有机金属催化剂的制备方法较复杂,生产成本较高。本申请人发现,手性催化剂的使用使得整个合成手性尼古丁的反应步骤较多,导致手性尼古丁的收率较低。
手性叔丁基亚磺酰胺是一种来源较广且价廉的原料,但目前还未见以手性叔丁基亚磺酰胺为原材料合成手性尼古丁的报道。
发明内容
为了减少手性尼古丁的反应步骤,本申请提供一种手性叔丁基亚磺酰胺合成手性尼古丁的制备方法。
第一方面,本申请提供一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,采用如下技术方案实现:
一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,包括如下步骤:
S1、3-吡啶甲醛与手性叔丁基亚磺酰胺在钛酸酯的作用下进行缩合反应,得手性2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺;
S2、手性-2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺与(1,3-二恶烷-2-基乙基)溴化镁反应,得手性N-(3-(1,3-二恶烷-2-基)-1-(吡啶-3-基)亚丙基)-2-甲基丙烷-2-亚磺酰胺;
S3、手性N-(3-(1,3-二恶烷-2-基)-1-(吡啶-3-基)亚丙基)-2-甲基丙烷-2-亚磺酰胺在酸 性条件下进行环合,得手性3-(3,4-二氢-2H-吡咯-2-基)吡啶;
S4、手性3-(3,4-二氢-2H-吡咯-2-基)吡啶经还原和胺甲基化,得手性尼古丁。
通过采取上述技术方案,本申请以手性叔丁基亚磺酰胺为起始原材料,手性叔丁基亚磺酰胺与3-吡啶甲醛缩合反应,再经(1,3-二恶烷-2-基乙基)溴化镁反应,经酸性条件下环合,最后经还原和胺甲基化,得手性尼古丁。本申请合成手性尼古丁的反应路线较短,原料易得且价廉,可以降低手性尼古丁的生产成本,且本申请的每步反应操作及处理操作均简单,反应生成的手性尼古丁的收率高、ee值高。本申请提供的由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法是一种合成单一构型的尼古丁的较优方法。
优选的,所述S1步骤中,所述3-吡啶甲醛、手性叔丁基亚磺酰胺和钛酸酯的摩尔比为1:1:(1~3);更优选的,所述3-吡啶甲醛、手性叔丁基亚磺酰胺和钛酸酯的摩尔比为1:1:2。
本申请中,所述手性叔丁基亚磺酰胺可以为(S)-叔丁基亚磺酰胺或(R)-叔丁基亚磺酰胺,是由最终产物手性尼古丁的构型决定的。当手性叔丁基亚磺酰胺为(S)-叔丁基亚磺酰胺时,手性尼古丁为(S)-尼古丁;当手性叔丁基亚磺酰胺为(R)-叔丁基亚磺酰胺时,手性尼古丁为(R)-尼古丁。
优选的,所述S1步骤中,所述钛酸酯选自钛酸四乙酯、钛酸四丙酯和钛酸四丁酯中的一种或多种;更优选的,所述钛酸酯为钛酸四乙酯。
优选的,所述S1步骤使用的溶剂为无水四氢呋喃或二甲基四氢呋喃;优选的,所述S1步骤使用的溶剂为无水四氢呋喃。
优选的,所述S1步骤的温度为50~90℃;更优选的,所述S1步骤的温度为60~80℃;最优选的,所述S1步骤的温度为70℃。
本申请中,所述S1步骤的反应时间为1.5~2.5h;优选的,所述S1步骤的反应时间为2h。
本申请中,所述S1步骤中缩合反应在氮气氛围下反应。氮气氛围可以提高3-吡啶甲醛的活性,减少其他副反应生成,保持手性叔丁基亚磺酰胺的构型,从而提高手性2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺的ee值和产率。
本申请中,所述S1步骤中缩合反应后还需要后处理才能得到手性2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺。该后处理主要包括加入盐水中剧烈搅拌、过滤、洗涤、分液、萃取、除水和除溶剂。
优选的,所述S2步骤中,所述手性-2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺和(1,3-二恶烷-2-基乙基)溴化镁的摩尔比为1:(1.1~1.3);更优选的,所述手性-2-甲基-N- (吡啶-3-基亚甲基)丙烷-2-亚磺酰胺和(1,3-二恶烷-2-基乙基)溴化镁的摩尔比为1:1.225。
本申请中,所述S2步骤中使用的溶剂为四氢呋喃。
本申请中,所述S2步骤中的加料顺序为:将S1步骤制备的手性2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺加入四氢呋喃中,再逐滴添加(1,3-二恶烷-2-基乙基)溴化镁溶液。
本申请中,所述S2步骤的反应阶段包括氮气氛围下的反应和密封下的反应。所述氮气氛围下的反应的温度为-30℃,反应时间为30min。所述密封下的反应的温度为0℃,反应时间为3h。
本申请中,所述S2步骤中密封下的反应后需要对反应液进行加热,加热至25℃后进行猝灭反应。所述猝灭反应采用的试剂为饱和NH
4Cl水溶液和乙酸乙酯的混合溶液,饱和NH
4Cl水溶液和乙酸乙酯的体积比为5:3。
本申请中,所述S2步骤中猝灭反应后还需要后处理步骤才能得到手性N-(3-(1,3-二恶烷-2-基)-1-(吡啶-3-基)亚丙基)-2-甲基丙烷-2-亚磺酰胺。该后处理步骤主要包括分液、萃取、洗涤、除水和除溶剂。
优选的,所述S3步骤中,所述酸性条件的pH为2~4;优选的,所述酸性条件的pH为3,采用的试剂为HCl含量20wt%的盐酸甲醇溶液。
本申请中,所述S2步骤制备的手性N-(3-(1,3-二恶烷-2-基)-1-(吡啶-3-基)亚丙基)-2-甲基丙烷-2-亚磺酰胺需要先溶于四氢呋喃中才能在盐酸甲醇溶液中环合。
本申请中,所述S3步骤中环合的反应温度为20~30℃,反应时间为1.5~2.5h;优选的,所述S3步骤中环合的反应温度为25℃,反应时间为2h。
本申请中,所述S3步骤中环合反应得含手性-3-(3,4-二氢-2H-吡咯-2-基)吡啶的混合物。
优选的,所述S4步骤中,所述还原使用的还原剂为硼氢化钠。硼氢化钠将手性3-(3,4-二氢-2H-吡咯-2-基)吡啶还原为手性去甲基尼古丁。
优选的,所述S4步骤中,所述硼氢化钠和手性3-(3,4-二氢-2H-吡咯-2-基)吡啶的摩尔比为(1.5~2.5):1;更优选的,所述硼氢化钠与手性3-(3,4-二氢-2H-吡咯-2-基)吡啶还原的摩尔比为2:1。
本申请中,所述S4步骤中,所述还原的反应温度为-5~5℃,反应时间为2.5~3.5h;优选的,所述还原的反应温度为0℃,反应时间为3h。
本申请中,所述S4步骤中,所述胺甲基化反应之前需要调节体系的pH为碱性。
本申请中,所述S4步骤中,所述胺甲基化反应需要使用碳酸铯和碘甲烷。
本申请中,所述手性去甲基尼古丁、碳酸铯和碘甲烷的摩尔比为1:(1.3~1.8):(1.1~1.3);更优选的,所述手性去甲基尼古丁、碳酸铯和碘甲烷的摩尔比为1:1.5:1.2。
本申请中,所述S4步骤中,所述胺甲基化反应的反应温度为20~30℃,优选为25℃,反应时间为3h。
本申请中,所述S4步骤中,所述胺甲基化反应后需要加酸调节体系的pH为中性,萃取,有机相经Na
2SO
4干燥,减压浓缩得手性尼古丁粗品,最后经一次常压蒸馏纯化,得手性尼古丁。
综上所述,本申请具有以下有益效果:
本申请提供了一种新的手性尼古丁的合成方法,以手性叔丁基亚磺酰胺为起始原材料,原料易得、廉价,手性叔丁基亚磺酰胺已经提供手性中心,无需高昂或制备复杂的手性催化剂,降低手性尼古丁的原料成本。且手性叔丁基亚磺酰胺与3-吡啶甲醛缩合反应,再经(1,3-二恶烷-2-基乙基)溴化镁反应,经酸性条件下环合,最后经还原和胺甲基化,得手性尼古丁。整个合成的反应路线短,每步反应操作简单,制备的手性尼古丁的收率高、ee值高,一次纯化后即可实现高纯度,降低了手性尼古丁的生产成本。
以下结合实施例对本申请作进一步详细说明。
本申请使用的原料均可通过市售获得,若无特殊说明,本申请未提及的原料均购买自国药集团化学试剂有限公司。
实施例1-15提供了一种手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,以下以实施例1为例进行说明。
实施例1提供的手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,其中,所述手性叔丁基亚磺酰胺为S-叔丁基亚磺酰胺,所述手性尼古丁为S-手性尼古丁,其合成路线如反应式1所示:
具体的制备步骤为:
S1、在氮气氛围下,将106.7g(1mol,1eq)3-吡啶甲醛、121.7g(1mol,1eq)(S)-叔丁基亚磺酰胺和455.5g(2mol,2eq)钛酸四乙酯溶解在6L无水四氢呋喃中,在70℃反应2h,反应结束后将反应液倒入10L饱和食盐水溶液中,以1000rpm的速度搅拌15min,过滤,取滤液,并用3L乙酸乙酯洗涤滤饼,收集滤液,将滤液分液,水层用6L乙酸乙酯-水(乙酸乙酯和水的体积比为2:1)萃取3次,合并有机层,用3L饱和食盐水溶液洗涤有机层,经无水Na
2SO
4干燥并真空浓缩去除溶剂,得淡黄色油状液体(S,E)-2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺。
S2、向S1步骤制得的(S,E)-2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺中加入8L四氢呋喃,混合均匀,在-30℃氮气氛围下,逐滴加入2.45L 0.5mol/L的(1,3-二恶烷-2-基乙基)溴化镁的四氢呋喃溶液(其中,(1,3-二恶烷-2-基乙基)溴化镁1.225mol,1.225eq),在-30℃、400rpm的条件下搅拌反应30min。然后去除氮气,密封反应容器,在0℃、400rpm的条件下搅拌反应3h。反应结束后将反应液加热至25℃,加入0.5L饱和NH
4Cl水溶液和0.3L乙酸乙酯的混合溶液进行猝灭反应。猝灭反应结束后对反应液进行分液,分离出有机层和水层,用10L乙酸乙酯萃取水层3次,分液,取水层中的有机层,合并所有的有机层,用15L饱和食盐水洗涤合并的有机层,用无水硫酸镁干燥,过滤并真空浓缩除去溶剂,得(S,E)-N-(3-(1,3-二恶烷-2-基)-1-(吡啶-3-基)亚丙基)-2-甲基丙烷-2-亚磺酰胺。
S3、向S2步骤制得的(S,E)-N-(3-(1,3-二恶烷-2-基)-1-(吡啶-3-基)亚丙基)-2-甲基丙烷-2-亚磺酰胺中加入8L四氢呋喃,加入HCl含量20wt%的盐酸甲醇溶液调节体系pH为3,在25℃反应2h,得含(S)-3-(3,4-二氢-2H-吡咯-2-基)吡啶的混合物;
S4、向S3步骤制得的含(S)-3-(3,4-二氢-2H-吡咯-2-基)吡啶的混合物中加入75.66g(2mol,2eq)硼氢化钠,在0℃反应3h,将(S)-3-(3,4-二氢-2H-吡咯-2-基)吡啶还原为(S)-去甲基尼古丁,得含(S)-去甲基尼古丁的混合液。用4mol/L NaOH调节含(S)-去甲基尼古丁的混合液的pH为9,再加入488.3g(1.5mol,1.5eq)碳酸铯和170g(1.2mmol,1.2eq)碘甲烷,25℃反应3h,用5mol/L HCl调节体系的pH为7,再用15L饱和食盐水和15L二氯甲烷萃取反应液,收集有机相,有机相中加入无水Na
2SO
4干燥,减压浓缩蒸干溶剂,得(S)-尼古丁粗品,再经过一次常压蒸馏纯化,得(S)-尼古丁,收率72%,ee值98%,纯度98%。
实施例2-3,与实施例1不同之处仅在于:所述S1步骤反应中,对钛酸酯的用量进行 调整,具体如表1所示。
表1钛酸酯的用量对(S)-尼古丁收率的影响
编号 | 钛酸酯的当量数(eq) | (S)-尼古丁收率(%) |
实施例1 | 2 | 72 |
实施例2 | 1 | 43 |
实施例3 | 3 | 68 |
实施例4,与实施例1不同之处仅在于:所述S1步骤反应中,对钛酸酯的种类进行调整,具体如表2所示。
表2钛酸酯的选择对(S)-尼古丁收率的影响
编号 | 钛酸酯选择 | (S)-尼古丁收率(%) |
实施例1 | 钛酸四乙酯 | 72 |
实施例4 | 钛酸四丁酯 | 70 |
实施例5-7,与实施例1不同之处仅在于:所述S1步骤反应中,对反应温度进行调整,具体如表3所示。
表3反应温度的对(S)-尼古丁收率的影响
编号 | 反应温度(℃) | (S)-尼古丁收率(%) |
实施例1 | 70 | 72 |
实施例5 | 90 | 65 |
实施例6 | 80 | 68 |
实施例7 | 50 | 54 |
实施例8-9,与实施例1不同之处仅在于:所述S1步骤反应中,对溶剂的种类进行调整,具体如表4所示。
表4溶剂对(S)-尼古丁收率的影响
编号 | 溶剂选择 | (S)-尼古丁收率(%) |
实施例1 | 无水四氢呋喃 | 72 |
实施例8 | 二甲基四氢呋喃 | 70 |
实施例9 | 二氯甲烷 | 53 |
实施例10-11,与实施例1不同之处仅在于:所述S2步骤反应中,对(1,3-二恶烷-2-基乙基)溴化镁的用量进行调整,具体如表5所示。
表5(1,3-二恶烷-2-基乙基)溴化镁用量对(S)-尼古丁收率的影响
实施例12,与实施例1不同之处仅在于:所述S3步骤反应中,对酸性条件进行调整,具体如表6所示。
表6酸性条件对(S)-尼古丁收率的影响
编号 | 酸性条件 | (S)-尼古丁收率(%) |
实施例1 | HCl含量20wt%的盐酸甲醇溶液 | 72 |
实施例12 | 90wt%的三氟醋酸水溶液 | 68 |
实施例13-14,与实施例1不同之处仅在于:所述S4步骤反应中,对还原条件进行调整,具体如表7所示。
表7还原条件对(S)-尼古丁收率的影响
编号 | 还原条件 | (S)-尼古丁收率(%) |
实施例1 | 硼氢化钠 | 72 |
实施例13 | 三乙酰基硼氢化钠 | 30 |
实施例14 | 连二亚硫酸钠 | 50 |
实施例15,与实施例1不同之处仅在于:所述S1步骤反应中,(S)-叔丁基亚磺酰胺等摩尔替换为(R)-叔丁基亚磺酰胺,(R)-尼古丁的收率71%,ee值98%,纯度98%。
对比例
对比例1,与实施例1不同之处仅在于:所述S1步骤反应中,钛酸酯等摩尔替换为碳酸铯,(S)-尼古丁的收率28%,ee值97%,纯度92%。
本具体实施例仅仅是对本申请的解释,其并不是对本申请的限制,本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改,但只要在本申请的权利要求范围内都受到专利法的保护。
Claims (10)
- 一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,其特征在于,包括如下步骤:S1、3-吡啶甲醛与手性叔丁基亚磺酰胺在钛酸酯的作用下进行缩合反应,得手性2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺;S2、手性-2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺与(1,3-二恶烷-2-基乙基)溴化镁反应,得手性N-(3-(1,3-二恶烷-2-基)-1-(吡啶-3-基)亚丙基)-2-甲基丙烷-2-亚磺酰胺;S3、手性N-(3-(1,3-二恶烷-2-基)-1-(吡啶-3-基)亚丙基)-2-甲基丙烷-2-亚磺酰胺在酸性条件下进行环合,得手性3-(3,4-二氢-2H-吡咯-2-基)吡啶;S4、手性3-(3,4-二氢-2H-吡咯-2-基)吡啶经还原和胺甲基化,得手性尼古丁。
- 根据权利要求1所述的一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,其特征在于,所述S1步骤中,所述3-吡啶甲醛、手性叔丁基亚磺酰胺和钛酸酯的摩尔比为1:1:(1~3)。
- 根据权利要求2所述的一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,其特征在于,所述S1步骤中,所述3-吡啶甲醛、手性叔丁基亚磺酰胺和钛酸酯的摩尔比为1:1:2。
- 根据权利要求1所述的一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,其特征在于,所述S1步骤中,所述钛酸酯选自钛酸四乙酯、钛酸四丙酯和钛酸四丁酯中的一种或多种。
- 根据权利要求1所述的一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,其特征在于,所述S1步骤的温度为30~70℃。
- 根据权利要求1所述的一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,其特征在于,所述S1步骤使用的溶剂为无水四氢呋喃或二甲基四氢呋喃。
- 根据权利要求1所述的一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,其特征在于,所述S2步骤中,所述手性-2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺和(1,3-二恶烷-2-基乙基)溴化镁的摩尔比为1:(1.1~1.3)。
- 根据权利要求7所述的一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,其特征在于,所述S2步骤中,所述手性-2-甲基-N-(吡啶-3-基亚甲基)丙烷-2-亚磺酰胺和(1,3-二恶烷-2-基乙基)溴化镁的摩尔比为1:1.225。
- 根据权利要求1所述的一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,其特征在于,所述S4步骤中,所述还原使用的还原剂为硼氢化钠。
- 根据权利要求9所述的一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法,其特征在于,所述硼氢化钠和手性3-(3,4-二氢-2H-吡咯-2-基)吡啶的摩尔比为(1.5~2.5):1。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP21810887.6A EP4151628A4 (en) | 2021-07-28 | 2021-08-30 | PRODUCTION PROCESS FOR SYNTHESIS OF CHIRAL NICOTINE FROM CHIRAL TERT-BUTYLSULFINAMIDE |
US17/547,242 US20230092227A1 (en) | 2021-07-28 | 2021-12-10 | Preparation method for synthesizing chiral nicotine from chiral tert-butylsulfenamide |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110860273.3A CN113444070A (zh) | 2021-07-28 | 2021-07-28 | 一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法 |
CN202110860273.3 | 2021-07-28 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/547,242 Continuation US20230092227A1 (en) | 2021-07-28 | 2021-12-10 | Preparation method for synthesizing chiral nicotine from chiral tert-butylsulfenamide |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023004918A1 true WO2023004918A1 (zh) | 2023-02-02 |
Family
ID=77817483
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2021/115386 WO2023004918A1 (zh) | 2021-07-28 | 2021-08-30 | 一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法 |
Country Status (4)
Country | Link |
---|---|
US (1) | US20230092227A1 (zh) |
EP (1) | EP4151628A4 (zh) |
CN (1) | CN113444070A (zh) |
WO (1) | WO2023004918A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113999084B (zh) * | 2021-11-03 | 2024-04-16 | 成昌梅 | 一种(s)-(-)-尼古丁的合成制备方法 |
CN113979993B (zh) * | 2021-11-29 | 2023-10-13 | 云南萃精生物科技有限责任公司 | 一种不对称合成(s)-烟碱的方法 |
CN114437029A (zh) * | 2022-01-24 | 2022-05-06 | 深圳市华加生物科技有限公司 | 不对称合成手性尼古丁的制备方法及手性尼古丁 |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1233829A (zh) | 1998-04-28 | 1999-11-03 | 索尼株式会社 | 盘片装载装置 |
WO2012021712A1 (en) * | 2010-08-12 | 2012-02-16 | Tetraphase Pharmaceuticals, Inc. | Tetracycline analogs |
WO2014036502A2 (en) * | 2012-08-31 | 2014-03-06 | Tetraphase Pharmaceuticals, Inc. | Tetracycline compounds |
CN104341390A (zh) | 2014-11-04 | 2015-02-11 | 南开大学 | 一种植物源农药烟碱和毒藜碱的不对称合成方法 |
WO2017201241A1 (en) * | 2016-05-18 | 2017-11-23 | Mark Reynolds | Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y l)-3-hydroxypyrrolidine-1-carboxamide |
WO2018081417A2 (en) * | 2016-10-26 | 2018-05-03 | Qian Zhao | PROCESS FOR THE PREPARATION OF PYRAZOLO[1,5-a]PYRIMIDINES AND SALTS THEREOF |
CN109053525A (zh) * | 2018-09-25 | 2018-12-21 | 成都福柯斯医药技术有限公司 | 一种(r)-2-(2-取代-5-氟苯)吡咯烷的制备方法 |
WO2020039209A1 (en) * | 2018-08-23 | 2020-02-27 | Benevolentai Bio Limited | Imidazo[1,2-b]pyridazines as trk inhibitors |
WO2020108415A1 (zh) * | 2018-11-30 | 2020-06-04 | 成都先导药物开发股份有限公司 | 一种trk激酶抑制剂化合物的中间体化合物及制备方法 |
CN112624950A (zh) * | 2020-12-10 | 2021-04-09 | 北京蓝博特科技有限公司 | 一种(r)-2-(2,5-二氟苯基)吡咯烷的合成方法 |
CN112679421A (zh) * | 2021-01-04 | 2021-04-20 | 都创(上海)医药科技股份有限公司 | 一种(r)-3-氯吡啶基-2-三氟乙胺盐酸盐的合成方法 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20190247398A1 (en) * | 2017-10-26 | 2019-08-15 | Array Biopharma Inc. | Formulations of a macrocyclic trk kinase inhibitor |
JP2021512960A (ja) * | 2018-02-06 | 2021-05-20 | シャンハイ ハイファ ファーマシューティカル カンパニー,リミティッド | Bet阻害活性を有する化合物並びにその製造方法及び使用 |
CN110156813B (zh) * | 2018-02-13 | 2023-07-25 | 北京诺诚健华医药科技有限公司 | 作为trk抑制剂的杂环化合物 |
CN110627812B (zh) * | 2018-06-25 | 2022-10-11 | 北京诺诚健华医药科技有限公司 | 作为trk抑制剂的杂环化合物 |
WO2021042890A1 (zh) * | 2019-09-04 | 2021-03-11 | 罗欣药业(上海)有限公司 | 杂环化合物及其作为Trk激酶抑制剂的应用 |
CN112876461B (zh) * | 2021-01-20 | 2022-12-30 | 上海零诺生物科技有限公司 | 尼古丁及其中间体的制备方法 |
-
2021
- 2021-07-28 CN CN202110860273.3A patent/CN113444070A/zh active Pending
- 2021-08-30 WO PCT/CN2021/115386 patent/WO2023004918A1/zh unknown
- 2021-08-30 EP EP21810887.6A patent/EP4151628A4/en active Pending
- 2021-12-10 US US17/547,242 patent/US20230092227A1/en active Pending
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1233829A (zh) | 1998-04-28 | 1999-11-03 | 索尼株式会社 | 盘片装载装置 |
WO2012021712A1 (en) * | 2010-08-12 | 2012-02-16 | Tetraphase Pharmaceuticals, Inc. | Tetracycline analogs |
WO2014036502A2 (en) * | 2012-08-31 | 2014-03-06 | Tetraphase Pharmaceuticals, Inc. | Tetracycline compounds |
CN104341390A (zh) | 2014-11-04 | 2015-02-11 | 南开大学 | 一种植物源农药烟碱和毒藜碱的不对称合成方法 |
WO2017201241A1 (en) * | 2016-05-18 | 2017-11-23 | Mark Reynolds | Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y l)-3-hydroxypyrrolidine-1-carboxamide |
WO2018081417A2 (en) * | 2016-10-26 | 2018-05-03 | Qian Zhao | PROCESS FOR THE PREPARATION OF PYRAZOLO[1,5-a]PYRIMIDINES AND SALTS THEREOF |
WO2020039209A1 (en) * | 2018-08-23 | 2020-02-27 | Benevolentai Bio Limited | Imidazo[1,2-b]pyridazines as trk inhibitors |
CN109053525A (zh) * | 2018-09-25 | 2018-12-21 | 成都福柯斯医药技术有限公司 | 一种(r)-2-(2-取代-5-氟苯)吡咯烷的制备方法 |
WO2020108415A1 (zh) * | 2018-11-30 | 2020-06-04 | 成都先导药物开发股份有限公司 | 一种trk激酶抑制剂化合物的中间体化合物及制备方法 |
CN112624950A (zh) * | 2020-12-10 | 2021-04-09 | 北京蓝博特科技有限公司 | 一种(r)-2-(2,5-二氟苯基)吡咯烷的合成方法 |
CN112679421A (zh) * | 2021-01-04 | 2021-04-20 | 都创(上海)医药科技股份有限公司 | 一种(r)-3-氯吡啶基-2-三氟乙胺盐酸盐的合成方法 |
Non-Patent Citations (2)
Title |
---|
GWENDOLYN A. MARRINER, SEAN M. KERWIN: "An Improved Synthesis of (±)- N ′-Nitrosonornicotine 5′-Acetate", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 74, no. 7, 3 April 2009 (2009-04-03), pages 2891 - 2892, XP055329311, ISSN: 0022-3263, DOI: 10.1021/jo9000417 * |
See also references of EP4151628A4 |
Also Published As
Publication number | Publication date |
---|---|
EP4151628A4 (en) | 2024-01-10 |
CN113444070A (zh) | 2021-09-28 |
EP4151628A1 (en) | 2023-03-22 |
US20230092227A1 (en) | 2023-03-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2023004918A1 (zh) | 一种由手性叔丁基亚磺酰胺合成手性尼古丁的制备方法 | |
WO2023284058A1 (zh) | 一种手性合成尼古丁的制备方法 | |
JP6799178B2 (ja) | 4−メトキシピロール誘導体の中間体の製造方法 | |
WO2016180275A1 (zh) | Ahu-377的制备方法、ahu-377中间体及ahu-377中间体的制备方法 | |
US7332614B2 (en) | Process for cross coupling indoles | |
CN108675943A (zh) | 一种沙库巴曲关键中间体的制备方法 | |
CN105254575B (zh) | 一种磺胺嘧啶的合成方法 | |
CN111320587A (zh) | 一种1h-1,2,3-三氮唑的制备方法 | |
CN113475739B (zh) | 一种s-尼古丁的制备方法 | |
CN110256441A (zh) | 一种巴瑞克替尼的制备方法 | |
JPH04225975A (ja) | N−[3−(1h−イミダゾール−1−イル)フエニル]−4−(置換)−2−ピリミジナミン合成の改良法 | |
CN112174837B (zh) | 一种合成(R)-4-甲氧基-α-甲基苯乙胺的方法 | |
CN109020977B (zh) | 一种Acalabrutinib的制备方法 | |
RU2781546C1 (ru) | Способ получения для синтеза хирального никотина из хирального трет-бутансульфинамида | |
CN106660984A (zh) | 杂芳基羧酸酯衍生物的制造方法、其制造中间体及晶体 | |
CN112851508A (zh) | 一种巴洛沙韦中间体的制备方法 | |
CN116444485B (zh) | 吡啶基取代不对称脲的非金属催化、免柱层析合成方法 | |
CN111004239A (zh) | 一种依替鲁尼的前体制备方法 | |
CN108586486A (zh) | 一种芳基取代噻吩并嘧啶类化合物的制备方法 | |
CN110551069B (zh) | 一种5-苯基戊醇类化合物及其中间体的合成方法 | |
KR20100020513A (ko) | 발사르탄을 제조하는데 효과적인 발사르탄 염 제조 방법 | |
CN107628968B (zh) | 一种简便合成1-氨基-1-腈基-环丙烷的方法 | |
CN115010639B (zh) | 一种中间体化合物及其制备方法和应用 | |
CN112574164B (zh) | 基于手性联萘酚合成手性螺环分子的方法 | |
CN111170927B (zh) | 一种沙格列汀中间体的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
ENP | Entry into the national phase |
Ref document number: 2021810887 Country of ref document: EP Effective date: 20211202 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |