KR20240019894A - Synthetic method of (S)-nicotine, and (S)-nicotine prepared by this method - Google Patents
Synthetic method of (S)-nicotine, and (S)-nicotine prepared by this method Download PDFInfo
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- KR20240019894A KR20240019894A KR1020220097684A KR20220097684A KR20240019894A KR 20240019894 A KR20240019894 A KR 20240019894A KR 1020220097684 A KR1020220097684 A KR 1020220097684A KR 20220097684 A KR20220097684 A KR 20220097684A KR 20240019894 A KR20240019894 A KR 20240019894A
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- nolnicotine
- nicotine
- solution
- racemic
- solvent
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- 229960002715 nicotine Drugs 0.000 title claims abstract description 50
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 37
- 229930182840 (S)-nicotine Natural products 0.000 title claims description 27
- 238000010189 synthetic method Methods 0.000 title 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims abstract description 30
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 15
- 230000001035 methylating effect Effects 0.000 claims abstract description 11
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims abstract description 7
- WMJNKBXKYHXOHC-PMACEKPBSA-N (2S,3S)-2,3-dihydroxy-2,3-bis(2-methylbenzoyl)butanedioic acid Chemical compound C=1(C(=CC=CC1)C(=O)[C@]([C@](C(=O)O)(O)C(=O)C=1C(=CC=CC1)C)(O)C(=O)O)C WMJNKBXKYHXOHC-PMACEKPBSA-N 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- 239000002904 solvent Substances 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 15
- 239000011259 mixed solution Substances 0.000 claims description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229940035423 ethyl ether Drugs 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000000284 extract Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 229940093499 ethyl acetate Drugs 0.000 claims description 9
- 235000019439 ethyl acetate Nutrition 0.000 claims description 9
- 235000019253 formic acid Nutrition 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- 229940073584 methylene chloride Drugs 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229960001270 d- tartaric acid Drugs 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- IRJNJBIOUYJBHG-LARVRRBISA-N 3-[(2S)-1-methylpyrrolidin-2-yl]pyridine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1.CN1CCC[C@H]1C1=CC=CN=C1 IRJNJBIOUYJBHG-LARVRRBISA-N 0.000 claims 1
- 238000004140 cleaning Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 abstract description 18
- 238000009938 salting Methods 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 9
- MYKUKUCHPMASKF-VIFPVBQESA-N (S)-nornicotine Chemical compound C1CCN[C@@H]1C1=CC=CN=C1 MYKUKUCHPMASKF-VIFPVBQESA-N 0.000 description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- MYKUKUCHPMASKF-UHFFFAOYSA-N Nornicotine Natural products C1CCNC1C1=CC=CN=C1 MYKUKUCHPMASKF-UHFFFAOYSA-N 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- SNICXCGAKADSCV-SNVBAGLBSA-N (+)-nicotine Chemical compound CN1CCC[C@@H]1C1=CC=CN=C1 SNICXCGAKADSCV-SNVBAGLBSA-N 0.000 description 5
- 229930182841 (R)-nicotine Natural products 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 241000208125 Nicotiana Species 0.000 description 4
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 4
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 4
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229960003638 dopamine Drugs 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 210000001577 neostriatum Anatomy 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 244000061176 Nicotiana tabacum Species 0.000 description 2
- 206010057852 Nicotine dependence Diseases 0.000 description 2
- 208000025569 Tobacco Use disease Diseases 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- IRJNJBIOUYJBHG-UHFFFAOYSA-N 3-(1-methylpyrrolidin-2-yl)pyridine Chemical compound CN1CCCC1C1=CC=CN=C1.CN1CCCC1C1=CC=CN=C1 IRJNJBIOUYJBHG-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000589776 Pseudomonas putida Species 0.000 description 1
- 241000813090 Rhizoctonia solani Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 102000015296 acetylcholine-gated cation-selective channel activity proteins Human genes 0.000 description 1
- 108040006409 acetylcholine-gated cation-selective channel activity proteins Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- DPNGWXJMIILTBS-UHFFFAOYSA-N dehydronornicotine Natural products C1CCN=C1C1=CC=CN=C1 DPNGWXJMIILTBS-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- -1 inhaler Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 238000002670 nicotine replacement therapy Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000004885 tandem mass spectrometry 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
- C07B57/00—Separation of optically-active compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
본 발명은 합성 라세믹(racemic) 놀니코틴으로부터 S-놀니코틴을 얻기위해 카이랄 분리 방법 및 이 방법에 의해 제조된 S-놀니코틴, (S)-놀니코틴을 메틸화시켜서 합성 S-니코틴을 합성하는 방법 및 이에 의하여 제조된 합성 S-니코틴에 관한 것으로, 보다 상세하게는 라세믹 놀니코틴을 합성하고, Ditoluoyl-L-tartaric acid 또는 Dibenzoyl-L-tartaric acid을 이용하여 (S)-놀니코틴 부분입체이성질체로 염이나 결정화하여서 라세믹 놀니코틴 중에 (S)-놀니코틴을 분리한 후, 분리된 (S)-놀니코틴을 메틸화시켜서 S-니코틴을 합성하는 방법 및 이에 의하여 제조된 (S)-니코틴에 관한 것이다. The present invention relates to a chiral separation method to obtain S-nolnicotine from synthetic racemic nolnicotine, and to synthesize synthetic S-nicotine by methylating S-nolnicotine and (S)-nolnicotine prepared by this method. It relates to a method and synthetic S-nicotine produced thereby, and more specifically, to synthesize racemic nolnicotine and to synthesize the (S)-nolnicotine portion using Ditoluoyl-L-tartaric acid or Dibenzoyl-L-tartaric acid. A method of synthesizing S-nicotine by separating (S)-nolnicotine from racemic nolnicotine by salting or crystallizing it as a stereoisomer and then methylating the separated (S)-nolnicotine, and (S)- produced thereby. It's about nicotine.
Description
본 발명은 합성 라세믹(racemic) 놀니코틴으로부터 S-놀니코틴을 얻기위해 카이랄 분리 방법 및 이 방법에 의해 제조된 S-놀니코틴, (S)-놀니코틴을 메틸화시켜서 합성 S-니코틴을 합성하는 방법 및 이에 의하여 제조된 합성 S-니코틴에 관한 것으로, 보다 상세하게는 라세믹 놀니코틴을 합성하고, Ditoluoyl-L-tartaric acid 또는 Dibenzoyl-L-tartaric acid을 이용하여 (S)-놀니코틴 부분입체이성질체로 염이나 결정화하여서 라세믹 놀니코틴 중에 (S)-놀니코틴을 분리한 후, 분리된 (S)-놀니코틴을 메틸화시켜서 S-니코틴을 합성하는 방법 및 이에 의하여 제조된 (S)-니코틴에 관한 것이다. The present invention relates to a chiral separation method to obtain S-nolnicotine from synthetic racemic nolnicotine, and to synthesize synthetic S-nicotine by methylating S-nolnicotine and (S)-nolnicotine prepared by this method. It relates to a method and synthetic S-nicotine produced thereby, and more specifically, to synthesize racemic nolnicotine and to synthesize the (S)-nolnicotine portion using Ditoluoyl-L-tartaric acid or Dibenzoyl-L-tartaric acid. A method of synthesizing S-nicotine by separating (S)-nolnicotine from racemic nolnicotine by salting or crystallizing it as a stereoisomer and then methylating the separated (S)-nolnicotine, and (S)- produced thereby. It's about nicotine.
니코틴(3-[1-메틸피롤리딘-2-일]피리딘)은 니코티아나(Nicotiana), 즉 담배 식물(tobacco plant)의 잎에서 얻을 수 있는 천연 산물이다. 담배 산업과 제약 분야 전반에 걸쳐 니코틴 제품에 대한 상당한 수요가 있다. 니코틴은 각종 치료의 목적으로 사용할 수 있다. 니코틴의 주요 치료 용도는 흡연과 건강에 미치는 손상을 줄이기 위해 니코틴 의존성을 치료하는 것이다. 환자의 잇몸, 피부 패치, 흡입기 또는 비강 스프레이를 통해 제한된 농도의 니코틴을 환자에게 제공함으로서 파킨슨병, 치매, ADHD, 우울증 및 육종에 대한 치료효과를 기대할 수 있다 (Hartmann-Boyce J et al., Nicotine replacement therapy versus control for smoking cessation, The Cochrane Database of Systematic Reviews, 2018, 5, CD000146).Nicotine (3-[1-methylpyrrolidin-2-yl]pyridine) is a natural product obtained from the leaves of the Nicotiana, or tobacco plant. There is significant demand for nicotine products across the tobacco industry and pharmaceutical sectors. Nicotine can be used for various therapeutic purposes. The main therapeutic use of nicotine is to treat nicotine dependence to reduce smoking and its damage to health. By providing a limited concentration of nicotine to the patient through the patient's gums, skin patch, inhaler, or nasal spray, therapeutic effects on Parkinson's disease, dementia, ADHD, depression, and sarcoma can be expected (Hartmann-Boyce J et al., Nicotine replacement therapy versus control for smoking cessation, The Cochrane Database of Systematic Reviews, 2018, 5, CD000146).
니코틴은 광학적으로 활성으로, 두 가지 가능한 거울상 이성질체 형태: (R)-니코틴 또는 (S)-니코틴 중 하나로 존재할 수 있다. (S)-니코틴 (즉, [(S)-3-(1-메틸피롤리딘-2-일)피리딘])의 분자구조는 하기와 같으며 (R)-니코틴보다 훨씬 더 활성이 있다는 점이 알려져 있어서, 담배 산업 및 제약 분야에서 높은 순도의 (S) 거울상 이성질체에 대해 수요가 높다. Nicotine is optically active and can exist in one of two possible enantiomeric forms: (R)-nicotine or (S)-nicotine. The molecular structure of (S)-nicotine (i.e., [(S)-3-(1-methylpyrrolidin-2-yl)pyridine]) is as follows and is much more active than (R)-nicotine. As is known, there is a high demand for high purity (S) enantiomers in the tobacco industry and pharmaceutical fields.
놀니코틴(nornicotine)은 담배 식물인 니코티아나를 비롯한 다양한 식물에서 발견되는 알칼로이드이다. 놀니코틴의 분자구조는 하기와 같으며, 화학적으로 니코틴과 유사하지만 메틸기를 포함하지 않는다.Nornicotine is an alkaloid found in various plants, including the tobacco plant Nicotiana. The molecular structure of nicotine is as follows, and is chemically similar to nicotine, but does not contain a methyl group.
놀니코틴은 nAChR의 알파-6 및 알파-7 소단위에 대해 높은 친화력을 가지고 있으며[Papke RL et al., The pharmacological activity of nicotine and nornicotine on nAChRs subtypes: relevance to nicotine dependence and drug discovery. J Neurochem, 2007, 101(1), 160] nAChR을 통해 선조체에서 DAT를 억제하고 쥐에서 도파민을 방출하는 효과가 입증되어 파킨스병 치료와 관련하여 의학적으로 활용도가 높다(Middleton LS et al., Nornicotine inhibition of dopamine transporter function in striatum via nicotinic receptor activation, Synapse, 2007, 61(3), 157; Dwoskin LP et al., Nornicotine, a nicotine metabolite and tobacco alkaloid: desensitization of nicotinic receptor-stimulated dopamine release from rat striatum, European J Pharmacol 2001, 428(1), 69; Dwoskin LP et al., S(-)-nornicotine increases dopamine release in a calcium-dependent manner from superfused rat striatal slices, J Neurochem 1993, 60(6), 2167). Nornicotine has high affinity for the alpha-6 and alpha-7 subunits of nAChRs [Papke RL et al., The pharmacological activity of nicotine and nornicotine on nAChRs subtypes: relevance to nicotine dependence and drug discovery. J Neurochem, 2007, 101(1), 160] It has been proven to be effective in suppressing DAT in the striatum and releasing dopamine in rats through nAChR, so it has high medical utility in relation to the treatment of Parkinson's disease (Middleton LS et al., Nornicotine inhibition of dopamine transporter function in striatum via nicotinic receptor activation, Synapse, 2007, 61(3), 157; Dwoskin LP et al., Nornicotine, a nicotine metabolite and tobacco alkaloid: desensitization of nicotinic receptor-stimulated dopamine release from rat striatum , European J Pharmacol 2001, 428(1), 69; Dwoskin LP et al., S(-)-nornicotine increases dopamine release in a calcium-dependent manner from superfused rat striatal slices, J Neurochem 1993, 60(6), 2167 ).
또한 놀니코틴은 파킨스병의 치료 목적으로 사용되어 왔으며 파킨스병 치료 관련 특허가 등록되었다(Nornicotine enantiomers for use as a treatment for dopamine related conditions and disease states, 미국 특허등록: US-5776957, 1998]In addition, nonicotine has been used for the purpose of treating Parkinson's disease, and a patent related to the treatment of Parkinson's disease has been registered (Nornicotine enantiomers for use as a treatment for dopamine related conditions and disease states, US patent registration: US-5776957, 1998]
종래 S-놀니코틴은 Pellicularia Filamentosa에 속하는 미생물을 사용하여 S-니코틴을 S-놀니코틴으로 전환시켜 생성하거나 미오스민을 NADH나 NADPH의 환원성 효소를 사용하여서 생성한다 (Production of S-Nornicotine, 일본 특허등록: JP-0081791, 1983; Process of making (S)-nicotine, 미국 특허등록: 10,913,962 B2, 2021). Conventionally, S-Nornicotine is produced by converting S-nicotine to S-Nornicotine using microorganisms belonging to Pellicularia Filamentosa, or myosmin is produced using NADH or NADPH reducing enzymes (Production of S-Nornicotine, Japanese patent) Registration: JP-0081791, 1983; Process of making (S)-nicotine, US Patent Registration: 10,913,962 B2, 2021).
그러나, 이러한 종래 S-놀니코틴 합성 방법은 소량 생산만 가능하고 비용이 많이 들기 때문에 대량으로 S-놀니코틴을 생산하는 데에는 적합하지 않다는 문제점이 있었다. However, this conventional S-nolnicotine synthesis method has the problem that it is not suitable for producing S-nolnicotine in large quantities because it can only produce small quantities and is expensive.
또한, 대량생산 규모의 (S)-니코틴의 합성은 일반적으로 (R,S)-니코틴을 합성한 후 원치 않는 (R)-니코틴의 분리 및 라세미화의 과정 후 재 분리 과정에 의해 제조한다. (R,S)-니코틴의 분리는 문헌 뿐만 아니라 특허로도 많이 보고되어 있다. Acetoet 등의 d-주석산 (d-tartaric acid)을 사용한 분리 (J. Med. Chem. 1979, 22, 174-177), DeTraglia 등의 Pseu domonas putida 배양을 사용한 분리 (Applied and Environmental Microbiology, 1980, 39, 1067-1069), Ditoluoyl-L-tartaric acid (L-DTTA) 또는 Dibenzoyl-L-tartaric acid (L-DBTA)를 사용한 분리 (미국 특허등록: 9,809,567 B2, 2017)가 있다. 그러나 이 방법은 (R,S)-놀니코틴을 합성한 후 원치 않는 (R)-놀니코틴을 포함한 전량을 메칠화시켜서 (R)-니코틴의 분리 및 라세미화의 과정을 거치기 때문에 추가 비용과 시간이 필요하다.In addition, the synthesis of (S)-nicotine on a mass production scale is generally prepared by synthesizing (R,S)-nicotine, followed by separation and racemization of unwanted (R)-nicotine, and then re-separation. The isolation of (R,S)-nicotine has been widely reported not only in the literature but also in patents. Separation using d-tartaric acid by Acetoet et al. (J. Med. Chem. 1979, 22, 174-177), isolation using Pseu domonas putida culture by DeTraglia et al. (Applied and Environmental Microbiology, 1980, 39 , 1067-1069), and separation using Ditoluoyl-L-tartaric acid (L-DTTA) or Dibenzoyl-L-tartaric acid (L-DBTA) (US Patent Registration: 9,809,567 B2, 2017). However, this method requires additional costs and time because it synthesizes (R,S)-nicotine and then methylates all of the unwanted (R)-nicotine, followed by separation and racemization of (R)-nicotine. This is needed.
이에 본 발명자는 라세믹 놀니코틴을 합성하여서 (S)-놀니코틴을 효과적으로 분리시킬 수 있는 방법, 및 제조된 (s)-놀니코틴을 사용한 효율적인 (S)-니코틴의 합성방법을 완성하였다. Accordingly, the present inventors have completed a method for effectively separating (S)-nolnicotine by synthesizing racemic nolnicotine, and an efficient method for synthesizing (S)-nicotine using the prepared (s)-nolnicotine.
본 발명은 상기와 같은 종래 기술의 문제점을 해결하기 위하여 합성된 라세믹 놀니코틴에서 S-놀니코틴을 효과적으로 분리시킬 수 있는 새로운 방법을 제공한다. The present invention provides a new method for effectively separating S-nolnicotine from synthesized racemic nolnicotine in order to solve the problems of the prior art as described above.
본 발명은 또한, 본 발명에 의하여 분리된 S-놀니코틴을 메틸화 시켜서 S-니코틴을 합성하는 새로운 합성 과정을 제공하는 것을 목적으로 한다.The present invention also aims to provide a new synthetic process for synthesizing S-nicotine by methylating S-nolnicotine isolated by the present invention.
본 발명은 상기와 같은 과제를 해결하기 위하여 The present invention is intended to solve the above problems.
R-놀니코틴과 S-놀니코틴이 혼합된 라세믹 놀니코틴을 제 1 용매에 용해시키는 제 1 단계; A first step of dissolving racemic nicotine, which is a mixture of R-nolnicotine and S-nolnicotine, in a first solvent;
결정화제를 제 1 용매에 용해시키는 제 2 단계; a second step of dissolving the crystallizing agent in the first solvent;
상기 제 1 단계의 용액과 상기 제 2 단계의 용액을 혼합하고 가열시키는 제 3 단계; A third step of mixing and heating the solution of the first step and the solution of the second step;
상기 제 3 단계의 혼합물을 20℃ 에서 10시간 동안 교반하여 침전시키는 제 4 단계; A fourth step of precipitating the mixture of the third step by stirring it at 20° C. for 10 hours;
상기 제 4 단계에서 생성된 침전물을 여과시키는 제 5 단계; A fifth step of filtering the precipitate produced in the fourth step;
상기 제 5 단계에서 여과된 여과물을 상기 제 1 용매로 세정 후 건조시키는 제 6 단계; A sixth step of washing the filtrate filtered in the fifth step with the first solvent and drying it;
상기 제 6 단계에서 건조된 건조물을 상기 제 1 용매에 용해시키고 상기 제 2 단계에서 제 6 단계를 반복하여 재결정화시키는 제 7 단계; A seventh step of dissolving the dried product in the sixth step in the first solvent and recrystallizing it by repeating the sixth step in the second step;
상기 제 7 단계에서 얻어진 건조물을 앝칼리 용액에 용해시켜 염을 제거하여 유리 (S)-놀니코틴으로 전환시키는 제 8 단계; An eighth step of dissolving the dried product obtained in the seventh step in an oxidizing solution to remove salts and converting it into free (S)-nolnicotine;
상기 제 8 단계의 용액에서 ethyl ether, ethyl acetate, methylene chloride, methyl tert-butyl ether 중에서 선택한 하나 이상의 추출 용매로 S-놀니코틴을 추출하는 제 9 단계; A ninth step of extracting S-nolnicotine from the solution of the eighth step with one or more extraction solvents selected from ethyl ether, ethyl acetate, methylene chloride, and methyl tert-butyl ether;
상기 제 9 단계의 추출된 S-놀니코틴을 포함하는 용액에서 용매를 증발 건조시키는 제 10 단계; 및 A tenth step of evaporating the solvent from the solution containing the S-nolnicotine extracted in the ninth step to dryness; and
상기 제 10 단계에서 건조시킨 S-놀니코틴을 제 2 용매에 용해시키는 제 11 단계;를 포함하는 라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법을 제공한다. An 11th step of dissolving the S-nolnicotine dried in the 10th step in a second solvent. A method for separating S-nolnicotine from racemic nolnicotine is provided.
본 발명은 또한, The present invention also,
상기 제 11 단계에서 건조시킨 S-놀니코틴에 포름산 및 triethylamine을 첨가하여 메틸화 시켜 (S)-니코틴을 합성하는 제 12 단계;A 12th step of synthesizing (S)-nicotine by methylating the S-nolnicotine dried in the 11th step by adding formic acid and triethylamine;
상기 제 12 단계의 (S)-니코틴 용액에 앝칼리화 ethyl ether, ethyl acetate, methylene chloride, methyl tert-butyl ether 중에서 선택한 용매로 추출하는 제 13 단계; 및 A 13th step of extracting the (S)-nicotine solution of the 12th step with a solvent selected from the group consisting of decalcified ethyl ether, ethyl acetate, methylene chloride, and methyl tert-butyl ether; and
상기 제 13 단계의 추출물을 모아서 용매를 증발 건조시는 제 14 단계; 를 더 포함하는 (S)-니코틴을 합성하는 방법을 제공한다. A 14th step of collecting the extracts of the 13th step and evaporating the solvent to dryness; It provides a method for synthesizing (S)-nicotine further comprising.
본 발명에 의한 라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법에 있어서, 상기 결정화제는 Ditoluoyl-L-tartaric acid(L-DTTA), Dibenzoyl-L-tartaric acid(L-DBTA), Ditoluoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid, D-Tartaric acid 및 L-Tartaric acid 로 이루어진 그룹에서 선택되는 하나 이상인 것을 특징으로 한다. 이러한 결정화제는 착물을 잘 생성시키되 어느 한 이성질체와 침전 또는 결정이 만들어지는 조건을 만족하는 화합물 중에 선택한다. In the method of separating S-nolnicotine from racemic nolnicotine according to the present invention, the crystallizing agent is Ditoluoyl-L-tartaric acid (L-DTTA), Dibenzoyl-L-tartaric acid (L-DBTA), Ditoluoyl-D -Tartaric acid, Dibenzoyl-D-tartaric acid, D-Tartaric acid, and L-Tartaric acid. These crystallizers are selected from compounds that form complexes well but satisfy the conditions for precipitation or crystal formation with one isomer.
본 발명에 의한 라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법에 있어서, 상기 제1 단계의 용액과 상기 제 2 단계의 용액을 혼합시 L-DTTA 또는 L-DBTA과 라세믹 놀니코틴의 몰비는 0.6 내지 1.0 인 것을 특징으로 한다. In the method of separating S-nolnicotine from racemic nolnicotine according to the present invention, when mixing the solution of the first step and the solution of the second step, the molar ratio of L-DTTA or L-DBTA and racemic nolnicotine is It is characterized in that it is 0.6 to 1.0.
본 발명에 의한 라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법에 있어서, 상기 제 1 용매 및 제 2 용매는 이소프로필알코올, 메탄올, 에탄올, 부탄올, 아세톤, 아세토니트릴, 및 에틸 아세테이트를 포함하는 그룹에서 선택되는 것을 특징으로 한다. 본 발명에 의한 라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법에 있어서, 상기 제 6 단계 및 제 10 단계에서는 세정을 위해 0.001 내지 2 M HCl 또는 0.001 내지 2 M HNO3, 또는 0.001 내지 2 M H2SO4 용액 또는 그와 유사한 pH의 산 용액을 사용하는 것을 특징으로 한다. In the method for separating S-nolnicotine from racemic nolnicotine according to the present invention, the first and second solvents are a group comprising isopropyl alcohol, methanol, ethanol, butanol, acetone, acetonitrile, and ethyl acetate. It is characterized by being selected from. In the method for separating S-nolnicotine from racemic nolnicotine according to the present invention, in the sixth and tenth steps, 0.001 to 2 M HCl, 0.001 to 2 M HNO3, or 0.001 to 2 M H2SO4 solution is used for washing. Or, it is characterized by using an acid solution of similar pH.
본 발명에 의한 라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법에 있어서, 상기 제 4 단계에서는 유리 S-놀니코틴(free S-nornicotine) 추출을 위해 MTBE, ethylether, ethylacetate, methylene chloride (MC), hexane, isopropanol 로 이루어진 그룹에서 선택되는 1개 이상의 용매를 사용하는 것을 특징으로 한다. In the method of separating S-nolnicotine from racemic nornicotine according to the present invention, in the fourth step, MTBE, ethylether, ethylacetate, methylene chloride (MC), It is characterized by using one or more solvents selected from the group consisting of hexane and isopropanol.
본 발명은 또한, 본 발명에 의하여 분리된 S-놀니코틴 포함하는 조성물을 제공한다. 본 발명에 의한 조성물 내의 상기 S-놀니코틴의 함량은 70 몰% 이상인 것을 특징으로 한다. The present invention also provides a composition containing S-nolnicotine isolated by the present invention. The content of S-nolnicotine in the composition according to the present invention is characterized in that it is 70 mol% or more.
본 발명은 또한, The present invention also,
상기 제 11 단계에서 건조시킨 S-놀니코틴을 메틸화 시켜 (S)-니코틴을 합성하는 제 12 단계;A twelfth step of synthesizing (S)-nicotine by methylating the S-nolnicotine dried in the eleventh step;
상기 제 12 단계의 (S)-니코틴 용액의 pH를 10 내지 12로 조정하고, ethyl ether, ethyl acetate, methylene chloride, methyl tert-butyl ether 중에서 선택한 용매로 추출하는 제 13 단계; 및 A 13th step of adjusting the pH of the (S)-nicotine solution of the 12th step to 10 to 12 and extracting it with a solvent selected from ethyl ether, ethyl acetate, methylene chloride, and methyl tert-butyl ether; and
상기 제 13 단계의 추출물을 모아서 용매를 증발 건조시는 제 14 단계; 를 더 포함하는 (S)-니코틴을 합성하는 방법을 제공한다. A 14th step of collecting the extracts of the 13th step and evaporating the solvent to dryness; It provides a method for synthesizing (S)-nicotine further comprising.
본 발명에 의한 (S)-니코틴을 합성하는 방법에 있어서, 상기 제 12 단계에서는 formaldehyde/formic acid의 혼합 용액 또는 DMSO, formic acid, 트리에틸아민의 혼합 용액에 S-놀니코틴을 첨가하고 80 내지 160℃ 에서 10 시간 내지 15시간 교반하여 (S)-놀니코틴을 메틸화시키는 것을 특징으로 한다. In the method for synthesizing (S)-nicotine according to the present invention, in the twelfth step, S-nolnicotine is added to a mixed solution of formaldehyde/formic acid or a mixed solution of DMSO, formic acid, and triethylamine, and the mixture is heated for 80 to 80 minutes. It is characterized in that (S)-nolnicotine is methylated by stirring at 160° C. for 10 to 15 hours.
본 발명은 또한, 본 발명의 제조방법에 의하여 제조된 (S)-니코틴 또는 이를 포함하는 조성물을 제공한다. The present invention also provides (S)-nicotine or a composition containing it prepared by the production method of the present invention.
본 발명에 의한 (S)-놀니코틴을 분리시키는 방법은 라세믹 놀니코틴에서 (S)-놀니코틴만을 효율적으로 분리할 수 있으며, 본 발명에 의한 (S)-니코틴의 합성방법은 이와 같이 분리된 (S)-놀니코틴을 사용하여 (S)-니코틴을 효율적으로 합성할 수 있다. The method for separating (S)-nolnicotine according to the present invention can efficiently separate only (S)-nolnicotine from racemic nolnicotine, and the method for synthesizing (S)-nicotine according to the present invention can be used to separate (S)-nicotine in this way. (S)-nicotine can be efficiently synthesized using (S)-nicotine.
도 1은 본 발명에 따른 라세믹 놀니코틴을 상기 L-DTTA 또는 L-DBTA을 사용할 때에 S-놀니코틴으로 분리 또는 농축이 되는 과정이다.
도 2는 카이랄 분리에 의하지 않고 합성한 라세믹 니코틴의 LC-MS/MS 피크(좌)와 본 발명에 따른 라세믹 놀니코틴을 상기 L-DTTA 또는 L-DBTA을 사용하여 S-놀니코틴으로 분리후 메틸화 후 합성한 S-니코틴의 LC-MS/MS 피크(우)이다.
도 3은 본 발명에 따른 L-DTTA 또는 L-DBTA과 라세믹 놀니코틴의 몰비의 변화에 따른 수율 변화에 대한 그래프 이다. Figure 1 shows the process of separating or concentrating racemic nolnicotine into S-nolnicotine when using L-DTTA or L-DBTA according to the present invention.
Figure 2 shows the LC-MS/MS peak (left) of racemic nicotine synthesized without chiral separation and the conversion of racemic nicotine according to the present invention to S-nolnicotine using L-DTTA or L-DBTA. This is the LC-MS/MS peak (right) of S-nicotine synthesized after separation and methylation.
Figure 3 is a graph of the change in yield according to the change in the molar ratio of L-DTTA or L-DBTA and racemic nicotine according to the present invention.
이하, 발명의 이해를 돕기 위해 다양한 실시예를 제시한다. 하기 실시예는 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐 발명의 보호범위가 하기 실시예에 한정되는 것은 아니다.Hereinafter, various embodiments are presented to aid understanding of the invention. The following examples are provided to make the invention easier to understand, and the scope of protection of the invention is not limited to the following examples.
<실시예 1> L-DTTA에 의한 라세믹 놀니코틴으로부터 S-놀니코틴의 분리<Example 1> Separation of S-nolnicotine from racemic nolnicotine by L-DTTA
멘틀 위에 500 mL 플라스크를 설치하고 스털러, 콘덴서를 연결한 다음 질소로 충진시킨 후 결정화제인 L-DTTA 38.6 g (0.1 mole)을 넣고 제1 용매로서 에탄올 100 mL를 넣은 다음 20 ℃에서 교반하였다. A 500 mL flask was installed on the mantle, a stirrer and a condenser were connected, and the flask was filled with nitrogen. 38.6 g (0.1 mole) of L-DTTA, a crystallizing agent, was added, 100 mL of ethanol was added as a first solvent, and the mixture was stirred at 20°C. .
교반용액 안에 라세믹 놀니코틴 17.8 g (0.12 mole)을 제1 용매로서 에탄올 60 mL에 녹인 용액을 조심하여 첨가한다. 위의 혼합용액을 가열시켜서 15분간 reflux시킨 후 20℃로 냉각시켜서 침전시켰다. Carefully add 17.8 g (0.12 mole) of racemic nicotine dissolved in 60 mL of ethanol as the first solvent into the stirred solution. The above mixed solution was heated and refluxed for 15 minutes, then cooled to 20°C to precipitate.
혼합용액을 20℃에서 10 시간 동안 교반한 다음 거름종이가 장착된 거름장치에 넣고 걸러준 후 거름종이에 여과된 고체 성분을 에탄올 10 mL로 4번을 닦아낸 다음 건조시켰다. The mixed solution was stirred at 20°C for 10 hours, then placed in a filter equipped with filter paper and filtered. The solid components filtered on the filter paper were wiped four times with 10 mL of ethanol and then dried.
건조된 염의 무게는 26.0 g(수율은 81%)이다. 이 염 고형물을 500 mL 플라스크에 넣고 스털러, 콘덴서를 연결한 다음 질소로 충진시킨 후 에탄올 80 mL를 넣은 다음 20℃에서 30 분 교반시킨다. 혼합용액을 가열시켜서 15분간 reflux시킨 후 20 ℃로 냉각시켜 침전시켰다. The weight of the dried salt was 26.0 g (yield 81%). Put this salt solid into a 500 mL flask, connect a stirrer and a condenser, fill it with nitrogen, add 80 mL of ethanol, and stir at 20°C for 30 minutes. The mixed solution was heated and refluxed for 15 minutes, then cooled to 20°C to precipitate.
혼합용액을 20 ℃에서 10 시간 동안 교반한 다음 거름종이가 장착된 거름장치에 넣고 걸러준 후 거름종이에 고체 성분을 에탄올 10 mL로 4번을 세정한 다음 건조시켰다. The mixed solution was stirred at 20°C for 10 hours, placed in a filter equipped with filter paper, filtered, and the solid components on the filter paper were washed four times with 10 mL of ethanol and then dried.
건조된 염의 무게는 24.7 g이었다(수율은 77%이다). 건조된 염은 순수한 S-(-)-nornicotine-L-DTTA이다. 건조된 24.7 g의 염은 100 mL separating funnel에 넣고 pH 10의 KOH 용액 50 mL를 넣은 다음 흔들어 섞어준다. The weight of the dried salt was 24.7 g (yield 77%). The dried salt is pure S-(-)-nornicotine-L-DTTA. Place 24.7 g of dried salt in a 100 mL separating funnel, add 50 mL of KOH solution at pH 10, and shake to mix.
추출용매로서 Ethyl ether 20 mL를 첨가하고 3번을 흔들어 추출한 다음 추출물을 모아서 용매를 증발시킨다. 건조된 무게는 6.7 g이었고 75.3%의 수율을 보였다.Add 20 mL of ethyl ether as an extraction solvent, shake three times for extraction, then collect the extracts and evaporate the solvent. The dried weight was 6.7 g and the yield was 75.3%.
<실험예> 결정화제에 의한 라세믹 놀니코틴으로부터 S-놀니코틴의 분리<Experimental Example> Separation of S-nolnicotine from racemic nolnicotine using a crystallizer
상기 실시예 1에서 제조된 염에서의 놀니코틴의 R과 S형의 비(ee)를 조사하기 위해 다음과 같은 방법에 따라 실험을 수행하였다. To investigate the ratio (ee) of the R and S types of nicotine in the salt prepared in Example 1, an experiment was performed according to the following method.
시료를 메탄올에 용해시킨 후 high performance liquid chromatography (HPLC)-tandem mass spectrometry로 측정하였다. 사용한 컬럼과 기기조건 및 MRM 조건은 아래 표 1 및 표 2 와 같다. The sample was dissolved in methanol and measured using high performance liquid chromatography (HPLC)-tandem mass spectrometry. The columns, instrument conditions, and MRM conditions used are shown in Tables 1 and 2 below.
chiral 분리 후 R과 S형의 비 (ee)는 99% 이었다. After chiral separation, the ratio (ee) between R and S types was 99%.
<실시예 2> L-DBTA에 의한 라세믹 놀니코틴으로부터 S-놀니코틴의 분리<Example 2> Separation of S-nolnicotine from racemic nolnicotine by L-DBTA
멘틀 위에 500 mL 플라스크를 설치하고 스털러, 콘덴서를 연결한 다음 질소로 충진시킨 후 결정화제로서 L-DBTA 35.8 g (0.1 mole)을 넣고 제1용매로서 에탄올 100 mL를 넣은 다음 20℃에서 교반한다. Install a 500 mL flask on the mantle, connect the stirrer and condenser, fill with nitrogen, add 35.8 g (0.1 mole) of L-DBTA as a crystallizer, add 100 mL of ethanol as the first solvent, and stir at 20°C. .
교반용액 안에 라세믹 놀니코틴 17.8 g (0.12 mole)을 에탄올 60 mL에 녹인 용액을 조심하여 첨가한다. Carefully add a solution of 17.8 g (0.12 mole) of racemic nicotine dissolved in 60 mL of ethanol into the stirred solution.
위의 혼합용액은 가열시켜서 15분간 reflux시킨 후 20 ℃로 냉각시키면 침전이 시작된다. 혼합물을 20 ℃에서 10 시간 동안 교반한다. 혼합물은 거름종이가 장착된 거름장치에 넣고 걸러준 후 에탄올 10 mL로 4번을 닦아낸 다음 건조시킨다. 건조된 염의 무게는 24.3 g이었다 (수율은 81%이다). The above mixed solution is heated and refluxed for 15 minutes and then cooled to 20°C to begin precipitation. The mixture is stirred at 20 °C for 10 hours. The mixture is placed in a filter equipped with filter paper, filtered, wiped four times with 10 mL of ethanol, and then dried. The weight of the dried salt was 24.3 g (yield 81%).
이 염 고형물은 500 mL 플라스크에 넣고 스털러, 콘덴서를 연결한 다음 질소로 충진시킨 후 에탄올 80 mL를 넣은 후 20 ℃에서 30 분 교반시킨다. 혼합용액은 가열시켜서 15분간 reflux시킨 후 20 ℃로 냉각시키면 침전이 시작된다. 계속하여 혼합용액을 20 ℃에서 10 시간 동안 교반한 다음 거름종이가 장착된 거름장치에서 걸러준 후 거름종이 위의 고체를 에탄올 10 mL로 4번을 닦아낸 다음 건조시킨다. 건조된 염의 무게는 24.0 g이었다 (수율은 78.9%이다). This salt solid is placed in a 500 mL flask, connected to a stirrer and condenser, filled with nitrogen, and then 80 mL of ethanol is added and stirred at 20°C for 30 minutes. The mixed solution is heated and refluxed for 15 minutes and then cooled to 20°C to begin precipitation. Continue to stir the mixed solution at 20°C for 10 hours, filter it through a filter equipped with filter paper, and wipe the solid on the filter paper with 10 mL of ethanol four times and then dry it. The weight of the dried salt was 24.0 g (yield 78.9%).
건조한 염은 순수한 S-(-)-nornicotine- L-DBTA이다. 건조된 24.0 g의 염은 100 mL separating funnel에 넣고 pH 10의 KOH 용액 50 mL를 넣은 다음 흔들어 섞어준다. Ethyl ether 20 mL로서 3번을 흔들어 추출한 다음 추출물을 모아서 용매를 증발시킨다. 이때의 고체를 chiral 분리 후 상기 실험예에서와 같이 분석한 결과 놀니코틴의 R과 S형의 비(ee)는 99% 이었고 건조된 무게는 6.9 g이었고 77.5%의 수율을 보였다.The dry salt is pure S-(-)-nornicotine-L-DBTA. Place 24.0 g of dried salt in a 100 mL separating funnel, add 50 mL of KOH solution at pH 10, and shake to mix. Extract by shaking 3 times with 20 mL of ethyl ether, then collect the extracts and evaporate the solvent. The solid at this time was analyzed as in the above experimental example after chiral separation. As a result, the ratio (ee) of the R and S forms of nolnicotine was 99%, the dried weight was 6.9 g, and the yield was 77.5%.
<실시예 3> L-DTTA 또는 L-DBTA과 라세믹 놀니코틴의 적정 몰비 <Example 3> Appropriate molar ratio of L-DTTA or L-DBTA and racemic nicotine
멘틀 위에 500 mL 플라스크를 설치하고 스털러, 콘덴서를 연결한 다음 질소로 충진시킨 후 L-DTTA 19.3 g (0.05 mole), 23.2 g (0.06 mole), 27.0 g (0.07 mole), 30.9 g (0.08 mole), 38.6 g (0.10 mole), 42.5 g (0.11 mole), 46.3 g (0.12 mole), 50.2 g (0.13 mole)을 넣고 에탄올 100 mL를 넣은 다음 20 ℃에서 교반한다. Install a 500 mL flask on the mantle, connect the stirrer and condenser, fill with nitrogen, and add 19.3 g (0.05 mole), 23.2 g (0.06 mole), 27.0 g (0.07 mole), 30.9 g (0.08 mole) of L-DTTA. ), 38.6 g (0.10 mole), 42.5 g (0.11 mole), 46.3 g (0.12 mole), 50.2 g (0.13 mole), add 100 mL of ethanol, and stir at 20°C.
교반용액 안에 라세믹 놀니코틴 14.8 g (0.10 mole)을 에탄올 60 mL에 녹인 용액을 조심하여 첨가한다. 위의 혼합용액은 가열시켜서 15분간 reflux시킨 후 20 ℃로 냉각시키면 침전이 시작된다. 혼합물을 20 ℃에서 10 시간 동안 교반한다. 혼합물은 거름종이가 장착된 거름장치에 넣고 걸러준 후 에탄올 10 mL로 4번을 닦아낸 다음 건조시킨다. Carefully add a solution of 14.8 g (0.10 mole) of racemic nicotine dissolved in 60 mL of ethanol into the stirred solution. The above mixed solution is heated and refluxed for 15 minutes and then cooled to 20°C to begin precipitation. The mixture is stirred at 20 °C for 10 hours. The mixture is placed in a filter equipped with filter paper, filtered, wiped four times with 10 mL of ethanol, and then dried.
이 실험이 3회 반복하였고 수율은 도 1에서 보는 바와 같이 68-81%의 수율을 보였고 L-DTTA와 라세믹 놀니코틴의 적정 몰비는 0.6-1.0이었다. This experiment was repeated three times, and the yield was 68-81% as shown in Figure 1, and the appropriate molar ratio of L-DTTA and racemic nicotine was 0.6-1.0.
멘틀 위에 500 mL 플라스크를 설치하고 스털러, 콘덴서를 연결한 다음 질소로 충진시킨 후 L-DBTA 17.9 g (0.05 mole), 21.5 g (0.06 mole), 25.1 g (0.07 mole), 28.6 g (0.08 mole), 35.8 g (0.1 mole), 39.4 g (0.11 mole), 43.0 g (0.12 mole), 46.5 g (0.13 mole)을 넣고 에탄올 100 mL를 넣은 다음 20 ℃에서 교반한다. 교반용액 안에 라세믹 놀니코틴 14.8 g (0.10 mole)을 에탄올 60 mL에 녹인 용액을 조심하여 첨가한다. 위의 혼합용액은 가열시켜서 15분간 reflux시킨 후 20 ℃로 냉각시키면 침전이 시작된다. 혼합물을 20 ℃에서 10 시간 동안 교반한다. 혼합물은 거름종이가 장착된 거름장치에 넣고 걸러준 후 에탄올 10 mL로 4번을 닦아낸 다음 건조시킨다. Install a 500 mL flask on the mantle, connect the stirrer and condenser, fill with nitrogen, and add 17.9 g (0.05 mole), 21.5 g (0.06 mole), 25.1 g (0.07 mole), 28.6 g (0.08 mole) of L-DBTA. ), 35.8 g (0.1 mole), 39.4 g (0.11 mole), 43.0 g (0.12 mole), 46.5 g (0.13 mole), add 100 mL of ethanol, and stir at 20°C. Carefully add a solution of 14.8 g (0.10 mole) of racemic nicotine dissolved in 60 mL of ethanol into the stirred solution. The above mixed solution is heated and refluxed for 15 minutes and then cooled to 20°C to begin precipitation. The mixture is stirred at 20 °C for 10 hours. The mixture is placed in a filter equipped with filter paper, filtered, wiped four times with 10 mL of ethanol, and then dried.
건조된 염의 무게로 수율을 계산하였을 때 아래 그림과 같이 65-81%의 수율을 보였고, 결정화제인 L-DBTA와 라세믹 놀니코틴의 적정 몰비는 0.6-1.0이었다. When the yield was calculated based on the weight of the dried salt, the yield was 65-81% as shown in the figure below, and the appropriate molar ratio between the crystallizing agent L-DBTA and racemic nolnicotine was 0.6-1.0.
< 실시예 4> 놀니코틴의 라세미화(Racemization) < Example 4> Racemization of nicotine
실시예 1과 2에서 라세믹 놀니코틴으로부터 S-놀니코틴의 분리 후에 남은 R-놀니코틴이 약 70:30 (R:S)로 농축된 놀니코틴을 라세믹화하여서 50:50 (R:S)로 바꾸는 과정이다. After separation of S-nolnicotine from racemic nolnicotine in Examples 1 and 2, the remaining R-nolnicotine was concentrated to about 70:30 (R:S) and racemicized to obtain 50:50 (R:S). It is a process of changing to .
실시예 1과 2에서 침전된 S-놀니코틴염을 거른 후 거름장치를 통과한 용액을 모아서 용매를 증발시켜 날린다. 잔류물에 pH 12의 KOH 용액 50 mL를 넣은 다음 흔들어 섞어준다. Ethyl ether 20 mL로서 3번을 흔들어 추출한 다음 추출물을 모아서 용매를 증발시킨다. 이때의 고체를 chiral 분리 후 ee는 70:30 (R:S)이었고 건조된 무게는 약 10 g이었다. After filtering the S-nolnicotine salt precipitated in Examples 1 and 2, the solution that passed through the filter was collected and the solvent was evaporated. Add 50 mL of KOH solution at pH 12 to the residue and shake to mix. Extract by shaking 3 times with 20 mL of ethyl ether, then collect the extracts and evaporate the solvent. After chiral separation of the solid at this time, ee was 70:30 (R:S) and the dried weight was about 10 g.
회수한 ee는 70:30 (R:S)인 놀니코틴 10 g에 potassium tert-butoxide 0.35 g을 넣고 160 ℃에서 1시간을 질소 분위기하에서 가열한 후 놀니코틴을 진공 증류하여서 회수한다. 이때 놀니코틴 약 10g 대부분 회수된다. The recovered ee is recovered by adding 0.35 g of potassium tert-butoxide to 10 g of 70:30 (R:S) nolnicotine, heating it at 160°C for 1 hour under a nitrogen atmosphere, and then vacuum distilling the nolnicotine. At this time, most of about 10g of nicotine was recovered.
본 발명에 따른 라세믹 놀니코틴을 상기 L-DTTA을 사용할 때에는 ee는 98%로 75.3%의 수율을 보였으며 L-DBTA을 사용할 때에는 ee는 99% 이었고 77.5%의 수율을 보였다. 따라서 본 발명에 의하여 라세믹 놀니코틴에서의 S-놀니코틴은 salt의 형태 또는 결정 상태로 분리가 되고, S-놀니코틴이 즉 ee가 적어도 90% 이상이 되도록 분리 및 농축된다. When the racemic nolnicotine according to the present invention was used with L-DTTA, the ee was 98%, showing a yield of 75.3%, and when L-DBTA was used, the ee was 99%, and the yield was 77.5%. Therefore, according to the present invention, S-nolnicotine from racemic nolnicotine is separated in salt form or crystalline state, and S-nolnicotine is separated and concentrated so that ee is at least 90% or more.
또한, 본 발명에서는 R-놀니코틴이 70:30 (R:S)로 농축된 놀니코틴을 potassium tert-butoxide을 사용하여서 가열 후 라세믹화 하는 과정이다.In addition, in the present invention, R-nolnicotine is concentrated in a ratio of 70:30 (R:S) and racemicized by heating using potassium tert-butoxide.
<실시예 5> 메틸화에 의한 (S)-놀니코틴에서 (S)-니코틴의 합성<Example 5> Synthesis of (S)-nicotine from (S)-nolnicotine by methylation
실시예 1과 2에서 제조된 라세믹 놀니코틴으로부터 분리한 S-놀니코틴을 메틸화하여서 S-니코틴을 합성하는 과정이다. This is a process of synthesizing S-nicotine by methylating S-nolnicotine isolated from the racemic nicotine prepared in Examples 1 and 2.
실시예 1과 2에서 회수한 S-놀니코틴 10 g(67.5 mmol)에 DMSO 25 mL, formic acid (HCOOH) 25 mL, triethylamine 10 g 및 자석 교반 막대를 압력 튜브에 넣는다. 혼합물을 아르곤으로 15분 동안 버블링한 다음, 150 ℃에서 12 시간 동안 교반한다. 교반 후 용액에 5 N KOH를 사용하여 pH 12로 조절한 다음 ethyl ether 20 mL로서 3번을 흔들어 추출한 다음 추출물을 모아서 용매를 증발시킨다. To 10 g (67.5 mmol) of S-nolnicotine recovered in Examples 1 and 2, 25 mL of DMSO, 25 mL of formic acid (HCOOH), 10 g of triethylamine, and a magnetic stirring bar were added to a pressure tube. The mixture is bubbled with argon for 15 minutes and then stirred at 150° C. for 12 hours. After stirring, the solution was adjusted to pH 12 using 5 N KOH, then extracted by shaking 3 times with 20 mL of ethyl ether, then the extracts were collected and the solvent was evaporated.
이때의 잔류 고체를 용매에 녹여서 chiral 분리 후 분석한 결과 (S)-니코틴이 99% 이상이었고 9.9 g이어서 90% 이상 수율을 보였다.The residual solid at this time was dissolved in a solvent and analyzed after chiral separation. As a result, (S)-nicotine was over 99% and the weight was 9.9 g, showing a yield of over 90%.
<실시예 6> 메틸화에 의한 (S)-놀니코틴으로부터 (S)-니코틴의 합성<Example 6> Synthesis of (S)-nicotine from (S)-nolnicotine by methylation
실시예 1과 2에서 제조된 라세믹 놀니코틴으로부터 분리한 S-놀니코틴을 메틸화하여서 S-니코틴을 합성하는 과정이다. This is a process of synthesizing S-nicotine by methylating S-nolnicotine isolated from the racemic nicotine prepared in Examples 1 and 2.
실시예 1과 2에서 회수한 S-놀니코틴 10 g(67.5 mmol)에 formaldehyde/formic acid (1:1) 50 mL 및 자석 교반 막대를 압력 튜브에 넣는다. 혼합물을 아르곤으로 15분 동안 버블링한 다음, 90 ℃에서 12 시간 동안 교반한다. 교반 후 용액에 5 N KOH를 사용하여 pH 12로 조절한 다음 ethyl ether 20 mL로서 3번을 흔들어 추출한 다음 추출물을 모아서 용매를 증발시킨다. To 10 g (67.5 mmol) of S-nolnicotine recovered in Examples 1 and 2, 50 mL of formaldehyde/formic acid (1:1) and a magnetic stirring bar were added to a pressure tube. The mixture is bubbled with argon for 15 minutes and then stirred at 90° C. for 12 hours. After stirring, the solution was adjusted to pH 12 using 5 N KOH, then extracted by shaking 3 times with 20 mL of ethyl ether, then the extracts were collected and the solvent was evaporated.
이때의 잔류 고체를 용매에 녹여서 chiral 분리 후 분석한 결과 (S)-니코틴이 99% 이상이었고 9.9 g이어서 90% 이상 수율을 보였다.The residual solid at this time was dissolved in a solvent and analyzed after chiral separation. As a result, (S)-nicotine was over 99% and the weight was 9.9 g, showing a yield of over 90%.
Claims (11)
결정화제를 제 1 용매에 용해시키는 제 2 단계;
상기 제 1 단계의 용액과 상기 제 2 단계의 용액을 혼합하고 가열시키는 제 3 단계;
상기 제 3 단계의 혼합물을 20℃ 에서 10시간 동안 교반하여 침전시키는 제 4 단계;
상기 제 4 단계에서 생성된 침전물을 여과시키는 제 5 단계;
상기 제 5 단계에서 여과된 여과물을 상기 제 1 용매로 세정 후 건조시키는 제 6 단계;
상기 제 6 단계에서 건조된 건조물을 상기 제 1 용매에 용해시키고 상기 제 2 단계에서 제 6 단계를 반복하여 재결정화시키는 제 7 단계;
상기 제 7 단계에서 얻어진 건조물을 앝칼리 용액에 용해시켜 염을 제거하여 유리 (S)-놀니코틴으로 전환시키는 제 8 단계;
상기 제 8 단계의 용액에서 ethyl ether, ethyl acetate, methylene chloride, methyl tert-butyl ether 중에서 선택한 하나 이상의 추출 용매로 S-놀니코틴을 추출하는 제 9 단계;
상기 제 9 단계의 추출된 S-놀니코틴을 포함하는 용액에서 용매를 증발 건조시키는 제 10 단계; 및
상기 제 10 단계에서 건조시킨 S-놀니코틴을 제 2 용매에 용해시키는 제 11 단계;를 포함하는
라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법
A first step of dissolving racemic nicotine, which is a mixture of R-nolnicotine and S-nolnicotine, in a first solvent;
a second step of dissolving the crystallizing agent in the first solvent;
A third step of mixing and heating the solution of the first step and the solution of the second step;
A fourth step of precipitating the mixture of the third step by stirring it at 20° C. for 10 hours;
A fifth step of filtering the precipitate produced in the fourth step;
A sixth step of washing the filtrate filtered in the fifth step with the first solvent and drying it;
A seventh step of dissolving the dried product in the sixth step in the first solvent and recrystallizing it by repeating the sixth step in the second step;
An eighth step of dissolving the dried product obtained in the seventh step in an oxidizing solution to remove salts and converting it into free (S)-nolnicotine;
A ninth step of extracting S-nolnicotine from the solution of the eighth step with one or more extraction solvents selected from ethyl ether, ethyl acetate, methylene chloride, and methyl tert-butyl ether;
A tenth step of evaporating the solvent from the solution containing the S-nolnicotine extracted in the ninth step to dryness; and
An 11th step of dissolving the S-nolnicotine dried in the 10th step in a second solvent.
Method for separating S-nolnicotine from racemic nolnicotine
상기 결정화제는 Ditoluoyl-L-tartaric acid(L-DTTA), Dibenzoyl-L-tartaric acid(L-DBTA), Ditoluoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid, D-Tartaric acid 및 L-Tartaric acid 로 이루어진 그룹에서 선택되는 하나 이상인 것인
라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법
According to paragraph 1,
The crystallizer is Ditoluoyl-L-tartaric acid (L-DTTA), Dibenzoyl-L-tartaric acid (L-DBTA), Ditoluoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid, D-Tartaric acid and L-Tartaric acid. At least one selected from the group consisting of acid
Method for separating S-nolnicotine from racemic nolnicotine
상기 제 3 단계에서는 제 1 단계의 용액과 상기 제 2 단계의 용액을 결정화제와 라세믹 놀니코틴의 몰비가 0.5 내지 1.2 가 되도록 혼합하는 것인
라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법
According to paragraph 1,
In the third step, the solution of the first step and the solution of the second step are mixed so that the molar ratio of the crystallizer and racemic nicotine is 0.5 to 1.2.
Method for separating S-nolnicotine from racemic nolnicotine
상기 제 1 용매 및 제 2 용매는 이소프로필알코올, 메탄올, 에탄올, 부탄올, 아세톤, 아세토니트릴, 및 에틸 아세테이트를 포함하는 그룹에서 선택되는 것인
라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법
According to paragraph 1,
The first and second solvents are selected from the group consisting of isopropyl alcohol, methanol, ethanol, butanol, acetone, acetonitrile, and ethyl acetate.
Method for separating S-nolnicotine from racemic nolnicotine
상기 제 6 단계 및 제 9 단계에서는 0.001 내지 2 M HCl 또는 0.001 내지 2 M HNO3, 또는 0.001 내지 2 M H2SO4 용액을 포함하는 그룹에서 선택되는 용액을 사용하여 세정하는 것인
라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법
According to paragraph 1,
In the sixth and ninth steps, cleaning is performed using a solution selected from the group consisting of 0.001 to 2 M HCl, 0.001 to 2 M HNO 3 , or 0.001 to 2 MH 2 SO 4 solution.
Method for separating S-nolnicotine from racemic nolnicotine
상기 제 4 단계에서는 유리 S-놀니코틴(free S-nornicotine) 추출을 위해 MTBE, ethylether, ethylacetate, methylene chloride (MC), hexane, isopropanol 로 이루어진 그룹에서 선택되는 1개 이상의 용매를 사용하는 것인
라세믹 놀니코틴으로부터 S-놀니코틴의 분리 방법
According to paragraph 1,
In the fourth step, one or more solvents selected from the group consisting of MTBE, ethylether, ethylacetate, methylene chloride (MC), hexane, and isopropanol are used to extract free S-nornicotine.
Method for separating S-nolnicotine from racemic nolnicotine
S-nolnicotine isolated by the method of any one of claims 1 to 6 or a composition containing the same.
상기 조성물 내의 상기 S-놀니코틴의 함량은 70 몰% 이상인 것인 조성물
In clause 7,
A composition wherein the content of S-nolnicotine in the composition is 70 mol% or more.
상기 제 11 단계에서 건조시킨 S-놀니코틴을 메틸화 시켜 (S)-니코틴을 합성하는 제 12 단계;
상기 제 12 단계의 (S)-니코틴 용액의 pH를 10 내지 12로 조정하고, ethyl ether, ethyl acetate, methylene chloride, methyl tert-butyl ether 중에서 선택한 용매로 추출하는 제 13 단계; 및
상기 제 13 단계의 추출물을 모아서 용매를 증발 건조시는 제 14 단계; 를 더 포함하는
(S)-니코틴을 합성하는 방법
According to paragraph 1,
A twelfth step of synthesizing (S)-nicotine by methylating the S-nolnicotine dried in the eleventh step;
A 13th step of adjusting the pH of the (S)-nicotine solution of the 12th step to 10 to 12 and extracting it with a solvent selected from ethyl ether, ethyl acetate, methylene chloride, and methyl tert-butyl ether; and
A 14th step of collecting the extracts of the 13th step and evaporating the solvent to dryness; containing more
How to synthesize (S)-nicotine
상기 제 12 단계에서는 formaldehyde/formic acid의 혼합 용액 또는 DMSO, formic acid, 트리에틸아민의 혼합 용액에 S-놀니코틴을 첨가하고 80 내지 160℃ 에서 10 시간 내지 15시간 교반하여 (S)-놀니코틴을 메틸화시키는 것인
(S)-니코틴을 합성하는 방법
According to clause 9,
In the twelfth step, S-nolnicotine is added to a mixed solution of formaldehyde/formic acid or a mixed solution of DMSO, formic acid, and triethylamine and stirred at 80 to 160° C. for 10 to 15 hours to produce (S)-nolnicotine. methylating
How to synthesize (S)-nicotine
(S)-nicotine prepared by the method of claim 9 or 10 or a composition containing the same
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