CN116622792A - Method for synthesizing (S) -nicotine by using enzyme catalysis - Google Patents
Method for synthesizing (S) -nicotine by using enzyme catalysis Download PDFInfo
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- CN116622792A CN116622792A CN202211280938.4A CN202211280938A CN116622792A CN 116622792 A CN116622792 A CN 116622792A CN 202211280938 A CN202211280938 A CN 202211280938A CN 116622792 A CN116622792 A CN 116622792A
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- 102000004190 Enzymes Human genes 0.000 title claims abstract description 31
- 108090000790 Enzymes Proteins 0.000 title claims abstract description 31
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 title claims abstract description 29
- 229960002715 nicotine Drugs 0.000 title claims abstract description 29
- 229930182840 (S)-nicotine Natural products 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 15
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 24
- 239000005515 coenzyme Substances 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- 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 claims description 11
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 11
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 10
- 108090000854 Oxidoreductases Proteins 0.000 claims description 10
- 102000004316 Oxidoreductases Human genes 0.000 claims description 10
- 238000007069 methylation reaction Methods 0.000 claims description 10
- MYKUKUCHPMASKF-UHFFFAOYSA-N nornicotine Chemical compound C1CCNC1C1=CC=CN=C1 MYKUKUCHPMASKF-UHFFFAOYSA-N 0.000 claims description 9
- 230000003287 optical effect Effects 0.000 claims description 9
- 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
- 108010050375 Glucose 1-Dehydrogenase Proteins 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 230000011987 methylation Effects 0.000 claims description 6
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 claims description 6
- 230000002255 enzymatic effect Effects 0.000 claims description 5
- 235000005152 nicotinamide Nutrition 0.000 claims description 5
- 239000011570 nicotinamide Substances 0.000 claims description 5
- 238000006722 reduction reaction Methods 0.000 claims description 5
- 101710088194 Dehydrogenase Proteins 0.000 claims description 4
- PWNROEPNAGOERJ-UHFFFAOYSA-N NCCCC(C(C(CCCN)C1=CC=CN=C1)=O)C1=CC=CN=C1 Chemical compound NCCCC(C(C(CCCN)C1=CC=CN=C1)=O)C1=CC=CN=C1 PWNROEPNAGOERJ-UHFFFAOYSA-N 0.000 claims description 4
- 241000316848 Rhodococcus <scale insect> Species 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 229960003966 nicotinamide Drugs 0.000 claims description 4
- 238000007036 catalytic synthesis reaction Methods 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 108010021809 Alcohol dehydrogenase Proteins 0.000 claims description 2
- 102000007698 Alcohol dehydrogenase Human genes 0.000 claims description 2
- 241000186073 Arthrobacter sp. Species 0.000 claims description 2
- 108090000698 Formate Dehydrogenases Proteins 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 2
- 241001524101 Rhodococcus opacus Species 0.000 claims description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 2
- 229960003512 nicotinic acid Drugs 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- 241000894007 species Species 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- 241000187681 Nocardia sp. Species 0.000 claims 1
- 235000001968 nicotinic acid Nutrition 0.000 claims 1
- 239000011664 nicotinic acid Substances 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract description 6
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- NUMQCACRALPSHD-UHFFFAOYSA-N tert-butyl ethyl ether Chemical compound CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 241000208125 Nicotiana Species 0.000 description 3
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 229960001031 glucose Drugs 0.000 description 3
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- 241000196324 Embryophyta Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 241000227653 Lycopersicon Species 0.000 description 2
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 2
- 241001495390 Nocardioides sp. Species 0.000 description 2
- 244000061458 Solanum melongena Species 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
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- 210000003169 central nervous system Anatomy 0.000 description 2
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- 239000008103 glucose Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- VLEIUWBSEKKKFX-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid Chemical compound OCC(N)(CO)CO.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O VLEIUWBSEKKKFX-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 241000901710 Arthrobacter sp. ZXY-2 Species 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion 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](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 1
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 1
- 241000203622 Nocardiopsis Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001113889 Rhodococcus opacus B4 Species 0.000 description 1
- 241000119319 Rhodococcus opacus PD630 Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000208292 Solanaceae Species 0.000 description 1
- 239000007984 Tris EDTA buffer Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
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- 230000003920 cognitive function Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
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- 239000013067 intermediate product Substances 0.000 description 1
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
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- 201000000980 schizophrenia Diseases 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- JNUMDLCHLVUHFS-QYZPTAICSA-M sodium;[[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-oxidophosphoryl] [(2r,3s,4r,5r)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical class [Na+].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 JNUMDLCHLVUHFS-QYZPTAICSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
- C12P17/165—Heterorings having nitrogen atoms as the only ring heteroatoms
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a method for synthesizing (S) -nicotine by using enzyme catalysis, which comprises the following steps: 1) Synthesizing a compound of formula II under the catalysis of biological enzyme; 2) Re-methylating the compound of formula II on the basis of step 1) to obtain the compound (S) -nicotine of formula III with high purity and high conversion rate. The method has simple steps and strong operability, and the addition of the biological enzyme ensures that the reaction rate of the reaction system is faster, thereby greatly reducing the reaction time; solves the problems of low selectivity, insufficient purity or large environmental pollution of pure chemical synthesis. In the prior art, the enzyme has obvious advantages in aspects of selectivity, sustainability, evolutionability and the like when being used as a biocatalyst for promoting synthesis.
Description
Technical Field
The invention belongs to the field of synthesis, and particularly relates to a method for synthesizing (S) -nicotine by using biological enzyme catalysis.
Technical Field
Nicotine, also known as nicotine, is the main pharmacologically active ingredient in traditional tobacco, and recent studies have found that nicotine can pass through the blood brain barrier and act on the nicotinic acetylcholine receptor, and that it can achieve regulatory function in the central nervous system by exhibiting pharmacological actions through binding, which means that it has great potential in the treatment of central nervous system-related diseases, especially for such common diseases as Alzheimer's disease, parkinson's disease, schizophrenia, and depression.
In addition, several related reports have shown that nicotine has many other pharmacological effects, such as treatment and functional modulation of some diseases: enhancing human-related auditory processing, cognitive function and adrenergic system stimulating sympathetic nerves, and has the potential of treating sarcoidosis, inhibiting inflammation exogenous stimulus caused by various inflammations, and exerting antioxidant and antiinflammatory properties. Therefore, the (S) -nicotine has good pharmaceutical market prospect and thus has research value.
The traditional method for obtaining (S) -nicotine is generally directly extracted from plants of the Solanaceae family of tobacco, tomatoes, eggplants and matrimonies, but the plants such as tomatoes, eggplants and matrimonies are more significant as daily food, the purity of the directly extracted L-nicotine is only about 93% due to the large planting area of the tobacco, and other related alkaloid impurities are difficult to separate due to the similarity of structures, so that the requirement of high purity is difficult to be achieved simply through a purification means.
As a potential formulation component for the treatment of diseases, strict chemical purity requirements in the pharmaceutical field need to be followed: synthetic methods have been developed to remove these difficult to separate impurities, with reference to the United states pharmacopoeia, which have a standard purity of at least 99% and a content of no more than 0.5% of any of these impurities.
The artificial synthesis uses a pure chemical synthesis means, and generally has the problems of low selectivity, insufficient purity or great environmental pollution. In the prior art, enzyme is taken as a biocatalyst to be an important means for promoting synthesis, and the advantages of selectivity, sustainability, evolutionability and the like are obvious.
Disclosure of Invention
Aiming at the defects of the prior art, the invention discloses a method for synthesizing (S) -nicotine by using enzyme catalysis, which has the advantages of high optical purity of a target product, high substrate conversion rate and recycling of enzyme regeneration.
The synthetic route of the invention is as follows:
the enzyme functions in the synthesis of the compound of formula II are shown below:
the synthesis steps are as follows:
1) And (3) reduction: the compound 4-amino-1- (3-pyridyl) -butyl ketone of the formula I is catalyzed by enzyme to generate 3- (pyrrolidin-2-yl) pyridine containing intermediate compound of the formula II;
2) Methylation: on the basis of the step 1), pure 3- (pyrrolidin-2-yl) pyridine as the compound of the formula II is put into a system in which organic substances such as sulfonate, halogenated substances or aldehyde exist, and the 3- (pyrrolidin-2-yl) pyridine as the compound of the formula II is subjected to re-methylation in the presence of a reducing agent to generate (S) -nicotine as the compound of the formula III.
As a further preferred embodiment of the present invention, the enzymes used in the step 1) are reductase, coenzyme NADPH, coenzyme NADP and dehydrogenase; the reductase is an enzyme of which nicotinic acid and nicotinamide are first related in anabolism, and the coenzyme NADPH is a reduced coenzyme and plays a role of hydrogen transfer body in an enzymatic reaction; the coenzyme NADP is oxidized coenzyme, the dehydrogenase is one or more of glucose dehydrogenase, formate dehydrogenase and alcohol dehydrogenase, preferably glucose dehydrogenase, and the glucose dehydrogenase is relatively ubiquitous enzyme in daily life, and is low in cost and easy to obtain.
By adopting the technical scheme, the recycling of the coenzyme can be realized, the consumption is reduced, and the emission is reduced.
Still further, the class of nicotinic acid and nicotinamide anabolism pro-enzyme may be isolated or derived from rhodococcus (Rhodococcus opacus), nocardioides sp.), arthrobacter sp or a homologue thereof, which refers to a biological enzyme comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any of the enzymes disclosed herein, said amino acid sequence being SEQ I.D.NO.1, SEQ I.D.NO.2, SEQ I.D.NO.3, SEQ I.D.NO.4 or SEQ I.D.NO.5, preferably the amino acid sequence being SEQ I.D.NO.5 or a homologue thereof, the amino acid sequence of which has the advantage of protruding substrate sensitivity upon saturation mutation at a specific site and is responsive to low concentrations.
By adopting the technical scheme, the substrate reaction can be catalyzed more efficiently, and the generated intermediate compound of the formula II has the aim of achieving the optical purity of 95 percent more easily.
Still further, the reaction system of step 2) is preferably an aldehyde species including, but not limited to, formaldehyde, polymers of formaldehyde or acetals of formaldehyde; the reducing agent in step 2) includes, but is not limited to, sodium cyanoborohydride, sodium borohydride, lithium borohydride, formic acid, methanol, dimethyl sulfate, lithium aluminum hydride, preferably formic acid; when the reduction reaction of step 1) is completed, the methylation reaction of step 2) can be directly carried out only when the optical purity of the intermediate compound of the formula II is 95% or more.
By adopting the technical scheme, the forward reaction of the methylation reduction type II compound is more thorough, and the (S) -nicotine with high yield and high purity can be obtained; the method reduces the steps of upper protection, deprotection and the like corresponding to the pure chemical method in the whole synthesis process, has small reagent consumption, can be recycled, and is beneficial to lean production.
The invention has the beneficial effects that: the biological enzyme has strong specificity and high substrate selectivity, including stereoselectivity, regioselectivity and chemoselectivity; the enzymatic synthesis has mild reaction conditions, low reaction energy consumption and high controllability compared with the chemical method; the enzyme method is environment-friendly, reduces the corresponding steps of upper protection, deprotection and the like, and can reduce the cost and reduce the pollutant emission.
The invention is further described by the following specific examples, which are not intended to limit the scope of the invention.
Detailed Description
The reductase involved in the present invention is as follows:
SEQ ID No.1: from rhodococcus turbidi (Rhodococcus opacus B4)
MTRDVIVVGAGLSGLRAARDLRAAGRSVLVIEGGSRLGGRLYRRPSVVDPAVDVEVGGAYFAPHHHKRMTEEIARHGLSTRPAALSDRRRGLSVPEHEKTATRAALHTVLRDAHRITVGVGLEYQGLDDLDIPAQDYLDALKLMPTTKQWVKAWCSTIVGSELSTVSALGLLMPIAAHQHRVSGAALSHSAEIATGTSSLVRALAGDVDEIRFNGVITALHQRHDGVEVCVGDGEVMTARHVVLATPLNSWRGIDFDPVLPARRAQVVMDSRGCRCVQLHIHARNVPVGLFRFGDGAIPVLFDTGADSGGGRILTGYTDGTAIDPKDPEHVHAAVRSYLPDAEIMGVDYHDWSADPLHRGAGIHARVGRPTIMHERLGADHGRIHFAGSDVALNYPGYMEGALEAAERAVEAVLASDR。
Seq id No. d. 2: from rhodococcus turbidi (Rhodococcus opacus PD 630)
MIEGGSRPGGRLYRRPSAVDPAADVEVGGAYFSPRHHKRMAAEIARYGLSTRPTALSRALRRSDRRNGLSFPEHEKAATRAALRTVLRDSRRITVGVGLEYQGLDDLDIPAQEYLDALDLTPTTKEWVMAWCSTIVGSDLNAVSALGILMPIAAHQHCVSGAALSHRAEIATGTSSLVSALAGDVDEIRFNGVITALHQRRDVVEVCVGDDEVITARHVVLATPLNGWRGIDFDPALPARRAHMVMDSRGCRCVRLHIHARNVPGGLFRLGDDAIPVLFDTGADSRGGRILTGYADGTAIDPRNLEHVRAAVRSYLPDAEIVGVDYHDWSADPLYRGSGTHARVGQPTIMHERLGADHGRIHFAGSDVALNYPRYMEGALEAAERAVEAVLASHRRPPPGTAPVQG。
Seq id No.3: nocardiopsis (Nocardioides sp.JSD14)
MVDSVEVAVVGAGFAGLRAARDLSTEGRSVVLLEAAGRVGGRAYSRESATDPGTTVEVGGAYFHRHHHARLAAEVDRYNIETQPAAPFKVFRNRLASGDHNAAFPIPPEELLEAERVLFCLIRDARRIDCHAGLENQNLKDLDISAHDYLNALNPPPVTSQLLRSWIWNMMGQRVEDASALWVLQLIASHDYSVLGVLLSLDEVMTSGTGTLTSAIASEVPDLRLGEAVHAIHQQADWVDLAYGAERALRAEHVVVAAPLNCMRELRFEPPLSGPRAEVVAEGHGGRGLKLLIHVQGVPEGISCTGDGVFPTLYDYLPATDGGRILVGFTDRDSFDPADNDAIEAAVHHYLPEAIIVGTDYHDWCADPYVRAPWVSPRIGQATRAHKSLGEPHGRVHFAGSDVSLLFPGYIEGALETADRVRAEING。
Seq id No. d. 4: from Arthrobacter sp.ZXY-2
MYDAIVVGGGFSGLKAARDLTNAGKKVLLLEGGERLGGRAYSRESRNV PGLRVEIGGAYLHRKHHPRLAAELDRYGIPTAAASEFTSFRHRLGPTAVDQAFPIPGSEAVAVEAATYTLLRDAHRIDLEKGLENQDLEDLDIPLNEYVDKLDLPPVSRQFLLAWAWNMLGQPADQASALWMLQLVAAHHYSILGVVLSLDEVFSNGSADLVDAMSQEIPEIRLQTVVTGIDQSGDVVNVTVKDGHAFQAHSVIVATPMNTWRRIVFTPALPERRRSVIEEGHGGQGLKILIHVRGAEAGIECVGGGIFPTLYDYCEVSESERLLVAFTDSGSFDPTDIGAVKDAVLYYLPEVEVLGIDYHDWIADPLFEGPWVAPRVGQFSRVHKELGEPAGRIHFVGSDVSLEFPGYIEGALETAECAVNAILHS。
SEQ ID No.5 is derived from the artificial sequence (Artificial Sequence):
MVDSVEVIVVGAGFSGLRAARDLSTEGRSVVLLEGGSRLGGRAYSRESATDPGTTVEVGGAYFHRHHHARLAAEVDRYGISTRPAALSDRRNGFPIPPEELLEAEAATYTLIRDARRIDCGVGLENQGLDDLDIPAQDYLDALNPPPVTKQLLRAWIWNMMGQRVEDASALWVLQLIAAHQYSVLGVLLSLDEVMTSGTSTLVSAIASEVPELRLGEAVTAIHQQADWVELAYGDERALRAEHVVVATPLNCMRELRFEPPLPGRRAEVVAEGHGGRGLKLLIHVRGVPEGISCTGDGVFPTLYDYLPATDGGRILVGFTDRDSFDPADNDAVEAAVHHYLPEAEIVGVDYHDWCADPLVRGPWVSPRVGQATRAHKSLGEPHGRVHFAGSDVSLLFPGYIEGALETAERAVEAVLAS。
example 1:
the four-necked flask of serial numbers 1 to 5 was charged with 0.5g of each of the respective reductase lyophilisates containing the amino acid sequences such as SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4, SEQ ID No.5, and 5 parts of the same molar ratio of the compound of formula I4-amino-1- (3-pyridyl) -butanone, anhydrous glucose, glucose dehydrogenase and coenzyme NADPH, respectively, were prepared, and the reaction system was maintained at pH 7 to 9 in the presence of Tris-EDTA buffer solution, and the reagents in the four-necked flask of serial numbers 1 to 5 were simultaneously subjected to bioconversion. Under the stirring action, the reaction bottle with the number of 1-5 carries out biocatalysis conversion reaction, and a comparison sample is simultaneously taken and analyzed once every 30min until HPLC analysis shows that the content of the compound with the formula of II in the reaction liquid is over 99 percent in the reaction bottle with the number of 1-5, and the reaction is stopped.
Enantiomeric purity as determined by HPLC: a Chiracel OD-H column was used, eluting with 95:5 n-hexane and 1-butanol and 0.1% diethylamine. The (R) -enantiomer was eluted at 6.1 minutes and the (S) -enantiomer was eluted at 5.6 minutes. Enantiomeric excess is determined by the peak area determined according to the formula [ (S) - (R) ]/(S) + (R) ].
The reaction results for comparative numbers 1-5 are shown in Table 1:
according to the analysis of the results in Table 1, the experimental results of No.5 are superior to the experimental results of No. 1-4, so that reductase with the amino acid sequence of SEQ ID.D.NO. 5 is selected as a comparative experiment related to the concentration of the reactants, five batches of sampling results of 1-3.5 h in the reaction process are written in "slightly" in Table 1, the data are long and have obvious trend, and the specific display is not performed.
Example 2:
preparing a four-mouth bottle with 1L at room temperature, firstly adding 200mL of buffer solution Tris-EDTA, keeping the pH value of a reaction system at 7-9, adding 100mM of a compound with the formula I, namely 4-amino-1- (3-pyridyl) -butyl ketone, 16.42g, 250mM of glucose, 49.54g, 5mM of nicotinamide adenine dinucleotide sodium phosphate sodium salt NADP+, 3.93g, 50U/mL of glucose dehydrogenase, 16mg and 0.5g of a freeze-dried product with an amino acid sequence of SEQ ID.D. NO.5, 1mg/mL; heating and heating, uniformly stirring, performing biocatalysis reaction, sampling and analyzing every 30min in the reaction process, analyzing the content of the compound of the formula II in the reaction system by using HPLC, and stopping the reaction after the content of the compound of the formula II reaches 76% after 2 hours and after the reaction is continued for 4 hours, the content of the compound of the formula II reaches more than 95%.
The biocatalytic reaction mixture was acidified with concentrated sulfuric acid to pH 1-2, then heated to 90℃and stirring continued for more than 20min to precipitate all protein, and the protein was filtered from the mixture with celite. The clear solution obtained after filtration was alkalified to neutrality with 40% naoh solution, extracted three times with 500mL ethyl tert-butyl ether, the organic phases were combined and added with anhydrous magnesium sulfate for preliminary drying, after drying, the solvent was further heated for separation, after distillation, the pure product of the compound of formula ii was isolated as a tan liquid from the remaining mixture of the system, weighed to 12.32g, the yield was 75.0%, and the optical purity was 99.2% by sampling analysis. The methylation reaction can be directly carried out.
Adding formaldehyde (2 g) and formic acid (13.12 g) into the pure product of the intermediate product of formula II after biocatalysis in sequence, heating and stirring, and when the temperature reaches 85 ℃, keeping sampling and analyzing once every 10min, wherein the content of the compound (S) -nicotine of formula III in the spectrum shows that the content reaches more than 99.5% and the enantiomer is over 99%, and ending the reaction. Chemical purity as determined by HPLC: using an X-Bridge C18 column, the eluate contained a mixture of (i) 20mM ammonium bicarbonate aqueous solution (ph=8.7) and (ii) acetonitrile, gradient procedure: 0-10 minutes, the ratio is 95:5;10-13 minutes, the ratio is 70:30;13-16 minutes, the ratio is 10:90; then 95:5. The temperature was 35 ℃. The detector conditions were UV absorption at a wavelength of 260 nm. Typically (S) -nicotine at 9.925 minutes, the others are impurities.
Example 3:
the procedure is similar to example 2 except that the starting amount of the compound of formula I4-amino-1- (3-pyridyl) -butyl ketone is equivalent 1, the starting amount of the compound of formula I4-amino-1- (3-pyridyl) -butyl ketone is 100mM,16.42g, 150mM glucose, 29.72g, nicotinamide adenine dinucleotide phosphate sodium salt NADP+ is 10mM,7.86g, glucose dehydrogenase 50U/mL,0.016g, reductase is selected from 0.5g,1mg/mL of a lyophilizate of amino acid sequence SEQ ID.NO. 5; in the reaction of biocatalysis to produce the compound of formula II, the result of sampling analysis shows that the content of the intermediate is 81% at the node of 2 hours, the intermediate continues to the node of 4 hours, the content reaches 97%, and the optical purity is 99.38% by sampling analysis, so that the methylation reaction can be directly carried out. The biocatalytic reaction solution is purified to obtain a pure compound of the formula II, 14.14g is weighed, the yield is 86.12%, and the optical purity is 99.4% by sampling analysis, so that the improvement of the feeding ratio is effective for improving the yield. The addition was carried out in the ratio of formic acid to formaldehyde according to example 1, the content of the compound of formula III (S) -nicotine according to the spectrum being shown to be above 99.5% and having an enantiomeric excess of above 99%, the reaction being ended.
Example 4:
this example is carried out in the same manner as example 3, except that the biocatalytically-produced compound of the formula II is not purified separately, but is subjected to methylation by adding formic acid and formaldehyde directly to the mixture containing the crude product. The compound of formula II, which has been separated from the enzyme-reduced product of the compound of formula I, 4-amino-1- (3-pyridinyl) -butyl ketone, 16.42g, is added to 800ml of water, formaldehyde and formic acid are added, stirred and warmed, the temperature of the mixture is maintained in the temperature range of 80-85℃for 2h, the sample analysis HPLC profile shows that the reaction is complete, and then cooled to room temperature. And then 50% sodium hydroxide solution is added to adjust the pH to about 13. 500ml of ethyl tert-butyl ether was added for 4 extractions and dried over magnesium sulfate, and (S) -nicotine was obtained by distillation under reduced pressure, weighing 11.16g, with a yield of 68%, and an optical purity of >99.6% as determined by chiral HPLC. This example shows that this reaction requires purification of the intermediate followed by methylation to obtain high purity, high conversion (S) -nicotine.
Experimental results in examples 1-4 show that the reductase with the amino acid sequence of SEQ ID.D. No.5 has obvious substrate selection advantages in the catalytic synthesis process, and the steps of performing intermediate refining treatment and measuring to obtain a pure compound of the formula II meeting the standard with the optical purity of more than or equal to 95% and then reacting are adopted before methylation, so that the reductase has obvious advantages of enzyme recycling, high conversion rate of target products, high yield and high purity.
Claims (9)
1. A method for the enzymatic synthesis of (S) -nicotine, characterized by the following synthetic route:
the synthesis steps are as follows:
1) And (3) reduction: the compound 4-amino-1- (3-pyridyl) -butyl ketone of the formula I is catalyzed by enzyme to generate 3- (pyrrolidin-2-yl) pyridine containing intermediate compound of the formula II;
2) Methylation: on the basis of the step 1), the pure 3- (pyrrolidine-2-yl) pyridine of the formula II is put into a reaction system in which sulfonate, halogenated or aldehyde substances exist, and then a reducing agent is added to generate the compound (S) -nicotine of the formula III.
2. A method for the catalytic synthesis of (S) -nicotine using an enzyme according to claim 1, wherein the enzyme acts during the catalytic synthesis of step 1) as follows:
3. the method of claim 2, wherein the enzymes in step 1) are reductase and coenzyme NADPH and coenzyme NADP and dehydrogenase.
4. A method of enzymatically synthesizing (S) -nicotine according to claim 3, wherein said reductase in step 1) is a class of enzymes involved in the anabolism of niacin and niacinamide, and said coenzyme NADPH is a reduced coenzyme; the coenzyme NADP is an oxidized coenzyme, and the dehydrogenase is one or more of glucose dehydrogenase, formate dehydrogenase and alcohol dehydrogenase.
5. A method of synthesizing (S) -nicotine using enzyme catalysis according to claim 4 characterized in that the class of nicotinic acid and nicotinamide anabolism related enzymes can be isolated or derived from rhodococcus turbidi (Rhodococcus opacus), nocardia sp., arthrobacter sp.) or homologues thereof.
6. A method of synthesizing (S) -nicotine using enzyme catalysis according to claim 5, characterized in that the homolog is an amino acid sequence comprising at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any of the enzymes disclosed herein, said amino acid sequence being SEQ i.d.no.1, SEQ i.d.no.2, SEQ i.d.no.3, SEQ i.d.no.4 or SEQ i.d.no.5.
7. A method for the enzymatic synthesis of (S) -nicotine according to claim 1, characterized in that the reaction system in step 2) is preferably an aldehyde species, including but not limited to formaldehyde, polymers of formaldehyde or acetals of formaldehyde.
8. A method for the enzymatic synthesis of (S) -nicotine according to claim 1, characterized in that the reducing agent in step 2) includes, but is not limited to, sodium cyanoborohydride, sodium borohydride, lithium borohydride, formic acid, methanol, dimethyl sulfate, lithium aluminum hydride.
9. A method for the enzymatic synthesis of (S) -nicotine according to claim 1, characterized in that said step 1): when the reduction reaction is completed, the optical purity of the intermediate compound of the formula II is 95% or more, and the step 2) reaction can be directly carried out.
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